A randomized, double-blinded, placebo-controlled clinical trial of sterile filtered human amniotic fluid for treatment of COVID-19.

IMPORTANCE: Acellular human amniotic fluid (hAF) is an antimicrobial and anti-inflammatory fluid that has been used to treat various pro-inflammatory conditions. In a feasibility study, we have previously demonstrated that hAF could be safely administered to severely ill patients with coronavirus disease-19 (COVID-19). The impact of acellular hAF on markers of systemic inflammation and clinical outcomes during COVID-19 infection remain unknown. OBJECTIVE: To determine the safety and efficacy of acellular, sterile processed intravenously administered hAF on markers of systemic inflammation during COVID-19. DESIGN, SETTINGS AND PARTICIPANTS: This single-center Phase I/II randomized, placebo controlled clinical trial enrolled adult (age ≥ 18 years) patients hospitalized for respiratory symptoms of COVID-19, including hypoxemia, tachypnea or dyspnea. The study was powered for outcomes with an anticipated enrollment of 60 patients. From 09/28/2020 to 02/04/2022 we enrolled and randomized 47 (of an anticipated 60) patients hospitalized due to COVID-19. One patient withdrew consent after randomization but prior to treatment. Safety outcomes to 30 days were collected through hospital discharge and were complete by the end of screening on 6/30/2022. INTERVENTIONS: Intravenous administration of 10 cc sterile processed acellular hAF once daily for up to 5 days vs placebo. MAIN OUTCOME AND MEASURES: Blood biomarkers of inflammation, including C-Reactive protein (CRP), lactate dehydrogenase, D-dimer, and interleukin-6 (IL-6), as well as safety outcomes. RESULTS: Patients who were randomized to hAF (n = 23) were no more likely to have improvements in CRP from baseline to Day 6 than patients who were randomized to placebo (n = 24) hAF: -5.9 [IQR -8.2, -0.6] vs placebo: -5.9 [-9.4, -2.05]; p = 0.6077). There were no significant differences in safety outcomes or adverse events. Secondary measures of inflammation including lactate dehydrogenase, D-dimer and IL-6 were not statistically different from baseline to day 6. CONCLUSIONS AND RELEVANCE: In this randomized clinical trial involving hospitalized patients with COVID-19, the intravenous administration of 10 cc of hAF daily for 5 days did not result in statistically significant differences in either safety or markers of systemic inflammation compared to placebo, though we did not achieve our enrollment target of 60 patients. TRIAL REGISTRATION: This trial was registered at ClinicalTrials.gov as #NCT04497389 on 04/08/2020.

Safety and feasibility of using acellular sterile filtered amniotic fluid as a treatment for patients with COVID-19: protocol for a randomised, double-blinded, placebo-controlled clinical trial.

INTRODUCTION: Human amniotic fluid (hAF) has been shown to reduce inflammation in multiple experimental models. hAF has previously been approved by the US Food and Drug Administration (FDA) as a human cellular and tissue product for tissue injury for human administration, and used safely in thousands of patients as a therapeutic treatment for diverse conditions. Given the profound inflammatory response observed in patients with COVID-19, and the successful completion of 10-patient pilot study of intravenous hAF, we present a trial design for a larger clinical trial of intravenous hAF for the treatment of COVID-19. METHODS AND ANALYSIS: This paper describes the methodology of a phase I/II randomised, double-blinded, placebo-controlled clinical trial to determine the safety and feasibility of using acellular sterile filtered amniotic fluid as a treatment for patients with COVID-19. Primary outcome will be the change in C-reactive protein. Secondary outcomes include safety, biomarker inflammatory levels and clinically relevant outcomes at 30 days, including mortality, ventilator-free days and hospital and intensive care unit length of stay. Exploratory outcomes of health-related quality-of-life patient-reported outcomes will be collected. Hospitalised patients with laboratory-confirmed COVID-19 will be recruited. ETHICS AND DISSEMINATION: This study was approved by the University of Utah Institutional Review Board (IRB_0013292), approved by the US FDA under Investigational New Drug (No 23369) and is registered on ClinicalTrials.gov. Results will be disseminated via peer-reviewed publications and conference presentations. TRIAL REGISTRATION NUMBER: NCT04497389; Pre-results.

Characteristics of Patients Managed without Positive Pressure Ventilation While on Extracorporeal Membrane Oxygenation for Acute Respiratory Distress Syndrome.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) has expanding indications for cardiopulmonary resuscitation including severe acute respiratory distress syndrome (ARDS). Despite the adjunct of ECMO for patients with severe ARDS, they often have prolonged mechanical ventilation and are subject to many of its inherent complications. Here, we describe patients who were cannulated for venovenous (VV) ECMO and were taken off positive pressure ventilation. METHODS: This is a primary analysis of patients admitted at a tertiary medical center between the dates of August 2014 to January 2020 who were cannulated to ECMO for refractory respiratory failure. We included all patients ≥18 years old. Patients who were extubated or had a tracheostomy and taken off positive pressure while on ECMO were classified as "off positive pressure ventilation (PPV)" and were compared to patients who remained "on PPV" while on ECMO. Primary outcome was survival to hospital discharge. Secondary outcomes were ventilator free days at 30 days and 60 days after ECMO cannulation, time from cannulation to date of first out-of-bed (OOB), and hospital length of stay (LOS). Patient characteristics were derived from routine clinical information in the electronic health record (EHR). Categorical characteristics were compared using chi-square test or Fisher exact test. Continuous characteristics were compared using independent samples t-test or Wilcoxon-Mann-Whitney test. p-values were reported from all analysis. RESULTS: Sixty-five patients were included in this retrospective analysis. Forty-eight were managed on ECMO with PPV and 17 patients were removed from PPV. Patients removed from PPV had significantly higher lung injury scores prior to cannulation (2.5 ± 0.6 vs. 1.04 ± 0.3; p = 0.031) and non-significantly longer duration of ventilation prior to ECMO (6.1 days ± 2.1 vs. 5.0 days ± 01.1; p = 0.634). One hundred percent (100%) of patients removed from PPV survived to hospital discharge compared to 45% who received PPV throughout their duration of ECMO management (p < 0.001). The mean ventilator free days at day 60 was 15 with PPV and 36 without PPV (p = 0.003). The average duration from cannulation to mobilization (i.e., out-of-bed) was 18 days with PPV and 7 days without PPV (p = 0.015). CONCLUSIONS: Patients taken off PPV while on ECMO had a very high likelihood of survival to discharge and were mobilized in half as many days. While this likely reflects patient selection, the benefit of early mobilization is well documented and the approach of extubating while on ECMO warrants further investigation.

Surgical explantation of atrial septal closure devices for refractory nickel allergy symptoms.

OBJECTIVES: Systemic allergic reactions to nickel alloys in percutaneous atrial septal defect occlusion devices have a poorly defined natural history. We describe our experience of surgical removal of the offending device in a series of patients with nickel allergy and refractory symptoms. METHODS: Patients with atrial septal defect device explants for nickel allergy were reviewed. Administered questionnaires focused on symptoms, quality of life, and satisfaction along with the 36-Item Short Form Health Survey to measure physical and mental health postsurgery. RESULTS: Atrial septal defect devices were removed for nickel allergy in 58 patients during the past 10 years. The median age was 42 years (range, 24-71 years) and 95% were women. Explantation occurred at a median of 8 years (range, 6 months-18 years) after insertion. Symptoms included fatigue (82%), chest pain (78%), headache (73%), and palpitation (58%). Surveys were available for 45 patients: 58% rated their quality of life as poor and 69% were not at all satisfied with their device. Postexplant, all patients reported improvement in their symptoms, with 18 patients (42%) noting complete resolution. In 12 patients prospectively studied, the preoperative scores in physical and mental health domains were lower than the validation group, indicating significant disability. Similarly, there was marked improvement in each domain postremoval. CONCLUSIONS: Patients with nickel allergy and severe refractory symptoms after atrial septal defect device implantation experience profound resolution of symptoms and improved quality of life after removal. Nickel allergy should be considered before device insertion, and a low threshold should exist for surgical removal for refractory symptoms.

Substance Use Among College Students.

Emerging adulthood has heightened risk for substance use. College students experience unique challenges, making them prone to use of alcohol, marijuana, and nonmedical use of prescription drugs. This article reviews rates of college students' substance use, risk factors, and populations at elevated risk. Consequences include legal, academic, and mental health problems; engagement in other risky behaviors; increased rates of injury; and death. Researchers, clinicians, and university administrators must identify those at greatest risk and provide prevention and intervention programs. Despite broad evidence supporting such programs, many students fail to access appropriate treatment. Future research should elucidate treatment barriers.

Testing the effectiveness of 3D film for laboratory-based studies of emotion.

Research in psychology and affective neuroscience often relies on film as a standardized and reliable method for evoking emotion. However, clip validation is not undertaken regularly. This presents a challenge for research with adolescent and young adult samples who are exposed routinely to high-definition (HD) three-dimensional (3D) stimuli and may not respond to older, validated film clips. Studies with young people inform understanding of emotional development, dysregulated affect, and psychopathology, making it critical to assess whether technological advances improve the study of emotion. In the present study, we examine whether 3D film is more evocative than 2D using a tightly controlled within-subjects design. Participants (n  =  408) viewed clips during a concurrent psychophysiological assessment. Results indicate that both 2D and 3D technology are highly effective tools for emotion elicitation. However, 3D does not add incremental benefit over 2D, even when individual differences in anxiety, emotion dysregulation, and novelty seeking are considered.