Multidrug resistant pulmonary tuberculosis treatment regimens and patient outcomes: an individual patient data meta-analysis of 9,153 patients.

Treatment of multidrug resistant tuberculosis (MDR-TB) is lengthy, toxic, expensive, and has generally poor outcomes. We undertook an individual patient data meta-analysis to assess the impact on outcomes of the type, number, and duration of drugs used to treat MDR-TB

Heterogeneous clinical phenotypes and cerebral malformations reflected by rotatin cellular dynamics

Recessive mutations in RTTN, encoding the protein rotatin, were originally identified as cause of polymicrogyria, a cortical malformation. With time, a wide variety of other brain malformations has been ascribed to RTTN mutations, including primary microcephaly. Rotatin is a centrosomal protein possibly involved in centriolar elongation and ciliogenesis. However, the function of rotatin in brain development is largely unknown and the molecular disease mechanism underlying cortical malformations has not yet been elucidated. We performed both clinical and cell biological studies, aimed at clarifying rotatin function and pathogenesis. Review of the 23 published and five unpublished clinical cases and genomic mutations, including the effect of novel deep intronic pathogenic mutations on RTTN transcripts, allowed us to extrapolate the core phenotype, consisting of intellectual disability, short stature, microcephaly, lissencephaly, periventricular heterotopia, polymicrogyria and other malformations. We show that the severity of the phenotype is related to residual function of the protein, not only the level of mRNA expression. Skin fibroblasts from eight affected individuals were studied by high resolution immunomicroscopy and flow cytometry, in parallel with in vitro expression of RTTN in HEK293T cells. We demonstrate that rotatin regulates different phases of the cell cycle and is mislocalized in affected individuals. Mutant cells showed consistent and severe mitotic failure with centrosome amplification and multipolar spindle formation, leading to aneuploidy and apoptosis, which could relate to depletion of neuronal progenitors often observed in microcephaly. We confirmed the role of rotatin in functional and structural maintenance of primary cilia and determined that the protein localized not only to the basal body, but also to the axoneme, proving the functional interconnectivity between ciliogenesis and cell cycle progression. Proteomics analysis of both native and exogenous rotatin uncovered that rotatin interacts with the neuronal (non-muscle) myosin heavy chain subunits, motors of nucleokinesis during neuronal migration, and in human induced pluripotent stem cell-derived bipolar mature neurons rotatin localizes at the centrosome in the leading edge. This illustrates the role of rotatin in neuronal migration. These different functions of rotatin explain why RTTN mutations can lead to heterogeneous cerebral malformations, both related to proliferation and migration defects.Genetics of disease, diagnosis and treatmen

Treatment Outcomes of Patients With Multidrug-Resistant and Extensively Drug-Resistant Tuberculosis According to Drug Susceptibility Testing to First- and Second-line Drugs: An Individual Patient Data Meta-analysis

The clinical validity of drug susceptibility testing (DST) for pyrazinamide, ethambutol, and second-line antituberculosis drugs is uncertain. In an individual patient data meta-analysis of 8955 patients with confirmed multidrug-resistant tuberculosis, DST results for these drugs were associated with treatment outcome

No evidence for the effectiveness of bracing in patients with thoracolumbar fractures

Background and purpose The use of braces is widespread in patients with thoracolumbar fractures. The effectiveness of bracing, however, is controversial. We sought evidence for the effect of bracing in patients with traumatic thoracolumbar fractures based on outcome and length of hospital stay (LOS). Furthermore, we evaluated the incidence of complications of bracing. Methods An electronic search strategy with extensive MeSH headings was used in various databases to identify studies that compared bracing and non-bracing therapies. Two reviewers independently selected systematic reviews, randomized controlled trials (RCTs), controlled clinical trials, and observational studies, and both assessed the methodological quality and extracted the data. Results No systematic reviews or RCTs were found. 7 retrospective studies were included. None of these studies showed an effect of bracing. Because of poor methodological quality, no best-evidence synthesis could be performed. One observational study was selected in which a complication of bracing was reported. Interpretation In the present literature, there is no evidence for the effectiveness of bracing in patients with traumatic thoracolumbar fractures. The lack of high-quality studies prevents relevant conclusions from being draw

Treatment and outcomes in children with multidrug-resistant tuberculosis: a systematic review and individual patient data meta-analysis.

CAPRISA, 2018.Abstract available in pdf

Dutch evidence-based guidelines for amputation and prosthetics of the lower extremity:Rehabilitation process and prosthetics. Part 2

Background: A structured, multidisciplinary approach in the rehabilitation process after amputation is needed that includes a greater focus on the involvement of both (para)medics and prosthetists. There is considerable variation in prosthetic prescription concerning the moment of initial prosthesis fitting and the use of replacement parts. Objectives: To produce an evidence-based guideline for the amputation and prosthetics of the lower extremities. This guideline provides recommendations in support of daily practice and is based on the results of scientific research and further discussions focussed on establishing good medical practice. Part 2 focuses on rehabilitation process and prosthetics. Study design: Systematic literature design. Methods: Literature search in five databases and quality assessment on the basis of evidence-based guideline development. Results: An evidence-based multidisciplinary guideline on amputation and prosthetics of the lower extremity. Conclusion: The best care (in general) for patients undergoing amputation of a lower extremity is presented and discussed. This part of the guideline provides recommendations for treatment and reintegration of patients undergoing amputation of a lower extremity and can be used to provide patient information. Clinical relevance This guideline provides recommendations in support of daily practice and is based on the results of scientific research and further discussions focussed on establishing good medical practice

Dutch evidence-based guidelines for amputation and prosthetics of the lower extremity:Amputation surgery and postoperative management. Part 1

BACKGROUND: Surgeons still use a range of criteria to determine whether amputation is indicated. In addition, there is considerable debate regarding immediate postoperative management, especially concerning the use of 'immediate/delayed fitting' versus conservative elastic bandaging.OBJECTIVES: To produce an evidence-based guideline for the amputation and prosthetics of the lower extremities. This guideline provides recommendations in support of daily practice and is based on the results of scientific research and further discussions focussed on establishing good medical practice. Part 1 focuses on amputation surgery and postoperative management.STUDY DESIGN: Systematic literature design.METHODS: Literature search in five databases. Quality assessment on the basis of evidence-based guideline development.RESULTS: An evidence-based multidisciplinary guideline on amputation and prosthetics of the lower extremity.CONCLUSION: The best care (in general) for patients undergoing amputation of a lower extremity is presented and discussed. This part of the guideline provides recommendations for diagnosis, referral, assessment, and undergoing amputation of a lower extremity and can be used to provide patient information.CLINICAL RELEVANCE: This guideline provides recommendations in support of daily practice and is based on the results of scientific research and further discussions focussed on establishing good medical practice.Geriatrics in primary car