Intravenous aviptadil and remdesivir for treatment of COVID-19-associated hypoxaemic respiratory failure in the USA (TESICO): a randomised, placebo-controlled trial.

BACKGROUND: There is a clinical need for therapeutics for COVID-19 patients with acute hypoxemic respiratory failure whose 60-day mortality remains at 30-50%. Aviptadil, a lung-protective neuropeptide, and remdesivir, a nucleotide prodrug of an adenosine analog, were compared with placebo among patients with COVID-19 acute hypoxaemic respiratory failure. METHODS: TESICO was a randomised trial of aviptadil and remdesivir versus placebo at 28 sites in the USA. Hospitalised adult patients were eligible for the study if they had acute hypoxaemic respiratory failure due to confirmed SARS-CoV-2 infection and were within 4 days of the onset of respiratory failure. Participants could be randomly assigned to both study treatments in a 2 × 2 factorial design or to just one of the agents. Participants were randomly assigned with a web-based application. For each site, randomisation was stratified by disease severity (high-flow nasal oxygen or non-invasive ventilation vs invasive mechanical ventilation or extracorporeal membrane oxygenation [ECMO]), and four strata were defined by remdesivir and aviptadil eligibility, as follows: (1) eligible for randomisation to aviptadil and remdesivir in the 2 × 2 factorial design; participants were equally randomly assigned (1:1:1:1) to intravenous aviptadil plus remdesivir, aviptadil plus remdesivir matched placebo, aviptadil matched placebo plus remdesvir, or aviptadil placebo plus remdesivir placebo; (2) eligible for randomisation to aviptadil only because remdesivir was started before randomisation; (3) eligible for randomisation to aviptadil only because remdesivir was contraindicated; and (4) eligible for randomisation to remdesivir only because aviptadil was contraindicated. For participants in strata 2-4, randomisation was 1:1 to the active agent or matched placebo. Aviptadil was administered as a daily 12-h infusion for 3 days, targeting 600 pmol/kg on infusion day 1, 1200 pmol/kg on day 2, and 1800 pmol/kg on day 3. Remdesivir was administered as a 200 mg loading dose, followed by 100 mg daily maintenance doses for up to a 10-day total course. For participants assigned to placebo for either agent, matched saline placebo was administered in identical volumes. For both treatment comparisons, the primary outcome, assessed at day 90, was a six-category ordinal outcome: (1) at home (defined as the type of residence before hospitalisation) and off oxygen (recovered) for at least 77 days, (2) at home and off oxygen for 49-76 days, (3) at home and off oxygen for 1-48 days, (4) not hospitalised but either on supplemental oxygen or not at home, (5) hospitalised or in hospice care, or (6) dead. Mortality up to day 90 was a key secondary outcome. The independent data and safety monitoring board recommended stopping the aviptadil trial on May 25, 2022, for futility. On June 9, 2022, the sponsor stopped the trial of remdesivir due to slow enrolment. The trial is registered with ClinicalTrials.gov, NCT04843761. FINDINGS: Between April 21, 2021, and May 24, 2022, we enrolled 473 participants in the study. For the aviptadil comparison, 471 participants were randomly assigned to aviptadil or matched placebo. The modified intention-to-treat population comprised 461 participants who received at least a partial infusion of aviptadil (231 participants) or aviptadil matched placebo (230 participants). For the remdesivir comparison, 87 participants were randomly assigned to remdesivir or matched placebo and all received some infusion of remdesivir (44 participants) or remdesivir matched placebo (43 participants). 85 participants were included in the modified intention-to-treat analyses for both agents (ie, those enrolled in the 2 x 2 factorial). For the aviptadil versus placebo comparison, the median age was 57 years (IQR 46-66), 178 (39%) of 461 participants were female, and 246 (53%) were Black, Hispanic, Asian or other (vs 215 [47%] White participants). 431 (94%) of 461 participants were in an intensive care unit at baseline, with 271 (59%) receiving high-flow nasal oxygen or non-invasive ventiliation, 185 (40%) receiving invasive mechanical ventilation, and five (1%) receiving ECMO. The odds ratio (OR) for being in a better category of the primary efficacy endpoint for aviptadil versus placebo at day 90, from a model stratified by baseline disease severity, was 1·11 (95% CI 0·80-1·55; p=0·54). Up to day 90, 86 participants in the aviptadil group and 83 in the placebo group died. The cumulative percentage who died up to day 90 was 38% in the aviptadil group and 36% in the placebo group (hazard ratio 1·04, 95% CI 0·77-1·41; p=0·78). The primary safety outcome of death, serious adverse events, organ failure, serious infection, or grade 3 or 4 adverse events up to day 5 occurred in 146 (63%) of 231 patients in the aviptadil group compared with 129 (56%) of 230 participants in the placebo group (OR 1·40, 95% CI 0·94-2·08; p=0·10). INTERPRETATION: Among patients with COVID-19-associated acute hypoxaemic respiratory failure, aviptadil did not significantly improve clinical outcomes up to day 90 when compared with placebo. The smaller than planned sample size for the remdesivir trial did not permit definitive conclusions regarding safety or efficacy. FUNDING: National Institutes of Health.

Driving Pressure, Elastance, and Outcomes in a Real-World Setting: A Bi-Center Analysis of Electronic Health Record Data.

Emerging evidence suggests the potential importance of inspiratory driving pressure (DP) and respiratory system elastance (ERS) on outcomes among patients with the acute respiratory distress syndrome. Their association with outcomes among heterogeneous populations outside of a controlled clinical trial is underexplored. We used electronic health record (EHR) data to characterize the associations of DP and ERS with clinical outcomes in a real-world heterogenous population. DESIGN: Observational cohort study. SETTING: Fourteen ICUs in two quaternary academic medical centers. PATIENTS: Adult patients who received mechanical ventilation for more than 48 hours and less than 30 days. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: EHR data from 4,233 ventilated patients from 2016 to 2018 were extracted, harmonized, and merged. A minority of the analytic cohort (37%) experienced a Pao2/Fio2 of less than 300. A time-weighted mean exposure was calculated for ventilatory variables including tidal volume (VT), plateau pressures (PPLAT), DP, and ERS. Lung-protective ventilation adherence was high (94% with VT < 8.5 mL/kg, time-weighted mean VT = 6. 8 mL/kg, 88% with PPLAT ≤ 30 cm H2O). Although time-weighted mean DP (12.2 cm H2O) and ERS (1.9 cm H2O/[mL/kg]) were modest, 29% and 39% of the cohort experienced a DP greater than 15 cm H2O or an ERS greater than 2 cm H2O/(mL/kg), respectively. Regression modeling with adjustment for relevant covariates determined that exposure to time-weighted mean DP (> 15 cm H2O) was associated with increased adjusted risk of mortality and reduced adjusted ventilator-free days independent of adherence to lung-protective ventilation. Similarly, exposure to time-weighted mean ERS greater than 2 cm H2O/(mL/kg) was associated with increased adjusted risk of mortality. CONCLUSIONS: Elevated DP and ERS are associated with increased risk of mortality among ventilated patients independent of severity of illness or oxygenation impairment. EHR data can enable assessment of time-weighted ventilator variables and their association with clinical outcomes in a multicenter real-world setting.

Elevated Driving Pressure and Elastance Does Not Increase In-Hospital Mortality Among Obese and Severely Obese Patients With Ventilator Dependent Respiratory Failure.

Existing recommendations for mechanical ventilation are based on studies that under-sampled or excluded obese and severely obese individuals. Objective: To determine if driving pressure (DP) and total respiratory system elastance (Ers) differ among normal/overweight (body mass index [BMI] < 30 kg/m2), obese, and severely obese ventilator-dependent respiratory failure (VDRF) patients and if there any associations with clinical outcomes. Design Setting and Participants: Retrospective observational cohort study during 2016-2018 at two tertiary care academic medical centers using electronic health record data from the first 2 full days of mechanical ventilation. The cohort was stratified by BMI classes to measure median DP, time-weighted mean tidal volume, plateau pressure, and Ers for each BMI class. Setting and Participants: Mechanically ventilated patients in medical and surgical ICUs. Main Outcomes and Measures: Primary outcome and effect measures included relative risk of in-hospital mortality, ventilator-free days, ICU length of stay, and hospital length of stay with multivariable adjustment. Results: The cohort included 3,204 patients with 976 (30.4%) and 382 (11.9%) obese and severely obese patients, respectively. Severe obesity was associated with a DP greater than or equal to 15 cm H2O (relative risk [RR], 1.51 [95% CI, 1.26-1.82]) and Ers greater than or equal to 2 cm H2O/(mL/kg) (RR, 1.31 [95% CI, 1.14-1.49]). Despite elevated DP and Ers, there were no differences in in-hospital mortality, ventilator-free days, or ICU length of stay among all three groups. Conclusions and Relevance: Despite higher DP and ERS among obese and severely obese VDRF patients, there were no differences in in-hospital mortality or duration of mechanical ventilation, suggesting that DP has less prognostic value in obese and severely obese VDRF patients.

Dyspnea and Pulmonary Function Among Participants in the Multicenter AIDS Cohort Study Using Protease Inhibitors: A Cross-Sectional Study.

People living with HIV (PLWH) have a higher prevalence of respiratory symptoms than people without human immunodeficiency virus (HIV). Antiretroviral therapy has been associated with worsened airflow limitation. This cross-sectional study assessed respiratory health impairment among PLWH and its association with protease inhibitor use using data from Multicenter AIDS Cohort Study visits between April 1, 2017 and March 31, 2018. Participants completed the St. George's Respiratory Questionnaire (SGRQ), modified Medical Research Council (mMRC) dyspnea scale, spirometry, and diffusion capacity measurement. Visit data were compared among PI users, non-PI users, and men without HIV. Binary and ordinal logistic models were used to determine the associations between HIV status, PI use, and covariates with primary outcomes of dichotomized SGRQ and mMRC dyspnea scores. Of PI users, 57/177 (32.2%) self-reported pulmonary disease compared with 132/501 (26.4%) of non-PI users and 105/547 (19.2%) men without HIV. Of PI users, 77/177 (45.3%) had SGRQ scores ≥10, while 171/501 (34.7%) of non-PI users and 162/549 (29.9%) of people living without HIV had SGRQ scores ≥10 (p = .001). Adjusted models found an association between PI use and SGRQ score ≥10 [odds ratio (OR) 1.91 (95% confidence interval [CI] 1.29-2.82), ref: HIV negative and OR 1.50 (95% CI 1.01-2.22) ref: non-PI users]. A similar association was found with mMRC scores and PI use [OR 1.79 (95% CI 1.21-2.64), ref: HIV negative and OR 1.53 (95% CI 1.04-2.25), ref: non-PI users]. PI use is associated with worse respiratory health status, increased dyspnea, and an increased prevalence of self-reported pulmonary disease.

Vitamin C in Sepsis - No Longer a Benign Intervention?

Scientists and laypeople have been captivated by the potential role of vitamin C in the treatment of infection since the publication of Linus Pauling's famed book, Vitamin C and the Common Cold in 1970.1 In a contemporaneous article, Pauling described the methodology he used to pool the results of four double-blind controlled trials to conclude that ascorbic acid prevented upper respiratory infections.2 Although these publications led to widespread use of vitamin C by the public, they were considered highly controversial by the scientific community and sparked debate over the veracity of Pauling's findings and the rigor of his meta-analysis methodology.

Hepatitis B Virus Reactivation During Successful Treatment of Hepatitis C Virus With Sofosbuvir and Simeprevir.

Treatment of hepatitis C virus with potent, interferon-free, direct-acting antiviral regimens with no activity against hepatitis B virus (HBV) may increase the risk for HBV reactivation in coinfected patients. We present 2 cases of HBV reactivation during treatment with an all-oral regimen of simeprevir and sofosbuvir and discuss strategies to prevent HBV flare.

Impact of NRAS mutations for patients with advanced melanoma treated with immune therapies.

Activating NRAS mutations are found in 15% to 20% of melanomas. Immune therapies have become a mainstay in advanced melanoma treatment. We sought to evaluate whether tumor genotype (e.g., NRAS mutations) correlates with benefit from immune therapy in melanoma. We identified 229 patients with melanoma treated with immune therapies [IL2, ipilimumab, or anti-programmed cell death-1/ligand-1 (PD-1/PD-L1)] at three centers and compared clinical outcomes following immune therapy for patients with or without NRAS mutations. Of the 229 patients with melanoma, 60 had NRAS mutation, 53 had BRAF mutation, and 116 had NRAS/BRAF wild type. The NRAS-mutant cohort had superior or a trend to superior outcomes compared with the other cohorts in terms of response to first-line immune therapy (28% vs. 16%, P = 0.04), response to any line of immune therapy (32% vs. 20%, P = 0.07), clinical benefit (response + stable disease lasting ≥ 24 weeks; 50% vs. 31%, P < 0.01), and progression-free survival (median, 4.1 vs. 2.9 months, P = 0.09). Benefit from anti-PD-1/PD-L1 was particularly marked in the NRAS cohort (clinical benefit rate 73% vs. 35%). In an independent group of patient samples, NRAS-mutant melanoma had higher PD-L1 expression (although not statistically significant) compared with other genotypes (8/12 vs. 9/20 samples with ≥ 1% expression; 6/12 vs. 6/20 samples with ≥ 5% expression), suggesting a potential mechanism for the clinical results. This retrospective study suggests that NRAS mutations in advanced melanoma correlate with increased benefit from immune-based therapies compared with other genetic subtypes. If confirmed by prospective studies, this may be explained in part by high rates of PD-L1 expression.

Routine multiplex mutational profiling of melanomas enables enrollment in genotype-driven therapeutic trials.

PURPOSE: Knowledge of tumor mutation status is becoming increasingly important for the treatment of cancer, as mutation-specific inhibitors are being developed for clinical use that target only sub-populations of patients with particular tumor genotypes. Melanoma provides a recent example of this paradigm. We report here development, validation, and implementation of an assay designed to simultaneously detect 43 common somatic point mutations in 6 genes (BRAF, NRAS, KIT, GNAQ, GNA11, and CTNNB1) potentially relevant to existing and emerging targeted therapies specifically in melanoma. METHODS: The test utilizes the SNaPshot method (multiplex PCR, multiplex primer extension, and capillary electrophoresis) and can be performed rapidly with high sensitivity (requiring 5-10% mutant allele frequency) and minimal amounts of DNA (10-20 nanograms). The assay was validated using cell lines, fresh-frozen tissue, and formalin-fixed paraffin embedded tissue. Clinical characteristics and the impact on clinical trial enrollment were then assessed for the first 150 melanoma patients whose tumors were genotyped in the Vanderbilt molecular diagnostics lab. RESULTS: Directing this test to a single disease, 90 of 150 (60%) melanomas from sites throughout the body harbored a mutation tested, including 57, 23, 6, 3, and 2 mutations in BRAF, NRAS, GNAQ, KIT, and CTNNB1, respectively. Among BRAF V600 mutations, 79%, 12%, 5%, and 4% were V600E, V600K, V600R, and V600M, respectively. 23 of 54 (43%) patients with mutation harboring metastatic disease were subsequently enrolled in genotype-driven trials. CONCLUSION: We present development of a simple mutational profiling screen for clinically relevant mutations in melanoma. Adoption of this genetically-informed approach to the treatment of melanoma has already had an impact on clinical trial enrollment and prioritization of therapy for patients with the disease.

The stoichiometry of the Escherichia coli Hfq protein bound to RNA.

The Escherichia coli RNA binding protein Hfq is involved in many aspects of post-transcriptional gene expression. Tight binding of Hfq to polyadenylate sequences at the 3' end of mRNAs influences exonucleolytic degradation, while Hfq binding to small noncoding RNAs (sRNA) and their targeted mRNAs facilitate their hybridization which in turn effects translation. Hfq binding to an A-rich tract in the 5' leader region of the rpoS mRNA and to the sRNA DsrA have been shown to be important for DsrA enhanced translation initiation of this mRNA. The complexes of Hfq-A(18) and Hfq-DsrA provide models for understanding how Hfq interacts with these two RNA sequence/structure motifs. Different methods have reported different values for the stoichiometry of Hfq-A(18) and Hfq-DsrA. In this work, mass spectrometry and analytical ultracentrifugation provide direct evidence that the strong binding mode of the Hfq hexamer (Hfq(6)) for A(18) and domain II of DsrA (DsrA(DII)) involve 1:1 complexes. This stoichiometry was also supported by fluorescence anisotropy and a competition gel mobility shift experiment using wild-type and truncated Hfq. More limited studies of Hfq binding to DsrA as well as to the sRNAs RprA, OxyS, and an 18-nt segment of OxyS were also consistent with 1:1 stoichiometry. Mass spectrometry of cross-linked samples of Hfq(6), A(18), and DsrA(DII) exhibit intensity corresponding to a ternary 1:1:1 complex; however, the small intensity of this peak and fluorescence anisotropy experiments did not provide evidence that this ternary complex is stable in solution.

The martial arts.

Given the increasing popularity of the martial arts, it is likely that physicians in all specialties encounter patients who participate. From pediatric patients, to geriatric patients, to those living with various disabilities, the martial arts may offer physical, psychologic, and therapeutic benefits. An appreciation of the physical demands of the martial arts is crucial to understanding the pathogenesis of injury as well as to planning treatment and prevention strategies and to determining safe return to participation after injury.

Dynamic imaging in mild traumatic brain injury: support for the theory of medial temporal vulnerability.

OBJECTIVE: To determine whether patients with mild traumatic brain injury (TBI) and persistent postconcussive symptoms have evidence of temporal lobe injury on dynamic imaging. DESIGN: Case series. SETTING: An academic medical center. PARTICIPANTS: Twenty patients with a clinical diagnosis of mild TBI and persistent postconcussive symptoms were referred for neuropsychologic evaluation and dynamic imaging. Fifteen (75%) had normal magnetic resonance imaging (MRI) and/or computed tomography (CT) scans at the time of injury. INTERVENTIONS: Neuropsychologic testing, positron-emission tomography (PET), and single-photon emission-computed tomography (SPECT). MAIN OUTCOME MEASURES: Temporal lobe findings on static imaging (MRI, CT) and dynamic imaging (PET, SPECT); neuropsychologic test findings on measures of verbal and visual memory. RESULTS: Testing documented neurobehavioral deficits in 19 patients (95%). Dynamic imaging documented abnormal findings in 18 patients (90%). Fifteen patients (75%) had temporal lobe abnormalities on PET and SPECT (primarily in medial temporal regions); abnormal findings were bilateral in 10 patients (50%) and unilateral in 5 (25%). Six patients (30%) had frontal abnormalities, and 8 (40%) had nonfrontotemporal abnormalities. Correlations between neuropsychologic testing and dynamic imaging could be established but not consistently across the whole group. CONCLUSIONS: Patients with mild TBI and persistent postconcussive symptoms have a high incidence of temporal lobe injury (presumably involving the hippocampus and related structures), which may explain the frequent finding of memory disorders in this population. The abnormal temporal lobe findings on PET and SPECT in humans may be analogous to the neuropathologic evidence of medial temporal injury provided by animal studies after mild TBI.