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Contains fulltext : 304858.pdf (Publisher’s version ) (Open Access), To date only a fraction of the genetic footprint of thyroid function has been clarified. We report a genome-wide association study meta-analysis of thyroid function in up to 271,040 individuals of European ancestry, including reference range thyrotropin (TSH), free thyroxine (FT4), free and total triiodothyronine (T3), proxies for metabolism (T3/FT4 ratio) as well as dichotomized high and low TSH levels. We revealed 259 independent significant associations for TSH (61% novel), 85 for FT4 (67% novel), and 62 novel signals for the T3 related traits. The loci explained 14.1%, 6.0%, 9.5% and 1.1% of the total variation in TSH, FT4, total T3 and free T3 concentrations, respectively. Genetic correlations indicate that TSH associated loci reflect the thyroid function determined by free T3, whereas the FT4 associations represent the thyroid hormone metabolism. Polygenic risk score and Mendelian randomization analyses showed the effects of genetically determined variation in thyroid function on various clinical outcomes, including cardiovascular risk factors and diseases, autoimmune diseases, and cancer. In conclusion, our results improve the understanding of thyroid hormone physiology and highlight the pleiotropic effects of thyroid function on various diseases.

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Contains fulltext : 297328.pdf (Publisher’s version ) (Closed access), BACKGROUND: Reference intervals of thyroid-stimulating hormone (TSH) and free thyroxine (FT(4)) are statistically defined by the 2·5-97·5th percentiles, without accounting for potential risk of clinical outcomes. We aimed to define the optimal healthy ranges of TSH and FT(4) based on the risk of cardiovascular disease and mortality. METHODS: This systematic review and individual participant data (IPD) meta-analysis identified eligible prospective cohorts through the Thyroid Studies Collaboration, supplemented with a systematic search via Embase, MEDLINE (Ovid), Web of science, the Cochrane Central Register of Controlled Trials, and Google Scholar from Jan 1, 2011, to Feb 12, 2017 with an updated search to Oct 13, 2022 (cohorts found in the second search were not included in the IPD). We included cohorts that collected TSH or FT(4), and cardiovascular outcomes or mortality for adults (aged ≥18 years). We excluded cohorts that included solely pregnant women, individuals with overt thyroid diseases, and individuals with cardiovascular disease. We contacted the study investigators of eligible cohorts to provide IPD on demographics, TSH, FT(4), thyroid peroxidase antibodies, history of cardiovascular disease and risk factors, medication use, cardiovascular disease events, cardiovascular disease mortality, and all-cause mortality. The primary outcome was a composite outcome including cardiovascular disease events (coronary heart disease, stroke, and heart failure) and all-cause mortality. Secondary outcomes were the separate assessment of cardiovascular disease events, all-cause mortality, and cardiovascular disease mortality. We performed one-step (cohort-stratified Cox models) and two-step (random-effects models) meta-analyses adjusting for age, sex, smoking, systolic blood pressure, diabetes, and total cholesterol. The study was registered with PROSPERO, CRD42017057576. FINDINGS: We identified 3935 studies, of which 53 cohorts fulfilled the inclusion criteria and 26 co

This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To assess the effects of interventions provided to support parents experiencing complex trauma or who have experienced childhood maltreatment (or both) on parenting capacity and parental psychological or socio‐emotional well‐being.

Objective: Victorian ED data show increased presentations for anxiety and depression in children. We aimed to determine parent-reported factors contributing to these presentations. Method(s): Qualitative study with parents of children and young people aged 0-17 years who attended one of four EDs across Victoria between October 2017 and September 2018 and received a primary diagnosis of anxiety or depression (excluding self-harm or suicide attempt). Eligible parents completed semi-structured phone interviews, which were audio-recorded and transcribed. Transcripts were coded and qualitatively analysed using thematic analysis. Result(s): Seventy parents completed interviews. The average age of children and young people was 14 years (standard deviation 2.4) and 63% (n = 44) identified as female. Thirty (43%) children received a primary diagnosis of depression, compared to 40 (57%) children who received a primary diagnosis of anxiety. The majority of respondents were mothers (n = 59; 84%). Key themes as to why families presented to EDs included: listening to trusted professionals, desperation, a feeling of no alternative, respecting their child's need to feel safe and to rule out a potentially serious medical condition. Conclusion(s): Parents bring their children to the ED for many reasons. Policy makers, managers and clinicians should work with parents to develop alternative approaches that provide families with community-based support, particularly for younger children and after hours, in order to provide an appropriate source of care for children and young people with anxiety and depression.Copyright © 2020 Australasian College for Emergency Medicine

Aim: The number of children and young people presenting to emergency departments (EDs) with anxiety and depression is increasing. We aimed to determine parent perspectives on: (i) barriers to accessing non-ED mental health services; and (ii) improving access in the paediatric mental health service system. Method(s): Qualitative study with parents of children and young people aged 0-19 years who attended one of four EDs across Victoria between October 2017 and September 2018 and received a primary diagnosis of anxiety or depression. Exclusion criteria: child or young person without a parent/guardian, or presented with self-harm or suicide attempt. Eligible participants completed semi-structured phone interviews. Interviews were recorded and transcripts were coded and analysed using content analysis. Result(s): A total of 72 parents completed interviews. The average child age was 14 years (standard deviation 2.5) and two thirds identified as female (64%). A total of 57% of children and young people presented with a primary diagnosis of anxiety. Parents reported barriers in accessing care including: service shortages and inaccessibility, underresourced schools, lack of clinician mental health expertise, lack of child-clinician rapport, inconsistent care, financial constraints, lack of mental health awareness among parents, and stigma. Parents want expanded and improved access to services, more respite and support services, supportive schools, and improved mental health education for parents. Conclusion(s): Parents of children and young people attending the ED for anxiety and depression are generally dissatisfied with services for child mental health. Solutions that enable parents to better care for their child in the community are needed to improve care.Copyright © 2020 Paediatrics and Child Health Division (The Royal Australasian College of Physicians)

Background: Active inflammatory bowel disease (IBD) adversely affects pregnancy outcomes. Little is known about the risk of relapse after stopping anti-tumor necrosis factor (anti-TNF) treatment during pregnancy. We assessed the risk of relapse before delivery in women who discontinued anti-TNF treatment before gestational week (GW) 30, predictors of reduced infant birth weight, a marker associated with long-term adverse outcomes, and rates and satisfaction with counseling. Method(s): Pregnant women with IBD receiving anti-TNF treatment were prospectively invited to participate in an electronic questionnaire carried out in 22 hospitals in Denmark, Australia, and New Zealand from 2011 to 2015. Risk estimates were calculated, and birth weight was investigated using t tests and linear regression. Result(s): Of 175 women invited, 153 (87%) responded. In women in remission, the relapse rate did not differ significantly between those who discontinued anti-TNF before GW 30 (1/46, 2%) compared with those who continued treatment (8/74, 11%; relative risk, 0.20; 95% confidence interval [CI], 0.02 to 1.56; P = 0.08). Relapse (P = 0.001) and continuation of anti-TNF therapy after GW 30 (P = 0.007) were independently associated with reduced mean birth weight by 367 g (95% CI, 145 to 589 g; relapse) and 274 g (95% CI, 77 to 471 g; anti-TNF exposure after GW 30). Of 134 (88%) women who received counseling, 116 (87%) were satisfied with the information provided. Conclusion(s): To minimize fetal exposure in women in remission, discontinuation of anti-TNF before GW 30 seems safe. Relapse and continuation of anti-TNF therapy after GW 30 were each independently associated with lower birth weight, although without an increased risk for birth weight <2500 g. Most women received and were satisfied with counseling.Copyright © 2019 Crohn's & Colitis Foundation. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Background and Purpose: Becoming a parent can be an exciting and also challenging transition, particularly for parents who have experienced significant hurt in their own childhoods, and may be experiencing ‘complex trauma.’ Aboriginal and Torres Strait Islander (Aboriginal) people also experience historical trauma. While the parenting transition is an important time to offer support for parents, it is essential to ensure that the benefits of identifying parents experiencing complex trauma outweigh any risks (e.g., stigmatization). This paper describes views of predominantly Aboriginal stakeholders regarding (1) the relative importance of domains proposed for complex trauma assessment, and (2) how to conduct these sensitive discussions with Aboriginal parents. Setting and Methods: A co-design workshop was held in Alice Springs (Central Australia) as part of an Aboriginal-led community-based participatory action research project. Workshop participants were 57 predominantly Aboriginal stakeholders with expertise in community, clinical, policy and academic settings. Twelve domains of complex trauma-related distress had been identified in existing assessment tools and through community consultation. Using story-telling and strategies to create safety for discussing complex and sensitive issues, and delphi-style methods, stakeholders rated the level of importance of the 12 domains; and discussed why, by whom, where and how experiences of complex trauma should be explored. Main Findings: The majority of stakeholders supported the importance of assessing each of the proposed complex trauma domains with Aboriginal parents. However, strong concerns were expressed regarding where, by whom and how this should occur. There was greater emphasis and consistency regarding ‘qualities’ (e.g., caring), rather than specific ‘attributes’ (e.g., clinician). Six critical overarching themes emerged: ensuring emotional and cultural safety; establishing relationships and trust; having capaci

Background. The red flour beetle Tribolium castaneum has emerged as an important model organism for the study of gene function in development and physiology, for ecological and evolutionary genomics, for pest control and a plethora of other topics. RNA interference (RNAi), transgenesis and genome editing are well established and the resources for genome-wide RNAi screening have become available in this model. All these techniques depend on a high quality genome assembly and precise gene models. However, the first version of the genome assembly was generated by Sanger sequencing, and with a small set of RNA sequence data limiting annotation quality. Results. Here, we present an improved genome assembly (Tcas5.2) and an enhanced genome annotation resulting in a new official gene set (OGS3) for Tribolium castaneum, which significantly increase the quality of the genomic resources. By adding large-distance jumping library DNA sequencing to join scaffolds and fill small gaps, the gaps in the genome assembly were reduced and the N50 increased to 4753kbp. The precision of the gene models was enhanced by the use of a large body of RNA-Seq reads of different life history stages and tissue types, leading to the discovery of 1452 novel gene sequences. We also added new features such as alternative splicing, well defined UTRs and microRNA target predictions. For quality control, 399 gene models were evaluated by manual inspection. The current gene set was submitted to Genbank and accepted as a RefSeq genome by NCBI. Conclusions. The new genome assembly (Tcas5.2) and the official gene set (OGS3) provide enhanced genomic resources for genetic work in Tribolium castaneum. The much improved information on transcription start sites supports transgenic and gene editing approaches. Further, novel types of information such as splice variants and microRNA target genes open additional possibilities for analysis.

Objective: The aim of this study was to investigate the relationship between perceived discrimination in perinatal care and birth outcomes of women giving birth to an Aboriginal baby in South Australia using methods designed to respect Aboriginal culture and communities. Design and setting: Population-based study of women giving birth to Aboriginal infants in South Australia, July 2011-June 2013. Women completed a structured questionnaire with an Aboriginal researcher. Study measures include: standardised measure of perceived discrimination in perinatal care; maternal smoking, cannabis use and exposure to stressful events and social health issues; infant birthweight and gestation. Participant(s): 344 women (mean age 25, range 15-43 years) living in urban, regional and remote areas of South Australia. Result(s): Half of women (51%) perceived that they had experienced discrimination or unfair treatment by hospitals or health services providing care during pregnancy and soon after childbirth. Women experiencing three or more stressful events or social health issues were more likely to perceive that care was discriminatory or unfair. Aboriginal women who perceived that they had experienced discrimination in perinatal care were more likely to have a baby with a low birthweight (Adj Odds Ratio 1.9, 95% CI 1.0-3.8) or small for gestational age (Adj Odds Ratio 1.9, 95% CI 1.0-3.5), adjusting for parity, smoking and cannabis use. Conclusion(s): The study provides evidence of the 'inverse care law'. Aboriginal women most at risk of poor infant health outcomes were the least likely to perceive that they received care well matched to their needs. Building stronger evidence about what works to create cultural safety in perinatal health care is an urgent priority.Copyright © 2019 Australian College of Midwives

Thyroid dysfunction is an important public health problem, which affects 10% of the general population and increases the risk of cardiovascular morbidity and mortality. Many aspects of thyroid hormone regulation have only partly been elucidated, including its transport, metabolism, and genetic determinants. Here we report a large meta-analysis of genome-wide association studies for thyroid function and dysfunction, testing 8 million genetic variants in up to 72,167 individuals. One-hundred-and-nine independent genetic variants are associated with these traits. A genetic risk score, calculated to assess their combined effects on clinical end points, shows significant associations with increased risk of both overt (Graves’ disease) and subclinical thyroid disease, as well as clinical complications. By functional follow-up on selected signals, we identify a novel thyroid hormone transporter (SLC17A4) and a metabolizing enzyme (AADAT). Together, these results provide new knowledge about thyroid hormone physiology and disease, opening new possibilities for therapeutic targets.

Objective Guidelines for thyroid function evaluation recommend testing TSH first, then assessing fT4 only if TSH is out of the reference range (two-step), but many clinicians initially request both TSH and fT4 (one-step). Given limitations of previous studies, we aimed to compare the two-step with the one-step approach in an unselected community-dwelling study population, and develop a prediction score based on clinical parameters that could identify at-risk patients for thyroid dysfunction. Design Cross-sectional analysis of the population-based Busselton Health Study. Methods We compared the two-step with the one-step approach, focusing on cases that would be missed by the two-step approach, i.e. those with normal TSH, but out-of-range fT4. We used likelihood ratio tests to identify demographic and clinical parameters associated with thyroid dysfunction and developed a clinical prediction score by using a beta-coefficient based scoring method. Results Following the two-step approach, 93.0% of all 4471 participants had normal TSH and would not need further testing. The two-step approach would have missed 3.8% of all participants (169 of 4471) with a normal TSH, but a fT4 outside the reference range. In 85% (144 of 169) of these cases, fT4 fell within 2 pmol/l of fT4 reference range limits, consistent with healthy outliers. The clinical prediction score that performed best excluded only 22.5% of participants from TSH testing. Conclusion The two-step approach may avoid measuring fT4 in as many as 93% of individuals with a very small risk of missing thyroid dysfunction. Our findings do not support the simultaneous initial measurement of both TSH and fT4.

The mechanisms responsible for the processing and quality control of the calcium-sensing receptor (CaSR) in the endoplasmic reticulum (ER) are largely unknown. In a yeast two-hybrid screen of the CaSR C-terminal tail (residues 865–1078), we identified osteosarcoma-9 (OS-9) protein as a binding partner. OS-9 is an ER-resident lectin that targets misfolded glycoproteins to the ER-associated degradation (ERAD) pathway through recognition of specific N-glycans by its mannose-6-phosphate receptor homology (MRH) domain. We show by confocal microscopy that the CaSR and OS-9 co-localize in the ER in COS-1 cells. In immunoprecipitation studies with co-expressed OS-9 and CaSR, OS-9 specifically bound the immature form of wild-type CaSR in the ER. OS-9 also bound the immature forms of a CaSR C-terminal deletion mutant and a C677A mutant that remains trapped in the ER, although binding to neither mutant was favored over wild-type receptor. OS-9 binding to immature CaSR required the MRH domain of OS-9 indicating that OS-9 acts as a lectin most likely to target misfolded CaSR to ERAD. Our results also identify two distinct binding interactions between OS-9 and the CaSR, one involving both C-terminal domains of the two proteins and the other involving both N-terminal domains. This suggests the possibility of more than one functional interaction between OS-9 and the CaSR. When we investigated the functional consequences of altered OS-9 expression, neither knockdown nor overexpression of OS-9 was found to have a significant effect on CaSR cell surface expression or CaSR-mediated ERK1/2 phosphorylation.

Contains fulltext : 177111.pdf (publisher's version ) (Closed access), BACKGROUND: Although most patients with atopic dermatitis (AD) are effectively managed with topical medication, a significant minority require systemic therapy. Guidelines for decision making about advancement to systemic therapy are lacking. OBJECTIVE: To guide those considering use of systemic therapy in AD and provide a framework for evaluation before making this therapeutic decision with the patient. METHODS: A subgroup of the International Eczema Council determined aspects to consider before prescribing systemic therapy. Topics were assigned to expert reviewers who performed a topic-specific literature review, referred to guidelines when available, and provided interpretation and expert opinion. RESULTS: We recommend a systematic and holistic approach to assess patients with severe signs and symptoms of AD and impact on quality of life before systemic therapy. Steps taken before commencing systemic therapy include considering alternate or concomitant diagnoses, avoiding trigger factors, optimizing topical therapy, ensuring adequate patient/caregiver education, treating coexistent infection, assessing the impact on quality of life, and considering phototherapy. LIMITATIONS: Our work is a consensus statement, not a systematic review. CONCLUSION: The decision to start systemic medication should include assessment of severity and quality of life while considering the individual's general health status, psychologic needs, and personal attitudes toward systemic therapies.

Summary Variation in stillbirth rates across high-income countries and large equity gaps within high-income countries persist. If all high-income countries achieved stillbirth rates equal to the best performing countries, 19 439 late gestation (28 weeks or more) stillbirths could have been avoided in 2015. The proportion of unexplained stillbirths is high and can be addressed through improvements in data collection, investigation, and classification, and with a better understanding of causal pathways. Substandard care contributes to 20-30% of all stillbirths and the contribution is even higher for late gestation intrapartum stillbirths. National perinatal mortality audit programmes need to be implemented in all high-income countries. The need to reduce stigma and fatalism related to stillbirth and to improve bereavement care are also clear, persisting priorities for action. In high-income countries, a woman living under adverse socioeconomic circumstances has twice the risk of having a stillborn child when compared to her more advantaged counterparts. Programmes at community and country level need to improve health in disadvantaged families to address these inequities.Copyright © 2016 Elsevier Ltd.