White Matter Hyperintensities and Cognition: Testing the Reserve Hypothesis

OBJECTIVE: White matter hyperintensities (WMH), visualized on T2-weighted MRI, are thought to reflect small-vessel vascular disease. Much like other markers of brain disease, the association between WMH and cognition is imperfect. The concept of reserve may account for this imperfect relationship. The purpose of this study was to test the reserve hypothesis in the association between WMH severity and cognition. We hypothesized that individuals with higher amounts of reserve would be able to tolerate greater amounts of pathology than those with lower reserve. METHODS: Neurologically healthy older adults (n=717) from a community-based study received structural MRI, neuropsychological assessment, and evaluation of reserve. WMH volume was quantified algorithmically. We derived latent constructs representing four neuropsychological domains, a measure of cognitive reserve, and a measure of brain reserve. Measures of cognitive and brain reserve consisted of psychosocial (e.g., education) and anthropometric (e.g., craniometry) variables, respectively. RESULTS: Increased WMH volume was associated with poorer cognition and higher cognitive and brain reserve were associated with better cognition. Controlling for speed/executive function or for language function, those with higher estimates of cognitive reserve had significantly greater degrees of WMH volume, particularly among women. Controlling for cognitive functioning across all domains, individuals with higher estimates of brain reserve had significantly greater WMH volume. CONCLUSIONS: For any given level of cognitive function, those with higher reserve had more pathology in the form of WMH, suggesting that they are better able to cope with pathology than those with lower reserve. Both brain reserve and cognitive reserve appear to mitigate the impact of pathology on cognition

Regional white matter hyperintensity volume, not hippocampal atrophy, predicts incident Alzheimer disease in the community

Background: New-onset Alzheimer disease (AD) is often attributed to degenerative changes in the hippocampus. However, the contribution of regionally distributed small vessel cerebrovascular disease, visualized as white matter hyperintensities (WMHs) on magnetic resonance imaging, remains unclear. Objective: To determine whether regional WMHs and hippocampal volume predict incident AD in an epidemiological study. Design: A longitudinal community-based epidemiological study of older adults from northern Manhattan, New York. Setting: The Washington Heights/Inwood Columbia Aging Project. Participants: Between 2005 and 2007, 717 participants without dementia received magnetic resonance imaging scans. A mean (SD) of 40.28 (9.77) months later, 503 returned for follow-up clinical examination and 46 met criteria for incident dementia (45 with AD). Regional WMHs and relative hippocampal volumes were derived. Three Cox proportional hazards models were run to predict incident dementia, controlling for relevant variables. The first included all WMH measurements; the second included relative hippocampal volume; and the third combined the 2 measurements. Main Outcome: Measure Incident AD. Results: White matter hyperintensity volume in the parietal lobe predicted time to incident dementia (hazard ratio [HR] = 1.194; P = .03). Relative hippocampal volume did not predict incident dementia when considered alone (HR = 0.419; P = .77) or with the WMH measures included in the model (HR = 0.302; P = .70). Including hippocampal volume in the model did not notably alter the predictive utility of parietal lobe WMHs (HR = 1.197; P = .049). Conclusions: The findings highlight the regional specificity of the association of WMHs with AD. It is not clear whether parietal WMHs solely represent a marker for cerebrovascular burden or point to distinct injury compared with other regions. Future work should elucidate pathogenic mechanisms linking WMHs and AD pathology

Competing for the Platform: How Organized Interests affect Party Positioning in the United States

What explains which groups are included in a party coalition in any given election cycle? Recent advances in political party theory suggest that policy demanders comprise parties, and that the composition of a party coalition varies from election to election. We theorize three conditions under which parties articulate an interest group?s preferred positions in its quadrennial platform: when groups are ideologically proximate to the party median, when groups display party loyalty, and when groups are flush with resources. Using computer-assisted content analysis on a unique and rich data source, we examine three cycles of testimony that 80 organized groups provided to the Democratic Party. The analysis compares group requests with the content of Democratic and Republican National Committee platforms in 1996, 2000, and 2004. Results show that parties reward loyal groups and those that are ideologically proximate to the party, but offer no confirmation of a resource effect

A Cis-Regulatory Map of the Drosophila Genome

Systematic annotation of gene regulatory elements is a major challenge in genome science. Direct mapping of chromatin modification marks and transcriptional factor binding sites genome-wide1, 2 has successfully identified specific subtypes of regulatory elements3. In Drosophila several pioneering studies have provided genome-wide identification of Polycomb response elements4, chromatin states5, transcription factor binding sites6, 7, 8, 9, RNA polymerase II regulation8 and insulator elements10; however, comprehensive annotation of the regulatory genome remains a significant challenge. Here we describe results from the modENCODE cis-regulatory annotation project. We produced a map of the Drosophila melanogaster regulatory genome on the basis of more than 300 chromatin immunoprecipitation data sets for eight chromatin features, five histone deacetylases and thirty-eight site-specific transcription factors at different stages of development. Using these data we inferred more than 20,000 candidate regulatory elements and validated a subset of predictions for promoters, enhancers and insulators in vivo. We identified also nearly 2,000 genomic regions of dense transcription factor binding associated with chromatin activity and accessibility. We discovered hundreds of new transcription factor co-binding relationships and defined a transcription factor network with over 800 potential regulatory relationships

The effectiveness of an intervention in increasing community health clinician provision of preventive care: a study protocol of a non-randomised, multiple-baseline trial

<p>Abstract</p> <p>Background</p> <p>The primary behavioural risks for the most common causes of mortality and morbidity in developed countries are tobacco smoking, poor nutrition, risky alcohol use, and physical inactivity. Evidence, guidelines and policies support routine clinician delivery of care to prevent these risks within primary care settings. Despite the potential afforded by community health services for the delivery of such preventive care, the limited evidence available suggests it is provided at suboptimal levels. This study aims to assess the effectiveness of a multi-strategic practice change intervention in increasing clinician's routine provision of preventive care across a network of community health services.</p> <p>Methods/Design</p> <p>A multiple baseline study will be conducted involving all 56 community health facilities in a single health district in New South Wales, Australia. The facilities will be allocated to one of three administratively-defined groups. A 12 month practice change intervention will be implemented in all facilities in each group to facilitate clinician risk assessment of eligible clients, and clinician provision of brief advice and referral to those identified as being 'at risk'. The intervention will be implemented in a non-random sequence across the three facility groups. Repeated, cross-sectional measurement of clinician provision of preventive care for four individual risks (smoking, poor nutrition, risky alcohol use, and physical inactivity) will occur continuously for all three facility groups for 54 months via telephone interviews. The interviews will be conducted with randomly selected clients who have visited a community health facility in the last two weeks. Data collection will commence 12 months prior to the implementation of the intervention in the first group, and continue for six months following the completion of the intervention in the last group. As a secondary source of data, telephone interviews will be undertaken prior to and following the intervention with randomly selected samples of clinicians from each facility group to assess the reported provision of preventive care, and the acceptability of the practice change intervention and implementation.</p> <p>Discussion</p> <p>The study will provide novel evidence regarding the ability to increase clinician's routine provision of preventive care across a network of community health facilities.</p> <p>Trial registration</p> <p>Australian Clinical Trials Registry <a href="http://www.anzctr.org.au/ACTRN12611001284954.aspx">ACTRN12611001284954</a></p> <p>Universal Trial Number (UTN)</p> <p>U1111-1126-3465</p

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570