Sex Differences in Tuberculosis Burden and Notifications in Low- and Middle-Income Countries: A Systematic Review and Meta-analysis

BACKGROUND: Tuberculosis (TB) case notification rates are usually higher in men than in women, but notification data are insufficient to measure sex differences in disease burden. This review set out to systematically investigate whether sex ratios in case notifications reflect differences in disease prevalence and to identify gaps in access to and/or utilisation of diagnostic services. METHODS AND FINDINGS: In accordance with the published protocol (CRD42015022163), TB prevalence surveys in nationally representative and sub-national adult populations (age ≥ 15 y) in low- and middle-income countries published between 1 January 1993 and 15 March 2016 were identified through searches of PubMed, Embase, Global Health, and the Cochrane Database of Systematic Reviews; review of abstracts; and correspondence with the World Health Organization. Random-effects meta-analyses examined male-to-female (M:F) ratios in TB prevalence and prevalence-to-notification (P:N) ratios for smear-positive TB. Meta-regression was done to identify factors associated with higher M:F ratios in prevalence and higher P:N ratios. Eighty-three publications describing 88 surveys with over 3.1 million participants in 28 countries were identified (36 surveys in Africa, three in the Americas, four in the Eastern Mediterranean, 28 in South-East Asia and 17 in the Western Pacific). Fifty-six surveys reported in 53 publications were included in quantitative analyses. Overall random-effects weighted M:F prevalence ratios were 2.21 (95% CI 1.92-2.54; 56 surveys) for bacteriologically positive TB and 2.51 (95% CI 2.07-3.04; 40 surveys) for smear-positive TB. M:F prevalence ratios were highest in South-East Asia and in surveys that did not require self-report of signs/symptoms in initial screening procedures. The summary random-effects weighted M:F ratio for P:N ratios was 1.55 (95% CI 1.25-1.91; 34 surveys). We intended to stratify the analyses by age, HIV status, and rural or urban setting; however, few studies reported such data. CONCLUSIONS: TB prevalence is significantly higher among men than women in low- and middle-income countries, with strong evidence that men are disadvantaged in seeking and/or accessing TB care in many settings. Global strategies and national TB programmes should recognise men as an underserved high-risk group and improve men's access to diagnostic and screening services to reduce the overall burden of TB more effectively and ensure gender equity in TB care

TB/HIV: an orphan disease?

No abstract available

Detection of skewed X-chromosome inactivation in Fragile X syndrome and X chromosome aneuploidy using quantitative melt analysis.

Methylation of the fragile X mental retardation 1 (FMR1) exon 1/intron 1 boundary positioned fragile X related epigenetic element 2 (FREE2), reveals skewed X-chromosome inactivation (XCI) in fragile X syndrome full mutation (FM: CGG > 200) females. XCI skewing has been also linked to abnormal X-linked gene expression with the broader clinical impact for sex chromosome aneuploidies (SCAs). In this study, 10 FREE2 CpG sites were targeted using methylation specific quantitative melt analysis (MS-QMA), including 3 sites that could not be analysed with previously used EpiTYPER system. The method was applied for detection of skewed XCI in FM females and in different types of SCA. We tested venous blood and saliva DNA collected from 107 controls (CGG < 40), and 148 FM and 90 SCA individuals. MS-QMA identified: (i) most SCAs if combined with a Y chromosome test; (ii) locus-specific XCI skewing towards the hypomethylated state in FM females; and (iii) skewed XCI towards the hypermethylated state in SCA with 3 or more X chromosomes, and in 5% of the 47,XXY individuals. MS-QMA output also showed significant correlation with the EpiTYPER reference method in FM males and females (P < 0.0001) and SCAs (P < 0.05). In conclusion, we demonstrate use of MS-QMA to quantify skewed XCI in two applications with diagnostic utility

Genomic Epidemiology of Multidrug-Resistant Mycobacterium tuberculosis During Transcontinental Spread

The transcontinental spread of multidrug-resistant (MDR) tuberculosis is poorly characterized in molecular epidemiologic studies. We used genomic sequencing to understand the establishment and dispersion of MDR Mycobacterium tuberculosis within a group of immigrants to the United States. We used a genomic epidemiology approach to study a genotypically matched (by spoligotype, IS6110 restriction fragment length polymorphism, and mycobacterial interspersed repetitive units-variable number of tandem repeat signature) lineage 2/Beijing MDR strain implicated in an outbreak of tuberculosis among refugees in Thailand and consecutive cases within California. All 46 MDR M. tuberculosis genomes from both Thailand and California were highly related, with a median difference of 10 single-nucleotide polymorphisms (SNPs). The Wat Tham Krabok (WTK) strain is a new sequence type distinguished from all known Beijing strains by 55 SNPs and a genomic deletion (Rv1267c) associated with increased fitness. Sequence data revealed a highly prevalent MDR strain that included several closely related but distinct allelic variants within Thailand, rather than the occurrence of a single outbreak. In California, sequencing data supported multiple independent introductions of WTK with subsequent transmission and reactivation within the state, as well as a potential super spreader with a prolonged infectious period. Twenty-seven drug resistance-conferring mutations and 4 putative compensatory mutations were found within WTK strains. Genomic sequencing has substantial epidemiologic value in both low- and high-burden settings in understanding transmission chains of highly prevalent MDR strain

Health care seeking patterns of rifampicin-resistant tuberculosis patients in Harare, Zimbabwe: A prospective cohort study

BACKGROUND: Delays in seeking and accessing treatment for rifampicin-resistant tuberculosis (RR-TB) and multi-drug resistant (MDR-TB) are major impediments to TB control in high-burden, resource-limited settings. METHOD: We prospectively determined health-seeking behavioural patterns and associations with treatment outcomes and costs among 68 RR-TB patients attending conveniently selected facilities in a decentralised system in Harare, Zimbabwe. RESULTS: From initial symptoms to initiation of effective treatment, patients made a median number of three health care visits (IQR 2-4 visits) at a median cost of 13% (IQR 6-31%) of their total annual household income (mean cost, US$410). Cumulatively, RR-TB patients most frequently first visited private facilities, i.e., private pharmacies (30%) and other private health care providers (24%) combined. Median patient delay was 26 days (IQR 14-42 days); median health system delay was 97 days (IQR 30-215 days) and median total delay from symptom onset to initiation of effective treatment was 132 days (IQR 51-287 days). The majority of patients (88%) attributed initial delay in seeking care to "not feeling sick enough." Total delay, total cost and number of health care visits were not associated with treatment or clinical outcomes, though our study was not adequately powered for these determinations. CONCLUSIONS: Despite the public availability of rapid molecular TB tests, patients experienced significant delays and high costs in accessing RR-TB treatment. Active case finding, integration of private health care providers and enhanced service delivery may reduce treatment delay and TB associated costs

Evaluation of Environmental Contamination and Estimated Radiation Doses for the Return to Residents’ Homes in Kawauchi Village, Fukushima Prefecture

To evaluate the environmental contamination and radiation exposure dose rates due to artificial radionuclides in Kawauchi Village, Fukushima Prefecture, the restricted area within a 30-km radius from the Fukushima Dai-ichi Nuclear Power Plant (FNPP), the concentrations of artificial radionuclides in soil samples, tree needles, and mushrooms were analyzed by gamma spectrometry. Nine months have passed since samples were collected on December 19 and 20, 2011, 9 months after the FNPP accident, and the prevalent dose-forming artificial radionuclides from all samples were 134Cs and 137Cs. The estimated external effective doses from soil samples were 0.42-7.2 μSv/h (3.7-63.0 mSv/y) within the 20-km radius from FNPP and 0.0011-0.38 μSv/h (0.010-3.3 mSv/y) within the 20-30 km radius from FNPP. The present study revealed that current levels are sufficiently decreasing in Kawauchi Village, especially in areas within the 20- to 30-km radius from FNPP. Thus, residents may return their homes with long-term follow-up of the environmental monitoring and countermeasures such as decontamination and restrictions of the intake of foods for reducing unnecessary exposure. The case of Kawauchi Village will be the first model for the return to residents\u27 homes after the FNPP accident

Isotopic evidence for long-distance connections of the AD thirteenth century Promontory caves occupants

Las cuevas Promontory (Utah) y la Cueva Franktown (Colorado) contienen registros de alta fidelidad en cuanto a las ocupaciones de corto término de grupos humanos con cultura material conectada al Subártico/Planicies del Norte. Esta investigación utiliza excremento, pelo, piel de cuero y colágeno del hueso de bisonte provenientes de los sitios Promontory y Franktown para establecer una base de datos isotópicos locales y variabilidad isotópica de carbono e identifica la piel de cuero de procedencia lejana. La envoltura de tobillo de un mocasín recuperado de la Cueva 1 de Promontory tuvo un valor δ13C que indica un componente C4 considerable en la dieta del animal, lo que es un resultado distinto a las dietas C3 que se identificaron a partir del análisis de 171 muestras de bisonte provenientes de Promontory y el norte de Utah. Aplicamos una combinación única de análisis isotópico de tejidos múltiples, mapas isotópicos (“isoscapes”) de carbono, ADN antiguo (identificación de sexo y especie), tasa de remodelación de tejidos, contextos arqueológicos y la ecología del bisonte para demonstrar que el valor alto δ13C probablemente no es un resultado debido al consumo de plantas locales, movilidad del bisonte o comercio. En cambio, la piel de cuero del bisonte fue probablemente adquirida a través de viajes de larga distancia hacia zonas con pastos C4 abundantes muy al sur o al este. El conocimiento extenso sobre el paisaje obtenido a través de asociaciones de larga distancia debió permitir a los habitantes de las cuevas Promontory tomar decisiones bien informadas sobre las direcciones y rutas de movimiento para realizar un cambio territorial, el cual parece haber ocurrido a finales del sigo XIII.The Promontory caves (Utah) and Franktown Cave (Colorado) contain high-fidelity records of short-term occupations by groups with material culture connections to the Subarctic/Northern Plains. This research uses Promontory and Franktown bison dung, hair, hide, and bone collagen to establish local baseline carbon isotopic variability and identify leather from a distant source. The ankle wrap of one Promontory Cave 1 moccasin had a δ13C value that indicates a substantial C4 component to the animal's diet, unlike the C3 diets inferred from 171 other Promontory and northern Utah bison samples. We draw on a unique combination of multitissue isotopic analysis, carbon isoscapes, ancient DNA (species and sex identification), tissue turnover rates, archaeological contexts, and bison ecology to show that the high δ13C value was not likely a result of local plant consumption, bison mobility, or trade. Instead, the bison hide was likely acquired via long-distance travel to/from an area of abundant C4 grasses far to the south or east. Expansive landscape knowledge gained through long-distance associations would have allowed Promontory caves inhabitants to make well-informed decisions about directions and routes of movement for a territorial shift, which seems to have occurred in the late thirteenth century

Prevalence of drug-resistant tuberculosis in Zimbabwe: A health facility-based cross-sectional survey.

OBJECTIVE: To determine the prevalence of resistance to rifampicin alone; rifampicin and isoniazid, and second-line anti-TB drugs among sputum smear-positive tuberculosis patients in Zimbabwe. DESIGN: A health facility-based cross-sectional survey. RESULTS: In total, 1114 (87.6%) new and 158 (12.4%) retreatment TB patients were enrolled. MTB was confirmed by Xpert MTB/RIF among 1184 (93%) smear-positive sputum samples. There were 64 samples with Xpert MTB/RIF-determined rifampicin resistance. However, two were rifampicin susceptible on phenotypic drug susceptibility testing. The prevalence of RR-TB was [4.0% (95% CI, 2.9, 5.4%), n=42/1043) and 14.2% (95% CI, 8.9, 21.1%; n=20/141) among new and retreatment patients, respectively. The prevalence of MDR-TB was 2.0% (95% CI, 1.3, 3.1%) and 6.4% (95% CI, 2.4, 10.3%) among new and retreatment TB patients, respectively. Risk factors for RR-TB included prior TB treatment, self-reported HIV infection, travel outside Zimbabwe for ≥one month (univariate), and age <15 years. Having at least a secondary education was protective against RR-TB. CONCLUSION: The prevalence of MDR-TB in Zimbabwe has remained stable since the 1994 subnational survey. However, the prevalence of rifampicin mono-resistance was double that of MDR-TB

Risk factors associated with default from multi- and extensively drug-resistant tuberculosis treatment, uzbekistan: a retrospective cohort analysis.

The Médecins Sans Frontières project of Uzbekistan has provided multidrug-resistant tuberculosis treatment in the Karakalpakstan region since 2003. Rates of default from treatment have been high, despite psychosocial support, increasing particularly since programme scale-up in 2007. We aimed to determine factors associated with default in multi- and extensively drug-resistant tuberculosis patients who started treatment between 2003 and 2008 and thus had finished approximately 2 years of treatment by the end of 2010

Associations of vitamin D pathway genes with circulating 25-hydroxyvitamin-D, 1,25-dihydroxyvitamin-D, and prostate cancer:a nested case-control study

Vitamin D pathway single nucleotide polymorphisms (SNPs) are potentially useful proxies for investigating whether circulating vitamin D metabolites [total 25-hydroxyvitamin-D, 25(OH)D; 1,25-dihydroxyvitamin, 1,25(OH)2D] are causally related to prostate cancer. We investigated associations of sixteen SNPs across seven genes with prostate-specific antigen-detected prostate cancer