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BackgroundCognitive reserve may protect against cognitive decline. However, its effect on physiological measures of cognitive workload in adults with cognitive impairments is unclear.ObjectiveThe aim was to determine the association between cognitive reserve and physiological measures of cognitive workload in older adults with and without cognitive impairments.Methods29 older adults with cognitive impairment (age: 75±6, 11 (38%) women, MOCA scores 20±7) and 19 with normal cognition (age: 74±6; 11 (58%) women; MOCA 28±2) completed a working memory test of increasing task demand (0-, 1-, 2-back). Cognitive workload was indexed using amplitude and latency of the P3 event-related potential (ERP) at electrode sites Fz, Cz, and Pz, and changes in pupillary size, converted to an index of cognitive activity (ICA). The Cognitive Reserve Index questionnaire (CRIq) evaluated Education, Work Activity, and Leisure Time as a proxy of cognitive reserve.ResultsHigher CRIq total scores were associated with larger P3 ERP amplitude (p=0.048), independent of cognitive status (p=0.80), task demand (p=0.003), and electrode site (pConclusionCognitive reserve affects cognitive workload and neural efficiency, regardless of cognitive status. Future longitudinal studies should investigate the causal relationship between cognitive reserve and physiological processes of neural efficiency across cognitive aging.

Background Improved control of glycemic control likely lowers the risk of diabetes complications and clinical pharmacy specialist (CPS) services can improve glycemic control. Though the pattern of control may also matter in terms of outcomes. Objectives The objective of this study was to examine the longitudinal trajectories of HbA1c among a large population of Veterans with type 2 diabetes who received CPS-led diabetes management. Methods This is an observational, multicenter cohort study of Veterans with type-2 diabetes managed by CPSs between 7/1/2013 and 7/1/2017 with baseline glycosylated hemoglobin (HbA1c) level ≥8%. Two years of HbA1c measurements were used to group patients into distinct patterns of HbA1c trajectories over time using group-based trajectory modeling. Characteristics associated with successful HbA1c trajectories and association of assigned trajectories with all-cause and diabetes-related hospitalizations were analyzed using logistic regression. Results A total of 4119 Veterans were included and able to be successfully segmented into six distinct HbA1c trajectory groups over time: High Gradually Decreasing (n = 325, 7.9%), Moderate Early Decline (n = 1692, 41.1%), Large Early Decline (n = 231, 5.6%), Uncontrolled Stable (n = 1468, 35.6%), Early Decline/Subsequent Increase (n = 266, 6.5%), and Very Uncontrolled Stable (n = 137, 3.3%). The distinguishing factor between successful and less successful trajectories appears to be the progress made within the first six months of pharmacist management. Conclusions Significant variability exists in the pattern of glycemic control over time of type 2 diabetes patients managed by clinical pharmacy specialists. Limited resources should be first prioritized to managing patients with very elevated HbA1c and into the first six months of CPS management.

Introduction Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive cyst growth and a loss of functioning renal mass, but a decline in glomerular filtration rate (GFR) and onset of end-stage renal disease (ESRD) occur late in the disease course. There is therefore a great need for early prognostic biomarkers in this disorder. Methods We measured baseline serum fibroblast growth factor 23 (FGF23) levels in 192 patients with ADPKD from the Consortium for Radiologic Imaging Studies of PKD (CRISP) cohort that were followed for a median of 13 years and tested the association between FGF23 levels and change over time in height-adjusted total kidney volume (htTKV), GFR, and time to the composite endpoints of ESRD, death, and doubling of serum creatinine. Results Patients in the highest quartile for baseline FGF23 level had a higher rate of increase in htTKV (0.95% per year, P = 0.0016), and faster rate of decline in GFR (difference of −1.03 ml/min/1.73 m2 per year, P = 0.005) compared with the lowest quartile, after adjusting for other covariates, including htTKV and genotype. The highest quartile of FGF23 was also associated with a substantial increase in risk for the composite endpoint of ESRD, death, or doubling of serum creatinine (hazard ratio [HR] of 2.45 in the fully adjusted model, P = 0.03). Conclusion FGF23 is a prognostic biomarker for disease progression and clinically important outcomes in ADPKD, and has additive value to established imaging and genetic biomarkers., Graphical abstract

Background Recent evidence suggests the systemic accumulation of by-products of gut microbes contributes to cardiovascular morbidity in patients with CKD. Limiting the generation of toxic bacterial by-products by manipulating the intestinal microbiota may be a novel strategy for reducing cardiovascular disease in CKD. Rifaximin is a minimally absorbed, oral antibiotic that targets intestinal pathogens and is commonly used as chronic therapy for the prevention of encephalopathy in patients with cirrhosis. Methods We conducted a randomized, double-blinded, placebo-controlled trial to determine the effect of a 10-day course of oral rifaximin 550 mg BID versus placebo on circulating concentrations of gut-derived cardiovascular toxins and proinflammatory cytokines in patients with stage 3–5 CKD (n=38). The primary clinical outcome was change in serum trimethylamine N-oxide (TMAO) concentrations from baseline to study end. Secondary outcomes included change in serum concentrations of p-cresol sulfate, indoxyl sulfate, kynurenic acid, deoxycholic acid, and inflammatory cytokines (C-reactive protein, IL-6, IL-1β), and change in composition and diversity of fecal microbiota. Results A total of 19 patients were randomized to each of the rifaximin and placebo arms, with n=17 and n=14 completing both study visits in these respective groups. We observed no difference in serum TMAO change (post-therapy minus baseline TMAO) between the rifaximin and placebo groups (mean TMAO change −3.9±15.4 for rifaximin versus 0.5±9.5 for placebo, P=0.49). Similarly, we found no significant change in serum concentrations for p-cresol sulfate, indoxyl sulfate, kynurenic acid, deoxycholic acid, and inflammatory cytokines. We did observe differences in colonic bacterial communities, with the rifaximin group exhibiting significant decreases in bacterial richness (Chao1, P=0.02) and diversity (Shannon H, P=0.05), along with altered abundance of several bacterial genera. Conclusions Short-term rifaximin treatment failed to reduce gut-derived cardiovascular toxins and inflammatory cytokines in patients with CKD. Clinical Trial registry name and registration number Rifaximin Therapy in Chronic Kidney Disease, NCT02342639

This article introduces a global hypothesis test intended for studies with multiple endpoints. Our test makes use of a priori predictions about the direction of the result of each endpoint and we weight these predictions using the sample correlation matrix. The global alternative hypothesis concerns a parameter, ϕ , defined as the researcher's ability to correctly predict the direction of each measure, essentially a binomial parameter. This allows for the test to include expected effects that are all positive, all negative or both while still using the cumulative information across those endpoints. A rejection of the null hypothesis ( H0:ϕ≤ϕ0 ) provides evidence that the researcher's underlying theory about the natural process provides a better prediction of the observed results relative to the null hypothesized predictive ability, thus indicating the theory is worthy of further study. We compare our test to O'Brien's ordinary least squares (OLS) test and show that for small samples and situations where the effect is not in the same direction across all endpoints our approach has better power, while if the effect is equidirectional across all endpoints the OLS test can have greater power.

Introduction Inherited mitochondrial DNA (mtDNA) variants may influence Alzheimer's disease (AD) risk. Methods We sequenced mtDNA from 146 AD and 265 cognitively normal (CN) subjects from the University of Kansas AD Center (KUADC) and assigned haplogroups. We further considered 244 AD and 242 CN AD Neuroimaging Initiative (ADNI) subjects with equivalent data. Results Without applying multiple comparisons corrections, KUADC haplogroup J AD and CN frequencies were 16.4% versus 7.6% (P = .007), and haplogroup K AD and CN frequencies were 4.8% versus 10.2% (P = .063). ADNI haplogroup J AD and CN frequencies were 10.7% versus 7.0% (P = .20), and haplogroup K frequencies were 4.9% versus 8.7% (P = .11). For the combined 390 AD and 507 CN cases haplogroup J frequencies were 12.8% versus 7.3% (P = .006), odds ratio (OR) = 1.87, and haplogroup K frequencies were 4.9% versus 9.5% (P = .010), OR = 0.49. Associations remained significant after adjusting for apolipoprotein E, age, and sex. Conclusion This exploratory analysis suggests inherited mtDNA variants influence AD risk.

Introduction Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive cyst enlargement, leading to kidney failure. Sirtuin-1 is upregulated in ADPKD and accelerates disease progression by deacetylating p53. Niacinamide is a dietary supplement that inhibits sirtuins at high doses. Methods We conducted an open-label, single-arm intervention trial (study 1, N = 10), and a randomized, double blinded, placebo-controlled trial (study 2, N = 36) to assess the biological activity and safety of niacinamide. Patients with ADPKD were given 30 mg/kg oral niacinamide or placebo, for 12 months. The primary endpoint was the ratio of acetylated p53 to total p53 protein in peripheral blood mononuclear cells (PBMCs). Results There was no sustained effect of niacinamide on acetylated/total p53 in either study and no difference between placebo and niacinamide arms. There was no difference in the change in height-adjusted total kidney volume over 12 months between niacinamide and placebo. Niacinamide was generally well tolerated. The most common adverse effects were nausea, diarrhea, gastroesophageal reflux, headache, and acneiform rash but there was no difference in their incidence between niacinamide and placebo. Conclusions In conclusion, niacinamide is safe and well-tolerated in patients with ADPKD. However, we were unable to detect a sustained inhibition of sirtuin activity over 12 months of treatment, and there was no signal to suggest a beneficial effect on any efficacy measure., Graphical abstract

BackgroundPhysical exercise may support brain health and cognition over the course of typical aging. The goal of this nonrandomized clinical trial was to examine the effect of an acute bout of aerobic exercise on brain blood flow and blood neurotrophic factors associated with exercise response and brain function in older adults with and without possession of the APOE4 allele, a genetic risk factor for developing Alzheimer’s. We hypothesized that older adult APOE4 carriers would have lower cerebral blood flow regulation and would demonstrate blunted neurotrophic response to exercise compared to noncarriers.MethodsSixty-two older adults (73±5 years old, 41 female) consented to this prospectively enrolling clinical trial, utilizing a single arm, single visit, experimental design, with post-hoc assessment of difference in outcomes based on APOE4 carriership. All participants completed a single 15-minute bout of moderate-intensity aerobic exercise. The primary outcome measure was change in cortical gray matter cerebral blood flow in cortical gray matter measured by magnetic resonance imaging (MRI) arterial spin labeling (ASL), defined as the total perfusion (area under the curve, AUC) following exercise. Secondary outcomes were changes in blood neurotrophin concentrations of insulin-like growth factor-1 (IGF-1), vascular endothelial growth factor (VEGF), and brain derived neurotrophic factor (BDNF).ResultsGenotyping failed in one individual (n=23 APOE4 carriers and n=38 APOE4 non-carriers) and two participants could not complete primary outcome testing. Cerebral blood flow AUC increased immediately following exercise, regardless of APOE4 carrier status. In an exploratory regional analyses, we found that cerebral blood flow increased in hippocampal brain regions, while showing no change in cerebellar brain regions across both groups. Among high interindividual variability, there were no significant changes in any of the 3 neurotrophic factors for either group immediately following exercise.ConclusionsOur findings show that both APOE4 carriers and non-carriers show similar effects of exercise-induced increases in cerebral blood flow and neurotrophic response to acute aerobic exercise. Our results provide further evidence that acute exercise-induced increases in cerebral blood flow may be regional specific, and that exercise-induced neurotrophin release may show a differential effect in the aging cardiovascular system. Results from this study build upon previous research in younger adults by providing an initial characterization of the acute brain blood flow and neurotrophin responses to a bout of exercise in older adults with and without this known risk allele for cardiovascular disease and Alzheimer’s disease.Trials registrationDementia Risk and Dynamic Response to Exercise (DYNAMIC); Identifier: NCT04009629FundingThis study was funded by grants from the national institutes of health R21 AG061548, P30 AG072973 and P30 AG035982, and the Leo and Anne Albert Charitable Trust. The Hoglund Biomedical Imaging Center is supported by a generous gift from Forrest and Sally Hoglund and funding from the National Institutes of Health including S10 RR29577, and UL1 TR002366.

During 2007-2019, the percentage of HIV Outpatient Study participants reporting anal or vaginal condomless sex in the past 6 months ranged from a low of 17% among heterosexual males to 59% for men who have sex with men (MSM). MSM reported having had condomless sex more frequently than heterosexual males and females and were the only group in which an increase in condomless sex was observed during the study period (from 39 to 59%). Although persons with undetectable HIV viral load have effectively no risk of transmitting HIV sexually (U = U), there is still the potential risk of transmission or acquisition of other sexually transmitted infections (STIs) when engaging in condomless sex. Continuing education about risks of HIV and STI transmission as well as ongoing screening for and treatment of STIs, retention in HIV treatment, and support for sexual health are critical components of care for people living with HIV.

Approximately 40% of patients with cancer are eligible for check-point inhibitor (CPI) therapy. Little research has examined the potential cognitive impact of CPIs. First-line CPI therapy offers a unique research opportunity without chemotherapy-related confounders. The purpose of this prospective, observational pilot was to (1) demonstrate the feasibility of prospective recruitment, retention, and neurocognitive assessment for older adults receiving first-line CPI(s) and (2) provide preliminary evidence of changes in cognitive function associated with CPI(s). Patients receiving first-line CPI(s) (CPI Group) were assessed at baseline (n = 20) and 6 months (n = 13) for self-report of cognitive function and neurocognitive test performance. Results were compared to age-matched controls without cognitive impairment assessed annually by the Alzheimer’s Disease Research Center (ADRC). Plasma biomarkers were measured at baseline and 6 months for the CPI Group. Estimated differences for CPI Group scores prior to initiating CPIs (baseline) trended to lower performance on the Montreal Cognitive Assessment-Blind (MOCA-Blind) test compared to the ADRC controls (p = 0.066). Controlling for age, the CPI Group’s 6-months MOCA-Blind performance was lower than the ADRC control group’s 12-months performance (p = 0.011). No significant differences in biomarkers were detected between baseline and 6 months, although significant correlations were noted for biomarker change and cognitive performance at 6 months. IFNγ, IL-1β, IL-2, FGF2, and VEGF were inversely associated with Craft Story Recall performance (p < 0.05), e.g., higher levels correlated with poorer memory performance. Higher IGF-1 and VEGF correlated with better letter-number sequencing and digit-span backwards performance, respectively. Unexpected inverse correlation was noted between IL-1α and Oral Trail-Making Test B completion time. CPI(s) may have a negative impact on some neurocognitive domains and warrant further investigation. A multi-site study design may be crucial to fully powering prospective investigation of the cognitive impact of CPIs. Establishment of a multi-site observational registry from collaborating cancer centers and ADRCs is recommended.

Background: After an acquired injury to the motor cortex, the ability to generate skilled movements is impaired, leading to long-term motor impairment and disability. While rehabilitative therapy can improve outcomes in some individuals, there are no treatments currently available that are able to fully restore lost function. Objective: We previously used activity-dependent stimulation (ADS), initiated immediately after an injury, to drive motor recovery. The objective of this study was to determine if delayed application of ADS would still lead to recovery and if the recovery would persist after treatment was stopped. Methods: Rats received a controlled cortical impact over primary motor cortex, microelectrode arrays were implanted in ipsilesional premotor and somatosensory areas, and a custom brain–machine interface was attached to perform the ADS. Stimulation was initiated either 1, 2, or 3 weeks after injury and delivered constantly over a 4-week period. An additional group was monitored for 8 weeks after terminating ADS to assess persistence of effect. Results were compared to rats receiving no stimulation. Results: ADS was delayed up to 3 weeks from injury onset and still resulted in significant motor recovery, with maximal recovery occurring in the 1-week delay group. The improvements in motor performance persisted for at least 8 weeks following the end of treatment. Conclusions: ADS is an effective method to treat motor impairments following acquired brain injury in rats. This study demonstrates the clinical relevance of this technique as it could be initiated in the post-acute period and could be explanted/ceased once recovery has occurred.

Background The University of Kansas Alzheimer’s Disease Center (KU ADC) maintains several large databases to track participant recruitment, enrollment, and capture various research-related activities. It is challenging to manage and coordinate all the research-related activities. One of the crucial activities involves generating a consensus diagnosis and communicating with participants and their primary care providers. Process To effectively manage the cohort, the KU ADC utilizes a combination of open-source electronic data capture (EDC) (i.e. REDCap), along with other homegrown data management and analytic systems developed using R-studio and Shiny. Process evaluation In this article, we describe the method and utility of the user-friendly dashboard that was developed for the rapid reporting of dementia evaluations which allows clinical researchers to summarize recruitment metrics, automatically generate letters to both participants and healthcare providers, which ultimately help optimize workflows. Conclusions We believe this general framework would be beneficial to any institution that build reports and summarizing key metrics of their research from longitudinal databases.

IntroductionA computationally fast machine learning method is introduced for uncovering the wholebrain voxel-level connectomic spectra that differentiates different status of Alzheimer’s disease (AD). The method is applied to the Alzheimer’s Disease Neuroimaging Initiative (ADNI) Fluorinefluorodeoxyglucose Positron Emission Tomography (FDG-PET) imaging and clinical data and identified novel AD/MCI differentiating connectomic neuroimaging biomarkers.MethodsA divide-and-conquer algorithm is introduced for detect informative local brain networks at voxel level and whole-brain scale. The connection information within the local networks is integrated into the node voxels, which makes detection of the marginally weak signals possible. Prediction accuracy is significantly improved by incorporating the local brain networks and marginally weak signals.ResultsBrain connectomic structures differentiating AD and mild cognitive impairment (MCI), AD and healthy, and MIC and healthy were discovered. We identified novel AD/MCI-associated neuroimaging biomarkers by integrating local brain networks and marginally weak signals. For example, networkbased signals in paracentral lobule (p-value=6.1e-5), olfactory cortex (p-value=4.6e-5), caudate nucleus (1.8e-3) and precentral gyrus (1.8e-3) are informative in differentiating AD and MCI. Connections between calcarine sulcus and lingual gyrus (p-value=0.049), between parahippocampal gyrus and Amygdala (p-value=0.025), between rolandic opercula and insula lobes (p-values=0.0028 and 0.0026). An overall prediction accuracy of 95.3% was achieved by integrating the selected local brain networks and marginally weak signals, compared to 84.0% by not considering the inter-voxel connections and using marginally strong signals only.Conclusion(i) The connectomic structures differentiating AD and MCI are significantly different to that differentiating MCI and healthy, which may indicate different neuronal etiology for AD and MCI. (ii) Many neuroimaging biomarkers exert their effects on the outcome diseases through their connections to other markers. Integrating such connections can help identify novel neuroimaging biomarkers and improve disease prediction accuracy.

Background: Growing evidence links beta-amyloid (Aβ) and neuronal hyperexcitability in preclinical mouse models of Alzheimer’s disease (AD). The aim of this study was to compare neuronal excitability between cognitively normal amyloid positive (CNAβ+) and those without elevated amyloid (CNAβ-) older adults. We hypothesized CNAβ+ participants would show hyperexcitability, indexed by greater peak P3 event-related potential peak amplitude, shorter peak latency, and changes in event-related power, compared to CNAβ-.Methods: CNAβ+ participants (n = 17, age: 73 ± 5, 11 women, MOCA scores 26 ± 2) and 17 CNAβ- participants group-matched for age, sex, and MOCA completed the a working memory task (n-back with n = 0, 1, 2) test while wearing a 256-channel EEG net. P3 peak amplitude and latency of the nontarget, target and task difference (nontarget – target), and event-related power, extracted from Fz (main outcome), Cz, and Pz were compared between groups using linear mixed models. Mean Aβ standard uptake value ratios (SUVR) were correlated with P3 amplitude and latency using Pearson r.Results: P3 peak amplitude of the task difference (p = 0.048) and P3 peak latency of non-targets trials (p = 0.006) at Fz differed between groups. Similarly, power was lower in the delta band (p = 0.04) for nontargets at Fz in CNAβ+ participants. CNAβ+ participants also demonstrated higher theta and alpha power in channels at Cz and Pz, but no changes in P3 ERP. Strong correlations were found between mean Aβ SUVR and latency of the 1-back (r = -0.69; p = 0.003) and 2-back (r = -0.69; p = 0.004) of the task difference at channel Fz in the CNAβ+ group.Conclusions: Our pilot data suggests that elevated amyloid in cognitive normal older adults is associated with hyperexcitability in P3 ERP. Further research is warranted to determine the validity of ERP in predicting clinical, neurobiological, and functional manifestations of AD.

Background Although growing evidence links beta-amyloid (Aβ) and neuronal hyperexcitability in preclinical mouse models of Alzheimer’s disease (AD), a similar association in humans is yet to be established. The first aim of the study was to determine the association between elevated Aβ (Aβ+) and cognitive processes measured by the P3 event-related potential (ERP) in cognitively normal (CN) older adults. The second aim was to compare the event-related power between CNAβ+ and CNAβ−. Methods Seventeen CNAβ+ participants (age: 73 ± 5, 11 females, Montreal Cognitive Assessment [MoCA] score 26 ± 2) and 17 CNAβ- participants group-matched for age, sex, and MOCA completed a working memory task (n-back with n = 0, 1, 2) test while wearing a 256-channel electro-encephalography net. P3 peak amplitude and latency of the target, nontarget and task difference effect (nontarget−target), and event-related power in the delta, theta, alpha, and beta bands, extracted from Fz, Cz, and Pz, were compared between groups using linear mixed models. P3 amplitude of the task difference effect at Fz and event-related power in the delta band were considered main outcomes. Correlations of mean Aβ standard uptake value ratios (SUVR) using positron emission tomography with P3 amplitude and latency of the task difference effect were analyzed using Pearson Correlation Coefficient r. Results The P3 peak amplitude of the task difference effect at Fz was lower in the CNAβ+ group (P = 0.048). Similarly, power was lower in the delta band for nontargets at Fz in the CNAβ+ participants (P = 0.04). The CNAβ+ participants also demonstrated higher theta and alpha power in channels at Cz and Pz, but no changes in P3 ERP. Strong correlations were found between the mean Aβ SUVR and the latency of the 1-back (r = − 0.69; P = 0.003) and 2-back (r = − 0.69; P = 0.004) of the task difference effect at channel Fz in the CNAβ+ group. Conclusions Our data suggest that the elevated amyloid in cognitively normal older adults is associated with neuronal hyperexcitability. The decreased P3 task difference likely reflects early impairments in working memory processes. Further research is warranted to determine the validity of ERP in predicting clinical, neurobiological, and functional manifestations of AD.

Background Trends and clinical factors associated with prescribing choices for oral P2Y12 inhibitors (P2Y12-I) remain unknown for patients on chronic dialysis, i.e., with end-stage renal disease (ESRD). Methods From 2011–2014 U.S. Renal Data System registry, we identified 36,542 ESRD patients who received new prescriptions for P2Y12-I (median age 64.0 years and 54% males). Of the cohort, 93% were receiving hemodialysis and 7% on peritoneal dialysis. We analyzed trends and investigated clinical factors associated with specific P2Y12-I prescribed. Results Clopidogrel was prescribed for 95%, prasugrel for 3%, and ticagrelor for 2%. Clopidogrel was favored for those ≥75 years (18% of cohort). Compared to Caucasians, African Americans (36% of cohort) and Hispanics (19% of cohort) were less likely to receive prasugrel and ticagrelor (P Conclusion Between 2011 and 2014, clopidogrel remained the most common P2Y12-I whereas ticagrelor and prasugrel remained underutilized in ESRD patients. Prescribing practices for these drugs were based upon clinically approved indication for their use in the general population as well as perceived complexity of an ESRD patient including demographics, dialysis-related factors and comorbidities. Comparative effectiveness studies involving ESRD patients are needed to prove that ticagrelor and prasugrel are just as safe and effective as clopidogrel before clinicians can make informed decisions for choice of P2Y12-I in this patient population.

Objective Managing registries with continual data collection poses challenges, such as following reproducible research protocols and guaranteeing data accessibility. The University of Kansas (KU) Alzheimer’s Disease Center (ADC) maintains one such registry: Curated Clinical Cohort Phenotypes and Observations (C3PO). We created an automated and reproducible process by which investigators have access to C3PO data. Materials and Methods Data was input into Research Electronic Data Capture. Monthly, data part of the Uniform Data Set (UDS), that is data also collected at other ADCs, was uploaded to the National Alzheimer’s Coordinating Center (NACC). Quarterly, NACC cleaned, curated, and returned the UDS to the KU Data Management and Statistics (DMS) Core, where it was stored in C3PO with other quarterly curated site-specific data. Investigators seeking to utilize C3PO submitted a research proposal and requested variables via the publicly accessible and searchable data dictionary. The DMS Core used this variable list and an automated SAS program to create a subset of C3PO. Results C3PO contained 1913 variables stored in 15 datasets. From 2017 to 2018, 38 data requests were completed for several KU departments and other research institutions. Completing data requests became more efficient; C3PO subsets were produced in under 10 seconds. Discussion The data management strategy outlined above facilitated reproducible research practices, which is fundamental to the future of research as it allows replication and verification to occur. Conclusion We created a transparent, automated, and efficient process of extracting subsets of data from a registry where data was changing daily.

Background and objectives Trimethylamine N-oxide (TMAO), a compound derived from byproducts of intestinal bacteria, has been shown to accelerate atherosclerosis in rodents. To date, there are conflicting data regarding the association of serum TMAO with cardiovascular outcomes in patients with ESKD, a population exhibiting both high serum TMAO and excessive atherosclerosis. Design, setting, participants, & measurements We measured baseline serum TMAO concentrations in a subset of participants (n=1243) from the Evaluation of Cinacalcet Hydrochloride Therapy to Lower Cardiovascular Events (EVOLVE) trial and conducted post hoc analyses evaluating the association between baseline serum TMAO and cardiovascular outcomes. Results We observed a wide distribution of serum TMAO in our cohort, with approximately 80% of participants exhibiting TMAO concentrations ≥56 µM and a maximum TMAO concentration of 1103.1 µM. We found no association between TMAO and our primary outcome, a composite of cardiovascular mortality, myocardial infarction, peripheral vascular event, stroke, and hospitalization for unstable angina. Moreover, in unadjusted and adjusted analyses, we observed no relation between TMAO and all-cause mortality, the independent components of our composite outcome, or the original EVOLVE primary outcome. Although we did observe higher TMAO concentrations in white participants, further subgroup analyses did not confirm the previously identified interaction between TMAO and race observed in a prior study in patients receiving dialysis. Conclusions We found no evidence linking TMAO to adverse clinical outcomes in patients receiving maintenance hemodialysis with moderate to severe secondary hyperparathyroidism.

Alzheimer's Disease (ad) associates with insulin resistance and low aerobic capacity, suggestive of impaired skeletal muscle mitochondrial function. However, this has not been directly measured in AD. This study ( n = 50) compared muscle mitochondrial respiratory function and gene expression profiling in cognitively healthy older adults (CH; n = 24) to 26 individuals in the earliest phase of ad-related cognitive decline, mild cognitive impairment (MCI; n = 11) or MCI taking the ad medication donepezil (MCI + med; n = 15). Mitochondrial respiratory kinetics were measured in permeabilized muscle fibers from muscle biopsies of the vastus lateralis. Untreated MCI exhibited lower lipid-stimulated skeletal muscle mitochondrial respiration (State 3, ADP-stimulated) than both CH ( P = .043) and MCI + med (P = .007) groups. MCI also exhibited poorer mitochondrial coupling control compared to CH (P = .014). RNA sequencing of skeletal muscle revealed unique differences in mitochondrial function and metabolism genes based on both MCI status (CH vs MCI) and medication treatment (MCI vs MCI + med). MCI + med modified over 600 skeletal muscle genes compared to MCI suggesting donepezil powerfully impacts the transcriptional profile of muscle. Overall, skeletal muscle mitochondrial respiration is altered in untreated MCI but normalized in donepezil-treated MCI participants while leak control is impaired regardless of medication status. These results provide evidence that mitochondrial changes occur in the early stages of AD, but are influenced by a common ad medicine. Further study of mitochondrial bioenergetics and the influence of transcriptional regulation in early ad is warranted., Graphical Abstract Graphical Abstract

Despite older racial and ethnic minorities (REMs) being more likely to develop dementia they are underrepresented in clinical trials focused on neurological disorders. Inclusion of REMs in dementia prevention studies is vital to reducing the impact of disparities in dementia risk. We conducted a systematic review to characterize the number of REM enrolled in brain health and prevention randomized controlled trials (RCTs). RTCs published from January 1, 2004 to April 21, 2020 were included. Participants were normal cognitive adults aged 45 years and older who participated in a Phase II or Phase III U.S. based preventative trial. Analyses were performed to examine differences in trial characteristics between RCTs that did and those that did not report race/ethnicity and to calculate the pooled proportion of each racial/ethnic group in randomized brain healthy prevention trials. A total of 42 studies consisting of 100,748 participants were included in the final analyses. A total of 26 (62%) reported some racial/ethnic identity data. The pooled proportion of REM participants was 0.256 (95% CI, 0.191, 0.326). There is a lack of racial/ethnic reporting of participants and REMs remain underrepresented in brain health prevention RCTs.

There is evidence that exercise benefits the brain, but the mechanisms for this benefit are unclear. The chronic benefits of exercise are likely a product of discreet, acute responses in exercise-related blood biomarkers and brain metabolism. This acute exercise response has not been compared in aging and Alzheimer's Disease (AD). It is known that acute exercise elicits a powerful peripheral response in young individuals, and exercise-related biomarkers such as glucose and lactate readily penetrate the brain. How this changes with aging and neurodegenerative disease is less clear. It is critical to characterize and understand the acute effects of exercise, including different exercise intensities, in terms of the peripheral metabolic response and relationship with brain metabolism. This will help determine potential mechanisms for brain benefits of exercise and better inform the design of future clinical trials. The primary goal of the AEROBIC study is to characterize the acute exercise response of brain glucose metabolism and exercise-related blood biomarkers. We will measure how cerebral metabolism is affected by an acute bout of moderate and higher intensity exercise and characterize the extent to which this differs between cognitively healthy older adults and individuals with AD. Related to this primary goal, we will quantify the peripheral biomarker response to moderate and higher intensity exercise and how this relates to brain metabolic change in both groups.

Cognitive workload (mental effort) is a measure of attention allocation to a task, which can be administered through self-report or physiological measures. Cognitive workload is increasingly recognized as an important determinant of performance in cognitive tests and daily life activities. However, the reliability and validity of these measures have not been established in older adults with a wide range of cognitive ability. The aim of this study was to establish the test-retest reliability of the NASA-Task Load Index (NASA-TLX) and Index of Cognitive Activity (ICA), extracted from pupillary size. The convergent validity of these measures against event-related potentials (ERPs) was also investigated. A total of 38 individuals with scores on the Montreal Cognitive Assessment ranging between 17 and 30 completed a working memory test (n-back) with three levels of difficulty at baseline and two-week follow-up. Intraclass correlation coefficients (ICC) values of the NASA-TLX ranged between 0.71 and 0.81, demonstrating good to excellent reliability. Mean ICA scores showed fair to good reliability, with ICC’s ranging between 0.56 and 0.73. Mean ICA and NASA-TLX scores showed significant and moderate correlations (Pearson r range between 0.30 and 0.33) with P3 ERP at the midline channels. We conclude that ICC and NASA-TLX are reliable measures of cognitive workload in older adults. Further research is needed in dissecting the subjective and objective constructs of cognitive workload.

The emphasis on team science in clinical and translational research increases the importance of collaborative biostatisticians (CBs) in healthcare. Adequate training and development of CBs ensure appropriate conduct of robust and meaningful research and, therefore, should be considered as a high-priority focus for biostatistics groups. Comprehensive training enhances clinical and translational research by facilitating more productive and efficient collaborations. While many graduate programs in Biostatistics and Epidemiology include training in research collaboration, it is often limited in scope and duration. Therefore, additional training is often required once a CB is hired into a full-time position. This article presents a comprehensive CB training strategy that can be adapted to any collaborative biostatistics group. This strategy follows a roadmap of the biostatistics collaboration process, which is also presented. A TIE approach (Teach the necessary skills, monitor the Implementation of these skills, and Evaluate the proficiency of these skills) was developed to support the adoption of key principles. The training strategy also incorporates a “train the trainer” approach to enable CBs who have successfully completed training to train new staff or faculty.

Alzheimer’s Disease (AD) is associated with insulin resistance and low cardiorespiratory fitness, suggestive of impaired skeletal muscle mitochondrial function. We examined if individuals with Mild Cognitive Impairment (MCI), the earliest phase of AD-related cognitive decline, exhibit reduced skeletal muscle mitochondrial function, and if AD medication impacted outcomes. We present data from 50 individuals, including cognitively healthy older adults (CH; n=24) 60+ years of age and clinically diagnosed MCI subjects (n=26). MCI subjects were sub-divided into two groups; no AD medication (MCI; n=11), or AD medication treated (MCI+med; n=15). A skeletal muscle biopsy (vastus lateralis) was obtained and mitochondrial respiratory kinetics was measured in permeabilized muscle fibers. MCI subjects exhibited lower lipid-stimulated skeletal muscle mitochondrial respiration (State 3, ADP-stimulated) than both CH individuals (p=0.043) and medication-treated MCI subjects (p=0.006). MCI also exhibited poorer mitochondrial coupling control compared to CH subjects (p=0.014), while MCI+med and CH subjects did not differ. Compared to CH individuals, skeletal muscle mitochondrial leak control ratio was lower for the MCI+med group (p=0.008) and trended lower for non-medicated MCI (p=0.06), which suggests greater mitochondrial uncoupling in MCI. Skeletal muscle mitochondrial respiration is impaired in untreated MCI but normalized in medication-treated MCI participants while mitochondrial leak control is impaired regardless of medication status. These results provide further evidence that systemic mitochondrial deficits occur in the very early stages of AD, and that mitochondrial function is partially influenced by AD medication. Further analysis for a role of muscle mitochondria in the progression of early AD is warranted.

Lifestyle interventions to increase exercise and improve diet have been the focus of recent clinical trials to potentially prevent Alzheimer’s disease (AD) [1,2]. However, despite the strong links between sleep disruptions, cognitive decline, and AD, sleep enhancement has yet to be targeted as a lifestyle intervention to prevent AD. A recent meta-analysis suggests that approximately 15% of AD may be prevented by an efficacious intervention aimed to reduce sleep disturbances and sleep disorders [3]. Chronic insomnia is the most frequent sleep disorder occurring in at least 40% of older adults [4]. Individuals with insomnia are more likely to be diagnosed with Alzheimer’s Disease (AD) [5,6] and demonstrate decline in cognitive function [7] at long-term follow-up. AD is characterized by the accumulation of amyloid-β (Aβ) plaques and tau tangles in the brain, and growing evidence shows impaired sleep contributes to the accumulation of Aβ [8–10]. An intervention aimed at improving insomnia may be a critical opportunity for primary prevention to slow cognitive decline and potentially delay the onset of AD. Cognitive behavioral therapy for insomnia (CBT-I) is an efficacious treatment for insomnia [11–14], but the use of CBT-I to improve cognitive function and potentially reduce the rate of Aβ accumulation has never been examined. Therefore, the objective of the proposed study is to examine the efficacy of CBT-I on improving cognitive function in older adults with symptoms of insomnia. An exploratory aim is to assess the effect of CBT-I on rate of Aβ accumulation.

BackgroundChronic kidney disease (CKD) is associated with abnormalities in cerebral blood flow (CBF), cerebral neurochemical concentrations and white matter integrity, each of which are associated with adverse clinical consequences in the non-CKD population, and may explain the high prevalence of dementia and stroke in end stage kidney disease (ESKD). Since cognition improves after kidney transplantation (KT), we examined these brain abnormalities pre-to post-KT to identify potential reversibility in ESKD-associated brain abnormalities.MethodsWe measured the effects of KT on CBF assessed by arterial spin labeling, cerebral neurochemical concentrations (N-acetylaspartate, choline, glutamate and glutamine, myoinositol and total creatine) measured by magnetic resonance spectroscopic imaging, and white matter integrity measured by fractional anisotropy (FA) and mean diffusivity (MD) with diffusion tensor imaging. We used a linear mixed model analysis to compare longitudinal, repeated brain MRI measurements pre-KT, and 3 months and 12 months post-KT, and also compared findings with healthy controls.Results29 ESKD patients and 19 age-matched healthy controls participated in the study. 22 patients underwent post-KT MRI. CBF, which was higher pre-KT than in controls (p=0.003), decreased post-KT (pConclusionsBrain abnormalities in CKD are reversible and normalize with KT. Further studies are needed to understand the mechanisms underlying these brain abnormalities and to explore interventions to mitigate them even in patients who cannot be transplanted.Significance statementKidney disease is accompanied by brain structural and physiological abnormalities and increased risk of dementia and stroke. Renal replacement therapy with dialysis does not normalize these brain abnormalities. We evaluated these brain abnormalities before and after kidney transplantation and demonstrated that unlike dialysis, kidney transplantation normalizes cerebral blood flow, neurochemical concentrations and white matter integrity. These changes persist beyond initial post-transplantation period and thus cannot be attributed to peri-procedural interventions like steroids. These results indicate reversibility of brain abnormalities in kidney disease. Further studies are needed to understand the mechanisms underlying these abnormalities and explore interventions for prevention and mitigation in patients who cannot be transplanted.

Introduction Individuals with Alzheimer's disease (AD) broadly exhibit lower cardiorespiratory fitness (CRF) compared to cognitively healthy older adults. Other factors, such as increasing age and female sex, are also known to track with lower CRF levels. However, it is unclear how these factors together with AD diagnosis and genetic risk (apolipoprotein e4 ; APOE4) collectively affect CRF. Methods Our primary objective was to characterize the collective relationship of age, sex, APOE4 carrier status , and cognitive status (nondemented or AD) with two commonly reported CRF outcomes, VO2 max and oxygen uptake efficiency slope (OUES). To interrogate the unique and combined effect of age, sex, APOE4, and cognitive status on CRF, we pooled multiple datasets and tested several statistical models allowing all possible interactions. Results AD diagnosis was consistently associated with lower maximal CRF, which declined with increasing age. APOE4 was also associated with lower maximal CRF (VO2max), but only in male subjects. Submaximal CRF (OUES) was lower in APOE4 carriers of both sexes, although this difference converged in male subjects with advancing age. Discussion This multi‐cohort analysis (n = 304) suggests that APOE4 carrier status and sex are important considerations for studies that evaluate maximal and submaximal CRF.

Introduction Within the first year of diagnosis, up to 1 in 3 multiple myeloma (MM) patients will experience a venous thromboembolism (VTE). The International Myeloma Working Group (IMWG) has thromboprophylaxis guidelines that stratify patients into low or high risk for thrombosis and subsequently recommend thromboprophylaxis, but it is unknown if these recommendations are being followed or if they are effective. The purpose of this study was to assess efficacy of the IMWG guidelines and investigate other potential VTE risk factors. Methods Study participants were treated at the University of Kansas Medical Center between 2007 and 2013, and charts were reviewed to extract data. Cases (MM and VTE) were matched to controls (MM and no VTE) at approximately 1:3 ratio based on gender, age (±5 years), and time of MM diagnosis (±5 years). Results A total of 80 cases and 211 controls were matched. Most patients (82%) were considered high risk for experiencing a VTE at the time of their MM diagnosis and 18% were considered low risk. Neither risk category (P = 0.16) nor thromboprophylaxis at baseline (P = 0.37) predicted VTE, though cases were more likely than controls to have an increased risk of thrombosis at the time of clot compared to their baseline risk (P = 0.09). Conclusion Our results suggest that IMWG guidelines are not being consistently followed and therefore could not be validated. Additional risk factors were not identified, but risk for VTE may change over time suggesting patients may require ongoing assessment of VTE risk and thromboprophylaxis throughout the disease course.

Background Caffeine has been proposed, based on in vitro cultured cell studies, to accelerate progression of autosomal dominant polycystic kidney disease (ADPKD) by increasing kidney size. Since ADPKD patients are advised to minimize caffeine intake, we investigated the effect of caffeine on disease progression in the Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP), a prospective, observational cohort study. Methods Our study included 239 patients (mean age = 32.3 ± 8.9 ys; 188 caffeine consumers) with a median follow-up time of 12.5 years. Caffeine intake reported at baseline was dichotomized (any vs. none). Linear mixed models, unadjusted and adjusted for age, race, sex, BMI, smoking, hypertension, genetics and time, were used to model height-adjusted total kidney volume (htTKV) and iothalamate clearance (mGFR). Cox proportional hazards models and Kaplan-Meier plots examined the effect of caffeine on time to ESRD or death. Results Caffeine-by-time was statistically significant when modeling ln(htTKV) in unadjusted and adjusted models (p 0.05). Moreover the results were similar when outcomes were modeled as a function of caffeine dose. Conclusion We conclude that caffeine does not have a significant detrimental effect on disease progression in ADPKD. Electronic supplementary material The online version of this article (10.1186/s12882-018-1182-0) contains supplementary material, which is available to authorized users.

We encountered a problem in which a study's experimental design called for the use of paired data, but the pairing between subjects had been lost during the data collection procedure. Thus we were presented with a data set consisting of pre and post responses but with no way of determining the dependencies between our observed pre and post values. The aim of the study was to assess whether an intervention called Self-Revelatory Performance had an impact on participant's perceptions of Alzheimer's disease. The participant's responses were measured on an Affect grid before the intervention and on a separate grid after. To address the underlying question in light of the lost pairing we utilized a modified bootstrap approach to create a null hypothesized distribution for our test statistic, which was the distance between the two Affect Grids' Centers of Mass. Using this approach we were able to reject our null hypothesis and conclude that there was evidence the intervention influenced perceptions abou...