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Abstract Background Fibroblast growth factor receptors inhibitors (FGFRi) are approved treatments for various malignancies. FGFRi-associated retinopathy is a class effect of FGFRi, including erdafitinib, pemigatinib, infigratinib, and rogaratinib. Patients and Methods We summarized FGFRi-associated retinopathy with erdafitinib across 5 clinical studies in patients with metastatic urothelial cancer (mUC pooled studies) and one study in patients with advanced solid tumors (RAGNAR). We also present changes in visual acuity, retinal pigment epithelial elevation, and subretinal fluid in RAGNAR. Results One hundred and three (21.5%) of 479 patients in the mUC pooled studies and 43/314 (13.7%) patients in RAGNAR experienced FGFRi-associated retinopathy. Most FGFRi-associated retinopathy were Grade 1/2 events. Grade 3 FGFRi-associated retinopathy were infrequent (mUC pooled studies, 11/479 [2.3%]; RAGNAR, 3/314 [1.0%]). No Grade 4 events occurred. Most FGFRi-associated retinopathy events (mUC pooled studies, 81/103 [78.6%]; RAGNAR, 30/43 [70.0%]) occurred within 90 days of treatment initiation and were managed with erdafitinib dose interruption (mUC pooled studies, 41/479 [8.6%]; RAGNAR, 23/314 [7.3%]) or reduction (mUC pooled studies, 58/479 [12.1%]; RAGNAR, 21/314 [6.7%]); few required treatment discontinuation (mUC pooled studies, 14/479 [2.9%]; RAGNAR, 3/314 [1.0%]). By the data cutoff, 63.1% (65/103) patients in the mUC pooled studies and 65.1% (28/43) patients in RAGNAR had their FGFRi-associated retinopathy events resolve. Most unresolved FGFRi-associated retinopathy events were persistent Grade 1 events. In RAGNAR, 92.0% of patients had their visual acuity return to baseline and 78.5% of patients had their retinal pigment epithelial elevation resolve. Conclusions FGFRi-associated retinopathy with erdafitinib can be managed with dose reductions, interruptions, or discontinuations. Proactive collaboration between oncologists and ophthalmologists is required to ensure that erdafitinib delivers clinical benefit to patients while managing their potential adverse symptoms of FGFRi-associated retinopathy.

Abstract Introduction AD109, an investigational oral anti-apneic neuromuscular modulator, combines in one tablet the novel antimuscarinic, aroxybutynin (2.5 mg), with the selective norepinephrine reuptake inhibitor, atomoxetine (75 mg). AD109 significantly improved the apnea-hypopnea index and oxygenation vs placebo (PBO) in two phase 3 clinical trials in OSA. This exploratory analysis evaluated concomitant administration of AD109 with glucagon-like peptide-1 receptor agonists (GLP-1 RA) on weight change in OSA. Methods SynAIRgy (NCT05813275; N=646) and LunAIRo (NCT05811247; N=660) were randomized, double-blinded, PBO-controlled, parallel-arm phase 3 trials of AD109 vs PBO in adults with mild-to-severe OSA (AHI >5) who failed or refused positive airway pressure therapy. Participants must have had a body mass index (BMI) 18.5–40 kg/m2 for males / 18.5–42 kg/m2 for females. Participants receiving GLP-1 RA for diabetes were permitted. Body weight was assessed throughout the trials. Results One-hundred and six participants were enrolled in the phase 3 trials taking a GLP-1 RA for diabetes (PBO+GLP-1 RA: n=48; AD109+GLP-1 RA: n=58). In participants receiving a GLP-1 RA with baseline BMI < 30, AD109 reduced weight by 2.7% (vs PBO: -1.4%, P=0.08) and 0.5% (vs PBO: 2.3%, P=0.60) at Week 26 and Week 51, respectively. In participants receiving a GLP-1 RA with baseline BMI 30 to 34.9, AD109 reduced weight by 0.9% (vs PBO: 1.2%, P=0.84) and 2.5% (vs PBO: 3.3%, P=0.85) at Week 26 and Week 51, respectively. In participants receiving a GLP-1 RA with baseline BMI ≥35, AD109 reduced weight by 5.5% (vs PBO: 0.9%, P=0.02) and 11.5% (vs PBO: 3.8%, P=0.04) at Week 26 and Week 51, respectively. Participants not receiving GLP-1 RA (n=979) showed smaller weight reductions across BMI classes; in participants with BMI ≥35, AD109 reduced weight by 1.4% (vs PBO: 0.2%, P=0.002) and 2.8% (vs PBO: 1.4%, P=0.19) at Week 26 and Week 51, respectively. Conclusion In this exploratory analysis using pooled data from SynAIRgy and LunAIRo, results indicate that participants with a baseline BMI ≥35 receiving AD109+GLP-1 RA experienced progressively greater weight loss over time relative to GLP-1 RA alone. Future studies are needed to further evaluate concomitant administration of AD109+GLP-1 RA in OSA. Support (if any) These studies were supported by Apnimed, Inc.

Abstract Aims Left bundle branch block (LBBB) is associated with mechanical dyssynchrony, heterogeneous perfusion, and adverse left ventricular (LV) remodelling. 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 remodelling and function in patients with and without LBBB. Methods and results We analysed 233 patients with LBBB and 932 matched controls who underwent PET myocardial perfusion imaging, assessing mechanical dyssynchrony (phase entropy), LV volumes, and ejection fraction (EF); coronary vascular resistance (CVR), myocardial blood flow (MBF), myocardial flow reserve (MFR) as markers of microvascular function; and septal-to-lateral MBF ratio (SLR) as a measure of regional perfusion heterogeneity. Compared with controls, LBBB patients had greater dyssynchrony (56% vs. 40%), larger LV volumes, and lower EF (54% vs. 67%) (all P < 0.001), as well as higher stress CVR (37 vs. 34 mmHg/mL·min−1·g−1), and lower MBF (2.4 vs. 2.6 mL/min/g), MFR (2.4 vs. 2.6), and SLR (0.95 vs. 1.00) (all P < 0.05). Among patients with dyssynchrony, SLR <1.0 identified greater remodelling. 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 Cox 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 death or heart failure hospitalization, whereas LBBB was not. Conclusion Mechanical dyssynchrony and perfusion heterogeneity independently predict adverse LV remodelling, irrespective of LBBB. Integrated imaging improves cardiomyopathy stratification.

Convergent framework for future POC cancer diagnostics aligning clinical needs (why), enabling technologies (how), and translational bridges. It integrates lab-on-chip biosensing and analytics for decentralized, early, longitudinal care.

Background: Running often elicits stress urinary incontinence (SUI) in parous athletes. While cadence retraining improves running biomechanics, its impact on incontinence is unclear. This feasibility study assessed the implementation and preliminary effects of a 6-week cadence retraining program in parous female runners with SUI. Methods: A total of 8 participants with self-reported SUI and a preferred running cadence ≤ 170 steps/minute underwent treadmill testing before and after the intervention. The program involved a 6-week cadence retraining program using a Garmin Forerunner 55 watch. Feasibility was assessed across 6 domains. Running outcome measures included cadence and vertical oscillation. SUI outcome measures included the Questionnaire for Urinary Incontinence Diagnosis and Urinary Distress Inventory-6 scores. Paired t-tests were conducted (α = .05). Results: Following the 6-week program, feasibility outcomes supported the viability of study procedures and high adherence. Statistically significant increases in cadence ( P = .016) and decreases in vertical oscillation ( P = .019) and concomitant decreases in Questionnaire for Urinary Incontinence Diagnosis ( P = .013) and Urinary Distress Inventory-6 ( P = .042) scores were observed. Discussion: This study demonstrated the feasibility and acceptability of a 6-week cadence retraining program for parous runners with SUI. Given the growing movement to foster athleticism after pregnancy, these findings will appeal to physical therapists searching for acceptable treatment options for SUI in parous runners. Preliminary running mechanics and SUI symptoms warrant a larger randomized controlled trial. A power analysis estimated a sample size of 66 participants for a future full-scale efficacy study.

Abstract Background: As with most Sub-Saharan African countries, Nigeria has a rising incidence of cancer, with disproportionate mortality rates. The financial burden of cancer care often results in catastrophic healthcare spending, leading to treatment refusal, disruption, and discontinuation. This is particularly significant in Nigeria, where nearly all patients are uninsured, and out-of-pocket costs often exceed households’ ability to pay. Financial Navigation Programs (FNPs) have been shown to mitigate treatment-related financial toxicity in cancer care and reduce treatment abandonment, but there is a paucity of high-quality data on this intervention in resource-constrained settings. Here, we present a randomized controlled trial to evaluate the impact of a novel FNP in Nigeria. Methods: We designed the COST-FIN trial, a multi-site pragmatic single-blinded randomized controlled trial of newly diagnosed (<6 weeks from diagnosis) adults (≥18 years) with breast, colorectal, or prostate cancer at two tertiary cancer centers in Nigeria. Participants (n=200) will be randomized (1:1) to either the intervention (FNP) or the control arm and followed for 12 months. Data on key individual, treatment, and financial parameters will be collected via structured interviews and chart abstraction at baseline, 3, 6, and 12-month follow-up. In addition, participants randomized to the FNP will receive a tailored financial literacy assessment, financial planning support, and enhanced access to resources by trained financial navigators. Primary and secondary outcomes are Financial Catastrophe (FC) and Financial Distress (FD), respectively. Exploratory outcomes will include cost-related non-adherence and cost-effectiveness of the program. An interim analysis will be conducted when 50% of the estimated accruals reach 6 months of follow-up, with crossover if compelling evidence of benefit is demonstrated at that time point. All participants will be followed for 12 months from recruitment. Discussion: This first-of-its-kind study will provide evidence on the role of FNP in potentially eliminating financial barriers to cancer care in Nigeria. Given the country’s renewed interest in cancer control through the passage of the National Cancer Control Plan, findings from this study have the potential to influence policy reform and set the stage for further studies to evaluate the scalability and implementation of similar interventions in resource-limited settings. Trial registration : ClinicalTrials.gov NCT06630962. Oct 8, 2024 (https://clinicaltrials.gov/study/NCT06630962)

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 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.

Background Advancement in neurointervention is frequently driven by the introduction of new technology and devices that improve procedural efficacy and patient outcomes. For physician-innovators, customer discovery—or the process of directly engaging with end users to explore workflows and associated challenges—offers a structured way to identify meaningful problems and guide early innovation. This primer aims to outline stepwise guidance for conducting customer discovery within neurointervention to characterize key areas of unmet need. Methods We detail stepwise guidance for conducting customer discovery founded on foundational business literature. To illustrate this process, we conducted five interviews with expert neurointerventionalists engaged in clinical innovation. Interview transcripts were reviewed and analyzed to track emerging themes, and responses were synthesized into a neurointerventionalist customer profile. Results Responses from interviewed neurointerventionalists suggested that safer vascular access, tools to support treatment prognostication, and condition-specific device design are unmet areas of need. Moreover, interviews revealed broader concerns about stagnation in device innovation and barriers within regulatory and institutional pathways. Conclusions Structured customer discovery identifies unmet needs that may be overlooked when device development is solely driven by technical breakthroughs or published outcomes. By outlining an actionable framework for customer discovery in neurointervention, we provide a practical model for aligning future innovation with real-world clinical challenges.

Background The association between lifestyle factors and Alzheimer's disease (AD) pathophysiology remains incompletely understood. Objective The aim of this study was to assess the association of alcohol consumption, smoking behavior, sleep quality and physical, cognitive, and social activity with cerebral amyloid pathology. Methods For this cross-sectional study, we selected participants from the Amyloid Biomarker Study data pooling initiative. We used generalized estimating equations to assess associations of dichotomized lifestyle measures with amyloid pathology. Results We included 9171 participants with normal cognition (NC) and 2555 participants with mild cognitive impairment (MCI) from the Amyloid Biomarker Study. Of participants with NC, 58% were women, 34% were APOE ε4 carrier, and 27% had amyloid pathology. Of participants with MCI, 48% were women, 47% were APOE ε4 carrier, and 57% had amyloid pathology. In NC, cognitively active participants were less likely to have amyloid pathology (OR = 0.77, 95%CI 0.66–0.89, p < 0.001). In MCI, participants who had ever smoked or had sleep problems were less likely to have amyloid pathology (OR = 0.85, 95%CI 0.73–0.99, p = 0.029; OR = 0.62, 95%CI 0.45–0.86, p = 0.004). Conclusions In NC, cognitive activity was associated with a lower frequency of amyloid pathology. In MCI, favorable lifestyle behaviors were not associated with a lower frequency of amyloid pathology. The results of the current study contribute to the broader evidence base on lifestyle and AD by further characterizing the role of lifestyle behaviors in AD pathology across different clinical stages.