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2.  Frequency and reasons for outcome reporting bias in clinical trials: interviews with trialists 
Objectives To provide information on the frequency and reasons for outcome reporting bias in clinical trials.
Design Trial protocols were compared with subsequent publication(s) to identify any discrepancies in the outcomes reported, and telephone interviews were conducted with the respective trialists to investigate more extensively the reporting of the research and the issue of unreported outcomes.
Participants Chief investigators, or lead or coauthors of trials, were identified from two sources: trials published since 2002 covered in Cochrane systematic reviews where at least one trial analysed was suspected of being at risk of outcome reporting bias (issue 4, 2006; issue 1, 2007, and issue 2, 2007 of the Cochrane library); and a random sample of trial reports indexed on PubMed between August 2007 and July 2008.
Setting Australia, Canada, Germany, the Netherlands, New Zealand, the United Kingdom, and the United States.
Main outcome measures Frequency of incomplete outcome reporting—signified by outcomes that were specified in a trial’s protocol but not fully reported in subsequent publications—and trialists’ reasons for incomplete reporting of outcomes.
Results 268 trials were identified for inclusion (183 from the cohort of Cochrane systematic reviews and 85 from PubMed). Initially, 161 respective investigators responded to our requests for interview, 130 (81%) of whom agreed to be interviewed. However, failure to achieve subsequent contact, obtain a copy of the study protocol, or both meant that final interviews were conducted with 59 (37%) of the 161 trialists. Sixteen trial investigators failed to report analysed outcomes at the time of the primary publication, 17 trialists collected outcome data that were subsequently not analysed, and five trialists did not measure a prespecified outcome over the course of the trial. In almost all trials in which prespecified outcomes had been analysed but not reported (15/16, 94%), this under-reporting resulted in bias. In nearly a quarter of trials in which prespecified outcomes had been measured but not analysed (4/17, 24%), the “direction” of the main findings influenced the investigators’ decision not to analyse the remaining data collected. In 14 (67%) of the 21 randomly selected PubMed trials, there was at least one unreported efficacy or harm outcome. More than a quarter (6/21, 29%) of these trials were found to have displayed outcome reporting bias.
Conclusion The prevalence of incomplete outcome reporting is high. Trialists seemed generally unaware of the implications for the evidence base of not reporting all outcomes and protocol changes. A general lack of consensus regarding the choice of outcomes in particular clinical settings was evident and affects trial design, conduct, analysis, and reporting.
PMCID: PMC3016816  PMID: 21212122
3.  VP35 Knockdown Inhibits Ebola Virus Amplification and Protects against Lethal Infection in Mice 
Phosphorodiamidate morpholino oligomers (PMO) are a class of uncharged single-stranded DNA analogs modified such that each subunit includes a phosphorodiamidate linkage and morpholine ring. PMO antisense agents have been reported to effectively interfere with the replication of several positive-strand RNA viruses in cell culture. The filoviruses, Marburg virus and Ebola virus (EBOV), are negative-strand RNA viruses that cause up to 90% lethality in human outbreaks. There is currently no commercially available vaccine or efficacious therapeutic for any filovirus. In this study, PMO conjugated to arginine-rich cell-penetrating peptide (P-PMO) and nonconjugated PMO were assayed for the ability to inhibit EBOV infection in cell culture and in a mouse model of lethal EBOV infection. A 22-mer P-PMO designed to base pair with the translation start site region of EBOV VP35 positive-sense RNA generated sequence-specific and time- and dose-dependent inhibition of EBOV amplification in cell culture. The same oligomer provided complete protection to mice when administered before or after an otherwise lethal infection of EBOV. A corresponding nonconjugated PMO, as well as nonconjugated truncated versions of 16 and 19 base residues, provided length-dependent protection to mice when administered prophylactically. Together, these data suggest that antisense PMO and P-PMO have the potential to control EBOV infection and are promising therapeutic candidates.
PMCID: PMC1426423  PMID: 16495261
4.  Syrian hamster dermal cell immortalization is not enhanced by power line frequency electromagnetic field exposure 
British Journal of Cancer  1999;81(3):377-380.
Several epidemiological studies have suggested associations between exposure to residential power line frequency electromagnetic fields and childhood leukaemia, and between occupational exposure and adult leukaemia. A variety of in vitro studies have provided limited supporting evidence for the role of such exposures in cancer induction in the form of acknowledged cellular end points, such as enhanced mutation rate and cell proliferation, though the former is seen only with extremely high flux density exposure or with co-exposure to ionizing radiation. However, in vitro experiments on a scale large enough to detect rare cancer-initiating events, such as primary cell immortalization following residential level exposures, have not thus far been reported. In this study, large cultures of primary Syrian hamster dermal cells were continuously exposed to power line frequency electromagnetic fields of 10 100 and 1000 μT for 60 h, with and without prior exposure to a threshold (1.5 Gy), or sub-threshold (0.5 Gy), immortalizing dose of ionizing radiation. Electromagnetic field exposure alone did not immortalize these cells at a detectable frequency (≥ 1 × 10−7); furthermore, such exposure did not enhance the frequency of ionizing radiation-induced immortalization. © 1999 Cancer Research Campaign
PMCID: PMC2362933  PMID: 10507759
electromagnetic fields; immortalization; mammalian cells
5.  Immunopathogenesis of Libman-Sacks endocarditis. Assessment by light and immunofluorescent microscopy in two patients. 
Annals of the Rheumatic Diseases  1977;36(6):508-516.
The possible contribution of immunological mechanisms in the development of Libman-Sacks endocarditis was studied in 2 patients with systemic lupus erythematosus who underwent aortic valve replacement. Sections of verrucous lesions, stained with haematoxylin and eosin, showed three apparently distinct zones: an outer exudative zone of fibrin, nuclear debris, and haematoxylin-stained bodies; a middle organizing zone of proliferating capillaries and fibroblasts; and an inner zone of neovascularization which showed distinct, thin-walled junctional vessels. The striking finding was the apparently selective deposition of immunoglobulins and complement identified by direct immunofluorescence, within the walls of the small junctional vessels of the zone of neovascularization. We suggest that the observed immune deposits are immune complexes and that circulating immune complexes may play a critical role in the growth and proliferation of the verrucous lesion.
PMCID: PMC1000155  PMID: 339850
6.  Melatonin for sleep problems in children with neurodevelopmental disorders: randomised double masked placebo controlled trial 
Objective To assess the effectiveness and safety of melatonin in treating severe sleep problems in children with neurodevelopmental disorders.
Design 12 week double masked randomised placebo controlled phase III trial.
Setting 19 hospitals across England and Wales.
Participants 146 children aged 3 years to 15 years 8 months were randomised. They had a range of neurological and developmental disorders and a severe sleep problem that had not responded to a standardised sleep behaviour advice booklet provided to parents four to six weeks before randomisation. A sleep problem was defined as the child not falling asleep within one hour of lights out or having less than six hours’ continuous sleep.
Interventions Immediate release melatonin or matching placebo capsules administered 45 minutes before the child’s bedtime for a period of 12 weeks. All children started with a 0.5 mg capsule, which was increased through 2 mg, 6 mg, and 12 mg depending on their response to treatment.
Main outcome measures Total sleep time at night after 12 weeks adjusted for baseline recorded in sleep diaries completed by the parent. Secondary outcomes included sleep onset latency, assessments of child behaviour, family functioning, and adverse events. Sleep was measured with diaries and actigraphy.
Results Melatonin increased total sleep time by 22.4 minutes (95% confidence interval 0.5 to 44.3 minutes) measured by sleep diaries (n=110) and 13.3 (−15.5 to 42.2) measured by actigraphy (n=59). Melatonin reduced sleep onset latency measured by sleep diaries (−37.5 minutes, −55.3 to −19.7 minutes) and actigraphy (−45.3 minutes, −68.8 to −21.9 minutes) and was most effective for children with the longest sleep latency (P=0.009). Melatonin was associated with earlier waking times than placebo (29.9 minutes, 13.6 to 46.3 minutes). Child behaviour and family functioning outcomes showed some improvement and favoured use of melatonin. Adverse events were mild and similar between the two groups.
Conclusions Children gained little additional sleep on melatonin; though they fell asleep significantly faster, waking times became earlier. Child behaviour and family functioning outcomes did not significantly improve. Melatonin was tolerable over this three month period. Comparisons with slow release melatonin preparations or melatonin analogues are required.
Trial registration ISRCT No 05534585.
PMCID: PMC3489506  PMID: 23129488

Results 1-9 (9)