Preventive therapy for latent tuberculosis infection-the promise and the challenges.

Around one third of the world's population may harbour latent tuberculosis infection (LTBI), an asymptomatic immunological state that confers a heightened risk of subsequently developing tuberculosis (TB). Effectively treating LTBI will be essential if the End TB Strategy is to be realized. This review evaluates the evidence in relation to the effectiveness of preventive antibiotic therapy to treat LTBI due to both drug-susceptible and drug-resistant bacteria. Current national and international preventive therapy guidelines are summarized, as well as ongoing randomized trials evaluating regimens to prevent drug-resistant TB. Populations that may benefit most from screening and treatment for LTBI include close contacts of patients with TB (particularly children under 5 years of age) and individuals with substantial immunological impairment. The risks and benefits of treatment must be carefully balanced for each individual. Electronic decision support tools offer one way in which clinicians can help patients to make informed decisions. Modelling studies indicate that the expanded use of preventive therapy will be essential to achieving substantial reductions in the global TB burden. However, the widespread scale-up of screening and treatment will require careful consideration of cost-effectiveness, while ensuring the drivers of ongoing disease transmission are also addressed.

Risk of tuberculosis during pregnancy in Mongolia, a high incidence setting with low HIV prevalence.

OBJECTIVE: To investigate the epidemiology and the relative risk of tuberculosis (TB) in pregnant women in Mongolia, a high TB incidence setting with a low rate of human immunodeficiency virus co-infection, where active case finding for TB in pregnancy is implemented. DESIGN: We retrospectively collected data on pregnant women diagnosed with TB during 2013. Data were collected through doctors at central TB dispensaries who extracted the relevant information from patients' clinical records. RESULTS: The overall incidence of TB among pregnant women was 228 (95%CI 187276) per 100000 person-years, resulting in an incidence rate ratio of 1.31 (95%CI 1.081.59) in pregnant women compared to the general population. Twelve per cent of the pregnant women with TB chose to have an abortion. CONCLUSIONS: In this study, pregnant women had a 1.3-fold higher risk of developing TB than the general population. Based on a moderately increased risk of TB during pregnancy in our study and the potential for adverse health outcomes, TB screening among pregnant women can currently be justified, but the cost-effectiveness of this intervention remains unclear. Patients and doctors need to be educated about the safety of standard TB treatment in pregnancy to reduce the rate of abortions.

Success of community-based directly observed anti-tuberculosis treatment in Mongolia.

BACKGROUND: Many countries restrict access to directly observed therapy (DOT) for tuberculosis (TB) to government health facilities. More innovative approaches are required to reduce non-adherence, improve patient outcomes and limit the risk of selecting drug-resistant strains. METHODS: We performed a retrospective cohort study in sputum smear-positive patients treated with community-based DOT (home-based DOT or 'lunch' DOT, whereby DOT is provided with a free daily meal once sputum smear conversion has been documented), and conventional clinic-based DOT in Ulaanbaatar, the capital of Mongolia, in 2010-2011. We compared treatment success using community-based home DOT vs. conventional clinic DOT and describe treatment completion rates using lunch DOT. RESULTS: The overall treatment success among new sputum smear-positive TB patients was 85.1% (1505/1768). Patients receiving community DOT had higher cure rates (294/327, 89.9% vs. 1112/1441, 77.2%; aOR 2.66, 95%CI 1.81-3.90) and higher treatment success (306/327, 93.6% vs. 1199/1441, 83.2%; aOR 2.95, 95%CI 1.85-4.71, P < 0.001) than those treated with clinic DOT. Apart from one death, treatment completion was 100% among patients who received lunch DOT after sputum smear conversion. CONCLUSIONS: Community DOT improved treatment success in Ulaanbaatar, Mongolia. It should now be scaled up to be made available for more patients and in all regions of the country.

Recurrence of tuberculosis in a low-incidence setting.

Recurrence of active tuberculosis following treatment of an initial disease episode can occur due to endogenous re-activation or exogenous re-infection. Cases of recurrent tuberculosis in the Australian state of New South Wales between 1994 and 2006 were identified by data linkage analysis with confirmatory review of case notes. Patients with more than one culture-positive disease episode during that time period who had completed treatment for the initial disease episode were included. Genotyping of Mycobacterium tuberculosis was used to determine whether recurrence was likely to be due to re-activation or re-infection. There were 5,723 tuberculosis notifications between 1994 and 2006, 3,731 of which were culture-positive. Fifteen (0.4%) patients had recurrent culture-positive disease over a mean 5.7 yrs of follow-up (crude annual incidence 71 per 100,000 population). Recurrent tuberculosis was attributable to re-activation (indistinguishable strains) in 11 (73%) cases and to re-infection (different strains) in four (27%). In a low-incidence setting of tuberculosis, a control programme incorporating directly observed therapy for active disease resulted in a very low rate of recurrent tuberculosis over a long period of follow-up. Re-infection is less likely than re-activation, but still contributes significantly to the number of cases with recurrent disease.

Bronchoscopic diagnosis of endoscopically visible lung malignancies: should cytological examinations be carried out routinely?

BACKGROUND: The aim of this study was to determine the diagnostic yield of flexible bronchoscopy in endoscopically visible malignancies and to evaluate whether cytological examination, including bronchial washings and brushings, increase the diagnostic yield compared with bronchial biopsy alone. METHODS: We reviewed a series of bronchoscopies over a period of 7.5 years in which an endoscopically visible tumour was identified and which had a definite cytological or histological diagnosis of pulmonary malignancy obtained by bronchoscopy or any other examination. RESULTS: The criteria were met by 174 bronchoscopies. In 155 bronchoscopies all specimens including bronchial washings, brushings and biopsies were obtained; the overall diagnostic yield was 88%. This compared with a diagnostic yield of 77% for biopsies only (P < 0.001). The individual diagnostic yields for biopsies, brushings and washings were 77, 50 and 38%, respectively. The overall diagnostic yield of cytology was 61%, providing a diagnosis in 95 patients. Of 11 repeat bronchoscopies after an initial non-diagnostic bronchoscopy, 9 were diagnostic. CONCLUSION: The tumour detection rate with flexible bronchoscopy in endoscopically visible lung malignancies is high. Cytology-based sampling techniques by means of bronchial washings and brushings significantly increase the overall diagnostic yield compared with forceps biopsy only. Repeat bronchoscopies after an initial non-diagnostic bronchoscopy have a relatively high diagnostic yield and should therefore be considered in all patients with endoscopically visible tumour.

Atom-Efficient Oxidation of Alkenes with Molecular Oxygen: Synthesis of Diols.

Dihydroxylations of simple alkenes were carried out for the first time in excellent yields and selectivities with molecular oxygen as oxidant [(Eq. (a)]. Both oxygen atoms are used productively and are incorporated into the product in this transition metal catalyzed alkene oxidation.

Asymmetric hydrogenation of dehydrodipeptide esters bearing different protective groups.

N-[(Z)-N-Benzoyl- or N-Boc-(2-fluorophenyl)dehydroalanyl]-(R)- or (S)-phenylalanine esters were synthesized and hydrogenated to give the corresponding dipeptide derivatives with optical yields in the range of 53-87% de using the cationic rhodium complexes of PROPRAPHOS and BPPM. The efficiency of chiral diphosphine ligands as well the effect of the chiral center in the substrate on the catalytic asymmetric induction was studied.

Unusual amino acids. VIII. Asymmetric hydrogenation of some heteroaryl-N-Cbz and N-Boc aminocinnamic acid derivatives.

(Z)-alpha-[(Benzyloxy)- or (tert.-butyloxy)carbonylamino]-beta (thienyl)- or (furyl)-acrylic acids and their esters were prepared by known methods and hydrogenated to the corresponding optically active alanine derivatives with optical yields in the range of 58-93% ee using the cationic rhodium complex of "PROPRAPHOS".

Synthesis of non proteinogenic dipeptides by asymmetric hydrogenation.

N-Boc protected non-proteinogenic dipeptides with D,L- and L,L-configuration were prepared by catalytic asymmetric hydrogenation of the corresponding dehydrophenylalanyl-(L)-phenylalanine derivatives. The configuration of the new stereogenic centre depends first of all on the catalyst configuration and is less influenced by the substrate configuration. Diastereomeric excesses in the range of 80-96% de could be increased up to 99% by recrystallization. Analytical data of selected new compounds are given.

Synthesis of non-proteinogenic (D)- or (L)-amino acids by asymmetric hydrogenation.

Non-proteinogenic amino acids play an increasing role in oligopeptide chemistry. Their pharmacological and chemical properties, caused by D-configuration and "unnatural" residues, are more and more used for drug design. Different methods of asymmetric synthesis have been developed during the last decade to prepare "unusual" amino acids. One of them, the asymmetric hydrogenation of dehydroamino aids catalyzed by chiral rhodium (I) complexes, will be described. A series of examples, D- and L-configured, like naphthyl-, thienyl-, furyl-, and pyridylalanines, as well as phenylalanines substituted by chlorine, fluorine, p-nitro, p-methyl, p-trifluoromethyl, p-isopropyl, and p-tert-butyl have been prepared and characterized. Some analytical data like melting points and values of optical rotation are summarized in tables.

Unusual amino acids. I: Asymmetric synthesis of furylalanine derivatives.

Nonproteinogenic amino acids are valuable active compounds from their pharmacological and biochemical effects and also as novel building blocks for peptides. The preparation of furylalanine derivatives by asymmetric hydrogenation is described. Amino-phosphine-phosphinite-rhodium complexes catalyzed the hydrogenation of the prochiral dehydroamino acid precursors in high rate and with enantioselectivities of 70-90% ee. Substrate-catalyst ratios up to 2,000 can be used depending on the catalyst applied. The procedure turns out to be suitable for larger scale preparations.