Stroke is a leading cause of disability; but no pharmacological therapy is currently available for promoting recovery. The brain region adjacent to stroke damage, the peri-infarct zone, is critical for rehabilitation, as it exhibits heightened neuroplasticity, allowing sensorimotor functions to re-map from damaged areas1–3. Thus, understanding the neuronal properties constraining this plasticity is important to developing new treatments. Here we show that after a stroke in mice, tonic neuronal inhibition is increased in the peri-infarct zone. This increased tonic inhibition is mediated by extrasynaptic GABAA receptors (GABAARs) and is caused by an impairment in GABA transporter (GAT-3/4) function. To counteract the heightened inhibition, we administered in vivo a benzodiazepine inverse agonist specific for the α5-subunit-containing extrasynaptic GABAARs at a delay after stroke. This treatment produced an early and sustained recovery of motor function. Genetically lowering the number of α5 or δ-subunit-containing GABAARs responsible for tonic inhibition also proved beneficial for post-stroke recovery, consistent with the therapeutic potential of diminishing extrasynaptic GABAAR function. Together, our results identify new pharmacological targets and provide the rationale for a novel strategy to promote recovery after stroke and possibly other brain injuries.

RationaleProgressive fibrosing interstitial lung disease (PF-ILD) is characterised by progressive physiologic, symptomatic, and/or radiographic worsening. The real-world prevalence and characteristics of PF-ILD remain uncertain.MethodsPatients were enrolled from the Canadian Registry for Pulmonary Fibrosis between 2015–2020. PF-ILD was defined as a relative forced vital capacity (FVC) decline ≥10%, death, lung transplantation, or any 2 of: relative FVC decline ≥5 and <10%, worsening respiratory symptoms, or worsening fibrosis on computed tomography of the chest, all within 24 months of diagnosis. Time-to-event analysis compared progression between key diagnostic subgroups. Characteristics associated with progression were determined by multivariable regression.ResultsOf 2746 patients with fibrotic ILD (mean age 65±12 years, 51% female), 1376 (50%) met PF-ILD criteria in the first 24 months of follow-up. PF-ILD occurred in 427 (59%) patients with idiopathic pulmonary fibrosis (IPF), 125 (58%) with fibrotic hypersensitivity pneumonitis (HP), 281 (51%) with unclassifiable ILD (U-ILD), and 402 (45%) with connective tissue disease-associated ILD (CTD-ILD). Compared to IPF, time to progression was similar in patients with HP (hazard ratio [HR] 0.96, 95% confidence interval, CI 0.79–1.17), but was delayed in patients with U-ILD (HR 0.82, 95% CI 0.71–0.96) and CTD-ILD (HR 0.65, 95% CI 0.56–0.74). Background treatment varied across diagnostic subtypes with 66% of IPF patients receiving antifibrotic therapy, while immunomodulatory therapy was utilised in 49%, 61%, and 37% of patients with CHP, CTD-ILD, and U-ILD respectively. Increasing age, male sex, gastroesophageal reflux disease, and lower baseline pulmonary function were independently associated with progression.InterpretationProgression is common in patients with fibrotic ILD, and is similarly prevalent in HP and IPF. Routinely collected variables help identify patients at risk for progression and may guide therapeutic strategies.

Increasingly, clinicians and researchers recognize that studies of interventions need to evaluate not only their therapeutic efficacy (i.e., the effect on an outcome in ideal, controlled settings) but also their real-world effectiveness in broad, unselected patient groups. Effectiveness trials inform clinical practice by comparing variations in therapeutic approaches that fall within the standard of care. In this article, we discuss the need for studies of comparative effectiveness in anesthesia and the limitations of individual patient randomized-controlled trials in determining comparative effectiveness. We introduce the concept of randomized cluster crossover trials as a means of answering questions of comparative effectiveness in anesthesia, using the design of the Benzodiazepine-Free Cardiac Anesthesia for Reduction in Postoperative Delirium (B-Free) trial (Clinicaltrials.gov identifier NCT03053869).

Managing severe valvular heart disease with mechanical valve replacement necessitates lifelong anticoagulation with a vitamin K antagonist. Optimal anticoagulation intensity for patients with mechanical valves remains uncertain; current recommendations are inconsistent across guideline bodies and largely based on expert opinion. In this review, we outline the history of anticoagulation therapy in patients with mechanical heart valves and critically evaluate current antithrombotic guidelines for these patients. We conclude that randomized trials evaluating optimal anticoagulation intensity in patients with mechanical valves are needed, and that future guidelines must better justify antithrombotic treatment recommendations.

Background: Delirium is common after cardiac surgery and is associated with adverse outcomes. Perioperative benzodiazepine use is associated with delirium and is common during cardiac surgery, which may increase the risk of postoperative delirium. We undertook a pilot study to inform the feasibility of a large randomised cluster crossover trial examining whether an institutional policy of restricted benzodiazepine administration during cardiac surgery (compared with liberal administration) would reduce delirium. Methods: We conducted a two-centre, pilot, randomised cluster crossover trial with four 4 week crossover periods. Each centre was randomised to a policy of restricted or liberal use, and then alternated between the two policies during the remaining three periods. Our feasibility outcomes were adherence to each policy (goal !80%) and outcome assessment (one delirium assessment per day in the ICU in !90% of participants). We also evaluated the incidence of intraoperative awareness in one site using serial Brice questionnaires. Results: Of 800 patients undergoing cardiac surgery during the trial period, 127/800 (15.9%) had delirium. Of these, 355/ 389 (91.3%) received benzodiazepines during the liberal benzodiazepine periods and 363/411 (88.3%) did not receive benzodiazepines during the restricted benzodiazepine periods. Amongst the 800 patients, 740 (92.5%) had !1 postoperative delirium assessment per day in the ICU. Of 521 patients screened for intraoperative awareness, one patient (0.2%), managed during the restricted benzodiazepine period (but who received benzodiazepine), experienced intraoperative awareness.

Objective We conducted a meta‐analysis to estimate the risk of adverse events, life expectancy, and event‐free life expectancy after the Ross procedure in adults. Methods We searched databases for reports evaluating the Ross procedure in patients aged more than or equal to 16 years of age. A microsimulation model was used to evaluate age‐ and gender‐specific life expectancy for patients undergoing the Ross procedure. Results Data were pooled from 63 articles totaling 19 155 patients from 20 countries. Perioperative mortality was 2.5% (95% confidence interval [CI]: 1.9‐3.1; N = 9978). We found a mortality risk of 5.9% (95% CI: 4.8‐7.2) at a mean follow‐up of 7.2 years (N = 7573). The rate of perioperative clinically significant bleeding was 1.0% (95% CI: 0.1‐3.0); re‐exploration for bleeding 4.6% (95% CI: 3.1‐6.3); postoperative clinically significant bleeding from 30 days until a mean of 7.1 years was 0.5% (95% CI: 0.2‐1.0). At a mean of 6.9 years of follow‐up, reintervention rate of any operated valve was 7.9% (95% CI: 5.7‐10.3). The risk of valve thrombosis was 0.3% (95% CI: 0.2‐0.5) at 7.6 years; peripheral embolism 0.3% (95% CI: 0.2‐0.4) at 6.4 years; stroke 0.9% (95% CI: 0.7‐1.2) at 6.5 years; and endocarditis 2.1% (95% CI: 1.6‐2.6) at 8.0 years. Microsimulation reported a 40‐year‐old undergoing the Ross procedure to have a life expectancy of 35.4 years and event‐free life expectancy of 26.6 years. Conclusions Ross procedure in nonelderly adults is associated with low mortality and low risk of adverse events both at short‐ and long‐term follow‐up. The surgical community must prioritize a large, expertize‐based randomized controlled trial to definitively address the risks and benefits of the Ross procedure compared to conventional aortic valve replacement.

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