Risk Factors for Treatment Default among Re-Treatment Tuberculosis Patients in India, 2006

Setting

Under India''s Revised National Tuberculosis Control Programme (RNTCP), >15% of previously-treated patients in the reported 2006 patient cohort defaulted from anti-tuberculosis treatment.

Objective

To assess the timing, characteristics, and risk factors for default amongst re-treatment TB patients.

Methodology

For this case-control study, in 90 randomly-selected programme units treatment records were abstracted from all 2006 defaulters from the RNTCP re-treatment regimen (cases), with one consecutively-selected non-defaulter per case. Patients who interrupted anti-tuberculosis treatment for >2 months were classified as defaulters.

Results

1,141 defaulters and 1,189 non-defaulters were included. The median duration of treatment prior to default was 81 days (25%–75% interquartile range 44–117 days) and documented retrieval efforts after treatment interruption were inadequate. Defaulters were more likely to have been male (adjusted odds ratio [aOR] 1.4, 95% confidence interval [CI] 1.2–1.7), have previously defaulted anti-tuberculosis treatment (aOR 1.3 95%CI 1.1–1.6], have previous treatment from non-RNTCP providers (AOR 1.3, 95%CI 1.0–1.6], or have public health facility-based treatment observation (aOR 1.3, 95%CI 1.1–1.6).

Conclusions

Amongst the large number of re-treatment patients in India, default occurs early and often. Improved pre-treatment counseling and community-based treatment provision may reduce default rates. Efforts to retrieve treatment interrupters prior to default require strengthening.     

Gain of Cellular Adaptation Due to Prolonged p53 Impairment Leads to Functional Switchover from p53 to p73 during DNA Damage in Acute Myeloid Leukemia Cells

Tumor suppressor p53 plays the central role in regulating apoptosis in response to genotoxic stress. From an evolutionary perspective, the activity of p53 has to be backed up by other protein(s) in case of any functional impairment of this protein, to trigger DNA damage-induced apoptosis in cancer cells. We adopted multiple experimental approaches to demonstrate that in p53-impaired cancer cells, DNA damage caused accumulation of p53 paralogue p73 via Chk-1 that strongly impacted Bax expression and p53-independent apoptosis. On the contrary, when p53 function was restored by ectopic expression, Chk-2 induced p53 accumulation that in turn overshadowed p73 activity, suggesting an antagonistic interaction between p53 family members. To understand such interaction better, p53-expressing cells were impaired differentially for p53 activity. In wild-type p53-expressing cancer cells that were silenced for p53 for several generations, p73 was activated, whereas no such trend was observed when p53 was transiently silenced. Prolonged p53 interference, even in functional p53 settings, therefore, leads to the “gain of cellular adaptation” in a way that alters the cellular microenvironment in favor of p73 activation by altering p73-regulatory proteins, e.g. Chk1 activation and dominant negative p73 down-regulation. These findings not only unveil a hitherto unexplained mechanism underlying the functional switchover from p53 to p73, but also validate p73 as a promising and potential target for cancer therapy in the absence of functional p53.     

Pathway-based genetic analysis of preterm birth

Preterm birth in the United States is now 12%. Multiple genes, gene networks, and variants have been associated with this disease. Using a custom database for preterm birth (dbPTB) with a refined set of genes extensively curated from literature and biological databases, we analyzed GWAS of preterm birth for complete genotype data on nearly 2000 preterm and term mothers. We used both the curated genes and a genome-wide approach to carry out a pathway-based analysis. There were 19 significant pathways, which withstood FDR correction for multiple testing that were identified using both the curated genes and the genome-wide approach. The analysis based on the curated genes was more significant than genome-wide in 15 out of 19 pathways. This approach demonstrates the use of a validated set of genes, in the analysis of otherwise unsuccessful GWAS data, to identify gene–gene interactions in a way that enhances statistical power and discovery.     

Arginine vasotocin neuronal phenotypes, telencephalic fiber varicosities, and social behavior in butterflyfishes (Chaetodontidae): potential similarities to birds and mammals

The neuropeptide arginine vasopressin (AVP) influences many social behaviors through its action in the forebrain of mammals. However, the function of the homologous arginine vasotocin (AVT) in the forebrain of fishes, specifically the telencephalon remains unresolved. We tested whether the density of AVT-immunoreactive (-ir) fiber varicosities, somata size or number of AVT-ir neuronal phenotypes within the forebrain were predictive of social behavior in reproductive males of seven species of butterflyfishes (family Chaetodontidae) in four phylogenetic clades. Similar to other fishes, the aggressive (often territorial) species in most cases had larger AVT-ir cells within the gigantocellular preoptic cell group. Linear discriminant function analyses demonstrated that the density of AVT-ir varicosities within homologous telencephalic nuclei to those important for social behavior in mammals and birds were predictive of aggressive behavior, social affiliations, and mating system. Of note, the density of AVT-ir varicosities within the ventral nucleus of the ventral telencephalon, thought to be homologous to the septum of other vertebrates, was the strongest predictor of aggressive behavior, social affiliation, and mating system. These results are consistent with the postulate that AVT within the telencephalon of fishes plays an important role in social behavior and may function in a similar manner to that of AVT / AVP in birds and mammals despite having cell populations solely within the preoptic area.     

From Where Are Tuberculosis Patients Accessing Treatment in India? Results from a Cross-Sectional Community Based Survey of 30 Districts

Background

Tuberculosis (TB) notification in India by the Revised National TB Control Programme (RNTCP) provides information on TB patients registered for treatment from the programme. There is limited information about the proportion of patients treated for TB outside RNTCP and where these patients access their treatment.

Objectives

To estimate the proportion of patients accessing TB treatment outside the RNTCP and to identify their basic demographic characteristics.

Methods

A cross sectional community-based survey in 30 districts. Patients were identified through a door-to-door survey and interviewed using a semi-structured questionnaire.

Results

Of the estimated 75,000 households enumerated, 73,249 households (97.6%) were visited. Of the 371,174 household members, 761 TB patients were identified (∼205 cases per 100,000 populations). Data were collected from 609 (80%) TB patients of which 331 [54% (95% CI: 42–66%)] were determined to be taking treatment ‘under DOTS/RNTCP’. The remaining 278 [46% (95% CI: 34–57%)] were on treatment from ‘outside DOTS/RNTCP’ sources and hence were unlikely to be part of the TB notification system. Patients who were accessing treatment from ‘outside DOTS/RNTCP’ were more likely to be patients from rural areas [adjusted Odds Ratio (aOR) 2.5, 95% CI (1.2–5.3)] and whose TB was diagnosed in a non-government health facility (aOR 14.0, 95% CI 7.9–24.9).

Conclusions

This community-based survey found that nearly half of self-reported TB patients were missed by TB notification system in these districts. The study highlights the need for 1) Reviewing and revising the scope of the TB notification system, 2) Strengthening and monitoring health care delivery systems with periodic assessment of the reach and utilisation of the RNTCP services especially among rural communities, 3) Advocacy, communication and social mobilisation activities focused at rural communities with low household incomes and 4) Inclusive involvement of all health-care providers, especially providers of poor rural communities.     

High Diabetes Prevalence among Tuberculosis Cases in Kerala,India

Background

While diabetes mellitus (DM) is a known risk factor for tuberculosis, the prevalence among TB patients in India is unknown. Routine screening of TB patients for DM may be an opportunity for its early diagnosis and improved management and might improve TB treatment outcomes. We conducted a cross-sectional survey of TB patients registered from June–July 2011 in the state of Kerala, India, to determine the prevalence of DM.

Methodology/Principal Findings

A state-wide representative sample of TB patients in Kerala was interviewed and screened for DM using glycosylated hemoglobin (HbA1c); patients self-reporting a history of DM or those with HbA1c ≥6.5% were defined as diabetic. Among 552 TB patients screened, 243(44%) had DM – 128(23%) had previously known DM and 115(21%) were newly diagnosed - with higher prevalence among males and those aged >50years. The number needed to screen(NNS) to find one newly diagnosed case of DM was just four. Of 128 TB patients with previously known DM, 107(84%) had HbA1c ≥7% indicating poor glycemic control.

Conclusions/Significance

Nearly half of TB patients in Kerala have DM, and approximately half of these patients were newly-diagnosed during this survey. Routine screening of TB patients for DM using HbA1c yielded a large number of DM cases and offered earlier management opportunities which may improve TB and DM outcomes. However, the most cost-effective ways of DM screening need to be established by futher operational research.     

Studying nanostructured nipple arrays of moth eye facets helps to design better thin film solar cells

Nipples on the surface of moth eye facets exhibit almost perfect broadband anti-reflection properties. We have studied the facet surface micro-protuberances, known as corneal nipples, of the chestnut leafminer moth Cameraria ohridella by atomic force microscopy, and simulated the optics of the nipple arrays by three-dimensional electromagnetic simulation. The influence of the dimensions and shapes of the nipples on the optics was studied. In particular, the shape of the nipples has a major influence on the anti-reflection properties. Furthermore, we transferred the structure of the almost perfect broadband anti-reflection coatings to amorphous silicon thin film solar cells. The coating that imitates the moth-eye array allows for an increase of the short circuit current and conversion efficiency of more than 40%.     

Genetic signatures of exceptional longevity in humans

Like most complex phenotypes, exceptional longevity is thought to reflect a combined influence of environmental (e.g., lifestyle choices, where we live) and genetic factors. To explore the genetic contribution, we undertook a genome-wide association study of exceptional longevity in 801 centenarians (median age at death 104 years) and 914 genetically matched healthy controls. Using these data, we built a genetic model that includes 281 single nucleotide polymorphisms (SNPs) and discriminated between cases and controls of the discovery set with 89% sensitivity and specificity, and with 58% specificity and 60% sensitivity in an independent cohort of 341 controls and 253 genetically matched nonagenarians and centenarians (median age 100 years). Consistent with the hypothesis that the genetic contribution is largest with the oldest ages, the sensitivity of the model increased in the independent cohort with older and older ages (71% to classify subjects with an age at death>102 and 85% to classify subjects with an age at death>105). For further validation, we applied the model to an additional, unmatched 60 centenarians (median age 107 years) resulting in 78% sensitivity, and 2863 unmatched controls with 61% specificity. The 281 SNPs include the SNP rs2075650 in TOMM40/APOE that reached irrefutable genome wide significance (posterior probability of association = 1) and replicated in the independent cohort. Removal of this SNP from the model reduced the accuracy by only 1%. Further in-silico analysis suggests that 90% of centenarians can be grouped into clusters characterized by different “genetic signatures” of varying predictive values for exceptional longevity. The correlation between 3 signatures and 3 different life spans was replicated in the combined replication sets. The different signatures may help dissect this complex phenotype into sub-phenotypes of exceptional longevity.     

AT1 receptor-mediated augmentation of angiotensinogen, oxidative stress, and inflammation in ANG II-salt hypertension

Augmentation of intrarenal angiotensinogen (AGT) synthesis, secretion, and excretion is associated with the development of hypertension, renal oxidative stress, and tissue injury during ANG II-dependent hypertension. High salt (HS) exacerbates hypertension and kidney injury, but the mechanisms remain unclear. In this study, we determined the consequences of HS intake alone compared with chronic ANG II infusion and combined HS plus ANG II on the stimulation of urinary AGT (uAGT), renal oxidative stress, and renal injury markers. Sprague-Dawley rats were subjected to 1) a normal-salt diet [NS, n = 5]; 2) HS diet [8% NaCl, n = 5]; 3) ANG II infusion in NS rats [ANG II 80 ng/min, n = 5]; 4) ANG II infusion in HS rats [ANG II+HS, n = 5]; and 5) ANG II infusion in HS rats treated with ANG II type 1 receptor blocker (ARB) [ANG II+HS+ARB, n = 5] for 14 days. Rats fed a HS diet alone did not show changes in systolic blood pressure (SBP), proteinuria, cell proliferation, or uAGT excretion although they did exhibit mesangial expansion, collagen deposition, and had increased NADPH oxidase activity accompanied by increased peroxynitrite formation in the kidneys. Compared with ANG II rats, the combination of ANG II infusion and a HS diet led to exacerbation in SBP (175 ± 10 vs. 221 ± 8 mmHg; P < 0.05), proteinuria (46 ± 7 vs. 127 ± 7 mg/day; P < 0.05), and uAGT (1,109 ± 70 vs.. 7,200 ± 614 ng/day; P < 0.05) associated with greater collagen deposition, mesangial expansion, interstitial cell proliferation, and macrophage infiltration. In both ANG II groups, the O(2)(-) levels were increased due to increased NADPH oxidase activity without concomitant increases in peroxynitrite formation. The responses in ANG II rats were prevented or ameliorated by ARB treatment. The results indicate that HS independently stimulates ROS formation, which may synergize with the effect of ANG II to limit peroxynitrite formation, leading to exacerbation of uAGT and greater injury during ANG II salt hypertension.