Citations

Abstract We present a comprehensive global analysis of genetic variants associated with autosomal-dominant Alzheimer’s disease (ADAD). A total of 550 variants in the APP, PSEN1 and PSEN2 genes were identified, of which 279 were classified as pathogenic or likely pathogenic based on American College of Medical Genetics and Genomics and the Association for Molecular Pathology criteria, utilizing data from the Dominantly Inherited Alzheimer Network (DIAN), literature and public databases. Symptomatic age at onset (AAO) data were estimated for 227 of these variants, allowing detailed characterization of their frequency, pathogenicity and AAO. Importantly, 226 variants met eligibility criteria for inclusion in disease-modifying clinical trials. Furthermore, we demonstrated the predictive value of mean variant AAO and parental AAO in predicting symptomatic AAO, validated against converters who became symptomatic during follow-up in the DIAN Observational Study. This dataset provides critical insights into the global landscape of ADAD and reveals the genetic and AAO heterogeneity of ADAD variants while refining variant trial eligibility criteria.

Abstract Background Treatment of high risk AmpC-producing Enterobacterales bloodstream infections (BSIs) is challenging due to the posibility of development of antibiotic resistance during treatment. The aim of this study was to analyze the impact of antimicrobial stewardship activity and IDSA guidelines adequacy in patients with high risk AmpC-producing Enterobacterales BSIs. Methods Patients with Citrobacter spp, Enterobacter spp and Klebsiella aerogenes BSIs were included between June 2019-March 2024. Outcomes of death and relapse of infection at 30 days were assessed. Adequacy of definitive antimicrobial treatment according to IDSA guidelines was evaluated. The impact of antimicrobial stewardship activity in treatment adequacy and outcome was analyzed. Analysis was performed using SPSS version 25. Results 2049 BSIs were evaluated and 67 were finally included. 80% were monomicrobial. Median patient age was 74 years, 73% were male. The most frequent microorganism isolated was Enterobacter cloacae (55%). 50% were nosocomial and the most frequent origen was biliary tract (35,8%). 35% met sepsis criteria. 30% of cases presented cefotaxim resistance. Empiric and definitive antibiotic treatment was prescribed according IDSA guidelinesi n 34% and 91% of cases, respectively.. Death at 30 days was 6% and a combination outcome of death and relapse of infection at 30 days was 11,9%. Definitive antibiotic treatment adequacy according to IDSA guidelines was associated with lower mortality and relapse at 30 days (OR 0,04; IC95 0,003-0,6; P=0,02). Antimicrobial stewardship team did an intervention in 34% cases. This intervention was associated with a trend toward of lower mortality and relapse (4% vs 15%, P=0,2), a trend toward of higher IDSA guidelines adequacy (100% vs 86%, P=0,08), and a higher switch to oral treatment (78% vs 52%; P=0,03). Conclusion Adequacy of definitive antimicrobial treatment in high risk AmpC producing Enterobacterales BSIs according to IDSA guidelines was associated with a better outcome. Antimicrobial stewardship is desired for management of these patients. Disclosures All Authors: No reported disclosures

Abstract Background Chlorhexidine gluconate (CHG) (0.05%) has recently been suggested as a dip and irrigation solution at time of inflatable penile prosthesis (IPP) surgery. Aim This study evaluated infection rates before and after implementing CHG protocol while investigating concurrent risk factors contributing to post operative infections. Methods A retrospective, consecutive cohort study was performed that included patients who underwent insertion of a Coloplast Titan IPP including both virgin and revision cases between 2021 and 2024. Cases performed from January 2021 to August 2022 utilized rifampin/gentamicin for dip and vancomycin/gentamicin for irrigation (ABX), whereas those from October 2022 to May 2024 utilized CHG for both dip and irrigation. Perioperative risk factors including dip and irrigation solution used at time of surgery were compared between groups. Outcomes We defined the incidence of postoperative infection and risk factors associated with infection in each group. Results The incidence of infection was significantly higher in the 0.05% CHG group (13/377) compared to the ABX group (0/320) (P < .001). When analyzed separately by subgroup, virgin cases treated with CHG for dip and irrigation demonstrated a significantly higher infection rate (7/315) compared to those in the ABX group (0/280) (P = .012). Similarly, in revision cases, the CHG group also exhibited a significantly higher infection rate (0/40) than the ABX group (6/62) (P = .043). Univariable analysis of the CHG cohort identified three significant risk factors for infection: diabetes mellitus (DM), extended operative time (OP), and revision surgery (P = .003, .001, and < .001, respectively). Multivariable regression analysis revealed that patients with DM had a 5.7-fold increased risk of infection (OR: 5.70, P = .004), while those undergoing revision surgery faced a 5.3-fold higher risk (OR: 5.26, P = .004). Additionally, each minute increase in OP was associated with a 1% higher infection risk (OR: 1.01 per minute, P = .007). These associations remained significant after adjusting for all variables in the model. Clinical Implications Prosthetic surgeons should be cautious about adopting 0.05% CHG for both dip and irrigation in the absence of strong clinical evidence demonstrating its non-inferiority to antibiotic solutions. Strengths and Limitations This is the first clinical study reporting infection rates after IPP surgery using 0.05% CHG for both dip and irrigation. While retrospective and non-randomized, we present a relatively large sample size of patients. Conclusions Our findings identify four risk factors for penile prosthesis infection: usage of the 0.05% CHG solution for dip and irrigation solution of Coloplast hydrophilic-coated devices, DM, revision surgery, and extended OP.

Importance There is a lack of long-term efficacy and safety data on hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN) and on RNA interference (RNAi) therapeutics in general. This study presents the longest-term data to date on patisiran for hATTR-PN. Objective To present the long-term efficacy and safety of patisiran in adults with hATTR-PN. Design, Setting, and Participants This global open-label extension (OLE) of the APOLLO randomized clinical trial and phase 2 OLE study enrolled patients from 43 hospitals or clinical centers across 19 countries between July 2015 and August 2017, with follow-up until November 2022. Of 212 eligible patients with hATTR who completed the phase 3 APOLLO or phase 2 OLE parent studies, 211 enrolled in and 138 completed the global OLE. Intervention Patisiran, 0.3 mg/kg, intravenously once every 3 weeks for up to 5 years. Main Outcomes and Measures Outcomes evaluated at year 5 of the global OLE included disability (polyneuropathy disability [PND] score); polyneuropathy severity (Neuropathy Impairment Score [NIS]), nutritional status (modified body mass index [mBMI]), quality of life (Norfolk Quality of Life–Diabetic Neuropathy [Norfolk QOL-DN]), and Rasch-Built Overall Disability Scale (R-ODS), with no statistical hierarchy. Safety, survival probability, and mortality were also assessed. Results At the global OLE baseline, the mean (SD) age was 61.3 (12.3) years, and 156 patients (73.9%) were male. In 138 patients completing the study, PND scores remained stable or improved in 89 patients (65.0%), NISs showed a mean (SD) change of 10.9 (14.7), and mean (SD) mBMI (calculated as weight in kilograms divided by height in meters squared times serum albumin in grams per liter) increased by 46.4 (120.7) over 5 years from baseline. Norfolk QOL-DN and R-ODS scores showed mean (SD) changes of 4.1 (16.7) and –3.7 (6.2), respectively. Adverse events (AEs) leading to study withdrawal occurred in 47 patients (22.3%). Infusion-related reactions were the most common treatment-related AE (n = 34 [16.1%]). Overall, 41 patients (19.4%) died during the study. Patisiran treatment in the parent study and low familial amyloid polyneuropathy score at parent study baseline were associated with significantly improved survival. Conclusions and Relevance In the longest study of an RNAi therapeutic for any disease, patisiran treatment resulted in modest changes for patients with hATTR-PN with an acceptable safety profile. These results highlight the importance of initiating early treatment for hATTR and the potential of RNAi therapeutics in medicine. Trial Registration ClinicalTrials.gov Identifier: NCT02510261

Abstract There are ~100 genes or copy number variants (CNVs) used in genetic testing for Autism Spectrum Disorder (ASD, or autism). These genes are protein-coding, and the associated phenotypes often extend beyond socio-behavioral traits seen in autism including cognitive/medical complexities, epilepsy, and ADHD. Here, we characterize 27 males with ASD through whole genome sequencing (WGS), delineating X-chromosome microdeletions that implicate the long non-coding RNA (lncRNA) PTCHD1-AS as an ASD-susceptibility gene (OR=2.56, p=0.01). Two Ptchd1-as knockout (KO) murine models, created by removing the evolutionarily conserved exon-3, show ASD-like features in males, increasing repetitive behaviors and impairing typical social behavior and communication without overt cognitive comorbidities or ADHD-like behaviors. Hippocampus-dependent synaptic function, complex learning, and locomotor activity are unaffected in KO mice. Native nuclear-enriched mouse Ptchd1-as showed sustained expression from post-natal day-7 onward in the dorsal striatum, a predominantly GABAergic brain region implicated in ASD. Multi-omics revealed transcriptomic alterations in striatal oligodendrocyte, astrocyte and neurons impacting myelination and plasticity pathways. Disrupting Ptchd1-as led to reductions in conventional Protein Kinase-C, altered Src and GSK3α/β phosphorylation, and an enhancement of synaptic plasticity (long-term potentiation and long-term depression). Together, these findings implicate striatal molecular and circuit level dysregulation via Ptchd1-as in ASD etiology.

Neurogastroenterology and motility disorders are complex gastrointestinal conditions that are prevalent worldwide, particularly affecting women and younger individuals. These conditions significantly impact the quality of life of people suffering from them. There is increasing evidence linking these disorders to cirrhosis, with a higher prevalence compared to the general population. However, the link between neurogastroenterology and motility disorders and cirrhosis remains unclear due to undefined mechanisms. In addition, managing these conditions in cirrhosis is often limited by the adverse effects of drugs commonly used for these disorders, presenting a significant clinical challenge in the routine management of patients with cirrhosis. This review delves into this connection, exploring potential pathophysiological links and clinical interventions between neurogastroenterology disorders and cirrhosis.

Abstract INTRODUCTION The Alzheimer's Association and the Society of Nuclear Medicine and Molecular Imaging convened a multidisciplinary workgroup to update appropriate use criteria (AUC) for amyloid positron emission tomography (PET) and to develop AUC for tau PET. METHODS The workgroup identified key research questions that guided a systematic literature review on clinical amyloid/tau PET. Building on this review, the workgroup developed 17 clinical scenarios in which amyloid or tau PET may be considered. A modified Delphi approach was used to rate each scenario by consensus as “rarely appropriate,” “uncertain,” or “appropriate.” Ratings were performed separately for amyloid and tau PET as stand‐alone modalities. RESULTS For amyloid PET, seven scenarios were rated as appropriate, two as uncertain, and eight as rarely appropriate. For tau PET, five scenarios were rated as appropriate, six as uncertain, and six as rarely appropriate. DISCUSSION AUC for amyloid and tau PET provide expert recommendations for clinical use of these technologies in the evolving landscape of diagnostics and therapeutics for Alzheimer's disease. Highlights A multidisciplinary workgroup convened by the Alzheimer's Association and the Society of Nuclear Medicine and Molecular Imaging updated the appropriate use criteria (AUC) for amyloid positron emission tomography (PET) and to develop AUC for tau PET. The goal of these updated AUC is to assist clinicians in identifying clinical scenarios in which amyloid or tau PET may be useful for guiding the diagnosis and management of patients who have, or are at risk for, cognitive decline These updated AUC are intended for dementia specialists who spend a significant proportion of their clinical effort caring for patients with cognitive complaints, as well as serve as a general reference for a broader audience interested in implementation of amyloid and tau PET in clinical practice.

Abstract High-dose methotrexate (MTX) results in high rates of acute kidney injury (AKI), neutropenia, and hepatotoxicity. Glucarpidase is a recombinant enzyme that cleaves MTX, but clinical data supporting its use are scarce. We examined the association between glucarpidase administration and outcomes in adults with MTX-AKI from 28 cancer centers across the United States using a sequential target trial emulation framework. The primary end point was kidney recovery at hospital discharge, defined as survival to discharge with serum creatinine <1.5-fold baseline and without dialysis dependence. Key secondary end points were time to kidney recovery, neutropenia, and transaminitis on day 7, and time to death. Using multivariable logistic and Cox regression models, we compared outcomes in patients who received glucarpidase within 4 days following MTX initiation with those in patients who did not. Among 708 patients with MTX-AKI, 209 (29.5%) received glucarpidase. Overall, 183 (25.8%) had a primary end point event. Glucarpidase receipt was associated with a 2.70-fold higher adjusted odds of kidney recovery (95% confidence interval [CI], 1.69–4.31) compared with no glucarpidase receipt. Patients treated with glucarpidase also had faster time to kidney recovery (adjusted hazard ratio [aHR], 1.88; 95% CI, 1.18–3.33) and lower risks of grade ≥2 neutropenia (adjusted odds ratio [aOR], 0.50; 95% CI, 0.28–0.91) and grade ≥2 transaminitis (aOR, 0.50; 95% CI, 0.28–0.91) on day 7. There was no difference in time to death (aHR, 0.76; 95% CI, 0.49–1.18). These data suggest glucarpidase may improve both renal and extrarenal outcomes in patients with MTX-AKI.

Background Immune checkpoint inhibitors (ICIs) are recommended to treat patients with deficient mismatch repair/microsatellite instability high (dMMR/MSI-H) metastatic colorectal cancer (mCRC). Pivotal trials have fixed a maximum ICI duration of 2 years, without a compelling rationale. A shorter treatment duration has the potential to improve patients' quality of life and reduce both toxicity and cost without compromising efficacy. Here we examine whether early treatment discontinuation (ETD) before 13 months in patients without progressive disease (PD) can lead to similar long-term disease control compared with a longer treatment duration (LTD). Methods To assess whether ETD is associated with similar outcomes compared with LTD, we assembled an international cohort of patients with dMMR/MSI-H mCRC treated with ICIs who stopped treatment for a reason other than PD within 395 days (ETD group) and compared them to those who continued for >395 days (LTD group). Outcomes were adjusted for patient/tumor characteristics. Primary endpoint was progression-free survival (PFS) and secondary endpoints were objective response rate (ORR), overall survival (OS) and safety. Results Of 976 patients, 137 and 394 were allocated to the ETD and LTD groups, respectively. In the ETD group, treatment was discontinued due to toxicity (n=56), objective response (n=43), surgery (n=28), patient decision (n=2) or other reasons (n=8). Baseline characteristics were well balanced between the two groups: 22% in both groups received both anti-programmed death-(ligand) 1 (anti-PD-(L)1) + anti-cytotoxic T-lymphocyte antigen-4 (anti-CTLA-4); all others received anti-PD-(L)1 monotherapy. ORR to ICIs was 81% in both groups. Median duration of treatment was ~7 months in the ETD and ~24 months in the LTD group. After a median follow-up of 44 months (IQR: 30–67), similar PFS (HR: 0.92, 95% CI: 0.60 to 1.40, p=0.69) and OS (HR: 1.15, 95% CI: 0.66 to 1.99, p=0.62) from the start of ICIs were observed in ETD and LTD patients. In the ETD group, 28 (20%) patients had a PFS event and 9 restarted ICIs with a disease control rate of 66%. Conclusions In our international series of dMMR/MSI-H mCRC, ETD of ICIs in the absence of PD did not seem detrimental in terms of PFS and OS compared with continuing treatment beyond 1 year. Randomized clinical trials to compare short and long treatment duration are now warranted.

AbstractBackgroundTau aggregates, a hallmark of Alzheimer’s disease (AD) and other tauopathies, spread throughout the brain, contributing to neurodegeneration. How this propagation occurs remains elusive. Previous research suggests that tau‐seed interactors play a crucial role. Based on this, the study aimed to identify novel tau‐seed interactors in AD brains and validate their impact in vivo.MethodAD and control brain extracts were separated in fractions by Size Exclusion Chromatography. Fractions with the highest tau seeding activity, measured using a tai‐biosensor cell line, were analyzed by mass spectrometry to identify interacting proteins. Bioinformatic tools dissected enriched pathways, identifying interactors that were validated in a Drosophila tauopathy model by genetically interfering with their homologs and assessing tau accumulation and eye degeneration.ResultsTau seeding activity was concentrated in high molecular weight fractions containing only a small portion of total tau in the AD brains. Compared to controls, AD brains revealed a distinct interactome for tau‐seeds, enriched in proteins associated with synaptic and mitochondrial pathways. Notably, Drosophila screening confirmed that several novel interactors significantly reduced tau accumulation and eye degeneration, suggesting their potential therapeutic relevance.ConclusionThis study sheds light on tau propagation mechanisms in AD by identifying novel tau‐seed interactors. These interactors, particularly those involved in synaptic and mitochondrial pathways, offer promising targets for therapeutic interventions aimed at decreasing tau spread and potentially preventing neurodegeneration in tauopathies. The findings add to the growing evidence that targeting tau‐seed interactors, like previously identified BSN, could represent a novel strategy for treating these debilitating conditions.