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Health-care-associated infections (HAIs) cause significant morbidity and mortality globally, including in low-income and middle-income countries (LMICs). Networks of hospitals implementing standardised HAI surveillance can provide valuable data on HAI burden, and identify and monitor HAI prevention gaps. Hospitals in many LMICs use HAI case definitions developed for higher-resourced settings, which require human resources and laboratory and imaging tests that are often not available.A network of 26 tertiary-level hospitals in India was created to implement HAI surveillance and prevention activities. Existing HAI case definitions were modified to facilitate standardised, resource-appropriate surveillance across hospitals. Hospitals identified health-care-associated bloodstream infections and urinary tract infections (UTIs) and reported clinical and microbiological data to the network for analysis.26 network hospitals reported 2622 health-care-associated bloodstream infections and 737 health-care-associated UTIs from 89 intensive care units (ICUs) between May 1, 2017, and Oct 31, 2018. Central line-associated bloodstream infection rates were highest in neonatal ICUs (20 per 1000 central line days). Catheter-associated UTI rates were highest in paediatric medical ICUs (4·5 per 1000 urinary catheter days). Klebsiella spp (24·8%) were the most frequent organism in bloodstream infections and Candida spp (29·4%) in UTIs. Carbapenem resistance was common in Gram-negative infections, occurring in 72% of bloodstream infections and 76% of UTIs caused by Klebsiella spp, 77% of bloodstream infections and 76% of UTIs caused by Acinetobacter spp, and 64% of bloodstream infections and 72% of UTIs caused by Pseudomonas spp.The first standardised HAI surveillance network in India has succeeded in implementing locally adapted and context-appropriate protocols consistently across hospitals and has been able to identify a large number of HAIs. Network data show high HAI and antimicrobial resistance rates in tertiary hospitals, showing the importance of implementing multimodal HAI prevention and antimicrobial resistance containment strategies.US Centers for Disease Control and Prevention cooperative agreement with All India Institute of Medical Sciences, New Delhi.For the Hindi translation of the abstract see Supplementary Materials section.

This paper has identified the impacts of climate change on fuel wood energy use in Drass, District Kargil, Ladakh in the Himalayan region and drawn the policy implication to improve the livelihoods of the people in the context of climate change using a case study approach. The study reveals that the major source of energy used and consumed in Drass is fuel wood. Almost all energy requirements for cooking and heating are met by burning fuel wood which produces smoke, cause air pollution, emits carbon dioxide and thereby contributes to climate change. Less than half of the farmers grow fuel wood in gardens or homesteads. Most farmers purchased fuel wood from the market. Awareness of environmental effects of using fuel wood is significant. Despite this, the exposure of women to indoor air pollution from biomass fuel combustion was significantly high. The use of cleaner energy was significantly low due to economic reasons as well as inadequate accessibility and availability. Forest resources are meager in Drass. Therefore, efforts should be made to increase forest cover with the stronger participation of local communities. The government sponsored schemes targeting efficient energy usage and energy insecurity should be implemented in letter and spirit through greater people's participation.

In past few years India has originated as one of the most important hubs for health tourism. There are several pull factors like excellent health facilities, low cost, easy accessibility, picturesque locations for excellent holiday etc. Globalized and modernized practices derived from Ayurveda traditions gave impetus to health tourism. Ayurvedic science is a monumental contribution of India to the world. Its main objective is preventive health care along with disease cure. The main attraction for tourists is rejuvenation promised by Yoga and Ayurvedic massage. Kerala is hub of health tourism just because of Panchkarma therapy. Despite it, ideal geographic location, salubrious climate and Samhita based approach are the other key factors. Other potential and developing fields in Ayurveda for Health Tourism are Swasthvritta (lifestyle modification), Pathya-apathya (dietary habits/Nutrigenomics), Garbha Sanskara (having a healthy and desired progeny), infertility management, Rasayana (rejuvenation), Vajikarana (aphrodisiac) etc. Ayurvedic medicines are herbal or herbo-mineral. Lack of identification, availability, proper collection and processing of herbs are the major hurdles that lead to contamination and affect the potency of preparation. Mineral compounds must be processed strictly following the guidelines mentioned in Ayurvedic texts. Otherwise, heavy metal contaminants left in the preparation might cause metal toxicity in consumers. Strict adherence to “Drug Standardization Protocols” is the need of hour by drug manufacturing units to remove the taboo of metallic toxicity and placebo for Ayurvedic preparations globally.

Background Healthcare-associated urinary tract infections (HAUTIs) caused by gram-negative pathogens have emerged as a global concern. So far, little is known about the epidemiology of extended-spectrum β lactamase (ESBL)-producing Escherichia coli and Klebsiella pneumoniae in HAUTIs in India. The study was carried to determine the antibiotic resistance pattern and ESBL-producing genes in E. coli and K. pneumoniae strains isolated from HAUTIs in a tertiary institute in North India. Methods A total of 200 consecutive, nonduplicate clinical isolates of E. coli and 140 isolates of K. pneumoniae from hospitalized patients with UTI were collected during a period of 1 year. Strains were studied for the presence of ESBL genes (blaCTX-M1, blaCTX-M2, blaCTX-M9, blaCTX-M15, blaSHV, blaTEM, blaOXA-1, blaVEB, blaPER-2, and blaGES) by multiplex polymerase chain reaction using gene-specific primers. Results ESBL was detected in 82.5% (165 out of 200) isolates of E. coli and 74.3% (104 out of 140) isolates of K. pneumoniae by phenotypic confirmatory testing. From 269 phenotypically positive ESBL isolates, blaTEM (49.4%) was the most common genotype followed by blaCTX-M1 (31.97%), blaOXA-1 (30.1%), and blaSHV(11.9%) either alone or in combination. In the present study, blaCTX-M-15 (84.89%) was the most common blaCTX-M1-type ESBL. In total, 2.6 and 5.2% of the isolates were positive for PER-2 and VEB genes, respectively. Conclusion To the best of our knowledge, this is the first study on ESBL resistance patterns and ESBL-producing genes in HAUTIs in North India. Our study reports high occurrence with ESBL types CTX-M-1, CTX-M-15, TEM, and SHV. Minor ESBL variants OXA-1, VEB-type, and PER-2-type β-lactamase are also emerging in HAUTIs infections in North India.

Inflammation of knee joint is called knee arthritis. Among various forms of knee arthritis common is degenerative type of knee osteoarthritis It is the major cause of loco motor disability in old age people particularly among women. Analgesics and Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) are the current available pharmaceutical management of knee osteoarthritis which are associated with adverse side effects. Thus, there is need of research in traditional system of medicines for cost effective and long-term management of knee OA. Degenerative Knee osteo arthritis is almost similar to the Sandhivata describes in Ayuveda with respect to aetiology, pathology and clinical features. With the use of medicines Ayurveda also employs the prospective of Panchakarma in the various therapeutic measures, which is a kind of Shodhan Chikitsa. Panchakarma provides various therapeutic benefits as detoxification, improved circulation, spasm and pain relief. Hence objective of this review article is to describe the efficacy of Panchakarma in knee-arthritis with taking consideration of disease mentioned in Ayurvedic classics as Sandhivata

Background: The prevalence of hypothyroidism is reported in 4%–5% of population in the developed world, while in Indian population it is reported in around one in ten adults. Aims & Objectives: This study was conducted to determine the prevalence of hypothyroidism in Indian patients with T2DM and hypertension. Material and methods: In this cross-sectional observational study, amongst adults who were aged 18 years and above and diagnosed T2DM, HTN, and T2DM + HTN who resided in the field practice areas of the Urban Health Training Centre of the Department of Community Medicine, Integral institute of medical sciences and research, Lucknow, India. The results were summarized by descriptive statistics. Results: Out of 300 persons questioned, 159 (53.0%) were females and 141 (47.0%) were males. It was found that the mean age of the overall population was 53.1±11.3 years, mean and standard deviation of thyroid function and glycemic indicators test, observed that the levels of fT3, fT4, TSH, and glycemic indicators like FPG, PPG and HbA1c were identical. Conclusion: Subclinical hypothyroid subjects should be regularly screened for HTN. Elderly patients had higher proportion of thyroid dysfunction.

Introduction: Diabetes and hypertension are among the most common non-communicable diseases affecting our population. They are the important risk factors for cardiovascular morbidity and mortality. Objective: The study was performed to estimate the association of hypertension and dyslipidaemia with increasing body weight and obesity in Type II diabetics. Methods: This one year cross sectional study was conducted by enrolling 677 diabetics subjects from rural health training centre of integral institute of medical sciences, Lucknow, India. MS excel was used for data analysis. Descriptive statistics were used for number and percentages and associations were estimated using chi-square test. Results: Most of the subjects belonged to overweight category (36.91%) followed by obese (32.3%). Majority of subjects (38.4%), were within 40 – 50 years of age in which most of them belonged to overweight category (39.2%) followed by obese (31.5%). Out of total study subjects, 62% were males and 38% were females. Means of HbA1C, lipid parameters, blood pressure were found significantly associated with dyslipidemia and hypertension Conclusion: Association of hypertension and dyslipidemia in obese diabetics signifies that these patients may be at a higher risk of developing cardiovascular diseases and a precise action or self-care management is required.

Hypothyroidism is one of the burning issues in the current scenario and is affecting the lives of many people on various levels. Autoimmunity is responsible for over 90% of non-iatrogenic hypothyroidism in iodine-sufficient area. In iodine-sufficient areas, the most common cause of hypothyroidism is chronic autoimmune thyroiditis (also known as Hashimoto’s disease). Subclinical hypothyroidism is a mild form of primary hypothyroidism. Signs and symptoms of hypothyroidism are weight gain, cold intolerance, fatigue, somnolence, dry skin, dry hair, menorrhagia are more common constipation, hoarseness of voice, aches and pains, muscle stiffness, deafness, depression, infertility is less common. As per Ayurveda (science of life), it is caused due to vitiation of Agni. Shilajit an exudate, contains mainly fulvic acid, humic acid, and trace element (iron, selenium) which includes anti-inflammatory, immune-stimulant, properties. Anaemia as a symptom is associated with Hypothyroidism. The constituent present in Shilajit that is Fulvic acid enhances the absorption of iron so that serum iron status increases and can be helpful in the management of hypothyroidism. Triphala is an Ayurvedic herbal formulation of dried fruits of Terminalia chebula, Terminalia bellerica and Phyllantus emblica. The major phytoconstituent of Terminalia bellerica, Terminalia chebula and Phyllantus emblica fruits is gallic acid, which is known to have a wide range of therapeutic activity, e.g. anti-atherosclerotic, cardioprotective. In this review paper, it is being established that all these characteristics of Shilajit with Triphala kwath may be the probable reason for its effect on the management of hypothyroidism.

Katishool, low back ache (lumbago) is the most common problem in middle and old age people hampering the normal activity. There are several reasons associated with the pain such as – neurological, metabolic, degenerative, traumatic, bad posture, restless lifestyle, etc. Gridhasi is one of the Nanatmaja Vata Vyadhi, characterised by Katishool where the site of pain starts from the Sphika (back region) and then radiates to Kati, Pristha, Uru, Janu, Jangha, Pada in order. The signs and symptoms mentioned in ayurvedic texts resembles the medical condition named sciatica. Sciatica describes leg pain that is localised in the distribu-tion of one or more lumbosacral nerve roots, typically L4-S2, with or without neurological deficit. This causes abnormality in the gait of the patient. Gridhasi being a dominant lifestyle disorder needs a proper management and Siravedhan is one of the propitious managements of Gridhasi described in Ayurveda classics. Acharya Sushruta explained the importance of Siravedhan by accepting it as Ardha Chikitsa (half of the therapeutic measure) in Shalya tantra like Basti in Kayachikitsa. Acharya Sushruta also mentioned that the diseases which are not relieved so quickly by Snehana, Lepanadi measure, in this Siravedhan do wonders by acting as an emergency management to achieve good results.

Background Comorbidities such as undernutrition and parasitic infections are widespread in India and other tuberculosis (TB)-endemic countries. This study examines how these conditions as well as food supplementation and parasite treatment might alter immune responses to Mycobacterium tuberculosis (Mtb) infection and risk of progression to TB disease. Methods This is a 5-year prospective clinical trial at Jawaharlal Institute of Post Graduate Medical Education and Research in Puducherry, Tamil Nadu, India. We aim to enroll 760 household contacts (HHC) of adults with active TB in order to identify 120 who are followed prospectively for 2 years: Thirty QuantiFERON-TB Gold Plus (QFT-Plus) positive HHCs ≥ 18 years of age in four proposed groups: (1) undernourished (body mass index [BMI] 2); (2) participants with a BMI ≥ 18.5 kg/m2 who have a parasitic infection (3) undernourished participants with a parasitic infection and (4) controls—participants with BMI ≥ 18.5 kg/m2 and without parasitic infection. We assess immune response at baseline and after food supplementation (for participants with BMI 2) and parasite treatment (for participants with parasites). Detailed nutritional assessments, anthropometry, and parasite testing through polymerase chain reaction (PCR) and microscopy are performed. In addition, at serial time points, these samples will be further analyzed using flow cytometry and whole blood transcriptomics to elucidate the immune mechanisms involved in disease progression. Conclusions This study will help determine whether undernutrition and parasite infection are associated with gene signatures that predict risk of TB and whether providing nutritional supplementation and/or treating parasitic infections improves immune response towards this infection. This study transcends individual level care and presents the opportunity to benefit the population at large by analyzing factors that affect disease progression potentially reducing the overall burden of people who progress to TB disease. Trial registration ClinicalTrials.gov; NCT03598842; Registered on July 26, 2018; https://clinicaltrials.gov/ct2/show/NCT03598842

Introduction Ventilator-associated pneumonia (VAP) may be a life threatening nosocomial infection encountered in intensive care units. Currently the emergence of carbapenem-resistant Gram-negative pathogens has become worrisome threat worldwide. Material and methods Endotracheal aspirates samples were collected from patients who were under mechanical ventilation for > 48 h. The bacterial isolates were identified by MALDI-TOF-MS and antibiotic susceptibility testing performed. All carbapenem resistant isolates were tested by Modified Hodge test (MHT), modified carbapenem inactivation method (mCIM), and EDTA-CIM (eCIM) and PCR were performed to detect blaIMP, blaVIM and blaNDM producing MBL genes. Results VAP occurred in 172/353(48.7%), 23.3% had early-onset VAP and 76.7% had late-onset VAP. Males (69.2%) were found to suffer more from VAP. Prior antibiotic therapy, CPI>6, prior surgery and tracheostomy were associated with VAP. The mortality in VAP (58.1%) contrasted with non-VAP (40%). 99/169 (58.6%) Gram-negative isolates were resistant to carbapenems. Acinetobacter baumannii, Pseudomonas aeruginosa and Klebsiella pneumoniae were common pathogens found in late onset VAP, whereas K. pneumoniae, A. baumannii and Staphylococcus aureus were common in early onset VAP. The PCR results detected blaNDM in 37/172(21.5%) and blaVIM in 30/172(17.4%); 15/172(8.7%) isolates carried both genes. Conclusion The blaNDM-1 and blaVIM genes are the main antibiotic-resistance genes that induce resistance patterns to carbapenems in VAP, highlighting CRE strains of potential public health concern and therapeutic challenge. Diagnostic laboratories in India must get on high caution for early MBL detection as it may limit the wide dispersal of MBL genes.

OBJECTIVE: The aim of the study was to assess the impact of non-surgical periodontal therapy (NSPT) on periodontal clinical parameters, spirometric indices, and salivary MMP-8 levels in patients with chronic obstructive pulmonary disease (COPD) with concurrence of chronic periodontitis (CP) compared with systemically healthy CP. MATERIAL AND METHODS: In this prospective clinico-biochemical study, a total of 75 patients belonging to various socioeconomic strata were randomly divided into cases, that is, COPD patients as per the Global Initiative for Obstructive Lung Disease (GOLD) criteria with concurrence of CP [at least ≥ 20 teeth with ≥ 2 tooth sites having pocket probing depth (PPD) or clinical attachment loss (CAL) ≥ 4mm and bleeding on probing (BOP)] and controls (systemically healthy CP). Both groups underwent NSPT and were evaluated for plaque index (PI), gingival index (GI), PPD, CAL, and BOP and spirometry (FEV(1)/forced vital capacity (FVC)) values at baseline, 3, 6, and 12 months and for salivary MMP-8 levels at baseline and 3 months. RESULTS: Statistical results showed that cases (COPD with CP; n = 37) were significantly older (mean age 56.16 ± 9.01 years), ex-smokers (48.6%) with male preponderance (78.4%), and belonged to the upper middle class (40.5%) as compared to controls (systemically healthy CP; n = 38). After NSPT, significant improvement in mean PI, GI, PPD, CAL, and BOP was observed in both groups at 3, 6, and 12 months with better results in controls. FEV(1)/FVC was significantly improved (P < .001) in cases with insignificant change in controls at 12 months. After 3 months, MMP-8 levels were significantly reduced in cases (P = .002) and controls (P < .001). CONCLUSION: The present study provided substantial evidence that COPD patients have poorer periodontal health as compared to systemically healthy counterparts. Further, these patients showed improvement in FEV1/FVC, however, with higher salivary MMP-8 levels despite NSPT at the end of the study, indicating a possible role of systemic inflammatory overburden of pulmonary disease.

Funding Information: The work was funded by the National Institute of Allergy and Infectious Diseases, National Institutes of Health grants U19AI111276 and U01AI065663 to R.R.R., R.D., J.J.E. and P.S., and NIAID training grant T32AI125185 to A.L. The study sponsors were not involved in the study design, in the collection, analysis, and interpretation of data; in the writing of the manuscript; or in the decision to submit the manuscript for publication. Publisher Copyright: © 2022, The Author(s). Mechanisms underlying variability in transmission of Mycobacterium tuberculosis strains remain undefined. By characterizing high and low transmission strains of M.tuberculosis in mice, we show here that high transmission M.tuberculosis strain induce rapid IL-1R-dependent alveolar macrophage migration from the alveolar space into the interstitium and that this action is key to subsequent temporal events of early dissemination of bacteria to the lymph nodes, Th1 priming, granulomatous response and bacterial control. In contrast, IL-1R-dependent alveolar macrophage migration and early dissemination of bacteria to lymph nodes is significantly impeded in infection with low transmission M.tuberculosis strain; these events promote the development of Th17 immunity, fostering neutrophilic inflammation and increased bacterial replication. Our results suggest that by inducing granulomas with the potential to develop into cavitary lesions that aids bacterial escape into the airways, high transmission M.tuberculosis strain is poised for greater transmissibility. These findings implicate bacterial heterogeneity as an important modifier of TB disease manifestations and transmission. publishersversion published

SETTING Accurate testing and treatment for latent tuberculous infection is necessary for tuberculosis elimination. Certain parasite infections are associated with increased tuberculin skin test positivity; species-specific effects on QuantiFERON®-TB Gold In-Tube (QGIT) have not been described. OBJECTIVE To determine whether infection with helminths or protozoa affects QGIT results. DESIGN We retrospectively analyzed QGIT and parasite testing results for immigrants screened in Boston, MA, USA, from 2012 to 2017. We also prospectively measured cytokines in QGIT supernatants for a subset (n = 68) with 1) helminths, 2) Blastocystis hominis, 3) other protozoa, and 4) no parasites. RESULTS Of 527 immigrants screened, 141 (26.8%) were QGIT-positive and 229 (43.4%) had parasites detected: 27/527 (5.1%) had helminths and 202/527 (38.3%) protozoa. Cytokine analysis revealed increased interleukin-10 concentrations with protozoa (P = 0.04), and non-significantly higher T-helper 2 concentrations with helminths compared with no parasites. No significant differences emerged in QGIT positivity or interferon-gamma concentrations in any group. CONCLUSION Study results support the use of QGIT in parasite-endemic settings. .

The high altitude trans-Himalayan region indeed is hostile domain for survival. Algae inhabiting this hostile terrain have evolutionarily developed mechanisms to produce unique adaptogenic molecules against climatic stressors. The present study has focused on the high altitude alga Spirogyra porticalis (Muell.) Cleve- a filamentous Charophyte, and reports the estimation of amino acids (AAs), fatty acids (FAs), vitamins and their efficacy against oxidative stress. Reverse phase-HPLC, GC-FID and rapid resolution-LC/tandem mass spectrometry were used for analysis of AAs, FAs and vitamins. Analysis of the alga revealed the presence of 19 AAs (239.51 ± 8.57 to 13102.40 ± 11.08 µg/g), dominated by alanine, proline and lysine. Enriched phenylalanine, cysteine-HCl and high lysine:arginine ratio could also have beneficial impact against hypoxia -induced cognitive impairment. A total of 9 FAs were detected (0.43 ± 0.00% to 34.76 ± 0.52%). Polyunsaturated and monounsaturated FAs were found to be dominant. The alga showed the presence of 8 vitamins within the range of 39.654 ± 3.198 to 5468.184 ± 106.859 µg/Kg, wherein Vitamin B5, B3 and B2 were dominant. 600 µg/ml of methanolic extract showed recovery of GSH and trolox equivalent antioxidants in rat blood/hemolysate, while 400 µg/ml of extract showed revival in superoxide dismutase (SOD) activity. The present study concludes that the alga S. porticalis has immense potential to counter oxidative stress as a nutraceutical supplement.

INTRODUCTION: Infectious diarrhea is leading infectious cause of childhood morbidity, hospitalizations, and mortality particularly in children living in developing countries like India. The etiological agents differ depending on geographical area, and recent data suggest increase in drug resistance to various enteropathogens. AIMS AND OBJECTIVES: The aim of the study was to investigate emerging diarrheal agents and antimicrobial resistance profile of bacterial pathogens from children ( MATERIALS AND METHODS: A cross-sectional, hospital-based observational study was conducted over 1 year in which 100 children RESULTS: Pathogenic diarrheal agents were found in 63% patients. Rotavirus was identified in 52.5%, DEC in 29%, Vibrio cholerae in 4%, Shigella flexneri in 3%, Aeromonas sp. in 1%, Giardia lamblia in 4%, and Entamoeba histolytica in 1% cases. Enteropathogenic E. coli (EPEC) in 19 (65.5%) cases was the most common agent followed by Enteroaggregative E. coli (EAEC) in 5 (17.2%), Enterotoxigenic E. coli (ETEC) in 2 (6%), and Enteroinvasive E. coli (EIEC) in 3 (10.3%) cases. Resistance rates of DEC to first-line therapeutic drugs were high, 97.3% to ampicillin and 95.95% to co-trimoxazole. DEC was susceptible to chloramphenicol in 58.11%, gentamicin in 48.19%, and amikacin in 58.11% cases. Shigella sp. and V. cholerae isolates were 100% sensitive to gentamicin and ofloxacin. CONCLUSION: EPEC is the most common DEC pathotype and EAEC, ETEC, and EIEC are also emerging as dominant diarrheal agents. Rotavirus was the most common causative agents of diarrhea especially in children

We have reported that TLR2 is crucial for host resistance against chronic Mycobacterium tuberculosis infection; however, which cell types are key players in this response remain unknown. This led us to decipher the relative contribution of TLR2 on nonhematopoietic and hematopoietic cells in resistance against chronic M. tuberculosis infection in mice infected with M. tuberculosis Erdman. Consistent with our previous report, at 8 wk of infection, TLR2 knockout (TLR2KO)→TLR2KO bone marrow chimeric mice exhibited increased bacterial burden, disorganized accumulation of lymphocytes and mononuclear cells, and extensive pulmonary immunopathology compared with wild-type (WT)→WT chimeric mice. Bacterial burden and pulmonary immunopathology of chimeric mice lacking TLR2 in the hematopoietic compartment (TLR2KO→WT) was comparable to TLR2KO mice. In contrast, chimeric mice deficient in TLR2 in the nonhematopoietic compartment (WT→TLR2KO) exhibited a marked attenuation in granulomatous inflammation compared with WT mice. Although the latter mice did not exhibit improved pulmonary bacterial control, significant reductions in bacterial burden in the draining lymph nodes, spleen, and liver were observed. These findings establish that the TLR2-mediated hematopoietic response promotes stable control of pulmonary bacterial burden and granuloma integrity, whereas TLR2 signaling on nonhematopoietic cells may partly facilitate granulomatous inflammation and bacterial dissemination.

In a study of household contacts (HHC), households were categorized into High (HT) and Low (LT) transmission groups based on the proportion of HHC with a positive tuberculin skin test. The Mycobacterium tuberculosis (Mtb) strains from HT and LT index cases of the households were designated Mtb-HT and Mtb-LT, respectively. We found that C3HeB/FeJ mice infected with Mtb-LT strains exhibited significantly higher bacterial burden compared to Mtb-HT strains and also developed diffused inflammatory lung pathology. In stark contrast, a significant number of mice infected with Mtb-HT strains developed caseating granulomas, a lesion type with high potential to cavitate. None of the Mtb-HT infected animals developed diffused inflammatory lung pathology. A link was observed between increased in vitro replication of Mtb-LT strains and their ability to induce significantly high lipid droplet formation in macrophages. These results support that distinct early interactions of Mtb-HT and Mtb-LT strains with macrophages and subsequent differential trajectories in pathological disease may be the mechanism underlying their transmission potential., Author summary Mycobacterium tuberculosis (Mtb), the bacteria that causes tuberculosis (TB), is spread through the air from infected patients to their close contacts. In a household contact (HHC) study of patients with TB, we found that in some households a larger proportion of contacts were infected with Mtb compared to other households. We categorized the households into High (HT) and Low (LT) transmission groups. The Mtb strains obtained from the TB patients of the HT and LT households were designated Mtb-HT and Mtb-LT, respectively. In this study, we investigated in a mouse model of TB, the mechanistic basis for the variability in transmission of Mtb from infected patients to their close contacts. We found that C3HeB/FeJ mice infected with Mtb-LT strains developed diffused inflammatory lesions characteristic of granulocytic tuberculous pneumonia. In stark contrast, a significant number of mice infected with Mtb-HT strains developed caseating granulomas, a lesion type with high potential to cavitate. In conclusion, we report that the segregation of Mtb strains into high and low transmission phenotype is mechanistically linked to their ability to induce distinct pulmonary pathology.

The W-Beijing strain family is globally distributed and is associated with multidrug-resistant tuberculosis (TB) and treatment failure. Therefore, in this study, we examined the contribution of Toll-like receptor 2 (TLR2) to host resistance against Mycobacterium tuberculosis HN878, a clinical isolate belonging to the W-Beijing family. We show that TLR2 knockout (TLR2KO) mice infected with M. tuberculosis HN878 exhibit increased bacterial burden and are unable to control tissue-damaging, pulmonary neutrophilic inflammation. Consistent with a critical role for CXCL5 in regulating neutrophil influx, expression of epithelial cell-derived CXCL5 is significantly enhanced in TLR2KO mice prior to their divergence from wild-type (WT) mice in M. tuberculosis replication and neutrophilic inflammation. Depletion of neutrophils in TLR2KO mice by targeting Ly6G reverts lung inflammation and bacterial burden to levels comparable to those of WT mice. Together, the results establish that TLR2 controls neutrophil-driven immunopathology during infection with M. tuberculosis HN878 infection, likely by curtailing CXCL5 production.

Cell wall biosynthesis inhibitors have proven highly effective for treating tuberculosis (TB). We discovered and validated members of the indazole sulfonamide class of small molecules as inhibitors of Mycobacterium tuberculosis KasA—a key component for biosynthesis of the mycolic acid layer of the bacterium’s cell wall and the same pathway as that inhibited by the first-line antitubercular drug isoniazid (INH). One lead compound, DG167, demonstrated synergistic lethality in combination with INH and a transcriptional pattern consistent with bactericidality and loss of persisters. Our results also detail a novel dual-binding mechanism for this compound as well as substantial structure-activity relationships (SAR) that may help in lead optimization activities. Together, these results suggest that KasA inhibition, specifically, that shown by the DG167 series, may be developed into a potent therapy that can synergize with existing antituberculars., We report GSK3011724A (DG167) as a binary inhibitor of β-ketoacyl-ACP synthase (KasA) in Mycobacterium tuberculosis. Genetic and biochemical studies established KasA as the primary target. The X-ray crystal structure of the KasA-DG167 complex refined to 2.0-Å resolution revealed two interacting DG167 molecules occupying nonidentical sites in the substrate-binding channel of KasA. The binding affinities of KasA to DG167 and its analog, 5g, which binds only once in the substrate-binding channel, were determined, along with the KasA-5g X-ray crystal structure. DG167 strongly augmented the in vitro activity of isoniazid (INH), leading to synergistic lethality, and also synergized in an acute mouse model of M. tuberculosis infection. Synergistic lethality correlated with a unique transcriptional signature, including upregulation of oxidoreductases and downregulation of molecular chaperones. The lead structure-activity relationships (SAR), pharmacokinetic profile, and detailed interactions with the KasA protein that we describe may be applied to evolve a next-generation therapeutic strategy for tuberculosis (TB).

Asthma is a respiratory disorder accounts for ~339 million cases per annum. The initial diagnosis of asthma relies on the symptomatic identification of characters, such as wheeze, shortness of breath, chest tightness, and cough. The presence of two or more of these symptoms may be considered as indicative of asthma. The asthma-diagnostic also involves spirometry test before and after inhaling a bronchodilator like albuterol. Because asthma pathophysiology involves participation of immune system, the cytokines play an important role. The review discusses various molecules that are or may be used as biomarkers for the asthma diagnosis.

In December 2019, a novel infectious disease, caused by Severe Acute Respiratory Syndrome-coronavirus 2 (SARS-CoV-2), was identified in Wuhan, China, now declared as a pandemic. The Renin–Angiotensin system (RAS) and angiotensin-converting enzyme 2 (ACE2) have drawn special attention, as ACE2 acts as a receptor for SARS-CoV2. No specific therapy against SARS-COV2 has been invented yet. There is a constant need towards understanding of the underlying pathophysiology to aid the pharmacological research. We have looked at the current evidence on the relationship between SARS-COV-2 and RAS and ACE2. Articles in English language published between 1st January 2003 and 15th June 2020 were searched using keywords and MeSH (Medical Subject Heading). We used Google Scholar and Pubmed as search engines. Conclusion: Bats serve as primary reservoir for SARS-CoV2, but its intermediate host has not been identified yet. ‘Hot spots’ on ACE2, serve as receptors for SARS-COV2. Imbalance in the activity of ACE/ACE2 is an important contribution towards the pathogenesis of coronavirus related diseases. ACE2 also has protective role and recombinant ACE2 has been shown to improve lung injury and it is a potential therapeutic agent.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Background Tuberculosis (TB) is the major cause of death in Human Immunodeficiency Virus (HIV)-infected individuals. However, diagnosis of TB in HIV remains challenging particularly when HIV infection is advanced. Several gene signatures and serum protein biomarkers have been identified that distinguish active TB from latent infection. Our study was designed to assess if gene expression signatures and cytokine levels would distinguish active TB in advanced HIV. Methods We conducted a case-control study of whole blood RNA-Seq and plasma cytokine/chemokine analysis in HIV-infected with CD4+ T cell count of ≤ 100 cells/μl, with and without active TB. Next, the overlap of the differentially expressed genes (DEG) with the published signatures was performed and then receiver operator characteristic (ROC) analysis was done on small gene discriminators to determine their performance in distinguishing TB in advanced HIV. ELISA was performed on plasma to evaluate cytokine and chemokine levels. Results Hierarchical clustering of the transcriptional profiles showed that, in general, HIV-infected individuals with TB (TB-HIV) clustered separately from those without TB. IPA indicated that the TB-HIV signature was characterized by an increase in inflammatory signaling pathways. Analysis of overlaps between DEG in our data set with published TB signatures revealed that significant overlap was seen with one TB signature and one TB-IRIS signature. ROC analysis revealed that transcript levels of FcGR1A (AUC = 0.85) and BATF2 (AUC = 0.82), previously reported as consistent single gene classifiers of active TB irrespective of HIV status, performed successfully even in advanced HIV. Plasma protein levels of IFNγ, a stimulator of FcGR1A and BATF2, and CXCL10, also up-regulated by IFNγ, accurately classified active TB (AUC = 0.98 and 0.91, respectively) in advanced HIV. Neither of these genes nor proteins distinguished between TB and TB-IRIS. Conclusions Gene expression of FcGR1A and BATF2, and plasma protein levels of IFNγ and CXCL10 have the potential to independently detect TB in advanced HIV. However, since other lung diseases were not included in this study, these final candidates need to be validated as specific to TB in the advanced HIV population with TB. Electronic supplementary material The online version of this article (10.1186/s12879-018-3127-4) contains supplementary material, which is available to authorized users.

A major impediment to tuberculosis (TB) vaccine development is the lack of reliable correlates of immune protection or biomarkers that would predict vaccine efficacy. Gamma interferon (IFN-γ) produced by CD4+T cells and, recently, multifunctional CD4+T cells secreting IFN-γ, tumor necrosis factor (TNF), and interleukin-2 (IL-2) have been used in vaccine studies as a measurable immune parameter, reflecting activity of a vaccine and potentially predicting protection. However, accumulating experimental evidence suggests that host resistance againstMycobacterium tuberculosisinfection is independent of IFN-γ and TNF secretion from CD4+T cells. Furthermore, the booster vaccine MVA85A, despite generating a high level of multifunctional CD4+T cell response in the host, failed to confer enhanced protection in vaccinated subjects. These findings suggest the need for identifying reliable correlates of protection to determine the efficacy of TB vaccine candidates. This article focuses on alternative pathways that mediateM. tuberculosiscontrol and their potential for serving as markers of protection. The review also discusses the significance of investigating the natural human immune response toM. tuberculosisto identify the correlates of protection in vaccination.

Background: Neonatal sepsis is a continuing problem causing significant burden on health care, especially in developing world. As blood culture has low sensitivity in diagnosis of neonatal sepsis, strong clinical suspicion along with combination of different laboratory tests is required. The data available for extensively studied acute phase reactant, procalcitonin (PCT) remains controversial. This study was done to assess role of PCT alone and in combination with different tests for diagnosing neonatal sepsis.Methods: Blood samples of 275 neonates (>35 weeks of gestation) admitted to NICU, with suspicion of neonatal sepsis were collected for bacterial culture, serum procalcitonin level and sepsis screen (CRP, mESR, I/T ratio, Total Leucocyte Count, Absolute Neutrophil Count).Results: Blood culture was positive in 30.5% of enrolled neonates. At a cut-off value of 0.5 ng/ml the sensitivity, specificity, PPV, NPV of serum PCT in neonatal sepsis cases was 73.8%, 47.1%, 48%, 80.4% respectively. Serum PCT was found raised in 60 (48.8%) clinically suspected cases of neonatal sepsis where sepsis screen and blood culture both were negative, also it was not raised in 17 (32.7%) of clinically suspected cases of septicemia where both blood culture and sepsis screen were positive. Amongst other individual tests, CRP was found to have best sensitivity (79.7%) and NPV (85%) followed by PCT (73.8% and 80.4%) while best specificity was found for I/T ratio (93.7%) followed by mESR (89%) for diagnosis of neonatal sepsis with positive blood culture. Best NPV was seen for combination of PCT+CRP+I/T ratio (95.6%) for the suspected cases of neonatal sepsis.Conclusions: Thus, we conclude that serum PCT can play a useful role when combined with other test markers but may not find its way as a sole diagnostic marker for diagnosing neonatal sepsis in term/near term babies.

The Grb-2 associated binder (Gab) family of scaffolding/adaptor/docking proteins is a group of three molecules with significant roles in cytokine receptor signaling. Gabs possess structural motifs for phosphorylation-dependent receptor recruitment, Grb2 binding, and activation of downstream signaling pathways through p85 and SHP-2. In addition, Gabs participate in hematopoiesis and regulation of immune response which can be aberrantly activated in cancer and inflammation. The multifunctionality of Gab adapters might suggest that they would be too difficult to consider as candidates for “targeted” therapy. However, the one drug/one target approach is giving way to the concept of one drug/multiple target approach since few cancers are addicted to a single signaling molecule for survival and combination drug therapies can be problematic. In this paper, we cover recent findings on Gab multi-functionality, binding partners, and their role in hematological malignancy and examine the concept of Gab-targeted therapy.