Showing papers by "Institute of Chartered Accountants of Nigeria published in 2017"

Evaluation of a melanocortin-4 receptor (MC4R) agonist (Setmelanotide) in MC4R deficiency.

Abstract: Objective Pro-opiomelanocortin (POMC)-derived peptides act on neurons expressing the Melanocortin 4 receptor (MC4R) to reduce body weight. Setmelanotide is a highly potent MC4R agonist that leads to weight loss in diet-induced obese animals and in obese individuals with complete POMC deficiency. While POMC deficiency is very rare, 1–5% of severely obese individuals harbor heterozygous mutations in MC4R. We sought to assess the efficacy of Setmelanotide in human MC4R deficiency.

Life-threatening massive pulmonary embolism rescued by venoarterial-extracorporeal membrane oxygenation

Abstract: Despite quick implementation of reperfusion therapies, a few patients with high-risk, acute, massive, pulmonary embolism (PE) remain highly hemodynamically unstable. Others have absolute contraindication to receive reperfusion therapies. Venoarterial-extracorporeal membrane oxygenation (VA-ECMO) might lower their right ventricular overload, improve hemodynamic status, and restore tissue oxygenation. ECMO-related complications and 90-day mortality were analyzed for 17 highly unstable, ECMO-treated, massive PE patients admitted to a tertiary-care center (2006–2015). Hospital- discharge survivors were assessed for long-term health-related quality of life. A systematic review of this topic was also conducted. Seventeen high-risk PE patients [median age 51 (range 18–70) years, Simplified Acute Physiology Score II (SAPS II) 78 (45–95)] were placed on VA-ECMO for 4 (1–12) days. Among 15 (82%) patients with pre-ECMO cardiac arrest, seven (41%) were cannulated during cardiopulmonary resuscitation, and eight (47%) underwent pre-ECMO thrombolysis. Pre-ECMO median blood pressure, pH, and blood lactate were, respectively: 42 (0–106) mmHg, 6.99 (6.54–7.37) and 13 (4–19) mmol/L. Ninety-day survival was 47%. Fifteen (88%) patients suffered in-ICU severe hemorrhages with no impact on survival. Like other ECMO-treated patients, ours reported limitations of all physical domains but preserved mental health 19 (4–69) months post-ICU discharge. VA-ECMO could be a lifesaving rescue therapy for patients with high-risk, acute, massive PE when thrombolytic therapy fails or the patient is too sick to benefit from surgical thrombectomy. Because heparin-induced clot dissolution and spontaneous fibrinolysis allows ECMO weaning within several days, future studies should investigate whether VA-ECMO should be the sole therapy or completed by additional mechanical clot-removal therapies in this setting.

Immune cell-derived cytokines contribute to obesity-related inflammation, fibrogenesis and metabolic deregulation in human adipose tissue.

Abstract: Adipose tissue contains a variety of immune cells, which vary in abundance and phenotype with obesity The contribution of immune cell-derived factors to inflammatory, fibrotic and metabolic alterations in adipose tissue is not well established in human obesity Human primary adipose tissue cells, including pre-adipocytes, endothelial cells and mature adipocytes, were used to investigate deregulation of cell- and pathway-specific gene profiles Among factors known to alter adipose tissue biology, we focus on inflammatory (IL-1β and IL-17) and pro-fibrotic (TGF-β1) factors rIL-1β and rIL-17 induced concordant pro-inflammatory transcriptional programs in pre-adipocytes and endothelial cells, with a markedly more potent effect of IL-1β than IL-17 None of these cytokines had significant effect on fibrogenesis-related gene expression, contrasting with rTGF-β1-induced up-regulation of extracellular matrix components and pro-fibrotic factors In mature adipocytes, all three factors promoted down-regulation of genes functionally involved in lipid storage and release IL-1β and IL-17 impacted adipocyte metabolic genes in relation with their respective pro-inflammatory capacity, while the effect of TGF-β1 occurred in face of an anti-inflammatory signature These data revealed that IL-1β and IL-17 had virtually no effect on pro-fibrotic alterations but promote inflammation and metabolic dysfunction in human adipose tissue, with a prominent role for IL-1β

Exome-wide association study reveals novel susceptibility genes to sporadic dilated cardiomyopathy

Abstract: Aims Dilated cardiomyopathy (DCM) is an important cause of heart failure with a strong familial component. We performed an exome-wide array-based association study (EWAS) to assess the contribution of missense variants to sporadic DCM. Methods and results 116,855 single nucleotide variants (SNVs) were analyzed in 2796 DCM patients and 6877 control subjects from 6 populations of European ancestry. We confirmed two previously identified associations with SNVs in BAG3 and ZBTB17 and discovered six novel DCM-associated loci (Q-value<0.01). The lead-SNVs at novel loci are common and located in TTN, SLC39A8, MLIP, FLNC, ALPK3 and FHOD3. In silico fine mapping identified HSPB7 as the most likely candidate at the ZBTB17 locus. Rare variant analysis (MAF<0.01) demonstrated significant association for TTN variants only (P = 0.0085). All candidate genes but one (SLC39A8) exhibit preferential expression in striated muscle tissues and mutations in TTN, BAG3, FLNC and FHOD3 are known to cause familial cardiomyopathy. We also investigated a panel of 48 known cardiomyopathy genes. Collectively, rare (n = 228, P = 0.0033) or common (n = 36, P = 0.019) variants with elevated in silico severity scores were associated with DCM, indicating that the spectrum of genes contributing to sporadic DCM extends beyond those identified here. Conclusion We identified eight loci independently associated with sporadic DCM. The functions of the best candidate genes at these loci suggest that proteostasis regulation might play a role in DCM pathophysiology.

Temporal trends, clinical patterns and outcomes of NAFLD‐related HCC in patients undergoing liver resection over a 20‐year period

Abstract: SummaryBackground Non-alcoholic fatty liver disease (NAFLD) is an increasing cause of hepatocellular carcinoma (HCC) worldwide. NAFLD-HCC often occurs in noncirrhotic liver raising important surveillance issues. Aim To determine the temporal trends for prevalence, clinical characteristics and outcomes of NAFLD-HCC in patients undergoing liver resection. Methods Consecutive patients with histologically confirmed HCC who underwent liver resection over a 20-year period (1995-2014). NAFLD was diagnosed based on past or present exposure to obesity or diabetes without other causes of chronic liver disease. Results A total of 323 HCC patients were included, 12% with NAFLD. From 1995-1999 to 2010-2014, the prevalence of NAFLD-HCC increased from 2.6% to 19.5%, respectively, P = .003, and followed the temporal trends in the prevalence of metabolic risk factors (28% vs 52%, P = .017), while hepatitis C-HCC decreased (from 43.6% to 19.5%, P = .003). NAFLD-HCC occurred more frequently in the absence of bridging fibrosis/cirrhosis (63% of cases, P < .001 compared to other aetiologies). Within the NAFLD group, tumour characteristics were similar between F0-F2 and F3-F4 patients, except for a higher proportion of single nodules (95% vs 54%, P < .01). A total of 53% patients had tumour recurrence and 40% died. NAFLD-HCC had similar time to recurrence and survival as HCCs of other aetiologies. Satellite nodules, tumour size, microvascular invasion and male sex but not the aetiology were independently associated with recurrence. Conclusion Non-alcoholic fatty liver disease increased substantially over the past 20 years among resectable HCCs. It is now the leading cause of HCC occuring without/or with only minimal fibrosis. NAFLD patients are older, with larger tumours while survival and recurrence rates are as severe as in other aetiologies.

The advanced-DiaRem score improves prediction of diabetes remission 1 year post-Roux-en-Y gastric bypass.

Abstract: Not all people with type 2 diabetes who undergo bariatric surgery achieve diabetes remission. Thus it is critical to develop methods for predicting outcomes that are applicable for clinical practice. The DiaRem score is relevant for predicting diabetes remission post-Roux-en-Y gastric bypass (RYGB), but it is not accurate for all individuals across the entire spectrum of scores. We aimed to develop an improved scoring system for predicting diabetes remission following RYGB (the Advanced-DiaRem [Ad-DiaRem]). We used a retrospective French cohort (n = 1866) that included 352 individuals with type 2 diabetes followed for 1 year post-RYGB. We developed the Ad-DiaRem in a test cohort (n = 213) and examined its accuracy in independent cohorts from France (n = 134) and Israel (n = 99). Adding two clinical variables (diabetes duration and number of glucose-lowering agents) to the original DiaRem and modifying the penalties for each category led to improved predictive performance for Ad-DiaRem. Ad-DiaRem displayed improved area under the receiver operating characteristic curve and predictive accuracy compared with DiaRem (0.911 vs 0.856 and 0.841 vs 0.789, respectively; p = 0.03); thus correcting classification for 8% of those initially misclassified with DiaRem. With Ad-DiaRem, there were also fewer misclassifications of individuals with mid-range scores. This improved predictive performance was confirmed in independent cohorts. We propose the Ad-DiaRem, which includes two additional clinical variables, as an optimised tool with improved accuracy to predict diabetes remission 1 year post-RYGB. This tool might be helpful for personalised management of individuals with diabetes when considering bariatric surgery in routine care, ultimately contributing to precision medicine.

Odd skipped-related 1 identifies a population of embryonic fibro-adipogenic progenitors regulating myogenesis during limb development

Abstract: Fibro-adipogenic progenitors (FAPs) are an interstitial cell population in adult skeletal muscle that support muscle regeneration. During development, interstitial muscle connective tissue (MCT) cells support proper muscle patterning, however the underlying molecular mechanisms are not well understood and it remains unclear whether adult FAPs and embryonic MCT cells share a common lineage. We show here that mouse embryonic limb MCT cells expressing the transcription factor Osr1, differentiate into fibrogenic and adipogenic cells in vivo and in vitro defining an embryonic FAP-like population. Genetic lineage tracing shows that developmental Osr1+ cells give rise to a subset of adult FAPs. Loss of Osr1 function leads to a reduction of myogenic progenitor proliferation and survival resulting in limb muscle patterning defects. Transcriptome and functional analyses reveal that Osr1+ cells provide a critical pro-myogenic niche via the production of MCT specific extracellular matrix components and secreted signaling factors. Fibro-adipogenic progenitors (FAPs) form part of interstitial muscle connective tissue (MCT) in adults but the origin of this non-myogenic lineage is unclear. Here, the authors show that Odd skipped related 1 (Osr1) in mice marks embryonic MCT, giving rise to FAPs, and loss of Osr1 in the limb causes muscle defects.

Use of HOMA-IR to diagnose non-alcoholic fatty liver disease: a population-based and inter-laboratory study

Abstract: Aims/hypothesis Recent European guidelines for non-alcoholic fatty liver disease (NAFLD) call for reference values for HOMA-IR. In this study, we aimed to determine: (1) the upper limit of normal HOMA-IR in two population-based cohorts; (2) the HOMA-IR corresponding to NAFLD; (3) the effect of sex and PNPLA3 genotype at rs738409 on HOMA-IR; and (4) inter-laboratory variations in HOMA-IR. Methods We identified healthy individuals in two population-based cohorts (FINRISK 2007 [n = 5024] and the Programme for Prevention of Type 2 Diabetes in Finland [FIN-D2D; n = 2849]) to define the upper 95th percentile of HOMA-IR. Non-obese individuals with normal fasting glucose levels, no excessive alcohol use, no known diseases and no use of any drugs were considered healthy. The optimal HOMA-IR cut-off for NAFLD (liver fat ≥5.56%, based on the Dallas Heart Study) was determined in 368 non-diabetic individuals (35% with NAFLD), whose liver fat was measured using proton magnetic resonance spectroscopy (1H-MRS). Samples from ten individuals were simultaneously analysed for HOMA-IR in seven European laboratories. Results The upper 95th percentiles of HOMA-IR were 1.9 and 2.0 in healthy individuals in the FINRISK (n = 1167) and FIN-D2D (n = 459) cohorts. Sex or PNPLA3 genotype did not influence these values. The optimal HOMA-IR cut-off for NAFLD was 1.9 (sensitivity 87%, specificity 79%). A HOMA-IR of 2.0 corresponded to normal liver fat (<5.56% on 1H-MRS) in linear regression analysis. The 2.0 HOMA-IR measured in Helsinki corresponded to 1.3, 1.6, 1.8, 1.8, 2.0 and 2.1 in six other laboratories. The inter-laboratory CV% of HOMA-IR was 25% due to inter-assay variation in insulin (25%) rather than glucose (5%) measurements. Conclusions/interpretation The upper limit of HOMA-IR in population-based cohorts closely corresponds to that of normal liver fat. Standardisation of insulin assays would be the first step towards definition of normal values for HOMA-IR.

Shared genetic regulatory networks for cardiovascular disease and type 2 diabetes in multiple populations of diverse ethnicities in the United States.

Abstract: Cardiovascular diseases (CVD) and type 2 diabetes (T2D) are closely interrelated complex diseases likely sharing overlapping pathogenesis driven by aberrant activities in gene networks. However, the molecular circuitries underlying the pathogenic commonalities remain poorly understood. We sought to identify the shared gene networks and their key intervening drivers for both CVD and T2D by conducting a comprehensive integrative analysis driven by five multi-ethnic genome-wide association studies (GWAS) for CVD and T2D, expression quantitative trait loci (eQTLs), ENCODE, and tissue-specific gene network models (both co-expression and graphical models) from CVD and T2D relevant tissues. We identified pathways regulating the metabolism of lipids, glucose, and branched-chain amino acids, along with those governing oxidation, extracellular matrix, immune response, and neuronal system as shared pathogenic processes for both diseases. Further, we uncovered 15 key drivers including HMGCR, CAV1, IGF1 and PCOLCE, whose network neighbors collectively account for approximately 35% of known GWAS hits for CVD and 22% for T2D. Finally, we cross-validated the regulatory role of the top key drivers using in vitro siRNA knockdown, in vivo gene knockout, and two Hybrid Mouse Diversity Panels each comprised of >100 strains. Findings from this in-depth assessment of genetic and functional data from multiple human cohorts provide strong support that common sets of tissue-specific molecular networks drive the pathogenesis of both CVD and T2D across ethnicities and help prioritize new therapeutic avenues for both CVD and T2D.

Natural genetic variation of the cardiac transcriptome in non-diseased donors and patients with dilated cardiomyopathy.

Abstract: Genetic variation is an important determinant of RNA transcription and splicing, which in turn contributes to variation in human traits, including cardiovascular diseases. Here we report the first in-depth survey of heart transcriptome variation using RNA-sequencing in 97 patients with dilated cardiomyopathy and 108 non-diseased controls. We reveal extensive differences of gene expression and splicing between dilated cardiomyopathy patients and controls, affecting known as well as novel dilated cardiomyopathy genes. Moreover, we show a widespread effect of genetic variation on the regulation of transcription, isoform usage, and allele-specific expression. Systematic annotation of genome-wide association SNPs identifies 60 functional candidate genes for heart phenotypes, representing 20% of all published heart genome-wide association loci. Focusing on the dilated cardiomyopathy phenotype we found that eQTL variants are also enriched for dilated cardiomyopathy genome-wide association signals in two independent cohorts. RNA transcription, splicing, and allele-specific expression are each important determinants of the dilated cardiomyopathy phenotype and are controlled by genetic factors. Our results represent a powerful resource for the field of cardiovascular genetics.

The contribution of microbial biotechnology to sustainable development goals

Abstract: The signature and almost unique characteristic of microbial technology is the exceptional diversity of applications it can address, and the exceptional range of human activities and needs to which it is and can be applied. Precisely because sustainability goals have very diverse and complex components and requirements, microbial technology has the ability to contribute substantively on many levels in many arenas to global efforts to achieve sustainability. Indeed, microbial technology could be viewed as a unifying element in our progress towards sustainability.

Germline variants in ETV6 underlie reduced platelet formation, platelet dysfunction and increased levels of circulating CD34 + progenitors

Abstract: Variants in ETV6, which encodes a transcription repressor of the E26 transformation-specific family, have recently been reported to be responsible for inherited thrombocytopenia and hematologic malignancy. We sequenced the DNA from cases with unexplained dominant thrombocytopenia and identified six likely pathogenic variants in ETV6, of which five are novel. We observed low repressive activity of all tested ETV6 variants, and variants located in the E26 transformation-specific binding domain (encoding p.A377T, p.Y401N) led to reduced binding to corepressors. We also observed a large expansion of megakaryocyte colony-forming units derived from variant carriers and reduced proplatelet formation with abnormal cytoskeletal organization. The defect in proplatelet formation was also observed in control CD34+ cell-derived megakaryocytes transduced with lentiviral particles encoding mutant ETV6. Reduced expression levels of key regulators of the actin cytoskeleton CDC42 and RHOA were measured. Moreover, changes in the actin structures are typically accompanied by a rounder platelet shape with a highly heterogeneous size, decreased platelet arachidonic response, and spreading and retarded clot retraction in ETV6 deficient platelets. Elevated numbers of circulating CD34+ cells were found in p.P214L and p.Y401N carriers, and two patients from different families suffered from refractory anemia with excess blasts, while one patient from a third family was successfully treated for acute myeloid leukemia. Overall, our study provides novel insights into the role of ETV6 as a driver of cytoskeletal regulatory gene expression during platelet production, and the impact of variants resulting in platelets with altered size, shape and function and potentially also in changes in circulating progenitor levels.

Use of HOMA-IR to diagnose non-alcoholic fatty liver disease: a population-based and inter-laboratory study

Abstract: Aims/hypothesis Recent European guidelines for non-alcoholic fatty liver disease (NAFLD) call for reference values for HOMA-IR. In this study, we aimed to determine: (1) the upper limit of normal HOMA-IR in two population-based cohorts; (2) the HOMA-IR corresponding to NAFLD; (3) the effect of sex and PNPLA3 genotype at rs738409 on HOMA-IR; and (4) inter-laboratory variations in HOMA-IR. Methods We identified healthy individuals in two population-based cohorts (FINRISK 2007 [n = 5024] and the Programme for Prevention of Type 2 Diabetes in Finland [FIN-D2D; n = 2849]) to define the upper 95th percentile of HOMA-IR. Non-obese individuals with normal fasting glucose levels, no excessive alcohol use, no known diseases and no use of any drugs were considered healthy. The optimal HOMA-IR cut-off for NAFLD (liver fat ≥5.56%, based on the Dallas Heart Study) was determined in 368 non-diabetic individuals (35% with NAFLD), whose liver fat was measured using proton magnetic resonance spectroscopy (1H-MRS). Samples from ten individuals were simultaneously analysed for HOMA-IR in seven European laboratories. Results The upper 95th percentiles of HOMA-IR were 1.9 and 2.0 in healthy individuals in the FINRISK (n = 1167) and FIN-D2D (n = 459) cohorts. Sex or PNPLA3 genotype did not influence these values. The optimal HOMA-IR cut-off for NAFLD was 1.9 (sensitivity 87%, specificity 79%). A HOMA-IR of 2.0 corresponded to normal liver fat (<5.56% on 1H-MRS) in linear regression analysis. The 2.0 HOMA-IR measured in Helsinki corresponded to 1.3, 1.6, 1.8, 1.8, 2.0 and 2.1 in six other laboratories. The inter-laboratory CV% of HOMA-IR was 25% due to inter-assay variation in insulin (25%) rather than glucose (5%) measurements. Conclusions/interpretation The upper limit of HOMA-IR in population-based cohorts closely corresponds to that of normal liver fat. Standardisation of insulin assays would be the first step towards definition of normal values for HOMA-IR.

Systematic review of bariatric surgery liver biopsies clarifies the natural history of liver disease in patients with severe obesity

Abstract: Objective Non-alcoholic fatty liver disease (NAFLD) is a frequent complication of morbid obesity, but its severity varies greatly and thus there is a strong need to better define its natural history in these patients. Design Liver biopsies were systematically performed in 798 consecutive patients with severe obesity undergoing bariatric surgery. Histology was compared with clinical, biological, anthropometrical and body composition characteristics. Results Patients with presumably normal liver (n=179, 22%) were significantly younger at bariatric surgery than patients with NAFLD (37.0 vs 44.4 years, p Conclusions These results suggest that young adults are more prone to store fat in subcutaneous tissue and reach the threshold of bariatric surgery indication before their liver is damaged. A shift of fat storage from subcutaneous to visceral adipose tissue compartment is associated with liver damages. Liver might also be targeted by subcutaneous hypertrophic adipocytes in females since hypertrophic adipocytes are more exposed to lipolysis and to the production of inflammatory mediators.

Nonalcoholic fatty liver disease in chronic obstructive pulmonary disease.

Abstract: Nonalcoholic fatty liver disease (NAFLD) is independently linked to cardiometabolic morbidity and mortality. Low-grade inflammation, oxidative stress and ectopic fat, common features of chronic obstructive pulmonary disease (COPD), might contribute to the development of NAFLD. We aimed to investigate the prevalence of NAFLD and to evaluate the relationship between various types of liver damage and COPD severity, comorbidities and circulating inflammatory cytokines. Validated noninvasive tests (FibroMax: SteatoTest, NashTest and FibroTest) were used to assess steatosis, nonalcoholic steatohepatitis (NASH) and liver fibrosis. Patients underwent an objective assessment of COPD comorbidities, including sleep studies. Biological parameters included a complete lipid profile and inflammatory markers. In COPD patients the prevalence of steatosis, NASH and fibrosis were 41.4%, 36.9% and 61.3%, respectively. In multivariate analysis, SteatoTest and FibroTest were significantly associated with sex, body mass index (BMI), untreated sleep apnoea and insulin resistance, and, in addition, COPD Global Initiative for Chronic Obstructive Lung Disease stage for SteatoTest. Patients with steatosis had higher tumour necrosis factor-α levels and those with NASH or a combination of liver damage types had raised leptin levels after adjustment for age, sex and BMI. We concluded that NAFLD is highly prevalent in COPD and might contribute to cardiometabolic comorbidities.

The FAT Score, a Fibrosis Score of Adipose Tissue: Predicting Weight-Loss Outcome After Gastric Bypass.

Abstract: Context Bariatric surgery (BS) induces major and sustainable weight loss in many patients. Factors predicting poor weight-loss response (PR) need to be identified to improve patient care. Quantification of subcutaneous adipose tissue (scAT) fibrosis is negatively associated with post-BS weight loss, but whether it could constitute a predictor applicable in clinical routine remains to be demonstrated. Objective To create a semiquantitative score evaluating scAT fibrosis and test its predictive value on weight-loss response after Roux-en-Y gastric bypass (RYGB). Methods We created a fibrosis score of adipose tissue (FAT score) integrating perilobular and pericellular fibrosis. Using this score, we characterized 183 perioperative scAT biopsy specimens from severely obese patients who underwent RYGB (n = 85 from a training cohort; n = 98 from a confirmation cohort). PR to RYGB was defined as <28% of total weight loss at 1 year (lowest tertile). The link between FAT score and PR was tested in univariate and multivariate models. Results FAT score was directly associated with increasing scAT fibrosis measured by a standard quantification method (P for trend <0.001). FAT score interobserver agreement was good (κ = 0.76). FAT score ≥2 was significantly associated with PR. The association remained significant after adjustment for age, diabetes status, hypertension, percent fat mass, and interleukin-6 level (adjusted odds ratio, 3.6; 95% confidence interval, 1.8 to 7.2; P = 0.003). Conclusion The FAT score is a new, simple, semiquantitative evaluation of human scAT fibrosis that may help identify patients with a potential limited weight-loss response to RYGB.

T Cell Populations and Functions Are Altered in Human Obesity and Type 2 Diabetes.

Abstract: Purpose of the Review: Obesity and type 2 diabetes (T2D) are considered chronic inflammatory diseases. While early publications have reported the implication of innate immune cells such as macrophages to promote systemic inflammation and metabolic dysfunctions, recent publications underline the alterations of the T cell compartment in human obesity and type 2 diabetes. These recent findings are the focus of this review. Recent Findings: In humans, obesity and T2D induce the expansion of proinflammatory T cells such as CD4 Th1, Th17 and CD8 populations whereas innate T cells such as MAIT and iNKT cells are decreased. These alterations reflect a loss of total T cell homeostasis that may contribute to tissue and systemic inflammation. Summary: Whether these changes are adaptive to nutritional variations and/or contribute to the progression of metabolic diseases remains to be clarified. T cell phenotyping may improve obese and/or T2D patient stratification with therapeutic and prognostic implications.

MANAGEMENT OF ENDOCRINE DISEASE: Congenital adrenal hyperplasia due to 21-hydroxylase deficiency: update on the management of adult patients and prenatal treatment.

Abstract: Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is characterized by cortisol and in some cases aldosterone deficiency associated with androgen excess. Goals of treatment are to replace deficient hormones and control androgen excess, while avoiding the adverse effects of exogenous glucocorticoid. Over the last 5 years, cohorts of adults with CAH due to 21-hydroxylase deficiency from Europe and the United States have been described, allowing us to have a better knowledge of long-term complications of the disease and its treatment. Patients with CAH have increased mortality, morbidity and risk for infertility and metabolic disorders. These comorbidities are due in part to the drawbacks of the currently available glucocorticoid therapy. Consequently, novel therapies are being developed and studied in an attempt to improve patient outcomes. New management strategies in the care of pregnancies at risk for congenital adrenal hyperplasia using fetal sex determination and dexamethasone have also been described, but remain a subject of debate. We focused the present overview on the data published in the last 5 years, concentrating on studies dealing with cardiovascular risk, fertility, treatment and prenatal management in adults with classic CAH to provide the reader with an updated review on this rapidly evolving field of knowledge.

Assessing the causal relationship between obesity and venous thromboembolism through a Mendelian Randomization study

Abstract: Observational studies have shown an association between obesity and venous thromboembolism (VTE) but it is not known if observed associations are causal, due to reverse causation or confounding bias. We conducted a Mendelian Randomization study of body mass index (BMI) and VTE. We identified 95 single nucleotide polymorphisms (SNPs) that have been previously associated with BMI and assessed the association between genetically predicted high BMI and VTE leveraging data from a previously conducted GWAS within the INVENT consortium comprising a total of 7507 VTE cases and 52,632 controls of European ancestry. Five BMI SNPs were associated with VTE at P < 0.05, with the strongest association seen for the FTO SNP rs1558902 (OR 1.07, 95% CI 1.02–1.12, P = 0.005). In addition, we observed a significant association between genetically predicted BMI and VTE (OR = 1.59, 95% CI 1.30–1.93 per standard deviation increase in BMI, P = 5.8 × 10−6). Our study provides evidence for a causal relationship between high BMI and risk of VTE. Reducing obesity levels will likely result in lower incidence in VTE.

Genome-wide association study with additional genetic and post-transcriptional analyses reveals novel regulators of plasma factor XI levels.

Abstract: Coagulation factor XI (FXI) has become increasingly interesting for its role in pathogenesis of thrombosis. While elevated plasma levels of FXI have been associated with venous thromboembolism and ischemic stroke, its deficiency is associated with mild bleeding. We aimed to determine novel genetic and post-transcriptional plasma FXI regulators. We performed a genome-wide association study (GWAS) for plasma FXI levels, using novel data imputed to the 1000 Genomes reference panel. Individual GWAS analyses, including a total of 16,169 European individuals from the ARIC, GHS, MARTHA and PROCARDIS studies, were meta-analysed and further replicated in 2,045 individuals from the F5L family, GAIT2 and MEGA studies. Additional association with activated partial thromboplastin time (aPTT) was tested for the top SNPs. In addition, a study on the effect of miRNA on FXI regulation was performed using in silico prediction tools and in vitro luciferase assays. Three loci showed robust, replicating association with circulating FXI levels: KNG1 (rs710446, P-value = 2.07 × 10−302), F11 (rs4253417, P-value = 2.86 × 10−193), and a novel association in GCKR (rs780094, P-value = 3.56 ×10−09), here for the first time implicated in FXI regulation. The two first SNPs (rs710446 and rs4253417) also associated with aPTT. Conditional and haplotype analyses demonstrated a complex association signal, with additional novel SNPs modulating plasma FXI levels in both the F11 and KNG1 loci. Finally, eight miRNAs were predicted to bind F11 mRNA. Over-expression of either miR-145 or miR-181 significantly reduced the luciferase activity in cells transfected with a plasmid containing FXI-3’UTR. These results should open the door to new therapeutic targets for thrombosis prevention.

Long‐term outcome of ovarian function in women with intermittent premature ovarian insufficiency

Abstract: Context Spontaneous resumption of ovarian function is not a rare phenomenon in patients with premature ovarian insufficiency (POI). The outcome of this resumption is not known. Objective To describe the outcome following the resumption of ovarian function in POI patients. Design Cross sectional study. Setting University medical centre. Patients and main outcome measures Cumulative incidence of ovarian function resumption and risk factors arresting this resumption during follow-up were determined in a large cohort of POI women. Results Five hundred and seven patients were included in the study, with a follow up of 3.44±4.05 years [0-29]. Of these, 117 (23%) had features of ovarian function resumption. The cumulative incidence of pregnancy was 3.5% among the whole cohort and 15.3% among patients with resumption of ovarian function. Fifty-five patients (47%) experienced an arrest of their resumption during the follow up period. In univariate analysis, high FSH and DHEA levels at initial evaluation were risk factors for the arrest of the resumption of ovarian function. In multivariate analysis, high FSH levels at the initial evaluation (1.89 [1.10-3.23], p=0.03) and older age at diagnosis (1.53 [1.01-2.33], p=0.04) were risk factors for the arrest of this resumption. Conclusion Resumption of ovarian function is not a rare or brief phenomenon in POI women. The identification of predictive factors of this resumption, as well as its duration, increases our knowledge of the natural history of POI, and will improve the medical management, especially infertility counselling of these patients.