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Background Renin-angiotensin system (RAS) signaling and angiotensin-converting enzyme 2 (ACE2) have been implicated in the pathogenesis of acute respiratory distress syndrome (ARDS). We postulated that repleting ACE2 using GSK2586881, a recombinant form of human angiotensin-converting enzyme 2 (rhACE2), could attenuate acute lung injury. Methods We conducted a two-part phase II trial comprising an open-label intrapatient dose escalation and a randomized, double-blind, placebo-controlled phase in ten intensive care units in North America. Patients were between the ages of 18 and 80 years, had an American-European Consensus Criteria consensus diagnosis of ARDS, and had been mechanically ventilated for less than 72 h. In part A, open-label GSK2586881 was administered at doses from 0.1 mg/kg to 0.8 mg/kg to assess safety, pharmacokinetics, and pharmacodynamics. Following review of data from part A, a randomized, double-blind, placebo-controlled investigation of twice-daily doses of GSK2586881 (0.4 mg/kg) for 3 days was conducted (part B). Biomarkers, physiological assessments, and clinical endpoints were collected over the dosing period and during follow-up. Results Dose escalation in part A was well-tolerated without clinically significant hemodynamic changes. Part B was terminated after 39 of the planned 60 patients following a planned futility analysis. Angiotensin II levels decreased rapidly following infusion of GSK2586881, whereas angiotensin-(1–7) and angiotensin-(1–5) levels increased and remained elevated for 48 h. Surfactant protein D concentrations were increased, whereas there was a trend for a decrease in interleukin-6 concentrations in rhACE2-treated subjects compared with placebo. No significant differences were noted in ratio of partial pressure of arterial oxygen to fraction of inspired oxygen, oxygenation index, or Sequential Organ Failure Assessment score. Conclusions GSK2586881 was well-tolerated in patients with ARDS, and the rapid modulation of RAS peptides suggests target engagement, although the study was not powered to detect changes in acute physiology or clinical outcomes. Trial registration ClinicalTrials.gov, NCT01597635 . Registered on 26 January 2012.

Background In patients with vasodilatory shock, plasma concentrations of angiotensin I (ANG I) and II (ANG II) and their ratio may reflect differences in the response to severe vasodilation, provide novel insights into its biology, and predict clinical outcomes. The objective of these protocol prespecified and subsequent post hoc analyses was to assess the epidemiology and outcome associations of plasma ANG I and ANG II levels and their ratio in patients with catecholamine-resistant vasodilatory shock (CRVS) enrolled in the Angiotensin II for the Treatment of High-Output Shock (ATHOS-3) study. Methods We measured ANG I and ANG II levels at baseline, calculated their ratio, and compared these results to values from healthy volunteers (controls). We dichotomized patients according to the median ANG I/II ratio (1.63) and compared demographics, clinical characteristics, and clinical outcomes. We constructed a Cox proportional hazards model to test the independent association of ANG I, ANG II, and their ratio with clinical outcomes. Results Median baseline ANG I level (253 pg/mL [interquartile range (IQR) 72.30–676.00 pg/mL] vs 42 pg/mL [IQR 30.46–87.34 pg/mL] in controls; P  <  0.0001) and median ANG I/II ratio (1.63 [IQR 0.98–5.25] vs 0.4 [IQR 0.28–0.64] in controls; P  <  0.0001) were elevated, whereas median ANG II levels were similar (84 pg/mL [IQR 23.85–299.50 pg/mL] vs 97 pg/mL [IQR 35.27–181.01 pg/mL] in controls; P  = 0.9895). At baseline, patients with a ratio above the median (≥1.63) had higher ANG I levels ( P  <  0.0001), lower ANG II levels ( P  <  0.0001), higher albumin concentrations ( P  = 0.007), and greater incidence of recent (within 1 week) exposure to angiotensin-converting enzyme inhibitors ( P  <  0.00001), and they received a higher norepinephrine-equivalent dose ( P  = 0.003). In the placebo group, a baseline ANG I/II ratio <1.63 was associated with improved survival (hazard ratio 0.56; 95% confidence interval 0.36–0.88; P  = 0.01) on unadjusted analyses. Conclusions Patients with CRVS have elevated ANG I levels and ANG I/II ratios compared with healthy controls. In such patients, a high ANG I/II ratio is associated with greater norepinephrine requirements and is an independent predictor of mortality, thus providing a biological rationale for interventions aimed at its correction. Trial registration ClinicalTrials.gov identifier NCT02338843 . Registered 14 January 2015.

Introduction: Topical salicylates are commonly found in over-the-counter medications and are applied for pain relief or to treat dermatologic conditions. While generally considered safe, they can cause systemic toxicity under certain conditions. We conducted a systematic review of topical salicylate toxicity. This comprehensive review of previously reported cases highlights the risks, clinical presentations, and management considerations of systemic toxicity from topical salicylates. Methods: We present a new case of topical salicylate toxicity and conducted a comprehensive systematic literature search from 1952-2024 using PubMed, Google, and Google Scholar. Our search was supplemented by cross-referencing previous studies to identify cases and reviews of topical salicylate toxicity. We then performed a descriptive analysis of the cases, summarizing key information such as clinical presentation, blood levels, and outcomes. Findings were used to contextualize the risks and clinical manifestations of topical salicylate toxicity. Results: A total of 44 cases of topical salicylate toxicity, including our index case, were identified and included in our analysis. Most cases involved patients > 40 years of age, but all age ranges were represented, including neonates. The most frequently reported symptoms included tachypnea (32.5%) and vomiting (25.5%). The new case was an elderly male with further altered mental status from baseline dementia and elevated anion gap. Conclusion: Both the new case and the literature review emphasize the continued potential systemic risks of topical salicylates among a broad demographic. Given the variable presentations, clinicians should maintain a high index of suspicion for salicylate toxicity in patients with unexplained altered metabolic and/or mental status. Early consideration, recognition, and intervention of topical salicylates-induced toxicity is essential for good outcomes. As many of these products are heavily advertised, patient education on the appropriate use of topical salicylates may be crucial to prevent inadvertent toxicity.

Rattlesnake envenomations account for many of the Crotalid envenomations in the United States annually. Two antivenoms are currently available to treat Crotalid envenomation in this country: Crotalidae-polyvalent ovine immune Fab antivenom (CroFab®; FabAV) and Crotalidae equine immune F(ab’)₂ antivenom (ANAVIP®; F(ab’)₂AV). Few studies have compared the adverse effect rates for each. We performed a retrospective chart review of rattlesnake envenomations called to the California Poison Control System from October 2018 to August 2022. Those treated at healthcare facilities with either antivenom were included. Those treated with both antivenoms were excluded. Records were obtained from the poison center electronic medical records system. Demographic and clinical data were abstracted. “Severe” adverse events were defined as multi-organ system involvement, swelling of the patient's airway, and/or hemodynamic instability. All others were categorized as “non-severe.” A total of 481 cases were included with 360 treated with FabAV and 121 with F(ab’)₂AV. The median age was 47 and 46 years, and 72 % and 73 % were male, respectively. Clinical signs and symptoms of envenomation were similar in each group. The FabAV group received a median of six vials. The F(ab’)₂AV group received a median of 10 vials, based on the recommended loading doses of FabAV and F(ab’)2AV. Following antivenom administration, 18 individual acute non-severe AEs were reported in 12 FabAV-treated patients. Two acute non-severe AEs were reported in two F(ab’)₂AV-treated patients. Rash or urticaria was the most commonly reported adverse effect in both groups after antivenom administration. Five patients (1.5 %) had severe adverse events reported in the poison center records following FabAV administration, and none were reported following F(ab’)₂AV administration (p = 0.025). Overall, our poison center data suggests the rate of adverse events is low following the use of either antivenom. Our findings are limited by the lack of consistent timing data, a smaller F(ab’)₂AV cohort, retrospective format, and use of poison center data.

Asthma-chronic obstructive pulmonary disease (COPD) overlap syndrome (ACOS) is a commonly encountered yet loosely defined clinical entity. ACOS accounts for approximately 15-25% of the obstructive airway diseases and patients experience worse outcomes compared with asthma or COPD alone. Patients with ACOS have the combined risk factors of smoking and atopy, are generally younger than patients with COPD and experience acute exacerbations with higher frequency and greater severity than lone COPD. Pharmacotherapeutic considerations require an integrated approach, first to identify the relevant clinical phenotype(s), then to determine the best available therapy. The authors discuss the array of existing and emerging classes of drugs that could benefit those with ACOS and share their therapeutic approach. A consensus international definition of ACOS is needed to design prospective, randomized clinical trials to evaluate specific drug interventions on important outcomes such as lung function, acute exacerbations, quality of life and mortality.

The E‐cigarette or Vaping product‐Associated Lung Injury (EVALI) causes severe acute respiratory failure and, in some cases, death. Most cases are linked to tetrahydrocannabinol‐containing e‐cigarette products adulterated with vitamin E acetate. Despite regulation and awareness efforts, VEA persists in biological samples from EVALI patients and remains a public health concern, particularly among adolescent males. The mechanisms driving VEA‐induced lung injury, and how they may be differentiated by sex, remain poorly understood. To address this, age‐ and size‐matched adolescent male and female mice were exposed to aerosolized VEA for 3 or 10 days. By Day 10, VEA exposure caused histopathologic lung injury and systemic inflammation, with alveolar barrier dysfunction evident on Day 3. Male mice developed more severe injury and immune dysregulation, with elevated lung interleukin‐1β, interleukin‐6, and keratinocyte chemoattractant and reduced expression of club cell secretory protein along the airway epithelium. Female mice showed higher serum levels of soluble receptor for advanced glycation end products, a biomarker of alveolar injury and inflammation that also functions as an immune modulator. This is the first study to identify sex‐specific differences in pulmonary responses to VEA exposure. These findings offer insight into EVALI immunopathogenesis and may explain population‐level sex disparities in disease severity.

Background Early diagnosis of pulmonary hypertension (PH) can potentially improve survival and quality of life. Detecting PH using echocardiography is often insensitive in subjects with lung fibrosis or hyperinflation. Right heart catheterization (RHC) for the diagnosis of PH adds risk and expense due to its invasive nature. Pre-defined measurements utilizing computed tomography (CT) of the chest may be an alternative non-invasive method of detecting PH. Methods This study retrospectively reviewed 101 acutely hospitalized inpatients with heterogeneous diagnoses, who consecutively underwent CT chest and RHC during the same admission. Two separate teams, each consisting of a radiologist and pulmonologist, blinded to clinical and RHC data, individually reviewed the chest CT's. Results Multiple regression analyses controlling for age, sex, ascending aortic diameter, body surface area, thoracic diameter and pulmonary wedge pressure showed that a main pulmonary artery (PA) diameter ≥29 mm (odds ratio (OR) = 4.8), right descending PA diameter ≥19 mm (OR = 7.0), true right descending PA diameter ≥ 16 mm (OR = 4.1), true left descending PA diameter ≥ 21 mm (OR = 15.5), right ventricular (RV) free wall ≥ 6 mm (OR = 30.5), RV wall/left ventricular (LV) wall ratio ≥0.32 (OR = 8.8), RV/LV lumen ratio ≥1.28 (OR = 28.8), main PA/ascending aorta ratio ≥0.84 (OR = 6.0) and main PA/descending aorta ratio ≥ 1.29 (OR = 5.7) were significant predictors of PH in this population of hospitalized patients. Conclusion This combination of easily measured CT-based metrics may, upon confirmatory studies, aid in the non-invasive detection of PH and hence in the determination of RHC candidacy in acutely hospitalized patients.

Introduction Rare myocarditis and pericarditis cases have occurred in coronavirus disease 2019 (COVID-19) messenger RNA (mRNA) vaccine recipients. Troponin levels, a potential marker of myocardial injury, were assessed in healthy participants before and after BNT162b2 vaccination. Methods Vaccine-experienced 12- to 30-year-olds in phase 3 crossover C4591031 Substudy B (NCT04955626) who had two or three prior BNT162b2 30-μg doses were randomized to receive BNT162b2 30 μg followed by placebo, or placebo followed by BNT162b2 30 µg, 1 month apart. A participant subset, previously unvaccinated against COVID-19, in the phase 3 C4591007 study (NCT04816643) received up to three vaccinations (BNT162b2 10 μg or placebo [5- to 11-year-olds]) or open-label BNT162b2 30 μg (12- to 15-year-olds). Blood samples collected pre-vaccination, 4 days post-vaccination, and 1-month post-vaccination (C4591031 Substudy B only) were analyzed. Frequencies of elevated troponin I levels (male, > 35 ng/l; female, > 17 ng/l) were assessed. Results Percentages of 12- to 30-year-olds ( n  = 1485) in C4591031 Substudy B with elevated troponin levels following BNT162b2 or placebo receipt were 0.5% and 0.8% before vaccination, 0.7% and 1.0% at day 4, and 0.7% and 0.5% at 1 month, respectively. In Study C4591007 ( n  = 1265), elevated troponin I levels were observed in 0.2, 0.4, and 0.2% of 5- to 11-year-old BNT162b2 recipients at baseline and 4 days post-dose 2 and 3, respectively; corresponding values in 12- to 15-year-olds were 0.4, 0.4, and 0.7%. No 5- to 11-year-old placebo recipients had elevated troponin levels. No myocarditis or pericarditis cases or deaths were reported. Conclusions Among 5- to  < 30-year-olds in both studies, troponin levels were rarely elevated (≤ 1.0%) and similar before and post-vaccination; troponin levels were also similar between BNT162b2 and placebo in 12- to 30-year-old and 5- to 11-year-old recipients in the respective studies. No myocarditis or pericarditis cases were reported. These findings did not provide evidence that BNT162b2 causes troponin elevations. No utility of routine measurement of troponin levels in asymptomatic BNT162b2 recipients was identified.