Timing of default from tuberculosis treatment: a systematic review

Objectives To provide a systematic assessment of the timing of default from tuberculosis (TB) treatment which could help to quantify the potential contribution of new shorter duration TB drugs to global TB control. Methods We performed a systematic review following QUOROM guidelines. MEDLINE was searched from 1998 to the present using the terms TB and default or drop‐out or compliance or adherence and therapy. A total of 840 articles were returned. A further detailed manual review selected 15 randomized trials and observational studies that reported timing of drop‐out and focused on developing countries. Results The selected studies comprised randomized controlled trials, retrospective record reviews, and qualitative assessments and spanned 10 countries. Both directly observed treatment (DOT) and non‐DOT programs were represented. Thus results were highly heterogeneous and not statistically aggregated. Data suggest, but do not conclude, that the majority of defaulters across the studies completed the 2‐month intensive phase of treatment. Conclusions There is insufficient high‐quality comparable information on the timing of default from TB treatment to permit any firm conclusions on trends in default. However, a substantial proportion of defaulters appear to leave treatment in the later stages of the current 6‐month regimen, suggesting that new TB chemotherapeutic agents which can reduce the length of treatment have the potential to improve global TB treatment success rates.     

Antidepressants and testicular cancer

Purpose

Re-examine association of fluoxetine and paroxetine with risk of testicular cancer noted in drug screening, with 4 years more follow-up and expanded study of these and other antidepressant drugs.

Methods

In the Kaiser Permanente Medical Care Program in Northern California, 906 men with testicular cancer diagnosed August 1996–December 2010 were compared with 38,253 matched controls with race/ethnicity recorded regarding receipt of antidepressant drugs at least 2 years before diagnosis or control index date. Analyses emphasized duration of use and histological subgroups.

Results

With control for race/ethnicity and use of other antidepressant drugs, odds ratios (OR) and 95 % confidence intervals (CI) for associations with testicular cancer were as follows: fluoxetine 1.22 (0.88–1.71), paroxetine 1.19 (0.78–1.83), and 1.21 (0.92–1.58) for all serotonin reuptake inhibitors. There was no statistically significant association with risk of all testicular cancers or their histological subtypes for any individual drug or for tricyclics or all antidepressants combined except for citalopram with all testicular cancers 2.55 (1.43–4.52) and those of mixed histology 4.36 (1.50–12.68) and nefazodone with embryonal cancers 9.79 (1.85–51.81). These could readily be chance findings in the context of the many analyses that were performed. Duration of use was not associated with risk of the drugs and drug groups with sufficient numbers of exposed cases for analysis.

Conclusions

We found little evidence to support a testicular carcinogenic effect of fluoxetine, paroxetine, or other antidepressant drugs, but a weakly positive association is not ruled out. The signals in prior screening may have been due to chance and/or uncontrolled confounding.     

MYC family amplification and clinical risk-factors interact to predict an extremely poor prognosis in childhood medulloblastoma

The MYC oncogenes are the most commonly amplified loci in medulloblastoma, and have previously been proposed as biomarkers of adverse disease prognosis by us and others. Here, we report focussed and comprehensive investigations of MYCC, MYCN and MYCL in an extensive medulloblastoma cohort (n?=?292), aimed to define more precisely their biological significance and optimal clinical application to direct improved disease risk-stratification and individualisation of therapy. MYCC and MYCN expression elevations were multifactorial, associated with high-risk (gene amplification, large-cell/anaplastic pathology (LCA)) and favourable-risk (WNT/SHH molecular subgroups) disease features. Highly variable cellular gene amplification patterns underlay overall MYC copy number elevations observed in tumour biopsies; we used these alternative measures together to define quantitative methodologies and thresholds for amplification detection in routinely collected tumour material. MYCC and MYCN amplification, but not gain, each had independent prognostic significance in non-infants (≥3.0-16.0?years), but MYCC conferred a greater hazard to survival than MYCN when considered across this treatment group. MYCN's weaker group-wide survival relationship may be explained by its pleiotropic behaviour between clinical disease-risk groups; MYCN predicted poor prognosis in clinical high-risk (metastatic (M+) or LCA), but not standard-risk, patients. Extending these findings, survival decreased in proportion to the total number of independently significant high-risk features present (LCA, M+ or MYCC/MYCN amplification). This cumulative-risk model defines a patient group characterised by ≥2 independent risk-factors and an extremely poor prognosis (<15% survival), which can be identified straightforwardly using the reported MYC amplification detection methodologies alongside clinical assessments, enabling targeting for novel/intensified therapies in future clinical studies.     

The geometry of N-hydroxymethyl compounds. Part 2: Crystal structures of 1-(4-carbethoxyphenyl)-3-hydroxymethyl-3-methyltriazene, N-hydroxymethylpentamethylmelamine and N-hydroxymethylbenzamide

Of the three N-hydroxymethyl compounds in the title, the first two have pronounced antineoplastic activity while the latter is biologically inactive. Crystals of the triazene have monoclinic symmetry with a = 8.540(1), b = 6.346(4), c = 22.460(5)A, beta = 98.75(2) degrees, and space group P21/c. The melamine forms disordered crystals of orthorhombic symmetry with a = 11.957(3), b = 17.267(3), c = 5.769(3)A. Of the symmetry elements in the observed space group Pnma, a mirror plane bisects the average molecule, implying that the hydroxymethyl group has equal probability of lying either side of this plane. Crystals of the benzamide show orthorhombic symmetry with a = 10.045(6), b = 7.763(3), c = 19.409(8)A, and space group Pbca. All three compounds are intermediates along biochemical demethylation pathways. The observed N-CH2OH distances, which are 1.469(5), 1.452(4), and 1.438(4)A respectively for the three compounds, correlate with the stability of this bond as measured by half-life. It is suggested that the correct degree of lability is important for biological activity, short strong bonds being too unreactive and excessively long ones being too unstable.     

International cooperation and health. Part I: Issues and concepts

The world is increasingly shaped by powerful global forces, many of which have consequences for human health and the social, economic, and environmental factors that influence health are increasingly determined at a supranational level. As a result, local or national level efforts to influence health determinants can have only a limited impact and it is all too easy for the individual public health practitioner to feel powerless. Yet while public health practitioners, on their own, may indeed be comparatively powerless, together they can achieve a great deal. Part I of this glossary explores a range of issues that arise as they seek to make a difference.     

Inequalities in birth outcomes in Russia: evidence from Tula oblast

This paper describes pregnancy outcomes and identifies their determinants in a Russian region, in the year 2000. It includes all births and perinatal deaths recorded as occurring in Tula oblast. The socio-economic correlates of adverse outcomes are explored using logistic regression; outcomes and their determinants are compared with other countries. Perinatal mortality in Tula in 2000 was 16.8/1000 births. The frequencies of low birthweight, low ponderal index and preterm birth were higher in Tula than in other industrialised countries. Mean birthweight increased with increasing education and was higher in married than in single mothers, and higher in ethnic Russians than in others. Survival in the perinatal period was substantially lower at all birthweights than in Sweden, which has the lowest neonatal mortality rate in Europe. There are wide inequalities in fetal development in Russia, especially in relation to maternal education, and the adverse outcomes appear to reflect a combination of adverse fetal development (implying the need for policies that improve the health of prospective mothers) and poor survival (implying the need for more effective care for newborn infants).     

Novel anti-bacterials against MRSA: synthesis of focussed combinatorial libraries of tri-substituted 2(5H)-furanones

Mucobromic and mucochloric acid were used as building blocks for the construction of a chemical combinatorial library of 3,4,5-trisubstituted 2(5H)-furanones. With these 2 butenolide building blocks, and eight alcohols a sublibrary of 16 dihalogenated 5-alkoxy-2(5H)-furanones was prepared. This sublibrary of 5-alkoxylated furanones was reacted with 16 amines generating a full size focussed combinatorial library of 256 individual compounds. This three dimensional combinatorial library of 3-halogen-4-amino-5-alkoxy-2(5H)-furanones was prepared around the benzimida-zolyl furanone lead structure by applying a solution phase combinatorial chemistry concept. Typical representatives of the library were purified and fully characterized and one x-ray structures was recorded, additionally. The 3-bromo-4-benzimizazolyl-5-methoxy-2(5H)furanone, Br-A-l, showed an MIC of 8 microg/ml against the multiresistant Staphylococcus aureus (MRSA).