Rare and Common Variants Conferring Risk of Tooth Agenesis

We present association results from a large genome-wide association study of tooth agenesis (TA) as well as selective TA, including 1,944 subjects with congenitally missing teeth, excluding third molars, and 338,554 controls, all of European ancestry. We also tested the association of previously identified risk variants, for timing of tooth eruption and orofacial clefts, with TA. We report associations between TA and 9 novel risk variants. Five of these variants associate with selective TA, including a variant conferring risk of orofacial clefts. These results contribute to a deeper understanding of the genetic architecture of tooth development and disease. The few variants previously associated with TA were uncovered through candidate gene studies guided by mouse knockouts. Knowing the etiology and clinical features of TA is important for planning oral rehabilitation that often involves an interdisciplinary approach

Structured headache services as the solution to the ill-health burden of headache: 1. Rationale and description

In countries where headache services exist at all, their focus is usually on specialist (tertiary) care. This is clinically and economically inappropriate: most headache disorders can effectively and more efficiently (and at lower cost) be treated in educationally supported primary care. At the same time, compartmentalizing divisions between primary, secondary and tertiary care in many health-care systems create multiple inefficiencies, confronting patients attempting to navigate these levels (the “patient journey”) with perplexing obstacles. High demand for headache care, estimated here in a needs-assessment exercise, is the biggest of the challenges to reform. It is also the principal reason why reform is necessary. The structured headache services model presented here by experts from all world regions on behalf of the Global Campaign against Headache is the suggested health-care solution to headache. It develops and refines previous proposals, responding to the challenge of high demand by basing headache services in primary care, with two supporting arguments. First, only primary care can deliver headache services equitably to the large numbers of people needing it. Second, with educational supports, they can do so effectively to most of these people. The model calls for vertical integration between care levels (primary, secondary and tertiary), and protection of the more advanced levels for the minority of patients who need them. At the same time, it is amenable to horizontal integration with other care services. It is adaptable according to the broader national or regional health services in which headache services should be embedded. It is, according to evidence and argument presented, an efficient and cost-effective model, but these are claims to be tested in formal economic analyses

Rare SLC13A1 variants associate with intervertebral disc disorder highlighting role of sulfate in disc pathology.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked DownloadBack pain is a common and debilitating disorder with largely unknown underlying biology. Here we report a genome-wide association study of back pain using diagnoses assigned in clinical practice; dorsalgia (119,100 cases, 909,847 controls) and intervertebral disc disorder (IDD) (58,854 cases, 922,958 controls). We identify 41 variants at 33 loci. The most significant association (ORIDD = 0.92, P = 1.6 × 10-39; ORdorsalgia = 0.92, P = 7.2 × 10-15) is with a 3'UTR variant (rs1871452-T) in CHST3, encoding a sulfotransferase enzyme expressed in intervertebral discs. The largest effects on IDD are conferred by rare (MAF = 0.07 - 0.32%) loss-of-function (LoF) variants in SLC13A1, encoding a sodium-sulfate co-transporter (LoF burden OR = 1.44, P = 3.1 × 10-11); variants that also associate with reduced serum sulfate. Genes implicated by this study are involved in cartilage and bone biology, as well as neurological and inflammatory processes.European Commission European Commission Joint Research Centre Novo Nordisk Foundation Novocure Limite

Multimorbidity and use of hypnotic and anxiolytic drugs: Cross-sectional and follow-up study in primary healthcare in Iceland

Background The prevalence of multimorbidity is increasing worldwide, presumably leading to an increased use of medicines. During the last decades the use of hypnotic and anxiolytic benzodiazepine derivatives and related drugs has increased dramatically. These drugs are frequently prescribed for people with a sleep disorder often merely designated as “insomnia” in the medical records and lacking a clear connection with the roots of the patients’ problems. Our aim was to analyse the prevalence of multimorbidity in primary healthcare in Iceland, while concurrently investigating a possible association with the prevalence and incidence of hypnotic/anxiolytic prescriptions, short-term versus chronic use. Methods Data were retrieved from a comprehensive database of medical records from primary healthcare in Iceland to find multimorbid patients and prescriptions for hypnotics and anxiolytics, linking diagnoses (ICD-10) and prescriptions (2009–2012) to examine a possible association. Nearly 222,000 patients, 83 % being local residents in the capital area, who contacted 16 healthcare centres served in total by 140 general practitioners, were set as a reference to find the prevalence of multimorbidity as well as the prevalence and incidence of hypnotic/anxiolytic prescriptions. Results The prevalence of multimorbidity in the primary care population was 35 %, lowest in the young, increasing with age up to the 80+ group where it dropped somewhat. The prevalence of hypnotic/anxiolytic prescriptions was 13.9 %. The incidence rate was 19.4 per 1000 persons per year in 2011, and 85 % of the patients prescribed hypnotics/anxiolytics were multimorbid. Compared to patients without multimorbidity, multimorbid patients were far more likely to be prescribed a hypnotic and/or an anxiolytic, OR = 14.9 (95 % CI = 14.4–15.4). Conclusions Patients with multiple chronic conditions are common in the primary care setting, and prevalence and incidence of hypnotic/anxiolytic prescriptions are high. Solely explaining use of these drugs by linear thinking, i.e. that “insomnia” leads to their prescription is probably simplistic, since the majority of patients prescribed these drugs are multimorbid having several chronic conditions which could lead to sleeping problems. However, multimorbidity as such is not an indication for hypnotics, and doctors should be urged to greater caution in their prescribing, bearing in mind non-pharmacological therapy options

A genetic risk factor for periodic limb movements in sleep

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldBACKGROUND: The restless legs syndrome (RLS) is a common neurologic disorder characterized by an irresistible urge to move the legs. It is a major cause of sleep disruption. Periodic limb movements in sleep are detectable in most patients with RLS and represent an objective physiological metric. METHODS: To search for sequence variants contributing to RLS, we performed a genomewide association study and two replication studies. To minimize phenotypic heterogeneity, we focused on patients with RLS who had objectively documented periodic limb movements in sleep. We measured serum ferritin levels, since iron depletion has been associated with the pathogenesis of RLS. RESULTS: In an Icelandic discovery sample of patients with RLS and periodic limb movements in sleep, we observed a genomewide significant association with a common variant in an intron of BTBD9 on chromosome 6p21.2 (odds ratio, 1.8; P=2x10(-9)). This association was replicated in a second Icelandic sample (odds ratio, 1.8; P=4x10(-4)) and a U.S. sample (odds ratio, 1.5; P=4x10(-3)). With this variant, the population attributable risk of RLS with periodic limb movements was approximately 50%. An association between the variant and periodic limb movements in sleep without RLS (and the absence of such an association for RLS without periodic limb movements) suggests that we have identified a genetic determinant of periodic limb movements in sleep (odds ratio, 1.9; P=1x10(-17)). Serum ferritin levels were decreased by 13% per allele of the at-risk variant (95% confidence interval, 5 to 20; P=0.002). CONCLUSIONS: We have discovered a variant associated with susceptibility to periodic limb movements in sleep. The inverse correlation of the variant with iron stores is consistent with the suspected involvement of iron depletion in the pathogenesis of the disease

Enzyme immunoassays in brown snake (Pseudonaja spp.) envenoming: Detecting venom, antivenom and venom-antivenom complexes

To access publisher's full text version of this article click on the hyperlink at the bottom of the pageIn a small fraction of patients with schizophrenia or autism, alleles of copy-number variants (CNVs) in their genomes are probably the strongest factors contributing to the pathogenesis of the disease. These CNVs may provide an entry point for investigations into the mechanisms of brain function and dysfunction alike. They are not fully penetrant and offer an opportunity to study their effects separate from that of manifest disease. Here we show in an Icelandic sample that a few of the CNVs clearly alter fecundity (measured as the number of children by age 45). Furthermore, we use various tests of cognitive function to demonstrate that control subjects carrying the CNVs perform at a level that is between that of schizophrenia patients and population controls. The CNVs do not all affect the same cognitive domains, hence the cognitive deficits that drive or accompany the pathogenesis vary from one CNV to another. Controls carrying the chromosome 15q11.2 deletion between breakpoints 1 and 2 (15q11.2(BP1-BP2) deletion) have a history of dyslexia and dyscalculia, even after adjusting for IQ in the analysis, and the CNV only confers modest effects on other cognitive traits. The 15q11.2(BP1-BP2) deletion affects brain structure in a pattern consistent with both that observed during first-episode psychosis in schizophrenia and that of structural correlates in dyslexia.info:eu-repo/grantAgreement/EC/FP/286213/EU//OpenAIREplusinfo:eu-repo/grantAgreement/EC/FP7/28621

Ron Clarke heads down the track with the Olympic torch, Melbourne Cricket Ground, 22 November, 1956 [picture] /

Part of the collection: Olympic Games, Melbourne, Victoria 1956.; Title devised by cataloguer from typed label on reverse.; Inscriptions: "Ron Clarke heads down the track with the Olympic torch, MCG. 22.11.1956"--Typed label on reverse.; Also available in electronic version via the Internet at: http//nla.gov.au/nla.pic-vn4278496-s44; Donated through the Australian Government's Cultural Gifts Program by Bruce Howard, 2007

Rare SLC13A1 variants associate with intervertebral disc disorder highlighting role of sulfate in disc pathology

Back pain is a common and debilitating disorder with largely unknown underlying biology. Here we report a genome-wide association study of back pain using diagnoses assigned in clinical practice; dorsalgia (119,100 cases, 909,847 controls) and intervertebral disc disorder (IDD) (58,854 cases, 922,958 controls). We identify 41 variants at 33 loci. The most significant association (ORIDD = 0.92, P = 1.6 × 10−39; ORdorsalgia = 0.92, P = 7.2 × 10−15) is with a 3’UTR variant (rs1871452-T) in CHST3, encoding a sulfotransferase enzyme expressed in intervertebral discs. The largest effects on IDD are conferred by rare (MAF = 0.07 − 0.32%) loss-of-function (LoF) variants in SLC13A1, encoding a sodium-sulfate co-transporter (LoF burden OR = 1.44, P = 3.1 × 10−11); variants that also associate with reduced serum sulfate. Genes implicated by this study are involved in cartilage and bone biology, as well as neurological and inflammatory processes