Citations

ABSTRACT Blood culture contamination can lead to false-positive blood culture results, potentially contributing to increased costs and unneeded antibiotic utilization. Initial specimen diversion devices (ISDD) have been proposed to reduce blood culture contamination rates. A single-center, observational study conducted at Mayo Clinic Rochester compared blood culture contamination rates using Steripath or Kurin ISDDs versus standard blood culture collection protocols. Over 255 phlebotomists were trained in the use of the ISDDs, with 31,215 blood cultures, 410 of which were contaminated, collected from adults in the emergency department and inpatient wards. Baseline contamination rates were 1.29%–2.53% with standard collection methods. The Steripath ISDD with direct-to-media inoculation of blood culture bottles (Steripath-DTM) reduced blood culture contamination compared to standard practice (0.34% vs. 1.43%, respectively, P < 0.001). Follow-up studies with the alternative Steripath configuration with an integrated syringe (Steripath-syringe), and then the Kurin ISDD with syringe collection (Kurin-syringe), did not meet the primary endpoint of <0.5% contamination (Steripath-syringe: 1.28%; Kurin-syringe: 1.76%). All three ISDD configurations failed to meet our goal of >75% utilization, with an average measured utilization of 26% for the Steripath-DTM, 26.4% for the Steripath ISDD (combined DTM and syringe) in a follow-up study, and 41.5% in the Kurin study. Additionally, a survey of phlebotomists revealed low staff satisfaction with both Steripath ISDD configurations. Staff reported multiple ergonomic barriers limiting the Steripath ISDD’s utility, which precluded implementation of the Steripath-DTM in routine clinical practice. IMPORTANCE We conducted a very large, real-world study of two blood diversion devices to determine whether either would meet goals for reduced blood culture contamination and a high rate of utilization by phlebotomists.

ABSTRACT Background Agrin‐congenital myasthenic syndrome ( AGRN ‐CMS) is a rare, heterogeneous genetic disorder of the neuromuscular transmission that can present from infancy to adulthood. The clinical phenotype includes distal weakness mimicking distal myopathies. Additionally, electromyography and muscle biopsy may demonstrate myopathic features, increasing the diagnostic challenge. Mitochondrial dysfunction has not been reported in the muscle of AGRN ‐CMS patients. Methods We report the clinical, electrophysiological, radiological, myopathological, and genetic findings of a patient with AGRN‐ CMS. Results A 47‐year‐old male presented at age 18 with sudden onset of eyelid ptosis, weakness, and fatigue, followed by dysphagia, dyspnea on exertion, exercise intolerance, and myalgias. Three sisters had similar symptoms. Neurological examination showed lower limb weakness, predominantly affecting the calf muscles with associated atrophy. Tendon reflexes were normal but absent at the ankles. Creatine kinase levels were normal. Electromyography demonstrated myopathic changes in distal muscles with fibrillation potentials in the gastrocnemius. 2 Hz‐Repetitive nerve stimulation of the fibular nerve revealed a 32% decrement in the extensor digitorum brevis without facilitation. Tibialis anterior biopsy showed non‐specific myopathic changes, neurogenic features, and histological evidence of mitochondrial dysfunction, as suggested by the scattered cytochrome c oxidase‐negative fibers. Whole exome sequencing detected a homozygous pathogenic AGRN variant (c.5012G>A, p.Arg1671Gln). No pathogenic or suspected pathogenic variants were detected in muscle mitochondrial DNA or in nuclear genes affecting mitochondrial function. Conclusions This patient expands the pathological spectrum of AGRN ‐CMS to include mitochondrial dysfunction and highlights the importance of low‐frequency repetitive nerve stimulation in the assessment of patients with distal weakness for differentiating myopathies from CMS.

Abstract Background Data on respiratory syncytial virus (RSV) acute respiratory infection (ARI) among community-dwelling U.S. adults aged 18 to 64 years, particularly those with high-risk conditions (HRC), remain limited. This study estimated incidence and attack rates of RSV-ARI and RSV lower respiratory tract disease (LRTD) in adults with and without HRCs. Methods A multistate, community-based prospective cohort of adults aged 18 to 64 years with and without HRCs was followed from October 2022 to September 2024. Incidence rates and annual attack rates of RSV-ARI and RSV-LRTD were calculated by HRC presence and age group. Results Of 3375 adults with at least 1 HRC, the RSV-ARI incidence rate was 17.9 per 1000 person-years (attack rates: year 1, 1.87%; year 2, 1.56%), compared with 14.8 per 1000 person-years (year 1, 1.33%; year 2, 1.50%) among adults without HRCs. RSV-LRTD incidence was 10.0 per 1000 person-years in adults with HRCs versus 5.7 per 1000 person-years in those without. Asthma, congenital immunodeficiency, and immunosuppressive medication use were associated with increased incidence of RSV-ARI and RSV-LRTD; whereas adults with solid organ transplant and chronic kidney disease had a significantly higher incidence rate of RSV-LRTD compared to those without these conditions. Adults aged 18 to 49 years with HRCs had significantly higher RSV-LRTD incidence (9.6 vs 4.3 per 1000 person-years). After adjustment for age and sex, having ≥1 HRC was associated with a 62% increased RSV-LRTD risk, rising to 117% among adults aged 18 to 49 years. Conclusions Adults with HRCs—particularly asthma, congenital immunodeficiency, chronic kidney disease, immunosuppressive medication use, and solid organ transplant—experienced higher RSV-ARI and RSV-LRTD incidence. The elevated RSV-LRTD burden was most pronounced in adults aged 18 to 49 years with HRCs.

Abstract Introduction Multiple pulmonary nodules (MPNs) are commonly encountered in patients at elevated risk for thoracic malignancy and represent a spectrum of disease states and stages. We evaluated the safety, and procedural outcomes of a combined robotic assisted bronchoscopy (RaB) and linear endobronchial ultrasound (EBUS) approach to patients with MPNs during a single bronchoscopic procedure. Methods This multicenter observational registry included patients who underwent RaB for evaluation of MPNs. Data were prospectively collected from six centers between 2019 and 2025. Demographics, imaging characteristics, safety events, and procedural outcomes were analyzed and associated with final diagnosis. Results A total of 191 patients underwent RaB with biopsy of MPN during a single procedure; 167 patients also underwent linear EBUS lymph node sampling. The strict per nodule diagnostic yield was 71.5% overall (first nodule 70.7%, second 74.3%, third 71.4%). At least one malignant nodule was identified in 127 patients (66.8%), and 85 patients (44.5%) had two or more malignant nodules; 15 patients (17.6%) demonstrated heterogeneous histopathology between malignant nodules. Among patients with non–small cell lung cancer, adequate cellularity for next generation sequencing was achieved in 82.6% of nodules. Malignant lymph nodes were identified in 10.8% (18/167). No patients with two pure ground glass nodules (0/8) had malignant nodal involvement. Pneumothorax occurred in 7.3% of cases, with 2.1% requiring chest tube placement; unplanned admissions occurred in 3.7%. Conclusion This study provides a large multisite registry evaluation of performance of simultaneous bronchoscopic sampling of multiple pulmonary nodules with EBUS staging during a single anesthesia event demonstrating an acceptable safety profile and adequacy for molecular profiling.

Background/Objectives: Novel vision-language models (VLMs) can integrate patient textual data with image data to support medical diagnosis. Recent studies reported conflicting results regarding the performance of multimodal VLMs compared to other models and physician performance. This systematic review aims to assess the diagnostic performance of multimodal VLMs integrating both patient textual and image data across diverse real-world hospital settings. Methods: We performed comprehensive searches of eight resources, including Embase, MEDLINE, and SCOPUS, on 17 December 2025. Eligible studies reporting diagnostic performance of VLMs integrating both image and patient history textual data from real-world adult patients compared to that of other models and physicians were included. The review adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The Prediction model study Risk Of Bias Assessment Tool + AI (PROBAST + AI) was used to assess the quality and risk of bias. The study protocol was registered in the PROSPERO database (CRD420251244054). This review received no external funding. Results: We screened 11,026 records, of which 18 studies met the inclusion criteria. Six studies comparing multimodal and unimodal models demonstrated the consistent superiority of the multimodal models. Four studies evaluating VLM accuracy as standalone agents compared with physician performance reported conflicting evidence. One study assessing VLMs as a clinical copilot demonstrated higher accuracy from the group of physicians using VLM assistance. A meta-analysis could not be performed due to the heterogeneity across study populations and outcomes. The majority of the studies were assessed as having a high risk of bias due to dataset quality. Primary limitations identified across studies include small sample size, a lack of external validation, and the need for prospective clinical deployment studies. No study provided documented considerations regarding model safety or data security. Conclusions: This systematic review suggests that multimodal VLMs consistently outperform unimodal models with access to only image or text. While model performance as standalone agents compared to humans remains inconclusive, a copilot model has demonstrated high diagnostic accuracy. Given substantial methodological concerns across studies, cautious interpretation is required, No firm clinical recommendation can be made regarding the use of standalone VLMs. Further research employing high-quality datasets is needed to ensure the reliability and clinical applicability of future VLMs.

Abstract Background In patients with suspected amyloid cardiomyopathy (CM) and a monoclonal protein, tissue biopsy is mandatory to exclude amyloid light-chain CM (AL-CM), the subtype requiring urgent therapy. We aimed to develop a pragmatic approach to estimate the most likely final diagnosis before biopsy. Methods We studied a multicenter cohort of adults referred for biopsy because of suspected amyloid CM. Clinical, laboratory, ECG/echocardiographic and bone-tracer scintigraphy data were collected at initial suspicion. In patients with a monoclonal protein, we derived age cut-offs overall and by carpal tunnel syndrome (CTS), defined an age-based "gray zone" (74–83 years), and evaluated risk modifiers for AL-CM and transthyretin CM (ATTR-CM). We built a points-based algorithm for "gray-zone" patients. Clinical utility was assessed using decision-curve analysis. Results Among 602 patients (median age 76 years; 81% male), 524 (87%) had a monoclonal protein. In the monoclonal-protein subgroup, ATTR-CM accounted for 49%, AL-CM for 30%, and neither ATTR- nor AL-CM for 21%. Age ≤73 years was the Youden-optimal threshold favoring AL-CM (sensitivity 66%, specificity 78%), whereas age &gt;84 years made AL-CM unlikely (sensitivity 98%, negative predictive value 94%), defining a "gray zone" (n=261; ATTR-CM 63%, AL-CM 18%, no amyloid CM 20%). Within the gray zone, abnormal free light-chain ratio, positive urine immunofixation, proteinuria, and higher troponin T and N-terminal pro-B-type natriuretic peptide (NT-proBNP) favored AL-CM, while higher Perugini grade, male sex, greater interventricular septal thickness, and higher NT-proBNP favored ATTR-CM. Penalized models achieved cross-validated area under the curves of 0.87 (AL-CM) and 0.94 (ATTR-CM). A two-score algorithm identified small gray-zone subsets enriched for AL-CM (positive predictive value 81.5%, specificity 98%) or ATTR-CM (positive predictive value 95.2%, specificity 94%). DCA showed higher net benefit for score- and model-based strategies versus treat-all/treat-none across clinically relevant threshold probabilities, with consistent patterns across regions. Conclusions In patients with suspected amyloid CM and a monoclonal protein, age- and CTS-anchored stratification refined by a compact set of routine laboratory and imaging features provides actionable pre-biopsy probabilities and may help prioritize urgent biopsy and AL-directed work-up while definitive tissue typing is pursued.For image description, please refer to the figure legend and surrounding text.

Abstract Background Immunosuppression (IS) is required in AAV-mediated gene therapy to maximize safety and efficacy, in part to mitigate potential hepatotoxicity and prevent immune-mediated loss of transgene expression. However, prolonged IS increases the risk of complications, including infections. MYBPC3-associated HCM patients have limited treatment options. MyPEAK-1 is a first-in-human trial to assess the safety and efficacy of TN-201, a gene replacement therapy, which was designed to address the underlying genetic cause of MYBPC3-associated HCM in symptomatic adults. Objective To describe the safety and refinement of the IS regimen and monitoring used during the dosing of Cohorts 1 and 2 in the MyPEAK-1 trial. Methods The dose-escalation study utilized two cohorts (n=3 each) receiving 3E13 vg/kg (Cohort 1) or 6E13 vg/kg (Cohort 2) of TN-201 as a single IV infusion. All patients received prophylactic prednisone (starting at 1 mg/kg, maximum 80 or 60 mg/day) and sirolimus (target trough level of 4–8 ng/mL). Prednisone was tapered over several weeks, with variable timing depending on safety laboratory results. The dose of prednisone and timing of sirolimus were adjusted to reduce IS burden in Cohort 2. Specifically, sirolimus was initiated earlier (Day -7 vs Day -3) and the maximum starting dose of prednisone was reduced (from 80 to 60 mg/day). Monitoring frequency was increased to weekly throughout the course of IS. An independent data safety monitoring board provided safety oversight. Results All six patients successfully completed the IS regimen. TN-201 was generally well-tolerated at both dose levels (follow-up &gt;52 weeks and &gt;12 weeks in Cohort 1 and 2, respectively). Adjustments to the IS regimen and monitoring during Cohort 1 facilitated a significantly shorter course of IS in Cohort 2, with a mean duration of prednisone use of 256 vs 81 days. Despite receiving a higher dose of TN-201, peak transaminase levels, reflecting liver inflammation, were lower in Cohort 2 than Cohort 1. There was no clinical TMA in either cohort. Mean sirolimus trough levels remained consistent between groups (7.2 vs 7.4 ng/mL). Increases in MyBP-C protein, decreases in circulating cardiac biomarkers, and a reduction in LV hypertrophy were observed during follow up. Conclusion Standardized adjustments to the prophylactic immunosuppressive regimen in the MyPEAK-1 trial successfully managed the immunogenicity of AAV9-based gene therapy. Cohort 2 patients required lower cumulative corticosteroid doses without compromising safety or cardiac transduction. These refinements enabled lower cumulative steroid exposure and shorter IS durations in the higher-dose cohort. These results suggest that individualized, protocol-driven IS is effective in controlling the immune response to TN-201 while supporting transgene expression, paving the way for continued investigation of this gene therapy clinical investigation in MYBPC3-associated HCM population.Corticosteroid duration and daily doseFor image description, please refer to the figure legend and surrounding text.

Abstract Background Tafamidis is a near-complete transthyretin kinetic stabiliser for the treatment of patients with transthyretin amyloid cardiomyopathy (ATTR-CM). It is administered orally, once daily, and has demonstrated a statistically significant reduction in mortality at 30 months vs placebo. Purpose Report findings from patients who received up to 7.5 years treatment with tafamidis in the phase 3 trial and its long-term extension (LTE) study. Methods In ATTR-ACT, patients were randomised (2:1:2) to blinded tafamidis meglumine 80 mg, 20 mg, or placebo for 30 months. Patients continued their blinded tafamidis dose into the up to 60-month LTE study, until commercial prescription availability, or study termination. Those who received placebo in ATTR-ACT were randomized (2:1) to blinded tafamidis meglumine 80 mg or 20 mg in the LTE study. All patients were subsequently switched to open label tafamidis free acid 61 mg (bioequivalent to meglumine 80 mg). Outcomes were assessed over the entire 90-month follow-up. Results Of the 264 patients randomised to tafamidis in ATTR-ACT, 173 completed the trial and 170 continued to receive tafamidis the LTE study (Taf/Taf group). Of 177 patients randomised to placebo in ATTR-ACT, 85 completed the trial and 82 initiated tafamidis in the LTE study (Pbo/Taf group). Over a median follow-up of 54.2 months in the Taf/Taf group and 30.5 months in the Pbo/Taf group, incidence of all-cause mortality (ACM) was 54.5% and 71.2%. Median time to ACM was 47.5 and 30.3 months, resulting in a hazard ratio of 0.62 (95% CI: 0.49-0.79; P=0.0001; Figure). Incidence of cardiovascular-related mortality (CVM) was 42.0% and 57.1% in the Taf/Taf and Pbo/Taf groups. Median time to CVM was 47.6 and 30.3 months, resulting in a hazard ratio of 0.61 (0.47-0.81; P=0.0005). The total annual rate of all-cause hospitalisation in the LTE study was 0.69 in the Taf/Taf group and 1.14 in the Pbo/Taf group, and the total annual rate of cardiovascular-related hospitalisation was 0.36 and 0.63. Among patients remaining at each LTE study visit and with available data, improvement in New York Heart Association functional classification was more commonly seen in the Taf/Taf vs Pbo/Taf group. Mean observed reduction from baseline in Kansas City Cardiomyopathy Questionnaire Overall Summary score was significantly smaller in the Taf/Taf vs Pbo/Taf group at most LTE study visits. Treatment-related adverse events occurred in 11.2% of the Taf/Taf and 23.2% of the Pbo/Taf groups during the LTE study and were consistent with the known safety profile of tafamidis. Conclusions With up to 7.5 years of follow-up data, this analysis of ATTR-ACT trial and its LTE study is the longest reported to date for an ATTR-CM population treated with disease-modifying therapy. Findings demonstrate better long-term outcomes including survival, hospitalisation rates, quality of life, and heart failure symptoms with long-term tafamidis treatment. For image description, please refer to the figure legend and surrounding text.

Abstract Background Cardiovascular inflammation is thought to play a central role in the pathogenesis of heart failure (HF) with preserved ejection fraction (HFpEF) and heart failure with mildly reduced ejection fraction (HFmrEF), but no therapies specifically targeting inflammation in this setting are currently available. Purpose Here we describe the rationale and design of two clinical trials (ATHENA and HERMES) investigating ziltivekimab, a human monoclonal antibody directed against the IL-6 ligand, in patients with HFpEF/HFmrEF and cardiovascular inflammation. Methods ATHENA and HERMES are international, multicenter, double-blind, placebo-controlled trials randomizing adults with HFpEF/HFmrEF and cardiovascular inflammation to ziltivekimab 15 mg or placebo, both administered subcutaneously once-monthly on top of standard of care. Eligible participants have a left ventricular ejection fraction &gt;40%, elevated NTproBNP and serum high sensitivity C reactive protein ≥2 mg/L. The primary endpoint in ATHENA (n=680) is the change in Kansas City Cardiomyopathy Questionnaire–Clinical Summary Score at 12 months. The primary endpoint in HERMES (n=4900) is the composite of CV death, hospitalization for HF or urgent HF visit. The study is event-driven and will target 845 primary events (Figure 1). Conclusions ATHENA and HERMES will investigate the effect of ziltivekimab in HFpEF/HFmrEF and cardiovascular inflammation. ATHENA will determine the effect of ziltivekimab on health status. HERMES will determine the efficacy and safety of ziltivekimab on morbidity and mortality.Fig 1.ATHENA and HERMES trial designsFor image description, please refer to the figure legend and surrounding text.

Abstract Background Renal dysfunction is a major determinant of outcomes after heart transplantation (HT). While baseline renal impairment and post-HT dialysis are known predictors of mortality, the prognostic impact of sustained pre-HT renal decline in patients bridged with durable left ventricular assist devices (LVADs) remains unclear. Methods We conducted a retrospective, multicenter cohort study using the United Network for Organ Sharing (UNOS) registry to identify adult patients who underwent HT following durable LVAD support between 2009 and 2024. Sustained renal decline was defined as a ≥40% reduction in estimated glomerular filtration rate (eGFR) from listing to HT. Multivariable logistic regression identified predictors of renal decline and post-HT dialysis,while Cox proportional hazards models assessed the impact on post-HT mortality. Results Among 10,454 eligible patients, 624 (6.0%) experienced sustained renal decline during LVAD bridging. Compared with patients without renal decline, affected patients had longer waitlist durations (median 297 vs. 197 days; p&lt;0.001), lower eGFR at HT (42.0 vs. 70.6 mL/min/1.73 m²; p&lt;0.001), and higher rates of post-HT dialysis (23.7% vs. 12.8%; p&lt;0.001). Independent predictors of sustained renal decline included longer waitlist time, perioperative blood transfusions, while the use of HeartMate 3 LVAD was protective. Sustained renal decline was independently associated with increased risk of post-HT dialysis (adjusted odds ratio [aOR] 2.64) and all-cause mortality (adjusted hazard ratio [aHR] 1.16),with post-HT dialysis strongly predicting mortality (aHR 3.48). Conclusions Sustained renal deterioration while awaiting HT is a significant predictor of post-HT dialysis and mortality in LVAD-bridged patients. Incorporating renal trajectory into risk stratification may enhance candidate selection and promote perioperative renal protection strategies.