In India, research prioritization in Maternal, Newborn, and Child Health and Nutrition (MNCHN) themes has traditionally involved only a handful of experts mostly from major cities. The Indian Council of Medical Research (ICMR)-INCLEN collaboration undertook a nationwide exercise engaging faculty from 256 institutions to identify top research priorities in the MNCHN themes for 2016-2025. The Child Health and Nutrition Research Initiative method of priority setting was adapted. The context of the exercise was defined by a National Steering Group (NSG) and guided by four Thematic Research Subcommittees. Research ideas were pooled from 498 experts located in different parts of India, iteratively consolidated into research options, scored by 893 experts against five pre-defined criteria (answerability, relevance, equity, investment and innovation) and weighed by a larger reference group. Ranked lists of priorities were generated for each of the four themes at national and three subnational (regional) levels [Empowered Action Group & North-Eastern States, Southern and Western States, & Northern States (including West Bengal)]. Research priorities differed between regions and from overall national priorities. Delivery domain of research which included implementation research constituted about 70 per cent of the top ten research options under all four themes. The results were endorsed in the NSG meeting. There was unanimity that the research priorities should be considered by different governmental and non-governmental agencies for investment with prioritization on implementation research and issues cutting across themes.

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Background & objectives: Gestational diabetes mellitus (GDM) can cause adverse perinatal outcome if not treated. Although insulin therapy has been the main treatment modality over decades but considering its cost and parenteral mode of administration, it does not seem to be appropriate, especially in low-resource settings. The objective of this study was to evaluate the role of metformin in GDM and know its efficacy as well as adverse effect on foetus and mother. Methods: All pregnant women with GDM who were not controlled on medical nutrition therapy and required metformin therapy were included in the study. Careful monitoring of blood sugar was done. Development of any maternal or foetal complications and adverse effect were recorded. Results: A total of 2797 pregnant women were screened, of whom 233 (8.3%) were found to have GDM. Of the 64 women with GDM (28.7%) who required metformin therapy, majority (93.8%) achieved blood sugar control, whereas three (4.7%) women failed. Caesarean section rate was 54 per cent, and 15.6 per cent neonates were large for gestational age. Only two (3.1%) women had gastrointestinal side effects which were minor and got resolved with time. No case of hypoglycaemia or perinatal mortality was reported. Interpretation & conclusions: Our findings indicate that metformin may be used as a safe and effective oral hypoglycaemic agent in GDM, especially in low-resource settings where cost, storage and compliance are logistic issues. However, long-term follow up studies are needed to solve issues related to its safety in pregnancy.

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Polymyalgia rheumatica (PMR) is a unique disease of elderly people, traditionally diagnosed based on a clinical picture. A typical case is a combination of severe musculoskeletal symptoms and systemic inflammatory response with spectacular response to corticosteroids treatment. The severity of symptoms may be surprising in older patients where immunosenescence is normally expected. However, PMR may be diagnosed in haste if there is a temptation to use this diagnosis as a shortcut to achieve rapid therapeutic success. Overdiagnosis of PMR may cause more problems compared to underdiagnosis. The 2012 PMR criteria proposed by European League against Rheumatism/American College of Rheumatology aim to minimize the role of clinical intuition and build on more objective features. However, questions arise if this is possible in PMR. This has been discussed in this review.

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Newly emerging and re-emerging viral infections are of major public health concern. Bunyaviridae family of viruses comprises a large group of animal viruses. Clinical symptoms exhibited by persons infected by viruses belonging to this family vary from mild-to-severe diseases i.e., febrile illness, encephalitis, haemorrhagic fever and acute respiratory illness. Several arthropods-borne viruses have been discovered and classified at serological level in India in the past. Some of these are highly pathogenic as the recent emergence and spread of Crimean-Congo haemorrhagic fever virus and presence of antibodies against Hantavirus in humans in India have provided evidences that it may become one of the emerging diseases in this country. For many of the discovered viruses, we still need to study their relevance to human and animal health. Chittoor virus, a variant of Batai virus; Ganjam virus, an Asian variant of Nairobi sheep disease virus; tick-borne viruses such as Bhanja, Palma and mosquito-borne viruses such as Sathuperi, Thimiri, Umbre and Ingwavuma viruses have been identified as the members of this family. As Bunyaviruses are three segmented RNA viruses, they can reassort the segments into genetically distinct viruses in target cells. This ability is believed to play a major role in evolution, pathogenesis and epidemiology of the viruses. Here, we provide a comprehensive overview of discovery, emergence and distribution of Bunyaviruses in India.

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Background & objectives: Glanzmann thrombasthenia (GT) is a rare, inherited autosomal recessive disorder characterized by qualitative or quantitative deficiency of integrin αIIbβ3 [glycoprotein IIb (GPIIb)/IIIa, CD41/CD61] diagnosed by absent or reduced platelet aggregation to physiological agonists, namely, collagen, adenosine-di-phosphate, epinephrine and arachidonic acid. The objective of this study was to quantitate platelet surface GPs, classify GT patients and relate the results with the severity of bleeding and platelet aggregation studies. Methods: Fifty one patients of GT diagnosed by platelet aggregation studies were evaluated for the expression of CD41, CD61, CD42a and CD42b on platelet surface by flow cytometry. The association between the clinical phenotype based on bleeding score and GT subtype on flow cytometric evaluation was assessed. Results: Twenty four (47%) patients of GT were classified as type I (as CD41/CD61 were virtually absent, <5%), six (11.8%) patients as type II (5-20% CD41/CD61) and 21 (41.2%) as type III or GT variants as they had near normal levels of CD41 and CD61. Type III GT patients had significantly lower numbers of severe bleeders (P=0.034), but the severity of bleeding did not vary significantly in type I and II GT patients. In all GT patients, mean CD41 expression was found to be lower than mean CD61 expression (P=0.002). Interpretation & conclusions: Type I GT was found most common in our patients and with lowered mean CD41 expression in comparison with CD61. Type III GT patients had significantly lower numbers of severe bleeders, but the severity of bleeding did not vary significantly in type I and II GT patients.

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Background & objectives: Differential diagnosis of Crimean-Congo haemorrhagic fever (CCHF) from other acute febrile illnesses with haemorrhagic manifestation is challenging in India. Nosocomial infection is a significant mode of transmission due to exposure of healthcare workers to blood and body fluids of infected patients. Being a risk group 4 virus, laboratory confirmation of infection is not widely available. In such a situation, early identification of potential CCHF patients would be useful in limiting the spread of the disease. The objective of this study was to retrospectively analyse clinical and laboratory findings of CCHF patients that might be useful in early detection of a CCHF case in limited resource settings. Methods: Retrospective analysis of clinical and laboratory data of patients suspected to have CCHF referred for diagnosis from Gujarat and Rajasthan States of India (2014-2015) was done. Samples were tested using CCHF-specific real time reverse transcription (RT)-PCR and IgM ELISA. Results: Among the 69 patients referred, 21 were laboratory confirmed CCHF cases of whom nine had a history of occupational exposure. No clustering of cases was noted. Platelet count cut-off for detection of positive cases by receiver operating characteristic curve was 21.5×10^[9]/l with sensitivity 82.4 per cent and specificity 82.1 per cent. Melaena was a significant clinical presentation in confirmed positive CCHF patients. Interpretation & conclusions: The study findings suggest that in endemic areas thrombocytopenia and melaena may be early indicators of CCHF. Further studies are needed to confirm these findings.

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Background & objectives: Matrix-assisted laser desorption ionization-time-of-flight mass spectrometry (MALDI-TOF MS) has been instrumental in revolutionizing microbiological identification, especially in high-throughput laboratories. It has enabled the identification of organisms like non-fermenting Gram-negative bacilli (NFGNB), which has been a challenging task using conventional methods alone. In this study an attempt was made to validate MALDI-TOF MS for the identification of clinical isolates of each of the three most common NFGNB, other than Pseudomonas spp., taking molecular methods as the gold standard. Methods: One hundred and fifty clinical isolates of NFGNB, confirmed by molecular methods such as Acinetobacter baumannii[oxa-51 polymerase chain reaction (PCR)], Burkholderia cepacia complex (expanded multilocus sequence typing) and Stenotrophomonas maltophilia (species-specific PCR), were taken. Isolated colonies from fresh cultures of all 150 isolates were smeared onto ground steel plate, with and without formic acid extraction step. The identification was carried out using MALDI-TOF MS Biotyper database. Results: A concordance of 100 and 73.33 per cent was found between the molecular techniques and MALDI-TOF MS system in the identification of these isolates up to genus and species levels, respectively. Using a cut-off of 1.9 for reliable identification, rate of species identification rose to 82.66 per cent. Principal component analysis dendrogram and cluster analysis further increased discrimination of isolates. Interpretation & conclusions: Our findings showed MALDI-TOF MS-based identification of NFGNB as a good, robust method for high-throughput laboratories.

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Background & objectives: Cardiovascular disease (CVD) risk with low high-density lipoprotein cholesterol (HDL-C) and high triglycerides is common in the general population in India. As nevirapine (NVP)-based antiretroviral therapy (ART) tends to increase HDL-C, gene polymorphisms associated with HDL-C metabolism in HIV-infected adults on stable NVP-based ART were studied. Methods: A cross-sectional study was conducted between January 2013 and July 2014 among adults receiving NVP-based ART for 12-15 months. Blood lipids were estimated and gene polymorphisms in apolipoprotein C3 (APOC3), cholesteryl ester transfer protein (CETP) and lipoprotein lipase (LPL) genes were analyzed by real-time polymerase chain reaction. Framingham's 10-yr CVD risk score was estimated. Logistic regression was done to show factors related to low HDL-C levels. Results: Of the 300 patients included (mean age: 38.6±8.7 yr; mean CD4 count 449±210 cell/μl), total cholesterol (TC) >200 mg/dl was observed in 116 (39%) patients. Thirty nine per cent males and 47 per cent females had HDL-C levels below normal while 32 per cent males and 37 per cent females had TC/HDL ratio of 4.5 and 4.0, respectively. Body mass index [adjusted odds ratio (aOR)=1.70, 95% confidence interval (CI) 1.01-2.84, P=0.04] and viral load (aOR=3.39, 95% CI: 1.52-7.52, P=0.003) were negatively associated with serum HDL-C levels. The 10-yr risk score of developing CVD was 11-20 per cent in 3 per cent patients. Allelic variants of APOC3 showed a trend towards low HDL-C. Interpretation & conclusions: High-risk lipid profiles for atherosclerosis and cardiovascular disease were common among HIV-infected individuals, even after 12 months of NVP-based ART. Targeted interventions to address these factors should be recommended in the national ART programmes.

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Background & objectives: Shigella dysenteriae is one of the most virulent pathogens causing bacillary dysentery and is responsible for high mortality in infants. To reduce the load of antibiotic therapy for treating shigellosis, this study was carried out to assess the ex vivo effect of novel probiotic lactobacilli, isolated from infant's stool samples, on killing S. dysenteriae type 1 residing in the rat macrophages. Methods: Stool samples from infants were collected, processed for the isolation of lactobacilli and screened for the probiotic attributes (acid tolerance, bile tolerance, ability to adhere intestinal cells and anti-S. dysenteriae activity). The effect of cell-free supernatant of lactobacilli on Shigella- infected macrophages in terms of phagocytic ability, extent of lipid peroxidation, nitrite, superoxide dismutase and glutathione levels was evaluated. Results: Based on the probiotic attributes, three lactobacilli were isolated from the stool samples of infants. Using classical and molecular tools, these isolates were identified as Lactobacillus pentosus, L. Paraplantarum and L. rhamnosus. All the three lactobacilli had the ability to kill intramacrophage S. dysentriae type 1. The anti-Shigella activity of the probiotic lactobacilli was attributed to increased antioxidative ability and decreased free radical production by the infected macrophages. Interpretation & conclusions: Probiotic cocktail of L. pentosus, L. paraplantarum and L. rhamnosus showed ex vivo killing of S. dysenteriae residing inside the rat macrophages significantly. This cocktail has the potential to be used as a natural alternative for treating S. dysenteriae infection, especially in infants, however, further studies need to be done to confirm these finding in vivo.

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Background & objectives: The emergence of resistance to fluoroquinolones in enteric fever despite the pathogen being susceptible by in vitro laboratory results, led to repeated changes in Clinical and Laboratory Standard Institute (CLSI) guidelines for this class of antibiotics to have specific and sensitive interpretative criteria. In 2015, CLSI added pefloxacin disk diffusion criteria as a surrogate marker for fluoroquinolone susceptibility. This study was carried out to evaluate the use of pefloxacin as a surrogate marker for ciprofloxacin, ofloxacin and levofloxacin susceptibility in clinical isolates of Salmonella Typhi and S. Paratyphi A. Methods: A total of 412 strains of S. Typhi and S. Paratyphi A were studied for pefloxacin disk diffusion test as a surrogate marker for susceptibility to ciprofloxacin, ofloxacin and levofloxacin as per CLSI and the European Committee on Antimicrobial Susceptibility Testing (EUCAST) guidelines. Molecular mechanisms of resistance to fluoroquinolones were also determined and correlated with pefloxacin susceptibility breakpoints. Results: Of the total 412 strains, 34 were susceptible to ciprofloxacin and 33 each to levofloxacin and ofloxacin using CLSI minimum inhibitory concentration (MIC) breakpoints. There was a positive correlation between MICs with correlation coefficients 0.917, 0.896 and 0.958 for the association between ciprofloxacin and ofloxacin, ciprofloxacin and levofloxacin and ofloxacin and levofloxacin, respectively (P <0.001). The sensitivity, specificity and positive predictive value of pefloxacin as a surrogate marker using ciprofloxacin MIC as a gold standard were 100, 99.5 and 94.4 per cent, while 100, 99.2 and 91.7 per cent taking ofloxacin and levofloxacin MIC as gold standard. Mutations in target genes correlated with the pefloxacin susceptibility results. Interpretation & conclusions: Our results showed that pefloxacin served as a good surrogate marker for the detection of susceptibility to ciprofloxacin, ofloxacin and levofloxacin in S. Typhi and S. Paratyphi A. Further studies are required to confirm these findings.

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Background & objectives: Candida, the most common opportunistic infection in acquired immunodeficiency syndrome (AIDS), attributes its pathogenicity to its virulence factors, mainly the biofilms, the proteinases and the phospholipases. There is a significant interplay of these factors during the HIV infection. This study was aimed to estimate the biofilm, proteinase and phospholipase production in Candida species isolated from the oropharyngeal samples in the HIV-infected patients. Methods: A total of 126 consecutive HIV-positive patients were screened for Candida growth using oropharyngeal swabs. Identification was done by Gram staining, germ tube test, chlamydospore identification, chromagar and biochemical tests on Vitek 2. Biofilm production was observed on Sabouraud's dextrose broth with glucose, phospholipase production in egg yolk agar medium and proteinase production in bovine serum albumin agar medium. Results: Of a total of 126 patients, 53 (42.06%) showed Candida growth: Candida albicans (n=46, 86.8%) was most common followed by the non-albicans Candida (NAC) (n=7, 13.93%). Of a total 33 (62.3%) biofilm positive isolates, significant production was observed in the NAC species (P <0.05). C. albicans reported the highest phospholipase (n=37/41, 90.24%) and proteinase (n=37/43, 86%) activities in a total of 41 (77%) phospholipase positive and 43 (81.1%) proteinase positive isolates. Interpretation & conclusions: Although C. albicans was the most common Candida species identified in HIV positive patients, the emergence of NAC was of special concern. Virulence factors such as biofilms, proteinases and phospholipases were noted in both these groups. Further research is required for better understanding of the pathogenic role of Candida species so as to aid in therapeutic interventions.

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Background & objectives: Pseudomonas aeruginosa possessing chromosomally inducible bla_PDCalong with other intrinsic mechanism causes infection with high mortality rate. It is difficult to detect inducible AmpC enzymes in this organism and is usually overlooked by routine testing that may lead to therapeutic failure. Therefore, three different inducers were evaluated in the present study to assess their ability of induction of bla_PDCin P. aeruginosa. Methods: A total of 189 consecutive Pseudomonas isolates recovered from different clinical specimens (November 2011-April 2013) were selected for the study. Isolates were screened with cefoxitin for AmpC β-lactamases and confirmed by modified three-dimensional extract test (M3DET). Inductions were checked using three inducers, namely, clavulanic acid, cefoxitin and imipenem along with ceftazidime. Molecular screening of AmpC β-lactamase genes was performed by PCR assay. Antimicrobial susceptibility and minimum inhibitory concentrations (MICs) were determined, and repetitive extragenic palindromic-PCR of all bla_PDCharbouring isolates was performed. Results: Inducible phenotype was observed in 42 (24.3%) of 97 (56%) isolates confirmed by M3DET. Among these, 22 isolates harboured chromosomal bla_PDCgene, and cocarriage of both chromosomal and plasmid-mediated bla_AmpC genes was observed in seven isolates. Cefoxitin-ceftazidime-based test gave good sensitivity and specificity for detecting inducible AmpC enzymes. Isolates harbouring bla_PDCshowed high MIC against all tested cephalosporins and monobactam. DNA fingerprinting of these isolates showed 22 different clones of P. aeruginosa. Interpretation & conclusions: P. aeruginosa harbouring inducible (chromosomal) and plasmid-mediated AmpC β-lactamase is a matter of concern as it may limit therapeutic option. Using cefoxitin-ceftazidime-based test is simple and may be used for detecting inducible AmpC β-lactamase amongst P. aeruginosa.

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Background & objectives: Chandipura virus (CHPV) is an emerging pathogenic rhabdovirus with a high case fatality rate. There are no reports of a minigenome system for CHPV, which could help its study without having to use the infectious agent. This study was, therefore, undertaken for the establishment of T7 polymerase-driven minigenome system for CHPV. Methods: The minigenome rescue system for CHPV consists of three helper plasmids expressing the nucleocapsid protein (N), phosphoprotein (P) and large protein (L) based on a recombinant vaccinia virus expressing bacteriophage T7 polymerase (vTF7-3). The minigenome construct is composed of a reporter gene, flanked by the non-coding regions of CHPV. Two minigenomes were constructed in an antigenome or complimentary sense, expressing luciferase or green fluorescent protein (GFP). The minigenome system was evaluated by co-transfection of the minigenome construct and three helper plasmids into CV-1 cells and analysis of the reporter gene activity. Results: All the helper proteins were expressed from the helper plasmids confirmed by Western blotting. Expression of reporter genes was observed from both the GFP and luciferase-based minigenomes. Green fluorescence could be visualized directly in live CV-1 cells. Luciferase activity was found to be significantly different from control. Interpretation & conclusions: The results showed that the helper plasmids provided all the necessary viral structural proteins required for the production of minigenome mRNA template, which in turn could rescue the expression of reporter genes. Thus, these minigenomes can be applied to mimic the manifestation of CHPV life cycle.

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