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Background:-Maintenance treatment with 5-aminosalicylic-acid (5-ASA) is recommended in ulcerative colitis, but accurate estimates of discontinuation and adherence in adolescents transitioning to young adulthood are lacking. Aim:-We aimed to determine rates and risk factors for discontinuation and adherence to oral 5-aminosalicylic-acid in adolescents and young adults aged 10-24-years in their first-year following diagnosis of ulcerative colitis. Design and setting:-Observational cohort study using the UK Clinical Practice Research Datalink amongst adolescents and young adults (aged 10-24 years) diagnosed with ulcerative colitis between 1.1.1998-1.5.2016. Methods:-We calculated time to oral 5-aminosalicylic-acid discontinuation (days) and adherence rates (proportion of days covered) during the first year of treatment using Kaplan Meier survival analysis and built Cox regression models to estimate the impact of sociodemographic and health-related risk factors. Results:-Among 607 adolescents and young adults aged 10-24 years starting oral 5-aminosalicylic-acid maintenance treatment, a quarter discontinued after one month, and 69% within a year. Discontinuation was higher among those aged 18-24 years (74%) than younger groups (61%, 56%, in 10-14, and 15-17-years respectively). Adherence was lower among those young adults than adolescents (69% for ages 18-24 vs 80% ages 10-14 years). Residents in deprived versus affluent postcodes were more likely to discontinue treatment (adjusted hazard ratio:1.46,-95%-CI:1.10-1.92). Early corticosteroid use for an acute flare, lowered the likelihood of oral 5-aminosalicylic-acid discontinuation (aHR:0.68, 95%-CI:0.51-0.90). Conclusion:-The first year of starting long term therapies in adolescents and young adults diagnosed with ulcerative colitis is a critical window for active follow up of maintenance treatment, particularly 18-24-year-olds and those living in deprived postcodes.

Among first order optimization methods, Polyak's heavy ball method has long been known to guarantee the asymptotic rate of convergence matching Nesterov's lower bound for functions defined in an infinite-dimensional space. In this paper, we use results on the robust gain margin of linear uncertain feedback control systems to show that the heavy ball method is provably worst-case asymptotically optimal when applied to quadratic functions in a finite dimensional space., Comment: Accepted for publication in Automatica

Irene Petersen,1 Alexander Crozier,2 Iain Buchan,3 Michael J Mina,4,5 Jonathan W Bartlett6 1Department of Primary Care & Population Health, University College London, London, UK; 2Division of Biosciences, University College London, London, UK; 3Institute of Population Health, University of Liverpool, Liverpool, UK; 4Department of Epidemiology, Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA; 5Department of Pathology, Clinical Microbiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA; 6Department of Mathematical Sciences, University of Bath, Bath, UKCorrespondence: Irene Petersen Email i.petersen@ucl.ac.ukABSTRACT: Testing for SARS-CoV-2 internationally has focused on COVID-19 diagnosis among symptomatic individuals using reverse transcriptase polymerase chain reaction (PCR) tests. Recently, however, SARS-CoV-2 antigen rapid lateral flow tests (LFT) have been rolled out in several countries for testing asymptomatic individuals in public health programmes. Validation studies for LFT have been largely cross-sectional, reporting sensitivity, specificity and predictive values of LFT relative to PCR. However, because PCR detects genetic material left behind for a long period when the individual is no longer infectious, these statistics can under-represent the sensitivity of LFT for detecting infectious individuals, especially when sampling asymptomatic populations. LFTs (intended to detect individuals shedding SARS-CoV-2 antigens) validated against PCR (intended to diagnose infection) are not reporting against a gold standard of equivalent measurements. Instead, these validation studies have reported relative performance statistics that need recalibrating to the purpose for which LFT is being used. We present an approach to this recalibration. We derive a formula for recalibrating relative performance statistics from LFT vs PCR validation studies to give likely absolute sensitivity of LFT for detecting individuals who are shedding shedding SARS-CoV-2 antigens. We contrast widely reported apparent sensitivities of LFT with recalibrated absolute sensitivity for detecting individuals shedding SARS-CoV-2 antigens. After accounting for within-individual viral kinetics and epidemic dynamics within asymptomatic populations we show that a highly performant test for SARS-CoV-2 antigen should show LFT-to-PCR relative sensitivity of less than 50% in conventional validation studies, which after re-calibration would be an absolute sensitivity of more than 80%. Further studies are needed to ascertain the absolute sensitivity of LFT as a test of infectiousness in COVID-19 responses. These studies should include longitudinal series of LFT and PCR, ideally in cohorts sampled from both contacts of cases and the general population.Keywords: rapid test, PCR, validation, recalibration, lateral flow tests

Juan Carlos Bazo-Alvarez,1,2 Tim P Morris,3 James R Carpenter,3,4 Irene Petersen1,5 1Research Department of Primary Care and Population Health, University College London (UCL), London, UK; 2School of Medicine, Universidad Cesar Vallejo, Trujillo, Peru; 3MRC Clinical Trials Unit at UCL, London, UK; 4Department of Medical Statistics, London School of Hygiene and Tropical Medicine, London, UK; 5Department of Clinical Epidemiology, Aarhus University, Aarhus, DenmarkCorrespondence: Juan Carlos Bazo-AlvarezResearch Department of Primary Care and Population Health, University College London (UCL), Rowland Hill Street, London, NW3 2PF, UKTel +44 7376076260Email juan.alvarez.16@ucl.ac.ukObjective: Missing data can produce biased estimates in interrupted time series (ITS) analyses. We reviewed recent ITS investigations on health topics for determining 1) the data management strategies and statistical analysis performed, 2) how often missing data were considered and, if so, how they were evaluated, reported and handled.Study Design and Setting: This was a scoping review following standard recommendations from the PRISMA Extension for Scoping Reviews. We included a random sample of all ITS studies that assessed any intervention relevant to health care (eg, policies or programmes) with individual-level data, published in 2019, with abstracts indexed on MEDLINE.Results: From 732 studies identified, we finally reviewed 60. Reporting of missing data was rare. Data aggregation, statistical tools for modelling population-level data and complete case analyses were preferred, but these can lead to bias when data are missing at random. Seasonality and other time-dependent confounders were rarely accounted for and, when they were, missing data implications were typically ignored. Very few studies reflected on the consequences of missing data.Conclusion: Handling and reporting of missing data in recent ITS studies performed for health research have many shortcomings compared with best practice.Keywords: interrupted time series analysis, segmented regression, missing data, multiple imputation, scoping review

Background\ud Despite high rates of depression and anxiety, little is known about the use of antidepressants amongst individuals diagnosed with inflammatory bowel disease (IBD).\ud \ud Aims\ud To evaluate temporal trends in the use of antidepressants; rates of antidepressant initiation and adherence of antidepressant use to international guidelines amongst individuals with IBD.\ud \ud Methods\ud This is a study of 14,525 incident IBD cases from 2004 to 2016 compared with 58,027 controls matched 1:4 for age and sex from the Clinical Practice Research Datalink. After excluding tricyclic antidepressants, we performed a Cox regression analysis to determine the risk associated with antidepressant use and logistic regression analysis to determine risk associated with antidepressant undertreatment.\ud \ud Results\ud Antidepressant use amongst individuals with IBD increased by 51% during the 12-year study period, who were 34% more likely to initiate antidepressants in the year after IBD diagnosis compared with controls (aHR:1.34, 95% CI 1.21-1.49). In those with IBD starting antidepressants, 67% received treatment lasting less than the duration recommended in international guidelines, of which 34% were treated for 1 month or less.\ud \ud 18-24 year olds were twice as likely to discontinue treatment within 1 month compared with those aged 40-60 years (aHR:2.03, 95% CI 1.40-2.95). Socioeconomic deprivation was also associated with early treatment discontinuation (aHR:1.40, 95% CI 1.07-1.83).\ud \ud Conclusions\ud In the year following IBD diagnosis individuals are significantly more likely to start antidepressants compared with controls, but treatment duration fell short of recommendations in the majority. Better integration of services may benefit individuals with IBD and psychiatric comorbidity.

Irene Petersen,1,2 Andrew Phillips3 1Research Department of Primary Care and Population Health, University College London, London, UK; 2Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; 3Institute for Global Health, University College London, London, UKCorrespondence: Irene PetersenResearch Department of Primary Care and Population Health, University College London, Rowland Hill St., London NW3 2PF, UKTel +44 020 801 68032Email i.petersen@ucl.ac.ukBackground: To reduce transmission of SARS-CoV-2, it is important to identify those who are infectious. However, little is known about what proportion of infectious people are asymptomatic and potential “silent” transmitters. We evaluated the value of COVID-19 symptoms as a marker for SARS-CoV-2 infection from a representative English survey.Methods: We used data from the Office for National Statistics Coronavirus (COVID-19) Infection Survey pilot study. We estimated sensitivity, specificity, the proportion of asymptomatic cases (1 – sensitivity), positive predictive value (PPV) and negative predictive value (NPV) of COVID-19 symptoms as a marker of infection using results of the SARS-CoV-2 test as the “gold standard”.Results: In total, there were 36,061 individuals with a SARS-CoV-2 test between 26 April and 27 June 2020. Of these, 625 (1.7%) reported symptoms on the day of the test. There were 115 (0.32%) with a positive SARS-CoV-2 test result. Of the 115, there were 27 (23.5%) who were symptomatic and 88 (76.5%) who were asymptomatic on the day of the test. Focusing on those with specific symptoms (cough, and/or fever, and/or loss of taste/smell), there were 158 (0.43%) with such symptoms on the day of the test. Of the 115 with a positive SARS-CoV-2, there were 16 (13.9%) reporting symptoms. In contrast, 99 (86.1%) did not report specific symptoms on the day of the test. The PPV for all symptoms was 4.3% and for the specific symptoms 10.1%. The specificity and NPV of symptoms were above 98%.Conclusion: COVID-19 symptoms are poor markers of SARS-CoV-2. Thus, 76.5% of this random sample who tested positive reported no symptoms, and 86.1% reported none of those specific to COVID-19. A more widespread testing programme is necessary to capture “silent” transmission and potentially prevent and reduce future outbreaks.Keywords: COVID-19 symptoms, SARS-CoV-2, sensitivity, asymptomatic SARS-CoV-2

Juan Carlos Bazo-Alvarez,1,2 Tim P Morris,3 Tra My Pham,3 James R Carpenter,3,4 Irene Petersen1,5 1Research Department of Primary Care and Population Health, University College London (UCL), London, UK; 2Instituto de Investigación, Universidad Católica Los Ángeles de Chimbote, Chimbote, Peru; 3MRC Clinical Trials Unit at UCL, London, UK; 4Department of Medical Statistics, London School of Hygiene and Tropical Medicine, London, UK; 5Department of Clinical Epidemiology, Aarhus University, Aarhus, DenmarkCorrespondence: Juan Carlos Bazo-AlvarezResearch Department of Primary Care and Population Health, University College London (UCL), Rowland Hill Street, London NW3 2PF, UKTel +44 7376076260Email juan.alvarez.16@ucl.ac.ukBackground: In the interrupted time series (ITS) approach, it is common to average the outcome of interest at each time point and then perform a segmented regression (SR) analysis. In this study, we illustrate that such ‘aggregate-level’ analysis is biased when data are missing at random (MAR) and provide alternative analysis methods.Methods: Using electronic health records from the UK, we evaluated weight change over time induced by the initiation of antipsychotic treatment. We contrasted estimates from aggregate-level SR analysis against estimates from mixed models with and without multiple imputation of missing covariates, using individual-level data. Then, we conducted a simulation study for insight about the different results in a controlled environment.Results: Aggregate-level SR analysis suggested a substantial weight gain after initiation of treatment (average short-term weight change: 0.799kg/week) compared to mixed models (0.412kg/week). Simulation studies confirmed that aggregate-level SR analysis was biased when data were MAR. In simulations, mixed models gave less biased estimates than SR analysis and, in combination with multilevel multiple imputation, provided unbiased estimates. Mixed models with multiple imputation can be used with other types of ITS outcomes (eg, proportions). Other standard methods applied in ITS do not help to correct this bias problem.Conclusion: Aggregate-level SR analysis can bias the ITS estimates when individual-level data are MAR, because taking averages of individual-level data before SR means that data at the cluster level are missing not at random. Avoiding the averaging-step and using mixed models with or without multilevel multiple imputation of covariates is recommended.Keywords: interrupted time series analysis, segmented regression, missing data, multiple imputation, mixed effects models, electronic health records, big data

Irene Petersen,1,2 Sia Kromann Nicolaisen,2 Federico Ricciardi,3 Manuj Sharma,1 Reimar W Thomsen,2 Gianluca Baio,3 Lars Pedersen2 1Department of Primary Care and Population Health, University College London, London, UK; 2Department of Clinical Epidemiology, Aarhus University, Aarhus, Denmark; 3Department of Statistical Science, University College London, London, UKCorrespondence: Irene PetersenDepartment of Primary Care and Population Health, University College London, London NW3 2PF, UKTel +44 20 801 68032Email i.petersen@ucl.ac.ukBackground: Individuals with type 2 diabetes (T2D) have a twofold increased risk for cardiovascular events (CVE), and CVE is responsible for nearly 80% of the mortality. Current treatment guidelines state that individuals should immediately initiate antidiabetic treatment and cardiovascular risk-factor management from T2D diagnosis. However, the evidence base is sparse, and randomized trials are unlikely to be conducted. We examined the impact of being eligible for T2D treatment, as determined by the threshold of HbA1c ≥ 6.5% (≥ 48 mmol/mol), on all-cause mortality and CVE. We hypothesised that individuals who were just above this threshold had a lower risk of CVE and all-cause mortality than individuals just below.Methods and Findings: We used the regression discontinuity design (RDD), a quasi-experimental design, comparing rates of all-cause mortality and CVE in people just below and just above the eligibility for treatment threshold. We included Danish healthcare records from 43,070 individuals aged 40– 80 years with no previous T2D record and the first record of HbA1c in the range of 6.0– 7.0% (42– 53 mmol/mol) between 2006 and 2014. In total, 36,360 individuals had the first record of HbA1c between 6.0% and 6.4% (42– 47 mmol/mol), and 6710 individuals had a first record between 6.5% and 7.0% (48– 53 mmol/mol). Individuals with a measurement just above 6.5% (48 mmol/mol) had a 21% lower rate of death or CVE, compared to those just below (hazard ratio: 0.79 (95% CI 0.69– 0.90)). Few individuals received early metformin treatment. However, the chance of metformin treatment initiation within 3 months was substantially higher for individuals with an HbA1c measurement above (14%) than below (1%) the threshold.Conclusion: Individuals with first record of HbA1c measure just above treatment threshold experienced a 21% lower rate of death or CVE than those just below. Lifestyle modifications and cardiovascular risk-factor management may contribute to this reduced rate.Keywords: type 2 diabetes, glycated hemoglobin A1c, regression discontinuity design, cardiovascular event, mortality

Mary Elizabeth Jones, 1 Irene Petersen, 1 Kate Walters, 1 Cini Bhanu, 1 Jill Manthorpe, 2 Rosalind Raine, 3 Naaheed Mukadam, 4 Claudia Cooper 4 1Department of Primary Care and Population Health, University College London, London, UK; 2NIHR Health and Social Care Workforce Research Unit, King’s College London, London, UK; 3Epidemiology and Public Health, University College London, London, UK; 4Division of Psychiatry, University College London, London, UKCorrespondence: Claudia CooperDivision of Psychiatry, University College London, 6th Floor, Maple House, Tottenham Court Road, London W1T 7BN, UKTel +44 7759703235Email claudia.cooper@ucl.ac.ukPurpose: To test hypotheses that minority ethnic people with dementia in the UK receive fewer anti-dementia drugs and more psychotropic and anticholinergic drugs associated with harms.Patients and Methods: We analyzed UK primary care electronic health records from The Health Improvement Network (THIN) database (2014– 2016), comparing psychotropic drug prescribing initiation and duration between people with dementia from White, Black, and Asian ethnic groups. We repeated analyses in people (aged 50+) without dementia, to explore whether any differences found reflected prescribing patterns in the general older population, or were specific to dementia.Results: We included 53,718 people with and 1,648,889 people without dementia. Among people with dementia, compared to White ethnic groups, Asian people were less likely to be prescribed anti-dementia drugs when they were potentially indicated (adjusted prevalence rate ratio 0.86 (95% Confidence Interval 0.76– 0.98)), and received them for on average 15 days/year less. Compared to White groups, Asian and Black individuals with dementia were no more likely to take an antipsychotic drug, but those that had were prescribed them for 17 and 27 days/year more, respectively (190.8 (179.6– 199.1) and 200.7 (191.1– 206.5) days). Black people were less likely to be prescribed anxiolytics/hypnotics (0.60 (0.44– 0.8)), but the duration these drugs were prescribed was similar across ethnic groups. Asian people were more likely to be prescribed anticholinergic drugs (1.43 (1.19– 1.73)), in analyses unadjusted for cardiovascular comorbidities. Among people without dementia, those in the Asian and Black ethnic groups were less likely to be prescribed psychotropic drugs, relative to people from White groups.Conclusion: Among people with dementia, Asian groups received less potentially beneficial symptomatic treatments, and Asian and Black groups were prescribed antipsychotic drugs for longer than White ethnic groups. Our findings may indicate care inequalities.Keywords: ethnicity, prevalence rate ratio, medication, prescription duration

BACKGROUND AND AIMS: The impact of a temporary or permanent stoma on mental health in Crohn's Disease (CD) is unknown. AIM: To examine the association between intestinal surgery and stoma formation and subsequent antidepressant medication (ADM) use. METHODS: Using the Clinical Practice Research Datalink, we identified individuals with CD who underwent intestinal surgery between 1998-2018. We excluded individuals with a prescription for an ADM in the 6 months before surgery. Individuals were stratified into three groups: no stoma, temporary stoma, and permanent stoma. We used Kaplan-Meier curves to examine initiation of ADM after intestinal surgery and Cox regression to identify risk factors for ADM use after intestinal surgery. RESULTS: We identified 1,272 cases of CD undergoing their first intestinal surgery. Of these, 871 (68.5%) had no stoma, 191 (15.0%) had a temporary stoma and 210 (16.5%) had a permanent stoma. The 10-year cumulative incidence of ADM use was 26.4%, 33.4% and 37.3% respectively. Individuals with a permanent stoma were 71% more likely to receive an ADM than those with no stoma (HR 1.71, 95% CI 1.20-2.44). Individuals with a temporary stoma reversed within 12 months had a similar likelihood of ADM use to those without stoma formation (HR 0.99, 95% CI 0.64-1.53) whereas temporary stoma formation with late reversal after 12 months was associated with significantly greater likelihood of ADM use (HR 1.85, 95% CI 1.15-2.96). CONCLUSION: Permanent stomas and temporary stomas with late reversal surgery are associated with increased ADM use after intestinal surgery, likely associated with increased anxiety and depression.

Tra My Pham,1,2 James R Carpenter,1,3 Tim P Morris,1 Manuj Sharma,2 Irene Petersen2,4 1MRC Clinical Trials Unit at UCL, London WC1V 6LJ, UK; 2Department of Primary Care and Population Health, University College London, London NW3 2PF, UK; 3Department of Medical Statistics, London School of Hygiene & Tropical Medicines, London WC1E 7HT, UK; 4Department of Clinical Epidemiology, Aarhus University, Aarhus N 8200, DenmarkCorrespondence: Tra My PhamMRC Clinical Trials Unit at UCL, 90 High Holborn, London WC1V 6LJ, UKTel +44207 670 4626Email tra.pham.09@ucl.ac.ukAims/Hypothesis: Type 2 diabetes mellitus is associated with high levels of disease burden, including increased mortality risk and significant long-term morbidity. The prevalence of diabetes differs substantially among ethnic groups. We examined the prevalence of type 2 diabetes diagnoses in the UK primary care setting.Methods: We analysed data from 404,318 individuals in The Health Improvement Network database, aged 0–99 years and permanently registered with general practices in London. The association between ethnicity and the prevalence of type 2 diabetes diagnoses in 2013 was estimated using a logistic regression model, adjusting for effect of age group, sex, and social deprivation. A multiple imputation approach utilising population-level information about ethnicity from the UK census was used for imputing missing data.Results: Compared with those of White ethnicity (5.04%, 95% CI 4.95 to 5.13), the crude percentage prevalence of type 2 diabetes was higher in the Asian (7.69%, 95% CI 7.46 to 7.92) and Black (5.58%, 95% CI 5.35 to 5.81) ethnic groups, while lower in the Mixed/Other group (3.42%, 95% CI 3.19 to 3.66). After adjusting for differences in age group, sex, and social deprivation, all minority ethnic groups were more likely to have a diagnosis of type 2 diabetes compared with the White group (OR Asian versus White 2.36, 95% CI 2.26 to 2.47; OR Black versus White 1.65, 95% CI 1.56 to 1.73; OR Mixed/Other versus White 1.17, 95% CI 1.08 to 1.27).Conclusion: The prevalence of type 2 diabetes was higher in the Asian and Black ethnic groups, compared with the White group. Accurate estimates of ethnic prevalence of type 2 diabetes based on large datasets are important for facilitating appropriate allocation of public health resources, and for allowing population-level research to be undertaken examining disease trajectories among minority ethnic groups, that might help reduce inequalities.Keywords: ethnicity, type 2 diabetes, primary care database, electronic health records, multiple imputation, missing not at random

Irene Petersen,1,2 Catherine A Welch,3 Irwin Nazareth,1 Kate Walters,1 Louise Marston,1 Richard W Morris,4 James R Carpenter,5,6 Tim P Morris,5 Tra My Pham1 1Department of Primary Care and Population Health, University College London, London NW3 2PF, UK; 2Department of Clinical Epidemiology, Aarhus University, 8200 Aarhus N, Denmark; 3Department of Health Sciences, University of Leicester, Leicester LE1 7RH, UK; 4Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol BS8 2PS, UK; 5MRC Clinical Trials Unit at UCL, London WC1V 6LJ, UK; 6Department of Medical Statistics, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK Background: Clinical databases are increasingly used for health research; many of them capture information on common health indicators including height, weight, blood pressure, cholesterol level, smoking status, and alcohol consumption. However, these are often not recorded on a regular basis; missing data are ubiquitous. We described the recording of health indicators in UK primary care and evaluated key implications for handling missing data.Methods: We examined the recording of health indicators in The Health Improvement Network (THIN) UK primary care database over time, by demographic variables (age and sex) and chronic diseases (diabetes, myocardial infarction, and stroke). Using weight as an example, we fitted linear and logistic regression models to examine the associations of weight measurements and the probability of having weight recorded with individuals’ demographic characteristics and chronic diseases.Results: In total, 6,345,851 individuals aged 18–99 years contributed data to THIN between 2000 and 2015. Women aged 18–65 years were more likely than men of the same age to have health indicators recorded; this gap narrowed after age 65. About 60–80% of individuals had their height, weight, blood pressure, smoking status, and alcohol consumption recorded during the first year of registration. In the years following registration, these proportions fell to 10%–40%. Individuals with chronic diseases were more likely to have health indicators recorded, particularly after the introduction of a General Practitioner incentive scheme. Individuals’ demographic characteristics and chronic diseases were associated with both observed weight measurements and missingness in weight.Conclusion: Missing data in common health indicators will affect statistical analysis in health research studies. A single analysis of primary care data using the available information alone may be misleading. Multiple imputation of missing values accounting for demographic characteristics and disease status is recommended but should be considered and implemented carefully. Sensitivity analysis exploring alternative assumptions for missing data should also be evaluated. Keywords: primary care, EHRs, recording, QOF, multiple imputation, statistics, epidemiology, research methods, data analysis

Background and Aims\ud Lack of timely referral and significant waits for specialist review amongst individuals with unresolved gastrointestinal (GI) symptoms can result in delayed diagnosis of Inflammatory Bowel Disease (IBD).\ud \ud Aims\ud To determine the frequency and duration of GI symptoms and predictors of timely specialist review before the diagnosis of both Crohn’s Disease (CD) and ulcerative colitis (UC).\ud \ud Methods\ud Case-control study of IBD matched 1:4 for age and sex to controls without IBD using the Clinical Practice Research Datalink from 1998-2016.\ud \ud Results\ud We identified 19,555 cases of IBD, and 78,114 controls. 1 in 4 cases of IBD reported gastrointestinal symptoms to their primary care physician more than 6 months before receiving a diagnosis. There is a significant excess prevalence of GI symptoms in each of the 10 years before IBD diagnosis. GI symptoms were reported by 9.6% and 10.4% at 5 years before CD and UC diagnosis respectively compared to 5.8% of controls. Amongst patients later diagnosed with IBD

Background: Many people with refugee backgrounds suffer from trauma-related complex social and psychological problems, and compliance with standard psychological treatment tends to be low. More culturally adaptable treatment options seem to be needed. Objective: We aimed to investigate whether the music therapy method: ‘trauma-focused music and imagery’ (tr-MI), characterized by a particular focus on arousal and affect regulation, would be equally effective as the standard psychological talk therapies for ameliorating trauma symptoms in Danish refugees. Methods: A pragmatic, noninferiority, parallel, randomized controlled trial with six-month follow-up was carried out at three clinics for refugees in the public mental health services of the Psychiatry (DK). Seventy-four adults diagnosed with posttraumatic stress disorder (PTSD) were allocated to either music therapy sessions (tr-MI, N = 39) or psychological treatment as usual (TAU, N = 35). Western classical music, new age music, and music from the participants’ own national culture were used to generate inner imagery, following a phased treatment protocol. Homework entailed listening to music. The primary outcome was the measurement of trauma symptoms by the Harvard Trauma Questionnaire, section IV (HTQ-IV); secondary measures were somatoform and psychoform dissociation (DSS-20), SDQ-20), attachment (RAAS), and well-being (WHO-5). Treatment effects reflected by primary and secondary measures were estimated using linear mixed models. Results: Tr-MI was noninferior to TAU (mean difference at follow-up HTQ-IV: 0.14, CI (−0.10; 0.38), with a − 0.3 noninferiority margin). A high dropout rate of 40% occurred in the TAU group, compared to 5% in the music therapy group. Secondary measures generated small to medium effect sizes in both groups, with significant medium effect sizes for well-being and psychoform dissociation at follow-up in tr-MI. Conclusions: Tr-MI is an innovative form of psychological treatment in refugee mental health services. Trials comparing music therapy to standardized therapy are needed to substantiate the evidence base for tr-MI therapy.

Importance:The Patient Health Questionnaire depression module (PHQ-9) is a 9-item self-administered instrument used for detecting depression and assessing severity of depression. The Patient Health Questionnaire-2 (PHQ-2) consists of the first 2 items of the PHQ-9 (which assess the frequency of depressed mood and anhedonia) and can be used as a first step to identify patients for evaluation with the full PHQ-9. Objective:To estimate PHQ-2 accuracy alone and combined with the PHQ-9 for detecting major depression. Data Sources:MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, PsycINFO, and Web of Science (January 2000-May 2018). Study Selection:Eligible data sets compared PHQ-2 scores with major depression diagnoses from a validated diagnostic interview. Data Extraction and Synthesis:Individual participant data were synthesized with bivariate random-effects meta-analysis to estimate pooled sensitivity and specificity of the PHQ-2 alone among studies using semistructured, fully structured, or Mini International Neuropsychiatric Interview (MINI) diagnostic interviews separately and in combination with the PHQ-9 vs the PHQ-9 alone for studies that used semistructured interviews. The PHQ-2 score ranges from 0 to 6, and the PHQ-9 score ranges from 0 to 27. Results:Individual participant data were obtained from 100 of 136 eligible studies (44 318 participants; 4572 with major depression [10%]; mean [SD] age, 49 [17] years; 59% female). Among studies that used semistructured interviews, PHQ-2 sensitivity and specificity (95% CI) were 0.91 (0.88-0.94) and 0.67 (0.64-0.71) for cutoff scores of 2 or greater and 0.72 (0.67-0.77) and 0.85 (0.83-0.87) for cutoff scores of 3 or greater. Sensitivity was significantly greater for semistructured vs fully structured interviews. Specificity was not significantly different across the types of interviews. The area under the receiver operating characteristic curve was 0.88 (0.86-0.89) for semistructured interviews, 0.82 (0.81-0.84) for fully structured interviews, and 0.87 (0.85-0.88) for the MINI. There were no significant subgroup differences. For semistructured interviews, sensitivity for PHQ-2 scores of 2 or greater followed by PHQ-9 scores of 10 or greater (0.82 [0.76-0.86]) was not significantly different than PHQ-9 scores of 10 or greater alone (0.86 [0.80-0.90]); specificity for the combination was significantly but minimally higher (0.87 [0.84-0.89] vs 0.85 [0.82-0.87]). The area under the curve was 0.90 (0.89-0.91). The combination was estimated to reduce the number of participants needing to complete the full PHQ-9 by 57% (56%-58%). Conclusions and Relevance:In an individual participant data meta-analysis of studies that compared PHQ scores with major depression diagnoses, the combination of PHQ-2 (with cutoff ≥2) followed by PHQ-9 (with cutoff ≥10) had similar sensitivity but higher specificity compared with PHQ-9 cutoff scores of 10 or greater alone. Further research is needed to understand the clinical and research value of this combined approach to screening.

Background: In the interrupted time series (ITS) approach, it is common to average the outcome of interest at each time point and then perform a segmented regression (SR) analysis. In this study, we illustrate that such ‘aggregate-level’ analysis is biased when data are missing at random (MAR) and provide alternative analysis methods. Methods: Using electronic health records from the UK, we evaluated weight change over time induced by the initiation of antipsychotic treatment. We contrasted estimates from aggregate-level SR analysis against estimates from mixed models with and without multiple imputation of missing covariates, using individual-level data. Then, we conducted a simulation study for insight about the different results in a controlled environment. Results: Aggregate-level SR analysis suggested a substantial weight gain after initiation of treatment (average short-term weight change: 0.799kg/week) compared to mixed models (0.412kg/week). Simulation studies confirmed that aggregate-level SR analysis was biased when data were MAR. In simulations, mixed models gave less biased estimates than SR analysis and, in combination with multilevel multiple imputation, provided unbiased estimates. Mixed models with multiple imputation can be used with other types of ITS outcomes (eg, proportions). Other standard methods applied in ITS do not help to correct this bias problem. Conclusion: Aggregate-level SR analysis can bias the ITS estimates when individual-level data are MAR, because taking averages of individual-level data before SR means that data at the cluster level are missing not at random. Avoiding the averaging-step and using mixed models with or without multilevel multiple imputation of covariates is recommended. © 2020 Bazo-Alvarez et al.

© 2020, Marine Ornithology. All rights reserved. Recently, Red-throated Loons Gavia stellata (RTL) have been the subject of increased interest due to their negative interactions with shipping, offshore wind farms, and other marine industry activities. This has driven a desire to quantify the behaviour and ecology of this understudied species, particularly during the non-breeding season. To achieve this, Time Depth Recorder (TDR) and Global Location Sensor (GLS) tags were deployed on individuals from several European locations. Due to an incidental mortality, one set of tags was retrieved early. The single set of tags recorded activity from June to August 2018. The TDR collected records for 14 d, providing the first ever biologging data on RTL foraging in Europe. The bird was tagged 90 km from the coast; therefore, it only used freshwater lakes and was never recorded entering saltwater. The individual mostly undertook shallow dives, with maximum and mean depths of 20 m and 5.4 m, respectively. Foraging constituted 22.9% of total activity during the sampling period. The RTL had diel foraging patterns, with dives being shallower and more frequent at times of “twilight” compared to “daylight.” These results provide novel information on an RTL’s diurnal patterns of water depth usage and foraging effort during the summer, demonstrating the potential of data loggers to provide key insights into the foraging ecology of this species.

Manuj Sharma,1 Irwin Nazareth,1 Irene Petersen1,2 1Department of Primary Care and Population Health, University College London, London, UK; 2Department of Clinical Epidemiology, Aarhus University, Aarhus, Denmark Abstract: Observational studies which evaluate effectiveness are often viewed with skepticism owing to the fact that patients are not randomized to treatment, meaning that results are more prone to bias. Therefore, randomized controlled trials remain the gold standard for evaluating treatment effectiveness. However, it is not always possible to conduct randomized trials. This may be due to financial constraints, for example, in identifying funding for a randomized trial for medicines that have already gained market authorization. There can also be challenges with recruitment, for example, of people with rare conditions or in hard-to-reach population subgroups. This is why observational studies are still needed. In this manuscript, we discuss how researchers can mitigate the risk of bias in the most common type of observational study design for evaluation of treatment effectiveness, the cohort study. We outline some key issues that warrant careful consideration at the outset when the question is being developed and the cohort study is being designed. We focus our discussion on the importance of deciding when to start follow-up in a study, choosing a comparator, managing confounding and measuring outcomes. We also illustrate the application of these considerations in a more detailed case study based on an examination of comparative effectiveness of two antidiabetic treatments using data collected during routine clinical practice. Keywords: epidemiology, therapeutics, diabetes mellitus, public health, effectiveness

Stine Bakkensen Bruun,1 Irene Petersen,1,2 Nickolaj Risbo Kristensen,1 Deirdre Cronin-Fenton,1 Alma Becic Pedersen1 1Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; 2Department of Primary Care and Population Health, University College London, London, UK Purpose: To examine the association between selective serotonin reuptake inhibitor (SSRI) use and mortality, postoperative complications, and quality of in-hospital care in hip fracture patients. Patients and methods: The study was a nationwide cohort study based on individual-level linked, prospectively collected data from Danish population-based national registries covering all hospitals in Denmark. The health care system in Denmark is tax-funded, and all citizens have equal access to health care services. We included patients with first-time hospitalization due to hip fracture undergoing surgery from 2006–2016. We estimated the risk of 30-day mortality, any unplanned readmission, any reoperation, specific postoperative complications including cardiovascular events and major bleeding, and quality of in-hospital care using Cox and Poisson regression analyses comparing current and former SSRI users with non-users. Results: In 68,487 hip fracture patients, 13,272 (19%) were current SSRI users, 2,777 (4%) were former SSRI users, and 52,438 (77%) were SSRI non-users. The 30-day mortality risk was 13% in current SSRI users (HR 1.16, 1.10–1.21) and 12% in former (HR 1.15, 1.04–1.27) compared with 10% in non-users. The HR for any unplanned readmission was 1.11 (1.02–1.20) in current and 1.13 (1.01–1.27) in former SSRI users and for any reoperation 1.21 (1.11–1.31) in current and 1.04 (0.84–1.28) in former SSRI users compared with non-users. The risk of venous thromboembolism, myocardial infarction, stroke, and bleeding were similar irrespective of SSRI use. No association between current and former SSRI use and quality of in-hospital care was found. Conclusion: In patients undergoing hip fracture surgery, 30-day mortality and overall readmission risk were elevated in both current and former SSRI users compared with non-users. Those currently using SSRI had a 26% increased reoperation risk compared with non-users. However, SSRI use was not associated with increased risk of other postoperative complications and lower quality of in-hospital care. A limitation of this study was the inability to control for potential confounding of social deprivation. Keywords: cohort studies, hip fracture, mortality, postoperative complications, quality of care, selective serotonin reuptake inhibitors

Tra My Pham,1 Irene Petersen,1,2 Kate Walters,1 Rosalind Raine,3 Jill Manthorpe,4 Naaheed Mukadam,5 Claudia Cooper5 1Department of Primary Care and Population Health, University College London, London, UK; 2Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; 3Department of Applied Health Research, University College London, London, UK; 4Social Care Workforce Research Unit, King’s College London, London, UK; 5Division of Psychiatry, University College London, London,UK Objectives: We compared incidence of dementia diagnosis by white, black, and Asian ethnic groups and estimated the proportion of UK white and black people developing dementia in 2015 who had a diagnosis for the first time in a UK-wide study. Methods: We analyzed primary care electronic health records from The Health Improvement Network database between 2007 and 2015 and compared incidence of dementia diagnosis to dementia incidence from community cohort studies. The study sample comprised of 2,511,681 individuals aged 50–105 years who did not have a dementia diagnosis prior to the start of follow-up. Results: A total of 66,083 individuals had a dementia diagnosis (4.87/1,000 person-years at risk, 95% CI 4.83–4.90); this incidence increased from 3.75 to 5.65/1,000 person-years at risk between 2007 and 2015. Compared with white women, the incidence of dementia diagnosis was 18% lower among Asian women (adjusted incidence rate ratio (IRR) 0.82, 95% CI 0.72–0.95) and 25% higher among black women (IRR 1.25, 95% CI 1.07–1.46). For men, incidence of dementia diagnosis was 28% higher in the black ethnic group (IRR 1.28, 95% CI 1.08–1.50) and 12% lower in the Asian ethnic group (IRR 0.88, 95% CI 0.76–1.01) relative to the white ethnic group. Based on diagnosis incidence in The Health Improvement Network data and projections of incidence from community cohort studies, we estimated that 42% of black men developing dementia in 2015 were diagnosed compared with 53% of white men. Conclusion: People from the black ethnic group had a higher incidence of dementia diagnosis and those from the Asian ethnic group had lower incidence compared with the white ethnic group. We estimated that black men developing dementia were less likely than white men to have a diagnosis of dementia, indicating that the increased risk of dementia diagnosis reported in the black ethnic group might underestimate the higher risk of dementia in this group. It is unclear whether the lower incidence of dementia diagnosis in the Asian ethnic group reflects lower community incidence or underdiagnosis. A cohort study to determine this is needed. Keywords: dementia, ethnicity, primary care, electronic health records

Kristina Laugesen,1 Henrik Støvring,2 Jesper Hallas,3 Anton Pottegård,3 Jens Otto Lunde Jørgensen,4 Henrik Toft Sørensen,1 Irene Petersen1,5 1Department of Clinical Epidemiology, Aarhus University Hospital, 2Department of Public Health, Aarhus University, Aarhus, 3Clinical Pharmacology and Pharmacy, Department of Public Health, University of Southern Denmark, Odense, 4Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark; 5Department of Primary Care and Population Health, University College London, London,UK Purpose: Glucocorticoids are widely used medications. In many pharmacoepidemiological studies, duration of individual prescriptions and definition of treatment episodes are important issues. However, many data sources lack this information. We aimed to estimate duration of individual prescriptions for oral glucocorticoids and to describe continuous treatment episodes using the parametric waiting time distribution.Methods: We used Danish nationwide registries to identify all prescriptions for oral glucocorticoids during 1996–2014. We applied the parametric waiting time distribution to estimate duration of individual prescriptions each year by estimating the 80th, 90th, 95th and 99th percentiles for the interarrival distribution. These corresponded to the time since last prescription during which 80%, 90%, 95% and 99% of users presented a new prescription for redemption. We used the Kaplan–Meier survival function to estimate length of first continuous treatment episodes by assigning estimated prescription duration to each prescription and thereby create treatment episodes from overlapping prescriptions.Results: We identified 5,691,985 prescriptions issued to 854,429 individuals of whom 351,202 (41%) only redeemed 1 prescription in the whole study period. The 80th percentile for prescription duration ranged from 87 to 120 days, the 90th percentile from 116 to 150 days, the 95th percentile from 147 to 181 days, and the 99th percentile from 228 to 259 days during 1996–2014. Based on the 80th, 90th, 95th and 99th percentiles of prescription duration, the median length of continuous treatment was 113, 141, 170 and 243 days, respectively.Conclusion: Our method and results may provide an important framework for future pharmacoepidemiological studies. The choice of which percentile of the interarrival distribution to apply as prescription duration has an impact on the level of misclassification. Use of the 80th percentile provides a measure of drug exposure that is specific, while the 99th percentile provides a sensitive measure. Keywords: glucocorticoids, pharmacoepidemiology, prescription duration, parametric waiting time distribution

Alma B Pedersen,1 Ellen M Mikkelsen,1 Deirdre Cronin-Fenton,1 Nickolaj R Kristensen,1 Tra My Pham,2 Lars Pedersen,1 Irene Petersen1,2 1Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus N, Denmark; 2Department of Primary Care and Population Health, University College London, London, UK Abstract: Missing data are ubiquitous in clinical epidemiological research. Individuals with missing data may differ from those with no missing data in terms of the outcome of interest and prognosis in general. Missing data are often categorized into the following three types: missing completely at random (MCAR), missing at random (MAR), and missing not at random (MNAR). In clinical epidemiological research, missing data are seldom MCAR. Missing data can constitute considerable challenges in the analyses and interpretation of results and can potentially weaken the validity of results and conclusions. A number of methods have been developed for dealing with missing data. These include complete-case analyses, missing indicator method, single value imputation, and sensitivity analyses incorporating worst-case and best-case scenarios. If applied under the MCAR assumption, some of these methods can provide unbiased but often less precise estimates. Multiple imputation is an alternative method to deal with missing data, which accounts for the uncertainty associated with missing data. Multiple imputation is implemented in most statistical software under the MAR assumption and provides unbiased and valid estimates of associations based on information from the available data. The method affects not only the coefficient estimates for variables with missing data but also the estimates for other variables with no missing data. Keywords: missing data, observational study, multiple imputation, MAR, MCAR, MNAR

Irene Petersen,1,2 Shuk-Li Collings,1,3 Rachel L McCrea,1 Irwin Nazareth,1 David P Osborn,4 Phil J Cowen,5 Cormac J Sammon1 1Department of Primary Care and Population Health, University College London, London, UK; 2Department of Clinical Epidemiology, Aarhus University, Aarhus N, Denmark; 3OXON Epidemiology, London, UK; 4Division of Psychiatry, University College London, London, UK; 5University Department of Psychiatry, Warneford Hospital, Oxford, UK Objective: The aim of this study was to examine the prevalence of major congenital malformations associated with antiepileptic drug (AED) treatment in pregnancy.Patients and methods: Using data from The Health Improvement Network, we identified women who have given live birth and their offspring. Four subgroups were selected based on the AED treatment in early pregnancy, valproate, carbamazepine, lamotrigine and women not receiving AED treatment. We compared the prevalence of major congenital malformations within children of these four groups and estimated prevalence ratios (PRs) using Poisson regression adjusted for maternal age, sex of child, quintiles of Townsend deprivation score and indication for treatment.Results: In total, 240,071 women were included in the study. A total of 229 women were prescribed valproate in pregnancy, 357 were prescribed lamotrigine and 334 were prescribed carbamazepine and 239,151 women were not prescribed AEDs. Fifteen out of 229 (6.6%) women prescribed valproate gave birth to a child with a major congenital malformation. The figures for lamotrigine, carbamazepine and women not prescribed AEDs were 2.7%, 3.3% and 2.2%, respectively. The prevalence of major congenital malformation was similar for women prescribed lamotrigine or carbamazepine compared to women with no AED treatment in pregnancy. For women prescribed valproate in polytherapy, the prevalence was fourfold higher. After adjustments, the effect of estimates attenuated, but the prevalence remained two- to threefold higher in women prescribed valproate.Conclusion: The results of our study suggest that lamotrigine and carbamazepine are safer treatment options than valproate in pregnancy and should be considered as alternative treatment options for women of childbearing potential and in pregnancy. Keywords: pregnancy, valproate, lamotrigine, carbamazepine, adverse drug effects

Manuj Sharma,1 Irene Petersen,1,2 Irwin Nazareth,1 Sonia J Coton,1 1Department of Primary Care and Population Health, University College London, London, UK; 2Department of Clinical Epidemiology, Aarhus University, Aarhus, Denmark Background: Research into diabetes mellitus (DM) often requires a reproducible method for identifying and distinguishing individuals with type 1 DM (T1DM) and type 2 DM (T2DM). Objectives: To develop a method to identify individuals with T1DM and T2DM using UK primary care electronic health records. Methods: Using data from The Health Improvement Network primary care database, we developed a two-step algorithm. The first algorithm step identified individuals with potential T1DM or T2DM based on diagnostic records, treatment, and clinical test results. We excluded individuals with records for rarer DM subtypes only. For individuals to be considered diabetic, they needed to have at least two records indicative of DM; one of which was required to be a diagnostic record. We then classified individuals with T1DM and T2DM using the second algorithm step. A combination of diagnostic codes, medication prescribed, age at diagnosis, and whether the case was incident or prevalent were used in this process. We internally validated this classification algorithm through comparison against an independent clinical examination of The Health Improvement Network electronic health records for a random sample of 500 DM individuals. Results: Out of 9,161,866 individuals aged 0–99 years from 2000 to 2014, we classified 37,693 individuals with T1DM and 418,433 with T2DM, while 1,792 individuals remained unclassified. A small proportion were classified with some uncertainty (1,155 [3.1%] of all individuals with T1DM and 6,139 [1.5%] with T2DM) due to unclear health records. During validation, manual assignment of DM type based on clinical assessment of the entire electronic record and algorithmic assignment led to equivalent classification in all instances. Conclusion: The majority of individuals with T1DM and T2DM can be readily identified from UK primary care electronic health records. Our approach can be adapted for use in other health care settings. Keywords: diabetes and endocrinology, epidemiology, public health, databases, algorithm&nbsp

Stuart G Nicholls,1,2 Sinead M Langan,3 Henrik Toft Sørensen,4 Irene Petersen,4,5 Eric I Benchimol1,6 1Children’s Hospital of Eastern Ontario (CHEO) Research Institute, 2School of Epidemiology, Public Health and Preventive Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada; 3London School of Hygiene and Tropical Medicine, London, UK; 4Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; 5Department of Primary Care and Population Health, University College London, London, UK; 6Department of Pediatrics and School of Epidemiology, Public Health and Preventive Medicine, University of Ottawa, Ottawa, ON, Canada Abstract: Routinely-collected health data (RCD) are now used for a wide range of studies, including observational studies, comparative effectiveness research, diagnostics, studies of adverse effects, and predictive analytics. At the same time, limitations inherent in using data collected without specific a priori research questions are increasingly recognized. There is also a growing awareness of the suboptimal quality of reports presenting research based on RCD. This has created a perfect storm of increased interest and use of RCD for research, together with inadequate reporting of the strengths and weaknesses of these data resources. The REporting of studies Conducted using Observational Routinely-collected Data (RECORD) statement was developed to address these limitations and to help researchers using RCD to meet their ethical obligations of complete and accurate reporting, as well as improve the utility of research conducted using RCD. The RECORD statement has been endorsed by more than 15 journals, including Clinical Epidemiology. This journal now recommends that authors submit the RECORD checklist together with any manuscript reporting on research using RCD. Keywords: observational studies, standards, research waste, assessment, publication

Aidan G O’Keeffe,1 Irwin Nazareth,2 Irene Petersen2 1Department of Statistical Science, 2Department of Primary Care and Population Health, University College London, London, UK Background: Statins are widely prescribed for the primary prevention of cardiovascular disease. Guidelines exist for statin prescriptions, but there is little recent analysis concerning prescription trends over time and how these vary with respect to demographic variables.Methods and results: Using The Health Improvement Network primary care database, statin therapy initiation and statin prescription prevalence rates were calculated using data from 7,027,711 individuals across the UK for the years 1995 to 2013, overall and stratified by sex, age group, and socioeconomic deprivation level (Townsend score). Statin therapy initiation rates rose sharply from 1995 (0.51 per 1,000 person-years) up to 2006 (19.83 per 1,000 person-years) and thereafter declined (10.76 per 1,000 person-years in 2013). Males had higher initiation rates than females and individuals aged 60–85 years had higher initiation rates than younger or more elderly age groups. Initiation rates were slightly higher as social deprivation level increased, after accounting for age and sex. Prescription prevalence increased sharply from 1995 (2.36 per 1,000 person-years) to 2013 (128.03 per 1,000 person-years) with males generally having a higher prevalence rate, over time, than females. Prevalence rates over time were generally higher for older age groups but were similar with respect to social deprivation level.Conclusion: The uptake of statins within UK primary care has increased greatly over time with statins being more commonly prescribed to older patients in general and, in recent years, males appear to have been prescribed statins at higher rates than females. After accounting for age and sex, the statin therapy initiation rate increases with the level of social deprivation. Keywords: cardiovascular disease, primary prevention, statin therapy, time trend, United Kingdom

Malaria transmission is in decline in some parts of Africa, partly due to the scaling up of control measures. If the goal of elimination is to be achieved, additional control measures including an effective and durable vaccine will be required. Studies utilising the prime-boost approach to deliver viral vectors encoding the pre-erythrocytic antigen ME-TRAP (multiple epitope thrombospondin-related adhesion protein) have shown promising safety, immunogenicity and efficacy in sporozoite challenge studies. More recently, a study in Kenyan adults, similar to that reported here, showed substantial efficacy against P. falciparum infection. One hundred and twenty healthy male volunteers, living in a malaria endemic area of Senegal were randomised to receive either the Chimpanzee adenovirus (ChAd63) ME-TRAP as prime vaccination, followed eight weeks later by modified vaccinia Ankara (MVA) also encoding ME-TRAP as booster, or two doses of anti-rabies vaccine as a comparator. Prior to follow-up, antimalarials were administered to clear parasitaemia and then participants were monitored by PCR for malaria infection for eight weeks. The primary endpoint was time-to-infection with P. falciparum malaria, determined by two consecutive positive PCR results. Secondary endpoints included adverse event reporting, measures of cellular and humoral immunogenicity and a meta-analysis of combined vaccine efficacy with the parallel study in Kenyan adults.We show that this pre-erythrocytic malaria vaccine is safe and induces significant immunogenicity, with a peak T-cell response at seven days after boosting of 932 Spot Forming Cells (SFC)/106 Peripheral Blood Mononuclear Cells(PBMC) compared to 57 SFC/ 106 PBMCs in the control group. However, a vaccine efficacy was not observed: 12 of 57 ME-TRAP vaccinees became PCR positive during the intensive monitoring period as compared to 13 of the 58 controls (P = 0.80). This trial confirms that vaccine efficacy against malaria infection in adults may be rapidly assessed using this efficient and cost-effective clinical trial design. Further efficacy evaluation of this vectored candidate vaccine approach in other malaria transmission settings and age-de-escalation into the main target age groups for a malaria vaccine is in progress.

Vera Ehrenstein,1 Irene Petersen,1,2 Liam Smeeth,3 Susan S Jick,4 Eric I Benchimol,5,6 Jonas F Ludvigsson,7,8 Henrik Toft Sørensen11Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; 2Department of Primary Care and Population Health, University College London, London, UK; 3Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK; 4Boston Collaborative Drug Surveillance Program, Boston University School of Public Health, Boston, MA, USA; 5Department of Pediatrics and School of Epidemiology, Public Health and Preventive Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada; 6Institute for Clinical Evaluative Sciences, Toronto, ON, Canada; 7Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, 8Department of Pediatrics, University Hospital of Örebro, SwedenThere has been a surge of availability and use for research of routinely collected electronic health data, such as electronic health records, health administrative data, and disease registries. Symptomatic of this surge, in 2012, Pharmacoepidemiology and Drug Safety (PDS) published a supplemental issue containing several reviews of validated methods for identifying health outcomes using routine health data,1 focusing on databases feeding the US Mini-Sentinel Program.2

Using a combination of transplacental carcinogen exposure and retrovirus-mediated oncogene transfer into fetal brain transplants, we have studied complementary transformation by N-ethyl-N-nitrosourea (NEU) and the v-myc oncogene in the nervous system. Previous experiments had demonstrated that both agents will not induce tumors independently whereas simultaneous expression of v-H-ras and v-gag/myc exerted a powerful transforming potential in neural grafts. In order to identify other genetic alterations that co-operate with an activated myc gene, the neurotropic carcinogen NEU was used to generate mutations of cellular genes. On embryonic day 14 (ED14), pregnant donor animals (F344 rats) received a single i.v. dose of NEU (50 mg/kg). Twenty-four hours later (ED15), the fetal brains were removed, triturated and incubated with a retroviral vector carrying the v-gag/myc oncogene. Subsequently, these primary cell suspensions were transplanted stereotactically into the caudate-putamen of syngenic adult recipients. After latency periods of 3-6 months, 5 of 10 recipients harboring ED15 fetal brain transplants developed malignant, poorly differentiated neuroectodermal tumors in the grafts. No tumor development was observed in seven recipients harboring ED16 neural grafts. Cell lines were established from three tumors and the 110 kd gag/myc fusion protein encoded by the retroviral construct was identified in the tumors by Western blotting. Several candidate genes for mutational activation by NEU including the H-ras, K-ras and neu oncogenes were analyzed for specific point mutations by polymerase chain reaction (PCR) and direct DNA sequencing of the PCR products. However, no mutations were found in any of these genes. These findings lend further support to the multistep hypothesis of neoplastic transformation in the brain. The tumors induced in this model provide an interesting tool for the identification of genes that co-operate with an activated myc gene in neurocarcinogenesis

Routinely collected health data, obtained for administrative and clinical purposes without specific a priori research goals, are increasingly used for research. The rapid evolution and availability of these data have revealed issues not addressed by existing reporting guidelines, such as Strengthening the Reporting of Observational Studies in Epidemiology (STROBE). The REporting of studies Conducted using Observational Routinely collected health Data (RECORD) statement was created to fill these gaps. RECORD was created as an extension to the STROBE statement to address reporting items specific to observational studies using routinely collected health data. RECORD consists of a checklist of 13 items related to the title, abstract, introduction, methods, results, and discussion section of articles, and other information required for inclusion in such research reports. This document contains the checklist as well as explanatory and elaboration information to enhance the use of the checklist. Examples of good reporting for each RECORD checklist item are also included. This document, as well as the accompanying website and message board (http://www.record-statement.org), will improve the implementation and understanding of RECORD. By implementing RECORD, authors, journals editors, and peer reviewers can enhance transparency of research reporting.

Question: In contrast to classic teaching, the introduction of buzz groups represents a more activating and interactive teaching method. Students discuss semi-structured content and new learning objectives with a peer sitting right next to them. We examined whether the introduction of buzz groups improves[for full text, please go to the a.m. URL], Joint-Meeting of the German Society for Neuropathology and Neuroanatomy (DGNN) and the Scandinavian Neuropathological Society (SNS)

Einleitung: Spontane periphere arterielle Aneurysmen im Säuglingsalter sind eine absolute Rarität. Lediglich kasuistisch beobachtet sind diese auf eine traumatische Genese zurückzuführen (Bahcivan 2009). Material und Methoden: Wir berichten über ein vier Monate altes,[zum vollständigen Text gelangen Sie über die oben angegebene URL], 133. Kongress der Deutschen Gesellschaft für Chirurgie

BackgroundPeople with severe mental illnesses die up to 20 years earlier than the general population, with cardiovascular disease being the leading cause of death. National guidelines recommend that the physical care of people with severe mental illnesses should be the responsibility of primary care; however, little is known about effective interventions to lower cardiovascular disease risk in this population and setting. Following extensive peer review, funding was secured from the United Kingdom National Institute for Health Research (NIHR) to deliver the proposed study. The aim of the trial is to test the effectiveness of a behavioural intervention to lower cardiovascular disease risk in people with severe mental illnesses in United Kingdom General Practices.Methods/DesignThe study is a cluster randomised controlled trial in 70 GP practices for people with severe mental illnesses, aged 30 to 75 years old, with elevated cardiovascular disease risk factors. The trial will compare the effectiveness of a behavioural intervention designed to lower cardiovascular disease risk and delivered by a practice nurse or healthcare assistant, with standard care offered in General Practice. A total of 350 people will be recruited and followed up at 6 and 12 months. The primary outcome is total cholesterol level at the 12-month follow-up and secondary outcomes include blood pressure, body mass index, waist circumference, smoking status, quality of life, adherence to treatments and services and behavioural measures for diet, physical activity and alcohol use. An economic evaluation will be carried out to determine the cost effectiveness of the intervention compared with standard care.DiscussionThe results of this pragmatic trial will provide evidence on the clinical and cost effectiveness of the intervention on lowering total cholesterol and addressing multiple cardiovascular disease risk factors in people with severe mental illnesses in GP Practices.Trial registrationCurrent Controlled Trials ISRCTN13762819. Date of Registration: 25 February 2013.Date and Version Number: 27 August 2014 Version 5.

Previous studies suggested that the lectin-complement pathway plays a complex role in cardiovascular disease (CVD). To date, no prospective human studies have investigated the relationship between the initiating factor of the lectin pathway, that is, mannose-binding lectin (MBL), and low-grade inflammation, endothelial dysfunction, or carotid intima–media thickness (cIMT). Moreover, MBL-associated proteases (MASPs) and MBL-associated proteins (MAps), which mediate downstream complement activation, have not been studied in the development of CVD.

In the current WHO classification, together with the subtype of combined small cell lung cancer, small cell lung cancers (SCLC) are listed as a special tumour entity. Their microscopic appearance is characterised by small tumour cells with scant cytoplasm and frequently hypodiploid nuclei. For the precise histological diagnosis of SCLC, especially for the diagnostic differentiation from pulmonary NHL infiltrates, additional immunohistochemical investigations are recommended. The presented core classification of lung cancer is intended to facilitate the semi-quantitative registration of "atypical" SCLC. Genetically SCLC is especially characterised by manifold chromosomal deletions with losses of whole chromosomes or chromosome arms, associated with the inactivation of numerous tumour suppressor genes. Whereas the extensive DNA losses may explain the marked sensitivity of SCLC to anti-neoplastic chemotherapy or radiotherapy, its considerable chromosomal instability is correlated with the development of resistance to therapy.

Fragestellung/Einleitung: Das JEnaer Neigungs-Orientierte Studium (JENOS) der Humanmedizin zeichnet sich durch ein kompaktes Kernstudium und eine Schwerpunktsetzung durch Wahl einer Linie im zweiten Studienabschnitt aus. Das 5. Fachsemester (FS) dient als Orientierungssemester. Vom 6. bis zum 10.[zum vollständigen Text gelangen Sie über die oben angegebene URL], Gemeinsame Jahrestagung der Gesellschaft für Medizinische Ausbildung (GMA) und des Arbeitskreises zur Weiterentwicklung der Lehre in der Zahnmedizin (AKWLZ)

Objective / Background Use of selective serotonin reuptake inhibitors (SSRIs) during pregnancy has been associated with adverse pregnancy outcomes, including congenital heart disease. Objectives: To describe utilisation patterns of SSRIs 1 year before, during and 1 year after pregnancy in primary care in Wales and 5 other European databases. Methods A common protocol was implemented across 6 databases in: Denmark, The Netherlands, Tuscany, Emilia Romagna, Wales, and the Clinical Practice Research Datalink (CPRD) representing the rest of the UK. All pregnancies starting 2004-2010 (2009 Denmark) were identified in each database. For those ending in a birth (live or still), prescriptions for SSRIs issued (UK) or dispensed (Denmark, Italy, The Netherlands) between 1 year before and 1 year after pregnancy were identified. Prescribing patterns were described and compared between databases. Where available, data were explored for associations with material deprivation, as Townsend scores. Results In the six databases 721,632 eligible women with 862,943 deliveries were identified. SSRI use was higher in Wales and the UK than in the other European databases: in the year leading up to pregnancy 9.6 % (CI95 9.4-9.8 %) of women inWales and 8.8 % (8.6-8.9%) in the CPRD, UK were prescribed an SSRI compared with 3.3 % (3.2- 3.4 %) in Emilia Romagna. During pregnancy exposure ranged from 1.2 % (1.1-1.3 %) (Emilia Romagna) to 3.7 % (3.6-3.8 %) (CPRD, UK) and 4.5 % (4.3-4.6 %) (Wales). Prescribing was at a nadir in the 2nd and 3rd trimesters in all databases. After pregnancy, SSRI prescribing increased more rapidly in Wales and the CPRD, UK than elsewhere. Of those who discontinued SSRI prescriptions before pregnancy or in the first trimester, a minority restarted in the year after birth, ranging from 36.5 % (35.2-37.7 %) in Wales to 15.3 % (14.3-16.3 %) in Emilia Romagna. Where data were available, material deprivation (Wales) and socioeconomic status (Denmark) were associated with SSRI prescription. In Wales, between 1 year before and 1 year after pregnancy: 11777/58073 (20.3 %) women received a prescription for an SSRI, 8527 (72.4 %) of whom were diagnosed with depression; 13475/58073 (23.2 %) women were diagnosed with depression, 8527 (63.3%) of whom were prescribed an SSRI; 15.1 % in the least deprived 25.3 % and in the most deprived fifth received an SSRI prescription (chi sq 456.3, df 1, p

Routinely collected health data, collected for administrative and clinical purposes, without specific a priori research questions, are increasingly used for observational, comparative effectiveness, health services research, and clinical trials. The rapid evolution and availability of routinely collected data for research has brought to light specific issues not addressed by existing reporting guidelines. The aim of the present project was to determine the priorities of stakeholders in order to guide the development of the REporting of studies Conducted using Observational Routinely-collected health Data (RECORD) statement. Two modified electronic Delphi surveys were sent to stakeholders. The first determined themes deemed important to include in the RECORD statement, and was analyzed using qualitative methods. The second determined quantitative prioritization of the themes based on categorization of manuscript headings. The surveys were followed by a meeting of RECORD working committee, and re-engagement with stakeholders via an online commentary period. The qualitative survey (76 responses of 123 surveys sent) generated 10 overarching themes and 13 themes derived from existing STROBE categories. Highest-rated overall items for inclusion were: Disease/exposure identification algorithms; Characteristics of the population included in databases; and Characteristics of the data. In the quantitative survey (71 responses of 135 sent), the importance assigned to each of the compiled themes varied depending on the manuscript section to which they were assigned. Following the working committee meeting, online ranking by stakeholders provided feedback and resulted in revision of the final checklist. The RECORD statement incorporated the suggestions provided by a large, diverse group of stakeholders to create a reporting checklist specific to observational research using routinely collected health data. Our findings point to unique aspects of studies conducted with routinely collected health data and the perceived need for better reporting of methodological issues.

Routinely collected health data, obtained for administrative and clinical purposes without specific a priori research goals, are increasingly used for research. The rapid evolution and availability of these data have revealed issues not addressed by existing reporting guidelines, such as Strengthening the Reporting of Observational Studies in Epidemiology (STROBE). The REporting of studies Conducted using Observational Routinely collected health Data (RECORD) statement was created to fill these gaps. RECORD was created as an extension to the STROBE statement to address reporting items specific to observational studies using routinely collected health data. RECORD consists of a checklist of 13 items related to the title, abstract, introduction, methods, results, and discussion section of articles, and other information required for inclusion in such research reports. This document contains the checklist and explanatory and elaboration information to enhance the use of the checklist. Examples of good reporting for each RECORD checklist item are also included herein. This document, as well as the accompanying website and message board (http://www.record-statement.org), will enhance the implementation and understanding of RECORD. Through implementation of RECORD, authors, journals editors, and peer reviewers can encourage transparency of research reporting.

論文(Article)

BACKGROUND: Women prescribed antipsychotics face the dilemma on whether to continue medication in pregnancy in terms of balancing risks and benefits. Previous research on other psychotropic medications suggests that many women discontinue treatment in early pregnancy. However, very limited evidence exists on discontinuation of antipsychotic medication. METHODS: We identified 495,953 pregnant women from THIN primary care database. Kaplan-Meier plots were used to examine time to last antipsychotic prescription. Poisson regression was used to examine characteristics of those who stopped treatment during pregnancy. RESULTS: There has been an overall increase in prevalence of antipsychotic prescribing since 2007. However, antipsychotics were more likely to be stopped in pregnant than non-pregnant women. Only 107/279 (38%) of women on atypical antipsychotics and 39/207 (19%) of women on typical antipsychotics before pregnancy still received treatment at the start of third trimester. Older women were more likely to continue typical antipsychotic treatment in pregnancy (35+ versus

A necessary and sufficient condition, expressed simply as the DC loop gain (ie the loop gain at zero frequency) being less than unity, is given in this paper to guarantee the internal stability of a feedback interconnection of Linear Time-Invariant (LTI) Multiple-Input Multiple-Output (MIMO) systems with negative imaginary frequency response. Systems with negative imaginary frequency response arise for example when considering transfer functions from force actuators to co-located position sensors, and are commonly important in for example lightly damped structures. The key result presented here has similar application to the small-gain theorem, which refers to the stability of feedback interconnections of contractive gain systems, and the passivity theorem (or more precisely the positive real theorem in the LTI case), which refers to the stability of feedback interconnections of positive real systems. A complete state-space characterisation of systems with negative imaginary frequency response is also given in this paper and also an example that demonstrates the application of the key result is provided.