Treatment Outcomes of Multidrug-Resistant Tuberculosis: A Systematic Review and Meta-Analysis

BACKGROUND:Treatment outcomes for multidrug-resistant Mycobacterium Tuberculosis (MDRTB) are generally poor compared to drug sensitive disease. We sought to estimate treatment outcomes and identify risk factors associated with poor outcomes in patients with MDRTB. METHODOLOGY/PRINCIPAL FINDINGS:We performed a systematic search (to December 2008) to identify trials describing outcomes of patients treated for MDRTB. We pooled appropriate data to estimate WHO-defined outcomes at the end of treatment and follow-up. Where appropriate, pooled covariates were analyzed to identify factors associated with worse outcomes. Among articles identified, 36 met our inclusion criteria, representing 31 treatment programmes from 21 countries. In a pooled analysis, 62% [95% CI 57-67] of patients had successful outcomes, while 13% [9]-[17] defaulted, 11% [9]-[13] died, and 2% [1]-[4] were transferred out. Factors associated with worse outcome included male gender 0.61 (OR for successful outcome) [0.46-0.82], alcohol abuse 0.49 [0.39-0.63], low BMI 0.41[0.23-0.72], smear positivity at diagnosis 0.53 [0.31-0.91], fluoroquinolone resistance 0.45 [0.22-0.91] and the presence of an XDR resistance pattern 0.57 [0.41-0.80]. Factors associated with successful outcome were surgical intervention 1.91 [1.44-2.53], no previous treatment 1.42 [1.05-1.94], and fluoroquinolone use 2.20 [1.19-4.09]. CONCLUSIONS/SIGNIFICANCE:We have identified several factors associated with poor outcomes where interventions may be targeted. In addition, we have identified high rates of default, which likely contributes to the development and spread of MDRTB

Characterization of bovine embryos cultured under conditions appropriate for sustaining human naïve pluripotency.

In mammalian preimplantation development, pluripotent cells are set aside from cells that contribute to extra-embryonic tissues. Although the pluripotent cell population of mouse and human embryos can be cultured as embryonic stem cells, little is known about the pathways involved in formation of a bovine pluripotent cell population, nor how to maintain these cells in vitro. The objective of this study was to determine the transcriptomic profile related to bovine pluripotency. Therefore, in vitro derived embryos were cultured in various culture media that recently have been reported capable of maintaining the naïve pluripotent state of human embryonic cells. Gene expression profiles of embryos cultured in these media were compared using microarray analysis and quantitative RT-PCR. Compared to standard culture conditions, embryo culture in 'naïve' media reduced mRNA expression levels of the key pluripotency markers NANOG and POU5F1. A relatively high percentage of genes with differential expression levels were located on the X-chromosome. In addition, reduced XIST expression was detected in embryos cultured in naïve media and female embryos contained fewer cells with H3K27me3 foci, indicating a delay in X-chromosome inactivation. Whole embryos cultured in one of the media, 5iLA, could be maintained until 23 days post fertilization. Together these data indicate that 'naïve' conditions do not lead to altered expression of known genes involved in pluripotency. Interestingly, X-chromosome inactivation and development of bovine embryos were dependent on the culture conditions

Pathogenic Huntingtin Repeat Expansions in Patients with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis.

We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40-64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington's disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

Efficacy and Safety of Dabigatran, Rivaroxaban and Warfarin for Stroke Prevention in patients with Atrial Fibrillation: The Hong Kong Atrial Fibrillation Project.

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Stroke prevention using dabigatran in elderly Chinese patients with atrial fibrillation

BACKGROUND: Little is known about the clinical benefit of a non-vitamin K antagonist oral anticoagulant compared with warfarin in elderly Chinese patients with atrial fibrillation (AF). OBJECTIVE: The purpose of this study was to evaluate the clinical benefit of dabigatran in elderly (age >/=80 years) Chinese patients with nonvalvular AF with regard to the risk of ischemic stroke and intracranial hemorrhage (ICH). METHODS: This was an observational study. RESULTS: We studied 571 Chinese patients (mean age 84.8 +/- 4.0 years; 58.1% women) with nonvalvular AF. The primary outcome was hospital admission for ischemic stroke, and the secondary outcome was admission for ICH. The mean CHA2DS2-VASc (congestive heart failure [1 point], hypertension [1 point], age 65-74 years [1 point] and age >/=75 years [2 points], diabetes mellitus [1 point], prior stroke or transient ischemic attack [2 points], vascular disease [1 point], sex category [female] [1 point]) and HAS-BLED (hypertension [1 point], abnormal renal/liver function [1 point], stroke [1 point], bleeding history [1 point] or predisposition [1 point], labile international normalized ratio [1 point], elderly [age >65 years] [1 point], drugs/alcohol concomitantly [1 point]) scores were 4.8 +/- 1.6 and 2.4 +/- 0.8, respectively. Of 571 patients, 129 (22.6%) were taking dabigatran 110 mg twice daily and the remaining were on warfarin. After a mean follow-up of 2.6 years (a total of 1471 patient-years), ischemic stroke occurred in 83 patients on warfarin (6.9% per year) compared with 4 patients on dabigatran (1.4% per year) (hazard ratio 0.22; 95% confidence interval 0.23-0.67). There were 8 incidences of ICH: 7 in patients on warfarin (0.59% per year) and 1 patient on dabigatran (0.35% per year). Dabigatran was associated with a substantially lower ischemic stroke risk (1.4% per year vs 5.4% per year) and similar ICH risk (0.35% per year vs 0.36% per year) as compared with warfarin with time in therapeutic range (TTR) >/=55%. CONCLUSION: In elderly Chinese patients with AF, this study suggested that dabigatran achieved superior stroke risk reduction and similar risk of ICH compared with warfarin with TTR >/=55%. Dabigatran may be preferable to warfarin in elderly patients with AF for stroke prevention, particularly in those with poor TTR