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.

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 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.

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.

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 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.

Cardiovascular Disease in Pregnancy: Clinical Outcomes and Cost-Associated Burdens From a National Cohort at Delivery.

Background: Cardiovascular disease (CVD) in pregnancy is a leading cause of maternal morbidity and mortality in the United States, with an increasing prevalence. Objectives: This study aimed to examine risk factors for adverse maternal cardiac, maternal obstetric, and neonatal outcomes as well as costs for pregnant people with CVD at delivery. Methods: Using the National Inpatient Sample 2010-2019 and the Internal Classification of Diseases diagnosis codes, all pregnant people admitted for their delivery hospitalization were included. CVD diagnoses included congenital heart disease, cardiomyopathy, ischemic heart disease, arrhythmias, and valvular disease. Multivariable regressions were used to analyze major adverse cardiovascular events (MACE), maternal and fetal complications, length of stay, and resource utilization. Results: Of the 33,639,831 birth hospitalizations included, 132,532 (0.39%) had CVD. These patients experienced more frequent MACE (8.5% vs 0.4%, P < 0.001), obstetric (24.1% vs 16.6%, P < 0.001), and neonatal complications (16.1% vs 9.5%, P < 0.001), and maternal mortality (0.16% vs 0.01%, P < 0.001). Factors associated with MACE included cardiomyopathy (adjusted OR [aOR]: 49.9, 95% CI: 45.2-55.1), congenital heart disease (aOR: 13.8, 95% CI: 12.0-15.9), Black race (aOR: 1.04, 95% CI: 1.00-1.08), low income (aOR: 1.06, 95% CI: 1.02-1.11), and governmental insurance (aOR: 1.03, 95% CI: 1.00-1.07). On adjusted analysis, CVD was associated with higher odds of maternal mortality (aOR: 9.28, 95% CI: 6.35-13.56), stillbirth (aOR: 1.66, 95% CI: 1.49-1.85), preterm birth (aOR: 1.33, 1.27-1.39), and congenital anomalies (aOR: 1.84, 95% CI: 1.69-1.99). CVD was also associated with an increase of $2,598 (95% CI: $2,419-2,777) per patient during admission for delivery. Conclusions: CVD in pregnancy is associated with higher rates of adverse outcomes. Our study highlights the association of key clinical and demographic factors with CVD during pregnancy to emphasize those at highest risk for complications.

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.

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.