Characteristics of drug-resistant tuberculosis in Abkhazia (Georgia), a high-prevalence area in Eastern Europe

Although multidrug-resistant (MDR) tuberculosis (TB) is a major public health problem in Eastern Europe, the factors contributing to emergence, spread and containment of MDR-TB are not well defined. Here, we analysed the characteristics of drug-resistant TB in a cross-sectional study in Abkhazia (Georgia) between 2003 and 2005, where standard short-course chemotherapy is supplemented with individualized drug-resistance therapy. Drug susceptibility testing (DST) and molecular typing were carried out for Mycobacterium tuberculosis complex strains from consecutive smear-positive TB patients. Out of 366 patients, 60.4% were resistant to any first-line drugs and 21% had MDR-TB. Overall, 25% of all strains belong to the Beijing genotype, which was found to be strongly associated with the risk of MDR-TB (OR 25.9, 95% CI 10.2-66.0) and transmission (OR 2.8, 95% CI 1.6-5.0). One dominant MDR Beijing clone represents 23% of all MDR-TB cases. The level of MDR-TB did not decline during the study period, coinciding with increasing levels of MDR Beijing strains among previously treated cases. Standard chemotherapy plus individualized drug-resistance therapy, guided by conventional DST, might be not sufficient to control MDR-TB in Eastern Europe in light of the spread of "highly transmissible" MDR Beijing strains circulating in the community

Treatment of tuberculosis in a region with high drug resistance: Outcomes, drug resistance amplification and re-infection

Introduction: Emerging antituberculosis drug resistance is a serious threat for tuberculosis (TB) control, especially in Eastern European countries. Methods: We combined drug susceptibility results and molecular strain typing data with treatment outcome reports to assess the influence of drug resistance on TB treatment outcomes in a prospective cohort of patients from Abkhazia (Georgia). Patients received individualized treatment regimens based on drug susceptibility testing (DST) results. Definitions for antituberculosis drug resistance and treatment outcomes were in line with current WHO recommendations. First and second line DST, and molecular typing were performed in a supranational laboratory for Mycobacterium tuberculosis (MTB) strains from consecutive sputum smear-positive TB patients at baseline and during treatment. Results: At baseline, MTB strains were fully drug-susceptible in 189/326 (58.0%) of patients. Resistance to at least H or R (PDR-TB) and multidrug-resistance (MDR-TB) were found in 69/326 (21.2%) and 68/326 (20.9%) of strains, respectively. Three MDR-TB strains were also extensively resistant (XDR-TB). During treatment, 3/189 (1.6%) fully susceptible patients at baseline were re-infected with a MDR-TB strain and 2/58 (3.4%) PDR-TB patients became MDR-TB due to resistance amplification. 5/ 47 (10.6%) MDR- patients became XDR-TB during treatment. Treatment success was observed in 161/189 (85.2%), 54/69 (78.3%) and 22/68 (32.3%) of patients with fully drug susceptible, PDR- and MDR-TB, respectively. Development of ofloxacin resistance was significantly associated with a negative treatment outcome. Conclusion: In Abkhazia, a region with high prevalence of drug resistant TB, the use of individualized MDR-TB treatment regimens resulted in poor treatment outcomes and XDR-TB amplification. Nosocomial transmission of MDR-TB emphasizes the importance of infection control in hospitals

Physical Aspects of Axonemal Beating and Swimming

We discuss a two-dimensional model for the dynamics of axonemal deformations driven by internally generated forces of molecular motors. Our model consists of an elastic filament pair connected by active elements. We derive the dynamic equations for this system in presence of internal forces. In the limit of small deformations, a perturbative approach allows us to calculate filament shapes and the tension profile. We demonstrate that periodic filament motion can be generated via a self-organization of elastic filaments and molecular motors. Oscillatory motion and the propagation of bending waves can occur for an initially non-moving state via an instability termed Hopf bifurcation. Close to this instability, the behavior of the system is shown to be independent of microscopic details of the axoneme and the force-generating mechanism. The oscillation frequency however does depend on properties of the molecular motors. We calculate the oscillation frequency at the bifurcation point and show that a large frequency range is accessible by varying the axonemal length between 1 and 50$\mu$m. We calculate the velocity of swimming of a flagellum and discuss the effects of boundary conditions and externally applied forces on the axonemal oscillations.Comment: 14 pages, 8 figures, REVTE

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

Reconstructing ‘the Alcoholic’: Recovering from Alcohol Addiction and the Stigma this Entails

Public perception of alcohol addiction is frequently negative, whilst an important part of recovery is the construction of a positive sense of self. In order to explore how this might be achieved, we investigated how those who self-identify as in recovery from alcohol problems view themselves and their difficulties with alcohol and how they make sense of others’ responses to their addiction. Semi-structured interviews with six individuals who had been in recovery between 5 and 35 years and in contact with Alcoholics Anonymous were analysed using Interpretative Phenomenological Analysis. The participants were acutely aware of stigmatising images of ‘alcoholics’ and described having struggled with a considerable dilemma in accepting this identity themselves. However, to some extent they were able to resist stigma by conceiving of an ‘aware alcoholic self’ which was divorced from their previously unaware self and formed the basis for a new more knowing and valued identity

Multidrug-Resistant Tuberculosis Treatment Outcomes in Karakalpakstan, Uzbekistan: Treatment Complexity and XDR-TB among Treatment Failures

BACKGROUND: A pilot programme to treat multidrug-resistant TB (MDR-TB) was implemented in Karakalpakstan, Uzbekistan in 2003. This region has particularly high levels of MDR-TB, with 13% and 40% among new and previously treated cases, respectively. METHODOLOGY: This study describes the treatment process and outcomes for the first cohort of patients enrolled in the programme, between October 2003 and January 2005. Confirmed MDR-TB cases were treated with an individualised, second-line drug regimen based on drug susceptibility test results, while suspected MDR-TB cases were treated with a standardised regimen pending susceptibility results. PRINCIPAL FINDINGS: Of 108 MDR-TB patients, 87 were started on treatment during the study period. Of these, 33 (38%) were infected with strains resistant to at least one second-line drug at baseline, but none had initial ofloxacin resistance. Treatment was successful for 54 (62%) patients, with 13 (15%) dying during treatment, 12 (14%) defaulting and 8 (8%) failing treatment. Poor clinical condition and baseline second-line resistance contributed to treatment failure or death. Treatment regimens were changed in 71 (82%) patients due to severe adverse events or drug resistance. Adverse events were most commonly attributed to cycloserine, ethionamide and p-aminosalicylic acid. Extensively drug resistant TB (XDR-TB) was found among 4 of the 6 patients who failed treatment and were still alive in November 2006. CONCLUSIONS: While acceptable treatment success was achieved, the complexity of treatment and the development of XDR-TB among treatment failures are important issues to be addressed when considering scaling up MDR-TB treatment

Mycobacterium tuberculosis Cluster with Developing Drug Resistance, New York, New York, USA, 2003–2009

In 2004, identification of patients infected with the same Mycobacterium tuberculosis strain in New York, New York, USA, resulted in an outbreak investigation. The investigation involved data collection and analysis, establishing links between patients, and forming transmission hypotheses. Fifty-four geographically clustered cases were identified during 2003–2009. Initially, the M. tuberculosis strain was drug susceptible. However, in 2006, isoniazid resistance emerged, resulting in isoniazid-resistant M. tuberculosis among 17 (31%) patients. Compared with patients with drug-susceptible M. tuberculosis, a greater proportion of patients with isoniazid-resistant M. tuberculosis were US born and had a history of illegal drug use. No patients named one another as contacts. We used patient photographs to identify links between patients. Three links were associated with drug use among patients infected with isoniazid-resistant M. tuberculosis. The photographic method would have been more successful if used earlier in the investigation. Name-based contact investigation might not identify all contacts, particularly when illegal drug use is involved

Childhood bullying victimization, self-labelling and help-seeking for mental health problems

Purpose: Previous research found sustained high levels of mental health service use among adults who experienced bullying victimization during childhood. This could be due to increased psychopathology among this group, but other factors, such as self-perception as having a mental health problem, might contribute to increased service use. Additionally, the relationship between informal help-seeking for mental health problems and bullying victimization is incompletely understood. Methods: The present study examined associations between the frequency of bullying victimization and both formal service use and informal help-seeking for mental health problems independent from psychopathology. Data on bullying victimization, service use, informal help-seeking for mental health problems, psychopathology, and self-labelling as a person with mental illness were collected among 422 young people aged 13-22 years. Results: In logistic regression models, controlling for past and current psychopathology and using no bullying victimization as the reference category, we identified a greater likelihood of mental health service use among persons who experienced frequent bullying victimization, as well as a greater likelihood of seeking informal help among persons who experienced occasional victimization. Increased self-identification as a person with mental illness completely mediated the positive association between frequent bullying victimization and mental health service use. Conclusions: Our findings suggest that services to support persons who experienced frequent bullying victimization should focus on improving empowerment and self-perception. Additionally, there might be unserved need for formal support among those who experienced occasional bullying victimization

HCN Channels Are Not Required for Mechanotransduction in Sensory Hair Cells of the Mouse Inner Ear

The molecular composition of the hair cell transduction channel has not been identified. Here we explore the novel hypothesis that hair cell transduction channels include HCN subunits. The HCN family of ion channels includes four members, HCN1-4. They were orginally identified as the molecular correlates of the hyperpolarization-activated, cyclic nucleotide gated ion channels that carry currents known as If, IQ or Ih. However, based on recent evidence it has been suggested that HCN subunits may also be components of the elusive hair cell transduction channel. To investigate this hypothesis we examined expression of mRNA that encodes HCN1-4 in sensory epithelia of the mouse inner ear, immunolocalization of HCN subunits 1, 2 and 4, uptake of the transduction channel permeable dye, FM1-43 and electrophysiological measurement of mechanotransduction current. Dye uptake and transduction current were assayed in cochlear and vestibular hair cells of wildtype mice exposed to HCN channel blockers or a dominant-negative form of HCN2 that contained a pore mutation and in mutant mice that lacked HCN1, HCN2 or both. We found robust expression of HCNs 1, 2 and 4 but little evidence that localized HCN subunits in hair bundles, the site of mechanotransduction. Although high concentrations of the HCN antagonist, ZD7288, blocked 50–70% of the transduction current, we found no reduction of transduction current in either cochlear or vestibular hair cells of HCN1- or HCN2- deficient mice relative to wild-type mice. Furthermore, mice that lacked both HCN1 and HCN2 also had normal transduction currents. Lastly, we found that mice exposed to the dominant-negative mutant form of HCN2 had normal transduction currents as well. Taken together, the evidence suggests that HCN subunits are not required for mechanotransduction in hair cells of the mouse inner ear