Impact of mental disorders on active TB treatment outcomes: a systematic review and meta-analysis.

BACKGROUND: Comorbid mental disorders in patients with TB may exacerbate TB treatment outcomes. We systematically reviewed current evidence on the association between mental disorders and TB outcomes.METHODS: We searched eight databases for studies published from 1990 to 2018 that compared TB treatment outcomes among patients with and without mental disorders. We excluded studies that did not systematically assess mental disorders and studies limited to substance use. We extracted study and patient characteristics and effect measures and performed a meta-analysis using random-effects models to calculate summary odds ratios (ORs) with 95% confidence intervals (CIs).RESULTS: Of 7687 studies identified, 10 were included in the systematic review and nine in the meta-analysis. Measurement of mental disorders and TB outcomes were heterogeneous across studies. The pooled association between mental disorders and any poor outcome, loss to follow-up, and non-adherence were OR 2.13 (95%CI 0.85-5.37), 1.90 (95%CI 0.33-10.91), and 1.60 (95%CI 0.81-3.02), respectively. High statistical heterogeneity was present.CONCLUSION: Our review suggests that mental disorders in TB patients increase the risk of poor TB outcomes, but pooled estimates were imprecise due to small number of eligible studies. Integration of psychological and TB services might improve TB outcomes and progress towards TB elimination.

Recommendations for Randomised Trials in Surgical Oncology.

Trials of surgical procedures in the treatment of malignant disease face a unique set of challenges. This review aimed to describe recommendations for the design, delivery and reporting of randomised trials in surgical oncology. A literature search was carried out without date limits to identify articles related to trial methodology research in surgery and surgical oncology. A narrative review was framed around two open National Institute of Health Research portfolio trials in colon and rectal cancer: the STAR-TREC trial (ISRCTN14240288) and the ROCCS trial (ISRCTN46330337). Twelve specific challenges were highlighted: standardisation of technique; pilot and feasibility studies; balancing treatments; the recruitment pathway; outcome measures; patient and public representation; trainee-led networks; randomisation; novel techniques and training; learning curves; blinding; follow-up. Evidence-based recommendations were made for the future design and conduct of surgical oncology trials. Better understanding of the challenges facing trials in the surgical treatment of cancer will accelerate high-quality evaluation and rapid adoption of innovation for the benefit of patient care.

Effects of overexpression of gamma-Glutamyl hydrolase on methotrexate metabolism and resistance.

Intracellular metabolism of methotrexate (MTX) to MTX-polyglutamates (MTXPG) is one determinant of cytotoxicity. Steady-state accumulation of MTXPG seems to depend on the activity of two enzymes: folylpolyglutamate synthetase (FPGS), which adds glutamate residues, and gamma-glutamyl hydrolase (GGH), which removes them. Overexpression of GGH would be expected to decrease intracellular MTXPG, thereby increasing efflux of MTX and decreasing cytotoxicity. Increased expression of GGH has been shown to be associated with resistance to MTX in human sarcoma cell lines and a rat hepatoma cell line. To clarify the specific role of GGH in determining MTX sensitivity, we investigated the phenotype produced by forced GGH overexpression in two cell types. Furthermore, because MTX and folic acid share metabolic pathways, we measured the effects of GGH overexpression on folic acid metabolism. The full-length cDNA for GGH, subcloned into a constitutive expression vector, was transfected into a human fibrosarcoma (HT-1080) and a human breast carcinoma (MCF-7) cell line. Compared with the clones containing an empty vector, the GGH-overexpressing cells express 15- to 30-fold more GGH mRNA, more GGH protein, and 15- to 90-fold more GGH enzyme activity. GGH overexpression altered MTX accumulation and metabolism to long-chain polyglutamates. In contrast to expectations, however, GGH overexpression did not confer resistance to short MTX exposures in either cell line. Changes in MTX metabolism were found to be balanced by alterations in accumulation and metabolism of folic acid. The ratio of MTX:folate accumulation may be a better predictor of MTX cytotoxicity than the accumulation of either alone. We conclude that, at least for these two cell lines, GGH overexpression alone is insufficient to produce clinical resistance to MTX.

Regulation of the leptin content of obese human adipose tissue.

The objective of this study was to determine whether obese human adipose tissue contains preformed stores of leptin and their relationship to secreted leptin. Detergent increased detectable leptin by about twofold, suggesting that leptin is stored in a membrane-bound location. Subcutaneous tissue leptin was approximately 1.6-fold higher than omental, paralleling known differences in leptin secretion and expression. The amount of leptin secreted during a 3-h incubation was similar to that of extractable tissue leptin. Tissue leptin levels were maintained over the incubation. Inhibition of protein synthesis decreased tissue leptin content but did not decrease leptin secretion until after 3 h of incubation. Culture of adipose tissue for 2 days with the combination of insulin and dexamethasone, but not with either hormone alone, increased tissue leptin content about twofold in both depots. Although insulin did not affect tissue leptin content, it potentiated leptin secretion (as a % of tissue stores). These data suggest that adipose tissue leptin storage and secretion per se are regulated. Regulation of the release of preformed leptin may modulate serum leptin levels in obese humans.

Growth of microorganisms in total parenteral nutrition mixtures and related clinical observations.

The effect of lipid addition to TPN (Total Parenteral Nutrition) solutions on microbial growth was investigated. Staphylococcus epidermidis, which failed to grow or grew poorly in the absence of lipid, reached greater than 10(4) cfu/ml (colony forming units per ml), from an initial inoculum of approximately 50 cfu/ml after 24 h when lipid was added. Candida albicans grew more slowly in the presence of lipid, but nevertheless reached 10(4) cfu/ml after 40 h incubation. Klebsiella aerogenes grew readily in all solutions, whereas Escherichia coli failed to grow in any solution. Growth of S. epidermidis and K. aerogenes was improved when the inoculum consisted of starved cells; however, growth of starved cells of C. albicans lagged behind that of unstarved cells. The ability of S. epidermidis to grow in lipid-containing TPN mixtures is particularly important, since this organism is frequently associated with sepsis. In an infant surgical unit, where TPN is under the care of a nutrition team, samples of TPN fluids and giving sets were examined for microbiological contamination at the end of the 24 h administration period. Contamination was found in eight of the 98 systems examined from eight patients. The organisms were identified as coagulase-negative staphylococci and diphtheroids.