Abatacept Pharmacokinetics and Exposure Response in Patients Hospitalized With COVID-19: A Secondary Analysis of the ACTIV-1 IM Randomized Clinical Trial.

Importance: The pharmacokinetics of abatacept and the association between abatacept exposure and outcomes in patients with severe COVID-19 are unknown. Objective: To characterize abatacept pharmacokinetics, relate drug exposure with clinical outcomes, and evaluate the need for dosage adjustments. Design, Setting, and Participants: This study is a secondary analysis of data from the ACTIV-1 (Accelerating COVID-19 Therapeutic Interventions and Vaccines) Immune Modulator (IM) randomized clinical trial conducted between October 16, 2020, and December 31, 2021. The trial included hospitalized adults who received abatacept in addition to standard of care for treatment of COVID-19 pneumonia. Data analysis was performed between September 2022 and February 2024. Exposure: Single intravenous infusion of abatacept (10 mg/kg with a maximum dose of 1000 mg). Main Outcomes and Measures: Mortality at day 28 was the primary outcome of interest, and time to recovery at day 28 was the secondary outcome. Drug exposure was assessed using the projected area under the serum concentration time curve over 28 days (AUC0-28). Logistic regression modeling was used to analyze the association between drug exposure and 28-day mortality, adjusted for age, sex, and disease severity. The association between time to recovery and abatacept exposure was examined using Fine-Gray modeling with death as a competing risk, and was adjusted for age, sex, and disease severity. Results: Of the 509 patients who received abatacept, 395 patients with 848 serum samples were included in the population pharmacokinetic analysis. Their median age was 55 (range, 19-89) years and most (250 [63.3%]) were men. Abatacept clearance increased with body weight and more severe disease activity at baseline. Drug exposure was higher in patients who survived vs those who died, with a median AUC0-28 of 21 428 (range, 8462-43 378) mg × h/L vs 18 262 (range, 9628-27 507) mg × h/L (P < .001). Controlling for age, sex, and disease severity, an increase of 5000 units in AUC0-28 was associated with lower odds of mortality at day 28 (OR, 0.52 [95% CI, 0.35-0.79]; P = .002). For an AUC0-28 of 19 400 mg × h/L or less, there was a higher probability of recovery at day 28 (hazard ratio, 2.63 [95% CI, 1.70-4.08] for every 5000-unit increase; P < .001). Controlling for age, sex, and disease severity, every 5000-unit increase in AUC0-28 was also associated with lower odds of a composite safety event at 28 days (OR, 0.46 [95% CI, 0.33-0.63]; P < .001). Using the dosing regimen studied in the ACTIV-1 IM trial, 121 of the 395 patients (30.6%) would not achieve an abatacept exposure of at least 19 400 mg × h/L, particularly at the extremes of body weight. Using a modified, higher-dose regimen, only 12 patients (3.0%) would not achieve the hypothesized target abatacept exposure. Conclusions and Relevance: In this study, patients who were hospitalized with severe COVID-19 and achieved higher projected abatacept exposure had reduced mortality and a higher probability of recovery with fewer safety events. However, abatacept clearance was high in this population, and the current abatacept dosing (10 mg/kg intravenously with a maximum of 1000 mg) may not achieve optimal exposure in all patients. Trial Registration: ClinicalTrials.gov Identifier: NCT04593940.

Abatacept, Cenicriviroc, or Infliximab for Treatment of Adults Hospitalized With COVID-19 Pneumonia: A Randomized Clinical Trial.

Importance: Immune dysregulation contributes to poorer outcomes in COVID-19. Objective: To investigate whether abatacept, cenicriviroc, or infliximab provides benefit when added to standard care for COVID-19 pneumonia. Design, Setting, and Participants: Randomized, double-masked, placebo-controlled clinical trial using a master protocol to investigate immunomodulators added to standard care for treatment of participants hospitalized with COVID-19 pneumonia. The results of 3 substudies are reported from 95 hospitals at 85 clinical research sites in the US and Latin America. Hospitalized patients 18 years or older with confirmed SARS-CoV-2 infection within 14 days and evidence of pulmonary involvement underwent randomization between October 2020 and December 2021. Interventions: Single infusion of abatacept (10 mg/kg; maximum dose, 1000 mg) or infliximab (5 mg/kg) or a 28-day oral course of cenicriviroc (300-mg loading dose followed by 150 mg twice per day). Main Outcomes and Measures: The primary outcome was time to recovery by day 28 evaluated using an 8-point ordinal scale (higher scores indicate better health). Recovery was defined as the first day the participant scored at least 6 on the ordinal scale. Results: Of the 1971 participants randomized across the 3 substudies, the mean (SD) age was 54.8 (14.6) years and 1218 (61.8%) were men. The primary end point of time to recovery from COVID-19 pneumonia was not significantly different for abatacept (recovery rate ratio [RRR], 1.12 [95% CI, 0.98-1.28]; P = .09), cenicriviroc (RRR, 1.01 [95% CI, 0.86-1.18]; P = .94), or infliximab (RRR, 1.12 [95% CI, 0.99-1.28]; P = .08) compared with placebo. All-cause 28-day mortality was 11.0% for abatacept vs 15.1% for placebo (odds ratio [OR], 0.62 [95% CI, 0.41-0.94]), 13.8% for cenicriviroc vs 11.9% for placebo (OR, 1.18 [95% CI 0.72-1.94]), and 10.1% for infliximab vs 14.5% for placebo (OR, 0.59 [95% CI, 0.39-0.90]). Safety outcomes were comparable between active treatment and placebo, including secondary infections, in all 3 substudies. Conclusions and Relevance: Time to recovery from COVID-19 pneumonia among hospitalized participants was not significantly different for abatacept, cenicriviroc, or infliximab vs placebo. Trial Registration: ClinicalTrials.gov Identifier: NCT04593940.

A Conceptual Framework for Instructional Design of a High Acuity and Low Occurrence Event - Simulation Based Education Training of Residents, Medical Students, and Nurses in Anaphylaxis Utilizing Curated Educational Theories.

The broad goal of this educational curriculum is utilization and optimization of Simulation-Based Education (SBE) in the training of residents, medical students, and nursing staff involved in the rapid and timely recognition of Anaphylaxis and its optimized treatment. A critical gap in Anaphylaxis Diagnosis, Management, and Treatment (ADAM) has been well established across medical disciplines. It is imperative to include all members of the healthcare team, as nurses and pharmacists play key roles in anaphylaxis recognition and care. Nurses and pharmacists are proficiently trained in the initial assessment of acute patient complaints, status, and in proper dosing/administration considerations. Anaphylaxis is a High Acuity and Low Occurrence (HALO) event. Delayed recognition and administration of epinephrine-autoinjector (EAI) is a patient safety concern. Suboptimal technique and expertise in this regard is common. Literature abounds with reports of physician trainee doubts and uncertainties in the recognition and optimized management of Anaphylaxis. Importantly, Anaphylaxis is frequently misdiagnosed in hospital emergency departments. SBE methodologies are ideal for instructing HALO experiences. The framework of the "Zone of Simulation Matrix" supports the utilization of a simulation experience in this instance. Learning will be effective, enhanced, and made durable by embedding numerous specifically curated educational theories. Given the paucity in training of residents and nursing staff in Anaphylaxis, such instruction is imperative. Of note, a special emphasis in this curricular framework is the debriefing experience. Considerations will be given to the psychological safety of the trainees and the importance of the heterogeneity of prior experiences. Precise diagnosis minimizes mortality. In the hospital setting, nurses are the first responders to critical HALO events, and there is a lack of awareness of ADAM by nursing students.

Abatacept for Treatment of Adults Hospitalized with Moderate or Severe Covid-19.

Background: We investigated whether abatacept, a selective costimulation modulator, provides additional benefit when added to standard-of-care for patients hospitalized with Covid-19. Methods: We conducted a master protocol to investigate immunomodulators for potential benefit treating patients hospitalized with Covid-19 and report results for abatacept. Intravenous abatacept (one-time dose 10 mg/kg, maximum dose 1000 mg) plus standard of care (SOC) was compared with shared placebo plus SOC. Primary outcome was time-to-recovery by day 28. Key secondary endpoints included 28-day mortality. Results: Between October 16, 2020 and December 31, 2021, a total of 1019 participants received study treatment (509 abatacept; 510 shared placebo), constituting the modified intention-to-treat cohort. Participants had a mean age 54.8 (SD 14.6) years, 60.5% were male, 44.2% Hispanic/Latino and 13.7% Black. No statistically significant difference for the primary endpoint of time-to-recovery was found with a recovery-rate-ratio of 1.14 (95% CI 1.00-1.29; p=0.057) compared with placebo. We observed a substantial improvement in 28-day all-cause mortality with abatacept versus placebo (11.0% vs. 15.1%; odds ratio [OR] 0.62 [95% CI 0.41- 0.94]), leading to 38% lower odds of dying. Improvement in mortality occurred for participants requiring oxygen/noninvasive ventilation at randomization. Subgroup analysis identified the strongest effect in those with baseline C-reactive protein >75mg/L. We found no statistically significant differences in adverse events, with safety composite index slightly favoring abatacept. Rates of secondary infections were similar (16.1% for abatacept; 14.3% for placebo). Conclusions: Addition of single-dose intravenous abatacept to standard-of-care demonstrated no statistically significant change in time-to-recovery, but improved 28-day mortality. Trial registration: ClinicalTrials.gov ( NCT04593940 ).

Infliximab for Treatment of Adults Hospitalized with Moderate or Severe Covid-19.

Background: Immune dysregulation contributes to poorer outcomes in severe Covid-19. Immunomodulators targeting various pathways have improved outcomes. We investigated whether infliximab provides benefit over standard of care. Methods: We conducted a master protocol investigating immunomodulators for potential benefit in treatment of participants hospitalized with Covid-19 pneumonia. We report results for infliximab (single dose infusion) versus shared placebo both with standard of care. Primary outcome was time to recovery by day 29 (28 days after randomization). Key secondary endpoints included 14-day clinical status and 28-day mortality. Results: A total of 1033 participants received study drug (517 infliximab, 516 placebo). Mean age was 54.8 years, 60.3% were male, 48.6% Hispanic or Latino, and 14% Black. No statistically significant difference in the primary endpoint was seen with infliximab compared with placebo (recovery rate ratio 1.13, 95% CI 0.99-1.29; p=0.063). Median (IQR) time to recovery was 8 days (7, 9) for infliximab and 9 days (8, 10) for placebo. Participants assigned to infliximab were more likely to have an improved clinical status at day 14 (OR 1.32, 95% CI 1.05-1.66). Twenty-eight-day mortality was 10.1% with infliximab versus 14.5% with placebo, with 41% lower odds of dying in those receiving infliximab (OR 0.59, 95% CI 0.39-0.90). No differences in risk of serious adverse events including secondary infections. Conclusions: Infliximab did not demonstrate statistically significant improvement in time to recovery. It was associated with improved 14-day clinical status and substantial reduction in 28- day mortality compared with standard of care. Trial registration: ClinicalTrials.gov ( NCT04593940 ).

A Guide for Medical Students and Residents Preparing for Formative, Summative, and Virtual Objective Structured Clinical Examination (OSCE): Twenty Tips and Pointers.

The most important core competencies for medical learners to master are reviewing history, performing physical examination, communication skills and clinical reasoning. The Objective Structured Clinical Examination (OSCE) provides a consistent, reliable, and valid assessment of these integrated skills and is considered to be the gold standard. OSCEs are advantageous because they provide opportunities in evaluating skills that written tests cannot do (stage 3 of Miller's Pyramid of Learning). In this article, we have provided tips and helpful pointers to medical students and residents, based on available literature and authors' expertise in managing formative, summative, and virtual OSCE experiences. In virtual OSCEs, in-person learning objectives need to be modified to the virtual milieu and new competencies such as "webside manner" need to be introduced. Harmonizing the process and content of the OSCEs create operational challenges, thus learning the various moving parts of the OSCEs such as psychometrics, tasks of the standardized patients and checklists will ease optimal performance.

Perspectives on Transitioning Step 1 of the United States Medical Licensing Examination to a Pass/Fail Scoring Model: Defining New Frameworks for Medical Students Applying for Residency.

For years, the USMLE Step 1 has acted as an unofficial "concours" for medical students applying to residency positions in the United States. The three-digit numeric score has been used to rank thousands of applicants without any evidence of validity. The USMLE will soon change score reporting to a pass/fail outcome. The main reason given was to address the concerns about its effects on the well-being of the students and medical education. It is argued that time for change has come. The authors discuss the various viewpoints of the stakeholders and the effects of this change on applicants and potential changes on the undergraduate medical curriculum. Furthermore, this article discusses several metrics that can be utilized in the application process in lieu of the USMLE Step 1. Additionally, some novel key metrics in the application process are identified, and their unique dynamic and adaptive characteristics are deliberated. Finally, the benefits of a transparent and holistic process are strongly advocated.

The association of D-dimer levels with clinical outcomes in patients presenting with acute pulmonary embolism.

The D-dimer fragment of fibrin degradation has been a useful adjunct in the diagnosis of venous thromboembolism (VTE). In conjunction with predictive algorithms, the high negative predictive value (NPV) of D-dimer measurements has provided this analyte with a prominent position in the diagnosis of pulmonary embolism (PE). The purpose of this study was to determine if D-dimer levels correlate with ventilation/perfusion (V/Q) derangements as assessed by the alveolar-arterial oxygen tension gradient (DeltaA-a) and to ascertain if quantitative measurements of D-dimer on admission have prognostic value in terms of during-admission mortality and recurrence over a 60-week period. The study utilized a retrospective cohort of 108 subjects admitted to a single institution and studied longitudinally. The cohort was divided into 4 groups representing degree of severity assessed by computed tomographic (CT) angiography: mild, moderate, severe, and very severe. Differences in D-dimer levels among these groups were strongly significant (P < .0001). A strong correlation was observed between D-dimer concentration and DeltaA-a (P < .0001). Logistic methods were used to calculate a "cut-off" level that would distinguish mild-moderate from severe-very severe PE. At a concentration of 12.35 mug/mL, this level yielded an odds ratio (OR) of 12.64 (P = .006) for during-admission mortality and a hazard ratio (HR) of 0.13 (P < .0001) for 60-week recurrence. These data suggest that D-dimer levels have utility beyond their NPV and should be considered as potential prognostic markers in subjects presenting with acute PE.

Efficacy of an expanded ventilator bundle for the reduction of ventilator-associated pneumonia in the medical intensive care unit.

The ventilator bundle (VB) includes a group of clinical maneuvers (head-of-bed elevation, "sedation vacation," deep vein thrombosis prophylaxis, and peptic ulcer disease prophylaxis) to improve outcomes in patients undergoing mechanical ventilation. We modified the standard VB in our medical intensive care unit to include a group of respiratory therapist-driven protocols and, postimplementation, observed a statistically significant (P = .0006) reduction in ventilator-associated pneumonia (VAP), from a median of 14.1 cases/10(3) ventilator-days (interquartile range [IQR] = 12.1 to 20.6) to 0 cases/10(3) ventilator-days (IQR = 0 to 1.1).