Citations

Abstract BRCA1 plays important roles in several biological events during the DNA damage response (DDR). We aimed to determine whether cytoplasmic accumulation of BRCA1 or its phosphorylated form, pBRCA1, is specific to cytoplasmic inclusions in tauopathies, or if it also occurs in α-synuclein-positive inclusions in Lewy body disease (LBD). Using brain tissue from pure LBD, LBD with Alzheimer disease (AD) co-pathology (LBD-AD), and control cases, the immunohistochemical distributions of BRCA1, pBRCA1, its binding partner BARD1, and 53BP1 were examined. The results showed that pBRCA1 (Ser1423) and BARD1 accumulated in brainstem-type Lewy bodies (LBs), whereas only pBRCA1 (Ser1423) was present in cortical-type LBs. There was no significant difference in the frequency of pBRCA1 (Ser1423)-positive LBs between the pure LBD and LBD-AD cases. pBRCA1 (Ser1423) was minimally detected in neuronal nuclei in controls and was absent in neuronal nuclei in LBD cases. In control and LBD cases, 53BP1-immunoreactive deposits were present in the neuronal nuclei. Thus, DDR dysfunction due to cytoplasmic sequestration of pBRCA1 (Ser1423) may play a role in LBD pathogenesis. Additionally, the selective accumulation of BARD1 in brainstem-type LBs, but not cortical-type LBs, points to distinct mechanisms in the formation of these inclusion types, offering further insights into LBD pathology.

Abstract Introduction Gastrointestinal bleeding (GIB) is often encountered among patients with atrial fibrillation (AF) due to the use of anticoagulation. This study assesses disparities in GIB‐related mortality among decedents with AF in the United States. Methods GIB mortality data in patients with AF from 1999 to 2020 was queried from the CDC database. Decedent demographic information (age, sex, race and ethnicity, and geographic residence) was obtained from death certificates. We calculated age‐adjusted mortality rates (AAMRs) through the direct method and estimated the annual percentage change (APC) in mortality using log‐linear regression models. Results From 11,209 GIB‐related deaths among AF decedents, we observed an increase in AAMR from 0.12 in 1999 to 0.21 in 2020, particularly during the 2009 to 2020 period (APC +4.8, p < .001). Disproportionate mortality rates were noted in males (AAMR 0.18) and White populations (AAMR 0.15) as compared to females (AAMR 0.13) and Black populations (AAMR 0.10), respectively. Rural regions also reported higher mortality (AAMR 0.18) than urban areas (AAMR 0.14). Mortality shifts in urban regions remained stagnant from 1999 to 2009 (APC –0.15, p = .806) followed by an increase from 2009 to 2020 (APC +4.83, p < .001). However, mortality increased consistently from 1999 to 2020 in rural regions (APC +4.08, p < .001). The Northeast US exhibited the highest mortality rate (AAMR 0.18), followed by the Midwest (AAMR 0.16), West (AAMR 0.14), and South (AAMR 0.13). Conclusions Disparities in GIB mortality among AF decedents were identified. These findings accentuate the need for targeted interventions to mitigate GIB risks in vulnerable subgroups.

Background: Cerebral venous sinus thrombosis (CVT) is a rare cause of stroke, constituting 0.5–3% of all strokes with an extremely varied spectrum of presentation, predisposing factors, neuroimaging findings, and eventual outcomes. A high index of suspicion is needed because timely diagnosis can significantly alter the natural course of the disease, reduce acute complications, and improve long-term outcomes. Due to its myriad causative factors, protean presentation, and association with several systemic diseases, CVT is encountered not only by neurologists but also by emergency care practitioners, internists, hematologists, obstetricians, and pediatricians. Discussion: Anticoagulation remains the mainstay of treatment for CVT. Heparin and warfarin previously had been the anticoagulation of choice. Recently there has been an increased interest in utilizing direct-acting oral anticoagulants in the treatment of CVT given comparable safety and efficacy with ease of utilization. However recent clinical guidelines given by multiple societies including the American Stroke guidelines and European guidelines do not include these agents so far in their treatment recommendations. Ongoing multicentric clinical trials are currently reviewing the role of these agents in both short-term as well as long-term. Our review of the literature supports the safety and reinforces the efficacy of DOAC in the treatment of CVT. Additionally, patient satisfaction has been shown to be better with the use of DOAC. In conclusion, DOAC continues to have a valid role in the management of CVT.

AbstractEUS-guided gallbladder drainage (EUS-GBD) using lumen apposing metal stents (LAMS) has excellent technical and short-term clinical success for acute cholecystitis (AC). The goals of this study were to determine the long-term clinical outcomes and adverse events (AEs) of EUS-GBD with LAMS.A multicenter, retrospective study was conducted at 18 US tertiary care institutions. Inclusion criteria: any AC patient with attempted EUS-GBD with LAMS and minimum 30-day post-procedure follow-up. Long-term clinical success was defined as absence of recurrent acute cholecystitis (RAC) > 30 days and long-term AE was defined as occurring > 30 days from the index procedure.A total of 109 patients were included. Technical success was achieved in 108 of 109 (99.1%) and initial clinical success in 106 of 109 (97.2%). Long-term clinical success was achieved in 98 of 109 (89.9%) over a median follow-up of 140 days (range 30–1188). On multivariable analysis (MVA), acalculous cholecystitis (odds ratio [OR] 15.93, 95% confidence interval [CI] 1.22–208.52, P = 0.04) and the occurrence of a LAMS-specific AE (OR 63.60, 95% CI 5.08–799.29, P <0.01) were associated with RAC. AEs occurred in 38 of 109 patients (34.9%) at any time, and in 10 of 109 (9.17%) > 30 days from the index procedure. Most long-term AEs (7 of 109; 6.42%) were LAMS-specific. No technical or clinical factors were associated with occurrence of AEs. LAMS were removed in 24 of 109 patients (22%). There was no difference in RAC or AEs whether LAMS was removed or not.EUS-GBD with LAMS has a high rate of long-term clinical success and modest AE rates in patients with AC and is a reasonable destination therapy for high-risk surgical candidates.

ABSTRACT Background and Hypothesis Teclistamab, a novel bispecific monoclonal antibody targeting CD3 and B cell maturation antigen (BCMA), and chimeric antigen receptor T cell (CAR-T) therapy are promising options for treating relapsed/refractory multiple myeloma (MM). However, the rates of acute kidney injury (AKI) associated with teclistamab remain inadequately characterized. This study aims to compare the incidence, severity, and outcomes of AKI between patients receiving teclistamab and CAR-T therapy. Methods This was a retrospective study involving 64 patients with relapsed/refractory MM treated with either teclistamab or CAR-T therapy. All patients had previously received at least four lines of chemotherapy before being treated with either teclistamab or CAR-T. The primary outcome was the incidence of AKI, and secondary outcomes included AKI severity, kidney recovery rates, and mortality. Kaplan–Meier estimates for AKI-free survival were calculated, and hazard ratios (HRs) for AKI risk were determined using Cox proportional hazards models. Results Sixty-four patients met inclusion criteria for this study (30 received CAR-T and 34 received teclistamab therapy). Among these patients, 14 AKI events occurred in total (22%), with 10 events (29%) in the teclistamab group and four events (13%) in the CAR-T group. AKI-free survival estimates at 180 days after treatment initiation were 68% [95% confidence interval (CI): 53%–87%] for teclistamab patients and 90% (95% CI: 79%–100%) for CAR-T patients. While patients receiving teclistamab were found to have an increased risk of an AKI event compared to those receiving CAR-T therapy, the results were not statistically significant [HR (95% CI): 3.38 (0.93–12.31), P = .065]. Conclusions This study suggests that patients treated with teclistamab may experience a higher incidence of AKI compared to those receiving CAR-T therapy. However, further research is required to determine whether this increased risk is attributable to disease progression or teclistamab itself. These results highlight the need for close kidney function monitoring in patients receiving teclistamab.

Abstract Background Clozapine is effective for treatment-resistant schizophrenia and bipolar disorder but is often discontinued due to adverse effects. This study compared early clozapine discontinuation rates and reasons in patients with mood and psychotic disorders. Methods Data from all individuals with mood or psychotic disorders who initiated clozapine for the first time at the inpatient psychiatric unit of Mayo Clinic, Rochester, Minnesota, between 2014 and 2022 were retrospectively analyzed. Early clozapine discontinuation, defined as discontinuation within 90 days of initiation, was the primary outcome. Cox proportional hazards regression was used to assess factors associated with discontinuation. Results Of 83 patients (mood group n = 37, psychosis group n = 46), those in the mood group were older (P = 0.022) and more likely to be nonsmokers (P = 0.034). The overall 90-day clozapine discontinuation rate was 45.7%. Early discontinuation was significantly higher in the mood group than in the psychosis group (hazard ratio = 2.41, 95% confidence interval = 1.26–4.64, P = 0.008). Other factors associated with early discontinuation were female sex (P = 0.033), older age (P = 0.026), and nonsmoking (P = 0.001). In multivariable analysis, smoking status was the only factor significantly inversely associated with early clozapine discontinuation (hazard ratio = 0.47, 95% confidence interval = 0.22–0.99, P = 0.048), while diagnostic group, sex, and age did not show significant associations (all P > 0.05). Discontinuations were primarily due to adverse drug reactions in both groups. Conclusions Nearly half of the patients discontinued clozapine early, with higher rates in the mood group. Studies should further explore potential pharmacodynamic and pharmacokinetic factors associated with discontinuation, including the influence of smoking. Careful monitoring and personalized management of side effects are crucial for optimizing clozapine therapy and improving treatment outcomes.

Objective The purpose of this review was to examine new evidence since the authors' 2019 guidelines for cervical cancer (CC) screening in non-HIV immunocompromised persons and to provide updated recommendations based on literature review and expert opinion. In addition, human papillomavirus (HPV) vaccine efficacy in these populations was reviewed. Methods A literature search was performed similar to the authors' previous publication but was conducted through March 2023. Risk of CC, squamous intraepithelial lesions, and HPV infection in those living with solid organ transplant (SOT), end-stage renal disease (ESRD), hematopoietic stem cell transplant (HSCT), and autoimmune diseases (AID), specifically systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and inflammatory bowel disease (IBD) with addition of multiple sclerosis (MS) were researched. This update also summarizes data available on newer disease-modifying therapies (DMTs) including monoclonal antibodies (MABs). The authors then made recommendations for HPV vaccine administration, and screening using either general population guidelines or increased surveillance, the latter based on following current recommendations for women living with HIV. Additionally, the literature search included antibody response to HPV vaccines and recommendations for their administration for these same conditions. Results Based on the reviewed risks, evidence continued to support those persons living with SOT, ESRD, HSCT, and SLE, whether on immunosuppressant therapy or not, had an increased risk of HPV, squamous intraepithelial lesions, and CC whereas there was weak evidence that those persons with IBD, RA, and MS not on immunosuppressants were at risk. Data on persons using DMT/MAB were conflicting. Data showed that patients on certain immunosuppressants had lower antibody titers following HPV vaccination. There were no studies on HPV vaccine efficacy. Conclusions Following US Center for Disease Control and Prevention HIV Cervical cancer screening (CCS) guidelines is recommended for the following: SOT, ESRD, HSCT, and SLE whether on immunosuppressants or not, and IBD, RA, and MS on immunosuppressants. Shared decision-making about increased surveillance for IBD and RA not on immunosuppressants and persons on any DMT or MAB is reasonable based on conflicting data. Human papillomavirus vaccination should not change the recommendations for increased CC surveillance. A 3-dose series of the HPV vaccine is recommended for all age-eligible patients starting at 9 years of age, with catch-up to 26 years of age. Vaccination from age 27 up to age 45 years per Advisory Committee on Immunization Practices guidelines should be considered in shared decision-making. When possible, HPV vaccine series should be initiated and completed before SOT or initiation of DMT/MAB. For HSCT, the vaccine series should be readministered along with other childhood vaccines.

This Viewpoint discusses addressing inadequate documentation of unilateral do-not-resuscitate orders in the electronic health record.