Citations

Abstract Background and Aims Type 1 short QT syndrome (SQT1) is a genetic channelopathy caused by gain-of-function variants in KCNH2, resulting in shortened cardiac repolarization and QT intervals, which predispose patients to ventricular arrhythmias and sudden cardiac death. This study aimed to investigate the therapeutic efficacy of KCNH2-specific suppression-and-replacement (KCNH2-SupRep) gene therapy in a transgenic rabbit model of SQT1. Methods KCNH2-SupRep was developed by combining a KCNH2-shRNA with its corresponding shRNA-immune KCNH2-cDNA into an AAV9 vector, delivered directly into the aortic root (1 × 1010 vg/kg). Therapeutic efficacy was evaluated in vivo by electrocardiogram, ex vivo by optical mapping, and at cellular levels by patch-clamp, calcium imaging, and qPCR in ventricular cardiomyocytes (VCMs). Results In vivo, KCNH2-SupRep normalized the heart rate-corrected QT interval (QTc) in SQT1 rabbits, without affecting repolarization heterogeneity. Ex vivo, KCNH2-SupRep corrected the action potential duration (APD90) and resolved the increased apicobasal APD90 heterogeneity observed in untreated (UT)-SQT1 hearts, supporting an antiarrhythmic effect, which was further validated by reduced re-entry formation in silico. At cellular levels, KCNH2-SupRep prolonged APD90 in VCMs from SupRep-SQT1 rabbits closer to wildtype levels compared with UT- and sham-SQT1. Additionally, KCNH2-SupRep restored the cellular surrogate of the electro-mechanical window and normalized IKr in nearly 50% of VCMs, in line with a 50%–60% suppression of the mutant KCNH2 transcript. Conclusions This proof-of-concept study is the first to demonstrate the efficacy of gene therapy for SQT1 in a medium-sized animal model. KCNH2-SupRep gene therapy successfully corrected the pathologic phenotype in vivo, ex vivo, and at cellular levels in transgenic SQT1 rabbits.

Abstract The aim of this international meta-analysis was to quantify the predictive value of BMI for incident fracture and relationship of this risk with age, sex, follow-up time, and BMD. A total of 1 667 922 men and women from 32 countries (63 cohorts), followed for a total of 16.0 million person-years were studied. 293 325 had FN BMD measured (2.2 million person-years follow-up). An extended Poisson model in each cohort was used to investigate relationships between WHO-defined BMI categories (Underweight: <18.5 kg/m2; Normal: 18.5-24.9 kg/m2; Overweight: 25.0-29.9 kg/m2; Obese I: 30.0-34.9 kg/m2; Obese II: ≥35.0 kg/m2) and risk of incident osteoporotic, major osteoporotic and hip fracture (HF). Inverse-variance weighted β-coefficients were used to merge the cohort-specific results. For the subset with BMD available, in models adjusted for age and follow-up time, the hazard ratio (95% CI) for HF comparing underweight with normal weight was 2.35 (2.10-2.60) in women and for men was 2.45 (1.90-3.17). Hip fracture risk was lower in overweight and obese categories compared to normal weight [obese II vs normal: women 0.66 (0.55-0.80); men 0.91 (0.66-1.26)]. Further adjustment for FN BMD T-score attenuated the increased risk associated with underweight [underweight vs normal: women 1.69 (1.47-1.96); men 1.46 (1.00-2.13)]. In these models, the protective effects of overweight and obesity were attenuated, and in both sexes, the direction of association reversed to higher fracture risk in Obese II category [Obese II vs Normal: women 1.24 (0.97-1.58); men 1.70 (1.06-2.75)]. Results were similar for other fracture outcomes. Underweight is a risk factor for fracture in both men and women regardless of adjustment for BMD. However, while overweight/obesity appeared protective in base models, they became risk factors after additional adjustment for FN BMD, particularly in the Obese II category. This effect in the highest BMI categories was of greater magnitude in men than women. These results will inform the second iteration of FRAX®.

Abstract Purpose: R,R-1,2 cyclohexanediamine-pyrophosphato-platinum(II) (PT-112) is a novel immunogenic cell death–inducing small molecule under phase II development in several cancer types. It inhibits ribosome biogenesis and causes organelle stresses, leading to selective immunogenic cell death in cancer cells. The possibility of PT-112’s pyrophosphate moiety driving high drug concentrations to bone sites of disease has led to an interest in PT-112’s use in multiple myeloma. In this study, we present findings from phase I and in vivo studies for PT-112 in relapsed or refractory multiple myeloma. Experimental Design: PT-112 biodistribution was analyzed in mice via laser ablation inductively coupled plasma mass spectrometry. The activity of PT-112 was assessed in de novo and transplantable Tg(Igkv3-5*-MYC)#Plbe (Vk*MYC) multiple myeloma mouse models as monotherapy or combination therapies. M-spike levels and survival were measured. A phase I dose escalation study of PT-112 monotherapy was conducted using a 3 + 3 design in patients with heavily pretreated relapsed or refractory multiple myeloma with exhausted available therapies. Results: In vivo biodistribution imaging revealed high concentrations in the bone, kidney, lung, skin, and liver. PT-112 was active in Vk*MYC multiple myeloma mouse models, both alone and in combination. Phase I data showed that PT-112 monotherapy was safe and well-tolerated, establishing a recommended phase II dose of 360 mg/m2 on days 1, 8, and 15 of a 28-day cycle. Confirmed responses and other signals of activity were observed. Conclusions: These results suggest a lack of cross-resistance with the standard of care and support the translational value of the Vk*MYC model system. Further clinical investigation of PT-112 is warranted in multiple myeloma.

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, contributing to significant morbidity and mortality worldwide. The relationship between physical exercise and AF is complex, with studies showing both beneficial and potentially adverse effects. Moreover, evidence suggests a U-shaped association between exercise intensity and AF risk. Moderate exercise has been shown to reduce AF burden by improving cardiovascular risk factors, enhancing autonomic regulation, and mitigating atrial fibrosis. In contrast, excessively high-intensity endurance exercise may increase AF risk, particularly in young athletes, due to atrial stretching, dilation, fibrosis, autonomic imbalances, and heightened inflammation. The current guidelines emphasize exercise as a core lifestyle intervention for AF management, recommending moderate-intensity aerobic activity for optimal outcomes. This review examines the current evidence on the effects of exercise on AF, identifies knowledge gaps, and proposes potential future research directions.

ABSTRACT Carbapenem‐resistant Acinetobacter baumannii (CRAB) are difficult‐to‐treat pathogens that primarily cause health care‐associated infections. Sulbactam/durlobactam (SUL/DUR) is a novel antibiotic combination that is uniquely formulated to target CRAB isolates. However, investigations of SUL/DUR's pharmacokinetics in obese patients are limited. Here, we report on the successful treatment of CRAB bacteremia in a patient with acute renal failure and severe obesity (weight 273 kg, body mass index 103 kg/m 2 ) with SUL/DUR and meropenem combination therapy. The patient had a calculated creatinine clearance of 25 mL/min and received therapy with intravenous SUL/DUR 1 g/1 g every 8 h over 3 h in combination with intravenous meropenem 500 mg every 8 h to complete 14 days of therapy. Pharmacokinetic analysis revealed target attainment with prolonged half‐life ( T 1/2 ) and volume of distribution (Vd) of 35.3 h and 81.3 L for sulbactam and 30.5 h and 169.1 L for durlobactam, respectively. Susceptibility testing using the broth disk elution test did not show synergy between SUL/DUR and meropenem. No adverse effects were observed, and the patient achieved clinical cure without recurrence of A. baumannii infection.

Abstract Aims Although cardiovascular disease (CVD) screening and preventive care in the early postpartum are recommended for women with prior gestational diabetes (GDM) and hypertensive disorders of pregnancy (HDP), certain barriers limit access to such services. We conducted a scoping review to summarize evidence on the barriers and facilitators of CVD prevention services among women with prior GDM or HDP. Methods and results A comprehensive search strategy was used to search articles published in three databases (Ovid Medline, CINAHL, Embase). Studies published in English or French that investigated and reported barriers or facilitators to postpartum CVD screening and preventive care among women with previous GDM and HDP were included. Out of 18 565 studies we screened, 29 studies (12 qualitative, 17 quantitative) were included. Main individual level barriers including lack of knowledge, health, and emotional factors were identified. Competing priorities, lack of family/friend support, and mistrust of healthcare providers were the most reported interpersonal level barriers, while gaps in communication were the most significant organizational barrier, and gaps in insurance coverage was the most reported system barrier. Individual level facilitators included a personal desire for better health and availability of postpartum programmes, and the most reported interpersonal facilitator was women's commitment to modelling a healthy lifestyle for their children. Organizational level facilitators were access to primary care providers and follow-up visit reminders, and programme availability in native languages. Conclusion Women with prior GDM or HDP face significant barriers to accessing postpartum CVD prevention services. These barriers ranged from individual-level knowledge gaps to system-level healthcare disparities.

Introduction: Ureteral stents are widely used in the specialty of urology to preserve renal function and provide ureteral patency in cases of urolithiasis, strictures, malignancy, and trauma. This paper presents a novel application of prophylactic ureteral stents deployed under MRI-guidance for ureteral protection in the setting of in-bore salvage cryoablation therapy for recurrent and metastatic prostate cancer. This is the first known case series of ureteral stent placement using near real-time MRI. Materials and Methods: A retrospective chart review was performed for all patients who underwent MRI-guided ureteral stent placement prior to in-bore cryoablation therapy from 2021 to 2022. Each case was managed by an interdisciplinary team of urologists and interventional radiologists. Preoperative and postoperative data were collected for descriptive analysis. Physics safety testing was conducted on the cystoscope and viewing apparatus prior to its implementation for stent deployment. Results: A total of seven males, mean age 73.4 years (range 65–81), underwent successful prophylactic, cystoscopic MRI-guided ureteral stent placement prior to cryoablation therapy of their prostate cancer. No intraoperative complications occurred. A Grade 2 postoperative complication of pyelonephritis and gross hematuria following stent removal occurred in one case. The majority of patients were discharged the same day as their procedure. Conclusions: This case series demonstrates the feasibility of in-bore cystoscopic aided MRI guidance for ureteral stent placement. Ureteral stents can be used to increase the safety margin of complex cryoablation treatments close to the ureter. Furthermore, by following the meticulous MRI safety protocols established by MRI facility safety design guidelines, MRI conditional tools can aid therapy in the burgeoning interventional MRI space.