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Aim: Nonvalvular atrial fibrillation (NVAF) requires long-term anticoagulation treatment, which may necessitate frequent primary care visits. Materials & methods: NVAF patients initiating warfarin or apixaban in 2012–2017 were identified from linked primary (Clinical Practice Research Datalink) and secondary care (Hospital Episode Statistics) data. A propensity score matched Cox regression model compared discontinuation risk. Primary care visits were compared via negative binomial regression. Results: A total of 2695 apixaban users were matched to warfarin patients. Discontinuation risk was lower with apixaban than warfarin (hazard ratio: 0.40; 95% CI: 0.35–0.46). Apixaban patients averaged 12.2 annual primary care visits, versus 17.1 for warfarin users (p Conclusion: Apixaban was associated with reduced rates of discontinuation and primary care visits compared with warfarin.

Understanding the patient perspective is fundamental to delivering patient-centred care. In most healthcare systems, however, patient-reported outcomes are not regularly collected or recorded as part of routine clinical care, despite evidence that doing so can have tangible clinical benefit. In the absence of the routine collection of these data, research is beginning to turn to social media as a novel means to capture the patient voice. Publicly available social media data can now be analysed with relative ease, bypassing many logistical hurdles associated with traditional approaches and allowing for accelerated and cost-effective data collection. Existing work has shown these data can offer credible insight into the patient experience, although more work is needed to understand limitations with respect to patient representativeness and nuances of captured experience. Nevertheless, linking social media to electronic medical records offers a significant opportunity for patient views to be systematically collected for health services research and ultimately to improve patient care.

9090 Background: Significant improvements in mortality among NSCLC cancer patients in the US over the past two decades have recently been reported based on SEER data. The timing of these improvements led to suggestions that they are primarily a result of the introduction of new and innovative treatments, however few studies have directly investigated this. Methods: We utilised the US Flatiron Health database to identify a cohort of non-biomarker (EGFR/ALK/ROS1/BRAF) positive metastatic NSCLC (mNSCLC) patients and a separate cohort of ALK positive (ALK+) patients diagnosed between 2012 and 2019. Multivariable Cox models adjusting for baseline characteristics and receipt of targeted and immunotherapy were utilised to explore the relationship between these variables and changes in the hazard of death by calendar year in each cohort. Results: We identified cohorts of 30,076 (54.7% Males) non-biomarker positive and 652 (45.4% males) ALK+ mNSCLC cancer patients in the database eligible for the analysis. Survival in both cohorts improved over time. After adjustment for differences in baseline characteristics the hazard of death in non-biomarker positive patients diagnosed in 2015, 2016, 2017, 2018 and 2019 was observed to be 14%, 13%, 16% 19% and 21% lower respectively than that in those diagnosed in 2012. Upon additionally adjusting for receipt of first line or second line immunotherapy the decrease in the hazard of death by calendar year was no longer observed, suggesting improvements in survival observed over time may be explained by the introduction of these innovative treatments. Similarly, decreases in the hazard of death were only observed in ALK+ patients diagnosed in 2018 and 2019 relative to 2012 and were no longer observed following adjustment for the use of ALK inhibitors. Conclusions: Our findings expand on the SEER data and provide direct evidence linking improvements in survival of NSCLC patients over the past decade with the introduction of innovative therapies.[Table: see text]

Background: Multiple sclerosis (MS) is an inflammatory disease while there are controversies regarding the role of vitamin D supplements in controlling relapse and disability improvement during treatment. Objective: The goal of this systematic review and meta-analysis was to evaluate the effect of vitamin D supplements on MS-related relapse and the Expanded Disability Status Scale (EDSS). Methods: We searched databases to include randomized clinical trials (RCTs) which were published up to October 2018. We included RCTs, being single-blinded or double-blinded or open-label trials in which one of the main outcomes was EDSS and/or relapse after vitamin D supplementation. All statistical analyses were performed using RevMan 5.3. Odds ratios (OR) and 95% confidence intervals (CI) were calculated for relapse between treatment arms. The mean difference was calculated for EDSS comparisons. Results: Nine articles were included for analysis. Of these nine studies, five compared vitamin D supplement groups with placebo (group 1 studies), and four compared high- and low-dose vitamin D groups. A total of 561 patients were analyzed. Being treated with vitamin D instead of placebo showed no effect on relapse rate (OR = 0.66, 95% CI = 0.28–1.54) as well as EDSS (mean difference = 0.06, 95%CI [-0.31, 0.42]). The results of studies comparing high- vs. low-dose vitamin D interventions showed no significant effect on relapse rate (OR = 1.08, 95%CI [0.29–4.08] as well as final EDSS (mean difference = 0.17, 95% CI = -0.73, 1.07). Conclusions: Our findings show that vitamin D supplements (high or low dose) have no significant effect on relapse rate and disability during treatment in MS patients.

A growing body of evidence suggests that angiogenesis plays a crucial role in the pathogenesis of multiple sclerosis (MS). Animal models of MS show a significant improvement when the process of angiogenesis is halted. In this study, we measured the serum levels of vascular-endothelial growth factor (VEGF), soluble Endoglin (sEng), angiopoietin 1(Ang-1), angiopoietin 2 (Ang-2), and uric acid (UA) as well as serum anti-Epstein-Barr virus (EBV) EBNA-1 IgG in 50 MS patients (including 20 newly diagnosed and 30 patients taking IFN-beta for >6months) and 40 healthy individuals. Enzyme-linked immunosorbent assays (ELISA) were used apart from UA where the uricase quantitative enzymatic assay was used. A significant increase of VEGF, Ang-1, Ang-2, and sEng in serum samples of MS patients with respect to healthy subjects was observed. VEGF was higher in newly diagnosed MS patients in comparison to patients taking interferon-beta and was associated with EDSS. The serum levels of UA were statistically lower in MS patients as compared to the healthy group. Higher levels of anti-EBV antibody titers were seen in MS patients than controls and anti-EBV titers correlated with angiogenic factors. It seems that in summary, angiogenesis may play an important role in MS and infection with EBV might be correlated with this phenomenon.

Multiple Sclerosis is a demyelinating disease of the central nervous system (CNS) affecting young individuals with age range of 20-40years of age. The precise mechanism underlying the disease is still unclear. Some viruses have been proposed to play roles in disease causation. In this study, we recruited 800 MS patients along with 1000 healthy individuals to determine the seropositivity of anti-CMV and anti-VZV IgG titers using enzyme-linked immunosorbent assay (ELISA). Our results showed significant higher titers of anti-CMV and anti-VZV IgG titers in serum of MS patients with respect to healthy individuals (for both p

Laura McDonald,1,* Cormac J Sammon,2,* Mihail Samnaliev,2 Sreeram Ramagopalan1 1Centre for Observational Research and Data Sciences, Bristol-Myers Squibb, Uxbridge, UK; 2PHMR, Berkeley Works, London, UK *These authors contributed equally to this work Background: Primary care databases represent a rich source of data for health care research; however, the quality of recording of secondary care events in these databases is uncertain. This study sought to investigate the completeness of recording of hospital admissions for bleeds in primary care records and explore the impact of incomplete recording on estimates of bleeding risk associated with antithrombotic treatment.Methods: The study population consisted of adults with non-valvular atrial fibrillation who had at least one bleed recorded in either the Clinical Practice Research Datalink (CPRD) or Hospital Episode Statistics (HES) while receiving prescriptions for an oral anticoagulant. The proportion of bleeds recorded in HES that had a corresponding bleed recorded in the subsequent 12 weeks in CPRD was calculated, and factors associated with having a corresponding record were identified. Cox proportional hazards analyses investigating the hazard of subsequent bleeding associated with antithrombotic treatment were carried out using linked CPRD-HES data and using CPRD only data, and the results were compared.Results: Less than 20% of the 14,361 bleeds recorded in the HES data had a corresponding bleed coded in the CPRD in the subsequent 12 weeks. This proportion varied by bleed characteristics, calendar time, day of week of admission (weekday vs weekend) and oral anticoagulant treatment at the time of the bleed. The hazard of subsequent bleeding associated with vitamin K antagonists (VKAs) and antiplatelet agents (APAs) relative to no antithrombotic treatment were similar using the linked primary and secondary care dataset (VKA HRadj 1.06 CI95 0.96–1.16; APA HRadj 1.08 CI95 0.96–1.21) and the unlinked primary care data (VKA HRadj 1.12 CI95 1.01–1.24; APA HRadj 1.06 CI95 0.95–1.20).Conclusion: Secondary care bleeding events are not completely recorded in primary care records and under-recording may be differential with respect to a variety of factors, including antithrombotic treatment. While the impact of under-recording on estimates of the comparative safety of antithrombotic drugs was limited, the extent of the under-recording suggests its potential impact should be considered, and ideally evaluated in future studies utilizing stand-alone primary care data. Keywords: real-world data, data linkage, comparative effectiveness, secondary care, atrial fibrillation

Recent reports have suggested that internet search behaviour may be a valuable tool to estimate melanoma incidence and mortality. Previous studies have used incorrect statistical methods, were focussed on the United States and/or did not use non-cancer control search terms to provide a context for interpreting the effects seen with the cancer-related terms. Using more robust statistical methods we found that no cancer search terms were significantly, or strongly correlated with melanoma incidence in 6 countries.

BACKGROUND Multiple sclerosis (MS) is an inflammatory disease, which has a wide range of effects on patients. There are controversies regarding the role of vitamin D in clinical and laboratory improvements in MS patients. OBJECTIVE The aim of this systematic review protocol is to evaluate the efficacy of vitamin D supplements on relapse rate, gadolinium-enhancing lesions of magnetic resonance imaging (MRI), and cytokine profiles. METHODS We will search PubMed, Scopus, EMBASE, CINAHL, Web of Science, Ovid, ProQuest, American College of Physicians Journal Club database, Health Technology Assessment Database (The Cochrane Collaboration), and National Health System Economic Evaluation Database (The Cochrane Collaboration) and gray literature including reference of included studies and conference abstracts. Clinical trials reporting the effect of any doses of vitamin D on relapse rate, gadolinium-enhancing lesions of MRI, and cytokine profiles will be included. In total, 2 independent researchers will independently assess the studies, extract data, and evaluate the quality of primary studies. RESULTS This systematic review was started in September 2017 and the process is continuing. The included articles are evaluated and researchers are going to extract the data. CONCLUSIONS To our knowledge, this will be the first comprehensive systematic review aiming to assess the effect of vitamin D supplements on clinical and para-clinical outcomes in patients with multiple sclerosis. INTERNATIONAL REGISTERED REPOR PRR1-10.2196/12045

Aim: This study aimed to evaluate the risk of major bleeding among two cohorts of nonvalvular atrial fibrillation patients newly initiating a vitamin K antagonist (VKA) or apixaban in a real-world setting in Italy. Patients & methods: A retrospective study using a large administrative database of Italian local health units was performed, using data from ten local health units and patients were included from the date of new initiation of apixaban or VKAs from January 2012 to June 2015. Results: Risk of major bleeding was calculated using an adjusted Cox regression model. Compared with VKA, apixaban had a significantly lower risk of major bleeding (hazard ratio = 0.44 [95% CI: 0.12–0.97]). Conclusion: In this analysis, apixaban was associated with a lower risk of major bleeding compared with VKA.

Comparative effectiveness research (CER) guidelines have been developed to direct the field toward the most rigorous study methodologies. A challenge, however, is how to ensure the best evidence is generated, and how to translate methodologically complex or nuanced CER findings into usable medical evidence. To reach that goal, it is important that both researchers and end users of CER output become knowledgeable about the elements that impact the quality and interpretability of CER. This paper distilled guidance on CER into a practical tool to assist both researchers and nonexperts with the critical review and interpretation of CER, with a focus on issues particularly relevant to CER in oncology.

OBJECTIVE Early diagnosis and treatment initiation significantly influence long-term disability outcome in multiple sclerosis (MS). We aimed at identifying prodromal symptoms of MS in primary care settings. METHODS This was a nested case-control study comparing the occurrence of various symptoms in MS patients versus controls at 0 to 2, 2 to 5, and 5 to 10 years before index date (first MS record). A total of 10,204 incident MS cases were identified within the United Kingdom Clinical Practice Research Datalink between January 1, 1987 and February 28, 2016 (median age = 47 years, interquartile range [IQR] = 39-57, females = 7,308 [71.6%]). Patients were matched to 39,448 controls with no MS record by sex, year of birth, general practitioner, and year of registration (age = 47 years, IQR = 39-56, females = 28,248 [71.6%]). Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using conditional logistic regression. RESULTS MS patients had significantly higher risk of presenting up to 10 years prior to index date with gastric, intestinal, urinary, and anorectal disturbances, anxiety, depression, insomnia, fatigue, headache, and various types of pain. MS risk progressively increased with each additional symptom presented (0-2 years: OR = 1.51, 95% CI = 1.47-1.55, p

Multiple sclerosis (MS) is a common, complex disorder. Associations of MS with Epstein-Barr virus (EBV) infection in Caucasian populations are well documented. However, in the Iranian population, previous studies have been conflicting. Sixty patients with MS and 50 healthy controls were tested for anti-EBV antibodies using chemiluminescent assays. All MS patients to be seropositive for EBV as compared to 82 % of controls (p = 0.0006). A strong, significant association of MS with EBV infection was documented, similar to studies in first world populations. Future studies should investigate the temporal sequence of infection to try to understand the cause of the recent increase in MS risk in Iran.

In order to understand the current state of data sharing in observational research studies, we reviewed data sharing statements of observational studies published in a general medical journal, the British Medical Journal. We found that the majority (63%) of observational studies published between 2015 and 2017 included a statement that implied that data used in the study could not be shared. If the findings of our exploratory study are confirmed, room for improvement in the sharing of real-world or observational research data exists.

ObjectiveTo describe the changes in prescribing of oral anticoagulant (AC) and antiplatelet (AP) agents in patients with non-valvular atrial fibrillation (NVAF) in the UK and to identify the characteristics associated with deviation from guideline-based recommendations.DesignFive cross-sectional analyses in a large retrospective population-based cohort study.SettingGeneral practices contributing data to the UK Clinical Practice Research Datalink.ParticipantsThe study included patients with a diagnosis of NVAF and eligible for anticoagulation (CHA2DS2-VASc score ≥2) on 1 April of 2012, 2013, 2014, 2015 and 1st January 2016.ResultsThe proportion of patients being treated with AC increased at each index date, showing an absolute rise of 16.7% over the study period. At the same time, the proportion of patients treated with an AP alone was reduced by half, showing an absolute decrease of 16.8%. The proportion of patients not receiving any antithrombotic (AT) treatment remained the same across the study period. A number of predictors were identified for AP alone or no treatment compared with AC treatment.ConclusionMajor improvements in the AT management of patients with NVAF for stroke prevention in the UK were observed between April 2012 and January 2016. Despite this, nearly 20% of at-risk patients still received AP alone and over 15% were on no AT agents in January 2016.

The Clinical Practice Research Datalink (CPRD) is a repository of electronic medical records collected during routine primary care clinical practice in the UK, and is one of the most widely used sources of real-world data for healthcare research. Although CPRD provides access to comprehensive longitudinal patient records, the data does not fully capture diagnoses or outcomes occurring in secondary care and/or mortality. We provide here an overview of CPRD and the potential bias when using unlinked data in certain situations. Linkage of CPRD to other datasets can help to overcome these limitations. We discuss when to consider linkage to secondary care, disease-specific data sources or the official mortality data when conducting research using CPRD data.

The contribution of British neurologist Russell Walter Brain (1895-1966) to the field of neurology is difficult to overestimate and his seminal work continues to influence modern neurological education and practice. In a landmark review published in the Quarterly Review of Medicine in 1930, he gives a critically important account summarising ideas of the time thought to underlie the then called 'disseminated sclerosis', a disease he notes to be, 'after syphilis, the most frequent disease of the nervous system' in the UK. Across a century and a half, vast progress has been made in attempting to elucidate the as yet unknown cause of MS, which is unravelling to be multifactorial, highly complex and likely dependent on both genetic and environmental risk factors. Brain's observations highlight the changing epidemiology of MS over the last century which are likely to provide the platform in striving towards elucidating MS causation, notably a seemingly reduced latitudinal gradient of MS incidence, an increasing female-to-male sex ratio and an increasing disease rate in dark-skinned compared to light-skinned individuals. In this report we aim to evaluate the relevance today of what we believe to have been an important review demonstrating a perspective on MS far ahead that of its time, with a focus on Brain's ideas on the aetiology of MS; many of which have stood the test of time.

Background: There is a well-documented increase in the risk of multiple sclerosis (MS) when migrating from a region of low prevalence to one of high prevalence. Objective: We present here an investigation of MS prevalence and candidate environmental and genetic risk factors among Iranian immigrants to British Columbia (BC), Canada. Methods: MS cases of Iranian ancestry were ascertained from a population-based Canadian study. We collected blood samples for genetic and serological analyses, and administered a personal history questionnaire to the cases. Results: The crude prevalence of MS in this population of Iranian ancestry was 287/100,000 (95% CI: 229 – 356/100,000). MS cases were more likely to have a history of infectious mononucleosis (odds ratio (OR) = 7.5; p = 0.005) and smoking (OR = 17.0; p < 0.0001), as compared to healthy controls from previous studies in Iran. Cases were also more likely than controls to have been born between April and September (OR = 2.1; p = 0.019). Conclusion: The prevalence of MS among Iranian immigrants to Canada is greater than the overall prevalence of MS in Iran by a factor of at least four, and is similar to that recently observed among Iranian immigrants in other western nations. No major genetic susceptibility variants were identified, suggesting the environment in Canada may be what is increasing the risk of MS in this population.

Genome-wide association studies (GWASs) have shown that approximately 60 genetic variants influence the risk of developing multiple sclerosis (MS). Our aim was to identify the cell types in which these variants are active. We used available data on MS-associated single nucleotide polymorphisms (SNPs) and deoxyribonuclease I hypersensitive sites (DHSs) from 112 different cell types. Genomic intervals were tested for overlap using the Genomic Hyperbrowser. The expression profile of the genes located nearby MS-associated SNPs was assessed using the software GRAIL (Gene Relationships Across Implicated Loci). Genomic regions associated with MS were significantly enriched for a number of immune DHSs and in particular T helper (Th) 1, Th17, CD8+ cytotoxic T cells, CD19+ B cells and CD56+ natural killer (NK) cells (enrichment = 2.34, 2.19, 2.27, 2.05 and 1.95, respectively; P < 0.0001 for all of them). Similar results were obtained when genomic regions with suggestive association with MS and additional immune-mediated traits were investigated. Several new candidate MS-associated genes located within regions of suggestive association were identified by GRAIL (CARD11, FCRL2, CHST12, SYK, TCF7, SOCS1, NFKBIZ and NPAS1). Genetic data indicate that Th1, Th17, cytotoxic T, B and NK cells play a prominent role in the etiology of MS. Regions with confirmed and suggestive association have a similar immunological profile, indicating that many SNPs truly influencing the risk of MS actually fail to reach genome-wide significance. Finally, similar cell types are involved in the etiology of other immune-mediated diseases.

Vitamin D and its metabolites have pleomorphic roles in both nervous system health and disease. Animal models have been paramount in contributing to our knowledge and understanding of the consequences of vitamin D deficiency on brain development and its implications for adult psychiatric and neurological diseases. The conflation of in vitro, ex vivo, and animal model data provide compelling evidence that vitamin D has a crucial role in proliferation, differentiation, neurotrophism, neuroprotection, neurotransmission, and neuroplasticity. Vitamin D exerts its biological function not only by influencing cellular processes directly, but also by influencing gene expression through vitamin D response elements. This review highlights the epidemiological, neuropathological, experimental and molecular genetic evidence implicating vitamin D as a candidate in influencing susceptibility to a number of psychiatric and neurological diseases. The strength of evidence varies for schizophrenia, autism, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease, and is especially strong for multiple sclerosis.

Multiple sclerosis (MS) is a multifactorial disease in which both genetic and environmental factors and their interactions underlie causation. The current evidence base supports a strong association between Epstein-Barr virus (EBV) and MS, but potential causality remains strongly debated. It is not possible to exclude the possibility that an abnormal response to EBV infection is a consequence, rather than a cause, of the underlying pathophysiology of MS, or indeed that the association may be a reflection of a similar underlying disease mechanism. Substantial experimental progress is necessary to achieve consistency of molecular findings to complement the strong epidemiological association between EBV and MS, which cannot alone show causation. Collectively, the strength of the association between EBV and MS warrants careful development and trial of anti-EBV drugs to observe any effect on MS disease course.

Background Oligoclonal bands (OCBs) unique to the cerebrospinal fluid are used in the diagnosis of multiple sclerosis (MS). The precise prevalence of OCBs in MS and clinically isolated syndrome (CIS) is unknown. The influence of OCBs on clinical outcomes has not been quantified. OCB prevalence has been associated with latitude in a single study, if confirmed this would provide avenues for further study. Methods Using a systematic review and meta-analysis approach, the proportion of OCB-positive MS and CIS and the influence of OCBs on clinical outcomes were calculated. The relationship between latitude and OCB prevalence was calculated using linear regression. Results Seventy-one articles were included. Overall, 87.7% of 12 253 MS and 68.6% of 2685 CIS patients were OCB positive. OCB-positive MS patients had an OR of 1.96 of reaching disability outcomes, although a number of negative studies did not provide data. OCB-positive CIS patients had an OR of 9.88 of conversion to MS. Latitude predicted OCB status in MS patients (p=0.009) but not in CIS patients. Conclusions This is the largest study of OCB prevalence in MS and CIS. OCB positivity strongly predicts conversion from CIS to MS. The relationship between latitude and OCBs is confirmed, and this finding warrants further investigation.

Next-generation sequencing techniques have made vast quantities of data on human genomes and transcriptomes available to researchers. Huge progress has been made towards understanding the basis of many Mendelian neurological conditions, but progress has been considerably slower in complex neurological diseases (multiple sclerosis, migraine, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and so on). The authors review current next-generation sequencing methodologies and present selected studies illustrating how these have been used to cast light on the genetic etiology of complex neurological diseases with specific focus on multiple sclerosis. The authors highlight particular pitfalls in next-generation sequencing experiments and speculate on both clinical and research applications of these sequencing platforms for complex neurological disorders in the future.

Large numbers of statistically significant associations between sentinel SNPs and case-control status have been replicated by genome-wide association studies. Nevertheless, few underlying molecular mechanisms of complex disease are currently known. We investigated whether variation in binding of a transcription factor, the vitamin D receptor (VDR) whose activating ligand vitamin D has been proposed as a modifiable factor in multiple disorders, could explain any of these associations. VDR modifies gene expression by binding DNA as a heterodimer with the Retinoid X receptor (RXR).We identified 43,332 genetic variants significantly associated with altered VDR binding affinity (VDR-BVs) using a high-resolution (ChIP-exo) genome-wide analysis of 27 HapMap lymphoblastoid cell lines. VDR-BVs are enriched in consensus RXR::VDR binding motifs, yet most fell outside of these motifs, implying that genetic variation often affects binding affinity only indirectly. Finally, we compared 341 VDR-BVs replicating by position in multiple individuals against background sets of variants lying within VDR-binding regions that had been matched in allele frequency and were independent with respect to linkage disequilibrium. In this stringent test, these replicated VDR-BVs were significantly (q< 0.1) and substantially (> 2-fold) enriched in genomic intervals associated with autoimmune and other diseases, including inflammatory bowel disease, Crohn’s disease and rheumatoid arthritis. The approach’s validity is underscored by RXR::VDR motif sequence being predictive of binding strength and being evolutionarily constrained.Our findings are consistent with altered RXR::VDR binding contributing to immunity-related diseases. Replicated VDR-BVs associated with these disorders could represent causal disease risk alleles whose effect may be modifiable by vitamin D levels.

Initially thought to play a restricted role in calcium homeostasis, the pleiotropic actions of vitamin D in biology and their clinical significance are only now becoming apparent. However, the mode of action of vitamin D, through its cognate nuclear vitamin D receptor (VDR), and its contribution to diverse disorders, remain poorly understood. We determined VDR binding throughout the human genome using chromatin immunoprecipitation followed by massively parallel DNA sequencing (ChIP-seq). After calcitriol stimulation, we identified 2776 genomic positions occupied by the VDR and 229 genes with significant changes in expression in response to vitamin D. VDR binding sites were significantly enriched near autoimmune and cancer associated genes identified from genome-wide association (GWA) studies. Notable genes with VDR binding included IRF8, associated with MS, and PTPN2 associated with Crohn's disease and T1D. Furthermore, a number of single nucleotide polymorphism associations from GWA were located directly within VDR binding intervals, for example, rs13385731 associated with SLE and rs947474 associated with T1D. We also observed significant enrichment of VDR intervals within regions of positive selection among individuals of Asian and European descent. ChIP-seq determination of transcription factor binding, in combination with GWA data, provides a powerful approach to further understanding the molecular bases of complex diseases.

We read with interest the recent study showing that gestational vitamin D deficiency significantly reduces the number of invariant NKT cells in mice and that later supplementation was not able to correct this. The authors conclude that low vitamin D levels in utero may result in long-term epigenetic

Autoimmune mechanisms are thought to have a major role in the pathogenesis of multiple sclerosis (MS) and vitamin D is hypothesised to contribute to disease susceptibility. Cow's milk allergy (CMA) is a common childhood allergy arising from an immune system imbalance and can also lead to vitamin D deficiency due to dairy food avoidance. Here, we investigated whether or not CMA influences the subsequent risk to develop MS in a population-based cohort. We identified 6638 MS index cases and 2509 spousal controls with CMA information from the Canadian Collaborative Project on Genetic Susceptibility to MS (CCPGSMS). Frequency of CMA was compared between index cases and controls. No significant differences were found. Childhood CMA thus does not appear to be a risk factor for MS.

Multiple sclerosis (MS) is a complex neurological disease with huge variability in disease outcome. The majority of MS genetic susceptibility is determined by major histocompatibility complex (MHC) alleles, in particular haplotypes carrying HLA-DRB1*1501. HLA-DRB1*1501 also affects the clinical outcome of the disease and animal research has suggested that HLA-DRB5 interacts with HLA-DRB1*1501 to influence disease severity. We used an extremes-of-outcome design with 48 benign and 20 malignant MS patients to assess whether or not DNA methylation at HLA-DRB1*1501 and/or HLA-DRB5 also contributes to MS phenotypic heterogeneity. We found no significant effect of DNA methylation across HLA-DRB1*1501 and HLA-DRB5 on severity, although we cannot rule out time- or tissue-specific effects of DNA methylation.

OBJECTIVES: To assess the extent to which funding and study design are associated with high reprint orders. DESIGN: Case-control study. SETTING: Top articles by size of reprint orders in seven journals, 2002-09. PARTICIPANTS: Lancet, Lancet Neurology, Lancet Oncology (Lancet Group), BMJ, Gut, Heart, and Journal of Neurology, Neurosurgery and Psychiatry (BMJ Group) matched to contemporaneous articles not in the list of high reprint orders. MAIN OUTCOME MEASURES: Funding and design of randomised controlled trials or other study designs. RESULTS: Median reprint orders for the seven journals ranged from 3000 to 126,350. Papers with high reprint orders were more likely to be funded by the pharmaceutical industry than were control papers (industry funding versus other or none: odds ratio 8.64, 95% confidence interval 5.09 to 14.68, and mixed funding versus other or none: 3.72, 2.43 to 5.70). CONCLUSIONS: Funding by the pharmaceutical industry is associated with high numbers of reprint orders.

Multiple sclerosis (MS) is a complex trait in which HLA-DRB1*15 bearing MHC haplotypes increase risk of MS in people of Northern European descent. In this investigation of 7,334 individuals from 1,515 MS families, the largest cohort used to study the HLA-DRB1 locus to date, we analysed the transmission of HLA-DRB1*15 haplotypes stratified by sex of transmitting parent. A significant over transmission of HLA-DRB1*15 from mothers was observed (chi (2) = 7.73, P = 0.0054), suggesting that parent of origin effects at the MHC determine susceptibility to MS.

Multiple sclerosis (MS) is a common, complex neurological disease. Epidemiological data implicate both genetic and environmental factors in the etiology of MS, with various factors interacting with one another. Environmental exposures might occur long before the disease becomes clinically evident, as suggested by the wide range in onset age. In this Review, we examine the key time periods during which the environment might contribute to MS susceptibility, as well as the potential environmental factors involved. Understanding the nature of environmental influences in MS is highly relevant to the development of public health measures that are aimed at preventing this debilitating disease.

Objective Pregnancy has a well documented effect on relapse risk in multiple sclerosis (MS). Prospective studies have reported a significant decline by two-thirds in the rate of relapses during the third trimester of pregnancy and a significant increase by two-thirds during the first 3 months postpartum. However, it is unclear as to whether there are any long term effects on disability. Methods Data were collated from clinical records and family histories systematically collected from the University of British Columbia MS Clinic. Results Clinical and term pregnancy data were available from 2105 female MS patients. MS patients having children after MS onset took the longest time to reach an Expanded Disability Status Scale (EDSS) score of 6 (mean 22.9 years) and patients having children before MS onset were the quickest (mean 13.2 years). However, these effects were not related to term pregnancy and were fully accounted for by age of MS onset. Conclusions Pregnancy had no effect on the time to reach an EDSS score 6. As MS predominantly affects women of childbearing age, women with MS can be reassured that term pregnancies do not appear to have any long term effects on disability.

Migraine is a common debilitating neurological disease characterised by attacks of severe headache with or without preceding aura. Its aetiology remains elusive; however it is clear that an interplay of genetic and environmental components play an important role. Familial hemiplegic migraine (FHM) is a rare and severe variant of migraine with aura and follows an autosomal dominant pattern of inheritance. This disease is genetically heterogeneous,with three causative genes having been identified. This review uses insights garnered from FHM to try and shed light on possible migraine disease pathogenesis.

Multiple sclerosis, the most common cause of progressive neurological disability in young adults, is a chronic inflammatory disease. There is solid evidence for a genetic influence in multiple sclerosis, and deciphering the causative genes could reveal key pathways influencing the disease. A genome region on rat chromosome 9 regulates experimental autoimmune encephalomyelitis, a model for multiple sclerosis. Using interval-specific congenic rat lines and association of single-nucleotide polymorphisms with inflammatory phenotypes, we localized the gene of influence to Vav1 , which codes for a signal-transducing protein in leukocytes. Analysis of seven human cohorts (12,735 individuals) demonstrated an association of rs2546133-rs2617822 haplotypes in the first VAV1 intron with multiple sclerosis (CA: odds ratio, 1.18; CG: odds ratio, 0.86; TG: odds ratio, 0.90). The risk CA haplotype also predisposed for higher VAV1 messenger RNA expression. VAV1 expression was increased in individuals with multiple sclerosis and correlated with tumor necrosis factor and interferon-γ expression in peripheral blood and cerebrospinal fluid cells. We conclude that VAV1 plays a central role in controlling central nervous system immune-mediated disease and proinflammatory cytokine production critical for disease pathogenesis.

Genome-wide association studies (GWAS) have been conducted on many complex diseases with the aim of identifying common genetic variants important in disease susceptibility. It is rare for these to consider environmental factors when calculating the odds ratios for variants associated with disease. We modelled the effect of an environmentally-dependent genetic risk locus and showed that, despite a relatively low overall odds ratio, environmental exposure was able to conceal a large true effect size on disease susceptibility in exposed individuals. This model was applied to vitamin D deficiency in multiple sclerosis and raised the possibility of large magnitudes of concealed effect in loci responsive to vitamin D in this disease. In the post-GWAS era, efforts should be made to elucidate potential gene-environment interactions involved in complex traits in order for true effects on disease risk to be realised.

Background Venous thromboembolism (VTE) is a common complication during and after a hospital admission. Although it is mainly considered a complication of surgery, it often occurs in people who have not undergone surgery, with recent evidence suggesting that immune-mediated diseases may play a role in VTE risk. We, therefore, decided to study the risk of deep vein thrombosis (DVT) and pulmonary embolism (PE) in people admitted to hospital with a range of immune-mediated diseases. Methods We analysed databases of linked statistical records of hospital admissions and death certificates for the Oxford Record Linkage Study area (ORLS1:1968 to 1998 and ORLS2:1999 to 2008) and the whole of England (1999 to 2008). Rate ratios for VTE were determined, comparing immune-mediated disease cohorts with comparison cohorts. Results Significantly elevated risks of VTE were found, in all three populations studied, in people with a hospital record of admission for autoimmune haemolytic anaemia, chronic active hepatitis, dermatomyositis/polymyositis, type 1 diabetes mellitus, multiple sclerosis, myasthenia gravis, myxoedema, pemphigus/pemphigoid, polyarteritis nodosa, psoriasis, rheumatoid arthritis, Sjogren's syndrome, and systemic lupus erythematosus. Rate ratios were considerably higher for some of these diseases than others: for example, for systemic lupus erythematosus the rate ratios were 3.61 (2.36 to 5.31) in the ORLS1 population, 4.60 (3.19 to 6.43) in ORLS2 and 3.71 (3.43 to 4.02) in the England dataset. Conclusions People admitted to hospital with immune-mediated diseases may be at an increased risk of subsequent VTE. Our findings need independent confirmation or refutation; but, if confirmed, there may be a role for thromboprophylaxis in some patients with these diseases.

The restricted use of immunoglobulin heavy chain variable (IGHV) family 4 gene segments by clonally expanded B cells in brain lesions and cerebrospinal fluid (CSF) of multiple sclerosis (MS) patients is well documented. Specifically, the overrepresentation of gene IGHV4-39 has been highlighted in multiple studies. To investigate the role of IGHV4-39 in MS, we screened 193 MS cases, representing the extremes of clinical outcome (benign and malignant), and 187 controls for a previously reported germline deletion polymorphism containing IGHV4-39. We did not reveal a genetic association linking this polymorphism to MS risk or progression.

Background Multiple sclerosis (MS) is determined by interactions between genes and environment and the influence of vitamin D adequacy has been proposed. Previous studies have shown that serum 25-hydroxyvitaminD (25(OH)D) levels are genetically influenced. Polymorphisms in vitamin D pathway genes are candidates for association with MS susceptibility. Methods MS patients ( n = 1364) and their unaffected first-degree relatives ( n = 1661) were ascertained through the Canadian Collaborative study. Seventy-one SNPs, across four genes [vitamin D receptor (VDR), 1-alpha-hydroxylase (CYP27B1) enzyme, vitamin D binding protein (DBP), 24-hydroxylase (CYP24)], were genotyped and tested for association with MS susceptibility using TDT in PLINK. Secondary analyses included stratification for HLA-DRB1*15 and parent of origin transmission effects. Results We found no significant association of vitamin D pathway genes with MS susceptibility after correction for multiple comparisons. However, the VDR Fok1 variant (rs2228570), selected for previously positive associations with MS susceptibility and 25(OH)D levels in MS patients showed marginally distorted transmission in DRB15-negative patients ( p = 0.03). There was no evidence for differential maternal versus paternal allele transmission. Conclusions The findings fail to directly connect vitamin D metabolism genes to MS susceptibility, despite a large sample size and comprehensive gene coverage.

els [1] . However, these data largely stem from studies in North American and European populations. In this edition of Neuroepidemiology, Maghzi et al. [3] report the results of a well-powered sibling case-control study of cigarette smoking and MS in Iran. MS in Iran is gaining attention due to reports of a recent substantial prevalence increase [4] . If true, causal factors may be more easily discovered in this population. The authors found that smoking history was associated with MS risk. Overall this is a similar finding to that reported by a previous case-control study conducted in multiple centres across Iran [5] . However, there are a number of unexplained discrepancies; Maghzi et al. report a positive association with a history of smoking drawn almost exclusively from the association observed in men since the frequency of smoking amongst women in the study was very low. In contrast, the other Iranian study found that smoking was significantly associated with MS susceptibility only in women and not in men. The two studies are quite similar in demographical characteristics and, indeed, the controls used in the first study were often family members, but the smoking rate in females reported by Maghzi et al. is much lower than that seen The aetiology of multiple sclerosis (MS) arises from the interaction of multiple different genetic and environmental risk factors [1] . Large-scale genome-wide association studies have identified multiple genetic risk loci but by far the most important association in MS susceptibility is with the class II human leukocyte antigen (HLA) region, specifically HLA-DRB1 * 1501 bearing haplotypes [2] . The environmental factors most consistently associated with risk of MS are Epstein-Barr virus infection, particularly infectious mononucleosis, cigarette smoking and low vitamin D levPublished online: December 7, 2011

It is now acknowledged that seasonality is a main feature of the complex neurological disorder multiple sclerosis (MS). Having a spring birthday and being exposed to low levels of sunshine significantly increase the risk of MS later in life.1,2 Although global environment is dominated by seasonality, the observation that vitamin D status is inversely associated with risk of MS later in life and that vitamin D regulates the expression of a large number of MS associated genes, strongly indicate that ultra-violet (UV) light exposure and consequent effects on vitamin D production are involved in MS etiology.3,4 Intriguingly this essential hormone appears to also play an important role in influencing MS disease course. Studies have shown an inverse association between 25-hydroxyvitamin D (25-OH-D) levels and clinical MS severity and relapse rate.5 Furthermore, in a recent prospective investigation of a large cohort of MS patients, vitamin D status inversely correlated with relapses over the subsequent 6 months.6 Similar …

Multiple sclerosis (MS) is a common, complex neurological disease. The precise aetiology of MS is not yet known, although epidemiological data indicate that both genetic and environmental factors are important. The evidence that the environment acts long before MS becomes clinically evident is well established and suggests the existence of a prodromal phase for the disease. The increasing incidence of MS emphasises the need for strategies to prevent this chronic disorder, and the possibility of a prodrome indicates a window of opportunity to potentially reverse early disease processes before clinical disease becomes evident. Studying a prodrome requires techniques other than clinical observation such as monitoring endophenotypes that result from associated risk factors. However, our current knowledge of causal pathways and endophenotypes in MS is limited. Identifying and studying individuals with a high risk of developing the disease provides a powerful opportunity to understand the MS causal cascade and is highly relevant to strategies that are aimed at preventing this debilitating disease.