Citations

Frontotemporal dementia and amyotrophic lateral sclerosis (FTD-ALS) are associated with both a repeat expansion in the C9orf72 gene and mutations in the TANK-binding kinase 1 ( TBK1 ) gene. We found that TBK1 is phosphorylated in response to C9orf72 poly(Gly-Ala) [poly(GA)] aggregation and sequestered into inclusions, which leads to a loss of TBK1 activity and contributes to neurodegeneration. When we reduced TBK1 activity using a TBK1-R228H (Arg 228 →His) mutation in mice, poly(GA)-induced phenotypes were exacerbated. These phenotypes included an increase in TAR DNA binding protein 43 (TDP-43) pathology and the accumulation of defective endosomes in poly(GA)-positive neurons. Inhibiting the endosomal pathway induced TDP-43 aggregation, which highlights the importance of this pathway and TBK1 activity in pathogenesis. This interplay between C9orf72 , TBK1 , and TDP-43 connects three different facets of FTD-ALS into one coherent pathway.

Abstract Aims To assess the impact of community‐level characteristics on the role of magnet designation in relation to hospital value‐based purchasing quality scores, as health disparities associated with geographical location could confound hospitals' ability to meet outcome metrics. Design This cross‐sectional study was carried out between October 2021 and March 2022 using data from 2016 to 2021. Methods Propensity score analysis was used to match hospital and community‐level characteristics, implementing nearest neighbour matching to adjust for pre‐treatment differences between magnet and non‐magnet hospitals to account for multi‐level differences. Secondary data were obtained from all operational acute‐care facilities in the United States that participated in the Centers for Medicare and Medicaid Services' hospital value‐based purchasing (HVBP) program. Dependent variables were the four value‐based purchasing domains that comprise the Total Performance Score (TPS; Clinical Care, Person and Community Engagement, Safety, and Efficiency and Cost Reduction). Results Magnet hospitals had increased odds for better scores in the HVBP domains of Clinical Care and Person and Community Engagement, and decreased odds for having better Safety. However, no statistically significant difference was found for the Efficiency domain or the TPS. Conclusion Measuring performance equitably across organizations of various sizes serving diverse communities remains a key factor in ensuring distributive justice. Analysing the TPS components can identify complex influences of community‐level characteristics not evident at the composite level. More research is needed where community and nurse‐level factors may indirectly affect patient safety. Impact This study's findings on the role of community contexts can inform policymakers designing value‐based care programs and healthcare management administrators deliberating on magnet certification investments across diverse community settings. No patient or public contribution For this study of US hospitals' organizational performance, we did not engage members of the patient population nor the general public. However, the multi‐disciplinary research team does include diverse perspectives.

Abstract A 70‐year‐old woman with longstanding persistent atrial fibrillation underwent Micra leadless pacemaker implantation and atrioventricular nodal ablation. No postprocedural complications were noted. She subsequently underwent surgical mitral valve replacement 4 years later. During the surgery, Micra tine perforation of the right ventricular free wall was seen. No device revision was performed due to her asymptomatic status and stable pacemaker position/function. Pericardial effusion is a known complication of Micra implantation. The incidence of tine perforation is unknown as many patients may be asymptomatic. The clinical consequences regarding adverse events, device functionality, and explantation/extraction risk profile remain to be determined.

AbstractIntroductionCardiac sarcoidosis (CS) is a nonischemic cardiomyopathy (NICM) characterized by infiltration of noncaseating granulomas involving the heart with highly variable clinical manifestations that can include conduction abnormalities and systolic heart failure. Cardiac resynchronization therapy (CRT) has shown significant promise in NICM, though little is known about its efficacy in patients with CS.ObjectiveTo determine if CRT improved cardiac remodeling in patients with CS.MethodsWe retrospectively reviewed all patients with a clinical or histological diagnosis of CS who underwent CRT implantation at the Mayo Clinic enterprise from 2000 to 2021. Baseline characteristics, imaging parameters, heart failure hospitalizations and need for advanced therapies, and major adverse cardiac events (MACE) were assessed.ResultsOur cohort was comprised of 55 patients with 61.8% male and a mean age of 58.7 ± 10.9 years. Eighteen (32.7%) patients had definite CS, 21 (38.2%) had probable CS, while 16 (29.1%) had presumed CS, and 26 (47.3%) with extracardiac sarcoidosis. The majority underwent CRT‐D implantation (n = 52, 94.5%) and 3 (5.5%) underwent CRT‐P implantation with 67.3% of implanted devices being upgrades from prior pacemakers or implantable cardioverter defibrillators. At 6 months postimplantation there was no significant improvement in ejection fraction (34.8 ± 10.9% vs. 37.7 ± 14.2%, p = .331) or left ventricular end‐diastolic diameter (58.5 ± 10.2 vs. 57.5 ± 8.1 mm, p = .236), though mild improvement in left ventricular end systolic diameter (49.1 ± 9.9 vs. 45.7± 9.9 mm, p < .0001). Within the first 6 months postimplantation, 5 (9.1%) patients sustained a heart failure hospitalization. At a mean follow‐up of 4.1± 3.7 years, 14 (25.5%) patients experienced a heart failure hospitalization, 11 (20.0%) underwent cardiac transplantation, 1 (1.8%) underwent left ventricular assist device implantation and 7 (12.7%) patients died.ConclusionsOur findings suggest variable response to CRT in patients with CS with no overall improvement in ventricular function within 6 months and a substantial proportion of patients progressing to advanced heart failure therapies.

A 70-year-old man with severe valvular cardiomyopathy, permanent atrial fibrillation (AF) with a slow ventricular response, and transient atrioventricular (AV) block, was admitted to our center for severe heart failure and recurrent presyncope. While hospitalized, the coronary computed tomography angiography (CTA) showed huge atriums. We tried His bundle pacing (HBP). HB potential was observed at site A, and the His-ventricular (HV) interval was 68 ms. The duration from the stimulus signal to the onset of paced QRS (S-QRSonset) at site A was 232 ms when pacing at 60 beats per minute (BPM) with the pacing threshold of 2.0 V/0.5 ms. The S-QRSonset was longer than the HV interval and had a notable and progressive prolongation from 252 ms to 456 ms during the pacing at 90 BPM. Then, we pushed another lead a little forward, and the S-QRSonset shortened back to 68 ms, and the paced QRS morphology was the same as the intrinsic QRS morphology with the pacing threshold of 1.5 V/0.5 ms. The progressively prolonged S-QRSonset demonstrated a Wenckebach phenomenon (WP), a well-known electrophysiological characteristic of the AV node (AVN). It is the first time to report an intraoperative AVN-pacing related-WP in a patient with persistent AF. The enlarged atrium might be convenient for capturing the AVN. There are some other potential explanations for this phenomenon. The diameters of atriums decreased significantly, and the symptoms improved after the procedure. This is the first reported case in which we might achieve AVN capture in a patient with persistent AF. Although we ultimately chose HBP for better long-term pacing thresholds, the result of this case suggested that AVN pacing may be possible.

Background: Autosomal dominant polycystic kidney disease (ADPKD) is a ciliopathy characterized by abnormal tubular epithelial proliferation and fluid secretion. Anoctamin 1 (ANO1) is a calcium-dependent chloride channel. However, how ANO1 contributes to ADPKD is largely unexplored. Methods: Kidney tissues from ADPKD patients, Pkd1RC/RC mice model, WT9-7 human PKD1+⁣/- cells, and 3D culture models in vitro were used. Localization of ANO1 and cilium length were investigated by confocal immunofluorescence. Results: We found that ANO1 was consistently upregulated in human and mouse PKD kidneys. Intriguingly, ANO1 located in a vesicle-like pattern at the ciliary base but not on the ciliary surface. ANO1 deficiency enhanced ciliogenesis and the ciliary dosage of polycystin-2 in human PKD cells, and reduced cyst formation in 3D culture models. Moreover, inhibition of ANO1 abolished the activation of STAT3 and ERK pathways in PKD cells. Conclusions: Our data indicate ANO1 is a negative regulator for both cilia length and cilia trafficking of polycystin-2 and provide mechanistic insights regarding the therapeutic potential of ANO1 pathway in ADPKD treatment.

The usage of beta blockers in breast cancer (BC) patients is implicated in the reduction in distant metastases, cancer recurrence, and cancer mortality. Studies suggest that the adrenergic pathway is directly involved in sympathetic-driven hematopoietic activation of pro-tumor microenvironmental proliferation and tumor cell trafficking into the circulation. Cancer-associated macrophage-like cells (CAMLs) are pro-tumor polynucleated monocytic cells of hematopoietic origin emanating from tumors which may aid in circulating tumor cell (CTC) dissemination into the circulation. We examined the linkage between Beta-2 adrenergic receptor (B2AR) signaling in CAMLs and CTCs by establishing expression profiles in a model BC cell line (MDA-MB-231). We compared the model to CAMLs and CTCs found in patents. Although internalization events were observed in patients, differences were found in the expression of B2AR between the tumor cell lines and the CAMLs found in patients. High B2AR expression on patients’ CAMLs was correlated with significantly more CAMLs in the circulation (p = 0.0093), but CTCs had no numerical relationship (p = 0.1565). High B2AR CAML expression was also significantly associated with a larger size of CAMLs (p = 0.0073), as well as being significantly associated with shorter progression-free survival (p = 0.0097) and overall survival (p = 0.0265). These data suggest that B2AR expression on CAMLs is closely related to the activation, intravasation, and growth of CAMLs in the circulation.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the basis of the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. Anaplastic oligodendroglial tumors (AOTs) are chemotherapy-sensitive brain tumors. We report the final very long-term survival results from European Organization for the Research and Treatment of Cancer 26951 and Radiation Therapy Oncology Group 9402 phase III trials initiated in 1990s, which both studied radiotherapy with/without neo/adjuvant procarbazine, lomustine, and vincristine (PCV) for newly diagnosed anaplastic oligodendroglial tumors. The median follow-up duration in both was 18-19 years. For European Organization for the Research and Treatment of Cancer 26951, median, 14-year, and probable 20-year overall survival rates without versus with PCV were 2.6 years, 13.4%, and 10.1% versus 3.5 years, 25.1%, and 16.8% (N = 368 overall; hazard ratio [HR] 0.78; 95% CI, 0.63 to 0.98; P = .033), with 1p19q codeletion 9.3 years, 26.2%, and 13.6% versus 14.2 years, 51.0%, and 37.1% (n = 80; HR 0.60; 95% CI, 0.35 to 1.03; P = .063), respectively. For Radiation Therapy Oncology Group 9402, analogous results were 4.8 years, 16.5%, and 11.2% versus 4.8 years, 29.1%, and 24.6% (N = 289 overall; HR 0.79; 95% CI, 0.61 to 1.03; P = .08), with codeletion 7.3 years, 25.0%, and 14.9% versus 13.2 years, 46.1%, and 37% (n = 125; HR 0.61; 95% CI, 0.40 to 0.94; P = .02), respectively. With that, the studies show similar long-term survival even without tumor recurrence in a significant proportion of patients after first-line treatment with radiotherapy/PCV.

AbstractBackgroundSudden cardiac death (SCD) is common after orthotopic heart transplant (OHT). No clear guidelines for implantable cardioverter defibrillator (ICD) implantation in OHT patients at high risk for SCD currently exist.ObjectivesTo assess the safety, efficacy, and benefit of ICDs and resynchronization therapy post‐OHT. We also provide a systematic review of previous reports.MethodsA retrospective multicenter cohort study within the United States. Patients with ICD post‐OHT between 2000 and 2020 were identified.ResultsWe analyzed 16 patients from 4 centers. The mean standard‐deviation (SD) age was 43 (18) years at OHT and 51 (20) years at ICD implantation. The mean (SD) duration from OHT to ICD implantation was 9 (5) years. The mean (SD) left ventricular ejection fraction (LVEF) was 35% (17%). There were 2 (13%) postprocedural complications: 1 hematoma and 1 death. Mean (SD) follow‐up was 24 (23) months. Survival rate was 63% (10/16) at 1 year and 56% (9/16) at 2 years, with 6/7 of those who died having LVEF < 35% at the time of the ICD implantation. Patients were more likely to receive appropriate therapy if their ICD was implanted for secondary (5/8) rather than primary (0/8) prevention (p = .007). Of those who did, 4 patients survived to 30 days post‐ICD therapy. Severe CAV was not associated with the rate of appropriate therapy.ConclusionsBeneficial outcomes were observed when ICDs were implanted for secondary prevention only, and in patients with higher baseline LVEF. We also observed benefits with resynchronization therapy.