Citations

BACKGROUND: Type 2 long-QT syndrome results from KCNH2 -encoded Kv11.1 loss-of-function, but whether secondary inward-current dysfunction amplifies dysfunction remains unclear. METHODS: We characterized sodium ( SCN5A , I Na ) and L-type calcium channel ( CACNA1C , I Ca ) function in KCNH2-G604S and variant-corrected isogenic control induced pluripotent stem cell–derived cardiomyocytes (iPSC-CMs). Whole-cell patch-clamp measured action potential duration at 90% repolarization (APD90), and potassium (I Kr ), sodium (I Na ), and calcium (I Ca, L ) currents. Fluo-4 imaging quantified calcium transients. A modified Kernik-Clancy iPSC-CM model incorporated experimentally measured persistent I Na,L and I Ca,L fractions and simulated isolated and combined current defects. RESULTS: KCNH2-G604S caused severe I Kr loss-of-function (72.5% reduction). APD90 was prolonged in G604S-iPSC-CMs (765±58 ms) compared with isogenic controls (368±37 ms; P <0.005), with early afterdepolarizations in 50% of G604S cells. Nifedipine, verapamil, and mexiletine successfully shortened APD90 and abolished early afterdepolarizations. Compared with isogenic control, I Na,L (0.60±0.1% versus 0.26±0.06%; P <0.01), persistent I Ca,L (2.88±0.55% versus 1.26±0.35%; P <0.05), and calcium transient decay times ( P <0.0001) were greater in G604S iPSC-CMs. Increased persistent I Ca,L was phenocopied by E-4031 in isogenic controls and reduced by nifedipine in G604S iPSC-CMs. In silico modeling revealed that the I Kr defect alone prolonged APD90 to only 620 ms. The addition of the observed I Na,L defect had a small additive effect (+20 ms); however, incorporating persistent I Ca,L synergistically extended APD90 to 758 ms, replicating the experimental phenotype. Flux dynamics analysis indicated that this persistent Ca 2+ entry suppresses the forward-mode sodium-calcium exchanger, forcing a compensatory reliance on sarcoplasmic-endoplasmic reticulum Ca-ATPase that primes for calcium instability. CONCLUSIONS: The KCNH2-G604S variant drives a severe multihit phenotype via primary I Kr loss-of-function and secondary state-dependent gain-of-function in persistent I Ca,L . These comprehensive validations demonstrate that the remodeled persistent I Ca,L acts as the essential amplifier driving extreme action potential duration prolongation and Ca 2+ mishandling.

Background: Cefazolin and antistaphylococcal penicillins (ASP) are first-line agents for methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia. These agents are substantially protein-bound; however, scant data exist evaluating the impact of hypoalbuminemia on microbiologic and patient outcomes for this indication. Objective: The purpose of this study was to assess whether hypoalbuminemia is associated with delayed blood culture clearance in patients with MSSA bacteremia being treated with cefazolin or ASPs as definitive therapy. Methods: This retrospective cohort study included patients admitted for MSSA bacteremia between January 1, 2006 and December 31, 2019, with a serum albumin obtained between the date of an initial positive blood culture result and 72 hours following initiation of definitive therapy with cefazolin or an ASP. The primary outcome was the rate of persistently positive blood cultures, defined as failure to clear blood cultures within 72 hours of definitive therapy initiation. Patients with a serum albumin ≤2.5 g/dL were compared with those with an albumin >2.5 g/dL. Propensity score weighting was used to account for differences in cohort characteristics. Results: A total of 123 patients were included. After propensity score weighting, patients with hypoalbuminemia had a higher rate of persistently positive blood cultures, both in the overall cohort (45.0% vs 13.2%, P < .001) and in the subgroups of cefazolin (33.0% vs 9.1%, P = .015) and ASP (60.1% vs 18.3%, P = .001) when analyzed separately. After propensity weighting in the combined cohort, the length of stay was longer in the hypoalbuminemic cohort, but no differences in mortality were observed. Conclusions and Relevance: Hypoalbuminemia was associated with a delayed 72-hour blood culture clearance in patients with MSSA bacteremia treated with either cefazolin or ASPs.

ABSTRACT Background Pectus excavatum (PE), the most common congenital chest wall deformity, has known associations with connective tissue disorders and may lead to cardiopulmonary impairment; however, its relationship with atrial fibrillation (AF) remains underexplored. Objectives This study aimed to describe the frequency, clinical characteristics, and management of AF within an institutional cohort of patients with PE, and to determine whether the outcomes observed in clinically distinct subgroups persisted after adjustment for baseline risk. Methods This was a retrospective cohort study design. Patients with both PE and documented AF between January 1, 1990, and November 10, 2024, were included. Clinical, echocardiographic, and therapeutic data were collected. Bleeding and thromboembolic outcomes were evaluated using multivariable logistic regression adjusted for age, sex, CHA 2 DS 2 ‐VASc score, and anticoagulant class, and the surgically treated subgroup was additionally compared using propensity score matching. Results Among 11,578 patients with PE, 1309 (11.3%) had AF. Of those who had AF, mean age was 66.9 years; 54% were female, and 83% had paroxysmal AF. The mean CHA 2 DS 2 ‐VASc and HAS‐BLED scores were 2.8 and 1.9, respectively. Thromboembolic events occurred in 196 (15%) patients, most commonly stroke (11%), followed by pulmonary embolism (4%) and deep venous thrombosis (4%). Bleeding events occurred in 313 patients (24%), most commonly hematuria (12%), gastrointestinal bleed (11%), epistaxis (5%), and intracranial hemorrhage (1%). Seventy‐two patients (6%) underwent the Nuss procedure and were younger (45.3 vs. 68.2 years, p < 0.001), predominantly male (65%), and had lower risk scores compared to the non‐Nuss cohort. Patients who underwent the Nuss procedure had significantly fewer bleeding events (5.6% vs. 25%, p < 0.001) with similar thromboembolic rates. The pectus severity index, available in the 370 patients who underwent dedicated radiologic review, was not associated with bleeding (adjusted OR 0.89, 95% CI 0.75–1.05). The difference in bleeding by surgical status persisted after multivariable adjustment (adjusted OR 0.28, 95% CI 0.10–0.79) and after propensity score matching (5.6% vs. 16.7%, p = 0.030). Conclusions AF was identified in approximately one in nine patients within this single‐institution cohort of adults with PE, with paroxysmal AF representing the predominant subtype. Patients who had undergone surgical repair demonstrated a lower incidence of bleeding events than anticipated based on their baseline risk profile; however, given the limited number of events observed, this finding should be interpreted with caution and requires validation in larger studies. In the absence of a non–PE comparator group, these data are insufficient to determine whether PE independently confers an elevated risk of AF, and prospective, controlled investigations are necessary to elucidate this relationship.

Background Disruption in rest‐activity rhythm (RAR) is an emerging risk factor for cardiovascular disease (CVD) and mortality, but the strength of evidence is unclear. Therefore, we conducted a systematic review and meta‐analysis to assess associations between RAR characteristics and cardiovascular disease incidence or prevalence, cardiovascular mortality, and all‐cause mortality. Methods A systematic search was conducted in PubMed, Web of Science, Cochrane Library, and Embase for cohort or cross‐sectional studies published up to August 2025. The exposure variables were nonparametric RAR parameters, including interdaily stability (describing day‐to‐day stability of the RAR), intradaily variability (a measure of RAR fragmentation), and relative amplitude (indicating robustness or strength of the RAR). The primary outcomes were cardiovascular mortality and all‐cause mortality. The secondary outcomes included cardiovascular disease prevalence and incidence. Results Seven studies involving 109 365 participants were included. Pooled results showed that higher intradaily variability was associated with a significantly increased risk of all‐cause mortality (hazard ratio [HR], 1.05 [95% CI, 1.02–1.09]) and cardiovascular disease prevalence (odds ratio, 1.73 [95% CI, 1.21–2.47]). Lower relative amplitude was significantly associated with higher cardiovascular mortality (HR, 1.50 [95% CI, 1.13–1.98]) and all‐cause mortality (HR, 1.46 [95% CI, 1.27–1.68]). Interdaily stability showed no significant associations with any outcome. Conclusions Measures of disrupted rest‐activity rhythms were associated with increased cardiovascular mortality, and all‐cause mortality. These findings support using RAR metrics as early, noninvasive risk indicators. Future work should investigate whether appropriately timed physical activity and sleep, as well as other interventions targeting RAR can mitigate cardiovascular risk.

Abstract Background Cardiac valve tissue obtained during the surgical management of infective endocarditis (IE) and sent for culture may influence postoperative antibiotic therapy. We sought to identify clinical and microbiologic risk factors associated with positive valve cultures (PVC) and IE relapses in a cohort of patients undergoing surgical management. Methods This is a retrospective, multi-center study of patients with surgical management during the acute (&lt;42 days) course of IE-directed antibiotic therapy. The rate of PVC, IE relapse, and mortality were collected. Univariate and multivariable logistic regressions were performed to identify risk factors associated with PVC. Results Of 113 patients included, 36 (31.9%) had PVC. Univariate and multivariable analyses showed preoperative antibiotic duration and pathogens were associated with PVC. Median (IQR) days of preoperative antibiotics were 6.5 (4.0-11.0) for patients with PVC compared to 13.0 (8.0-21.0) for those with negative valve cultures (NVC). In a multivariable model, preoperative antibiotic administration decreased the risk of PVC (OR 0.85 per day, CI 0.77-0.91). Enterococcal IE increased the risk of PVC compared to streptococcal IE (OR 4.16, CI 1.07-17.48). Of note, 33 (63.2%) patients with NVC received a median (IQR) of 8 (5, 18.5) days of intravenous antibiotics per patient. Only one IE relapse was identified and occurred in a patient with NVC. Conclusions Both preoperative antibiotic duration and causative pathogen were associated with PVC. IE relapses were rare and unrelated to PVC. There may be an opportunity to shorten postoperative antibiotic durations following surgical management in patients with IE.

ABSTRACT Purpose This study assesses the association between colorectal cancer (CRC) screening and a validated, housing-based measure of individual-level socioeconomic status (SES, called HOUSES hereafter) within rural communities and determines whether HOUSES-integrated geospatial analysis can be used to tailor interventions. Methods We used CRC screening data from a subset of Mayo Clinic Midwest patients living in cities without ready access to routine care in the Mayo Clinic Health System in 2019 to represent rural communities. At the individual level, we assessed the association between CRC screening rates and the HOUSES index, adjusting for age, sex, race/ethnicity, comorbidity, distance from home address to clinic, and area deprivation index, using a multilevel mixed-effects logistic regression model. Additionally, we conducted geospatial analysis to examine the correlation between hotspots of 1) lower CRC screening rates and 2) lower SES of the subject population (HOUSES quartile 1). Findings Among 34,489 individuals (median age 64.0 years, 52.4% female), those with the lowest SES (HOUSES Q1) had 37% lower odds of being CRC screening adherent than those with the highest SES (HOUSES Q4) (adj. OR [95% CI]: 0.63 [0.58-0.69]). In the 14 identified HOUSES Q1 hotspots, there was a significant correlation in counts of HOUSES Q1 and low CRC screening (correlation coefficient=0.81). Conclusion Lower SES was significantly associated with lower CRC screening among rural populations. HOUSES-enabled geospatial analysis identified geographic hotspots with lower CRC screening rates for targeted interventions to address disparities in CRC screening in rural communities. HOUSES may be a useful digital tool for cancer preventive care and research.

Introduction: Autosomal-dominant tubulointerstitial kidney disease (ADTKD) is characterized by chronic kidney disease (CKD) with an average age of end-stage renal disease (ESRD) of approximately 45 years, bland urinary sediment, the absence of proteinuria and autosomal dominant inheritance. While several causative genes have been found, there remain families in whom no molecular diagnosis has been identified (ADTKD-NMD). Methods: We identified BICC1 truncating variants in several families with ADTKD-NMD in the Wake Forest Rare Inherited Kidney Disease Registry and then screened families in our database and other referred families for BICC1 truncating variants. We performed segregation analysis and characterized affected individuals for clinical and histopathologic phenotypes. We analyzed oligomer formation of BICC1 mutants with wild-type BICC1-, ANKS3- and ANKS6 proteins through co-immunoprecipitation and Western blotting, and we tested for posttranscriptional regulation of the BICC1 target mRNA, Dand5, in a Luciferase reporter assay. Results: We found 6 heterozygous truncating mutations in BICC1 segregating with the ADTKD phenotype in 8 independent pedigrees worldwide. Affected individuals developed kidney failure in the 6th to 7th decade of life that was characterized pathologically by tubular atrophy and interstitial fibrosis. The truncated gene products localized to cytoplasmic bodies and demonstrated various degrees of self-association or binding to the known interaction partners, ANKS3 and ANKS6. While the wild-type BICC1 gene product acts as a posttranscriptional repressor of target mRNAs, all truncation variants exhibited increased expression of substrate mRNA. Conclusions: Truncating variants in BICC1 are a novel cause of ADTKD, segregating with the disease phenotype and upregulating BICC1 target gene expression through a dominant-negative- or a gain-of-function mode of action.

Abstract Background Recurrence of symptomatic atrial fibrillation (AF) after catheter ablation (CA) is not uncommon. However, real-world long-term data on clinical outcomes of rhythm control strategies in patients with recurrent AF after CA remain limited. Methods Using the TriNetX database, we identified adult patients (≥18 years) with recurrent AF after index CA. A 3-month blanking period was applied, during which no rhythm-control therapy was received. Patients were classified into two groups: repeat CA or initiation of antiarrhythmic drug (AAD) therapy. Propensity score matching (PSM) was performed to balance baseline characteristics. Hazard ratios (HR) with 95% confidence intervals (CI) were calculated. Outcomes included all-cause mortality, all-cause hospitalization, heart failure (HF) exacerbation, ischemic stroke, and major bleeding over 5 years. Results Among 4,056 patients with recurrent AF post-CA, 17.2% underwent repeat CA. After PSM, 697 patients in the repeat CA group (mean age 68.9 ± 9.6 years; 35.7% female) and 697 in the AAD group (mean age 68.4 ± 10.0 years; 37.6% female) were analyzed. Repeat CA was associated with lower all-cause mortality (3.3% vs 8.2%; HR 0.44; 95% CI, 0.27–0.72; P &lt; 0.01), all-cause hospitalization (42.8% vs 56.4%; HR 0.71; 95% CI, 0.61–0.82; P &lt; 0.01) and HF exacerbation (12.5% vs 24.8%; HR 0.50; 95% CI, 0.39–0.64; P &lt; 0.01). No differences were observed in ischemic stroke (5.3% vs 4.7%; HR 1.22; 95% CI, 0.77–1.96; P = 0.40) or major bleeding (4.6% vs 6.2%; HR 0.82; 95% CI, 0.52–1.29; P = 0.39). Conclusions Repeat CA was associated with lower mortality, hospitalization, and HF exacerbation over 5 years.