Clinical and biological progress over 50 years in Rett syndrome

In the 50 years since Andreas Rett first described the syndrome that came to bear his name, and is now known to be caused by a mutation in the methyl-CpG-binding protein 2 (MECP2) gene, a compelling blend of astute clinical observations and clinical and laboratory research has substantially enhanced our understanding of this rare disorder. Here, we document the contributions of the early pioneers in Rett syndrome (RTT) research, and describe the evolution of knowledge in terms of diagnostic criteria, clinical variation, and the interplay with other Rett-related disorders. We provide a synthesis of what is known about the neurobiology of MeCP2, considering the lessons learned from both cell and animal models, and how they might inform future clinical trials. With a focus on the core criteria, we examine the relationships between genotype and clinical severity. We review current knowledge about the many comorbidities that occur in RTT, and how genotype may modify their presentation. We also acknowledge the important drivers that are accelerating this research programme, including the roles of research infrastructure, international collaboration and advocacy groups. Finally, we highlight the major milestones since 1966, and what they mean for the day-to-day lives of individuals with RTT and their families

Comparative efficacy of antibiotics for the treatment of acute bacterial skin and skin structure infections (ABSSSI): a systematic review and network meta-analysis

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