Vertex Pharmaceuticals

Guidelines recommend structured self-reported functional capacity assessment for preoperative cardiac risk stratification, including the Duke Activity Status Index (DASI). However, evidence supporting its incremental prognostic value beyond established risk factors remains limited. We evaluated the prognostic performance of the DASI using pooled data from two prospective cohorts. We conducted a pooled cohort analysis of adults undergoing elective major non-cardiac surgery enrolled in the Measurement of Exercise Tolerance before Surgery (METS) and Functional Improvement Trajectories After Surgery (FIT After Surgery) studies, including data collected between March 2013 and April 2023. Before surgery, participants completed the Duke Activity Status Index (DASI), a structured 12-item questionnaire based on daily physical activities, and underwent routine preoperative biomarker measurement. The primary outcome was 30-day major cardiac complications (myocardial infarction or non-fatal cardiac arrest) or death. The secondary outcome was all-cause major complications. Hierarchical logistic regression assessed the incremental prognostic value of the DASI beyond age, Revised Cardiac Risk Index (RCRI), and natriuretic peptide concentration. Prognostic performance was evaluated using the likelihood ratio test (LRT), fraction of new predictive information, net reclassification improvement, c-index, calibration plots, and decision curve analysis. Among 3485 patients, 3.6% (n = 126) experienced the primary outcome and 19% (n = 647) experienced the secondary outcome. The DASI provided prognostic information beyond age, RCRI, and natriuretic peptide concentration for the primary outcome (LRT p = 0.009), and beyond age, sex, and surgery type for the secondary outcome (LRT p < 0.001). Inclusion of the DASI improved prognostic performance across multiple metrics, but overall discrimination of the final models remained modest (c-index 0.70-0.71), with limited net clinical benefit. Predicted risk associated with a given DASI score varied substantially by age, RCRI, and natriuretic peptide concentration, supporting interpretation of the DASI as a continuous prognostic marker rather than a dichotomous screening test. The DASI provides incremental prognostic information for preoperative cardiac risk assessment beyond guideline-recommended predictors. Its prognostic implications are modest, context-dependent, and best interpreted as a continuous prognostic marker alongside established risk factors, rather than as a stand-alone threshold-based tool. Canadian Institutes of Health Research; PSI Foundation; and the Elizabeth A. and Richard J. Currie, O.C. Chair in Translational Anesthesia Research at St. Michael's Hospital and the University of Toronto; The Ottawa Hospital Academic Medical Organization Innovation Fund; Heart and Stroke Foundation of Canada; Ontario Ministry of Health and Long-Term Care; Ontario Ministry of Research, Innovation and Science; UK National Institute of Academic Anaesthesia; UK Clinical Research Collaboration; Australian and New Zealand College of Anaesthetists; Monash University.

The inward rectifying human potassium channel 7.1 (Kir7.1) is a vital ion channel involved in maintaining cellular homoeostasis and electrical signalling across various tissues and organs, activated by phosphatidylinositol 4,5-bisphosphate (PIP2). A genetically inherited loss-of-function mutation in Kir7.1 (R162W) has been linked to the rare retinal disease Snowflake Vitreoretinal Degeneration (SVD), for which there are currently no curative treatment options. Here, the cryo-EM structures of wild type Kir7.1 and the R162W disease-related variant are presented, which unveil the molecular basis of SVD: the reorientation of the mutant tryptophan side chains into the pore impedes the flow of potassium ions, which would result in the loss of Kir7.1 transport function. Furthermore, this investigation shows that PIP2 binding widens the helix bundle crossing gate diameter, even in the absence of a docked cytoplasmic domain. This observation contrasts with other Kir-PIP₂ complexes and suggests that Kir7.1 may adopt an intermediate conformation during channel activation. These findings provide a structural basis for Kir7.1 loss of function in SVD and provide a framework for future therapeutic development.

Elexacaftor/tezacaftor/ivacaftor(ELX/TEZ/IVA) was safe and efficacious in children with CF 2-5y with at least one F508del allele in 24-week phase 3 Trial 445-111. Children who completed 445-111 were eligible for the long-term safety and efficacy extension trial. This 2-part (part A and B), open-label, phase 3, 192-week trial enrolled children ≥ 2y who completed 445-111. safety and tolerability. Secondary endpoints: absolute changes in sweat chloride(SwCl) concentration and lung clearance index 2.5(LCI2.5). 96-week analysis (Part A) is reported. Seventy children received ELX/TEZ/IVA and mean exposure was 89.9 (SD: 17.0) weeks. All children had ≥1 adverse event(AE), most AEs were mild (35.7%) or moderate (52.9%) in severity. Most AEs were generally consistent with known manifestations of CF in children. Fifteen children had ≥1 serious AE, of which 1 (DIOS) was considered related to ELX/TEZ/IVA. Three children discontinued due to AEs. Decreases in SwCl (-57.0 mmol/L [95%CI: -61.5, -52.6]) and LCI2.5 (-0.90 [95%CI: -1.14, -0.67]) were sustained from parent trial baseline, 80.8% of children achieved SwCl<60 mmol/L (below diagnostic threshold) and 28.8% achieved SwCl<30 mmol/L (normal). Growth remained in normal range throughout treatment period. Increases in fecal elastase-1 from parent trial baseline were maintained through Week 96, with 9 children above the pancreatic sufficiency threshold. ELX/TEZ/IVA remained generally safe and well-tolerated in this extension trial. SwCl and lung function improvements reported in parent trial were maintained through additional 96 w of treatment. These results demonstrate long-term safety and efficacy, and CF disease-modifying potential of ELX/TEZ/IVA in children ≥2y.

Trapped gas (TG) and ventilation inhomogeneity (VI) are early markers of altered small airway function (SAF) in cystic fibrosis (CF) lung disease. The evolution of these markers in children with CF (chCF) treated with elexacaftor-tezacaftor-ivacaftor (ETI) remains poorly understood. Using data from multiple breath washout (MBW) and body plethysmography (pleth) from a national, real-world cohort of school-aged chCF, we tested the hypothesis that VI and TG do not consistently return to normal levels following ETI therapy. Data from MBW and pleth tests were collected from seven centres prior to ETI initiation (month 0 (M0)), after a year of treatment (M12) and at M6 (when available). Analyses were conducted to assess the evolution of per cent predicted (pp) residual volume (ppRV), total lung capacity (ppTLC) and the ppRV/TLC ratio, as well as the difference between pp functional residual capacity (ppFRC)pleth and ppFRCMBW as markers of TG. Global and regional VI indices were compared to those of age- and sex-matched healthy controls. A total of 192 chCF aged from 6 to 18 years at ETI initiation underwent MBW at M0 and M12. Significant reductions were observed in ppRV, ppTLC, ppRV/TLC and TG. However, 28% of the chCF cohort had ppRV/TLC values >120% at M12. MBW-derived outcomes improved significantly, but 51.9% of the cohort had lung clearance index (LCI2.5) values at M12 that had not returned to healthy control levels. ETI significantly improved SAF. However, not all outcome measures returned to normal, indicating residual lung disease in some chCF.

Previously considered rare, penicillin-susceptible Staphylococcus aureus (PSSA) bacteraemia has re-emerged worldwide. Although benzylpenicillin might offer advantages in terms of pharmacokinetic and adverse effect profiles, anti-staphylococcal penicillins are recommended for serious infections because of concern over undetected penicillin resistance. We aimed to compare benzylpenicillin with anti-staphylococcal penicillins (cloxacillin or flucloxacillin) for the treatment of PSSA bacteraemia in adults. This investigator-initiated, international, multicentre, open-label, non-inferiority, randomised controlled trial was conducted within the PSSA silo of the backbone domain of the ongoing S aureus Network Adaptive Platform (SNAP) trial. We enrolled patients of all ages who were admitted with S aureus bacteraemia at 67 hospitals across Australia, New Zealand, Canada, Israel, the Netherlands, the UK, Singapore, and South Africa. Herein, we report results for adult patients (aged ≥18 years). Participants were randomly allocated 1:1 to receive either benzylpenicillin, or flucloxacillin or cloxacillin. Trial staff, staff caring for participants, and participants were aware of the treatment allocated and received. Cloxacillin was used only where flucloxacillin was not available (ie, Canada, Israel, Singapore, and South Africa). Recommended standard dosing for benzylpenicillin was 1·8 g intravenously once every 4 h or 2·4 g once every 6 h; for flucloxacillin 2·0 g intravenously once every 6 h; and for cloxacillin 2·0 g intravenously once every 4 h. The primary outcome was all-cause mortality 90 days after platform entry, assessed in the intention-to-treat population, including all patients with available data. The primary outcome was analysed by use of a hierarchical Bayesian logistic regression model, with non-inferiority of benzylpenicillin defined as an adjusted odds ratio (OR) of less than 1·20. Analyses occurred after every 500 participants reached 90-day follow-up. The SNAP trial is registered with ClinicalTrials.gov (NCT05137119) and is ongoing. Following the fourth interim analysis, the data and safety monitoring committee recommended ceasing recruitment before prespecified stopping thresholds were reached because of increased acute kidney injury (AKI) in participants receiving flucloxacillin or cloxacillin, and the PSSA silo was closed for recruitment on Aug 7, 2024. Between Feb 18, 2022, and June 21, 2024, of 493 adults with PSSA bacteraemia, 125 were randomly assigned to the flucloxacillin or cloxacillin group and 156 to the benzylpenicillin group. The median age was 67 years (IQR 56-77), 87 (31%) were female, and 194 (69%) were male. 21 (14%) of 152 in the benzylpenicillin group and 26 (22%) of 121 in the flucloxacillin or cloxacillin group met the primary outcome of death at 90 days (adjusted OR 0·67, 95% credible interval [CrI] 0·35-1·28), with a posterior probability of benzylpenicillin non-inferiority of 96·1% and of benzylpenicillin superiority of 88·9%. AKI occurred in 17 (11%) of 153 patients in the benzylpenicillin group and 27 (22%) of 124 patients in the flucloxacillin or cloxacillin group (adjusted OR 0·50, 95% CrI 0·26-0·94), corresponding to a posterior probability of non-inferiority of benzylpenicillin of 99·8% and superiority of benzylpenicillin of 98·4%. Seven total serious adverse reactions were reported from six (4%) of 156 participants in the benzylpenicillin group and ten were reported from nine (7%) of 125 participants in the flucloxacillin or cloxacillin group. Although the prespecified non-inferiority criterion for benzylpenicillin was not met, the probability of benzylpenicillin being non-inferior for mortality, along with a reduction in risk of AKI, indicates that benzylpenicillin should be preferred over flucloxacillin or cloxacillin for treatment of PSSA bacteraemia in adults. National Health and Medical Research Council, Medical Research Future Fund, Canadian Institutes of Health Research, Accelerating Clinical Trials Consortium, UMC Utrecht, ZonMW Good Use of Medicines programme, Health Research Council of New Zealand, Starship Foundation, National Healthcare Group Fund, National Medical Research Council, National Institute for Health and Care Research, Medical Research Council, and Paterson Family Foundation.

Pain is often the presenting symptom of acute pancreatitis (AP) and has a prognostic significance, with poorly treated pain affecting patient outcomes. Despite this, there are currently no international recommendations for pain management in patients admitted with AP. This current guideline was developed following the United European Gastroenterology framework for the development of high-quality clinical guidelines. Nine working groups were formed to develop statements on pain management in AP from admission to discharge. After systematic literature reviews, the evidence was evaluated according to the Grading of Recommendations Assessment, Development, and Evaluation methodology, as appropriate. Statements and comments were developed by the working groups and voted using three rounds of Delphi method. The guidelines concluded that acute postoperative pain management guidelines are applicable for treating acute pain due to AP. The numerical rating scale is preferred for pain assessment because of better compliance. Opioids currently form the cornerstone of severe pain management. Potent opioids such as buprenorphine and pentazocine provide superior pain relief over non-opioid medications and decrease the need for rescue analgesia. Current evidence does not consistently demonstrate harm from opioids in AP. In patients with severe pain, safety concerns should not delay the timely use of opioids to ensure adequate pain management. Specific recommendations concerning the use of epidural analgesia, acupuncture and management of pain in the paediatric population and during pregnancy are provided based on evidence and expert opinions. Finally, the unmet needs for future research were discussed and proposed.