Is Mandatory Prospective Trial Registration Working to Prevent Publication of Unregistered Trials and Selective Outcome Reporting? An Observational Study of Five Psychiatry Journals That Mandate Prospective Clinical Trial Registration

Objective

To address the bias occurring in the medical literature associated with selective outcome reporting, in 2005, the International Committee of Medical Journal Editors (ICMJE) introduced mandatory trial registration guidelines and member journals required prospective registration of trials prior to patient enrolment as a condition of publication. No research has examined whether these guidelines are impacting psychiatry publications. Our objectives were to determine the extent to which articles published in psychiatry journals adhering to ICMJE guidelines were correctly prospectively registered, whether there was evidence of selective outcome reporting and changes to participant numbers, and whether there was a relationship between registration status and source of funding.

Materials and Methods

Any clinical trial (as defined by ICMJE) published between 1 January 2009 and 31 July 2013 in the top five psychiatry journals adhering to ICMJE guidelines (The American Journal of Psychiatry, Archives of General Psychiatry/JAMA Psychiatry, Biological Psychiatry, Journal of the American Academy of Child and Adolescent Psychiatry, and The Journal of Clinical Psychiatry) and conducted after July 2005 (or 2007 for two journals) was included. For each identified trial, where possible we extracted trial registration information, changes to POMs between publication and registry to assess selective outcome reporting, changes to participant numbers, and funding type.

Results

Out of 3305 articles, 181 studies were identified as clinical trials requiring registration: 21 (11.6%) were deemed unregistered, 61 (33.7%) were retrospectively registered, 37 (20.4%) had unclear POMs either in the article or the registry and 2 (1.1%) were registered in an inaccessible trial registry. Only 60 (33.1%) studies were prospectively registered with clearly defined POMs; 17 of these 60 (28.3%) showed evidence of selective outcome reporting and 16 (26.7%) demonstrated a change in participant numbers of 20% or more; only 26 (14.4%) of the 181 the trials were prospectively registered and did not alter their POMs or the time frames at which they were measured. Prospective registration with no changes in POMs occurred more frequently with pharmaceutical funding.

Discussion

Although standards are in place to improve prospective registration and transparency in clinical trials, less than 15% of psychiatry trials were prospectively registered with no changes in POMs. Most trials were either not prospectively registered, changed POMs or the timeframes at some point after registration or changed participant numbers. Authors, journal editors and reviewers need to further efforts to highlight the value of prospective trial registration.     

Is the Relationship between Common Mental Disorder and Adiposity Bidirectional? Prospective Analyses of a UK General Population-Based Study

The direction of the association between mental health and adiposity is poorly understood. Our objective was to empirically examine this link in a UK study. This is a prospective cohort study of 3 388 people (men) aged ≥ 18 years at study induction who participated in both the UK Health and Lifestyle Survey at baseline (HALS-1, 1984/1985) and the re-survey (HALS-2, 1991/1992). At both survey examinations, body mass index, waist circumference and self-reported common mental disorder (the 30-item General Health Questionnaire, GHQ) were measured. Logistic regression models were used to compute odds ratios (OR) and accompanying 95% confidence intervals (CI) for the associations between (1) baseline common mental disorder (QHQ score > 4) and subsequent general and abdominal obesity and (2) baseline general and abdominal obesity and re-survey common mental disorders. After controlling for a range of covariates, participants with common mental disorder at baseline experienced greater odds of subsequently becoming overweight (women, OR: 1.30, 1.03 – 1.64; men, 1.05, 0.81 – 1.38) and obese (women, 1.26, 0.82 – 1.94; men, OR: 2.10, 1.23 – 3.55) than those who were free of common mental disorder. Similarly, having baseline common mental health disorder was also related to a greater risk of developing moderate (1.57, 1.21 – 2.04) and severe (1.48, 1.09 – 2.01) abdominal obesity (women only). Baseline general or abdominal obesity was not associated with the risk of future common mental disorder. These findings of the present study suggest that the direction of association between common mental disorders and adiposity is from common mental disorder to increased future risk of adiposity as opposed to the converse.     

Is hyperglycaemia an independent predictor of poor outcome after acute stroke? Results of a long-term follow up study.

OBJECTIVE: To determine whether raised plasma glucose concentration independently influences outcome after acute stroke or is a stress response reflecting increased stroke severity. DESIGN: Long-term follow up study of patients admitted to an acute stroke unit. SETTING: Western Infirmary, Glasgow. SUBJECTS: 811 patients with acute stroke confirmed by computed tomography. Analysis was restricted to the 750 non-diabetic patients. MAIN OUTCOME MEASURES: Survival time and placement three months after stroke. RESULTS: 645 patients (86%) had ischaemic stroke and 105 patients (14%) haemorrhagic stroke. Cox''s proportional hazards modelling with stratification according to Oxfordshire Community Stroke Project categories identified increased age (relative hazard 1.36 per decade; 95% confidence interval 1.21 to 1.53), haemorrhagic stroke (relative hazard 1.67; 1.22 to 2.28), time to resolution of symptoms > 72 hours (relative hazard 2.15; 1.15 to 4.05), and hyperglycaemia (relative hazard 1.87; 1.43 to 2.45) as predictors of mortality. The effect of glucose concentration on survival was greatest in the first month. CONCLUSIONS: Plasma glucose concentration above 8 mmol/l after acute stroke predicts a poor prognosis after correcting for age, stroke severity, and stroke subtype. Raised plasma glucose concentration is therefore unlikely to be solely a stress response and should arguably be treated actively. A randomised trial is warranted.     

Is the Concept of Quality of Life Relevant for Multiple Sclerosis Patients with Cognitive Impairment? Preliminary Results of a Cross-Sectional Study

Background

Cognitive impairment occurs in about 50% of multiple sclerosis (MS) patients, and the use of self-reported outcomes for evaluating treatment and managing care among subjects with cognitive dysfunction has been questioned. The aim of this study was to provide new evidence about the suitability of self-reported outcomes for use in this specific population by exploring the internal structure, reliability and external validity of a specific quality of life (QoL) instrument, the Multiple Sclerosis International Quality of Life questionnaire (MusiQoL).

Methods

Design: cross-sectional study. Inclusion criteria: MS patients of any disease subtype. Data collection: sociodemographic (age, gender, marital status, education level, and occupational activity) and clinical data (MS subtype, Expanded Disability Status Scale, disease duration); QoL (MusiQoL and SF36); and neuropsychological performance (Stroop color-word test). Statistical analysis: confirmatory factor analysis, item-dimension correlations, Cronbach''s alpha coefficients, Rasch statistics, relationships between MusiQoL dimensions and other parameters.

Principal Findings

One hundred and twenty-four consecutive patients were enrolled. QoL scores did not differ between the 69 cognitively non-impaired patients and the 55 cognitively impaired patients, except for the symptoms dimension. The confirmatory factor analysis performed among the impaired subjects showed that the structure of the questionnaire matched with the initial structure of the MusiQoL. The unidimensionality of the MusiQoL dimensions was preserved, and the internal validity indices were satisfactory and close to those of the reference population.

Conclusions/Significance

Our study suggests that executive dysfunction did not compromise the reliability and the validity of the self-reported QoL questionnaires.     

Is Postoperative Wound Infection Following Simple Inguinal Herniorrhaphy a Predisposing Cause of Recurrent Hernia?

The significance of postoperative wound infection in simple inguinal herniorrhaphy was studied in a series of almost 26,000 simple inguinal herniorrhaphies. There was a recurrence rate of about 1% in uninfected cases and 4% in infected cases. The wound infection rate was 1.8%. Of about 2500 patients with recurrent inguinal hernia admitted to the Shouldice Hospital, Toronto, following an initial operation of elsewhere, about 4% gave a history of postoperative wound infection. Postoperative wound infection after simple inguinal herniorrhaphy increased the risk of a subsequent recurrent hernia about four times. However, in more than 95% of cases other etiological factors were responsible for the recurrence. No relation between infection and type of recurrent inguinal hernia subsequently developing was demonstrable.     

Is productivity of mesic savannas light limited or water limited? Results of a simulation study

A soil–plant–atmosphere model was used to estimate gross primary productivity (GPP) and evapotranspiration (ET) of a tropical savanna in Australia. This paper describes model modifications required to simulate the substantial C4 grass understory together with C3 trees. The model was further improved to include a seasonal distribution of leaf area and foliar nitrogen through 10 canopy layers. Model outputs were compared with a 5‐year eddy covariance dataset. Adding the C4 photosynthesis component improved the model efficiency and root‐mean‐squared error (RMSE) for total ecosystem GPP by better emulating annual peaks and troughs in GPP across wet and dry seasons. The C4 photosynthesis component had minimal impact on modelled values of ET. Outputs of GPP from the modified model agreed well with measured values, explaining between 79% and 90% of the variance and having a low RMSE (0.003–0.281 g C m^?2 day^?1). Approximately, 40% of total annual GPP was contributed by C4 grasses. Total (trees and grasses) wet season GPP was approximately 75–80% of total annual GPP. Light‐use efficiency (LUE) was largest for the wet season and smallest in the dry season and C4 LUE was larger than that of the trees. A sensitivity analysis of GPP revealed that daily GPP was most sensitive to changes in leaf area index (LAI) and foliar nitrogen (N_f) and relatively insensitive to changes in maximum carboxylation rate (V_cmax), maximum electron transport rate (J_max) and minimum leaf water potential (ψ_min). The modified model was also able to represent daily and seasonal patterns in ET, (explaining 68–81% of variance) with a low RMSE (0.038–0.19 mm day^?1). Current values of N_f, LAI and other parameters appear to be colimiting for maximizing GPP. By manipulating LAI and soil moisture content inputs, we show that modelled GPP is limited by light interception rather than water availability at this site.     

Is the orcadian clock of gonyaulax held stationary after a strong pulse of anisomycin?

• 1.1. Gonyaulax polyedra cells were treated with two sequential pulses of a protein synthesis inhibitor (anisomycin) in order to analyse a possible stopping of the circadian clock by the first pulse.
• 2.2. Inhibition of protein synthesis during these pulses and after centrifugation and resuspension of the cells was determined by measuring the incorporation of labelled amino acids.
• 3.3. The effects of the second pulses on the clock were measured as phase shifts of the glow rhythm with respect to a control rhythm that had been subjected to the initial pulse only.
• 4.4. From the observed phase shifts of the second pulses we conclude that the clock is not stopped by the first pulse but is immediately shifted to a different phase.

     

Myelin Water Fraction Is Transiently Reduced after a Single Mild Traumatic Brain Injury – A Prospective Cohort Study in Collegiate Hockey Players

Impact-related mild traumatic brain injuries (mTBI) are a major public health concern, and remain as one of the most poorly understood injuries in the field of neuroscience. Currently, the diagnosis and management of such injuries are based largely on patient-reported symptoms. An improved understanding of the underlying pathophysiology of mTBI is urgently needed in order to develop better diagnostic and management protocols. Specifically, dynamic post-injury changes to the myelin sheath in the human brain have not been examined, despite ‘compromised white matter integrity’ often being described as a consequence of mTBI. In this preliminary cohort study, myelin water imaging was used to prospectively evaluate changes in myelin water fraction, derived from the T2 decay signal, in two varsity hockey teams (45 players) over one season of athletic competition. 11 players sustained a concussion during competition, and were scanned at 72 hours, 2 weeks, and 2 months post-injury. Results demonstrated a reduction in myelin water fraction at 2 weeks post-injury in several brain areas relative to preseason scans, including the splenium of the corpus callosum, right posterior thalamic radiation, left superior corona radiata, left superior longitudinal fasciculus, and left posterior limb of the internal capsule. Myelin water fraction recovered to pre-season values by 2 months post-injury. These results may indicate transient myelin disruption following a single mTBI, with subsequent remyelination of affected neurons. Myelin disruption was not apparent in the athletes who did not experience a concussion, despite exposure to repetitive subconcussive trauma over a season of collegiate hockey. These findings may help to explain many of the metabolic and neurological deficits observed clinically following mTBI.     

Do Dietary Trajectories between Infancy and Toddlerhood Influence IQ in Childhood and Adolescence? Results from a Prospective Birth Cohort Study

Objective

We examined whether trajectories of dietary patterns from 6 to 24 months of age are associated with intelligence quotient (IQ) in childhood and adolescence.

Methods

Participants were children enrolled in a prospective UK birth cohort (n = 7652) who had IQ measured at age 8 and/or 15 years. Dietary patterns were previously extracted from questionnaires when children were aged 6, 15 and 24 months using principal component analysis. Dietary trajectories were generated by combining scores on similar dietary patterns across each age, using multilevel mixed models. Associations between dietary trajectories and IQ were examined in generalized linear models with adjustment for potential confounders.

Results

Four dietary pattern trajectories were constructed from 6 to 24 months of age and were named according to foods that made the strongest contribution to trajectory scores; Healthy (characterised by breastfeeding at 6 months, raw fruit and vegetables, cheese and herbs at 15 and 24 months); Discretionary (biscuits, chocolate, crisps at all ages), Traditional (meat, cooked vegetables and puddings at all ages) and, Ready-to-eat (use of ready-prepared baby foods at 6 and 15 months, biscuits, bread and breakfast cereals at 24 months). In fully-adjusted models, a 1 SD change in the Healthy trajectory was weakly associated with higher IQ at age 8 (1.07 (95%CI 0.17, 1.97)) but not 15 years (0.49 (−0.28, 1.26)). Associations between the Discretionary and Traditional trajectories with IQ at 8 and 15 years were as follows; Discretionary; 8 years −0.35(−1.03, 0.33), 15 years −0.73(−1.33, −0.14) Traditional; 8 years −0.19(−0.71, 0.33)15 years −0.41(−0.77, −0.04)). The Ready-to-eat trajectory had no association with IQ at either age (8 years 0.32(−4.31, 4.95), 15 years 1.11(−3.10, 5.33).

Conclusions

The Discretionary and Traditional dietary pattern trajectories from 6 to 24 months of age, over the period when food patterns begin to emerge, are weakly associated with IQ in adolescence.     

Should Prior FIT Results Be Incorporated as an Additional Variable to Estimate Risk of Colorectal Neoplasia? A Prospective Study of 5,813 Screening Colonoscopies

Background

Recent studies showed that previous negative results from faecal immunochemical tests (FITs) for colorectal cancer (CRC) screening was associated with lower risk of advanced neoplasia (AN). We evaluated whether prior FIT results should be included to estimate the risk of AN in 2008–2012.

Methods

A community-based screening practice recruited 5,813 asymptomatic residents aged 50 to 70 years in Hong Kong for CRC screening. We included study participants who had (1). positive FIT with subsequent colonoscopy workup (FIT+ group; n = 356); (2). negative FIT in three consecutive years and received a colonoscopy (FIT- group; n = 857); (3). received colonoscopy without FIT (colonoscopy group; n = 473); and (4). received both colonoscopy and FIT at the same time (combined group; n = 4,127). One binary logistic regression model evaluated whether prior FIT results were associated with colonoscopy findings of AN.

Results

The proportion of participants having AN/CRC was 18.0% (FIT+), 5.5% (FIT-), 8.0% (colonoscopy group), and 4.3% (combined group), respectively. When compared with the colonoscopy group, those in the FIT- group were not significantly more or less likely to have AN/CRC (AOR  = 0.77, 95% C.I. = 0.51 to 1.18, p  = 0.230). Having one (AOR = 0.73, 95% C.I. 0.48–1.12, p = 0.151) or three consecutive negative FIT result (AOR = 0.98, 95% C.I. 0.60–1.62, p = 0.944) were not associated with lower risks of AN/CRC. Subjects in the FIT+ group was 3.32-fold (95% C.I. 2.07 to 5.32, p<0.001) more likely to have AN/CRC.

Conclusions

These findings indicated that subjects with negative FIT findings could be risk stratified similarly as those who had not previously received FIT.     

Is “Appearing Chronically Ill” a Sign of Poor Health? A Study of Diagnostic Accuracy

Objective

To determine the sensitivity and specificity of a physician’s assessment that a patient “appears chronically ill” for the detection of poor health status.

Methods

The health status of 126 adult outpatients was determined using the 12-Item Short Form Health Survey (SF-12). Physician participants (n = 111 residents and faculty) viewed photographs of each patient participant and assessed whether or not the patient appeared chronically ill. For the entire group of physicians, the median sensitivity and specificity of “appearing chronically ill” for the detection of poor health status (defined as SF-12 physical health score below age group norms by at least 1 SD) were calculated. The study took place from February 2009 to January 2011.

Results

Forty-two participants (33%) had an SF-12 physical health score ≥1 SD below age group norms, and 22 (18%) had a score ≥2 SD below age group norms. When poor health status was defined as an SF-12 physical score ≥1 SD below age group norms, the median sensitivity was 38.1% (IQR 28.6–47.6%), specificity 78.6% (IQR 69.0–84.0%), positive likelihood ratio 1.64 (IQR 1.42–2.15), and negative likelihood ratio 0.82 (IQR 0.74–0.87). For an SF-12 physical score ≥2 SD below age group norms, the median sensitivity was 45.5% (IQR 36.4–54.5%), specificity 76.9% (IQR 66.3–83.7%), positive likelihood ratio 1.77 (IQR 1.49–2.25), and negative likelihood ratio 0.75 (IQR 0.66–0.86).

Conclusions

Our study suggests that a physician’s assessment that a patient “appears chronically ill” has poor sensitivity and modest specificity for the detection of poor health status in adult outpatients. The associated likelihood ratios indicate that this assessment may have limited diagnostic value.     

Is Sonic Hedgehog Involved in Human Fracture Healing? - A Prospective Study on Local and Systemic Concentrations of SHH

Introduction

Sonic Hedgehog (SHH) is a new signalling pathway in bone repair. Evidence exist that SHH pathway plays a significant role in vasculogenesis and limb development during embryogenesis. Some in vitro and animal studies has already proven its potential for bone regeneration. However, no data on the role of SHH in the human fracture healing have been published so far.

Methods

Seventy-five patients with long bone fractures were included into the study and divided in 2 groups. First group contained 69 patients with normal fracture healing. Four patients with impaired fracture healing formed the second group. 34 volunteers donated blood samples as control. Serum samples were collected over a period of 1 year following a standardized time schedule. In addition, SHH levels were measured in fracture haematoma and serum of 16 patients with bone fractures.

Results

Fracture haematoma and patients serum both contained lower SHH concentrations compared to control serum. The comparison between the patients'' serum SHH level and the control serum revealed lower levels for the patients at all measurement time points. Significantly lower concentrations were observed at weeks 1 and 2 after fracture. SHH levels were slightly decreased in patients with impaired fracture healing without statistical significance.

Conclusion

This is the first study to report local and systemic concentration of SHH in human fracture healing and SHH serum levels in healthy adults. A significant reduction of the SHH levels during the inflammatory phase of fracture healing was found. SHH concentrations in fracture haematoma and serum were lower than the concentration in control serum for the rest of the healing period. Our findings indicate that there is no relevant involvement of SHH in human fracture healing. Fracture repair process seem to reduce the SHH level in human. Further studies are definitely needed to clarify the underlying mechanisms.     

Can Honey Bees Learn the Removal of a Stimulus as a Conditioning Cue?

Experiments investigated a Pavlovian conditioning situation where the presence and absence of the stimulus are reversed temporally with respect to the presentation of a reward. Instead of a conditioned stimulus (e.g. odor) signaling the presence of a reward, the stimulus (e.g. odor) is present in the environment except just prior to the presence of the reward. Thus, the absence of the stimulus, or offset of the stimulus (e.g. absence of odor), serves as a conditioned stimulus and is the reward cue. Honey bees (Apis mellifera) were used as a model invertebrate system, and the proboscis‐conditioning paradigm was used as the test procedure. Using both simple Pavlovian conditioning and discrimination‐learning protocols, animals learned to associate the onset of an odor as conditioned stimuli when paired with a sucrose reward. They could also learn to associate the onset of a puff of air with a sucrose reward. However, bees could not associate the offset of an order stimulus with the presentation of a sucrose reward in either a simple conditioning or a discrimination‐learning situation. These results support the model that a very different cognitive architecture is used by invertebrates to deal with certain environmental situations, including signaled avoidance.