Citations

Abstract Clinical question What are the benefits and harms of medications for adults with type 2 diabetes at varied risks of cardiovascular and kidney related complications? Context Emerging clinical trials of novel medications have demonstrated benefits on cardiovascular, kidney, and weight related outcomes in people with type 2 diabetes. Dynamically updated practice guidelines adhering to standards of trustworthiness are necessary in response to a rapidly evolving evidence base and the availability of multiple medication alternatives. This living practice guideline incorporates the latest available medications and evidence and provides recommendations stratified by risks of cardiovascular and kidney complications to inform diabetes management. Recommendations The panel issued risk-stratified recommendations regarding four prioritised medications for adults with type 2 diabetes (SGLT-2 inhibitors, GLP-1 receptor agonists, finerenone and tirzepatide): • Lower risk (three or fewer cardiovascular risk factors without established cardiovascular disease (CVD) or chronic kidney disease (CKD)): weak recommendation against SGLT-2 inhibitors or GLP-1 receptor agonists. • Moderate risk (more than three cardiovascular risk factors without established CVD or CKD; or established CVD and/or CKD at lower risk of complications): weak recommendation in favour of SGLT-2 inhibitors or GLP-1 receptor agonists; and a weak recommendation against finerenone in adults with CKD. • Higher risk (established CVD and/or CKD at higher risk of complications, or established heart failure): strong recommendation in favour of SGLT-2 inhibitors or GLP-1 receptor agonists; and a weak recommendation in favour of finerenone in adults with CKD. • Across risk strata: weak recommendation in favour of tirzepatide in adults with obesity. About this guideline and how it was created An international panel including two patient partners, clinicians, and methodologists produced these recommendations. The panel followed standards for trustworthy guidelines and used the GRADE approach, explicitly considering the balance of benefits, harms and burdens of treatment from an individual patient perspective. Recommendations were informed by a linked living systematic review and network meta-analysis evaluating relative benefits and harms updated to 31 July 2024; and by linked systematic reviews addressing risk prediction models and values and preferences of adults with type 2 diabetes. Candidate therapeutics are prioritised based on availability of sufficient randomised trial data, relevance to a global audience and likelihood of changing practice. This is the first version of the living guideline. The guideline is part of the BMJ Rapid Recommendations series. MAGICapp displays the most recent version of the guideline and full content including evidence summaries and decision aids; major updates will be published in The BMJ . We encourage re-use, adaptation and translation of these living guidelines, and recognise that the lack of availability or high costs of some medications may be prohibitive and will impact on how these recommendations are implemented across different health care systems.

Abstract Background Cabozantinib is indicated for hepatocellular carcinoma (HCC) following first-line (1L) sorafenib, but the 1L standard has shifted to immuno-oncology (IO)-based regimens. This study evaluated real-world outcomes among patients with advanced HCC receiving second-line (2L) cabozantinib following 1L therapies, including newer regimens. Patients and Methods US claims data were used to identify adults with advanced HCC initiating 2L cabozantinib monotherapy (index date). Patients were stratified into three 1L treatment cohorts: IO monotherapy/IO + IO combination therapy; IO + non–IO combination therapy; or tyrosine kinase inhibitor (TKI) monotherapy. Real-world time to treatment discontinuation (rwTTD), real-world time to next treatment or death (rwTNTD), real-world overall survival (rwOS), and cabozantinib dosing were assessed collectively and by cohort. Adverse events were assessed before/after cabozantinib initiation. Results Among 148 patients who received 2L cabozantinib, 28 were in the IO monotherapy/IO + IO combination therapy cohort, 54 in the IO + non–IO combination therapy cohort, and 66 in the TKI monotherapy cohort. Median rwTTD among all patients was 3.2 months; median rwTNTD was 7.6 months; 12-month rwOS rate was 61.6%. There were no significant differences in these outcomes among the three cohorts. Overall, 44.6% of patients initiated 2L cabozantinib at 60 mg/day, of whom 39.4% required a dose reduction; 37.8% initiated at 40 mg/day, of whom 16.1% had a dose reduction. Adverse event rates were similar before/after cabozantinib initiation. Conclusions Cabozantinib shows consistent effectiveness and safety in the 2L HCC setting following prior TKIs or IO-based regimens in real-world clinical practice. These findings may inform 2L treatment decisions.

Background: Surgeons often recommend weight loss for patients with obesity before total knee arthroplasty (TKA). However, it is unknown whether preoperative weight loss affects outcomes. The goals of this study were to determine how many patients with obesity lost weight before TKA, to identify weight loss predictors, and to evaluate if preoperative weight loss affected postoperative outcomes. Methods: Among 23,726 primary TKAs performed between 2002 and 2019, we identified 3,665 patients who had a body mass index (BMI) of ≥30 kg/m 2 measured 1 to 24 months before surgery and had a weight measured at surgery. The mean patient age was 68 years, and 59% of patients were female. The mean patient BMI was 36 kg/m 2 . Univariable linear regressions evaluated weight loss predictors. Univariable and multivariable logistic regressions and Cox proportional hazards models evaluated the impact of preoperative weight change on discharge, operative time, periprosthetic joint infections (PJIs), complications, revisions, and reoperations. The mean follow-up was 6 years. Results: Overall, 20% of patients gained ≥5 pounds (1 pound = 0.45 kg), 39% maintained weight, 17% lost 5 to <10 pounds, 15% lost 10 to <20 pounds, and 9% lost ≥20 pounds before TKA. Male patients lost slightly more weight (−4.6 pounds) than female patients (−4.3 pounds) (p = 0.05). In univariable analyses, gaining >5 pounds was associated with increased odds of extended hospital length of stay (odds ratio [OR], 1.4; p = 0.01) and risk of complications (hazard ratio [HR], 1.7; p < 0.01). Losing 10 to <20 pounds was associated with increased risks of revision (HR, 2.0; p = 0.01), PJI (HR, 3.1; p < 0.01), and complications (HR, 1.6; p = 0.03). In multivariable analyses, compared with maintaining weight, losing 10 to <20 pounds was associated with an increased risk of PJI (HR, 2.6; p = 0.01), whereas gaining >5 pounds was associated with an increased risk of complications (HR, 1.5; p = 0.03). Conclusions: Few patients with obesity lost substantial weight before primary TKA, and reaching common preoperative weight loss goals was not associated with improved outcomes. Although a healthy weight is important for general health, weight loss before TKA may not be sufficient to improve postoperative outcomes for most patients with obesity. Level of Evidence: Prognostic Level III . See Instructions for Authors for a complete description of levels of evidence.

ABSTRACTBackgroundMetabolic and bariatric surgery (MBS) is the most effective and durable approach to treating obesity, yet recurrent weight gain occurs in a subset of patients. Primary care often serves as a routine point of contact for patients following MBS and is a potential gateway for addressing and/or preventing recurrent weight gain.MethodsAlthough guidelines for the management of recurrent weight gain after MBS exist, this narrative review was undertaken to clarify the role of the primary care providers in enhancing long‐term outcomes and preventing weight gain after MBS.FindingsRegular follow‐up in primary care provides an opportunity to identify challenges related to weight management and overall health outcomes, which may include concerns related to nutrition, mental or physical well‐being, body image, motivation, and behavior change, for example. The availability of multidisciplinary providers within primary care settings, including behavioral health specialists, dietitians, and physical therapists, is an important strength of this setting in addressing potential post‐MBS concerns such as recurrent weight gain.ConclusionThis review outlines clinical considerations for managing recurrent weight gain post‐MBS in primary care and includes recommendations for both primary care providers and specialty clinicians working in primary care to deliver care effectively and mitigate weight stigma post‐MBS.

Abstract Sex differences in cancer outcome, including that of glioblastoma (GBM), are shaped by biological, hormonal, and immunological factors and impact disease progression, treatment responses, survival, and tumor microenvironment (TME) interactions. Platelets regulate the immune responses and tumor progression in many cancers, but it is not clear how they contribute to these sex-based differences by affecting the dynamics of the TME. Here, we show that GBM patients exhibit heightened platelet reactivity driven by PAR4 signaling. In murine GBM models, both pharmacological inhibition of PAR4 using BMS986120 and genetic deletion of PAR4 significantly prolong survival in females but not males. This survival advantage is estrogen dependent: it is preserved in chromosomal male-hormonal female mice within the four-core genotype model and is rescued in ovariectomized mice treated with estrogen. The survival benefit is TME specific and is mediated by platelet-driven enhancement of CD8⁺ T cell infiltration into the tumor. Inhibition of platelet PAR4 signaling increases calcium signaling through an estrogen-dependent interaction between PAR4 and estrogen receptor β (ERβ)—a receptor interaction not previously described. PAR4-activated platelets within the TME suppress CD8⁺ T cell function, and depletion of CD8⁺ T cells abolishes both the tumor-induced platelet reactivity and the survival benefit conferred by PAR4 inhibition. These findings establish platelet-mediated PAR4 signaling as a critical driver of tumor progression and identify sex-specific immune responses as key to therapeutic efficacy.

Importance Diagnostic errors represent a major patient safety concern, with the potential to significantly impact patient outcomes. To address this, various trigger-based strategies have been developed to identify diagnostic errors, aiming to enhance clinical decision-making and improve patient safety. Objective To evaluate the performance of three pre-established triggers (T) in the emergency department (ED) setting and assess their effectiveness in detecting diagnostic errors. Design Consecutive cohort, retrospective observational design. Setting Academic ED with 80 000 annual visits. Participants Adults and children presenting to a single ED in the USA between 1 May 2018 and 1 January 2020. Intervention/outcomes Electronic health records (EHRs) were retrieved and categorised into trigger-positive and trigger-negative cases using the following criteria: T1—unscheduled returnvisits to the ED with admission within 7–10 days of theinitial visit; T2—care escalation from the inpatient unitto the intensive care unit (ICU) within 6, 12 or 24 hoursof ED admission; and T3—all deaths in the ED or within24 hours of ED admission, excluding palliative care. A random sample of trigger-positive cases was reviewed using the SaferDx tool to determine the presence or absence of a diagnostic error. Results A total of 5791 trigger-positive and 118262 trigger-negative cases were identified. Among trigger-positive cases, 4159 (72%) were associated with T1, 1415 (24%) with T2, and 217 (4%) with T3. A preliminary chart review of 462 trigger-positive and 251 trigger-negative cases showed most were error-negative (279 and 217, respectively). Detailed reviews found 32 diagnostic errors among 183 trigger-positive cases, yielding PPVs of 5.4% (T1), 8.9% (T2), and 6.9% (T3). No errors were found in 34 reviewed trigger-negative cases, resulting in a 100% NPV. Sepsis was the most common diagnosis among error-positive cases (n=11, 34.4%). Those with non-specific chief complaints like altered mental status or shortness of breath had higher diagnostic error risk. Conclusion and relevance While previously proposed EHR-based triggers can identify some diagnostic errors, they are insufficient for detecting all cases. To improve error detection performance, we recommend exploring data-driven strategies, such as machine learning techniques, to more effectively identify underlying contributing factors to diagnostic errors and enhance detection accuracy in the ED.

ABSTRACT Rationale Longer duration of epilepsy before surgery is a predictor of poor outcome. While referral delays of surgical candidates are well documented, factors causing delay during the presurgical evaluation remain unclear and may vary depending on institutional characteristics. By benchmarking the duration of presurgical evaluation across multiple centers and identifying patient and evaluation characteristics contributing to duration, we can ascertain best practices and address modifiable contributors to reduce delays. Methods We queried the Pediatric Epilepsy Research Consortium Surgery Database, a prospective, observational multicenter study enrolling children 0–18 years at 27 US pediatric epilepsy centers, for all patients undergoing initial presurgical evaluation for drug‐resistant epilepsy (DRE). We included patients with completed evaluations and data on duration from initiation of presurgical evaluation to final surgical decision. We compared patient characteristics and evaluation components between those with long duration evaluations (> 75% quartile) and those with short evaluations (< 25% quartile). Akaike information criteria selection identified variables associated with longer duration. From these, we developed a logistic prediction model for evaluation duration, using a random 80/20 training/testing split of the entire cohort. The model was tested among institutions with ≥ 10 patients in the cohort to assess its accuracy in predicting long durations. Linear models for each site assessed each variable's impact on duration. Variables with < 10% of the patient population at each site were excluded. Beta values were compared to identify intra‐ and inter‐institution variability and to delineate institutions with the shortest added duration for each variable. Results Of 2318 patients undergoing surgical evaluation, 1655 (71%) from 23 sites had complete data. Median evaluation duration was 8 weeks (interquartile range 3–22); 453 (27%) were short‐duration evaluations and 414 (25%) were long‐duration evaluations. Multiple patient and evaluation characteristics were associated with duration (Table 1). Table 6 provides the average duration each variable contributes to evaluation by site, highlighting the shortest durations compared with other groups. Conclusions Duration of presurgical evaluation for DRE can be accurately modeled using multiple patient characteristics and testing strategies commonly employed in epilepsy surgery evaluations. This predictive model can not only estimate evaluation duration but also identify opportunities to improve systemic efficiency. Institution‐level modeling identifies specific program strengths, providing an opportunity to learn from successful processes. Subsequent research will focus on institutional process mapping to better understand systemic practices that lead to improved efficiencies, then sharing these processes across the consortium to shorten evaluation durations.

Background Percutaneous left atrial appendage occlusion (LAAO) is an alternative to long‐term anticoagulation for preventing ischemic stroke in patients with atrial fibrillation. There are limited long‐term outcomes data for “real‐world” patients undergoing LAAO. Methods We performed a retrospective cohort study using the National Cardiovascular Data Registry LAAO registry from January 1, 2016, through December 31, 2019. We linked LAAO data to inpatient Medicare fee‐for‐service claims data using probabilistic matching to establish a cohort of patients 65 years and older undergoing LAAO with a WATCHMAN device. The primary outcomes were any stroke and all‐cause mortality. Results A total of 34 975 patients with a mean±SD CHA 2 DS 2 ‐VASc (congestive heart failure, hypertension, age ≥75 years, diabetes, previous stroke or transient ischemic attack, vascular disease, age 65 to 74 years, and sex category) score of 4.7±1.4 were included. The median follow‐up was 2.8 years (interquartile range, 2.2–3.7 years). The cumulative incidence of any stroke was 1.57 per 100 person‐years (95% CI, 1.45–1.70), with a 1‐year and 5‐year any stroke estimate of 1.70% (95% CI, 1.57–1.84%) and 5.70% (95% CI, 5.37–6.05%), respectively. The cumulative incidence of ischemic stroke was 1.36 per 100 person‐years (95% CI, 1.25–1.48), with a 1‐year and 5‐year ischemic stroke estimate of 1.42% (95% CI, 1.30–1.54%) and 5.03% (95% CI, 4.71–5.36%), respectively. The cumulative incidence of death was 10.82 per 100 person‐years (95% CI, 10.49–11.13), with a 5‐year mortality estimate of 44.34% (95% CI, 43.35–45.23%). Conclusions Long‐term stroke rates in a large nationally representative cohort of Medicare patients following LAAO were low and durably consistent during long‐term follow‐up despite a high thromboembolic risk. High mortality rates in this elderly population underscore the importance of incorporating patient values and preferences when considering LAAO.