Effects of strategic white matter hyperintensities of cholinergic pathways on basal forebrain volume in patients with amyloid-negative neurocognitive disorders.

BACKGROUND: The cholinergic neurotransmitter system is crucial to cognitive function, with the basal forebrain (BF) being particularly susceptible to Alzheimer's disease (AD) pathology. However, the interaction of white matter hyperintensities (WMH) in cholinergic pathways and BF atrophy without amyloid pathology remains poorly understood. METHODS: We enrolled patients who underwent neuropsychological tests, magnetic resonance imaging, and 18F-florbetaben positron emission tomography due to cognitive impairment at the teaching university hospital from 2015 to 2022. Among these, we selected patients with negative amyloid scans and additionally excluded those with Parkinson's dementia that may be accompanied by BF atrophy. The WMH burden of cholinergic pathways was quantified by the Cholinergic Pathways Hyperintensities Scale (CHIPS) score, and categorized into tertile groups because the CHIPS score did not meet normal distribution. Segmentation of the BF on volumetric T1-weighted MRI was performed using FreeSurfer, then was normalized for total intracranial volume. Multivariable regression analysis was performed to investigate the association between BF volumes and CHIPS scores. RESULTS: A total of 187 patients were enrolled. The median CHIPS score was 12 [IQR 5.0; 24.0]. The BF volume of the highest CHIPS tertile group (mean ± SD, 3.51 ± 0.49, CHIPSt3) was significantly decreased than those of the lower CHIPS tertile groups (3.75 ± 0.53, CHIPSt2; 3.83 ± 0.53, CHIPSt1; P = 0.02). In the univariable regression analysis, factors showing significant associations with the BF volume were the CHIPSt3 group, age, female, education, diabetes mellitus, smoking, previous stroke history, periventricular WMH, and cerebral microbleeds. In multivariable regression analysis, the CHIPSt3 group (standardized beta [ßstd] = -0.25, P = 0.01), female (ßstd = 0.20, P = 0.04), and diabetes mellitus (ßstd = -0.22, P < 0.01) showed a significant association with the BF volume. Sensitivity analyses showed a negative correlation between CHIPS score and normalized BF volume, regardless of WMH severity. CONCLUSIONS: We identified a significant correlation between strategic WMH burden in the cholinergic pathway and BF atrophy independently of amyloid positivity and WMH severity. These results suggest a mechanism of cholinergic neuronal loss through the dying-back phenomenon and provide a rationale that strategic WMH assessment may help identify target groups that may benefit from acetylcholinesterase inhibitor treatment.

Antiplatelet and Anticoagulant Use in Nursing Home Residents With Atrial Fibrillation.

This cross-sectional study evaluates the use of oral anticoagulants and antiplatelets, including aspirin, among nursing home residents with atrial fibrillation.

Potential association between suicide risk, aggression, impulsivity, and the somatosensory system.

Aggression and impulsivity are linked to suicidal behaviors, but their relationship to the suicidal crisis remains unclear. This magnetoencephalography (MEG) study investigated the link between aggression, impulsivity, and resting-state MEG power and connectivity. Four risk groups were enrolled: high-risk (HR; n = 14), who had a recent suicidal crisis; lower-risk (LR; n = 41), who had a history of suicide attempts but no suicide attempt or ideation in the past year; clinical control (CC; n = 38), who had anxiety/mood disorders but no suicidal history; and minimal risk (MR; n = 28), who had no psychiatric/suicidal history. No difference in resting-state MEG power was observed between the groups. Individuals in the HR group with high self-reported aggression and impulsivity scores had reduced MEG power in regions responsible for sensory/emotion regulation vs. those in the HR group with low scores. The HR group also showed downregulated bidirectional glutamatergic feedback between the precuneus (PRE) and insula (INS) compared to the LR, CC, and MR groups. High self-reported impulsivity was linked to reduced PRE to INS feedback, whereas high risk-taking impulsivity was linked to upregulated INS to postcentral gyrus (PCG) and PCG to INS feedback. These preliminary findings suggest that glutamatergic-mediated sensory and emotion-regulation processes may function as potential suicide risk markers.

Phase 3 randomized COMMODORE 1 trial: Crovalimab versus eculizumab in complement inhibitor-experienced patients with paroxysmal nocturnal hemoglobinuria.

Crovalimab, a novel C5 inhibitor, allows for low-volume, every-4- week, subcutaneous self-administration. COMMODORE 1 (NCT04432584) is a phase 3, global, randomized trial evaluating crovalimab versus eculizumab in C5 inhibitor-experienced patients with paroxysmal nocturnal hemoglobinuria (PNH). Adults with lactate dehydrogenase ≤1.5 × upper limit of normal and receiving approved eculizumab doses for ≥24 weeks were randomized 1:1 to receive crovalimab (weight-based tiered dosing) or continue eculizumab. The original primary study objective was efficacy; however, given the evolving treatment landscape, target recruitment was not met, and all efficacy endpoints became exploratory, with safety as the new primary objective. Exploratory efficacy endpoints included transfusion avoidance, hemolysis control, breakthrough hemolysis, hemoglobin stabilization, FACIT-Fatigue score, and patient preference (crovalimab vs. eculizumab). Eighty-nine patients were randomized (45 to crovalimab; 44 to eculizumab). During the 24-week primary treatment period, adverse events (AEs) occurred in 77% of patients receiving crovalimab and 67% receiving eculizumab. No AEs led to treatment withdrawal or death, and no meningococcal infections occurred. 16% of crovalimab-treated patients had transient immune complex reactions (also known as Type III hypersensitivity events), an expected risk when switching between C5 inhibitors that bind to different C5 epitopes; most were mild/moderate and all resolved without treatment modification. Crovalimab-treated patients had sustained terminal complement activity inhibition, maintained disease control, and 85% preferred crovalimab over eculizumab. Together with phase 3 COMMODORE 2 results in complement inhibitor-naive patients, these data support crovalimab's favorable benefit-risk profile. Crovalimab is a new C5 inhibitor for PNH that is potentially less burdensome than existing therapies for this lifelong disease.

Pay-for-Performance Incentives for Home Dialysis Use and Kidney Transplant.

Importance: The Centers for Medicare & Medicaid Services' mandatory End-Stage Renal Disease Treatment Choices (ETC) model, launched on January 1, 2021, randomly assigned approximately 30% of US dialysis facilities and managing clinicians to financial incentives to increase the use of home dialysis and kidney transplant. Objective: To assess the ETC's association with use of home dialysis and kidney transplant during the model's first 2 years and examine changes in these outcomes by race, ethnicity, and socioeconomic status. Design, Setting, and Participants: This retrospective cross-sectional study used claims and enrollment data for traditional Medicare beneficiaries with kidney failure from 2017 to 2022 linked to same-period transplant data from the United Network for Organ Sharing. The study data span 4 years (2017-2020) before the implementation of the ETC model on January 1, 2021, and 2 years (2021-2022) following the model's implementation. Exposure: Receiving dialysis treatment in a region randomly assigned to the ETC model. Main Outcomes and Measures: Primary outcomes were use of home dialysis and kidney transplant. A difference-in-differences (DiD) approach was used to estimate changes in outcomes among patients treated in regions randomly selected for ETC participation compared with concurrent changes among patients treated in control regions. Results: The study population included 724 406 persons with kidney failure (mean [IQR] age, 62.2 [53-72] years; 42.5% female). The proportion of patients receiving home dialysis increased from 12.1% to 14.3% in ETC regions and from 12.9% to 15.1% in control regions, yielding an adjusted DiD estimate of -0.2 percentage points (pp; 95% CI, -0.7 to 0.3 pp). Similar analysis for transplant yielded an adjusted DiD estimate of 0.02 pp (95% CI, -0.01 to 0.04 pp). When further stratified by sociodemographic measures, including age, sex, race and ethnicity, dual Medicare and Medicaid enrollment, and poverty quartile, there was not a statistically significant difference in home dialysis use across joint strata of characteristics and ETC participation. Conclusions and Relevance: In this cross-sectional study, the first 2 years of the ETC model were not associated with increased use of home dialysis or kidney transplant, nor changes in racial, ethnic, and socioeconomic disparities in these outcomes.

Temporal pattern classification of PM2.5 chemical compositions in Seoul, Korea using K-means clustering analysis.

Particulate matter with a diameter ≤ 2.5 µm (PM2.5) is a complex mixture of particles with a variety of compositions potentially including sulfate ions (SO42-), nitrate ions (NO3-), ammonium ions (NH4+), organic and inorganic elemental carbon, and metals. Here, the temporal composition evolution of PM2.5 was analyzed to characterize its emission source, origin, and external influences. The concentrations of wintertime PM2.5 chemical compositions in Seoul, Korea during the period of 2012-2021 were classified into four representative clusters using a K-means cluster analysis method. Cluster 1 exhibited high concentrations of NO3- and NH4+ ions mainly due to the prevalence of emissions from domestic manure and fertilizer sources in the northeast. High concentrations of these two ions are conducive to generation of ammonium nitrate (NH4NO3) through atmospheric chemical reactions, resulting in relatively long-lasting high PM2.5 concentrations in Seoul. In cluster 2, high concentrations of SO42-, vanadium, and nickel were observed in frequent south-westerly winds, indicating the domestic influence of industrial facilities. Cluster 3 showed high concentrations of potassium ions and organic carbon, highlighting a pronounced external influence transported from China via prevailing westerly winds. Cluster 4 showed low PM2.5 concentrations accompanied by strong winds in warm environments, which are uncommon in winter. This study revealed that the air quality in Seoul, which was influenced by many factors, could be classified into four representative patterns. Our results provide insights into the emission sources, major influences, and responsible mechanisms of high PM2.5 concentrations in Seoul, which can help with air quality policies.

The relationship of age and comorbid conditions to hospital and nursing home days in Medicaid recipients with HIV.

OBJECTIVE: To determine how aging impacts healthcare utilization in persons with HIV (PWH) compared with persons without HIV (PWoH). DESIGN: Matched case-control study. METHODS: We studied Medicaid recipients in the United States, aged 18-64 years, from 2001 to 2012. We matched each of 270 074 PWH to three PWoH by baseline year, age, gender, and zip code. Outcomes were hospital and nursing home days per month (DPM). Comorbid condition groups were cardiovascular disease, diabetes, liver disease, mental health conditions, pulmonary disease, and renal disease. We used linear regression to examine the joint relationships of age and comorbid conditions on the two outcomes, stratified by sex at birth. RESULTS: We found small excesses in hospital DPM for PWH compared with PWoH. There were 0.03 and 0.07 extra hospital DPM for female and male individuals, respectively, and no increases with age. In contrast, excess nursing home DPM for PWH compared with PWoH rose linearly with age, peaking at 0.35 extra days for female individuals and 0.4 extra days for male individuals. HIV-associated excess nursing home DPM were greatest for persons with cardiovascular disease, diabetes, mental health conditions, and renal disease. For PWH at age 55 years, this represents an 81% increase in the nursing home DPM for male individuals, and a 110% increase for female individuals, compared PWoH. CONCLUSION: Efforts to understand and interrupt this pronounced excess pattern of nursing home DPM among PWH compared with PWoH are needed and may new insights into how HIV and comorbid conditions jointly impact aging with HIV.

Millennial-scale variability of Greenland dust provenance during the last glacial maximum as determined by single particle analysis.

Greenland ice core records exhibited 100-fold higher dust concentrations during the Last Glacial Maximum (LGM) than during the Holocene, and dust input temporal variability corresponded to different climate states in the LGM. While East Asian deserts, the Sahara, and European loess have been suggested as the potential source areas (PSAs) for Greenland LGM dust, millennial-scale variability in their relative contributions within the LGM remains poorly constrained. Here, we present the morphological, mineralogical, and geochemical characteristics of insoluble microparticles to constrain the provenance of dust in Greenland NEEM ice core samples covering cold Greenland Stadials (GS)-2.1a to GS-3 (~ 14.7 to 27.1 kyr ago) in the LGM. The analysis was conducted on individual particles in microdroplet samples by scanning electron microscopy with energy dispersive X-ray spectroscopy and Raman microspectroscopy. We found that the kaolinite-to-chlorite (K/C) ratios and chemical index of alteration (CIA) values were substantially higher (K/C: 1.4 ± 0.7, CIA: 74.7 ± 2.9) during GS-2.1a to 2.1c than during GS-3 (K/C: 0.5 ± 0.1, CIA: 65.8 ± 2.8). Our records revealed a significant increase in Saharan dust contributions from GS-2.1a to GS-2.1c and that the Gobi Desert and/or European loess were potential source(s) during GS-3. This conclusion is further supported by distinctly different carbon contents in particles corresponding to GS-2.1 and GS-3. These results are consistent with previous estimates of proportional dust source contributions obtained using a mixing model based on Pb and Sr isotopic compositions in NEEM LGM ice and indicate millennial-scale changes in Greenland dust provenance that are probably linked to large-scale atmospheric circulation variabilities during the LGM.