Objective
To examine region‐ and substrate‐specific autoradiographic and in vitro binding patterns of positron emission tomography tracer F‐18‐AV‐1451 (previously known as T807), tailored to allow in ...vivo detection of paired helical filament‐tau–containing lesions, and to determine whether there is off‐target binding to other amyloid/non‐amyloid proteins.
Methods
We applied F‐18‐AV‐1451 phosphor screen autoradiography, F‐18‐AV‐1451 nuclear emulsion autoradiography, and H‐3‐AV‐1451 in vitro binding assays to the study of postmortem samples from patients with a definite pathological diagnosis of Alzheimer disease, frontotemporal lobar degeneration–tau, frontotemporal lobar degeneration–transactive response DNA binding protein 43 (TDP‐43), progressive supranuclear palsy, corticobasal degeneration, dementia with Lewy bodies, multiple system atrophy, cerebral amyloid angiopathy and elderly controls free of pathology.
Results
Our data suggest that F‐18‐AV‐1451 strongly binds to tau lesions primarily made of paired helical filaments in Alzheimer brains (eg, intraneuronal and extraneuronal tangles and dystrophic neurites), but does not seem to bind to a significant extent to neuronal and glial inclusions mainly composed of straight tau filaments in non‐Alzheimer tauopathy brains or to lesions containing β‐amyloid, α‐synuclein, or TDP‐43. F‐18‐AV‐1451 off‐target binding to neuromelanin‐ and melanin‐containing cells and, to a lesser extent, to brain hemorrhagic lesions was identified.
Interpretation
Our data suggest that F‐18‐AV‐1451 holds promise as a surrogate marker for the detection of brain tau pathology in the form of tangles and paired helical filament‐tau–containing neurites in Alzheimer brains but also point to its relatively lower affinity for lesions primarily made of straight tau filaments in non‐Alzheimer tauopathy cases and to the existence of some F‐18‐AV‐1451 off‐target binding. These findings provide important insights for interpreting in vivo patterns of F‐18‐AV‐1451 retention. Ann Neurol 2015 Ann Neurol 2015;78:Ann Neurol 2015;78:679–696
To understand the genetic heterogeneity underlying developmental delay, we compared copy number variants (CNVs) in 15,767 children with intellectual disability and various congenital defects (cases) ...to CNVs in 8,329 unaffected adult controls. We estimate that ∼14.2% of disease in these children is caused by CNVs >400 kb. We observed a greater enrichment of CNVs in individuals with craniofacial anomalies and cardiovascular defects compared to those with epilepsy or autism. We identified 59 pathogenic CNVs, including 14 new or previously weakly supported candidates, refined the critical interval for several genomic disorders, such as the 17q21.31 microdeletion syndrome, and identified 940 candidate dosage-sensitive genes. We also developed methods to opportunistically discover small, disruptive CNVs within the large and growing diagnostic array datasets. This evolving CNV morbidity map, combined with exome and genome sequencing, will be critical for deciphering the genetic basis of developmental delay, intellectual disability and autism spectrum disorders.
Cocoa extract is a source of flavanols that favorably influence vascular risk factors in small and short-term trials, yet effects on clinical cardiovascular events are untested.
We examined whether ...cocoa extract supplementation decreases total cardiovascular disease (CVD) among older adults.
We conducted a randomized, double-blind, placebo-controlled, 2-by-2 factorial trial of cocoa extract supplementation and multivitamins for prevention of CVD and cancer among 21,442 US adults (12,666 women aged ≥65 y and 8776 men aged ≥60 y), free of major CVD and recently diagnosed cancer. The intervention phase was June 2015 through December 2020. This article reports on the cocoa extract intervention. Participants were randomly assigned to a cocoa extract supplement 500 mg flavanols/d, including 80 mg (–)-epicatechin or placebo. The primary outcome was a composite of confirmed incident total cardiovascular events, including myocardial infarction (MI), stroke, coronary revascularization, cardiovascular death, carotid artery disease, peripheral artery surgery, and unstable angina.
During a median follow-up of 3.6 y, 410 participants taking cocoa extract and 456 taking placebo had confirmed total cardiovascular events (HR: 0.90; 95% CI: 0.78, 1.02; P = 0.11). For secondary endpoints, HRs were 0.73 (95% CI: 0.54, 0.98) for CVD death, 0.87 (95% CI: 0.66, 1.16) for MI, 0.91 (95% CI: 0.70, 1.17) for stroke, 0.95 (95% CI: 0.77, 1.17) for coronary revascularization, neutral for other individual cardiovascular endpoints, and 0.89 (95% CI: 0.77, 1.03) for all-cause mortality. Per-protocol analyses censoring follow-up at nonadherence supported a lower risk of total cardiovascular events (HR: 0.85; 95% CI: 0.72, 0.99). There were no safety concerns.
Cocoa extract supplementation did not significantly reduce total cardiovascular events among older adults but reduced CVD death by 27%. Potential reductions in total cardiovascular events were supported in per-protocol analyses. Additional research is warranted to clarify whether cocoa extract may reduce clinical cardiovascular events. This trial is registered at www.clinicaltrials.gov as NCT02422745.
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Globally 38.9 million children under age 5 have overweight or obesity, leading to type 2 diabetes, cardiovascular complications, depression, and poor educational outcomes. Obesity is difficult to ...reverse and lifestyle behaviors (healthy or unhealthy) can persist from 1.5 years of age. Targeting caregivers to help address modifiable behaviors may offer a viable solution.
Evaluate the impact of multicomponent family interventions on weight-based outcomes in early childhood and explore related secondary behavior outcomes.
Four databases were searched (1/2017–6/2022) for randomized controlled trials (RCTs) of obesity-prevention interventions for children (1–5 years). Eligible studies included an objectively measured weight-based outcome, family interventions targeting the caregiver or family, and interventions including at least two behavioral components of nutrition, physical activity, or sleep.
Eleven interventions were identified consisting of four delivery modes: self-guided (n = 3), face-to-face group instruction (n = 3), face-to-face home visits (n = 2), and multiple levels of influence (n = 3). The reviewed studies reported almost no significant effects on child weight-based outcomes. Only two studies (one was an underpowered pilot study) resulted in significant positive child weight-management outcomes. Seven of the interventions significantly improved children's dietary intake.
Except for one, the reviewed studies reported that family based interventions had no significant effects on child weight-based outcomes. Future studies of this type should include measurements of age and sex-based body mass index (BMI) and trajectories, and also examine other important benefits to the children and families.
•Systematic review of multicomponent family RCTs on weight-based outcomes.•Eleven studies were identified consisting of four delivery modes.•Results indicated no significant effects on child weight-based outcomes.•Explored multiple lifestyle behaviors, nutrition showed the greatest impact.•Future studies should focus on similar parent and child outcomes.
To describe prevalence and estimated attribution of human papillomavirus (HPV) types in U.S. cervical, vaginal, and vulvar precancers and cancers.
U.S. studies reporting HPV typing for cervical ...intraepithelial neoplasia (CIN), vulvar intraepithelial neoplasia (VIN), and vaginal intraepithelial neoplasia (VaIN) and/or invasive cancers of those sites were gathered from the PubMed database (http://www.ncbi.nlm.nih.gov/sites/entrez/). Selected studies had PCR testing data for > or =10 cases for a disease endpoint. Analytic methods augmented prior reviews of cervical disease with an updated and expanded analysis (including vulvar and vaginal disease), new selection criteria for specimens, and adjustment for histologic type, where possible, among pooled cancer cases. In addition, for analyses of estimated attribution of HPV types, we incorporated accounting methods for lesions infected with multiple HPV types.
Data from 22 U.S. studies meeting review eligibility criteria were tabulated. Following adjustment for the presence of multiple HPV types in a single specimen, the top two HPV types contributing to disease were CIN 1 (HPV 16/66; 15.3%), CIN 2/3 (HPV 16/31; 61.9%), cervical cancer (HPV 16/18; 79.2%), VIN 1 (HPV 6/11; 41.7%), VIN 3 (HPV 16/18; 84.0%), vulvar cancer (HPV 16/33; 55.5%), VaIN 3 (HPV 16/18; 65.1%), and vaginal cancer (HPV 16/18; 72.7%).
The HPV type distribution and proportion of cases testing positive for any HPV type were observed to vary among U.S. cervical, vulvar, and vaginal neoplasias and by grade of disease. Adjustment for the presence of multitype HPV infections can have an important effect on the estimated attribution of HPV types to disease, particularly for types other than HPV 16.
A small percentage of women with cervical HPV infection progress to cervical neoplasia, and the risk factors determining progression are incompletely understood. We sought to define the genetic loci ...involved in cervical neoplasia and to assess its heritability using unbiased unrelated case/control statistical approaches. We demonstrated strong association of cervical neoplasia with risk and protective HLA haplotypes that are determined by the amino-acids carried at positions 13 and 71 in pocket 4 of HLA-DRB1 and position 156 in HLA-B. Furthermore, 36% (standard error 2.4%) of liability of HPV-associated cervical pre-cancer and cancer is determined by common genetic variants. Women in the highest 10% of genetic risk scores have approximately >7.1% risk, and those in the highest 5% have approximately >21.6% risk, of developing cervical neoplasia. Future studies should examine genetic risk prediction in assessing the risk of cervical neoplasia further, in combination with other screening methods.
Objective: Stress associated with global health threats such as the coronavirus disease 2019 (COVID-19) pandemic and related containment efforts may be associated with significant sleep disruption. ...Stress-related sleep disturbance is an established transdiagnostic risk factor; thus, identifying associations with coping strategies may inform future intervention efforts. The current study examined secondary control-oriented coping strategies, including positive reappraisal, which may be particularly effective in the context of stressors characterized by high uncertainty and low controllability such as a pandemic. Method: The current study (total N = 227 undergraduate students, predominantly female) examined the associations among primary and secondary control-oriented coping strategies, positive and negative affect (PA, NA), and the development of acute sleep disturbance in the month after the declaration of the COVID-19 pandemic. Control of prepandemic reported sleep disturbance allowed for prospective analyses of pandemic-related change. Results: Participants reported high levels of stress due to the pandemic onset, including difficulties with time management, difficulties with work or school, and worry about the future. Reappraisal and acceptance were both associated with higher concurrent PA, lower NA, and less increase in sleep disturbance; however, positive reappraisal was the only coping strategy that predicted unique variance in increased sleep disturbance. Conclusions: Current findings add to our understanding of stress adaptation in response to stressors characterized by high severity, high uncertainty, and low controllability, such as the COVID-19 pandemic, and suggest that positive reappraisal and PA may foster resilience to stress-related sleep disturbance.
Major ecological realignments are already occurring in response to climate change. To be successful, conservation strategies now need to account for geographical patterns in traits sensitive to ...climate change, as well as climate threats to species-level diversity. As part of an effort to provide such information, we conducted a climate vulnerability assessment that included all anadromous Pacific salmon and steelhead (Oncorhynchus spp.) population units listed under the U.S. Endangered Species Act. Using an expert-based scoring system, we ranked 20 attributes for the 28 listed units and 5 additional units. Attributes captured biological sensitivity, or the strength of linkages between each listing unit and the present climate; climate exposure, or the magnitude of projected change in local environmental conditions; and adaptive capacity, or the ability to modify phenotypes to cope with new climatic conditions. Each listing unit was then assigned one of four vulnerability categories. Units ranked most vulnerable overall were Chinook (O. tshawytscha) in the California Central Valley, coho (O. kisutch) in California and southern Oregon, sockeye (O. nerka) in the Snake River Basin, and spring-run Chinook in the interior Columbia and Willamette River Basins. We identified units with similar vulnerability profiles using a hierarchical cluster analysis. Life history characteristics, especially freshwater and estuary residence times, interplayed with gradations in exposure from south to north and from coastal to interior regions to generate landscape-level patterns within each species. Nearly all listing units faced high exposures to projected increases in stream temperature, sea surface temperature, and ocean acidification, but other aspects of exposure peaked in particular regions. Anthropogenic factors, especially migration barriers, habitat degradation, and hatchery influence, have reduced the adaptive capacity of most steelhead and salmon populations. Enhancing adaptive capacity is essential to mitigate for the increasing threat of climate change. Collectively, these results provide a framework to support recovery planning that considers climate impacts on the majority of West Coast anadromous salmonids.
High-affinity class-switched Abs and memory B cells are products of the germinal center (GC). The CD4+ T cell help required for the development and maintenance of the GC is delivered by follicular Th ...cells (T(FH)), a CD4+ Th cell subset characterized by expression of Bcl-6 and secretion of IL-21. The cellular interactions that mediate differentiation of TFH and GC B cells remain an important area of investigation. We previously showed that MHC class II (MHCII)-dependent dendritic cell Ag presentation is sufficient for the differentiation of a T(FH) intermediate (termed pre-T(FH)), characterized by Bcl-6 expression but lacking IL-21 secretion. In this article, we examine the contributions of MHCII Ag presentation by B cells to T(FH) differentiation and GC responses in several contexts. B cells alone do not efficiently prime naive CD4+ T cells or induce T(FH) after protein immunization; however, during lymphocytic choriomeningitis virus infection, B cells induce T(FH) differentiation despite the lack of effector CD4+ T cell generation. Still, MHCII+ dendritic cells and B cells cooperate for optimal T(FH) and GC B cell differentiation in response to both model Ags and viral infection. This study highlights the roles for B cells in both CD4+ T cell priming and T(FH) differentiation, and demonstrates that different APC subsets work in tandem to mediate the GC response.
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