Citations

Daptomycin-resistant Enterococcus faecium (DRE) poses an increasing therapeutic challenge, particularly in immunocompromised patients and solid organ transplant recipients. Surveillance data from the Centers for Disease Control and Prevention indicate that approximately 6.5% of E. faecium isolates are daptomycin-resistant, underscoring the need for heightened clinical vigilance, particularly for prompt identification and treatment. In this case series, three patients with advanced liver disease, including two status post orthotopic liver transplantation, are described who developed DRE during treatment for bloodstream infection. These cases illustrate the dynamic nature of antimicrobial susceptibility under daptomycin exposure and highlight the contributions of persistent source control issues, intravascular infection, and altered host factors to treatment failure. All patients were successfully managed by escalating to combination therapy with high-dose daptomycin and ceftaroline, alongside appropriate source control. This series emphasizes the importance of periodic susceptibility reassessment during daptomycin therapy and cautions clinicians against assuming sustained susceptibility in patients with prolonged bacteremia or complex infections. Early recognition of evolving resistance and timely therapeutic adjustment may improve outcomes in this high-risk population.

Background/Objectives: Streptococcus intermedius, a member of the Streptococcus anginosus group, is characterized by a marked propensity for abscess formation but only rarely causes native-joint septic arthritis. Involvement of the acromioclavicular (AC) joint is particularly uncommon. We describe a case of native AC joint septic arthritis due to S. intermedius in a patient with multiple predisposing factors and highlight diagnostic and management considerations. Methods: We report the clinical course of a 72-year-old man with poorly controlled type 2 diabetes mellitus who presented with progressive right shoulder pain, erythema, and swelling following recurrent minor skin abrasions from a newly adopted dog. Initial management for presumed inflammatory shoulder pathology included brief systemic corticosteroids and an ultrasound-guided intra-articular ketorolac injection. Magnetic resonance imaging (MRI) was performed after symptom progression. The patient underwent operative irrigation and debridement with collection of synovial fluid and deep tissue cultures. Blood cultures and transthoracic echocardiography were obtained to evaluate for systemic involvement. Results: MRI demonstrated multiloculated periarticular abscesses and osteolysis centered on the AC joint. Operative cultures yielded high colony counts of S. intermedius from synovial fluid and deep tissues. Blood cultures and echocardiography were negative. The patient required multiple operative debridements with irrigation, adjunctive local antibiotic therapy, and prolonged targeted β-lactam treatment. Clinical and radiographic improvement was achieved following surgical source control and antimicrobial therapy. Conclusions: Native AC joint septic arthritis due to S. intermedius is rare. Older age, uncontrolled diabetes, recent intra-articular intervention, and possible zoonotic inoculation from canine wound licking may represent contributory risk factors. Early imaging, prompt surgical source control, and guideline-concordant antimicrobial therapy are essential when bone and soft tissue involvement is present.

Abstract The adoption of electronic health records (EHRs) has transformed health care, improving efficiency and chart accessibility. However, the widespread reliance on unstructured data entry and the lack of standardized documentation frameworks have resulted in significant data fragmentation across health care systems. The prevalence of unstructured data in EHRs limits their potential for clinical decision support, trial matching, real‐world evidence (RWE) generation, and quality measurement. Data fragmentation in health care triggers a cascade of challenges that ultimately compromise patient care. Clinicians face an excessive documentation burden and struggle to locate critical information buried in unstructured notes. Researchers encounter difficulties in extracting reliable clinical data. EHR vendors grapple with standardizing unstructured information for interoperability, and payers are unable to process unstructured clinical data efficiently to support value‐based care models. These challenges are particularly acute in oncology, where complex clinical elements like cancer staging, disease status, and treatment changes require precise, structured documentation. Emerging artificial intelligence (AI) technologies, such as large language models (LLMs) and ambient listening, offer a path to automate structured data generation while reducing the workload on providers. Here, the authors propose LLM‐based workflows that balance automation with clinician verification, streamlining data entry without compromising accuracy. Realizing these benefits requires coordinated efforts among clinicians, researchers, EHR vendors, payers, and policymakers to align regulatory frameworks with AI‐driven innovations. This article outlines a strategy to enhance structured data capture within EHRs, ultimately improving patient care, research, and health care efficiency.

Stereotactic arrhythmia radiotherapy (STAR) is emerging as a highly effective treatment for ventricular tachycardia (VT). Growing evidence indicates that STAR favorably reprograms the electrical substrate by speeding conduction and/or prolonging repolarization via modulation of ion channel expression, although the mechanisms by which single-fraction radiation mediates durable changes in gene expression are incompletely understood. Here, we identify dynamic changes in the cardiomyocyte epigenome and transcriptome after irradiation (IR) in vivo and in vitro, including durably increased expression and chromatin accessibility of Scn5a (encodes the α subunit of the sodium channel, Na V 1.5), demonstrating a role for epigenetic memory in conduction velocity (CV) increases observed after STAR. Transcriptomic and epigenetic sequencing further identified dynamic changes in gene expression and regulatory regions involved in cellular repolarization, calcium handling, and metabolism after IR. These changes were mirrored by dose-dependent and cell-autonomous changes in repolarization, calcium flux, and mitochondrial respiration, highlighting important cellular processes that may mediate the therapeutic effects of STAR. Overall, we found that cardiomyocytes exposed to a single fraction of high-dose IR exhibited epigenetic reprogramming that mediated broad and dynamic physiologic responses.

INTRODUCTION: Chronic gastroduodenal disorders are highly prevalent and encompass heterogeneous pathophysiology. Autonomic dysfunction may contribute, but its relative contribution to disease pathophysiology and symptoms is unclear. This study aimed to clarify the contributions of autonomic dysfunction in gastroduodenal disorders and symptom associations using multimodal testing, hypothesizing that distinct disorder subgroups would be revealed. METHODS: This prospective observational cohort study included 80 patients with chronic gastroduodenal symptoms. Participants underwent expert clinician-led autonomic evaluation, body surface gastric mapping (BSGM; Gastric Alimetry, New Zealand), and gastric emptying scintigraphy testing. BSGM phenotyping, gastric emptying cutoffs, and autonomic criteria followed standard criteria. RESULTS: Gastroparesis was diagnosed in 27 (33.8%) patients. Autonomic dysfunction was present in 21 (26.3%) patients, and abnormal BSGM in 20 (25%). Autonomic dysfunction and abnormal BSGM were both more prevalent in gastroparesis (51.9% vs 13.2%, P = 0.001; and 44.4% vs 15.1%, P = 0.005, respectively). However, these diagnoses tended not to overlap, with patients having autonomic dysfunction generally exhibiting normal BSGM tests. Autonomic dysfunction independently predicted delayed gastric emptying (OR 13.8, P < 0.001) and was associated with earlier meal responses (higher meal response ratio, P = 0.04) and worse postprandial distress symptoms ( P < 0.05). DISCUSSION: Autonomic dysfunction independently predicted delayed gastric emptying and revealed a gastroparesis mechanism distinct from gastric myoelectrical impairment. Autonomic dysfunction altered the postprandial gastric motor response and was associated with a greater symptom burden. Multimodal physiological testing including autonomic profiling reveals distinct mechanistic subgroups in patients with chronic gastroduodenal symptoms.

ABSTRACT Background Immune checkpoint inhibitors (ICIs) have emerged as promising agents for the management of advanced HCC. By reducing tumour burden, ICIs may serve as a downstaging/bridging tool to improve transplant candidacy. The aim of this study was to assess the safety of patients receiving pre‐LT ICIs. Methods Multicenter, retrospective cohort study from January 2018 to December 2024, including 48 patients who received ICIs prior to LT (ICI cohort). A control cohort (non‐ICI cohort) was built (1:3) using propensity score matching including 144 patients who underwent LT for HCC without prior ICI. Results Within the ICI cohort ( N = 48) rejection occurred in 9 patients (18.8%), all biopsy‐proven, with a median onset of 31 days post‐LT (12.0–182.0). The median washout period was 60 days (13–96). Patients experiencing rejection had shorter washout periods ( p = 0.029). All rejection episodes were successfully managed; two were steroid‐resistant, one requiring re‐transplantation. There were no rejection‐related deaths. Of the 5 patients with HCC recurrence, 60% received ICI for < 90 days ( p = 0.027). Comparison between the ICI and non‐ICI cohort revealed no significant differences in rejection rates (18.8% vs. 19.4%, p = 0.916), graft failure, HCC recurrence, or overall mortality. Overall survival (OS) did not differ between ICI and non‐ICI patients ( p = 0.625) or between those with and without rejection ( p = 0.119). Rejection was not associated with increased mortality, with deaths primarily attributed to infection or HCC recurrence. Conclusion Our results demonstrate that rejection rates were similar in patients receiving ICIs pre‐LT and it can be safely managed.

Abstract Background Implantable cardioverter-defibrillator (ICD) is a well-established therapeutic option associated with decreased mortality in patients with ischemic and non-ischemic cardiomyopathies. However, the indications for patients with chronic Chagas cardiomyopathy (CCC) are not well established since these patients were underrepresented in the trials validating ICD use. Purpose This systematic review and single-arm meta-analysis aims to synthetize the available evidence in the literature on the role and outcomes of ICD in CCC. Methods A systematic search of PubMed, Web of Science, Cochrane, and LILACS registries was performed following PRISMA guidelines. Studies evaluating the response to ICD in CCC were included. There were no language restrictions. Data were collected and synthesized using a meta-analysis of proportions with Freeman-Tukey double-arcsine transformation as needed. Results We included 14 observational studies and 1 randomized clinical trial (RCT), comprising 1315 patients with CCC. Mean age at ICD implantation was 58.2 ± 11.8, 65% were male, and 77% received an ICD for secondary prevention. During a mean follow up of 37.3 ± 37.0 months, the all-cause death rate was 22% (95% CI 15 to 29%; Figure 1A), the cardiovascular death rate was 16% (95% CI 11 to 22%; Figure 1B), the sudden cardiac death rate was 3% (95% CI 2 to 5%), and the non-cardiovascular death rate was 7% (95% CI 2 to 5%). In addition, 55% (95% CI 43 to 67%; Figure 1C) of patients received ≥1 appropriate ICD therapy (shocks or antitachycardia pacing), 8% (95% CI 5 to 12%) received inappropriate ICD shocks, and 23% (95% CI 11 to 37%) experienced electrical storms. Conclusion Despite ICD, the mortality rate in patients with CCC remains unacceptably high, primarily driven by cardiovascular causes, with frequent appropriate ICD therapies and electrical storms. Further studies are needed to better delineate the benefits and risks of ICD therapy in patients with CCC.Figure 1

Abstract Background Short QT syndrome type 1 (SQT1) is a genetic channelopathy caused by gain-of-function variants in the KCNH2-encoded Kv11.1 potassium channel, responsible for the repolarising IKr current. These variants lead to pathologically shortened cardiac repolarisation and QT intervals on 12-lead ECG, predisposing patients to life-threatening ventricular arrhythmias and sudden cardiac death. Purpose To investigate the therapeutic efficacy of our KCNH2-specific suppression-replacement gene therapy (KCNH2-SupRep) in transgenic SQT1 rabbits generated by cardiac-specific overexpression of KCNH2-N588K. Methods KCNH2-SupRep was developed by combining a custom-designed KCNH2 shRNA with its corresponding shRNA-immune KCNH2 cDNA, packaged into a single AAV9 vector and delivered directly into the aortic root via a Swan Ganz catheter (1E10 vg/kg). Therapeutic efficacy was evaluated in vivo by 12-lead ECG recordings pre- and three weeks post-therapy, ex vivo by optical voltage mapping, and at the cellular level by patch-clamp, calcium imaging, and qPCR in ventricular cardiomyocytes (VCMs) isolated from adult transgenic SQT1 and wild-type (WT) rabbits. Results In vivo, KCNH2-SupRep normalized the heart-rate corrected QT interval (QTc) in transgenic SQT1 rabbits towards WT levels (baseline-SQT1: 153±4ms vs SupRep-SQT1: 167±5ms, p=0.0002; Fig. 1A), without adversely impacting repolarisation heterogeneity. No such QTc changes were observed in sham-treated SQT1 rabbits (sham-SQT1) (baseline-SQT1: 155±4ms vs sham-SQT1: 146±5ms, p=0.1422). Ex vivo, at a 2.5Hz stimulation frequency, KCNH2-SupRep therapeutically prolonged the APD90 in SupRep-SQT1 hearts (176±4ms) near WT levels (179±4ms), compared to untreated (UT)-SQT1 (154±4), and resolved the pathologically increased apicobasal APD90 heterogeneity observed in UT-SQT1 hearts, supporting an anti-arrhythmic effect of KCNH2-SupRep (Fig. 1B). At the cellular level, at a 1Hz stimulation frequency, KCNH2-SupRep prolonged the APD90 in VCMs isolated from SupRep-SQT1 rabbits (363±11ms) closer to WT levels (404±14ms) as compared to UT- (314±12ms) and sham-SQT1 (322±11ms; Fig. 1C). Moreover, KCNH2-SupRep restored the cellular surrogate of the electro-mechanical window (cEMW, Ca2+ transient duration – APD) and normalized IKr in nearly 50% of VCMs (Fig. 1D), in line with a 50-60% suppression of the mutant KCNH2 transcript. This partial therapeutic effect on IKr may explain the incomplete APD90 normalization in individual VCMs. Nonetheless, both in vivo and ex vivo, this partial therapeutic effect was sufficient to completely restore the electrical properties. Conclusion This proof-of-concept study is the first to demonstrate the efficacy of gene therapy in treating SQT1 in a medium-sized animal model. KCNH2-SupRep rescued the disease phenotype in vivo, ex vivo and at cellular levels in transgenic SQT1 rabbits.Therapeutic efficacy of KCNH2-SupRep

Objective Age of symptom onset is highly variable in familial frontotemporal lobar degeneration (f‐FTLD). Accurate prediction of onset would inform clinical management and trial enrollment. Prior studies indicate that individualized maps of brain atrophy can predict conversion to dementia in f‐FTLD. We used a Bayesian linear mixed‐effect (BLME) prediction method for identifying accelerated brain volume loss to predict conversion to dementia. Methods Participants included 234 asymptomatic or prodromal carriers of C9orf72 , GRN , or MAPT mutations (including 21 dementia converters) with ≥3 longitudinal magnetic resonance imaging (MRI) T1‐weighted scans. The BLME models established individual voxel‐wise gray matter trajectories using the first 2 scans. Person‐specific clusters of accelerated volume loss were estimated in subsequent scans and tested as predictors of dementia conversion compared with other approaches in time‐varying Cox proportional hazard models covarying for age. Receiver‐operating characteristic (ROC) curves estimated utility of cluster volume in discriminating which participants converted to dementia within 24 months. Results The BLME cluster volume predicted conversion to dementia in f‐FTLD mutation carriers overall and separately in C9orf72 , GRN , and MAPT , with comparable hazard ratios observed for atrophy W‐maps and regional volumes. Within a 24‐month timeframe, BLME cluster volume discriminated dementia converters from non‐converters with larger areas under the curve (AUCs) than other approaches. Interpretation Bayesian‐modeled individualized atrophy scores predict dementia progression among asymptomatic f‐FTLD mutation carriers and may have increased utility compared with other structural imaging methods when studying individuals over shorter timeframes that align with clinical trial design. ANN NEUROL 20269999:n/a–n/a