Bayesian Methods in Human Drug and Biological Products Development in CDER and CBER.

The Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) of the U.S. Food and Drug Administration (FDA) have been leaders in protecting and promoting the U.S. public health by helping to ensure that safe and effective drugs and biological products are available in the United States for those who need them. The null hypothesis significance testing approach, along with other considerations, is typically used to demonstrate the effectiveness of a drug or biological product. The Bayesian framework presents an alternative approach to demonstrate the effectiveness of a treatment. This article discusses the Bayesian framework for drug and biological product development, highlights key settings in which Bayesian approaches may be appropriate, and provides recent examples of the use of Bayesian approaches within CDER and CBER.

Patient adverse financial outcomes before and after COVID-19 infection.

Adverse financial outcomes after COVID-19 infection and hospitalization have not been assessed with appropriate comparators to account for other financial disruptions of 2020-2021. Using credit report data from 132,109 commercially insured COVID-19 survivors, we compared the rates of adverse financial outcomes for two cohorts of individuals with credit outcomes measured before and after COVID-19 infection, using an interaction term between cohort and hospitalization to test whether adverse credit outcomes changed more for hospitalized than nonhospitalized COVID-19 patients. Covariates included age group, gender, and several area-level social determinants of health. Adverse financial outcomes were significantly more common after COVID-19 infection than before COVID-19 infection, with greater increases among those hospitalized with COVID-19 (5-8 percentage points) than among nonhospitalized patients (1-3 percentage points). Future work examining longitudinal financial outcomes before and after COVID-19 infection is needed to determine the causal mechanisms of this association to reduce financial hardship from COVID-19 and other conditions.

COVID-19 and liver cancer: lost patients and larger tumours.

BACKGROUND: Northern England has been experiencing a persistent rise in the number of primary liver cancers, largely driven by an increasing incidence of hepatocellular carcinoma (HCC) secondary to alcohol-related liver disease and non-alcoholic fatty liver disease. Here we review the effect of the COVID-19 pandemic on primary liver cancer services and patients in our region. OBJECTIVE: To assess the impact of the COVID-19 pandemic on patients with newly diagnosed liver cancer in our region. DESIGN: We prospectively audited our service for the first year of the pandemic (March 2020-February 2021), comparing mode of presentation, disease stage, treatments and outcomes to a retrospective observational consecutive cohort immediately prepandemic (March 2019-February 2020). RESULTS: We observed a marked decrease in HCC referrals compared with previous years, falling from 190 confirmed new cases to 120 (37%). Symptomatic became the the most common mode of presentation, with fewer tumours detected by surveillance or incidentally (% surveillance/incidental/symptomatic; 34/42/24 prepandemic vs 27/33/40 in the pandemic, p=0.013). HCC tumour size was larger in the pandemic year (60±4.6 mm vs 48±2.6 mm, p=0.017), with a higher incidence of spontaneous tumour haemorrhage. The number of new cases of intrahepatic cholangiocarcinoma (ICC) fell only slightly, with symptomatic presentation typical. Patients received treatment appropriate for their cancer stage, with waiting times shorter for patients with HCC and unchanged for patients with ICC. Survival was associated with stage both before and during the pandemic. 9% acquired COVID-19 infection. CONCLUSION: The pandemic-associated reduction in referred patients in our region was attributed to the disruption of routine healthcare. For those referred, treatments and survival were appropriate for their stage at presentation. Non-referred or missing patients are expected to present with more advanced disease, with poorer outcomes. While protective measures are necessary during the pandemic, we recommend routine healthcare services continue, with patients encouraged to engage.

Detection of Anaplasma phagocytophilum, Babesia odocoilei, Babesia sp., Borrelia burgdorferi Sensu Lato, and Hepatozoon canis in Ixodes scapularis Ticks Collected in Eastern Canada.

Tick-borne pathogens cause infectious diseases that inflict much societal and financial hardship worldwide. Blacklegged ticks, Ixodes scapularis, are primary vectors of several epizootic and zoonotic pathogens. The aim was to find varius pathogens of I. scapularis and to determine their prevalence. In Ontario and Quebec, 113 I. scapularis ticks were collected from songbirds, mammals, including humans, and by flagging. PCR and DNA sequencing detected five different microorganisms: Anaplasma phagocytophilum, 1 (0.9%); Babesia odocoilei, 17 (15.3%); Babesia microti-like sp., 1 (0.9%); Borrelia burgdorferi sensu lato (Bbsl), 29 (26.1%); and Hepatozoon canis, 1 (0.9%). Five coinfections of Bbsl and Babesia odocoilei occurred. Notably, H. canis was documented for the first time in Canada and, at the same time, demonstrates the first transstadial passage of H. canis in I. scapularis. Transstadial passage of Bbsl and B. odocoilei was also witnessed. A novel undescribed piroplasm (Babesia microti-like) was detected. An established population of I. scapularis ticks was detected at Ste-Anne-de-Bellevue, Quebec. Because songbirds widely disperse I. scapularis larvae and nymphs, exposure in an endemic area is not required to contract tick-borne zoonoses. Based on the diversity of zoonotic pathogens in I. scapularis ticks, clinicians need to be aware that people who are bitten by I. scapularis ticks may require select antimicrobial regimens.

SARS-CoV-2 one year on – the worrying impact on early detection of liver cancers

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Automated Processing and Phenotype Extraction of Ovine Medical Images Using a Combined Generative Adversarial Network and Computer Vision Pipeline.

The speed and accuracy of phenotype detection from medical images are some of the most important qualities needed for any informed and timely response such as early detection of cancer or detection of desirable phenotypes for animal breeding. To improve both these qualities, the world is leveraging artificial intelligence and machine learning against this challenge. Most recently, deep learning has successfully been applied to the medical field to improve detection accuracies and speed for conditions including cancer and COVID-19. In this study, we applied deep neural networks, in the form of a generative adversarial network (GAN), to perform image-to-image processing steps needed for ovine phenotype analysis from CT scans of sheep. Key phenotypes such as gigot geometry and tissue distribution were determined using a computer vision (CV) pipeline. The results of the image processing using a trained GAN are strikingly similar (a similarity index of 98%) when used on unseen test images. The combined GAN-CV pipeline was able to process and determine the phenotypes at a speed of 0.11 s per medical image compared to approximately 30 min for manual processing. We hope this pipeline represents the first step towards automated phenotype extraction for ovine genetic breeding programmes.

Advancing Digital Health Equity: A Policy Paper of the Infectious Diseases Society of America and the HIV Medicine Association.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has revolutionized the practice of ambulatory medicine, triggering rapid dissemination of digital healthcare modalities, including synchronous video visits. However, social determinants of health, such as age, race, income, and others, predict readiness for telemedicine and individuals who are not able to connect virtually may become lost to care. This is particularly relevant to the practice of infectious diseases (ID) and human immunodeficiency virus (HIV) medicine, as we care for high proportions of individuals whose health outcomes are affected by such factors. Furthermore, delivering high-quality clinical care in ID and HIV practice necessitates discussion of sensitive topics, which is challenging over video without proper preparation. We describe the "digital divide," emphasize the relevance to ID and HIV practice, underscore the need to study the issue and develop interventions to mitigate its impact, and provide suggestions for optimizing telemedicine in ID and HIV clinics.

Ct Values Do Not Predict Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Transmissibility in College Students.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is highly contagious and has caused significant medical/socioeconomic impacts. Other than vaccination, effective public health measures, including contact tracing, isolation, and quarantine, is critical for deterring viral transmission, preventing infection progression and resuming normal activities. Viral transmission is affected by many factors, but the viral load and vitality could be among the most important ones. Although in vitro studies have indicated that the amount of virus isolated from infected individuals affects the successful rate of virus isolation, whether the viral load carried at the individual level would determine the transmissibility was unknown. We examined whether the cycle threshold (Ct) value, a measurement of viral load by RT-PCR assay, could differentiate the spreaders from the non-spreaders in a population of college students. Our results indicate that while at the population level the Ct value is lower, suggesting a higher viral load, in the symptomatic spreaders than that in the asymptomatic non-spreaders, there is a significant overlap in the Ct values between the two groups. Thus, Ct value, or the viral load, at the individual level could not predict the transmissibility. Instead, a sensitive method to detect the presence of virus is needed to identify asymptomatic individuals who may carry a low viral load but can still be infectious.

Liposome-mediated detection of SARS-CoV-2 RNA-positive extracellular vesicles in plasma.

Plasma SARS-CoV-2 RNA may represent a viable diagnostic alternative to respiratory RNA levels, which rapidly decline after infection. Quantitative PCR with reverse transcription (RT-qPCR) reference assays exhibit poor performance with plasma, probably reflecting the dilution and degradation of viral RNA released into the circulation, but these issues could be addressed by analysing viral RNA packaged into extracellular vesicles. Here we describe an assay approach in which extracellular vesicles directly captured from plasma are fused with reagent-loaded liposomes to sensitively amplify and detect a SARS-CoV-2 gene target. This approach accurately identified patients with COVID-19, including challenging cases missed by RT-qPCR. SARS-CoV-2-positive extracellular vesicles were detected at day 1 post-infection, and plateaued from day 6 to the day 28 endpoint in a non-human primate model, while signal durations for 20-60 days were observed in young children. This nanotechnology approach uses a non-infectious sample and extends virus detection windows, offering a tool to support COVID-19 diagnosis in patients without SARS-CoV-2 RNA detectable in the respiratory tract.

Virtualizing Soil Science Field Trips

In response to the coronavirus pandemic in the fall of 2020, we created hybrid-virtual or fully virtual field trips to replace in-person field trips in two courses. For an introductory soil science course with 178 students enrolled, we used a narrative format supported by 360° ground-level and drone photos, newspaper articles, videos, websites, and landscape diagrams. After reading the narratives, the students took a quiz and then visited the sites (public parks near campus) on their own. For the advanced pedology course with seven students enrolled, a virtual trip replaced an all-day field trip that travels a 100-mile route from West Lafayette to Michigan City, IN. The virtual trip was created within the Soil Explorer platform and consists of >50 points of interest (POIs) overlayed on detailed soil maps. Each POI includes relevant information about the soils, agriculture, geology, geomorphology, or history at that point. At two POIs students examined four or five soils along two transects by filling in worksheets using the official series descriptions. Learning was facilitated by a study guide. Effectiveness was assessed by anonymous surveys. Students found the hybrid-virtual or fully virtual field trips informative, interesting, enjoyable, and appropriate given the pandemic. For the introductory class, 42% preferred a virtual field trip format, 39% preferred an in-person format, and 19% were neutral. In the advanced class there was with a clear preference for in-person field trips.

The Impact of COVID-19 on HIV Care Provided via Telemedicine-Past, Present, and Future.

PURPOSE OF REVIEW: This review summarizes HIV care delivered via telemedicine before and during the COVID-19 pandemic and highlights areas of study to inform optimal usage of telemedicine in HIV clinical practice in the future. RECENT FINDINGS: To address barriers to care created by the COVID-19 pandemic, regulatory agencies and payors waived longstanding restrictions, which enabled rapid expansion of telemedicine across the country. Preliminary data show that providers and persons with HIV (PWH) view telemedicine favorably. Some data suggest telemedicine has facilitated retention in care, but other studies have found increasing numbers of PWH lost to follow-up and worsened virologic suppression rates despite offering video and/or telephone visits. The COVID-19 pandemic has exacerbated gaps in the HIV care continuum. To help mitigate the impact, most clinics have adopted new virtual care options and are now evaluating usage, impact, and concerns. Further research into the effects of telemedicine on HIV care and continued work towards universal access are needed.

Sexual health (excluding reproductive health, intimate partner violence and gender-based violence) and COVID-19: a scoping review.

OBJECTIVES: The COVID-19 pandemic has exposed and exacerbated existing socioeconomic and health disparities, including disparities in sexual health and well-being. While there have been several reviews published on COVID-19 and population health disparities generally-including some with attention to HIV-none has focused on sexual health (ie, STI care, female sexual health, sexual behaviour). We have conducted a scoping review focused on sexual health (excluding reproductive health (RH), intimate partner violence (IPV) and gender-based violence (GBV)) in the COVID-19 era, examining sexual behaviours and sexual health outcomes. METHODS: A scoping review, compiling both peer-reviewed and grey literature, focused on sexual health (excluding RH, IPV and GBV) and COVID-19 was conducted on 15 September 2020. Multiple bibliographical databases were searched. Study selection conformed to Joanna Briggs Institute (JBI) Reviewers' Manual 2015 Methodology for JBI Scoping Reviews. We only included English-language original studies. RESULTS: We found that men who have sex with men may be moving back toward pre-pandemic levels of sexual activity, and that STI and HIV testing rates seem to have decreased. There was minimal focus on outcomes such as the economic impact on sexual health (excluding RH, IPV and GBV) and STI care, especially STI care of marginalised populations. In terms of population groups, there was limited focus on sex workers or on women, especially women's sexual behaviour and mental health. We noticed limited use of qualitative techniques. Very few studies were in low/middle-income countries (LMICs). CONCLUSIONS: Sexual health research is critical during a global infectious disease pandemic and our review of studies suggested notable research gaps. Researchers can focus efforts on LMICs and under-researched topics within sexual health and explore the use of qualitative techniques and interventions where appropriate.

COVID-19 pre-procedural testing strategy and early outcomes at a large tertiary care children's hospital.

PURPOSE: With the emergence of the coronavirus disease-2019 (COVID-19) pandemic, institutions were tasked with developing individualized pre-procedural testing strategies that allowed for re-initiation of elective procedures within national and state guidelines. This report describes the experience of a single US children's hospital (Children's Wisconsin, CW) in developing a universal pre-procedural COVID-19 testing protocol and reports early outcomes. METHODS: The CW pre-procedural COVID-19 response began with the creation of a multi-disciplinary taskforce that sought to develop a strategy for universal pre-procedural COVID-19 testing which (1) maximized patient safety, (2) prevented in-hospital viral transmission, (3) conserved resources, and (4) allowed for resumption of procedural care within institutional capacity. RESULTS: Of 11,209 general anesthetics performed at CW from March 16, 2020 to October 31, 2020, 11,150 patients (99.5%) underwent pre-procedural COVID-19 testing. Overall, 1.4% of pre-procedural patients tested positive for COVID-19. By June 2020, CW was operating at near-normal procedural volume and there were no documented cases of in-hospital viral transmission. Only 0.5% of procedures were performed under augmented COVID-19 precautions (negative pressure environment and highest-level personal protective equipment). CONCLUSION: CW successfully developed a multi-disciplinary pre-procedural COVID-19 testing protocol that enabled resumption of near-normal procedural volume within three months while limiting in-hospital viral transmission and resource use.

Sensitive tracking of circulating viral RNA through all stages of SARS-CoV-2 infection.

BACKGROUNDCirculating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA may represent a more reliable indicator of infection than nasal RNA, but quantitative reverse transcription PCR (RT-qPCR) lacks diagnostic sensitivity for blood samples.METHODSA CRISPR-augmented RT-PCR assay that sensitively detects SARS-CoV-2 RNA was employed to analyze viral RNA kinetics in longitudinal plasma samples from nonhuman primates (NHPs) after virus exposure; to evaluate the utility of blood SARS-CoV-2 RNA detection for coronavirus disease 2019 (COVID-19) diagnosis in adults cases confirmed by nasal/nasopharyngeal swab RT-PCR results; and to identify suspected COVID-19 cases in pediatric and at-risk adult populations with negative nasal swab RT-qPCR results. All blood samples were analyzed by RT-qPCR to allow direct comparisons.RESULTSCRISPR-augmented RT-PCR consistently detected SARS-CoV-2 RNA in the plasma of experimentally infected NHPs from 1 to 28 days after infection, and these increases preceded and correlated with rectal swab viral RNA increases. In a patient cohort (n = 159), this blood-based assay demonstrated 91.2% diagnostic sensitivity and 99.2% diagnostic specificity versus a comparator RT-qPCR nasal/nasopharyngeal test, whereas RT-qPCR exhibited 44.1% diagnostic sensitivity and 100% specificity for the same blood samples. This CRISPR-augmented RT-PCR assay also accurately identified patients with COVID-19 using one or more negative nasal swab RT-qPCR results.CONCLUSIONResults of this study indicate that sensitive detection of SARS-CoV-2 RNA in blood by CRISPR-augmented RT-PCR permits accurate COVID-19 diagnosis, and can detect COVID-19 cases with transient or negative nasal swab RT-qPCR results, suggesting that this approach could improve COVID-19 diagnosis and the evaluation of SARS-CoV-2 infection clearance, and predict the severity of infection.TRIAL REGISTRATIONClinicalTrials.gov. NCT04358211.FUNDINGDepartment of Defense, National Institute of Allergy and Infectious Diseases, National Institute of Child Health and Human Development, and the National Center for Research Resources.

Sexual health and COVID-19: protocol for a scoping review.

BACKGROUND: Global responses to the COVID-19 pandemic have exposed and exacerbated existing socioeconomic and health inequities that disproportionately affect the sexual health and well-being of many populations, including people of color, ethnic minority groups, women, and sexual and gender minority populations. Although there have been several reviews published on COVID-19 and health disparities across various populations, none has focused on sexual health. We plan to conduct a scoping review that seeks to fill several of the gaps in the current knowledge of sexual health in the COVID-19 era. METHODS: A scoping review focusing on sexual health and COVID-19 will be conducted. We will search (from January 2020 onwards) CINAHL, Africa-Wide Information, Web of Science Core Collection, Embase, Gender Studies Database, Gender Watch, Global Health, WHO Global Literature on Coronavirus Disease Database, WHO Global Index Medicus, PsycINFO, MEDLINE, and Sociological Abstracts. Grey literature will be identified using Disaster Lit, Google Scholar, governmental websites, and clinical trials registries (e.g., ClinicalTrial.gov , World Health Organization, International Clinical Trials Registry Platform, and International Standard Randomized Controlled Trial Number Registry). Study selection will conform to the Joanna Briggs Institute Reviewers' Manual 2015 Methodology for JBI Scoping Reviews. Only English language, original studies will be considered for inclusion. Two reviewers will independently screen all citations, full-text articles, and abstract data. A narrative summary of findings will be conducted. Data analysis will involve quantitative (e.g., frequencies) and qualitative (e.g., content and thematic analysis) methods. DISCUSSION: Original research is urgently needed to mitigate the risks of COVID-19 on sexual health. The planned scoping review will help to address this gap. SYSTEMATIC REVIEW REGISTRATIONS: Systematic Review Registration: Open Science Framework osf/io/PRX8E.

CSO (Canadian Society of Otolaryngology - Head & Neck Surgery) position paper on rhinologic and skull base surgery during the COVID-19 pandemic.

Healthcare services in many countries have been partially or completely disrupted by the Coronavirus (COVID-19) pandemic since its onset in the end of 2019. Amongst the most impacted are the elective medical and surgical services in order to conserve resources to care for COVID-19 patients. As the number of infected patients decrease across Canada, elective surgeries are being restarted in a staged manner. Since Otolaryngologists - Head & Neck Surgeons manage surgical diseases of the upper aerodigestive tract where the highest viral load reside, it is imperative that these surgeries resume in a safe manner. The aim of this document is to compile the current best evidence available and provide expert consensus on the safe restart of rhinologic and skull base surgeries while discussing the pre-operative, intra-operative, and post-operative care and tips. Risk assessment, patient selection, case triage, and pre-operative COVID-19 testing will be analyzed and discussed. These guidelines will also consider the optimal use of personal protective equipment for specific cases, general and specific operative room precautions, and practical tips of intra-operative maneuvers to optimize patient and provider safety. Given that the literature surrounding COVID-19 is rapidly evolving, these recommendations will serve to start our specialty back into elective rhinologic surgeries over the next months and they may change as we learn more about this disease.