There are no widely available mechanisms to conduct large-scale, rigorous clinical trials in real time. In this critical care review, we outline lessons learned during COVID-19 and prior respiratory pandemics in which ECMO was used, and we describe how we might apply these lessons going forward, both during the ongoing COVID-19 pandemic and in the future.Rationale The inspiratory rise in transpulmonary pressure during mechanical ventilation increases right ventricular (RV) afterload. One mechanism is that when Palv exceeds left atrial pressure, West zone 1 or 2 (non-zone 3) conditions develop, and Palv becomes the downstream pressure opposing RV ejection. The Vt at which this impact on the right ventricle becomes hemodynamically evident is not well established. Objectives To determine the magnitude of RV afterload and prevalence of significant non-zone 3 conditions during inspiration across the range of Vt currently prescribed in clinical practice. Methods In postoperative passively ventilated cardiac surgery patients, we measured right atrial, right ventricle, pulmonary artery, pulmonary artery occlusion pressure, plateau pressure, and esophageal pressure during short periods of controlled ventilation, with Vt increments ranging between 2 and 12 ml/kg predicted body weight (PBW). The inspiratory increase in RV afterload was evaluated hemodynamically and echocardiographically. The prevalence of non-zone 3 conditions was determined using two definitions based on changes in esophageal pressure, pulmonary artery occlusion pressure, and plateau pressure. Measurements and Main Results Fifty-one patients were studied. There was a linear relationship between Vt, driving pressure, transpulmonary pressure, and the inspiratory increase in the RV isovolumetric contraction pressure. Echocardiographically, increasing Vt was associated with a greater inspiratory increase in markers of afterload and a decrease in stroke volume. Non-zone 3 conditions were present in >50% of subjects at a Vt ⩾ 6 ml/kg PBW. Conclusions In the Vt range currently prescribed, RV afterload increases with increasing Vt. A mechanical ventilation strategy that limits Vt and driving pressure is cardioprotective.Gay-fatherhood raises questions about hegemonic gender norms and traditional family systems in different contexts and countries. This study explores gay fathers’ desires, motivations, and experiences of having a child. Participants’ challenges and concerns regarding having and raising children also were explored. Data were obtained through in-person interviews of 11 self-identified gay fathers. The data were then analyzed using interpretive phenomenological analysis (IPA) analysis. The analytical results identified three themes that shed light on participants’ desires and experiences of parenthood. These were (1) innate motives to parent and gender role strains, (2) enacted stigma (i.e., acts of rejection due to sexual orientation and traditional gender roles), and (3) children’s social rejection due to their parents’ sexuality. The findings of this study stress the influence of contextual factors (stigma) and intrapersonal factors (internalized anti-gay prejudice) in participants’ health and well-being. This study potentially tries to expand cultural awareness of research in this field.Access to the opioid antidote naloxone is a critical component of addressing the opioid crisis. Naloxone is a population-level prevention intervention associated with substantial reductions in overdose mortality and reduction of nonfatal overdose. Pharmacies’ pivotal role in dispensing medications like buprenorphine for the treatment of opioid use disorder and selling nonprescription syringes places them at the crossroads of opioid access and risk mitigation methods like naloxone provision. Testing ways to optimize pharmacy-based naloxone provision will be key as the country expands the implementation of naloxone through the medical system. In the Respond to Prevent Study, we conducted a large, practical study of a pharmacy-focused intervention in a sample of Washington, Oregon, Massachusetts and New Hampshire community chain pharmacies to increase naloxone dispensing and improve opioid safety. The intervention integrated two evidence-based educational toolkits and streamlined materials to enhance the focus on naloxone policy, stigma reduction, and patient communications around naloxone, nonprescription syringes and buprenorphine access. The real-world study implemented a stepped wedge, clustered randomized trial design across 175 community chain pharmacies to evaluate the effectiveness of the Respond to Prevent intervention in increasing (a) pharmacy based naloxone distribution rates, naloxone-related patient engagement, and pharmacist and technicians’ attitudes, knowledge, perceived behavioral control and self-efficacy toward naloxone; and (b) pharmacy nonprescription syringe sales, and pharmacist and technicians’ attitudes, knowledge, perceived behavioral control and self-efficacy toward dispensing buprenorphine for opioid use disorder (secondary outcomes). This commentary provides a brief narrative about the study and presents insights on the design and adaptations to our study protocol, including those adopted during the unprecedented COVID-19 pandemic further compounded by Western wildfires in 2020.

During the first wave of the coronavirus disease 2019 (COVID-19) pandemic in New York City, the number of mechanically ventilated COVID-19 patients rapidly surpassed the capacity of traditional Intensive Care Units (ICUs), resulting in health systems utilizing other areas as expanded ICUs to provide critical care.

To evaluate the mortality of patients admitted to expanded ICUs compared with those admitted to traditional ICUs.

Multicenter, retrospective, cohort study of mechanically ventilated patients with COVID-19 admitted to the ICUs at 11 Northwell Health hospitals in the greater New York City area between March 1, 2020 and April 30, 2020.

In-hospital mortality up to 28 days after intubation of COVID-19 patients.

Among 1,966 mechanically ventilated patients with COVID-19, 1,198 (61%) died within 28 days after intubation, 46 (2%) were transferred to other hospitals outside of the Northwell Health system, 722 (37%) survived in the hospital until 28 days or were discharged after recovery. The risk of mortality of mechanically ventilated patients admitted to expanded ICUs was not different from those admitted to traditional ICUs (HR, 1.07; 95% CI, 0.95-1.20; p = 0.28), while hospital occupancy for critically ill patients itself was associated with increased risk of mortality (HR, 1.28; 95% CI, 1.12-1.45; p < 0.001).

Although increased hospital occupancy for critically ill patients itself was associated with increased mortality, the risk of 28-day in-hospital mortality of mechanically ventilated patients with COVID-19 who were admitted to expanded ICUs was not different from those admitted to traditional ICUs.

Although increased hospital occupancy for critically ill patients itself was associated with increased mortality, the risk of 28-day in-hospital mortality of mechanically ventilated patients with COVID-19 who were admitted to expanded ICUs was not different from those admitted to traditional ICUs.Mitochondria are the main source of reactive oxygen species (ROS) in cells. Early studies have shown that mitochondrial reactive oxygen species (mROS) are related to the occurrence and adverse outcomes of many diseases, and are thus regarded as an important risk factor that threaten human health. Recently, increasing evidence has shown that mROS are very important for an organism’s homeostasis. mROS can regulate a variety of signaling pathways and activate the adaptation and protection behaviors of an organism under stress. In addition, mROS also regulate important physiological processes, such as cell proliferation, differentiation, aging, and apoptosis. Herein, we review the mechanisms of production, transformation, and clearance of mROS and their biological roles in different physiological processes.m6A (N6-methyladenosine) is the most common type of RNA methylation modification, mainly occurring on mRNA. Whether m6A-modified circular RNAs (circRNAs) are involved in pulmonary fibrosis in different settings remains unclear. Using an m6A-circRNA epitranscriptomic chip, candidate circRNAs were selected, among which hsa_circ_0000672 and hsa_circ_0005654 were specifically involved in SiO2-induced pulmonary fibrosis by targeting the same protein, eIF4A3, indicating that the m6A modification of these two circRNAs has a synergistic effect on fibroblast dysfunction induced by SiO2. A mechanistic study revealed that the m6A modification of circRNAs was mainly mediated by the methyltransferase METTL3. Furthermore, METTL3 promoted the activation, migration, and activity of pulmonary fibroblasts and participated in SiO2-induced pulmonary fibrosis via the circRNA m6A modification. m6A methylation of circRNAs mediates silica-induced fibrosis, enriching the understanding of circRNAs and uncovering a potential new target for treating fibrosis-related diseases.Essential hypertension remains the leading risk factor of global disease burden, but its treatment goals are often not met. We investigated whether DNA methylation is associated with antihypertensive responses to a diuretic, a beta-blocker, a calcium channel blocker or an angiotensin receptor antagonist. In addition, since we previously showed an SNP at the transcription start site (TSS) of the catecholamine biosynthesis-related ACY3 gene to associate with blood pressure (BP) response to beta-blockers, we specifically analysed the association of methylation sites close to the ACY3 TSS with BP responses to beta-blockers. We conducted an epigenome-wide association study between leukocyte DNA methylation and BP responses to antihypertensive monotherapies in two hypertensive Finnish cohorts the GENRES (https//clinicaltrials.gov/ct2/show/NCT03276598; amlodipine 5 mg, bisoprolol 5 mg, hydrochlorothiazide 25 mg, or losartan 50 mg daily) and the LIFE-Fin studies (https//clinicaltrials.gov/ct2/show/NCT00338260; atenolol 50 mg or losartan 50 mg daily). The monotherapy groups consisted of approximately 200 individuals each. We identified 64 methylation sites to suggestively associate (P less then 1E-5) with either systolic or diastolic BP responses to a particular study drug in GENRES. These associations did not replicate in LIFE-Fin . Three methylation sites close to the ACY3 TSS were associated with systolic BP responses to bisoprolol in GENRES but not genome-wide significantly (P less then 0.05). No robust associations between DNA methylation and BP responses to four different antihypertensive drugs were identified. However, the findings on the methylation sites close to the ACY3 TSS may support the role of ACY3 genetic and epigenetic variation in BP response to bisoprolol.Estimating a treatment effect from observational data requires modeling treatment and outcome subject to uncertainty/misspecification. A previous research has shown that it is not possible to find a uniformly best strategy. In this article we propose a novel Frequentist Model Averaging (FMA) framework encompassing any estimation strategy and accounting for model uncertainty by computing a cross-validated estimate of Mean Squared Prediction Error (MSPE). We present a simulation study with data mimicking an observational database. Model averaging over 15+ strategies was compared with individual strategies as well as the best strategy selected by minimum MSPE. FMA showed robust performance (Bias, Mean Squared Error (MSE), and Confidence Interval (CI) coverage). Other strategies, such as linear regression, did well in simple scenarios but were inferior to the FMA in a scenario with complex confounding.