QT prolongation in the STREAM Stage 1 Trial

BACKGROUND: STREAM (Standardized Treatment Regimen of Anti-TB Drugs for Patients with MDR-TB) Stage 1 demonstrated non-inferior efficacy of a shortened regimen (the Short regimen) for rifampicin-resistant TB (RR-TB) compared to the contemporaneous WHO-recommended regimen. This regimen included moxifloxacin and clofazimine, known to cause QT prolongation, and severe prolongation was more common on the Short regimen. Here we investigate risk factors for QT prolongation with the Short regimen.METHODS: Data from patients prescribed the Short regimen (n = 282) were analysed to identify risk factors for severe QT prolongation (QT/QTcF ≥500 ms or ≥60 ms increase in QTcF from baseline).RESULTS: Of the 282 patients on the Short regimen, 94 (33.3%) developed severe QT prolongation: 31 QT/QTcF ≥500 ms; 92 experienced ≥60 ms QTcF increase from baseline. The median time to QT/QTcF ≥500 ms was 20 weeks (IQR 8-28), and the time to ≥60 ms increase from baseline was 18 weeks (IQR 8-28). Prolongation ≥500 ms was most frequent in patients from Mongolia (10/22, 45.5%) compared with 3.5-11.9% at other sites, P < 0.001. Higher baseline QTcF increased risk of prolongation to ≥500 ms (QTcF ≥400 ms: OR 5.99, 95% CI 2.04-17.62).CONCLUSION: One third of patients on the Short regimen developed severe QT prolongation. QT/QTcF ≥500 ms was more common in patients from Mongolia and in those with a higher baseline QTcF, which may have implications for implementation of treatment

Treatment outcome of rhabdomyosarcoma in Hong Kong Chinese children

Objectives: To review the treatment outcome of rhabdomyosarcoma in Hong Kong Chinese children. Design: Retrospective review. Setting: University teaching hospital, Hong Kong. Patients: Consecutive cases of rhabdomyosarcoma diagnosed and treated by the Department of Paediatrics and Adolescent Medicine of Queen Mary Hospital between 1989 and 2005. Each patient was staged and treated according to the Intergroup Rhabdomyosarcoma Study guidelines. Main outcome measures: Overall and event-free survival rates, and toxicity data. Results: Of 19 patients (8 males and 11 females), 14 (74%) were younger than 10 years old. The median age at diagnosis was 6 (range, 0.5-17) years. Primary sites of rhabdomyosarcoma included: the head and neck (n=8; 6 classified as cranial parameningeal), genitourinary (3), extremity (3), pelvis (3), and trunk (2). Thirteen (68%) had embryonal and six (32%) had alveolar histology. Two, 2, 9, and 6 were classified as belonging to Intergroup Rhabdomyosarcoma Study groups 1, 2, 3, and 4, respectively. Respective 5-year overall and event-free survival rates of the entire cohort were 49% (95% confidence interval, 26-73%) and 32% (10-55%), with a median follow-up of 3.4 (range, 0.2-16.7) years. In non-metastatic cases (Intergroup Rhabdomyosarcoma Study groups 1-3), the 5-year overall survival rate was 66% (95% confidence interval, 39-93%) and in metastatic cases (group 4) it was 17% (0-46%). The 5-year overall survival rate for patients aged less than 10 years was 60% (95% confidence interval, 33-87%) compared to 20% (0-55%) in those aged 10 years and over. Significant treatment-related toxicities including myelosuppression, infections, peripheral neuropathy, and second cancers were encountered. Conclusions: Treatment outcome of rhabdomyosarcoma in this cohort of Chinese children was less favourable than that reported in international studies. Whilst the main reason could have been related to the high proportion of metastatic cases, also non-metastatic cases faired worse. Improved outcomes may be achieved by advances in multidisciplinary (paediatric oncology, pathology, radiotherapy, and surgery) management and supportive care.published_or_final_versio

Investigation of the efficacy of the short regimen for rifampicin-resistant TB from the STREAM trial

Background: The STREAM trial demonstrated that a 9–11-month “short” regimen had non-inferior efficacy and comparable safety to a 20+ month “long” regimen for the treatment of rifampicin-resistant tuberculosis. Imbalance in the components of the composite primary outcome merited further investigation. / Methods: Firstly, the STREAM primary outcomes were mapped to alternatives in current use, including WHO programmatic outcome definitions and other recently proposed modifications for programmatic or research purposes. Secondly, the outcomes were re-classified according to the likelihood that it was a Failure or Relapse (FoR) event on a 5-point Likert scale: Definite, Probable, Possible, Unlikely, and Highly Unlikely. Sensitivity analyses were employed to explore the impact of informative censoring. The protocol-defined modified intention-to-treat (MITT) analysis population was used for all analyses. / Results: Cure on the short regimen ranged from 75.1 to 84.2% across five alternative outcomes. However, between-regimens results did not exceed 1.3% in favor of the long regimen (95% CI upper bound 10.1%), similar to the primary efficacy results from the trial. Considering only Definite or Probable FoR events, there was weak evidence of a higher risk of FoR in the short regimen, HR 2.19 (95%CI 0.90, 5.35), p = 0.076; considering only Definite FoR events, the evidence was stronger, HR 3.53 (95%CI 1.05, 11.87), p = 0.030. Cumulative number of grade 3–4 AEs was the strongest predictor of censoring. Considering a larger effect of informative censoring attenuated treatment differences, although 95% CI were very wide. / Conclusion: Five alternative outcome definitions gave similar overall results. The risk of failure or relapse (FoR) may be higher in the short regimen than in the long regimen, highlighting the importance of how loss to follow-up and other censoring is accounted for in analyses. The outcome of time to FoR should be considered as a primary outcome for future drug-sensitive and drug-resistant TB treatment trials, provided sensitivity analyses exploring the impact of departures from independent censoring are also included

Failure or relapse predictors for the STREAM Stage 1 short regimen for RR-TB

BACKGROUND: STREAM (Standardised Treatment Regimens of Anti-tuberculosis drugs for Multidrug-Resistant Tuberculosis) Stage 1 demonstrated non-inferior efficacy of a short regimen for rifampicin-resistant TB (RR-TB) compared to a long regimen as recommended by the WHO. The present paper analyses factors associated with a definite or probable failure or relapse (FoR) event in participants receiving the Short regimen.METHODS: This analysis is restricted to 253 participants allocated to the Short regimen and is based on the protocol-defined modified intention to treat (mITT) population. Multivariable Cox regression models were built using backwards elimination with an exit probability of P = 0.157, equivalent to the Akaike Information Criterion, to identify factors independently associated with a definite or probable FoR event.RESULTS: Four baseline factors were identified as being significantly associated with the risk of definite or probable FoR (male sex, a heavily positive baseline smear grade, HIV co-infection and the presence of costophrenic obliteration). There was evidence of association of culture positivity at Week 8 and FoR in a second model and Week 16 smear positivity, presence of diabetes and of smoking in a third model.CONCLUSION: The factors associated with FoR outcomes identified in this analysis should be considered when determining the optimal shortened treatment regimen

Modeling of single mode optical fiber having a complicated refractive index profile by using modified scalar finite element method

A numerical method based on modified scalar finite element method (SC-FEM) is presented and programmed on MATLAB platform for optical fiber modeling purpose. We have estimated the dispersion graph, mode cut off condition, and group delay and waveguide dispersion for highly complicated chirped type refractive index profile fiber. The convergence study of our FEM formulation is carried out with respect to the number of division in core. It has been found that the numerical error becomes less than 2 % when the number of divisions in the core is more then 30. To predict the accurate waveguide dispersion characteristics, we need to compute expression (d^2 (Vb))/(dV^2 ) numerically by the FEM method. For that the normalized propagation constant b (in terms of β) should be an accurate enough up to around 6 decimal points. To achieve this target, we have used 1 million sampling points in our FEM simulations. Further to validate our results we have derived the higher order polynomial expression for each case. Comparison with other methods in calculation of normalized propagation constant is found to be satisfactory. In traditional FEM analysis a spurious solution is generated because the functional does not satisfy the boundary conditions in the original waveguide problem, However in our analysis a new term that compensate the missing boundary condition has been added in the functional to eliminate the spurious solutions. Our study will be useful for the analysis of optical fiber having varying refractive index profile

Macrodystrophia lipomatosa involving multiple nerves

Macrodystrophia lipomatosa (MDL), a rare congenital disorder, is considered by some to be a localized form of Proteus syndrome. The implication of the PTEN (phosphatase and tensin homolog deleted on chromosome 10) gene in both strengthens this belief. We present a case who had MDL in multiple nerve territories—all on the same side of the body—with hypertrophy of mainly fibroadipose tissue throughout their distribution, thus pointing to a form of localized hemihypertrophy; both hemihypertrophy and lipomatous tumors are components of Proteus syndrome

A local survey on skeletal related complications in patients with carcinoma of prostate having hormonal therapy

Moderated Poster (Free Paper) Session I - Prostate : Benign and Malignant: MP.1-5香港泌尿外科學會published_or_final_versionThe 17th Annual Scientific Meeting of the Hong Kong Urological Association, Hong Kong, 6 November 2011. In Program Book, 2011, p. 5

A human MAP kinase interactome.

Mitogen-activated protein kinase (MAPK) pathways form the backbone of signal transduction in the mammalian cell. Here we applied a systematic experimental and computational approach to map 2,269 interactions between human MAPK-related proteins and other cellular machinery and to assemble these data into functional modules. Multiple lines of evidence including conservation with yeast supported a core network of 641 interactions. Using small interfering RNA knockdowns, we observed that approximately one-third of MAPK-interacting proteins modulated MAPK-mediated signaling. We uncovered the Na-H exchanger NHE1 as a potential MAPK scaffold, found links between HSP90 chaperones and MAPK pathways and identified MUC12 as the human analog to the yeast signaling mucin Msb2. This study makes available a large resource of MAPK interactions and clone libraries, and it illustrates a methodology for probing signaling networks based on functional refinement of experimentally derived protein-interaction maps

Brief Overview of Bioinformatics Activities in Singapore

10.1371/journal.pcbi.1000508PLoS Computational Biology5

The Evaluation of a Standardised Treatment Regimen of anti-Tuberculosis Drugs for Patients with MDR-TB (STREAM): study protocol for a randomised controlled trial

Background: In contrast to drug-sensitive tuberculosis, the guidelines for the treatment of multi-drug-resistant tuberculosis (MDR-TB) have a very poor evidence base; current recommendations, based on expert opinion, are that patients should be treated for a minimum of 20 months. A series of cohort studies conducted in Bangladesh identified a nine-month regimen with very promising results. There is a need to evaluate this regimen in comparison with the currently recommended regimen in a randomized controlled trial in a variety of settings, including patients with HIV-coinfection. Methods/Design: STREAM is a multi-centre randomized trial of n on-inferiority design comparing a nine-month regimen to the treatment currently recommended by th e World Health Organization in patients with MDR pulmonary TB with no evidence on line probe assay of fluoroquinolone or kanamycin resistance. The nine-month regimen includes clofazimine and high-dose moxifloxacin and can be extended to 11 months in the event of delay in smear conversion. The primary outcome is based on the bacteriological status of the patients at 27 months post-randomization. Based on the assumption that the nine-month regimen will be slightly more effective than the control regimen and, given a 10% margin of non-inferiority, a total of 400 patients are required to be enrolled. Health economics data are being collected on all patients in selected sites. Discussion: The results from the study in Bangladesh and cohorts in progress elsewhere are encouraging, but for this regimen to be recommended more widely than in a research setting, robust evidence is needed from a randomized clinical trial. Results from the STREAM t rial together with data fr om ongoing cohorts should provide the evidence necessary to revise current recommendations for the treatment for MDR-TB. Trial registration: This trial was registered with clincaltrials.gov (registration number: ISRCTN78372190) on 14 October 2010