Characterization of Genomic Variants Associated with Resistance to Bedaquiline and Delamanid in Naive Mycobacterium tuberculosis Clinical Strains.

The role of mutations in genes associated with phenotypic resistance to bedaquiline (BDQ) and delamanid (DLM) in Mycobacterium tuberculosis complex (MTBc) strains is poorly characterized. A clear understanding of the genetic variants' role is crucial to guide the development of molecular-based drug susceptibility testing (DST). In this work, we analyzed all mutations in candidate genomic regions associated with BDQ- and DLM-resistant phenotypes using a whole-genome sequencing (WGS) data set from a collection of 4,795 MTBc clinical isolates from six countries with a high burden of tuberculosis (TB). From WGS analysis, we identified 61 and 163 unique mutations in genomic regions potentially involved in BDQ- and DLM-resistant phenotypes, respectively. Importantly, all strains were isolated from patients who likely have never been exposed to these medicines. To characterize the role of mutations, we calculated the free energy variation upon mutations in the available protein structures of Ddn (DLM), Fgd1 (DLM), and Rv0678 (BDQ) and performed MIC assays on a subset of MTBc strains carrying mutations to assess their phenotypic effect. The combination of structural and phenotypic data allowed for cataloguing the mutations clearly associated with resistance to BDQ (n = 4) and DLM (n = 35), only two of which were previously described, as well as about a hundred genetic variants without any correlation with resistance. Significantly, these results show that both BDQ and DLM resistance-related mutations are diverse and distributed across the entire region of each gene target, which is of critical importance for the development of comprehensive molecular diagnostic tools.

Epidemiology of hip fracture and the development of a FRAX model for Uzbekistan.

A prospective population-based survey in a region of the Republic of Uzbekistan determined the incidence of fractures at the hip. The hip fracture rates were used to create a FRAX® model to facilitate fracture risk assessment in Uzbekistan. OBJECTIVE: This paper describes the epidemiology of hip fracture in the Republic of Uzbekistan that was used to develop a country-specific FRAX® tool for fracture prediction. METHODS: During a 1-year (2016/17) prospective population-based survey in the Pap district of the Republic of Uzbekistan, hip fractures were prospectively identified from hospital registers, trauma centres and primary care and community sources. Age- and sex-specific incidence of hip fracture and national mortality rates were incorporated into a FRAX model for Uzbekistan. Fracture probabilities were compared with those from neighbouring Kazakhstan and Kyrgystan. RESULTS: Approximately 41% of hip fracture cases did not come to medical attention, and two thirds of patients overall were not admitted to hospital. The incidence of hip fracture applied nationally suggested that the estimated number of hip fractures nationwide in persons over the age of 50 years for 2015 was 16,764 and is predicted to increase more than three-fold to 60,272 in 2050. FRAX-based probabilities were higher in Uzbekistan than Kazakhstan or Kyrgystan. CONCLUSION: The FRAX model should enhance accuracy of determining fracture probability among the Uzbek population and help guide decisions about treatment.

[Associations of lipoproteins with bone mass in postmenopausal women].

AIM: To study an association between blood lipid composition and bone mass in Russian postmenopausal women. SUBJECTS AND METHODS: The cross-sectional study included 373 postmenopausal women aged 45-80 years who were examined to diagnose osteoporosis in outpatient settings. Height, body weight, and waist and hip circumferences (WC and HC) were measured before densitometry. Quetelet's index was calculated as a ratio of weight (kg) to height (m2). The concentration of lipids and apolipoproteins (apo) AІ and B were measured by enzyme immunoassay. Bone mineral density (BMD) in the spine and proximal femur (PF) was estimated by dual-energy X-ray absorptiometry. RESULTS: According to bone mass, the patients were divided into three groups: 1) osteoporosis (OP); 2) osteopenia; 3) normal BMD. The levels of total cholesterol and high-density lipoprotein (HDL) cholesterol were significantly higher in the postmenopausal women with OP than in those with normal bone mass. There was a negative correlation of cholesterol and HDL cholesterol levels with lumbar spine BMD and that of HDL levels with BMD in the femoral neck (FN) and entire PF. The level of lipoprotein (a) (LPa) was significantly lower in the group of patients with OP and positively correlated with BMD in FN and entire PF. After adjustment for age, the duration of menopause, Quetelet's index, and WC/HC association remained only between LPa and FN BMD. CONCLUSION: Multivariate regression analysis failed to confirm a trend towards decreased BMD and increased HDL cholesterol. This suggests that the association of HDL cholesterol with bone mass is apparently mediated by other factors and, above all, with age, postmenopausal hormonal status and body weight.

First national survey of anti-tuberculosis drug resistance in Azerbaijan and risk factors analysis.

SETTING: Civilian population of the Republic of Azerbaijan. OBJECTIVES: To determine patterns of anti-tuberculosis drug resistance among new and previously treated pulmonary tuberculosis (TB) cases, and explore their association with socio-demographic and clinical characteristics. DESIGN: National cross-sectional survey conducted in 2012-2013. RESULTS: Of 789 patients (549 new and 240 previously treated) who met the enrolment criteria, 231 (42%) new and 146 (61%) previously treated patients were resistant to any anti-tuberculosis drug; 72 (13%) new and 66 (28%) previously treated patients had multidrug-resistant TB (MDR-TB). Among MDR-TB cases, 38% of new and 46% of previously treated cases had pre-extensively drug-resistant TB (pre-XDR-TB) or XDR-TB. In previously treated cases, 51% of those who had failed treatment had MDR-TB, which was 15 times higher than in relapse cases (OR 15.2, 95%CI 6-39). The only characteristic significantly associated with MDR-TB was a history of previous treatment (OR 3.1, 95%CI 2.1-4.7); for this group, history of incarceration was an additional risk factor for MDR-TB (OR 2.8, 95%CI 1.1-7.4). CONCLUSION: Azerbaijan remains a high MDR-TB burden country. There is a need to implement countrywide control and innovative measures to accelerate early diagnosis of drug resistance in individual patients, improve treatment adherence and strengthen routine surveillance of drug resistance.

[Topicality of an individual computer-aided database for the analysis of epidemiological indices in Azerbaijan].

The prevalence of drug-resistant tuberculosis and especially multidrug-resistant tuberculosis arouses special alarm and these forms of tuberculosis are widespread in the countries of the former Soviet countries. To study this problem in the republic, the authors analyze the records obtained by the Research Institute of Pulmonary Diseases from all TB facilities in 2000-2007 and the data of a test for drug sensitivity in Mycobacterium tuberculosis in the cohort of new cases of tuberculosis in 2006-2007. Sixty-nine (100%) TB service facilities have submitted the records. A total of 33 019 new cases of tuberculosis in 2000-2007 have been analyzed. The results of a test for drug resistance in MBT in 503 new cases have been included into the study and analyzed. The analysis suggests that there is a certain share of conventionality and inadequate validity of the data obtained from consolidated areas. In each of the 11 zones, there are areas with great variations in morbidity and morbidity rates. This shows it necessary to make a target monitoring of the epidemic situation in the regions and to strive not to consolidate for ease the neighboring administrative areas for ease during an analysis; it is expedient to divide the areas into adequately minimum ones. This point monitoring requires individualized electronic systems that provide the input of personified information on each new case of tuberculosis. It is recommended that the individualized electronic system for monitoring the basic epidemiological parameters, including the prevalence of drug-resistant tuberculosis, to be introduced, by taking into account the demographic, social, and geographical features of administrative areas.