Lower Prevalence of Asymptomatic Alzheimer's Disease Among Healthy African Americans.

OBJECTIVE: Alzheimer's disease (AD) is believed to be more common in African Americans (AA), but biomarker studies in AA populations are limited. This report represents the largest study to date examining cerebrospinal fluid AD biomarkers in AA individuals. METHODS: We analyzed 3,006 cerebrospinal fluid samples from controls, AD cases, and non-AD cases, including 495 (16.5%) self-identified black/AA and 2,456 (81.7%) white/European individuals using cutoffs derived from the Alzheimer's Disease Neuroimaging Initiative, and using a data-driven multivariate Gaussian mixture of regressions. RESULTS: Distinct effects of race were found in different groups. Total Tauand phospho181-Tau were lower among AA individuals in all groups (p < 0.0001), and Aß42 was markedly lower in AA controls compared with white controls (p < 0.0001). Gaussian mixture of regressions modeling of cerebrospinal fluid distributions incorporating adjustments for covariates revealed coefficient estimates for AA race comparable with 2-decade change in age. Using Alzheimer's Disease Neuroimaging Initiative cutoffs, fewer AA controls were classified as biomarker-positive asymptomatic AD (8.0% vs 13.4%). After adjusting for covariates, our Gaussian mixture of regressions model reduced this difference, but continued to predict lower prevalence of asymptomatic AD among AA controls (9.3% vs 13.5%). INTERPRETATION: Although the risk of dementia is higher, data-driven modeling indicates lower frequency of asymptomatic AD in AA controls, suggesting that dementia among AA populations may not be driven by higher rates of AD. ANN NEUROL 2024.

Mixture of regressions with multivariate responses for discovering subtypes in Alzheimer's biomarkers with detection limits.

There is no gold standard for the diagnosis of Alzheimer's disease (AD), except from autopsies, which motivates the use of unsupervised learning. A mixture of regressions is an unsupervised method that can simultaneously identify clusters from multiple biomarkers while learning within-cluster demographic effects. Cerebrospinal fluid (CSF) biomarkers for AD have detection limits, which create additional challenges. We apply a mixture of regressions with a multivariate truncated Gaussian distribution (also called a censored multivariate Gaussian mixture of regressions or a mixture of multivariate tobit regressions) to over 3,000 participants from the Emory Goizueta Alzheimer's Disease Research Center and Emory Healthy Brain Study to examine amyloid-beta peptide 1-42 (Abeta42), total tau protein and phosphorylated tau protein in CSF with known detection limits. We address three gaps in the literature on mixture of regressions with a truncated multivariate Gaussian distribution: software availability; inference; and clustering accuracy. We discovered three clusters that tend to align with an AD group, a normal control profile and non-AD pathology. The CSF profiles differed by race, gender and the genetic marker ApoE4, highlighting the importance of considering demographic factors in unsupervised learning with detection limits. Notably, African American participants in the AD-like group had significantly lower tau burden.

Feasibility of autologous intraoperative blood collection and retransfusion in small children with complex congenital heart defects undergoing cardiopulmonary bypass.

INTRODUCTION: Allogeneic blood product transfusion is common in pediatric patients undergoing cardiopulmonary bypass although it is associated with an increased risk for adverse events. Furthermore, numerous donor exposures may affect future blood transfusion needs and human leukocyte antigen matching for patients who may ultimately require cardiac transplantation. Autologous intraoperative blood collection and retransfusion is a known method of blood preservation, but has not been extensively practiced in pediatric patients. In this study we assess the feasibility of this blood conservation technique in small children with complex congenital heart defects undergoing cardiopulmonary bypass. METHODS: After Institutional Review Board approval, we retrospectively reviewed the medical records of children weighing <10 kg who underwent cardiopulmonary bypass over a 2-year period. Eighteen patients underwent autologous intraoperative blood collection and retransfusion and comprised the study group. Eighteen control patients were chosen by a 1:1 matched design using preoperative hematocrit, surgical procedure, and body weight. Multiple corresponding demographic and surgical variables, transfusion data, and clinical outcomes were compared. RESULTS: Patient demographics, operative parameters and preoperative laboratory, and coagulation values were similar between the two groups. Despite the removal of autologous blood, study patients did not require more inotropic support prior to cardiopulmonary bypass. They also did not experience a significant increase in bleeding as measured by 24-hour postoperative chest tube output. Study patients were exposed to significantly fewer donor units intraoperatively and within the first 24 hours postoperatively. DISCUSSION: The use of autologous intraoperative blood collection and retransfusion is a feasible option for small children with complex congenital heart defects undergoing cardiopulmonary bypass. Study patients received significantly fewer donor exposures without an increase in postoperative bleeding. Children who require multiple cardiac surgeries or eventually transplantation could benefit from this blood conservation technique.

Association of Overlapping Surgery With Patient Outcomes in a Large Series of Neurosurgical Cases.

Importance: Overlapping surgery (OS) is common. However, there is a dearth of evidence to support or refute the safety of this practice. Objective: To determine whether OS is associated with worsened morbidity and mortality in a large series of neurosurgical cases. Design, Setting, and Participants: A retrospective cohort study was completed for patients who underwent neurosurgical procedures at Emory University Hospital, a large academic referral hospital, between January 1, 2014, and December 31, 2015. Patients were operated on for pathologies across the spectrum of neurosurgical disorders. Propensity score weighting and logistic regression models were executed to compare outcomes for patients who received nonoverlapping surgery and OS. Investigators were blinded to study cohorts during data collection and analysis. Main Outcomes and Measures: The primary outcome measures were 90-day postoperative mortality, morbidity, and functional status. Results: In this cohort of 2275 patients who underwent neurosurgery, 1259 (55.3%) were female, and the mean (SD) age was 52.1 (16.4) years. A total of 972 surgeries (42.7%) were nonoverlapping while 1303 (57.3%) were overlapping. The distribution of American Society of Anesthesiologists score was similar between nonoverlapping surgery and OS cohorts. Median surgical times were significantly longer for patients in the OS cohort vs the nonoverlapping surgery cohort (in-room time, 219 vs 188 minutes; skin-to-skin time, 141 vs 113 minutes; both P < .001). Overlapping surgery was more frequently elective (93% vs 87%; P < .001). Regression analysis failed to demonstrate an association between OS and complications, such as mortality, morbidity, or worsened functional status. Measures of baseline severity of illness, such as admission to the intensive care unit and increased length of stay, were associated with mortality (intensive care unit: odds ratio [OR], 25.5; 95% CI, 6.22-104.67; length of stay: OR, 1.03; 95% CI, 1.00-1.05), morbidity (intensive care unit: OR, 1.85; 95% CI, 1.43-2.40; length of stay: OR, 1.06; 95% CI, 1.04-1.08), and unfavorable functional status (length of stay: OR, 1.03; 95% CI, 1.02-1.05). Conclusions and Relevance: These data suggest that OS can be safely performed if appropriate precautions and patient selection are followed. Data such as these will help determine health care policy to maximize patient safety.

Pharmacokinetic model of unfractionated heparin during and after cardiopulmonary bypass in cardiac surgery.

BACKGROUND: Unfractionated heparin (UFH) is widely used as a reversible anti-coagulant in cardiopulmonary bypass (CPB). However, the pharmacokinetic characteristics of UFH in CPB surgeries remain unknown because of the lack of means to directly determine plasma UFH concentrations. The aim of this study was to establish a pharmacokinetic model to predict plasma UFH concentrations at the end of CPB for optimal neutralization with protamine sulfate. METHODS: Forty-one patients undergoing CPB during cardiac surgery were enrolled in this observational clinical study of UFH pharmacokinetics. Patients received intravenous injections of UFH, and plasma anti-FIIa activity was measured with commercial anti-FIIa assay kits. A population pharmacokinetic model was established by using nonlinear mixed-effects modeling (NONMEM) software and validated by visual predictive check and Bootstrap analyses. Estimated parameters in the final model were used to simulate additional protamine administration after cardiac surgery in order to eliminate heparin rebound. Plans for postoperative protamine intravenous injections and infusions were quantitatively compared and evaluated during the simulation. RESULTS: A two-compartment pharmacokinetic model with first-order elimination provided the best fit. Subsequent simulation of postoperative protamine administration suggested that a lower-dose protamine infusion over 24 h may provide better elimination and prevent heparin rebound than bolus injection and other infusion regimens that have higher infusion rates and shorter duration. CONCLUSION: A two-compartment model accurately reflects the pharmacokinetics of UFH in Chinese patients during CPB and can be used to explain postoperative heparin rebound after protamine neutralization. Simulations suggest a 24-h protamine infusion is more effective for heparin rebound prevention than a 6-h protamine infusion.

Simultaneous determination of nitrendipine and hydrochlorothiazide in spontaneously hypertensive rat plasma using HPLC with on-line solid-phase extraction.

A HPLC method with on-line solid phase extraction (SPE) and DAD detection was developed for the simultaneous determination of nitrendipine and hydrochlorothiazide in spontaneously hypertensive rat (SHR) plasma. Plasma samples (100 µL) were injected directly onto a CAPCELL MF C(8) SPE column. High-abundance proteins and most matrixes in plasma were removed by on-line SPE technology, while nitrendipine and hydrochlorothiazide trapped on the SPE column were effectively separated on a C(18) analytical column. The column temperature was maintained at 20°C. The optimal detection wavelength was 237 nm for NTDP and 271 nm for HCTZ. The total analytical run time was 34 min. The proposed method was linear over the range 5-500 ng mL(-1) for nitrendipine and 10-1000 ng mL(-1) for hydrochlorothiazide. The lower limit of detection (LLOD) was 0.5 and 0.6 ng mL(-1) for nitrendipine and hydrochlorothiazide, respectively. The sensitivity and precision of the method were within acceptable limits during validation period. The method was successfully used to investigate the pharmacokinetic characteristics of nitrendipine and hydrochlorothiazide in spontaneously hypertensive rats.