Gender differences in tuberculosis treatment outcomes: a post hoc analysis of the REMoxTB study

BACKGROUND: In the REMoxTB study of 4-month treatment-shortening regimens containing moxifloxacin compared to the standard 6-month regimen for tuberculosis, the proportion of unfavourable outcomes for women was similar in all study arms, but men had more frequent unfavourable outcomes (bacteriologically or clinically defined failure or relapse within 18 months after randomisation) on the shortened moxifloxacin-containing regimens. The reason for this gender disparity in treatment outcome is poorly understood. METHODS: The gender differences in baseline variables were calculated, as was time to smear and culture conversion and Kaplan-Meier plots were constructed. In post hoc exploratory analyses, multivariable logistic regression modelling and an observed case analysis were used to explore factors associated with both gender and unfavourable treatment outcome. RESULTS: The per-protocol population included 472/1548 (30%) women. Women were younger and had lower rates of cavitation, smoking and weight (all p < 0.05) and higher prevalence of HIV (10% vs 6%, p = 0.001). They received higher doses (mg/kg) than men of rifampicin, isoniazid, pyrazinamide and moxifloxacin (p ≤ 0.005). There was no difference in baseline smear grading or mycobacterial growth indicator tube (MGIT) time to positivity. Women converted to negative cultures more quickly than men on Lowenstein-Jensen (HR 1.14, p = 0.008) and MGIT media (HR 1.19, p < 0.001). In men, the presence of cavitation, positive HIV status, higher age, lower BMI and 'ever smoked' were independently associated with unfavourable treatment outcome. In women, only 'ever smoked' was independently associated with unfavourable treatment outcome. Only for cavitation was there a gender difference in treatment outcomes by regimen; their outcome in the 4-month arms was significantly poorer compared to the 6-month treatment arm (p < 0.001). Women, with or without cavities, and men without cavities had a similar outcome on all treatment arms (p = 0.218, 0.224 and 0.689 respectively). For all other covariate subgroups, there were no differences in treatment effects for men or women. CONCLUSIONS: Gender differences in TB treatment responses for the shorter regimens in the REMoxTB study may be explained by poor outcomes in men with cavitation on the moxifloxacin-containing regimens. We observed that women with cavities, or without, on the 4-month moxifloxacin regimens had similar outcomes to all patients on the standard 6-month treatment. The biological reasons for this difference are poorly understood and require further exploration

New Insights into Fluoroquinolone Resistance in Mycobacterium tuberculosis: Functional Genetic Analysis of gyrA and gyrB Mutations

Fluoroquinolone antibiotics are among the most potent second-line drugs used for treatment of multidrug-resistant tuberculosis (MDR TB), and resistance to this class of antibiotics is one criterion for defining extensively drug resistant tuberculosis (XDR TB). Fluoroquinolone resistance in Mycobacterium tuberculosis has been associated with modification of the quinolone resistance determining region (QRDR) of gyrA. Recent studies suggest that amino acid substitutions in gyrB may also play a crucial role in resistance, but functional genetic studies of these mutations in M. tuberculosis are lacking. In this study, we examined twenty six mutations in gyrase genes gyrA (seven) and gyrB (nineteen) to determine the clinical relevance and role of these mutations in fluoroquinolone resistance. Transductants or clinical isolates harboring T80A, T80A+A90G, A90G, G247S and A384V gyrA mutations were susceptible to all fluoroquinolones tested. The A74S mutation conferred low-level resistance to moxifloxacin but susceptibility to ciprofloxacin, levofloxacin and ofloxacin, and the A74S+D94G double mutation conferred cross resistance to all the fluoroquinolones tested. Functional genetic analysis and structural modeling of gyrB suggest that M330I, V340L, R485C, D500A, D533A, A543T, A543V and T546M mutations are not sufficient to confer resistance as determined by agar proportion. Only three mutations, N538D, E540V and R485C+T539N, conferred resistance to all four fluoroquinolones in at least one genetic background. The D500H and D500N mutations conferred resistance only to levofloxacin and ofloxacin while N538K and E540D consistently conferred resistance to moxifloxacin only. Transductants and clinical isolates harboring T539N, T539P or N538T+T546M mutations exhibited low-level resistance to moxifloxacin only but not consistently. These findings indicate that certain mutations in gyrB confer fluoroquinolone resistance, but the level and pattern of resistance varies among the different mutations. The results from this study provide support for the inclusion of the QRDR of gyrB in molecular assays used to detect fluoroquinolone resistance in M. tuberculosis

Two years survival rate of class II composite resin restorations prepared by ART with and without a chemomechanical caries removal gel in primary molars

The aim was to test the null hypotheses that there is no difference: (1) in carious lesion development at the restoration margin between class II composite resin restorations in primary molars produced through the atraumatic restorative treatment (ART) with and without a chemomechanical caries removal gel and (2) in the survival rate of class II composite resin restorations between two treatment groups after 2 years. Three hundred twenty-seven children with 568 class II cavitated lesions were included in a parallel mouth study design. Four operators placed resin composite (Filtek Z 250) restorations bonded with a self-etch adhesive (Adper prompt L pop). Two independent examiners evaluated the restorations after 0.5, 1, and 2 years using the modified Ryge criteria. The Kaplan–Meier survival method was applied to estimate survival percentages. A high proportion of restorations were lost during the study period. Therefore, the first hypothesis could not be tested. No statistically significant difference was observed between the cumulative survival percentages of restorations produced by the two treatment approaches over the 2-year period (ART, 54.1 ± 3.4%; ART with Carisolv™, 46.0 ± 3.4%). This hypothesis was accepted. ART with chemomechanical gel might not provide an added benefit increasing the survival percentages of ART class II composite resin restorations in primary teeth

The role of non-medical therapeutic approaches in the rehabilitation of Complex Regional Pain Syndrome

Purpose of the review: Non-medical therapeutic approaches are fundamental to the management of Complex Regional Pain Syndrome (CRPS) in order to promote the best outcome for patients. This review focuses on three key approaches underpinning CRPS rehabilitation, namely: physiotherapy and occupational therapy, psychological approaches and education and self-management. Recent Findings: Recently published European standards outline the quality of therapeutic care that people with CRPS must receive. Early initiated therapy is essential to optimise outcomes, underpinned by patient education. Therapists should promote early movement of the affected limb and encourage re-engagement with usual activities as immobilisation is known to have negative outcomes. There is evidence to support the possible long-term benefit of graded motor imagery and mirror therapy. Psychological assessment should include identification of depression and post-traumatic stress disorder, as treatment of these conditions may improve the trajectory of CRPS. Novel therapies include neurocognitive approaches and those addressing spatial bias, both of which should provide a focus for future research.Summary: There exists a broad range of non-medical therapeutic approaches to rehabilitation for CPRS that are thought to be important. However, the evidence for their efficacy is limited. Further research using standardised outcomes would be helpful in developing targeted therapies for the future

Gastric cancers of Western European and African patients show different patterns of genomic instability

<p>Abstract</p> <p>Background</p> <p>Infection with <it>H. pylori </it>is important in the etiology of gastric cancer. Gastric cancer is infrequent in Africa, despite high frequencies of <it>H. pylori </it>infection, referred to as the African enigma. Variation in environmental and host factors influencing gastric cancer risk between different populations have been reported but little is known about the biological differences between gastric cancers from different geographic locations. We aim to study genomic instability patterns of gastric cancers obtained from patients from United Kingdom (UK) and South Africa (SA), in an attempt to support the African enigma hypothesis at the biological level.</p> <p>Methods</p> <p>DNA was isolated from 67 gastric adenocarcinomas, 33 UK patients, 9 Caucasian SA patients and 25 native SA patients. Microsatellite instability and chromosomal instability were analyzed by PCR and microarray comparative genomic hybridization, respectively. Data was analyzed by supervised univariate and multivariate analyses as well as unsupervised hierarchical cluster analysis.</p> <p>Results</p> <p>Tumors from Caucasian and native SA patients showed significantly more microsatellite instable tumors (p < 0.05). For the microsatellite stable tumors, geographical origin of the patients correlated with cluster membership, derived from unsupervised hierarchical cluster analysis (p = 0.001). Several chromosomal alterations showed significantly different frequencies in tumors from UK patients and native SA patients, but not between UK and Caucasian SA patients and between native and Caucasian SA patients.</p> <p>Conclusions</p> <p>Gastric cancers from SA and UK patients show differences in genetic instability patterns, indicating possible different biological mechanisms in patients from different geographical origin. This is of future clinical relevance for stratification of gastric cancer therapy.</p

Positive End-Expiratory Pressure may alter breathing cardiovascular variability and baroreflex gain in mechanically ventilated patients

<p>Abstract</p> <p>Background</p> <p>Baroreflex allows to reduce sudden rises or falls of arterial pressure through parallel RR interval fluctuations induced by autonomic nervous system. During spontaneous breathing, the application of positive end-expiratory pressure (PEEP) may affect the autonomic nervous system, as suggested by changes in baroreflex efficiency and RR variability. During mechanical ventilation, some patients have stable cardiorespiratory phase difference and high-frequency amplitude of RR variability (HF-RR amplitude) over time and others do not. Our first hypothesis was that a steady pattern could be associated with reduced baroreflex sensitivity and HF-RR amplitude, reflecting a blunted autonomic nervous function. Our second hypothesis was that PEEP, widely used in critical care patients, could affect their autonomic function, promoting both steady pattern and reduced baroreflex sensitivity.</p> <p>Methods</p> <p>We tested the effect of increasing PEEP from 5 to 10 cm H2O on the breathing variability of arterial pressure and RR intervals, and on the baroreflex. Invasive arterial pressure, ECG and ventilatory flow were recorded in 23 mechanically ventilated patients during 15 minutes for both PEEP levels. HF amplitude of RR and systolic blood pressure (SBP) time series and HF phase differences between RR, SBP and ventilatory signals were continuously computed by complex demodulation. Cross-spectral analysis was used to assess the coherence and gain functions between RR and SBP, yielding baroreflex-sensitivity indices.</p> <p>Results</p> <p>At PEEP 10, the 12 patients with a stable pattern had lower baroreflex gain and HF-RR amplitude of variability than the 11 other patients. Increasing PEEP was generally associated with a decreased baroreflex gain and a greater stability of HF-RR amplitude and cardiorespiratory phase difference. Four patients who exhibited a variable pattern at PEEP 5 became stable at PEEP 10. At PEEP 10, a stable pattern was associated with higher organ failure score and catecholamine dosage.</p> <p>Conclusions</p> <p>During mechanical ventilation, stable HF-RR amplitude and cardiorespiratory phase difference over time reflect a blunted autonomic nervous function which might worsen as PEEP increases.</p

Survival of atraumatic restorative treatment (ART) sealants and restorations: a meta-analysis

The purpose of this study is to perform a systematic investigation plus meta-analysis into survival of atraumatic restorative treatment (ART) sealants and restorations using high-viscosity glass ionomers and to compare the results with those from the 2005 ART meta-analysis. Until February 2010, four databases were searched. Two hundred four publications were found, and 66 reported on ART restorations or sealant survival. Based on five exclusion criteria, two independent reviewers selected the 29 publications that accounted for the meta-analysis. Confidence intervals (CI) and or standard errors were calculated and the heterogeneity variance of the survival rates was estimated. Location (school/clinic) was an independent variable. The survival rates of single-surface and multiple-surface ART restorations in primary teeth over the first 2 years were 93% (CI, 91–94%) and 62% (CI, 51–73%), respectively; for single-surface ART restorations in permanent teeth over the first 3 and 5 years it was 85% (CI, 77–91%) and 80% (CI, 76–83%), respectively and for multiple-surface ART restorations in permanent teeth over 1 year it was 86% (CI, 59–98%). The mean annual dentine lesion incidence rate, in pits and fissures previously sealed using ART, over the first 3 years was 1%. No location effect and no differences between the 2005 and 2010 survival rates of ART restorations and sealants were observed. The short-term survival rates of single-surface ART restorations in primary and permanent teeth, and the caries-preventive effect of ART sealants were high. Clinical relevance: ART can safely be used in single-surface cavities in both primary and permanent teeth. ART sealants have a high caries preventive effect