Duration of untreated psychosis and social function: 1-year follow-up study of first-episode schizophrenia.

BACKGROUND: In first-episode schizophrenia, longer duration of untreated psychosis (DUP) predicts poorer outcomes. AIMS: To address whether the relationship between DUP and outcome is a direct causal one or the result of association between symptoms and/or cognitive functioning and social functioning at the same time point. METHOD: Symptoms, social function and cognitive function were assessed in 98 patients with first-episode schizphrenia at presentation and 1 year later. RESULTS: There was no significant clinical difference between participants with short and long DUP at presentation. Linear regression analyses revealed that longer DUP significantly predicted more severe positive and negative symptoms and poorer social function at 1 year, independent of scores at presentation. Path analyses revealed independent direct relationships between DUP and social function, core negative symptoms and positive symptoms. There was no significant association between DUP and cognition. CONCLUSIONS: Longer DUP predicts poor social function independently of symptoms. The findings underline the importance of taking account of the phenomenological overlap between measures of negative symptoms and social function when investigating the effects of DUP

The Association Between Chronic Pain and Cardiac Disease: A Cross-sectional Population Study.

OBJECTIVES: Chronic pain may increase the risk of cardiac disease, but the extent to which confounding variables account for this association has yet to be satisfactorily established. This study aims to examine the possibility of an independent association between these 2 variables. METHODS: We applied logistic regression analysis to data from 8596 adults surveyed in a population study of the health of the population of England. The association between cardiac disease (angina and/or myocardial infarction) and chronic pain (pain lasting >3 months) was explored, taking account of 10 potentially confounding variables including the regular use of nonsteroidal anti-inflammatory drugs. RESULTS: Participants reporting chronic pain (n=3023) were more likely to experience cardiac disease than those without pain: odds ratio (OR), 1.55; 95% confidence interval (CI), 1.15-2.07. Subsets of participants fulfilling various criteria for high-intensity chronic pain demonstrated stronger associations with cardiac disease suggesting a "dose-response" element to the relationship: chronic widespread pain (OR, 3.3; 95% CI, 1.42-7.68); higher-disability chronic pain (OR, 2.35; 95% CI, 1.71-3.23); and higher average chronic pain score (OR, 1.95; 95% CI, 1.40-2.71). Adjustment for regular prescription of nonsteroidal anti-inflammatory drugs did not reduce the association of chronic pain with cardiac disease. DISCUSSION: Patients reporting chronic pain, in particular those most severely affected, may be at significantly increased risk of cardiac disease. Future studies should focus on determining whether reducing the impact of chronic pain can improve cardiac health

Access to general practice and visits to accident and emergency departments in England: cross-sectional analysis of a national patient survey.

BACKGROUND: The annual number of unplanned attendances at accident and emergency (A&E) departments in England increased by 11% (2.2 million attendances) between 2008-2009 and 2012-2013. A national review of urgent and emergency care has emphasised the role of access to primary care services in preventing A&E attendances. AIM: To estimate the number of A&E attendances in England in 2012-2013 that were preceded by the attending patient being unable to obtain an appointment or a convenient appointment at their general practice. DESIGN AND SETTING: Cross-sectional analysis of a national survey of adults registered with a GP in England. METHOD: The number of general practice consultations in England in 2012-2013 was estimated by extrapolating the linear trend of published data for 2000-2001 to 2008-2009. This parameter was multiplied by the ratio of attempts to obtain a general practice appointment that resulted in an A&E attendance to attempts that resulted in a general practice consultation estimated using the GP Patient Survey 2012-2013. A sensitivity analysis varied the number of consultations by ±12% and the ratio by ±25%. RESULTS: An estimated 5.77 million (99.9% confidence interval = 5.49 to 6.05 million) A&E attendances were preceded by the attending patient being unable to obtain a general practice appointment or a convenient appointment, comprising 26.5% of unplanned A&E attendances in England in 2012-2013. The sensitivity analysis produced values between 17.5% and 37.2% of unplanned A&E attendances. CONCLUSION: A large number of A&E attendances are likely to be preceded by unsuccessful attempts to obtain convenient general practice appointments in England each year

Development of a composite outcome score for a complex intervention - measuring the impact of Community Health Workers.

BACKGROUND: In health services research, composite scores to measure changes in health-seeking behaviour and uptake of services do not exist. We describe the rationale and analytical considerations for a composite primary outcome for primary care research. We simulate its use in a large hypothetical population and use it to calculate sample sizes. We apply it within the context of a proposed cluster randomised controlled trial (RCT) of a Community Health Worker (CHW) intervention. METHODS: We define the outcome as the proportion of the services (immunizations, screening tests, stop-smoking clinics) received by household members, of those that they were eligible to receive. First, we simulated a population household structure (by age and sex), based on household composition data from the 2011 England and Wales census. The ratio of eligible to received services was calculated for each simulated household based on published eligibility criteria and service uptake rates, and was used to calculate sample size scenarios for a cluster RCT of a CHW intervention. We assume varying intervention percentage effects and varying levels of clustering. RESULTS: Assuming no disease risk factor clustering at the household level, 11.7% of households in the hypothetical population of 20,000 households were eligible for no services, 26.4% for 1, 20.7% for 2, 15.3% for 3 and 25.8% for 4 or more. To demonstrate a small CHW intervention percentage effect (10% improvement in uptake of services out of those who would not otherwise have taken them up, and additionally assuming intra-class correlation of 0.01 between households served by different CHWs), around 4,000 households would be needed in each of the intervention and control arms. This equates to 40 CHWs (each servicing 100 households) needed in the intervention arm. If the CHWs were more effective (20%), then only 170 households would be needed in each of the intervention and control arms. CONCLUSIONS: This is a useful first step towards a process-centred composite score of practical value in complex community-based interventions. Firstly, it is likely to result in increased statistical power compared with multiple outcomes. Second, it avoids over-emphasis of any single outcome from a complex intervention

Telomerecat: A ploidy-agnostic method for estimating telomere length from whole genome sequencing data.

Telomere length is a risk factor in disease and the dynamics of telomere length are crucial to our understanding of cell replication and vitality. The proliferation of whole genome sequencing represents an unprecedented opportunity to glean new insights into telomere biology on a previously unimaginable scale. To this end, a number of approaches for estimating telomere length from whole-genome sequencing data have been proposed. Here we present Telomerecat, a novel approach to the estimation of telomere length. Previous methods have been dependent on the number of telomeres present in a cell being known, which may be problematic when analysing aneuploid cancer data and non-human samples. Telomerecat is designed to be agnostic to the number of telomeres present, making it suited for the purpose of estimating telomere length in cancer studies. Telomerecat also accounts for interstitial telomeric reads and presents a novel approach to dealing with sequencing errors. We show that Telomerecat performs well at telomere length estimation when compared to leading experimental and computational methods. Furthermore, we show that it detects expected patterns in longitudinal data, repeated measurements, and cross-species comparisons. We also apply the method to a cancer cell data, uncovering an interesting relationship with the underlying telomerase genotype

Autosomal dominant STAT6 Gain of function causes severe atopy associated with lymphoma

The transcription factor STAT6 (Signal Transducer and Activator of Transcription 6) is a key regulator of Th2 (T-helper 2) mediated allergic inflammation via the IL-4 (interleukin-4) JAK (Janus kinase)/STAT signalling pathway. We identified a novel heterozygous germline mutation STAT6 c.1255G > C, p.D419H leading to overactivity of IL-4 JAK/STAT signalling pathway, in a kindred affected by early-onset atopic dermatitis, food allergy, eosinophilic asthma, anaphylaxis and follicular lymphoma. STAT6 D419H expression and functional activity were compared with wild type STAT6 in transduced HEK293T cells and to healthy control primary skin fibroblasts and peripheral blood mononuclear cells (PBMC). We observed consistently higher STAT6 levels at baseline and higher STAT6 and phosphorylated STAT6 following IL-4 stimulation in D419H cell lines and primary cells compared to wild type controls. The pSTAT6/STAT6 ratios were unchanged between D419H and control cells suggesting that elevated pSTAT6 levels resulted from higher total basal STAT6 expression. The selective JAK1/JAK2 inhibitor ruxolitinib reduced pSTAT6 levels in D419H HEK293T cells and patient PBMC. Nuclear staining demonstrated increased STAT6 in patient fibroblasts at baseline and both STAT6 and pSTAT6 after IL-4 stimulation. We also observed higher transcriptional upregulation of downstream genes (XBP1 and EPAS1) in patient PBMC. Our study confirms STAT6 gain of function (GOF) as a novel monogenetic cause of early onset atopic disease. The clinical association of lymphoma in our kindred, along with previous data linking somatic STAT6 D419H mutations to follicular lymphoma suggest that patients with STAT6 GOF disease may be at higher risk of lymphomagenesis

GWAS meta-analysis of intrahepatic cholestasis of pregnancy implicates multiple hepatic genes and regulatory elements

Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disorder affecting 0.5–2% of pregnancies. The majority of cases present in the third trimester with pruritus, elevated serum bile acids and abnormal serum liver tests. ICP is associated with an increased risk of adverse outcomes, including spontaneous preterm birth and stillbirth. Whilst rare mutations affecting hepatobiliary transporters contribute to the aetiology of ICP, the role of common genetic variation in ICP has not been systematically characterised to date. Here, we perform genome-wide association studies (GWAS) and meta-analyses for ICP across three studies including 1138 cases and 153,642 controls. Eleven loci achieve genome-wide significance and have been further investigated and fine-mapped using functional genomics approaches. Our results pinpoint common sequence variation in liver-enriched genes and liver-specific cis-regulatory elements as contributing mechanisms to ICP susceptibility

Publisher Correction: Telomerecat: A ploidy-agnostic method for estimating telomere length from whole genome sequencing data.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper

Endometrial thickness as a test for endometrial cancer in women with postmenopausal vaginal bleeding.

OBJECTIVE: To assess the value of endometrial thickness measurement as a test for endometrial cancer in postmenopausal women with vaginal bleeding (symptomatic women). DATA SOURCES: We conducted a literature search using the MEDLINE database from 1991 to 1997, and the key words "vaginal ultrasonography" and "endometrial thickness measurement." The review was limited to original research reports written in English, concerning symptomatic women having vaginal ultrasonography before a diagnostic test and not receiving tamoxifen. STUDY SELECTION: A total of 48 studies were identified. A questionnaire was sent to the corresponding author of each paper requesting supplementary information. Data were included in our analysis if the corresponding author was able to supply information on the median endometrial thickness in unaffected symptomatic women and the endometrial thickness values in affected women. Nine studies were thus included in our meta-analysis, representing 3483 women without endometrial cancer and 330 women with endometrial cancer. TABULATION, INTEGRATION, AND RESULTS: The median endometrial thickness in women with endometrial cancer was 3.7 times that in unaffected women at the same center, and with the same menopausal status and same hormone replacement therapy use category. The detection rate was 63% (95% confidence interval 58, 69) for a 10% false-positive rate, or 96% (95% confidence interval 94, 98) for a 50% false-positive rate. CONCLUSION: Endometrial thickness measurement in symptomatic women does not reduce the need for invasive diagnostic testing because 4% of the endometrial cancers would still be missed with a false-positive rate as high as 50%

The underlying risk of death after myocardial infarction in the absence of treatment.

BACKGROUND: The underlying risk of death in the absence of treatment after a myocardial infarction (MI) is poorly documented. METHODS: Analysis of 23 published studies in which 14 211 patients were followed prospectively after MI; 6817 deaths were recorded. We restricted the analysis to studies in which follow-up was completed by 1980 to quantify the underlying risk in the absence of effective treatments. RESULTS: After a first MI, on average, 23% of patients died before reaching the hospital and another 13% died during hospital admission; these rates increased with age. After hospital discharge cardiovascular mortality was approximately 10% in the first year and 5% per year thereafter, rates that were unrelated to age or sex. The yearly death rate of 5% persisted indefinitely; after 15 years, cumulative cardiovascular mortality was 70%. After a subsequent MI, 33% of patients died before reaching the hospital, and 20% died in hospital. After discharge, cardiovascular mortality was approximately 20% in the first year and 10% per year thereafter, rates again unrelated to age and sex. Approximately a third of all heart disease deaths occurred minutes after the first MI, a sixth during the first hospitalization, and half after a subsequent MI, which could occur many years after the first. CONCLUSIONS: In persons with a history of MI, cardiovascular mortality in the absence of treatment is high-5% per year after a first MI and 10% per year after a subsequent MI, persisting for many years and probably for the rest of a person's life. The high mortality rate emphasizes the need to ensure that everyone who has had an MI, even years previously, receives effective preventive treatment