Big Read: Collaborations Between a University and a Community

University and community partners write about their collaborations around the reading of Ernest Gaines’ A Lesson Before Dying. When an urban university received a National Endowment of the Arts Big Read Grant, they immediately began making connections to existing key initiatives within the university and in the surrounding community. As the partners collaborated within and among the university and community programs and events created for the Big Read they made multiple discoveries regarding the importance of planning together, analyzing the intended audience for each program and event, including multiple ways to access the text, and considering the ways that readers can personalize the issues, synthesize what they have learned and apply it in discussion or action

The stress regulator FKBP51 drives chronic pain by modulating spinal glucocorticoid signaling

Polymorphisms in FKBP51 are associated with stress-related psychiatric disorders and influence the severity of pain symptoms experienced after trauma. We report that FKBP51 (FK506 binding protein 51) is crucial for the full development and maintenance of long-term pain states. Indeed, FKBP51 knockout mice, as well as mice in which silencing of FKBP51 is restricted to the spinal cord, showed reduced hypersensitivity in several persistent pain models in rodents. FKBP51 deletion did not compromise the detection of acute painful stimuli, a critical protective mechanism. Moreover, the intrathecal administration of the specific FKBP51 inhibitor SAFit2 reduced the severity of an established pain state, confirming the crucial role of spinal FKBP51 in nociceptive processing. Finally, glucocorticoid signaling, which is known to modulate persistent pain states in rodents, was impaired in FKBP51 knockout mice. This finding suggested that FKBP51 regulates chronic pain by modulation of glucocorticoid signaling. Thus, FKBP51 is a central mediator of chronic pain, likely in humans as well as rodents, and is a new pharmacologically tractable target for the treatment of long-term pain states

Recommendations for the design of laboratory studies on non-target arthropods for risk assessment of genetically engineered plants

This paper provides recommendations on experimental design for early-tier laboratory studies used in risk assessments to evaluate potential adverse impacts of arthropod-resistant genetically engineered (GE) plants on non-target arthropods (NTAs). While we rely heavily on the currently used proteins from Bacillus thuringiensis (Bt) in this discussion, the concepts apply to other arthropod-active proteins. A risk may exist if the newly acquired trait of the GE plant has adverse effects on NTAs when they are exposed to the arthropod-active protein. Typically, the risk assessment follows a tiered approach that starts with laboratory studies under worst-case exposure conditions; such studies have a high ability to detect adverse effects on non-target species. Clear guidance on how such data are produced in laboratory studies assists the product developers and risk assessors. The studies should be reproducible and test clearly defined risk hypotheses. These properties contribute to the robustness of, and confidence in, environmental risk assessments for GE plants. Data from NTA studies, collected during the analysis phase of an environmental risk assessment, are critical to the outcome of the assessment and ultimately the decision taken by regulatory authorities on the release of a GE plant. Confidence in the results of early-tier laboratory studies is a precondition for the acceptance of data across regulatory jurisdictions and should encourage agencies to share useful information and thus avoid redundant testing

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.

OBJECTIVE: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS: We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS: Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS: We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis

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

An out-of-hours protocol for community palliative care: practitioners perspectives

Much of palliative care takes place in the patient's home. Out-of-hours service provision can be an area of concern. With the aim of improving this service, the former Calderdale and Kirklees Health Authority introduced an out-of-hours protocol for palliative care in the community. After 1year the authors examined the experiences of primary care practitioners in using the protocol. Twenty district nurses and 15GPs from 25general practices in Calderdale, Huddersfield and North Kirklees took part in the study, which involved face-to-face group and individual telephone interviews. Practitioners felt that the out-of-hours protocol had made a positive contribution to palliative care in the community and that the out-of-hours handover form played a key role in improving communication and the coordination of services. For many participants, the protocol encouraged a more anticipatory approach to care and enabled better access to drugs and to specialist advice. The main areas of concern related to updating patient information on the handover forms, and to shortcomings in the support offered to carers. Future developments should address these issues. Although recognizing the dangers of generalization from research of this type, the findings offer encouragement to others considering similar schemes

Family carers' experiences of out-of-hours community palliative care: a qualitative study

Carers’ feelings of uncertainty and anxiety can be particularly acute out-of-hours, when they may not have access to familiar sources of professional help and advice. The present study used qualitative semi-structured interviews to explore carers’ experiences of out-of-hours care and support services. Fifteen bereaved carers in the Calderdale and Kirklees area were interviewed, and the interview transcripts analysed thematically. In general, carers felt well supported out-of-hours, especially by the nursing services. They appreciated opportunities to develop some degree of personal relationship with those they saw out-of-hours. However, in some cases problems were apparent. These were associated with poor provision of information, inadequate communication with carers, difficulties in accessing night-sitter services, or the inflexibility of services. The findings underline the importance of primary care practitioners taking an anticipatory approach to community palliative car

A Community-wide Media Campaign to Promote Walking in a Missouri Town

Introduction Engaging in moderate physical activity for 30 minutes five or more times per week substantially reduces the risk of coronary heart disease, stroke, colon cancer, diabetes, high blood pressure, and obesity, and walking is an easy and accessible way to achieve this goal. A theory-based mass media campaign promoted walking and local community-sponsored wellness initiatives through four types of media (billboard, newspaper, radio, and poster advertisements) in St Joseph, Mo, over 5 months during the summer of 2003. Methods The Walk Missouri campaign was conducted in four phases: 1) formative research, 2) program design and pretesting, 3) implementation, and 4) impact assessment. Using a postcampaign-only, cross-sectional design, a telephone survey (N = 297) was conducted in St Joseph to assess campaign impact. Study outcomes were pro-walking beliefs and behaviors. Results One in three survey respondents reported seeing or hearing campaign messages on one or more types of media. Reported exposure to the campaign was significantly associated with two of four pro-walking belief scales (social and pleasure benefits) and with one of three community-sponsored activities (participation in a community-sponsored walk) controlling for demographic, health status, and environmental factors. Exposure was also significantly associated with one of three general walking behaviors (number of days per week walking) when controlling for age and health status but not when beliefs were introduced into the model, consistent with an a priori theoretical mechanism: the mediating effect of pro-walking beliefs on the exposure–walking association. Conclusion These results suggest that a media campaign can enhance the success of community-based efforts to promote pro-walking beliefs and behaviors