Search

Age, disease stage and treatment of patients from the cohort used for plasma IgG1,2,3 and 4 dosage

Supplementary Material and Methods describing in vivo, mass spectrometry and immunocytofluorescence experiments; Supplementary Figures 1,2 and 3 and Supplementary figures and tables legends.

Cohort per experiment

Purpose: The purpose of this study was to assess the effect of neoadjuvant chemotherapy (NACT) on immune activation in stage IIIC/IV tubo-ovarian high-grade serous carcinoma (HGSC), and its relationship to treatment response.Experimental Design: We obtained pre- and posttreatment omental biopsies and blood samples from a total of 54 patients undergoing platinum-based NACT and 6 patients undergoing primary debulking surgery. We measured T-cell density and phenotype, immune activation, and markers of cancer-related inflammation using IHC, flow cytometry, electrochemiluminescence assays, and RNA sequencing and related our findings to the histopathologic treatment response.Results: There was evidence of T-cell activation in omental biopsies after NACT: CD4+ T cells showed enhanced IFNγ production and antitumor Th1 gene signatures were increased. T-cell activation was more pronounced with good response to NACT. The CD8+ T-cell and CD45RO+ memory cell density in the tumor microenvironment was unchanged after NACT but biopsies showing a good therapeutic response had significantly fewer FoxP3+ T regulatory (Treg) cells. This finding was supported by a reduction in a Treg cell gene signature in post- versus pre-NACT samples that was more pronounced in good responders. Plasma levels of proinflammatory cytokines decreased in all patients after NACT. However, a high proportion of T cells in biopsies expressed immune checkpoint molecules PD-1 and CTLA4, and PD-L1 levels were significantly increased after NACT.Conclusions: NACT may enhance host immune response but this effect is tempered by high/increased levels of PD-1, CTLA4, and PD-L1. Sequential chemoimmunotherapy may improve disease control in advanced HGSC. Clin Cancer Res; 22(12); 3025–36. ©2016 AACR.

Total patient cohort

PDS cohort

Purpose: In high-grade serous ovarian cancer (HGSOC), higher densities of both B cells and the CD8+ T-cell infiltrate were associated with a better prognosis. However, the precise role of B cells in the antitumor response remains unknown. As peritoneal metastases are often responsible for relapse, our aim was to characterize the role of B cells in the antitumor immune response in HGSOC metastases.Experimental Design: Unmatched pre and post-chemotherapy HGSOC metastases were studied. B-cell localization was assessed by immunostaining. Their cytokines and chemokines were measured by a multiplex assay, and their phenotype was assessed by flow cytometry. Further in vitro and in vivo assays highlighted the role of B cells and plasma cell IgGs in the development of cytotoxic responses and dendritic cell activation.Results: B cells mainly infiltrated lymphoid structures in the stroma of HGSOC metastases. There was a strong B-cell memory response directed at a restricted repertoire of antigens and production of tumor-specific IgGs by plasma cells. These responses were enhanced by chemotherapy. Interestingly, transcript levels of CD20 correlated with markers of immune cytolytic responses and immune complexes with tumor-derived IgGs stimulated the expression of the costimulatory molecule CD86 on antigen-presenting cells. A positive role for B cells in the antitumor response was also supported by B-cell depletion in a syngeneic mouse model of peritoneal metastasis.Conclusions: Our data showed that B cells infiltrating HGSOC omental metastases support the development of an antitumor response. Clin Cancer Res; 23(1); 250–62. ©2016 AACR.

The NLRP3 inflammasome is a vital mediator of innate immune responses. There are numerous NLRP3 mutations that cause NLRP3-associated autoinflammatory diseases (NLRP3-AIDs), mostly in or around the NACHT domain. Here, we present a patient with a rare leucine-rich repeat (LRR) domain mutation, p.Arg920Gln (p.R920Q), associated with an atypical NLRP3-AID with recurrent episodes of sore throat and extensive oropharyngeal ulceration. Unlike previously reported patients, who responded well to anakinra, her oral ulcers did not significantly improve until the PDE4 inhibitor, apremilast, was added to her treatment regimen. Here, we show that this mutation enhances interactions between NLRP3 and its endogenous inhibitor, NIMA-related kinase 7 (NEK7), by affecting charge complementarity between the two proteins. We also demonstrate that additional inflammatory mediators, including the NF-кB and IL-17 signalling pathways and IL-8 chemokine, are upregulated in the patient’s macrophages and may be directly involved in disease pathogenesis. These results highlight the role of the NLRP3 LRR domain in NLRP3-AIDs and demonstrate that the p.R920Q mutation can cause diverse phenotypes between families.

Obstructive sleep apnoea (OSA) is an often-overlooked diagnosis, more prevalent in the obese population. Screening method accuracy, uptake and hence diagnosis is variable. There is limited data available regarding the obese pregnant population; however, many studies highlight potential risks of apnoeic episodes to mother and foetus, including hypertension, diabetes and preeclampsia. A total of 162 women with a body mass index (BMI) ≥ 35 were recruited from a tertiary referral hospital in the northwest of England. They were invited to attend three research antenatal clinics, completing an Epworth Sleepiness Scale (ESS) questionnaire at each visit. A monitor measuring the apnoea hypopnoea index (AHI) was offered at the second visit. Data taken from consent forms, hospital notes and hospital computer records were collated and anonymized prior to statistical analysis. A total of 12.1% of women had an ESS score of >10, suggesting possible OSA. Rates increased throughout pregnancy, although unfortunately, the attrition rate was high; 29.0% of women used the RUSleeping (RUS) meter, and only one (2.1%) met pre-specified criteria for OSA (AHI ≥ 15). This individual had OSA categorized as severe and underwent investigations for preeclampsia, eventually delivering by emergency caesarean section due to foetal distress. The accuracy of the ESS questionnaire, particularly the RUS monitor, to screen for OSA in the pregnant population remains unclear. Further research on a larger sample size using more user-friendly technology to confidently measure AHI would be beneficial. There are currently no guidelines regarding screening for OSA in the obese pregnant population, yet risks to both mother and foetus are well researched.

Contains fulltext : 174538.pdf (Publisher’s version ) (Closed access) Familial exudative vitreoretinopathy (FEVR) is an inherited blinding disorder characterized by the abnormal development of the retinal vasculature. The majority of mutations identified in FEVR are found within four genes that encode the receptor complex (FZD4, LRP5, and TSPAN12) and ligand (NDP) of a molecular pathway that controls angiogenesis, the Norrin-beta-catenin signaling pathway. However, half of all FEVR-affected case subjects do not harbor mutations in these genes, indicating that further mutated genes remain to be identified. Here we report the identification of mutations in CTNNB1, the gene encoding beta-catenin, as a cause of FEVR. We describe heterozygous mutations (c.2142_2157dup [p.His720 *] and c.2128C>T [p.Arg710Cys]) in two dominant FEVR-affected families and a de novo mutation (c.1434_1435insC [p.Glu479Argfs *18]) in a simplex case subject. Previous studies have reported heterozygous de novo CTNNB1 mutations as a cause of syndromic intellectual disability (ID) and autism spectrum disorder, and somatic mutations are linked to many cancers. However, in this study we show that Mendelian inherited CTNNB1 mutations can cause non-syndromic FEVR and that FEVR can be a part of the syndromic ID phenotype, further establishing the role that beta-catenin signaling plays in the development of the retinal vasculature.

Purpose: The purpose of this study was to assess the effect of neoadjuvant chemotherapy (NACT) on immune activation in stage IIIC/IV tubo-ovarian high-grade serous carcinoma (HGSC), and its relationship to treatment response. Experimental Design: We obtained pre- and posttreatment omental biopsies and blood samples from a total of 54 patients undergoing platinum-based NACT and 6 patients undergoing primary debulking surgery. We measured T-cell density and phenotype, immune activation, and markers of cancer-related inflammation using IHC, flow cytometry, electrochemiluminescence assays, and RNA sequencing and related our findings to the histopathologic treatment response. Results: There was evidence of T-cell activation in omental biopsies after NACT: CD4+ T cells showed enhanced IFNγ production and antitumor Th1 gene signatures were increased. T-cell activation was more pronounced with good response to NACT. The CD8+ T-cell and CD45RO+ memory cell density in the tumor microenvironment was unchanged after NACT but biopsies showing a good therapeutic response had significantly fewer FoxP3+ T regulatory (Treg) cells. This finding was supported by a reduction in a Treg cell gene signature in post- versus pre-NACT samples that was more pronounced in good responders. Plasma levels of proinflammatory cytokines decreased in all patients after NACT. However, a high proportion of T cells in biopsies expressed immune checkpoint molecules PD-1 and CTLA4, and PD-L1 levels were significantly increased after NACT. Conclusions: NACT may enhance host immune response but this effect is tempered by high/increased levels of PD-1, CTLA4, and PD-L1. Sequential chemoimmunotherapy may improve disease control in advanced HGSC. Clin Cancer Res; 22(12); 3025–36. ©2016 AACR.

Objectives Clinical trials of IV-rituximab have proved successful. It is unclear whether intrathecal (IT)-rituximab is more efficacious at lower doses. We examine its effects on B-cell biomarkers. Methods MS patients received IT-rituximab at 3 time-points. CSF and serum samples were obtained at up to 5 time-points (days 0, 7, 14, 56 and 112). Serum and CSF BAFF and CXCL13, and CSF kappa and lambda free light chains (FLC) were measured. Flow cytometry was performed, examining effects on lymphocytes, CD3-19+ and CD3-20+ cells. Results CSF BAFF fell following rituximab ( p =0.0091 absolute values, p =0.0284 change from baseline) whilst serum BAFF increased across time-points 1–4 ( p =0.0005 absolute values, p =0.0017 change from baseline). There were significant reductions in CD20+ and CD19+ cells in blood from baseline ( p p =0.0480). Conclusions BAFF levels fall in CSF but increase in serum following IT-rituximab. Rituximab appears to act peripherally with dramatic decreases in peripheral CD20+ and CD19+ cells. It is likely that CSF B-cell counts were too low to enable differences to be seen. The rapid reduction in B-cells suggests rituximab has immediate effects. The profound depletion of B-cells, despite low doses of rituximab, underlines rituximab's efficacy.

Purpose: In high-grade serous ovarian cancer (HGSOC), higher densities of both B cells and the CD8+ T-cell infiltrate were associated with a better prognosis. However, the precise role of B cells in the antitumor response remains unknown. As peritoneal metastases are often responsible for relapse, our aim was to characterize the role of B cells in the antitumor immune response in HGSOC metastases. Experimental Design: Unmatched pre and post-chemotherapy HGSOC metastases were studied. B-cell localization was assessed by immunostaining. Their cytokines and chemokines were measured by a multiplex assay, and their phenotype was assessed by flow cytometry. Further in vitro and in vivo assays highlighted the role of B cells and plasma cell IgGs in the development of cytotoxic responses and dendritic cell activation. Results: B cells mainly infiltrated lymphoid structures in the stroma of HGSOC metastases. There was a strong B-cell memory response directed at a restricted repertoire of antigens and production of tumor-specific IgGs by plasma cells. These responses were enhanced by chemotherapy. Interestingly, transcript levels of CD20 correlated with markers of immune cytolytic responses and immune complexes with tumor-derived IgGs stimulated the expression of the costimulatory molecule CD86 on antigen-presenting cells. A positive role for B cells in the antitumor response was also supported by B-cell depletion in a syngeneic mouse model of peritoneal metastasis. Conclusions: Our data showed that B cells infiltrating HGSOC omental metastases support the development of an antitumor response. Clin Cancer Res; 23(1); 250–62. ©2016 AACR.

OBJECTIVE: Multiple sclerosis (MS) develops as a result of environmental influences on the genetically susceptible. Siblings of people with MS have an increased risk of both MS and demonstrating asymptomatic changes in keeping with MS. We set out to develop an MS risk score integrating both genetic and environmental risk factors. We used this score to identify siblings at extremes of MS risk and attempted to validate the score using brain MRI. METHODS: 78 probands with MS, 121 of their unaffected siblings and 103 healthy controls were studied. Personal history was taken, and serological and genetic analysis using the illumina immunochip was performed. Odds ratios for MS associated with each risk factor were derived from existing literature, and the log values of the odds ratios from each of the risk factors were combined in an additive model to provide an overall score. Scores were initially calculated using log odds ratio from the HLA-DRB1*1501 allele only, secondly using data from all MS-associated SNPs identified in the 2011 GWAS. Subjects with extreme risk scores underwent validation studies. MRI was performed on selected individuals. RESULTS: There was a significant difference in the both risk scores between people with MS, their unaffected siblings and healthy controls (p

Objectives: To determine the role of maternal CYP1A1, GSTT1, and GSTM1 metabolic gene polymorphisms in modulating the association between pregnancy smoking exposure and fetal growth restriction. Study design: A case-control study was conducted to investigate if the association of pregnancy smoking and birth outcome was modulated by maternal gene polymorphisms. A total of 90 mothers with an IUGR baby (cases) and 180 mothers without IUGR (controls) were enrolled. Results: Almost half of smokers who carried a CYP1A1 variant (51.3%), GSTT1 null (43.6%), or GSTM1 null genotypes (64.1%) delivered a baby with IUGR. Smokers with the variant CYP1A1 "aa" genotype had babies with lower mean birthweight than non-smokers with the same genotype (p = 0.004). An interaction test showed increased prevalence of IUGR in smokers with the CYP1A1 (Aa/aa) variant (adjusted OR, 1.9; 95% CI, 1.4-5.5, p = 0.01), or with the GSTT1 null (AOR, 1.5; 1.1-3.1, p = 0.001), or GSTM1 null genotypes (AOR, 1.5; 1.2-3.7, p = 0.001). Conclusions: Risk of fetal growth restriction in mothers who smoked during pregnancy was modulated by maternal metabolic gene polymorphisms. The genetic control of the conversion of toxic metabolites of tobacco smoke to less damaging substances is important for maternal and fetal health. (C) 2008 Elsevier Ireland Ltd. All rights reserved.

The role of salivary cotinine for monitoring maternal pregnancy smoking as an alternative to self-reported smoking exposure is not well established. This was a case-control study to assess the correlation between maternal self-reported pregnancy smoking exposure and postnatal salivary cotinine levels in 90 mothers with a baby with fetal growth restriction (cases) and 180 mothers with a normal birthweight for gestational age infant (controls) attending the Liverpool Women's Hospital for delivery between 2004 and 2005. Cases had increased exposure to cigarette smoke during pregnancy compared to controls. Using the salivary cotinine assay as the reference two-thirds of women, both cases and controls, correctly reported their smoking status during pregnancy. There are limitations with the accuracy of self-reported pregnancy smoking as an exposure indicator, especially in mothers delivering babies with Intrauterine fetal growth restriction (IUGR) who are also those most likely to smoke. In view of this there is a need to consider using salivary cotinine measurements in antenatal settings in order to facilitate monitoring of smoking exposure in pregnancy and for evaluation of deterrent interventions.

Background and objective: We explored which clinical and biochemical variables predict conversion from clinically isolated syndrome (CIS) to clinically definite multiple sclerosis (CDMS) in a large international cohort. Methods: Thirty-three centres provided serum samples from 1047 CIS cases with at least two years’ follow-up. Age, sex, clinical presentation, T2-hyperintense lesions, cerebrospinal fluid (CSF) oligoclonal bands (OCBs), CSF IgG index, CSF cell count, serum 25-hydroxyvitamin D3 (25-OH-D), cotinine and IgG titres against Epstein-Barr nuclear antigen 1 (EBNA-1) and cytomegalovirus were tested for association with risk of CDMS. Results: At median follow-up of 4.31 years, 623 CIS cases converted to CDMS. Predictors of conversion in multivariable analyses were OCB (HR = 2.18, 95% CI = 1.71–2.77, p < 0.001), number of T2 lesions (two to nine lesions vs 0/1 lesions: HR = 1.97, 95% CI = 1.52–2.55, p < 0.001; >9 lesions vs 0/1 lesions: HR = 2.74, 95% CI = 2.04–3.68, p < 0.001) and age at CIS (HR per year inversely increase = 0.98, 95% CI = 0.98–0.99, p < 0.001). Lower 25-OH-D levels were associated with CDMS in univariable analysis, but this was attenuated in the multivariable model. OCB positivity was associated with higher EBNA-1 IgG titres. Conclusions: We validated MRI lesion load, OCB and age at CIS as the strongest independent predictors of conversion to CDMS in this multicentre setting. A role for vitamin D is suggested but requires further investigation.

Objective: Neuronal damage is the morphological substrate of persisting neurological disability. Neurofilaments (Nf) are cytoskeletal proteins of neurons and their release into cerebrospinal fluid has shown encouraging results as a biomarker for neurodegeneration. This study aimed to validate the quantification of the Nf light chain (NfL) in blood samples, as a biofluid source easily accessible for longitudinal studies. Methods: We developed and applied a highly sensitive electrochemiluminescence (ECL) based immunoassay for quantification of NfL in blood and CSF. Results: Patients with Alzheimer’s disease (AD) (30.8 pg/ml, n=20), Guillain-Barre-syndrome (GBS) (79.4 pg/ml, n=19) or amyotrophic lateral sclerosis (ALS) (95.4 pg/ml, n=46) had higher serum NfL values than a control group of neurological patients without evidence of structural CNS damage (control patients, CP) (4.4 pg/ml, n=68, p

This book lays out the fundamentals of both the investigation and management of children with gynaecological conditions - an area of work which can be intimidating for many gynaecologists. The contents cover: pubertal growth and development; indeterminate genitalia; gynaecological problems in childhood; endocrine disorders; child sexual abuse; amenorrhoea; menstrual problems in teenagers; contraception; female genital mutilation; and gynaecological tumours. The book is primarily designed to provide a comprehensive summary for candidates preparing for the Part 2 MRCOG examination, and as such covers the RCOG curriculum for paediatric and adolescent gynaecology. It is also a valuable guide for all healthcare professionals working in the field, at any level of practice.

Child abuse has existed for centuries but society has been slow to acknowledge it. It can constitute physical, emotional and sexual abuse as well as neglect. Up until the 17th century, children were considered to be the possessions of their parents and it was accepted that they might harm them. It was only in the 1970s that non-accidental injury of children was accepted as a common occurrence, following the description of battered child syndrome in 1962. Corporal punishment existed in schools in Britain until 30 years ago and was thought to be a necessity. Now there is debate regarding the smacking of children. The first child protection agency was formed in Liverpool in 1883, followed by the National Society for the Prevention of Cruelty to Children (NSPCC) in 1890. The start of the education system in 1870 allowed for children to be observed at school every day for the first time. Child sexual abuse was less talked about. Incest was a crime according to the Christian Church from the 1700s but was only made a criminal offence in the UK in 1908. Papers in the literature relating to child sexual abuse start mainly from the 1980s. There have been many high-profile cases reported in the press over the years, such as Maria Colwell in 1974, the Cleveland Inquiry in 1987 and, more recently, Victoria Climbie, who died in 2000 with 108 injuries on her body. All have highlighted loopholes in the child protection system.

Objective: To determine the association of maternal CYP17 gene polymorphisms and prenatal alcohol consumption with intrauterine growth restriction (IUGR). Study design: A case-control study in singleton livebirths was conducted at the Liverpool Women's Hospital between 2004 and 2005. Cases (n = 90) were mothers with an IUGR baby and controls (n = 180) those with a normal birthweight infant. Maternal genomic DNA was extracted from buccal smears and PCR (RFLP) was used for genotyping. Results: Amongst cases, the prevalence of the maternal CYP17 homozygous wild type "AlA1", heterozygouts "AlA2" and homozygous "A2A2" variants was 36.7%, 47.7% and 15.6%, which did not differ significantly from their prevalence amongst controls (p = 0.6). The proportion with prenatal alcohol exposure was significantly higher in cases than controls (45.6% versus 30.6%, p = 0.01). Mean birthweight was significantly lower in mothers with the CYP17 A(AlA2/A2A2)1A1 genotype compared to those with variant genotypes (AlA2/A2A2) in both the alcohol-exposed (p = 0.03) and non-exposed groups (p = 0.01). In all women regardless of genotype, IUGR risk increased in mothers exposed to alcohol during pregnancy (OR, 2.9, 95% Cl; 1.8-4.2, p = 0.01). There was a significant interaction between the CYP17 AlA1 genotype and prenatal alcohol consumption for fetal growth restriction (adjusted OR, 1.4, 95 % CI; 1.1-1.9, p = 0.04). Conclusion: The association between prenatal alcohol exposure and intrauterine fetal growth restriction was modulated by the maternal CYP17 AlAl genotype. (c) 2007 Elsevier Ireland Ltd. All rights reserved.

Intra-tumor B cells and immunoglobulin signatures have been associated with a better clinical prognosis in ovarian cancer (Iglesia et al, 2014; Nielsen et al, 2012). However little is known about the mechanisms by which B cells influence the anti-cancer immune response. The aim of our research is to evaluate B cell dependent anti-cancer immune responses in peritoneal metastases in high grade serous ovarian cancer (HGSOC) patients. We have found that in these peritoneal metastases, B cells are mainly located in lymphoid structures and a high proportion of these (60%) display a CD27+ memory phenotype. HGSOC B cells are able to secrete Th1 related cytokines as well as high levels of IL8, which is a chemo-attractant for T cells, granulocytes and macrophages. Interestingly CD4+ and CD8+ T cells express high levels of the IL8 receptor, CXCR1, which suggests B cells help recruiting T cells to lymphoid structures. Plasma cells were also detected in the peritoneal metastases along with IgG deposits. Secreted IgGs were mainly located in stromal areas suggesting that the associated matrix may prevent their infiltration into tumour islets and/or that they target specific stromal antigens. Interestingly, we observed that neoadjuvant chemotherapy and residual disease after chemotherapy influence the type of IgG subclasses expressed in the omentum of HGSOC patients. Chemotherapy enhances the expression of IgG1, IgG2 and IgG3 immunoglobulins in omentum with residual disease. This supports the notion that B cells are involved in the anti-tumor immune response in HGSOC metastases. In conclusion, our data suggest that B cells actively participate to the anti-tumor immune response in HGSOC metastases. This response is preferentially Th1 oriented through the production of cytokines and dominant expression of IgG1 immunoglobulins. Enhancing the B cell dependent anti-tumor immune response could be a potential strategy for the treatment of HGSOC patients. Iglesia MD, Vincent BG, Parker JS, Hoadley KA, Carey LA, Perou CM, Serody JS (2014) Prognostic B-cell signatures using mRNA-seq in patients with subtype-specific breast and ovarian cancer. Clin Cancer Res 20: 3818-3829 Nielsen JS, Sahota RA, Milne K, Kost SE, Nesslinger NJ, Watson PH, Nelson BH (2012) CD20+ tumor-infiltrating lymphocytes have an atypical CD27- memory phenotype and together with CD8+ T cells promote favorable prognosis in ovarian cancer. Clin Cancer Res 18: 3281-3292 Citation Format: Anne Montfort, Steffen Boehm, Thomas Dowe, Joanne Topping, Michelle Lockley, Melania Capasso, Frances Balkwill. B cells actively participate to the anti-cancer immune response in high grade serous ovarian cancer metastases. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 455. doi:10.1158/1538-7445.AM2015-455

Breast-milk is the optimum form of nutrition for the first 6 months of life. However, breastfeeding rates in the UK are low and static compared to other European countries and those in the North-west of England in the UK are even lower. Of the women who initiate breastfeeding, many cease in the first month following the birth for reasons that might be avoided. To try and prevent this, UNICEF Baby Friendly Hospital Initiative (BFHI) 'Ten Steps to Successful Breastfeeding' state that maternity facilities should foster the development of support groups for breastfeeding women. The aim of the present study was to describe breastfeeding difficulties reported by women who attended the infant feeding clinic at a Women's Hospital in the North-west of England. During the study period, the clinic was attended mainly by primiparous mothers who were educated beyond 18 years of age and of higher socio-economic status. They presented with a variety of problems including baby not latching on, concerns about baby's weight gain/loss, sore nipples and advice about expressing milk in preparation for return to work. The women highlighted the importance of meeting other mothers and having someone to talk to who understood what they were going through. Inconsistent information/lack of detailed knowledge from health professionals was cited as contributing to breastfeeding difficulties. A number of women reported that expert hands-on, one-to-one support, was invaluable and many felt they were able to continue breastfeeding but without the support, they may have given up.

Objective An endophenotype is a concept that allows us to describe complex diseases with genetic and environmental contributions. This enables the identification of an “at risk” population. We aim to describe an endophenotypic gradient between healthy controls (HC), siblings of people with MS (PwMS) and PwMS. Background Siblings of PwMS have an increased risk of developing MS. This increased risk is thought to be a result of genetic and environmental contributions. Epidemiological studies have identified factors contributing to MS including smoking, vitamin–D, infection with and IgG titres against Epstein–Barr virus and HLA–DRB1*1501. A genome wide association study (GWAS) in 2011 gave information regarding the contribution of HLA–type and non–HLA SNPs to MS risk. We set out to integrate these into an endophenotypic risk score for MS. Methods PwMS (n=78), their unaffected siblings (n=121) and healthy controls (HC; n=103) were recruited. Serum anti–EBNA–1 IgG, vitamin D and cotinine were measured. Subjects were genotyped for HLA–DRB1*1501 and all HLA and non–HLA SNPs associated with MS using the Illumina immunochip. Previous infectious mononucleosis, smoking and month of birth were recorded. The relative risks associated with these factors were established from meta–analyses and integrated into an overall risk score for each individual. Full genetic data was available for 73 people with MS, 107 siblings and 99 HC. Risk scores with genetic contribution from HLA–DRB1*1501 only, and from all MS–associated genetic variants were calculated. Results When the genetic contribution from HLA–DRB1*1501 alone was used, the mean risk score was significantly higher for PwMS (2.82; SD 1.18) than for siblings (1.98; SD 1.38) or HC (1.53; SD 1.34) (p 1.25 SD higher than the mean HC score. When full genetic data was included, the mean risk score was highest for people with MS (9.71; SD 1.38) intermediate for siblings (8.83; SD 1.47) and lowest for HC (8.00; SD 1.49) (p Conclusions This study demonstrates the validity of the risk score generated, which integrates genetic and environmental risk factors. Siblings have a risk score intermediate to PwMS and HC, confirming their “at risk” position in the endophenotype construct. Much of the MS risk in siblings can be attributed to genetics, with environmental factors potentially providing the trigger for clinically apparent disease.

Background: Obesity and being underweight in pregnancy are related to an increased risk of maternal and foetal morbidity, yet their prevalence is often unknown. The present study aimed to identify neighbourhoods with a higher than average prevalence or ‘hot spots’ of obesity and/or being underweight among first trimester pregnant women. Methods: A database was compiled consisting of postcode, height and weight for 7981 women who had booked-in for antenatal care between July 2004 and June 2005 at Liverpool Women’s Hospital. Body mass index (BMI) was calculated and women were categorised accordingly. Postcodes for 6865 cases across Merseyside were converted to geolocations (pin-points on a map) using conversion software (http://www.census.ac.uk/cdu/). Results: There was a very high prevalence of being overweight (27%) and obesity (17%); 3.8% of women were underweight and probably malnourished (BMI

Pregnant women with a body mass index (BMI) greater than 30 or less than 18.5 kg/m2 have greater risk of maternal and/or fetal mortality. The aim of this study was to determine the prevalence of obesity and underweight among women booking at a Liverpool hospital and to estimate dietetic resources needed. A report was compiled consisting of height, weight, age and parity for 7,981 women booking between July 2004 and June 2005. BMI was calculated and women were categorized: underweight (BMI < 18.5); normal weight (BMI 18.5–24.9); overweight (BMI 25.0–29.9) and obese (BMI > 30). There was a high prevalence of overweight and obesity, 26.7% and 17.2%respectively and 267 women (3.8%) were underweight. A positive relationship with obesity and both age and parity was observed (p < 0.001). An increase in dietetic provision would help to improve diet and optimize weight gain and may also prevent complications, reducing maternal and infant death risk.