Occurrence of Hypothyroidism, Diabetes Mellitus, and Celiac Disease in Emirati Children with Down’s Syndrome

Objectives: Autoimmune diseases are known to occur in people with Down’s syndrome (DS), especially celiac disease, type 1 diabetes mellitus (DM), and hypothyroidism. Since there are common genetic risk factors involved in the occurrence of these autoimmune disorders, the risks would differ in different populations. We sought to determine the prevalence of type 1 DM, celiac disease, and hypothyroidism in Emirati patients with DS in Abu Dhabi, UAE. Methods: Ninety-two patients with DS were investigated for the presence of anti-thyroid antibodies, antithyroglobulin, and anti-thyroid peroxidase antibodies for hypothyroidism, anti-glutamic acid decarboxylase antibodies for type 1 DM, and anti-tissue transglutaminase immunoglobulin A antibodies for celiac disease. Results: Karyotyping was performed on 89 patients. Eighty-seven had non-disjunction of chromosome 21 (97.8%), one was a mosaic, and one had translocation. Of the patients studied, 19.6% had hypothyroidism, 4.3% had type 1 DM, and 1.1% had celiac disease. Out of the 92 patients studied, 66 (71.7%) did not have any autoimmune disease, 25 (27.2%) had one autoimmune disease, and one (1.1%) had two autoimmune diseases. Conclusions: Celiac disease was the least prevalent autoimmune disease in patients with DS patients, while type 1 DM and hypothyroidism were both significantly associated with DS

International Regulations and Recommendations for Utility Data for Health Technology Assessment

Recommendations and guidelines for the collection, generation, source and usage of utility data for health technology assessment (HTA) vary across different countries, with no international consensus. Many international agencies generate their own guidelines providing details on their preferred methods for HTA submissions, and there is variability in both what they recommend and the clarity and amount of detail provided in their guidelines. This article provides an overview of international regulations and recommendations for utility data in HTA for a selection of key HTA countries: Australia, Canada, France, Germany, the Netherlands, Spain (Catalonia), Sweden and the UK (England/Wales and Scotland). International guidelines are typically clear and detailed for the selection of countries assessed regarding the source description of health states (e.g. generic preference-based measure) and who should provide preference weights for these health states (e.g. general population for own country). Many guidelines specify the use of off-the-shelf generic preference-based measures, and some further specify a measure, such as EQ-5D. However, international guidelines are either unclear or lack detailed guidance regarding the collection (e.g. patients report own health), source (e.g. clinical trial) and usage (e.g. adjusting for comorbidities) of utility values. It is argued that there is a need for transparent and detailed international guidelines on utility data recommendations to provide decision makers with the best possible evidence. Where this is not possible it is recommended that best practice should be used to inform the collection, source and usage of utility values in HTA

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

The Role Of Condition-Specific Preference-Based Measures In Health Technology Assessment

A condition-specific preference-based measure (CSPBM) is a measure of health related quality of life (HRQoL) that is specific to a certain condition or disease and that can be used to obtain the quality adjustment weight of the quality adjusted life year (QALY) for use in economic models. This article provides an overview of the role of CSPBMs, the development of CSPBMs, and presents a description of existing CSPBMs in the literature. The article also provides an overview of the psychometric properties of CSPBMs in comparison to generic preference-based measures (generic PBMs), and considers the advantages and disadvantages of CSPBMs in comparison to generic PBMs. CSPBMs typically include dimensions that are important for that condition but may not be important across all patient groups. There are a large number of CSPBMs across a wide range of conditions, and these vary from covering a wide range of dimensions to more symptomatic or uni-dimensional measures. Psychometric evidence is limited but suggests that CSPBMs offer an advantage in more accurate measurement of milder health states. The mean change and standard deviation can differ for CSPBMs and generic PBMs, and this may impact on incremental cost-effectiveness ratios. CSPBMs have a useful role in HTA where a generic PBM is not appropriate, sensitive or responsive. However due to issues of comparability across different patient groups and interventions, their usage in health technology assessment is often limited to conditions where it is inappropriate to use a generic PBM or sensitivity analyses

Glucose controls CREB activity in islet cells via regulated phosphorylation of TORC2

CREB is a cAMP- and calcium-responsive transcriptional activator that is required for islet beta cell proliferation and survival. Glucose and incretin hormones elicit beta cell insulin secretion and promote synergistic CREB activity by inducing the nuclear relocalization of TORC2 (also known as Crtc2), a coactivator for CREB. In islet cells under basal conditions when CREB activity is low, TORC2 is phosphorylated and sequestered in the cytoplasm by 14-3-3 proteins. In response to feeding stimuli, TORC2 is dephosphorylated, enters the nucleus, and binds to CREB located at target gene promoters. The dephosphorylation of TORC2 at Ser-171 in response to cAMP is insufficient to account for the dynamics of TORC2 localization and CREB activity in islet cells. Here, we identify Ser-275 of TORC2 as a 14-3-3 binding site that is phosphorylated under low glucose conditions and which becomes dephosphorylated by calcineurin in response to glucose influx. Dephosphorylation of Ser-275 is essential for both glucose and cAMP-mediated activation of CREB in beta cells and islets. Using a cell-based screen of 180 human protein kinases, we identified MARK2, a member of the AMPK family of Ser/Thr kinases, as a Ser-275 kinase that blocks TORC2:CREB activity. Taken together, these data provide the mechanistic underpinning for how cAMP and glucose cooperatively promote a transcriptional program critical for islet cell survival, and identifies MARK2 as a potential target for diabetes treatment

Interim Results from the IMPACT Study : Evidence for Prostate-specific Antigen Screening in BRCA2 Mutation Carriers

Mutations in BRCA2 cause a higher risk of early-onset aggressive prostate cancer (PrCa). The IMPACT study is evaluating targeted PrCa screening using prostate-specific-antigen (PSA) in men with germline BRCA1/2 mutations. To report the utility of PSA screening, PrCa incidence, positive predictive value of PSA, biopsy, and tumour characteristics after 3 yr of screening, by BRCA status. Men aged 40-69 yr with a germline pathogenic BRCA1/2 mutation and male controls testing negative for a familial BRCA1/2 mutation were recruited. Participants underwent PSA screening for 3 yr, and if PSA > 3.0 ng/ml, men were offered prostate biopsy. PSA levels, PrCa incidence, and tumour characteristics were evaluated. Statistical analyses included Poisson regression offset by person-year follow-up, chi-square tests for proportion t tests for means, and Kruskal-Wallis for medians. A total of 3027 patients (2932 unique individuals) were recruited (919 BRCA1 carriers, 709 BRCA1 noncarriers, 902 BRCA2 carriers, and 497 BRCA2 noncarriers). After 3 yr of screening, 527 men had PSA > 3.0 ng/ml, 357 biopsies were performed, and 112 PrCa cases were diagnosed (31 BRCA1 carriers, 19 BRCA1 noncarriers, 47 BRCA2 carriers, and 15 BRCA2 noncarriers). Higher compliance with biopsy was observed in BRCA2 carriers compared with noncarriers (73% vs 60%). Cancer incidence rate per 1000 person years was higher in BRCA2 carriers than in noncarriers (19.4 vs 12.0; p = 0.03); BRCA2 carriers were diagnosed at a younger age (61 vs 64 yr; p = 0.04) and were more likely to have clinically significant disease than BRCA2 noncarriers (77% vs 40%; p = 0.01). No differences in age or tumour characteristics were detected between BRCA1 carriers and BRCA1 noncarriers. The 4 kallikrein marker model discriminated better (area under the curve [AUC] = 0.73) for clinically significant cancer at biopsy than PSA alone (AUC = 0.65). After 3 yr of screening, compared with noncarriers, BRCA2 mutation carriers were associated with a higher incidence of PrCa, younger age of diagnosis, and clinically significant tumours. Therefore, systematic PSA screening is indicated for men with a BRCA2 mutation. Further follow-up is required to assess the role of screening in BRCA1 mutation carriers. Patient summary: We demonstrate that after 3 yr of prostate-specific antigen (PSA) testing, we detect more serious prostate cancers in men with BRCA2 mutations than in those without these mutations. We recommend that male BRCA2 carriers are offered systematic PSA screening

An international expanded-access programme of Everolimus : Addressing safety and efficacy in patients with metastatic renal cell carcinoma who progress after initial vascular endothelial growth factor receptor-tyrosine kinase inhibitor therapy

BACKGROUND AND OBJECTIVES: The RECORD-1 trial established the clinical benefit of everolimus in patients with metastatic renal cell carcinoma (mRCC) after failure of initial vascular endothelial growth factor receptor-tyrosine kinase inhibitor (VEGFr-TKI) therapy. The REACT (RAD001 Expanded Access Clinical Trial in RCC) study was initiated to address an unmet medical need by providing everolimus prior to commercial availability, and also to further assess the safety and efficacy of everolimus in patients with VEGFr-TKI-refractory mRCC. PATIENTS AND METHODS: REACT (Clinicaltrials.gov: NCT00655252) was a global, open-label, expanded-access programme in patients with mRCC who were intolerant of, or who had progressed on or after stopping treatment with, any available VEGFr-TKI therapy. Patients received everolimus 10mg once daily, with dose and schedule modifications allowed for toxicity. Patients were closely monitored for the development of serious and grades 3/4 adverse events (AEs). Response was assessed by RECIST every 3months for the first year and every 6months thereafter. RESULTS: A total of 1367 patients were enroled. Safety findings and tumour responses were consistent with those observed in RECORD-1, with no new safety issues identified. The most commonly reported serious AEs were dyspnoea (5.0%), pneumonia (4.7%) and anaemia (4.1%), and the most commonly reported grades 3/4 AEs were anaemia (13.4%), fatigue (6.7%) and dyspnoea (6.5%). Best overall response was stable disease in 51.6% and partial response in 1.7% of patients. Median everolimus treatment duration was 14weeks. CONCLUSION: Everolimus is well tolerated in patients with mRCC and demonstrates a favourable risk-benefit ratio

Kuntayhtymien talous vuonna 1968

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Common variation near CDKN1A, POLD3 and SHROOM2 influences colorectal cancer risk

We performed a meta-analysis of five genome-wide association studies to identify common variants influencing colorectal cancer (CRC) risk comprising 8,682 cases and 9,649 controls. Replication analysis was performed in case-control sets totaling 21,096 cases and 19,555 controls. We identified three new CRC risk loci at 6p21 (rs1321311, near CDKN1A; P = 1.14 × 10 -10), 11q13.4 (rs3824999, intronic to POLD3; P = 3.65 × 10 -10) and Xp22.2 (rs5934683, near SHROOM2; P = 7.30 × 10 -10) This brings the number of independent loci associated with CRC risk to 20 and provides further insight into the genetic architecture of inherited susceptibility to CRC.</p