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ObjectiveTo compare secondary patient reported outcomes of perceptions of treatment success and function for patients treated for appendicitis with appendectomy vs. antibiotics at 30 days.Summary background dataThe Comparison of Outcomes of antibiotic Drugs and Appendectomy trial found antibiotics noninferior to appendectomy based on 30-day health status. To address questions about outcomes among participants with lower socioeconomic status, we explored the relationship of sociodemographic and clinical factors and outcomes.MethodsWe focused on 4 patient reported outcomes at 30 days: high decisional regret, dissatisfaction with treatment, problems performing usual activities, and missing >10 days of work. The randomized (RCT) and observational cohorts were pooled for exploration of baseline factors. The RCT cohort alone was used for comparison of treatments. Logistic regression was used to assess associations.ResultsThe pooled cohort contained 2062 participants; 1552 from the RCT. Overall, regret and dissatisfaction were low whereas problems with usual activities and prolonged missed work occurred more frequently. In the RCT, those assigned to antibiotics had more regret (Odd ratios (OR) 2.97, 95% Confidence intervals (CI) 2.05-4.31) and dissatisfaction (OR 1.98, 95%CI 1.25-3.12), and reported less missed work (OR 0.39, 95%CI 0.27-0.56). Factors associated with function outcomes included sociodemographic and clinical variables for both treatment arms. Fewer factors were associated with dissatisfaction and regret.ConclusionsOverall, participants reported high satisfaction, low regret, and were frequently able to resume usual activities and return to work. When comparing treatments for appendicitis, no single measure defines success or failure for all people. The reported data may inform discussions regarding the most appropriate treatment for individuals.Trial registrationClinicaltrials.gov Identifier: NCT02800785.

IntroductionSeveral European studies suggest that some patients with appendicitis can be treated safely with antibiotics. A portion of patients eventually undergo appendectomy within a year, with 10%-15% failing to respond in the initial period and a similar additional proportion with suspected recurrent episodes requiring appendectomy. Nearly all patients with appendicitis in the USA are still treated with surgery. A rigorous comparative effectiveness trial in the USA that is sufficiently large and pragmatic to incorporate usual variations in care and measures the patient experience is needed to determine whether antibiotics are as good as appendectomy.ObjectivesThe Comparing Outcomes of Antibiotic Drugs and Appendectomy (CODA) trial for acute appendicitis aims to determine whether the antibiotic treatment strategy is non-inferior to appendectomy.Methods/analysisCODA is a randomised, pragmatic non-inferiority trial that aims to recruit 1552 English-speaking and Spanish-speaking adults with imaging-confirmed appendicitis. Participants are randomised to appendectomy or 10 days of antibiotics (including an option for complete outpatient therapy). A total of 500 patients who decline randomisation but consent to follow-up will be included in a parallel observational cohort. The primary analytic outcome is quality of life (measured by the EuroQol five dimension index) at 4 weeks. Clinical adverse events, rate of eventual appendectomy, decisional regret, return to work/school, work productivity and healthcare utilisation will be compared. Planned exploratory analyses will identify subpopulations that may have a differential risk of eventual appendectomy in the antibiotic treatment arm.Ethics and disseminationThis trial was approved by the University of Washington's Human Subjects Division. Results from this trial will be presented in international conferences and published in peer-reviewed journals.Trial registration numberNCT02800785.

Introduction: Erythropoietin (Epo) is a putative neuroprotective therapy that did not improve overall outcomes in a phase 3 randomized controlled trial for neonates with moderate or severe hypoxic-ischemic encephalopathy (HIE). However, HIE is a heterogeneous disorder, and it remains to be determined whether Epo had beneficial effects on a subset of perinatal brain injuries. Methods: This study was a secondary analysis of neuroimaging data from the High-dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) Trial, which was conducted from 2016 to 2021 at 17 sites involving 23 US academic medical centers. Participants were neonates >36 weeks' gestation undergoing therapeutic hypothermia for moderate or severe HIE who received 5 doses of study drug (Epoetin alpha 1,000 U/kg/dose) or placebo in the first week of life. Treatment assignment was stratified by trial site and severity of encephalopathy. The primary outcome was the locus, pattern, and acuity of brain injury as determined by three independent readers using a validated HIE Magnetic Resonance Imaging (MRI) scoring system. Results: Of the 500 infants enrolled in HEAL, 470 (94%) had high quality MRI data obtained at a median of 4.9 days of age (IQR: 4.5–5.8). The incidence of injury to the deep gray nuclei, cortex, white matter, brainstem and cerebellum was similar between Epo and placebo groups. Likewise, the distribution of injury patterns was similar between groups. Among infants imaged at less than 8 days (n = 414), 94 (23%) evidenced only acute, 93 (22%) only subacute and 89 (21%) both acute and subacute injuries, with similar distribution across treatment groups. Conclusion: Adjuvant erythropoietin did not reduce the incidence of regional brain injury. Subacute brain injury was more common than previously reported, which has key implications for the development of adjuvant neuroprotective therapies for this population. [ABSTRACT FROM AUTHOR]

Studies have demonstrated associations between cardiovascular factors and Alzheimer disease (AD) with minimal focus on other neurodegenerative diseases. Utilizing cross-sectional data from 17,532 individuals in the National Alzheimer's Coordinating Center, Uniform Data Set, we compared the presence of cardiovascular factors [body mass index (BMI), atrial fibrillation, hypertension, hyperlipidemia, and diabetes] in individuals carrying a diagnosis of Probable AD (ProbAD), Possible AD, vascular dementia, dementia with Lewy bodies (DLB), frontotemporal dementia, Parkinson disease, progressive supranuclear palsy, or corticobasal degeneration, with that of normals. Generalized linear mixed models were fitted with age at visit, gender, and cardiovascular factors as fixed effects and Alzheimer's Disease Centers as random effects. In late life, only BMI of ProbAD and DLB patients was statistically significantly lower than that in normals (P-values

IntroductionNo known studies have compared longitudinal characteristics between individuals with incident mild cognitive impairment due to Parkinson's disease (PD-MCI) versus Alzheimer's Disease (AD-MCI).MethodsWe used longitudinal data from the National Alzheimer's Coordinating Center's Uniform Data Set to compare 41 PD-MCI and 191 AD-MCI participants according to their demographics, presence of ≥1 APOE e4 allele, and baseline and change over time in clinical characteristics, neuropsychological test scores, and Clinical Dementia Rating sum of boxes (CDR-SB). Multivariable linear regression models with generalized estimating equations were used to account for clustered data and to test for baseline and longitudinal differences in neuropsychological test scores.ResultsPD-MCI and AD-MCI participants differed by many demographic and clinical characteristics. Significantly fewer PD-MCI participants developed dementia over one year. Compared to AD-MCI participants, PD-MCI participants performed better at baseline and over time on a global measure of cognition (Mini Mental State Exam), memory measures (immediate and delayed Logical Memory), and a language measure (Boston Naming Test), and additionally performed better over time on an attention measure (Digit Span Forward), a language measure (Vegetable List), a processing speed measure (Digit Symbol), and an overall measure of memory and functional impairment (CDR-SB).ConclusionOur study provides further evidence that PD-MCI is clinically distinct from AD-MCI and requires different tools for diagnosis and monitoring clinical progression. More importantly, this study suggests that PD-MCI takes longer to convert into dementia than AD-MCI, findings that require replication by other studies.

IntroductionFour new nonproprietary tests were recommended for use in the National Alzheimer's Coordinating Center's Uniform Data Set Neuropsychological Battery. These tests are similar to previous tests but also allow for continuity of longitudinal data collection and wide dissemination among research collaborators.MethodsA Crosswalk Study was conducted in early 2014 to assess the correlation between each set of new and previous tests. Tests with good correlation were equated using equipercentile equating. The resulting conversion tables allow scores on the new tests to be converted to equivalent scores on the previous tests.ResultsAll pairs of tests had good correlation (ρ=0.68 to 0.78). Learning effects were detected for Logical Memory only. Confidence intervals were narrow at each point estimate, and prediction accuracy was high.DiscussionThe recommended new tests are well correlated with the previous tests. The equipercentile equating method produced conversion tables that provide a useful reference for clinicians and researchers.

IntroductionNeuropathologic assessment is the current "gold standard" for evaluating the Alzheimer's disease (AD), but there is no consensus on the methods used.MethodsFifteen unstained slides (8 brain regions) from each of the 14 cases were prepared and distributed to 10 different National Institute on Aging AD Centers for application of usual staining and evaluation following recently revised guidelines for AD neuropathologic change.ResultsCurrent practice used in the AD Centers Program achieved robustly excellent agreement for the severity score for AD neuropathologic change (average weighted κ = .88, 95% confidence interval: 0.77-0.95) and good-to-excellent agreement for the three supporting scores. Some improvement was observed with consensus evaluation but not with central staining of slides. Evaluation of glass slides and digitally prepared whole-slide images was comparable.DiscussionAD neuropathologic evaluation as performed across AD Centers yields data that have high agreement with potential modifications for modest improvements.

In 2012, florbetapir (F) (Amyvid) received US Food and Drug Administration approval as a diagnostic agent for detecting neuritic (β-amyloid) plaques in living patients. Although such approval is specifically not extended to the use of florbetapir as a single definitive diagnostic test for Alzheimer disease dementia (ADD), it is of considerable importance to examine its potential in this regard. To estimate the ability of florbetapir amyloid imaging to detect specified densities of postmortem-identified neuritic plaques, we used the data of Clark et al [Clark CM, Pontecorvo MJ, Beach TG, et al. Cerebral PET with florbetapir compared with neuropathology at autopsy for detection of neuritic amyloid-beta plaques: A prospective cohort study. Lancet Neurol 2012;11:669-78]. We then used the data of Beach et al [Beach TG, Monsell SE, Phillips LE, et al. Accuracy of the clinical diagnosis of Alzheimer disease at National Institute on Aging Alzheimer Disease Centers, 2005-2010. J Neuropathol Exp Neurol 2012;71:266-73], derived from the National Alzheimer's Coordinating Center, to estimate the fraction of subjects who would have been called florbetapir-positive and, among these, the fraction of subjects who would also meet neuropathologic criteria for the presence of ADD. The accuracy of a positive florbetapir β-amyloid scan for the detection of neuropathologically defined ADD is estimated at between 69% and 95% sensitivity and between 83% and 89% specificity. From the same National Alzheimer's Coordinating Center data set, 144 subjects were recorded as having normal cognition. Among these, 84 (58%) had at least sparse neuritic plaques at autopsy and, among these, florbetapir imaging was estimated to detect 47 (56%). These findings suggest that amyloid imaging may significantly improve the clinical identification of ADD.

ImportanceAlthough cerebral amyloid angiopathy (CAA) has important clinical implications, our understanding of it and ability to diagnose it are limited.ObjectiveTo determine pathological correlates and clinical factors identifiable during life that predict the presence of severe CAA in persons with pathologically confirmed Alzheimer disease (AD).Design, setting, and participantsWe compared demographic and clinical variables at the earliest visit during life at which participants were found to have cognitive impairment and compared pathological variables between persons ultimately found to have no or severe CAA at autopsy using logistic regression. Analyses were repeated separately for carriers and noncarriers of the APOE ε4 allele. Data were obtained from the Uniform Data Set, which comprises longitudinal clinical assessments performed in the Alzheimer's Disease Centers funded by the National Institute on Aging. Participants included 193 persons with AD and severe CAA and 232 persons with AD and no CAA. All participants had cognitive impairment and met National Institute on Aging-Reagan Institute neuropathological criteria for AD.Main outcomes and measuresPrevalence of demographic characteristics and the APOE ε4 allele and odds ratios (ORs) of clinical variables for the prediction of severe CAA.ResultsPersons with severe CAA compared with those without CAA were more likely to carry an APOE ε4 allele (64.9% vs 42.8%, respectively; P

Hippocampal sclerosis of aging (HS-Aging) is a high-morbidity brain disease in the elderly but risk factors are largely unknown. We report the first genome-wide association study (GWAS) with HS-Aging pathology as an endophenotype. In collaboration with the Alzheimer's Disease Genetics Consortium, data were analyzed from large autopsy cohorts: (#1) National Alzheimer's Coordinating Center (NACC); (#2) Rush University Religious Orders Study and Memory and Aging Project; (#3) Group Health Research Institute Adult Changes in Thought study; (#4) University of California at Irvine 90+ Study; and (#5) University of Kentucky Alzheimer's Disease Center. Altogether, 363 HS-Aging cases and 2,303 controls, all pathologically confirmed, provided statistical power to test for risk alleles with large effect size. A two-tier study design included GWAS from cohorts #1-3 (Stage I) to identify promising SNP candidates, followed by focused evaluation of particular SNPs in cohorts #4-5 (Stage II). Polymorphism in the ATP-binding cassette, sub-family C member 9 (ABCC9) gene, also known as sulfonylurea receptor 2, was associated with HS-Aging pathology. In the meta-analyzed Stage I GWAS, ABCC9 polymorphisms yielded the lowest p values, and factoring in the Stage II results, the meta-analyzed risk SNP (rs704178:G) attained genome-wide statistical significance (p = 1.4 × 10(-9)), with odds ratio (OR) of 2.13 (recessive mode of inheritance). For SNPs previously linked to hippocampal sclerosis, meta-analyses of Stage I results show OR = 1.16 for rs5848 (GRN) and OR = 1.22 rs1990622 (TMEM106B), with the risk alleles as previously described. Sulfonylureas, a widely prescribed drug class used to treat diabetes, also modify human ABCC9 protein function. A subsample of patients from the NACC database (n = 624) were identified who were older than age 85 at death with known drug history. Controlling for important confounders such as diabetes itself, exposure to a sulfonylurea drug was associated with risk for HS-Aging pathology (p = 0.03). Thus, we describe a novel and targetable dementia risk factor.

BackgroundApolipoprotein (APOE) e4 allele status has been linked to clinical presentation and progression in Alzheimer's disease; however, evidence for a role of APOE e4 in Parkinson's disease (PD) remains largely inconclusive. In this analysis we explored potential significant associations between APOE e4 allele status and characteristics of clinical presentation in patients with PD.MethodsData came from 424 subjects evaluated using the Uniform Data Set (UDS) assessment collected by the National Alzheimer's Coordinating Center. Subjects had a known year of diagnosis of PD and experienced change in motor function prior to any change in cognition. Linear and logistic regression were used to model the association between APOE e4 carrier status and clinical characteristics including measures of cognitive decline and motor and neuropsychiatric symptoms. Amyloid burden was also evaluated for a subset of patients who died and consented to autopsy.ResultsOdds of dementia were higher in APOE e4 carriers (OR = 5.15), and, on average, APOE e4 carriers scored two points worse on tests of episodic memory and the Clinical Dementia Rating Sum of Boxes assessment. There was little evidence to support an association between e4 carrier status and severity of motor features, and, of the four neuropsychiatric symptoms evaluated, only presence of hallucinations was significantly associated with APOE e4 carrier status (OR = 5.29). Neuropathology data revealed higher frequencies of neuritic and diffuse amyloid plaques in APOE e4 carriers compared to non-carriers.ConclusionsAPOE e4 allele status is associated with dementia and severity of Alzheimer's disease pathologic features in PD.

To assist investigators in making design choices, we modeled Alzheimer's disease prevention clinical trials. We used longitudinal Clinical Dementia Rating Scale Sum of Boxes data, retention rates, and the proportions of trial-eligible cognitively normal participants age 65 and older in the National Alzheimer's Coordinating Center Uniform Data Set to model trial sample sizes, the numbers needed to enroll to account for drop out, and the numbers needed to screen to successfully complete enrollment. We examined how enrichment strategies affected each component of the model. Relative to trials enrolling 65-year-old individuals, trials enriching for older (minimum 70 or 75) age required reduced sample sizes, numbers needed to enroll, and numbers needed to screen. Enriching for subjective memory complaints reduced sample sizes and numbers needed to enroll more than age enrichment, but increased the number needed to screen. We conclude that Alzheimer's disease prevention trials can enroll elderly participants with minimal effect on trial retention and that enriching for older individuals with memory complaints might afford efficient trial designs.