Search

The genetic gain in yield and quality are two major targets of wheat breeding programs around the world. In this study, a high density genetic map consisting of 10,172 SNP markers identified a total of 43 genomic regions associated with three quality traits, three yield traits and two agronomic traits in hard red spring wheat (HRSW). When compared with six grain shape and size traits, the quality traits showed mostly independent genetic control (~18% common loci), while the yield traits showed moderate association (~53% common loci). Association of genomic regions for grain area (GA) and thousand-grain weight (TGW), with yield suggests that targeting an increase in GA may help enhancing wheat yield through an increase in TGW. Flour extraction (FE), although has a weak positive phenotypic association with grain shape and size, they do not share any common genetic loci. A major contributor to plant height was the Rht8 locus and the reduced height allele was associated with significant increase in grains per spike (GPS) and FE, and decrease in number of spikes per square meter and test weight. Stable loci were identified for almost all the traits. However, we could not find any QTL in the region of major known genes like GPC-B1, Ha, Rht-1, and Ppd-1. Epistasis also played an important role in the genetics of majority of the traits. In addition to enhancing our knowledge about the association of wheat quality and yield with grain shape and size, this study provides novel loci, genetic information and pre-breeding material (combining positive alleles from both parents) to enhance the cultivated gene pool in wheat germplasm. These resources are valuable in facilitating molecular breeding for wheat quality and yield improvement. [ABSTRACT FROM AUTHOR]

Purpose: The efficacy and safety of insulin degludec/insulin aspart (IDegAsp) once daily (OD) compared with insulin glargine U100 (IGlar) OD over 52 weeks in insulin-naïve adults with type 2 diabetes mellitus (T2DM) was investigated. Methods: In this open-label, parallel-group treat-to-target trial, participants were randomized (1:1) to receive IDegAsp OD (breakfast, n = 266) or IGlar OD (as per label, n = 264). Participants then entered a 26-week extension phase (IDegAsp OD, n = 192; IGlar OD, n = 221). The primary endpoint was change from baseline to Week 26 in HbA1c. Results: After 26 and 52 weeks, mean HbA1c decreased to similar levels in both groups. After 52 weeks, the mean estimated treatment difference was –0.08% (–0.26, 0.09 95%CI), confirming the non-inferiority of IDegAsp OD versus IGlar OD evaluated at Week 26. After 52 weeks, there was a similar reduction in mean fasting plasma glucose in both treatment groups. The rate of confirmed hypoglycemic episodes was 86% higher (p < 0.0001) whereas the rate of nocturnal hypoglycemia was 75% lower (p < 0.0001) for IDegAsp versus IGlar. Conclusion: Nocturnal-confirmed hypoglycemia was higher with IGlar whereas overall and diurnal hypoglycemia were higher with IDegAsp dosed at breakfast. These results highlight the importance of administration of IDegAsp with the main meal of the day, tailored to the individual patient’s needs. Trial Registration: ClinicalTrials.gov: [core]) and [ext] [ABSTRACT FROM AUTHOR]

Minnelide/Triptolide (TL) has recently emerged as a potent anticancer drug in non-small cell lung cancer (NSCLC). However, the precise mechanism of its action remains ambiguous. In this study, we elucidated the molecular basis for TL-induced cell death in context to p53 status. Cell death was attributed to dysfunction of mitochondrial bioenergetics in p53-deficient cells, which was characterized by decreased mitochondrial respiration, steady-state ATP level and membrane potential, but augmented reactive oxygen species (ROS). Increased ROS production resulted in oxidative stress in TL-treated cells. This was exhibited by elevated nuclear levels of a redox-sensitive transcriptional factor, NF-E2-related factor-2 (NRF2), along with diminished cellular glutathione (GSH) content. We further demonstrated that in the absence of p53, TL blunted the expression of mitochondrial SIRT3 triggering increased acetylation of NDUAF9 and succinate dehydrogenase, components of complexes I and II of the electron transport chain (ETC). TL-mediated hyperacetylation of complexes I and II proteins and these complexes displayed decreased enzymatic activities. We also provide the evidence that P53 regulate steady-state level of SIRT3 through Proteasome-Pathway. Finally, forced overexpression of Sirt3, but not deacetylase-deficient mutant of Sirt3 (H243Y), restored the deleterious effect of TL on p53-deficient cells by rescuing mitochondrial bioenergetics. On contrary, Sirt3 deficiency in the background of wild-type p53 triggered TL-induced mitochondrial impairment that echoed TL effect in p53-deficeint cells. These findings illustrate a novel mechanism by which TL exerts its potent effects on mitochondrial function and ultimately the viability of NSCLC tumor. [ABSTRACT FROM AUTHOR]

Background: In March 2012, World Health Organization recommended that HIV testing should be offered to all patients with presumptive TB (previously called TB suspects). How this is best implemented and monitored in routine health care settings in India was not known. An operational research was conducted in Karnataka State (South India, population 64 million, accounts for 10% of India’s HIV burden), to test processes and learn results and challenges of screening presumptive TB patients for HIV within routine health care settings. Methods: In this cross-sectional study conducted between January-March 2012, all presumptive TB patients attending public sector sputum microscopy centres state-wide were offered HIV testing by the laboratory technician, and referred to the nearest public sector HIV counselling and testing services, usually within the same facility. The HIV status of the patients was recorded in the routine TB laboratory form and TB laboratory register. The laboratory register was compiled to obtain the number of presumptive TB patients whose HIV status was ascertained, and the number found HIV positive. Aggregate data on reasons for non-testing were compiled at district level. Results: Overall, 115,308 patients with presumptive TB were examined for sputum smear microscopy at 645 microscopy centres state-wide. Of these, HIV status was ascertained for 62,847(55%) among whom 7,559(12%) were HIV-positive, and of these, 3,034(40%) were newly diagnosed. Reasons for non-testing were reported for 37,700(72%) of the 52,461 patients without HIV testing; non-availability of testing services at site of sputum collection was cited by health staff in 54% of respondents. Only 4% of patients opted out of HIV testing. Conclusion: Offering HIV testing routinely to presumptive TB patients detected large numbers of previously-undetected instances of HIV infection. Several operational challenges were noted which provide useful lessons for improving uptake of HIV testing in this important group. [ABSTRACT FROM AUTHOR]

Background: The National AIDS control programme (NACP) in India is currently following the World Health Organization (WHO) 2010 antiretroviral therapy (ART) guidelines. In 2013, the WHO revised its recommendations for initiating ART among people living with HIV (PLHIV) by increasing the threshold for ART initiation to a CD4 count ≤500 cells/uL. For certain patient groups, ART is recommended irrespective of CD4 count (PLHIV with active tuberculosis, hepatitis B virus infection, pregnant and breast feeding women, children aged under five years and those living in a sero-discordant relationship). In this operational research, we assess the effect of applying this recommendation on the number of PLHIV additionally eligible for ART. Methods: This was a cross-sectional analysis of routinely collected programme data from all PLHIV registered in Karnataka State (population 60 million), India in 2012. Results: Of 37,044 PLHIV, 27,074 (73%) were eligible for initiating ART as per WHO-2010 criteria. As per the WHO-2013 criteria (CD4 count ≤500 and all pregnant women and under-five children irrespective of CD4 count), an additional 5104 (14%) HIV-infected people would be eligible for initiating ART. There were no data to inform the additional patient load due to sero-discordance. Conclusion: Adopting the WHO-2013 guidelines for India has important resource implications. However, given the significant patient and programmatic benefits of adopting the new guidelines, this has been considered favourably by the NACP in India and steps are being planned to integrate ART care into the general health system to cope with the increased numbers of patients. [ABSTRACT FROM AUTHOR]

Background: The number of people living with HIV on antiretroviral treatment (ART) in Myanmar has been increasing rapidly in recent years. This study aimed to estimate rates of virological failure on first-line ART and switching to second-line ART due to treatment failure at the Integrated HIV Care program (IHC). Methods: Routinely collected data of all adolescent and adult patients living with HIV who were initiated on first-line ART at IHC between 2005 and 2015 were retrospectively analyzed. The cumulative hazard of virological failure on first-line ART and switching to second-line ART were estimated. Crude and adjusted hazard ratios were calculated using the Cox regression model to identify risk factors associated with the two outcomes. Results: Of 23,248 adults and adolescents, 7,888 (34%) were tested for HIV viral load. The incidence rate of virological failure among those tested was 3.2 per 100 person-years follow-up and the rate of switching to second-line ART among all patients was 1.4 per 100 person-years follow-up. Factors associated with virological failure included: being adolescent; being lost to follow-up at least once; having WHO stage 3 and 4 at ART initiation; and having taken first-line ART elsewhere before coming to IHC. Of the 1032 patients who met virological failure criteria, 762 (74%) switched to second-line ART. Conclusions: We found high rates of virological failure among one third of patients in the cohort who were tested for viral load. Of those failing virologically on first-line ART, about one quarter were not switched to second-line ART. Routine viral load monitoring, especially for those identified as having a higher risk of treatment failure, should be considered in this setting to detect all patients failing on first-line ART. Strategies also need to be put in place to prevent treatment failure and to treat more of those patients who are actually failing. [ABSTRACT FROM AUTHOR]

Background: Drug-resistant tuberculosis (DR-TB) is a looming threat to tuberculosis control in India. However, no countrywide prevalence data are available. The burden of DR-TB in HIV-co-infected patients is likewise unknown. Undiagnosed and untreated DR-TB among HIV-infected patients is a major cause of mortality and morbidity. We aimed to assess the prevalence of DR-TB (defined as resistance to any anti-TB drug) in patients attending public antiretroviral treatment (ART) centers in greater metropolitan Mumbai, India. Methods: A cross-sectional survey was conducted among adults and children ART-center attendees. Smear microscopy, culture and drug-susceptibility-testing (DST) against all first and second-line TB-drugs using phenotypic liquid culture (MGIT) were conducted on all presumptive tuberculosis patients. Analyses were performed to determine DR-TB prevalence and resistance patterns separately for new and previously treated, culture-positive TB-cases. Results: Between March 2013 and January 2014, ART-center attendees were screened during 14135 visits, of whom 1724 had presumptive TB. Of 1724 attendees, 72 (4%) were smear-positive and 202 (12%) had a positive culture for Mycobacterium tuberculosis. Overall DR-TB was diagnosed in 68 (34%, 95% CI: 27%–40%) TB-patients. The proportions of DR-TB were 25% (29/114) and 44% (39/88) among new and previously treated cases respectively. The patterns of DR-TB were: 21% mono-resistant, 12% poly-resistant, 38% multidrug-resistant (MDR-TB), 21% pre-extensively-drug-resistant (MDR-TB plus resistance to either a fluoroquinolone or second-line injectable), 6% extensively drug-resistant (XDR-TB) and 2% extremely drug-resistant TB (XDR-TB plus resistance to any group-IV/V drug). Only previous history of TB was significantly associated with the diagnosis of DR-TB in multivariate models. Conclusion: The burden of DR-TB among HIV-infected patients attending public ART-centers in Mumbai was alarmingly high, likely representing ongoing transmission in the community and health facilities. These data highlight the need to promptly diagnose drug-resistance among all HIV-infected patients by systematically offering access to first and second-line DST to all patients with ‘presumptive TB’ rather than ‘presumptive DR-TB’ and tailor the treatment regimen based on the resistance patterns. [ABSTRACT FROM AUTHOR]

Background: Endoplasmic reticulum (ER) stress generated unfolded stress response (UPR) is a basic survival mechanism which protects cell under unfavourable conditions. Leishmania parasite modulates host macrophages in various ways to ensure its survival. Modulation of PI3K-Akt pathway in delayed apoptotic induction of host; enables parasite to stabilize the infection for further propagation. Methodology: Infected RAW macrophages were exposed to campothecin or thagsigargin and phosphorylation status of PERK, Akt, BAD and Cyt-C was determined through western blotting using phospho specific antibody. Expression at transcriptional level for cIAP1 &2, ATF4, CHOP, ATF3, HO-1 and sXBP1 was determined using real time PCR. For inhibition studies, RAW macrophages were pre-treated with PERK inhibitor GSK2606414 before infection. Findings: Our studies in RAW macrophages showed that induction of host UPR against L.donovani infection activates Akt mediated pathway which delays apoptotic induction of the host. Moreover, Leishmania infection results in phosphorylation and activation of host PERK enzyme and increased transcription of genes of inhibitor of apoptosis gene family (cIAP) mRNA. In our inhibition studies, we found that inhibition of infection induced PERK phosphorylation under apoptotic inducers reduces the Akt phosphorylation and fails to activate further downstream molecules involved in protection against apoptosis. Also, inhibition of PERK phosphorylation under oxidative exposure leads to increased Nitric Oxide production. Simultaneously, decreased transcription of cIAP mRNA upon PERK phosphorylation fates the host cell towards apoptosis hence decreased infection rate. Conclusion: Overall the findings from the study suggests that Leishmania modulated host UPR and PERK phosphorylation delays apoptotic induction in host macrophage, hence supports parasite invasion at early stages of infection. [ABSTRACT FROM AUTHOR]

Background: In a study conducted in Bhopal district (a setting with facility for molecular drug susceptibility testing (DST)) located in central India in 2014–15, we found high levels of pre-diagnosis attrition among patients with presumptive multi drug-resistant tuberculosis (MDR-TB)–meaning TB patients who were eligible for DST, were not being tested. Objectives: In this study, we explored the health care provider perspectives into barriers and suggested solutions for improving DST. Methods: This was a descriptive qualitative study. One to one interviews (n = 10) and focus group discussions (n = 2) with experienced key informants involved in programmatic management of DR-TB were conducted in April 2017. Manual descriptive thematic analysis was performed. Results: The key barriers reported were a) lack of or delay in identification of patients eligible for DST because of using treatment register as the source for identifying patients b) lack of assured specimen transport after patient identification and c) lack of tracking. Extra pulmonary TB patients were not getting identified as eligible for DST. Solutions suggested by the health care providers were i) generation of unique identifier at identification in designated microscopy center (DMC), immediate intimation of unique identifier to district and regular monitoring by senior TB laboratory and senior treatment supervisors of patients eligible for DST that were missed; ii) documentation of unique identifier at each step of cascade; iii) use of human carriers/couriers to transport specimen from DMCs especially in rural areas; and iv) routine entry of all presumptive extra-pulmonary TB specimen, as far as possible, in DMC laboratory register. Conclusion: Lack of assured specimen transport and lack of accountability for tracking patient after identification and referral were the key barriers. The identification of patients eligible for DST among microbiologically confirmed TB at the time of diagnosis and among clinically confirmed TB at the time of treatment initiation is the key. Use of unique identifier at identification and its use to ensure cohort wise tracking has to be complemented with specimen transport support and prompt feedback to the DMC. The study has implications to improve detection of MDR-TB among diagnosed/notified TB patients. [ABSTRACT FROM AUTHOR]

Background: Stringent glycemic control by using insulin as a replacement or in addition to oral hypoglycemic agents (OHAs) has been recommended for people with tuberculosis and diabetes mellitus (TB-DM). This systematic review (PROSPERO 2016:CRD42016039101) analyses whether this improves TB treatment outcomes. Objectives: Among people with drug-susceptible TB and DM on anti-TB treatment, to determine the effect of i) glycemic control (stringent or less stringent) compared to poor glycemic control and ii) insulin (only or with OHAs) compared to ‘OHAs only’ on unsuccessful TB treatment outcome(s). We looked for unfavourable TB treatment outcomes at the end of intensive phase and/or end of TB treatment (minimum six months and maximum 12 months follow up). Secondary outcomes were development of MDR-TB during the course of treatment, recurrence after 6 months and/or after 1 year post successful treatment completion and development of adverse events related to glucose lowering treatment (including hypoglycemic episodes). Methods: All interventional studies (with comparison arm) and cohort studies on people with TB-DM on anti-TB treatment reporting glycemic control, DM treatment details and TB treatment outcomes were eligible. We searched electronic databases (EMBASE, PubMed, Google Scholar) and grey literature between 1996 and April 2017. Screening, data extraction and risk of bias assessment were done independently by two investigators and recourse to a third investigator, for resolution of differences. Results: After removal of duplicates from 2326 identified articles, 2054 underwent title and abstract screening. Following full text screening of 56 articles, nine cohort studies were included. Considering high methodological and clinical heterogeneity, we decided to report the results qualitatively and not perform a meta-analysis. Eight studies dealt with glycemic control, of which only two were free of the risk of bias (with confounder-adjusted measures of effect). An Indian study reported 30% fewer unsuccessful treatment outcomes (aOR (0.95 CI): 0.72 (0.64−0.81)) and 2.8 times higher odds of ‘no recurrence’ (aOR (0.95 CI): 2.83 (2.60−2.92)) among patients with optimal glycemic control at baseline. A Peruvian study reported faster culture conversion among those with glycemic control (aHR (0.95 CI): 2.2 (1.1,4)). Two poor quality studies reported the effect of insulin on TB treatment outcomes. Conclusion: We identified few studies that were free of the risk of bias. There were limited data and inconsistent findings among available studies. We recommend robustly designed and analyzed studies including randomized controlled trials on the effect of glucose lowering treatment options on TB treatment outcomes. [ABSTRACT FROM AUTHOR]

Altered metabolism is an emerging hallmark of cancer, as malignant cells display a mammoth up-regulation of enzymes responsible for steering their bioenergetic and biosynthetic machinery. Thus, the recent anticancer therapeutic strategies focus on the targeting of metabolic enzymes, which has led to the identification of specific metabolic inhibitors. One of such inhibitors is 3-bromopyruvate (3-BP), with broad spectrum of anticancer activity due to its ability to inhibit multiple metabolic enzymes. However, the molecular characterization of its binding to the wide spectrum of target enzymes remains largely elusive. Therefore, in the present study we undertook in silico investigations to decipher the molecular nature of the docking of 3-BP with key target enzymes of glycolysis and TCA cycle by PatchDock and YASARA docking tools. Additionally, derivatives of 3-BP, dibromopyruvate (DBPA) and propionic acid (PA), with reported biological activity, were also investigated for docking to important target metabolic enzymes of 3-BP, in order to predict their therapeutic efficacy versus that of 3-BP. A comparison of the docking scores with respect to 3-BP indicated that both of these derivatives display a better binding strength to metabolic enzymes. Further, analysis of the drug likeness of 3-BP, DBPA and PA by Lipinski filter, admetSAR and FAF Drug3 indicated that all of these agents showed desirable drug-like criteria. The outcome of this investigation sheds light on the molecular characteristics of the binding of 3-BP and its derivatives with metabolic enzymes and thus may significantly contribute in designing and optimizing therapeutic strategies against cancer by using these agents. [ABSTRACT FROM AUTHOR]

Background: Currently, only 62% of incident tuberculosis (TB) cases are reported to the national programme in Pakistan. Several innovative interventions are being recommended to detect the remaining ‘missed’ TB cases. One such intervention involved expanding contact investigation to the community using the Xpert MTB/RIF test. Methods: This was a before and after intervention study involving retrospective record review. Passive case finding and household contact investigation was routinely done in the pre-intervention period July 2011-June 2013. Four districts with a high concentration of slums were selected as intervention areas; Lahore, Rawalpindi, Faisalabad and Islamabad. Here, in the intervention period, July 2013-June 2015, contact investigation beyond household was conducted: all people staying within a radius of 50 metres (using Geographical Information System) from the household of smear positive TB patients were screened for tuberculosis. Those with presumptive TB were investigated using smear microscopy and the Xpert MTB/RIF test was performed on smear negative patients. All the diagnosed TB patients were linked to TB treatment and care. Results: A total of 783043 contacts were screened for tuberculosis: 23741(3.0%) presumptive TB patients were identified of whom, 4710 (19.8%) all forms and 4084(17.2%) bacteriologically confirmed TB patients were detected. The contribution of Xpert MTB/RIF to bacteriologically confirmed TB patients was 7.6%. The yield among investigated presumptive child TB patients was 5.1%. The overall yield of all forms TB patients among investigated was 22.3% among household and 19.1% in close community. The intervention contributed an increase of case detection of bacteriologically confirmed tuberculosis by 6.8% and all forms TB patients by 7.9%. Conclusion: Community contact investigation beyond household not only detected additional TB patients but also increased TB case detection. However, further long term assessments and cost-effectiveness studies are required before national scale-up. [ABSTRACT FROM AUTHOR]

Setting: Research capacity is weakest in low and middle-income countries (LMICs) where operational research is highly relevant and needed. Structured Operational Research and Training Initiative (SORT IT) courses have been developed to train participants to conduct and publish operational research and influence policy and practice. Twenty courses were completed in Asia, Africa, Europe and the South Pacific between 2009 and 2014. Objectives: In the 20 completed SORT IT courses, to assess where the research was conducted, who was trained, who became facilitators in subsequent courses and course outcomes. Design: A cohort study of completed SORT IT courses Results: There were 236 participants (41% female) including 64 nationalities who conducted research in 59 countries, mostly from Asia and Africa (mean course duration = 9.7 months). Most participants (68%) were from government health programs and non-governmental agencies. A total of 213(90%) participants completed all milestones successfully with 41(19%) becoming subsequent course facilitators, 88% of whom were from LMICs. Of 228 manuscripts submitted to scientific journals, 197(86%) were either published or in press; in 86%, the principal investigator (first author) was a LMIC national. Papers were published in 23 scientific journals (impact factor 0.5–4.4) and covered 21 disease categories (median publication time = 5.7 months). Published papers (186) had 94,794 cumulative article views/downloads. Article views/downloads for immediate open access articles were double those from closed access journals. Conclusion: The SORT IT model has been effective in training personnel to produce relevant operational research in LMICs. It merits continued commitment and support for further scale-up and development. [ABSTRACT FROM AUTHOR]

Reactive oxygen and nitrogen species (ROS and RNS) produced by the phagocytic cells are the most common arsenals used to kill the intracellular pathogens. However, Leishmania, an intracellular pathogen, has evolved mechanisms to survive by counterbalancing the toxic oxygen metabolites produced during infection. Polyamines, the major contributor in this anti-oxidant machinery, are largely dependent on the availability of L-arginine in the intracellular milieu. Argininosuccinate synthase (ASS) plays an important role as the rate-limiting step required for converting L-citrulline to argininosuccinate to provide arginine for an assortment of metabolic processes. Leishmania produce an active ASS enzyme, yet it has an incomplete urea cycle as it lacks an argininosuccinate lyase (ASL). There is no evidence for endogenous synthesis of L-arginine in Leishmania, which suggests that these parasites salvage L-arginine from extracellular milieu and makes the biological function of ASS and the production of argininosuccinate in Leishmania unclear. Our previous quantitative proteomic analysis of Leishmania promastigotes treated with sub-lethal doses of ROS, RNS, or a combination of both, led to the identification of several differentially expressed proteins which included ASS. To assess the involvement of ASS in stress management, a mutant cell line with greatly reduced ASS activity was created by a double-targeted gene replacement strategy in L. donovani promastigote. Interestingly, LdASS is encoded by three copies of allele, but Western blot analysis showed the third allele did not appear to express ASS. The free thiol levels in the mutant LdASS-/-/+ cell line were decreased. Furthermore, the cell viability in L-arginine depleted medium was greatly attenuated on exposure to different stress environments and was adversely impacted in its ability to infect mice. These findings suggest that ASS is important for Leishmania donovani to counterbalance the stressed environments encountered during infection and can be targeted for chemotherapeutic purpose to treat visceral leishmaniasis. [ABSTRACT FROM AUTHOR]

Christian Lienhardt and colleagues describe the research efforts needed to end the global tuberculosis epidemic by 2035. [ABSTRACT FROM AUTHOR]

Background: The World Health Organization recommends direct observation of treatment (DOT) to support patients with tuberculosis (TB) and to ensure treatment completion. As per national programme guidelines in India, a DOT provider can be anyone who is acceptable and accessible to the patient and accountable to the health system, except a family member. This poses challenges among children with TB who may be more comfortable receiving medicines from their parents or family members than from unfamiliar DOT providers. We conducted a non-inferiority trial to assess the effect of family DOT on treatment success rates among children with newly diagnosed TB registered for treatment during June–September 2012. Methods: We randomly assigned all districts (n = 30) in Gujarat to the intervention (n = 15) or usual-practice group (n = 15). Adult family members in the intervention districts were given the choice to become their child’s DOT provider. DOT was provided by a non-family member in the usual-practice districts. Using routinely collected clinic-based TB treatment cards, we compared treatment success rates (cured and treatment completed) between the two groups and the non-inferiority limit was kept at 5%. Results: Of 624 children with newly diagnosed TB, 359 (58%) were from intervention districts and 265 (42%) were from usual-practice districts. The two groups were similar with respect to baseline characteristics including age, sex, type of TB, and initial body weight. The treatment success rates were 344 (95.8%) and 247 (93.2%) (p = 0.11) among the intervention and usual-practice groups respectively. Conclusion: DOT provided by a family member is not inferior to DOT provided by a non-family member among new TB cases in children and can attain international targets for treatment success. Trial Registration: Clinical Trials Registry–India, National Institute of Medical Statistics (Indian Council of Medical Research) [ABSTRACT FROM AUTHOR]

Tryptanthrin is a natural product which has been reported to have several medicinal properties. In this study, we tried to investigate the detailed molecular mechanism of its bromo analogue (TBr), a potent cytotoxic agent in the induction of cancer cell death. It was found that TBr primarily targets STAT3 and ERK signaling during the induction of apoptosis in several human leukemia cell lines. In HL-60 cells, TBr treatment caused early down regulation of p-STAT3 with concomitant up regulation of p-ERK which led to the activation of intrinsic and extrinsic pathways of apoptosis. The mechanism of TBr mediated inhibition of p-STAT3 was found to be due to the activation of ubiquitin dependent degradation of tyrosine 705 and serine 727 p-STAT3. As IL-6 is the main driver of the STAT3 pathway, the effect of TBr on cell death was subdued when treated in the combination with IL-6 in HL60 cells. Interestingly, PD98059 significantly reduced the apoptotic effects of TBr, thus showing the direct involvement of p-ERK in TBr mediated cell death. It was further shown that apoptotic protein Bax silencing in HL-60 cells resists TBr mediated ERK dependent apoptosis. In summary, for the first time we report the mechanism of TBr mediated cell death in human leukemia cell lines by targeting STAT3 and ERK pathways. [ABSTRACT FROM AUTHOR]

Introduction: Each SAARC nation falls in the zone of high incidence of pneumococcal disease but there is a paucity of literature estimating the burden of pneumococcal disease in this region. Objective: To identify the prevalent serotypes causing invasive pneumococcal disease in children of SAARC countries, to determine the coverage of these serotypes by the available vaccines, and to determine the antibiotic resistance pattern of Streptococcus pneumoniae. Methods: We searched major electronic databases using a comprehensive search strategy, and additionally searched the bibliography of the included studies and retrieved articles till July 2014. Both community and hospital based observational studies which included children aged ≤12 years as/or part of the studied population in SAARC countries were included. Results: A total of 17 studies were included in the final analysis. The period of surveillance varied from 12–96 months (median, 24 months). The most common serotypes country-wise were as follows: serotype 1 in Nepal; serotype 14 in Bangladesh and India; serotype 19F in Sri Lanka and Pakistan. PCV-10 was found to be suitable for countries like India, Nepal, Bangladesh, and Sri Lanka, whereas PCV-13 may be more suitable for Pakistan. An increasing trend of non-susceptibility to antibiotics was noted for co-trimoxazole, erythromycin and chloramphenicol, whereas an increasing trend of susceptibility was noted for penicillin. Conclusion: Due to paucity of recent data in majority of the SAARC countries, urgent large size prospective studies are needed to formulate recommendations for specific pneumococcal vaccine introduction and usage of antimicrobial agents in these regions. [ABSTRACT FROM AUTHOR]

Background: IPT with or without concomitant administration of ART is a proven intervention to prevent tuberculosis among PLHIV. However, there are few data on the routine implementation of this intervention and its effectiveness in settings with limited resources. Objectives: To measure the level of uptake and effectiveness of IPT in reducing tuberculosis incidence in a cohort of PLHIV enrolled into HIV care between 2007 and 2010 in five hospitals in southern Ethiopia. Methods: A retrospective cohort analysis of electronic patient database was done. The independent effects of no intervention, “IPT-only,” “IPT-before-ART,” “IPT-and-ART started simultaneously,” “ART-only,” and “IPT-after-ART” on TB incidence were measured. Cox-proportional hazards regression was used to assess association of treatment categories with TB incidence. Results: Of 7,097 patients, 867 were excluded because they were transferred-in; a further 823 (12%) were excluded from the study because they were either identified to have TB through screening (292 patients) or were on TB treatment (531). Among the remaining 5,407 patients observed, IPT had been initiated for 39% of eligible patients. Children, male sex, advanced disease, and those in Pre-ART were less likely to be initiated on IPT. The overall TB incidence was 2.6 per 100 person-years. As compared to those with no intervention, use of “IPT-only” (aHR = 0.36, 95% CI = 0.19–0.66) and “ART-only” (aHR = 0.32, 95% CI = 0.24–0.43) were associated with significant reduction in TB incidence rate. Combining ART and IPT had a more profound effect. Starting IPT-before-ART (aHR = 0.18, 95% CI = 0.08–0.42) or simultaneously with ART (aHR = 0.20, 95% CI = 0.10–0.42) provided further reduction of TB at ∼80%. Conclusions: IPT was found to be effective in reducing TB incidence, independently and with concomitant ART, under programme conditions in resource-limited settings. The level of IPT provision and effectiveness in reducing TB was encouraging in the study setting. Scaling up and strengthening IPT service in addition to ART can have beneficial effect in reducing TB burden among PLHIV in settings with high TB/HIV burden. [ABSTRACT FROM AUTHOR]

Background: Private Practitioners (PP) are the primary source of health care for patients in India. Limited representative information is available on TB management practices of Indian PP or on the efficacy of India’s Revised National Tuberculosis Control Programme (RNTCP) to improve the quality of TB management through training of PP. Methods: We conducted a cross-sectional survey of a systematic random sample of PP in one urban area in Western India (Pune, Maharashtra). We presented sample clinical vignettes and determined the proportions of PPs who reported practices consistent with International Standards of TB Care (ISTC). We examined the association between RNTCP training and adherence to ISTC by calculating odds ratios and 95% confidence intervals. Results: Of 3,391 PP practicing allopathic medicine, 249 were interviewed. Of these, 55% had been exposed to RNTCP. For new pulmonary TB patients, 63% (158/249) of provider responses were consistent with ISTC diagnostic practices, and 34% (84/249) of responses were consistent with ISTC treatment practices. However, 48% (120/249) PP also reported use of serological tests for TB diagnosis. In the new TB case vignette, 38% (94/249) PP reported use of at least one second line anti-TB drug in the treatment regimen. RNTCP training was not associated with diagnostic or treatment practices. Conclusion: In Pune, India, despite a decade of training activities by the RNTCP, high proportions of providers resorted to TB serology for diagnosis and second-line anti-TB drug use in new TB patients. Efforts to achieve universal access to quality TB management must account for the low quality of care by PP and the lack of demonstrated effect of current training efforts. [ABSTRACT FROM AUTHOR]

Objective: The primary objective was to estimate the burden of invasive pneumococcal disease (IPD) in children aged 1 month to 12 years in South Asian countries. Methods: We searched three electronic databases (PubMed, Embase and the Cochrane Library) using a comprehensive search strategy, we manually searched published databases (Index Medicus and Current Contents) and we also searched the bibliographies of the included studies and retrieved reviews. The searches were current through June 2013. Eligible studies (community-based and hospital-based) were pooled and a separate analysis for India was also completed. A meta-regression analysis and heterogeneity analysis were performed. The protocol was registered with PROSPERO registration number CRD42013004483. Results: A total of 22 studies surveying 36,714 children were included in the systematic review. Hospital-based prospective studies from South Asia showed that 3.57% of children had IPD, and 15% of all bacterial pneumonia cases were due to Streptococcus pneumoniae. Indian studies showed that the incidence of IPD was 10.58% in children admitted to hospitals with suspected invasive bacterial diseases, and 24% of all bacterial pneumonia cases were due to S. pneumonia. Population-based studies from South Asian countries showed that 12.8% of confirmed invasive bacterial diseases were caused by S. pneumonia whereas retrospective hospital-based studies showed that 28% of invasive bacterial diseases were due to S. pneumoniae. Meta-regression showed that there was a significant influence of the antigen testing method for diagnosing IPD on IPD prevalence. Conclusion: S. pneumoniae is responsible for a substantial bacterial disease burden in children of South Asian countries including India despite the presence of high heterogeneity in this meta-analysis. Treatment guidelines must be formulated, and preventive measures like vaccines must also be considered. [ABSTRACT FROM AUTHOR]

Background: Nigeria is faced with a high burden of Human Immunodeficiency Virus (HIV) infection and multidrug-resistant tuberculosis (MDR-TB). Treatment outcomes among MDR-TB patients registered across the globe have been poor, partly due to high loss-to-follow-up. To address this challenge, MDR-TB patients in Nigeria are hospitalized during the intensive-phase(IP) of treatment (first 6–8 months) and are provided with a package of care including standardized MDR-TB treatment regimen, antiretroviral therapy (ART) and cotrimoxazole prophylaxis (CPT) for HIV-infected patients, nutritional and psychosocial support. In this study, we report the end-IP treatment outcomes among them. Methods: In this retrospective cohort study, we reviewed the patient records of all bacteriologically-confirmed MDR-TB patients admitted for treatment between July 2010 and October 2012. Results: Of 162 patients, 105(65%) were male, median age was 34 years and 28(17%) were HIV-infected; all 28 received ART and CPT. Overall, 138(85%) were alive and culture negative at the end of IP, 24(15%) died and there was no loss-to-follow-up. Mortality was related to low CD4-counts at baseline among HIV-positive patients. The median increase in body mass index among those documented to be underweight was 2.6 kg/m2 (p<0.01) and CD4-counts improved by a median of 52 cells/microL among the HIV-infected patients (p<0.01). Conclusions: End-IP treatment outcomes were exceptional compared to previously published data from international cohorts, thus confirming the usefulness of a hospitalized model of care. However, less than five percent of all estimated 3600 MDR-TB patients in Nigeria were initiated on treatment during the study period. Given the expected scale-up of MDR-TB care, the hospitalized model is challenging to sustain and the national TB programme is contemplating to move to ambulatory care. Hence, we recommend using both ambulatory and hospitalized approaches, with the latter being reserved for selected high-risk groups. [ABSTRACT FROM AUTHOR]