Treatment outcomes for children with multidrug-resistant tuberculosis: a systematic review and meta-analysis

BACKGROUND: Paediatric multidrug-resistant (MDR) tuberculosis is a public health challenge of growing concern, accounting for an estimated 15% of all global cases of MDR tuberculosis. Clinical management is especially challenging, and recommendations are based on restricted evidence. We aimed to assess existing evidence for the treatment of MDR tuberculosis in children. METHODS: We did a systematic review and meta-analysis of published and unpublished studies reporting treatment outcomes for children with MDR tuberculosis. We searched PubMed, Ovid, Embase, Cochrane Library, PsychINFO, and BioMedCentral databases up to Oct 31, 2011. Eligible studies included five or more children (aged ≤16 years) with MDR tuberculosis within a defined treatment cohort. The primary outcome was treatment success, defined as a composite of cure and treatment completion. RESULTS: We identified eight studies, which reported treatment outcomes for a total of 315 patients. We recorded much variation in the characteristics of patients and programmes. Time to appropriate treatment varied from 2 days to 46 months. Average duration of treatment ranged from 6 months to 34 months, and duration of follow-up ranged from 12 months to 37 months. The pooled estimate for treatment success was 81·67% (95% CI 72·54-90·80). Across all studies, 5·9% (95% CI 1·3-10·5) died, 6·2% (2·3-10·2) defaulted, and 39·1% (28·7-49·4) had an adverse event. The most common drug-related adverse events were nausea and vomiting. Other serious adverse events were hearing loss, psychiatric effects, and hypothyroidism. INTERPRETATION: The treatment of paediatric MDR tuberculosis has been neglected, but when children are treated outcomes can be achieved that are at least as good as those reported for adults. Programmes should be encouraged to report outcomes in children to improve the knowledge base for care, especially as new drugs become available. FUNDING: None

Same-Sex Marriage: The Evolving Landscape for Employee Benefits

This article deals with the aftermath of the Goodridge decision in terms of employment benefits for partners in a same-sex marriage, particularly in the interstate context. Because marriages in one state are generally recognized in all other states, the article focuses on how employers must treat a Massachusetts same-sex marriage in light of the Defense of Marriage Act and its prohibition of same-sex marriage for the purpose of federal employment benefits

Multidrug resistant pulmonary tuberculosis treatment regimens and patient outcomes: an individual patient data meta-analysis of 9,153 patients.

Treatment of multidrug resistant tuberculosis (MDR-TB) is lengthy, toxic, expensive, and has generally poor outcomes. We undertook an individual patient data meta-analysis to assess the impact on outcomes of the type, number, and duration of drugs used to treat MDR-TB

Retail ring-fencing of banks and its implications

Financial stability remains a key theme globally in view of the Euro zone debt crisis. The latest strategy by Germany and France is to ring-fence the crisis among the PIIGS countries (Portugal, Greece, Ireland, Italy and Spain). In the United Kingdom, the big four major banks have all responded to the Independent Commission of Bankings interim report key recommendation: ring-fencing retail operations into a separate subsidiary of any bank that wishes to operate in the United Kingdom. The report has clearly discussed the advantages and disadvantages of various types of subsidiarisation. Retail ring-fencing is considered a compromise as full subsidiarisation is too costly and operational subsidiarisation is too minimal. The Independent Commission of Banking published its final report on 12 September 2011. They recommended ring-fencing retail banking and a 10 per cent equity baseline. This article focuses on structural reforms of UK banks. It aims to address the question of financial stability from a wider European perspective. The first question is whether cross-border retail banking in the European Economic Area (EEA) is best served by branches or subsidiaries? The second question concerns the legality of setting up subsidiaries in the European Union (EU). Although there are no legal problems for UK-based banks setting up subsidiaries for their retail activities, there might be a legal hurdle for requiring foreign banks setting up subsidiaries in the United Kingdom. The third question concerns EU cross-border banking regulation and supervision. Are the passporting system and the home country supervisory approach still applicable in this post-financial crisis era? Many factors influence the choice of setting up branches or subsidiaries. However, the general position is that branches are more suited for wholesale/investment activities because of ease of funds transfer. Subsidiaries are more suitable for retail banking because of the limited liability principle and extensive local network. Effective cross-border banking must be accompanied by effective supervision and resolution regimes. The passporting concept under EU law and home country dominance are somewhat dated post-financial crisis. Host country control should play a dominant part in financial regulation, especially in the light of the importance of subsidiaries and the limited liability principle associated with them. The Icelandic bank crisis and collapse of Lehman Brothers International Europe illustrate the importance of host country control. Finally, the author argues that requiring banks to hold its retail activities in the form of subsidiaries in another European country is necessary to achieve financial stability. © 2012 Macmillan Publishers Ltd

Aggressive Regimens for Multidrug-Resistant Tuberculosis Decrease All-Cause Mortality

Rationale: A better understanding of the composition of optimal treatment regimens for multidrug-resistant tuberculosis (MDR-TB) is essential for expanding universal access to effective treatment and for developing new therapies for MDR-TB. Analysis of observational data may inform the definition of an optimized regimen. Objectives: This study assessed the impact of an aggressive regimen–one containing at least five likely effective drugs, including a fluoroquinolone and injectable–on treatment outcomes in a large MDR-TB patient cohort. Methods: This was a retrospective cohort study of patients treated in a national outpatient program in Peru between 1999 and 2002. We examined the association between receiving an aggressive regimen and the rate of death. Measurements and Main Results: In total, 669 patients were treated with individualized regimens for laboratory-confirmed MDR-TB. Isolates were resistant to a mean of 5.4 (SD 1.7) drugs. Cure or completion was achieved in 66.1% (442) of patients; death occurred in 20.8% (139). Patients who received an aggressive regimen were less likely to die (crude hazard ratio [HR]: 0.62; 95% CI: 0.44,0.89), compared to those who did not receive such a regimen. This association held in analyses adjusted for comorbidities and indicators of severity (adjusted HR: 0.63; 95% CI: 0.43,0.93). Conclusions: The aggressive regimen is a robust predictor of MDR-TB treatment outcome. TB policy makers and program directors should consider this standard as they design and implement regimens for patients with drug-resistant disease. Furthermore, the aggressive regimen should be considered the standard background regimen when designing randomized trials of treatment for drug-resistant TB

The Use of Case Study Competitions to Prepare Students for the World of Work

As we continue into the new millennium, it is imperative that educational institutions equip graduates with the knowledge and skills that are increasingly needed and valued by business and industry. In this article, the authors argue that the case study approach and, specifically, case study competitions constitute an ideal pedagogical strategy for achieving this objective in an effective and efficient manner, with resulting benefits for both students and employers

A genealogy of hacking

Hacking is now a widely discussed and known phenomenon, but remains difficult to define and empirically identify because it has come to refer to many different, sometimes incompatible, material practices. This paper proposes genealogy as a framework for understanding hacking by briefly revisiting Foucault’s concept of genealogy and interpreting its perspectival stance through the feminist materialist concept of the situated observer. Using genealogy as a theoretical frame a history of hacking will be proposed in four phases. The first phase is the ‘pre-history’ of hacking in which four core practices were developed. The second phase is the ‘golden age of cracking’ in which hacking becomes a self-conscious identity and community and is for many identified with breaking into computers, even while non-cracking practices such as free software mature. The third phase sees hacking divide into a number of new practices even while old practices continue, including the rise of serious cybercrime, hacktivism, the division of Open Source and Free Software and hacking as an ethic of business and work. The final phase sees broad consciousness of state-sponsored hacking, the re-rise of hardware hacking in maker labs and hack spaces and the diffusion of hacking into a broad ‘clever’ practice. In conclusion it will be argued that hacking consists across all the practices surveyed of an interrogation of the rationality of information techno-cultures enacted by each hacker practice situating itself within a particular techno-culture and then using that techno-culture to change itself, both in changing potential actions that can be taken and changing the nature of the techno-culture itself

Sustained release formulation of an anti-tuberculosis drug based on para-amino salicylic acid-zinc layered hydroxide nanocomposite

Background: Tuberculosis (TB), is caused by the bacteria, Mycobacterium tuberculosis and its a threat to humans since centuries. Depending on the type of TB, its treatment can last for 6-24 months which is a major cause for patients non-compliance and treatment failure. Many adverse effects are associated with the currently available TB medicines, and there has been no new anti-tuberculosis drug on the market for more than 50 year, as the drug development is very lengthy and budget consuming process.Development of the biocompatible nano drug delivery systems with the ability to minimize the side effects of the drugs, protection of the drug from enzymatic degradation. And most importantly the drug delivery systems which can deliver the drug at target site would increase the therapeutic efficacy. Nanovehicles with their tendency to release the drug in a sustained manner would result in the bioavalibilty of the drugs in the body for a longer period of time and this would reduce the dosing frequency in drug administration. The biocompatible nanovehicles with the properties like sustained release of drug of the target site, protection of the drug from physio-chemical degradation, reduction in dosing frequency, and prolong bioavailability of drug in the body would result in the shortening of the treatment duration. All of these factors would improve the patient compliance with chemotherapy of TB.Result: An anti-tuberculosis drug, 4-amino salicylic acid (4-ASA) was successfully intercalated into the interlamellae of zinc layered hydroxide (ZLH) via direct reaction with zinc oxide suspension. The X-ray diffraction patterns and FTIR analyses indicate that the molecule was successfully intercalated into the ZLH interlayer space with an average basal spacing of 24 Å. Furthermore, TGA and DTG results show that the drug 4-ASA is stabilized in the interlayers by electrostatic interaction. The release of 4-ASA from the nanocomposite was found to be in a sustained manner. The nanocomposite treated with normal 3T3 cells shows it reduces cell viability in a dose- and time-dependent manner.Conclusions: Sustained release formulation of the nanocomposite, 4-ASA intercalated into zinc layered hydroxides, with its ease of preparation, sustained release of the active and less-toxic to the cell is a step forward for a more patient-friendly chemotherapy of Tuberculosis

Treatment Outcomes of Patients With Multidrug-Resistant and Extensively Drug-Resistant Tuberculosis According to Drug Susceptibility Testing to First- and Second-line Drugs: An Individual Patient Data Meta-analysis

The clinical validity of drug susceptibility testing (DST) for pyrazinamide, ethambutol, and second-line antituberculosis drugs is uncertain. In an individual patient data meta-analysis of 8955 patients with confirmed multidrug-resistant tuberculosis, DST results for these drugs were associated with treatment outcome

Systematic Identification of Combinatorial Drivers and Targets in Cancer Cell Lines

There is an urgent need to elicit and validate highly efficacious targets for combinatorial intervention from large scale ongoing molecular characterization efforts of tumors. We established an in silico bioinformatic platform in concert with a high throughput screening platform evaluating 37 novel targeted agents in 669 extensively characterized cancer cell lines reflecting the genomic and tissue-type diversity of human cancers, to systematically identify combinatorial biomarkers of response and co-actionable targets in cancer. Genomic biomarkers discovered in a 141 cell line training set were validated in an independent 359 cell line test set. We identified co-occurring and mutually exclusive genomic events that represent potential drivers and combinatorial targets in cancer. We demonstrate multiple cooperating genomic events that predict sensitivity to drug intervention independent of tumor lineage. The coupling of scalable in silico and biologic high throughput cancer cell line platforms for the identification of co-events in cancer delivers rational combinatorial targets for synthetic lethal approaches with a high potential to pre-empt the emergence of resistance