Temporal trends and characteristics associated with racial, ethnic, and sex representation in COVID-19 clinical trials: A systematic review and meta-analysis.

BACKGROUND: Early in the pandemic, extensive attention was cast on limited inclusion of historically underrepresented patient populations in COVID-19 clinical trials. How diverse representation improved following these initial reports remains unclear. METHODS: PubMed, Embase and the Cochrane Library were searched (through April 2024) for US-based COVID-19 trials. Utilizing random-effects, we compared expected proportions of trial participants from racial and ethnic groups and of female sex between trials enrolling primarily in 2020 versus primarily 2021-2022. Meta-regression was performed to assess associations between trial characteristics and group representation. RESULTS: We retrieved 157 studies comprising 198,012 participants. White (2020: 63.1% [95% CI, 60.8%-67.3%]; 2021-2022: 73.8% [95% CI, 71.5%-76.0%]) and female representation (2020: 46.1% [95% CI, 44.7%-47.4%)]; 2021-2022: 51.1% [95% CI, 49.3%-52.8%) increased across enrollment periods. Industry-sponsored trials were associated with higher White (coefficient, 0.10 [95% CI, 0.03-0.18]) and Hispanic or Latinx representation (coefficient, 0.16 [95% CI, 0.08-0.25]) and lower Asian (coefficient, -0.03 [95% CI, -0.06- -0.003]) and female representation (coefficient, -0.03 [95% CI, -0.07- -0.002]). Outpatient trials were associated with higher White (coefficient, 0.20 [95% CI, 0.13-0.26]) and female representation (coefficient, 0.16 [95% CI, 0.13-0.18]), and lower Black representation (coefficient, -0.10 [95% CI, -0.10- -0.08]). CONCLUSIONS: Despite improved female representation in COVID-19 trials over time, there was no clear increase in non-White representation. Trial characteristics such as primary sponsor, clinical setting, and intervention type correlate with representation of specific demographic groups and should be considered in future efforts to improve participant diversity.

Factors Associated With Enrollment into Inpatient Coronavirus Disease 2019 Randomized Controlled Trials: A Cross-sectional Analysis.

Background: Clinical trials for coronavirus disease 2019 (COVID-19) have struggled to achieve diverse patient enrollment, despite underrepresented groups bearing the largest burden of the disease and, presumably, being most in need of the treatments under investigation. Methods: To assess the willingness of patients to enroll into inpatient COVID-19 clinical trials when invited, we conducted a cross-sectional analysis of adults hospitalized with COVID-19 who were approached regarding enrollment. Associations between patient and temporal factors and enrollment were assessed by multivariable logistic regression analysis. Results: A total of 926 patients were included in this analysis. Overall, Hispanic/Latinx ethnicity was associated with a nearly half-fold decrease in the likelihood to enroll (adjusted odds ratio [aOR], 0.60 [95% confidence interval {CI}, .41-.88]). Greater baseline disease severity (aOR, 1.09 [95% CI, 1.02-1.17]), age 40-64 years (aOR, 1.83 [95% CI, 1.03-3.25]), and age ≥65 years (aOR, 1.92 [95% CI, 1.08-3.42]) were each independently associated with higher likelihood to enroll. Over the course of the pandemic, patients were less likely to enroll during the summer 2021 wave in COVID-19-related hospitalizations (aOR, 0.14 [95% CI, .10-.19]) compared with patients from the first wave in winter 2020. Conclusions: The decision to enroll into clinical trials is multifactorial. Amid a pandemic disproportionately affecting vulnerable groups, Hispanic/Latinx patients were less likely to participate when invited, whereas older adults were more likely. Future recruitment strategies must consider the nuanced perceptions and needs of diverse patient populations to ensure equitable trial participation that advances the quality of healthcare for all.

A Pilot Trial of Thymalfasin (Thymosin-α-1) to Treat Hospitalized Patients With Hypoxemia and Lymphocytopenia Due to Coronavirus Disease 2019 Infection.

BACKGROUND: Thymosin-α-1 (Tα1) may be a treatment option for coronavirus disease 2019 (COVID-19), but efficacy and safety data remain limited. METHODS: Prospective, open-label, randomized trial assessing preliminary efficacy and safety of thymalfasin (synthetic form of Tα1), compared with the standard of care, among hospitalized patients with hypoxemia and lymphocytopenia due to COVID-19. RESULTS: A total of 49 patients were included in this analysis. Compared with control patients, the incidence of clinical recovery was higher for treated patients with either baseline low-flow oxygen (subdistribution hazard ratio, 1.48 [95% confidence interval, .68-3.25]) or baseline high-flow oxygen (1.28 [.35-4.63]), although neither difference was significant. Among patients with baseline low-flow oxygen, treated patients, compared with control patients, had an average difference of 3.84 times more CD4+ T cells on day 5 than on day 1 (P = .01). Nine serious adverse events among treated patients were deemed not related to Tα1. CONCLUSIONS: Tα1 increases CD4+ T-cell count among patients with baseline low-flow oxygen support faster than the standard of care and may have a role in the management of hospitalized patients with hypoxemia and lymphocytopenia due to COVID-19. CLINICAL TRIALS REGISTRATION: NCT04487444.

Targeted therapies in CLL/SLL and the cumulative incidence of infection: A systematic review and meta-analysis.

Background: Patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) are prone to infections. Aims: Provide a pooled estimate of the cumulative incidence for infections that fulfilled the criteria associated with severe infectious adverse events for grade 3 or higher (including pneumonia, febrile neutropenia and sepsis) in patients who receive targeted therapies. Methods: We searched PubMed and EMBASE for randomized controlled trials (RCT) that included patients with CLL/SLL who received targeted therapies and performed a random-effects meta-analysis to estimate the cumulative incidence of infections. Results: Of 2,914 studies screened, we retrieved 31 which evaluated 11,660 patients. The pooled cumulative incidence of infections for patients who received treatment regimens based on a BTK inhibitors was 19.86%. For patients who received treatment based on rituximab and second generation anti-CD20 monoclonal antibodies, the pooled cumulative incidence of infections was 19.85 and 13.46%, respectively. Regarding PI3K inhibitor-based regimens the cumulative incidence of severe infections was 30.89%. BCL-2 inhibitors had a cumulative incidence of infections of 17.49% while lenalidomide and alemtuzumab had an incidence of 13.33 and 45.09%, respectively. The cumulative incidence of pneumonia ranged from 3.01 to 8.45% while febrile neutropenia ranged from 2.68 to 10.80%. Regarding sepsis, the cumulative incidence ranged from 0.9 to 4.48%. Conclusion: Patients with CLL/SLL who receive targeted therapies may develop severe infections at significant rates that, in addition to disease stage and other complications, depend on the mechanism of action of the used drug. Surveillance for infections and development of effective prophylactic strategies are critical for patients with CLL/SLL who receive targeted therapies. Systematic Review Registration: [https://systematicreview.gov/], identifier [registration number].

Filamentous bacteriophage delays healing of Pseudomonas-infected wounds.

Chronic wounds infected by Pseudomonas aeruginosa (Pa) are characterized by disease progression and increased mortality. We reveal Pf, a bacteriophage produced by Pa that delays healing of chronically infected wounds in human subjects and animal models of disease. Interestingly, impairment of wound closure by Pf is independent of its effects on Pa pathogenesis. Rather, Pf impedes keratinocyte migration, which is essential for wound healing, through direct inhibition of CXCL1 signaling. In support of these findings, a prospective cohort study of 36 human patients with chronic Pa wound infections reveals that wounds infected with Pf-positive strains of Pa are more likely to progress in size compared with wounds infected with Pf-negative strains. Together, these data implicate Pf phage in the delayed wound healing associated with Pa infection through direct manipulation of mammalian cells. These findings suggest Pf may have potential as a biomarker and therapeutic target in chronic wounds.

Risk Factors for Hospital Readmission for Clostridioides difficile Infection: A Statewide Retrospective Cohort Study.

(1) Background: Clostridioides difficile infection (CDI) is associated with a high recurrence rate, and a significant proportion of patients with CDI are readmitted following discharge. We aimed to identify the risk factors for CDI-related readmission within 90 days following an index hospital stay for CDI. (2) Methods: We analyzed the electronic medical data of admitted patients in our health system over a two-year period. A multivariate logistic regression model, supplemented with bias-corrected and accelerated confidence intervals (BCa-CI), was implemented to assess the risk factors. (3) Results: A total of 1253 adult CDI index cases were included in the analysis. The readmission rate for CDI within 90 days of discharge was 11% (140/1253). The risk factors for CDI-related readmission were fluoroquinolone exposure within 90 days before the day of index CDI diagnosis (aOR: 1.58, 95% CI: 1.05-2.37), higher Elixhauser comorbidity score (aOR: 1.05, 95% CI: 1.02-1.07), and being discharged home (aOR: 1.64, 95% CI: 1.06-2.54). In contrast, a longer length of index stay (aOR: 0.97, 95% BCa-CI: 0.95-0.99) was associated with reduced odds of readmission for CDI. (4) Conclusion: More than 1 out of 10 patients were readmitted for CDI following an index hospital stay for CDI. Patients with recent previous fluoroquinolone exposure, greater overall comorbidity burden, and those discharged home are at higher risk of readmission for CDI.

Clinical Outcomes Associated with SARS-CoV-2 Co-Infection with Rhinovirus and Adenovirus in Adults-A Retrospective Matched Cohort Study.

(1) Background: Respiratory co-infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other viruses are common, but data on clinical outcomes and laboratory biomarkers indicative of disease severity are limited. We aimed to compare clinical outcomes and laboratory biomarkers of patients with SARS-CoV-2 alone to those of patients with SARS-CoV-2 and either rhinovirus or adenovirus. (2) Methods: Hospitalized patients co-infected with SARS-CoV-2 and rhinovirus and patients co-infected with SARS-CoV-2 and adenovirus were matched to patients infected with SARS-CoV-2 alone. Outcomes of interest were the cumulative incidences of mechanical ventilation use, intensive care unit (ICU) admission, 30-day all-cause mortality, and 30-day all-cause readmission from the day of discharge. We also assessed differences in laboratory biomarkers from the day of specimen collection. (3) Results: Patients co-infected with SARS-CoV-2 and rhinovirus, compared with patients infected with SARS-CoV-2, had significantly greater 30-day all-cause mortality (8/23 (34.8%) vs. 8/69 (11.6%), p = 0.02). Additionally, median alanine transaminase (13 IU/L vs. 24 IU/L, p = 0.03), aspartate transaminase (25 IU/L vs. 36 IU/L, p = 0.04), and C-reactive protein (34.86 mg/L vs. 94.68 mg/L, p = 0.02) on day of specimen collection were significantly lower in patients co-infected with SARS-CoV-2 and rhinovirus in comparison to patients infected with SARS-CoV-2 alone. Clinical outcomes and laboratory markers did not differ significantly between patients with SARS-CoV-2 and adenovirus co-infection and patients with SARS-CoV-2 mono-infection. (4) Conclusion: SARS-CoV-2 and rhinovirus co-infection, compared with SARS-CoV-2 mono-infection alone, is positively associated with 30-day all-cause mortality among hospitalized patients. However, our lack of significant findings in our analysis of patients with SARS-CoV-2 and adenovirus co-infection may suggest that SARS-CoV-2 co-infections have variable significance, and further study is warranted.

Hyaluronan synthesis inhibition impairs antigen presentation and delays transplantation rejection.

A coat of pericellular hyaluronan surrounds mature dendritic cells (DC) and contributes to cell-cell interactions. We asked whether 4-methylumbelliferone (4MU), an oral inhibitor of HA synthesis, could inhibit antigen presentation. We find that 4MU treatment reduces pericellular hyaluronan, destabilizes interactions between DC and T-cells, and prevents T-cell proliferation in vitro and in vivo. These effects were observed only when 4MU was added prior to initial antigen presentation but not later, consistent with 4MU-mediated inhibition of de novo antigenic responses. Building on these findings, we find that 4MU delays rejection of allogeneic pancreatic islet transplant and allogeneic cardiac transplants in mice and suppresses allogeneic T-cell activation in human mixed lymphocyte reactions. We conclude that 4MU, an approved drug, may have benefit as an adjunctive agent to delay transplantation rejection.