Microglia protect against age-associated brain pathologies.

Microglia are brain-resident macrophages that contribute to central nervous system (CNS) development, maturation, and preservation. Here, we examine the consequences of permanent microglial deficiencies on brain aging using the Csf1rΔFIRE/ΔFIRE mouse model. In juvenile Csf1rΔFIRE/ΔFIRE mice, we show that microglia are dispensable for the transcriptomic maturation of other brain cell types. By contrast, with advancing age, pathologies accumulate in Csf1rΔFIRE/ΔFIRE brains, macroglia become increasingly dysregulated, and white matter integrity declines, mimicking many pathological features of human CSF1R-related leukoencephalopathy. The thalamus is particularly vulnerable to neuropathological changes in the absence of microglia, with atrophy, neuron loss, vascular alterations, macroglial dysregulation, and severe tissue calcification. We show that populating Csf1rΔFIRE/ΔFIRE brains with wild-type microglia protects against many of these pathological changes. Together with the accompanying study by Chadarevian and colleagues1, our results indicate that the lifelong absence of microglia results in an age-related neurodegenerative condition that can be counteracted via transplantation of healthy microglia.

The need for an intersectionality framework in precision medicine research.

Precision medicine research has seen growing efforts to increase participation of communities that have been historically underrepresented in biomedical research. Marginalized racial and ethnic communities have received particular attention, toward the goal of improving the generalizability of scientific knowledge and promoting health equity. Against this backdrop, research has highlighted three key issues that could impede the promise of precision medicine research: issues surrounding (dis)trust and representation, challenges in translational efforts to improve health outcomes, and the need for responsive community engagement. Existing efforts to address these challenges have predominantly centered on single-dimensional demographic criteria such as race, ethnicity, or sex, while overlooking how these and additional variables, such as disability, gender identity, and socioeconomic factors, can confound and jointly impact research participation. We argue that increasing cohort diversity and the responsiveness of precision medicine research studies to community needs requires an approach that transcends conventional boundaries and embraces a more nuanced, multi-layered, and intersectional framework for data collection, analyses, and implementation. We draw attention to gaps in existing work, highlight how overlapping layers of marginalization might shape and substantiate one another and affect the precision-medicine research cycle, and put forth strategies to facilitate equitable advantages from precision-medicine research to diverse participants and internally heterogeneous communities.

Risk of Cardiovascular Events after Covid-19: a double-cohort study

ObjectiveTo determine absolute and relative risks of either symptomatic or asymptomatic SARS-CoV-2 infection for late cardiovascular events and all-cause mortality. MethodsWe conducted a retrospective double-cohort study of patients with either symptomatic or asymptomatic SARS-CoV-2 infection [COVID-19(+) cohort] and its documented absence [COVID-19(-) cohort]. The study investigators drew a simple random sample of records from all Oregon Health & Science University (OHSU) Healthcare patients (N=65,585) with available COVID-19 test results, performed 03.01.2020 - 09.13.2020. Exclusion criteria were age < 18y and no established OHSU care. The primary outcome was a composite of cardiovascular morbidity and mortality. All-cause mortality was the secondary outcome. ResultsThe study population included 1355 patients (mean age 48.7{+/-}20.5 y; 770(57%) female, 977(72%) white non-Hispanic; 1072(79%) insured; 563(42%) with cardiovascular disease (CVD) history). During a median 6 months at risk, the primary composite outcome was observed in 38/319 (12%) COVID-19(+) and 65/1036 (6%) COVID-19(-) patients (p=0.001). In Cox regression adjusted for demographics, health insurance, and reason for COVID-19 testing, SARS-CoV-2 infection was associated with the risk of the primary composite outcome (HR 1.71; 95%CI 1.06-2.78; p=0.029). Inverse-probability-weighted estimation, conditioned for 31 covariates, showed that for every COVID-19(+) patient, the average time to all-cause death was 65.5 days less than when all these patients were COVID-19(-): average treatment effect on the treated -65.5 (95%CI -125.4 to -5.61) days; p=0.032. ConclusionsEither symptomatic or asymptomatic SARS-CoV-2 infection is associated with increased risk of late cardiovascular outcomes and has causal effect on all-cause mortality in a late post-COVID-19 period. ClinicalTrials.gov Identifier: NCT04555187 Key messagesO_ST_ABSWhat is already known about this subjectC_ST_ABSO_LIAcute, symptomatic COVID-19 can cause acute cardiovascular manifestations. C_LIO_LIPost-acute or "long" COVID-19 can be a debilitating disease following acute infection with a heterogenous presentation. C_LI What might this study add?O_LIEither symptomatic or asymptomatic SARS-CoV-2 infection is associated with increased risk of late cardiovascular outcomes. C_LIO_LIEither symptomatic or asymptomatic SARS-CoV-2 infection has causal effect on all-cause mortality in a late post-COVID-19 period. C_LI How might this impact on clinical practice?O_LIAs we begin to care for more survivors of COVID-19, we will need to better understand not only how to care for their acute symptoms and complications following infection, but also recognize future cardiovascular risk and mitigate such risk with appropriate screening and preventative measures. C_LI

The influence of COMT rs4680 on functional connectivity in healthy adults: A systematic review.

The aim of this systematic review was to qualitatively synthesise the available research that investigated the influence of COMT genotype at SNP rs4680 on both task-based and resting-state connectivity in healthy adults. Thirty-five studies were identified that met inclusion criteria. Of the included studies, 20 studies reported resting-state findings and 16 studies reported task-based findings (emotion-processing, memory, working memory, reward-based learning and executive function). Studies were highly heterogeneous but an overall trend towards an association of the Val allele with greater resting-state connectivity and the Met allele with greater task-based connectivity is reported. A possible interpretation of current findings is discussed, whereby the Val allele is associated with improved cognitive flexibility allowing integration of novel relevant stimuli, and the Met allele allows improved sustained attention and targeted neural processing, particularly between limbic regions and prefrontal cortex. The most promising brain regions implicated in a COMT genotype influence on functional connectivity include prefrontal regions, amygdala and hippocampus.

Rigid gas-permeable contact lenses and severe higher-order aberrations in postsurgical corneas.

PURPOSE: Even in the absence of significant residual refractive error, patients can be highly symptomatic after corneal refractive surgery. The presence of glare, halos, monocular polyopia, and loss of contrast are principally caused by the presence of higher-order aberrations. This study investigated the efficacy of rigid gas-permeable contact lenses in reducing these higher-order aberrations. METHODS: In a prospective study, 20 eyes of 10 consecutive, highly symptomatic patients who had undergone refractive surgery were fitted with semiscleral rigid gas-permeable lenses (Macrolenses). The most successful lens design for each patient was evaluated by using ray-tracing aberrometry (iTrace). RESULTS: The cohort had a mean uncorrected visual acuity of 20/30 and a mean best spectacle-corrected visual acuity of 20/25. The mean visual acuity with the treatment lenses was 20/20. The contact lenses reduced the combined higher-order aberrations by a mean of 65% (range, 30%-77%), combined coma by 71% (range, 39%-93%), spherical aberration by 82% (range, 41%-100%), and trefoil by 44% (range, 90% reduction to 727% increase). Multiple linear regression showed a high correlation with preoperative levels of myopia and mesopic pupil area as independent variables and postoperative spherical aberration as the dependent variable (R(2) = 0.82, SE = 0.09, F = 31.08, P<0.0001). CONCLUSIONS: Rigid gas-permeable contact lenses were shown to reduce elevated total higher order aberrations to normal levels in all cases following corneal refractive surgery. The mean reduction was 66% for total higher order aberrations and 83% for spherical aberration. Correlation was shown between high preoperative refractive error and pupil size in relation to postoperative spherical aberration.