Fate of clinical research studies after ethical approval--follow-up of study protocols until publication.

BACKGROUND: Many clinical studies are ultimately not fully published in peer-reviewed journals. Underreporting of clinical research is wasteful and can result in biased estimates of treatment effect or harm, leading to recommendations that are inappropriate or even dangerous. METHODS: We assembled a cohort of clinical studies approved 2000-2002 by the Research Ethics Committee of the University of Freiburg, Germany. Published full articles were searched in electronic databases and investigators contacted. Data on study characteristics were extracted from protocols and corresponding publications. We characterized the cohort, quantified its publication outcome and compared protocols and publications for selected aspects. RESULTS: Of 917 approved studies, 807 were started and 110 were not, either locally or as a whole. Of the started studies, 576 (71%) were completed according to protocol, 128 (16%) discontinued and 42 (5%) are still ongoing; for 61 (8%) there was no information about their course. We identified 782 full publications corresponding to 419 of the 807 initiated studies; the publication proportion was 52% (95% CI: 0.48-0.55). Study design was not significantly associated with subsequent publication. Multicentre status, international collaboration, large sample size and commercial or non-commercial funding were positively associated with subsequent publication. Commercial funding was mentioned in 203 (48%) protocols and in 205 (49%) of the publications. In most published studies (339; 81%) this information corresponded between protocol and publication. Most studies were published in English (367; 88%); some in German (25; 6%) or both languages (27; 6%). The local investigators were listed as (co-)authors in the publications corresponding to 259 (62%) studies. CONCLUSION: Half of the clinical research conducted at a large German university medical centre remains unpublished; future research is built on an incomplete database. Research resources are likely wasted as neither health care professionals nor patients nor policy makers can use the results when making decisions.

Determinants of methicillin-susceptible Staphylococcus aureus native bone and joint infection treatment failure: a retrospective cohort study.

BACKGROUND: Although methicillin-susceptible Staphylococcus aureus (MSSA) native bone and joint infection (BJI) constitutes the more frequent clinical entity of BJI, prognostic studies mostly focused on methicillin-resistant S. aureus prosthetic joint infection. We aimed to assess the determinants of native MSSA BJI outcomes. METHODS: Retrospective cohort study (2001-2011) of patients admitted in a reference hospital centre for native MSSA BJI. Treatment failure determinants were assessed using Kaplan-Meier curves and binary logistic regression. RESULTS: Sixty-six patients (42 males [63.6%]; median age 61.2 years; interquartile range [IQR] 45.9-71.9) presented an acute (n = 38; 57.6%) or chronic (n = 28; 42.4%) native MSSA arthritis (n = 15; 22.7%), osteomyelitis (n = 19; 28.8%) or spondylodiscitis (n = 32; 48.5%), considered as "difficult-to-treat" in 61 cases (92.4%). All received a prolonged (27.1 weeks; IQR, 16.9-36.1) combined antimicrobial therapy, after surgical management in 37 cases (56.1%). Sixteen treatment failures (24.2%) were observed during a median follow-up period of 63.3 weeks (IQR, 44.7-103.1), including 13 persisting infections, 1 relapse after treatment disruption, and 2 super-infections. Independent determinants of treatment failure were the existence of a sinus tract (odds ratio [OR], 5.300; 95% confidence interval [CI], 1.166-24.103) and a prolonged delay to infectious disease specialist referral (OR, 1.134; 95% CI 1.013-1.271). CONCLUSIONS: The important treatment failure rate pinpointed the difficulty of cure encountered in complicated native MSSA BJI. An early infectious disease specialist referral is essential, especially in debilitated patients or in presence of sinus tract.

Contribution of modifiable risk factors to social inequalities in type 2 diabetes: prospective Whitehall II cohort study.

OBJECTIVE: To assess the contribution of modifiable risk factors to social inequalities in the incidence of type 2 diabetes when these factors are measured at study baseline or repeatedly over follow-up and when long term exposure is accounted for. DESIGN: Prospective cohort study with risk factors (health behaviours (smoking, alcohol consumption, diet, and physical activity), body mass index, and biological risk markers (systolic blood pressure, triglycerides and high density lipoprotein cholesterol)) measured four times and diabetes status assessed seven times between 1991-93 and 2007-09. SETTING: Civil service departments in London (Whitehall II study). PARTICIPANTS: 7237 adults without diabetes (mean age 49.4 years; 2196 women). MAIN OUTCOME MEASURES: Incidence of type 2 diabetes and contribution of risk factors to its association with socioeconomic status. RESULTS: Over a mean follow-up of 14.2 years, 818 incident cases of diabetes were identified. Participants in the lowest occupational category had a 1.86-fold (hazard ratio 1.86, 95% confidence interval 1.48 to 2.32) greater risk of developing diabetes relative to those in the highest occupational category. Health behaviours and body mass index explained 33% (-1% to 78%) of this socioeconomic differential when risk factors were assessed at study baseline (attenuation of hazard ratio from 1.86 to 1.51), 36% (22% to 66%) when they were assessed repeatedly over the follow-up (attenuated hazard ratio 1.48), and 45% (28% to 75%) when long term exposure over the follow-up was accounted for (attenuated hazard ratio 1.41). With additional adjustment for biological risk markers, a total of 53% (29% to 88%) of the socioeconomic differential was explained (attenuated hazard ratio 1.35, 1.05 to 1.72). CONCLUSIONS: Modifiable risk factors such as health behaviours and obesity, when measured repeatedly over time, explain almost half of the social inequalities in incidence of type 2 diabetes. This is more than was seen in previous studies based on single measurement of risk factors.

Cohort profile: the Swiss HIV Cohort study.

The substantial recurrence rate of colorectal cancer following potentially curative resection has fuelled the search for effective adjuvant therapy. Previous trials using 5-fluorouracil (5-FU) as a single agent or in combination chemotherapy regimens have not demonstrated meaningful benefits, an impression reflected in the results of a meta-analysis encompassing large patient numbers. Newer developments utilizing intraportal chemotherapy and the combination of 5-FU and levamisole have resulted in lower recurrence rates and improved survival in patients with colon cancer. In advanced disease, the biochemical modulation of 5-FU by Leucovorin has been shown to prolong survival in some studies. Combined chemotherapy and radiotherapy or chemotherapy alone have showed promising results in rectal cancer. These developments have now been incorporated into ongoing trials.

Current features of infective endocarditis in elderly patients: results of the International Collaboration on Endocarditis Prospective Cohort Study.

BACKGROUND: Elderly patients are emerging as a population at high risk for infective endocarditis (IE). However, adequately sized prospective studies on the features of IE in elderly patients are lacking. METHODS: In this multinational, prospective, observational cohort study within the International Collaboration on Endocarditis, 2759 consecutive patients were enrolled from June 15, 2000, to December 1, 2005; 1056 patients with IE 65 years or older were compared with 1703 patients younger than 65 years. Risk factors, predisposing conditions, origin, clinical features, course, and outcome of IE were comprehensively analyzed. RESULTS: Elderly patients reported more frequently a hospitalization or an invasive procedure before IE onset. Diabetes mellitus and genitourinary and gastrointestinal cancer were the major predisposing conditions. Blood culture yield was higher among elderly patients with IE. The leading causative organism was Staphylococcus aureus, with a higher rate of methicillin resistance. Streptococcus bovis and enterococci were also significantly more prevalent. The clinical presentation of elderly patients with IE was remarkable for lower rates of embolism, immune-mediated phenomena, or septic complications. At both echocardiography and surgery, fewer vegetations and more abscesses were found, and the gain in the diagnostic yield of transesophageal echocardiography was significantly larger. Significantly fewer elderly patients underwent cardiac surgery (38.9% vs 53.5%; P < .001). Elderly patients with IE showed a higher rate of in-hospital death (24.9% vs 12.8%; P < .001), and age older than 65 years was an independent predictor of mortality. CONCLUSIONS: In this large prospective study, increasing age emerges as a major determinant of the clinical characteristics of IE. Lower rates of surgical treatment and high mortality are the most prominent features of elderly patients with IE. Efforts should be made to prevent health care-associated acquisition and improve outcomes in this major subgroup of patients with IE.

The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement: Guidelines for reporting observational studies.

Much biomedical research is observational. The reporting of such research is often inadequate, which hampers the assessment of its strengths and weaknesses and of a study's generalisability. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Initiative developed recommendations on what should be included in an accurate and complete report of an observational study. We defined the scope of the recommendations to cover three main study designs: cohort, case-control, and cross-sectional studies. We convened a 2-day workshop in September 2004, with methodologists, researchers, and journal editors to draft a checklist of items. This list was subsequently revised during several meetings of the coordinating group and in e-mail discussions with the larger group of STROBE contributors, taking into account empirical evidence and methodological considerations. The workshop and the subsequent iterative process of consultation and revision resulted in a checklist of 22 items (the STROBE Statement) that relate to the title, abstract, introduction, methods, results, and discussion sections of articles. 18 items are common to all three study designs and four are specific for cohort, case-control, or cross-sectional studies. A detailed Explanation and Elaboration document is published separately and is freely available on the Web sites of PLoS Medicine, Annals of Internal Medicine, and Epidemiology. We hope that the STROBE Statement will contribute to improving the quality of reporting of observational studies.

Exposure to radio-frequency electromagnetic fields from broadcast transmitters and risk of childhood cancer: a census-based cohort study.

We investigated the association between exposure to radio-frequency electromagnetic fields (RF-EMFs) from broadcast transmitters and childhood cancer. First, we conducted a time-to-event analysis including children under age 16 years living in Switzerland on December 5, 2000. Follow-up lasted until December 31, 2008. Second, all children living in Switzerland for some time between 1985 and 2008 were included in an incidence density cohort. RF-EMF exposure from broadcast transmitters was modeled. Based on 997 cancer cases, adjusted hazard ratios in the time-to-event analysis for the highest exposure category (>0.2 V/m) as compared with the reference category (<0.05 V/m) were 1.03 (95% confidence interval (CI): 0.74, 1.43) for all cancers, 0.55 (95% CI: 0.26, 1.19) for childhood leukemia, and 1.68 (95% CI: 0.98, 2.91) for childhood central nervous system (CNS) tumors. Results of the incidence density analysis, based on 4,246 cancer cases, were similar for all types of cancer and leukemia but did not indicate a CNS tumor risk (incidence rate ratio = 1.03, 95% CI: 0.73, 1.46). This large census-based cohort study did not suggest an association between predicted RF-EMF exposure from broadcasting and childhood leukemia. Results for CNS tumors were less consistent, but the most comprehensive analysis did not suggest an association.

Protocol for a systematic review on the extent of non-publication of research studies and associated study characteristics.

BACKGROUND: Methodological research has found that non-published studies often have different results than those that are published, a phenomenon known as publication bias. When results are not published, or are published selectively based on the direction or the strength of the findings, healthcare professionals and consumers of healthcare cannot base their decision-making on the full body of current evidence. METHODS: As part of the OPEN project (http://www.open-project.eu) we will conduct a systematic review with the following objectives:1. To determine the proportion and/or rate of non-publication of studies by systematically reviewing methodological research projects that followed up a cohort of studies that a. received research ethics committee (REC) approval,b. were registered in trial registries, orc. were presented as abstracts at conferences.2. To assess the association of study characteristics (for example, direction and/or strength of findings) with likelihood of full publication.To identify reports of relevant methodological research projects we will conduct electronic database searches, check reference lists, and contact experts. Published and unpublished projects will be included. The inclusion criteria are as follows:a. RECs: methodological research projects that examined the subsequent proportion and/or rate of publication of studies that received approval from RECs;b. Trial registries: methodological research projects that examine the subsequent proportion and/or rate of publication of studies registered in trial registries;c. Conference abstracts: methodological research projects that examine the subsequent proportion and/or rate of full publication of studies which were initially presented at conferences as abstracts.Primary outcomes: Proportion/rate of published studies; time to full publication (mean/median; cumulative publication rate by time).Secondary outcomes: Association of study characteristics with full publication.The different questions (a, b, and c) will be investigated separately. Data synthesis will involve a combination of descriptive and statistical summaries of the included methodological research projects. DISCUSSION: Results are expected to be publicly available in mid 2013.

Mycobacterium avium subsp. paratuberculosis in an Italian Cohort of Type 1 Diabetes Pediatric Patients.

Mycobacterium avium subsp. paratuberculosis (MAP) is the etiological agent of Johne's disease in ruminants. Recent studies have linked MAP to type 1 diabetes (T1D) in the Sardinian population. The aim of this study was to investigate the prevalence of MAP infection in a T1D cohort from continental Italy compared with healthy control subjects. 247 T1D subjects and 110 healthy controls were tested for the presence of MAP. MAP DNA was detected using IS900-specific polymerase chain reaction (PCR). The presence of antibodies towards a MAP antigen, heparin binding hemoagglutinin (HBHA), was detected by ELISA. We demonstrated a higher MAP DNA prevalence in plasma samples from T1D patients and a stronger immune response towards MAP HBHA, compared with healthy control subjects. Moreover, in the recent onset patients, we observed an association between anti-MAP antibodies and HLA DQ2 (DQA1 0201/DQB1 0202). These findings taken together support the hypothesis of MAP as an environmental risk factor for the development of T1D in genetically predisposed subjects, probably involving a mechanism of molecular mimicry between MAP antigens and pancreatic islet β-cells.

Long term retention of retigabine in a cohort of people with drug resistant epilepsy.

PURPOSE: To assess the utility of retigabine (RTG) for epilepsy in clinical practice at a single UK tertiary centre. METHODS: We identified all individuals who were offered RTG from April 2011 to May 2013. We collected demographics, seizure types, previous and current antiepileptic drugs (AEDs), starting and maximum attained daily dose of RTG, clinical benefits, side effects, and reason to discontinue RTG from in- and outpatient encounters until February 28, 2014. RESULTS: 145 people who had failed a median of 11 AEDs took at least one dose of RTG. One year retention was 32% and decreased following the safety alert by the US Federal Drug Administration (FDA) in April 2013. None became seizure free. 34 people (24%) reported a benefit that was ongoing at last assessment in five (3%). The most relevant benefit was the significant reduction or cessation of drop attacks or seizure-related falls in four women, this persisted at last assessment in two. The presence of simple partial seizures was associated with longer retention, as was a higher attained dose of RTG. Adverse effects were seen in 74% and largely CNS-related or nonspecific and affected the genitourinary system in 13%. CONCLUSION: Retention of RTG was less favourable compared to data from open label extension studies of the regulatory trials. In comparison with historical data on similar retention audits retention of RTG at one year appears to be less than lamotrigine, topiramate, levetiracetam, pregabalin, zonisamide, and lacosamide, and slightly higher than gabapentin.

A protocol for a systematic review on the impact of unpublished studies and studies published in the gray literature in meta-analyses.

BACKGROUND: Meta-analyses are particularly vulnerable to the effects of publication bias. Despite methodologists' best efforts to locate all evidence for a given topic the most comprehensive searches are likely to miss unpublished studies and studies that are published in the gray literature only. If the results of the missing studies differ systematically from the published ones, a meta-analysis will be biased with an inaccurate assessment of the intervention's effects.As part of the OPEN project (http://www.open-project.eu) we will conduct a systematic review with the following objectives:â-ª To assess the impact of studies that are not published or published in the gray literature on pooled effect estimates in meta-analyses (quantitative measure).â-ª To assess whether the inclusion of unpublished studies or studies published in the gray literature leads to different conclusions in meta-analyses (qualitative measure). METHODS/DESIGN: Inclusion criteria: Methodological research projects of a cohort of meta-analyses which compare the effect of the inclusion or exclusion of unpublished studies or studies published in the gray literature.Literature search: To identify relevant research projects we will conduct electronic searches in Medline, Embase and The Cochrane Library; check reference lists; and contact experts.Outcomes: 1) The extent to which the effect estimate in a meta-analyses changes with the inclusion or exclusion of studies that were not published or published in the gray literature; and 2) the extent to which the inclusion of unpublished studies impacts the meta-analyses' conclusions.Data collection: Information will be collected on the area of health care; the number of meta-analyses included in the methodological research project; the number of studies included in the meta-analyses; the number of study participants; the number and type of unpublished studies; studies published in the gray literature and published studies; the sources used to retrieve studies that are unpublished, published in the gray literature, or commercially published; and the validity of the methodological research project.Data synthesis: Data synthesis will involve descriptive and statistical summaries of the findings of the included methodological research projects. DISCUSSION: Results are expected to be publicly available in the middle of 2013.

FM127: Systemic metal ion levels in patients with modular neck total hip arthroplasties: a prospective cohort study

There is increasing evidence that modular neck stems are prone to corrosion-related complications. Recent studies showed elevated metal ions levels and occasional pseudotumor formation in patients with such implants. The purpose of this study was to compare systemic metal-ion levels in patients after primary THA with modular neck stems to those of patients after non-modular implants. To our knowledge, this is the first cohort study including a control group, THA without CoCr heads and dry-assembled neck-stem connections. Methods: 50 patients after THA at a minimum follow-up of 1 year have been selected for the study. Patients with multiple prosthesis or other implants have been deselected. All received a cementless SPS stem from Symbios (Ti6Al4V). 40 patients have the modular neck (CoCr) version and 10 a monobloc version. All bearings were either ceramic-ceramic or ceramic-polyethylene to minimize other sources of CoCr ion release. In the modular group, the neck was chosen pre-operatively based on a 3D planning, allowing for a dry assembly of the stem and neck on the back table before implantation. A plasma system coupled to mass spectrometry was used for a complete elementary quantification in blood and serum separately. Clinical outcome was measured using the Oxford Hip Score. Results : Complete data sets of 29 patients (24 in the modular neck-group (10male, mean age 63y, 35-84y) and 5 in the monobloc-group (3 male, 69 y, 51-83y) are available to date. Mean Co blood levels were .95 ug/L (.14-12.4) in the modular group vs .27 ug/L (.10-.73) in the monobloc group (p=.2). Respective values for Cr were significantly higher in the modular group (.99 g/L; range .75-1.21) compared to those in the monobloc group (.74 g/L ;.62-.86; p=.001). No significant difference was found when comparing serum levels. 5/24 patients had Co levels above 1 g/L (12/24 for Cr), which is by some considered as a relevant elevation. The maximum Co level was measured in an asymptomatic patient. The Oxford Hip Scores were similar in both groups. Conclusion: Cr levels were significantly elevated in the modular neck group compared to those in the monobloc group. 1/24 patients with a modular prosthesis exhibited Co levels, which are beyond the threshold accepted even for metal-on-metal bearing couples. These results have contributed to our decision to abandon the use of modular neck stems. Routine follow-up including annual measurements of systemic CoCr concentrations should be considered.

Rate of undesirable events at beginning of academic year: retrospective cohort study.

OBJECTIVE: To determine whether an increase in the rate of undesirable events occurs after care provided by trainees at the beginning of the academic year. DESIGN: Retrospective cohort study using administrative and patient record data. SETTING: University affiliated hospital in Melbourne, Australia. PARTICIPANTS: 19,560 patients having an anaesthetic procedure carried out by first to fifth year trainees starting work for the first time at the hospital over a period of five years (1995-2000). MAIN OUTCOME MEASURES: Absolute event rates, absolute rate reduction, and rate ratios of undesirable events. RESULTS: The rate of undesirable events was higher at the beginning of the academic year compared with the rest of the year (absolute event rate 137 v 107 per 1000 patient hours, relative rate reduction 28%, P<0.001). The overall adjusted rate ratio for undesirable events was 1.40, 95% confidence interval 1.24 to 1.58. This excess risk was seen for all residents, regardless of their level of seniority. The excess risk decreased progressively after the first month, and the trend disappeared fully after the fourth month of the year (rate ratio for fourth month 1.21, 0.93 to 1.57). The most important decreases were for central and peripheral nerve injuries (relative difference 82%), inadequate oxygenation of the patient (66%), vomiting/aspiration in theatre (53%), and technical failures of tracheal tube placement (49%). CONCLUSIONS: The rate of undesirable events was greater among trainees at the beginning of the academic year regardless of their level of clinical experience. This suggests that several additional factors, such as knowledge of the working environment, teamwork, and communication, may contribute to the increase.

Association of socioeconomic status with inflammatory markers: a two cohort comparison.

OBJECTIVE: To assess the association between socioeconomic status (SES) and inflammatory markers using two different European population samples. METHODS: We used data from the CoLaus (N=6412, Lausanne, Switzerland) and EPIPorto (N=1205, Porto, Portugal) studies. Education and occupational position were used as indicators of socioeconomic status (SES). High-sensitivity C-reactive protein (hs-CRP) was available for both cohorts. Interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α) were available in CoLaus; leukocyte count and fibrinogen in EPIPorto. RESULTS: We showed that low SES was significantly associated with high inflammation in both studies. We also showed that behavioural factors contributed the most to SES differences in inflammation. In both studies the larger difference between the lowest and the highest SES was observed for hs-CRP. In the Swiss sample, a linear association between education and hs-CRP persisted after adjustment for all mediating factors and confounders considered (p for linear trend <0.001). CONCLUSION: Large social differences exist in inflammatory activity, in part independently from demographic and behavioural factors, chronic conditions and medication use. SES differences in inflammation are also similar in countries with different underlying socioeconomic conditions.