Rapid Direct Action of Estradiol in GnRH Neurons: Findings and Implications

Estradiol plays a pivotal role in the control of gonadotropin-releasing hormone (GnRH) neuronal function and female reproduction. While positive and negative feedback actions of estradiol that enhance and suppress release of GnRH and LH are primarily mediated through estrogen receptor alpha located in interneurons, a series of recent studies in our laboratory indicate that rapid excitatory actions of estradiol also directly modify GnRH neuronal activity. We observed this phenomenon in cultured primate GnRH neurons, but similar rapid direct actions of estradiol are also described in cultured GnRH neurons and green fluorescent protein-labeled GnRH neurons of mice. Importantly, rapid direct action of estradiol in GnRH neurons is mediated through membrane or membrane associated receptors, such as GPR30, STX-sensitive receptors, and ERβ. In this review, possible implications of this rapid estradiol action in GnRH neurons are discussed

Mapping for Conceptual Clarity: Exploring Implementation of Integrated Community-Based Primary Health Care from a Whole Systems Perspective.

Published source must be acknowledged with citationIntroduction: Studying implementation of integrated models of community-based primary health care requires a "whole systems" multidisciplinary approach to capture micro, meso and macro factors. However, there is, as yet, no clear operationalization of a "whole systems" approach to guide multidisciplinary research programs. Theoretical frameworks and approaches from diverse academic traditions specify different aspects of the health system in more depth. Enabling analysis across the system, when data and ideas are captured using different taxonomies, requires that we map terms and constructs across the models. Theory and methods: This paper uses concept mapping techniques to compare and contrast the theoretical frameworks and approaches used in the iCOACH project including: Ham's Ten Characteristics of the High-Performing Chronic Care System (capturing patient/carer and provider perspectives), the Organizational Context and Capabilities for Integrating Care framework (capturing the organizational perspective), and the Health Policy Monitor framework (capturing the policy system perspective). The aim of the paper is to link concepts across different theoretical framework to guide the iCOACH study. Results: A concept map was developed that identifies 8 overarching concepts across the heuristic models. A preliminary analysis of one of these overarching concepts, care coordination, demonstrates how different perspectives will assign different meanings, values, and drivers of seemingly similar ideas. For patients and carers care coordination is about having a responsive team of health care providers. Building relationships in teams that exist within and across different organizations is essential for providers to achieve care coordination, where managers and policy makers see care coordination as being more about creating linkages and addressing systems gaps. Discussion and conclusion: This work represents a first step towards development of a fully formed conceptual framework that includes key domains, concepts, and mechanisms of implementing integrated community-based primary health care.Published onlin

Empirical Evidence on the Use of Credit Scoring for Predicting Insurance Losses with Psycho-social and Biochemical Explanations

An important development in personal lines of insurance in the United States is the use of credit history data for insurance risk classification to predict losses. This research presents the results of collaboration with industry conducted by a university at the request of its state legislature. The purpose was to see the viability and validity of the use of credit scoring to predict insurance losses given its controversial nature and criticism as redundant of other predictive variables currently used. Working with industry and government, this study analyzed more than 175,000 policyholders’ information for the relationship between credit score and claims. Credit scores were significantly related to incurred losses, evidencing both statistical and practical significance. We investigate whether the revealed relationship between credit score and incurred losses was explainable by overlap with existing underwriting variables or whether the credit score adds new information about losses not contained in existing underwriting variables. The results show that credit scores contain significant information not already incorporated into other traditional rating variables (e.g., age, sex, driving history). We discuss how sensation seeking and self-control theory provide a partial explanation of why credit scoring works (the psycho-social perspective). This article also presents an overview of biological and chemical correlates of risk taking that helps explain why knowing risk-taking behavior in one realm (e.g., risky financial behavior and poor credit history) transits to predicting risk-taking behavior in other realms (e.g., automobile insurance incurred losses). Additional research is needed to advance new nontraditional loss prediction variables from social media consumer information to using information provided by technological advances. The evolving and dynamic nature of the insurance marketplace makes it imperative that professionals continue to evolve predictive variables and for academics to assist with understanding the whys of the relationships through theory development.IC2 Institut

SNPs in Multi-Species Conserved Sequences (MCS) as useful markers in association studies: a practical approach

<p>Abstract</p> <p>Background</p> <p>Although genes play a key role in many complex diseases, the specific genes involved in most complex diseases remain largely unidentified. Their discovery will hinge on the identification of key sequence variants that are conclusively associated with disease. While much attention has been focused on variants in protein-coding DNA, variants in noncoding regions may also play many important roles in complex disease by altering gene regulation. Since the vast majority of noncoding genomic sequence is of unknown function, this increases the challenge of identifying "functional" variants that cause disease. However, evolutionary conservation can be used as a guide to indicate regions of noncoding or coding DNA that are likely to have biological function, and thus may be more likely to harbor SNP variants with functional consequences. To help bias marker selection in favor of such variants, we devised a process that prioritizes annotated SNPs for genotyping studies based on their location within Multi-species Conserved Sequences (MCSs) and used this process to select SNPs in a region of linkage to a complex disease. This allowed us to evaluate the utility of the chosen SNPs for further association studies. Previously, a region of chromosome 1q43 was linked to Multiple Sclerosis (MS) in a genome-wide screen. We chose annotated SNPs in the region based on location within MCSs (termed MCS-SNPs). We then obtained genotypes for 478 MCS-SNPs in 989 individuals from MS families.</p> <p>Results</p> <p>Analysis of our MCS-SNP genotypes from the 1q43 region and comparison to HapMap data confirmed that annotated SNPs in MCS regions are frequently polymorphic and show subtle signatures of selective pressure, consistent with previous reports of genome-wide variation in conserved regions. We also present an online tool that allows MCS data to be directly exported to the UCSC genome browser so that MCS-SNPs can be easily identified within genomic regions of interest.</p> <p>Conclusion</p> <p>Our results showed that MCS can easily be used to prioritize markers for follow-up and candidate gene association studies. We believe that this novel approach demonstrates a paradigm for expediting the search for genes contributing to complex diseases.</p

Health equity in the New Zealand health care system: a national survey

<p>Abstract</p> <p>Introduction</p> <p>In all countries people experience different social circumstances that result in avoidable differences in health. In New Zealand, Māori, Pacific peoples, and those with lower socioeconomic status experience higher levels of chronic illness, which is the leading cause of mortality, morbidity and inequitable health outcomes. Whilst the health system can enable a fairer distribution of good health, limited national data is available to measure health equity. Therefore, we sought to find out whether health services in New Zealand were equitable by measuring the level of development of components of chronic care management systems across district health boards. Variation in provision by geography, condition or ethnicity can be interpreted as inequitable.</p> <p>Methods</p> <p>A national survey of district health boards (DHBs) was undertaken on macro approaches to chronic condition management with detail on cardiovascular disease, chronic obstructive pulmonary disease, congestive heart failure, stroke and diabetes. Additional data from expert informant interviews on program reach and the cultural needs of Māori and Pacific peoples was sought. Survey data were analyzed on dimensions of health equity relevant to strategic planning and program delivery. Results are presented as descriptive statistics and free text. Interviews were transcribed and NVivo 8 software supported a general inductive approach to identify common themes.</p> <p>Results</p> <p>Survey responses were received from the majority of DHBs (15/21), some PHOs (21/84) and 31 expert informants. Measuring, monitoring and targeting equity is not systematically undertaken. The Health Equity Assessment Tool is used in strategic planning but not in decisions about implementing or monitoring disease programs. Variable implementation of evidence-based practices in disease management and multiple funding streams made program implementation difficult. Equity for Māori is embedded in policy, this is not so for other ethnic groups or by geography. Populations that conventional practitioners find hard to reach, despite recognized needs, are often underserved. Nurses and community health workers carried a disproportionate burden of care. Cultural and diversity training is not a condition of employment.</p> <p>Conclusions</p> <p>There is a struggle to put equity principles into practice, indicating will without enactment. Equity is not addressed systematically below strategic levels and equity does not shape funding decisions, program development, implementation and monitoring. Equity is not incentivized although examples of exceptional practice, driven by individuals, are evident across New Zealand.</p

Impact of age at type 2 diabetes mellitus diagnosis on mortality and vascular complications: systematic review and meta-analyses

AIMS/HYPOTHESIS: Few studies examine the association between age at diagnosis and subsequent complications from type 2 diabetes. This paper aims to summarise the risk of mortality, macrovascular complications and microvascular complications associated with age at diagnosis of type 2 diabetes. METHODS: Data were sourced from MEDLINE and All EBM (Evidence Based Medicine) databases from inception to July 2018. Observational studies, investigating the effect of age at diabetes diagnosis on macrovascular and microvascular diabetes complications in adults with type 2 diabetes were selected according to pre-specified criteria. Two investigators independently extracted data and evaluated all studies. If data were not reported in a comparable format, data were obtained from authors, presented as minimally adjusted ORs (and 95% CIs) per 1 year increase in age at diabetes diagnosis, adjusted for current age for each outcome of interest. The study protocol was recorded with PROSPERO International Prospective Register of Systematic Reviews (CRD42016043593). RESULTS: Data from 26 observational studies comprising 1,325,493 individuals from 30 countries were included. Random-effects meta-analyses with inverse variance weighting were used to obtain the pooled ORs. Age at diabetes diagnosis was inversely associated with risk of all-cause mortality and macrovascular and microvascular disease (all p < 0.001). Each 1 year increase in age at diabetes diagnosis was associated with a 4%, 3% and 5% decreased risk of all-cause mortality, macrovascular disease and microvascular disease, respectively, adjusted for current age. The effects were consistent for the individual components of the composite outcomes (all p < 0.001). CONCLUSIONS/INTERPRETATION: Younger, rather than older, age at diabetes diagnosis was associated with higher risk of mortality and vascular disease. Early and sustained interventions to delay type 2 diabetes onset and improve blood glucose levels and cardiovascular risk profiles of those already diagnosed are essential to reduce morbidity and mortality. Graphical abstract

Anti-tumour necrosis factor therapy for early-stage Dupuytren's disease (RIDD): a phase 2b, randomised, double-blind, placebo-controlled trial

Background Dupuytren's disease is a common fibrotic condition that causes the fingers to flex irreversibly into the palm. Treatments for late-stage disease all have limitations, and there is no approved treatment for early-stage disease. We identified tumour necrosis factor as a therapeutic target in Dupuytren's disease, and in a dose ranging trial found 40 mg adalimumab in 0·4 mL to be most efficacious. Here we aimed to assess the effects of intranodular injection of adalimumab in early-stage disease. Methods In this phase 2b, randomised, double-blind, placebo-controlled trial adults with early-stage Dupuytren's disease and an established clinically distinct nodule with a clear history of progression in the preceding 6 months were recruited from two clinical centres in the UK and were randomly assigned 1:1 to receive four injections of adalimumab or saline every 3 months. Participants and assessors were masked. The primary outcome was nodule hardness measured with a durometer at 12 months. Data were analysed by linear mixed effects regression models in the intention-to-treat population with multiple imputation for missing primary outcome data. The trial is registered at the ISRCTN registry, ISRCTN 27786905 and is complete. Findings Between Feb 17, 2017, and Jan 11, 2019, 284 participants were screened in the UK and 140 were enrolled. 47 (34%) participants were female and 93 (66%) were male. Mean age of participants was 59·7 years (SD 10·0). Primary outcome data were available from 113 participants. Nodule hardness was lower (−4·6 AU [95% CI −7·1 to −2·2], p=0·0002) in the adalimumab compared with the saline group at 12 months. There were no related serious adverse events; the most common adverse events were minor injection site reactions. Interpretation Intranodular injections of adalimumab in participants with early-stage Dupuytren's disease resulted in softening and reduction in size of the nodules. Longer follow-up would be required to assess the effect of tumour necrosis factor inhibition on disease progression, extension deficit and hand function. Funding Health Innovation Challenge Fund (Wellcome Trust, Department of Health) and 180 Life Sciences

The effect of feedback to general practitioners on quality of care for people with type 2 diabetes. A systematic review of the literature

<p>Abstract</p> <p>Background</p> <p>There have been numerous efforts to improve and assure the quality of treatment and follow-up of people with Type 2 diabetes (PT2D) in general practice. Facilitated by the increasing usability and validity of guidelines, indicators and databases, feedback on diabetes care is a promising tool in this aspect. Our goal was to assess the effect of feedback to general practitioners (GPs) on the quality of care for PT2D based on the available literature.</p> <p>Methods</p> <p>Systematic review searches were conducted using October 2008 updates of Medline (Pubmed), Cochrane library and Embase databases. Additional searches in reference lists and related articles were conducted. Papers were included if published in English, performed as randomized controlled trials, studying diabetes, having general practice as setting and using feedback to GPs on diabetes care. The papers were assessed according to predefined criteria.</p> <p>Results</p> <p>Ten studies complied with the inclusion criteria. Feedback improved the care for PT2D, particularly process outcomes such as foot exams, eye exams and Hba1c measurements. Clinical outcomes like lowering of blood pressure, Hba1c and cholesterol levels were seen in few studies. Many process and outcome measures did not improve, while none deteriorated. Meta analysis was unfeasible due to heterogeneity of the studies included. Two studies used electronic feedback.</p> <p>Conclusion</p> <p>Based on this review, feedback seems a promising tool for quality improvement in diabetes care, but more research is needed, especially of electronic feedback.</p