LAMP-Based Point-of-Care Biosensors for Rapid Pathogen Detection.

Seeking optimized infectious pathogen detection tools is of primary importance to lessen the spread of infections, allowing prompt medical attention for the infected. Among nucleic-acid-based sensing techniques, loop-mediated isothermal amplification is a promising method, as it provides rapid, sensitive, and specific detection of microbial and viral pathogens and has enormous potential to transform current point-of-care molecular diagnostics. In this review, the advances in LAMP-based point-of-care diagnostics assays developed during the past few years for rapid and sensitive detection of infectious pathogens are outlined. The numerous detection methods of LAMP-based biosensors are discussed in an end-point and real-time manner with ideal examples. We also summarize the trends in LAMP-on-a-chip modalities, such as classical microfluidic, paper-based, and digital LAMP, with their merits and limitations. Finally, we provide our opinion on the future improvement of on-chip LAMP methods. This review serves as an overview of recent breakthroughs in the LAMP approach and their potential for use in the diagnosis of existing and emerging diseases.

Cost-Effectiveness of 12 First-Line Treatments for Patients With Advanced EGFR Mutated NSCLC in the United Kingdom and China.

Background: Lung cancer is imposing significant pressure on the national health insurance system worldwide, especially under the COVID-19 pandemic. However, the cost-effectiveness of all available first-line treatments for patients with advanced epidermal growth factor receptor (EGFR) mutated non-small cell lung cancer (NSCLC) is still uncertain. The aim of this study was to evaluate the cost-effectiveness of 12 first-line treatments for patients with advanced EGFR mutated NSCLC from the perspective of the United Kingdom (UK) National Health Service and Chinese health care system. Methods: We used a Markov model to estimate the cost-effectiveness of 12 treatments, including 6 EGFR tyrosine kinase inhibitors, 4 combination treatments and 2 chemotherapies. The key clinical efficacy and safety data were from a network meta-analysis. The cost and health preference were mainly collected from the literature. The most cost-effective treatment was inferred through a sequential analysis. Uncertainty was tested with one-way sensitivity analyses, scenario analyses, and probabilistic sensitivity analyses. Quality-adjusted life years (QALYs), direct medical costs, and incremental cost-effectiveness ratio (ICER) were estimated, at willingness-to-pay thresholds of £20000 to £50000 and £8000 to £24000 per QALY in the UK and China respectively. Results: For clinical effectiveness, osimertinib and gefitinib plus pemetrexed based chemotherapy (PbCT) yielded the highest QALYs, while two chemotherapy treatments gained the lowest QALYs. For costs, gefitinib treatment was the cheapest option in both countries (£24529 in the UK and £12961 in China). For cost-effectiveness, 4 treatments including gefitinib, gefitinib plus pemetrexed, gefitinib plus PbCT, and osimertinib formed the cost-effectiveness frontier in both countries. Gefitinib alone (70.7% and 80.0% under the threshold of £20000 and £8000 per QALY in the UK and China, respectively) and gefitinib plus PbCT (62.3% and 71.2% under the threshold of £50000 and £24000 per QALY in the UK and China, respectively) were most likely to be cost-effective compared with other first-line treatments. Conclusions: Gefitinib and gefitinib plus PbCT were likely to be cost-effective for patients with advanced EGFR mutated NSCLC in both countries.

Discovery of highly potent SARS-CoV-2 Mpro inhibitors based on benzoisothiazolone scaffold.

The COVID-19 pandemic has drastically impacted global economies and public health. Although vaccine development has been successful, it was not sufficient against more infectious mutant strains including the Delta variant indicating a need for alternative treatment strategies such as small molecular compound development. In this work, a series of SARS-CoV-2 main protease (Mpro) inhibitors were designed and tested based on the active compound from high-throughput diverse compound library screens. The most efficacious compound (16b-3) displayed potent SARS-CoV-2 Mpro inhibition with an IC50 value of 116 nM and selectivity against SARS-CoV-2 Mpro when compared to PLpro and RdRp. This new class of compounds could be used as potential leads for further optimization in anti COVID-19 drug discovery.

Rotational diffusometric sensor with isothermal amplification for ultra-sensitive and rapid detection of SARS-CoV-2 nsp2 cDNA.

In the wake of a pandemic, the development of rapid, simple, and accurate molecular diagnostic tests can significantly aid in reducing the spread of infections. By combining particle imaging with molecular assays, a quick and highly sensitive biosensor can readily identify a pathogen at low concentrations. Here, we implement functionalized particle-enabled rotational diffusometry in combination with loop-mediated isothermal amplification for the rapid detection of the SARS-CoV-2 nsp2 gene in the recombinant plasmid as a proof of concept for COVID-19 diagnostics. By analyzing the images of blinking signals generated by these modified particles, the change in micro-level viscosity due to nucleic acid amplification was measured. The high sensitivity of rotational diffusometry enabled facile detection within 10 min, with a limit of detection of 70 ag/µL and a sample volume of 2 µL. Tenfold higher detection sensitivity was observed for rotational diffusometry in comparison with real-time PCR. In addition, the system stability and the effect of temperature on rotational diffusometric measurements were studied and reported. These results demonstrated the utility of a rotational diffusometric platform for the rapid and sensitive detection of SARS-CoV-2 cDNA fragments.

Exhausting T Cells During HIV Infection May Improve the Prognosis of Patients with COVID-19.

T-cell reduction is an important characteristic of coronavirus disease 2019 (COVID-19), and its immunopathology is a subject of debate. It may be due to the direct effect of the virus on T-cell exhaustion or indirectly due to T cells redistributing to the lungs. HIV/AIDS naturally served as a T-cell exhaustion disease model for recognizing how the immune system works in the course of COVID-19. In this study, we collected the clinical charts, T-lymphocyte analysis, and chest CT of HIV patients with laboratory-confirmed COVID-19 infection who were admitted to Jin Yin-tan Hospital (Wuhan, China). The median age of the 21 patients was 47 years [interquartile range (IQR) = 40-50 years] and the median CD4 T-cell count was 183 cells/µl (IQR = 96-289 cells/µl). Eleven HIV patients were in the non-AIDS stage and 10 were in the AIDS stage. Nine patients received antiretroviral treatment (ART) and 12 patients did not receive any treatment. Compared to the reported mortality rate (nearly 4%-10%) and severity rate (up to 20%-40%) among COVID-19 patients in hospital, a benign duration with 0% severity and mortality rates was shown by 21 HIV/AIDS patients. The severity rates of COVID-19 were comparable between non-AIDS (median CD4 = 287 cells/µl) and AIDS (median CD4 = 97 cells/µl) patients, despite some of the AIDS patients having baseline lung injury stimulated by HIV: 7 patients (33%) were mild (five in the non-AIDS group and two in the AIDS group) and 14 patients (67%) were moderate (six in the non-AIDS group and eight in the AIDS group). More importantly, we found that a reduction in T-cell number positively correlates with the serum levels of interleukin 6 (IL-6) and C-reactive protein (CRP), which is contrary to the reported findings on the immune response of COVID-19 patients (lower CD4 T-cell counts with higher levels of IL-6 and CRP). In HIV/AIDS, a compromised immune system with lower CD4 T-cell counts might waive the clinical symptoms and inflammatory responses, which suggests lymphocyte redistribution as an immunopathology leading to lymphopenia in COVID-19.

Longitudinal Trajectories of Post Traumatic Stress Disorder(PTSD) in Medical Staff After Outbreak of Coronavirus (COVID-19) in China (preprint)

Background: In the novel coronavirus disease (COVID-19) pandemic, medical staff is the main force for aiding in the control of the rapid spread. They have to risk lives to undertake the high-pressure task which may cause immediate and long-term psychological problems. This study aims to explore the trajectories of post-traumatic stress disorder (PTSD) over time after the outbreak and determine predictors associated with each trajectory. Methods: : 448 medical workers participated in the investigation and completed the Posttraumatic Stress Disorder Self-Rating Scale (PTSD-SS) for the first PTSD screening at 1 month after the outbreak and 259 (57.81%) of them finished the second round at 12 months. According to whether the medical staff had close contact with the COVID-19 patient, participants were divided into close contact group (CC group) and non-close contact group (non-CC group). While in each group, subgroups were created based on the time-varying changes of developing PTSD. Distinct patterns of PTSD symptom trajectories were established according to the different development of PTSD in respective subgroup. Then, repeated-measure analysis of variance(ANOVA), bivariate and multivariate logistic regressions were used to examine predictors for trajectory membership. Results: : Four trajectories of PTSD symptoms were found both in CC and non-CC group, namely, resilience (25.28%, 45.24%, respectively), recovery (36.26%, 32.74%, respectively), chronic (16.48%, 10.71%, respectively), and delayed (21.98%, 11.31%, respectively). ANOVA revealed that PTSD scores were significantly changed through time both in CCs and non- CCs. With bivariate and multivariate analyses, several socio-demographic predictors and work experience related factors were found in the CC group, while limited ones in the non-CC group. This means that although the trajectory trends are similar between these two groups, the methods of psychological intervention may need to be treated differently. Furthermore, CC group had less resilient individuals ( p =0.002) and more delayed PTSD sufferers ( p =0.022) compared with non-CC medical staff, which suggest that CCs were more likely to experience PTSD course and encounter long-term psychological problems. Conclusions: : A considerable number of medical personnel have long-term PTSD, both in CC group and non-CC group, which deserve public attention. Identified factors may indicate preventive and treatment interventions for medical workers with PTSD symptoms.

The experience of contact tracing in Singapore in the control of COVID-19: highlighting the use of digital technology.

PURPOSE: Containing the coronavirus disease 2019 (COVID-19) pandemic would require aggressive contact tracing and isolation of suspected or confirmed COVID-19 cases. Models in published literature have suggested that digital rather than manual contact tracing might be more effective in containing the pandemic. This article seeks to examine the forms of contact tracing that Singapore, a highly dense city-state, adopts with a focus on new innovations including the use of digital technology. METHODS: An exploratory literature search in PubMed, MEDLINE and EMBASE for studies reviewing technological approaches and responses to COVID-19 was performed. Information published by national agencies was also analysed to ascertain how technology was utilised in contact tracing. RESULTS: Contact tracing in Singapore is overseen by the Ministry of Health (MOH). COVID-19 cases are interviewed on their whereabouts during a backward and forward activity mapping process to identify close contacts. Extensive contact tracing even involving the police and serological tools have helped to establish links between cases and closed several local clusters. Examination of patient's digital footprint has helped in contact tracing. Other digital technology introduced includes SafeEntry and TraceTogether. SafeEntry is a cloud-based visitor registration system while TraceTogether is a mobile phone application which operates by exchanging anonymised identifiers between nearby phones via Bluetooth connection. CONCLUSION: Digital contact tracing is likely to expand and continue to complement human-based contact tracing for the current and future pandemics. However, at this juncture, it is not ready to replace the manual and meticulous work that only Singapore contact tracers can achieve.