Deciphering The Consequences Of Yolk Testosterone Metabolism In Birds

Maternal steroids transferred to eggs can elicit permanent effects on various aspects of offspring phenotype. Although, testosterone was thought to be a key mediator of maternal effects in birds, we now know that vertebrate embryos actively regulate their exposure to maternal testosterone through steroid metabolism, suggesting testosterone metabolites may elicit the observed phenotypic effects. To address the role steroid metabolism plays in mediating yolk testosterone effects, we used European starling (Sturnus vulgaris) eggs to characterize the timing of testosterone metabolism and determine whether etiocholanolone, a prominent testosterone metabolite in avian embryos, is capable of influencing early embryonic development. Tritiated testosterone (3H-T) was injected into freshly laid eggs to characterize the movement and metabolism during early development. Varying levels of etiocholanolone were also injected into starling eggs and incubated for either three or five days to test whether etiocholanolone influences the early growth of embryonic tissues. Interestingly, the conversion of testosterone to etiocholanolone is initiated within the first 12 hours of embryonic development, but the increase in etiocholanolone is transient; etiocholanolone is also subject to metabolism, suggesting embryos are exposed to elevated levels of etiocholanolone for a short period of time in early development. We found exogenous etiocholanolone manipulation had no significant effect on the growth rate of the embryos or extra-embryonic membranes early in development. These findings suggest the conversion of yolk testosterone to etiocholanolone may be an inactivation pathway that buffers the embryo from the effects of maternal steroids and the observed effects of yolk testosterone may be modulated by the fraction of testosterone that escapes metabolism

Rethinking norms in educational practices to promote appreciation of variation: Lessons from human anatomy

Across disciplines, teaching approaches and educational resources that are based on norms prevail—a norm is defined as a standard or typical practice, convention, or procedure. Although norms often have a historical basis and may be used to simplify complex content, their frequent use in education often disregards and disvalues variation. Variation can present valuable learning opportunities for students, promoting the development of problem solving and critical thinking skills, and humanizing their learning. An example of norms and variation in the discipline of gross anatomy is the frequent use of the “standard human body” in teaching. This idealized view typically does not account for anatomical variations despite their prevalence across the human population. This practice can contribute to alienation within gross anatomy classrooms, with students not feeling represented in the images and terms that they are exposed to. The main aim of this study is to investigate the impact of anatomical variations in gross anatomy courses to inform the creation of updated educational resources. A scoping review was conducted to explore teaching approaches for, and student outcomes of, including anatomical variations in undergraduate, graduate, and professional gross anatomy courses. Scoping reviews are a valuable approach in educational research to systematically explore available evidence related to a problem, elucidate knowledge gaps, and inform updated inclusive practices. Awareness of the norms present in one’s discipline can inform the intentional inclusion of variations in educational approaches and resources, contributing to the inclusion and appreciation of diversity within and across fields of study

A Clinical Prediction Score to Guide Referral of Elderly Dialysis Patients for Kidney Transplant Evaluation.

IntroductionDialysis patients aged ≥70 years derive improved life expectancy through kidney transplantation compared to their waitlisted counterparts, but guidelines are not clear about how to identify appropriate transplantation candidates. We developed a clinical prediction score to identify elderly dialysis patients with expected 5-year survival appropriate for kidney transplantation (>5 years).MethodsIncident dialysis patients in 2006-2009 aged ≥70 were identified from the United States Renal Data System database and divided into derivation and validation cohorts. Using the derivation cohort, candidate variables with a significant crude association with 5-year all-cause mortality were included in a multivariable logistic regression model to generate a scoring system. The scoring system was tested in the validation cohort and a cohort of elderly transplant recipients.ResultsCharacteristics most predictive of 5-year mortality included age >80, body mass index (BMI) <18, the presence of congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), immobility, and being institutionalized. Factors associated with increased 5-year survival were non-white race, a primary cause of end stage renal disease (ESRD) other than diabetes, employment within 6 months of dialysis initiation, and dialysis start via arteriovenous fistula (AVF). 5-year mortality was 47% for the lowest risk score group (3.6% of the validation cohort) and >90% for the highest risk cohort (42% of the validation cohort).ConclusionThis clinical prediction score could be useful for physicians to identify potentially suitable candidates for kidney transplantation

Ocean Acidification Partially Mitigates the Negative Effects of Warming on the Recruitment of the Coral Orbicella faveolata

Ocean acidification and ocean warming constitute major threats to many calcifying reef organisms, including scleractinian corals. The combined effects of these two environmental stressors on the earliest life history stages of reef calcifiers remain poorly studied, particularly for Atlantic corals. Here, we investigate how acidification and warming influence the fertilization success, larval survivorship, and larval settlement of the threatened Atlantic coral, Orbicella faveolata. Gametes and larvae from O. faveolata were subjected to a factorial combination of warming (ambient versus + 1.5 °C) and acidification (ambient versus − 0.2 pH units) projected to occur by the year 2050. O. faveolata individuals were maintained in the same treatments throughout all early life history stages investigated. The fertilization success of O. faveolata was not affected by acidification, warming, or their combination. However, during larval development, warming caused complete mortality and prevented any subsequent settlement. Interestingly, these negative effects of warming were mitigated when combined with ocean acidification, such that both larval survivorship and settlement increased by 41% in the combined treatment relative to the isolated warming treatment. Our research suggests that temperature-induced increases in larval metabolism may be counterbalanced by acidification, which serves to reduce larval metabolism. Notwithstanding, larval survivorship and settlement were still reduced by 50% under combined acidification and warming relative to the ambient treatment, indicating that climate change will continue to serve as major stressor during the early life history stages of corals, jeopardizing the resilience of Caribbean reefs

Adherence and Tolerability of Alzheimer's Disease Medications: A Pragmatic Randomized Trial

BACKGROUND/OBJECTIVES: Post-marketing comparative trials describe medication use patterns in diverse, real-world populations. Our objective was to determine if differences in rates of adherence and tolerability exist among new users to acetylcholinesterase inhibitors (AChEI's). DESIGN: Pragmatic randomized, open label comparative trial of AChEI's currently available in the United States. SETTING: Four memory care practices within four healthcare systems in the greater Indianapolis area. PARTICIPANTS: Eligibility criteria included older adults with a diagnosis of possible or probable Alzheimer's disease (AD) who were initiating treatment with an AChEI. Participants were required to have a caregiver to complete assessments, access to a telephone, and be able to understand English. Exclusion criteria consisted of a prior severe adverse event from AChEIs. INTERVENTION: Participants were randomized to one of three AChEIs in a 1:1:1 ratio and followed for 18 weeks. MEASUREMENTS: Caregiver-reported adherence, defined as taking or not taking study medication, and caregiver-reported adverse events, defined as the presence of an adverse event. RESULTS: 196 participants were included with 74.0% female, 30.6% African Americans, and 72.9% who completed at least twelfth grade. Discontinuation rates after 18 weeks were 38.8% for donepezil, 53.0% for galantamine, and 58.7% for rivastigmine (P = .063) in the intent to treat analysis. Adverse events and cost explained 73.1% and 25.4% of discontinuation. No participants discontinued donepezil due to cost. Adverse events were reported by 81.2% of all participants; no between-group differences in total adverse events were statistically significant. CONCLUSIONS: This pragmatic comparative trial showed high rates of adverse events and cost-related non-adherence with AChEIs. Interventions improving adherence and persistence to AChEIs may improve AD management. TRIAL REGISTRATION: Clinicaltrials.gov: NCT01362686 (https://clinicaltrials.gov/ct2/show/NCT01362686)

A brief mindfulness-based intervention reduces eating disorder symptoms and improves eating self-efficacy and emotion regulation among adults seeking bariatric surgery

Background Up to 64% of bariatric (weight-loss) surgery-seeking adults report eating disorder (ED) symptoms (i.e., binge eating, emotional eating, addictive-like eating, and grazing) that can interfere with surgery outcomes. Well-designed pre-surgical interventions targeting eating behaviours may reduce ED symptoms and protect against suboptimal surgery outcomes. Objectives Provide proof-of-concept data to inform the design and optimization of a pre-surgical mindfulness-based intervention (MBI) for ED symptoms. Evaluate whether the MBI produces meaningful improvements in ED symptoms and clarify the mechanisms-of-action by which the MBI impacts ED symptoms. Methods Twenty-one pre-surgical patients with obesity and ED symptoms referred to a MBI completed self-report measures of addictive-like eating, binge eating, emotional eating, grazing, mindful eating, eating self-efficacy, and emotion regulation pre-(T1) and post-(T2) MBI. Results Repeated-measures ANOVAs revealed improvements in binge eating symptoms (F (1,20) = 30.38, ηp2 = .60, p < .001) and grazing (F (1,20) = 7.57, ηp2 = .28, p = .012), pre- to post-MBI. Adjusting for multiple comparisons, no significant improvements were found for addictive-like eating or emotional eating. Eating self-efficacy (F (1,20) = 29.70, ηp2 = .60, p < .001) and emotion regulation (F (1,20) = 7.18, ηp2 = .26, p = .014) improved, while mindful eating decreased (F (1,20) = 16.25, ηp2 = .45, p = .001), following the MBI. Bivariate correlations found associations between improvements in the mechanism of eating self-efficacy and improvements in the ED symptom of grazing pre- to post-MBI (r = 0.46, p < .05).  As well, improvements in emotion regulation were associated with positive changes in binge and emotional eating and grazing (r = 0.55, p < .001, r = 0.66, p < .001, r = 0.61, p < .05, respectively). Conclusions After participating in the MBI binge eating, grazing, eating self-efficacy, and emotion regulation abilities improved. Further work is needed to understand and mitigate deterioration in mindful eating. Moreover, acceptability and feasibility of the MBI should be assessed prior to testing the MBI in a large-scale efficacy trial. Future research should assess the the impact of this intervention on post-surgery weight-loss, weight-loss maintenance, and maintenance of improvements in ED symptoms

Effects of Deepwater Horizon oil on feather structure and thermoregulation in gulls: Does rehabilitation work?

Impacts of large-scale oil spills on avian species are far-reaching.While media attention often focuses on lethal impacts, sub-lethal effects and the impacts of rehabilitation receive less attention. The objective of our study was to characterize effects of moderate external oiling and subsequent rehabilitation on feather structure and thermoregulation in gulls. We captured 30 wild ring-billed gulls (Larus delawarensis) and randomly assigned each individual to an experimental group: 1) controls, 2) rehabilitated birds (externally oiled, rehabilitated by washing), or 3) oiled birds (externally oiled, not rehabilitated). We externally oiled birds with weathered MC252 Deepwater Horizon oil (water for controls) and collected feathers and thermography imagery (FLIR) approximately weekly for four weeks to investigate feather structure (quantified using a barbule clumping index) and thermoregulatory ability (characterized by internal body temperature and external surface temperature). Post-oiling feather clumping was significantly higher in oiled and rehabilitated birds compared to controls, but steadily declined over time in both groups. However, feather microstructure in rehabilitated birds was indistinguishable from controls within three weeks of washing whereas the feathers of oiled birds were still significantly clumped a month post oiling. Internal body temperatures didn\u27t differ in any of the groups, suggesting birds maintain thermoregulatory homeostasis in spite of moderate external oiling. External temperatures for rehabilitated birds didn\u27t differ from controls within a week of rehabilitation. Overall, rehabilitation procedures were effective and washed birds were in better condition compared to non-rehabilitated, oiled birds. This study provides evidence that the benefits of rehabilitation for moderately oiled birds likely outweigh the costs with regard to feather structure and thermoregulation.While feather preening and time were insufficient to reestablish baseline fine scale feather structure in moderately oiled birds, the significant clumping reduction over time may indicate that rehabilitation of lightly oiled birds may not be necessary and deserves further study

CRISPR Knockout of the HuR Gene Causes a Xenograft Lethal Phenotype.

Pancreatic ductal adenocarcinoma (PDA) is the third leading cause of cancer-related deaths in the United States, whereas colorectal cancer is the third most common cancer. The RNA-binding protein HuR (ELAVL1) supports a pro-oncogenic network in gastrointestinal (GI) cancer cells through enhanced HuR expression. Using a publically available database, HuR expression levels were determined to be increased in primary PDA and colorectal cancer tumor cohorts as compared with normal pancreas and colon tissues, respectively. CRISPR/Cas9 technology was successfully used to delete the HuR gene in both PDA (MIA PaCa-2 and Hs 766T) and colorectal cancer (HCT116) cell lines. HuR deficiency has a mild phenotype

Large-scale electron microscopy database for human type 1 diabetes

Autoimmune β-cell destruction leads to type 1 diabetes, but the pathophysiological mechanisms remain unclear. To help address this void, we created an open-access online repository, unprecedented in its size, composed of large-scale electron microscopy images ('nanotomy') of human pancreas tissue obtained from the Network for Pancreatic Organ donors with Diabetes (nPOD; www.nanotomy.org). Nanotomy allows analyses of complete donor islets with up to macromolecular resolution. Anomalies we found in type 1 diabetes included (i) an increase of 'intermediate cells' containing granules resembling those of exocrine zymogen and endocrine hormone secreting cells; and (ii) elevated presence of innate immune cells. These are our first results of mining the database and support recent findings that suggest that type 1 diabetes includes abnormalities in the exocrine pancreas that may induce endocrine cellular stress as a trigger for autoimmunity

Protocol: Barriers and facilitators to stakeholder engagement in health guideline development: a qualitative evidence synthesis

Background There is a need for the development of comprehensive, global, evidence-based guidance for stakeholder engagement in guideline development. Stakeholders are any individual or group who is responsible for or affected by health- and healthcare-related decisions. This includes patients, the public, providers of health care and policymakers for example. As part of the guidance development process, Multi-Stakeholder Engagement (MuSE) Consortium set out to conduct four concurrent systematic reviews to summarise the evidence on: (1) existing guidance for stakeholder engagement in guideline development, (2) barriers and facilitators to stakeholder engagement in guideline development, (3) managing conflicts of interest in stakeholder engagement in guideline development and (4) measuring the impact of stakeholder engagement in guideline development. This protocol addresses the second systematic review in the series. Objectives The objective of this review is to identify and synthesise the existing evidence on barriers and facilitators to stakeholder engagement in health guideline development. We will address this objective through two research questions: (1) What are the barriers to multi-stakeholder engagement in health guideline development across any of the 18 steps of the GIN-McMaster checklist? (2) What are the facilitators to multi-stakeholder engagement in health guideline development across any of the 18 steps of the GIN-McMaster checklist? Search Methods A comprehensive search strategy will be developed and peer-reviewed in consultation with a medical librarian. We will search the following databases: MEDLINE, Cumulative Index to Nursing & Allied Health Literature (CINAHL), EMBASE, PsycInfo, Scopus, and Sociological Abstracts. To identify grey literature, we will search the websites of agencies who actively engage stakeholder groups such as the AHRQ, Canadian Institutes of Health Research (CIHR) Strategy for Patient-Oriented Research (SPOR), INVOLVE, the National Institute for Health and Care Excellence (NICE) and the PCORI. We will also search the websites of guideline-producing agencies, such as the American Academy of Pediatrics, Australia's National Health Medical Research Council (NHMRC) and the WHO. We will invite members of the team to suggest grey literature sources and we plan to broaden the search by soliciting suggestions via social media, such as Twitter. Selection Criteria We will include empirical qualitative and mixed-method primary research studies which qualitatively report on the barriers or facilitators to stakeholder engagement in health guideline development. The population of interest is stakeholders in health guideline development. Building on previous work, we have identified 13 types of stakeholders whose input can enhance the relevance and uptake of guidelines: Patients, caregivers and patient advocates; Public; Providers of health care; Payers of health services; Payers of research; Policy makers; Program managers; Product makers; Purchasers; Principal investigators and their research teams; and Peer-review editors/publishers. Eligible studies must describe stakeholder engagement at any of the following steps of the GIN-McMaster Checklist for Guideline Development. Data Collection and Analysis All identified citations from electronic databases will be imported into Covidence software for screening and selection. Documents identified through our grey literature search will be managed and screened using an Excel spreadsheet. A two-part study selection process will be used for all identified citations: (1) a title and abstract review and (2) full-text review. At each stage, teams of two review authors will independently assess all potential studies in duplicate using a priori inclusion and exclusion criteria. Data will be extracted by two review authors independently and in duplicate according to a standardised data extraction form. Main Results The results of this review will be used to inform the development of guidance for multi-stakeholder engagement in guideline development and implementation. This guidance will be official GRADE (Grading of Recommendations Assessment, Development and Evaluation) Working Group guidance. The GRADE system is internationally recognised as a standard for guideline development. The findings of this review will assist organisations who develop healthcare, public health and health policy guidelines, such as the World Health Organization, to involve multiple stakeholders in the guideline development process to ensure the development of relevant, high quality and transparent guidelines