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Abstract Approximately 5% of Alzheimer’s disease patients develop symptoms before age 65 (early-onset Alzheimer’s disease), with either sporadic (sporadic early-onset Alzheimer’s disease) or dominantly inherited (dominantly inherited Alzheimer’s disease) presentations. Both sporadic early-onset Alzheimer’s disease and dominantly inherited Alzheimer’s disease are characterized by brain amyloid-β accumulation, tau tangles, hypometabolism and neurodegeneration, but differences in topography and magnitude of these pathological changes are not fully elucidated. In this study, we directly compared patterns of amyloid-β plaque deposition and glucose hypometabolism in sporadic early-onset Alzheimer’s disease and dominantly inherited Alzheimer’s disease individuals. Our analysis included 134 symptomatic sporadic early-onset Alzheimer’s disease amyloid-Positron Emission Tomography (PET)-positive cases from the University of California, San Francisco, Alzheimer’s Disease Research Center (mean ± SD age 59.7 ± 5.6 years), 89 symptomatic dominantly inherited Alzheimer’s disease cases (age 45.8 ± 9.3 years) and 102 cognitively unimpaired non-mutation carriers from the Dominantly Inherited Alzheimer Network study (age 44.9 ± 9.2). Each group underwent clinical and cognitive examinations, 11C-labelled Pittsburgh Compound B-PET and structural MRI. 18F-Fluorodeoxyglucose-PET was also available for most participants. Positron Emission Tomography scans from both studies were uniformly processed to obtain a standardized uptake value ratio (PIB50–70 cerebellar grey reference and FDG30–60 pons reference) images. Statistical analyses included pairwise global and voxelwise group comparisons and group-independent component analyses. Analyses were performed also adjusting for covariates including age, sex, Mini-Mental State Examination, apolipoprotein ε4 status and average composite cortical of standardized uptake value ratio. Compared with dominantly inherited Alzheimer’s disease, sporadic early-onset Alzheimer’s disease participants were older at age of onset (mean ± SD, 54.8 ± 8.2 versus 41.9 ± 8.2, Cohen’s d = 1.91), with more years of education (16.4 ± 2.8 versus 13.5 ± 3.2, d = 1) and more likely to be apolipoprotein ε4 carriers (54.6% ε4 versus 28.1%, Cramer’s V = 0.26), but similar Mini-Mental State Examination (20.6 ± 6.1 versus 21.2 ± 7.4, d = 0.08). Sporadic early-onset Alzheimer’s disease had higher global cortical Pittsburgh Compound B-PET binding (mean ± SD standardized uptake value ratio, 1.92 ± 0.29 versus 1.58 ± 0.44, d = 0.96) and greater global cortical 18F-fluorodeoxyglucose-PET hypometabolism (mean ± SD standardized uptake value ratio, 1.32 ± 0.1 versus 1.39 ± 0.19, d = 0.48) compared with dominantly inherited Alzheimer’s disease. Fully adjusted comparisons demonstrated relatively higher Pittsburgh Compound B-PET standardized uptake value ratio in the medial occipital, thalami, basal ganglia and medial/dorsal frontal regions in dominantly inherited Alzheimer’s disease versus sporadic early-onset Alzheimer’s disease. Sporadic early-onset Alzheimer’s disease showed relatively greater 18F-fluorodeoxyglucose-PET hypometabolism in Alzheimer’s disease signature temporoparietal regions and caudate nuclei, whereas dominantly inherited Alzheimer’s disease showed relatively greater hypometabolism in frontal white matter and pericentral regions. Independent component analyses largely replicated these findings by highlighting common and unique Pittsburgh Compound B-PET and 18F-fluorodeoxyglucose-PET binding patterns. In summary, our findings suggest both common and distinct patterns of amyloid and glucose hypometabolism in sporadic and dominantly inherited early-onset Alzheimer’s disease.

Background: Treatment of progressive heart failure, due to left ventricular (LV) outflow tract obstruction has been a major component of hypertrophic cardiomyopathy (HCM) disease management for 50 years. Septal myectomy has been the primary treatment option to abolish gradients and relieve heart failure symptoms. The role of myectomy in HCM management has depended on effectiveness in relieving heart failure symptoms, but also an acceptable operative risk. Methods: Over the most recent 15-year period, we reviewed 3,700 consecutive isolated myectomy operations performed at major North American HCM institutions. Composite operative mortality (first 30 days) was only 0.4%. Seventeen operative deaths were at ages 24 to 82 (≥70 years), and only 6 occurred after 2010. Notably, 2 of the 4 Mayo Clinic deaths were in patients with prior alcohol septal ablation. Septal myectomy, when performed in experienced HCM centers, was much safer when compared to operative mortality with coronary artery bypass grafting (2.3%); valve replacement (3.5%); mitral valve replacement specifically (5.7%) (STS Database), similar to atrial or ventricular septal defect closure and 15-fold less than myectomy in community hospital or low volume surgical settings. Conclusions: Surgical myectomy performed in dedicated HCM centers with experienced surgeons and staff is one of the safest open-heart procedures currently practiced, with a mortality rate as low as 0.4%. The large mortality discrepancy for myectomy between community hospitals and dedicated HCM centers underscores that this operation should be considered a specialized procedure best performed in high volume HCM institutions.

Background: Left ventricle assist device (LVAD) support, a well established therapy in advanced CHF, improves renal function assessed by creatinine. While renal function in large numbers of continuous flow (CF) LVADs vs pulsatile flow (PF) LVADs has been evaluated at 3 mo., long term studies are needed with large numbers of CF vs PF devices. To date longer term analysis comparing renal function in CF vs PF devices have relied on a small number of CF devices. We evaluated renal function assessed by creatinine in a large number of CF (HM II) (n=119) devices and compared this to renal function in a group of subjects treated with PF devices (HM XVE) (n=8) at 6 mo. post implant. Our aim was to evaluate change in creatinine between 3 and 6 months in these groups. Methods and Results: Plasma creatinine was evaluated at 3 and 6 months in two groups: subjects with CF HM II (n=119) and PF LVAD (HM XVE, n=8). The data were collected from two centers in patients undergoing implant for destination or bridge to transplant therapy. Baseline creatinine was higher in the HM XVE group at baseline (BL), and decreased at 3 mo. (1.7 [1.1-2.1] vs 1.1 [0.8-1.5] mg/dL, p<0.05). BL creatine in the HM II group decreased at 3 mo as well (1.2 [1-1.5] vs 1.1 [0.9-1.3] mg/dL, p,0.05). Between 3 and 6 months there was no difference in degree of creatinine change in CF vs PF, however both groups had an increase in Creatinine in this time frame: PF (1.1 [0.8-1.5] vs 1.35 [1.05-1.9] mg/dL, p<0.05); CF (1.1 [0.9-1.3] vs 1.2 [0.92-1.4] mg/dL, p<0.05). Conclusion: This is the first study to demonstrate with large numbers of CF LVAD that creatinine does not incrementally increase between 3 and 6 mo. in comparison to PF LVAD. Further studies are required with large numbers of continuos flow LVADs evaluating the comparative effect of long term continuous flow vs pulsatile flow. Additionally, it remains important to identify surrogates of pulsatility in subjects with continuous flow devices and evaluate prognostic impact on renal function long term.

Introduction: Cardiac veins serve as substrate for arrhythmogenesis, and are especially involved as foci in atrial fibrillation. Understanding cardiac vein anatomy along with myocardial extension into these structures can improve electrophysiological mapping and electrical isolation of arrhythmogenic substrate. Accurately defining cardiac vein anatomy is critical in improving success of ablation therapy for atrial fibrillation. Methods: We performed measurements on 620 formalin-fixed autopsy hearts explanted from October 1998 to July 2003. The integrity of the thoracic veins and their cardiac connections were examined and systematic measurements of the superior and inferior vena cavae, azygous vein, vein of Marshall, coronary sinus, and pulmonary veins were performed and data were analyzed using univariate statistics. Results: We found that muscular extensions into the pulmonary veins were visible in 99% of the examined hearts, and were circumferential around the vein ostia (99.6%). Muscle extension into the SVC was found in 78% of examined hearts. These extensions were largely circumferential around the ostium (39%), but were also found to be asymmetric in a majority of hearts. Asymmetry was found in hearts with longer muscle extensions; no symmetry was observed in extensions greater than 0.8cm. Muscle extensions into the IVC were not seen. Occasionally, macroscopic muscle extensions into the azygous vein were visible (6%). The vein of Marshall was found to be patent to probing in the majority of hearts examined (72%) and was almost always overlying the lateral left atrial endocardial ridge. Conclusions: Our data suggest that all pulmonary veins need to be electrically isolated during atrial fibrillation ablation because of the almost universal presence of myocardial tissue extending into the veins. Mapping of the SVC should be done circumferentially and if potentials are noted isolation should also be performed. The IVC did not have muscle extensions and is unlikely to be a site of arrhythmogenesis. The azygous vein occasionally had muscle extensions and thus requires mapping and possible isolation. The vein of Marshall can be a substrate for arrhythmogenesis and is accessible for ablation by targeting the lateral left atrial endocardial ridge.

BACKGROUND: The immunologic risk associated with preformed donor-specific allo-antibodies (DSA) against human leukocyte antigens (HLA) in heart transplant (HTX) recipients is unclear. The goal of this study was to evaluate potential role of DSA on the progression of cardiac allograft vasculopathy (CAV) in HTX recipients. METHODS: The presence of DSA against HLA was evaluated using solid phase Single Antigen Bead assay (One Lambda, Inc., Canoga Park, CA; Luminex platform) before transplant in 35 HTX recipients. Using alloantibody specification analysis, 11% (4/35) and 20% (7/35) had DSA against donor Class I and II HLA respectively including the one patient who had both (DSA I & II+) . 71% (25/35) of patients had no demonstrable DSA (DSA-). All patients had negative cytotoxicity cross match. Baseline three-dimensional intravascular ultrasound studies (3D IVUS) were performed at 1.0 [0.18, 1.4] year after transplant. Follow up 3D IVUS exams were performed 0.92 [0.85, 1.04] years after the baseline exam. RESULTS: The increase in mean plaque (media and intima) volume (PV) was accelerated in the DSA II+ group as compared to the DSA- group (0.87±1.9 mm (3)/mm vs. 0.16±1.8 mm (3)/mm) but the vessel volume index (follow up vessel volume/ baseline vessel volume) was similar between groups (1.08±0.5 vs. 1.09± 0.4; p=0.9). Plaque index (PI) (PV/vessel volume x 100 [%]) increased significantly in the DSA II+ group (17.9±6.3%) but not in the DSA- group (-13.6±13.2%, P=0.02). None of these values were significant in the DSA I+ only group. Treatment with Sirolimus did not affect PI progression between the DSA II+ and DSA- groups (PI progression: 15.9±8.7% vs. -11.7±7.1%, P=0.03). Age, gender, lipid and uric acid levels, prevalence of diabetes, ischemic time, time between IVUS examinations, the use of steroids, mycophenolate vs. azathioprine or calcineurin inhibitors vs. sirolimus were not different between the groups (P>0.4 for all). CONCLUSIONS: Heart transplant recipients with clearly defined anti-Class II DSA are at risk for accelerated cardiac allograft vasculopathy. Whether interventions to minimize the risk of DSA such as virtual crossmatch, desensitization and complement inhibition will retard CAV remains to be proven.

Abstract Apilimod dimesylate is a first-in-class phosphoinositide kinase, FYVE-type zinc finger-containing (PIKfyve) inhibitor with a favourable clinical safety profile and has demonstrated activity in preclinical C9orf72 and TDP-43 amyotrophic lateral sclerosis (ALS) models. In this ALS clinical trial, the safety, tolerability, CNS penetrance and modulation of pharmacodynamic target engagement biomarkers were evaluated. This phase 2a, randomized, double-blind, placebo-controlled, biomarker-end-point clinical trial was conducted in four US centres (ClinicalTrials.gov NCT05163886). Participants with C9orf72 repeat expansions were randomly assigned (2:1) to receive twice-daily oral treatment with 125 mg apilimod dimesylate capsules or matching placebo for 12 weeks, followed by a 12-week open-label extension. Safety was measured as the occurrence of treatment-emergent or serious adverse events attributable to the study drug and tolerability at trial completion or treatment over 12 weeks. Changes from baseline in plasma and CSF and concentrations of apilimod dimesylate and its active metabolites and of pharmacodynamic biomarkers of PIKfyve inhibition [soluble glycoprotein nonmetastatic melanoma protein B (sGPNMB) upregulation] and disease-specific CNS target engagement [poly(GP)] were measured. Between 16 December 2021 and 7 July 2022, 15 eligible participants were enrolled. There were no drug-related serious adverse events reported in the trial. Fourteen (93%) participants completed the double-blind period with 99% dose compliance [n = 9 (90%) apilimod dimesylate; n = 5 (100%) placebo]. At Week 12, apilimod dimesylate was measurable in CSF at 1.63 ng/ml [standard deviation (SD): 0.937]. At Week 12, apilimod dimesylate increased plasma sGPNMB by &gt;2.5-fold (P &lt; 0.001), indicating PIKfyve inhibition, and lowered CSF poly(GP) protein levels by 73% (P &lt; 0.001), indicating CNS tissue-level proof of mechanism. Apilimod dimesylate met prespecified key safety and biomarker end-points in this phase 2a trial and demonstrated CNS penetrance and pharmacodynamic target engagement. Apilimod dimesylate was observed to result in the greatest reduction in CSF poly(GP) levels observed to date in C9orf72 clinical trials.

Background Rather than considering carotid stenting and endarterectomy to be rival procedures, they ought to be seen as complementary, with some patients more suited to one procedure over another. The respective patient populations best suited for optimal outcomes with stenting and endarterectomy differ substantially. Hence, the CREST‐2 (Carotid Revascularization, Endarterectomy Versus Stent Trial‐2) ( study was designed as 2 separate 2‐arm randomized trials run in parallel. One trial compares intensive medical management with and without stenting; the other, intensive medical management with and without endarterectomy. Each trial has a recruitment target of 1240 patients with ≥70% asymptomatic carotid stenosis, randomized 1:1 in each arm. To ensure patient safety and give stenting the best possible chance of demonstrating net benefits in stroke prevention, CREST‐2 adopted a rigorous procedure for evaluating, monitoring, and approving operators to enroll in the trial. The CREST‐2 Registry was established to allow for recent experience for applicant stent operators. Methods The CREST‐2 Registry is a prospective, multicenter, short‐term observational study of carotid stenting allowing use of multiple devices. Results The registry enrolled its first patient in September 2014, and as of October 2, 2023, a total of 9830 patients have been treated by 207 different stent operators from 103 different clinical centers. In this mixed cohort of asymptomatic (61.1% of the cohort) and symptomatic (38.9%) patients, the 30‐day stroke rate is 1.8% and the combined 30‐day stroke or death rate is 2.6%. At its peak in March 2016, the registry achieved an enrollment rate of 142 cases/month. As of October 20, 2023, a total of 104 patients remain to be enrolled in the CREST‐2 stenting trial. Conclusion The registry has facilitated assembly of a high‐performing team of stent operators for the CREST‐2 trial. With continued support of the many operators, we anticipate completing enrollment by the summer of 2024.

Importance Normothermic regional perfusion (NRP) is an emerging recovery modality for transplantable allografts from controlled donation after circulatory death (cDCD) donors. In the US, only 11.4% of liver recipients who are transplanted from a deceased donor receive a cDCD liver. NRP has the potential to safely expand the US donor pool with improved transplant outcomes as compared with standard super rapid recovery (SRR). Objective To assess outcomes of US liver transplants using controlled donation after circulatory death livers recovered with normothermic regional perfusion vs standard super rapid recovery. Design, Setting, and Participants This was a retrospective, observational cohort study comparing liver transplant outcomes from cDCD donors recovered by NRP vs SRR. Outcomes of cDCD liver transplant from January 2017 to May 2023 were collated from 17 US transplant centers and included livers recovered by SRR and NRP (thoracoabdominal NRP [TA-NRP] and abdominal NRP [A-NRP]). Seven transplant centers used NRP, allowing for liver allografts to be transplanted at 17 centers; 10 centers imported livers recovered via NRP from other centers. Exposures cDCD livers were recovered by either NRP or SRR. Main Outcomes and Measures The primary outcome was ischemic cholangiopathy (IC). Secondary end points included primary nonfunction (PNF), early allograft dysfunction (EAD), biliary anastomotic strictures, posttransplant length of stay (LOS), and patient and graft survival. Results A total of 242 cDCD livers were included in this study: 136 recovered by SRR and 106 recovered by NRP (TA-NRP, 79 and A-NRP, 27). Median (IQR) NRP and SRR donor age was 30.5 (22-44) years and 36 (27-49) years, respectively. Median (IQR) posttransplant LOS was significantly shorter in the NRP cohort (7 [5-11] days vs 10 [7-16] days; P &amp;lt; .001). PNF occurred only in the SRR allografts group (n = 2). EAD was more common in the SRR cohort (123 of 136 [56.1%] vs 77 of 106 [36.4%]; P = .007). Biliary anastomotic strictures were increased 2.8-fold in SRR recipients (7 of 105 [6.7%] vs 30 of 134 [22.4%]; P = .001). Only SRR recipients had IC (0 vs 12 of 133 [9.0%]; P = .002); IC-free survival by Kaplan-Meier was significantly improved in NRP recipients. Patient and graft survival were comparable between cohorts. Conclusion and Relevance There was comparable patient and graft survival in liver transplant recipients of cDCD donors recovered by NRP vs SRR, with reduced rates of IC, biliary complications, and EAD in NRP recipients. The feasibility of A-NRP and TA-NRP implementation across multiple US transplant centers supports increasing adoption of NRP to improve organ use, access to transplant, and risk of wait-list mortality.

ImportanceRedirection of care refers to withdrawal, withholding, or limiting escalation of treatment. Whether maternal social determinants of health are associated with redirection of care discussions merits understanding.ObjectiveTo examine associations between maternal social determinants of health and redirection of care discussions for infants born extremely preterm.Design, Setting, and ParticipantsThis is a retrospective analysis of a prospective cohort of infants born at less than 29 weeks’ gestation between April 2011 and December 2020 at 19 National Institute of Child Health and Human Development Neonatal Research Network centers in the US. Follow-up occurred between January 2013 and October 2023. Included infants received active treatment at birth and had mothers who identified as Black or White. Race was limited to Black and White based on service disparities between these groups and limited sample size for other races. Maternal social determinant of health exposures were education level (high school nongraduate or graduate), insurance type (public/none or private), race (Black or White), and ethnicity (Hispanic or non-Hispanic).Main Outcomes and MeasuresThe primary outcome was documented discussion about redirection of infant care. Secondary outcomes included subsequent redirection of care occurrence and, for those born at less than 27 weeks’ gestation, death and neurodevelopmental impairment at 22 to 26 months’ corrected age.ResultsOf the 15 629 infants (mean [SD] gestational age, 26 [2] weeks; 7961 [51%] male) from 13 643 mothers, 2324 (15%) had documented redirection of care discussions. In unadjusted comparisons, there was no significant difference in the percentage of infants with redirection of care discussions by race (Black, 1004/6793 [15%]; White, 1320/8836 [15%]) or ethnicity (Hispanic, 291/2105 [14%]; non-Hispanic, 2020/13 408 [15%]). However, after controlling for maternal and neonatal factors, infants whose mothers identified as Black or as Hispanic were less likely to have documented redirection of care discussions than infants whose mothers identified as White (Black vs White adjusted odds ratio [aOR], 0.84; 95% CI, 0.75-0.96) or as non-Hispanic (Hispanic vs non-Hispanic aOR, 0.72; 95% CI, 0.60-0.87). Redirection of care discussion occurrence did not differ by maternal education level or insurance type.Conclusions and RelevanceFor infants born extremely preterm, redirection of care discussions occurred less often for Black and Hispanic infants than for White and non-Hispanic infants. It is important to explore the possible reasons underlying these differences.

BACKGROUND: Venous thromboembolism occurs in approximately 2% of patients undergoing abdominal and pelvic surgery for cancers of the colon, rectum, and anus and is considered preventable. The American Society of Colon and Rectal Surgeons recommends extended prophylaxis in high-risk patients, but there is low adherence to the guidelines. OBJECTIVE: This study aims to analyze the impact of venous thromboembolism risk-guided prophylaxis in patients undergoing elective abdominal and pelvic surgeries for colorectal and anal cancers from 2016 to 2021. DESIGN: This was a retrospective analysis. SETTING: The study was conducted at a multisite tertiary referral academic health care system. PATIENTS: Patients who underwent elective abdominal or pelvic surgery for colon, rectal, or anal cancer. MAIN OUTCOME MEASURES: Receipt of Caprini-guided venous thromboembolism prophylaxis, 90-day postoperative rate of deep vein thrombosis, pulmonary embolism, venous thromboembolism, and bleeding events. RESULTS: A total of 3504 patients underwent elective operations, of whom 2224 (63%) received appropriate thromboprophylaxis in the inpatient setting. In the postdischarged cohort of 2769 patients, only 2% received appropriate thromboprophylaxis and no thromboembolic events were observed. In the group receiving inappropriate thromboprophylaxis, at 90 days postdischarge, the deep vein thrombosis, pulmonary embolism, and venous thromboembolism rates were 0.60%, 0.40%, and 0.88%, respectively. Postoperative bleeding was not different between the 2 groups. LIMITATIONS: Limitations to our study include its retrospective nature, use of aggregated electronic medical records, and single health care system experience. CONCLUSION: Most patients in our health care system undergoing abdominal or pelvic surgery for cancers of the colon, rectum, and anus were discharged without appropriate Caprini-guided venous thromboembolism prophylaxis. Risk-guided prophylaxis was associated with decreased rates of inhospital and postdischarge venous thromboembolism without increased bleeding complications. See Video Abstract. MARGEN DE MEJORA: EL IMPACTO DE LA TROMBOPROFILAXIS RECOMENDADA POR LAS DIRECTRICES EN PACIENTES SOMETIDOS A CIRUGÍA ABDOMINAL POR CÁNCER COLORRECTAL Y ANAL EN UN CENTRO DE REFERENCIA TERCIARIO ANTECEDENTES: El tromboembolismo venoso ocurre en aproximadamente el 2% de los pacientes sometidos a cirugía abdominal y pélvica por cánceres de colon, recto y ano, y se considera prevenible. La Sociedad Estadounidense de Cirujanos de Colon y Recto recomienda una profilaxis prolongada en pacientes de alto riesgo, pero el cumplimiento de las directrices es bajo. OBJETIVO: Este estudio tiene como objetivo analizar el impacto de la profilaxis guiada por el riesgo de tromboembolismo venoso (TEV) en pacientes sometidos a cirugías abdominales y pélvicas electivas por cáncer colorrectal y anal entre 2016 y 2021. DISEÑO: Este fue un análisis retrospectivo. AJUSTE: El estudio se llevó a cabo en un sistema de salud académico de referencia terciaria de múltiples sitios. PACIENTES: Pacientes sometidos a cirugía abdominal o pélvica electiva por cáncer de colon, recto o ano. PRINCIPALES MEDIDAS DE RESULTADO: Recepción de profilaxis de tromboembolismo venoso guiada por Caprini, tasa postoperatoria de 90 días de trombosis venosa profunda, embolia pulmonar, tromboembolismo venoso y eventos de sangrado. RESULTADOS: Un total de 3.504 pacientes se sometieron a operaciones electivas, de los cuales 2.224 (63%) recibieron tromboprofilaxis adecuada en el ámbito hospitalario. En el cohorte de 2.769 pacientes después del alta, solo el 2% recibió tromboprofilaxis adecuada en la que no se observaron eventos tromboembólicos. En el grupo que recibió tromboprofilaxis inadecuada, a los 90 días después del alta, las tasas de trombosis venosa profunda, embolia pulmonar y tromboembolia venosa fueron del 0,60%, 0,40% y 0,88%, respectivamente. El sangrado posoperatorio no fue diferente entre los dos grupos. LIMITACIONES: Las limitaciones de nuestro estudio incluyen su naturaleza retrospectiva, el uso de registros médicos electrónicos agregados y la experiencia de un solo sistema de atención médica. CONCLUSIÓN: La mayoría de los pacientes en nuestro sistema de salud sometidos a cirugía abdominal o pélvica por cánceres de colon, recto y ano fueron dados de alta sin una profilaxis adecuada de TEV guiada por Caprini. La profilaxis guiada por el riesgo se asoció con menores tasas de tromboembolismo venoso hospitalario y dado de alta sin un aumento de las complicaciones de sangrado. (Traducción—Dr. Aurian Garcia Gonzalez)