Summary Background Vitamin D is crucial for maintenance of musculoskeletal health, and might also have a role in extraskeletal tissues. Determinants of circulating 25-hydroxyvitamin D concentrations ...include sun exposure and diet, but high heritability suggests that genetic factors could also play a part. We aimed to identify common genetic variants affecting vitamin D concentrations and risk of insufficiency. Methods We undertook a genome-wide association study of 25-hydroxyvitamin D concentrations in 33 996 individuals of European descent from 15 cohorts. Five epidemiological cohorts were designated as discovery cohorts (n=16 125), five as in-silico replication cohorts (n=9367), and five as de-novo replication cohorts (n=8504). 25-hydroxyvitamin D concentrations were measured by radioimmunoassay, chemiluminescent assay, ELISA, or mass spectrometry. Vitamin D insufficiency was defined as concentrations lower than 75 nmol/L or 50 nmol/L. We combined results of genome-wide analyses across cohorts using Z -score-weighted meta-analysis. Genotype scores were constructed for confirmed variants. Findings Variants at three loci reached genome-wide significance in discovery cohorts for association with 25-hydroxyvitamin D concentrations, and were confirmed in replication cohorts: 4p12 (overall p=1·9×10−109 for rs2282679, in GC ); 11q12 (p=2·1×10−27 for rs12785878, near DHCR7 ); and 11p15 (p=3·3×10−20 for rs10741657, near CYP2R1 ). Variants at an additional locus (20q13, CYP24A1 ) were genome-wide significant in the pooled sample (p=6·0×10−10 for rs6013897). Participants with a genotype score (combining the three confirmed variants) in the highest quartile were at increased risk of having 25-hydroxyvitamin D concentrations lower than 75 nmol/L (OR 2·47, 95% CI 2·20–2·78, p=2·3×10−48 ) or lower than 50 nmol/L (1·92, 1·70–2·16, p=1·0×10−26 ) compared with those in the lowest quartile. Interpretation Variants near genes involved in cholesterol synthesis, hydroxylation, and vitamin D transport affect vitamin D status. Genetic variation at these loci identifies individuals who have substantially raised risk of vitamin D insufficiency. Funding Full funding sources listed at end of paper (see Acknowledgments).
Subclinical thyroid diseases—subclinical hyperthyroidism and subclinical hypothyroidism—are common clinical entities that encompass mild degrees of thyroid dysfunction. The clinical significance of ...mild thyroid overactivity and underactivity is uncertain, which has led to controversy over the appropriateness of diagnostic testing and possible treatment. In this Seminar, we discuss the definition, epidemiology, differential diagnoses, risks of progression to overt thyroid disease, potential effects on various health outcomes, and management of subclinical hyperthyroidism and subclinical hypothyroidism. Treatment recommendations are based on the degree to which thyroid-stimulating hormone concentrations have deviated from normal and underlying comorbidities. Large-scale randomised trials are urgently needed to inform how to best care for individuals with subclinical thyroid disease.
Summary Background Primary angle-closure glaucoma is a leading cause of irreversible blindness worldwide. In early-stage disease, intraocular pressure is raised without visual loss. Because the ...crystalline lens has a major mechanistic role, lens extraction might be a useful initial treatment. Methods From Jan 8, 2009, to Dec 28, 2011, we enrolled patients from 30 hospital eye services in five countries. Randomisation was done by a web-based application. Patients were assigned to undergo clear-lens extraction or receive standard care with laser peripheral iridotomy and topical medical treatment. Eligible patients were aged 50 years or older, did not have cataracts, and had newly diagnosed primary angle closure with intraocular pressure 30 mm Hg or greater or primary angle-closure glaucoma. The co-primary endpoints were patient-reported health status, intraocular pressure, and incremental cost-effectiveness ratio per quality-adjusted life-year gained 36 months after treatment. Analysis was by intention to treat. This study is registered, number ISRCTN44464607. Findings Of 419 participants enrolled, 155 had primary angle closure and 263 primary angle-closure glaucoma. 208 were assigned to clear-lens extraction and 211 to standard care, of whom 351 (84%) had complete data on health status and 366 (87%) on intraocular pressure. The mean health status score (0·87 SD 0·12), assessed with the European Quality of Life-5 Dimensions questionnaire, was 0·052 higher (95% CI 0·015–0·088, p=0·005) and mean intraocular pressure (16·6 SD 3·5 mm Hg) 1·18 mm Hg lower (95% CI –1·99 to –0·38, p=0·004) after clear-lens extraction than after standard care. The incremental cost-effectiveness ratio was £14 284 for initial lens extraction versus standard care. Irreversible loss of vision occurred in one participant who underwent clear-lens extraction and three who received standard care. No patients had serious adverse events. Interpretation Clear-lens extraction showed greater efficacy and was more cost-effective than laser peripheral iridotomy, and should be considered as an option for first-line treatment. Funding Medical Research Council.
Hyperthyroidism in pregnancy Cooper, David S; Laurberg, Peter
The lancet. Diabetes & endocrinology,
11/2013, Volume:
1, Issue:
3
Journal Article
Peer reviewed
Changes in thyroid hormone concentrations that are characteristic of hyperthyroidism must be distinguished from physiological changes in thyroid hormone economy that occur in pregnancy, especially in ...the first trimester. Approximately one to two cases of gestational hyperthyroidism occur per 1000 pregnancies. Identification of hyperthyroidism in a pregnant woman is important because adverse outcomes can occur in both the mother and the offspring. Graves' disease, which is autoimmune in nature, is the usual cause; but hyperthyroidism in pregnancy can be caused by any type of hyperthyroidism--eg, toxic multinodular goitre or solitary autonomously functioning nodule. Gestational transient thyrotoxicosis is typically reported in women with hyperemesis gravidarum, and is mediated by high circulating concentrations of human chorionic gonadotropin. Post-partum thyroiditis occurs in 5-10% of women, and many of those affected ultimately develop permanent hypothyroidism. Antithyroid drug treatment of hyperthyroidism in pregnant women is controversial because the usual drugs--methimazole or carbimazole--are occasionally teratogenic; and the alternative--propylthiouracil--can be hepatotoxic. Fetal hyperthyroidism can be life-threatening, and needs to be recognised as soon as possible so that treatment of the fetus with antithyroid drugs via the mother can be initiated. In this Review, we discuss physiological and pathophysiological changes in thyroid hormone economy in pregnancy, the diagnosis and management of hyperthyroidism during pregnancy, severe life-threatening thyrotoxicosis in pregnancy, neonatal thyrotoxicosis, and post-partum hyperthyroidism.
In many parts of the world, incidence of papillary thyroid cancer is increasing faster than any other malignancy. Most papillary thyroid cancers that are diagnosed are small and are generally ...regarded as being low risk, with little or no effect on mortality. Papillary thyroid cancer is a clinical challenge because it is difficult to prove benefit from the traditional therapeutic triad for this disorder (ie, total thyroidectomy with or without prophylactic central neck dissection, radioiodine remnant ablation, and suppression of serum thyroid-stimulating hormone with levothyroxine). However, risk of disease recurrence might be reduced by these therapies in a subset of patients with more aggressive disease. In the past decade, professional societies and other groups have established evidence-based clinical practice guidelines for management of papillary thyroid cancer, but these efforts have been made difficult by a paucity of randomised controlled trials. In this review, we summarise epidemiological data for disease incidence, discuss some controversies in disease management, and outline a therapeutic framework founded in the best available medical evidence and existing recommendations from clinical practice guidelines.
Hypothyroidism is the most common pregnancy-related thyroid disorder, affecting 3-5% of all pregnant women. Subclinical hypothyroidism is more common than is overt hypothyroidism, and is usually ...defined as a serum thyroid-stimulating hormone (TSH) concentration greater than the pregnancy-specific reference range for each laboratory value, or by serum TSH concentrations greater than 2·5 mIU/L in the first trimester and greater than 3 mIU/L in the second and third trimesters. Some authors have defined subclinical hypothyroidism as a serum TSH between 5 and 10 mIU/L, and overt hypothyroidism as a serum TSH greater than 10 mIU/L, but this is not the commonly accepted definition. Once overt hypothyroidism is diagnosed, treatment with levothyroxine should be started to achieve serum TSH concentrations within the reference ranges for pregnancy as soon as possible. For patients with subclinical hypothyroidism, recommendations for therapy differ between various professional groups as a result of inconsistent data from both observational studies and clinical trials regarding the benefits for the mother or the child. Similarly, because benefits of therapy are still uncertain, universal screening of all pregnant women for subclinical hypothyroidism or thyroid autoimmunity is not recommended by most professional groups. During gestation, an increase in levothyroxine dose is required in more than 50% of women with previously diagnosed hypothyroidism, and can be managed by increasing the levothyroxine dose by 30% when pregnancy is confirmed.
Summary Background Two randomised, placebo-controlled trials—BENCHMRK-1 and BENCHMRK-2—investigated the efficacy and safety of raltegravir, an HIV-1 integrase strand-transfer inhibitor. We report ...final results of BENCHMRK-1 and BENCHMRK-2 combined at 3 years (the end of the double-blind phase) and 5 years (the end of the study). Methods Integrase-inhibitor-naive patients with HIV resistant to three classes of drug and who were failing antiretroviral therapy were enrolled. Patients were randomly assigned (2:1) to raltegravir 400 mg twice daily or placebo, both with optimised background treatment. Patients and investigators were masked to treatment allocation until week 156, after which all patients were offered open-label raltegravir until week 240. The primary endpoint was previously assessed at 16 weeks. We assessed long-term efficacy with endpoints of the proportion of patients with an HIV viral load of less than 50 copies per mL and less than 400 copies per mL, and mean change in CD4 cell count, at weeks 156 and 240. Findings 1012 patients were screened for inclusion. 462 were treated with raltegravir and 237 with placebo. At week 156, 51% in the raltegravir group versus 22% in the placebo group (non-completer classed as failure) had viral loads of less than 50 copies per mL, and 54% versus 23% had viral loads of less than 400 copies per mL. Mean CD4 cell count increase (analysed by an observed failure approach) was 164 cells per μL versus 63 cells per μL. After week 156, 251 patients (54%) from the raltegravir group and 47 (20%) from the placebo group entered the open-label raltergravir phase; 221 (47%) versus 44 (19%) completed the entire study. At week 240, viral load was less than 50 copies per mL in 193 (42%) of all patients initially assigned to raltegravir and less than 400 copies per mL in 210 (45%); mean CD4 cell count increased by 183 cells per μL. Virological failure occurred in 166 raltegravir recipients (36%) during the double-blind phase and in 17 of all patients (6%) during the open-label phase. The most common drug-related adverse events at 5 years in both groups were nausea, headache, and diarrhoea, and occurred in similar proportions in each group. Laboratory test results were similar in both treatment groups and showed little change after year 2. Interpretation Raltegravir has a favourable long-term efficacy and safety profile in integrase-inhibitor-naive patients with triple-class resistant HIV in whom antiretroviral therapy is failing. Raltegravir is an alternative for treatment-experienced patients, particularly those with few treatment options. Funding Merck Sharp & Dohme.
Statin treatment and variants in the gene encoding HMG-CoA reductase are associated with reductions in both the concentration of LDL cholesterol and the risk of coronary heart disease, but also with ...modest hyperglycaemia, increased bodyweight, and modestly increased risk of type 2 diabetes, which in no way offsets their substantial benefits. We sought to investigate the associations of LDL cholesterol-lowering PCSK9 variants with type 2 diabetes and related biomarkers to gauge the likely effects of PCSK9 inhibitors on diabetes risk.
In this mendelian randomisation study, we used data from cohort studies, randomised controlled trials, case control studies, and genetic consortia to estimate associations of PCSK9 genetic variants with LDL cholesterol, fasting blood glucose, HbA1c, fasting insulin, bodyweight, waist-to-hip ratio, BMI, and risk of type 2 diabetes, using a standardised analysis plan, meta-analyses, and weighted gene-centric scores.
Data were available for more than 550 000 individuals and 51 623 cases of type 2 diabetes. Combined analyses of four independent PCSK9 variants (rs11583680, rs11591147, rs2479409, and rs11206510) scaled to 1 mmol/L lower LDL cholesterol showed associations with increased fasting glucose (0·09 mmol/L, 95% CI 0·02 to 0·15), bodyweight (1·03 kg, 0·24 to 1·82), waist-to-hip ratio (0·006, 0·003 to 0·010), and an odds ratio for type diabetes of 1·29 (1·11 to 1·50). Based on the collected data, we did not identify associations with HbA1c (0·03%, −0·01 to 0·08), fasting insulin (0·00%, −0·06 to 0·07), and BMI (0·11 kg/m2, −0·09 to 0·30).
PCSK9 variants associated with lower LDL cholesterol were also associated with circulating higher fasting glucose concentration, bodyweight, and waist-to-hip ratio, and an increased risk of type 2 diabetes. In trials of PCSK9 inhibitor drugs, investigators should carefully assess these safety outcomes and quantify the risks and benefits of PCSK9 inhibitor treatment, as was previously done for statins.
British Heart Foundation, and University College London Hospitals NHS Foundation Trust (UCLH) National Institute for Health Research (NIHR) Biomedical Research Centre.
The shortage of organs and cells from deceased individuals continues to restrict allotransplantation. Pigs could provide an alternative source of tissue and cells but the immunological challenges and ...other barriers associated with xenotransplantation need to be overcome. Transplantation of organs from genetically modified pigs into non-human primates is now not substantially limited by hyperacute, acute antibody-mediated, or cellular rejection, but other issues have become more prominent, such as development of thrombotic microangiopathy in the graft or systemic consumptive coagulopathy in the recipient. To address these problems, pigs that express one or more human thromboregulatory or anti-inflammatory genes are being developed. The results of preclinical transplantation of pig cells—eg, islets, neuronal cells, hepatocytes, or corneas—are much more encouraging than they are for organ transplantation, with survival times greater than 1 year in all cases. Risk of transfer of an infectious microorganism to the recipient is small.
Summary Background A consensus statement released on behalf of the Swiss Federal Commission for HIV/AIDS suggests that people receiving effective antiretroviral therapy—ie, those with undetectable ...plasma HIV RNA (<40 copies per mL)—are sexually non-infectious. We analysed the implications of this statement at a population level. Methods We used a simple mathematical model to estimate the cumulative risk of HIV transmission from effectively treated HIV-infected patients (HIV RNA <10 copies per mL) over a prolonged period. We investigated the risk of unprotected sexual transmission per act and cumulatively over many exposures, within couples initially discordant for HIV status. Findings Assuming that each couple had 100 sexual encounters per year, the cumulative probability of transmission to the serodiscordant partner each year is 0·0022 (uncertainty bounds 0·0008–0·0058) for female-to-male transmission, 0·0043 (0·0016–0·0115) for male-to-female transmission, and 0·043 (0·0159–0·1097) for male-to-male transmission. In a population of 10 000 serodiscordant partnerships, over 10 years the expected number of seroconversions would be 215 (80–564) for female-to-male transmission, 425 (159–1096) for male-to-female transmission, and 3524 (1477–6871) for male-to-male transmission, corresponding to an increase in incidence of four times compared with incidence under current rates of condom use. Interpretation Our analyses suggest that the risk of HIV transmission in heterosexual partnerships in the presence of effective treatment is low but non-zero and that the transmission risk in male homosexual partnerships is high over repeated exposures. If the claim of non-infectiousness in effectively treated patients was widely accepted, and condom use subsequently declined, then there is the potential for substantial increases in HIV incidence. Funding Australian Research Council.
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