Effect of mechanical insufflation-exsufflation for ineffective cough on weaning duration in diseases of the peripheral or central nervous system (MEDINE): study protocol for a randomised controlled trial in a neurological weaning centre.

INTRODUCTION: Patients with neurological or neurosurgical disease can suffer from impaired cough, which may result in life-threatening retention of tracheobronchial secretions, atelectasis, pneumonia and finally death. Due to a lack of alternatives and pathophysiological plausibility, the application of mechanical insufflation-exsufflation (MI-E) has already become international standard care in neuromuscular disease and spinal cord injury although a lack of evidence for efficacy. High-quality studies to support the use of MI-E in neurological and neurosurgical patients during weaning from mechanical ventilation are missing. The goal of this exploratory study is to display the effect size of MI-E intervention on the duration of mechanical ventilation and additional outcomes. METHODS AND ANALYSIS: One hundred adult patients with a cough deficiency or retention of secretion admitted to a neurological intensive care unit (ICU) are planned to be recruited for this randomised controlled trial. Patients are randomised 1:1 to receive either MI-E or best standard care. Observation will take place until discharge from the hospital, death or end of the study period. The primary endpoint of this trial is the duration of mechanical ventilation from randomisation until successful weaning. The outcome will be analysed with Kaplan-Meier estimation and competing risks analyses. Secondary endpoint is the proportion of patients with successful weaning. Further outcomes will include the incidence of hospital-acquired pneumonia, mortality, decannulation rate, length of stay on the ICU and the total score of the Glasgow Coma Scale. ETHICS AND DISSEMINATION: The study was approved by the Medical Ethics Committee of the University of Oldenburg. The findings of this study will be submitted for publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: DRKS00020981.

Flexible semiparametric mode regression for time-to-event data.

The distribution of time-to-event outcomes is usually right-skewed. While for symmetric and moderately skewed data the mean and median are appropriate location measures, the mode is preferable for heavily skewed data as it better represents the center of the distribution. Mode regression has been introduced for uncensored data to model the relationship between covariates and the mode of the outcome. Starting from nonparametric kernel density based mode regression, we examine the use of inverse probability of censoring weights to extend mode regression to handle right-censored data. We add a semiparametric predictor to add further flexibility to the model and we construct a pseudo Akaike's information criterion to select the bandwidth and smoothing parameters. We use simulations to evaluate the performance of our proposed approach. We demonstrate the benefit of adding mode regression to one's toolbox for analyzing survival data on a pancreatic cancer data set from a prospectively maintained cancer registry.

Psychological interventions for inflammatory bowel disease: a systematic review and component network meta-analysis protocol.

INTRODUCTION: Patients with inflammatory bowel diseases (IBD) often report psychological problems, unemployment, disability, sick leave and compromised quality of life. The effect of psychological interventions on health-related outcomes in IBD is controversial as previous reviews faced the obstacle of high heterogeneity among provided multimodular interventions. The heterogeneity can be addressed with network meta-analysis (NMA) and (multi)component NMA (CNMA). We aim to investigate whether psychological interventions can improve quality of life, clinical and social outcomes in IBD using NMA and CNMA. This is the study protocol. METHODS AND ANALYSIS: We will consider randomised, quasi-randomised and non-randomised controlled trials, including cluster randomised and cross-over trials with 2 months of minimum follow-up. The conditions to be studied comprise Crohn's disease and ulcerative colitis in children, adolescents and adults. We will include any psychological intervention aiming to change the health status of the study participant.We will search Medline, Embase, Web of Science, CENTRAL, LILACS, Psyndex, PsycINFO, Google Scholar and trial registries from inception (the search will be updated before the review completion). Two authors will independently screen all references based on titles and abstracts. For data extraction, standard forms are developed and tested before extraction. All information will be assessed independently by at least two reviewers, and disagreements solved by consensus discussion or a third rater if necessary.The data synthesis will include a pairwise meta-analysis supported by meta-regression. We will conduct NMA (all treatments will constitute single nodes of the network) and CNMA (we will define all treatments as sums of core components, eg, cognitive +behaviour, or cognitive +behaviour + relaxation, and additionally consider interactions) using the R Package netmeta. ETHICS AND DISSEMINATION: No ethical approval is required. Reports will include the final report to the funder, conference presentation, peer-reviewed publication and a patient report. PROSPERO REGISTRATION NUMBER: CRD42021250446.

Validity of hospital ICD-10-GM codes to identify anaphylaxis.

PURPOSE: Anaphylaxis (ANA) is an important adverse drug reaction. We examined positive predictive values (PPV) and other test characteristics of ICD-10-GM code algorithms for detecting ANA as used in a multinational safety study (PASS). METHODS: We performed a cross-sectional study on routine data from a German academic hospital (2004-2019, age ≥ 18). Chart review was used for case verification. Potential cases were identified from the hospital administration system. The main outcome required at least one of the following: any type of specific in-hospital code (T78.2, T88.6, and T80.5) OR specific outpatient code in combination with a symptom code OR in-hospital non-specific code (T78.4, T88.7, and Y57.9) in combination with two symptom codes. PPV were calculated with 95% confidence interval. Sensitivity analyses modified type of codes, unit of analysis, verification criteria and time period. The most specific algorithm used only primary codes for ANA (numbers added in brackets). RESULTS: Four hundred and sixteen eligible cases were evaluated, and 78 (37) potential ANA cases were identified. PPV were 62.8% (95% CI 51.1-73.5) (main) and 77.4% (58.9-90.4) (most specific). PPV from all modifications ranged from 12.9% to 80.6%. The sensitivity of the main algorithm was 66.2%, specificity 91.5%, and negative predictive value 92.6%. Corresponding figures for the most specific algorithm were 32.4%, 98.0%, and 87.0%. CONCLUSIONS: The PPV of the main algorithm seems of acceptable validity for use in comparative safety research but will underestimate absolute risks by about a third. Restriction to primary discharge codes markedly improves PPV to the expense of reducing sensitivity.

Weighted expectile regression for right-censored data.

Expectile regression can be used to analyze the entire conditional distribution of a response, omitting all distributional assumptions. Among its benefits are computational simplicity, efficiency, and the possibility to incorporate a semiparametric predictor. Due to its advantages in full data settings, we propose an extension to right-censored data situations, where conventional methods typically focus only on mean effects. We propose to extend expectile regression with inverse probability weights. Estimates are easy to implement and computationally simple. Expectiles can be converted to more easily interpreted tail expectations, that is, the expected residual life. It provides a meaningful effect measure, similar to the hazard rate. The results from an extensive simulation study are presented, evaluating consistency and sensitivity to violations of assumptions. We use the proposed method to analyze survival times of colorectal cancer patients from a regional certified high volume cancer center.

Use of intravenous iron and risk of anaphylaxis: A multinational observational post-authorisation safety study in Europe.

PURPOSE: This post-authorisation safety study estimated the risk of anaphylaxis in patients receiving intravenous (IV) iron in Europe, with interest in iron dextran and iron non-dextrans. Studies conducted in the United States have reported risk of anaphylaxis to IV iron ranging from 2.0 to 6.8 per 10 000 first treatments. METHODS: Cohort study of IV iron new users, captured mostly through pharmacy ambulatory dispensing, from populations covered by health and administrative data sources in five European countries from 1999 to 2017. Anaphylaxis events were identified through an algorithm that used parenteral penicillin as a positive control. RESULTS: A total of 304 210 patients with a first IV iron treatment (6367 iron dextran), among whom 13-16 anaphylaxis cases were identified and reported as a range to comply with data protection regulations. The pooled unadjusted incidence proportion (IP) ranged from 0.4 (95% confidence interval [CI], 0.2-0.9) to 0.5 (95% CI, 0.3-1.0) per 10 000 first treatments. No events were identified at first dextran treatments. There were 231 294 first penicillin treatments with 30 potential cases of anaphylaxis (IP = 1.2; 95% CI, 0.8-1.7 per 10 000 treatments). CONCLUSION: We found an IP of anaphylaxis from 0.4 to 0.5 per 10 000 first IV iron treatments. The study captured only a fraction of IV iron treatments administered in hospitals, where most first treatments are likely to happen. Due to this limitation, the study could not exclude a differential risk of anaphylaxis between iron dextran and iron non-dextrans. The IP of anaphylaxis in users of penicillin was consistent with incidences reported in the literature.

General practitioners' approaches to prostate-specific antigen testing in the north-east of the Netherlands.

BACKGROUND: There is wide variation in clinical practice for the early detection of prostate cancer, not least because of the ongoing debate about the benefits of prostate-specific antigen (PSA) testing. In this study, we aimed to assess the approaches, attitudes, and knowledge of general practitioners (GPs) regarding PSA testing in primary care in the Netherlands, particularly regarding recommendations for prostate cancer. METHODS: Questionnaire surveys were sent to 179 GPs in the north-east of the Netherlands, of which 65 (36%) were completed and returned. We also surveyed 23 GPs attending a postgraduate train-the-trainer day (100%). In addition to demographic data and practice characteristics, the 31-item questionnaire covered the attitudes, clinical practice, adherence to PSA screening recommendations, and knowledge concerning the recommendations for prostate cancer early detection. Statistical analysis was limited to the descriptive level. RESULTS: Most GPs (95%; n = 82) stated that they had at least read the Dutch GP guideline, but just half (50%; n = 43) also stated that they knew the content. Almost half (46%; n = 39) stated they would offer detailed counseling before ordering a PSA test to an asymptomatic man requesting a test. Overall, prostate cancer screening was reported to be of minor importance compared to other types of cancer screening. CONCLUSIONS: Clinical PSA testing in primary care in this region of the Netherlands seems generally to be consistent with the relevant guideline for Dutch GPs that is restrictive to PSA testing. The next step will be to further evaluate the effects of the several PSA testing strategies.

Validity of hospital ICD-10-GM codes to identify acute liver injury in Germany.

PURPOSE: Acute liver injury (ALI) is an important adverse drug reaction. We estimated the positive predictive values (PPVs) of ICD-10-GM codes of ALI used in an international postauthorisation safety study (PASS). METHODS: Analyses used routine data (2007 to 2016, adults) from a German academic hospital in a cross-sectional design. Two algorithms from the PASS were applied to extract potential cases from the hospital information system: specific end point (A) (discharge diagnosis of liver disease-specific codes) and less specific end point (B) (discharge and outpatient-specific and nonspecific codes suggestive of liver injury). ALI cases were confirmed on the basis of plasma liver enzyme activity elevation. Secondary analysis was performed following exclusion of cases with known cancer, chronic liver, biliary and pancreatic disease, heart failure, and alcohol-related disorders, as applied in the PASS. RESULTS: On the basis of ICD codes: outcome A, 154 cases (143 with case notes and lab data for case verification); outcome B, 485 cases (357 with case notes and lab data). ALI was confirmed in 71 outcome A cases, PPV of 49.7% (95% confidence interval [CI], 41.2%-58.1%), and 100 outcome B cases, PPV of 28.0% (95% CI, 23.4%-33.0%). Applying exclusion criteria increased PPV (95% CI) to 62.7% (50.0%-74.2%) for outcome A and 45.7% (37.2%-54.3%) for outcome B. CONCLUSIONS: In safety studies on hepatotoxicity based on routine data using ICD-10-GM discharge codes and when validation of potential cases is not feasible, only the more specific codes should be used to describe ALI, and competing diagnoses for liver injury should be excluded to avoid substantial misclassification.

Modeling determinants of satisfaction with health care in youth with inflammatory bowel disease part 2: semiparametric distributional regression.

Background: Methodological challenges arise with the analysis of patient satisfaction as a measure of health care quality. One of them is the necessity to adjust for differences in patient characteristics or other variables. A combination of several helpful extensions to regression analysis is shown based on patients with inflammatory bowel disease (IBD) to help identify important covariates associated with the distribution of satisfaction. Patients and methods: Analyses were based on cross-sectional data from a postal survey on the health care of patients with IBD aged 15-25, with satisfaction assessed using a 32-item validated questionnaire weighing experience by perceived relevance. The weighted summary score was modeled using a Beta distribution in a generalized additive model for location, scale and shape. Covariates were distinguished in 3 groups and the model was entered in separate, consecutive analyses. First, demographic and disease-related variables were included. Next, information about the IBD specialist was added. The third step added care quality indicators. Results are presented as OR with 95% CI. Results: In the survey, 619 questionnaires were returned and the data set had 453 complete cases for analysis. Satisfaction appeared increased for patients working (OR 1.59, 95% CI: 1.19-2.11) or studying (1.25, 1.00-1.56) as compared to those still at school or in non-academic job training. High anxiety scores and an older age of onset were associated with lower satisfaction. The variation of satisfaction is higher for patients with Crohn's disease or who have statutory insurance (1.19, 1.01-1.40 and 1.22, 1.06-1.40). Conclusion: Modeling the entire distribution of the response uncovered additional influences on the variance of patient satisfaction not previously identified by classical regression. It also resulted in a richer model for the mean. The construction of a combined model for different features of the distribution also helped to improve the control of confounding.

Risk of Acute Liver Injury in Agomelatine and Other Antidepressant Users in Four European Countries: A Cohort and Nested Case-Control Study Using Automated Health Data Sources.

BACKGROUND: Agomelatine is a melatonin receptor agonist and serotonin 5-HT2C receptor antagonist indicated for depression in adults. Hepatotoxic reactions like acute liver injury (ALI) are an identified risk in the European risk management plan for agomelatine. Hepatotoxic reactions have been reported for other antidepressants, but population studies quantifying these risks are scarce. Antidepressants are widely prescribed, and users often have risk factors for ALI (e.g. metabolic syndrome). OBJECTIVE: The goal was to estimate the risk of ALI associated with agomelatine and other antidepressants (fluoxetine, paroxetine, sertraline, escitalopram, mirtazapine, venlafaxine, duloxetine, and amitriptyline) when compared with citalopram in routine clinical practice. METHOD: A nested case-control study was conducted using data sources in Denmark, Germany, Spain, and Sweden (study period 2009-2014). Three ALI endpoints were defined using International Classification of Diseases (ICD) codes: primary (specific codes) and secondary (all codes) endpoints used only hospital discharge codes; the tertiary endpoint included both inpatient and outpatient settings (all codes). Validation of endpoints was implemented. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for current use were estimated for each data source and combined. RESULTS: We evaluated 3,238,495 new antidepressant and 74,440 agomelatine users. For the primary endpoint, the OR for agomelatine versus citalopram was 0.48 (CI 0.13-1.71). Results were also < 1 when no exclusion criteria were applied (OR 0.37; CI 0.19-0.74), when all exclusion criteria except alcohol and drug abuse were applied (OR 0.47; CI 0.20-1.07), and for the secondary (OR 0.40; CI 0.05-3.11) and tertiary (OR 0.79; CI 0.50-1.25) endpoints. Regarding other antidepressants versus citalopram, most OR point estimates were also below one, although with varying widths of the 95% CIs. The result of the tertiary endpoint and the sensitivity analyses of the primary endpoint were the most precise. CONCLUSION: In this study, using citalopram as a comparator, agomelatine was not associated with an increased risk of ALI hospitalisation. The results for agomelatine should be interpreted in the context of the European risk minimisation measures in place. Those measures may have induced selective prescribing and could explain the lower risk of ALI for agomelatine when compared with citalopram. Most other antidepressants evaluated had ORs suggesting a lower risk than citalopram, but additional studies are required to confirm or refute these results.

School-related experience and performance with inflammatory bowel disease: results from a cross-sectional survey in 675 children and their parents.

OBJECTIVE: We describe school performance and experience in children with inflammatory bowel disease (IBD) across Germany and Austria. Predictors of compromised performance and satisfaction were evaluated to identify subgroups of increased risk. DESIGN: This cross-sectional analysis was based on a postal survey in children aged 10-15 with Crohn's disease, ulcerative colitis or unclassified IBD and their families. Multivariate regression analysis was used to assess influential factors on parental satisfaction with school, attending advanced secondary education (ASE), having good marks and having to repeat a class. Satisfaction was assessed based on the Child Healthcare-Satisfaction, Utilisation and Needs instrument (possible range 1.00-5.00). RESULTS: Of 1367 families contacted, 675 participated in the study (49.4%). Sixty-eight participants (10.2%) had repeated a year, 312 (46.2%) attended ASE. The median school satisfaction score was 2.67 (IQR 2.00-3.33). High socioeconomic status (SES) and region within Germany were predictive for ASE (OR high SES 8.2, 95% CI 4.7 to 14.2). SES, female sex and region of residence predicted good marks. Grade retention was associated with an active disease course (OR 2.7, 95% CI 1.4 to 5.3) and prolonged periods off school due to IBD (OR 3.9, 95% CI 1.8 to 8.6). CONCLUSIONS: A severe disease course impacted on the risk of grade retention, but not on type of school attended and school marks. Low satisfaction of parents of chronically ill children with the school situation underlines the need for a more interdisciplinary approach in health services and health services research in young people.

Modeling determinants of satisfaction with health care in youth with inflammatory bowel disease: a cross-sectional survey.

PURPOSE: Patient satisfaction is frequently used as a health care quality measure despite methodological challenges. By the example of pediatric inflammatory bowel disease (IBD), we assessed factors associated with low satisfaction and examined differences by type of provider. PATIENTS AND METHODS: In a cross-sectional design, a 32-item questionnaire and global questioning were used to assess satisfaction in patients aged 15-25 years. Determinants of low satisfaction were identified by logistic regression (OR with 95% CI). Separate models were calculated for patient-related variables such as age, socioeconomic status (SES), health status (emotional, somatic, quality of life) or region of residence (step 1), and impact of provider (pediatric specialist, adult specialist, no specialist) (step 2). As secondary analysis, we studied the effect of additional indicators such as waiting time, consultation time, and an IBD Management Quality Index (IMQI) on effect estimates (step 3). RESULTS: A total of 567 cases were available for analysis (response 48.2%). The strongest predictors of low satisfaction were anxiety symptoms (OR 2.49, CI 1.14 to 5.45). In step 2, not being seen by a specialist (1.89, 1.16 to 3.10) and having been with the new provider for less than 12 months (1.71, 1.03 to 2.83) were associated with low satisfaction. Satisfaction with adult care provider was similar to pediatric care if adjusted for anxiety, health status, and time with provider (0.95, 0.59 to 1.51). Presence of other quality indicators (step 3), waiting time >30 minutes, consultation time <15 minutes, and low IMQI were all associated with low satisfaction. Age, SES, and region of residence were not found to affect satisfaction in any of the models. CONCLUSION: Anxiety symptoms were most strongly associated with low patient satisfaction. The relevance of recent provider change and not being seen by a specialist underlines the importance of well-planned transition in this age group.

Sequential tests for monitoring methods to detect elevated incidence - a simulation study.

BACKGROUND: Common cancer monitoring practice is seldom prospective and rather driven by public requests. This study aims to assess the performance of a recently developed prospective cancer monitoring method and the statistical tools used, in particular the sequential probability ratio test in regard to specificity, sensitivity, observation time and heterogeneity of size of the geographical unit. METHODS: A simulation study based on a predefined selection of cancer types, geographical unit and time period was set up. Based on the population structure of Lower Saxony the mean number of cases of three diagnoses were randomly assigned to the geographical units during 2008-2012. A two-stage monitoring procedure was then executed considering the standardized incidence ratio and sequential probability ratio test. Scenarios were constructed differing by the simulation of clusters, significance level and test parameter indicating a risk to be elevated. RESULTS: Performance strongly depended on the choice of the test parameter. If the expected numbers of cases were low, the significance level was not fully exhausted. Hence, the number of false positives was lower than the chosen significance level suggested, leading to a high specificity. Sensitivity increased with the expected number of cases and the amount of risk and decreased with the size of the geographical unit. CONCLUSIONS: The procedure showed some desirable properties and is ready to use for a few settings but demands adjustments for others. Future work might consider refinements of the geographical structure. Inhomogeneous unit size could be addressed by a flexible choice of the test parameter related to the observation time.

Current health status and medical therapy of patients with pediatric-onset inflammatory bowel disease: a survey-based analysis on 1280 patients aged 10-25 years focusing on differences by age of onset.

OBJECTIVE: There are inconsistent reports on age-related differences in inflammatory bowel disease (IBD). On the basis of patient information, we describe the clinical presentation and therapy in relation to age at diagnosis in longstanding pediatric IBD. PATIENTS AND METHODS: Two surveys were conducted in children and young adults (age: 10-25 years) by pretested postal questionnaires. The main analyses are descriptive, showing proportions and distributions per grouped age of diagnosis. Exploratory logistic regression was used to identify sociodemographic and disease-related factors associated with prognosis. Recent disease course, use of biological therapy, and resecting surgery were chosen as indicators of disease severity. Patients with a diagnosis in infancy (<2 years of age) are presented as a case series. RESULTS: Information of 1280 cases was available [804 Crohn's disease (CD), 382 ulcerative colitis (UC), 94 IBD not specified] (response: 44.6 and 49.6%). Stable remission during the preceding year was reported by 675 (56.7%) patients; 825 (60.9%) patients reported feeling currenty well. Anti-tumor necrosis factor therapy was reported by 33% of CD patients and 9.3% of UC patients, immunomodulation in 82.1 and 63.2%, and corticosteroids by 78.4 and 76.1%, respectively (ever use). Age at diagnosis was not associated with indicators of severe disease. Diagnosis in infancy was reported by 37 patients. CONCLUSION: Our data do not support age at diagnosis-related differences in prognosis in pediatric-onset IBD.

Transition from pediatric to adult medical care - A survey in young persons with inflammatory bowel disease.

BACKGROUND: Transition to adult health services is a vulnerable phase in young persons with chronic disease. We describe how young persons with inflammatory bowel disease in Germany and Austria experience care during the transitional age, focusing on differences by type of provider (pediatric vs. adult specialist, no specialist). METHODS: This was a follow up survey in patients previously registered with a pediatric IBD registry. Patients aged 15 to 25 received a postal questionnaire, including a measure of health care experience and satisfaction. Descriptive analyses were stratified by age. Sub-analyses in the 18-20 year age group compared health care experience by type of provider. Determinants of early or late transfer were examined using multinomial logistic regression. RESULTS: 619 patients responded to the survey; 605 questionnaires were available for analysis. Usual age of completing transition was 18. Earlier transfer was more common with low parental SES (OR 1.8, 95% CI 0.7 to 4.6), and less common with advanced schooling (OR 0.5, 95% CI 0.2 to 1.2). Structured transition was uncommon. 48% of the respondents had not received any preceding transition advice. Overall satisfaction with IBD care was high, especially with respect to interpersonal aspects, but less so in aspects of continuity of care. CONCLUSIONS: Despite high overall patient satisfaction, relevant deficiencies in transitional care were documented. Some of these were associated with lower parental social status. Differences in health care satisfaction by type of provider (adult vs. pediatric) were small.

Anti-IL-12/23p40 antibodies for induction of remission in Crohn's disease.

BACKGROUND: Ustekinumab (CNTO 1275) and briakinumab (ABT-874) are monoclonal antibodies that target the standard p40 subunit of the cytokines interleukin-12 and interleukin-23 (IL-12/23p40), which are involved in the pathogenesis of Crohn's disease. OBJECTIVES: The objectives of this review were to assess the efficacy and safety of anti-IL-12/23p40 antibodies for induction of remission in Crohn's disease. SEARCH METHODS: We searched the following databases from inception to 12 September 2016: PubMed, MEDLINE, EMBASE, and the Cochrane Library (CENTRAL). References and conference abstracts were searched to identify additional studies. SELECTION CRITERIA: Randomized controlled trials (RCTs) trials in which monoclonal antibodies against IL-12/23p40 were compared to placebo or another active comparator in patients with active Crohn's disease were included.  DATA COLLECTION AND ANALYSIS: Two authors independently screened  studies for inclusion and extracted data. Methodological quality was assessed using the Cochrane risk of bias tool. The primary outcome was failure to induce clinical remission, defined as a Crohn's disease activity index (CDAI) of < 150 points. Secondary outcomes included failure to induce clinical improvement, adverse events, serious adverse events, and withdrawals due to adverse events. Clinical improvement was defined as decreases of > 70 or > 100 points in the CDAI from baseline. We calculated the risk ratio (RR) and 95% confidence intervals (95% CI) for each outcome. Data were analyzed on an intention-to-treat basis. The overall quality of the evidence supporting the outcomes was evaluated using the GRADE criteria. MAIN RESULTS: Six RCTs (n = 2324 patients) met the inclusion criteria. A low risk of bias was assigned to all studies. The two briakinumab trials were not pooled due to differences in doses and time points for analysis. In both studies there was no statistically significant difference in remission rates. One study (n = 79) compared doses of 1 mg/kg and 3 mg/kg to placebo. In the briakinumab group 70% (44/63) of patients failed to enter clinical remission at 6 or 9 weeks compared to 81% (13/16) of placebo patients (RR 0.86, 95% CI 0.65 to 1.14). Subgroup analysis revealed no significant differences by dose. The other briakinumab study (n = 230) compared intravenous doses of 200 mg, 400 mg and 700 mg with placebo. Eighty-four per cent (154/184) of briakinumab patients failed to enter clinical remission at six weeks compared to 91% (42/46) of placebo patients (RR 0.92, 95% CI 0.83 to 1.03). Subgroup analysis revealed no significant differences by dose. GRADE analyses of the briakinumab studies rated the overall quality of the evidence for the outcome clinical remission as low. Based on the results of these two studies the manufacturers of briakinumab stopped production of this medication. The ustekinumab studies were pooled despite differences in intravenous doses (i.e. 1mg/kg, 3 mg/kg, 4.5 mg/kg, and 6 mg/kg), however the subcutaneous dose group was not included in the analysis, as it was unclear if subcutaneous was equivalent to intravenous dosing. There was a statistically significant difference in remission rates. At week six, 84% (764/914) of ustekinumab patients failed to enter remission compared to 90% (367/406) of placebo patients (RR 0.92, 95% CI 0.88 to 0.96; 3 studies; high-quality evidence). Subgroup analysis showed a statistically significant difference for the 6.0 mg/kg dose group (moderate-quality evidence). There were statistically significant differences in clinical improvement between ustekinumab and placebo-treated patients. In the ustekinumab group, 55% (502/914) of patients failed to improve clinically (i.e. 70-point decline in CDAI score), compared to 71% (287/406) of placebo patients (RR 0.78, 95% CI 0.71 to 0.85; 3 studies). Subgroup analysis revealed significant differences compared to placebo for the 1 mg/kg, 4.5 mg/kg and 6 mg/kg dosage subgroups. Similarly for a 100-point decline in CDAI, 64% (588/914) of patients in the ustekinumab group failed to improve clinically compared to 78% (318/406) of placebo patients (RR 0.82, 95% CI 0.77 to 0.88; 3 studies; high-quality evidence). Subgroup analysis showed a significant difference compared to placebo for the 4.5 mg/kg and 6.0 mg/kg (high-quality evidence) dose groups. There were no statistically significant differences in the incidence of adverse events, serious adverse events or withdrawal due to adverse events. Sixty-two per cent (860/1386) of ustekinumab patients developed at least one adverse event compared to 64% (407/637) of placebo patients (RR 0.97, 95% CI 0.90 to 1.04; 4 studies; high-quality evidence). Five per cent (75/1386) of ustekinumab patients had a serious adverse event compared to 6% (41/637) of placebo patients (RR 0.83, 95% CI 0.58 to 1.20; 4 studies; moderate-quality evidence). The most common adverse events in briakinumab patients were injection site reactions and infections. Infections were the most common adverse event in ustekinumab patients. Worsening of Crohn's disease and serious infections were the most common serious adverse events. AUTHORS' CONCLUSIONS: High quality evidence suggests that ustekinumab is effective for induction of clinical remission and clinical improvement in patients with moderate to severe Crohn's disease. Moderate to high quality evidence suggests that the optimal dosage of ustekinumab is 6 mg/kg. Briakinumab and ustekinumab appear to be safe. Moderate quality evidence suggests no increased risk of serious adverse events. Future studies are required to determine the long-term efficacy and safety of ustekinumab in patients with moderate to severe Crohn's disease.

Data Integration for Integrated Research and Care.

A national German funding initiative for Medical Informatics focusing at data integration for medicine gives an opportunity to reopen a window to Germany. In the open window appears a best paper selection of the 2015 annual conference of the German Society of Medical Informatics, Biometry and Epidemiology and papers of the German journal GMS Medical Informatics, Biometry and Epidemiology (MIBE). The publications in focus deal with data integration by transferring clinical routine data into an electronic data capture (EDC) system, using natural language processing to make unstructured date processable, measuring quality of record linkage, and by using a unified metadata scheme for integrated documentation in laboratories. Two additional papers present methods for data analysis especially for change point detection in binary sequences and for analyzing categorial data.

Azathioprine and 6-mercaptopurine for maintenance of remission in ulcerative colitis.

BACKGROUND: Maintenance of remission is a major issue in inflammatory bowel disease. In ulcerative colitis, the evidence for the effectiveness of azathioprine and 6-mercaptopurine for the maintenance of remission is still controversial. OBJECTIVES: To assess the effectiveness and safety of azathioprine and 6-mercaptopurine for maintaining remission of ulcerative colitis. SEARCH METHODS: The MEDLINE, EMBASE and Cochrane Library databases were searched from inception to 30 July 2015. Both full randomized controlled trials and associated abstracts were included. SELECTION CRITERIA: Randomized controlled trials of at least 12 months duration that compared azathioprine or 6-mercaptopurine with placebo or standard maintenance therapy (e.g. mesalazine) were included. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data using standard forms. Disagreements were solved by consensus including a third author. Study quality was assessed using the Cochrane risk of bias tool. The primary outcome was failure to maintain clinical or endoscopic remission. Secondary outcomes included adverse events and withdrawal due to adverse events. Analyses were performed separately by type of control (placebo, or active comparator). Pooled risk ratios were calculated based on the fixed-effect model unless heterogeneity was shown. The GRADE approach was used to assess the overall quality of evidence for pooled outcomes. MAIN RESULTS: Seven studies including 302 patients with ulcerative colitis were included in the review. The risk of bias was high in three of the studies due to lack of blinding. Azathioprine was shown to be significantly superior to placebo for maintenance of remission. Fourty-four per cent (51/115) of azathioprine patients failed to maintain remission compared to 65% (76/117) of placebo patients (4 studies, 232 patients; RR 0.68, 95% CI 0.54 to 0.86). A GRADE analysis rated the overall quality of the evidence for this outcome as low due to risk of bias and imprecision (sparse data). Two trials that compared 6-mercaptopurine to mesalazine, or azathioprine to sulfasalazine showed significant heterogeneity and thus were not pooled. Fifty per cent (7/14) of 6-mercaptopurine patients failed to maintain remission compared to 100% (8/8) of mesalazine patients (1 study, 22 patients; RR 0.53, 95% CI 0.31 to 0.90). Fifty-eight per cent (7/12) of azathioprine patients failed to maintain remission compared to 38% (5/13) of sulfasalazine patients (1 study, 25 patients; RR 1.52, 95% CI 0.66 to 3.50). One small study found that 6-mercaptopurine was superior to methotrexate for maintenance of remission. In the study, 50% (7/14) of 6-mercaptopurine patients and 92% (11/12) of methotrexate patients failed to maintain remission (1 study, 26 patients; RR 0.55, 95% CI 0.31 to 0.95). One very small study compared azathioprine with cyclosporin and found that there was no significant difference between patients failing remission on azathioprine (50%, 4/8) or cyclosporin (62.5%, 5/8) (1 study, 16 patients, RR 0.80 95% CI 0.33 to 1.92). When placebo-controlled studies were pooled with aminosalicylate-comparator studies to assess adverse events, there was no statistically significant difference between azathioprine and control in the incidence of adverse events. Nine per cent (11/127) of azathioprine patients experienced at least one adverse event compared to 2% (3/130) of placebo patients (5 studies, 257 patients; RR 2.82, 95% CI 0.99 to 8.01). Patients receiving azathioprine were at significantly increased risk of withdrawing due to adverse events. Eight per cent (8/101) of azathioprine patients withdrew due to adverse events compared to 0% (0/98) of control patients (5 studies, 199 patients; RR 5.43, 95% CI 1.02 to 28.75). Adverse events related to study medication included acute pancreatitis (3 cases, plus 1 case on cyclosporin) and significant bone marrow suppression (5 cases). Deaths, opportunistic infection or neoplasia were not reported. AUTHORS' CONCLUSIONS: Azathioprine therapy appears to be more effective than placebo for maintenance of remission in ulcerative colitis. Azathioprine or 6-mercaptopurine may be effective as maintenance therapy for patients who have failed or cannot tolerate mesalazine or sulfasalazine and for patients who require repeated courses of steroids. More research is needed to evaluate superiority over standard maintenance therapy, especially in the light of a potential for adverse events from azathioprine. This review updates the existing review of azathioprine and 6-mercaptopurine for maintenance of remission in ulcerative colitis which was published in the Cochrane Library (September 2012).

Anti-IL-12/23p40 antibodies for induction of remission in Crohn's disease.

BACKGROUND: Ustekinumab (CNTO 1275) and briakinumab (ABT-874) are monoclonal antibodies that target the standard p40 subunit of the cytokines interleukin-12 and interleukin-23 (IL-12/23p40), which are involved in the pathogenesis of Crohn's disease. OBJECTIVES: The objectives of this review were to assess the efficacy and safety of anti-IL-12/23p40 antibodies for induction of remission in Crohn's disease. SEARCH METHODS: The following databases were searched from inception to September 16, 2014: PubMed, MEDLINE, EMBASE, and the Cochrane Library (CENTRAL). References and conference abstracts were searched to identify additional studies. SELECTION CRITERIA: Randomized controlled trials (RCTs) trials in which monoclonal antibodies against IL-12/23p40 were compared to placebo or another active comparator in patients with active Crohn's disease were included.  DATA COLLECTION AND ANALYSIS: Two authors independently screened  studies for inclusion and extracted data. Methodological quality was assessed using the Cochrane risk of bias tool. The primary outcome was failure to induce clinical remission, defined as a Crohn's disease activity index (CDAI) of < 150 points. Secondary outcomes included failure to induce clinical improvement, serious adverse events, and withdrawals due to adverse events. Clinical improvement was defined as decreases of > 70 or > 100 points in the CDAI from baseline. We calculated the risk ratio (RR) and 95% confidence intervals (95% CI) for each outcome. A fixed-effect model was used to pool data. Data were analyzed on an intention-to-treat basis. The overall quality of the evidence supporting the outcomes was evaluated using the GRADE criteria. MAIN RESULTS: Four randomized controlled trials (n = 955 patients) met the inclusion criteria. A low risk of bias was assigned to all studies. The two briakinumab trials were not pooled due to differences in doses and time points for analysis. In both studies there was no statistically significant difference in remission rates. One study (n = 79) compared doses of 1 mg/kg and 3 mg/kg to placebo. In the briakinumab group 70% (44/63) of patients failed to enter clinical remission at 6 or 9 weeks compared to 81% (13/16) of placebo patients (RR 0.86, 95% CI 0.65 to 1.14). Subgroup analysis revealed no significant differences by dose. The other briakinumab study (n = 230) compared intravenous doses of 200 mg, 400 mg and 700 mg with placebo. Eighty-four per cent (154/184) of briakinumab patients failed to enter clinical remission at six weeks compared to 91% (42/46) of placebo patients (RR 0.92, 95% CI 0.83 to 1.03). Subgroup analysis revealed no significant differences by dose. GRADE analyses of the briakinumab studies rated the overall quality of the evidence for the outcome clinical remission as low due. Based on the results of these two studies the manufacturers of briakinumab stopped production of this medication. The two ustekinumab studies (630 patients) were pooled despite differences in intravenous doses (i.e. 1mg/kg, 3 mg/kg, 4.5 mg/kg, and 6 mg/kg), however the subcutaneous dose group was not included in the analysis, as it was unclear if subcutaneous was equivalent to intravenous dosing. There was no statistically significant difference in remission rates. At week six, 85% (356/420) of ustekinumab patients failed to enter remission compared to 89% (142/159) of placebo patients (RR 0.94, 95% CI 0.88 to 1.01). Subgroup analysis showed no statistically significant difference by dose. There were statistically significant differences in clinical improvement between ustekinumab and placebo-treated patients. In the ustekinumab group, 55% (230/420) of patients failed to improve clinically (i.e. 70-point decline in CDAI score), compared to 72% (115/159) of placebo patients (RR 0.75, 95% CI 0.66 to 0.86). Subgroup analysis revealed significant differences compared to placebo for the 1 mg/kg, 4.5 mg/kg and 6 mg/kg dosage subgroups. Similarly for a 100-point decline in CDAI, 62% (262/420) of patients in the ustekinumab group failed to improve clinically compared to 78% (124/159) of placebo patients (RR 0.79, 95% CI 0.71 to 0.89). Subgroup analysis showed a significant difference compared to placebo for the 4.5 mg/kg dose group. GRADE analyses of the ustekinumab studies rated the overall quality of the evidence for the outcomes clinical remission and clinical response as moderate. There were no statistically significant differences in the incidence of adverse events, serious adverse events or withdrawal due to adverse events. Sixty-seven per cent (316/473) of ustekinumab patients developed at least one adverse event compared to 73% (135/184) of placebo patients (RR 0.92, 95% CI 0.83 to 1.03). A GRADE analysis indicated that the overall quality of the evidence for this outcome was high. Six per cent (29/473) of ustekinumab patients had a serious adverse event compared to 8% (14/184) of placebo patients (RR 0.81, 95% CI 0.44 to 1.49). A GRADE analysis indicated that the overall quality of the evidence for this outcome was low. The most common adverse events in briakinumab patients were injection site reactions and infections. Infections were the most common adverse event in ustekinumab patients. Worsening of Crohn's disease and serious infections were the most common serious adverse events. AUTHORS' CONCLUSIONS: Although we are uncertain about the efficacy of ustekinumab for induction of remission, moderate quality evidence suggests that ustekinumab may be effective for induction of clinical improvement in patients with moderate to severe CD. Due to small numbers of patients in dose subgroups the optimal dosage of ustekinumab is unclear. Briakinumab and ustekinumab appear to be safe. Due to sparse data we were unable to determine the risk of serious adverse events. Further studies are required to determine the efficacy and safety of ustekinumab in patients with moderate to severe CD. The results of three phase III trials that are currently underway will provide important new information.