Genomic and epigenomic active vitamin D responses in human colonic organoids.

Active vitamin D, 1α,25(OH)2D3, is a nuclear hormone with roles in colonic homeostasis and carcinogenesis; yet, mechanisms underlying these effects are incompletely understood. Human organoids are an ideal system to study genomic and epigenomic host-environment interactions. Here, we use human colonic organoids to measure 1α,25(OH)2D3 responses on genome-wide gene expression and chromatin accessibility over time. Human colonic organoids were cultured and treated in triplicate with 100 nM 1α,25(OH)2D3 or vehicle control for 4 h and 18 h for chromatin accessibility, and 6 h and 24 h for gene expression. ATAC- and RNA-sequencing were performed. Differentially accessible peaks were analyzed using DiffBind and edgeR; differentially expressed genes were analyzed using DESeq2. Motif enrichment was determined using HOMER. At 6 h and 24 h, 2,870 and 2,721 differentially expressed genes, respectively (false discovery rate, FDR < 5%), were identified with overall stronger responses with 1α,25(OH)2D3. Similarly, 1α,25(OH)2D3 treatment led to stronger chromatin accessibility especially at 4 h. The vitamin D receptor (VDR) motif was strongly enriched among accessible chromatin peaks with 1α,25(OH)2D3 treatment accounting for 30.5% and 11% of target sequences at 4 h and 18 h, respectively (FDR < 1%). A number of genes such as CYP24A1, FGF19, MYC, FOS, and TGFBR2 showed significant transcriptional and chromatin accessibility responses to 1α,25(OH)2D3 treatment with accessible chromatin located distant from promoters for some gene regions. Assessment of chromatin accessibility and transcriptional responses to 1α,25(OH)2D3 yielded new observations about vitamin D genome-wide effects in the colon facilitated by application of human colonic organoids. This framework can be applied to study host-environment interactions between individuals and populations in the future.

Regional cerebral tau predicts decline in everyday functioning across the Alzheimer's disease spectrum.

BACKGROUND: Emerging difficulty performing cognitively complex everyday tasks, or 'instrumental activities of daily living' (IADL) may be an early clinical sign of Alzheimer's disease (AD). We aimed to investigate how changes over time in everyday functioning relate to cerebral tau burden across the AD clinical spectrum. METHODS: We included 581 participants (73.9 ± 7.6 years old; 52% female) from the Alzheimer's Disease Neuroimaging Initiative who underwent tau positron emission tomography (PET) and completed at least two assessments of the Functional Activities Questionnaire (FAQ). Participants were classified as cognitively normal (n = 334) or symptomatic (n = 247). We analyzed the association between longitudinal FAQ scores and baseline tau in six temporal, parietal, and frontal brain regions in mixed-effects models. Models were run in the entire sample, as well as stratified by diagnostic group (cognitively normal or symptomatic). We additionally investigated tau-PET adjusted for, as well as interacting with, amyloid-ß. RESULTS: Greater tau burden in several frontal, temporal, and parietal regions was associated with steeper decline over time in everyday functioning. These findings remained when adjusting for baseline global cortical amyloid-ß; amyloid-ß itself was only associated with change over time in FAQ scores when tau was not included in the model. When stratifying by diagnostic group, most associations between tau and everyday functioning, adjusted for amyloid-ß, were present only in the symptomatic group. CONCLUSIONS: The rate of change in everyday functioning is related to baseline tau burden in various brain regions, more strongly so than global cortical amyloid-ß, specifically in cognitively symptomatic individuals. Longitudinal studies in incident dementia populations are needed to better understand functional changes in response to AD pathology across the disease.

A New Perspective on Spiritual Care: Collaborative Chaplaincy and Nursing Practice.

Spirituality is a key focus and ethical obligation of nursing practice, but many nurses express uncertainty or discomfort with this aspect of their role. The purpose of this article is to explore the domains of religion, spirituality, and culture as commonly conceptualized by chaplains, as a framework for nurses to provide spiritual care interventions to patients in acute care hospitals. Using anecdotes and illustrations from palliative care practice, this article discusses the enhanced benefits to patients and families when spiritual needs are addressed, with specialty-level chaplain interventions, primary spiritual interventions provided uniquely by nurses, or interventions that require the cooperation of both professions. Lessons learned from the inpatient palliative care team experience can also apply to chaplaincy and nursing care for patients in settings beyond the acute care hospital and in disciplines beyond palliative care.

The influence of road salt on seasonal mixing, redox stratification and methane concentrations in urban kettle lakes.

Influxes of saline water from roads treated with deicers can alter the density structure of urban lakes. This can diminish or halt turnover events, such that lakes may transition from dimixis to monomixis or meromixis. In nutrient-rich lakes, this lack of turnover can produce persistent hypolimnetic anoxia. We hypothesized that diminished turnover in urban lakes impacted by road salt inputs would lead to increased accumulation of methane in the hypolimnia, with the potential for greater release of methane to the atmosphere via ebullition and from larger storage fluxes of methane when turnover events do occur. The lake water columns of two urban lakes (Woods Lake and Asylum Lake), previously suggested to have transitioned to meromixis and monomixis because of road salt deicer inputs, were sampled monthly from March 2016 to June 2017. A nearby rural lake (North Lake) less likely to be impacted by road salt and maintaining seasonal mixing, was also sampled for comparison. Lake column water was analyzed for conductivity, temperature, dissolved oxygen, ferrous iron, manganese, sulfide, calcium, magnesium, sodium, chloride and methane concentrations as a function of depth. All three lakes are eutrophic with at least seasonally anoxic hypolimnia. Our data are consistent with prior studies suggesting that Woods Lake has transitioned to meromixis and Asylum Lake to monomixis due to an influx of dense saline water from roads treated with deicers. In contrast, rural North Lake, which had much lower chloride, sodium and conductivity levels, was dimictic. The diminished or absent turnover in the two urban lakes during fall and spring resulted in persistently anoxic, redox-stratified hypolimnia, with much larger accumulations of methane compared to the rural lake. This study demonstrates that road salt deicers impact lake mixing and biogeochemistry, especially methane concentrations, with the potential for significant increases in greenhouse gas emissions from urban lakes.

Knowledge, Attitudes, and Beliefs Regarding Cardiovascular Disease in Women: The Women's Heart Alliance.

BACKGROUND: Cardiovascular disease (CVD) is the number 1 killer of women in the United States, yet few younger women are aware of this fact. CVD campaigns focus little attention on physicians and their roles in assessing risk. OBJECTIVES: In 2014, the Women's Heart Alliance (WHA) conducted a nationwide survey to determine barriers and opportunities for women and physicians with regard to CVD. METHODS: From September 18 to 26, 2014, a total of 1,011 U.S. women (age 25 to 60 years) were interviewed using the GfK ("Gesellschaft für Konsumforschung" Knowledge Panel). From May 6 to 12, 2014, the e-Rewards Inc. Physician and Healthcare Professional Panel surveyed 200 primary care physicians (PCPs) and 100 cardiologists. RESULTS: Overall, 45% of women were unaware that CVD is the number 1 killer of women; only 11% knew a woman who died from CVD. Overall, 45% of women reported it was common to cancel or postpone a physician appointment until losing weight. CVD was rated as the top concern by only 39% of PCPs, after weight and breast health. Only 22% of PCPs and 42% of cardiologists (p = 0.0477) felt extremely well prepared to assess CVD risk in women, while 42% and 40% felt well-prepared (p = NS), respectively. Few comprehensively implemented guidelines. CONCLUSIONS: CVD was rated as the top concern less frequently than weight issues by both women and physicians. Social stigma particularly regarding body weight appeared to be a barrier. Physicians reported limited training and use of guideline assessment, whereas most supported a campaign and improved physician education. Campaigns should make CVD "real" to U.S. women, countering stereotypes with facts and validated assessments. Both community women and physicians endorsed investment in women's CVD research and physician education.