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Trop Med Int Health ; 24(10): 1243-1258, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31390108

RESUMO

OBJECTIVES: Provision of drug-resistant tuberculosis (DR-TB) treatment is scarce in resource-limited settings. We assessed the feasibility of ambulatory DR-TB care for treatment expansion in rural Eswatini. METHODS: Retrospective patient-level data were used to evaluate ambulatory DR-TB treatment provision in rural Shiselweni (Eswatini), from 2008 to 2016. DR-TB care was either clinic-based led by nurses or community-based at the patient's home with involvement of community treatment supporters for provision of treatment to patients with difficulties in accessing facilities. We describe programmatic outcomes and used multivariate flexible parametric survival models to assess time to adverse outcomes. Both care models were costed in supplementary analyses. RESULTS: Of 698 patients initiated on DR-TB treatment, 57% were women and 84% were HIV-positive. Treatment initiations increased from 27 in 2008 to 127 in 2011 and decreased thereafter to 51 in 2016. Proportionally, community-based care increased from 19% in 2009 to 77% in 2016. Treatment success was higher for community-based care (79%) than clinic-based care (68%, P = 0.002). After adjustment for covariate factors among adults (n = 552), the risk of adverse outcomes (death, loss to follow-up, treatment failure) in community-based care was reduced by 41% (adjusted hazard ratio 0.59, 95% CI: 0.39-0.91). Findings were supported by sensitivity analyses. The care provider's per-patient costs for community-based (USD13 345) and clinic-based (USD12 990) care were similar. CONCLUSIONS: Ambulatory treatment outcomes were good, and community-based care achieved better treatment outcomes than clinic-based care at comparable costs. Contextualised DR-TB care programmes are feasible and can support treatment expansion in rural settings.

4.
Am J Hum Genet ; 104(6): 1210-1222, 2019 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-31079897

RESUMO

We delineate a KMT2E-related neurodevelopmental disorder on the basis of 38 individuals in 36 families. This study includes 31 distinct heterozygous variants in KMT2E (28 ascertained from Matchmaker Exchange and three previously reported), and four individuals with chromosome 7q22.2-22.23 microdeletions encompassing KMT2E (one previously reported). Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intellectual disability. One-quarter of individuals met criteria for autism. Additional common features include macrocephaly, hypotonia, functional gastrointestinal abnormalities, and a subtle facial gestalt. Epilepsy was present in about one-fifth of individuals with truncating variants and was responsive to treatment with anti-epileptic medications in almost all. More than 70% of the individuals were male, and expressivity was variable by sex; epilepsy was more common in females and autism more common in males. The four individuals with microdeletions encompassing KMT2E generally presented similarly to those with truncating variants, but the degree of developmental delay was greater. The group of four individuals with missense variants in KMT2E presented with the most severe developmental delays. Epilepsy was present in all individuals with missense variants, often manifesting as treatment-resistant infantile epileptic encephalopathy. Microcephaly was also common in this group. Haploinsufficiency versus gain-of-function or dominant-negative effects specific to these missense variants in KMT2E might explain this divergence in phenotype, but requires independent validation. Disruptive variants in KMT2E are an under-recognized cause of neurodevelopmental abnormalities.

6.
J Med Chem ; 62(6): 2988-3008, 2019 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-30840447

RESUMO

Genetic and pharmacological evidence indicates that the reduction of ataxia telangiectasia-mutated (ATM) kinase activity can ameliorate mutant huntingtin (mHTT) toxicity in cellular and animal models of Huntington's disease (HD), suggesting that selective inhibition of ATM could provide a novel clinical intervention to treat HD. Here, we describe the development and characterization of ATM inhibitor molecules to enable in vivo proof-of-concept studies in HD animal models. Starting from previously reported ATM inhibitors, we aimed with few modifications to increase brain exposure by decreasing P-glycoprotein liability while maintaining potency and selectivity. Here, we report brain-penetrant ATM inhibitors that have robust pharmacodynamic (PD) effects consistent with ATM kinase inhibition in the mouse brain and an understandable pharmacokinetic/PD (PK/PD) relationship. Compound 17 engages ATM kinase and shows robust dose-dependent inhibition of X-ray irradiation-induced KAP1 phosphorylation in the mouse brain. Furthermore, compound 17 protects against mHTT (Q73)-induced cytotoxicity in a cortical-striatal cell model of HD.

7.
Lancet ; 393(10181): 1642-1656, 2019 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-30904262

RESUMO

Tuberculosis remains the leading cause of death from an infectious disease among adults worldwide, with more than 10 million people becoming newly sick from tuberculosis each year. Advances in diagnosis, including the use of rapid molecular testing and whole-genome sequencing in both sputum and non-sputum samples, could change this situation. Although little has changed in the treatment of drug-susceptible tuberculosis, data on increased efficacy with new and repurposed drugs have led WHO to recommend all-oral therapy for drug-resistant tuberculosis for the first time ever in 2018. Studies have shown that shorter latent tuberculosis prevention regimens containing rifampicin or rifapentine are as effective as longer, isoniazid-based regimens, and there is a promising vaccine candidate to prevent the progression of infection to the disease. But new tools alone are not sufficient. Advances must be made in providing high-quality, people-centred care for tuberculosis. Renewed political will, coupled with improved access to quality care, could relegate the morbidity, mortality, and stigma long associated with tuberculosis, to the past.


Assuntos
Carga Global da Doença , Tuberculose , Antituberculosos/uso terapêutico , Resistência a Medicamentos/efeitos dos fármacos , Humanos , Avaliação de Resultados (Cuidados de Saúde) , Tuberculose/diagnóstico , Tuberculose/tratamento farmacológico , Tuberculose/epidemiologia , Tuberculose/prevenção & controle
8.
Lancet ; 393(10178): 1331-1384, 2019 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-30904263
9.
Ethn Dis ; 29(Suppl 1): 77-82, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30906153

RESUMO

Rapid advancements in translational research have produced innovative clinical discoveries and evidence-based interventions that are ready for uptake in real-world settings, creating vast opportunities and challenges for implementation science. However, there is an inadequate research workforce to study effective strategies and delivery of implementation to advance the field. Novel career development initiatives will build scholars for the next generation of implementation science to bridge research to practice for diverse populations to advance health equity, specifically with a strategic focus on heart, lung, blood and sleep diseases and conditions. Along with traditional mentoring and curricula, research training includes state-of-the-art approaches using complex methods and multi-disciplinary collaborations between researchers, practice settings, and diverse communities. Implementation science scholars strive not only to decrease the lag time between the discovery of evidence-based interventions and successful implementation but also how to advance health equity and to reduce disparities for underserved populations that suffer disproportionally.

10.
Lancet Infect Dis ; 19(3): 298-307, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30744962

RESUMO

BACKGROUND: Drug resistance is a challenge for the global control of tuberculosis. We examined mortality in patients with tuberculosis from high-burden countries, according to concordance or discordance of results from drug susceptibility testing done locally and in a reference laboratory. METHODS: This multicentre cohort study was done in Côte d'Ivoire, Democratic Republic of the Congo, Kenya, Nigeria, South Africa, Peru, and Thailand. We collected Mycobacterium tuberculosis isolates and clinical data from adult patients aged 16 years or older. Patients were stratified by HIV status and tuberculosis drug resistance. Molecular or phenotypic drug susceptibility testing was done locally and at the Swiss National Center for Mycobacteria, Zurich, Switzerland. We examined mortality during treatment according to drug susceptibility test results and treatment adequacy in multivariable logistic regression models adjusting for sex, age, sputum microscopy, and HIV status. FINDINGS: We obtained M tuberculosis isolates from 871 patients diagnosed between 2013 and 2016. After exclusion of 237 patients, 634 patients with tuberculosis were included in this analysis; the median age was 33·2 years (IQR 26·9-42·5), 239 (38%) were women, 272 (43%) were HIV-positive, and 69 (11%) patients died. Based on the reference laboratory drug susceptibility test, 394 (62%) strains were pan-susceptible, 45 (7%) monoresistant, 163 (26%) multidrug-resistant (MDR), and 30 (5%) had pre-extensively or extensively drug resistant (pre-XDR or XDR) tuberculosis. Results of reference and local laboratories were concordant for 513 (81%) of 634 patients and discordant for 121 (19%) of 634. Overall, sensitivity to detect any resistance was 90·8% (95% CI 86·5-94·2) and specificity 84·3% (80·3-87·7). Mortality ranged from 6% (20 of 336) in patients with pan-susceptible tuberculosis treated according to WHO guidelines to 57% (eight of 14) in patients with resistant strains who were under-treated. In logistic regression models, compared with concordant drug susceptibility test results, the adjusted odds ratio of death was 7·33 (95% CI 2·70-19·95) for patients with discordant results potentially leading to under-treatment. INTERPRETATION: Inaccurate drug susceptibility testing by comparison with a reference standard leads to under-treatment of drug-resistant tuberculosis and increased mortality. Rapid molecular drug susceptibility test of first-line and second-line drugs at diagnosis is required to improve outcomes in patients with MDR tuberculosis and pre-XDR or XDR tuberculosis. FUNDING: National Institutes of Allergy and Infectious Diseases, Swiss National Science Foundation, Swiss National Center for Mycobacteria.

11.
Clin Genet ; 95(4): 496-506, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30666632

RESUMO

Whole-exome sequencing has established IQSEC2 as a neurodevelopmental disability gene. The IQSEC2 variant phenotype includes developmental delay, intellectual disability, epilepsy, hypotonia, autism, developmental regression, microcephaly and stereotypies but is yet to be fully described. Presented here are 14 new patients with IQSEC2 variants. In addition to the established features, we observed: gait ataxia in 7 of 9 (77.8%), drooling in 9 of 14 (64.2%), early feeding difficulties in 7 of 14 (50%), structural brain abnormalities in 6 of 13 (46.2%), brachycephaly in 5 of 14 (35.7%), and scoliosis and paroxysms of laughter each in 4 of 14 (28.6%). We suggest that these are features of the IQSEC2-related disorder. Gastrostomy requirement, plagiocephaly, strabismus and cortical blindness, each seen in 2 of 14 (14.3%), may also be associated. Shared facial features were noted in 8 of 14 patients, and shared hair patterning was identified in 5 of 14 patients. This study further delineates the IQSEC2 phenotypic spectrum and supports the notion of an emerging IQSEC2 syndrome. We draw parallels between the IQSEC2-related disorder and the Angelman-/Rett-/Pitt-Hopkins syndrome group of conditions and recommend the addition of IQSEC2 to epilepsy and developmental delay gene panels. We observed discordant phenotypes in monozygotic twins and apparent gonadal mosaicism, which has implications for recurrence risk counselling in the IQSEC2-related disorder.

12.
Lancet Glob Health ; 7(2): e191-e199, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30683238

RESUMO

BACKGROUND: Xpert MTB/RIF, the most widely used automated nucleic acid amplification test for tuberculosis, is available in more than 130 countries. Although diagnostic accuracy is well documented, anticipated improvements in patient outcomes have not been clearly identified. We performed an individual patient data meta-analysis to examine improvements in patient outcomes associated with Xpert MTB/RIF. METHODS: We searched PubMed, Embase, ClinicalTrials.gov, and the Pan African Clinical Trials Registry from inception to Feb 1, 2018, for randomised controlled trials (RCTs) comparing the use of Xpert MTB/RIF with sputum smear microscopy as tests for tuberculosis diagnosis in adults (aged 18 years or older). We excluded studies of patients with extrapulmonary tuberculosis, and studies in which mortality was not assessed. We used a two-stage approach for our primary analysis and a one-stage approach for the sensitivity analysis. To assess the primary outcome of cumulative 6-month all-cause mortality, we first performed logistic regression models (random effects for cluster randomised trials, with robust SEs for multicentre studies) for each trial, and then pooled the odds ratio (OR) estimates by a fixed-effects (inverse variance) or random-effects (Der Simonian Laird) meta-analysis. We adjusted for age and gender, and stratified by HIV status and previous tuberculosis-treatment history. The study protocol has been registered with PROSPERO, number CRD42014013394. FINDINGS: Our search identified 387 studies, of which five RCTs were eligible for analysis. 8567 adult clinic attendees (4490 [63·5%] of 7074 participants for whom data were available were HIV-positive) were tested for tuberculosis with Xpert MTB/RIF (Xpert group) versus sputum smear microscopy (sputum smear group), across five low-income and middle-income countries (South Africa, Brazil, Zimbabwe, Zambia, and Tanzania). The primary outcome (reported in three studies) occurred in 182 (4·5%) of 4050 patients in the Xpert group and 217 (5·3%) of 4093 patients in the smear group (pooled adjusted OR 0·88, 95% CI 0·68-1·14 [p=0·34]; for HIV-positive individuals OR 0·83, 0·65-1·05 [p=0·12]). Kaplan-Meier estimates showed a lower rate of death (12·73 per 100 person-years in the Xpert group vs 16·38 per 100 person-years in the sputum smear group) for HIV-positive patients (hazard ratio 0·76, 95% CI 0·60-0·97; p=0·03). The risk of bias was assessed as reasonable and the statistical heterogeneity across studies was low (I2<20% for the primary outcome). INTERPRETATION: Despite individual patient data analysis from five RCTs, we were unable to confidently rule in nor rule out an Xpert MTB/RIF-associated reduction in mortality among outpatients tested for tuberculosis. Reduction in mortality among HIV-positive patients in a secondary analysis suggests the possibility of population-level impact. FUNDING: US National Institutes of Health.

13.
Elife ; 72018 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-30373719

RESUMO

Bacterial factors favoring the unprecedented multidrug-resistant tuberculosis (MDR-TB) epidemic in the former Soviet Union remain unclear. We utilized whole genome sequencing and Bayesian statistics to analyze the evolutionary history, temporal emergence of resistance and transmission networks of MDR Mycobacterium tuberculosis complex isolates from Karakalpakstan, Uzbekistan (2001-2006). One clade (termed Central Asian outbreak, CAO) dating back to 1974 (95% HPD 1969-1982) subsequently acquired resistance mediating mutations to eight anti-TB drugs. Introduction of standardized WHO-endorsed directly observed treatment, short-course in Karakalpakstan in 1998 likely selected for CAO-strains, comprising 75% of sampled MDR-TB isolates in 2005/2006. CAO-isolates were also identified in a published cohort from Russia (2008-2010). Similarly, the presence of mutations supposed to compensate bacterial fitness deficits was associated with transmission success and higher drug resistance rates. The genetic make-up of these MDR-strains threatens the success of both empirical and standardized MDR-TB therapies, including the newly WHO-endorsed short MDR-TB regimen in Uzbekistan.

15.
Br J Nurs ; 27(16): S16, 2018 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-30187799
16.
Neurogastroenterol Motil ; 30(12): e13454, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30136343

RESUMO

BACKGROUND: Propionate exhibits affinity for free fatty acid receptor 2 (FFA2, formerly GPR43) and FFA3 (GPR41). These two G protein-coupled receptors (GPCRs) are expressed by enteroendocrine L cells that contain anorectic peptide YY (PYY) and glucagon-like peptide 1 (GLP-1), while FFA3 is also expressed by enteric neurons. Few studies have investigated the individual roles of FFA2 and FFA3 in propionate's gastrointestinal (GI) effects. Here, we compared FFA2, FFA3, and propionate mucosal responses utilizing selective ligands including an FFA3 antagonist, in mouse and human colonic mucosa. METHODS: Vectorial ion transport was measured in native colonic preparations from normal mouse and human colon with intact submucosal innervation. Endogenous fecal pellet propulsion was monitored in colons isolated from wild-type (WT) and PYY-/- mice. KEY RESULTS: FFA2 and FFA3 signaling differed significantly. FFA2 agonism involved endogenous L cell-derived PYY and was glucose dependent, while FFA3 agonism was independent of PYY and glucose, but required submucosal enteric neurons for activity. Tonic FFA3 activity was observed in mouse and human colon mucosa. Apical propionate responses were a combination of FFA2-PYY mediation and FFA3 neuronal GLP-1- and CGRP-dependent signaling in mouse ascending colon mucosa. Propionate also slowed WT and PYY-/- colonic transit, and this effect was blocked by a GLP-1 receptor antagonist. CONCLUSIONS & INFERENCES: We conclude that luminal propionate costimulates FFA2 and FFA3 pathways, reducing anion secretion and slowing colonic motility; FFA2 via PYY mediation and FFA3 signaling by activation of enteric sensory neurons.

17.
Exp Dermatol ; 2018 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-29952037

RESUMO

In ATP6V0A2-related cutis laxa, the skin phenotype varies from a wrinkly skin to prominent cutis laxa and typically associates with skeletal and neurological manifestations. The phenotype remains incompletely characterized, especially in adult patients. Glycosylation defects and reduced acidification of secretory vesicles contribute to the pathogenesis, but the consequences at the clinical level remain to be determined. Moreover, the morphology of the elastic fibres has not been studied in ATP6V0A2-related cutis laxa, nor its relation with potential clinical risks. We report on the extreme variability in ATP6V0A2-related cutis laxa in 10 novel patients, expand the phenotype with emphysema and von Willebrand disease and hypothesize on the pathogenesis that might link both with deficiency of glycosylation and with elastic fibre anomalies. Our data will affect clinical management of patients with ATP6V0A2-related cutis laxa.

18.
J Physiol ; 596(17): 4237-4251, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29917237

RESUMO

KEY POINTS: Tenascin-X (TNX) is an extracellular matrix glycoprotein with anti-adhesive properties in skin and joints. Here we report the novel finding that TNX is expressed in human and mouse gut tissue where it is exclusive to specific subpopulations of neurones. Our studies with TNX-deficient mice show impaired defecation and neural control of distal colonic motility that can be rescued with a 5-HT4 receptor agonist. However, colonic secretion is unchanged. They are also susceptible to internal rectal intussusception. Colonic afferent sensitivity is increased in TNX-deficient mice. Correspondingly, there is increased density of and sensitivity of putative nociceptive fibres in TNX-deficient mucosa. A group of TNX-deficient patients report symptoms highly consistent with those in the mouse model. These findings suggest TNX plays entirely different roles in gut to non-visceral tissues - firstly a role in enteric motor neurones and secondly a role influencing nociceptive sensory neurones Studying further the mechanisms by which TNX influences neuronal function will lead to new targets for future treatment. ABSTRACT: The extracellular matrix (ECM) is not only an integral structural molecule, but is also critical for a wide range of cellular functions. The glycoprotein tenascin-X (TNX) predominates in the ECM of tissues like skin and regulates tissue structure through anti-adhesive interactions with collagen. Monogenic TNX deficiency causes painful joint hypermobility and skin hyperelasticity, symptoms characteristic of hypermobility Ehlers Danlos syndrome (hEDS). hEDS patients also report consistently increased visceral pain and gastrointestinal (GI) dysfunction. We investigated whether there is a direct link between TNX deficiency and GI pain or motor dysfunction. We set out first to learn where TNX is expressed in human and mouse, then determine how GI function, specifically in the colon, is disordered in TNX-deficient mice and humans of either sex. In human and mouse tissue, TNX was predominantly associated with cholinergic colonic enteric neurones, which are involved in motor control. TNX was absent from extrinsic nociceptive peptidergic neurones. TNX-deficient mice had internal rectal prolapse and a loss of distal colonic contractility which could be rescued by prokinetic drug treatment. TNX-deficient patients reported increased sensory and motor GI symptoms including abdominal pain and constipation compared to controls. Despite absence of TNX from nociceptive colonic neurones, neuronal sprouting and hyper-responsiveness to colonic distension was observed in the TNX-deficient mice. We conclude that ECM molecules are not merely support structures but an integral part of the microenvironment particularly for specific populations of colonic motor neurones where TNX exerts functional influences.

19.
Curr Opin Pharmacol ; 42: 7-15, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29885623

RESUMO

With an estimated incidence of 490000 cases in 2016, multidrug resistant tuberculosis (TB), against which key first-line anti-tuberculars are less efficacious, presents major challenges for global health. Poor treatment outcomes coupled with a yawning treatment gap between those in need of second-line therapy and those who receive it, underscore the urgent need for new approaches to tackle the scourge of drug-resistant TB. Against this background, significant progress has been made in understanding the complex biology of TB drug resistance and disease pathogenesis, and in establishing a pipeline for delivering new drugs and drug combinations. In this review, we highlight the challenges of drug-resistant TB and the ways in which new advances could be harnessed to improve treatment outcomes.

20.
Eur Respir J ; 51(6)2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29724920

RESUMO

Experience with delamanid (Dlm) is limited, particularly among HIV-positive individuals. We describe early efficacy and safety data from a programmatic setting in South Africa.This was a retrospective cohort study of patients receiving Dlm-containing treatment regimens between November 2015 and August 2017. We report 12-month interim outcomes, sputum culture conversion (SCC) by months 2 and 6, serious adverse events (SAEs) and QT intervals corrected using the Frederica formula (QTcF).Overall, 103 patients were initiated on Dlm; 79 (77%) were HIV positive. The main indication for Dlm was intolerance to second-line anti-tuberculosis (TB) drugs (n=58, 56%). There were 12 months of follow-up for 46 patients; 28 (61%) had a favourable outcome (cure, treatment completion or culture negativity). Positive cultures were found for 57 patients at Dlm initiation; 16 out of 31 (52%) had SCC within 2 months and 25 out of 31 (81%) within 6 months. There were 67 SAEs reported in 29 patients (28%). There were four instances of QTcF prolongation >500 ms in two patients (2%), leading to permanent discontinuation in one case; however, no cardiac arrhythmias occurred.This large cohort of difficult-to-treat patients receiving Dlm for rifampicin-resistant TB treatment in a programmatic setting with high HIV prevalence had favourable early treatment response and tolerated treatment well. Dlm should remain available, particularly for those who cannot be treated with conventional regimens or with limited treatment options.

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