WHO guidelines for the programmatic management of drug-resistant tuberculosis: 2011 update.

The production of guidelines for the management of drug-resistant tuberculosis (TB) fits the mandate of the World Health Organization (WHO) to support countries in the reinforcement of patient care. WHO commissioned external reviews to summarise evidence on priority questions regarding case-finding, treatment regimens for multidrug-resistant TB (MDR-TB), monitoring the response to MDR-TB treatment, and models of care. A multidisciplinary expert panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to develop recommendations. The recommendations support the wider use of rapid drug susceptibility testing for isoniazid and rifampicin or rifampicin alone using molecular techniques. Monitoring by sputum culture is important for early detection of failure during treatment. Regimens lasting ≥ 20 months and containing pyrazinamide, a fluoroquinolone, a second-line injectable drug, ethionamide (or prothionamide), and either cycloserine or p-aminosalicylic acid are recommended. The guidelines promote the early use of antiretroviral agents for TB patients with HIV on second-line drug regimens. Systems that primarily employ ambulatory models of care are recommended over others based mainly on hospitalisation. Scientific and medical associations should promote the recommendations among practitioners and public health decision makers involved in MDR-TB care. Controlled trials are needed to improve the quality of existing evidence, particularly on the optimal composition and duration of MDR-TB treatment regimens.

Is effective patient support missing in the global response to multidrug-resistant tuberculosis?

Multidrug-resistant tuberculosis (MDR-TB) is a threat to the achievement of the global targets to the World Health Organization (WHO) End TB by 2030 Strategy. The WHO consolidated guidelines for the treatment of drug-resistant TB emphasise the importance of addressing health systems issues, including supporting patients during treatment, contributing to improved adherence, reduced catastrophic costs and better treatment outcomes. The recently published results of the STREAM (Standardised Treatment Regimen of Anti-TB Drugs for Patients with MDR-TB) clinical trial and the Delamanid 213 Trial suggest that the implementation of a proper patient-centred approach to the clinical and programmatic management of MDR-TB as per the WHO guidelines is key to improving treatment outcomes in MDR-TB patients.

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.

An assessment of current tuberculosis patient care and support policies in high-burden countries.

CONTEXT: Adherence to treatment for tuberculosis (TB) is an important predictor of treatment outcomes. The World Health Organization guidelines recommend a patient-centred approach to adherence support; however, the extent to which policies in high-burden countries facilitate this approach remains uncertain.DESIGN: A cross-sectional survey of current national patient care and support policies in high TB burden countries was performed.RESULT: Responses were provided by TB care programmes in 23 of the 30 high TB burden countries, comprising 77.4% of TB cases globally. Clinic-based and household adherence support and patient education were recommended in all countries, while policies for digital technologies and social supports have been adopted in a small minority of countries. Financial or material support (such as reimbursement for transportation) and psychological support to patients-if included in the policies-was mainly recommended only for specific sub-groups of patients.CONCLUSION: National policies in many countries have not yet fully adopted global recommendations for patient care and support. Further scale-up of evidence-based approaches to care is required to improve quality of care for patients in high TB burden settings.

Trends in tuberculosis incidence and their determinants in 134 countries.

OBJECTIVE: To determine whether differences in national trends in tuberculosis incidence are attributable to the variable success of control programmes or to biological, social and economic factors. METHODS: We used trends in case notifications as a measure of trends in incidence in 134 countries, from 1997 to 2006, and used regression analysis to explore the associations between these trends and 32 measures covering various aspects of development (1), the economy (6), the population (3), behavioural and biological risk factors (9), health services (6) and tuberculosis (TB) control (7). FINDINGS: The TB incidence rate changed annually within a range of +/-10% over the study period in the 134 countries examined, and its average value declined in 93 countries. The rate was declining more quickly in countries that had a higher human development index, lower child mortality and access to improved sanitation. General development measures were also dominant explanatory variables within regions, though correlation with TB incidence trends varied geographically. The TB incidence rate was falling more quickly in countries with greater health expenditure (situated in central and eastern Europe and the eastern Mediterranean), high-income countries with lower immigration, and countries with lower child mortality and HIV infection rates (located in Latin America and the Caribbean). The intensity of TB control varied widely, and a possible causal link with TB incidence was found only in Latin America and the Caribbean, where the rate of detection of smear-positive cases showed a negative correlation with national incidence trends. CONCLUSION: Although TB control programmes have averted millions of deaths, their effects on transmission and incidence rates are not yet widely detectable.

Grain grinding size of cereals in complete pelleted diets for growing lambs: Effects on animal performance, carcass and meat quality traits.

The main goal of the present study was to clarify the effects of different grinding particle size of grains (2-mm vs. 6-mm) included in complete pelleted diets (CPD) for fattening lambs on animal performance, carcass and meat quality. Twenty male merino lambs (14.8 kg; n = 10 per group) were fed the corresponding diet ad libitum and slaughtered when they reached 27 kg. No differences were observed in the feed conversion ratio or carcass characteristics. However, lambs fed coarser diets (6 mm) were more efficient with less residual feed intake (-14.0 vs. 15.4 g DM/animal/d; P < .05) than lambs fed the 2 mm CPD. Lambs fed the 6-mm CPD showed higher levels of intramuscular fat and saturated fatty acids. Consequently, increasing the particle size of the grains included in CPD allows for improving feed efficiency and intramuscular fat in fattening lambs.

Palliative care and symptom relief for people affected by multidrug-resistant tuberculosis.

The World Health Organization (WHO) defines palliative care as the prevention and relief of the physical, psychological, social and spiritual suffering of adults and children with life-threatening illnesses and psycho-social support for their families. Palliative care and symptom relief (PCSR) also addresses suffering in nonlife-threatening situations such as after cure. PCSR should never be considered a substitute for tuberculosis (TB) prevention and treatment, but should be accessible by everyone in need. PCSR can reduce suffering and improve quality of life of patients with end-stage chronic illnesses while reducing costs for health care systems and providing financial risk protection for patients' families. It also may help enable patients to adhere to long and noxious treatments and thereby reduce mortality and help protect public health. Basic PCSR can be taught easily to TB specialists as well as primary care clinicians and delivered in hospitals, clinics or patients' homes combined with infection control. For these reasons, integration of PCSR into multidrug-resistant (MDR) and extensively drug-resistant TB (XDR-TB) treatment programs is medically and morally imperative. We propose an essential package of PCSR for people with M/XDR-TB that includes a set of safe, effective and inexpensive medicines and equipment, social supports for patients and caregivers living in extreme poverty, and necessary human resources. The package aligns with WHO guidance on programmatic management of drug-resistant (DR) TB and should be universally accessible by people affected by M/XDR-TB. We also describe the ethical practice of PCSR for people with M/XDR-TB and identify needed areas of research in PCSR for people with M/XDR-TB.

Development of Lactococcus lactis encoding fluorescent proteins, GFP, mCherry and iRFP regulated by the nisin-controlled gene expression system.

Fluorescent proteins are useful reporter molecules for a variety of biological systems. We present an alternative strategy for cloning reporter genes that are regulated by the nisin-controlled gene expression (NICE) system. Lactoccocus lactis was genetically engineered to express green fluorescent protein (GFP), mCherry or near-infrared fluorescent protein (iRFP). The reporter gene sequences were optimized to be expressed by L. lactis using inducible promoter pNis within the pNZ8048 vector. Expression of constructions that carry mCherry or GFP was observed by fluorescence microscopy 2 h after induction with nisin. Expression of iRFP was evaluated at 700 nm using an infrared scanner; cultures induced for 6 h showed greater iRFP expression than non-induced cultures or those expressing GFP. We demonstrated that L. lactis can express efficiently GFP, mCherry and iRFP fluorescent proteins using an inducible expression system. These strains will be useful for live cell imaging studies in vitro or for imaging studies in vivo in the case of iRFP.

Defining the research agenda to measure and reduce tuberculosis stigmas.

Crucial to finding and treating the 4 million tuberculosis (TB) patients currently missed by national TB programmes, TB stigma is receiving well-deserved and long-delayed attention at the global level. However, the ability to measure and evaluate the success of TB stigma-reduction efforts is limited by the need for additional tools. At a 2016 TB stigma-measurement meeting held in The Hague, The Netherlands, stigma experts discussed and proposed a research agenda around four themes: 1) drivers: what are the main drivers and domains of TB stigma(s)?; 2) consequences: how consequential are TB stigmas and how are negative impacts most felt?; 3) burden: what is the global prevalence and distribution of TB stigma(s) and what explains any variation? 4): intervention: what can be done to reduce the extent and impact of TB stigma(s)? Each theme was further subdivided into research topics to be addressed to move the agenda forward. These include greater clarity on what causes TB stigmas to emerge and thrive, the difficulty of measuring the complexity of stigma, and the improbability of a universal stigma 'cure'. Nevertheless, these challenges should not hinder investments in the measurement and reduction of TB stigma. We believe it is time to focus on how, and not whether, the global community should measure and reduce TB stigma.

Preliminary results of a two-layered prosthetic repair for recurrent inguinal and ventral hernias combining open and laparoscopic techniques.

The use of prosthetic mesh has become the standard of care in the management of hernias because of its association with a low rate of recurrence. However, despite its use, recurrence rates of 1% have been reported in primary inguinal repair and rates as high as 15% with ventral hernia repair. When dealing with difficult recurrent hernias, the two-layer prosthetic repair technique is a good option. In the event of incarcerated or strangulated hernias, however; placement of prosthetic material is controversial due to the increased risk of infection. The same is true when hernia repairs are performed concurrently with potentially contaminated procedures such as cholecystectomy, appendectomy, or colectomy. The purpose of this study is to report our preliminary results on the treatment of recurrent hernias by combining laparoscopic and open techniques to construct a two-layered prosthetic repair using a four ply mesh of porcine small intestine submucosa (Surgisis, Cook Surgical, Bloomington, IN, USA) in a potentially infected field and a combination of polypropylene and ePTFE (Gore-Tex, W.L. Gore and Associates, Flagstaff, AZ, USA) in a clean field. From September 2002 to January 2004, nine patients (three males and six females) underwent laparoscopic and open placement of surgisis mesh in a two layered fashion for either recurrent incisional or inguinal hernias in a contaminated field. A total of eight recurrent hernia repairs were performed (five incisional, three inguinal) and one abdominal wall repair after resection of a metastatic tumor following open colectomy for colon carcinoma. Six procedures were performed in a potentially contaminated field (incarcerated or strangulated bowel within the hernia), two procedures were performed in a contaminated field because of infected polypropylene mesh, and one was in a clean field. Mean patient age was 56.4 years. The average operating time was 156.8 min. Operative findings included seven incarcerated hernias (four incisional and three inguinal), one strangulated inguinal hernia, and one ventral defect after resection of an abdominal wall metastasis for a previous colon cancer resection. In two of the cases, there was an abscess of a previously placed polypropylene mesh. All procedures were completed with two layers of mesh (eight cases with surgisis and one with combination of polypropylene/ePTFE). Median follow up was 10 months. Complications included two seromas, one urinary tract infection, two cases of atelectasis and one prolonged ileus. There were no wound infections. The average postoperative length of stay was 7.8 days. There have been no mesh-related complications or recurrent hernias in our early postoperative follow-up period. The use of a new prosthetic device in infected or potentially infected fields, and the two-layered approach shows promising results. This is encouraging and provides an alternative approach for the management of difficult, recurrent hernias.

Genetic pathways in the evolution of morphologically distinct colorectal neoplasms.

Colorectal adenomas can be morphologically classified as exophytic or flat. Polypoid cancers and cancers arising de novo (ie., without any adenomatous component) might be the results of genetic progression from exophytic and flat adenomas, respectively. In this study, we examined 94 morphologically distinct neoplastic specimens for mutations in K-RAS and analyzed 10 microsatellite loci tightly linked to the tumor suppressor genes APC, p53, DCC/SMAD4, hMSH2, and hMLH1. K-RAS mutations were significantly associated with exophytic adenomas [11 of 21 (52%)] compared to flat adenomas [2 of 13(15%), P < 0.03] and polypoid cancers [17 of 25 (68%)] compared to cancers arising de novo [7 of 25 (28%), P < 0.01]. Two polypoid cancer cases demonstrated three and four different K-RAS mutations, respectively, suggesting multiple areas of clonal expansion. Cancers arising de novo were significantly associated with loss of heterozygosity (LOH) at chromosome 3p compared to pol ypoid cancers [6 of 18(33%) versus 1 of 20(5%), P < 0.03], whereas the prevalence of LOH at chromosomes 2p, 5q, 17p, and 18q and microsatellite instability were not different between the groups. For all cancers, LOH at chromosomes 17p and 18q occurred in 47 and 51%, respectively. However, LOH at 17p and 18q occurred in 0 and 16% of benign lesions, respectively, suggesting their role in malignant transformation. There was no difference in LOH at chromosomes 17p and 18q between exophytic and flat lesions. These findings suggest that (a) mutant K-RAS is associated with the exophytic growth of colonic neoplasms, and that (b) some colorectal cancers arising de novo lose chromosome 3p during their evolution, which is not seen in polypoid cancers. Half of all cancers lose chromosomes 17p and 18q at or near the malignant transition of benign lesions as reported previously, irrespective of morphology. There may be more than one genetic avenue for colorectal cancer formation, and this correlates with the morphological characteristics.

Individuals with an increased risk of colorectal cancer: perceived benefits and psychological aspects of surveillance by means of regular colonoscopies.

PURPOSE: To evaluate the psychological consequences of genetic counseling followed by a surveillance program using colonoscopy among individuals with increased risk of colorectal cancer. PATIENTS AND METHODS: Two hundred sixty-five individuals, participating in a surveillance program with colonoscopy, were mailed a survey questionnaire that assessed their experience of the surveillance program and their perception of the risk of colorectal cancer. The Hospital Anxiety and Depression scale and the Swedish Short Form-36 Health Survey was also included. RESULTS: Two hundred forty individuals completed the questionnaire and were divided into the following risk groups: risk group 1, an individual with a mutation in hMLH1 or hMSH2 and a lifetime colorectal cancer risk of 80% (n = 28); risk group 2, a lifetime colorectal cancer risk of 40% (n = 129); and risk group 3, a lifetime colorectal cancer risk of 20% (n = 83). Among all individuals, the mean for perceived benefit was 8.0, and the perception of discomfort was 3.3 on the visual analog scale (1-10). In risk group 1, 61% underestimated personal risks as being 40% or less. Approximately 50% of the subjects in risk groups 2 and 3 either under- or overestimated their lifetime risk. According to the Swedish Short Form-36 Health Survey and the Hospital Anxiety and Depression scale, the study sample resembled the reference population. CONCLUSION: A majority of the study sample understood why they were under surveillance, and regular colonoscopies were well-tolerated. The wide range of risk perception as well as low-risk perception in mutation positive subjects is acceptable, as long as these individuals adhere to surveillance programs and do not demonstrate increased levels of anxiety or depression.

Multiple APC mutations in sporadic flat colorectal adenomas.

Adenomas are established pre-malignant lesions in colorectal carcinogenesis. To date the adenoma-carcinoma sequence for the development of colorectal carcinoma (CRC) has been based largely on molecular data of exophytic, polypoid-type adenomas. Subsequently, a different type of adenoma has been identified: the flat adenoma, so called for its flat, non-exophytic appearance, making it less likely to be detected during conventional endoscopy. However, due to technological advances in endoscopic methods, flat-type adenomas can now frequently be detected and are no longer considered rare colorectal lesions. The phenotype of flat colorectal adenomas differs macroscopically and histologically from exophytic adenomas. Flat colorectal adenomas, as a rule, are tubular structures often revealing high-grade dysplasia, irrespective of the size or villous component. Flat adenomas have also been recognised as pre-cancerous lesions in gastric cancer. Unlike the wealth of clinical and molecular information available for polypoid (exophytic) adenomas, molecular profiles of flat-type lesions have not yet been characterised systematically and the full clinical significance hereto realised. Previous molecular investigation of the K-ras gene in flat colorectal adenomas suggests a distinct pathway in their development. In this study, mutation analysis of the adenomatous polyposis coli (APC) gene using the protein truncation test (PTT) in 20 flat colorectal adenomas in a selected group of 16 patients without hereditary predisposition to colorectal cancer, revealed double truncations of the APC gene in four adenomas. In one of these adenomas a third mutation was detected by DNA sequence analysis.

Coordinate increases and decreases in mitochondrial RNA and ATP syntheses produced by propranolol and rifampicin.

A variety of compounds were examined for their capacity to alter RNA synthesis in isolated rat cardiac and hepatic mitochondria. The beta-adrenergic blocking agents propranolol and butoxamine, and the antiarrhythmic agent quinidine, produced a concentration-dependent stimulation of RNA synthesis in cardiac and hepatic mitochondria. In contrast, the antitubercular antibiotic rifampicin produced a concentration-dependent inhibition of RNA synthesis in cardiac and hepatic mitochondria. Propranolol, as a representative compound which stimulated RNA synthesis, was also found to stimulate ATP synthesis in isolated mitochondria, whereas rifampicin inhibited ATP synthesis. Coordinate increases and decreases in RNA and ATP syntheses suggest that agents which stimulate or inhibit RNA synthesis may rapidly alter ATP synthesis. This finding is consistent with the rapid turn-over of mitochondrial RNA with a messenger function (1.4 and 3.3 min in isolated rat cardiac and hepatic mitochondria), and it suggests that mitochondrial RNA must continue to be synthesized to maintain inner membrane systems required for ATP synthesis. Stimulation of RNA and ATP syntheses by propranolol through membrane stabilization or other actions represents a heretofore unrecognized action of propranolol which may contribute to its beneficial therapeutic effects.

Cellular localization of a Hsp90 homologue in Porphyromonas gingivalis.

We previously reported an association between elevated serum antibody titers to the 90-kDa human heat shock protein (Hsp90), periodontal health and colonization by Porphyromonas gingivalis. In this study, we examined the cellular localization of the Hsp90 homologue of P. gingivalis. Cultures of P. gingivalis were heat-stressed (45 degrees C) and examined for localization of the Hsp90 homologue. Heat stress induced a 4-5-fold increase in anti-Hsp90 antibody reactivity over that of the unstressed controls. Western blot analysis revealed two bands (44 and 68 kDa) that reacted with anti-Hsp90 antibodies. The 68-kDa band was heat-inducible, while the 44-kDa band was not. Immunogold staining revealed that the Hsp90 homologue localized principally to the membrane and extracellular vesicles. Subcellular fractionation confirmed that the Hsp90 homologue was primarily membrane-associated.

Tuberculosis in children: reassessing the need for improved diagnosis in global control strategies.

Pediatric pulmonary tuberculosis (PPTB) remains a major cause of morbidity and mortality worldwide, particularly in less developed countries. Current techniques are inadequate for diagnosing PPTB. This is an impediment not only for the diagnosis and treatment of PPTB cases, but also for epidemiological investigations assessing PPTB burden and disease transmission. Causes of misdiagnosis of PPTB include non-specific signs/symptoms, low bacillary load, recovery methods (sputum or gastric aspirate) for obtaining a clinical sample with low bacillary yield, and the inherent low sensitivities of the diagnostic tests themselves. New diagnostic and recovery methods have recently been evaluated which may provide a means of overcoming some of these obstacles. Unfortunately, progress in developing and implementing improved diagnostic tests for PPTB has been partially impeded by the very low priority of PPTB in global TB control programs based on cost-effective strategies. Regardless of the cost-effectiveness of diagnosing and treating PPTB, our moral obligation to provide access to health care demands that we evaluate and deal with this neglected group of patients. Furthermore, recent evidence indicates that PPTB may actually be responsible for more disease transmission than previously thought. In this review, we present compelling evidence that research agendas and TB control programs should be reassessed and possibly revised to deal with the global disease caused by PPTB.