Bisphosphonates in multicentric osteolysis, nodulosis and arthropathy (MONA) spectrum disorder - an alternative therapeutic approach.

Multicentric osteolysis, nodulosis and arthropathy (MONA) spectrum disorder is a rare inherited progressive skeletal disorder caused by mutations in the matrix metalloproteinase 2 (MMP2) gene. Treatment options are limited. Herein we present successful bisphosphonate therapy in three affected patients. Patients were treated with bisphosphonates (either pamidronate or zoledronate) for different time periods. The following outcome variables were assessed: skeletal pain, range of motion, bone densitometry, internal medical problems as well as neurocognitive function. Skeletal pain was dramatically reduced in all patients soon after initiation of therapy and bone mineral density increased. Range of motion did not significantly improve. One patient is still able to walk with aids at the age of 14 years. Neurocognitive development was normal in all patients. Bisphosphonate therapy was effective especially in controlling skeletal pain in MONA spectrum disorder. Early initiation of treatment seems to be particularly important in order to achieve the best possible outcome

Development and validation of MIX: comprehensive free software for meta-analysis of causal research data

BACKGROUND: Meta-analysis has become a well-known method for synthesis of quantitative data from previously conducted research in applied health sciences. So far, meta-analysis has been particularly useful in evaluating and comparing therapies and in assessing causes of disease. Consequently, the number of software packages that can perform meta-analysis has increased over the years. Unfortunately, it can take a substantial amount of time to get acquainted with some of these programs and most contain little or no interactive educational material. We set out to create and validate an easy-to-use and comprehensive meta-analysis package that would be simple enough programming-wise to remain available as a free download. We specifically aimed at students and researchers who are new to meta-analysis, with important parts of the development oriented towards creating internal interactive tutoring tools and designing features that would facilitate usage of the software as a companion to existing books on meta-analysis. RESULTS: We took an unconventional approach and created a program that uses Excel as a calculation and programming platform. The main programming language was Visual Basic, as implemented in Visual Basic 6 and Visual Basic for Applications in Excel 2000 and higher. The development took approximately two years and resulted in the 'MIX' program, which can be downloaded from the program's website free of charge. Next, we set out to validate the MIX output with two major software packages as reference standards, namely STATA (metan, metabias, and metatrim) and Comprehensive Meta-Analysis Version 2. Eight meta-analyses that had been published in major journals were used as data sources. All numerical and graphical results from analyses with MIX were identical to their counterparts in STATA and CMA. The MIX program distinguishes itself from most other programs by the extensive graphical output, the click-and-go (Excel) interface, and the educational features. CONCLUSION: The MIX program is a valid tool for performing meta-analysis and may be particularly useful in educational environments. It can be downloaded free of charge via or

Improved hospital-level risk adjustment for surveillance of healthcare-associated bloodstream infections: a retrospective cohort study

Background: To allow direct comparison of bloodstream infection (BSI) rates between hospitals for performance measurement, observed rates need to be risk adjusted according to the types of patients cared for by the hospital. However, attribute data on all individual patients are often unavailable and hospital-level risk adjustment needs to be done using indirect indicator variables of patient case mix, such as hospital level. We aimed to identify medical services associated with high or low BSI rates, and to evaluate the services provided by the hospital as indicators that can be used for more objective hospital-level risk adjustment

FRA2A is a CGG repeat expansion associated with silencing of AFF3

Folate-sensitive fragile sites (FSFS) are a rare cytogenetically visible subset of dynamic mutations. Of the eight molecularly characterized FSFS, four are associated with intellectual disability (ID). Cytogenetic expression results from CGG tri-nucleotide-repeat expansion mutation associated with local CpG hypermethylation and transcriptional silencing. The best studied is the FRAXA site in the FMR1 gene, where large expansions cause fragile X syndrome, the most common inherited ID syndrome. Here we studied three families with FRA2A expression at 2q11 associated with a wide spectrum of neurodevelopmental phenotypes. We identified a polymorphic CGG repeat in a conserved, brain-active alternative promoter of the AFF3 gene, an autosomal homolog of the X-linked AFF2/FMR2 gene: Expansion of the AFF2 CGG repeat causes FRAXE ID. We found that FRA2A-expressing individuals have mosaic expansions of the AFF3 CGG repeat in the range of several hundred repeat units. Moreover, bisulfite sequencing and pyrosequencing both suggest AFF3 promoter hypermethylation. cSNP-analysis demonstrates monoallelic expression of the AFF3 gene in FRA2A carriers thus predicting that FRA2A expression results in functional haploinsufficiency for AFF3 at least in a subset of tissues. By whole-mount in situ hybridization the mouse AFF3 ortholog shows strong regional expression in the developing brain, somites and limb buds in 9.5-12.5dpc mouse embryos. Our data suggest that there may be an association between FRA2A and a delay in the acquisition of motor and language skills in the families studied here. However, additional cases are required to firmly establish a causal relationship

Proteomic Analysis of Neisseria gonorrhoeae Biofilms Shows Shift to Anaerobic Respiration and Changes in Nutrient Transport and Outermembrane Proteins

Neisseria gonorrhoeae, the causative agent of gonorrhea, can form biofilms in vitro and in vivo. In biofilms, the organism is more resistant to antibiotic treatment and can serve as a reservoir for chronic infection. We have used stable isotope labeling by amino acids in cell culture (SILAC) to compare protein expression in biofilm and planktonic organisms. Two parallel populations of N. gonorrhoeae strain 1291, which is an arginine auxotroph, were grown for 48 h in continuous-flow chambers over glass, one supplemented with 13C6-arginine for planktonic organisms and the other with unlabeled arginine for biofilm growth. The biofilm and planktonic cells were harvested and lysed separately, and fractionated into three sequential protein extracts. Corresponding heavy (H) planktonic and light (L) biofilm protein extracts were mixed and separated by 1D SDS-PAGE gels, and samples were extensively analyzed by liquid chromatography-mass spectrometry. Overall, 757 proteins were identified, and 152 unique proteins met a 1.5-fold cutoff threshold for differential expression with p-values <0.05. Comparing biofilm to planktonic organisms, this set included 73 upregulated and 54 downregulated proteins. Nearly a third of the upregulated proteins were involved in energy metabolism, with cell envelope proteins making up the next largest group. Of the downregulated proteins, the largest groups were involved in protein synthesis and energy metabolism. These proteomics results were compared with our previously reported results from transcriptional profiling of gonococcal biofilms using microarrays. Nitrite reductase and cytochrome c peroxidase, key enzymes required for anaerobic growth, were detected as highly upregulated in both the proteomic and transcriptomic datasets. These and other protein expression changes observed in the present study were consistent with a shift to anaerobic respiration in gonococcal biofilms, although changes in membrane proteins not explicitly related to this shift may have other functions

Health Related Quality of Life among Patients with Tuberculosis and HIV in Thailand

INTRODUCTION: Health utilities of tuberculosis (TB) patients may be diminished by side effects from medication, prolonged treatment duration, physical effects of the disease itself, and social stigma attached to the disease. METHODS: We collected health utility data from Thai patients who were on TB treatment or had been successfully treated for TB for the purpose of economic modeling. Structured questionnaire and EuroQol (EQ-5D) and EuroQol visual analog scale (EQ-VAS) instruments were used as data collection tools. We compared utility of patients with two co-morbidities calculated using multiplicative model (U(CAL)) with the direct measures and fitted Tobit regression models to examine factors predictive of health utility and to assess difference in health utilities of patients in various medical conditions. RESULTS: Of 222 patients analyzed, 138 (62%) were male; median age at enrollment was 40 years (interquartile range [IQR], 35-47). Median monthly household income was 6,000 Baht (187 US$; IQR, 4,000-15,000 Baht [125-469 US$]). Concordance correlation coefficient between utilities measured using EQ-5D and EQ-VAS (U(EQ-5D) and U(VAS), respectively) was 0.6. U(CAL) for HIV-infected TB patients was statistically different from the measured U(EQ-5D) (p-value<0.01) and U(VAS) (p-value<0.01). In tobit regression analysis, factors independently predictive of U(EQ-5D) included age and monthly household income. Patients aged ≥40 years old rated U(EQ-5D) significantly lower than younger persons. Higher U(EQ-5D) was significantly associated with higher monthly household income in a dose response fashion. The median U(EQ-5D) was highest among patients who had been successfully treated for TB and lowest among multi-drug resistant TB (MDR-TB) patients who were on treatment. CONCLUSIONS: U(CAL) of patients with two co-morbidities overestimated the measured utilities, warranting further research of how best to estimate utilities of patients with such conditions. TB and MDR-TB treatments impacted on patients' self perceived health status. This effect diminished after successful treatment

Assessment of regression-based methods to adjust for publication bias through a comprehensive simulation study

<p>Abstract</p> <p>Background</p> <p>In meta-analysis, the presence of funnel plot asymmetry is attributed to publication or other small-study effects, which causes larger effects to be observed in the smaller studies. This issue potentially mean inappropriate conclusions are drawn from a meta-analysis. If meta-analysis is to be used to inform decision-making, a reliable way to adjust pooled estimates for potential funnel plot asymmetry is required.</p> <p>Methods</p> <p>A comprehensive simulation study is presented to assess the performance of different adjustment methods including the novel application of several regression-based methods (which are commonly applied to detect publication bias rather than adjust for it) and the popular Trim & Fill algorithm. Meta-analyses with binary outcomes, analysed on the log odds ratio scale, were simulated by considering scenarios with and without i) publication bias and; ii) heterogeneity. Publication bias was induced through two underlying mechanisms assuming the probability of publication depends on i) the study effect size; or ii) the p-value.</p> <p>Results</p> <p>The performance of all methods tended to worsen as unexplained heterogeneity increased and the number of studies in the meta-analysis decreased. Applying the methods conditional on an initial test for the presence of funnel plot asymmetry generally provided poorer performance than the unconditional use of the adjustment method. Several of the regression based methods consistently outperformed the Trim & Fill estimators.</p> <p>Conclusion</p> <p>Regression-based adjustments for publication bias and other small study effects are easy to conduct and outperformed more established methods over a wide range of simulation scenarios.</p

Excision Repair Cross-Complementation Group 1 (ERCC1) Status and Lung Cancer Outcomes: A Meta-Analysis of Published Studies and Recommendations

Despite discrepant results on clinical utility, several trials are already prospectively randomizing non-small cell lung cancer (NSCLC) patients by ERCC1 status. We aimed to characterize the prognostic and predictive effect of ERCC1 by systematic review and meta-analysis.Eligible studies assessed survival and/or chemotherapy response in NSCLC or SCLC by ERCC1 status. Effect measures of interest were hazard ratio (HR) for survival or relative risk (RR) for chemotherapy response. Random-effects meta-analyses were used to account for between-study heterogeneity, with unadjusted/adjusted effect estimates considered separately.23 eligible studies provided survival results in 2,726 patients. Substantial heterogeneity was observed in all meta-analyses (I(2) always >30%), partly due to variability in thresholds defining 'low' and 'high' ERCC1. Meta-analysis of unadjusted estimates showed high ERCC1 was associated with significantly worse overall survival in platinum-treated NSCLC (average unadjusted HR = 1.61, 95%CI:1.23-2.1, p = 0.014), but not in NSCLC untreated with chemotherapy (average unadjusted HR = 0.82, 95%CI:0.51-1.31). Meta-analysis of adjusted estimates was limited by variable choice of adjustment factors and potential publication bias (Egger's p<0.0001). There was evidence that high ERCC1 was associated with reduced response to platinum (average RR = 0.80; 95%CI:0.64-0.99). SCLC data were inadequate to draw firm conclusions.Current evidence suggests high ERCC1 may adversely influence survival and response in platinum-treated NSCLC patients, but not in non-platinum treated, although definitive evidence of a predictive influence is lacking. International consensus is urgently required to provide consistent, validated ERCC1 assessment methodology. ERCC1 assessment for treatment selection should currently be restricted to, and evaluated within, clinical trials