Human microglial state dynamics in Alzheimer's disease progression.

Altered microglial states affect neuroinflammation, neurodegeneration, and disease but remain poorly understood. Here, we report 194,000 single-nucleus microglial transcriptomes and epigenomes across 443 human subjects and diverse Alzheimer's disease (AD) pathological phenotypes. We annotate 12 microglial transcriptional states, including AD-dysregulated homeostatic, inflammatory, and lipid-processing states. We identify 1,542 AD-differentially-expressed genes, including both microglia-state-specific and disease-stage-specific alterations. By integrating epigenomic, transcriptomic, and motif information, we infer upstream regulators of microglial cell states, gene-regulatory networks, enhancer-gene links, and transcription-factor-driven microglial state transitions. We demonstrate that ectopic expression of our predicted homeostatic-state activators induces homeostatic features in human iPSC-derived microglia-like cells, while inhibiting activators of inflammation can block inflammatory progression. Lastly, we pinpoint the expression of AD-risk genes in microglial states and differential expression of AD-risk genes and their regulators during AD progression. Overall, we provide insights underlying microglial states, including state-specific and AD-stage-specific microglial alterations at unprecedented resolution.

Single-cell atlas reveals correlates of high cognitive function, dementia, and resilience to Alzheimer's disease pathology.

Alzheimer's disease (AD) is the most common cause of dementia worldwide, but the molecular and cellular mechanisms underlying cognitive impairment remain poorly understood. To address this, we generated a single-cell transcriptomic atlas of the aged human prefrontal cortex covering 2.3 million cells from postmortem human brain samples of 427 individuals with varying degrees of AD pathology and cognitive impairment. Our analyses identified AD-pathology-associated alterations shared between excitatory neuron subtypes, revealed a coordinated increase of the cohesin complex and DNA damage response factors in excitatory neurons and in oligodendrocytes, and uncovered genes and pathways associated with high cognitive function, dementia, and resilience to AD pathology. Furthermore, we identified selectively vulnerable somatostatin inhibitory neuron subtypes depleted in AD, discovered two distinct groups of inhibitory neurons that were more abundant in individuals with preserved high cognitive function late in life, and uncovered a link between inhibitory neurons and resilience to AD pathology.

Single-cell multiregion dissection of Alzheimer's disease.

Alzheimer's disease is the leading cause of dementia worldwide, but the cellular pathways that underlie its pathological progression across brain regions remain poorly understood1-3. Here we report a single-cell transcriptomic atlas of six different brain regions in the aged human brain, covering 1.3 million cells from 283 post-mortem human brain samples across 48 individuals with and without Alzheimer's disease. We identify 76 cell types, including region-specific subtypes of astrocytes and excitatory neurons and an inhibitory interneuron population unique to the thalamus and distinct from canonical inhibitory subclasses. We identify vulnerable populations of excitatory and inhibitory neurons that are depleted in specific brain regions in Alzheimer's disease, and provide evidence that the Reelin signalling pathway is involved in modulating the vulnerability of these neurons. We develop a scalable method for discovering gene modules, which we use to identify cell-type-specific and region-specific modules that are altered in Alzheimer's disease and to annotate transcriptomic differences associated with diverse pathological variables. We identify an astrocyte program that is associated with cognitive resilience to Alzheimer's disease pathology, tying choline metabolism and polyamine biosynthesis in astrocytes to preserved cognitive function late in life. Together, our study develops a regional atlas of the ageing human brain and provides insights into cellular vulnerability, response and resilience to Alzheimer's disease pathology.

Single-cell dissection of the human brain vasculature.

Despite the importance of the cerebrovasculature in maintaining normal brain physiology and in understanding neurodegeneration and drug delivery to the central nervous system1, human cerebrovascular cells remain poorly characterized owing to their sparsity and dispersion. Here we perform single-cell characterization of the human cerebrovasculature using both ex vivo fresh tissue experimental enrichment and post mortem in silico sorting of human cortical tissue samples. We capture 16,681 cerebrovascular nuclei across 11 subtypes, including endothelial cells, mural cells and three distinct subtypes of perivascular fibroblast along the vasculature. We uncover human-specific expression patterns along the arteriovenous axis and determine previously uncharacterized cell-type-specific markers. We use these human-specific signatures to study changes in 3,945 cerebrovascular cells from patients with Huntington's disease, which reveal activation of innate immune signalling in vascular and glial cell types and a concomitant reduction in the levels of proteins critical for maintenance of blood-brain barrier integrity. Finally, our study provides a comprehensive molecular atlas of the human cerebrovasculature to guide future biological and therapeutic studies.

Insurance-based disparities and risk of financial toxicity among patients undergoing gynecologic cancer operations.

OBJECTIVE: To evaluate the risk of financial toxicity (FT) among inpatients undergoing gynecologic cancer resections and the association of insurance status with clinical and financial outcomes. METHODS: Using the 2008-2019 National Inpatient Sample, we identified adult hospitalizations for hysterectomy or oophorectomy with a diagnosis of cancer. Hospitalization costs, length of stay (LOS), mortality, and complications were assessed by insurance status. Risk of FT was defined as health expenditure exceeding 40% of post-subsistence income. Multivariable regressions were used to analyze costs and factors associated with FT risk. RESULTS: Of 462,529 patients, 49.4% had government-funded insurance, 44.3% private, and 3.2% were uninsured. Compared to insured, uninsured patients were more commonly Black and Hispanic, admitted emergently, and underwent open operations. Uninsured patients experienced similar mortality but greater rates of complications, LOS, and costs. Overall, ovarian cancer resections had the highest median costs of $17,258 (interquartile range: 12,187-25,491) compared to cervical and uterine. Approximately 52.8% of uninsured and 15.4% of insured patients were at risk of FT. As costs increased across both cohorts over the 12-year study period, the disparity in FT risk by payer status broadened. After risk adjustment, perioperative complications were associated with nearly 2-fold increased risk of FT among uninsured (adjusted odds ratio 1.75, 95% confidence interval 1.46-2.09, p < 0.001). Among the insured, Black and Hispanic race, public insurance, and open operative approach exhibited greater odds of FT. CONCLUSION: Patients undergoing gynecologic cancer operations are at substantial risk of FT, particularly those uninsured. Targeted cost-mitigation strategies are warranted to minimize financial burden.

National analysis of racial disparities in emergent surgery for colorectal cancer.

Background: Racial disparities in access to preoperative evaluation for colorectal cancer remain unclear. Emergent admission may indicate lack of access to timely care. The present work aimed to evaluate the association of admission type with race among patients undergoing colorectal cancer surgery. Methods: All adults undergoing resection for colorectal cancer in 2011-2020 National Inpatient Sample were identified. Multivariable regression models were developed to examine the association of admission type with race. Primary outcome was major adverse events (MAE), including mortality and complications. Secondary outcomes included costs and length of stay (LOS). Interaction terms between year, admission type, and race were used to analyze trends. Results: Of 722,736 patients, 67.6 % had Elective and 32.4 % Emergent admission. Black (AOR 1.38 [95 % CI 1.33-1.44]), Hispanic (1.45 [1.38-1.53]), and Asian/Pacific Islander or Native American (1.25 [1.18-1.32]) race were associated with significantly increased odds of Emergent operation relative to White. Over the study period, non-White patients consistently comprised over 5 % greater proportion of the Emergent cohort compared to Elective. Furthermore, Emergent admission was associated with 3-fold increase in mortality and complications, 5-day increment in LOS, and $10,100 increase in costs. MAE rates among Emergent patients remained greater than Elective with a widening gap over time. Non-White patients experienced significantly increased MAE regardless of admission type. Conclusion: Non-White race was associated with increased odds of emergent colorectal cancer resection. Given the persistent disparity over the past decade, systematic approaches to alleviate racial inequities in colorectal cancer screening and improve access to timely surgical treatment are warranted.

Outcomes of surgery for inflammatory bowel disease among patients with psychiatric disorders.

BACKGROUND: Psychiatric disorders (PDs) are common among patients with inflammatory bowel disease (IBD). Brain-gut dysfunction and psychotropic medications may have adverse effects on postoperative outcomes in patients with IBD. This study aimed to evaluate the association between PD and outcomes after surgery for IBD. METHODS: This was a retrospective study of adult patients with IBD who underwent small bowel, colon, or rectal resection in the 2016 to 2021 Nationwide Readmissions Database. PDs, including psychotic, mood, anxiety, eating, sleep, personality, and childhood-onset behavioral disorders, were identified. Records about colorectal cancer were excluded. Multivariate regressions were used to examine the association of PD with outcomes. RESULTS: Of 81,955 patients included in the study, 21,800 (26.6%) had PDs. On risk adjustment, PD was associated with significantly increased postoperative ileus (adjusted odds ratio [AOR], 1.11; 95% CI, 1.03-1.19), length of stay (ß, +1.4 days; 95% CI, 1.1-1.7), and costs (ß, +$2100; 95% CI, $1200-$3100) compared with no PD. In addition, patients with PDs experienced increased odds of nonhome discharge (AOR, 1.23; 95% CI, 1.12-1.34) and 30-day readmission (AOR, 1.32; 95% CI, 1.22-1.43). Over the study period, the prevalence of PDs significantly increased from 24.3% to 28.5% (P < .001), along with an increase in the rates of ileus among patients with PDs (8.1%-15.8%; P < .001). CONCLUSION: PD is associated with a significantly greater burden of adverse clinical and financial outcomes after IBD operations. Given the growing prevalence of mental health conditions among patients with IBD, further efforts to optimize preoperative psychiatric care may enhance the quality of colorectal surgery.

Disparities in outcomes of colorectal cancer surgery among adults with intellectual and developmental disabilities.

BACKGROUND: Disparities in colorectal cancer screening have been documented among people with intellectual and developmental disabilities (IDD). However, surgical outcomes in this population have yet to be studied. The present work aimed to evaluate the association of IDD with outcomes following colorectal cancer resection. METHODS: All adults undergoing resection for colorectal cancer in the 2011-2020 National Inpatient Sample were identified. Multivariable linear and logistic regression models were developed to examine the association of IDD with risk factors as well as outcomes including mortality, complications, costs, length of stay (LOS), and non-home discharge. The study is limited by its retrospective nature and did not capture disease staging or time of diagnosis. RESULTS: Among 722,736 patients undergoing colorectal cancer resection, 2,846 (0.39%) had IDD. Compared to patients without IDD, IDD patients were younger and had a higher burden of comorbidities. IDD status was associated with increased odds of non-elective admission (AOR 1.40 [95% CI 1.14-1.73]) and decreased odds of treatment at high-volume centers (AOR 0.64 [95% CI 0.51-0.81]). Furthermore, IDD patients experienced significantly greater LOS (9 vs 6 days, p<0.001) and hospitalization costs ($23,500 vs $19,800, p<0.001) relative to neurotypical patients. Upon risk adjustment, IDD was significantly associated with 2-fold increased odds of mortality (AOR 2.34 [95% CI 1.48-3.71]), 1.4-fold increase in complications (AOR 1.41 [95% CI 1.15-1.74]), and 6.8-fold increase in non-home discharge (AOR 6.83 [95% CI 5.46-8.56]). CONCLUSIONS: IDD patients undergoing colorectal cancer resection experience increased likelihood of non-elective admission, adverse clinical outcomes, and resource use. Our findings highlight the need for more accessible screening and patient-centered interventions to improve quality of surgical care for this at-risk population.

National clinical and financial outcomes associated with acute kidney injury following esophagectomy for cancer.

BACKGROUND: Esophagectomy is a complex oncologic operation associated with high rates of postoperative complications. While respiratory and septic complications have been well-defined, the implications of acute kidney injury (AKI) remain unclear. Using a nationally representative database, we aimed to characterize the association of AKI with mortality, resource use, and 30-day readmission. METHODS: All adults undergoing elective esophagectomy with a diagnosis of esophageal or gastric cancer were identified in the 2010-2019 Nationwide Readmissions Database. Study cohorts were stratified based on presence of AKI. Multivariable regressions and Royston-Parmar survival analysis were used to evaluate the independent association between AKI and outcomes of interest. RESULTS: Of an estimated 40,438 patients, 3,210 (7.9%) developed AKI. Over the 10-year study period, the incidence of AKI increased from 6.4% to 9.7%. Prior radiation/chemotherapy and minimally invasive operations were associated with reduced odds of AKI, whereas public insurance coverage and concurrent infectious and respiratory complications had greater risk of AKI. After risk adjustment, AKI remained independently associated with greater odds of in-hospital mortality (AOR: 4.59, 95% CI: 3.62-5.83) and had significantly increased attributable costs ($112,000 vs $54,000) and length of stay (25.7 vs 13.3 days) compared to patients without AKI. Furthermore, AKI demonstrated significantly increased hazard of 30-day readmission (hazard ratio: 1.16, 95% CI: 1.01-1.32). CONCLUSIONS: AKI after esophagectomy is associated with greater risk of mortality, hospitalization costs, and 30-day readmission. Given the significant adverse consequences of AKI, careful perioperative management to mitigate this complication may improve quality of esophageal surgical care at the national level.

Cost variation of nonelective surgery for ulcerative colitis across the United States.

BACKGROUND: Although clinical outcomes of surgery for ulcerative colitis (UC) have improved in the modern biologic era, expenditures continue to increase. A contemporary cost analysis of UC operative care is lacking. The present study aimed to characterize risk factors and center-level variation in hospitalization costs after nonelective resection for UC. METHODS: All adults with UC in the 2016-2020 Nationwide Readmissions Database undergoing nonelective colectomy or rectal resection were identified. Mixed-effects models were developed to evaluate patient and hospital factors associated with costs. Random effects were estimated and used to rank hospitals by increasing risk-adjusted center-level costs. High-cost hospitals (HCHs) in the top decile of expenditure were identified, and their association with select outcomes was subsequently assessed. RESULTS: An estimated 10,280 patients met study criteria with median index hospitalization costs of $40,300 (IQR, $26,400-$65,000). Increased time to surgery was significantly associated with a +$2500 increment in costs per day. Compared with low-volume hospitals, medium- and high-volume centers demonstrated a -$5900 and -$8200 reduction in costs, respectively. Approximately 19.2% of variability in costs was attributable to interhospital differences rather than patient factors. Although mortality and readmission rates were similar, HCH status was significantly associated with increased complications (adjusted odds ratio [AOR], 1.39), length of stay (+10.1 days), and nonhome discharge (AOR, 1.78). CONCLUSION: The present work identified significant hospital-level variation in the costs of nonelective operations for UC. Further efforts to optimize time to surgery and regionalize care to higher-volume centers may improve the value of UC surgical care in the United States.

National analysis of outcomes in timing of cholecystectomy for acute cholangitis.

BACKGROUND: The present study aimed to compare outcomes between cholecystectomy on index versus delayed admission for acute cholangitis. METHODS: The 2011-2020 Nationwide Readmissions Database was used to identify adult patients admitted for acute cholangitis who underwent cholecystectomy. Study cohorts were defined based on timing of surgery. Multivariable regressions and Royston-Parmar time-adjusted analysis were used to evaluate the association of cholecystectomy timing and outcomes. RESULTS: Of 65,753 patients, 82.0 â€‹% received surgery on Index and 18.0 â€‹% on Delayed admissions. Following adjustment, Delayed operation was associated with significantly increased odds of mortality (AOR 1.67 [95 â€‹% CI 1.10-2.54]), complications (1.25 [1.13-1.40]), repair of bile duct injury (1.66 [1.15-2.41]), conversion to open (1.69 [1.48-1.93]), and 30-day readmission (3.52 [3.21-3.86]). The Delayed cohort experienced a +$14,200 increment in hospitalization costs relative to Index. CONCLUSIONS: Delayed cholecystectomy for acute cholangitis is significantly associated with adverse postoperative outcomes, suggesting that index cholecystectomy may be safe to perform.

Development and preliminary assessment of a machine learning model to predict myocardial infarction and cardiac arrest after major operations.

INTRODUCTION: Accurate prediction of complications often informs shared decision-making. Derived over 10 years ago to enhance prediction of intra/post-operative myocardial infarction and cardiac arrest (MI/CA), the Gupta score has been criticized for unreliable calibration and inclusion of a wide spectrum of unrelated operations. In the present study, we developed a novel machine learning (ML) model to estimate perioperative risk of MI/CA and compared it to the Gupta score. METHODS: Patients undergoing major operations were identified from the 2016-2020 ACS-NSQIP. The Gupta score was calculated for each patient, and a novel ML model was developed to predict MI/CA using ACS NSQIP-provided data fields as covariates. Discrimination (C-statistic) and calibration (Brier score) of the ML model were compared to the existing Gupta score within the entire cohort and across operative subgroups. RESULTS: Of 2,473,487 patients included for analysis, 25,177 (1.0%) experienced MI/CA (55.2% MI, 39.1% CA, 5.6% MI and CA). The ML model, which was fit using a randomly selected training cohort, exhibited higher discrimination within the testing dataset compared to the Gupta score (C-statistic 0.84 vs 0.80, p < 0.001). Furthermore, the ML model had significantly better calibration in the entire cohort (Brier score 0.0097 vs 0.0100). Model performance was markedly improved among patients undergoing thoracic, aortic, peripheral vascular and foregut surgery. CONCLUSIONS: The present ML model outperformed the Gupta score in the prognostication of MI/CA across a heterogenous range of operations. Given the growing integration of ML into healthcare, such models may be readily incorporated into clinical practice and guide benchmarking efforts.

National analysis of cost disparities in robotic-assisted versus laparoscopic abdominal operations.

BACKGROUND: Although the use of robotic-assisted surgery continues to expand, the cost-effectiveness of this platform remains unclear. The present study aimed to compare hospitalization costs and clinical outcomes between robotic-assisted surgery and laparoscopic approaches for major abdominal operations. METHODS: All adults receiving minimally invasive gastrectomy, cholecystectomy, colectomy (right, left, transverse, sigmoid), ventral hernia repair, hysterectomy, and abdominoperineal resection were identified in the 2012 to 2019 National Inpatient Sample. Records with concurrent operations were excluded. Multivariable linear and logistic regressions were developed to examine the association of the operative approach with costs, length of stay, and complications. An interaction term between the year and operative approach was used to analyze cost differences over time. RESULTS: Of an estimated 1,124,450 patients, 75.8% had laparoscopic surgery, and 24.2% had robotic-assisted surgery. Compared to laparoscopic, patients with robotic-assisted operations were younger and more commonly privately insured. The average hospitalization cost for laparoscopic cases was $16,000 ± 14,800 and robotic-assisted cases was $18,300 ± 13,900 (P < .001). Regardless of procedure type, all robotic-assisted operations had higher costs compared to laparoscopic operations. Risk-adjusted trend analysis revealed that the discrepancy in costs between laparoscopic and robotic-assisted surgery persisted and widened over time from $1,600 in 2012 to $2,600 in 2019. Compared to laparoscopic procedures, robotic procedures had a 2.2% reduction in complications (9.4 vs 11.6%, P < .001) and a 0.7-day decrement in the length of stay (95% confidence interval -0.8 to -0.7). CONCLUSION: Disparities in costs between robotic and laparoscopic abdominal operations have persisted over time. Given the modest decrement in adverse outcomes, further investigation into the clinical benefits of robotic surgery is warranted to justify its greater costs.

Sociodemographic disparities in concomitant left atrial appendage occlusion during cardiac valve operations.

BACKGROUND: Sociodemographic disparities in atrial fibrillation (AF) management and thromboembolic prophylaxis have previously been reported, which may involve inequitable access to left atrial appendage occlusion (LAAO) during cardiac surgery. The present study aimed to evaluate the association of LAAO utilization with sex, race, and hospital region among patients with AF undergoing heart valve operations. METHODS: Adults with AF undergoing valve replacement/repair in the 2012-2019 National Inpatient Sample were identified and stratified based on concurrent LAAO. Multivariable linear and logistic regressions were developed to identify factors associated with LAAO utilization. Mortality, complications including stroke and thromboembolism, hospitalization costs and length of stay (LOS) were secondarily assessed. RESULTS: Of 382,580 patients undergoing valve operations, 18.7% underwent concomitant LAAO. Over the study period, the proportion of female patients receiving LAAO significantly decreased from 44.8% to 38.9% (p<0.001). Upon risk adjustment, female (AOR 0.93 [95% CI 0.89-0.97]) and Black patients (0.91 [0.83-0.99]) had significantly reduced odds of undergoing LAAO compared to males and Whites, respectively. Additionally, hospitals in the Midwest (1.38 [1.24-1.51]) and West (1.26 [1.15-1.36]) had increased likelihood of LAAO whereas Northeast hospitals (0.85 [0.77-0.94)] had decreased odds relative to the South. Furthermore, LAAO was associated with decreased stroke (0.71 [0.60-0.84]) and thromboembolism (0.68 [0.54-0.86]), $4,200 reduction in costs and 1-day decrement in LOS. CONCLUSIONS: Female and Black patients had significantly lower odds while Midwest and Western hospitals had greater odds of LAAO utilization. Enhancing access to LAAO during valvular surgery is warranted to improve clinical and financial outcomes for patients with AF.

Maternal and Fetal Outcomes in Pregnant Patients With Mechanical and Bioprosthetic Heart Valves.

Background Guidelines for choice of prosthetic heart valve in people of reproductive age are not well established. Although biologic heart valves (BHVs) have risk of deterioration, mechanical heart valves (MHVs) require lifelong anticoagulation. This study aimed to characterize the association of prosthetic valve type with maternal and fetal outcomes in pregnant patients. Methods and Results Using the 2008 to 2019 National Inpatient Sample, we identified all adult patients hospitalized for delivery with prior heart valve implantation. Multivariable regressions were used to analyze the primary outcome, major adverse cardiovascular events, and secondary outcomes, including maternal and fetal complications, length of stay, and costs. Among 39 871 862 birth hospitalizations, 4152 had MHVs and 874 had BHVs. Age, comorbidities, and cesarean birth rates were similar between patients with MHVs and BHVs. The presence of a prosthetic valve was associated with over 22-fold increase in likelihood of major adverse cardiovascular events (MHV: adjusted odds ratio, 22.1 [95% CI, 17.3-28.2]; BHV: adjusted odds ratio, 22.5 [95% CI, 13.9-36.5]) as well as increased duration of stay and hospitalization costs. However, patients with MHVs and BHVs had no significant difference in the odds of any maternal outcome, including major adverse cardiovascular events, hypertensive disease of pregnancy, and ante/postpartum hemorrhage. Similarly, fetal complications were more likely in patients with valve prostheses, including a 4-fold increase in odds of stillbirth, but remained comparable between MHVs and BHVs. Conclusions Patients hospitalized for delivery with prior valve replacement carry substantial risk of adverse maternal and fetal events, regardless of valve type. Our findings reveal comparable outcomes between MHVs and BHVs.

Cost Variation in Bariatric Surgery Across the United States.

BACKGROUND: High costs have been cited as a barrier to utilization of bariatric surgery despite the increasing prevalence of obesity in the United States. The present work characterizes the center-level variation and risk factors for increased hospitalization costs following bariatric operations. STUDY DESIGN: The 2016-2019 Nationwide Readmissions Database was queried to identify all adults undergoing elective laparoscopic sleeve gastrectomy (SG) or Roux-en-Y gastric bypass (RYGB). Random effects were estimated using Bayesian methodology and used to rank hospitals by increasing risk-adjusted center-level costs. RESULTS: Of an estimated 687,866 patients at an annual 2435 hospitals, 69.9% underwent SG and 30.1% RYGB, with median costs of $10,900 (interquartile range: 8600-14,000) and $13,600 (10,300-18,000), respectively. Hospitals in the highest tertile of annual SG and RYGB volume were associated with a $1500 (95% CI - 2,100, -800) and $3400 reduction in costs (95% CI -4,200, -2600). Approximately 37.2% (95% CI 35.8-38.6) of variation in hospitalization costs was attributable to the hospital. Hospitals in the top decile of center-level costs were associated with increased odds of developing complications (AOR 1.22, 95% CI 1.05-1.40) but not mortality. CONCLUSION: The present work identified significant interhospital variation in the costs of bariatric operations. Further efforts to standardize costs may enhance the value of bariatric surgical care in the US.

Lateral mammillary body neurons in mouse brain are disproportionately vulnerable in Alzheimer's disease.

The neural circuits governing the induction and progression of neurodegeneration and memory impairment in Alzheimer's disease (AD) are incompletely understood. The mammillary body (MB), a subcortical node of the medial limbic circuit, is one of the first brain regions to exhibit amyloid deposition in the 5xFAD mouse model of AD. Amyloid burden in the MB correlates with pathological diagnosis of AD in human postmortem brain tissue. Whether and how MB neuronal circuitry contributes to neurodegeneration and memory deficits in AD are unknown. Using 5xFAD mice and postmortem MB samples from individuals with varying degrees of AD pathology, we identified two neuronal cell types in the MB harboring distinct electrophysiological properties and long-range projections: lateral neurons and medial neurons. lateral MB neurons harbored aberrant hyperactivity and exhibited early neurodegeneration in 5xFAD mice compared with lateral MB neurons in wild-type littermates. Inducing hyperactivity in lateral MB neurons in wild-type mice impaired performance on memory tasks, whereas attenuating aberrant hyperactivity in lateral MB neurons ameliorated memory deficits in 5xFAD mice. Our findings suggest that neurodegeneration may be a result of genetically distinct, projection-specific cellular dysfunction and that dysregulated lateral MB neurons may be causally linked to memory deficits in AD.

Single-nucleus multiregion transcriptomic analysis of brain vasculature in Alzheimer's disease.

Cerebrovascular dysregulation is a hallmark of Alzheimer's disease (AD), but the changes that occur in specific cell types have not been fully characterized. Here, we profile single-nucleus transcriptomes in the human cerebrovasculature in six brain regions from 220 individuals with AD and 208 age-matched controls. We annotate 22,514 cerebrovascular cells, including 11 subtypes of endothelial, pericyte, smooth muscle, perivascular fibroblast and ependymal cells. We identify 2,676 differentially expressed genes in AD, including downregulation of PDGFRB in pericytes, and of ABCB1 and ATP10A in endothelial cells, and validate the downregulation of SLC6A1 and upregulation of APOD, INSR and COL4A1 in postmortem AD brain tissues. We detect vasculature, glial and neuronal coexpressed gene modules, suggesting coordinated neurovascular unit dysregulation in AD. Integration with AD genetics reveals 125 AD differentially expressed genes directly linked to AD-associated genetic variants. Lastly, we show that APOE4 genotype-associated differences are significantly enriched among AD-associated genes in capillary and venule endothelial cells, as well as subsets of pericytes and fibroblasts.

Assessment of Racial and Ethnic Disparities in Outcomes of Pediatric Hospitalizations for Sepsis Across the United States.

This cross-sectional study examines mortality, prevalence of complex chronic conditions, and admission rates by race and ethnicity of hospitalized children.