Showing papers by "Royal Devon and Exeter Hospital published in 2016"

Genome-wide associations for birth weight and correlations with adult disease

Abstract: Birth weight (BW) has been shown to be influenced by both fetal and maternal factors and in observational studies is reproducibly associated with future risk of adult metabolic diseases including type 2 diabetes (T2D) and cardiovascular disease1. These life-course associations have often been attributed to the impact of an adverse early life environment. Here, we performed a multi-ancestry genome-wide association study (GWAS) meta-analysis of BW in 153,781 individuals, identifying 60 loci where fetal genotype was associated with BW (P < 5 × 10−8). Overall, approximately 15% of variance in BW was captured by assays of fetal genetic variation. Using genetic association alone, we found strong inverse genetic correlations between BW and systolic blood pressure (Rg = −0.22, P = 5.5 × 10−13), T2D (Rg = −0.27, P = 1.1 × 10−6) and coronary artery disease (Rg = −0.30, P = 6.5 × 10−9). In addition, using large -cohort datasets, we demonstrated that genetic factors were the major contributor to the negative covariance between BW and future cardiometabolic risk. Pathway analyses indicated that the protein products of genes within BW-associated regions were enriched for diverse processes including insulin signalling, glucose homeostasis, glycogen biosynthesis and chromatin remodelling. There was also enrichment of associations with BW in known imprinted regions (P = 1.9 × 10−4). We demonstrate that life-course associations between early growth phenotypes and adult cardiometabolic disease are in part the result of shared genetic effects and identify some of the pathways through which these causal genetic effects are mediated.

Global patient outcomes after elective surgery: Prospective cohort study in 27 low-, middle- and high-income countries

Abstract: Background As global initiatives increase patient access to surgical treatments, there remains a need to understand the adverse effects of surgery and define appropriate levels of perioperative care. Methods We designed a prospective international 7-day cohort study of outcomes following elective adult inpatient surgery in 27 countries. The primary outcome was in-hospital complications. Secondary outcomes were death following a complication (failure to rescue) and death in hospital. Process measures were admission to critical care immediately after surgery or to treat a complication and duration of hospital stay. A single definition of critical care was used for all countries. Results A total of 474 hospitals in 19 high-, 7 middle- and 1 low-income country were included in the primary analysis. Data included 44 814 patients with a median hospital stay of 4 (range 2–7) days. A total of 7508 patients (16.8%) developed one or more postoperative complication and 207 died (0.5%). The overall mortality among patients who developed complications was 2.8%. Mortality following complications ranged from 2.4% for pulmonary embolism to 43.9% for cardiac arrest. A total of 4360 (9.7%) patients were admitted to a critical care unit as routine immediately after surgery, of whom 2198 (50.4%) developed a complication, with 105 (2.4%) deaths. A total of 1233 patients (16.4%) were admitted to a critical care unit to treat complications, with 119 (9.7%) deaths. Despite lower baseline risk, outcomes were similar in low- and middle-income compared with high-income countries. Conclusions Poor patient outcomes are common after inpatient surgery. Global initiatives to increase access to surgical treatments should also address the need for safe perioperative care.

Height, body mass index, and socioeconomic status: mendelian randomisation study in UK Biobank

Abstract: Objective To determine whether height and body mass index (BMI) have a causal role in five measures of socioeconomic status. Design Mendelian randomisation study to test for causal effects of differences in stature and BMI on five measures of socioeconomic status. Mendelian randomisation exploits the fact that genotypes are randomly assigned at conception and thus not confounded by non-genetic factors. Setting UK Biobank. Participants 119 669 men and women of British ancestry, aged between 37 and 73 years. Main outcome measures Age completed full time education, degree level education, job class, annual household income, and Townsend deprivation index. Results In the UK Biobank study, shorter stature and higher BMI were observationally associated with several measures of lower socioeconomic status. The associations between shorter stature and lower socioeconomic status tended to be stronger in men, and the associations between higher BMI and lower socioeconomic status tended to be stronger in women. For example, a 1 standard deviation (SD) higher BMI was associated with a £210 (€276; $300; 95% confidence interval £84 to £420; P=6×10 −3 ) lower annual household income in men and a £1890 (£1680 to £2100; P=6×10 −15 ) lower annual household income in women. Genetic analysis provided evidence that these associations were partly causal. A genetically determined 1 SD (6.3 cm) taller stature caused a 0.06 (0.02 to 0.09) year older age of completing full time education (P=0.01), a 1.12 (1.07 to 1.18) times higher odds of working in a skilled profession (P=6×10 −7 ), and a £1130 (£680 to £1580) higher annual household income (P=4×10 −8 ). Associations were stronger in men. A genetically determined 1 SD higher BMI (4.6 kg/m 2 ) caused a £2940 (£1680 to £4200; P=1×10 −5 ) lower annual household income and a 0.10 (0.04 to 0.16) SD (P=0.001) higher level of deprivation in women only. Conclusions These data support evidence that height and BMI play an important partial role in determining several aspects of a person’s socioeconomic status, especially women’s BMI for income and deprivation and men’s height for education, income, and job class. These findings have important social and health implications, supporting evidence that overweight people, especially women, are at a disadvantage and that taller people, especially men, are at an advantage.

An integrated genetic-epigenetic analysis of schizophrenia : evidence for co-localization of genetic associations and differential DNA methylation

Abstract: Schizophrenia is a highly heritable, neuropsychiatric disorder characterized by episodic psychosis and altered cognitive function. Despite success in identifying genetic variants associated with schizophrenia, there remains uncertainty about the causal genes involved in disease pathogenesis and how their function is regulated. We performed a multi-stage epigenome-wide association study, quantifying genome-wide patterns of DNA methylation in a total of 1714 individuals from three independent sample cohorts. We have identified multiple differentially methylated positions and regions consistently associated with schizophrenia across the three cohorts; these effects are independent of important confounders such as smoking. We also show that epigenetic variation at multiple loci across the genome contributes to the polygenic nature of schizophrenia. Finally, we show how DNA methylation quantitative trait loci in combination with Bayesian co-localization analyses can be used to annotate extended genomic regions nominated by studies of schizophrenia, and to identify potential regulatory variation causally involved in disease. This study represents the first systematic integrated analysis of genetic and epigenetic variation in schizophrenia, introducing a methodological approach that can be used to inform epigenome-wide association study analyses of other complex traits and diseases. We demonstrate the utility of using a polygenic risk score to identify molecular variation associated with etiological variation, and of using DNA methylation quantitative trait loci to refine the functional and regulatory variation associated with schizophrenia risk variants. Finally, we present strong evidence for the co-localization of genetic associations for schizophrenia and differential DNA methylation.

Genetic evidence for causal relationships between maternal obesity-related traits and birth weight

Abstract: Importance Neonates born to overweight or obese women are larger and at higher risk of birth complications. Many maternal obesity-related traits are observationally associated with birth weight, but the causal nature of these associations is uncertain. Objective To test for genetic evidence of causal associations of maternal body mass index (BMI) and related traits with birth weight. Design, Setting, and Participants Mendelian randomization to test whether maternal BMI and obesity-related traits are potentially causally related to offspring birth weight. Data from 30 487 women in 18 studies were analyzed. Participants were of European ancestry from population- or community-based studies in Europe, North America, or Australia and were part of the Early Growth Genetics Consortium. Live, term, singleton offspring born between 1929 and 2013 were included. Exposures Genetic scores for BMI, fasting glucose level, type 2 diabetes, systolic blood pressure (SBP), triglyceride level, high-density lipoprotein cholesterol (HDL-C) level, vitamin D status, and adiponectin level. Main Outcome and Measure Offspring birth weight from 18 studies. Results Among the 30 487 newborns the mean birth weight in the various cohorts ranged from 3325 g to 3679 g. The maternal genetic score for BMI was associated with a 2-g (95% CI, 0 to 3 g) higher offspring birth weight per maternal BMI-raising allele ( P = .008). The maternal genetic scores for fasting glucose and SBP were also associated with birth weight with effect sizes of 8 g (95% CI, 6 to 10 g) per glucose-raising allele ( P = 7 × 10 −14 ) and −4 g (95% CI, −6 to −2g) per SBP-raising allele ( P = 1×10 −5 ), respectively. A 1-SD ( ≈ 4 points) genetically higher maternal BMI was associated with a 55-g higher offspring birth weight (95% CI, 17 to 93 g). A 1-SD ( ≈ 7.2 mg/dL) genetically higher maternal fasting glucose concentration was associated with 114-g higher offspring birth weight (95% CI, 80 to 147 g). However, a 1-SD ( ≈ 10 mm Hg) genetically higher maternal SBP was associated with a 208-g lower offspring birth weight (95% CI, −394 to −21 g). For BMI and fasting glucose, genetic associations were consistent with the observational associations, but for systolic blood pressure, the genetic and observational associations were in opposite directions. Conclusions and Relevance In this mendelian randomization study, genetically elevated maternal BMI and blood glucose levels were potentially causally associated with higher offspring birth weight, whereas genetically elevated maternal SBP was potentially causally related to lower birth weight. If replicated, these findings may have implications for counseling and managing pregnancies to avoid adverse weight-related birth outcomes.

A review of national guidelines for management of COPD in Europe

Abstract: The quality of care can be improved by the development and implementation of evidence-based treatment guidelines. Different national guidelines for chronic obstructive pulmonary disease (COPD) exis ...

The early outcome of kinematic versus mechanical alignment in total knee arthroplasty: a prospective randomised control trial.

Abstract: Aims Our aim was to compare kinematic with mechanical alignment in total knee arthroplasty (TKA). Patients and Methods We performed a prospective blinded randomised controlled trial to compare the functional outcome of patients undergoing TKA in mechanical alignment (MA) with those in kinematic alignment (KA). A total of 71 patients undergoing TKA were randomised to either kinematic (n = 36) or mechanical alignment (n = 35). Pre- and post-operative hip-knee-ankle radiographs were analysed. The knee injury and osteoarthritis outcome score (KOOS), American Knee Society Score, Short Form-36, Euro-Qol (EQ-5D), range of movement (ROM), two minute walk, and timed up and go tests were assessed pre-operatively and at six weeks, three and six months and one year post-operatively. Results A total of 78% of the kinematically aligned group (28 patients) and 77% of the mechanically aligned group (27 patients) were within 3° of their pre-operative plan. There were no statistically significant differences in the mean KOOS (difference 1.3, 95% confidence interval (CI) -9.4 to 12.1, p = 0.80), EQ-5D (difference 0.8, 95% CI -7.9 to 9.6, p = 0.84), ROM (difference 0.1, 95% CI -6.0 to 6.1, p = 0.99), two minute distance tolerance (difference 20.0, 95% CI -52.8 to 92.8, p = 0.58), or timed up and go (difference 0.78, 95% CI -2.3 to 3.9, p = 0.62) between the groups at one year. Conclusion Kinematically aligned TKAs appear to have comparable short-term results to mechanically aligned TKAs with no significant differences in function one year post-operatively. Further research is required to see if any theoretical long-term functional benefits of kinematic alignment are realised or if there are any potential effects on implant survival. Cite this article: Bone Joint J 2016;98-B:1360–8.

BCL11A Haploinsufficiency Causes an Intellectual Disability Syndrome and Dysregulates Transcription

Abstract: Intellectual disability (ID) is a common condition with considerable genetic heterogeneity. Next-generation sequencing of large cohorts has identified an increasing number of genes implicated in ID, but their roles in neurodevelopment remain largely unexplored. Here we report an ID syndrome caused by de novo heterozygous missense, nonsense, and frameshift mutations in BCL11A, encoding a transcription factor that is a putative member of the BAF swi/snf chromatin-remodeling complex. Using a comprehensive integrated approach to ID disease modeling, involving human cellular analyses coupled to mouse behavioral, neuroanatomical, and molecular phenotyping, we provide multiple lines of functional evidence for phenotypic effects. The etiological missense variants cluster in the amino-terminal region of human BCL11A, and we demonstrate that they all disrupt its localization, dimerization, and transcriptional regulatory activity, consistent with a loss of function. We show that Bcl11a haploinsufficiency in mice causes impaired cognition, abnormal social behavior, and microcephaly in accordance with the human phenotype. Furthermore, we identify shared aberrant transcriptional profiles in the cortex and hippocampus of these mouse models. Thus, our work implicates BCL11A haploinsufficiency in neurodevelopmental disorders and defines additional targets regulated by this gene, with broad relevance for our understanding of ID and related syndromes.

Complications associated with opening wedge high tibial osteotomy--A review of the literature and of 15 years of experience.

Abstract: Background Complication rates following opening wedge high tibial osteotomy (OWHTO) is an issue that has not been comprehensively addressed in current literature. Methods We performed a retrospective study of local patients who underwent OWHTO for isolated medial compartment knee osteoarthritis from 1997 to 2013. We analysed survivorship and complication rates and compared this to a literature review of previously reported data. Results One hundred and fifteen patients met the inclusion criteria. Mean follow-up = 8.4 years. Mean age = 47 (range 32 to 62). Mean Body Mass Index (BMI) = 29.1 (range 20.3 to 40.2). Devices used consisted of Tomofix (72%), Puddu plate (21%) and Orthofix (seven percent) (no significant differences in age/sex/BMI). Wedge defects were filled with autologous graft (30%), Chronos (35%) or left empty (35%). Five years survival rate (without requiring conversion to arthroplasty) = 80%. Overall complication rate = 31%. Twenty five percent of patients suffered 36 complications including minor wound infections (9.6%), major wound infections (3.5%), metalwork irritation necessitating plate removal (seven percent), non-union requiring revision (4.3%), vascular injury (1.7%), compartment syndrome (0.9%), and other minor complications (four percent). No thromboembolic complications were observed. Conclusion No significant differences existed in complication rates following OWHTO relative to BMI, implant type, type of bone graft used or patient age at surgery. When the complications from OWHTO were analysed closely they appear higher than previously reported in the literature; however serious complications appear rare. Level of Evidence 3 Retrospective cohort study

Human longevity is influenced by many genetic variants: evidence from 75,000 UK Biobank participants

Abstract: Variation in human lifespan is 20 to 30% heritable in twins but few genetic variants have been identified. We undertook a Genome Wide Association Study (GWAS) using age at death of parents of middle-aged UK Biobank participants of European decent (n=75,244 with father's and/or mother's data, excluding early deaths). Genetic risk scores for 19 phenotypes (n=777 proven variants) were also tested. In GWAS, a nicotine receptor locus(CHRNA3, previously associated with increased smoking and lung cancer) was associated with fathers' survival. Less common variants requiring further confirmation were also identified. Offspring of longer lived parents had more protective alleles for coronary artery disease, systolic blood pressure, body mass index, cholesterol and triglyceride levels, type-1 diabetes, inflammatory bowel disease and Alzheimer's disease. In candidate analyses, variants in the TOMM40/APOE locus were associated with longevity, but FOXO variants were not. Associations between extreme longevity (mother >=98 years, fathers >=95 years, n=1,339) and disease alleles were similar, with an additional association with HDL cholesterol (p=5.7x10-3). These results support a multiple protective factors model influencing lifespan and longevity (top 1% survival) in humans, with prominent roles for cardiovascular-related pathways. Several of these genetically influenced risks, including blood pressure and tobacco exposure, are potentially modifiable.

Epidemiology of developmental dysplasia of the hip within the UK: refining the risk factors

Abstract: The epidemiology and risk factors for developmental dysplasia of the hip (DDH) are still being refined. We investigated the local epidemiology of DDH in order to define incidence, identify risk factors, and refine our policy on selective ultrasound screening. With a cohort study design, data were prospectively recorded on all live births in our region from January 1998 to December 2008. We compared data on babies treated for DDH with data for all other children. Crude odds ratios (ORs) were calculated to identify potential risk factors. Logistic regression was then used to control for interactions between variables. There were 182 children born with DDH (with a total of 245 dysplastic hips) and 37,051 without. The incidence was 4.9 per 1000 live births. Female sex (adjusted OR 7.2, 95% confidence interval [CI] 4.6–11.2), breech presentation (adjusted OR 24.3, 95% CI 13.1–44.9), positive family history (adjusted OR 15.9, 95% CI 11.0–22.9) and first or second pregnancy (adjusted OR 1.8, 95% CI 1.5–2.3) were confirmed as risk factors (p < 0.001). In addition, there was an increased risk with vaginal delivery (adjusted OR 2.7, 1.6–4.5, p < 0.001) and post-maturity (OR 1.7, 1.2–2.4, p < 0.002). One in 200 children born within our region requires treatment for DDH. Using both established and novel risk factors, we can potentially calculate an individual child’s risk. Our findings may contribute to the debate regarding selective versus universal ultrasound screening. Prognostic Study: Level 1.

Diagnosis, assessment, and phenotyping of COPD: beyond FEV1

Abstract: COPD is now widely recognized as a complex heterogeneous syndrome, having both pulmonary and extrapulmonary features. In clinical practice, the diagnosis of COPD is based on the presence of chronic airflow limitation, as assessed by post-bronchodilator spirometry. The severity of the airflow limitation, as measured by percent predicted FEV1, provides important information to the physician to enable optimization of management. However, in order to accurately assess the complexity of COPD, there need to be other measures made beyond FEV1. At present, there is a lack of reliable and simple blood biomarkers to confirm and further assess the diagnosis of COPD. However, it is possible to identify patients who display different phenotypic characteristics of COPD that relate to clinically relevant outcomes. Currently, validated phenotypes of COPD include alpha-1 antitrypsin deficiency, and "frequent exacerbators". Recently, a definition and assessment of a new phenotype comprising patients with overlapping features of asthma and COPD has been suggested and is known as "asthma COPD overlap syndrome". Several other phenotypes have been proposed, but require validation against clinical outcomes. Defining phenotypes requires the assessment of multiple factors indicating disease severity, its impact, and its activity. Recognition and validation of COPD phenotypes has an important role to play in the selection of evidence-based targeted therapy in the future management of COPD, but regardless of the diagnostic terms, patients with COPD should be assessed and treated according to their individual treatable characteristics.

Clinical and genetic aspects of KBG syndrome

Abstract: KBG syndrome is characterized by short stature, distinctive facial features, and developmental/cognitive delay and is caused by mutations in ANKRD11, one of the ankyrin repeat-containing cofactors. We describe 32 KBG patients aged 2-47 years from 27 families ascertained via two pathways: targeted ANKRD11 sequencing (TS) in a group who had a clinical diagnosis of KBG and whole exome sequencing (ES) in a second group in whom the diagnosis was unknown. Speech delay and learning difficulties were almost universal and variable behavioral problems frequent. Macrodontia of permanent upper central incisors was seen in 85%. Other clinical features included short stature, conductive hearing loss, recurrent middle ear infection, palatal abnormalities, and feeding difficulties. We recognized a new feature of a wide anterior fontanelle with delayed closure in 22%. The subtle facial features of KBG syndrome were recognizable in half the patients. We identified 20 ANKRD11 mutations (18 novel: all truncating) confirmed by Sanger sequencing in 32 patients. Comparison of the two ascertainment groups demonstrated that facial/other typical features were more subtle in the ES group. There were no conclusive phenotype-genotype correlations. Our findings suggest that mutation of ANKRD11 is a common Mendelian cause of developmental delay. Affected patients may not show the characteristic KBG phenotype and the diagnosis is therefore easily missed. We propose updated diagnostic criteria/clinical recommendations for KBG syndrome and suggest that inclusion of ANKRD11 will increase the utility of gene panels designed to investigate developmental delay. © 2016 The Authors. American Journal of Medical Genetics Part A Published by Wiley Periodicals, Inc.

Combined genetic and splicing analysis of BRCA1 c.[594-2A>C; 641A>G] highlights the relevance of naturally occurring in-frame transcripts for developing disease gene variant classification algorithms.

Abstract: A recent analysis using family history weighting and co-observation classification modeling indicated that BRCA1 c.594-2A > C (IVS9-2A > C), previously described to cause exon 10 skipping (a truncating alteration), displays characteristics inconsistent with those of a high risk pathogenic BRCA1 variant. We used large-scale genetic and clinical resources from the ENIGMA, CIMBA and BCAC consortia to assess pathogenicity of c.594-2A > C. The combined odds for causality considering case-control, segregation and breast tumor pathology information was 3.23 × 10-8 Our data indicate that c.594-2A > C is always in cis with c.641A > G. The spliceogenic effect of c.[594-2A > C;641A > G] was characterized using RNA analysis of human samples and splicing minigenes. As expected, c.[594-2A > C; 641A > G] caused exon 10 skipping, albeit not due to c.594-2A > C impairing the acceptor site but rather by c.641A > G modifying exon 10 splicing regulatory element(s). Multiple blood-based RNA assays indicated that the variant allele did not produce detectable levels of full-length transcripts, with a per allele BRCA1 expression profile composed of ≈70-80% truncating transcripts, and ≈20-30% of in-frame Δ9,10 transcripts predicted to encode a BRCA1 protein with tumor suppression function.We confirm that BRCA1c.[594-2A > C;641A > G] should not be considered a high-risk pathogenic variant. Importantly, results from our detailed mRNA analysis suggest that BRCA-associated cancer risk is likely not markedly increased for individuals who carry a truncating variant in BRCA1 exons 9 or 10, or any other BRCA1 allele that permits 20-30% of tumor suppressor function. More generally, our findings highlight the importance of assessing naturally occurring alternative splicing for clinical evaluation of variants in disease-causing genes.

Current Controversies in the Pharmacological Treatment of Chronic Obstructive Pulmonary Disease

Abstract: Clinical phenotyping is currently used to guide pharmacological treatment decisions in chronic obstructive pulmonary disease (COPD), a personalized approach to care. Precision medicine integrates biological (endotype) and clinical (phenotype) information for a more individualized approach to pharmacotherapy, to maximize the benefit versus risk ratio. Biomarkers can be used to identify endotypes. To evolve toward precision medicine in COPD, the most appropriate biomarkers and clinical characteristics that reliably predict treatment responses need to be identified. FEV1 is a marker of COPD severity and has historically been used to guide pharmacotherapy choices. However, we now understand that the trajectory of FEV1 change, as an indicator of disease activity, is more important than a single FEV1 measurement. There is a need to develop biomarkers of disease activity to enable a more targeted and individualized approach to pharmacotherapy. Recent clinical trials testing commonly used COPD treatments have provided new information that is likely to influence pharmacological treatment decisions both at initial presentation and at follow up. In this Perspective, we consider the impact of recent clinical trials on current COPD treatment recommendations. We also focus on the movement toward precision medicine and propose how this field needs to evolve in terms of using clinical characteristics and biomarkers to identify the most appropriate patients for a given pharmacological treatment.

Methods of abdominal wall expansion for repair of incisional herniae: a systematic review.

Abstract: To systematically review the available literature regarding methods for abdominal wall expansion and compare the outcome of primary fascial closure rates. A systematic search of Pubmed and Embase databases was conducted using the search terms “Abdominal wall hernia”, “ventral hernia”, “midline hernia”, “Botulinum toxin”, “botox”, “dysport”, “progressive preoperative pneumoperitoneum”, and “tissue expanders”. Study quality was assessed using the Methodological Index for Non-Randomised Studies. 21 of the105 studies identified met the inclusion criteria. Progressive preoperative pneumoperitoneum (PPP) was performed in 269 patients across 15 studies with primary fascial closure being achieved in 226 (84 %). 16 patients had a recurrence (7.2 %) and the complication rate was 12 % with 2 reported mortalities. There were 4 studies with 14 patients in total undergoing abdominal wall expansion using tissue expanders with a fascial closure rate of 92.9 % (n = 13). A recurrence rate of 10.0 % (n = 1) was reported with 1 complication and no mortalities. Follow up ranged from 3 to 36 months across the studies. There were 2 studies reporting the use of botulinum toxin with 29 patients in total. A primary fascial closure rate of 100 % (n = 29) was demonstrated although a combination of techniques including component separation and Rives-Stoppa repair were used. There were no reported complications related to the use of Botulinum Toxin. However, the short-term follow up in many cases and the lack of routine radiological assessment for recurrence suggests that the recurrence rate has been underestimated. PPP, tissue expanders and Botulinum toxin are safe and feasible methods for abdominal wall expansion prior to incisional hernia repair. In combination with existing techniques for repair, these methods may help provide the crucial extra tissue mobility required to achieve primary closure.

Variants in the FTO and CDKAL1 loci have recessive effects on risk of obesity and type 2 diabetes, respectively

Abstract: Aims/hypothesis Genome-wide association (GWA) studies have identified hundreds of common genetic variants associated with obesity and type 2 diabetes. These studies have usually focused on additive association tests. Identifying deviations from additivity may provide new biological insights and explain some of the missing heritability for these diseases.

Genetic Evidence for Causal Relationships Between Maternal Obesity-Related Traits and Birth Weight

Abstract: Importance Neonates born to overweight or obese women are larger and at higher risk of birth complications. Many maternal obesity-related traits are observationally associated with birth weight, but the causal nature of these associations is uncertain. Objective To test for genetic evidence of causal associations of maternal body mass index (BMI) and related traits with birth weight. Design, Setting, and Participants Mendelian randomization to test whether maternal BMI and obesity-related traits are potentially causally related to offspring birth weight. Data from 30 487 women in 18 studies were analyzed. Participants were of European ancestry from population- or community-based studies in Europe, North America, or Australia and were part of the Early Growth Genetics Consortium. Live, term, singleton offspring born between 1929 and 2013 were included. Exposures Genetic scores for BMI, fasting glucose level, type 2 diabetes, systolic blood pressure (SBP), triglyceride level, high-density lipoprotein cholesterol (HDL-C) level, vitamin D status, and adiponectin level. Main Outcome and Measure Offspring birth weight from 18 studies. Results Among the 30 487 newborns the mean birth weight in the various cohorts ranged from 3325 g to 3679 g. The maternal genetic score for BMI was associated with a 2-g (95% CI, 0 to 3 g) higher offspring birth weight per maternal BMI-raising allele ( P = .008). The maternal genetic scores for fasting glucose and SBP were also associated with birth weight with effect sizes of 8 g (95% CI, 6 to 10 g) per glucose-raising allele ( P = 7 × 10 −14 ) and −4 g (95% CI, −6 to −2g) per SBP-raising allele ( P = 1×10 −5 ), respectively. A 1-SD ( ≈ 4 points) genetically higher maternal BMI was associated with a 55-g higher offspring birth weight (95% CI, 17 to 93 g). A 1-SD ( ≈ 7.2 mg/dL) genetically higher maternal fasting glucose concentration was associated with 114-g higher offspring birth weight (95% CI, 80 to 147 g). However, a 1-SD ( ≈ 10 mm Hg) genetically higher maternal SBP was associated with a 208-g lower offspring birth weight (95% CI, −394 to −21 g). For BMI and fasting glucose, genetic associations were consistent with the observational associations, but for systolic blood pressure, the genetic and observational associations were in opposite directions. Conclusions and Relevance In this mendelian randomization study, genetically elevated maternal BMI and blood glucose levels were potentially causally associated with higher offspring birth weight, whereas genetically elevated maternal SBP was potentially causally related to lower birth weight. If replicated, these findings may have implications for counseling and managing pregnancies to avoid adverse weight-related birth outcomes.

Prevalence of systolic inter-arm differences in blood pressure for different primary care populations: systematic review and meta-analysis

Abstract: Background Various prevalence figures have been reported for inter-arm differences in blood pressure (IAD); variation may be explained by differing population vascular risk and by measurement method. Aim To review the literature to derive robust estimates of IAD prevalence relevant to community populations. Design and setting Systematic review and meta-analysis. Method MEDLINE, Embase, and CINAHL were searched for cross-sectional studies likely to represent general or primary care populations, reporting prevalence of IAD and employing a simultaneous method of measurement. Using study-level data, pooled estimates of mean prevalence of systolic IADs were calculated and compared using a random effects model. Results Eighty IAD studies were identified. Sixteen met inclusion criteria: pooled estimates of prevalence for systolic IAD ≥10 mmHg were 11.2% (95% confidence interval [CI] = 9.1 to 13.6) in hypertension, 7.4% (95% CI = 5.8 to 9.2) in diabetes, and 3.6% (95% CI = 2.3 to 5.0) for a general adult population ( P <0.001 for subgroup differences). Differences persisted for higher cut-off values. Prevalences were lower for East Asian than for Western populations and were overestimated by sequential measurement where this could be compared with simultaneous measurement within studies (relative risk for IAD: 2.9 [95% CI = 2.1 to 4.1]). Studies with higher mean absolute systolic pressures had higher prevalences for a systolic IAD ≥10 mmHg ( P = 0.04). Conclusion Prevalences of IADs rise in relation to underlying cardiovascular comorbidities of the population studied, and are overestimated threefold when sequential measurement is used. Population-specific variation in prevalences of IAD should be taken into account in delivering clinical care and in planning future studies.

Events in Early Life are Associated with Female Reproductive Ageing: A UK Biobank Study.

Abstract: The available oocyte pool is determined before birth, with the majority of oocytes lost before puberty. We hypothesised that events occurring before birth, in childhood or in adolescence (‘early-life risk factors’) could influence the size of the oocyte pool and thus the timing of menopause. We included cross-sectional data from 273,474 women from the UK Biobank, recruited in 2006–2010 from across the UK. We analysed the association of early menopause with events occurring before adulthood in 11,781 cases (menopause aged under 45) and 173,641 controls (menopause/pre-menopausal at ≥45 years), in models controlling for potential confounding variables. Being part of a multiple birth was strongly associated with early menopause (odds ratio = 1.42, confidence interval: 1.11, 1.82, P = 8.0 × 10−9, fully-adjusted model). Earlier age at menarche (odds ratio = 1.03, confidence interval: 1.01, 1.06, P = 2.5 × 10−6) and earlier year of birth were also associated with EM (odds ratio = 1.02, confidence interval: 1.00, 1.04, P = 8.0 × 10−6). We also confirmed previously reported associations with smoking, drinking alcohol, educational level and number of births. We identified an association between multiple births and early menopause, which connects events pre-birth, when the oocyte pool is formed, with reproductive ageing in later life.

Hormone replacement therapy for women previously treated for endometrial cancer.

Abstract: Background Endometrial cancer is the sixth most common cancer in women worldwide and most commonly occurs after the menopause (75%) (globocan.iarc.fr). About 319,000 new cases were diagnosed worldwide in 2012. Endometrial cancer is commonly considered as a potentially 'curable cancer,' as approximately 75% of cases are diagnosed before disease has spread outside the uterus (FIGO (International Federation of Gynecology and Obstetrics) stage I). The overall five-year survival for all stages is about 86%, and, if the cancer is confined to the uterus, the five-year survival rate may increase to 97%. The majority of women diagnosed with endometrial cancer have early-stage disease, leading to a good prognosis after hysterectomy and removal of the ovaries (oophorectomy), with or without radiotherapy. However, women may have early physiological and psychological postmenopausal changes, either pre-existing or as a result of oophorectomy, depending on age and menopausal status at the time of diagnosis. Lack of oestrogen can cause hot flushes, night sweats, genital tract atrophy and longer-term adverse effects, such as osteoporosis and cardiovascular disease. These changes may be temporarily managed by using oestrogens, in the form of hormone replacement therapy (HRT). However, there is a theoretical risk of promoting residual tumour cell growth and increasing cancer recurrence. Therefore, this is a potential survival disadvantage in a woman who has a potentially curable cancer. In premenopausal women with endometrial cancer, treatment induces early menopause and this may adversely affect overall survival. Additionally, most women with early-stage disease will be cured of their cancer, making longer-term quality of life (QoL) issues more pertinent. Following bilateral oophorectomy, premenopausal women may develop significant and debilitating menopausal symptoms, so there is a need for information about the risk and benefits of taking HRT, enabling women to make an informed decision, weighing the advantages and disadvantages of using HRT for their individual circumstances. Objectives To assess the risks and benefits of HRT (oestrogen alone or oestrogen with progestogen) for women previously treated for endometrial cancer. Search methods We searched the Cochrane Register of Controlled Trials (CENTRAL 2017, Issue 5), MEDLINE (1946 to April, week 4, 2017) and Embase (1980 to 2017, week 18). We also searched registers of clinical trials, abstracts of scientific meetings and reference lists of review articles. Selection criteria We included randomised controlled trials (RCTs), in all languages, that examined the efficacy of symptom relief and the safety of using HRT in women treated for endometrial cancer, where safety in this situation was considered as not increasing the risk of recurrence of endometrial cancer above that of women not taking HRT. Data collection and analysis Two review authors independently assessed whether potentially relevant studies met the inclusion criteria. We used standard methodological procedures expected by Cochrane. Main results We identified 2190 unique records, evaluated the full text of seven studies and included one study with 1236 participants. This study reported tumour recurrence in 2.3% of women in the oestrogen arm versus 1.9% of women receiving placebo (risk ratio (RR) 1.17, 95% confidence interval (CI) 0.54 to 2.50; very low-certainty evidence). The study reported one woman in the HRT arm (0.16%) and three women in the placebo arm (0.49%) who developed breast cancer (new malignancy) during follow-up (RR 0.80, 95% CI 0.32 to 2.01; 1236 participants, 1 study; very low-certainty evidence). The study did not report on symptom relief, overall survival or progression-free survival for HRT versus placebo. However, they did report the percentage of women alive with no evidence of disease (94.3% in the HRT group and 95.6% in the placebo group) and the percentage of women alive irrespective of disease progression (95.8% in the HRT group and 96.9% in the placebo group) at the end of the 36 months' follow-up. The study did not report time to recurrence and it was underpowered due to closing early. The authors closed it as a result of the publication of the Women's Health Initiative (WHI) study, which, at that time, suggested that risks of exogenous hormone therapy outweighed benefits and had an impact on study recruitment. No assessment of efficacy was reported. Authors' conclusions Currently, there is insufficient high-quality evidence to inform women considering HRT after treatment for endometrial cancer. The available evidence (both the single RCT and non-randomised evidence) does not suggest significant harm, if HRT is used after surgical treatment for early-stage endometrial cancer. There is no information available regarding use of HRT in higher-stage endometrial cancer (FIGO stage II and above). The use of HRT after endometrial cancer treatment should be individualised, taking account of the woman's symptoms and preferences, and the uncertainty of evidence for and against HRT use.

Eligibility of real-life patients with COPD for inclusion in trials of inhaled long-acting bronchodilator therapy

Abstract: Management guidelines of chronic obstructive pulmonary disease (COPD) are mainly based on results of randomised controlled trials (RCTs), but some authors have suggested limited representativeness of patients included in these trials. No previous studies have applied the full range of selection criteria to a broad COPD patient population in a real-life setting. We identified all RCTs of inhaled long-acting bronchodilator therapy, during 1999–2013, at ClinicalTrials.gov and translated trial selection criteria into definitions compatible with electronic medical records. Eligibility was calculated for each RCT by applying these criteria to a uniquely representative, well-characterised population of patients with COPD from the Optimum Patient Care Research Database (OPCRD). Median eligibility of 36 893 patients with COPD for participation in 31 RCTs was 23 % (interquartile range 12–38). Two studies of olodaterol showed the highest eligibility of 55 and 58 %. Conversely, the lowest eligibility was observed in two studies that required a history of exacerbations in the past year (3.5 and 3.9 %). For the patient subgroup with modified Medical Research Council score ≥2, the overall median eligibility was 27 %. By applying an extensive range of RCT selection criteria to a large, representative COPD patient population, this study highlights that the interpretation of results from RCTs must take into account that RCT participants are variably, but generally more representative of patients in the community than previously believed.

Genetic evidence that lower circulating FSH levels lengthen menstrual cycle, increase age at menopause and impact female reproductive health

Abstract: Study question How does a genetic variant in the FSHB promoter, known to alter FSH levels, impact female reproductive health? Summary answer The T allele of the FSHB promoter polymorphism (rs10835638; c.-211G>T) results in longer menstrual cycles and later menopause and, while having detrimental effects on fertility, is protective against endometriosis. What is known already The FSHB promoter polymorphism (rs10835638; c.-211G>T) affects levels of FSHB transcription and, as a result, circulating levels of FSH. FSH is required for normal fertility and genetic variants at the FSHB locus are associated with age at menopause and polycystic ovary syndrome (PCOS). Study design, size, duration We used cross-sectional data from the UK Biobank to look at associations between the FSHB promoter polymorphism and reproductive traits, and performed a genome-wide association study (GWAS) for length of menstrual cycle. Participants/materials, setting, methods We included white British individuals aged 40-69 years in 2006-2010, in the May 2015 release of genetic data from UK Biobank. We tested the FSH-lowering T allele of the FSHB promoter polymorphism (rs10835638; c.-211G>T) for associations with 29, mainly female, reproductive phenotypes in up to 63 350 women and 56 608 men. We conducted a GWAS in 9534 individuals to identify genetic variants associated with length of menstrual cycle. Main results and the role of chance The FSH-lowering T allele of the FSHB promoter polymorphism (rs10835638; MAF 0.16) was associated with longer menstrual cycles [0.16 SD (c. 1 day) per minor allele; 95% confidence interval (CI) 0.12-0.20; P = 6 × 10(-16)], later age at menopause (0.13 years per minor allele; 95% CI 0.04-0.22; P = 5.7 × 10(-3)), greater female nulliparity [odds ratio (OR) = 1.06; 95% CI 1.02-1.11; P = 4.8 × 10(-3)] and lower risk of endometriosis (OR = 0.79; 95% CI 0.69-0.90; P = 4.1 × 10(-4)). The FSH-lowering T allele was not associated with other female reproductive illnesses or conditions in our study and we did not replicate associations with male infertility or PCOS. In the GWAS for menstrual cycle length, only variants near the FSHB gene reached genome-wide significance (P Limitations, reasons for caution The data included might be affected by recall bias. Cycle length was not available for 25% of women still cycling (1% did not answer, 6% did not know and for 18% cycle length was recorded as 'irregular'). Women with a cycle length recorded were aged over 40 and were approaching menopause; however, we did not find evidence that this affected the results. Many of the groups with illnesses had relatively small sample sizes and so the study may have been under-powered to detect an effect. Wider implications of the findings We found a strong novel association between a genetic variant that lowers FSH levels and longer menstrual cycles, at a locus previously robustly associated with age at menopause. The variant was also associated with nulliparity and endometriosis risk. These findings should now be verified in a second independent group of patients. We conclude that lifetime differences in circulating levels of FSH between individuals can influence menstrual cycle length and a range of reproductive outcomes, including menopause timing, infertility, endometriosis and PCOS. Study funding/competing interests None. Trial registration number Not applicable.

Inter-arm blood pressure difference and mortality: a cohort study in an asymptomatic primary care population at elevated cardiovascular risk.

Abstract: Background Differences in blood pressure between arms are associated with increased cardiovascular mortality in cohorts with established vascular disease or substantially elevated cardiovascular risk. Aim To explore the association of inter-arm difference (IAD) with mortality in a community-dwelling cohort that is free of cardiovascular disease. Design and setting Cohort analysis of a randomised controlled trial in central Scotland, from April 1998 to October 2008. Method Volunteers from Lanarkshire, Glasgow, and Edinburgh, free of pre-existing vascular disease and with an ankle-brachial index ≤0.95, had systolic blood pressure measured in both arms at recruitment. Inter-arm blood pressure differences were calculated and examined for cross-sectional associations and differences in prospective survival. Outcome measures were cardiovascular events and all-cause mortality during mean follow-up of 8.2 years. Results Based on a single pair of measurements, 60% of 3350 participants had a systolic IAD ≥5 mmHg and 38% ≥10 mmHg. An IAD ≥5 mmHg was associated with increased cardiovascular mortality (adjusted hazard ratio [HR] 1.91, 95% confidence interval [CI] = 1.19 to 3.07) and all-cause mortality (adjusted HR 1.44, 95% CI = 1.15 to 1.79). Within the subgroup of 764 participants who had hypertension, IADs of ≥5 mmHg or ≥10 mmHg were associated with both cardiovascular mortality (adjusted HR 2.63, 95% CI = 0.97 to 7.02, and adjusted HR 2.96, 95% CI = 1.27 to 6.88, respectively) and all-cause mortality (adjusted HR 1.67, 95% CI = 1.05 to 2.66, and adjusted HR 1.63, 95% CI = 1.06 to 2.50, respectively). IADs ≥15 mmHg were not associated with survival differences in this population. Conclusion Systolic IADs in blood pressure are associated with increased risk of cardiovascular events, including mortality, in a large cohort of people free of pre-existing vascular disease.

The anterolateral ligament of the knee: unwrapping the enigma. Anatomical study and comparison to previous reports.

Abstract: It has been suggested that the anterolateral ligament (ALL) of the knee may have importance in limiting rotational instability, and reconstruction may prevent a continued pivot-shift following anterior cruciate ligament surgery. However, the anatomy of this ligament has not been consistently reported in recent publications. We describe our experience of cadaveric dissection with reference to other published work. Eleven fresh-frozen cadaveric knees were dissected using a standard technique. The ALL tissue was identified with internal rotation of the tibia and varus stress. Measurements were made using a digital caliper and details of the origin and insertion were recorded. The ALL was identified in ten of the 11 cadavers. The only specimen in which it was not identified was found to also have an anterior cruciate ligament deficiency. The mean dimensions were: length 40.1 (± 5.53) mm, width 4.63 (± 1.39) mm, thickness 0.87 (± 0.18) mm. The femoral origin was posterior and proximal to the lateral collateral ligament attachment in six knees, anterior and distal in three knees, and at the same site in one knee. The tibial insertion was a mean 17.7 (± 2.95) mm from Gerdy’s tubercle (GT) and 12.3 (± 3.55) mm from the fibula head (FH). This was 59.5 (± 5.44) % from GT to FH. This anatomical data adds to previous information about the ALL. Our results support the finding that the ALL is a capsular thickening with meniscal attachment. The findings will help to guide the further work required to define the indications for reconstruction and appropriate grafts.