University of California, Irvine Medical Center,UC Irvine Health

Birt-Hogg-Dubé (BHD) syndrome is an autosomal dominant disorder caused by germline inactivation of the folliculin gene (FLCN). Approximately 25

Frailty is a multidimensional state of reduced physiological reserve that is increasingly recognized as a major determinant of outcomes in cardiovascular diseases (CVDs). As populations age and cardiometabolic multimorbidity becomes more prevalent, understanding how frailty interacts with CVD pathology has important implications for risk stratification, clinical decision-making, and patient-centered care. Across diverse cardiovascular conditions and interventions, frailty independently predicts higher risks of mortality, major adverse cardiovascular events (MACE), rehospitalization, procedural complications, functional decline, and reduced quality of life. Shared biological mechanisms—including chronic inflammation, sarcopenia, endothelial dysfunction, and the effects of multimorbidity and polypharmacy—help explain the strong and often bidirectional relationship between frailty and CVD, one that is reported by recent data to be multiplicative as well as additive. Importantly, frailty demonstrates prognostic value beyond traditional risk factors and varies in predictive performance depending on the assessment tool used. Finally, frailty should not be viewed as immutable; evidence shows that appropriate conditioning may slow the decline or even reverse frail or prefrail states. This narrative review aims to synthesize contemporary evidence on frailty definitions and assessment, epidemiology, mechanistic pathways linking frailty with CVD, associated outcomes, prognostic value, and emerging interventions relevant to CVD prevention and management.

BACKGROUND:Analyses of statin trials by the Cholesterol Treatment Trialists' Collaboration have suggested larger relative risk reduction (RRR) for major adverse cardiovascular events (MACE) per 1 mmol/L (38.7 mg/dL) low-density lipoprotein cholesterol (LDL-C) lowering in primary prevention than in secondary prevention. However, controversy remains about the value of LDL-C lowering in primary prevention. OBJECTIVE:This meta-analysis examined the relationship between LDL-C reduction and MACE risk in primary prevention with statin and nonstatin LDL-C-lowering therapies in cardiovascular outcomes trials (CVOTs). METHODS:PubMed and Cochrane Central Register of Controlled Trials were searched from inception through August 26, 2025. The primary endpoint was the pooled RRR vs controls for 4-point composite MACE (coronary heart disease death, nonfatal myocardial infarction, fatal and nonfatal stroke, and coronary revascularization) per 1 mmol/L LDL-C lowering. RESULTS:Eleven CVOTs of solely primary prevention participants (n = 74,466) and 3 in which >80% of participants were primary prevention (n = 24,071) were identified (11 statin, 1 bempedoic acid, 1 ezetimibe, 1 statin+ezetimibe). In 13 trials, the pooled mean difference between groups in LDL-C reduction was 1.00 mmol/L (95% CI: 0.82-1.18 mmol/L) with a pooled estimate of 30% (relative risk: 0.70; 95% CI: 0.67-0.74) RRR for 4-point MACE per 1 mmol/L LDL-C reduction vs control. CONCLUSION:In CVOTs of solely or predominantly primary prevention participants, each 1 mmol/L reduction in LDL-C was associated with a 30% RRR in 4-point MACE. These results strengthen the evidence and rationale for the benefits of LDL-C lowering in primary prevention.

Patients (pts) with uncontrolled diabetes mellitus (DM) pose a greater challenge in the treatment of urinary tract infections (UTIs) than pts with controlled DM. We compared treatment failure (TF) rates in female pts with varying DM control, who were treated for otherwise uncomplicated UTI (uUTI). This observational, retrospective analysis of the real-world deidentified Inovalon MORE2 Registry included female pts aged ≥ 12 years with a uUTI diagnosis (Dx) between Jan 2018 and Dec 2022. Index date was the first oral antibiotic (ABX) claim observed ± 5 days of uUTI Dx. Pts were included if either of the following was observed in the 12 months prior to the index date: ≥ 1 claim with a Dx of DM and ≥ 1 claim for an antidiabetic treatment, or ≥ 2 claims with a Dx of DM 1–365 days apart. DM control was based on pts’ age (years) and 12-month pre-index glycosylated hemoglobin (HbA1c [mmol/mol]): controlled DM = age < 65 with a HbA1c < 7 or age ≥ 65 with a HbA1c < 8; uncontrolled DM = age < 65 with a HbA1c ≥ 7 or age ≥ 65 and HbA1c ≥ 8; and, unknown control = pts without a HbA1c. TF was defined as having a second oral ABX, intravenous ABX, or emergency department or inpatient stay with a primary Dx of UTI ≤ 28 days after the index date. Pairwise comparisons of TF between control groups were made using Z-tests for proportions and t-tests for means. Overall, 212,355 female uUTI pts with DM were identified: uncontrolled DM, 36,575 (17.2%); controlled DM, 41,235 (19.4%); unknown control, 134,545 (63.4%). Pts with controlled DM were older while the uncontrolled group was comprised of greater percentages of minority and managed Medicaid pts (Table 1). TF occurred in 18.9%, 19.4%, and 19.8% of the uncontrolled, controlled, and unknown control groups, respectively (p=0.0976, unadjusted comparison: uncontrolled vs controlled; Table 2). Mean time to first observed TF ranged from 10.5 to 10.9 days (median = 8, all groups). This descriptive analysis found high TF in female uUTI pts with DM; however, minimal differences were seen in TF rates across levels of DM control. Given the imbalance observed in various baseline characteristics and the majority of study pts having unknown control status, further research is warranted to ascertain the independent impact of DM control. Funding: GSK study 222865. Pamela Kushner, MD, GSK: Advisor/Consultant|GSK: Speaker Seth Kuranz, PhD, Inovalon: Employee of Inovalon, a consulting company that received funding from GSK to conduct this study. Virginia Noxon-Wood, PhD, Inovalon: Employee of Inovalon, a consulting company that received funding from GSK to conduct this study. Meghan E. Luck, PharmD, GSK: Employee|GSK: Stocks/Bonds (Public Company) Darrian Tattoli, PharmD, GSK: Employee|GSK: Stocks/Bonds (Public Company) Tien-Huei Hsu, PhD, GSK: Employee|GSK: Stocks/Bonds (Public Company) Jeffrey J. Ellis, PharmD, MS, GSK: Employee|GSK: Stocks/Bonds (Public Company)

Minimally invasive surgical repair options for mid-substance Achilles tendon ruptures may pose some limitations in regard to complex tear patterns or poor overall tendon quality. We have encountered cases where percutaneously passed sutures with the help of a targeting device fail to adequately capture the proximal tendon stump. In this technical report, we report a salvage technique for such cases that prevents the need for conversion to an extensile open approach, relying on smaller mini-open incisions.