Early onset obesity and adrenal insufficiency associated with a homozygous POMC mutation

Isolated hypocortisolism due to ACTH deficiency is a rare condition that can be caused by homozygous or compound heterozygous mutations in the gene encoding proopiomelanocortin (POMC). Loss of function mutations of POMC gene typically results in adrenal insufficiency, obesity and red hair. We describe an 18 month old Hispanic female with congenital adrenal insufficiency, a novel POMC mutation and atypical clinical features. The patient presented at the age of 9 months with hypoglycemia and the endocrine evaluation resulted in a diagnosis of ACTH deficiency. She developed extreme weight gain prompting sequence analysis of POMC, which revealed a homozygous c.231C > A change which is predicted to result in a premature termination codon. The case we report had obesity, hypocortisolism but lacked red hair which is typical for subjects with POMC mutations. Mutations of POMC should be considered in individuals with severe early onset obesity and adrenal insufficiency even when they lack the typical pigmentary phenotype

A relação entre o nível voluntário de transparência e o custo de capital próprio das empresas brasileiras não-financeiras

O objetivo principal desta pesquisa é verificar empiricamente a existência de relação significativa entre o nível de disclosure voluntário de informações e custo de capital próprio de empresas brasileiras não financeiras. É esperado que um maior nível de disclosure esteja relacionado a um menor custo de capital próprio pela redução do risco percebido pelos investidores. A fim de medir o nível de disclosure voluntário das empresas foi utilizado um questionário desenvolvido para este fim. O custo de capital próprio foi obtido com base em informações publicamente disponíveis das empresas. Foi encontrada uma relação negativa e significante entre as variáveis de interesse, indicando que as empresas que mais divulgam informações voluntariamente conseguem captar capital próprio a uma taxa mais barata

Beyond adoption: A new framework for theorising and evaluating Non-adoption, Abandonment and challenges to Scale-up, Spread and Sustainability (NASSS) of health and care technologies

© 2017 The Author(s). This is an open-access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work, first published in the Journal of Medical Internet Research, is properly cited. The complete bibliographic information, a link to the original publication on http://www.jmir.org/, as well as this copyright and license information must be included.Background: Many promising technological innovations in health and social care are characterized by nonadoption or abandonment by individuals or by failed attempts to scale up locally, spread distantly, or sustain the innovation long term at the organization or system level. Objective: Our objective was to produce an evidence-based, theory-informed, and pragmatic framework to help predict and evaluate the success of a technology-supported health or social care program. Methods: The study had 2 parallel components: (1) secondary research (hermeneutic systematic review) to identify key domains, and (2) empirical case studies of technology implementation to explore, test, and refine these domains. We studied 6 technology-supported programs—video outpatient consultations, global positioning system tracking for cognitive impairment, pendant alarm services, remote biomarker monitoring for heart failure, care organizing software, and integrated case management via data sharing—using longitudinal ethnography and action research for up to 3 years across more than 20 organizations. Data were collected at micro level (individual technology users), meso level (organizational processes and systems), and macro level (national policy and wider context). Analysis and synthesis was aided by sociotechnically informed theories of individual, organizational, and system change. The draft framework was shared with colleagues who were introducing or evaluating other technology-supported health or care programs and refined in response to feedback. Results: The literature review identified 28 previous technology implementation frameworks, of which 14 had taken a dynamic systems approach (including 2 integrative reviews of previous work). Our empirical dataset consisted of over 400 hours of ethnographic observation, 165 semistructured interviews, and 200 documents. The final nonadoption, abandonment, scale-up, spread, and sustainability (NASSS) framework included questions in 7 domains: the condition or illness, the technology, the value proposition, the adopter system (comprising professional staff, patient, and lay caregivers), the organization(s), the wider (institutional and societal) context, and the interaction and mutual adaptation between all these domains over time. Our empirical case studies raised a variety of challenges across all 7 domains, each classified as simple (straightforward, predictable, few components), complicated (multiple interacting components or issues), or complex (dynamic, unpredictable, not easily disaggregated into constituent components). Programs characterized by complicatedness proved difficult but not impossible to implement. Those characterized by complexity in multiple NASSS domains rarely, if ever, became mainstreamed. The framework showed promise when applied (both prospectively and retrospectively) to other programs.Peer reviewe

Lessons learned from additional research analyses of unsolved clinical exome cases

BACKGROUND: Given the rarity of most single-gene Mendelian disorders, concerted efforts of data exchange between clinical and scientific communities are critical to optimize molecular diagnosis and novel disease gene discovery. METHODS: We designed and implemented protocols for the study of cases for which a plausible molecular diagnosis was not achieved in a clinical genomics diagnostic laboratory (i.e. unsolved clinical exomes). Such cases were recruited to a research laboratory for further analyses, in order to potentially: (1) accelerate novel disease gene discovery; (2) increase the molecular diagnostic yield of whole exome sequencing (WES); and (3) gain insight into the genetic mechanisms of disease. Pilot project data included 74 families, consisting mostly of parent-offspring trios. Analyses performed on a research basis employed both WES from additional family members and complementary bioinformatics approaches and protocols. RESULTS: Analysis of all possible modes of Mendelian inheritance, focusing on both single nucleotide variants (SNV) and copy number variant (CNV) alleles, yielded a likely contributory variant in 36% (27/74) of cases. If one includes candidate genes with variants identified within a single family, a potential contributory variant was identified in a total of ~51% (38/74) of cases enrolled in this pilot study. The molecular diagnosis was achieved in 30/63 trios (47.6%). Besides this, the analysis workflow yielded evidence for pathogenic variants in disease-associated genes in 4/6 singleton cases (66.6%), 1/1 multiplex family involving three affected siblings, and 3/4 (75%) quartet families. Both the analytical pipeline and the collaborative efforts between the diagnostic and research laboratories provided insights that allowed recent disease gene discoveries (PURA, TANGO2, EMC1, GNB5, ATAD3A, and MIPEP) and increased the number of novel genes, defined in this study as genes identified in more than one family (DHX30 and EBF3). CONCLUSION: An efficient genomics pipeline in which clinical sequencing in a diagnostic laboratory is followed by the detailed reanalysis of unsolved cases in a research environment, supplemented with WES data from additional family members, and subject to adjuvant bioinformatics analyses including relaxed variant filtering parameters in informatics pipelines, can enhance the molecular diagnostic yield and provide mechanistic insights into Mendelian disorders. Implementing these approaches requires collaborative clinical molecular diagnostic and research efforts

Processes and preliminary outputs for identification of actionable genes as incidental findings in genomic sequence data in the Clinical Sequencing Exploratory Research Consortium

As genomic and exomic testing expands in both the research and clinical arenas, determining whether, how, and which incidental findings to return to the ordering clinician and patient becomes increasingly important. Although opinion is varied on what should be returned to consenting patients or research participants, most experts agree that return of medically actionable results should be considered. There is insufficient evidence to fully inform evidence-based clinical practice guidelines regarding return of results from genome-scale sequencing, and thus generation of such evidence is imperative, given the rapidity with which genome-scale diagnostic tests are being incorporated into clinical care. We present an overview of the approaches to incidental findings by members of the Clinical Sequencing Exploratory Research network, funded by the National Human Genome Research Institute, to generate discussion of these approaches by the clinical genomics community. We also report specific lists of “medically actionable” genes that have been generated by a subset of investigators in order to explore what types of findings have been included or excluded in various contexts. A discussion of the general principles regarding reporting of novel variants, challenging cases (genes for which consensus was difficult to achieve across Clinical Sequencing Exploratory Research network sites), solicitation of preferences from participants regarding return of incidental findings, and the timing and context of return of incidental findings are provided

Hormone Therapy and the Risk of Breast Cancer in BRCA1 Mutation Carriers

Background: Hormone therapy (HT) is commonly given to women to alleviate the climacteric symptoms associated with menopause. There is concern that this treatment may increase the risk of breast cancer. The potential association of HT and breast cancer risk is of particular interest to women who carry a mutation in BRCA1 because they face a high lifetime risk of breast cancer and because many of these women take HT after undergoing prophylactic surgical oophorectomy at a young age. Methods: We conducted a matched case-control study of 472 postmenopausal women with a BRCA1 mutation to examine whether or not the use of HT is associated with subsequent risk of breast cancer. Breast cancer case patients and control subjects were matched with respect to age, age at menopause, and type of menopause (surgical or natural). Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated with conditional logistic regression. Statistical tests were two-sided. Results: In this group of BRCA1 mutation carriers, the adjusted OR for breast cancer associated with ever use of HT compared with never use was 0.58 (95% CI = 0.35 to 0.96; P =. 03). In analyses by type of HT, an inverse association with breast cancer risk was observed with use of estrogen only (OR = 0.51, 95% CI = 0.27 to 0.98; P =. 04); the association with use of estrogen plus progesterone was not statistically significant (OR = 0.66, 95% CI = 0.34 to 1.27; P =. 21). Conclusion: Among postmenopausal women with a BRCA1 mutation, HT use was not associated with increased risk of breast cancer; indeed, in this population, it was associated with a decreased risk

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Genetic determinants of telomere length from 109,122 ancestrally diverse whole-genome sequences in TOPMed

Genetic studies on telomere length are important for understanding age-related diseases. Prior GWAS for leukocyte TL have been limited to European and Asian populations. Here, we report the first sequencing-based association study for TL across ancestrally-diverse individuals (European, African, Asian and Hispanic/Latino) from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program. We used whole genome sequencing (WGS) of whole blood for variant genotype calling and the bioinformatic estimation of telomere length in n=109,122 individuals. We identified 59 sentinel variants (p-value OBFC1indicated the independent signals colocalized with cell-type specific eQTLs for OBFC1 (STN1). Using a multi-variant gene-based approach, we identified two genes newly implicated in telomere length, DCLRE1B (SNM1B) and PARN. In PheWAS, we demonstrated our TL polygenic trait scores (PTS) were associated with increased risk of cancer-related phenotypes

Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with risk of clear cell ovarian cancer.

BACKGROUND: Regulatory T (Treg) cells, a subset of CD4+ T lymphocytes, are mediators of immunosuppression in cancer, and, thus, variants in genes encoding Treg cell immune molecules could be associated with ovarian cancer. METHODS: In a population of 15,596 epithelial ovarian cancer (EOC) cases and 23,236 controls, we measured genetic associations of 1,351 SNPs in Treg cell pathway genes with odds of ovarian cancer and tested pathway and gene-level associations, overall and by histotype, for the 25 genes, using the admixture likelihood (AML) method. The most significant single SNP associations were tested for correlation with expression levels in 44 ovarian cancer patients. RESULTS: The most significant global associations for all genes in the pathway were seen in endometrioid ( p = 0.082) and clear cell ( p = 0.083), with the most significant gene level association seen with TGFBR2 ( p = 0.001) and clear cell EOC. Gene associations with histotypes at p < 0.05 included: IL12 ( p = 0.005 and p = 0.008, serous and high-grade serous, respectively), IL8RA ( p = 0.035, endometrioid and mucinous), LGALS1 ( p = 0.03, mucinous), STAT5B ( p = 0.022, clear cell), TGFBR1 ( p = 0.021 endometrioid) and TGFBR2 ( p = 0.017 and p = 0.025, endometrioid and mucinous, respectively). CONCLUSIONS: Common inherited gene variation in Treg cell pathways shows some evidence of germline genetic contribution to odds of EOC that varies by histologic subtype and may be associated with mRNA expression of immune-complex receptor in EOC patients

Identification of ejaculated proteins in the house mouse (Mus domesticus) via isotopic labeling

<p>Abstract</p> <p>Background</p> <p>Seminal fluid plays an important role in successful fertilization, but knowledge of the full suite of proteins transferred from males to females during copulation is incomplete. The list of ejaculated proteins remains particularly scant in one of the best-studied mammalian systems, the house mouse (<it>Mus domesticus</it>), where artificial ejaculation techniques have proven inadequate. Here we investigate an alternative method for identifying ejaculated proteins, by isotopically labeling females with ¹⁵N and then mating them to unlabeled, vasectomized males. Proteins were then isolated from mated females and identified using mass spectrometry. In addition to gaining insights into possible functions and fates of ejaculated proteins, our study serves as proof of concept that isotopic labeling is a powerful means to study reproductive proteins.</p> <p>Results</p> <p>We identified 69 male-derived proteins from the female reproductive tract following copulation. More than a third of all spectra detected mapped to just seven genes known to be structurally important in the formation of the copulatory plug, a hard coagulum that forms shortly after mating. Seminal fluid is significantly enriched for proteins that function in protection from oxidative stress and endopeptidase inhibition. Females, on the other hand, produce endopeptidases in response to mating. The 69 ejaculated proteins evolve significantly more rapidly than other proteins that we previously identified directly from dissection of the male reproductive tract.</p> <p>Conclusion</p> <p>Our study attempts to comprehensively identify the proteins transferred from males to females during mating, expanding the application of isotopic labeling to mammalian reproductive genomics. This technique opens the way to the targeted monitoring of the fate of ejaculated proteins as they incubate in the female reproductive tract.</p