An Overview of Current Clinical Trials of Agents for the Treatment and Prevention of COVID-19 in the United States

Introduction: Given the rapid worldwide spread of SARS-CoV-2 and the attendant risks for severe complications and mortality, numerous clinical trials for its treatment and prevention have been generated in a short period. This report focuses on the categories of the wide spectrum of agents being studied in the United States and the intensity of effort involved with each so that clinicians may consider whether suggesting enrollment may be appropriate for their patients. Methods: A search was completed of the ClinicalTrials.gov database on May 28, 2020 for all such trials underway as of that date in the US. A total 190 trials were identified; of these, 151 trials that included 83 distinct agents met the specified delimiting criteria. The salient features of each, including medication class, the total number of trials involving either treatment or ongoing prevention strategies, and the total patient enrollment, were captured in a summary table. Comprehensive descriptors of all 190 trials are made available in an appendix. Results: The antimalarial agent hydroxychloroquine was the most frequently studied single agent by both number of trials and number of subjects involved. Antivirals were the next largest group, followed by immunomodulators, antibacterials, vaccines, renin-angiotensin-aldosterone system (RAAS) antagonists, and convalescent plasma. Of note, repurposed antineoplastic agents, stem cell therapies, steroids, and a diverse range of miscellaneous agents were also included in the list. Conclusions: The agents currently under study for the prevention or treatment of COVID-19 include several highly publicized pharmaceuticals as well as a wide array of other experimental medications and novel applications of established drugs. In the absence of an approved vaccine at this time, it is essential that clinicians be aware of the range of trials from which important new therapeutic and prophylactic advances may rapidly emerge

Epidemiology and Outcomes of Hospitalized Adults with SARS-CoV-2 Community-Acquired Pneumonia in Louisville, Kentucky

Background: During the ongoing pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), SARS-CoV-2 community-acquired pneumonia (CAP) has been the primary cause of hospitalization. The objective of this study was to evaluate the clinical characteristics and outcomes of 1,013 patients hospitalized with SARS-CoV-2 CAP from September 2020 through March 2021 in Louisville, Kentucky. Methods: This was a retrospective observational study of 1,013 patients hospitalized with SARS-CoV-2 CAP at eight of the adult hospitals in the city of Louisville from September 2020 through March 2021. Patients with 1) a positive reverse transcriptase-polymerase chain reaction (RT-PCR) for SARS-CoV-2, 2) fever, cough, or shortness of breath, and 3) an infiltrate on chest imaging were defined as having SARS-CoV-2 CAP. Data were abstracted from each hospital’s electronic health record. Descriptive statistics were performed on clinical and epidemiological characteristics of hospitalized patients with SARS-CoV-2 CAP. Demographic characteristics of the study population were compared with census data from the city of Louisville. Data were analyzed by descriptive and inferential statistics using R version 3.4.0. Results: Of the 1,013 patients hospitalized with SARS-CoV-2 CAP, the median age was 65 years, 53% were males, 24% reported their race as African American or Black, and 6% identified as Hispanic. The most frequent comorbidities were hypertension (73%), obesity (56%), and diabetes (43%). At the time of admission, 60% required supplemental oxygen. The mortality rate was 19% for the total population and 45% for the 359 patients admitted to the intensive care unit (ICU). For each comorbidity, the proportion of hospitalized patients with SARS-CoV-2 CAP was significantly different from the Louisville population (P Conclusions: The elderly, males, and patients with a history of coronary artery disease, cerebrovascular disease, chronic obstructive pulmonary disease, hypertension, diabetes, renal disease, or obesity are overrepresented among hospitalized patients with SARS-CoV-2 CAP compared to the Louisville population. These patients are also more likely to require ICU care and experience worse clinical outcomes, with death occurring in approximately one in every five hospitalizations

Transcriptional networks in at-risk individuals identify signatures of type 1 diabetes progression.

Type 1 diabetes (T1D) is a disease of insulin deficiency that results from autoimmune destruction of pancreatic islet β cells. The exact cause of T1D remains unknown, although asymptomatic islet autoimmunity lasting from weeks to years before diagnosis raises the possibility of intervention before the onset of clinical disease. The number, type, and titer of islet autoantibodies are associated with long-term disease risk but do not cause disease, and robust early predictors of individual progression to T1D onset remain elusive. The Environmental Determinants of Diabetes in the Young (TEDDY) consortium is a prospective cohort study aiming to determine genetic and environmental interactions causing T1D. Here, we analyzed longitudinal blood transcriptomes of 2013 samples from 400 individuals in the TEDDY study before both T1D and islet autoimmunity. We identified and interpreted age-associated gene expression changes in healthy infancy and age-independent changes tracking with progression to both T1D and islet autoimmunity, beginning before other evidence of islet autoimmunity was present. We combined multivariate longitudinal data in a Bayesian joint model to predict individual risk of T1D onset and validated the association of a natural killer cell signature with progression and the model's predictive performance on an additional 356 samples from 56 individuals in the independent Type 1 Diabetes Prediction and Prevention study. Together, our results indicate that T1D is characterized by early and longitudinal changes in gene expression, informing the immunopathology of disease progression and facilitating prediction of its course.The TEDDY Study is funded by U01 DK63829, U01 DK63861, U01 DK63821, U01 DK63865, U01 DK63863, U01 DK63836, U01 DK63790, UC4 DK63829, UC4 DK63861, UC4 DK63821, UC4 DK63865, UC4 DK63863, UC4 DK63836, UC4 DK95300, UC4 DK100238, UC4 DK106955, UC4 DK112243, UC4 DK117483, and Contract No. HHSN267200700014C from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of Allergy and Infectious Diseases (NIAID), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institute of Environmental Health Sciences (NIEHS), Centers for Disease Control and Prevention (CDC), and JDRF. This work supported in part by the NIH/NCATS Clinical and Translational Science Awards to the University of Florida (UL1 TR000064) and the University of Colorado (UL1 TR001082). KGCS is a Lister Prize fellow and is supported by a Wellcome Trust Senior Investigator award (200871/Z/16/Z). EFM is a Wellcome-Beit prize fellow (10406/Z/14/A) supported by the Wellcome Trust and Beit Foundation (10406/Z/14/Z) and by the National Institutes for Health Research Biomedical Research Centre (Cambridge). LPX’s affiliation changed after completion of the manuscript and is now Département d'informatique et de recherche opérationnelle, Université de Montréal, Montréal, Canada and Mila, Quebec Institute for Learning Algorithms, Montréal, Canada

Characteristics and Outcomes of Adults Hospitalized with SARS-CoV-2 Community-Acquired Pneumonia in Louisville, Kentucky

Background: Patients infected with the novel coronavirus SARS-CoV-2 are frequently hospitalized with community-acquired pneumonia (CAP). The objective of this study was to define the clinical characteristics and outcomes of hospitalized patients with SARS-CoV-2 CAP in the city of Louisville, KY. Methods: This was a retrospective observational study of 700 patients with SARS-CoV-2 infection hospitalized to eight of the adult hospitals in the city of Louisville. Patients with 1) a positive RT-PCR for SARS-CoV-2, 2) fever, cough, or shortness of breath, and 3) an infiltrate at chest imaging were defined as having SARS-CoV-2 CAP. Demographic characteristics of the study population were compared with census data from the city of Louisville. For each patient more than 500 variables were abstracted from electronic medical records and recorded using Research Electronic Data Capture software. Data was analyzed by descriptive and inferential statistics using R version 3.4.0. Results: SARS-CoV-2 CAP was identified in 632 (90%) patients hospitalized with COVID-19. The median age of the patients was 63 years, 53% were females, 31% were black and 12% Hispanic. The most frequent comorbidities were hypertension (56%), obesity (50%), and diabetes (33%). Mortality was 17% for the total population and 34% for the 249 patients admitted to ICU. For each category of race, ethnicity and comorbidities, the proportion of hospitalized patients with SARS-CoV-2 CAP was significantly different when compared to the Louisville population (p \u3c 0.001). Conclusion: Patients of black race, Hispanic ethnicity, and patients with history of hypertension, obesity or diabetes are overrepresented among hospitalized patients with SARS-CoV-2 CAP when compared to the Louisville population. Hospitalized patients with SARS-CoV-2 CAP are likely to require ICU care, with death occurring in approximately one of six hospitalizations

No difference in clinical outcomes for African American and White patients hospitalized with SARS-CoV-2 pneumonia in Louisville, Kentucky

Introduction: Current literature indicates that African American individuals are at increased risk of becoming infected with the SARS-CoV-2 virus and suffer higher SARS-CoV-2-related mortality rates. However, there is a lack of consensus as to how the clinical outcomes of African American patients differ from those of other groups. The objective of this study was to define the clinical outcomes of African American and White hospitalized patients with SARS-CoV-2 community-acquired pneumonia (CAP) in Louisville, Kentucky. Methods: This was a retrospective cohort study of hospitalized patients with SARS-CoV-2 CAP at eight hospitals in Louisville, Kentucky. Severity of CAP at time of hospitalization was evaluated using the pneumonia severity index (PSI), CURB-65 score and SARS-CoV-2 viral load. The following thirteen clinical outcomes were compared: discharge alive to home, time to home discharge, admission to the ICU, length of ICU stay, need for invasive mechanical ventilation (IMV), duration of IMV, development of acute respiratory distress syndrome (ARDS), development of septic shock, need for vasopressors, development of cardiovascular events, time to cardiovascular events, in-hospital mortality, and time to death. Results: A total of 541 patients were eligible for this study, 343 White (63%) and 198 African American (37%). None of the thirteen clinical outcomes were statistically significantly different between the two groups. Conclusions: This study indicates that African American and White patients do not have different clinical outcomes after the point of hospitalization due to SARS-CoV-2 CAP

Genome-Wide Association of Bipolar Disorder Suggests an Enrichment of Replicable Associations in Regions near Genes

Although a highly heritable and disabling disease, bipolar disorder's (BD) genetic variants have been challenging to identify. We present new genotype data for 1,190 cases and 401 controls and perform a genome-wide association study including additional samples for a total of 2,191 cases and 1,434 controls. We do not detect genome-wide significant associations for individual loci; however, across all SNPs, we show an association between the power to detect effects calculated from a previous genome-wide association study and evidence for replication (P = 1.5×10−7). To demonstrate that this result is not likely to be a false positive, we analyze replication rates in a large meta-analysis of height and show that, in a large enough study, associations replicate as a function of power, approaching a linear relationship. Within BD, SNPs near exons exhibit a greater probability of replication, supporting an enrichment of reproducible associations near functional regions of genes. These results indicate that there is likely common genetic variation associated with BD near exons (±10 kb) that could be identified in larger studies and, further, provide a framework for assessing the potential for replication when combining results from multiple studies

Facial Mask Use and COVID-19 Protection Measures in Jefferson County, Kentucky: Results from an Observational Survey, November 5−11, 2020

Introduction: The transmission of respiratory infectious diseases such as COVID-19 can significantly decrease by mask-wearing. However, accurate information about the extent and proper use of the facial mask is scarce. This study’s main objective was to observe and analyze mask-wearing behavior and the level of COVID-19 protection measures in indoor public areas (PAs) of Jefferson County, Kentucky. Methods: For conducting the observational survey study, targets were indoor PAs, and zip codes were defined as surveying clusters. The number of selected PAs in each zip code was proportional to the population and the total number of PAs in that zip code. The PA pool in a zip code was divided into four groups, followed by random selection without replacement from each group. Results: A total of 191 PAs were surveyed: 50 of them were grocery stores, 56 were convenience stores or pharmacies, 39 were wine and liquor stores, and 46 were other stores. At least one unmasked and one incorrectly masked staff were observed in 26% and 40% of the sampled PAs, respectively. Also, in 29% and 35% of the PAs, at least one unmasked and one incorrectly masked visitor were observed, respectively. The rates varied by PA size and county district. Eighty percent of unmasked staff and 75% of the unmasked visitors were male. The rate of unmasked males varied from 50% to 100% across districts. About 66% of unmasked staff among all Jefferson County districts were young adults. More than one-fourth of all the PAs provided hand sanitizer for visitors’ use, and only 2% of the PAs provided masks to their visitors. Conclusion: Messaging about mask use and correct usage may need to particularly target the 19-44-year-old male population, as these individuals were the most prevalent among those unmasked and masked incorrectly. Additionally, businesses’ protective measures may depend on their resources to operate in such a manner. Hand sanitizer is easier to offer visitors, while staffing to regularly sanitize carts or funds to provide a sufficient number of wipes, gloves, or masks may present further opportunities for government assistance

How should beta-diversity inform biodiversity conservation?

To design robust protected area networks, accurately measure species losses, or understand the processes that maintain species diversity, conservation science must consider the organization of biodiversity in space. Central is beta-diversity - the component of regional diversity that accumulates from compositional differences between local species assemblages. We review how beta-diversity is impacted by human activities, including farming, selective logging, urbanization, species invasions, overhunting, and climate change. Beta-diversity increases, decreases, or remains unchanged by these impacts, depending on the balance of processes that cause species composition to become more different (biotic heterogenization) or more similar (biotic homogenization) between sites. While maintaining high beta-diversity is not always a desirable conservation outcome, understanding beta-diversity is essential for protecting regional diversity and can directly assist conservation planning. Beta-diversity reveals the spatial scaling of diversity loss.Beta-diversity illuminates mechanisms of regional diversity maintenance.Human activities cause beta-diversity to increase, decrease, or remain unchanged.Conservation significance of beta-diversity shift depends on local diversity dynamics

The American Congress of Rehabilitation Medicine Diagnostic Criteria for Mild Traumatic Brain Injury

Objective: To develop new diagnostic criteria for mild traumatic brain injury (TBI) that are appropriate for use across the lifespan and in sports, civilian trauma, and military settings. Design: Rapid evidence reviews on 12 clinical questions and Delphi method for expert consensus. Participants: The Mild Traumatic Brain Injury Task Force of the American Congress of Rehabilitation Medicine Brain Injury Special Interest Group convened a Working Group of 17 members and an external interdisciplinary expert panel of 32 clinician-scientists. Public stakeholder feedback was analyzed from 68 individuals and 23 organizations. Results: The first 2 Delphi votes asked the expert panel to rate their agreement with both the diagnostic criteria for mild TBI and the supporting evidence statements. In the first round, 10 of 12 evidence statements reached consensus agreement. Revised evidence statements underwent a second round of expert panel voting, where consensus was achieved for all. For the diagnostic criteria, the final agreement rate, after the third vote, was 90.7%. Public stakeholder feedback was incorporated into the diagnostic criteria revision prior to the third expert panel vote. A terminology question was added to the third round of Delphi voting, where 30 of 32 (93.8%) expert panel members agreed that ‘the diagnostic label ‘concussion’ may be used interchangeably with ‘mild TBI’ when neuroimaging is normal or not clinically indicated.’ Conclusions: New diagnostic criteria for mild TBI were developed through an evidence review and expert consensus process. Having unified diagnostic criteria for mild TBI can improve the quality and consistency of mild TBI research and clinical care.</p