Citations

Background Valve-in-valve transcatheter aortic valve replacement (ViV-TAVR) is increasingly used to treat structural valve degeneration. Permanent pacemaker implantation (PPI) following TAVR is associated with increased morbidity and mortality, yet predictors specific to ViV-TAVR remain poorly defined. Objective To identify clinical and procedural predictors of PPI in patients undergoing ViV-TAVR. Methods We conducted a retrospective observational study of consecutive ViV-TAVR cases at the Mayo Clinic from 2012 to 2022. Clinical, ECG, procedural data and fluoroscopic measurements were analyzed, and propensity score matching was used to adjust for confounding. Predictors of PPI were identified using multivariable logistic regression. Results Among 261 patients, 24 (9.2%) required PPI. Balloon-expandable valves were used in 66.7% and self-expanding valves in 33.3%. Predictors of PPI included pre-procedural bifascicular block (OR 12.15, 95% CI: 2.52–68.89, p=0.003), greater septal implantation depth (OR 1.29, 95% CI: 1.04–1.65, p=0.019), and post-procedural new left (OR 23.56, 95% CI: 4.91–48.52, p=0.0004) and right bundle branch blocks (OR 24.4, 95% CI: 3.82–30.51, p=0.001). Aortic regurgitation as the mechanism of prosthetic valve failure was associated with reduced PPI odds (OR 0.28, 95% CI: 0.10–0.76, p=0.014). Pacing requirement—defined as >90% ventricular pacing—increased from 25% at 3 months to 56.25% at 12 months. At a median follow-up of 962.5 days (IQR 481.5–1555.3), adjusted mortality was significantly higher in the PPI group (aOR 9.4, 95% CI: 1.9–60.4, p=0.028). Conclusion Bifascicular block, greater septal depth, and new bundle branch blocks predict PPI post-ViV-TAVR, while aortic regurgitation appears protective. Risk stratification and procedural planning are critical.

Abstract NF-κB signaling can be subdivided into canonical and noncanonical pathways, culminating in the transcriptional activity of RELA and RELB, respectively. However, the upstream signals that activate these transcription factors and their specific regulatory roles in pancreatic ductal adenocarcinoma (PDAC) remain incompletely understood. Here, we demonstrate that TNFα is the primary activator of canonical NF-κB signaling via RELA, while TWEAK engages noncanonical signaling through RELB in PDAC. Using transcriptome-wide gene expression, genome-wide occupancy profiling, and epigenome mapping, we delineate distinct temporal dynamics and regulatory activities of each pathway. Single-cell RNA-seq analysis and multiplex immunofluorescence staining in primary PDAC samples further reveal extensive and distinct interactions with components of the tumor microenvironment. Motif analysis of RELA- and RELB-bound regions uncovers a particularly strong association of RELB with AP1 elements. Notably, while RELA binds to both open and closed chromatin, RELB exclusively occupies regions with pre-existing chromatin accessibility and AP1 co-binding. Collectively, these findings underscore the distinct and complementary roles of TNFα and TWEAK in PDAC, with TNFα engaging a broader transcriptional program via RELA and TWEAK selectively targeting genes marked by accessible chromatin and epigenetic activity. This study provides critical insights into the regulatory dynamics of NF-κB signaling in PDAC, highlighting unique and complementary functions of RELA and RELB in modulating downstream gene expression. Significance TNFα and TWEAK selectively activate RELA and RELB in pancreatic cancer, revealing that RELB-driven noncanonical signaling depends on chromatin accessibility and AP-1, uncovering distinct, targetable epigenetic dependencies from canonical signaling. Graphical abstract

Abstract There is limited data on the effect of antiobesity medications in individuals with Bardet-Biedl syndrome (BBS). Here, we present a case of an adult with BBS who experienced significant weight loss following treatment with a combination of topiramate and phentermine. A 31-year-old female with BBS, with homozygous pathogenic variant in the BBS2 gene, presented with obesity, dyslipidemia, and obstructive sleep apnea. At 29 years of age, her body mass index (BMI) was 43.3 kg/m2 (reference range 18.5-24.9 kg/m2), and she was initiated on 50 mg topiramate daily for migraine prophylaxis. With lifestyle modifications, BMI dropped to 40.5 kg/m2. Subsequently, phentermine 30 mg daily was added. Eight months after adding phentermine, BMI significantly decreased to 31.5 kg/m² (27% decrease in BMI), with improvement in glycemic and lipid parameters. She developed paranoia due to a social stressor prompting a brief hold of phentermine and resumption at a lower dose. This case highlights the weight loss response with phentermine and topiramate combination therapy in a patient with BBS. Further research is needed to explore the efficacy and safety of conventional antiobesity medications in isolation, as sequential or combination therapy to setmelanotide, to most effectively impact weight and metabolic burden in patients with BBS.

Abstract Background Pneumocystis jirovecii pneumonia (PCP) is increasingly seen in patients who are non-HIV immunocompromised hosts, yet modern risk factors and outcomes are poorly recognized and defined. Methods A retrospective review was conducted of adult patients who met criteria for proven or probable PCP from 2017 to 2024 across a large academic multicenter health system. The primary outcome was mortality among cohorts, defined by etiology of immunosuppression through univariate and age-adjusted logistic regression. Secondary analyses included trends in annual diagnoses and testing patterns. Results A total of 701 patients met criteria for inclusion, representing one of the largest clinically characterized cohorts of PCP to date. The median age was 65 years (IQR, 54–73) and 62% were male. The most common risk groups were hematologic malignancy (32.2%), solid tumor cancers receiving chemotherapy (22.4%), and autoimmune disease with immunosuppression (17.7%). Annual PCP diagnoses increased at a rate of 15.8% (95% CI, 8.9%–23.2%) in parallel with increased testing. Only 5.4% of patients were receiving prophylaxis at the time of diagnosis. Overall mortality was 20% (95% CI, 17%–23%) and highest in cirrhosis (adjusted odds ratio, 6.24; 95% CI, 2.84–13.69; P < .001). Conclusions PCP in the current era affects a broad range of patients who are immunocompromised, with high associated mortality and low rates of prophylaxis. Patients with solid tumors and those with cirrhosis are at particularly high risk of mortality. These findings highlight the need to reassess and redefine PCP prophylaxis guidelines in specific populations and our understanding of who is at risk.

Introduction: Workplace violence (WPV) in healthcare is detrimental to staff and institutions. The prevalence of events continues to increase despite efforts to mitigate events. WPV is associated with psychological and physical consequences and has been attributed to healthcare workers leaving the field, further contributing to the shortage of frontline healthcare staff. Healthcare workers often underreport WPV events due to cultures of acceptance, lack of knowledge of resources, and feeling unsupported during or after an event. Aim: This quality improvement project aimed to implement a WPV bundle and evaluate the effectiveness of staff utilization of WPV resources, perceived confidence, knowledge, and support during and after WPV events in a general surgery unit. Method: A hybrid education bundle, named the Violet Education Bundle, includes education for nurses on de-escalation techniques, incident reporting, standardization of shift-change huddle reporting, and resources for psychological support. A single-group, pre- and post-test design was utilized, and a paired t -test was employed to test for statistical significance. Results: With 23.2% of staff ( N = 20) completing both the pre-/post-survey (support, confidence, knowledge, and resource utilization sections) at both time points, no pre- to post-implementation outcome increases were statistically significant. Conclusion: Though the 60-day follow-up might have contributed to the null findings, nurses anecdotally expressed that they found the resources valuable and appreciated having them in one place. Future research should include an assessment of effectiveness for improving staff confidence, knowledge, perceived support, and reduced incidence and complications of WPV events over a sustained period of time.

OBJECTIVE The aim of this study was to evaluate mortality and progression outcomes in patients undergoing stereotactic radiosurgery (SRS) for breast cancer brain metastases and to identify associated risk factors using a national quality registry. METHODS The NeuroPoint Alliance (NPA) SRS Registry was employed for this study, which conducted prospective enrollment of patients undergoing SRS at 16 participating centers from 2017 to 2024. Outcomes of interest included the post-SRS EQ-5D score change, overall survival, local progression, out-of-field progression, and overall intracranial progression. For all time-to-event analyses, Kaplan-Meier curves and multivariable Cox regressions with hazard ratios were used. RESULTS A total of 138 patients (127 female, mean age 59.8 years) were identified; 46.4% had a single lesion, 42.0% had 2–4 lesions, and 11.6% had ≥ 5 lesions, while 87.0% had a Karnofsky Performance Status (KPS) score between 80 and 100. The median overall survival was 17.9 months, and independent predictors of all-cause mortality included a KPS score ≤ 90 (HR 6.73) and diabetes mellitus (HR 3.35). The median time to local progression was 19.8 months. More than 5 lesions at baseline (HR 9.03) and a marginal dose ≤ 17.6 Gy (HR 8.00) were predictive of local recurrence. The median was not reached for out-of-field progression, and predictors included ≥ 2 lesions at the time of SRS (HR 3.20) and a marginal dose ≤ 17.6 Gy (HR 4.61). At the final follow-up assessment, 17.1% of patients experienced no change according to the EQ-5D, while 34.3% had improvement, 11.4% had mixed results, and 37.1% had worsened health. In the multivariable linear regression model, pre-SRS resection (r = 1.92) and baseline EQ-5D score (r = 1.29) were statistically significant predictors of quality of life at the final follow-up assessment. CONCLUSIONS Using real-world data from the NPA SRS Registry, this study demonstrated comparable outcomes in patients who underwent SRS for breast cancer brain metastases compared with those of previous literature. The number of lesions at the time of SRS and the marginal dose were independent risk factors for local recurrence, out-of-field progression, and overall intracranial progression. Pre-SRS resection and baseline EQ-5D score were independent predictors of quality of life following SRS.

OBJECTIVE Idiopathic normal pressure hydrocephalus (iNPH) is characterized by gait deterioration, cognitive disturbances, and urinary incontinence. Gait deficits pose safety hazards due to frequent falls, yet objective investigations of gait improvement following ventriculoperitoneal shunt (VPS) placement are limited. Therefore, the aim of this study was to assess objective improvement in gait parameters for patients with iNPH after VPS placement. METHODS All patients treated with a VPS for iNPH by the senior author at a single tertiary care center from December 2017 to January 2023 were retrospectively reviewed. Patients who underwent detailed motion analysis testing before surgery with > 1 follow-up assessment were included. Analyzed parameters included gait velocity, gait cadence, stride length, stride width, gait stability ratio, total support, and single support. Time-dependent linear mixed-effects models and generalized additive mixed-effects models (GAMMs) were used to model short-term and longitudinal gait parameter changes, respectively. RESULTS A total of 212 patients (137 male, median age was 75.2 years) who underwent VPS placement for iNPH were included, with a total of 747 gait analyses performed at a median last-gait analysis follow-up duration of 12.0 months. Statistically significant changes in all gait parameter values were seen between the preoperative time point and first postoperative follow-up (within 3 months) time point (paired Wilcoxon p < 0.001), with a statistically significant majority of patients experiencing improvement (binominal p < 0.0001). Longitudinal analyses using a GAMM showed increased gait velocity, single support, and stride length, with decreased stability ratio, step width, and total support at early time points, while a plateau was achieved around 6 months. CONCLUSIONS A detailed gait analysis demonstrated significant improvements in objective ambulation metrics, particularly in the gait velocity, stride length, and gait stability ratio, following VPS placement in patients with iNPH. Most patients maintained marked improvement from baseline to the last follow-up assessment, although a plateau of the benefit was experienced over longer follow-up.