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Nanodiagnostics to Face SARS-CoV-2 and Future Pandemics: From an Idea to the Market and Beyond

Cite this: ACS Nano 2021, 15, 11, 17137–17149
Publication Date (Web):October 27, 2021
https://doi.org/10.1021/acsnano.1c06839

Copyright © 2021 The Authors. Published by American Chemical Society. This publication is licensed under

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Abstract

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The COVID-19 pandemic made clear how our society requires quickly available tools to address emerging healthcare issues. Diagnostic assays and devices are used every day to screen for COVID-19 positive patients, with the aim to decide the appropriate treatment and containment measures. In this context, we would have expected to see the use of the most recent diagnostic technologies worldwide, including the advanced ones such as nano-biosensors capable to provide faster, more sensitive, cheaper, and high-throughput results than the standard polymerase chain reaction and lateral flow assays. Here we discuss why that has not been the case and why all the exciting diagnostic strategies published on a daily basis in peer-reviewed journals are not yet successful in reaching the market and being implemented in the clinical practice.

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During the last decades and even more specifically during the last few months, we all became familiar with the term “diagnostics”, which includes devices and methods used for identifying a particular disease. Diagnostic devices and assays are now routinely used by medical doctors as a valuable aid for the diagnosis of the patient. In fact, once we analyze what it would take to perform a diagnosis without a diagnostic device, we find many variables to take into account, making an accurate diagnosis far from being simple. For example, with the coronavirus 2019 (COVID-19) pandemic, medical doctors have to diagnose a patient that shows influenza-like symptoms. For this, they would have to consider factors such as the prevalence of a specific disease during that time of the year (i.e., flu season or not), the severity of the symptoms, the overall status of that specific patient, chronic or seasonal conditions (i.e., allergies), general patient behavior (i.e., travels, vaccinations), etc. Performing this type of assessment for each patient takes time (which may be limited during a pandemic or in busy hospitals), and, above all, it is heavily subjective. On one hand, the doctor needs to rely on the answers of the patient, which may differ from individual to individual experiencing the same symptoms. On the other hand, even the best doctors can diverge in the diagnosis of the same individual. In this context, diagnostic tests reveal themselves as great tools to help medical doctors to precisely diagnose patients at the first visit, without additional examinations.
Imagine what can be done with a portable, low-cost sensing device that could be able to rapidly detect in a single step any arbitrary infectious agent in a biological fluid. Such a technology would revolutionize our current approach for handling infectious diseases, because it could enable nearly real-time detection of a pathogen at the population level. This would have multiple positive repercussions: (1) it would allow decreasing the number of undetected cases; (2) it would improve our knowledge of the epidemiology of the disease; (3) we could make timely decisions on the treatment of infected patients, maximizing their chances of recovery; (4) we could more effectively control the propagation of the disease. As a result, this could dramatically impact the public health system and economy of whole countries via more granular and timely measures such as lockdowns and border closings. In this manuscript, taking COVID-19 diagnostic as model, we analyze every step (from the definition of the idea to the market placement) that can stop or slow down the development of a diagnostic device.

The SARS-CoV-2 Pandemic and Other Recent Outbreaks

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SARS-CoV-2 is a human-pathogenic strain of coronavirus that was discovered in Wuhan (Hubei Province, China) at the end of 2019. (1) SARS-CoV-2 stands for severe acute respiratory syndrome-related coronavirus 2 and is responsible for the COVID-19 disease, which causes from mild to severe respiratory symptoms in humans. (2) By October 27th of 2021, SARS-CoV-2 has officially infected more than 243 million people and killed 4 953 246 people worldwide. (3,4) The high infectivity of the virus is due to its ability to be transmitted through the direct contact with droplets produced by sneezes or coughs of infected people (thus involving airborne transmission, more probable in closed spaces) and indirectly through contact with contaminated surfaces (World Health Organization - WHO indications). The reproduction number (R0) gives a measure of the infectivity of a virus, representing the expected number of new cases in a community directly generated by an infected person. Initially, the R0 of SARS-CoV-2 was estimated between 1.4 and 3.9. (5) However, with the emergence of the Delta variant this value increased almost to 7. (6,7) While the first steps for containing an outbreak are to identify transmission pathways and estimate the R0, the management of a pandemic also requires knowing the infectious agent structure and genome in order to develop effective diagnostic tools in the shortest possible time.
For diagnostic purposes, in support of the clinical examinations, the first step is the identification of a specific biomarker, the concentration of which should vary sensitively and concurrently in the presence of the infection. In the case of SARS-CoV-2, as for other viruses, we can identify two major classes of viral biomarkers: nucleic acids and proteins. Regarding the former, as for all coronaviruses, SARS-CoV-2 has a positive-sense single-stranded RNA (+ssRNA) that allows for a direct translation of the viral genetic material into viral proteins within the cytoplasm of the infected cells. (5,8) Regarding the latter, SARS-CoV-2 displays four structural proteins, named as the spike protein (S protein), the envelope protein (E protein), the membrane protein (M protein), and the nucleoprotein (N protein). (9) The S, E, and M proteins are actually glycoproteins present on the outer membrane of the virus, whereas the N protein holds the genome within the viral particle. The S protein is composed of two subunits named S1 and S2. During the infection, the subunit S1 enables the attachment of the virus to the host cell, whereas the subunit S2 triggers the internalization of the virus within the cell. (10,11) Then, the E protein, which is the smallest structural protein of SARS-CoV-2, helps the dissemination and replication within the host cell. (12) Next, the M protein is the main structural protein of the viral membrane and determines the shape and size of the virion, stabilizing the nucleocapsid and promoting the overall assembly. (5) Eventually, the N protein is involved in the viral replication and triggers the cellular immune response of the host against the virus. (13) Because of the ability of the virus to spread and circulate throughout the body, these biomarkers have been found in several biological fluids, including saliva, blood, stool, feces, and semen of infected people. (14,15)
Looking back to other viruses’ outbreaks, we can observe many efforts done to improve the time required for the development of diagnostic approaches. Indeed, if we compare the 2003 SARS-CoV, 2009 A/H1N1, 2014 Ebola, and 2019 SARS-CoV-2 outbreaks, we can observe a reduction in the reaction time toward the monitoring and estimation of infected cases during the epidemics (Figure 1a). This quicker response is mainly due to the technological advances achieved over the last 20 years on DNA sequencing, which have allowed us to save time in the identification of clinically relevant biomarkers as well as to improve the performance of molecular kits based on the nucleic acid detection (e.g., polymerase chain reaction (PCR) and isothermal amplification techniques). Although there are several factors involved in the spreading of an epidemic, such as the mortality of the pathogen, the geographical impact, or the economic resources of the affected countries, the use of these molecular diagnostic tools allowed the World Health Organization (WHO) and the other national agencies to agree in the implementation of the same guidelines to control the pandemics. More specifically, these actions are based on the achievement of frequent testing: pathogen isolation/identification, pathogen sequencing, the design and release of a PCR protocol (namely, molecular kits), and the development of rapid tests.

Figure 1

Figure 1. Visual description of the duration of the phases required to develop a rapid test for previous outbreaks (the dates refer to each phase thanks to a color code) (a) and of the current SARS-CoV-2 detection technologies (b). PCR, antigen, and serological tests with the respective criteria for results interpretation (T = test line, C = control line). The bottom plot gives an outlook of the infection progression and the phases in which each test result is more effective.

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The ability to sequence the viral genome influenced deeply also the discovery of protein biomarkers. Indeed, thanks to current molecular biology techniques, we can now mass-produce virtually any protein as soon as its sequence is identified. This allows the selection of suitable bioreceptors (e.g., antibodies and aptamers) for the development of several laboratory-based assays (e.g. enzyme-linked immunosorbent assay (ELISA) and western blots) and point-of-care (POC) systems (e.g., lateral flow assay (LFA), electrochemical sensors, and microfluidic devices). (16−18) For example, only 43 d after the publication of the SARS-CoV-2 genome, two different LFAs for the detection of SARS-CoV-2-specific antibodies were being distributed in China under an Emergency Use Approval (EUA) authorization. (19) Thanks to their low cost, easy operation, and fast response compared with PCR, the use of LFAs has allowed the decentralized high-frequency testing of millions of individuals leading to an effective containment of the virus spread. (20)
Despite the COVID-19 outbreak having been faced with the quickest global response, regarding diagnostic devices, much still needs to be done if we want to prevent the damage caused by future pandemics. Specifically, current techniques for the detection of a nucleic acid are still too slow (∼1 h), cumbersome (multistep), and expensive (requiring costly equipment) to be effectively deployed at the point of care. (21) Instead, antigenic POC tests based on the detection of protein biomarkers (i.e., antigens and antibodies) are now widely used and deployed in order to highlight a positive case and thus limit virus transmission. (22,23) Fortunately, during the last decades, researchers have been publishing exciting methods and technologies that address those issues, and their further development into commercial products could revolutionize the way we diagnose diseases. (24,25)

Current Testing Methods

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The diagnosis of COVID-19 currently relies on the detection of two viral biomarkers (i.e., viral RNA and antigens) and one host biomarker (i.e., SARS-CoV-2-specific antibodies). Each target can provide different information about the clinical status of the patient. Generally, the SARS-CoV-2 virus clinically relevant concentrations are between 102 and 1011 viral particles per milliliter in saliva. (26,27) The virus RNA is indirectly detected by means of molecular techniques, with the quantitative reverse transcription polymerase chain reaction (qRT-PCR) being the most used. As depicted in Figure 1b, with this technique, RNA is converted into a complementary DNA chain by an RNA-dependent DNA polymerase (reverse transcriptase) and is subsequently amplified by a DNA polymerase following thermal cycles. Primers (i.e., nucleic acids used for the initiation of the DNA synthesis), probes, and the transcribed DNA are required to perform qRT-PCR; therefore, it is necessary to know the genome sequence beforehand. The SARS-CoV-2 genome sequence was reported 10 d after announcement of the outbreak in China, (28,29) and the first PCR tests were produced and distributed after less than two weeks. (30) The main disadvantages of qRT-PCR tests are the turnaround time required to obtain a result (not shorter than 1 h, with commercial assays such as GenXpert or Filmarray) (31) and the need for skilled personnel and expensive laboratory equipment. (32)
Rapid antigen tests, such as LFA, represent one of the most recognized diagnostic tools used during this pandemic to perform a fast screening. Basically, they are based on the same sampling method used for PCR, but the swab is introduced in the LFA with the use of a working solution, which let the sample flow through a paper membrane. When the solution comes in contact with the sample pad, the viral particles are recognized by nano- or microparticles (e.g., gold nanoparticles (AuNPs), latex beads) functionalized with specific antibodies that recognize the proteins of the virus membrane. The AuNPs-virus complexes are then trapped by secondary SARS-CoV-2 binding antibodies immobilized on the test line, and their accumulation generates a visible color (positive test). The unbound AuNPs are recognized by the control line, which permits the test administrator to distinguish a negative test (only control line present) from an unsuccessful test where, for example, the solution did not flow properly (no line present). Although a rapid antigen test can provide results in a few minutes, they are less sensitive than PCR, often leading to false-negative results. Information about the analytical performance of such devices based on LFA technology can be found in the FIND database, as highlighted at the end of this section.
Rapid tests for measuring the immune response of patients are also mostly based on LFAs. These tests, often referred to as serological tests, permit a determination of the presence and type (mostly IgA, IgG, or IgM) of SARS-CoV-2-specific antibodies. (32) The sensing mechanism is similar to those of antigen-based LFA; however, the targets of the test are not the viral particles but the IgG and IgM antibodies, and the sample used can either be a drop of blood (for IgG and IgM, with two test lines) or saliva (for IgA and IgG). Although a serological test cannot be used for an early diagnostic, because the immune system requires several days to develop an immune response strong enough to be accurately measured, they can provide complementary diagnostic information on patients having symptoms and negative rRT-PCR results, (33) and they are particularly useful to monitor the patient’s immunity acquired either via an infection or vaccination.
Because each biomarker can describe a different phase of the infection process, the estimation and relative concentrations of biomarkers strongly depend on the time chosen for the test, as highlighted in Figure 1b. More specifically, PCR testing is effective in detecting the virus 10 d after the infection occurred and until the sixth week after it. Antigen tests are usually effective in detecting it between the second and the fifth week, while serological tests can detect the infection only three to four weeks after the infection started. (34) Generally, there are two main parameters used to define the performance of a diagnostic test: sensitivity and specificity. They refer to the proportion of true positives or true negatives when being compared to a standard technique (here PCR), respectively. (35,36) Thus, a final interpretation of a diagnostic test is not just given by its operating features but also for the prevalence or pretest probability of disease. (31)
Recently, the Foundation for Innovative New Diagnostics (FIND) set up a database of the commercially available COVID19 diagnostic devices, which is updated on a regular basis. Of the current 544 diagnostic devices available (data updated May 2nd, 2021), 158 are based on RNA detection and 276 on antigen detection, and 101 are serological. FIND also conducts the independent evaluation of these commercially available technologies, comparing them analytically by their effective specificity, sensitivity, and response time and giving many additional information such as the type of sample used, the connectivity, etc. Both the database and the results comparison are publicly available in the FIND Web site. (37)

The Nanodiagnostic Devices Scenario

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The ideal characteristics of a POC test for antigen detection are described and summarized by the REASSURED criteria coined by Land and Peeling et al. (38) Specifically, it states that a sensor should provide (i) real-time connectivity, (ii) ease of specimen collection, with all the required protocols or sample treatment steps integrated in the device. The device should also be (iii) affordable, (iv) sensitive, (v) user-friendly, (vi) rapid and robust, (vii) equipment-free, and (viii) deliverable to end-users. Important efforts are currently directed to the improvement of these diagnostic devices. Furthermore, research groups from all over the world are proposing innovative solutions based on nanomaterials to radically decrease the minimum detectable antigen concentrations and thus the time gap between infection and diagnosis.
The peculiar characteristics of nanomaterials (materials with features of 100 nm or smaller) have the potential to dramatically improve the performance of the diagnostic device toward achieving the REASSURED characteristics. (39) In fact, nanomaterials have properties that differ from those of the same materials at the macroscopic scale, showing phenomena such as quantum confinement, electromagnetic field enhancement, and signal amplification. Consequently, these can be harnessed to include signaling and recognition phenomena in diagnostic devices, such as narrow emission band fluorescence, surface plasmon resonance, and conductivity. (40,41) The nanometer size enables the performance of analytical measurements with high functionality and sensitivity. (42) For example, zero-dimensional (0D) nanomaterials such as nanoparticles are the basis of LFAs, transducing the color change of the test and control lines in the presence of the analyte. (43) Furthermore, nanoparticles allow the increase of electrochemical sensors surface area and the control of their functionalization with bioreceptors such as DNA, aptamers, and antibodies. (44,45) Two-dimensional (2D) nanomaterials such as graphene permit the fabrication of ultrasensitive semiconductors functionalized with bioreceptors for the specific detection of small molecules, proteins, and DNA. (45−48)
Besides nanomaterials, another key nanoscience area with a huge potential to improve the performance of diagnostic test is nano-biotechnology. For example, the selection of more effective bioreceptors (e.g., nanoswitching DNA fragments, aptamers, nanobodies) can contribute enormously to the enhancement of sensing performances; (49−51) this can be seen very well in the recent work of Idili et al., (51) in which the authors showed the development of an electrochemical aptamer-based (EAB) sensor able to achieve the rapid, reagentless, and quantitative measurement of the SARS-CoV-2 spike protein. These technologies are well-understood from a theoretical and proof-of-concept level and need now to be adapted for a more practical sampling and ensure a specific detection, quantitative and portable measurement and analysis, rapid response time, and high reliability. In Table 1 we report some of the latest and most promising nanotechnological devices for SARS-CoV-2 detection, illustrating in Figure 2 some of the respective detection mechanisms.
Table 1. Comparison of Some of the Most Promising Results Available Currently in the Scientific Literature for Nanomaterial-Based Diagnostic Devices
analyte receptor nanomaterial transduction LoD resp time ref
Nucleocapsid phospho-protein (N gene) DNA Graphene paper-based device decorated with AuNPs Electrochemical interdigitated electrodes 6.9 cP/μL 5 min Figure 4A (52)
S1 Spike glycoprotein N-acetyl neuraminic acid Glyco-gold nanoparticles Colorimetric with lateral flow assay 5 μg/mL 30 min Figure 4B (53)
IgG, IgM and antigen Antibodies AuNPs Fluorescence   15 min (54)
S1 Spike glycoprotein Membrane engineered mammalian cells Membrane modified cells Bioelectric recognition assay 1 fg/mL 3 min (55)
Nucleocapsid phospho-protein (N gene) Antisense oligo-nucleotides AuNPs Optical colorimetric (plasmonic) 0.18 ng/μL 10 min Figure 4C (56)
Membrane, Nucleocapsid and spike protein genes DNA 2D gold nanoislands Plasmonic photothermal effect 0.22 pM   Figure 4D (57)
S1 Spike glycoprotein Antibody Graphene FET-based detection 1 fg/mL (S1) 2.42e2 cP/ml (virus) Real time Figure 4E (58)
S1 Spike glycoprotein and Nucleocapsid protein Antibody Semiconductor single walled carbon nanotubes (sc-SWCNTs) FET-based detection 0.55 fg/mL(S1) and 0.016 fg/mL(N) 2 min (59)
Nucleocapsid protein, IgG, IgM, C-reactive protein Antibodies Laser engraved graphene Electrochemical   1 min Figure 4F (60)
Viral RNA DNA Graphene and AuNPs Electrochemical 200 cP/ml 3 h (61)
ORF1ab, N gene DNA/Antibodies AuNPs LAMP lateral flow assay 12 cP/reaction 1 h (62)
Volatile organic compounds (VOC) Organicligands AuNPs Chemiresistors–breath sensor Accur. 95% 19 s (63)
Two viral RNA target sites Cas12a enzyme none Fluorescence 5 cP/reaction 20–40 min Figure 4G (64)

Figure 2

Figure 2. Examples of nano-biosensors for the detection of the SARS-CoV-2 virus and published in 2020. (A) Electrochemical paper-based interdigitated device for N gene detection using graphene and AuNPs. (52) Adapted with permission from ref (52). Copyright © 2020 American Chemical Society. (B) Spike protein lateral flow device using AuNPs and glycan anchors. (53) Adapted with permission from ref (53). Copyright © 2020 American Chemical Society. (C) Colorimetric (plasmonic) viral RNA detection method with the use of DNA-functionalized AuNPs. (56) Adapted with permission from ref (56). Copyright © 2020 American Chemical Society. (D) Thermoplasmonic device for the detection of membrane, spike, and nucleocapsid protein genes with DNA immobilized on 2D nanoislands. (57) Adapted with permission from ref (57). Copyright © 2020 American Chemical Society. (E) Graphene-based FET for real-time immune-based spike protein detection. (58) Adapted with permission from ref (58). Copyright © 2020 American Chemical Society. (F) Multiplexed electrochemical detection on laser-engraved graphene electrodes. (60) Adapted with permission from ref (60). Copyright © 2020 Elsevier. (G) CRISPR-based ultrasensitive fluorescent detection of two sites of the viral RNA genome. (64) Adapted with permission under a Creative Commons Attribution 4.0 International License from ref (64). Copyright © 2020 Springer Nature.

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The Phases of Diagnostic Devices Development

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The complete development of a diagnostic device, from its conception to the market, takes, on average, from 3 to 5 years. (65) Despite a faster time compared to the commercialization of a drug (normally taking from 12 to 15 years) due to the need of less preclinical and clinical data for the regulatory aspects, safety and performance validation remain key milestones in every diagnostic device development. The recently coined Technology Readiness Level (TRL) defines a score system identifying the key milestones during the development of a diagnostic device. TRL incrementally ranges from 1 (observation of the fundamental principles of the device technology) to 9 (real system tested in operative environment).
Typically, the research and the development of a diagnostic device takes slightly different ways with respect to which type of entity is developing it. In fact, even with some exceptions, business-related entities (e.g., spin-off, small and medium-sized enterprises (SMEs), and/or big companies in the sector) are more focused on the innovation related to the application. In this case, even a slight improvement with respect to the previously available technologies is considered relevant having a potentially strong economic impact. Conversely, academic research entities but also parts of the research and development (R&D) divisions of big companies in the sector are more interested in the discovery of novel detection mechanisms and mainly pursue the reduction of the detection limits of the currently available diagnostic devices. Although these look like opposite directions, they are actually two faces of the same coin, and they both represent innovation.
The phases of the development of a diagnostic device, both from the business and research points of view, are summarized in Figure 3, accompanied by their respective TRLs and discussed in the following paragraphs.

Figure 3

Figure 3. Current development process of diagnostic devices with the phases from conception to the market launch and corresponding TRLs.

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Conception and Design

The first action to be taken to develop a diagnostic device is a precise definition of the problem that will be solved through this sensing technology. The problem must have specific and quantifiable characteristics, such as impacting the lives of a significant number of people, represent a new or severe disease, which early diagnosis is essential to improve the recovery rate of patients, be a disease with a high transmission rate, etc. (24) The design of a diagnostic device should meet the needs of the end-users (clinicians and patients) in a specific context. On the basis of that, different types of transducers (electrochemical, optical, piezoelectric, etc.), platforms (paper, plastic, silicon dioxide, etc.), fabrication technologies (microfabrication in clean room, printing, laser scribing, etc.), and bioreceptors types (antibodies, aptamers, enzymes, etc.) can be selected and explored. The output of this process is the definition of the type of diagnostic device required, spacing from a low-cost disposable naked-eye device (such as an LFA) to a reusable precision benchtop system (such as a fluorescence, interferometric, or SPR test). Both the definition of the problem and of the user needs with the appropriate choice of all the future diagnostic device components strongly benefit from interdisciplinary teams and collaborative environments, being a key point for a good diagnostic device conception and design.

Laboratory Testing

In practice, the first step in developing a diagnostic device is to demonstrate its feasibility or its ability to detect the target analyte in ideal conditions, such as the pure analyte in a buffer solution and in commercially available biological fluids (artificial saliva and urine, serum, blood, etc.). This proof-of-concept system is usually bulky and laboratory-based, working only in a controlled environment and under very specific conditions. Nevertheless, this stage for a biosensor is crucial, and its related work is often under-appreciated: work in this stage is rarely covered by funding through public project calls and rarely published in leading journals unless the underlying technology is extremely innovative. The link between innovation and the social utility of the related diagnostic test is not always evident. Many of the technologies published in high-impact journals never reach the market, and a few, marginally innovative technologies are broadly used in the clinics having a strong impact on the life of millions of patients. If the proof-of-concept system is working, the following phase consists in the determination of analytical metrics such as analytical sensitivity, the limit of detection (LoD), analytical selectivity, trueness, and precision of these devices in biological fluids. (36) Extensive and time-consuming studies are performed to define the best combination of a system’s parameters to achieve a sufficiently high performance for its specific application. This is typically the stage at which patenting is considered and assessed.

Clinical Trials

After the device has been successfully characterized and tested in a laboratory setting, the next step is its clinical validation using real clinical samples, in the conditions of the intended use. Even clinical entities sometimes have difficulties to find clinically relevant specimens, depending on the type of biological sample to be collected, required storage conditions, and the number of patients related to a particular type of infection. Ebola samples, for example, are difficult to find, since there are only few cases in the world, but even influenza samples have become difficult to find, since it became very rare after the COVID-19 pandemic. For a nonclinical entity, things are even more complicated. The three main obstacles that nonclinical entities must face are (1) the inadequacy of the developer infrastructure to deal with patient samples with a level of biosafety (BSL) above 1, which requires dedicated areas and facilities, (55) (2) the ethical issues to obtain and work with such samples and the ethical committee approval related costs, (66,67) and (3) the unavoidable worsening of the analytical performance of the test moving from in vitro conditions to the complexity and patient-to-patient variability of body fluid samples. Collaboration with clinical partners is the best solution to the first two obstacles, using appropriate spaces and harnessing ongoing or past clinical trials samples, already approved for research purposes. Alternatively, it is possible to purchase validated samples from companies, which takes care of both the sample collection and the ethical aspects, with the related costs in terms of money and time. The last critical obstacle is to avoid sample preprocessing steps, if possible. The technologies able to avoid it typically required many years of R&D to reach that goal.

Regulatory Review

Regulatory agencies evaluate in vitro diagnostics (IVDs) and medical devices. Each country has its regulatory agency that should ensure that all the IVDs available on the market have been adequately assessed for analytical and clinical validity. (68) Additionally, the regulatory agencies contribute to the control of the IVDs in the premarket step and in the postmarket surveillance, to ensure that the IVDs that are used remain safe and effective for the final users. (69) In Europe, most IVDs can still be placed on the market by their manufacturers solely based on an EC Declaration of Conformity (known as “Self-Certification”). (70) This applies to all CE-marked IVD kits for COVID-19 testing, regardless of their underlying technology and operating principle and of their use environment. (71) This current lack of regulatory oversight for IVDs is even more striking, as these kits will be considered of the highest-risk class under the new Regulation EU/2017/746 for IVDs (IVDR) and therefore subject to a stringent conformity assessment procedure for CE certification, with involvement of third parties, including Notified Bodies and EU Reference Laboratories. (72) The IVDR will be applicable in one year (May 26th, 2022), and in the meantime several initiatives have been launched to provide a minimum assurance of reliability for such tests.
In the United States, a temporary Emergency Use Authorization (EUA) from the Food and Drug Administration (FDA) can be sought by manufacturers and laboratories for IVDs for the detection and/or diagnosis of SARS-CoV-2. Unlike the more restrictive EU approach, developers of tests based on other technologies are encouraged to discuss with the FDA the most suitable approach to obtain the corresponding EUA. In addition, in the U.S. the so-called laboratory-developed tests (or LDT) are much more widespread and accepted than the in-house test concept in the EU, and the FDA considers them appropriate for COVID-19 testing when based on molecular assays and performed in accredited, Clinical Laboratory Improvement Amendments (CLIA)-certified laboratories. (73,74)

Scaleup and Market Launch

Although scaleup might be the last item on the agenda, plans to bring the technology to market should be considered and well-defined from the initial stages. It is critical to consider from the beginning the scalability of the proposed fabrication and functionalization technology. In this way, the scale-up phase time could be drastically reduced, producing a market-winning product. As scientists, the know-how of planning a scale-up is very daunting, so usually this is outsourced to pilot plants, or ad-hoc spin-offs are created with this purpose. These partners will work closely with the (scientific) development team to ensure that the design protocols and resources adhere to manufacturing principles (Good Manufacturing Practices (GMP)) (75) and that the target quantities can meet the anticipated volumes for the pilot launch. Furthermore, having a comprehensive, yet adaptable, quality assurance/control (QA/QC) plan is very important for the scaleup. This mitigates any unforeseeable situations, that is, amounts or costs of resources, and ensures that the pilot launch will not be delayed.

The Bottlenecks

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Efficient diagnostic devices are one of the most sought-after elements in a pandemic situation, as seen in the ongoing COVID-19 case. (76) Given the surge in demand, it is of utmost importance to do a thorough study of the process of development and production of diagnostic tests in order to elucidate its bottlenecks, both in terms of time and funding. Each stage of the process is characterized by limitations related to the different stakeholders involved. These stakeholders include patients, clinicians, researchers, companies, investors, and policy makers. (77)

Bottlenecks in Research Stages

A major bottleneck in the early stages of the development of diagnostic tests in pandemic situations is the availability of information regarding the etiological agent (i.e., the agent causing the disease). Indeed, it is not possible to develop a diagnostic device without knowing either the etiological agent’s genome (78) or antigens (79) or the elicited immunological response. (80) Additionally, access to materials and supplies necessary for the regular development of research can be compromised if the supply chain is interrupted either by the severity of the pandemic or because of the policies followed to halt its expansion. (81)
In the conception and design phase it is fundamental to define the type of biological sample that is going to be analyzed, the clinical range that needs to be reached, the techniques or molecules that are going to be used to perform the detection, the platform used, the user’s needs, etc. The initial idea of the device needs to be carefully described, justified, and classified according to the corresponding regulatory entity rules in order to, eventually, expedite the process of approval of the device. (82) Any difficulty to have access to this information can potentially cause a significant delay of the overall process. Even worse, if this information is imprecise or wrong the process could be conducted toward a wrong direction resulting in the complete failure of the development process of the diagnostic test.
Prototyping, or preclinical research stage, also entails certain bottlenecks. It is during this stage that users’ expectations and usability as well as a future scaleup of the product should be addressed to avoid future redesigns of the device, which may cause important delays due to unnecessary iterations and extra costs. Appearance and user-friendliness of the device, supply chain limitations, and a simple and optimal industrial fabrication guide all need to be considered. Experience in similar endeavors by researchers and engineers is key to address all these possible sources of future complications sooner rather than later, minimizing the unnecessary iterations. In this regard, a smooth interdisciplinary communication between researchers and clinicians is necessary to approach the final users’ preferences, and communication between researchers and the industry is important to avoid setbacks. (83)
Clinical trials with the developed diagnostic tests involve testing real samples, whether directly from patients or using samples collected by a healthcare center. In this and the previous phase, the highest obstacle usually is specificity (i.e., interference by other molecules in the sample of interest and variability of their concentrations in samples collected in different moments from different individuals). Facing this obstacle can lead to a severe prolongation of the development period. After the clinical trials, diagnostic tests undergo scrutiny from the pertinent regulatory authority. For a fluent process, all requirements from the authority should have been accounted for in all previous stages before presenting the device. (84)

Bottlenecks in Market Stages

Once a diagnostic test enters the market, a lot of work is still required to improve the device’s performance and guarantee its success. User feedback, particularly from clinical personnel, and refinement are essential for improving the accuracy of the diagnostic device. Over- or under-confidence on a diagnostic test can lead to a misdiagnosis and its undesirable side effects. (85) Aside from lab-tested and validated performance aspects, such as accuracy, repeatability, sensitivity, and meeting clinical requirements, the translation of a POC technology to a large-scale production is not always as straightforward as it seems. Planning for the success of a diagnostic product also includes an understanding of the demands of production and extensive market research. For example, unlike in lab settings, mass production can mean the consumption of materials and reagents 100 times faster with rigid and unforgiving deadlines. Moreover, the adaptability of production should also be considered especially in terms of variability between batches of raw material─will a change part way through affect the device performance? Although in theory, all batches should be the same and be of high quality and purity, in practice, this does not happen in all the cases. Assay performances may also vary batch-to-batch, as many biological reagents are sold in terms of purity without an assessment of their reactivity. Mass production is also a critical point for diagnostic tests involving nanomaterials. The large-scale production of some nanomaterials still poses a challenge with respect to controlling the size, defects, and stability of the nanomaterials during a large-scale production. In addition, the synthesis methods should ideally be low-cost. Protocols that integrate the nanomaterials into the diagnostic devices during a large-scale production must preserve the outstanding properties of the nanomaterials. Another challenge is the biofunctionalization of nanomaterials at scale and with high reproducibility. The shelf life and storage should be assessed early on and can be critical for POC diagnostics including biological reagents and materials (polymeric housing, metallic electrodes, adhesives). Exposure to heat or moisture can degrade both materials and reagents.

Regulatory Bottlenecks

The regulatory aspects have a central role in the introduction of a POC device. In the case of the current pandemic, the WHO has established the Emergency Use Listing (EUL) procedure for IVDs to detect SARS-CoV-2 in order to determine their eligibility through a procurement process by the WHO or its partners. In this procedure, data pertaining to the quality, safety, and performance of IVDs are critically assessed by the WHO, and upon review a recommendation for EUL to the assessed product is eventually granted. (78,86) The European Commission recently published a working document to establish proposed performance criteria for COVID-19 tests, which includes molecular- and immunologic-based methods. Despite this effort, such a document highlights the difficulty in establishing a clear link between validation data and specific commercial devices or in defining the reliability of the identified performance data, often not validated by third parties. (87) Beyond performance criteria, other aspects may be critical for the certification of the devices, especially if intended to be developed as tests for lay users (known as “self-tests”).
When it comes to the development of IVDs based on nanomaterials, regulatory aspects become even more challenging. A representative class of nanomaterials that is explored in academic research for the development of IVDs still does not have its biosafety level fully understood and its use regulated. Even though there have been some advances, such as the publication of ISO/TR 10993-22:2017, (88) which describes considerations for the biological evaluation of medical devices that are composed of or contain nanomaterials, we still have a lack of international regulatory guidelines for evaluating the safety of different types of nanomaterials integrated into IVDs.

Privacy Issues

The widespread usage of mobile technologies generates clear synergies with diagnostic tests, but it also brings ethical issues concerning the privacy of patients. (89,90) Coupling diagnostic devices to contact-tracing apps might not receive trust from users who may fear that the collected data regarding their location might be used for non-COVID-19 related purposes. Many questions must be answered in order to understand to what extent contact-tracing apps are ethically justifiable. (91) Although the purpose of surveillance testing is not ultimately that of returning a diagnostic result to an individual but to obtain information at a population level, (92) public authorities must remain aware that trust from citizens is earned but not enforced. This is common in different organizational environments. (93) In this regard, it is possible to implement nonmandatory contact-tracing apps that preserve privacy, thus balancing the needs and goals of users, policy makers, and developers. Ideally, this should be the case when the values of each stakeholder are aligned. (94) Moreover, a transparent and clear communication with the user is fundamental to gain their trust and successfully implement the adoption of these advantageous technologies.

Improvements for Facing Future Pandemics

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There is no doubt that high-performance and reliable devices need high-quality research efforts and time for their development. However, on the basis of our analysis of the bottlenecks during the development process, and from our direct experience in the preclinical and clinical stages, we have suggestions for the minimization of unnecessary time loss and for the improvement of the preparedness for the next pandemics.
The first concept we think should be explored is the “a test for each purpose” paradigm. Currently, we pursue the development of a sensor with very high performance/manufacturability and low cost to be used as a valid alternative to the gold standard molecular testing. As we have seen, this takes time, but more importantly, that performance may not be needed for every testing purpose.
Models of the infection spreading could in fact give a “score” to different places and events on the basis of their frequency, prevalence in the area, and of the potential consequences of a false positive, for example, with a color scale. Accordingly, different diagnostic tests designed for that color code may be employed, each with an optimized performance/cost/response time for the respective color code. It is evident that testing in an airport before an international flight would need a higher sensitivity with respect to a daily test in a small school.
To make this paradigm possible and the development process lean and faster, we think that the consolidation of a reduced set of technologies for the rapid targeting, monitoring, and tracking of new pathogens should be prioritized. The concept is to have an “outbreak nanodiagnostic survival kit”, that is, a minimum set of already-verified materials, techniques, and methods for the fast production and scaling of a first screening tool. Many nanomaterials and nanotechnological methods are good candidates to be included in the kit due to the astonishing properties they confer to the diagnostic devices, but it is fundamental to set up routes for their scale-up. As we have seen, critical data about new pathogens can be obtained and communicated in fast times; thus, such a kit would ensure its rapid and proper use minimizing the development process risks and times.
Driving the scientific community in these directions may be easier if the implementation research and advancements at the highest TRLs may be better considered by high-impact journals, encouraging them.
Another issue that could be faced is the one related to statistical illiteracy. Most of the people are not confident about the implications and effects of different sensitivity and accuracy values that characterize the performance of each diagnostic test. First, these should be certified by independent entities and available to the user (e.g., on a public downloadable database, such as the FIND one). Second, their meaning should be made clear for everybody and enter in the common culture.
In all these approaches to the future pandemics a transversal factor, which makes the difference, is interdisciplinary research teams and tight collaborations between all the actors involved in the development process. The collaboration of these actors as a unique unit and not as a chain of independent black boxes would allow a drastic optimization of the time and effort needed for the development of a nanodiagnostic device.
Finally, the last innovation we envision is the establishment of international biobanks containing verified patient samples. Having access to those samples could be either related to specific grants or by an employment of strict criteria, such as proven high-enough TRLs. Potentially the biobanks may also provide laboratory spaces with BSL 2 and 3, which are generally difficult to find and even more difficult to get access into. This would allow research groups even with limited collaborations with clinicians to get access to readily available samples and facilities to perform the development of diagnostic devices. We understand this is far from being simple and straightforward, but we believe it is worth pursuing.

Author Information

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  • Corresponding Author
  • Authors
    • Giulio Rosati - Institut Català de Nanociència i Nanotecnologia, Edifici ICN2 Campus UAB, 08193 Bellaterra, Barcelona, Spain;  Orcidhttps://orcid.org/0000-0002-0227-4561
    • Andrea Idili - Institut Català de Nanociència i Nanotecnologia, Edifici ICN2 Campus UAB, 08193 Bellaterra, Barcelona, Spain;  Present Address: (A.I.) Department of Chemical Science and Technologies, University of Rome, Tor Vergata, 00133 Rome, Italy;  Orcidhttps://orcid.org/0000-0002-6004-270X
    • Claudio Parolo - Institut Català de Nanociència i Nanotecnologia, Edifici ICN2 Campus UAB, 08193 Bellaterra, Barcelona, Spain;  Present Address: (C.P.) ISGlobal–Barcelona Institute for Global Health, Carrer del Rosselló, 132, 08036 Barcelona, Spain;  Orcidhttps://orcid.org/0000-0001-9481-4408
    • Celia Fuentes-Chust - Institut Català de Nanociència i Nanotecnologia, Edifici ICN2 Campus UAB, 08193 Bellaterra, Barcelona, Spain;  Orcidhttps://orcid.org/0000-0002-8945-8514
    • Enric Calucho - Institut Català de Nanociència i Nanotecnologia, Edifici ICN2 Campus UAB, 08193 Bellaterra, Barcelona, Spain
    • Liming Hu - Institut Català de Nanociència i Nanotecnologia, Edifici ICN2 Campus UAB, 08193 Bellaterra, Barcelona, Spain;  Orcidhttps://orcid.org/0000-0002-8666-9287
    • Cecilia de Carvalho Castro e Silva - Institut Català de Nanociència i Nanotecnologia, Edifici ICN2 Campus UAB, 08193 Bellaterra, Barcelona, Spain;  MackGraphe-Mackenzie Institute for Research in Graphene and Nanotechnologies, Mackenzie Presbyterian University, Consolação street 930, 01302-907 São Paulo, Brazil;  Orcidhttps://orcid.org/0000-0003-3933-1838
    • Lourdes Rivas - Institut Català de Nanociència i Nanotecnologia, Edifici ICN2 Campus UAB, 08193 Bellaterra, Barcelona, Spain;  Present Address: (L.R.) Paperdrop Diagnostics S. L. Edificio Eureka, Av. de Can Domènech, 08193 Bellaterra, Spain;  Orcidhttps://orcid.org/0000-0002-1510-5927
    • Emily P. Nguyen - Institut Català de Nanociència i Nanotecnologia, Edifici ICN2 Campus UAB, 08193 Bellaterra, Barcelona, Spain;  Present Address: (E.N.) 509/11 Flockhart Street, Abbotsford 3067 Victoria, Australia;  Orcidhttps://orcid.org/0000-0003-4299-2055
    • José F. Bergua - Institut Català de Nanociència i Nanotecnologia, Edifici ICN2 Campus UAB, 08193 Bellaterra, Barcelona, Spain;  Present Address: (J.F.B.) Biokit S.A., Lliçà d’Amunt 08186, Barcelona, Spain;  Orcidhttps://orcid.org/0000-0002-5969-193X
    • Ruslan Alvárez-Diduk - Institut Català de Nanociència i Nanotecnologia, Edifici ICN2 Campus UAB, 08193 Bellaterra, Barcelona, Spain;  Orcidhttps://orcid.org/0000-0002-9876-1574
    • José Muñoz - Institut Català de Nanociència i Nanotecnologia, Edifici ICN2 Campus UAB, 08193 Bellaterra, Barcelona, Spain;  ISGlobal-Barcelona Institute for Global Health, Carrer del Rosselló, 132, 08036 Barcelona, Spain
    • Christophe Junot - Université Paris-Saclay, CEA, INRAE Departement Médicaments et Technologies pour la Santé SPI, 91191 Gif-sur-Yvette cedex, France
    • Oriol Penon - Asphalion, Carrer de Tarragona 151-157, 08014 Barcelona, Spain
    • Dominique Monferrer - Asphalion, Carrer de Tarragona 151-157, 08014 Barcelona, Spain
    • Emmanuel Delamarche - IBM Research−Zurich, 8803 Rüschlikon, Switzerland;  Orcidhttps://orcid.org/0000-0002-8753-8895
  • Author Contributions

    Conceptualization: G.R., A.I., and C.P. Investigation: G.R., A.I., C.P., C.F., E.C., L.H., C.C.C.S., L.R., E.P.N., J.B., O.P., and D.M. Methodology: G.R., L.R., C.C.C.S., and E.P.N. Supervision: A.M. and E.D. Visualization: G.R. and L.R. Writing─original draft: G.R., A.I., C.P., C.F., E.C., L.H., C.C.C.S., L.R., E.P.N., J.B., O.P., D.M., and E.D. Writing─review and editing: E.D., C.J., J.M., R.A., and A.M.

  • Notes
    The authors declare no competing financial interest.

Acknowledgments

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We acknowledge funding from the European Union Horizon2020 Programme under Grant No. 881603 (Graphene Flagship Core 3). We acknowledge Consejo Superior de Investigaciones Científicas (CSIC) for the project “COVID19-122” granted in the call “Nuevas ayudas extraordinarias a proyectos de investigación en el marco de las medidas urgentes extraordinarias para hacer frente al impacto económico y social del COVID-19 (Ayudas CSIC–COVID-19)”. We acknowledge the MICROB-PREDICT Project for partially supporting the work. The MICROB-PREDICT project has received funding from the European Union’s Horizon 2020 research and innovation programme under Grant No. 825694. This reflects only the author’s view, and the European Commission is not responsible for any use that may be made of the information it contains. We also acknowledge Agencia Estatal de Investigación (AEI) and Fondo Europeo de Desarrollo Regional (FEDER) for the project MAT2017-87202-P. A.I. was supported by a PROBIST postdoctoral fellowship funded by European Research Council (Marie Skłodowska-Curie Grant No. 754510). C.C.C.S. acknowledges funding through CAPES–PRINT (Programa Institucional de Internacionalização; Grant Nos. 88887.310281/2018-00 and 88887.467442/2019-00) and Mackpesquisa-UPM. L.H. acknowledges funding through the China Scholarship Council. ICN2 is funded by the CERCA Programme/Generalitat de Catalunya and supported by the Severo Ochoa programme (MINECO Grant No. SEV-2017-0706).

Vocabulary

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SARS-CoV-2

The acronym given to the severe acute respiratory syndrome coronavirus 2, causing the coronavirus disease (COVID-19)
Nanodiagnostics

A term intended to indicate diagnostic devices that include a nanotechnological component (e.g., nanoparticles, 2D nanomaterials, quantum dots, etc.) to perform the detection. Most often the nanocomponent increases the sensitivity with respect to standard diagnostic devices
Molecular test

This refers to a PCR-based test to diagnose COVID-19 by analyzing the RNA present in an oral sample of the patient
Antigenic test

This refers to a diagnostic test to analyze an oral sample detecting the presence of the antigens (proteins) of the SARS-CoV-2 virus, typically through a protein-antibody interaction
Serological test

This refers to a diagnostic test for the detection of specific anti-SARS-CoV-2 antibodies in a blood sample of the patient, with the aim to check for his/her immunization against SARS-CoV-2
TRL

This stands for Technology Readiness Level, and it is a score to define the level of advancement of a new technological product/idea. It is used to classify research projects, starting levels, and advancements but also business ideas and plans.

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    Since 2002, beta coronaviruses (CoV) have caused three zoonotic outbreaks, SARS-CoV in 2002-2003, MERS-CoV in 2012, and the newly emerged SARS-CoV-2 in late 2019. However, little is currently known about the biol. of SARS-CoV-2. Here, using SARS-CoV-2 S protein pseudovirus system, we confirm that human angiotensin converting enzyme 2 (hACE2) is the receptor for SARS-CoV-2, find that SARS-CoV-2 enters 293/hACE2 cells mainly through endocytosis, that PIKfyve, TPC2, and cathepsin L are crit. for entry, and that SARS-CoV-2 S protein is less stable than SARS-CoV S. Polyclonal anti-SARS S1 antibodies T62 inhibit entry of SARS-CoV S but not SARS-CoV-2 S pseudovirions. Further studies using recovered SARS and COVID-19 patients' sera show limited cross-neutralization, suggesting that recovery from one infection might not protect against the other. Our results present potential targets for development of drugs and vaccines for SARS-CoV-2.
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  11. 11
    Walls, A. C.; Park, Y.-J.; Tortorici, M. A.; Wall, A.; McGuire, A. T.; Veesler, D. Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein. Cell 2020, 181 (2), 281– 292,  DOI: 10.1016/j.cell.2020.02.058
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    11
    Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein
    Walls, Alexandra C.; Park, Young-Jun; Tortorici, M. Alejandra; Wall, Abigail; McGuire, Andrew T.; Veesler, David
    Cell (Cambridge, MA, United States) (2020), 181 (2), 281-292.e6CODEN: CELLB5; ISSN:0092-8674. (Cell Press)
    The emergence of SARS-CoV-2 has resulted in >90,000 infections and >3000 deaths. Coronavirus spike (S) glycoproteins promote entry into cells and are the main target of antibodies. We show that SARS-CoV-2 S uses ACE2 to enter cells and that the receptor-binding domains of SARS-CoV-2 S and SARS-CoV S bind with similar affinities to human ACE2, correlating with the efficient spread of SARS-CoV-2 among humans. We found that the SARS-CoV-2 S glycoprotein harbors a furin cleavage site at the boundary between the S1/S2 subunits, which is processed during biogenesis and sets this virus apart from SARS-CoV and SARS-related CoVs. We detd. cryo-EM structures of the SARS-CoV-2 S ectodomain trimer, providing a blueprint for the design of vaccines and inhibitors of viral entry. Finally, we demonstrate that SARS-CoV S murine polyclonal antibodies potently inhibited SARS-CoV-2 S mediated entry into cells, indicating that cross-neutralizing antibodies targeting conserved S epitopes can be elicited upon vaccination.
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  12. 12
    Tilocca, B.; Soggiu, A.; Sanguinetti, M.; Babini, G.; De Maio, F.; Britti, D.; Zecconi, A.; Bonizzi, L.; Urbani, A.; Roncada, P. Immunoinformatic Analysis of the SARS-CoV-2 Envelope Protein as a Strategy to Assess Cross-Protection against COVID-19. Microbes Infect. 2020, 22 (4–5), 182– 187,  DOI: 10.1016/j.micinf.2020.05.013
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    12
    Immunoinformatic analysis of the SARS-CoV-2 envelope protein as a strategy to assess cross-protection against COVID-19
    Tilocca, Bruno; Soggiu, Alessio; Sanguinetti, Maurizio; Babini, Gabriele; De Maio, Flavio; Britti, Domenico; Zecconi, Alfonso; Bonizzi, Luigi; Urbani, Andrea; Roncada, Paola
    Microbes and Infection (2020), 22 (4-5), 182-187CODEN: MCINFS; ISSN:1286-4579. (Elsevier Masson SAS)
    Envelope protein of coronaviruses is a structural protein existing in both monomeric and homo-pentameric form. It has been related to a multitude of roles including virus infection, replication, dissemination, and immune response stimulation. We employed an immunoinformatic approach to investigate the major immunogenic domains of the SARS-CoV-2 envelope protein and map them among the homolog proteins of coronaviruses with tropism for animal species that are closely inter-related with the human beings population all over the world. Also, when not available, we predicted the envelope protein structural folding and mapped SARS-CoV-2 epitopes. Envelope sequences alignment provides evidence of high sequence homol. for some of the investigated virus specimens; while the structural mapping of epitopes resulted in the interesting maintenance of the structural folding and epitope sequence localization also in the envelope proteins scoring a lower alignment score. In line with the One-Health approach, our evidences provide a mol. structural rationale for a potential role of taxonomically related coronaviruses in conferring protection from SARS-CoV-2 infection and identifying potential candidates for the development of diagnostic tools and prophylactic-oriented strategies.
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  13. 13
    Yin, C. Genotyping Coronavirus SARS-CoV-2: Methods and Implications. Genomics 2020, 112 (5), 3588– 3596,  DOI: 10.1016/j.ygeno.2020.04.016
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    13
    Genotyping coronavirus SARS-CoV-2: methods and implications
    Yin, Changchuan
    Genomics (2020), 112 (5), 3588-3596CODEN: GNMCEP; ISSN:0888-7543. (Elsevier Inc.)
    The emerging global infectious COVID-19 disease by novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) presents crit. threats to global public health and the economy since it was identified in late Dec. 2019 in China. The virus has gone through various pathways of evolution. To understand the evolution and transmission of SARS-CoV-2, genotyping of virus isolates is of great importance. This study presents an accurate method for effectively genotyping SARS-CoV-2 viruses using complete genomes. The method employs the multiple sequence alignments of the genome isolates with the SARS-CoV-2 ref. genome. The single-nucleotide polymorphism (SNP) genotypes are then measured by Jaccard distances to track the relationship of virus isolates. The genotyping anal. of SARS-CoV-2 isolates from the globe reveals that specific multiple mutations are the predominated mutation type during the current epidemic. The proposed method serves an effective tool for monitoring and tracking the epidemic of pathogenic viruses in their global and local genetic variations. The genotyping anal. shows that the genes encoding the S proteins and RNA polymerase, RNA primase, and nucleoprotein, undergo frequent mutations. These mutations are crit. for vaccine development in disease control.
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  14. 14
    Li, Q.; Guan, X.; Wu, P.; Wang, X.; Zhou, L.; Tong, Y.; Ren, R.; Leung, K. S. M.; Lau, E. H. Y.; Wong, J. Y.; Xing, X.; Xiang, N.; Wu, Y.; Li, C.; Chen, Q.; Li, D.; Liu, T.; Zhao, J.; Liu, M.; Tu, W. Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus-Infected Pneumonia. N. Engl. J. Med. 2020, 382 (13), 1199– 1207,  DOI: 10.1056/NEJMoa2001316
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    14
    Early transmission dynamics in Wuhan, China, of novel coronavirus-infected pneumonia
    Li, Qun; Guan, Xuhua; Wu, Peng; Wang, Xiaoye; Zhou, Lei; Tong, Yeqing; Ren, Ruiqi; Leung, Kathy S. M.; Lau, Eric H. Y.; Wong, Jessica Y.; Xing, Xuesen; Xiang, Nijuan; Wu, Yang; Li, Chao; Chen, Qi; Li, Dan; Liu, Tian; Zhao, Jing; Liu, Man; Tu, Wenxiao; Chen, Chuding; Jin, Lianmei; Yang, Rui; Wang, Qi; Zhou, Suhua; Wang, Rui; Liu, Hui; Luo, Yinbo; Liu, Yuan; Shao, Ge; Li, Huan; Tao, Zhongfa; Yang, Yang; Deng, Zhiqiang; Liu, Boxi; Ma, Zhitao; Zhang, Yanping; Shi, Guoqing; Lam, Tommy T. Y.; Wu, Joseph T.; Gao, George F.; Cowling, Benjamin J.; Yang, Bo; Leung, Gabriel M.; Feng, Zijian
    New England Journal of Medicine (2020), 382 (13), 1199-1207CODEN: NEJMAG; ISSN:1533-4406. (Massachusetts Medical Society)
    The initial cases of novel coronavirus (2019-nCoV)-infected pneumonia (NCIP) occurred in Wuhan, Hubei Province, China, in Dec. 2019 and Jan. 2020. We analyzed data on the 1st 425 confirmed cases in Wuhan to det. the epidemiol. characteristics of NCIP. We collected information on demog. characteristics, exposure history, and illness timelines of lab.-confirmed cases of NCIP that had been reported by Jan. 22, 2020. We described characteristics of the cases and estd. the key epidemiol. time-delay distributions. In the early period of exponential growth, we estd. the epidemic doubling time and the basic reproductive no. Among the 1st 425 patients with confirmed NCIP, the median age was 59 yr and 56% were male. The majority of cases (55%) with onset before Jan. 1, 2020, were linked to the Huanan Seafood Wholesale Market, as compared with 8.6% of the subsequent cases. The mean incubation period was 5.2 days, with the 95th percentile of the distribution at 12.5 days. In its early stages, the epidemic doubled in size every 7.4 days. With a mean serial interval of 7.5 days, the basic reproductive no. was estd. to be 2.2. On the basis of this information, there is evidence that human-to-human transmission has occurred among close contacts since the middle of Dec. 2019. Considerable efforts to reduce transmission will be required to control outbreaks if similar dynamics apply elsewhere. Measures to prevent or reduce transmission should be implemented in populations at risk.
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  15. 15
    Andersen, K. G.; Rambaut, A.; Lipkin, W. I.; Holmes, E. C.; Garry, R. F. The Proximal Origin of SARS-CoV-2. Nat. Med. 2020, 26 (4), 450– 452,  DOI: 10.1038/s41591-020-0820-9
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    15
    The proximal origin of SARS-CoV-2
    Andersen, Kristian G.; Rambaut, Andrew; Lipkin, W. Ian; Holmes, Edward C.; Garry, Robert F.
    Nature Medicine (New York, NY, United States) (2020), 26 (4), 450-452CODEN: NAMEFI; ISSN:1078-8956. (Nature Research)
    There is no expanded citation for this reference.
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  16. 16
    St John, A.; Price, C. P. Existing and Emerging Technologies for Point-of-Care Testing. Clin. Biochem. Rev. 2014, 35 (3), 155– 167
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    Existing and Emerging Technologies for Point-of-Care Testing
    St John Andrew; Price Christopher P
    The Clinical biochemist. Reviews (2014), 35 (3), 155-67 ISSN:0159-8090.
    The volume of point-of-care testing (PoCT) has steadily increased over the 40 or so years since its widespread introduction. That growth is likely to continue, driven by changes in healthcare delivery which are aimed at delivering less costly care closer to the patient's home. In the developing world there is the challenge of more effective care for infectious diseases and PoCT may play a much greater role here in the future. PoCT technologies can be split into two categories, but in both, testing is generally performed by technologies first devised more than two decades ago. These technologies have undoubtedly been refined and improved to deliver easier-to-use devices with incremental improvements in analytical performance. Of the two major categories the first is small handheld devices, providing qualitative or quantitative determination of an increasing range of analytes. The dominant technologies here are glucose biosensor strips and lateral flow strips using immobilised antibodies to determine a range of parameters including cardiac markers and infectious pathogens. The second category of devices are larger, often bench-top devices which are essentially laboratory instruments which have been reduced in both size and complexity. These include critical care analysers and, more recently, small haematology and immunology analysers. New emerging devices include those that are utilising molecular techniques such as PCR to provide infectious disease testing in a sufficiently small device to be used at the point of care. This area is likely to grow with many devices being developed and likely to reach the commercial market in the next few years.
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    Gervais, L.; de Rooij, N.; Delamarche, E. Microfluidic Diagnostic Devices: Microfluidic Chips for Point-of-Care Immunodiagnostics. Adv. Mater. 2011, 23 (24), H208– H208,  DOI: 10.1002/adma.201190098
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    Delamarche, E.; Bernard, A.; Schmid, H.; Michel, B.; Biebuyck, H. Patterned Delivery of Immunoglobulins to Surfaces Using Microfluidic Networks. Science 1997, 276 (5313), 779– 781,  DOI: 10.1126/science.276.5313.779
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    Patterned delivery of immunoglobulins to surfaces using microfluidic networks
    Delamarche, Emmanuel; Bernard, Anre; Schmid, Heinz; Michael, Bruno; Biebuyck, Hans
    Science (Washington, D. C.) (1997), 276 (5313), 779-781CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
    Microfluidic networks (μFNs) were used to pattern biomols. with high resoln. on a variety of substrates (gold, glass, or polystyrene). Elastomeric μFNs localized chem. reactions between the biomols. and the surface, requiring only microliters of reagent to cover square millimeter-sized areas. The networks were designed to ensure stability and filling of the μFN and allowed a homogeneous distribution and robust attachment of material to the substrate along the conduits in the μFN. Igs patterned on substrates by means of μFNs remained strictly confined to areas enclosed by the approach is simple and general enough to suggest a practical way to incorporate biol. material on technol. substrates.
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    Guangzhou Wondfo Biotech Co. LTD. COVID-19 - Wondfo https://en.wondfo.com.cn/es/covid-19-5/ (accessed 2020-04-28).
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    Crozier, A.; Rajan, S.; Buchan, I.; McKee, M. Put to the Test: Use of Rapid Testing Technologies for Covid-19. BMJ. 2021, 372, n208  DOI: 10.1136/bmj.n208
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    Niemz, A.; Ferguson, T. M.; Boyle, D. S. Point-of-Care Nucleic Acid Testing for Infectious Diseases. Trends Biotechnol. 2011, 29 (5), 240– 250,  DOI: 10.1016/j.tibtech.2011.01.007
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    Point-of-care nucleic acid testing for infectious diseases
    Niemz, Angelika; Ferguson, Tanya M.; Boyle, David S.
    Trends in Biotechnology (2011), 29 (5), 240-250CODEN: TRBIDM; ISSN:0167-7799. (Elsevier B.V.)
    A review. Nucleic acid testing for infectious diseases at the point of care is beginning to enter clin. practice in developed and developing countries; esp. for applications requiring fast turnaround times, and in settings where a centralized lab. approach faces limitations. Current systems for clin. diagnostic applications are mainly PCR-based, can only be used in hospitals, and are still relatively complex and expensive. Integrating sample prepn. with nucleic acid amplification and detection in a cost-effective, robust, and user-friendly format remains challenging. This review describes recent tech. advances that might be able to address these limitations, with a focus on isothermal nucleic acid amplification methods. It briefly discusses selected applications related to the diagnosis and management of tuberculosis, HIV, and perinatal and nosocomial infections.
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    Nichols, J. H. Reducing Medical Errors at the Point of Care. Lab. Med. 2005, 36 (5), 275– 277,  DOI: 10.1309/NXXWJ31PWFHT7L1Q
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    Shaw, J. L. V. Practical Challenges Related to Point of Care Testing. Pract. Lab. Med. 2016, 4, 22– 29,  DOI: 10.1016/j.plabm.2015.12.002
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    23
    Practical challenges related to point of care testing
    Shaw Julie L V; Shaw Julie L V; Shaw Julie L V
    Practical laboratory medicine (2016), 4 (), 22-29 ISSN:2352-5517.
    Point of care testing (POCT) refers to laboratory testing that occurs near to the patient, often at the patient bedside. POCT can be advantageous in situations requiring rapid turnaround time of test results for clinical decision making. There are many challenges associated with POCT, mainly related to quality assurance. POCT is performed by clinical staff rather than laboratory trained individuals which can lead to errors resulting from a lack of understanding of the importance of quality control and quality assurance practices. POCT is usually more expensive than testing performed in the central laboratory and requires a significant amount of support from the laboratory to ensure the quality testing and meet accreditation requirements. Here, specific challenges related to POCT compliance with accreditation standards are discussed along with strategies that can be used to overcome these challenges. These areas include: documentation of POCT orders, charting of POCT results as well as training and certification of individuals performing POCT. Factors to consider when implementing connectivity between POCT instruments and the electronic medical record are also discussed in detail and include: uni-directional versus bidirectional communication, linking patient demographic information with POCT software, the importance of positive patient identification and considering where to chart POCT results in the electronic medical record.
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  24. 24
    Kumar, A. A.; Hennek, J. W.; Smith, B. S.; Kumar, S.; Beattie, P.; Jain, S.; Rolland, J. P.; Stossel, T. P.; Chunda-Liyoka, C.; Whitesides, G. M. From the Bench to the Field in Low-Cost Diagnostics: Two Case Studies. Angew. Chem., Int. Ed. 2015, 54 (20), 5836– 5853,  DOI: 10.1002/anie.201411741
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    24
    From the Bench to the Field in Low-Cost Diagnostics: Two Case Studies
    Kumar, Ashok A.; Hennek, Jonathan W.; Smith, Barbara S.; Kumar, Shailendra; Beattie, Patrick; Jain, Sidhartha; Rolland, Jason P.; Stossel, Thomas P.; Chunda-Liyoka, Catherine; Whitesides, George M.
    Angewandte Chemie, International Edition (2015), 54 (20), 5836-5853CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    A review on two case studies of (liver injury, sickle cell disease) on the processes that move point-of-care (POC) diagnostic technol. from a lab. to a field, esp., to a resource-limited environment.
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  25. 25
    Sachdeva, S.; Davis, R. W.; Saha, A. K. Microfluidic Point-of-Care Testing: Commercial Landscape and Future Directions. Front. Bioeng. Biotechnol. 2021, 8, 1537,  DOI: 10.3389/fbioe.2020.602659
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    Kelley, S. O. COVID-19: A Crisis Creating New Opportunities for Sensing. ACS Sensors 2021, 6 (4), 1407– 1407,  DOI: 10.1021/acssensors.1c00687
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    26
    COVID-19: A Crisis Creating New Opportunities for Sensing
    Kelley, Shana O.
    ACS Sensors (2021), 6 (4), 1407CODEN: ASCEFJ; ISSN:2379-3694. (American Chemical Society)
    A review. In this month's issue of ACS Sensors, several new approaches and areas are covered that will contribute to the sensor revolution that is to come. The pace of innovation in sensor science is impressive and in these exceptional times, it will accelerate further.
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  27. 27
    Yousefi, H.; Mahmud, A.; Chang, D.; Das, J.; Gomis, S.; Chen, J. B.; Wang, H.; Been, T.; Yip, L.; Coomes, E.; Li, Z.; Mubareka, S.; McGeer, A.; Christie, N.; Gray-Owen, S.; Cochrane, A.; Rini, J. M.; Sargent, E. H.; Kelley, S. O. Detection of SARS-CoV-2 Viral Particles Using Direct, Reagent-Free Electrochemical Sensing. J. Am. Chem. Soc. 2021, 143 (4), 1722– 1727,  DOI: 10.1021/jacs.0c10810
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    27
    Detection of SARS-CoV-2 Viral Particles Using Direct, Reagent-Free Electrochemical Sensing
    Yousefi, Hanie; Mahmud, Alam; Chang, Dingran; Das, Jagotamoy; Gomis, Surath; Chen, Jenise B.; Wang, Hansen; Been, Terek; Yip, Lily; Coomes, Eric; Li, Zhijie; Mubareka, Samira; McGeer, Allison; Christie, Natasha; Gray-Owen, Scott; Cochrane, Alan; Rini, James M.; Sargent, Edward H.; Kelley, Shana O.
    Journal of the American Chemical Society (2021), 143 (4), 1722-1727CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    The development of new methods for direct viral detection using streamlined and ideally reagent-free assays is a timely and important, but challenging, problem. The challenge of combating the COVID-19 pandemic has been exacerbated by the lack of rapid and effective methods to identify viral pathogens like SARS-CoV-2 on-demand. Existing gold std. nucleic acid-based approaches require enzymic amplification to achieve clin. relevant levels of sensitivity and are not typically used outside of a lab. setting. We report reagent-free viral sensing that directly reads out the presence of viral particles in 5 min using only a sensor-modified electrode chip. The approach relies on a class of electrode-tethered sensors bearing an analyte-binding antibody displayed on a neg. charged DNA linker that also features a tethered redox probe. When a pos. potential is applied, the sensor is transported to the electrode surface. Using chronoamperometry, the presence of viral particles and proteins can be detected as these species increase the hydrodynamic drag on the sensor. This report is the 1st virus-detecting assay that uses the kinetic response of a probe/virus complex to analyze the complexation state of the antibody. We demonstrate the performance of this sensing approach as a means to detect, within 5 min, the presence of the SARS-CoV-2 virus and its assocd. spike protein in test samples and in unprocessed patient saliva.
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  28. 28
    Wu, F.; Zhao, S.; Yu, B.; Chen, Y.-M.; Wang, W.; Song, Z.-G.; Hu, Y.; Tao, Z.-W.; Tian, J.-H.; Pei, Y.-Y.; Yuan, M.-L.; Zhang, Y.-L.; Dai, F.-H.; Liu, Y.; Wang, Q.-M.; Zheng, J.-J.; Xu, L.; Holmes, E. C.; Zhang, Y.-Z. A New Coronavirus Associated with Human Respiratory Disease in China. Nature 2020, 579 (7798), 265– 269,  DOI: 10.1038/s41586-020-2008-3
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    28
    A new coronavirus associated with human respiratory disease in China
    Wu, Fan; Zhao, Su; Yu, Bin; Chen, Yan-Mei; Wang, Wen; Song, Zhi-Gang; Hu, Yi; Tao, Zhao-Wu; Tian, Jun-Hua; Pei, Yuan-Yuan; Yuan, Ming-Li; Zhang, Yu-Ling; Dai, Fa-Hui; Liu, Yi; Wang, Qi-Min; Zheng, Jiao-Jiao; Xu, Lin; Holmes, Edward C.; Zhang, Yong-Zhen
    Nature (London, United Kingdom) (2020), 579 (7798), 265-269CODEN: NATUAS; ISSN:0028-0836. (Nature Research)
    Emerging infectious diseases, such as severe acute respiratory syndrome (SARS) and Zika virus disease, present a major threat to public health. Despite intense research efforts, how, when and where new diseases appear are still a source of considerable uncertainty. A severe respiratory disease was recently reported in Wuhan, Hubei province, China. As of 25 Jan. 2020, at least 1,975 cases had been reported since the first patient was hospitalized on 12 Dec. 2019. Epidemiol. investigations have suggested that the outbreak was assocd. with a seafood market in Wuhan. Here we study a single patient who was a worker at the market and who was admitted to the Central Hospital of Wuhan on 26 Dec. 2019 while experiencing a severe respiratory syndrome that included fever, dizziness and a cough. Metagenomic RNA sequencing of a sample of bronchoalveolar lavage fluid from the patient identified a new RNA virus strain from the family Coronaviridae, which is designated here 'WH-Human 1' coronavirus (and has also been referred to as '2019-nCoV'). Phylogenetic anal. of the complete viral genome (29,903 nucleotides) revealed that the virus was most closely related (89.1% nucleotide similarity) to a group of SARS-like coronaviruses (genus Betacoronavirus, subgenus Sarbecovirus) that had previously been found in bats in China. This outbreak highlights the ongoing ability of viral spill-over from animals to cause severe disease in humans.
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    Zhou, P.; Yang, X.-L.; Wang, X.-G.; Hu, B.; Zhang, L.; Zhang, W.; Si, H.-R.; Zhu, Y.; Li, B.; Huang, C.-L.; Chen, H.-D.; Chen, J.; Luo, Y.; Guo, H.; Jiang, R.-D.; Liu, M.-Q.; Chen, Y.; Shen, X.-R.; Wang, X.; Zheng, X.-S. A Pneumonia Outbreak Associated with a New Coronavirus of Probable Bat Origin. Nature 2020, 579 (7798), 270– 273,  DOI: 10.1038/s41586-020-2012-7
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    A pneumonia outbreak associated with a new coronavirus of probable bat origin
    Zhou, Peng; Yang, Xing-Lou; Wang, Xian-Guang; Hu, Ben; Zhang, Lei; Zhang, Wei; Si, Hao-Rui; Zhu, Yan; Li, Bei; Huang, Chao-Lin; Chen, Hui-Dong; Chen, Jing; Luo, Yun; Guo, Hua; Jiang, Ren-Di; Liu, Mei-Qin; Chen, Ying; Shen, Xu-Rui; Wang, Xi; Zheng, Xiao-Shuang; Zhao, Kai; Chen, Quan-Jiao; Deng, Fei; Liu, Lin-Lin; Yan, Bing; Zhan, Fa-Xian; Wang, Yan-Yi; Xiao, Geng-Fu; Shi, Zheng-Li
    Nature (London, United Kingdom) (2020), 579 (7798), 270-273CODEN: NATUAS; ISSN:0028-0836. (Nature Research)
    Abstr.: Since the outbreak of severe acute respiratory syndrome (SARS) 18 years ago, a large no. of SARS-related coronaviruses (SARSr-CoVs) have been discovered in their natural reservoir host, bats1-4. Previous studies have shown that some bat SARSr-CoVs have the potential to infect humans5-7. Here we report the identification and characterization of a new coronavirus (2019-nCoV), which caused an epidemic of acute respiratory syndrome in humans in Wuhan, China. The epidemic, which started on 12 Dec. 2019, had caused 2,794 lab.-confirmed infections including 80 deaths by 26 Jan. 2020. Full-length genome sequences were obtained from five patients at an early stage of the outbreak. The sequences are almost identical and share 79.6% sequence identity to SARS-CoV. Furthermore, we show that 2019-nCoV is 96% identical at the whole-genome level to a bat coronavirus. Pairwise protein sequence anal. of seven conserved non-structural proteins domains show that this virus belongs to the species of SARSr-CoV. In addn., 2019-nCoV virus isolated from the bronchoalveolar lavage fluid of a critically ill patient could be neutralized by sera from several patients. Notably, we confirmed that 2019-nCoV uses the same cell entry receptor-angiotensin converting enzyme II (ACE2)-as SARS-CoV.
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    Deeks, J. J.; Dinnes, J.; Takwoingi, Y.; Davenport, C.; Leeflang, M. M. G.; Spijker, R.; Hooft, L.; Van den Bruel, A.; Emperador, D.; Dittrich, S. Diagnosis of SARS-CoV-2 Infection and COVID-19: Accuracy of Signs and Symptoms; Molecular, Antigen, and Antibody Tests; and Routine Laboratory Markers. Cochrane Database Syst. Rev. 2020, (4), 1– 14,  DOI: 10.1002/14651858.CD013596
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    A review. A reviews. An ongoing theme of the COVID-19 pandemic is the need for widespread availability of accurate and efficient diagnostic testing for detection of SARS-CoV-2 and antiviral antibodies in infected individuals. This report describes various assay techniques and tests for COVID-19 diagnosis. Most tests for early detection of SARS-CoV-2 RNA rely on the reverse transcription-polymerase chain reaction, but isothermal nucleic acid amplification assays, including transcription-mediated amplification and CRISPR-based methodologies, are promising alternatives. Identification of individuals who have developed antibodies to the SARS-CoV-2 virus requires serol. tests, including ELISA (ELISA) and lateral flow immunoassay. This report also provides an overview of current development in COVID-19 diagnostic techniques and products to facilitate future improvement and innovation.
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    Dortet, L.; Emeraud, C.; Vauloup-Fellous, C.; Khecharem, M.; Ronat, J.-B.; Fortineau, N.; Roque-Afonso, A.-M.; Naas, T. Rapid Determination of SARS-CoV-2 Antibodies Using a Bedside, Point-of-Care, Serological Test. Emerging Microbes Infect. 2020, 9 (1), 2212– 2221,  DOI: 10.1080/22221751.2020.1826892
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    Rapid determination of SARS-CoV-2 antibodies using a bedside, point-of-care, serological test
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    Background: Several serol. tests for SARS-CoV-2 have been developed or use, but most have only been validated on few samples, and none provide medical practitioners with an easy-to-use, self-contained, bedside test with high accuracy. Material and methods: Two-hundred fifty-six sera from 101 patients hospitalized with SARS-CoV-2 infection (pos. RT-PCR) and 50 control sera were tested for IgM/IgG using the NG-Test IgM-IgG COVID all-in-one assay. The seroconversion dynamic was assessed by symptom onset and day of RT-PCR diagnosis. Results: Among the SARS-CoV-2 infected patients, pos. IgG and/or IgM result was obsd. for 67.3% of patients (68/101), including 17 (16.8%) already pos. at the day of RT-PCR, and 51 (50.5%) with observable seroconversion, and 32.7% (33/101) remained neg. as subsequent sampling was not possible (patient discharge or death). The sensitivity increased with the delay between onset of symptoms and sampling, going from 29.1%, 78.2% and 86.5% for the time periods of 0-9-, 10-14- and >14-days after the onset of symptoms, resp. Cumulative sensitivity, specificity, Pos. Predictive Value and Neg. Predictive Value were 97.0%, 100%, 100% and 96.2%, resp. 15-days after the onset of symptoms. No difference in seroconversion delay was obsd. regardless of whether patients received ventilation. Conclusions: The NG-test is a bedside serol. assay that could serve as a complementary source of diagnostic information to RT-PCR and chest imaging. It may also be useful to monitor immunol. status of medical and non-medical workers during the ongoing pandemic, and the general population after social distancing measures have eased.
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    Testing at scale during the COVID-19 pandemic
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    Nature Reviews Genetics (2021), 22 (7), 415-426CODEN: NRGAAM; ISSN:1471-0056. (Nature Portfolio)
    Abstr.: Assembly and publication of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome in Jan. 2020 enabled the immediate development of tests to detect the new virus. This began the largest global testing program in history, in which hundreds of millions of individuals have been tested to date. The unprecedented scale of testing has driven innovation in the strategies, technologies and concepts that govern testing in public health. This Review describes the changing role of testing during the COVID-19 pandemic, including the use of genomic surveillance to track SARS-CoV-2 transmission around the world, the use of contact tracing to contain disease outbreaks and testing for the presence of the virus circulating in the environment. Despite these efforts, widespread community transmission has become entrenched in many countries and has required the testing of populations to identify and isolate infected individuals, many of whom are asymptomatic. The diagnostic and epidemiol. principles that underpin such population-scale testing are also considered, as are the high-throughput and point-of-care technologies that make testing feasible on a massive scale.
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    Understanding and using sensitivity, specificity and predictive values
    Parikh Rajul; Mathai Annie; Parikh Shefali; Chandra Sekhar G; Thomas Ravi
    Indian journal of ophthalmology (2008), 56 (1), 45-50 ISSN:0301-4738.
    In this article, we have discussed the basic knowledge to calculate sensitivity, specificity, positive predictive value and negative predictive value. We have discussed the advantage and limitations of these measures and have provided how we should use these measures in our day-to-day clinical practice. We also have illustrated how to calculate sensitivity and specificity while combining two tests and how to use these results for our patients in day-to-day practice.
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    Borysiak, M. D.; Thompson, M. J.; Posner, J. D. Translating Diagnostic Assays from the Laboratory to the Clinic: Analytical and Clinical Metrics for Device Development and Evaluation. Lab Chip 2016, 16 (8), 1293– 1313,  DOI: 10.1039/C6LC00015K
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    Translating diagnostic assays from the laboratory to the clinic: analytical and clinical metrics for device development and evaluation
    Borysiak, Mark D.; Thompson, Matthew J.; Posner, Jonathan D.
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    As lab-on-a-chip health diagnostic technologies mature, there is a push to translate them from the lab. to the clinic. For these diagnostics to achieve max. impact on patient care, scientists and engineers developing the tests should understand the anal. and clin. statistical metrics that det. the efficacy of the test. Appreciating and using these metrics will benefit test developers by providing consistent measures to evaluate anal. and clin. test performance, as well as guide the design of tests that will most benefit clinicians and patients. This paper is broken into four sections that discuss metrics related to general stages of development including: (1) lab. assay development (anal. sensitivity, limit of detection, anal. selectivity, and trueness/precision), (2) pre-clin. development (diagnostic sensitivity, diagnostic specificity, clin. cutoffs, and receiver-operator curves), (3) clin. use (prevalence, predictive values, and likelihood ratios), and (4) case studies from existing clin. data for tests relevant to the lab-on-a-chip community (HIV, group A strep, and chlamydia). Each section contains definitions of recommended statistical measures, as well as examples demonstrating the importance of these metrics at various stages of the development process. Increasing the use of these metrics in lab-on-a-chip research will improve the rigor of diagnostic performance reporting and provide a better understanding of how to design tests that will ultimately meet clin. needs.
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    Land, K. J.; Boeras, D. I.; Chen, X.-S.; Ramsay, A. R.; Peeling, R. W. REASSURED Diagnostics to Inform Disease Control Strategies, Strengthen Health Systems and Improve Patient Outcomes. Nat. Microbiol. 2019, 4 (1), 46– 54,  DOI: 10.1038/s41564-018-0295-3
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    REASSURED diagnostics to inform disease control strategies, strengthen health systems and improve patient outcomes
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    Lack of access to quality diagnostics remains a major contributor to health burden in resource-limited settings. It has been more than 10 years since ASSURED (affordable, sensitive, specific, user-friendly, rapid, equipment-free, delivered) was coined to describe the ideal test to meet the needs of the developing world. Since its initial publication, technol. innovations have led to the development of diagnostics that address the ASSURED criteria, but challenges remain. From this perspective, we assess factors contributing to the success and failure of ASSURED diagnostics, lessons learnt in the implementation of ASSURED tests over the past decade, and highlight addnl. conditions that should be considered in addressing point-of-care needs. With rapid advances in digital technol. and mobile health (m-health), future diagnostics should incorporate these elements to give us REASSURED diagnostic systems that can inform disease control strategies in real-time, strengthen the efficiency of health care systems and improve patient outcomes.
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    Nanoparticle-based bio-bar codes for the ultrasensitive detection of proteins
    Nam, Jwa-Min; Thaxton, C. Shad; Mirkin, Chad A.
    Science (Washington, DC, United States) (2003), 301 (5641), 1884-1886CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
    An ultrasensitive method for detecting protein analytes has been developed. The system relies on magnetic microparticle probes with antibodies that specifically bind a target of interest [prostate-specific antigen (PSA) in this case] and nanoparticle probes that are encoded with DNA that is unique to the protein target of interest and antibodies that can sandwich the target captured by the microparticle probes. Magnetic sepn. of the complexed probes and target followed by dehybridization of the oligonucleotides on the nanoparticle probe surface allows the detn. of the presence of the target protein by identifying the oligonucleotide sequence released from the nanoparticle probe. Because the nanoparticle probe carries with it a large no. of oligonucleotides per protein binding event, there is substantial amplification and PSA can be detected at 30 attomolar concn. Alternatively, a polymerase chain reaction on the oligonucleotide bar codes can boost the sensitivity to 3 attomolar. Comparable clin. accepted conventional assays for detecting the same target have sensitivity limits of ∼3 picomdar, six orders of magnitude less sensitive than what is obsd. with this method.
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    Walt, David R.
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    A review.
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    Pérez-López, B.; Merkoçi, A. Nanomaterials Based Biosensors for Food Analysis Applications. Trends Food Sci. Technol. 2011, 22 (11), 625– 639,  DOI: 10.1016/j.tifs.2011.04.001
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    Nanomaterials based biosensors for food analysis applications
    Perez-Lopez, Briza; Merkoci, Arben
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    A review. The development of novel sensors and biosensors with interest for food industry is one of the key fields for the nowadays nanobiotechnol. and nanomaterial science. The functionalized nanomaterials are used as catalytic tools, immobilization platforms or as optical or electroactive labels to improve the bio-sensing performance exhibiting higher sensitivity, stability, and selectivity. Nanomaterials, such as carbon nanotubes, metal nanoparticles, nanowires, nanocomposite and nanostructured materials are playing an increasing role in the design of sensing and biosensing systems with interest for applications in food anal. Furthermore, these nanobiosystems are also bringing advantages in terms of the design of novel food detection strategies.
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    Weiss, C.; Carriere, M.; Fusco, L.; Capua, I.; Regla-Nava, J. A.; Pasquali, M.; Scott, J. A.; Vitale, F.; Unal, M. A.; Mattevi, C.; Bedognetti, D.; Merkoçi, A.; Tasciotti, E.; Yilmazer, A.; Gogotsi, Yu; Stellacci, F.; Delogu, L. G. Toward Nanotechnology-Enabled Approaches against the COVID-19 Pandemic. ACS Nano 2020, 14 (6), 6383– 6406,  DOI: 10.1021/acsnano.0c03697
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    Toward Nanotechnology-Enabled Approaches against the COVID-19 Pandemic
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    ACS Nano (2020), 14 (6), 6383-6406CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
    A review. The COVID-19 outbreak has fueled a global demand for effective diagnosis and treatment as well as mitigation of the spread of infection, all through large-scale approaches such as specific alternative antiviral methods and classical disinfection protocols. Based on an abundance of engineered materials identifiable by their useful physicochem. properties through versatile chem. functionalization, nanotechnol. offers a no. of approaches to cope with this emergency. Here, through a multidisciplinary Perspective encompassing diverse fields such as virol., biol., medicine, engineering, chem., materials science, and computational science, we outline how nanotechnol.-based strategies can support the fight against COVID-19, as well as infectious diseases in general, including future pandemics. Considering what we know so far about the life cycle of the virus, we envision key steps where nanotechnol. could counter the disease. First, nanoparticles (NPs) can offer alternative methods to classical disinfection protocols used in healthcare settings, thanks to their intrinsic antipathogenic properties and(or) their ability to inactivate viruses, bacteria, fungi, or yeasts either photothermally or via photocatalysis-induced reactive oxygen species (ROS) generation. Nanotechnol. tools to inactivate SARS-CoV-2 in patients could also be explored. In this case, nanomaterials could be used to deliver drugs to the pulmonary system to inhibit interaction between angiotensin-converting enzyme 2 (ACE2) receptors and viral S protein. Moreover, the concept of nanoimmunity by design can help us to design materials for immune modulation, either stimulating or suppressing the immune response, which would find applications in the context of vaccine development for SARS-CoV-2 or in counteracting the cytokine storm, resp. In addn. to disease prevention and therapeutic potential, nanotechnol. has important roles in diagnostics, with potential to support the development of simple, fast, and cost-effective nanotechnol.-based assays to monitor the presence of SARS-CoV-2 and related biomarkers. In summary, nanotechnol. is crit. in counteracting COVID-19 and will be vital when prepg. for future pandemics.
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    Parolo, C.; Sena-Torralba, A.; Bergua, J. F.; Calucho, E.; Fuentes-Chust, C.; Hu, L.; Rivas, L.; Álvarez-Diduk, R.; Nguyen, E. P.; Cinti, S.; Quesada-González, D.; Merkoçi, A. Tutorial: Design and Fabrication of Nanoparticle-Based Lateral-Flow Immunoassays. Nat. Protoc. 2020, 15 (12), 3788– 3816,  DOI: 10.1038/s41596-020-0357-x
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    Parolo, Claudio; Sena-Torralba, Amadeo; Bergua, Jose Francisco; Calucho, Enric; Fuentes-Chust, Celia; Hu, Liming; Rivas, Lourdes; Alvarez-Diduk, Ruslan; Nguyen, Emily P.; Cinti, Stefano; Quesada-Gonzalez, Daniel; Merkoci, Arben
    Nature Protocols (2020), 15 (12), 3788-3816CODEN: NPARDW; ISSN:1750-2799. (Nature Research)
    A review. Lateral-flow assays (LFAs) are quick, simple and cheap assays to analyze various samples at the point of care or in the field, making them one of the most widespread biosensors currently available. They have been successfully employed for the detection of a myriad of different targets (ranging from atoms up to whole cells) in all type of samples (including water, blood, foodstuff and environmental samples). Their operation relies on the capillary flow of the sample throughout a series of sequential pads, each with different functionalities aiming to generate a signal to indicate the absence/presence (and, in some cases, the concn.) of the analyte of interest. To have a user-friendly operation, their development requires the optimization of multiple, interconnected parameters that may overwhelm new developers. In this tutorial, we provide the readers with: (i) the basic knowledge to understand the principles governing an LFA and to take informed decisions during lateral flow strip design and fabrication, (ii) a roadmap for optimal LFA development independent of the specific application, (iii) a step-by-step example procedure for the assembly and operation of an LF strip for the detection of human IgG and (iv) an extensive troubleshooting section addressing the most frequent issues in designing, assembling and using LFAs. By changing only the receptors, the provided example procedure can easily be adapted for cost-efficient detection of a broad variety of targets.
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    Kurbanoglu, S.; Ozkan, S. A.; Merkoçi, A. Nanomaterials-Based Enzyme Electrochemical Biosensors Operating through Inhibition for Biosensing Applications. Biosens. Bioelectron. 2017, 89, 886– 898,  DOI: 10.1016/j.bios.2016.09.102
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    Biosensors & Bioelectronics (2017), 89 (Part_2), 886-898CODEN: BBIOE4; ISSN:0956-5663. (Elsevier B.V.)
    In recent years great progress has been made in applying nanomaterials to design novel biosensors. Use of nanomaterials offers to biosensing platforms exceptional optical, electronic and magnetic properties. Nanomaterials can increase the surface of the transducing area of the sensors that in turn bring an increase in catalytic behaviors. They have large surface-to-vol. ratio, controlled morphol. and structure that also favor miniaturization, an interesting advantage when the sample vol. is a crit. issue. Biosensors have great potential for achieving detect-to-protect devices: devices that can be used in detections of pollutants and other treating compds./analytes (drugs) protecting citizens' life. After a long term focused scientific and financial efforts/supports biosensors are expected now to fulfill their promise such as being able to perform sampling and anal. of complex samples with interest for clin. or environment fields. Among all types of biosensors, enzymic biosensors, the most explored biosensing devices, have an interesting property, the inherent inhibition phenomena given the enzyme-substrate complex formation. The exploration of such phenomena is making remarkably important their application as research and applied tools in diagnostics. Different inhibition biosensor systems based on nanomaterials modification has been proposed and applied. The role of nanomaterials in inhibition-based biosensors for the analyses of different groups of drugs as well as contaminants such as pesticides, phenolic compds. and others, are discussed in this review. This deep anal. of inhibition-based biosensors that employ nanomaterials will serve researchers as a guideline for further improvements and approaching of these devices to real sample applications so as to reach society needs and such biosensor market demands.
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    Morales-Narváez, E.; Merkoçi, A. Graphene Oxide as an Optical Biosensing Platform. Adv. Mater. 2012, 24 (25), 3298– 3308,  DOI: 10.1002/adma.201200373
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    Graphene Oxide as an Optical Biosensing Platform
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    Advanced Materials (Weinheim, Germany) (2012), 24 (25), 3298-3308CODEN: ADVMEW; ISSN:0935-9648. (Wiley-VCH Verlag GmbH & Co. KGaA)
    A review. Since graphene exhibits innovative mech., elec., thermal, and optical properties, this 2D material is increasingly attracting attention and is under active research. Among the various graphene forms with lattice-like nanostructure, graphene oxide (GO) displays advantageous characteristics as a biosensing platform due to its excellent capabilities for direct wiring with biomols., a heterogeneous chem. and electronic structure, the possibility to be processed in soln. and the ability to be tuned as insulator, semiconductor or semi-metal. Moreover, GO photoluminescences with energy transfer donor/acceptor mols. exposed in a planar surface and is even proposed as a universal highly efficient long-range quencher, which is opening the way to several unprecedented biosensing strategies. Here, the rationale behind the use of GO in optical biosensing applications is discussed by describing different potentially exploitable properties of GO, and an overview of the current approaches are presented along with future perspectives and challenges.
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    Mokhtarzadeh, A.; Eivazzadeh-Keihan, R.; Pashazadeh, P.; Hejazi, M.; Gharaatifar, N.; Hasanzadeh, M.; Baradaran, B.; de la Guardia, M. Nanomaterial-Based Biosensors for Detection of Pathogenic Virus. TrAC, Trends Anal. Chem. 2017, 97, 445– 457,  DOI: 10.1016/j.trac.2017.10.005
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    Mokhtarzadeh, Ahad; Eivazzadeh-Keihan, Reza; Pashazadeh, Paria; Hejazi, Maryam; Gharaatifar, Nasrin; Hasanzadeh, Mohammad; Baradaran, Behzad; de la Guardia, Miguel
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    Viruses are real menace to human safety that cause devastating viral disease. The high prevalence of these diseases is due to improper detecting tools. Therefore, there is a remarkable demand to identify viruses in a fast, selective and accurate way. Several biosensors have been designed and commercialized for detection of pathogenic viruses. However, they present many challenges. Nanotechnol. overcomes these challenges and performs direct detection of mol. targets in real time. In this overview, studies concerning nanotechnol.-based biosensors for pathogenic virus detection have been summarized, paying special attention to biosensors based on graphene oxide, silica, carbon nanotubes, gold, silver, zinc oxide and magnetic nanoparticles, which could pave the way to detect viral diseases and provide healthy life for infected patients.
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  47. 47
    Morales-Narváez, E.; Baptista-Pires, L.; Zamora-Gálvez, A.; Merkoçi, A. Graphene-Based Biosensors: Going Simple. Adv. Mater. 2017, 29, 1604905,  DOI: 10.1002/adma.201604905
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    Nguyen, E. P.; de Carvalho Castro Silva, C.; Merkoçi, A. Recent Advancement in Biomedical Applications on the Surface of Two-Dimensional Materials: From Biosensing to Tissue Engineering. Nanoscale 2020, 12 (37), 19043– 19067,  DOI: 10.1039/D0NR05287F
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    48
    Recent advancement in biomedical applications on the surface of two-dimensional materials: from biosensing to tissue engineering
    Nguyen, Emily P.; de Carvalho Castro Silva, Cecilia; Merkoci, Arben
    Nanoscale (2020), 12 (37), 19043-19067CODEN: NANOHL; ISSN:2040-3372. (Royal Society of Chemistry)
    A review. As biosensors and biomedical devices have become increasingly important to everyday diagnostics and monitoring, there are tremendous, and const. efforts towards developing and improving the reliability and versatility of such technol. As they offer high surface area-to-vol. ratios and a diverse range of properties, from electronic to optical, two dimensional (2D) materials have proven to be very promising candidates for biol. applications and technologies. Due to the dimensionality, 2D materials facilitate many interfacial phenomena that have shown to significantly improve the performance of biosensors, while recent advances in synthesis techniques and surface engineering methods also enable the realization of future biomedical devices. This short review aims to highlight the influence of 2D material surfaces and the properties that arise due to their 2D structure. Using recent (within the last few years) examples of biosensors and biomedical applications, we emphasize the important role of 2D materials in advancing developments and research for biosensing and healthcare.
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  49. 49
    Nakatsuka, N.; Yang, K.-A.; Abendroth, J. M.; Cheung, K. M.; Xu, X.; Yang, H.; Zhao, C.; Zhu, B.; Rim, Y. S.; Yang, Y.; Weiss, P. S.; Stojanovic, M. N.; Andrews, A. M. Aptamer-Field-Effect Transistors Overcome Debye Length Limitations for Small-Molecule Sensing. Science 2018, 362 (6412), 319– 324,  DOI: 10.1126/science.aao6750
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    Aptamer-field-effect transistors overcome Debye length limitations for small-molecule sensing
    Nakatsuka, Nako; Yang, Kyung-Ae; Abendroth, John M.; Cheung, Kevin M.; Xu, Xiaobin; Yang, Hongyan; Zhao, Chuanzhen; Zhu, Bowen; Rim, You Seung; Yang, Yang; Weiss, Paul S.; Stojanovic, Milan N.; Andrews, Anne M.
    Science (Washington, DC, United States) (2018), 362 (6412), 319-324CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
    Detection of analytes by means of field-effect transistors bearing ligand-specific receptors is fundamentally limited by the shielding created by the elec. double layer (the "Debye length" limitation). We detected small mols. under physiol. high-ionic strength conditions by modifying printed ultrathin metal-oxide field-effect transistor arrays with deoxyribonucleotide aptamers selected to bind their targets adaptively. Target-induced conformational changes of neg. charged aptamer phosphodiester backbones in close proximity to semiconductor channels gated conductance in physiol. buffers, resulting in highly sensitive detection. Sensing of charged and electroneutral targets (serotonin, dopamine, glucose, and sphingosine-1-phosphate) was enabled by specifically isolated aptameric stem-loop receptors.
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    Roche, E. T. A Protein Sandwich Enables Real-Time in Vivo Biomarker Measurement. Sci. Transl. Med. 2021, 13 (575), eabg1758  DOI: 10.1126/scitranslmed.abg1758
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    Idili, A.; Parolo, C.; Alvarez-Diduk, R.; Merkoçi, A. Rapid and Efficient Detection of the SARS-CoV-2 Spike Protein Using an Electrochemical Aptamer-Based Sensor. ACS Sensors 2021, 6 (8), 3093– 3101,  DOI: 10.1021/acssensors.1c01222
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    51
    Rapid and Efficient Detection of the SARS-CoV-2 Spike Protein Using an Electrochemical Aptamer-Based Sensor
    Idili, Andrea; Parolo, Claudio; Alvarez-Diduk, Ruslan; Merkoci, Arben
    ACS Sensors (2021), 6 (8), 3093-3101CODEN: ASCEFJ; ISSN:2379-3694. (American Chemical Society)
    The availability of sensors able to rapidly detect SARS-CoV-2 directly in biol. fluids in a single step would allow performing massive diagnostic testing to track in real time and contain the spread of COVID-19. Motivated by this, here, we developed an electrochem. aptamer-based (EAB) sensor able to achieve the rapid, reagentless, and quant. measurement of the SARS-CoV-2 spike (S) protein. First, we demonstrated the ability of the selected aptamer to undergo a binding-induced conformational change in the presence of its target using fluorescence spectroscopy. Then, we engineered the aptamer to work as a bioreceptor in the EAB platform and we demonstrated its sensitivity and specificity. Finally, to demonstrate the clin. potential of the sensor, we tested it directly in biol. fluids (serum and artificial saliva), achieving the rapid (minutes) and single-step detection of the S protein in its clin. range.
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    Alafeef, M.; Dighe, K.; Moitra, P.; Pan, D. Rapid, Ultrasensitive, and Quantitative Detection of SARS-CoV-2 Using Antisense Oligonucleotides Directed Electrochemical Biosensor Chip. ACS Nano 2020, 14 (12), 17028– 17045,  DOI: 10.1021/acsnano.0c06392
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    52
    Rapid, Ultrasensitive, and Quantitative Detection of SARS-CoV-2 Using Antisense Oligonucleotides Directed Electrochemical Biosensor Chip
    Alafeef, Maha; Dighe, Ketan; Moitra, Parikshit; Pan, Dipanjan
    ACS Nano (2020), 14 (12), 17028-17045CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
    A large-scale diagnosis of the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) is essential to downregulate its spread within as well as across communities and mitigate the current outbreak of the pandemic novel coronavirus disease 2019 (COVID-19). Herein, we report the development of a rapid (<5 min), low-cost, easy-to-implement, and quant. paper-based electrochem. sensor chip to enable the digital detection of SARS-CoV-2 genetic material. The biosensor uses gold nanoparticles (AuNPs), capped with highly specific antisense oligonucleotides (ssDNA) targeting viral nucleocapsid phosphoprotein (N-gene). The sensing probes are immobilized on a paper-based electrochem. platform to yield a nucleic-acid-testing device with a readout that can be recorded with a simple hand-held reader. The biosensor chip has been tested using samples collected from Vero cells infected with SARS-CoV-2 virus and clin. samples. The sensor provides a significant improvement in output signal only in the presence of its target-SARS-CoV-2 RNA-within <5 min of incubation time, with a sensitivity of 231 copies/μL and limit of detection of 6.9 copies/μL without the need for any further amplification. The sensor chip performance has been tested using clin. samples from 22 COVID-19 pos. patients and 26 healthy asymptomatic subjects confirmed using the FDA-approved RT-PCR COVID-19 diagnostic kit. The sensor successfully distinguishes the pos. COVID-19 samples from the neg. ones with almost 100% accuracy, sensitivity, and specificity and exhibits an insignificant change in output signal for the samples lacking a SARS-CoV-2 viral target segment (e.g., SARS-CoV, MERS-CoV, or neg. COVID-19 samples collected from healthy subjects). The feasibility of the sensor even during the genomic mutation of the virus is also ensured from the design of the ssDNA-conjugated AuNPs that simultaneously target 2 sep. regions of the same SARS-CoV-2 N-gene.
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  53. 53
    Baker, A. N.; Richards, S.-J.; Guy, C. S.; Congdon, T. R.; Hasan, M.; Zwetsloot, A. J.; Gallo, A.; Lewandowski, J. R.; Stansfeld, P. J.; Straube, A.; Walker, M.; Chessa, S.; Pergolizzi, G.; Dedola, S.; Field, R. A.; Gibson, M. I. The SARS-COV-2 Spike Protein Binds Sialic Acids and Enables Rapid Detection in a Lateral Flow Point of Care Diagnostic Device. ACS Cent. Sci. 2020, 6 (11), 2046– 2052,  DOI: 10.1021/acscentsci.0c00855
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    53
    The SARS-COV-2 Spike Protein Binds Sialic Acids and Enables Rapid Detection in a Lateral Flow Point of Care Diagnostic Device
    Baker, Alexander N.; Richards, Sarah-Jane; Guy, Collette S.; Congdon, Thomas R.; Hasan, Muhammad; Zwetsloot, Alexander J.; Gallo, Angelo; Lewandowski, Jozef R.; Stansfeld, Phillip J.; Straube, Anne; Walker, Marc; Chessa, Simona; Pergolizzi, Giulia; Dedola, Simone; Field, Robert A.; Gibson, Matthew I.
    ACS Central Science (2020), 6 (11), 2046-2052CODEN: ACSCII; ISSN:2374-7951. (American Chemical Society)
    There is an urgent need to understand the behavior of the novel coronavirus (SARS-COV-2), which is the causative agent of COVID-19, and to develop point-of-care diagnostics. Here, a glyconanoparticle platform is used to discover that N-acetyl neuraminic acid has affinity toward the SARS-COV-2 spike glycoprotein, demonstrating its glycan-binding function. Optimization of the particle size and coating enabled detection of the spike glycoprotein in lateral flow and showed selectivity over the SARS-COV-1 spike protein. Using a virus-like particle and a pseudotyped lentivirus model, paper-based lateral flow detection was demonstrated in under 30 min, showing the potential of this system as a low-cost detection platform. The spike-protein from SARS-COV-2 is shown to bind sialic acids, which is exploited to assemble a lateral flow diagnostic tool, using glycans rather than antibodies, as the recognition unit.
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  54. 54
    Lin, Q.; Wen, D.; Wu, J.; Liu, L.; Wu, W.; Fang, X.; Kong, J. Microfluidic Immunoassays for Sensitive and Simultaneous Detection of IgG/IgM/Antigen of SARS-CoV-2 within 15 min. Anal. Chem. 2020, 92 (14), 9454– 9458,  DOI: 10.1021/acs.analchem.0c01635
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    54
    Microfluidic Immunoassays for Sensitive and Simultaneous Detection of IgG/IgM/Antigen of SARS-CoV-2 within 15 min
    Lin, Qiuyuan; Wen, Donghua; Wu, Jing; Liu, Liling; Wu, Wenjuan; Fang, Xueen; Kong, Jilie
    Analytical Chemistry (Washington, DC, United States) (2020), 92 (14), 9454-9458CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
    The outbreak of SARS-CoV-2 is posing serious global public health problems. Facing the emergence of this pandemic, we established a portable microfluidic immunoassay system for easy-to-use, sensitive, rapid (<15 min), multiple, and on-site detection of IgG/IgM/Antigen of SARS-CoV-2 simultaneously. This integrated method was successfully applied for detecting SARS-CoV-2 IgM and IgG antibodies in clin. human serum as well as SARS-CoV-2 antigen in pharyngeal swabs from 26 patients with COVID-19 infection and 28 uninfected people. The assay demonstrated high sensitivity and specificity, which is promising for the diagnosis and monitoring as well as control of SARS-CoV-2 worldwide.
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  55. 55
    Mavrikou, S.; Moschopoulou, G.; Tsekouras, V.; Kintzios, S. Development of a Portable, Ultra-Rapid and Ultra-Sensitive Cell-Based Biosensor for the Direct Detection of the SARS-CoV-2 S1 Spike Protein Antigen. Sensors 2020, 20 (11), 3121,  DOI: 10.3390/s20113121
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    55
    Development of a portable, ultra-rapid and ultra-sensitive cell-based biosensor for the direct detection of the SARS-CoV-2 S1 spike protein antigen
    Mavrikou, Sophie; Moschopoulou, Georgia; Tsekouras, Vasileios; Kintzios, Spyridon
    Sensors (2020), 20 (11), 3121CODEN: SENSC9; ISSN:1424-8220. (MDPI AG)
    One of the key challenges of the recent COVID-19 pandemic is the ability to accurately est. the no. of infected individuals, particularly asymptomatic and/or early-stage patients. We herewith report the proof-of-concept development of a biosensor able to detect the SARS-CoV-2 S1 spike protein expressed on the surface of the virus. The biosensor is based on membrane-engineered mammalian cells bearing the human chimeric spike S1 antibody. We demonstrate that the attachment of the protein to the membrane-bound antibodies resulted in a selective and considerable change in the cellular bioelec. properties measured by means of a Bioelec. Recognition Assay. The novel biosensor provided results in an ultra-rapid manner (3 min), with a detection limit of 1 fg/mL and a semi-linear range of response between 10 fg and 1μg/mL. In addn., no cross-reactivity was obsd. against the SARS-CoV-2 nucleocapsid protein. Furthermore, the biosensor was configured as a ready-to-use platform, including a portable read-out device operated via smartphone/tablet. In this way, we demonstrate that the novel biosensor can be potentially applied for the mass screening of SARS-CoV-2 surface antigens without prior sample processing, therefore offering a possible soln. for the timely monitoring and eventual control of the global coronavirus pandemic.
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  56. 56
    Moitra, P.; Alafeef, M.; Dighe, K.; Frieman, M. B.; Pan, D. Selective Naked-Eye Detection of SARS-CoV-2 Mediated by N Gene Targeted Antisense Oligonucleotide Capped Plasmonic Nanoparticles. ACS Nano 2020, 14 (6), 7617– 7627,  DOI: 10.1021/acsnano.0c03822
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    56
    Selective Naked-Eye Detection of SARS-CoV-2 Mediated by N Gene Targeted Antisense Oligonucleotide Capped Plasmonic Nanoparticles
    Moitra, Parikshit; Alafeef, Maha; Dighe, Ketan; Frieman, Matthew B.; Pan, Dipanjan
    ACS Nano (2020), 14 (6), 7617-7627CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
    The current outbreak of the pandemic coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) demands its rapid, convenient, and large-scale diagnosis to downregulate its spread within as well as across the communities. But the reliability, reproducibility, and selectivity of majority of such diagnostic tests fail when they are tested either to a viral load at its early representation or to a viral gene mutated during its current spread. In this regard, a selective "naked-eye" detection of SARS-CoV-2 is highly desirable, which can be tested without accessing any advanced instrumental techniques. We herein report the development of a colorimetric assay based on gold nanoparticles (AuNPs), when capped with suitably designed thiol-modified antisense oligonucleotides (ASOs) specific for N-gene (nucleocapsid phosphoprotein) of SARS-CoV-2, could be used for diagnosing pos. COVID-19 cases within 10 min from the isolated RNA samples. The thiol-modified ASO-capped AuNPs agglomerate selectively in the presence of its target RNA sequence of SARS-CoV-2 and demonstrate a change in its surface plasmon resonance. Further, the addn. of RNaseH cleaves the RNA strand from the RNA-DNA hybrid leading to a visually detectable ppt. from the soln. mediated by the addnl. agglomeration among the AuNPs. The selectivity of the assay has been monitored in the presence of MERS-CoV viral RNA with a limit of detection of 0.18 ng/μL of RNA having SARS-CoV-2 viral load. Thus, the current study reports a selective and visual "naked-eye" detection of COVID-19 causative virus, SARS-CoV-2, without the requirement of any sophisticated instrumental techniques.
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  57. 57
    Qiu, G.; Gai, Z.; Tao, Y.; Schmitt, J.; Kullak-Ublick, G. A.; Wang, J. Dual-Functional Plasmonic Photothermal Biosensors for Highly Accurate Severe Acute Respiratory Syndrome Coronavirus 2 Detection. ACS Nano 2020, 14 (5), 5268– 5277,  DOI: 10.1021/acsnano.0c02439
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    57
    Dual-Functional Plasmonic Photothermal Biosensors for Highly Accurate Severe Acute Respiratory Syndrome Coronavirus 2 Detection
    Qiu, Guangyu; Gai, Zhibo; Tao, Yile; Schmitt, Jean; Kullak-Ublick, Gerd A.; Wang, Jing
    ACS Nano (2020), 14 (5), 5268-5277CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
    The ongoing outbreak of the novel coronavirus disease (COVID-19) has spread globally and poses a threat to public health in more than 200 countries. Reliable lab. diagnosis of the disease has been one of the foremost priorities for promoting public health interventions. The routinely used reverse transcription polymerase chain reaction (RT-PCR) is currently the ref. method for COVID-19 diagnosis. However, it also reported a no. of false-pos. or -neg. cases, esp. in the early stages of the novel virus outbreak. In this work, a dual-functional plasmonic biosensor combining the plasmonic photothermal (PPT) effect and localized surface plasmon resonance (LSPR) sensing transduction provides an alternative and promising soln. for the clin. COVID-19 diagnosis. The two-dimensional gold nanoislands (AuNIs) functionalized with complementary DNA receptors can perform a sensitive detection of the selected sequences from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) through nucleic acid hybridization. For better sensing performance, the thermoplasmonic heat is generated on the same AuNIs chip when illuminated at their plasmonic resonance frequency. The localized PPT heat is capable to elevate the in situ hybridization temp. and facilitate the accurate discrimination of two similar gene sequences. Our dual-functional LSPR biosensor exhibits a high sensitivity toward the selected SARS-CoV-2 sequences with a lower detection limit down to the concn. of 0.22 pM and allows precise detection of the specific target in a multigene mixt. This study gains insight into the thermoplasmonic enhancement and its applicability in the nucleic acid tests and viral disease diagnosis.
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  58. 58
    Seo, G.; Lee, G.; Kim, M. J.; Baek, S.-H.; Choi, M.; Ku, K. B.; Lee, C.-S.; Jun, S.; Park, D.; Kim, H. G.; Kim, S.-J.; Lee, J.-O.; Kim, B. T.; Park, E. C.; Kim, S. I. Rapid Detection of COVID-19 Causative Virus (SARS-CoV-2) in Human Nasopharyngeal Swab Specimens Using Field-Effect Transistor-Based Biosensor. ACS Nano 2020, 14 (4), 5135– 5142,  DOI: 10.1021/acsnano.0c02823
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    58
    Rapid Detection of COVID-19 Causative Virus (SARS-CoV-2) in Human Nasopharyngeal Swab Specimens Using Field-Effect Transistor-Based Biosensor
    Seo, Giwan; Lee, Geonhee; Kim, Mi Jeong; Baek, Seung-Hwa; Choi, Minsuk; Ku, Keun Bon; Lee, Chang-Seop; Jun, Sangmi; Park, Daeui; Kim, Hong Gi; Kim, Seong-Jun; Lee, Jeong-O.; Kim, Bum Tae; Park, Edmond Changkyun; Kim, Seung Il
    ACS Nano (2020), 14 (4), 5135-5142CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
    Coronavirus disease 2019 (COVID-19) is a newly emerging human infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, previously called 2019-nCoV). Based on the rapid increase in the rate of human infection, the World Health Organization (WHO) has classified the COVID-19 outbreak as a pandemic. Because no specific drugs or vaccines for COVID-19 are yet available, early diagnosis and management are crucial for contg. the outbreak. Here, we report a field-effect transistor (FET)-based biosensing device for detecting SARS-CoV-2 in clin. samples. The sensor was produced by coating graphene sheets of the FET with a specific antibody against SARS-CoV-2 spike protein. The performance of the sensor was detd. using antigen protein, cultured virus, and nasopharyngeal swab specimens from COVID-19 patients. Our FET device could detect the SARS-CoV-2 spike protein at concns. of 1 fg/mL in phosphate-buffered saline and 100 fg/mL clin. transport medium. In addn., the FET sensor successfully detected SARS-CoV-2 in culture medium (limit of detection [LOD]: 1.6 x 101 pfu/mL) and clin. samples (LOD: 2.42 x 102 copies/mL). Thus, we have successfully fabricated a promising FET biosensor for SARS-CoV-2; our device is a highly sensitive immunol. diagnostic method for COVID-19 that requires no sample pretreatment or labeling.
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  59. 59
    Shao, W.; Shurin, M. R.; Wheeler, S. E.; He, X.; Star, A. Rapid Detection of SARS-CoV-2 Antigens Using High-Purity Semiconducting Single-Walled Carbon Nanotube-Based Field-Effect Transistors. ACS Appl. Mater. Interfaces 2021, 13 (8), 10321– 10327,  DOI: 10.1021/acsami.0c22589
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    59
    Rapid detection of SARS-CoV-2 antigens using high-purity semiconducting single-walled carbon nanotube-based field-effect transistors
    Shao, Wenting; Shurin, Michael R.; Wheeler, Sarah E.; He, Xiaoyun; Star, Alexander
    ACS Applied Materials & Interfaces (2021), 13 (8), 10321-10327CODEN: AAMICK; ISSN:1944-8244. (American Chemical Society)
    Early diagnosis of SARS-CoV-2 infection is crit. for facilitating proper containment procedures, and a rapid, sensitive antigen assay is a crit. step in curbing the pandemic. In this work, we report the use of a high-purity semiconducting (s.c.) single-walled carbon nanotube (SWCNT)-based field-effect transistor (FET) decorated with specific binding chem. to assess the presence of SARS-CoV-2 antigens in clin. nasopharyngeal samples. Our SWCNT FET sensors, with functionalization of the anti-SARS-CoV-2 spike protein antibody (SAb) and anti-nucleocapsid protein antibody, detected the S antigen (SAg) and N antigen (NAg), reaching a limit of detection of 0.55 fg/mL for SAg and 0.016 fg/mL for NAg in calibration samples. SAb-functionalized FET sensors also exhibited good sensing performance in discriminating pos. and neg. clin. samples, indicating a proof of principle for use as a rapid COVID-19 antigen diagnostic tool with high anal. sensitivity and specificity at low cost.
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    Torrente-Rodríguez, R. M.; Lukas, H.; Tu, J.; Min, J.; Yang, Y.; Xu, C.; Rossiter, H. B.; Gao, W. SARS-CoV-2 RapidPlex: A Graphene-Based Multiplexed Telemedicine Platform for Rapid and Low-Cost COVID-19 Diagnosis and Monitoring. Matter 2020, 3 (6), 1981– 1998,  DOI: 10.1016/j.matt.2020.09.027
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    60
    SARS-CoV-2 RapidPlex: A Graphene-Based Multiplexed Telemedicine Platform for Rapid and Low-Cost COVID-19 Diagnosis and Monitoring
    Torrente-Rodriguez Rebeca M; Lukas Heather; Tu Jiaobing; Min Jihong; Yang Yiran; Xu Changhao; Gao Wei; Rossiter Harry B
    Matter (2020), 3 (6), 1981-1998 ISSN:.
    The COVID-19 pandemic is an ongoing global challenge for public health systems. Ultrasensitive and early identification of infection is critical in preventing widespread COVID-19 infection by presymptomatic and asymptomatic individuals, especially in the community and in-home settings. We demonstrate a multiplexed, portable, wireless electrochemical platform for ultra-rapid detection of COVID-19: the SARS-CoV-2 RapidPlex. It detects viral antigen nucleocapsid protein, IgM and IgG antibodies, as well as the inflammatory biomarker C-reactive protein, based on our mass-producible laser-engraved graphene electrodes. We demonstrate ultrasensitive, highly selective, and rapid electrochemical detection in the physiologically relevant ranges. We successfully evaluated the applicability of our SARS-CoV-2 RapidPlex platform with COVID-19-positive and COVID-19-negative blood and saliva samples. Based on this pilot study, our multiplexed immunosensor platform may allow for high-frequency at-home testing for COVID-19 telemedicine diagnosis and monitoring.
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  61. 61
    Zhao, H.; Liu, F.; Xie, W.; Zhou, T.-C.; OuYang, J.; Jin, L.; Li, H.; Zhao, C.-Y.; Zhang, L.; Wei, J.; Zhang, Y.-P.; Li, C.-P. Ultrasensitive Supersandwich-Type Electrochemical Sensor for SARS-CoV-2 from the Infected COVID-19 Patients Using a Smartphone. Sens. Actuators, B 2021, 327, 128899,  DOI: 10.1016/j.snb.2020.128899
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    61
    Ultrasensitive supersandwich-type electrochemical sensor for SARS-CoV-2 from the infected COVID-19 patients using a smartphone
    Zhao, Hui; Liu, Feng; Xie, Wei; Zhou, Tai-Cheng; OuYang, Jun; Jin, Lian; Li, Hui; Zhao, Chun-Yan; Zhang, Liang; Wei, Jia; Zhang, Ya-Ping; Li, Can-Peng
    Sensors and Actuators, B: Chemical (2021), 327 (), 128899CODEN: SABCEB; ISSN:0925-4005. (Elsevier B.V.)
    The recent pandemic outbreak of COVID-19 caused by a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), poses a threat to public health globally. Thus, developing a rapid, accurate, and easy-to-implement diagnostic system for SARS-CoV-2 is crucial for controlling infection sources and monitoring illness progression. We reported an ultrasensitive electrochem. detection technol. using calixarene functionalized graphene oxide for targeting RNA of SARS-CoV-2. Based on a supersandwich-type recognition strategy, the technol. was confirmed to practicably detect the RNA of SARS-CoV-2 without nucleic acid amplification and reverse-transcription by using a portable electrochem. smartphone. The biosensor showed high specificity and selectivity during in silico anal. and actual testing. A total of 88 RNA exts. from 25 SARS-CoV-2-confirmed patients and 8 recovery patients were detected using the biosensor. The detectable ratios (85.5% and 46.2%) were higher than those obtained using RT-qPCR (56.5% and 7.7%). The limit of detection (LOD) of the clin. specimen was 200 copies/mL, which is the lowest LOD among the published RNA measurement of SARS-CoV-2 to date. Addnl., only 2 copies (10μL) of SARS-CoV-2 were required for assay. Therefore, we developed an ultrasensitive, accurate, and convenient assay for SARS-CoV-2 detection, providing a potential method for point-of-care testing.
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    Zhu, X.; Wang, X.; Han, L.; Chen, T.; Wang, L.; Li, H.; Li, S.; He, L.; Fu, X.; Chen, S.; Xing, M.; Chen, H.; Wang, Y. Multiplex Reverse Transcription Loop-Mediated Isothermal Amplification Combined with Nanoparticle-Based Lateral Flow Biosensor for the Diagnosis of COVID-19. Biosens. Bioelectron. 2020, 166, 112437,  DOI: 10.1016/j.bios.2020.112437
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    Multiplex reverse transcription loop-mediated isothermal amplification combined with nanoparticle-based lateral flow biosensor for the diagnosis of COVID-19
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    Biosensors & Bioelectronics (2020), 166 (), 112437CODEN: BBIOE4; ISSN:0956-5663. (Elsevier B.V.)
    The ongoing global pandemic (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a huge public health issue. Hence, we devised a multiplex reverse transcription loop-mediated isothermal amplification (mRT-LAMP) coupled with a nanoparticle-based lateral flow biosensor (LFB) assay (mRT-LAMP-LFB) for diagnosing COVID-19. Using two LAMP primer sets, the ORF1ab (opening reading frame 1a/b) and N (nucleoprotein) genes of SARS-CoV-2 were simultaneously amplified in a single-tube reaction, and detected with the diagnosis results easily interpreted by LFB. In presence of FITC (fluorescein)-/digoxin- and biotin-labeled primers, mRT-LAMP produced numerous FITC-/digoxin- and biotin-attached duplex amplicons, which were detd. by LFB through immunoreactions (FITC/digoxin on the duplex and anti-FITC/digoxin on the test line of LFB) and biotin/streptavidin interaction (biotin on the duplex and streptavidin on the polymerase nanoparticle). The accumulation of nanoparticles leaded a characteristic crimson band, enabling multiplex anal. of ORF1ab and N gene without instrumentation. The limit of detection (LoD) of COVID-19 mRT-LAMP-LFB was 12 copies (for each detection target) per reaction, and no cross-reactivity was generated from non-SARS-CoV-2 templates. The anal. sensitivity of SARS-CoV-2 was 100% (33/33 oropharynx swab samples collected from COVID-19 patients), and the assay's specificity was also 100% (96/96 oropharynx swab samples collected from non-COVID-19 patients). The total diagnostic test can be completed within 1 h from sample collection to result interpretation. In sum, the COVID-19 mRT-LAMP-LFB assay is a promising tool for diagnosing SARS-CoV-2 infections in frontline public health field and clin. labs., esp. from resource-poor regions.
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    Shan, B.; Broza, Y. Y.; Li, W.; Wang, Y.; Wu, S.; Liu, Z.; Wang, J.; Gui, S.; Wang, L.; Zhang, Z.; Liu, W.; Zhou, S.; Jin, W.; Zhang, Q.; Hu, D.; Lin, L.; Zhang, Q.; Li, W.; Wang, J.; Liu, H. Multiplexed Nanomaterial-Based Sensor Array for Detection of COVID-19 in Exhaled Breath. ACS Nano 2020, 14 (9), 12125– 12132,  DOI: 10.1021/acsnano.0c05657
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    Multiplexed Nanomaterial-Based Sensor Array for Detection of COVID-19 in Exhaled Breath
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    ACS Nano (2020), 14 (9), 12125-12132CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
    This article reports on a noninvasive approach in detecting and following-up individuals who are at-risk or have an existing COVID-19 infection, with a potential ability to serve as an epidemic control tool. The proposed method uses a developed breath device composed of a nanomaterial-based hybrid sensor array with multiplexed detection capabilities that can detect disease-specific biomarkers from exhaled breath, thus enabling rapid and accurate diagnosis. An exploratory clin. study with this approach was examd. in Wuhan, China, during March 2020. The study cohort included 49 confirmed COVID-19 patients, 58 healthy controls, and 33 non-COVID lung infection controls. When applicable, pos. COVID-19 patients were sampled twice: during the active disease and after recovery. Discriminant anal. of the obtained signals from the nanomaterial-based sensors achieved very good test discriminations between the different groups. The training and test set data exhibited resp. 94% and 76% accuracy in differentiating patients from controls as well as 90% and 95% accuracy in differentiating between patients with COVID-19 and patients with other lung infections. While further validation studies are needed, the results may serve as a base for technol. that would lead to a redn. in the no. of unneeded confirmatory tests and lower the burden on hospitals, while allowing individuals a screening soln. that can be performed in PoC facilities. The proposed method can be considered as a platform that could be applied for any other disease infection with proper modifications to the artificial intelligence and would therefore be available to serve as a diagnostic tool in case of a new disease outbreak.
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    Ding, X.; Yin, K.; Li, Z.; Lalla, R. V.; Ballesteros, E.; Sfeir, M. M.; Liu, C. Ultrasensitive and Visual Detection of SARS-CoV-2 Using All-in-One Dual CRISPR-Cas12a Assay. Nat. Commun. 2020, 11 (1), 4711,  DOI: 10.1038/s41467-020-18575-6
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    Ultrasensitive and visual detection of SARS-CoV-2 using all-in-one dual CRISPR-Cas12a assay
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    Nature Communications (2020), 11 (1), 4711CODEN: NCAOBW; ISSN:2041-1723. (Nature Research)
    Abstr.: The recent outbreak of novel coronavirus (SARS-CoV-2) causing COVID-19 disease spreads rapidly in the world. Rapid and early detection of SARS-CoV-2 facilitates early intervention and prevents the disease spread. Here, we present an All-In-One Dual CRISPR-Cas12a (AIOD-CRISPR) assay for one-pot, ultrasensitive, and visual SARS-CoV-2 detection. By targeting SARS-CoV-2's nucleoprotein gene, two CRISPR RNAs without protospacer adjacent motif (PAM) site limitation are introduced to develop the AIOD-CRISPR assay and detect the nucleic acids with a sensitivity of few copies. We validate the assay by using COVID-19 clin. swab samples and obtain consistent results with RT-PCR assay. Furthermore, a low-cost hand warmer (∼$0.3) is used as an incubator of the AIOD-CRISPR assay to detect clin. samples within 20 min, enabling an instrument-free, visual SARS-CoV-2 detection at the point of care. Thus, our method has the significant potential to provide a rapid, sensitive, one-pot point-of-care assay for SARS-CoV-2.
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    Altawalbeh, S. M.; Alkhateeb, F. M.; Attarabeen, O. F. Ethical Issues in Consenting Older Adults: Academic Researchers and Community Perspectives. J. Pharm. Heal. Serv. Res. 2020, 11 (1), 25– 32,  DOI: 10.1111/jphs.12327
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    Ethical Issues in Consenting Older Adults: Academic Researchers and Community Perspectives
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    Journal of pharmaceutical health services research : an official journal of the Royal Pharmaceutical Society of Great Britain (2020), 11 (1), 25-32 ISSN:1759-8885.
    Objectives: Obtaining informed consents from older adults is surrounded by many ethical and practical challenges. The objective of this study was to evaluate ethical issues and strategies in consenting older adults in Jordan as perceived by academic researchers and older adults. Methods: An anonymous questionnaire was distributed to academic researchers in the Jordanian health sciences colleges, and a sample of older adults. The study survey included items eliciting demographics, professional characteristics, and perceptions regarding the consenting process in older adults, consent-related skills in elderly, and strategies to improve the consenting process in older adults. The survey was then modified to assess the consent-related ethical issues and challenges as viewed by a sample of older adults after explaining the concept of the consenting process to them. Key findings: A total of 250 academic researchers and 233 older adults participated in the study. Both researchers and older adults reported that having to sign the written forms and the impact of age-related physical impairments were the most challenging obstacles when consenting older adults. Lack of consistency and repeating questions were the most frequently encountered obstacles by researchers in consenting older adults. Ensuring privacy (anonymity/confidentiality), dedicating more time for the consenting process, treating older adults as autonomous individuals and respecting their cultural beliefs were the most helpful strategies recommended by both academic researchers and older adults. Conclusions: Obtaining informed consents from older adults is a challenging process. Researchers should be aware of the special needs and strategies to achieve realistic and ethical informed consents from older adults.
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    Tindana, P.; Molyneux, C. S.; Bull, S.; Parker, M. Ethical Issues in the Export, Storage and Reuse of Human Biological Samples in Biomedical Research: Perspectives of Key Stakeholders in Ghana and Kenya. BMC Med. Ethics 2014, 15 (1), 76,  DOI: 10.1186/1472-6939-15-76
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    Ethical issues in the export, storage and reuse of human biological samples in biomedical research: perspectives of key stakeholders in Ghana and Kenya
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    BACKGROUND: For many decades, access to human biological samples, such as cells, tissues, organs, blood, and sub-cellular materials such as DNA, for use in biomedical research, has been central in understanding the nature and transmission of diseases across the globe. However, the limitations of current ethical and regulatory frameworks in sub-Saharan Africa to govern the collection, export, storage and reuse of these samples have resulted in inconsistencies in practice and a number of ethical concerns for sample donors, researchers and research ethics committees. This paper examines stakeholders' perspectives of and responses to the ethical issues arising from these research practices. METHODS: We employed a qualitative strategy of inquiry for this research including in-depth interviews and focus group discussions with key research stakeholders in Kenya (Nairobi and Kilifi), and Ghana (Accra and Navrongo). RESULTS: The stakeholders interviewed emphasised the compelling scientific importance of sample export, storage and reuse, and acknowledged the existence of some structures governing these research practices, but they also highlighted the pressing need for a number of practical ethical concerns to be addressed in order to ensure high standards of practice and to maintain public confidence in international research collaborations. These concerns relate to obtaining culturally appropriate consent for sample export and reuse, understanding cultural sensitivities around the use of blood samples, facilitating a degree of local control of samples and sustainable scientific capacity building. CONCLUSION: Drawing on these findings and existing literature, we argue that the ethical issues arising in practice need to be understood in the context of the interactions between host research institutions and local communities and between collaborating institutions. We propose a set of 'key points-to-consider' for research institutions, ethics committees and funding agencies to address these issues.
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    Drugs, Devices, and the FDA: Part 2: An Overview of Approval Processes: FDA Approval of Medical Devices
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    As with new drugs, the U.S. Food and Drug Administration's approval process is intended to provide consumers with assurance that, once it reaches the market place, a medical device is safe and effective in its intended use. Bringing a device to market takes an average of 3 to 7 years, compared with an average of 12 years for drugs. However, there are concerns that Food and Drug Administration processes may not be sufficient to meet the assurances of safety and efficacy as intended. This second part of a 2-part series reviews the basic steps in development and Food and Drug Administration approval of medical devices, and summarizes post-marketing processes for drugs and devices.
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    A novel coronavirus from patients with pneumonia in China, 2019
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    New England Journal of Medicine (2020), 382 (8), 727-733CODEN: NEJMAG; ISSN:1533-4406. (Massachusetts Medical Society)
    In Dec. 2019, a cluster of patients with pneumonia of unknown cause was linked to a seafood wholesale market in Wuhan, China. A previously unknown betacoronavirus was discovered through the use of unbiased sequencing in samples from patients with pneumonia. Human airway epithelial cells were used to isolate a novel coronavirus, named 2019-nCoV, which formed a clade within the subgenus sarbecovirus, Orthocoronavirinae subfamily. Different from both MERS-CoV and SARS-CoV, 2019-nCoV is the seventh member of the family of coronaviruses that infect humans. Enhanced surveillance and further investigation are ongoing. Complete genome sequences of the three novel coronaviruses were submitted to GISAID (BetaCoV/Wuhan/ IVDC-HB-01/2019, accession ID: EPI_ISL_402119; BetaCoV/Wuhan/IVDC-HB-04/2020, accession ID: EPI_ISL_402120; BetaCoV/Wuhan/IVDC-HB-05/2019, accession ID: EPI_ISL_402121).
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    Li, Q.; Wu, J.; Nie, J.; Zhang, L.; Hao, H.; Liu, S.; Zhao, C.; Zhang, Q.; Liu, H.; Nie, L.; Qin, H.; Wang, M.; Lu, Q.; Li, X.; Sun, Q.; Liu, J.; Zhang, L.; Li, X.; Huang, W.; Wang, Y. The Impact of Mutations in SARS-CoV-2 Spike on Viral Infectivity and Antigenicity. Cell 2020, 182 (5), 1284– 1294,  DOI: 10.1016/j.cell.2020.07.012
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    The impact of mutations in SARS-CoV-2 spike on viral infectivity and antigenicity
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    Cell (Cambridge, MA, United States) (2020), 182 (5), 1284-1294.e9CODEN: CELLB5; ISSN:0092-8674. (Cell Press)
    The spike protein of SARS-CoV-2 has been undergoing mutations and is highly glycosylated. It is critically important to investigate the biol. significance of these mutations. Here, we investigated 80 variants and 26 glycosylation site modifications for the infectivity and reactivity to a panel of neutralizing antibodies and sera from convalescent patients. D614G, along with several variants contg. both D614G and another amino acid change, were significantly more infectious. Most variants with amino acid change at receptor binding domain were less infectious, but variants including A475V, L452R, V483A, and F490L became resistant to some neutralizing antibodies. Moreover, the majority of glycosylation deletions were less infectious, whereas deletion of both N331 and N343 glycosylation drastically reduced infectivity, revealing the importance of glycosylation for viral infectivity. Interestingly, N234Q was markedly resistant to neutralizing antibodies, whereas N165Q became more sensitive. These findings could be of value in the development of vaccine and therapeutic antibodies.
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    Cao, Y.; Su, B.; Guo, X.; Sun, W.; Deng, Y.; Bao, L.; Zhu, Q.; Zhang, X.; Zheng, Y.; Geng, C.; Chai, X.; He, R.; Li, X.; Lv, Q.; Zhu, H.; Deng, W.; Xu, Y.; Wang, Y.; Qiao, L.; Tan, Y. Potent Neutralizing Antibodies against SARS-CoV-2 Identified by High-Throughput Single-Cell Sequencing of Convalescent Patients’ B Cells. Cell 2020, 182 (1), 73– 84,  DOI: 10.1016/j.cell.2020.05.025
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    Potent Neutralizing Antibodies against SARS-CoV-2 Identified by High-Throughput Single-Cell Sequencing of Convalescent Patients' B Cells
    Cao, Yunlong; Su, Bin; Guo, Xianghua; Sun, Wenjie; Deng, Yongqiang; Bao, Linlin; Zhu, Qinyu; Zhang, Xu; Zheng, Yinghui; Geng, Chenyang; Chai, Xiaoran; He, Runsheng; Li, Xiaofeng; Lv, Qi; Zhu, Hua; Deng, Wei; Xu, Yanfeng; Wang, Yanjun; Qiao, Luxin; Tan, Yafang; Song, Liyang; Wang, Guopeng; Du, Xiaoxia; Gao, Ning; Liu, Jiangning; Xiao, Junyu; Su, Xiao-dong; Du, Zongmin; Feng, Yingmei; Qin, Chuan; Qin, Chengfeng; Jin, Ronghua; Xie, X. Sunney
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    The COVID-19 pandemic urgently needs therapeutic and prophylactic interventions. Here, we report the rapid identification of SARS-CoV-2-neutralizing antibodies by high-throughput single-cell RNA and VDJ sequencing of antigen-enriched B cells from 60 convalescent patients. From 8,558 antigen-binding IgG1+ clonotypes, 14 potent neutralizing antibodies were identified, with the most potent one, BD-368-2, exhibiting an IC50 of 1.2 and 15 ng/mL against pseudotyped and authentic SARS-CoV-2, resp. BD-368-2 also displayed strong therapeutic and prophylactic efficacy in SARS-CoV-2-infected hACE2-transgenic mice. Addnl., the 3.8 Å cryo-EM structure of a neutralizing antibody in complex with the spike-ectodomain trimer revealed the antibody's epitope overlaps with the ACE2 binding site. Moreover, we demonstrated that SARS-CoV-2-neutralizing antibodies could be directly selected based on similarities of their predicted CDR3H structures to those of SARS-CoV-neutralizing antibodies. Altogether, we showed that human neutralizing antibodies could be efficiently discovered by high-throughput single B cell sequencing in response to pandemic infectious diseases.
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    A review. The decrease in the rate at which novel medical products are reaching the market, despite major scientific achievements and investment that might have predicted otherwise, is causing much concern. Although this 'pipeline problem' has often been discussed in the context of drug development, it is also crucial to examine the unique characteristics of the pipeline for biomarkers and diagnostics. Here, the authors characterize the pipeline problem for biomarkers and diagnostics, and consider what steps could be taken to solve it.
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  • Abstract

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    Figure 1

    Figure 1. Visual description of the duration of the phases required to develop a rapid test for previous outbreaks (the dates refer to each phase thanks to a color code) (a) and of the current SARS-CoV-2 detection technologies (b). PCR, antigen, and serological tests with the respective criteria for results interpretation (T = test line, C = control line). The bottom plot gives an outlook of the infection progression and the phases in which each test result is more effective.

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    Figure 2

    Figure 2. Examples of nano-biosensors for the detection of the SARS-CoV-2 virus and published in 2020. (A) Electrochemical paper-based interdigitated device for N gene detection using graphene and AuNPs. (52) Adapted with permission from ref (52). Copyright © 2020 American Chemical Society. (B) Spike protein lateral flow device using AuNPs and glycan anchors. (53) Adapted with permission from ref (53). Copyright © 2020 American Chemical Society. (C) Colorimetric (plasmonic) viral RNA detection method with the use of DNA-functionalized AuNPs. (56) Adapted with permission from ref (56). Copyright © 2020 American Chemical Society. (D) Thermoplasmonic device for the detection of membrane, spike, and nucleocapsid protein genes with DNA immobilized on 2D nanoislands. (57) Adapted with permission from ref (57). Copyright © 2020 American Chemical Society. (E) Graphene-based FET for real-time immune-based spike protein detection. (58) Adapted with permission from ref (58). Copyright © 2020 American Chemical Society. (F) Multiplexed electrochemical detection on laser-engraved graphene electrodes. (60) Adapted with permission from ref (60). Copyright © 2020 Elsevier. (G) CRISPR-based ultrasensitive fluorescent detection of two sites of the viral RNA genome. (64) Adapted with permission under a Creative Commons Attribution 4.0 International License from ref (64). Copyright © 2020 Springer Nature.

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    Figure 3

    Figure 3. Current development process of diagnostic devices with the phases from conception to the market launch and corresponding TRLs.

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      Petrosillo, N.; Viceconte, G.; Ergonul, O.; Ippolito, G.; Petersen, E.
      Clinical Microbiology and Infection (2020), 26 (6), 729-734CODEN: CMINFM; ISSN:1198-743X. (Elsevier Ltd.)
      A review. The 2019 novel coronavirus (SARS-CoV-2) is a new human coronavirus which is spreading with epidemic features in China and other Asian countries; cases have also been reported worldwide. This novel coronavirus disease (COVID-19) is assocd. with a respiratory illness that may lead to severe pneumonia and acute respiratory distress syndrome (ARDS). Although related to the severe acute respiratory syndrome (SARS) and the Middle East respiratory syndrome (MERS), COVID-19 shows some peculiar pathogenetic, epidemiol. and clin. features which to date are not completely understood.To provide a review of the differences in pathogenesis, epidemiol. and clin. features of COVID-19, SARS and MERS.The most recent literature in the English language regarding COVID-19 has been reviewed, and extd. data have been compared with the current scientific evidence about SARS and MERS epidemics.COVID-19 seems not to be very different from SARS regarding its clin. features. However, it has a fatality rate of 2.3%, lower than that of SARS (9.5%) and much lower than that of MERS (34.4%). The possibility cannot be excluded that because of the less severe clin. picture of COVID-19 it can spread in the community more easily than MERS and SARS. The actual basic reproductive no. (R0) of COVID-19 (2.0-2.5) is still controversial. It is probably slightly higher than the R0 of SARS (1.7-1.9) and higher than that of MERS (<1). A gastrointestinal route of transmission for SARS-CoV-2, which has been assumed for SARS-CoV and MERS-CoV, cannot be ruled out and needs further investigation.There is still much more to know about COVID-19, esp. as concerns mortality and its capacity to spread on a pandemic level. Nonetheless, all of the lessons we learned in the past from the SARS and MERS epidemics are the best cultural weapons with which to face this new global threat.
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    10. 10
      Ou, X.; Liu, Y.; Lei, X.; Li, P.; Mi, D.; Ren, L.; Guo, L.; Guo, R.; Chen, T.; Hu, J.; Xiang, Z.; Mu, Z.; Chen, X.; Chen, J.; Hu, K.; Jin, Q.; Wang, J.; Qian, Z. Characterization of Spike Glycoprotein of SARS-CoV-2 on Virus Entry and Its Immune Cross-Reactivity with SARS-CoV. Nat. Commun. 2020, 11 (1), 1620,  DOI: 10.1038/s41467-020-15562-9
      10
      Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV
      Ou, Xiuyuan; Liu, Yan; Lei, Xiaobo; Li, Pei; Mi, Dan; Ren, Lili; Guo, Li; Guo, Ruixuan; Chen, Ting; Hu, Jiaxin; Xiang, Zichun; Mu, Zhixia; Chen, Xing; Chen, Jieyong; Hu, Keping; Jin, Qi; Wang, Jianwei; Qian, Zhaohui
      Nature Communications (2020), 11 (1), 1620CODEN: NCAOBW; ISSN:2041-1723. (Nature Research)
      Since 2002, beta coronaviruses (CoV) have caused three zoonotic outbreaks, SARS-CoV in 2002-2003, MERS-CoV in 2012, and the newly emerged SARS-CoV-2 in late 2019. However, little is currently known about the biol. of SARS-CoV-2. Here, using SARS-CoV-2 S protein pseudovirus system, we confirm that human angiotensin converting enzyme 2 (hACE2) is the receptor for SARS-CoV-2, find that SARS-CoV-2 enters 293/hACE2 cells mainly through endocytosis, that PIKfyve, TPC2, and cathepsin L are crit. for entry, and that SARS-CoV-2 S protein is less stable than SARS-CoV S. Polyclonal anti-SARS S1 antibodies T62 inhibit entry of SARS-CoV S but not SARS-CoV-2 S pseudovirions. Further studies using recovered SARS and COVID-19 patients' sera show limited cross-neutralization, suggesting that recovery from one infection might not protect against the other. Our results present potential targets for development of drugs and vaccines for SARS-CoV-2.
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    11. 11
      Walls, A. C.; Park, Y.-J.; Tortorici, M. A.; Wall, A.; McGuire, A. T.; Veesler, D. Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein. Cell 2020, 181 (2), 281– 292,  DOI: 10.1016/j.cell.2020.02.058
      11
      Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein
      Walls, Alexandra C.; Park, Young-Jun; Tortorici, M. Alejandra; Wall, Abigail; McGuire, Andrew T.; Veesler, David
      Cell (Cambridge, MA, United States) (2020), 181 (2), 281-292.e6CODEN: CELLB5; ISSN:0092-8674. (Cell Press)
      The emergence of SARS-CoV-2 has resulted in >90,000 infections and >3000 deaths. Coronavirus spike (S) glycoproteins promote entry into cells and are the main target of antibodies. We show that SARS-CoV-2 S uses ACE2 to enter cells and that the receptor-binding domains of SARS-CoV-2 S and SARS-CoV S bind with similar affinities to human ACE2, correlating with the efficient spread of SARS-CoV-2 among humans. We found that the SARS-CoV-2 S glycoprotein harbors a furin cleavage site at the boundary between the S1/S2 subunits, which is processed during biogenesis and sets this virus apart from SARS-CoV and SARS-related CoVs. We detd. cryo-EM structures of the SARS-CoV-2 S ectodomain trimer, providing a blueprint for the design of vaccines and inhibitors of viral entry. Finally, we demonstrate that SARS-CoV S murine polyclonal antibodies potently inhibited SARS-CoV-2 S mediated entry into cells, indicating that cross-neutralizing antibodies targeting conserved S epitopes can be elicited upon vaccination.
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    12. 12
      Tilocca, B.; Soggiu, A.; Sanguinetti, M.; Babini, G.; De Maio, F.; Britti, D.; Zecconi, A.; Bonizzi, L.; Urbani, A.; Roncada, P. Immunoinformatic Analysis of the SARS-CoV-2 Envelope Protein as a Strategy to Assess Cross-Protection against COVID-19. Microbes Infect. 2020, 22 (4–5), 182– 187,  DOI: 10.1016/j.micinf.2020.05.013
      12
      Immunoinformatic analysis of the SARS-CoV-2 envelope protein as a strategy to assess cross-protection against COVID-19
      Tilocca, Bruno; Soggiu, Alessio; Sanguinetti, Maurizio; Babini, Gabriele; De Maio, Flavio; Britti, Domenico; Zecconi, Alfonso; Bonizzi, Luigi; Urbani, Andrea; Roncada, Paola
      Microbes and Infection (2020), 22 (4-5), 182-187CODEN: MCINFS; ISSN:1286-4579. (Elsevier Masson SAS)
      Envelope protein of coronaviruses is a structural protein existing in both monomeric and homo-pentameric form. It has been related to a multitude of roles including virus infection, replication, dissemination, and immune response stimulation. We employed an immunoinformatic approach to investigate the major immunogenic domains of the SARS-CoV-2 envelope protein and map them among the homolog proteins of coronaviruses with tropism for animal species that are closely inter-related with the human beings population all over the world. Also, when not available, we predicted the envelope protein structural folding and mapped SARS-CoV-2 epitopes. Envelope sequences alignment provides evidence of high sequence homol. for some of the investigated virus specimens; while the structural mapping of epitopes resulted in the interesting maintenance of the structural folding and epitope sequence localization also in the envelope proteins scoring a lower alignment score. In line with the One-Health approach, our evidences provide a mol. structural rationale for a potential role of taxonomically related coronaviruses in conferring protection from SARS-CoV-2 infection and identifying potential candidates for the development of diagnostic tools and prophylactic-oriented strategies.
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    13. 13
      Yin, C. Genotyping Coronavirus SARS-CoV-2: Methods and Implications. Genomics 2020, 112 (5), 3588– 3596,  DOI: 10.1016/j.ygeno.2020.04.016
      13
      Genotyping coronavirus SARS-CoV-2: methods and implications
      Yin, Changchuan
      Genomics (2020), 112 (5), 3588-3596CODEN: GNMCEP; ISSN:0888-7543. (Elsevier Inc.)
      The emerging global infectious COVID-19 disease by novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) presents crit. threats to global public health and the economy since it was identified in late Dec. 2019 in China. The virus has gone through various pathways of evolution. To understand the evolution and transmission of SARS-CoV-2, genotyping of virus isolates is of great importance. This study presents an accurate method for effectively genotyping SARS-CoV-2 viruses using complete genomes. The method employs the multiple sequence alignments of the genome isolates with the SARS-CoV-2 ref. genome. The single-nucleotide polymorphism (SNP) genotypes are then measured by Jaccard distances to track the relationship of virus isolates. The genotyping anal. of SARS-CoV-2 isolates from the globe reveals that specific multiple mutations are the predominated mutation type during the current epidemic. The proposed method serves an effective tool for monitoring and tracking the epidemic of pathogenic viruses in their global and local genetic variations. The genotyping anal. shows that the genes encoding the S proteins and RNA polymerase, RNA primase, and nucleoprotein, undergo frequent mutations. These mutations are crit. for vaccine development in disease control.
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    14. 14
      Li, Q.; Guan, X.; Wu, P.; Wang, X.; Zhou, L.; Tong, Y.; Ren, R.; Leung, K. S. M.; Lau, E. H. Y.; Wong, J. Y.; Xing, X.; Xiang, N.; Wu, Y.; Li, C.; Chen, Q.; Li, D.; Liu, T.; Zhao, J.; Liu, M.; Tu, W. Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus-Infected Pneumonia. N. Engl. J. Med. 2020, 382 (13), 1199– 1207,  DOI: 10.1056/NEJMoa2001316
      14
      Early transmission dynamics in Wuhan, China, of novel coronavirus-infected pneumonia
      Li, Qun; Guan, Xuhua; Wu, Peng; Wang, Xiaoye; Zhou, Lei; Tong, Yeqing; Ren, Ruiqi; Leung, Kathy S. M.; Lau, Eric H. Y.; Wong, Jessica Y.; Xing, Xuesen; Xiang, Nijuan; Wu, Yang; Li, Chao; Chen, Qi; Li, Dan; Liu, Tian; Zhao, Jing; Liu, Man; Tu, Wenxiao; Chen, Chuding; Jin, Lianmei; Yang, Rui; Wang, Qi; Zhou, Suhua; Wang, Rui; Liu, Hui; Luo, Yinbo; Liu, Yuan; Shao, Ge; Li, Huan; Tao, Zhongfa; Yang, Yang; Deng, Zhiqiang; Liu, Boxi; Ma, Zhitao; Zhang, Yanping; Shi, Guoqing; Lam, Tommy T. Y.; Wu, Joseph T.; Gao, George F.; Cowling, Benjamin J.; Yang, Bo; Leung, Gabriel M.; Feng, Zijian
      New England Journal of Medicine (2020), 382 (13), 1199-1207CODEN: NEJMAG; ISSN:1533-4406. (Massachusetts Medical Society)
      The initial cases of novel coronavirus (2019-nCoV)-infected pneumonia (NCIP) occurred in Wuhan, Hubei Province, China, in Dec. 2019 and Jan. 2020. We analyzed data on the 1st 425 confirmed cases in Wuhan to det. the epidemiol. characteristics of NCIP. We collected information on demog. characteristics, exposure history, and illness timelines of lab.-confirmed cases of NCIP that had been reported by Jan. 22, 2020. We described characteristics of the cases and estd. the key epidemiol. time-delay distributions. In the early period of exponential growth, we estd. the epidemic doubling time and the basic reproductive no. Among the 1st 425 patients with confirmed NCIP, the median age was 59 yr and 56% were male. The majority of cases (55%) with onset before Jan. 1, 2020, were linked to the Huanan Seafood Wholesale Market, as compared with 8.6% of the subsequent cases. The mean incubation period was 5.2 days, with the 95th percentile of the distribution at 12.5 days. In its early stages, the epidemic doubled in size every 7.4 days. With a mean serial interval of 7.5 days, the basic reproductive no. was estd. to be 2.2. On the basis of this information, there is evidence that human-to-human transmission has occurred among close contacts since the middle of Dec. 2019. Considerable efforts to reduce transmission will be required to control outbreaks if similar dynamics apply elsewhere. Measures to prevent or reduce transmission should be implemented in populations at risk.
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    15. 15
      Andersen, K. G.; Rambaut, A.; Lipkin, W. I.; Holmes, E. C.; Garry, R. F. The Proximal Origin of SARS-CoV-2. Nat. Med. 2020, 26 (4), 450– 452,  DOI: 10.1038/s41591-020-0820-9
      15
      The proximal origin of SARS-CoV-2
      Andersen, Kristian G.; Rambaut, Andrew; Lipkin, W. Ian; Holmes, Edward C.; Garry, Robert F.
      Nature Medicine (New York, NY, United States) (2020), 26 (4), 450-452CODEN: NAMEFI; ISSN:1078-8956. (Nature Research)
      There is no expanded citation for this reference.
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    16. 16
      St John, A.; Price, C. P. Existing and Emerging Technologies for Point-of-Care Testing. Clin. Biochem. Rev. 2014, 35 (3), 155– 167
      16
      Existing and Emerging Technologies for Point-of-Care Testing
      St John Andrew; Price Christopher P
      The Clinical biochemist. Reviews (2014), 35 (3), 155-67 ISSN:0159-8090.
      The volume of point-of-care testing (PoCT) has steadily increased over the 40 or so years since its widespread introduction. That growth is likely to continue, driven by changes in healthcare delivery which are aimed at delivering less costly care closer to the patient's home. In the developing world there is the challenge of more effective care for infectious diseases and PoCT may play a much greater role here in the future. PoCT technologies can be split into two categories, but in both, testing is generally performed by technologies first devised more than two decades ago. These technologies have undoubtedly been refined and improved to deliver easier-to-use devices with incremental improvements in analytical performance. Of the two major categories the first is small handheld devices, providing qualitative or quantitative determination of an increasing range of analytes. The dominant technologies here are glucose biosensor strips and lateral flow strips using immobilised antibodies to determine a range of parameters including cardiac markers and infectious pathogens. The second category of devices are larger, often bench-top devices which are essentially laboratory instruments which have been reduced in both size and complexity. These include critical care analysers and, more recently, small haematology and immunology analysers. New emerging devices include those that are utilising molecular techniques such as PCR to provide infectious disease testing in a sufficiently small device to be used at the point of care. This area is likely to grow with many devices being developed and likely to reach the commercial market in the next few years.
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    17. 17
      Gervais, L.; de Rooij, N.; Delamarche, E. Microfluidic Diagnostic Devices: Microfluidic Chips for Point-of-Care Immunodiagnostics. Adv. Mater. 2011, 23 (24), H208– H208,  DOI: 10.1002/adma.201190098
      There is no corresponding record for this reference.
    18. 18
      Delamarche, E.; Bernard, A.; Schmid, H.; Michel, B.; Biebuyck, H. Patterned Delivery of Immunoglobulins to Surfaces Using Microfluidic Networks. Science 1997, 276 (5313), 779– 781,  DOI: 10.1126/science.276.5313.779
      18
      Patterned delivery of immunoglobulins to surfaces using microfluidic networks
      Delamarche, Emmanuel; Bernard, Anre; Schmid, Heinz; Michael, Bruno; Biebuyck, Hans
      Science (Washington, D. C.) (1997), 276 (5313), 779-781CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
      Microfluidic networks (μFNs) were used to pattern biomols. with high resoln. on a variety of substrates (gold, glass, or polystyrene). Elastomeric μFNs localized chem. reactions between the biomols. and the surface, requiring only microliters of reagent to cover square millimeter-sized areas. The networks were designed to ensure stability and filling of the μFN and allowed a homogeneous distribution and robust attachment of material to the substrate along the conduits in the μFN. Igs patterned on substrates by means of μFNs remained strictly confined to areas enclosed by the approach is simple and general enough to suggest a practical way to incorporate biol. material on technol. substrates.
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    19. 19
      Guangzhou Wondfo Biotech Co. LTD. COVID-19 - Wondfo https://en.wondfo.com.cn/es/covid-19-5/ (accessed 2020-04-28).
      There is no corresponding record for this reference.
    20. 20
      Crozier, A.; Rajan, S.; Buchan, I.; McKee, M. Put to the Test: Use of Rapid Testing Technologies for Covid-19. BMJ. 2021, 372, n208  DOI: 10.1136/bmj.n208
      There is no corresponding record for this reference.
    21. 21
      Niemz, A.; Ferguson, T. M.; Boyle, D. S. Point-of-Care Nucleic Acid Testing for Infectious Diseases. Trends Biotechnol. 2011, 29 (5), 240– 250,  DOI: 10.1016/j.tibtech.2011.01.007
      21
      Point-of-care nucleic acid testing for infectious diseases
      Niemz, Angelika; Ferguson, Tanya M.; Boyle, David S.
      Trends in Biotechnology (2011), 29 (5), 240-250CODEN: TRBIDM; ISSN:0167-7799. (Elsevier B.V.)
      A review. Nucleic acid testing for infectious diseases at the point of care is beginning to enter clin. practice in developed and developing countries; esp. for applications requiring fast turnaround times, and in settings where a centralized lab. approach faces limitations. Current systems for clin. diagnostic applications are mainly PCR-based, can only be used in hospitals, and are still relatively complex and expensive. Integrating sample prepn. with nucleic acid amplification and detection in a cost-effective, robust, and user-friendly format remains challenging. This review describes recent tech. advances that might be able to address these limitations, with a focus on isothermal nucleic acid amplification methods. It briefly discusses selected applications related to the diagnosis and management of tuberculosis, HIV, and perinatal and nosocomial infections.
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    22. 22
      Nichols, J. H. Reducing Medical Errors at the Point of Care. Lab. Med. 2005, 36 (5), 275– 277,  DOI: 10.1309/NXXWJ31PWFHT7L1Q
      There is no corresponding record for this reference.
    23. 23
      Shaw, J. L. V. Practical Challenges Related to Point of Care Testing. Pract. Lab. Med. 2016, 4, 22– 29,  DOI: 10.1016/j.plabm.2015.12.002
      23
      Practical challenges related to point of care testing
      Shaw Julie L V; Shaw Julie L V; Shaw Julie L V
      Practical laboratory medicine (2016), 4 (), 22-29 ISSN:2352-5517.
      Point of care testing (POCT) refers to laboratory testing that occurs near to the patient, often at the patient bedside. POCT can be advantageous in situations requiring rapid turnaround time of test results for clinical decision making. There are many challenges associated with POCT, mainly related to quality assurance. POCT is performed by clinical staff rather than laboratory trained individuals which can lead to errors resulting from a lack of understanding of the importance of quality control and quality assurance practices. POCT is usually more expensive than testing performed in the central laboratory and requires a significant amount of support from the laboratory to ensure the quality testing and meet accreditation requirements. Here, specific challenges related to POCT compliance with accreditation standards are discussed along with strategies that can be used to overcome these challenges. These areas include: documentation of POCT orders, charting of POCT results as well as training and certification of individuals performing POCT. Factors to consider when implementing connectivity between POCT instruments and the electronic medical record are also discussed in detail and include: uni-directional versus bidirectional communication, linking patient demographic information with POCT software, the importance of positive patient identification and considering where to chart POCT results in the electronic medical record.
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    24. 24
      Kumar, A. A.; Hennek, J. W.; Smith, B. S.; Kumar, S.; Beattie, P.; Jain, S.; Rolland, J. P.; Stossel, T. P.; Chunda-Liyoka, C.; Whitesides, G. M. From the Bench to the Field in Low-Cost Diagnostics: Two Case Studies. Angew. Chem., Int. Ed. 2015, 54 (20), 5836– 5853,  DOI: 10.1002/anie.201411741
      24
      From the Bench to the Field in Low-Cost Diagnostics: Two Case Studies
      Kumar, Ashok A.; Hennek, Jonathan W.; Smith, Barbara S.; Kumar, Shailendra; Beattie, Patrick; Jain, Sidhartha; Rolland, Jason P.; Stossel, Thomas P.; Chunda-Liyoka, Catherine; Whitesides, George M.
      Angewandte Chemie, International Edition (2015), 54 (20), 5836-5853CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      A review on two case studies of (liver injury, sickle cell disease) on the processes that move point-of-care (POC) diagnostic technol. from a lab. to a field, esp., to a resource-limited environment.
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    25. 25
      Sachdeva, S.; Davis, R. W.; Saha, A. K. Microfluidic Point-of-Care Testing: Commercial Landscape and Future Directions. Front. Bioeng. Biotechnol. 2021, 8, 1537,  DOI: 10.3389/fbioe.2020.602659
      There is no corresponding record for this reference.
    26. 26
      Kelley, S. O. COVID-19: A Crisis Creating New Opportunities for Sensing. ACS Sensors 2021, 6 (4), 1407– 1407,  DOI: 10.1021/acssensors.1c00687
      26
      COVID-19: A Crisis Creating New Opportunities for Sensing
      Kelley, Shana O.
      ACS Sensors (2021), 6 (4), 1407CODEN: ASCEFJ; ISSN:2379-3694. (American Chemical Society)
      A review. In this month's issue of ACS Sensors, several new approaches and areas are covered that will contribute to the sensor revolution that is to come. The pace of innovation in sensor science is impressive and in these exceptional times, it will accelerate further.
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    27. 27
      Yousefi, H.; Mahmud, A.; Chang, D.; Das, J.; Gomis, S.; Chen, J. B.; Wang, H.; Been, T.; Yip, L.; Coomes, E.; Li, Z.; Mubareka, S.; McGeer, A.; Christie, N.; Gray-Owen, S.; Cochrane, A.; Rini, J. M.; Sargent, E. H.; Kelley, S. O. Detection of SARS-CoV-2 Viral Particles Using Direct, Reagent-Free Electrochemical Sensing. J. Am. Chem. Soc. 2021, 143 (4), 1722– 1727,  DOI: 10.1021/jacs.0c10810
      27
      Detection of SARS-CoV-2 Viral Particles Using Direct, Reagent-Free Electrochemical Sensing
      Yousefi, Hanie; Mahmud, Alam; Chang, Dingran; Das, Jagotamoy; Gomis, Surath; Chen, Jenise B.; Wang, Hansen; Been, Terek; Yip, Lily; Coomes, Eric; Li, Zhijie; Mubareka, Samira; McGeer, Allison; Christie, Natasha; Gray-Owen, Scott; Cochrane, Alan; Rini, James M.; Sargent, Edward H.; Kelley, Shana O.
      Journal of the American Chemical Society (2021), 143 (4), 1722-1727CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      The development of new methods for direct viral detection using streamlined and ideally reagent-free assays is a timely and important, but challenging, problem. The challenge of combating the COVID-19 pandemic has been exacerbated by the lack of rapid and effective methods to identify viral pathogens like SARS-CoV-2 on-demand. Existing gold std. nucleic acid-based approaches require enzymic amplification to achieve clin. relevant levels of sensitivity and are not typically used outside of a lab. setting. We report reagent-free viral sensing that directly reads out the presence of viral particles in 5 min using only a sensor-modified electrode chip. The approach relies on a class of electrode-tethered sensors bearing an analyte-binding antibody displayed on a neg. charged DNA linker that also features a tethered redox probe. When a pos. potential is applied, the sensor is transported to the electrode surface. Using chronoamperometry, the presence of viral particles and proteins can be detected as these species increase the hydrodynamic drag on the sensor. This report is the 1st virus-detecting assay that uses the kinetic response of a probe/virus complex to analyze the complexation state of the antibody. We demonstrate the performance of this sensing approach as a means to detect, within 5 min, the presence of the SARS-CoV-2 virus and its assocd. spike protein in test samples and in unprocessed patient saliva.
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    28. 28
      Wu, F.; Zhao, S.; Yu, B.; Chen, Y.-M.; Wang, W.; Song, Z.-G.; Hu, Y.; Tao, Z.-W.; Tian, J.-H.; Pei, Y.-Y.; Yuan, M.-L.; Zhang, Y.-L.; Dai, F.-H.; Liu, Y.; Wang, Q.-M.; Zheng, J.-J.; Xu, L.; Holmes, E. C.; Zhang, Y.-Z. A New Coronavirus Associated with Human Respiratory Disease in China. Nature 2020, 579 (7798), 265– 269,  DOI: 10.1038/s41586-020-2008-3
      28
      A new coronavirus associated with human respiratory disease in China
      Wu, Fan; Zhao, Su; Yu, Bin; Chen, Yan-Mei; Wang, Wen; Song, Zhi-Gang; Hu, Yi; Tao, Zhao-Wu; Tian, Jun-Hua; Pei, Yuan-Yuan; Yuan, Ming-Li; Zhang, Yu-Ling; Dai, Fa-Hui; Liu, Yi; Wang, Qi-Min; Zheng, Jiao-Jiao; Xu, Lin; Holmes, Edward C.; Zhang, Yong-Zhen
      Nature (London, United Kingdom) (2020), 579 (7798), 265-269CODEN: NATUAS; ISSN:0028-0836. (Nature Research)
      Emerging infectious diseases, such as severe acute respiratory syndrome (SARS) and Zika virus disease, present a major threat to public health. Despite intense research efforts, how, when and where new diseases appear are still a source of considerable uncertainty. A severe respiratory disease was recently reported in Wuhan, Hubei province, China. As of 25 Jan. 2020, at least 1,975 cases had been reported since the first patient was hospitalized on 12 Dec. 2019. Epidemiol. investigations have suggested that the outbreak was assocd. with a seafood market in Wuhan. Here we study a single patient who was a worker at the market and who was admitted to the Central Hospital of Wuhan on 26 Dec. 2019 while experiencing a severe respiratory syndrome that included fever, dizziness and a cough. Metagenomic RNA sequencing of a sample of bronchoalveolar lavage fluid from the patient identified a new RNA virus strain from the family Coronaviridae, which is designated here 'WH-Human 1' coronavirus (and has also been referred to as '2019-nCoV'). Phylogenetic anal. of the complete viral genome (29,903 nucleotides) revealed that the virus was most closely related (89.1% nucleotide similarity) to a group of SARS-like coronaviruses (genus Betacoronavirus, subgenus Sarbecovirus) that had previously been found in bats in China. This outbreak highlights the ongoing ability of viral spill-over from animals to cause severe disease in humans.
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    29. 29
      Zhou, P.; Yang, X.-L.; Wang, X.-G.; Hu, B.; Zhang, L.; Zhang, W.; Si, H.-R.; Zhu, Y.; Li, B.; Huang, C.-L.; Chen, H.-D.; Chen, J.; Luo, Y.; Guo, H.; Jiang, R.-D.; Liu, M.-Q.; Chen, Y.; Shen, X.-R.; Wang, X.; Zheng, X.-S. A Pneumonia Outbreak Associated with a New Coronavirus of Probable Bat Origin. Nature 2020, 579 (7798), 270– 273,  DOI: 10.1038/s41586-020-2012-7
      29
      A pneumonia outbreak associated with a new coronavirus of probable bat origin
      Zhou, Peng; Yang, Xing-Lou; Wang, Xian-Guang; Hu, Ben; Zhang, Lei; Zhang, Wei; Si, Hao-Rui; Zhu, Yan; Li, Bei; Huang, Chao-Lin; Chen, Hui-Dong; Chen, Jing; Luo, Yun; Guo, Hua; Jiang, Ren-Di; Liu, Mei-Qin; Chen, Ying; Shen, Xu-Rui; Wang, Xi; Zheng, Xiao-Shuang; Zhao, Kai; Chen, Quan-Jiao; Deng, Fei; Liu, Lin-Lin; Yan, Bing; Zhan, Fa-Xian; Wang, Yan-Yi; Xiao, Geng-Fu; Shi, Zheng-Li
      Nature (London, United Kingdom) (2020), 579 (7798), 270-273CODEN: NATUAS; ISSN:0028-0836. (Nature Research)
      Abstr.: Since the outbreak of severe acute respiratory syndrome (SARS) 18 years ago, a large no. of SARS-related coronaviruses (SARSr-CoVs) have been discovered in their natural reservoir host, bats1-4. Previous studies have shown that some bat SARSr-CoVs have the potential to infect humans5-7. Here we report the identification and characterization of a new coronavirus (2019-nCoV), which caused an epidemic of acute respiratory syndrome in humans in Wuhan, China. The epidemic, which started on 12 Dec. 2019, had caused 2,794 lab.-confirmed infections including 80 deaths by 26 Jan. 2020. Full-length genome sequences were obtained from five patients at an early stage of the outbreak. The sequences are almost identical and share 79.6% sequence identity to SARS-CoV. Furthermore, we show that 2019-nCoV is 96% identical at the whole-genome level to a bat coronavirus. Pairwise protein sequence anal. of seven conserved non-structural proteins domains show that this virus belongs to the species of SARSr-CoV. In addn., 2019-nCoV virus isolated from the bronchoalveolar lavage fluid of a critically ill patient could be neutralized by sera from several patients. Notably, we confirmed that 2019-nCoV uses the same cell entry receptor-angiotensin converting enzyme II (ACE2)-as SARS-CoV.
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    30. 30
      SARS-CoV-2 Molecular Assay Evaluation: Results. https://www.finddx.org/sarscov2-eval-molecular/molecular-eval-results/ (accessed 2020-08-01).
      There is no corresponding record for this reference.
    31. 31
      Deeks, J. J.; Dinnes, J.; Takwoingi, Y.; Davenport, C.; Leeflang, M. M. G.; Spijker, R.; Hooft, L.; Van den Bruel, A.; Emperador, D.; Dittrich, S. Diagnosis of SARS-CoV-2 Infection and COVID-19: Accuracy of Signs and Symptoms; Molecular, Antigen, and Antibody Tests; and Routine Laboratory Markers. Cochrane Database Syst. Rev. 2020, (4), 1– 14,  DOI: 10.1002/14651858.CD013596
      There is no corresponding record for this reference.
    32. 32
      Carter, L. J.; Garner, L. V.; Smoot, J. W.; Li, Y.; Zhou, Q.; Saveson, C. J.; Sasso, J. M.; Gregg, A. C.; Soares, D. J.; Beskid, T. R.; Jervey, S. R.; Liu, C. Assay Techniques and Test Development for COVID-19 Diagnosis. ACS Cent. Sci. 2020, 6 (5), 591– 605,  DOI: 10.1021/acscentsci.0c00501
      32
      Assay Techniques and Test Development for COVID-19 Diagnosis
      Carter, Linda J.; Garner, Linda V.; Smoot, Jeffrey W.; Li, Yingzhu; Zhou, Qiongqiong; Saveson, Catherine J.; Sasso, Janet M.; Gregg, Anne C.; Soares, Divya J.; Beskid, Tiffany R.; Jervey, Susan R.; Liu, Cynthia
      ACS Central Science (2020), 6 (5), 591-605CODEN: ACSCII; ISSN:2374-7951. (American Chemical Society)
      A review. A reviews. An ongoing theme of the COVID-19 pandemic is the need for widespread availability of accurate and efficient diagnostic testing for detection of SARS-CoV-2 and antiviral antibodies in infected individuals. This report describes various assay techniques and tests for COVID-19 diagnosis. Most tests for early detection of SARS-CoV-2 RNA rely on the reverse transcription-polymerase chain reaction, but isothermal nucleic acid amplification assays, including transcription-mediated amplification and CRISPR-based methodologies, are promising alternatives. Identification of individuals who have developed antibodies to the SARS-CoV-2 virus requires serol. tests, including ELISA (ELISA) and lateral flow immunoassay. This report also provides an overview of current development in COVID-19 diagnostic techniques and products to facilitate future improvement and innovation.
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    33. 33
      Dortet, L.; Emeraud, C.; Vauloup-Fellous, C.; Khecharem, M.; Ronat, J.-B.; Fortineau, N.; Roque-Afonso, A.-M.; Naas, T. Rapid Determination of SARS-CoV-2 Antibodies Using a Bedside, Point-of-Care, Serological Test. Emerging Microbes Infect. 2020, 9 (1), 2212– 2221,  DOI: 10.1080/22221751.2020.1826892
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      Rapid determination of SARS-CoV-2 antibodies using a bedside, point-of-care, serological test
      Dortet, Laurent; Emeraud, Cecile; Vauloup-Fellous, Christelle; Khecharem, Mouna; Ronat, Jean-Baptiste; Fortineau, Nicolas; Roque-Afonso, Anne-Marie; Naas, Thierry
      Emerging Microbes & Infections (2020), 9 (1), 2212-2221CODEN: EMIMC4; ISSN:2222-1751. (Taylor & Francis Ltd.)
      Background: Several serol. tests for SARS-CoV-2 have been developed or use, but most have only been validated on few samples, and none provide medical practitioners with an easy-to-use, self-contained, bedside test with high accuracy. Material and methods: Two-hundred fifty-six sera from 101 patients hospitalized with SARS-CoV-2 infection (pos. RT-PCR) and 50 control sera were tested for IgM/IgG using the NG-Test IgM-IgG COVID all-in-one assay. The seroconversion dynamic was assessed by symptom onset and day of RT-PCR diagnosis. Results: Among the SARS-CoV-2 infected patients, pos. IgG and/or IgM result was obsd. for 67.3% of patients (68/101), including 17 (16.8%) already pos. at the day of RT-PCR, and 51 (50.5%) with observable seroconversion, and 32.7% (33/101) remained neg. as subsequent sampling was not possible (patient discharge or death). The sensitivity increased with the delay between onset of symptoms and sampling, going from 29.1%, 78.2% and 86.5% for the time periods of 0-9-, 10-14- and >14-days after the onset of symptoms, resp. Cumulative sensitivity, specificity, Pos. Predictive Value and Neg. Predictive Value were 97.0%, 100%, 100% and 96.2%, resp. 15-days after the onset of symptoms. No difference in seroconversion delay was obsd. regardless of whether patients received ventilation. Conclusions: The NG-test is a bedside serol. assay that could serve as a complementary source of diagnostic information to RT-PCR and chest imaging. It may also be useful to monitor immunol. status of medical and non-medical workers during the ongoing pandemic, and the general population after social distancing measures have eased.
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    34. 34
      Mercer, T. R.; Salit, M. Testing at Scale during the COVID-19 Pandemic. Nat. Rev. Genet. 2021, 22, 415,  DOI: 10.1038/s41576-021-00360-w
      34
      Testing at scale during the COVID-19 pandemic
      Mercer, Tim R.; Salit, Marc
      Nature Reviews Genetics (2021), 22 (7), 415-426CODEN: NRGAAM; ISSN:1471-0056. (Nature Portfolio)
      Abstr.: Assembly and publication of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome in Jan. 2020 enabled the immediate development of tests to detect the new virus. This began the largest global testing program in history, in which hundreds of millions of individuals have been tested to date. The unprecedented scale of testing has driven innovation in the strategies, technologies and concepts that govern testing in public health. This Review describes the changing role of testing during the COVID-19 pandemic, including the use of genomic surveillance to track SARS-CoV-2 transmission around the world, the use of contact tracing to contain disease outbreaks and testing for the presence of the virus circulating in the environment. Despite these efforts, widespread community transmission has become entrenched in many countries and has required the testing of populations to identify and isolate infected individuals, many of whom are asymptomatic. The diagnostic and epidemiol. principles that underpin such population-scale testing are also considered, as are the high-throughput and point-of-care technologies that make testing feasible on a massive scale.
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    35. 35
      Parikh, R.; Mathai, A.; Parikh, S.; Chandra Sekhar, G.; Thomas, R. Understanding and Using Sensitivity, Specificity and Predictive Values. Indian J. Ophthalmol. 2008, 56 (1), 45,  DOI: 10.4103/0301-4738.37595
      35
      Understanding and using sensitivity, specificity and predictive values
      Parikh Rajul; Mathai Annie; Parikh Shefali; Chandra Sekhar G; Thomas Ravi
      Indian journal of ophthalmology (2008), 56 (1), 45-50 ISSN:0301-4738.
      In this article, we have discussed the basic knowledge to calculate sensitivity, specificity, positive predictive value and negative predictive value. We have discussed the advantage and limitations of these measures and have provided how we should use these measures in our day-to-day clinical practice. We also have illustrated how to calculate sensitivity and specificity while combining two tests and how to use these results for our patients in day-to-day practice.
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    36. 36
      Borysiak, M. D.; Thompson, M. J.; Posner, J. D. Translating Diagnostic Assays from the Laboratory to the Clinic: Analytical and Clinical Metrics for Device Development and Evaluation. Lab Chip 2016, 16 (8), 1293– 1313,  DOI: 10.1039/C6LC00015K
      36
      Translating diagnostic assays from the laboratory to the clinic: analytical and clinical metrics for device development and evaluation
      Borysiak, Mark D.; Thompson, Matthew J.; Posner, Jonathan D.
      Lab on a Chip (2016), 16 (8), 1293-1313CODEN: LCAHAM; ISSN:1473-0189. (Royal Society of Chemistry)
      As lab-on-a-chip health diagnostic technologies mature, there is a push to translate them from the lab. to the clinic. For these diagnostics to achieve max. impact on patient care, scientists and engineers developing the tests should understand the anal. and clin. statistical metrics that det. the efficacy of the test. Appreciating and using these metrics will benefit test developers by providing consistent measures to evaluate anal. and clin. test performance, as well as guide the design of tests that will most benefit clinicians and patients. This paper is broken into four sections that discuss metrics related to general stages of development including: (1) lab. assay development (anal. sensitivity, limit of detection, anal. selectivity, and trueness/precision), (2) pre-clin. development (diagnostic sensitivity, diagnostic specificity, clin. cutoffs, and receiver-operator curves), (3) clin. use (prevalence, predictive values, and likelihood ratios), and (4) case studies from existing clin. data for tests relevant to the lab-on-a-chip community (HIV, group A strep, and chlamydia). Each section contains definitions of recommended statistical measures, as well as examples demonstrating the importance of these metrics at various stages of the development process. Increasing the use of these metrics in lab-on-a-chip research will improve the rigor of diagnostic performance reporting and provide a better understanding of how to design tests that will ultimately meet clin. needs.
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    37. 37
      FIND. Foundation for Innovative New Diagnostics - Test Directory. https://www.finddx.org/test-directory/ (accessed 2021-05-05).
      There is no corresponding record for this reference.
    38. 38
      Land, K. J.; Boeras, D. I.; Chen, X.-S.; Ramsay, A. R.; Peeling, R. W. REASSURED Diagnostics to Inform Disease Control Strategies, Strengthen Health Systems and Improve Patient Outcomes. Nat. Microbiol. 2019, 4 (1), 46– 54,  DOI: 10.1038/s41564-018-0295-3
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      REASSURED diagnostics to inform disease control strategies, strengthen health systems and improve patient outcomes
      Land, Kevin J.; Boeras, Debrah I.; Chen, Xiang-Sheng; Ramsay, Andrew R.; Peeling, Rosanna W.
      Nature Microbiology (2019), 4 (1), 46-54CODEN: NMAICH; ISSN:2058-5276. (Nature Research)
      Lack of access to quality diagnostics remains a major contributor to health burden in resource-limited settings. It has been more than 10 years since ASSURED (affordable, sensitive, specific, user-friendly, rapid, equipment-free, delivered) was coined to describe the ideal test to meet the needs of the developing world. Since its initial publication, technol. innovations have led to the development of diagnostics that address the ASSURED criteria, but challenges remain. From this perspective, we assess factors contributing to the success and failure of ASSURED diagnostics, lessons learnt in the implementation of ASSURED tests over the past decade, and highlight addnl. conditions that should be considered in addressing point-of-care needs. With rapid advances in digital technol. and mobile health (m-health), future diagnostics should incorporate these elements to give us REASSURED diagnostic systems that can inform disease control strategies in real-time, strengthen the efficiency of health care systems and improve patient outcomes.
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    39. 39
      Nam, J.-M. Nanoparticle-Based Bio-Bar Codes for the Ultrasensitive Detection of Proteins. Science 2003, 301 (5641), 1884– 1886,  DOI: 10.1126/science.1088755
      39
      Nanoparticle-based bio-bar codes for the ultrasensitive detection of proteins
      Nam, Jwa-Min; Thaxton, C. Shad; Mirkin, Chad A.
      Science (Washington, DC, United States) (2003), 301 (5641), 1884-1886CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
      An ultrasensitive method for detecting protein analytes has been developed. The system relies on magnetic microparticle probes with antibodies that specifically bind a target of interest [prostate-specific antigen (PSA) in this case] and nanoparticle probes that are encoded with DNA that is unique to the protein target of interest and antibodies that can sandwich the target captured by the microparticle probes. Magnetic sepn. of the complexed probes and target followed by dehybridization of the oligonucleotides on the nanoparticle probe surface allows the detn. of the presence of the target protein by identifying the oligonucleotide sequence released from the nanoparticle probe. Because the nanoparticle probe carries with it a large no. of oligonucleotides per protein binding event, there is substantial amplification and PSA can be detected at 30 attomolar concn. Alternatively, a polymerase chain reaction on the oligonucleotide bar codes can boost the sensitivity to 3 attomolar. Comparable clin. accepted conventional assays for detecting the same target have sensitivity limits of ∼3 picomdar, six orders of magnitude less sensitive than what is obsd. with this method.
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    40. 40
      Walt, D. R. CHEMISTRY: Miniature Analytical Methods for Medical Diagnostics. Science 2005, 308 (5719), 217– 219,  DOI: 10.1126/science.1108161
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      Chemistry: Miniature analytical methods for medical diagnostics
      Walt, David R.
      Science (Washington, DC, United States) (2005), 308 (5719), 217-219CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
      A review.
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    41. 41
      Pérez-López, B.; Merkoçi, A. Nanomaterials Based Biosensors for Food Analysis Applications. Trends Food Sci. Technol. 2011, 22 (11), 625– 639,  DOI: 10.1016/j.tifs.2011.04.001
      41
      Nanomaterials based biosensors for food analysis applications
      Perez-Lopez, Briza; Merkoci, Arben
      Trends in Food Science & Technology (2011), 22 (11), 625-639CODEN: TFTEEH; ISSN:0924-2244. (Elsevier Ltd.)
      A review. The development of novel sensors and biosensors with interest for food industry is one of the key fields for the nowadays nanobiotechnol. and nanomaterial science. The functionalized nanomaterials are used as catalytic tools, immobilization platforms or as optical or electroactive labels to improve the bio-sensing performance exhibiting higher sensitivity, stability, and selectivity. Nanomaterials, such as carbon nanotubes, metal nanoparticles, nanowires, nanocomposite and nanostructured materials are playing an increasing role in the design of sensing and biosensing systems with interest for applications in food anal. Furthermore, these nanobiosystems are also bringing advantages in terms of the design of novel food detection strategies.
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    42. 42
      Weiss, C.; Carriere, M.; Fusco, L.; Capua, I.; Regla-Nava, J. A.; Pasquali, M.; Scott, J. A.; Vitale, F.; Unal, M. A.; Mattevi, C.; Bedognetti, D.; Merkoçi, A.; Tasciotti, E.; Yilmazer, A.; Gogotsi, Yu; Stellacci, F.; Delogu, L. G. Toward Nanotechnology-Enabled Approaches against the COVID-19 Pandemic. ACS Nano 2020, 14 (6), 6383– 6406,  DOI: 10.1021/acsnano.0c03697
      42
      Toward Nanotechnology-Enabled Approaches against the COVID-19 Pandemic
      Weiss, Carsten; Carriere, Marie; Fusco, Laura; Capua, Ilaria; Regla-Nava, Jose Angel; Pasquali, Matteo; Scott, James A.; Vitale, Flavia; Unal, Mehmet Altay; Mattevi, Cecilia; Bedognetti, Davide; Merkoci, Arben; Tasciotti, Ennio; Yilmazer, Acelya; Gogotsi, Yury; Stellacci, Francesco; Delogu, Lucia Gemma
      ACS Nano (2020), 14 (6), 6383-6406CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
      A review. The COVID-19 outbreak has fueled a global demand for effective diagnosis and treatment as well as mitigation of the spread of infection, all through large-scale approaches such as specific alternative antiviral methods and classical disinfection protocols. Based on an abundance of engineered materials identifiable by their useful physicochem. properties through versatile chem. functionalization, nanotechnol. offers a no. of approaches to cope with this emergency. Here, through a multidisciplinary Perspective encompassing diverse fields such as virol., biol., medicine, engineering, chem., materials science, and computational science, we outline how nanotechnol.-based strategies can support the fight against COVID-19, as well as infectious diseases in general, including future pandemics. Considering what we know so far about the life cycle of the virus, we envision key steps where nanotechnol. could counter the disease. First, nanoparticles (NPs) can offer alternative methods to classical disinfection protocols used in healthcare settings, thanks to their intrinsic antipathogenic properties and(or) their ability to inactivate viruses, bacteria, fungi, or yeasts either photothermally or via photocatalysis-induced reactive oxygen species (ROS) generation. Nanotechnol. tools to inactivate SARS-CoV-2 in patients could also be explored. In this case, nanomaterials could be used to deliver drugs to the pulmonary system to inhibit interaction between angiotensin-converting enzyme 2 (ACE2) receptors and viral S protein. Moreover, the concept of nanoimmunity by design can help us to design materials for immune modulation, either stimulating or suppressing the immune response, which would find applications in the context of vaccine development for SARS-CoV-2 or in counteracting the cytokine storm, resp. In addn. to disease prevention and therapeutic potential, nanotechnol. has important roles in diagnostics, with potential to support the development of simple, fast, and cost-effective nanotechnol.-based assays to monitor the presence of SARS-CoV-2 and related biomarkers. In summary, nanotechnol. is crit. in counteracting COVID-19 and will be vital when prepg. for future pandemics.
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    43. 43
      Parolo, C.; Sena-Torralba, A.; Bergua, J. F.; Calucho, E.; Fuentes-Chust, C.; Hu, L.; Rivas, L.; Álvarez-Diduk, R.; Nguyen, E. P.; Cinti, S.; Quesada-González, D.; Merkoçi, A. Tutorial: Design and Fabrication of Nanoparticle-Based Lateral-Flow Immunoassays. Nat. Protoc. 2020, 15 (12), 3788– 3816,  DOI: 10.1038/s41596-020-0357-x
      43
      Tutorial: design and fabrication of nanoparticle-based lateral-flow immunoassays
      Parolo, Claudio; Sena-Torralba, Amadeo; Bergua, Jose Francisco; Calucho, Enric; Fuentes-Chust, Celia; Hu, Liming; Rivas, Lourdes; Alvarez-Diduk, Ruslan; Nguyen, Emily P.; Cinti, Stefano; Quesada-Gonzalez, Daniel; Merkoci, Arben
      Nature Protocols (2020), 15 (12), 3788-3816CODEN: NPARDW; ISSN:1750-2799. (Nature Research)
      A review. Lateral-flow assays (LFAs) are quick, simple and cheap assays to analyze various samples at the point of care or in the field, making them one of the most widespread biosensors currently available. They have been successfully employed for the detection of a myriad of different targets (ranging from atoms up to whole cells) in all type of samples (including water, blood, foodstuff and environmental samples). Their operation relies on the capillary flow of the sample throughout a series of sequential pads, each with different functionalities aiming to generate a signal to indicate the absence/presence (and, in some cases, the concn.) of the analyte of interest. To have a user-friendly operation, their development requires the optimization of multiple, interconnected parameters that may overwhelm new developers. In this tutorial, we provide the readers with: (i) the basic knowledge to understand the principles governing an LFA and to take informed decisions during lateral flow strip design and fabrication, (ii) a roadmap for optimal LFA development independent of the specific application, (iii) a step-by-step example procedure for the assembly and operation of an LF strip for the detection of human IgG and (iv) an extensive troubleshooting section addressing the most frequent issues in designing, assembling and using LFAs. By changing only the receptors, the provided example procedure can easily be adapted for cost-efficient detection of a broad variety of targets.
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    44. 44
      Kurbanoglu, S.; Ozkan, S. A.; Merkoçi, A. Nanomaterials-Based Enzyme Electrochemical Biosensors Operating through Inhibition for Biosensing Applications. Biosens. Bioelectron. 2017, 89, 886– 898,  DOI: 10.1016/j.bios.2016.09.102
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      Nanomaterials-based enzyme electrochemical biosensors operating through inhibition for biosensing applications
      Kurbanoglu, Sevinc; Ozkan, Sibel A.; Merkoci, Arben
      Biosensors & Bioelectronics (2017), 89 (Part_2), 886-898CODEN: BBIOE4; ISSN:0956-5663. (Elsevier B.V.)
      In recent years great progress has been made in applying nanomaterials to design novel biosensors. Use of nanomaterials offers to biosensing platforms exceptional optical, electronic and magnetic properties. Nanomaterials can increase the surface of the transducing area of the sensors that in turn bring an increase in catalytic behaviors. They have large surface-to-vol. ratio, controlled morphol. and structure that also favor miniaturization, an interesting advantage when the sample vol. is a crit. issue. Biosensors have great potential for achieving detect-to-protect devices: devices that can be used in detections of pollutants and other treating compds./analytes (drugs) protecting citizens' life. After a long term focused scientific and financial efforts/supports biosensors are expected now to fulfill their promise such as being able to perform sampling and anal. of complex samples with interest for clin. or environment fields. Among all types of biosensors, enzymic biosensors, the most explored biosensing devices, have an interesting property, the inherent inhibition phenomena given the enzyme-substrate complex formation. The exploration of such phenomena is making remarkably important their application as research and applied tools in diagnostics. Different inhibition biosensor systems based on nanomaterials modification has been proposed and applied. The role of nanomaterials in inhibition-based biosensors for the analyses of different groups of drugs as well as contaminants such as pesticides, phenolic compds. and others, are discussed in this review. This deep anal. of inhibition-based biosensors that employ nanomaterials will serve researchers as a guideline for further improvements and approaching of these devices to real sample applications so as to reach society needs and such biosensor market demands.
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    45. 45
      Morales-Narváez, E.; Merkoçi, A. Graphene Oxide as an Optical Biosensing Platform. Adv. Mater. 2012, 24 (25), 3298– 3308,  DOI: 10.1002/adma.201200373
      45
      Graphene Oxide as an Optical Biosensing Platform
      Morales-Narvaez, Eden; Merkoci, Arben
      Advanced Materials (Weinheim, Germany) (2012), 24 (25), 3298-3308CODEN: ADVMEW; ISSN:0935-9648. (Wiley-VCH Verlag GmbH & Co. KGaA)
      A review. Since graphene exhibits innovative mech., elec., thermal, and optical properties, this 2D material is increasingly attracting attention and is under active research. Among the various graphene forms with lattice-like nanostructure, graphene oxide (GO) displays advantageous characteristics as a biosensing platform due to its excellent capabilities for direct wiring with biomols., a heterogeneous chem. and electronic structure, the possibility to be processed in soln. and the ability to be tuned as insulator, semiconductor or semi-metal. Moreover, GO photoluminescences with energy transfer donor/acceptor mols. exposed in a planar surface and is even proposed as a universal highly efficient long-range quencher, which is opening the way to several unprecedented biosensing strategies. Here, the rationale behind the use of GO in optical biosensing applications is discussed by describing different potentially exploitable properties of GO, and an overview of the current approaches are presented along with future perspectives and challenges.
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    46. 46
      Mokhtarzadeh, A.; Eivazzadeh-Keihan, R.; Pashazadeh, P.; Hejazi, M.; Gharaatifar, N.; Hasanzadeh, M.; Baradaran, B.; de la Guardia, M. Nanomaterial-Based Biosensors for Detection of Pathogenic Virus. TrAC, Trends Anal. Chem. 2017, 97, 445– 457,  DOI: 10.1016/j.trac.2017.10.005
      46
      Nanomaterial-based biosensors for detection of pathogenic virus
      Mokhtarzadeh, Ahad; Eivazzadeh-Keihan, Reza; Pashazadeh, Paria; Hejazi, Maryam; Gharaatifar, Nasrin; Hasanzadeh, Mohammad; Baradaran, Behzad; de la Guardia, Miguel
      TrAC, Trends in Analytical Chemistry (2017), 97 (), 445-457CODEN: TTAEDJ; ISSN:0165-9936. (Elsevier B.V.)
      Viruses are real menace to human safety that cause devastating viral disease. The high prevalence of these diseases is due to improper detecting tools. Therefore, there is a remarkable demand to identify viruses in a fast, selective and accurate way. Several biosensors have been designed and commercialized for detection of pathogenic viruses. However, they present many challenges. Nanotechnol. overcomes these challenges and performs direct detection of mol. targets in real time. In this overview, studies concerning nanotechnol.-based biosensors for pathogenic virus detection have been summarized, paying special attention to biosensors based on graphene oxide, silica, carbon nanotubes, gold, silver, zinc oxide and magnetic nanoparticles, which could pave the way to detect viral diseases and provide healthy life for infected patients.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhslagtbnE&md5=37de1c8ce7bc63421d640769e8676faf
    47. 47
      Morales-Narváez, E.; Baptista-Pires, L.; Zamora-Gálvez, A.; Merkoçi, A. Graphene-Based Biosensors: Going Simple. Adv. Mater. 2017, 29, 1604905,  DOI: 10.1002/adma.201604905
      There is no corresponding record for this reference.
    48. 48
      Nguyen, E. P.; de Carvalho Castro Silva, C.; Merkoçi, A. Recent Advancement in Biomedical Applications on the Surface of Two-Dimensional Materials: From Biosensing to Tissue Engineering. Nanoscale 2020, 12 (37), 19043– 19067,  DOI: 10.1039/D0NR05287F
      48
      Recent advancement in biomedical applications on the surface of two-dimensional materials: from biosensing to tissue engineering
      Nguyen, Emily P.; de Carvalho Castro Silva, Cecilia; Merkoci, Arben
      Nanoscale (2020), 12 (37), 19043-19067CODEN: NANOHL; ISSN:2040-3372. (Royal Society of Chemistry)
      A review. As biosensors and biomedical devices have become increasingly important to everyday diagnostics and monitoring, there are tremendous, and const. efforts towards developing and improving the reliability and versatility of such technol. As they offer high surface area-to-vol. ratios and a diverse range of properties, from electronic to optical, two dimensional (2D) materials have proven to be very promising candidates for biol. applications and technologies. Due to the dimensionality, 2D materials facilitate many interfacial phenomena that have shown to significantly improve the performance of biosensors, while recent advances in synthesis techniques and surface engineering methods also enable the realization of future biomedical devices. This short review aims to highlight the influence of 2D material surfaces and the properties that arise due to their 2D structure. Using recent (within the last few years) examples of biosensors and biomedical applications, we emphasize the important role of 2D materials in advancing developments and research for biosensing and healthcare.
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    49. 49
      Nakatsuka, N.; Yang, K.-A.; Abendroth, J. M.; Cheung, K. M.; Xu, X.; Yang, H.; Zhao, C.; Zhu, B.; Rim, Y. S.; Yang, Y.; Weiss, P. S.; Stojanovic, M. N.; Andrews, A. M. Aptamer-Field-Effect Transistors Overcome Debye Length Limitations for Small-Molecule Sensing. Science 2018, 362 (6412), 319– 324,  DOI: 10.1126/science.aao6750
      49
      Aptamer-field-effect transistors overcome Debye length limitations for small-molecule sensing
      Nakatsuka, Nako; Yang, Kyung-Ae; Abendroth, John M.; Cheung, Kevin M.; Xu, Xiaobin; Yang, Hongyan; Zhao, Chuanzhen; Zhu, Bowen; Rim, You Seung; Yang, Yang; Weiss, Paul S.; Stojanovic, Milan N.; Andrews, Anne M.
      Science (Washington, DC, United States) (2018), 362 (6412), 319-324CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
      Detection of analytes by means of field-effect transistors bearing ligand-specific receptors is fundamentally limited by the shielding created by the elec. double layer (the "Debye length" limitation). We detected small mols. under physiol. high-ionic strength conditions by modifying printed ultrathin metal-oxide field-effect transistor arrays with deoxyribonucleotide aptamers selected to bind their targets adaptively. Target-induced conformational changes of neg. charged aptamer phosphodiester backbones in close proximity to semiconductor channels gated conductance in physiol. buffers, resulting in highly sensitive detection. Sensing of charged and electroneutral targets (serotonin, dopamine, glucose, and sphingosine-1-phosphate) was enabled by specifically isolated aptameric stem-loop receptors.
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    50. 50
      Roche, E. T. A Protein Sandwich Enables Real-Time in Vivo Biomarker Measurement. Sci. Transl. Med. 2021, 13 (575), eabg1758  DOI: 10.1126/scitranslmed.abg1758
      There is no corresponding record for this reference.
    51. 51
      Idili, A.; Parolo, C.; Alvarez-Diduk, R.; Merkoçi, A. Rapid and Efficient Detection of the SARS-CoV-2 Spike Protein Using an Electrochemical Aptamer-Based Sensor. ACS Sensors 2021, 6 (8), 3093– 3101,  DOI: 10.1021/acssensors.1c01222
      51
      Rapid and Efficient Detection of the SARS-CoV-2 Spike Protein Using an Electrochemical Aptamer-Based Sensor
      Idili, Andrea; Parolo, Claudio; Alvarez-Diduk, Ruslan; Merkoci, Arben
      ACS Sensors (2021), 6 (8), 3093-3101CODEN: ASCEFJ; ISSN:2379-3694. (American Chemical Society)
      The availability of sensors able to rapidly detect SARS-CoV-2 directly in biol. fluids in a single step would allow performing massive diagnostic testing to track in real time and contain the spread of COVID-19. Motivated by this, here, we developed an electrochem. aptamer-based (EAB) sensor able to achieve the rapid, reagentless, and quant. measurement of the SARS-CoV-2 spike (S) protein. First, we demonstrated the ability of the selected aptamer to undergo a binding-induced conformational change in the presence of its target using fluorescence spectroscopy. Then, we engineered the aptamer to work as a bioreceptor in the EAB platform and we demonstrated its sensitivity and specificity. Finally, to demonstrate the clin. potential of the sensor, we tested it directly in biol. fluids (serum and artificial saliva), achieving the rapid (minutes) and single-step detection of the S protein in its clin. range.
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    52. 52
      Alafeef, M.; Dighe, K.; Moitra, P.; Pan, D. Rapid, Ultrasensitive, and Quantitative Detection of SARS-CoV-2 Using Antisense Oligonucleotides Directed Electrochemical Biosensor Chip. ACS Nano 2020, 14 (12), 17028– 17045,  DOI: 10.1021/acsnano.0c06392
      52
      Rapid, Ultrasensitive, and Quantitative Detection of SARS-CoV-2 Using Antisense Oligonucleotides Directed Electrochemical Biosensor Chip
      Alafeef, Maha; Dighe, Ketan; Moitra, Parikshit; Pan, Dipanjan
      ACS Nano (2020), 14 (12), 17028-17045CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
      A large-scale diagnosis of the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) is essential to downregulate its spread within as well as across communities and mitigate the current outbreak of the pandemic novel coronavirus disease 2019 (COVID-19). Herein, we report the development of a rapid (<5 min), low-cost, easy-to-implement, and quant. paper-based electrochem. sensor chip to enable the digital detection of SARS-CoV-2 genetic material. The biosensor uses gold nanoparticles (AuNPs), capped with highly specific antisense oligonucleotides (ssDNA) targeting viral nucleocapsid phosphoprotein (N-gene). The sensing probes are immobilized on a paper-based electrochem. platform to yield a nucleic-acid-testing device with a readout that can be recorded with a simple hand-held reader. The biosensor chip has been tested using samples collected from Vero cells infected with SARS-CoV-2 virus and clin. samples. The sensor provides a significant improvement in output signal only in the presence of its target-SARS-CoV-2 RNA-within <5 min of incubation time, with a sensitivity of 231 copies/μL and limit of detection of 6.9 copies/μL without the need for any further amplification. The sensor chip performance has been tested using clin. samples from 22 COVID-19 pos. patients and 26 healthy asymptomatic subjects confirmed using the FDA-approved RT-PCR COVID-19 diagnostic kit. The sensor successfully distinguishes the pos. COVID-19 samples from the neg. ones with almost 100% accuracy, sensitivity, and specificity and exhibits an insignificant change in output signal for the samples lacking a SARS-CoV-2 viral target segment (e.g., SARS-CoV, MERS-CoV, or neg. COVID-19 samples collected from healthy subjects). The feasibility of the sensor even during the genomic mutation of the virus is also ensured from the design of the ssDNA-conjugated AuNPs that simultaneously target 2 sep. regions of the same SARS-CoV-2 N-gene.
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    53. 53
      Baker, A. N.; Richards, S.-J.; Guy, C. S.; Congdon, T. R.; Hasan, M.; Zwetsloot, A. J.; Gallo, A.; Lewandowski, J. R.; Stansfeld, P. J.; Straube, A.; Walker, M.; Chessa, S.; Pergolizzi, G.; Dedola, S.; Field, R. A.; Gibson, M. I. The SARS-COV-2 Spike Protein Binds Sialic Acids and Enables Rapid Detection in a Lateral Flow Point of Care Diagnostic Device. ACS Cent. Sci. 2020, 6 (11), 2046– 2052,  DOI: 10.1021/acscentsci.0c00855
      53
      The SARS-COV-2 Spike Protein Binds Sialic Acids and Enables Rapid Detection in a Lateral Flow Point of Care Diagnostic Device
      Baker, Alexander N.; Richards, Sarah-Jane; Guy, Collette S.; Congdon, Thomas R.; Hasan, Muhammad; Zwetsloot, Alexander J.; Gallo, Angelo; Lewandowski, Jozef R.; Stansfeld, Phillip J.; Straube, Anne; Walker, Marc; Chessa, Simona; Pergolizzi, Giulia; Dedola, Simone; Field, Robert A.; Gibson, Matthew I.
      ACS Central Science (2020), 6 (11), 2046-2052CODEN: ACSCII; ISSN:2374-7951. (American Chemical Society)
      There is an urgent need to understand the behavior of the novel coronavirus (SARS-COV-2), which is the causative agent of COVID-19, and to develop point-of-care diagnostics. Here, a glyconanoparticle platform is used to discover that N-acetyl neuraminic acid has affinity toward the SARS-COV-2 spike glycoprotein, demonstrating its glycan-binding function. Optimization of the particle size and coating enabled detection of the spike glycoprotein in lateral flow and showed selectivity over the SARS-COV-1 spike protein. Using a virus-like particle and a pseudotyped lentivirus model, paper-based lateral flow detection was demonstrated in under 30 min, showing the potential of this system as a low-cost detection platform. The spike-protein from SARS-COV-2 is shown to bind sialic acids, which is exploited to assemble a lateral flow diagnostic tool, using glycans rather than antibodies, as the recognition unit.
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    54. 54
      Lin, Q.; Wen, D.; Wu, J.; Liu, L.; Wu, W.; Fang, X.; Kong, J. Microfluidic Immunoassays for Sensitive and Simultaneous Detection of IgG/IgM/Antigen of SARS-CoV-2 within 15 min. Anal. Chem. 2020, 92 (14), 9454– 9458,  DOI: 10.1021/acs.analchem.0c01635
      54
      Microfluidic Immunoassays for Sensitive and Simultaneous Detection of IgG/IgM/Antigen of SARS-CoV-2 within 15 min
      Lin, Qiuyuan; Wen, Donghua; Wu, Jing; Liu, Liling; Wu, Wenjuan; Fang, Xueen; Kong, Jilie
      Analytical Chemistry (Washington, DC, United States) (2020), 92 (14), 9454-9458CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
      The outbreak of SARS-CoV-2 is posing serious global public health problems. Facing the emergence of this pandemic, we established a portable microfluidic immunoassay system for easy-to-use, sensitive, rapid (<15 min), multiple, and on-site detection of IgG/IgM/Antigen of SARS-CoV-2 simultaneously. This integrated method was successfully applied for detecting SARS-CoV-2 IgM and IgG antibodies in clin. human serum as well as SARS-CoV-2 antigen in pharyngeal swabs from 26 patients with COVID-19 infection and 28 uninfected people. The assay demonstrated high sensitivity and specificity, which is promising for the diagnosis and monitoring as well as control of SARS-CoV-2 worldwide.
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    55. 55
      Mavrikou, S.; Moschopoulou, G.; Tsekouras, V.; Kintzios, S. Development of a Portable, Ultra-Rapid and Ultra-Sensitive Cell-Based Biosensor for the Direct Detection of the SARS-CoV-2 S1 Spike Protein Antigen. Sensors 2020, 20 (11), 3121,  DOI: 10.3390/s20113121
      55
      Development of a portable, ultra-rapid and ultra-sensitive cell-based biosensor for the direct detection of the SARS-CoV-2 S1 spike protein antigen
      Mavrikou, Sophie; Moschopoulou, Georgia; Tsekouras, Vasileios; Kintzios, Spyridon
      Sensors (2020), 20 (11), 3121CODEN: SENSC9; ISSN:1424-8220. (MDPI AG)
      One of the key challenges of the recent COVID-19 pandemic is the ability to accurately est. the no. of infected individuals, particularly asymptomatic and/or early-stage patients. We herewith report the proof-of-concept development of a biosensor able to detect the SARS-CoV-2 S1 spike protein expressed on the surface of the virus. The biosensor is based on membrane-engineered mammalian cells bearing the human chimeric spike S1 antibody. We demonstrate that the attachment of the protein to the membrane-bound antibodies resulted in a selective and considerable change in the cellular bioelec. properties measured by means of a Bioelec. Recognition Assay. The novel biosensor provided results in an ultra-rapid manner (3 min), with a detection limit of 1 fg/mL and a semi-linear range of response between 10 fg and 1μg/mL. In addn., no cross-reactivity was obsd. against the SARS-CoV-2 nucleocapsid protein. Furthermore, the biosensor was configured as a ready-to-use platform, including a portable read-out device operated via smartphone/tablet. In this way, we demonstrate that the novel biosensor can be potentially applied for the mass screening of SARS-CoV-2 surface antigens without prior sample processing, therefore offering a possible soln. for the timely monitoring and eventual control of the global coronavirus pandemic.
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    56. 56
      Moitra, P.; Alafeef, M.; Dighe, K.; Frieman, M. B.; Pan, D. Selective Naked-Eye Detection of SARS-CoV-2 Mediated by N Gene Targeted Antisense Oligonucleotide Capped Plasmonic Nanoparticles. ACS Nano 2020, 14 (6), 7617– 7627,  DOI: 10.1021/acsnano.0c03822
      56
      Selective Naked-Eye Detection of SARS-CoV-2 Mediated by N Gene Targeted Antisense Oligonucleotide Capped Plasmonic Nanoparticles
      Moitra, Parikshit; Alafeef, Maha; Dighe, Ketan; Frieman, Matthew B.; Pan, Dipanjan
      ACS Nano (2020), 14 (6), 7617-7627CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
      The current outbreak of the pandemic coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) demands its rapid, convenient, and large-scale diagnosis to downregulate its spread within as well as across the communities. But the reliability, reproducibility, and selectivity of majority of such diagnostic tests fail when they are tested either to a viral load at its early representation or to a viral gene mutated during its current spread. In this regard, a selective "naked-eye" detection of SARS-CoV-2 is highly desirable, which can be tested without accessing any advanced instrumental techniques. We herein report the development of a colorimetric assay based on gold nanoparticles (AuNPs), when capped with suitably designed thiol-modified antisense oligonucleotides (ASOs) specific for N-gene (nucleocapsid phosphoprotein) of SARS-CoV-2, could be used for diagnosing pos. COVID-19 cases within 10 min from the isolated RNA samples. The thiol-modified ASO-capped AuNPs agglomerate selectively in the presence of its target RNA sequence of SARS-CoV-2 and demonstrate a change in its surface plasmon resonance. Further, the addn. of RNaseH cleaves the RNA strand from the RNA-DNA hybrid leading to a visually detectable ppt. from the soln. mediated by the addnl. agglomeration among the AuNPs. The selectivity of the assay has been monitored in the presence of MERS-CoV viral RNA with a limit of detection of 0.18 ng/μL of RNA having SARS-CoV-2 viral load. Thus, the current study reports a selective and visual "naked-eye" detection of COVID-19 causative virus, SARS-CoV-2, without the requirement of any sophisticated instrumental techniques.
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    57. 57
      Qiu, G.; Gai, Z.; Tao, Y.; Schmitt, J.; Kullak-Ublick, G. A.; Wang, J. Dual-Functional Plasmonic Photothermal Biosensors for Highly Accurate Severe Acute Respiratory Syndrome Coronavirus 2 Detection. ACS Nano 2020, 14 (5), 5268– 5277,  DOI: 10.1021/acsnano.0c02439
      57
      Dual-Functional Plasmonic Photothermal Biosensors for Highly Accurate Severe Acute Respiratory Syndrome Coronavirus 2 Detection
      Qiu, Guangyu; Gai, Zhibo; Tao, Yile; Schmitt, Jean; Kullak-Ublick, Gerd A.; Wang, Jing
      ACS Nano (2020), 14 (5), 5268-5277CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
      The ongoing outbreak of the novel coronavirus disease (COVID-19) has spread globally and poses a threat to public health in more than 200 countries. Reliable lab. diagnosis of the disease has been one of the foremost priorities for promoting public health interventions. The routinely used reverse transcription polymerase chain reaction (RT-PCR) is currently the ref. method for COVID-19 diagnosis. However, it also reported a no. of false-pos. or -neg. cases, esp. in the early stages of the novel virus outbreak. In this work, a dual-functional plasmonic biosensor combining the plasmonic photothermal (PPT) effect and localized surface plasmon resonance (LSPR) sensing transduction provides an alternative and promising soln. for the clin. COVID-19 diagnosis. The two-dimensional gold nanoislands (AuNIs) functionalized with complementary DNA receptors can perform a sensitive detection of the selected sequences from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) through nucleic acid hybridization. For better sensing performance, the thermoplasmonic heat is generated on the same AuNIs chip when illuminated at their plasmonic resonance frequency. The localized PPT heat is capable to elevate the in situ hybridization temp. and facilitate the accurate discrimination of two similar gene sequences. Our dual-functional LSPR biosensor exhibits a high sensitivity toward the selected SARS-CoV-2 sequences with a lower detection limit down to the concn. of 0.22 pM and allows precise detection of the specific target in a multigene mixt. This study gains insight into the thermoplasmonic enhancement and its applicability in the nucleic acid tests and viral disease diagnosis.
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    58. 58
      Seo, G.; Lee, G.; Kim, M. J.; Baek, S.-H.; Choi, M.; Ku, K. B.; Lee, C.-S.; Jun, S.; Park, D.; Kim, H. G.; Kim, S.-J.; Lee, J.-O.; Kim, B. T.; Park, E. C.; Kim, S. I. Rapid Detection of COVID-19 Causative Virus (SARS-CoV-2) in Human Nasopharyngeal Swab Specimens Using Field-Effect Transistor-Based Biosensor. ACS Nano 2020, 14 (4), 5135– 5142,  DOI: 10.1021/acsnano.0c02823
      58
      Rapid Detection of COVID-19 Causative Virus (SARS-CoV-2) in Human Nasopharyngeal Swab Specimens Using Field-Effect Transistor-Based Biosensor
      Seo, Giwan; Lee, Geonhee; Kim, Mi Jeong; Baek, Seung-Hwa; Choi, Minsuk; Ku, Keun Bon; Lee, Chang-Seop; Jun, Sangmi; Park, Daeui; Kim, Hong Gi; Kim, Seong-Jun; Lee, Jeong-O.; Kim, Bum Tae; Park, Edmond Changkyun; Kim, Seung Il
      ACS Nano (2020), 14 (4), 5135-5142CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
      Coronavirus disease 2019 (COVID-19) is a newly emerging human infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, previously called 2019-nCoV). Based on the rapid increase in the rate of human infection, the World Health Organization (WHO) has classified the COVID-19 outbreak as a pandemic. Because no specific drugs or vaccines for COVID-19 are yet available, early diagnosis and management are crucial for contg. the outbreak. Here, we report a field-effect transistor (FET)-based biosensing device for detecting SARS-CoV-2 in clin. samples. The sensor was produced by coating graphene sheets of the FET with a specific antibody against SARS-CoV-2 spike protein. The performance of the sensor was detd. using antigen protein, cultured virus, and nasopharyngeal swab specimens from COVID-19 patients. Our FET device could detect the SARS-CoV-2 spike protein at concns. of 1 fg/mL in phosphate-buffered saline and 100 fg/mL clin. transport medium. In addn., the FET sensor successfully detected SARS-CoV-2 in culture medium (limit of detection [LOD]: 1.6 x 101 pfu/mL) and clin. samples (LOD: 2.42 x 102 copies/mL). Thus, we have successfully fabricated a promising FET biosensor for SARS-CoV-2; our device is a highly sensitive immunol. diagnostic method for COVID-19 that requires no sample pretreatment or labeling.
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    59. 59
      Shao, W.; Shurin, M. R.; Wheeler, S. E.; He, X.; Star, A. Rapid Detection of SARS-CoV-2 Antigens Using High-Purity Semiconducting Single-Walled Carbon Nanotube-Based Field-Effect Transistors. ACS Appl. Mater. Interfaces 2021, 13 (8), 10321– 10327,  DOI: 10.1021/acsami.0c22589
      59
      Rapid detection of SARS-CoV-2 antigens using high-purity semiconducting single-walled carbon nanotube-based field-effect transistors
      Shao, Wenting; Shurin, Michael R.; Wheeler, Sarah E.; He, Xiaoyun; Star, Alexander
      ACS Applied Materials & Interfaces (2021), 13 (8), 10321-10327CODEN: AAMICK; ISSN:1944-8244. (American Chemical Society)
      Early diagnosis of SARS-CoV-2 infection is crit. for facilitating proper containment procedures, and a rapid, sensitive antigen assay is a crit. step in curbing the pandemic. In this work, we report the use of a high-purity semiconducting (s.c.) single-walled carbon nanotube (SWCNT)-based field-effect transistor (FET) decorated with specific binding chem. to assess the presence of SARS-CoV-2 antigens in clin. nasopharyngeal samples. Our SWCNT FET sensors, with functionalization of the anti-SARS-CoV-2 spike protein antibody (SAb) and anti-nucleocapsid protein antibody, detected the S antigen (SAg) and N antigen (NAg), reaching a limit of detection of 0.55 fg/mL for SAg and 0.016 fg/mL for NAg in calibration samples. SAb-functionalized FET sensors also exhibited good sensing performance in discriminating pos. and neg. clin. samples, indicating a proof of principle for use as a rapid COVID-19 antigen diagnostic tool with high anal. sensitivity and specificity at low cost.
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    60. 60
      Torrente-Rodríguez, R. M.; Lukas, H.; Tu, J.; Min, J.; Yang, Y.; Xu, C.; Rossiter, H. B.; Gao, W. SARS-CoV-2 RapidPlex: A Graphene-Based Multiplexed Telemedicine Platform for Rapid and Low-Cost COVID-19 Diagnosis and Monitoring. Matter 2020, 3 (6), 1981– 1998,  DOI: 10.1016/j.matt.2020.09.027
      60
      SARS-CoV-2 RapidPlex: A Graphene-Based Multiplexed Telemedicine Platform for Rapid and Low-Cost COVID-19 Diagnosis and Monitoring
      Torrente-Rodriguez Rebeca M; Lukas Heather; Tu Jiaobing; Min Jihong; Yang Yiran; Xu Changhao; Gao Wei; Rossiter Harry B
      Matter (2020), 3 (6), 1981-1998 ISSN:.
      The COVID-19 pandemic is an ongoing global challenge for public health systems. Ultrasensitive and early identification of infection is critical in preventing widespread COVID-19 infection by presymptomatic and asymptomatic individuals, especially in the community and in-home settings. We demonstrate a multiplexed, portable, wireless electrochemical platform for ultra-rapid detection of COVID-19: the SARS-CoV-2 RapidPlex. It detects viral antigen nucleocapsid protein, IgM and IgG antibodies, as well as the inflammatory biomarker C-reactive protein, based on our mass-producible laser-engraved graphene electrodes. We demonstrate ultrasensitive, highly selective, and rapid electrochemical detection in the physiologically relevant ranges. We successfully evaluated the applicability of our SARS-CoV-2 RapidPlex platform with COVID-19-positive and COVID-19-negative blood and saliva samples. Based on this pilot study, our multiplexed immunosensor platform may allow for high-frequency at-home testing for COVID-19 telemedicine diagnosis and monitoring.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3s7gtFKjtA%253D%253D&md5=6d838d44c03518f2f757d11bf8dacbcb
    61. 61
      Zhao, H.; Liu, F.; Xie, W.; Zhou, T.-C.; OuYang, J.; Jin, L.; Li, H.; Zhao, C.-Y.; Zhang, L.; Wei, J.; Zhang, Y.-P.; Li, C.-P. Ultrasensitive Supersandwich-Type Electrochemical Sensor for SARS-CoV-2 from the Infected COVID-19 Patients Using a Smartphone. Sens. Actuators, B 2021, 327, 128899,  DOI: 10.1016/j.snb.2020.128899
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      Ultrasensitive supersandwich-type electrochemical sensor for SARS-CoV-2 from the infected COVID-19 patients using a smartphone
      Zhao, Hui; Liu, Feng; Xie, Wei; Zhou, Tai-Cheng; OuYang, Jun; Jin, Lian; Li, Hui; Zhao, Chun-Yan; Zhang, Liang; Wei, Jia; Zhang, Ya-Ping; Li, Can-Peng
      Sensors and Actuators, B: Chemical (2021), 327 (), 128899CODEN: SABCEB; ISSN:0925-4005. (Elsevier B.V.)
      The recent pandemic outbreak of COVID-19 caused by a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), poses a threat to public health globally. Thus, developing a rapid, accurate, and easy-to-implement diagnostic system for SARS-CoV-2 is crucial for controlling infection sources and monitoring illness progression. We reported an ultrasensitive electrochem. detection technol. using calixarene functionalized graphene oxide for targeting RNA of SARS-CoV-2. Based on a supersandwich-type recognition strategy, the technol. was confirmed to practicably detect the RNA of SARS-CoV-2 without nucleic acid amplification and reverse-transcription by using a portable electrochem. smartphone. The biosensor showed high specificity and selectivity during in silico anal. and actual testing. A total of 88 RNA exts. from 25 SARS-CoV-2-confirmed patients and 8 recovery patients were detected using the biosensor. The detectable ratios (85.5% and 46.2%) were higher than those obtained using RT-qPCR (56.5% and 7.7%). The limit of detection (LOD) of the clin. specimen was 200 copies/mL, which is the lowest LOD among the published RNA measurement of SARS-CoV-2 to date. Addnl., only 2 copies (10μL) of SARS-CoV-2 were required for assay. Therefore, we developed an ultrasensitive, accurate, and convenient assay for SARS-CoV-2 detection, providing a potential method for point-of-care testing.
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    62. 62
      Zhu, X.; Wang, X.; Han, L.; Chen, T.; Wang, L.; Li, H.; Li, S.; He, L.; Fu, X.; Chen, S.; Xing, M.; Chen, H.; Wang, Y. Multiplex Reverse Transcription Loop-Mediated Isothermal Amplification Combined with Nanoparticle-Based Lateral Flow Biosensor for the Diagnosis of COVID-19. Biosens. Bioelectron. 2020, 166, 112437,  DOI: 10.1016/j.bios.2020.112437
      62
      Multiplex reverse transcription loop-mediated isothermal amplification combined with nanoparticle-based lateral flow biosensor for the diagnosis of COVID-19
      Zhu, Xiong; Wang, Xiaoxia; Han, Limei; Chen, Ting; Wang, Licheng; Li, Huan; Li, Sha; He, Lvfen; Fu, Xiaoying; Chen, Shaojin; Xing, Mei; Chen, Hai; Wang, Yi
      Biosensors & Bioelectronics (2020), 166 (), 112437CODEN: BBIOE4; ISSN:0956-5663. (Elsevier B.V.)
      The ongoing global pandemic (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a huge public health issue. Hence, we devised a multiplex reverse transcription loop-mediated isothermal amplification (mRT-LAMP) coupled with a nanoparticle-based lateral flow biosensor (LFB) assay (mRT-LAMP-LFB) for diagnosing COVID-19. Using two LAMP primer sets, the ORF1ab (opening reading frame 1a/b) and N (nucleoprotein) genes of SARS-CoV-2 were simultaneously amplified in a single-tube reaction, and detected with the diagnosis results easily interpreted by LFB. In presence of FITC (fluorescein)-/digoxin- and biotin-labeled primers, mRT-LAMP produced numerous FITC-/digoxin- and biotin-attached duplex amplicons, which were detd. by LFB through immunoreactions (FITC/digoxin on the duplex and anti-FITC/digoxin on the test line of LFB) and biotin/streptavidin interaction (biotin on the duplex and streptavidin on the polymerase nanoparticle). The accumulation of nanoparticles leaded a characteristic crimson band, enabling multiplex anal. of ORF1ab and N gene without instrumentation. The limit of detection (LoD) of COVID-19 mRT-LAMP-LFB was 12 copies (for each detection target) per reaction, and no cross-reactivity was generated from non-SARS-CoV-2 templates. The anal. sensitivity of SARS-CoV-2 was 100% (33/33 oropharynx swab samples collected from COVID-19 patients), and the assay's specificity was also 100% (96/96 oropharynx swab samples collected from non-COVID-19 patients). The total diagnostic test can be completed within 1 h from sample collection to result interpretation. In sum, the COVID-19 mRT-LAMP-LFB assay is a promising tool for diagnosing SARS-CoV-2 infections in frontline public health field and clin. labs., esp. from resource-poor regions.
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    63. 63
      Shan, B.; Broza, Y. Y.; Li, W.; Wang, Y.; Wu, S.; Liu, Z.; Wang, J.; Gui, S.; Wang, L.; Zhang, Z.; Liu, W.; Zhou, S.; Jin, W.; Zhang, Q.; Hu, D.; Lin, L.; Zhang, Q.; Li, W.; Wang, J.; Liu, H. Multiplexed Nanomaterial-Based Sensor Array for Detection of COVID-19 in Exhaled Breath. ACS Nano 2020, 14 (9), 12125– 12132,  DOI: 10.1021/acsnano.0c05657
      63
      Multiplexed Nanomaterial-Based Sensor Array for Detection of COVID-19 in Exhaled Breath
      Shan, Benjie; Broza, Yoav Y.; Li, Wenjuan; Wang, Yong; Wu, Sihan; Liu, Zhengzheng; Wang, Jiong; Gui, Shuyu; Wang, Lin; Zhang, Zhihong; Liu, Wei; Zhou, Shoubing; Jin, Wei; Zhang, Qianyu; Hu, Dandan; Lin, Lin; Zhang, Qiujun; Li, Wenyu; Wang, Jinquan; Liu, Hu; Pan, Yueyin; Haick, Hossam
      ACS Nano (2020), 14 (9), 12125-12132CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
      This article reports on a noninvasive approach in detecting and following-up individuals who are at-risk or have an existing COVID-19 infection, with a potential ability to serve as an epidemic control tool. The proposed method uses a developed breath device composed of a nanomaterial-based hybrid sensor array with multiplexed detection capabilities that can detect disease-specific biomarkers from exhaled breath, thus enabling rapid and accurate diagnosis. An exploratory clin. study with this approach was examd. in Wuhan, China, during March 2020. The study cohort included 49 confirmed COVID-19 patients, 58 healthy controls, and 33 non-COVID lung infection controls. When applicable, pos. COVID-19 patients were sampled twice: during the active disease and after recovery. Discriminant anal. of the obtained signals from the nanomaterial-based sensors achieved very good test discriminations between the different groups. The training and test set data exhibited resp. 94% and 76% accuracy in differentiating patients from controls as well as 90% and 95% accuracy in differentiating between patients with COVID-19 and patients with other lung infections. While further validation studies are needed, the results may serve as a base for technol. that would lead to a redn. in the no. of unneeded confirmatory tests and lower the burden on hospitals, while allowing individuals a screening soln. that can be performed in PoC facilities. The proposed method can be considered as a platform that could be applied for any other disease infection with proper modifications to the artificial intelligence and would therefore be available to serve as a diagnostic tool in case of a new disease outbreak.
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    64. 64
      Ding, X.; Yin, K.; Li, Z.; Lalla, R. V.; Ballesteros, E.; Sfeir, M. M.; Liu, C. Ultrasensitive and Visual Detection of SARS-CoV-2 Using All-in-One Dual CRISPR-Cas12a Assay. Nat. Commun. 2020, 11 (1), 4711,  DOI: 10.1038/s41467-020-18575-6
      64
      Ultrasensitive and visual detection of SARS-CoV-2 using all-in-one dual CRISPR-Cas12a assay
      Ding, Xiong; Yin, Kun; Li, Ziyue; Lalla, Rajesh V.; Ballesteros, Enrique; Sfeir, Maroun M.; Liu, Changchun
      Nature Communications (2020), 11 (1), 4711CODEN: NCAOBW; ISSN:2041-1723. (Nature Research)
      Abstr.: The recent outbreak of novel coronavirus (SARS-CoV-2) causing COVID-19 disease spreads rapidly in the world. Rapid and early detection of SARS-CoV-2 facilitates early intervention and prevents the disease spread. Here, we present an All-In-One Dual CRISPR-Cas12a (AIOD-CRISPR) assay for one-pot, ultrasensitive, and visual SARS-CoV-2 detection. By targeting SARS-CoV-2's nucleoprotein gene, two CRISPR RNAs without protospacer adjacent motif (PAM) site limitation are introduced to develop the AIOD-CRISPR assay and detect the nucleic acids with a sensitivity of few copies. We validate the assay by using COVID-19 clin. swab samples and obtain consistent results with RT-PCR assay. Furthermore, a low-cost hand warmer (∼$0.3) is used as an incubator of the AIOD-CRISPR assay to detect clin. samples within 20 min, enabling an instrument-free, visual SARS-CoV-2 detection at the point of care. Thus, our method has the significant potential to provide a rapid, sensitive, one-pot point-of-care assay for SARS-CoV-2.
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    65. 65
      Sadana, A. Market Size and Economics for Biosensors. In Fractal Binding and Dissociation Kinetics for Different Biosensor Applications; Sadana, A., Ed.; Elsevier: Amsterdam, The Netherlands, 2005; pp 265– 299.  DOI: 10.1016/B978-044451945-0/50014-5 .
      There is no corresponding record for this reference.
    66. 66
      Altawalbeh, S. M.; Alkhateeb, F. M.; Attarabeen, O. F. Ethical Issues in Consenting Older Adults: Academic Researchers and Community Perspectives. J. Pharm. Heal. Serv. Res. 2020, 11 (1), 25– 32,  DOI: 10.1111/jphs.12327
      66
      Ethical Issues in Consenting Older Adults: Academic Researchers and Community Perspectives
      Altawalbeh Shoroq M; Alkhateeb Fadi M; Attarabeen Omar F
      Journal of pharmaceutical health services research : an official journal of the Royal Pharmaceutical Society of Great Britain (2020), 11 (1), 25-32 ISSN:1759-8885.
      Objectives: Obtaining informed consents from older adults is surrounded by many ethical and practical challenges. The objective of this study was to evaluate ethical issues and strategies in consenting older adults in Jordan as perceived by academic researchers and older adults. Methods: An anonymous questionnaire was distributed to academic researchers in the Jordanian health sciences colleges, and a sample of older adults. The study survey included items eliciting demographics, professional characteristics, and perceptions regarding the consenting process in older adults, consent-related skills in elderly, and strategies to improve the consenting process in older adults. The survey was then modified to assess the consent-related ethical issues and challenges as viewed by a sample of older adults after explaining the concept of the consenting process to them. Key findings: A total of 250 academic researchers and 233 older adults participated in the study. Both researchers and older adults reported that having to sign the written forms and the impact of age-related physical impairments were the most challenging obstacles when consenting older adults. Lack of consistency and repeating questions were the most frequently encountered obstacles by researchers in consenting older adults. Ensuring privacy (anonymity/confidentiality), dedicating more time for the consenting process, treating older adults as autonomous individuals and respecting their cultural beliefs were the most helpful strategies recommended by both academic researchers and older adults. Conclusions: Obtaining informed consents from older adults is a challenging process. Researchers should be aware of the special needs and strategies to achieve realistic and ethical informed consents from older adults.
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    67. 67
      Tindana, P.; Molyneux, C. S.; Bull, S.; Parker, M. Ethical Issues in the Export, Storage and Reuse of Human Biological Samples in Biomedical Research: Perspectives of Key Stakeholders in Ghana and Kenya. BMC Med. Ethics 2014, 15 (1), 76,  DOI: 10.1186/1472-6939-15-76
      67
      Ethical issues in the export, storage and reuse of human biological samples in biomedical research: perspectives of key stakeholders in Ghana and Kenya
      Tindana Paulina; Molyneux Catherine S; Bull Susan; Parker Michael
      BMC medical ethics (2014), 15 (), 76 ISSN:.
      BACKGROUND: For many decades, access to human biological samples, such as cells, tissues, organs, blood, and sub-cellular materials such as DNA, for use in biomedical research, has been central in understanding the nature and transmission of diseases across the globe. However, the limitations of current ethical and regulatory frameworks in sub-Saharan Africa to govern the collection, export, storage and reuse of these samples have resulted in inconsistencies in practice and a number of ethical concerns for sample donors, researchers and research ethics committees. This paper examines stakeholders' perspectives of and responses to the ethical issues arising from these research practices. METHODS: We employed a qualitative strategy of inquiry for this research including in-depth interviews and focus group discussions with key research stakeholders in Kenya (Nairobi and Kilifi), and Ghana (Accra and Navrongo). RESULTS: The stakeholders interviewed emphasised the compelling scientific importance of sample export, storage and reuse, and acknowledged the existence of some structures governing these research practices, but they also highlighted the pressing need for a number of practical ethical concerns to be addressed in order to ensure high standards of practice and to maintain public confidence in international research collaborations. These concerns relate to obtaining culturally appropriate consent for sample export and reuse, understanding cultural sensitivities around the use of blood samples, facilitating a degree of local control of samples and sustainable scientific capacity building. CONCLUSION: Drawing on these findings and existing literature, we argue that the ethical issues arising in practice need to be understood in the context of the interactions between host research institutions and local communities and between collaborating institutions. We propose a set of 'key points-to-consider' for research institutions, ethics committees and funding agencies to address these issues.
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    68. 68
      Van Norman, G. A. Drugs, Devices, and the FDA: Part 2. JACC Basic to Transl. Sci. 2016, 1 (4), 277– 287,  DOI: 10.1016/j.jacbts.2016.03.009
      68
      Drugs, Devices, and the FDA: Part 2: An Overview of Approval Processes: FDA Approval of Medical Devices
      Van Norman Gail A
      JACC. Basic to translational science (2016), 1 (4), 277-287 ISSN:.
      As with new drugs, the U.S. Food and Drug Administration's approval process is intended to provide consumers with assurance that, once it reaches the market place, a medical device is safe and effective in its intended use. Bringing a device to market takes an average of 3 to 7 years, compared with an average of 12 years for drugs. However, there are concerns that Food and Drug Administration processes may not be sufficient to meet the assurances of safety and efficacy as intended. This second part of a 2-part series reviews the basic steps in development and Food and Drug Administration approval of medical devices, and summarizes post-marketing processes for drugs and devices.
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    69. 69
      Cheng, M. Medical Device Regulations - Global Overview and Guiding Principles; WHO Library Cataloguing-in-Publication: Geneva, Switzerland, 2003; pp 1– 43. https://apps.who.int/iris/handle/10665/42744 (accessed 2020-05-03).
      There is no corresponding record for this reference.
    70. 70
      World Health Organization. Advice on the Use of Point-of-Care Immunodiagnostic Tests for COVID-19 - Rapid Diagnostic Tests Based on Antigen Detection. https://www.who.int/news-room/commentaries/detail/advice-on-the-use-of-point-of-care-immunodiagnostic-tests-for-covid-19 (accessed 2021-02-23).
      There is no corresponding record for this reference.
    71. 71
      European Commission Enterprise and Industry DG, Directive 98/79/EC of the European Parliament and of the Council of 27 October 1998 on in Vitro Diagnostic Medical Devices. EUR-Lex; 1998; pp 0001– 0037. https://www.gmp-compliance.org/files/guidemgr/IVD_Directive.pdf (accessed 2021-02-23).
      There is no corresponding record for this reference.
    72. 72
      The European Parliament and of the Council. Regulation (EU) 2017/746 of the European Parliament and of the Council of 5 April 2017 - On in Vitro Diagnostic Medical Devices and Repealing Directive 98/79/EC and Commission Decision 2010/227/EU; EUR-Lex; 2017; pp 176– 332. https://eur-lex.europa.eu/eli/reg/2017/746/oj (accessed 2021-02-23).
      There is no corresponding record for this reference.
    73. 73
      U.S. Food and Drug Administration (FDA). Policy for Diagnostic Tests for Coronavirus Disease-2019 during the Public Health Emergency: Immediately in Effect Guidance for Clinical Laboratories, Commercial Manufacturers, and Food and Drug Administration Staff. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/policy-coronavirus-disease-2019-tests-during-public-health-emergency-revised (accessed 2020-05-01).
      There is no corresponding record for this reference.
    74. 74
      Centers for Disease Control and Prevention. Clinical Laboratory Improvement Amendments (CLIA). https://www.cdc.gov/clia/index.html (accessed 2021-09-20).
      There is no corresponding record for this reference.
    75. 75
      U.S. Food and Drug Administration (FDA). Quality System (QS) Regulation/Medical Device Good Manufacturing Practices. https://www.fda.gov/medical-devices/postmarket-requirements-devices/quality-system-qs-regulationmedical-device-good-manufacturing-practices (accessed 2021-05-19).
      There is no corresponding record for this reference.
    76. 76
      World Health Organization, Department of Blood Safety and Clinical Technology. Current Performance of COVID-19 Test Methods and Devices and Proposed Performance Criteria; 2003; pp 1– 43. https://ec.europa.eu/docsroom/documents/40805 (accessed 2021-05-19).
      There is no corresponding record for this reference.
    77. 77
      World Health Organization, Prequalification Team - Diagnostics. Instructions for Submission Requirements: In Vitro Diagnostics (IVDs) Detecting Antibodies to SARS-CoV-2 Virus. World Health Organization, 2020; pp 1– 21. https://www.who.int/diagnostics_laboratory/200703_pqt_ivd_352_v2_eul_immunoassay_requirements_ncov.pdf. (accessed 2020-12-19).
      There is no corresponding record for this reference.
    78. 78
      Zhu, N.; Zhang, D.; Wang, W.; Li, X.; Yang, B.; Song, J.; Zhao, X.; Huang, B.; Shi, W.; Lu, R.; Niu, P.; Zhan, F.; Ma, X.; Wang, D.; Xu, W.; Wu, G.; Gao, G. F.; Tan, W. A Novel Coronavirus from Patients with Pneumonia in China, 2019. N. Engl. J. Med. 2020, 382 (8), 727– 733,  DOI: 10.1056/NEJMoa2001017
      78
      A novel coronavirus from patients with pneumonia in China, 2019
      Zhu, Na; Zhang, Dingyu; Wang, Wenling; Li, Xingwang; Yang, Bo; Song, Jingdong; Zhao, Xiang; Huang, Baoying; Shi, Weifeng; Lu, Roujian; Niu, Peihua; Zhan, Faxian; Ma, Xuejun; Wang, Dayan; Xu, Wenbo; Wu, Guizhen; Gao, George F.; Tan, Wenjie
      New England Journal of Medicine (2020), 382 (8), 727-733CODEN: NEJMAG; ISSN:1533-4406. (Massachusetts Medical Society)
      In Dec. 2019, a cluster of patients with pneumonia of unknown cause was linked to a seafood wholesale market in Wuhan, China. A previously unknown betacoronavirus was discovered through the use of unbiased sequencing in samples from patients with pneumonia. Human airway epithelial cells were used to isolate a novel coronavirus, named 2019-nCoV, which formed a clade within the subgenus sarbecovirus, Orthocoronavirinae subfamily. Different from both MERS-CoV and SARS-CoV, 2019-nCoV is the seventh member of the family of coronaviruses that infect humans. Enhanced surveillance and further investigation are ongoing. Complete genome sequences of the three novel coronaviruses were submitted to GISAID (BetaCoV/Wuhan/ IVDC-HB-01/2019, accession ID: EPI_ISL_402119; BetaCoV/Wuhan/IVDC-HB-04/2020, accession ID: EPI_ISL_402120; BetaCoV/Wuhan/IVDC-HB-05/2019, accession ID: EPI_ISL_402121).
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    79. 79
      Li, Q.; Wu, J.; Nie, J.; Zhang, L.; Hao, H.; Liu, S.; Zhao, C.; Zhang, Q.; Liu, H.; Nie, L.; Qin, H.; Wang, M.; Lu, Q.; Li, X.; Sun, Q.; Liu, J.; Zhang, L.; Li, X.; Huang, W.; Wang, Y. The Impact of Mutations in SARS-CoV-2 Spike on Viral Infectivity and Antigenicity. Cell 2020, 182 (5), 1284– 1294,  DOI: 10.1016/j.cell.2020.07.012
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      The impact of mutations in SARS-CoV-2 spike on viral infectivity and antigenicity
      Li, Qianqian; Wu, Jiajing; Nie, Jianhui; Zhang, Li; Hao, Huan; Liu, Shuo; Zhao, Chenyan; Zhang, Qi; Liu, Huan; Nie, Lingling; Qin, Haiyang; Wang, Meng; Lu, Qiong; Li, Xiaoyu; Sun, Qiyu; Liu, Junkai; Zhang, Linqi; Li, Xuguang; Huang, Weijin; Wang, Youchun
      Cell (Cambridge, MA, United States) (2020), 182 (5), 1284-1294.e9CODEN: CELLB5; ISSN:0092-8674. (Cell Press)
      The spike protein of SARS-CoV-2 has been undergoing mutations and is highly glycosylated. It is critically important to investigate the biol. significance of these mutations. Here, we investigated 80 variants and 26 glycosylation site modifications for the infectivity and reactivity to a panel of neutralizing antibodies and sera from convalescent patients. D614G, along with several variants contg. both D614G and another amino acid change, were significantly more infectious. Most variants with amino acid change at receptor binding domain were less infectious, but variants including A475V, L452R, V483A, and F490L became resistant to some neutralizing antibodies. Moreover, the majority of glycosylation deletions were less infectious, whereas deletion of both N331 and N343 glycosylation drastically reduced infectivity, revealing the importance of glycosylation for viral infectivity. Interestingly, N234Q was markedly resistant to neutralizing antibodies, whereas N165Q became more sensitive. These findings could be of value in the development of vaccine and therapeutic antibodies.
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    80. 80
      Cao, Y.; Su, B.; Guo, X.; Sun, W.; Deng, Y.; Bao, L.; Zhu, Q.; Zhang, X.; Zheng, Y.; Geng, C.; Chai, X.; He, R.; Li, X.; Lv, Q.; Zhu, H.; Deng, W.; Xu, Y.; Wang, Y.; Qiao, L.; Tan, Y. Potent Neutralizing Antibodies against SARS-CoV-2 Identified by High-Throughput Single-Cell Sequencing of Convalescent Patients’ B Cells. Cell 2020, 182 (1), 73– 84,  DOI: 10.1016/j.cell.2020.05.025
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      Potent Neutralizing Antibodies against SARS-CoV-2 Identified by High-Throughput Single-Cell Sequencing of Convalescent Patients' B Cells
      Cao, Yunlong; Su, Bin; Guo, Xianghua; Sun, Wenjie; Deng, Yongqiang; Bao, Linlin; Zhu, Qinyu; Zhang, Xu; Zheng, Yinghui; Geng, Chenyang; Chai, Xiaoran; He, Runsheng; Li, Xiaofeng; Lv, Qi; Zhu, Hua; Deng, Wei; Xu, Yanfeng; Wang, Yanjun; Qiao, Luxin; Tan, Yafang; Song, Liyang; Wang, Guopeng; Du, Xiaoxia; Gao, Ning; Liu, Jiangning; Xiao, Junyu; Su, Xiao-dong; Du, Zongmin; Feng, Yingmei; Qin, Chuan; Qin, Chengfeng; Jin, Ronghua; Xie, X. Sunney
      Cell (Cambridge, MA, United States) (2020), 182 (1), 73-84.e16CODEN: CELLB5; ISSN:0092-8674. (Cell Press)
      The COVID-19 pandemic urgently needs therapeutic and prophylactic interventions. Here, we report the rapid identification of SARS-CoV-2-neutralizing antibodies by high-throughput single-cell RNA and VDJ sequencing of antigen-enriched B cells from 60 convalescent patients. From 8,558 antigen-binding IgG1+ clonotypes, 14 potent neutralizing antibodies were identified, with the most potent one, BD-368-2, exhibiting an IC50 of 1.2 and 15 ng/mL against pseudotyped and authentic SARS-CoV-2, resp. BD-368-2 also displayed strong therapeutic and prophylactic efficacy in SARS-CoV-2-infected hACE2-transgenic mice. Addnl., the 3.8 Å cryo-EM structure of a neutralizing antibody in complex with the spike-ectodomain trimer revealed the antibody's epitope overlaps with the ACE2 binding site. Moreover, we demonstrated that SARS-CoV-2-neutralizing antibodies could be directly selected based on similarities of their predicted CDR3H structures to those of SARS-CoV-neutralizing antibodies. Altogether, we showed that human neutralizing antibodies could be efficiently discovered by high-throughput single B cell sequencing in response to pandemic infectious diseases.
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    81. 81
      Ensuring Innovation in Diagnostics for Bacterial Infection Implications for Policy. European Observatory Health Policy Series; Morel, C., McClure, L., Edwards, S., Goodfellow, V., Sandberg, D., Thomas, J., Mossialos, E., Eds.; European Observatory on Health Systems and Policies, 2016. PMID: 28806042.
      There is no corresponding record for this reference.
    82. 82
      Metcalfe, T. A. Development of Novel IVD Assays: A Manufacturer’s Perspective. Scand. J. Clin. Lab. Invest. 2010, 70, 23– 26,  DOI: 10.3109/00365513.2010.493361
      There is no corresponding record for this reference.
    83. 83
      Borsci, S.; Kuljis, J.; Barnett, J.; Pecchia, L. Beyond the User Preferences: Aligning the Prototype Design to the Users’ Expectations. Hum. Factors Ergon. Manuf. Serv. Ind. 2016, 26 (1), 16– 39,  DOI: 10.1002/hfm.20611
      There is no corresponding record for this reference.
    84. 84
      Phillips, K. A.; Van Bebber, S.; Issa, A. M. Diagnostics and Biomarker Development: Priming the Pipeline. Nat. Rev. Drug Discovery 2006, 5 (6), 463– 469,  DOI: 10.1038/nrd2033
      84
      Diagnostics and biomarker development: priming the pipeline
      Phillips, Kathryn A.; Van Bebber, Stephanie; Issa, Amalia M.
      Nature Reviews Drug Discovery (2006), 5 (6), 463-469CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)
      A review. The decrease in the rate at which novel medical products are reaching the market, despite major scientific achievements and investment that might have predicted otherwise, is causing much concern. Although this 'pipeline problem' has often been discussed in the context of drug development, it is also crucial to examine the unique characteristics of the pipeline for biomarkers and diagnostics. Here, the authors characterize the pipeline problem for biomarkers and diagnostics, and consider what steps could be taken to solve it.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XlsV2jtbg%253D&md5=c3ffc2530fc49ad1a3098e84e0cdb207
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