The mechanisms leading to latency and reactivation of human tuberculosis are still unclear, mainly due to the lack of standardized animal models for latent mycobacterial infection. In this longitudinal study of the progression of a mycobacterial disease in adult zebrafish, we show that an experimental intraperitoneal infection with a low dose (∼35 bacteria) of Mycobacterium marinum, results in the development of a latent disease in most individuals. The infection is characterized by limited mortality (25%), stable bacterial loads 4 weeks following infection and constant numbers of highly organized granulomas in few target organs. The majority of bacteria are dormant during a latent mycobacterial infection in zebrafish, and can be activated by resuscitation promoting factor ex vivo. In 5–10% of tuberculosis cases in humans, the disease is reactivated usually as a consequence of immune suppression. In our model, we are able to show that reactivation can be efficiently induced in infected zebrafish by γ-irradiation that transiently depletes granulo/monocyte and lymphocyte pools, as determined by flow cytometry. This immunosuppression causes reactivation of the dormant mycobacterial population and a rapid outgrowth of bacteria, leading to 88% mortality in four weeks. In this study, the adult zebrafish presents itself as a unique non-mammalian vertebrate model for studying the development of latency, regulation of mycobacterial dormancy, as well as reactivation of latent or subclinical tuberculosis. The possibilities for screening for host and pathogen factors affecting the disease progression, and identifying novel therapeutic agents and vaccine targets make this established model especially attractive.

There is no consensus between HTA groups on the preferred appraisal tool. Reviewers should select from a suite of tools on the basis of the design of studies included in their review.

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Background The objective of this study was to assess the durability of response of dolutegravir (DTG) as an antiretroviral core agent by comparing its efficacy and safety with other recommended or commonly used core agents up to 96-weeks (W96). Methods A previously published systematic review was updated to identify phase 3/4 randomised controlled trials (RCTs) of core agents in treatment-naïve HIV-1 patients. Efficacy [virologic suppression (VS), CD4+ cell change from baseline] and safety [adverse events [AEs], discontinuations, drug-related AEs [DRAEs]] were analysed at W96 using Bayesian network meta-analysis (NMA) adjusting for nucleoside/nucleotide reverse transcriptase inhibitors' (NRTIs') backbone. Subgroups of patients with VL > 100,000 copies/mL or CD4+ ≤ 200 cells/μL at baseline were analysed separately. Results The NMA included 20 studies reporting data at W96. A higher proportion of patients receiving DTG achieved VS compared to those on protease inhibitors [PI:Range:8.7%(CrI:3.1,16.0)-19.9%(10.8,30.5)], efavirenz [EFV:6.9%(1.3,10.8)] and cobicistat-boosted elvitegravir [EVG/c:8.2%(0.2,17.4)], and similar but numerically higher compared to rilpivirine [RPV:5.0%(− 2.8,12.5)], raltegravir [RAL:2.9%(− 1.6,7.7)] and bictegravir [BIC:2.7%(− 2.7,10.6)]. The probability that more patients on DTG would achieve VS at W96 compared to any other core agent was greater than 80%. A higher proportion of patients on DTG achieved VS compared to PI/rs [Range:33.1%(13.6,50.4)-45.3%(24.1,61.6)] and RAL [16.7%(3.3,31.2)] in patients with VL > 100,000 copies/mL at baseline, and similar VS was achieved in patients with CD4+ ≤ 200 cells/μL at baseline. DTG also achieved greater increase in CD4+ cells from baseline compared to EFV [32.6(10.7,54.7)], ritonavir-boosted darunavir [DRV/r:25.7(3.6,48.1)] and BIC [24.7(1.5,47.7)]. Patients receiving DTG had lower odds of discontinuing therapy by W96 compared to PI/rs, EFV, RAL and EVG/c. Patients on DTG had lower odds of experiencing an adverse event (AE) compared to patients on EFV [odds ratio:0.6(0.3,0.9)], ATV/r [0.4(0.3,0.6)] and LPV/r [0.3(0.2,0.5)]. For patients on DTG, the odds of experiencing a drug-related AE were lower than the odds for patients on EFV [0.3(0.2,0.4)], comparable to patients on RAL [1.1(0.8,1.4)] and higher than those on BIC [1.5(1.1,2.0)]. Conclusion Un-boosted integrase inhibitors had better efficacy and similar safety compared to PI/rs at W96 in treatment-naïve patients with HIV-1, with DTG being among the most efficacious core agent, particularly in patients with baseline VL > 100,000 copies/mL or ≤ 200 CD4+ cells/μL, who can be difficult to treat.

Objective:The objective was to conduct a systematic review and network meta-analysis (NMA) of existing treatments for ABSSSI focusing on the novel lipoglycopeptide oritavancin. Methods:EMBASE, MEDLINE, MEDLINE in Process, CENTRAL (Cochrane), and select conferences were searched for randomized controlled trials investigating antimicrobial agents for the treatment of ABSSSI. NMA was used to estimate the odds ratios of the Test-Of-Cure (TOC) and Early Clinical Response (ECR) outcomes for treatments relative to vancomycin in the ITT populations. Sub-group analyses in MRSA and MSSA populations were conducted for TOC; sensitivity analyses investigated the use of the clinically evaluable (CE) populations and the restriction to trials following the recent FDA guidelines for clinical trials. Results:The systematic review identified 52 trials. The most commonly investigated treatments were vancomycin and linezolid; most trials reported TOC, but not ECR. The posterior mean and 95% credible intervals for odds ratios of TOC for antimicrobial agents relative to vancomycin were: linezolid (1.55; 0.91-2.57), daptomycin (2.18; 0.90-5.42), and oritavancin 1200 mg (1.06; 0.80-1.43). The odds ratio of ECR for oritavancin 1200 mg was 1.02 (0.23-4.33). In the MRSA sub-group the odds ratios relative to vancomycin for TOC were: linezolid (1.55; 0.96-2.46), daptomycin (0.74; 0.13-3.66), and oritavancin 1200 mg (0.94; 0.44-2.02). In the MSSA sub-group they were linezolid (1.36; 0.15-13.34) and oritavancin 1200 mg (0.82; 0.08-7.83). These results were robust to the sensitivity analyses. Conclusions:This NMA provides a unified framework for the comparison of all available antimicrobial agents used in the treatment of ABSSSI and is the first to assess the ECR end-point. The results suggest equivalence of clinical efficacy between vancomycin, daptomycin, linezolid, and novel antimicrobial agents including oritavancin for the treatment of ABSSSI at TOC. The wide uncertainty margins indicate the heterogeneity of the available evidence and the need for further research.

Peer-reviewed publications and conference proceedings are the mainstay of data sources for systematic reviews and network meta-analyses (NMA), but access to informative unpublished data is now becoming commonplace. To explore the usefulness of three types of 'grey' literature-clinical trials registries, clinical study reports and data from regulatory authorities-we conducted four case studies. The reporting of outcome data in peer-reviewed publications, the clinical trials registries and the clinical study reports for two clinical trials-one in melanoma, one in juvenile idiopathic arthritis (JIA)-was examined. In addition, we assessed the value of including unpublished data from the European Medicines Agency (EMA) and US Food and Drug Administration (FDA) in evidence syntheses of hepatitis C virus (HCV) and chronic obstructive pulmonary disease (COPD), respectively. For the clinical trials in melanoma and JIA, we identified outcome parameters on ClinicalTrials.gov additional to those reported in the peer-reviewed publications: subgroup data and additional efficacy end points/extended follow-up, respectively. The clinical study report also provided results for several subgroups unavailable elsewhere. For HCV and COPD, additional outcome data were obtained from the EMA European Public Assessment Report (EPAR) and the FDA, respectively, including data on subgroups and mortality. We conclude that data from these grey literature sources have the potential to influence results of systematic reviews and NMAs, and may thus have implications for healthcare decisions. However, it is important to consider carefully the availability, reliability and consequent usability of these data sources in systematic reviews and NMAs.

Objectives: A common problem in systematic reviews are incomplete data extraction forms resulting in problems attempting evidence synthesis; we rarely have all the data for the endpoints of interest for all studies, and parameters that inform meta-analysis or connect networks are missing. Increased transparency in clinical trial reporting means this problem is slowly disappearing. From January 2015 the European Medicines Agency (EMA) will publish clinical study reports submitted with marketing-authorisation applications for human medicines. MethOds: We identified several data sources outside the primary publication. Standard data sources for systematic reviews of interventions include peer-reviewed publications, conference abstracts and clinical trial registries. Clinical study protocols are often published but are not identifiable through searches in online databases, therefore, to find these, systematic reviewers must visit the journal website. Manufacturer submissions to health regulators are also increasingly made available; these give detailed trial descriptions and results presented are more likely to be comprehensive. Results: In a recent example in Hepatitis-C we utilised several additional data sources in our evidence synthesis. Clinical trial protocols were used to identify definitions of endpoints included and to fulfil aspects of the critical appraisal. Fibrosis stage is an accepted treatment effect modifier in Hepatitis-C; our review therefore collected subgroup data for this. However, this was not readily available in peer-reviewed publications; we thus obtained data from EMA submission documents and UK and German reimbursement submissions. Other examples include a 2013 COPD systematic review which retrieved mortality data from the FDA website for three studies reporting cardiovascular-related death and for one study reporting overall death. cOnclusiOns: Systematic reviewers should be aware of additional data sources that are publically available. Whilst peer-reviewed data is preferential, incorporation of this grey literature into an evidence synthesis could lead to a more informed overview of clinical efficacy and thereby healthcare decision making.Objectives: Assess the potential relationships between Biomarkers of Potential Harm (BOPH), specifically WBC, Apo lipoprotein, C-reactive protein, HDL, LDL, total cholesterol, and biomarkers of cigarette smoke exposure (BOE), specifically serum cotinine, creatinine adjusted urinary total NNAL and 1-hydroxypyrene (1-OHP), using National Health and Nutrition Examination Survey (NHANES) data from 2007 till 2012. Secondary objective was to assess the relationship between BOPH and smoking status (past, current or never), and cigarette per day (CPD) use in current smokers. MethOds: Data were obtained from NHANES 2007 to 2012. The study sample included 17,293 respondents age 21 years and above who had answered questions on cigarette smoking and had complete laboratory values for their biomarkers measurement. The population was categorized as current (CS), past...

In an attempt to keep pace with the increasing number of trials being conducted each year, journals make articles available as E-publications ahead of print. E-publications are not available to search through the conventional databases (MEDLINE, EMBASE, CENTRAL) used in systematic reviews, but are searchable using PubMed. We used a search syntax designed to exclusively identify E-publications in PubMed to assess the importance of searching for E-publications in systematic reviews. Two case studies were conducted: updating de novo systematic reviews in particularly active areas of current research, type 2 diabetes mellitus and advanced melanoma. A search for E-publications was conducted concurrently to the conventional systematic reviews. Network diagrams were constructed with and without the results of the E-publications search to demonstrate the potential impact E-publications could have on any evidence synthesis. The advanced melanoma systematic review conducted in conventional databases identified nine studies. The E-publication search identified three additional studies reporting information for three new interventions and additional information for five interventions. Critically, if an evidence synthesis were to be conducted the identification of one of the pivotal nivolumab trials, CheckMate 067, (ipilimumab, nivolumab and ipilimumab+nivolumab) allows the connection of an otherwise disconnected evidence network. The diabetes systematic review conducted in conventional databases identified 28 studies. The E-publication search identified one additional study including an extra intervention; if evidence synthesis were feasible, the E-publication would add a loop to the evidence network which could influence analysis results. Failure to search for E-publications ahead of print may mean that evidence syntheses do not take into account all the data publicly available at the time of review.