HIV-infected presumptive tuberculosis patients without tuberculosis: How many are eligible for antiretroviral therapy in Karnataka, India?

For certain subgroups within people living with the human immunodeficiency virus (HIV) [active tuberculosis (TB), pregnant women, children <5years old, and serodiscordant couples], the World Health Organization recommends antiretroviral therapy (ART) irrespective of CD4 count. Another subgroup which has received increased attention is "HIV-infected presumptive TB patients without TB". In this study, we assess the proportion of HIV-infected presumptive TB patients eligible for ART in Karnataka State (population 60million), India. This was a cross-sectional analysis of data of HIV-infected presumptive TB patients diagnosed in May 2015 abstracted from national TB and HIV program records. Of 42,585 presumptive TB patients, 28,964 (68%) were tested for HIV and 2262 (8%) were HIV positive. Of the latter, 377 (17%) had active TB. Of 1885 "presumptive TB patients without active TB", 1100 (58%) were already receiving ART. Of the remaining 785 who were not receiving ART, 617 (79%) were assessed for ART eligibility and of those, 548 (89%) were eligible for ART. About 90% of "HIV-infected presumptive TB patients without TB" were eligible for ART. This evidence supports a public health approach of starting all "HIV-infected presumptive TB patients without TB" on ART irrespective of CD4 count in line with global thinking about 'test and treat'

Atomic excitation during recollision-free ultrafast multi-electron tunnel ionization

Modern intense ultrafast pulsed lasers generate an electric field of sufficient strength to permit tunnel ionization of the valence electrons in atoms. This process is usually treated as a rapid succession of isolated events, in which the states of the remaining electrons are neglected. Such electronic interactions are predicted to be weak, the exception being recollision excitation and ionization caused by linearly-polarized radiation. In contrast, it has recently been suggested that intense field ionization may be accompanied by a two-stage `shake-up' reaction. Here we report a unique combination of experimental techniques that enables us to accurately measure the tunnel ionization probability for argon exposed to 50 femtosecond laser pulses. Most significantly for the current study, this measurement is independent of the optical focal geometry, equivalent to a homogenous electric field. Furthermore, circularly-polarized radiation negates recollision. The present measurements indicate that tunnel ionization results in simultaneous excitation of one or more remaining electrons through shake-up. From an atomic physics standpoint, it may be possible to induce ionization from specific states, and will influence the development of coherent attosecond XUV radiation sources. Such pulses have vital scientific and economic potential in areas such as high-resolution imaging of in-vivo cells and nanoscale XUV lithography.Comment: 17 pages, 4 figures, original format as accepted by Nature Physic

HIV Testing among Patients with Presumptive Tuberculosis: How Do We Implement in a Routine Programmatic Setting? Results of a Large Operational Research from India.

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

'I am on treatment since 5 months but I have not received any money': coverage, delays and implementation challenges of 'Direct Benefit Transfer' for tuberculosis patients - a mixed-methods study from South India.

Background: In March 2018, the Government of India launched a direct benefit transfer (DBT) scheme to provide nutritional support for all tuberculosis (TB) patients in line with END TB strategy. Here, the money (@INR 500 [~8 USD] per month) is deposited electronically into the bank accounts of beneficiaries. To avail the benefit, patients are to be notified in NIKSHAY (web-based notification portal of India's national TB programme) and provide bank account details. Once these details are entered into NIKSHAY, checked and approved by the TB programme officials, it is sent to the public financial management system (PFMS) portal for further processing and payment. Objectives: To assess the coverage and implementation barriers of DBT among TB patients notified during April-June 2018 and residing in Dakshina Kannada, a district in South India. Methods: This was a convergent mixed-methods study involving cohort analysis of patient data from NIKSHAY and thematic analysis of in-depth interviews of providers and patients. Results: Of 417 patients, 208 (49.9%) received approvals for payment by PFMS and 119 (28.7%) got paid by 1 December 2018 (censor date). Reasons for not receiving DBT included (i) not having a bank account especially among migrant labourers in urban areas, (ii) refusal to avail DBT by rich patients and those with confidentiality concerns, (iii) lack of knowledge and (iv) perception that money was too little to meet the needs. The median (IQR) delay from diagnosis to payment was 101 (67-173) days. Delays were related to the complexity of processes requiring multiple layers of approval and paper-based documentation which overburdened the staff, bulk processing once-a-month and technological challenges (poor connectivity and issues related to NIKSHAY and PFMS portals). Conclusion: DBT coverage was low and there were substantial delays. Implementation barriers need to be addressed urgently to improve uptake and efficiency. The TB programme has begun to take action

Transcription factor AP-1 in esophageal squamous cell carcinoma: Alterations in activity and expression during Human Papillomavirus infection

<p>Abstract</p> <p>Background</p> <p>Esophageal squamous cell carcinoma (ESCC) is a leading cause of cancer-related deaths in Jammu and Kashmir (J&K) region of India. A substantial proportion of esophageal carcinoma is associated with infection of high-risk HPV type 16 and HPV18, the oncogenic expression of which is controlled by host cell transcription factor Activator Protein-1 (AP-1). We, therefore, have investigated the role of DNA binding and expression pattern of AP-1 in esophageal cancer with or without HPV infection.</p> <p>Methods</p> <p>Seventy five histopathologically-confirmed esophageal cancer and an equal number of corresponding adjacent normal tissue biopsies from Kashmir were analyzed for HPV infection, DNA binding activity and expression of AP-1 family of proteins by PCR, gel shift assay and immunoblotting respectively.</p> <p>Results</p> <p>A high DNA binding activity and elevated expression of AP-1 proteins were observed in esophageal cancer, which differed between HPV positive (19%) and HPV negative (81%) carcinomas. While JunB, c-Fos and Fra-1 were the major contributors to AP-1 binding activity in HPV negative cases, Fra-1 was completely absent in HPV16 positive cancers. Comparison of AP-1 family proteins demonstrated high expression of JunD and c-Fos in HPV positive tumors, but interestingly, Fra-1 expression was extremely low or nil in these tumor tissues.</p> <p>Conclusion</p> <p>Differential AP-1 binding activity and expression of its specific proteins between HPV - positive and HPV - negative cases indicate that AP-1 may play an important role during HPV-induced esophageal carcinogenesis.</p

Food loss and waste metrics: a proposed nutritional cost footprint linking linear programming and life cycle assessment

Purpose: The main purpose of this article is to assess the nutritional and economic efficiency of food loss and waste (FLW) along the supply of 13 food categories included in the Spanish food basket by means of the definition of a new method which combines two indexes. Methods: The nutrient-rich foods index and the economic food loss and waste (EFLW) index were combined by means of linear programming to obtain the nutritional cost footprint (NCF) indicator under a life cycle perspective. The functional unit used was the daily supply of food for a Spanish citizen in year 2015. Results and discussion: Results showed that vegetables and cereals were the food categories most affected by the inefficiencies in the food supply chain under a nutritional perspective, being agricultural production and household consumption the main stages in which the nutritional content of food is lost or wasted. Moreover, according to the NCF index, vegetables represented 27% of total nutritional-economic wastage throughout the entire Spanish agri-food chain. They are followed by fruits, which add up to 19%. Hence, specific food waste management strategies should be established for these specific products and supply stages. Finally, the sensitivity analysis performed highlighted that results were mostly independent from the importance attributed to either nutritional or economic variables. Conclusions: The methodology described in this study proposes an indicator quantifying the nutritional-economic cost of different food categories in the Spanish food basket. This NCF indicator makes it possible to define reduction strategies to promote the use of food waste fractions for waste-to-energy valorization approaches or the extraction of different types of pharmacological, chemical, or cosmetic compounds.The authors are grateful for the funding of the Spanish Ministry of Economy and Competitiveness through the Ceres-Procom: Food production and consumption strategies for climate change mitigation (CTM2016-76176-C2-1-R) (AEI/FEDER, UE)

A Computational and Experimental Study of the Regulatory Mechanisms of the Complement System

The complement system is key to innate immunity and its activation is necessary for the clearance of bacteria and apoptotic cells. However, insufficient or excessive complement activation will lead to immune-related diseases. It is so far unknown how the complement activity is up- or down- regulated and what the associated pathophysiological mechanisms are. To quantitatively understand the modulatory mechanisms of the complement system, we built a computational model involving the enhancement and suppression mechanisms that regulate complement activity. Our model consists of a large system of Ordinary Differential Equations (ODEs) accompanied by a dynamic Bayesian network as a probabilistic approximation of the ODE dynamics. Applying Bayesian inference techniques, this approximation was used to perform parameter estimation and sensitivity analysis. Our combined computational and experimental study showed that the antimicrobial response is sensitive to changes in pH and calcium levels, which determines the strength of the crosstalk between CRP and L-ficolin. Our study also revealed differential regulatory effects of C4BP. While C4BP delays but does not decrease the classical complement activation, it attenuates but does not significantly delay the lectin pathway activation. We also found that the major inhibitory role of C4BP is to facilitate the decay of C3 convertase. In summary, the present work elucidates the regulatory mechanisms of the complement system and demonstrates how the bio-pathway machinery maintains the balance between activation and inhibition. The insights we have gained could contribute to the development of therapies targeting the complement system.Singapore. Ministry of Education (Grant T208B3109)Singapore. Agency for Science, Technology and Research (BMRC 08/1/21/19/574)Singapore-MIT Alliance (Computational and Systems Biology Flagship Project)Swedish Research Counci

Local Inflammation Induces Complement Crosstalk Which Amplifies the Antimicrobial Response

By eliciting inflammatory responses, the human immunosurveillance system notably combats invading pathogens, during which acute phase proteins (CRP and cytokines) are elevated markedly. However, the Pseudomonas aeruginosa is a persistent opportunistic pathogen prevalent at the site of local inflammation, and its acquisition of multiple antibiotic-resistance factors poses grave challenges to patient healthcare management. Using blood samples from infected patients, we demonstrate that P. aeruginosa is effectively killed in the plasma under defined local infection-inflammation condition, where slight acidosis and reduced calcium levels (pH 6.5, 2 mM calcium) typically prevail. We showed that this powerful antimicrobial activity is provoked by crosstalk between two plasma proteins; CRP∶L-ficolin interaction led to communication between the complement classical and lectin pathways from which two amplification events emerged. Assays for C4 deposition, phagocytosis, and protein competition consistently proved the functional significance of the amplification pathways in boosting complement-mediated antimicrobial activity. The infection-inflammation condition induced a 100-fold increase in CRP∶L-ficolin interaction in a pH- and calcium-sensitive manner. We conclude that the infection-induced local inflammatory conditions trigger a strong interaction between CRP∶L-ficolin, eliciting complement-amplification pathways which are autonomous and which co-exist with and reinforce the classical and lectin pathways. Our findings provide new insights into the host immune response to P. aeruginosa infection under pathological conditions and the potential development of new therapeutic strategies against bacterial infection

Protective Effect of Curcumin on Pulmonary and Cardiovascular Effects Induced by Repeated Exposure to Diesel Exhaust Particles in Mice

Particulate air pollution has been associated with increased risk of cardiopulmonary diseases. However, the underlying mechanisms are not fully understood. We have previously demonstrated that single dose exposure to diesel exhaust particle (DEP) causes lung inflammation and peripheral thrombotic events. Here, we exposed mice with repeated doses of DEP (15µg/animal) every 2nd day for 6 days (a total of 4 exposures), and measured several cardiopulmonary endpoints 48 h after the end of the treatments. Moreover, the potential protective effect of curcumin (the yellow pigment isolated from turmeric) on DEP-induced cardiopulmonary toxicity was assessed. DEP exposure increased macrophage and neutrophil numbers, tumor necrosis factor α (TNF α) in the bronchoalveolar lavage (BAL) fluid, and enhanced airway resistance to methacoline measured invasively using Flexivent. DEP also significantly increased plasma C-reactive protein (CRP) and TNF α concentrations, systolic blood pressure (SBP) as well as the pial arteriolar thrombosis. It also significantly enhanced the plasma D-dimer and plasminogen activator inhibitor-1 (PAI-1). Pretreatment with curcumin by oral gavage (45 mg/kg) 1h before exposure to DEP significantly prevented the influx of inflammatory cells and the increase of TNF α in BAL, and the increased airway resistance caused by DEP. Likewise, curcumin prevented the increase of SBP, CRP, TNF α, D-dimer and PAI-1. The thrombosis was partially but significantly mitigated. In conclusion, repeated exposure to DEP induced lung and systemic inflammation characterized by TNFα release, increased SBP, and accelerated coagulation. Our findings indicate that curcumin is a potent anti-inflammatory agent that prevents the release of TNFα and protects against the pulmonary and cardiovascular effects of DEP