Center-level variation in hospitalization costs of pancreaticoduodenectomy for pancreatic cancer.

BACKGROUND: Pancreaticoduodenectomy is a highly morbid operation with significant resource utilization. Using a national cohort, we examined the interhospital variation in pancreaticoduodenectomy hospitalization cost in the United States. METHODS: Adults undergoing elective pancreaticoduodenectomy in the setting of pancreatic cancer were tabulated from the 2016-2020 Nationwide Readmissions Database. A 2-level mixed-effects model was developed to evaluate the interhospital variation in pancreaticoduodenectomy hospitalization costs. Institutions within the top decile of risk-adjusted expenditures were defined as high-cost hospitals. Multivariable regression models were fitted to examine the association between high-cost hospital status and outcomes of interest. To account for the effects of complications on expenditures, a subgroup analysis comprising of patients with no adverse events was conducted. RESULTS: The study included an estimated 24,779 patients with a median hospitalization cost of $38,800. After mixed-effects modeling, 40.9% of the cost variation was attributable to hospital, rather than patient, factors. Multivariable regression models revealed an association between high-cost hospital status and greater odds of complications and longer length of stay. Among patients without an adverse event, interhospital cost variation remained significant at 61.0%, and treatment at high-cost hospitals was similarly linked to longer length of stay. CONCLUSION: Our study identified significant interhospital variation in pancreaticoduodenectomy hospitalization costs in the United States. Although high-cost hospital status was associated with increased odds of complications, variation remained significant even among patients without an adverse event. These results suggest the important role of hospital practices as contributors to expenditures. Further efforts to identify drivers of costs and standardize pancreatic surgical care are warranted.

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.

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.

Trends in the adoption of diverting loop ileostomy for acute complicated diverticulitis in the United States.

BACKGROUND: Acute complicated diverticulitis poses a substantial burden to individual patients and the health care system. A significant proportion of the cases necessitate emergency operations. The choice between Hartmann's procedure and primary anastomosis with diverting loop ileostomy remains controversial. METHODS: Using American College of Surgeons National Surgical Quality Improvement Program patient user file data from 2012 to 2020, patients undergoing Hartmann's procedure and primary anastomosis with diverting loop ileostomy for nonelective sigmoidectomy for complicated diverticulitis were identified. Major adverse events, 30-day mortality, perioperative complications, operative duration, reoperation, and 30-day readmissions were assessed. RESULTS: Of 16,921 cases, 6.3% underwent primary anastomosis with diverting loop ileostomy, showing a rising trend from 5.3% in 2012 to 8.4% in 2020. Primary anastomosis with diverting loop ileostomy patients, compared to Hartmann's procedure, had similar demographics and fewer severe comorbidities. Primary anastomosis with diverting loop ileostomy exhibited lower rates of major adverse events (24.6% vs 29.3%, P = .001). After risk adjustment, primary anastomosis with diverting loop ileostomy had similar risks of major adverse events and 30-day mortality compared to Hartmann's procedure. While having lower odds of respiratory (adjusted odds ratio 0.61, 95% confidence interval 0.45-0.83) and infectious (adjusted odds ratio 0.78, 95% confidence interval 0.66-0.93) complications, primary anastomosis with diverting loop ileostomy was associated with a 36-minute increment in operative duration and increased odds of 30-day readmission (adjusted odds ratio 1.30, 95% confidence interval 1.07-1.57) compared to Hartmann's procedure. CONCLUSION: Primary anastomosis with diverting loop ileostomy displayed comparable odds of major adverse events compared to Hartmann's procedure in acute complicated diverticulitis while mitigating infectious and respiratory complication risks. However, primary anastomosis with diverting loop ileostomy was associated with longer operative times and greater odds of 30-day readmission. Evolving guidelines and increasing primary anastomosis with diverting loop ileostomy use suggest a shift favoring primary anastomosis, especially in complicated diverticulitis. Future investigation of disparities in surgical approaches and patient outcomes is warranted to optimize acute diverticulitis care pathways.

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.

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.

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.

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.

Impact of delayed intervention following admission for small bowel obstruction: A contemporary analysis.

Background: The optimal timing of surgical intervention for small bowel obstruction (SBO) remains debated. Methods: All adults admitted for SBO were identified in the 2018-2019 National Inpatient Sample. Patients undergoing small bowel resection or lysis of adhesion after three days were considered part of the Delayed cohort. All others were classified as Early. Multivariable regressions were used to assess independent predictors of delayed surgical intervention as well as associations between delayed management and in-hospital mortality, major adverse events (MAE), perioperative complications, postoperative length of stay (LOS), hospitalization costs and non-home discharge. Results: Among 28,440 patients who met study criteria, 52.0 % underwent delayed intervention. Black race (AOR 1.19, 95 % CI 1.03-1.36, ref.: White) and Medicare coverage (AOR 1.16, 95 % CI 1.01-1.33, ref.: private payer) were associated with increased odds of delayed surgical management. While delayed intervention was not significantly associated with death (AOR 1.27, 95 % CI 0.97-1.68), it was linked to greater odds of MAE (AOR 1.30, 95 % CI 1.16-1.45) and several perioperative complications. The Delayed cohort also faced an incremental increase in postoperative LOS (+1.29 days, 95 % CI 0.89-1.70) and hospitalization costs (+$11,000, 95 % CI 10,000-12,000). Moreover, delayed intervention was linked to increased odds of non-home discharge (AOR 1.64, 95 % CI 1.47-1.84). Conclusions: Delay in surgical management following SBO is linked to inferior clinical outcomes and increased resource use. Our findings highlight the need to ensure proper timing of surgery for SBO as well as efforts to standardize these practices across all demographics of patients.

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.

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.

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.

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.

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.

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.

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.

Impact of inter-hospital transfer on outcomes of urgent cholecystectomy.

BACKGROUND: This study used a national cohort to characterize the impact of inter-hospital transfer status on outcomes following nonelective cholecystectomy for cholecystitis. METHODS: Nonelective cholecystectomies were identified using the 2016-2019 National Inpatient Sample. Multivariable models adjusting for patient and hospital characteristics were utilized to assess outcomes of interest. RESULTS: Of an estimated 530,696 patients, 5.3% were transferred. Transferred patients were older, more often male, and more likely to report income in the 0th-25th percentile, compared to others. After adjustment, transfer was associated with increased odds of infectious complications (AOR 1.31, 95%CI 1.06-1.60) and non-home discharge (AOR 1.59, 95%CI 1.45-1.74), but not mortality. Transfer was linked to a $600 cost decrement at the operating hospital (95%CI -$880-330). CONCLUSIONS: Transfer status is associated with greater postoperative infection, but not mortality. Given that disparities may play a role in transfer decisions, more work must be done to identify transfer drivers and improve patient outcomes.

APOE4 impairs myelination via cholesterol dysregulation in oligodendrocytes.

APOE4 is the strongest genetic risk factor for Alzheimer's disease1-3. However, the effects of APOE4 on the human brain are not fully understood, limiting opportunities to develop targeted therapeutics for individuals carrying APOE4 and other risk factors for Alzheimer's disease4-8. Here, to gain more comprehensive insights into the impact of APOE4 on the human brain, we performed single-cell transcriptomics profiling of post-mortem human brains from APOE4 carriers compared with non-carriers. This revealed that APOE4 is associated with widespread gene expression changes across all cell types of the human brain. Consistent with the biological function of APOE2-6, APOE4 significantly altered signalling pathways associated with cholesterol homeostasis and transport. Confirming these findings with histological and lipidomic analysis of the post-mortem human brain, induced pluripotent stem-cell-derived cells and targeted-replacement mice, we show that cholesterol is aberrantly deposited in oligodendrocytes-myelinating cells that are responsible for insulating and promoting the electrical activity of neurons. We show that altered cholesterol localization in the APOE4 brain coincides with reduced myelination. Pharmacologically facilitating cholesterol transport increases axonal myelination and improves learning and memory in APOE4 mice. We provide a single-cell atlas describing the transcriptional effects of APOE4 on the aging human brain and establish a functional link between APOE4, cholesterol, myelination and memory, offering therapeutic opportunities for Alzheimer's disease.

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.