Genital tract lesions in sexually mature Göttingen minipigs during the initial stages of experimental vaginal infection with <em>Chlamydia trachomatis </em>serovar D

BACKGROUND: Chlamydia is one of the most common sexually transmitted diseases in humans worldwide, causing chronic lesions in the reproductive tract. Due to its often asymptomatic course, there is limited knowledge about the initial changes in the genital tract following infection. This study employs a novel sexually mature minipig model to investigate the initial histopathological changes following vaginal infection with Chlamydia trachomatis serovar D. RESULTS: A vaginal inoculation resulted in an infection primarily affecting the lower genital tract. The histopathological changes were characterized by a subepithelial inflammation consisting of neutrophils and mononuclear cells, followed by an increase in the number of plasma cells within the sub-epithelial stroma of the vagina. Detection of Chlamydia was associated with expression of cyclooxygenase-2 and interleukin-8 by superficial epithelial cells. The infection was self-limiting, with a duration of 7 days. CONCLUSION: Neutrophils, plasma cells and IL-8 have been linked with Chlamydia genital infection of unknown duration in human patients. In this study, we observe a similar pattern of local immune response/inflammation following experimental inoculation suggesting this porcine model shows promise as a model for translational chlamydia research. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12917-016-0793-6) contains supplementary material, which is available to authorized users

The statistical analysis of a clinical trial when a protocol amendment changed the inclusion criteria

Abstract Background Sometimes, protocol amendments that change the inclusion and exclusion criteria are required in clinical trials. Then, the patient populations before and after the amendment may differ. Methods We propose to perform separate statistical tests for the different phases, i.e. for the patients recruited before and after the amendment, and to combine the tests using Fisher's combination test. After a significant combination test a multiple testing procedure can be applied to identify the phase(s) to which a proof of efficacy refers. We assume that the amendment(s) are not based on any type of unblinded data. The proposed method is investigated within a simulation study. Results The proposed combination approach is superior to the 'naïve' strategy to ignore the differences between the phases and pooling the data to perform just one statistical test. This superiority disappears when there are hardly any differences between the two phases. Conclusion When one or more protocol amendments change the inclusion and exclusion criteria, one should realize that the populations may differ. In this case, separate tests for the different phases together with a combination test are a powerful method that can be applied in a variety of settings. The (first) amendment should specify the combination test to be applied in order to combine the different phases.</p

Benefits and harms of annual, biennial, or triennial breast cancer mammography screening for women at average risk of breast cancer : a systematic review for the European Commission Initiative on Breast Cancer (ECIBC)

Background: Although mammography screening is recommended in most European countries, the balance between the benefits and harms of different screening intervals is still a matter of debate. This review informed the European Commission Initiative on Breast Cancer (BC) recommendations. Methods: We searched PubMed, EMBASE, and the Cochrane Library to identify RCTs, observational or modelling studies, comparing desirable (BC deaths averted, QALYs, BC stage, interval cancer) and undesirable (overdiagnosis, false positive related, radiation related) effects from annual, biennial, or triennial mammography screening in women of average risk for BC. We assessed the certainty of the evidence using the GRADE approach. Results: We included one RCT, 13 observational, and 11 modelling studies. In women 50-69, annual compared to biennial screening may have small additional benefits but an important increase in false positive results; triennial compared to biennial screening may have smaller benefits while avoiding some harms. In younger women (aged 45-49), annual compared to biennial screening had a smaller gain in benefits and larger harms, showing a less favourable balance in this age group than in women 50-69. In women 70-74, there were fewer additional harms and similar benefits with shorter screening intervals. The overall certainty of the evidence for each of these comparisons was very low. Conclusions: In women of average BC risk, screening intervals have different trade-offs for each age group. The balance probably favours biennial screening in women 50-69. In younger women, annual screening may have a less favourable balance, while in women aged 70-74 years longer screening intervals may be more favourable

Safety and immunogenicity of the chlamydia vaccine candidate CTH522 adjuvanted with CAF01 liposomes or aluminium hydroxide: a first-in-human, randomised, double-blind, placebo-controlled, phase 1 trial

BACKGROUND: Chlamydia is the most common sexually transmitted bacterial infection worldwide. National screening programmes and antibiotic treatment have failed to decrease incidence, and to date no vaccines against genital chlamydia have been tested in clinical trials. We aimed to assess the safety and immunogenicity, in humans, of a novel chlamydia vaccine based on a recombinant protein subunit (CTH522) in a prime-boost immunisation schedule. METHODS: This phase 1, first-in-human, double-blind, parallel, randomised, placebo-controlled trial was done at Hammersmith Hospital in London, UK, in healthy women aged 19-45 years. Participants were randomly assigned (3:3:1) to three groups: CTH522 adjuvanted with CAF01 liposomes (CTH522:CAF01), CTH522 adjuvanted with aluminium hydroxide (CTH522:AH), or placebo (saline). Participants received three intramuscular injections of 85 μg vaccine (with adjuvant) or placebo to the deltoid region of the arm at 0, 1, and 4 months, followed by two intranasal administrations of 30 μg unadjuvanted vaccine or placebo (one in each nostril) at months 4·5 and 5·0. The primary outcome was safety and the secondary outcome was humoral immunogenicity (anti-CTH522 IgG seroconversion). This study is registered with Clinicaltrials.gov, number NCT02787109. FINDINGS: Between Aug 15, 2016, and Feb 13, 2017, 35 women were randomly assigned (15 to CTH522:CAF01, 15 to CTH522:AH, and five to placebo). 32 (91%) received all five vaccinations and all participants were included in the intention-to-treat analyses. No related serious adverse reactions were reported, and the most frequent adverse events were mild local injection-site reactions, which were reported in all (15 [100%] of 15) participants in the two vaccine groups and in three (60%) of five participants in the placebo group (p=0·0526 for both comparisons). Intranasal vaccination was not associated with a higher frequency of related local reactions (reported in seven [47%] of 15 participants in the active treatment groups vs three [60%] of five in the placebo group; p=1·000). Both CTH522:CAF01 and CTH522:AH induced anti-CTH522 IgG seroconversion in 15 (100%) of 15 participants after five immunisations, whereas no participants in the placebo group seroconverted. CTH522:CAF01 showed accelerated seroconversion, increased IgG titres, an enhanced mucosal antibody profile, and a more consistent cell-mediated immune response profile compared with CTH522:AH. INTERPRETATION: CTH522 adjuvanted with either CAF01 or aluminium hydroxide appears to be safe and well tolerated. Both vaccines were immunogenic, although CTH522:CAF01 had a better immunogenicity profile, holding promise for further clinical development. FUNDING: European Commission and The Innovation Fund Denmark

Assessing potential sources of clustering in individually randomised trials

Recent reviews have shown that while clustering is extremely common in individually randomised trials (for example, clustering within centre, therapist, or surgeon), it is rarely accounted for in the trial analysis. Our aim is to develop a general framework for assessing whether potential sources of clustering must be accounted for in the trial analysis to obtain valid type I error rates (non-ignorable clustering), with a particular focus on individually randomised trials

A systematic review of intravenous gamma globulin for therapy of acute myocarditis

BACKGROUND: Intravenous gamma globulin (IVGG) is commonly used in the management of acute myocarditis. The objective of this study was to systematically review the literature evaluating this practice. METHODS: We conducted a comprehensive search (electronic databases, trials registries, conference proceedings, reference lists, contact with authors) to identify studies evaluating the use of IVGG in adults and children with a clinical or histologically proven diagnosis of myocarditis of possible viral etiology and symptoms of less than six months duration. Two reviewers independently screened the searches, applied inclusion criteria, and graded the evidence. RESULTS: Results were described qualitatively; data were not pooled because only one randomized controlled trial (RCT) with 62 patients was identified. The RCT showed no benefit with respect to cardiac function, functional outcome, or event-free survival. A small, uncontrolled trial (n = 10) showed significant improvement in LVEF from a mean of 24% to 41% 12 months after IVGG in nine survivors. A retrospective cohort study of pediatric patients showed improvement in cardiac function and a trend towards improved survival in patients receiving IVGG (n = 21) versus historic controls (n = 25). Ten case reports and two case series (total n = 21) described improvement in cardiac function after administration of IVGG; two case reports showed no benefit of IVGG. One case of hemolytic anemia was attributed to IVGG. CONCLUSION: There is insufficient data from methodologically strong studies to recommend routine use of IVGG for acute myocarditis. Future randomized studies that take into account the etiology of acute myocarditis will be required to determine the efficacy of IVGG

Oxygen for relief of dyspnoea in mildly- or non-hypoxaemic patients with cancer: a systematic review and meta-analysis

The aim of this study was to determine the efficacy of palliative oxygen for relief of dyspnoea in cancer patients. MEDLINE and EMBASE were searched for randomised controlled trials, comparing oxygen and medical air in cancer patients not qualifying for home oxygen therapy. Abstracts were reviewed and studies were selected using Cochrane methodology. The included studies provided oxygen at rest or during a 6-min walk. The primary outcome was dyspnoea. Standardised mean differences (SMDs) were used to combine scores. Five studies were identified; one was excluded from meta-analysis due to data presentation. Individual patient data were obtained from the authors of the three of the four remaining studies (one each from England, Australia, and the United States). A total of 134 patients were included in the meta-analysis. Oxygen failed to improve dyspnoea in mildly- or non-hypoxaemic cancer patients (SMD=−0.09, 95% confidence interval −0.22 to 0.04; P=0.16). Results were stable to a sensitivity analysis, excluding studies requiring the use of imputed quantities. In this small meta-analysis, oxygen did not provide symptomatic benefit for cancer patients with refractory dyspnoea, who would not normally qualify for home oxygen therapy. Further study of the use of oxygen in this population is warranted given its widespread use

Testing for heterogeneity among the components of a binary composite outcome in a clinical trial

<p>Abstract</p> <p>Background</p> <p>Investigators designing clinical trials often use composite outcomes to overcome many statistical issues. Trialists want to maximize power to show a statistically significant treatment effect and avoid inflation of Type I error rate due to evaluation of multiple individual clinical outcomes. However, if the treatment effect is not similar among the components of this composite outcome, we are left not knowing how to interpret the treatment effect on the composite itself. Given significant heterogeneity among these components, a composite outcome may be judged as being invalid or un-interpretable for estimation of the treatment effect. This paper compares the power of different tests to detect heterogeneity of treatment effect across components of a composite binary outcome.</p> <p>Methods</p> <p>Simulations were done comparing four different models commonly used to analyze correlated binary data. These models included: logistic regression for ignoring correlation, logistic regression weighted by the intra cluster correlation coefficient, population average logistic regression using generalized estimating equations (GEE), and random effects logistic regression.</p> <p>Results</p> <p>We found that the population average model based on generalized estimating equations (GEE) had the greatest power across most scenarios. Adequate power to detect possible composite heterogeneity or variation between treatment effects of individual components of a composite outcome was seen when the power for detecting the main study treatment effect for the composite outcome was also reasonably high.</p> <p>Conclusions</p> <p>It is recommended that authors report tests of composite heterogeneity for composite outcomes and that this accompany the publication of the statistically significant results of the main effect on the composite along with individual components of composite outcomes.</p