Citations

Abstract Background The self-management of type 2 diabetes (T2D) typically requires enacting various lifestyle changes, which can challenge people living with T2D. Clinical encounters between people with T2D and their clinicians, however, are often focused on metabolic management, leaving less time available for other self-management topics. The QBSAFE cards help patients articulate aspects of their experience with diabetes and prioritize issues for discussion. Methods This report details secondary outcomes of a randomized controlled trial; primary outcomes are reported elsewhere. All data was collected at Fair Haven Community Health Care, a federally qualified primary care clinic. 11 clinicians were randomly assigned to provide either usual care or usual care with QBSAFE cards to 155 of their patients with type 2 diabetes and hemoglobin A1c >8%. All patient encounters were video recorded for analysis. Patients and clinicians were not blinded to arm allocation but were kept unaware of the specific aims of the trial. Encounter video reviewers were blinded to arm allocation, but not to specific aims of the trial. The outcomes of interest for this report were the extent to which the QBSAFE cards were used as intended, their effect on the topics of discussion, and whether they enabled clinicians to notice and respond to each patient’s situation; comparisons between arms were conducted by a linear mixed model with fixed effect of arm and cluster effect of clinician, analyzed in both intent-to-treat and per-protocol populations. Findings 12 patients were excluded post-randomization (A1c <8%). Of 143 eligible patients, 137 encounters (65 in the usual care arm, 72 in QBSAFE) yielded evaluable videos. QBSAFE was used as intended in 61 (85%) QBSAFE arm encounters. Conversations about burden of treatment related to non-pharmacological interventions (17 vs 33, p = 0·04) and taking medications (11 vs 33, p = 0·0008) and about the patient’s challenging environment (2 vs 10, p = 0·04) were more prevalent in the QBSAFE group. There was no difference in the rate of conversations about metabolic management or of new care plans as a result of conversations between groups. Interpretation While there was a difference in the types of conversations observed between the two study arms, this difference was small and only apparent in a few domains. Future work could aim to modify the QBSAFE cards to more effectively stimulate patient-centered discussions and to further prepare clinicians to respond to a variety of issues raised during the clinical visit. Funding This work was supported by funding from the National Institute of Diabetes and Digestive and Kidney Diseases (R01DK129616).

BACKGROUND: No large registries of patients with acute eosinophilic myocarditis (EM) are available. However, EM is perceived as a cardiac disease with high mortality, affecting mainly young and middle-aged adults according to small series and case reports. Awareness of the clinical presentation, associated systemic conditions, treatments, and outcomes of this uncommon condition is an unmet need. METHODS: In this international, multicenter, retrospective cohort study, 53 centers screened 193 patients with histologically proven acute EM between 1992 and 2023. After the exclusion of patients with insufficient data (n=10), symptoms lasting >30 days (n=19), or histological diagnosis not confirmed after review (n=8), 156 patients were included. RESULTS: Median age at presentation was 48 years (first to third quartile, 34–59 years) with male predominance (67.3%), and only 2 were pediatric cases (≤16 years of age; 1.3%). The main signs and symptoms at presentation were dyspnea (75.6%), fever (61.3%), and chest pain (53.2%). Unexpectedly, peripheral eosinophilia was reported in only 57.4% of cases, with a median cell count of 630 eosinophils/μL. The median left ventricular ejection fraction at presentation was 32% (first to third quartile, 25%–48%). The disorders most frequently associated with EM were eosinophilic granulomatosis with polyangiitis (22.4% of cases) and hypersensitivity forms (14.1%). Idiopathic/undefined forms accounted for 44.9% of cases, and miscellaneous causes accounted for 18.6%. In-hospital death or need for heart transplantation (HTx) occurred in 23 patients (14.7%; 22 deaths and 1 HTx), despite 43.6% being treated with temporary mechanical circulatory support and 92.9% being treated with immunosuppressive agents. Estimated rates of death or HTx at 1 and 3 years were 19.0% and 23.8%. Increased age, decreased left ventricular ejection fraction on admission, and no immunosuppressive therapy during hospitalization were independent predictors of death or HTx. A nonsignificant higher occurrence of deaths or HTx was observed in the hypersensitivity form (46.1%) compared with the eosinophilic granulomatosis with polyangiitis–associated form (13.1%) at 3 years ( P =0.15). CONCLUSIONS: Acute EM can often present without peripheral eosinophilia, and rates of in-hospital and midterm mortality or HTx are high. Endomyocardial biopsy is required to reach the final diagnosis of EM because relying on peripheral eosinophilia can lead to missing diagnosis. In-hospital immunosuppression is associated with HTx-free survival, although tailored immunosuppressive therapies are needed to improve outcomes. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT06447935.

ABSTRACT Skeletal muscle (SM) is an integral organ component in the pathophysiology of many acute and chronic diseases. But is there a ‘gold’ standard or accepted reference method for quantifying the amount and composition of human SM mass? Exploring that question led us to recognize the existence of a SM measurement paradigm that divides methods into two broad categories, in vitro and in vivo. In vitro methods quantify SM mass, weighing intact muscles as part of whole cadaver evaluations, only 51 of which are reported in medical literature with no recent additions. In vivo methods are used to evaluate SM in vivo, and two tiers were revealed in our analyses. An upper tier that included three methods considered ‘reference’ approaches for their accuracy and precision: computed tomography, magnetic resonance imaging and dual‐energy X‐ray absorptiometry. A lower in vivo method tier included bioimpedance analysis, three‐dimensional imaging, several approaches involving creatine metabolism, ultrasound and anthropometry. A feature common to all of the lower tier methods is their need for calibration or validation against reference approaches in the upper in vivo method tier. A critical review of the three in vivo reference methods in the upper tier revealed widely variable SM volume/mass acquisition protocols, image analysis methods and applied terminology. Some reports espouse an upper tier reference method as the ‘gold’ standard while providing minimal details of exactly how and what was measured, thus making replication in follow‐up studies difficult. Any technical issues related to an in vivo reference method are propagated to the in vivo methods in the lower tier that are calibrated or validated against them. Our review of in vivo reference methods of quantifying SM mass and composition led us to two broad recommendations. First, published reports including these reference methods should provide enough details related to acquisition and analysis protocols so that readers can replicate their findings. Second, an effort should be made to apply precise terminology in published reports in order to avoid confusion on exactly what was measured; suggestions are made on definitions of commonly used terms when referring to body composition compartments. Lastly, because there is no consensus on what constitutes a ‘gold’ standard for SM measurement, we suggest expert groups convene in the future to recommend optimum approaches and working guidelines for quantifying muscle mass and composition in vivo.

Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPis) are an important therapy for high-grade serous ovarian cancer (HGSOC). However, PARPi resistance frequently emerges, necessitating previously unrecognized approaches to improve HGSOC responses. Here, we showed that the anaplastic lymphoma kinase (ALK) inhibitor brigatinib enhances PARPi activity in HGSOC cells by disrupting an adaptive survival mechanism orchestrated by Fos-related antigen 1 (FRA1) in response to PARPi. This effect of brigatinib occurred through an ALK-independent pathway, wherein brigatinib induced a dual blockade of focal adhesion kinase (FAK) and EPH receptor A2 (EPHA2) tyrosine kinases, leading to the suppression of protein kinase B (Akt) and extracellular-regulated kinase (ERK) signaling accompanied by disruption of a phosphorylation event crucial for FRA1 protein stability. Moreover, in HGSOC patient-derived xenograft (PDX) models, brigatinib and PARPi combination therapy induced tumor regression and improved overall survival compared with PARPi alone, particularly in models with high FAK and EPHA2. These findings support dual targeting of FAK and EPHA2 as a strategy to achieve effective and durable PARPi responses and identify a promising biomarker-based combinatorial approach using brigatinib and PARPi for HGSOC, particularly the subset characterized by high FAK and EPHA2.

Abstract Patent foramen ovale (PFO) has a prevalence of approximately 25%. Its association with pyogenic brain abscess (PBA) is unclear. We reviewed adults with PBA and known PFO status from 1 January 2009 through 31 December 2021 at Mayo Clinic. High PFO prevalence (40.5%) was seen. PBA patients with PFO had distinct abscess characteristics but unchanged 1-year, all-cause mortality.

Abstract Aims Left bundle branch block (LBBB) is associated with mechanical dyssynchrony, heterogeneous perfusion, and adverse left ventricular (LV) remodeling. However, not all patients with LBBB develop cardiomyopathy, and dyssynchrony can occur without conduction defects. The role of microvascular dysfunction remains uncertain. We aimed to assess how mechanical dyssynchrony and perfusion heterogeneity relate to LV remodeling and function in patients with and without LBBB. Methods and results We retrospectively analyzed 233 patients with isolated LBBB and 932 matched controls who underwent PET myocardial perfusion imaging, assessing mechanical dyssynchrony (phase entropy), myocardial blood flow (MBF), coronary vascular resistance (CVR), myocardial flow reserve (MFR), septal-to-lateral MBF ratio (SLR) for perfusion heterogeneity, LV volumes, and ejection fraction (EF). Compared to controls, patients with LBBB had greater dyssynchrony (56% vs. 40%), larger LV volumes, and lower EF (54% vs. 67%) (all p <0.001), and had higher stress CVR (37 vs. 34 mmHg/mL·min⁻¹·g⁻¹), lower stress MBF (2.4 vs. 2.6 mL/min/g), reduced MFR (2.4 vs. 2.6), and lower SLR (0.95 vs. 1.00) (all p <0.05). Among patients with dyssynchrony, SLR<1.0 identified those with more adverse remodeling. In multivariable regression, phase entropy and SLR independently predicted LV volumes and EF, with adverse effects of SLR reduction amplified in LBBB (interaction p <0.01). In the Cox proportional hazards analysis, phase entropy (HR:1.02, p =0.01), MFR (HR:0.62, p <0.001), and LVEF (HR:0.97, p <0.001) were independently associated with mortality and heart failure hospitalization, whereas LBBB was not. Conclusions Mechanical dyssynchrony and perfusion heterogeneity independently predict adverse LV remodeling, irrespective of LBBB. Integrated imaging enhances cardiomyopathy stratification.

Abstract Background Spinal cord injury causes motor, sensory, and autonomic impairments. Transcutaneous spinal cord stimulation (tSCS) has shown potential to improve autonomic regulation, particularly cardiovascular and bladder control. Heart rate variability (HRV) serves as a non-invasive marker of autonomic balance, reflecting modulation of cardiac sympathetic and parasympathetic activity. The purpose of this study was to evaluate the effect of combined tSCS and physical therapy (tSCS + PT) on HRV and autonomic function metrics in chronic spinal cord injury. Methods. Eight participants (2 with tetraplegia, 6 with paraplegia) received tSCS at 30 Hz targeting T11–L1 or C5–T1, depending on injury level. Each underwent two tSCS + PT sessions per week for 12 weeks, followed by a 4-week washout period. Autonomic assessments included the Autonomic Standard Evaluation Form (ASAF), Neurologic Bladder Symptoms Score (NBSS), blood pressure, heart rate, SpO2%, and core temperature. Electrocardiograms were recorded pre- and post-tSCS + PT at baseline, 12, and 16 weeks. Results. Baseline effects of tSCS + PT revealed increased time-domain HRV parameters, suggesting enhanced cardiac parasympathetic activation (PSA). After 12 weeks, these parameters decreased, suggesting reduced cardiac PSA and enhanced sympathetic activation (SA). Similar results were found with frequency-domain parameters. Time-and frequency-domain parameters tended to return toward baseline after the 4-week therapy suspension. Two commonly reported HRV parameters, SDNN and RMSSD, showed large effects (g = 1.64, CI 95% [0.30, 2.98], and g = 1.23, CI 95% [0.11, 2.42], respectively) at 12 weeks when comparing pre- vs. post-tSCS + PT. Moderate, subject-related differences across evaluations were found in ASAF and NBSS (p > 0.05). Physiological metrics across time points did not show statistically significant differences (p > 0.05). Physiological metrics across time points did not show statistically significant differences (p > 0.05). Conclusions Combined tSCS + PT elicited improvements in autonomic clinical measures, without statistically significant changes in time-domain or frequency-domain HRV parameters. Nonetheless, trends and size effect in SDNN and RMSSD suggested that tSCS + PT induced midterm SA and a transient PSA immediately post-tSCS + PT. The partial recovery of HRV after tSCS withdrawal indicates that the observed autonomic changes were therapy-related.

ABSTRACT Musculoskeletal infection (MSKI) remains a major problem after trauma and elective orthopedic surgery. Chronic MSKI is related to the formation of biofilm, which impairs diagnosis and effective treatments. Therefore, to understand and communicate global standards and best practices, the 2025 International Consensus Meeting (ICM) on MSKI created a Biofilm Section to address crucial aspects of biofilm biology pertaining to its mechanisms of drug resistance and immune evasion, and potential approaches to overcome them. This featured a 2‐year process, with final voting and discussion on May 8–10, 2025, in Istanbul, Turkey. This Consensus Article is the effort of the Biofilm Basic Mechanisms Workgroup, which interpreted the results on ICM questions related to (1) the infectious microenvironment; (2) appropriate inocula in preclinical research; (3) biofilm behavior in infected tissues; and (4) synergy within biofilms and with other comorbidities. Collectively, we find that this field has the necessary research tools to discover the pathophysiology of orthopedic implant‐associated biofilm development and maturation, perform clinically relevant studies in animal models, and elucidate mechanisms that allow opportunistic infections in compromised tissues and patients with other health issues.

ABSTRACT Introduction Positron emission tomography (PET) myocardial flow reserve (MFR) is a robust indicator of coronary vascular health and a strong predictor of cardiovascular risk. Clinical guidelines typically use fixed MFR thresholds (e.g., <2.0) to stratify risk, yet this approach overlooks individual variation, particularly by age and sex. We aimed to establish age- and sex-adjusted MFR percentiles and to evaluate their prognostic and predictive performance for cardiovascular risk assessment, in comparison with conventional fixed-threshold MFR approach. Methods Using data from the REFINE PET registry (24,820 patients from 12 sites), we measured PET MFR and derived age- and sex-adjusted MFR reference percentiles using quantile regression in patients without known coronary artery disease. All patients were categorized into percentile-based quartile groups. The primary outcome for prognostic and prediction analyses was major adverse cardiovascular events (MACE), defined as all-cause mortality, myocardial infarction, or heart-failure hospitalization. Time-to-event associations were evaluated using covariate-adjusted survival models, with cumulative incidence and hazard ratios (HR) estimated at 1 and 5 years in the derivation dataset, an independent but similar validation dataset A, and a high-risk validation dataset B. Predictive performance for MACE was assessed using discrimination, calibration, and reclassification metrics, comparing percentile-based models with models using a fixed MFR threshold (<2.0). Results Among participants (mean age 66.5 years; median follow-up 3.6 years), age- and sex-adjusted MFR quartile groups were strong independent predictors of MACE, with adjusted HR increasing stepwise across quartile groups at both early and later follow-up. At 1 year, HR (95% CI) comparing the lowest to the highest quartile group were 4.06 (3.41–4.82) in the derivation cohort, 3.31 (2.32–4.71) in validation cohort A, and 2.35 (2.05–2.70) in validation cohort B. At 5 years, the corresponding HR were 2.18 (1.86–2.56), 1.77 (1.31–2.40), and 1.59 (1.36–1.86). Percentile-based models demonstrated consistently higher discrimination, better calibration, and greater net reclassification for MACE at both time points compared with fixed-threshold MFR models. Although 67.2% of patients had preserved MFR (>2.0), cardiovascular risk increased steadily across MFR percentiles even within this range. Conclusion Age- and sex-adjusted MFR percentiles provide a reliable, clinically actionable measure of vascular health, improving cardiovascular risk stratification by better capturing age- and sex-related heterogeneity in vascular risk. Compared with traditional fixed-threshold approaches, MFR percentiles demonstrate improved predictive performance for cardiovascular risk assessment across diverse patient populations. CLINICAL PERSPECTIVE What is new? In a large, multinational real-world registry of more than 24,000 patients undergoing PET MPI, we derived age- and sex-adjusted myocardial flow reserve (MFR) percentiles, establishing a lifespan-based reference framework with age-specific reference values. Age- and sex-adjusted MFR percentiles showed a strong, graded association with 1- and 5-year cardiovascular risk and demonstrated improved prognostic and predictive performance compared with fixed MFR thresholds and models without MFR across independent derivation and validation datasets, including a higher-risk cohort. Lower adjusted MFR percentiles were consistently associated with higher risk of major adverse cardiovascular events, including all-cause mortality, myocardial infarction, and heart-failure hospitalization. What are the clinical implications? Age- and sex-adjusted MFR percentiles provide a personalized, dynamic measure of coronary vascular health that improves cardiovascular risk stratification by accounting for age- and sex-related heterogeneity. A percentile-based approach may help clinicians better identify patients at elevated cardiovascular risk who may warrant closer monitoring or intensified preventive strategies, while avoiding unnecessary intervention in lower-risk individuals. By integrating macrovascular and microvascular dysfunction, age- and sex-adjusted MFR percentiles offer a clinically interpretable marker of vascular aging that may inform future research on aging biomarkers, novel therapeutics and cardiovascular risk assessment across the spectrum of atherosclerotic and microvascular disease.

Objectives: To evaluate evolving management, ICU admission, and outcomes for critically ill chimeric antigen receptor (CAR) T-cell patients over a 6-year period. Design: Multicenter retrospective cohort study from January 2018 to September 2023. Setting: Eight U.S. centers. Patients: Adult CAR T-cell patients requiring ICU admission. Interventions: None. Methods: Summary statistics included mean, sd , median, and interquartile range (IQR). Fisher exact test or chi-square test were used to evaluate association between year treated and other categorical variables. Cochran-Armitage test was performed to assess significance of trends across years. Multivariable logistic regression was performed to assess covariates associated with mortality. Measurements and Main Results: Demographics, toxicity management, ICU admission, support modalities, toxicity severity, and survival (ICU, hospital, and 3-mo) were compared year-to-year. From 2018 to 2023, 2238 patients received CAR T cells, with increasing number of patients treated yearly; 398 (17.8%) required ICU care. Of those admitted to the ICU, 66.1% were male, 89.2% had lymphoma, and median age was 64 years (53–71 yr). ICU admission rates declined from 38.5% (95% CI, 31.6–45.8%) in 2018 to 16.4% in 2023 (95% CI, 13.5–19.7%; p < 0.0001). Cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome was the reason for ICU admission in 87.9%. In 2023 vs. 2018, ICU patients were older (median, 65 yr [IQR, 55–73 yr] vs. 58 yr [48–67 yr]; p = 0.003) with higher comorbidity indices (4 [4–6] vs. 3 [2–4]; p = 0.005) and more severe toxicities (≥ grade 3: 90.1% vs. 69.9%; p = 0.004). Corticosteroid use for less severe toxicities (≤ grade 2 toxicity: 73.8% vs. 40.6%; p = 0.0001) and anakinra use (56% vs. 5.5%; p < 0.0001) increased throughout the years. Mortality from cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome remained low (5.5%). Age, Sequential Organ Failure Assessment greater than or equal to 10 at ICU admission, and ICU admission for noncytokine release/neurotoxicity syndrome reasons were associated with hospital mortality (odds ratios, 1.02 [95% CI, 1–1.04; p = 0.046], 4.69 [2.44–9.01; p < 0.0001], and 3.74 [1.91–7.3; p = 0.0001], respectively). Conclusions: ICU admission rates after CAR T-cell treatment are declining. Although ICU patients are older with higher severity of illness and toxicity grades, ICU mortality after CAR T-cell therapy remains low.