Completion and Publication Rates of Randomized Controlled Trials in Surgery: An Empirical Study.

OBJECTIVE: To investigate the prevalence of discontinuation and nonpublication of surgical versus medical randomized controlled trials (RCTs) and to explore risk factors for discontinuation and nonpublication of surgical RCTs. BACKGROUND: Trial discontinuation has significant scientific, ethical, and economic implications. To date, the prevalence of discontinuation of surgical RCTs is unknown. METHODS: All RCT protocols approved between 2000 and 2003 by 6 ethics committees in Canada, Germany, and Switzerland were screened. Baseline characteristics were collected and, if published, full reports retrieved. Risk factors for early discontinuation for slow recruitment and nonpublication were explored using multivariable logistic regression analyses. RESULTS: In total, 863 RCT protocols involving adult patients were identified, 127 in surgery (15%) and 736 in medicine (85%). Surgical trials were discontinued for any reason more often than medical trials [43% vs 27%, risk difference 16% (95% confidence interval [CI]: 5%-26%); P = 0.001] and more often discontinued for slow recruitment [18% vs 11%, risk difference 8% (95% CI: 0.1%-16%); P = 0.020]. The percentage of trials not published as full journal article was similar in surgical and medical trials (44% vs 40%, risk difference 4% (95% CI: -5% to 14%); P = 0.373). Discontinuation of surgical trials was a strong risk factor for nonpublication (odds ratio = 4.18, 95% CI: 1.45-12.06; P = 0.008). CONCLUSIONS: Discontinuation and nonpublication rates were substantial in surgical RCTs and trial discontinuation was strongly associated with nonpublication. These findings need to be taken into account when interpreting surgical literature. Surgical trialists should consider feasibility studies before embarking on full-scale trials.

The Prevention of Delirium and Complications Associated with Surgical Treatments (PODCAST) study: protocol for an international multicentre randomised controlled trial

INTRODUCTION Postoperative delirium is one of the most common complications of major surgery, affecting 10-70% of surgical patients 60 years and older. Delirium is an acute change in cognition that manifests as poor attention and illogical thinking and is associated with longer intensive care unit (ICU) and hospital stay, long-lasting cognitive deterioration and increased mortality. Ketamine has been used as an anaesthetic drug for over 50 years and has an established safety record. Recent research suggests that, in addition to preventing acute postoperative pain, a subanaesthetic dose of intraoperative ketamine could decrease the incidence of postoperative delirium as well as other neurological and psychiatric outcomes. However, these proposed benefits of ketamine have not been tested in a large clinical trial. METHODS The Prevention of Delirium and Complications Associated with Surgical Treatments (PODCAST) study is an international, multicentre, randomised controlled trial. 600 cardiac and major non-cardiac surgery patients will be randomised to receive ketamine (0.5 or 1 mg/kg) or placebo following anaesthetic induction and prior to surgical incision. For the primary outcome, blinded observers will assess delirium on the day of surgery (postoperative day 0) and twice daily from postoperative days 1-3 using the Confusion Assessment Method or the Confusion Assessment Method for the ICU. For the secondary outcomes, blinded observers will estimate pain using the Behavioral Pain Scale or the Behavioral Pain Scale for Non-Intubated Patients and patient self-report. ETHICS AND DISSEMINATION The PODCAST trial has been approved by the ethics boards of five participating institutions; approval is ongoing at other sites. Recruitment began in February 2014 and will continue until the end of 2016. Dissemination plans include presentations at scientific conferences, scientific publications, stakeholder engagement and popular media. REGISTRATION DETAILS The study is registered at clinicaltrials.gov, NCT01690988 (last updated March 2014). The PODCAST trial is being conducted under the auspices of the Neurological Outcomes Network for Surgery (NEURONS). TRIAL REGISTRATION NUMBER NCT01690988 (last updated December 2013).

Early Improvement As a Predictor of Later Response to Antipsychotics in Schizophrenia: A Diagnostic Test Review

OBJECTIVE How long clinicians should wait before considering an antipsychotic ineffective and changing treatment in schizophrenia is an unresolved clinical question. Guidelines differ substantially in this regard. The authors conducted a diagnostic test meta-analysis using mostly individual patient data to assess whether lack of improvement at week 2 predicts later nonresponse. METHOD The search included EMBASE, MEDLINE, BIOSIS, PsycINFO, Cochrane Library, CINAHL, and reference lists of relevant articles, supplemented by requests to authors of all relevant studies. The main outcome was prediction of nonresponse, defined as <50% reduction in total score on either the Positive and Negative Syndrome Scale (PANSS) or Brief Psychiatric Rating Scale (BPRS) (corresponding to at least much improved) from baseline to endpoint (4-12 weeks), by <20% PANSS or BPRS improvement (corresponding to less than minimally improved) at week 2. Secondary outcomes were absent cross-sectional symptomatic remission and <20% PANSS or BPRS reduction at endpoint. Potential moderator variables were examined by meta-regression. RESULTS In 34 studies (N=9,460) a <20% PANSS or BPRS reduction at week 2 predicted nonresponse at endpoint with a specificity of 86% and a positive predictive value (PPV) of 90%. Using data for observed cases (specificity=86%, PPV=85%) or lack of remission (specificity=77%, PPV=88%) yielded similar results. Conversely, using the definition of <20% reduction at endpoint yielded worse results (specificity=70%, PPV=55%). The test specificity was significantly moderated by a trial duration of <6 weeks, higher baseline illness severity, and shorter illness duration. CONCLUSIONS Patients not even minimally improved by week 2 of antipsychotic treatment are unlikely to respond later and may benefit from a treatment change.

Cathodal HD-tDCS on the right V5 improves motion perception in humans

Brain lesions in the visual associative cortex are known to impair visual perception, i.e., the capacity to correctly perceive different aspects of the visual world, such as motion, color, or shapes. Visual perception can be influenced by non-invasive brain stimulation such as transcranial direct current stimulation (tDCS). In a recently developed technique called high definition (HD) tDCS, small HD-electrodes are used instead of the sponge electrodes in the conventional approach. This is believed to achieve high focality and precision over the target area. In this paper we tested the effects of cathodal and anodal HD-tDCS over the right V5 on motion and shape perception in a single blind, within-subject, sham controlled, cross-over trial. The purpose of the study was to prove the high focality of the stimulation only over the target area. Twenty one healthy volunteers received 20 min of 2 mA cathodal, anodal and sham stimulation over the right V5 and their performance on a visual test was recorded. The results showed significant improvement in motion perception in the left hemifield after cathodal HD-tDCS, but not in shape perception. Sham and anodal HD-tDCS did not affect performance. The specific effect of influencing performance of visual tasks by modulating the excitability of the neurons in the visual cortex might be explained by the complexity of perceptual information needed for the tasks. This provokes a "noisy" activation state of the encoding neuronal patterns. We speculate that in this case cathodal HD-tDCS may focus the correct perception by decreasing global excitation and thus diminishing the "noise" below threshold.

Epithelial-intrinsic IKKα expression regulates group 3 innate lymphoid cell responses and antibacterial immunity

Innate lymphoid cells (ILCs) are critical for maintaining epithelial barrier integrity at mucosal surfaces; however, the tissue-specific factors that regulate ILC responses remain poorly characterized. Using mice with intestinal epithelial cell (IEC)-specific deletions in either inhibitor of κB kinase (IKK)α or IKKβ, two critical regulators of NFκB activation, we demonstrate that IEC-intrinsic IKKα expression selectively regulates group 3 ILC (ILC3)-dependent antibacterial immunity in the intestine. Although IKKβ(ΔIEC) mice efficiently controlled Citrobacter rodentium infection, IKKα(ΔIEC) mice exhibited severe intestinal inflammation, increased bacterial dissemination to peripheral organs, and increased host mortality. Consistent with weakened innate immunity to C. rodentium, IKKα(ΔIEC) mice displayed impaired IL-22 production by RORγt(+) ILC3s, and therapeutic delivery of rIL-22 or transfer of sort-purified IL-22-competent ILCs from control mice could protect IKKα(ΔIEC) mice from C. rodentium-induced morbidity. Defective ILC3 responses in IKKα(ΔIEC) mice were associated with overproduction of thymic stromal lymphopoietin (TSLP) by IECs, which negatively regulated IL-22 production by ILC3s and impaired innate immunity to C. rodentium. IEC-intrinsic IKKα expression was similarly critical for regulation of intestinal inflammation after chemically induced intestinal damage and colitis. Collectively, these data identify a previously unrecognized role for epithelial cell-intrinsic IKKα expression and TSLP in regulating ILC3 responses required to maintain intestinal barrier immunity.

An analysis of protocols and publications suggested that most discontinuations of clinical trials were not based on preplanned interim analyses or stopping rules.

OBJECTIVES To investigate the frequency of interim analyses, stopping rules, and data safety and monitoring boards (DSMBs) in protocols of randomized controlled trials (RCTs); to examine these features across different reasons for trial discontinuation; and to identify discrepancies in reporting between protocols and publications. STUDY DESIGN AND SETTING We used data from a cohort of RCT protocols approved between 2000 and 2003 by six research ethics committees in Switzerland, Germany, and Canada. RESULTS Of 894 RCT protocols, 289 prespecified interim analyses (32.3%), 153 stopping rules (17.1%), and 257 DSMBs (28.7%). Overall, 249 of 894 RCTs (27.9%) were prematurely discontinued; mostly due to reasons such as poor recruitment, administrative reasons, or unexpected harm. Forty-six of 249 RCTs (18.4%) were discontinued due to early benefit or futility; of those, 37 (80.4%) were stopped outside a formal interim analysis or stopping rule. Of 515 published RCTs, there were discrepancies between protocols and publications for interim analyses (21.1%), stopping rules (14.4%), and DSMBs (19.6%). CONCLUSION Two-thirds of RCT protocols did not consider interim analyses, stopping rules, or DSMBs. Most RCTs discontinued for early benefit or futility were stopped without a prespecified mechanism. When assessing trial manuscripts, journals should require access to the protocol.

Premature Discontinuation of Randomized Trials in Critical and Emergency Care: A Retrospective Cohort Study.

OBJECTIVES Randomized clinical trials that enroll patients in critical or emergency care (acute care) setting are challenging because of narrow time windows for recruitment and the inability of many patients to provide informed consent. To assess the extent that recruitment challenges lead to randomized clinical trial discontinuation, we compared the discontinuation of acute care and nonacute care randomized clinical trials. DESIGN Retrospective cohort of 894 randomized clinical trials approved by six institutional review boards in Switzerland, Germany, and Canada between 2000 and 2003. SETTING Randomized clinical trials involving patients in an acute or nonacute care setting. SUBJECTS AND INTERVENTIONS We recorded trial characteristics, self-reported trial discontinuation, and self-reported reasons for discontinuation from protocols, corresponding publications, institutional review board files, and a survey of investigators. MEASUREMENTS AND MAIN RESULTS Of 894 randomized clinical trials, 64 (7%) were acute care randomized clinical trials (29 critical care and 35 emergency care). Compared with the 830 nonacute care randomized clinical trials, acute care randomized clinical trials were more frequently discontinued (28 of 64, 44% vs 221 of 830, 27%; p = 0.004). Slow recruitment was the most frequent reason for discontinuation, both in acute care (13 of 64, 20%) and in nonacute care randomized clinical trials (7 of 64, 11%). Logistic regression analyses suggested the acute care setting as an independent risk factor for randomized clinical trial discontinuation specifically as a result of slow recruitment (odds ratio, 4.00; 95% CI, 1.72-9.31) after adjusting for other established risk factors, including nonindustry sponsorship and small sample size. CONCLUSIONS Acute care randomized clinical trials are more vulnerable to premature discontinuation than nonacute care randomized clinical trials and have an approximately four-fold higher risk of discontinuation due to slow recruitment. These results highlight the need for strategies to reliably prevent and resolve slow patient recruitment in randomized clinical trials conducted in the critical and emergency care setting.

Esophageal hiatal hernia in three exotic felines--Lynx lynx, Puma concolore, Panthera leo.

Hiatal hernia was diagnosed in three exotic felines-lynx (Lynx lynx), cougar (Puma concolore), and lion (Panthera leo). All cats had a history of anorexia. Thoracic and abdominal radiographs showed evidence of a soft tissue mass within the caudal mediastinum suggestive of a hiatal hernia in all animals. A barium esophagram was performed in one case. All animals underwent thoracic or abdominal surgery for hernia reduction. Surgical procedures included: intercostal thoracotomy with herniorrhaphy and esophagopexy (lynx and cougar), and incisional gastropexy (lion). Concurrent surgical procedures performed were gastrotomy for gastric foreign body removal and jejunostomy tube placement. Clinical signs related to the hiatal hernia disappeared after surgery and recurrence of signs was not reported for the time of follow-up.

Reflections on the Nature of Preferentialism in Services Trade

The Graduate Institute organized an academic workshop and roundtable on the occasion of EFTA's 50th Anniversary in Geneva under the chairmanship of H.E. Doris Leuthard, President of the Swiss Confederation. Pierre Sauve, Deputy Managing Director and Director of Studies, WTI and Co-leader, NCCR-Trade work programme on preferentialism and Anirudh Shingal, Senior Research Fellow, WTI and Co-leader, NCCR-Trade work programme on impact assessment of trade, co-authored a paper on the nature of preferentialism in services trade, which Anirudh presented at the workshop. The event was extremely well-attended by high profile dignitaries and academics including President Leuthard; Director General of the WTO, Pascal Lamy; trade ministers of Brazil and Finland; Jan Kubis, Executive Secretary of the UNECE and several current and former ambassadors. The academic workshop, moderated by Theresa Carpenter (Graduate Institute, Geneva), began in the morning with Prof. Victor Norman's (Norwegian School of Economics & Business Administration) presentation on the future of EFTA. Other presentations included those by Prof. Peter Egger (ETH Zurich) on the structural estimation of gravity models with market entry dynamics and by Prof. Richard Baldwin (Graduate Institute, Geneva) on 21st century regionalism. The high-profile Panel in the afternoon, moderated by Prof. Richard Baldwin, was led by President Leuthard who spoke on free trade agreements and the multilateral trading system in 2020. The keynote address at the Panel was delivered by Prof. Jagdish Bhagwati (Coulmbia University), who spoke on strengthening defences against protectionism and liberalizing trade.

Novel multiple sclerosis susceptibility loci implicated in epigenetic regulation.

We conducted a genome-wide association study (GWAS) on multiple sclerosis (MS) susceptibility in German cohorts with 4888 cases and 10,395 controls. In addition to associations within the major histocompatibility complex (MHC) region, 15 non-MHC loci reached genome-wide significance. Four of these loci are novel MS susceptibility loci. They map to the genes L3MBTL3, MAZ, ERG, and SHMT1. The lead variant at SHMT1 was replicated in an independent Sardinian cohort. Products of the genes L3MBTL3, MAZ, and ERG play important roles in immune cell regulation. SHMT1 encodes a serine hydroxymethyltransferase catalyzing the transfer of a carbon unit to the folate cycle. This reaction is required for regulation of methylation homeostasis, which is important for establishment and maintenance of epigenetic signatures. Our GWAS approach in a defined population with limited genetic substructure detected associations not found in larger, more heterogeneous cohorts, thus providing new clues regarding MS pathogenesis.