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2.
Lancet Respir Med ; 2020 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-32192585

RESUMO

BACKGROUND: Treatment of multidrug-resistant tuberculosis requires long-term therapy with a combination of multiple second-line drugs. These drugs are associated with numerous adverse events that can cause severe morbidity, such as deafness, and in some instances can lead to death. Our aim was to estimate the absolute and relative frequency of adverse events associated with different tuberculosis drugs to provide useful information for clinicians and tuberculosis programmes in selecting optimal treatment regimens. METHODS: We did a meta-analysis using individual-level patient data that were obtained from studies that reported adverse events that resulted in permanent discontinuation of anti-tuberculosis medications. We used a database created for our previous meta-analysis of multidrug-resistant tuberculosis treatment and outcomes, for which we did a systematic review of literature published between Jan 1, 2009, and Aug 31, 2015 (updated April 15, 2016), and requested individual patient-level information from authors. We also considered for this analysis studies contributing patient-level data in response to a public call made by WHO in 2018. Meta-analysis for proportions and arm-based network meta-analysis were done to estimate the incidence of adverse events for each tuberculosis drug. FINDINGS: 58 studies were identified, including 50 studies from the updated individual patient data meta-analysis for multidrug-resistant tuberculosis treatment. 35 of these studies, with 9178 patients, were included in our analysis. Using meta-analysis of proportions, drugs with low risks of adverse event occurrence leading to permanent discontinuation included levofloxacin (1·3% [95% CI 0·3-5·0]), moxifloxacin (2·9% [1·6-5·0]), bedaquiline (1·7% [0·7-4·2]), and clofazimine (1·6% [0·5-5·3]). Relatively high incidence of adverse events leading to permanent discontinuation was seen with three second-line injectable drugs (amikacin: 10·2% [6·3-16·0]; kanamycin: 7·5% [4·6-11·9]; capreomycin: 8·2% [6·3-10·7]), aminosalicylic acid (11·6% [7·1-18·3]), and linezolid (14·1% [9·9-19·6]). Risk of bias in selection of studies was judged to be low because there were no important differences between included and excluded studies. Variability between studies was significant for most outcomes analysed. INTERPRETATION: Fluoroquinolones, clofazimine, and bedaquiline had the lowest incidence of adverse events leading to permanent drug discontinuation, whereas second-line injectable drugs, aminosalicylic acid, and linezolid had the highest incidence. These results suggest that close monitoring of adverse events is important for patients being treated for multidrug-resistant tuberculosis. Our results also underscore the urgent need for safer and better-tolerated drugs to reduce morbidity from treatment itself for patients with multidrug-resistant tuberculosis. FUNDING: Canadian Institutes of Health Research, Centers for Disease Control and Prevention (USA), American Thoracic Society, European Respiratory Society, and Infectious Diseases Society of America.

4.
Sci Rep ; 10(1): 5029, 2020 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-32193444

RESUMO

With the advent of whole genome-sequencing (WGS) studies, family-based designs enable sex-specific analysis approaches that can be applied to only affected individuals; tests using family-based designs are attractive because they are completely robust against the effects of population substructure. These advantages make family-based association tests (FBATs) that use siblings as well as parents especially suited for the analysis of late-onset diseases such as Alzheimer's Disease (AD). However, the application of FBATs to assess sex-specific effects can require additional filtering steps, as sensitivity to sequencing errors is amplified in this type of analysis. Here, we illustrate the implementation of robust analysis approaches and additional filtering steps that can minimize the chances of false positive-findings due to sex-specific sequencing errors. We apply this approach to two family-based AD datasets and identify four novel loci (GRID1, RIOK3, MCPH1, ZBTB7C) showing sex-specific association with AD risk. Following stringent quality control filtering, the strongest candidate is ZBTB7C (Pinter = 1.83 × 10-7), in which the minor allele of rs1944572 confers increased risk for AD in females and protection in males. ZBTB7C encodes the Zinc Finger and BTB Domain Containing 7C, a transcriptional repressor of membrane metalloproteases (MMP). Members of this MMP family were implicated in AD neuropathology.

7.
Infection ; 48(2): 289-293, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31900872

RESUMO

INTRODUCTION: Central nervous system (CNS) tuberculomas are a challenging manifestation of extrapulmonary tuberculosis often leading to neurological complications and post-treatment sequelae. The role of adjunctive corticosteroid treatment is not fully understood. Most guidelines on management of tuberculosis do not distinguish between tuberculous meningitis and CNS tuberculomas in terms of corticosteroid therapy. METHODS: We describe five patients with CNS tuberculomas who required intensified dexamethasone treatment for several months, in two cases up to 18 months. RESULTS: These patients were initially treated with the standard four-drug tuberculosis regimen and adjuvant dexamethasone. Neurological symptoms improved rapidly. However, multiple attempts to reduce or discontinue corticosteroids according to guideline recommendations led to clinical deterioration with generalized seizures or new CNS lesions. Thus, duration of adjunctive corticosteroid therapy was extended eventually leading to clinical cure and resolution of lesions. CONCLUSION: In contrast to tuberculous meningitis, the treatment for CNS tuberculomas appears to require a prolonged administration of corticosteroids. These findings need to be verified in controlled clinical studies.

8.
Genet Epidemiol ; 44(2): 139-147, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31713269

RESUMO

In the analysis of current life science datasets, we often encounter scenarios in which the application of asymptotic theory to hypothesis testing can be problematic. Besides improved asymptotic results, permutation/simulation-based tests are a general approach to address this issue. However, these randomized tests can impose a massive computational burden, for example, in scenarios in which large numbers of statistical tests are computed, and the specified significance level is very small. Stopping rules aim to assess significance with the smallest possible number of draws while controlling the probabilities of errors due to statistical uncertainty. In this communication, we derive a general stopping rule, QUICK-STOP, based on the sequential testing theory that is easy to implement, controls the error probabilities rigorously, and is nearly optimal in terms of expected draws. In a simulation study, we show that our approach outperforms current stopping approaches for general randomized tests by factor 10 and does not impose an additional computational burden. We illustrate our approach by applying our stopping rule to a single-variant analysis of a whole-genome sequencing study for lung function.

9.
Eur Respir J ; 55(3)2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31862767

RESUMO

We sought to compare the effectiveness of two World Health Organization (WHO)-recommended regimens for the treatment of rifampin- or multidrug-resistant (RR/MDR) tuberculosis (TB): a standardised regimen of 9-12 months (the "shorter regimen") and individualised regimens of ≥20 months ("longer regimens").We collected individual patient data from observational studies identified through systematic reviews and a public call for data. We included patients meeting WHO eligibility criteria for the shorter regimen: not previously treated with second-line drugs, and with fluoroquinolone- and second-line injectable agent-susceptible RR/MDR-TB. We used propensity score matched, mixed effects meta-regression to calculate adjusted odds ratios and adjusted risk differences (aRDs) for failure or relapse, death within 12 months of treatment initiation and loss to follow-up.We included 2625 out of 3378 (77.7%) individuals from nine studies of shorter regimens and 2717 out of 13 104 (20.7%) individuals from 53 studies of longer regimens. Treatment success was higher with the shorter regimen than with longer regimens (pooled proportions 80.0% versus 75.3%), due to less loss to follow-up with the former (aRD -0.15, 95% CI -0.17- -0.12). The risk difference for failure or relapse was slightly higher with the shorter regimen overall (aRD 0.02, 95% CI 0-0.05) and greater in magnitude with baseline resistance to pyrazinamide (aRD 0.12, 95% CI 0.07-0.16), prothionamide/ethionamide (aRD 0.07, 95% CI -0.01-0.16) or ethambutol (aRD 0.09, 95% CI 0.04-0.13).In patients meeting WHO criteria for its use, the standardised shorter regimen was associated with substantially less loss to follow-up during treatment compared with individualised longer regimens and with more failure or relapse in the presence of resistance to component medications. Our findings support the need to improve access to reliable drug susceptibility testing.

10.
Internist (Berl) ; 60(11): 1155-1175, 2019 Nov.
Artigo em Alemão | MEDLINE | ID: mdl-31641790

RESUMO

Tuberculosis is a bacterial infectious disease that is usually transmitted by inhalation of droplets containing the bacteria. The World Health Organization (WHO) estimates that approximately 10 million patients were newly diagnosed with tuberculosis in 2017. Rapid diagnosis relies on a combination of imaging and microbiological, molecular, and, rarely, immunological tests. Genotypic methods enable early diagnosis and allow highly accurate prediction of drug resistance. Phenotypic (culture-based) methods are the diagnostic gold standard. Standard management of patients with pan drug-susceptible pulmonary tuberculosis includes a combination of rifampicin, isoniazid, ethambutol and pyrazinamide for 2 months followed by rifampicin and isoniazid for additional 4 months, which leads to cure rates of >80%. With individualized treatment schemes, similar cure rates can be achieved for patients with multidrug-resistant tuberculosis.


Assuntos
Antituberculosos/uso terapêutico , Mycobacterium tuberculosis/isolamento & purificação , Tuberculose Resistente a Múltiplos Medicamentos/diagnóstico , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose/diagnóstico , Tuberculose/tratamento farmacológico , Etambutol/uso terapêutico , Humanos , Isoniazida/uso terapêutico , Pirazinamida/uso terapêutico , Rifampina/uso terapêutico , Tuberculose/microbiologia , Tuberculose Resistente a Múltiplos Medicamentos/microbiologia
11.
Nano Lett ; 19(10): 7287-7292, 2019 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-31525062

RESUMO

The ability to tailor waveguide cavities and couple them with quantum emitters has developed a realm of nanophotonics encompassing, for example, highly efficient single photon generation or the control of giant photon nonlinearities. Opening new grounds by pushing the interaction of the waveguide cavity and integrated emitters further into the deep subwavelength regime, however, has been complicated by nonradiative losses due to the increasing importance of surface defects when decreasing cavity dimensions. Here, we show efficient suppression of nonradiative recombination for thin waveguide cavities using core-shell semiconductor nanowires. We experimentally reveal the advantages of such nanowires, which host mobile emitters, that is, free excitons, in a one-dimensional (1D) waveguide, highlighting the resulting potential for tunable, active, nanophotonic devices. In our experiment, controlling the nanowire waveguide diameter tunes the luminescence lifetime of excitons in the nanowires across 2 orders of magnitude up to 80 ns. At the smallest wire diameters, we show that this luminescence lifetime can be manipulated by engineering the dielectric environment of the nanowires. Exploiting this unique handle on the spontaneous emission of mobile emitters, we demonstrate an all-dielectric spatial control of the mobile emitters along the axis of the 1D nanowire waveguide.

12.
Lancet ; 394(10202): 953-966, 2019 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-31526739

RESUMO

Drug-resistant tuberculosis is a major public health concern in many countries. Over the past decade, the number of patients infected with Mycobacterium tuberculosis resistant to the most effective drugs against tuberculosis (ie, rifampicin and isoniazid), which is called multidrug-resistant tuberculosis, has continued to increase. Globally, 4·6% of patients with tuberculosis have multidrug-resistant tuberculosis, but in some areas, like Kazakhstan, Kyrgyzstan, Moldova, and Ukraine, this proportion exceeds 25%. Treatment for patients with multidrug-resistant tuberculosis is prolonged (ie, 9-24 months) and patients with multidrug-resistant tuberculosis have less favourable outcomes than those treated for drug-susceptible tuberculosis. Individualised multidrug-resistant tuberculosis treatment with novel (eg, bedaquiline) and repurposed (eg, linezolid, clofazimine, or meropenem) drugs and guided by genotypic and phenotypic drug susceptibility testing can improve treatment outcomes. Some clinical trials are evaluating 6-month regimens to simplify management and improve outcomes of patients with multidrug-resistant tuberculosis. Here we review optimal diagnostic and treatment strategies for patients with drug-resistant tuberculosis and their contacts.


Assuntos
Antituberculosos/uso terapêutico , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Antituberculosos/administração & dosagem , Esquema de Medicação , Farmacorresistência Bacteriana Múltipla/genética , Saúde Global , Humanos , Testes de Sensibilidade Microbiana/métodos , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/genética , Tuberculose Resistente a Múltiplos Medicamentos/diagnóstico , Tuberculose Resistente a Múltiplos Medicamentos/epidemiologia
13.
Chest ; 156(6): 1068-1079, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31557467

RESUMO

BACKGROUND: Asthma is a common respiratory disorder with a highly heterogeneous nature that remains poorly understood. The objective was to use whole genome sequencing (WGS) data to identify regions of common genetic variation contributing to lung function in individuals with a diagnosis of asthma. METHODS: WGS data were generated for 1,053 individuals from trios and extended pedigrees participating in the family-based Genetic Epidemiology of Asthma in Costa Rica study. Asthma affection status was defined through a physician's diagnosis of asthma, and most participants with asthma also had airway hyperresponsiveness (AHR) to methacholine. Family-based association tests for single variants were performed to assess the associations with lung function phenotypes. RESULTS: A genome-wide significant association was identified between baseline FEV1/FVC ratio and a single-nucleotide polymorphism in the top hit cysteine-rich secretory protein LCCL domain-containing 2 (CRISPLD2) (rs12051168; P = 3.6 × 10-8 in the unadjusted model) that retained suggestive significance in the covariate-adjusted model (P = 5.6 × 10-6). Rs12051168 was also nominally associated with other related phenotypes: baseline FEV1 (P = 3.3 × 10-3), postbronchodilator (PB) FEV1 (7.3 × 10-3), and PB FEV1/FVC ratio (P = 2.7 × 10-3). The identified baseline FEV1/FVC ratio and rs12051168 association was meta-analyzed and replicated in three independent cohorts in which most participants with asthma also had confirmed AHR (combined weighted z-score P = .015) but not in cohorts without information about AHR. CONCLUSIONS: These findings suggest that using specific asthma characteristics, such as AHR, can help identify more genetically homogeneous asthma subgroups with genotype-phenotype associations that may not be observed in all children with asthma. CRISPLD2 also may be important for baseline lung function in individuals with asthma who also may have AHR.

14.
Genet Epidemiol ; 43(8): 1046-1055, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31429121

RESUMO

Proportions of false-positive rates in genome-wide association analysis are affected by population stratification, and if it is not correctly adjusted, the statistical analysis can produce the large false-negative finding. Therefore various approaches have been proposed to adjust such problems in genome-wide association studies. However, in spite of its importance, a few studies have been conducted in genome-wide single nucleotide polymorphism (SNP)-by-environment interaction studies. In this report, we illustrate in which scenarios can lead to the false-positive rates in association mapping and approach to maintaining the overall type-1 error rate.


Assuntos
Interação Gene-Ambiente , Polimorfismo de Nucleotídeo Único , Idoso , Idoso de 80 Anos ou mais , Genética Populacional , Estudo de Associação Genômica Ampla , Humanos , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/genética
15.
Nervenarzt ; 90(12): 1245-1253, 2019 Dec.
Artigo em Alemão | MEDLINE | ID: mdl-31297574

RESUMO

After years of low incidence, a large increase of new tuberculosis (TB) cases has been reported in Germany since 2015. New immunotherapies for the treatment of multiple sclerosis (MS) are associated with a reduced immune competence and a potential increased risk for infections. Most neurologists lack specific experiences with TB infections. This article summarizes specific recommendations for the diagnostics and treatment of TB under MS immunotherapies with a focus on the situation in Germany. Due to low case numbers and little experience with the risk of TB under the new immunotherapies, the clinical competence network for MS (KKNMS) consensus recommendations have a low grade of evidence.


Assuntos
Esclerose Múltipla , Tuberculose , Alemanha , Humanos , Imunoterapia , Esclerose Múltipla/complicações , Esclerose Múltipla/terapia , Tuberculose/complicações , Tuberculose/diagnóstico , Tuberculose/terapia
17.
Front Genet ; 10: 572, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31275357

RESUMO

Family-based designs have been shown to be powerful in detecting the significant rare variants associated with human diseases. However, very few significant results have been found owing to relatively small sample sizes and the fact that statistical analyses often suffer from high false-negative error rates. These limitations can be avoided by combining results from multiple studies via meta-analysis. However, statistical methods for meta-analysis with rare variants are limited for family-based samples. In this report, we propose a tool for the meta-analysis of family-based rare variant associations, metaFARVAT. metaFARVAT is based on a quasi-likelihood score for each variant. These scores are combined to generate burden test, variable-threshold test, sequence kernel association test (SKAT), and optimal SKAT statistics. The proposed method tests homogeneous and heterogeneous effects of variants among different studies and can be applied to both quantitative and dichotomous phenotypes. Simulation results demonstrated the robustness and efficiency of the proposed method in different scenarios. By applying metaFARVAT to data from a family-based study and a case-control study, we identified a few promising candidate genes, including DLEC1, which is associated with chronic obstructive pulmonary disease.

20.
Am J Respir Crit Care Med ; 200(6): 677-690, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-30908940

RESUMO

Chronic obstructive pulmonary disease (COPD) is a common and progressive disease that is influenced by both genetic and environmental factors. For many years, knowledge of the genetic basis of COPD was limited to Mendelian syndromes, such as alpha-1 antitrypsin deficiency and cutis laxa, caused by rare genetic variants. Over the past decade, the proliferation of genome-wide association studies, the accessibility of whole-genome sequencing, and the development of novel methods for analyzing genetic variation data have led to a substantial increase in the understanding of genetic variants that play a role in COPD susceptibility and COPD-related phenotypes. COPDGene (Genetic Epidemiology of COPD), a multicenter, longitudinal study of over 10,000 current and former cigarette smokers, has been pivotal to these breakthroughs in understanding the genetic basis of COPD. To date, over 20 genetic loci have been convincingly associated with COPD affection status, with additional loci demonstrating association with COPD-related phenotypes such as emphysema, chronic bronchitis, and hypoxemia. In this review, we discuss the contributions of the COPDGene study to the discovery of these genetic associations as well as the ongoing genetic investigations of COPD subtypes, protein biomarkers, and post-genome-wide association study analysis.

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