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Acute Encephalitis Syndrome (AES) is a major seasonal public health problem in Bihar, India. Despite efforts of the Bihar health department and the Government of India, burden and mortality of AES cases have not decreased, and definitive etiologies for the illness have yet to be identified. The present study was undertaken to study the specific etiology of AES in Bihar. Cerebrospinal fluid and/or serum samples from AES patients were collected and tested for various pathogens, including viruses and bacteria by ELISA and/or Real Time PCR. Of 540 enrolled patients, 33.3% (180) tested positive for at least one pathogen of which 23.3% were co-positive for more than one pathogen. Most samples were positive for scrub typhus IgM or PCR (25%), followed by IgM positivity for JEV (8.1%), WNV (6.8%), DV (6.1%), and ChikV (4.5%).M. tuberculosis and S. pneumoniae each was detected in ~ 1% cases. H. influenzae, adenovirus, Herpes Simplex Virus -1, enterovirus, and measles virus, each was detected occasionally. The presence of Scrub typhus was confirmed by PCR and sequencing. Bihar strains resembled Gilliam-like strains from Thailand, Combodia and Vietnam. The highlights of this pilot AES study were detection of an infectious etiology in one third of the AES cases, multiple etiologies, and emergence of O. tsutsugamushi infection as an important causative agent of AES in India.

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. 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. 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. 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.

Large-scale cancer sequencing data enable discovery of rare germline cancer susceptibility variants. Here we systematically analyse 4,034 cases from The Cancer Genome Atlas cancer cases representing 12 cancer types. We find that the frequency of rare germline truncations in 114 cancer-susceptibility-associated genes varies widely, from 4% (acute myeloid leukaemia (AML)) to 19% (ovarian cancer), with a notably high frequency of 11% in stomach cancer. Burden testing identifies 13 cancer genes with significant enrichment of rare truncations, some associated with specific cancers (for example, RAD51C , PALB2 and MSH6 in AML, stomach and endometrial cancers, respectively). Significant, tumour-specific loss of heterozygosity occurs in nine genes ( ATM , BAP1 , BRCA1/2 , BRIP1 , FANCM , PALB2 and RAD51C/D ). Moreover, our homology-directed repair assay of 68 BRCA1 rare missense variants supports the utility of allelic enrichment analysis for characterizing variants of unknown significance. The scale of this analysis and the somatic-germline integration enable the detection of rare variants that may affect individual susceptibility to tumour development, a critical step toward precision medicine. Published sequencing data sets of cancer samples could be used to identify genetic variants associated with the risk of developing cancer. Here, Lu et al . analyse over 4,000 tumour-normal pairs to reveal variable frequencies of inherited susceptibilities across 12 cancer types and find enrichment of functionally validated missense variants of unknown significance.

Li Ding, Feng Chen and colleagues report a pan-cancer analysis using a new computational tool, HotSpot3D, to identify mutational hotspots in the encoded three-dimensional protein structure, which suggest their functional involvement in cancer. They use a mutation–drug cluster analysis to predict more than 800 potentially druggable mutations. Local concentrations of mutations are well known in human cancers. However, their three-dimensional spatial relationships in the encoded protein have yet to be systematically explored. We developed a computational tool, HotSpot3D, to identify such spatial hotspots (clusters) and to interpret the potential function of variants within them. We applied HotSpot3D to >4,400 TCGA tumors across 19 cancer types, discovering >6,000 intra- and intermolecular clusters, some of which showed tumor and/or tissue specificity. In addition, we identified 369 rare mutations in genes including TP53 , PTEN , VHL , EGFR , and FBXW7 and 99 medium-recurrence mutations in genes such as RUNX1 , MTOR , CA3 , PI3 , and PTPN11 , all mapping within clusters having potential functional implications. As a proof of concept, we validated our predictions in EGFR using high-throughput phosphorylation data and cell-line-based experimental evaluation. Finally, mutation–drug cluster and network analysis predicted over 800 promising candidates for druggable mutations, raising new possibilities for designing personalized treatments for patients carrying specific mutations.

The purpose of transfer learning is to utilize the knowledge gained from the existing (source) domain to enhance the performance on a distinct but related (target) domain. Existing works on transfer learning are not capable of optimizing different quality measures (components) such as minimizing the marginal distribution, minimizing the conditional distribution, maximizing the target domain variance, modeling the manifold by utilizing the common geometric properties in the source as well as the target domain at the same time. Moreover, existing transfer learning methods use conventional approaches to determine the appropriate values of their parameters, which is very hectic and time-consuming. Therefore, in order to overcome the drawbacks of existing approaches, we propose a Particle Swarm Optimization based Parameter Selection Approach for Unsupervised Discriminant Analysis (UDATL-PSO) in transfer learning framework. In UDATL-PSO, all the quality measures are considered at the same time, as well as the PSO approach has been used to select the best values of their parameters. Extensive experiments on various transfer learning tasks show that the proposed method has a significant influence on state-of-the-art methods.

Background. Japanese encephalitis is associated with high rates of mortality and disabling sequelae. To date, no specific antiviral has proven to be of benefit for this condition. We attempted to determine the efficacy of oral ribavirin treatment for reducing early mortality among children with Japanese encephalitis in Uttar Pradesh, India. Methods. Children (age, 6 months to 15 years) who had been hospitalized with acute febrile encephalopathy (a ⩽2-week history of fever plus altered sensorium) were tested for the presence of immunoglobulin M antibodies to Japanese encephalitis virus with commercial immunoglobulin M capture enzyme-linked immunosorbent assay. Children with positive results were randomized to receive either ribavirin (10 mg/kg per day in 4 divided doses for 7 days) or placebo syrup through nasogastric tube or by mouth. The primary outcome was early mortality; secondary outcome measures were early (at hospital discharge; normal or nearly normal, independent functioning, dependent, vegetative state, or death) outcome, time to resolution of fever, time to resumption of oral feeding, duration of hospitalization, and late outcome (⩾3 months after hospital discharge). The study was double-blind, and analysis was by intention to treat. Results. A total of 153 patients were enrolled during a 3-year period; 70 patients received ribavirin, and 83 received placebo. There was no statistically significant difference between the 2 groups in the early mortality rate: 19 (27.1%) of 70 ribavirin recipients and 21 (25.3%) of 83 placebo recipients died (odds ratio, 1.10; 95% confidence interval, 0.5–2.4). No statistically significant differences in secondary outcome measures were found. Conclusions. For the dosage schedule used in our study, oral ribavirin has no effect in reducing early mortality associated with Japanese encephalitis. Trial registration. ClinicalTrials.gov identifier: .

Significance How the kidney handles chloride reabsorption has long been a mystery. Here, we have discovered a pathway in the kidney that utilizes channel-activating protease 1 and claudin-4 to physiologically regulate tight junction permeability to chloride. Such a pathway not only is important in renal regulation of chloride but also may play key roles in chloride transport across many other epithelia such as the lung, the salivary gland, and the skin. This discovery also attests to a concept of “druggable” tight junction. Proteases or protease-dependent mechanisms may be developed as pharmacological tools to transiently regulate tight junction permeability in the kidney, the intestine, and the blood–brain barrier.

Background Acute encephalitis syndrome (AES) is a public health problem in India. Neuroinfections are believed to be the most important etiology. Minocycline is a semisythetic tetracycline having excellent penetration into cerebrospinal fluid, established neuroprotective and antiviral properties besides action on nonviral causes of AES. It has been shown to be effective in animal model of Japanese encephalitis (JE). A randomized, controlled trial of nasogastric/oral minocycline in JE and AES at a single centre in Uttar Pradesh, northern India, was therefore conducted. Methods Patients beyond 3 years of age - but excluding women aged 16–44 years - hospitalized with AES of < =7 days duration were enrolled and block randomized to receive nasogastric/oral minocycline or placebo suspension and followed up. Patients, study personnel and those entering data were blinded as to drug or placebo received. Primary outcome was cumulative mortality at 3 months from hospitalization. Analysis was by intention to treat. Results 281 patients were enrolled, 140 received drug and 141 placebo. While there was no overall statistically significant difference in 3 month mortality between drug and placebo groups [RR = 0 · 83 (0 · 6-1 · 1)], there were encouraging trends in patients older than 12 years [RR = 0.70 (0.41-1.18)] and in Glasgow Outcome Score (GOS) at 3 months (χ 2  = 7 · 44, p = 0 · 059). These trends were further accentuated if patients dying within one day of reaching hospital were excluded [OR for 3 month mortality =0 · 70 (0 · 46-1 · 07), p = 0.090; 3 month GOS p = 0 · 028]. Conclusions A trend towards better outcomes was observed with minocycline, especially in those patients who survived the initial day in hospital. These findings should form the basis for planning a larger study and possibly including minocycline in the initial management of AES as seen here. Trial registration The trial was registered with Clinical Trials Registry of India (CTRI) - CTRI/2010/091/006143

Background. Japanese encephalitis is a disease that affects the rural poor in Asia. In August–September 2005, a severe epidemic of Japanese encephalitis occurred in Uttar Pradesh, one of India's poorest states. Methods. Children admitted to the King George Medical University hospital (Lucknow, Uttar Pradesh, India) with acute febrile encephalopathy (defined as fever plus encephalopathy of ⩽2 weeks' duration) from July to October 2005 underwent ELISA for Japanese encephalitis virus immunoglobulin M in cerebrospinal fluid or serum on hospital admission. Clinicolaboratory features of patients with positive test results were recorded. Results. of the 223 children tested, 77 had positive results for Japanese encephalitis immunoglobulin M. Patients were from 18 districts of Uttar Pradesh. All but 1 were from rural areas, and none were <2 years of age. The prodromal period was very short (mean ± standard deviation, 2.61 ± 2.23days). Convulsions were present in 76 patients (98.7%). The mean (± standard deviation) Glasgow Coma Scale score was 7.4 ± 2.7. Generalized hypertonia was found in 39 patients (50.6%), and focal deficits were found in 35 patients (45.4%), including 19 cases of monoparesis and 16 cases of hemiparesis. Gastric hemorrhage was found in 42 patients (54.5%). Extrapyramidal features were found in 24 (31.1%), a hyperepneic breathing pattern was found in 20 (26%), and thrombocytopenia was found in 5 (15.6%) of 32 patients. The mean cerebrospinal fluid cell count was 48.3 cells/mm3. The serum bilirubin level was normal in all patients, but the aspartate aminotransferase level was elevated in all 21 patients (100%) tested and the alanine aminotranferase level was elevated in 25 (47.2%) of 53 patients. In-hospital mortality was 34%. Conclusions. Clinical features of Japanese encephalitis were severe. Derangements in liver function and thrombocytopenia were found in a significant proportion of patients. These findings were not highlighted during earlier epidemics of the illness and could suggest a possible mutation of the virus towards other flaviviruses.

Background: Carbapenemase-producing Klebsiella pneumoniae (CRKP) has become a menace in several intensive care units, which needs to be controlled immediately after being reported by a laboratory. Detection in the laboratory is usually done using phenotypic methods and it is not known whether knowledge of these genes helps in individual patient management. This study aimed to compare the outcomes of oxacillinases β-lactamases (OXA-48) and New Delhi metallo-β-lactamase (NDM-1)-producing CRKP isolates, the two most common carbapenemases reported from India, obtained from patients with bloodstream infections in an ICU in a tertiary care center in North India and to compare the different laboratory methods for their detection.Materials and methods: Klebsiella pneumoniae isolates obtained from the blood culture of patients admitted to various ICUs were subjected to conventional polymerase chain reaction (PCRs) for blaNDM and blaOXA48-like genes. Those positive for any of the genes were tested by the modified carbapenem inactivation method (mCIM) and if found positive were also subjected to ethylenediamine tetraacetic acid (EDTA)-modified carbapenem inactivation method (eCIM). Antibiotic susceptibility tests (AST) were performed and clinical data were recorded.Results: A total of 49 isolates were positive for one or more carbapenemase genes (30 {61.2%} for blaNDM gene only, 13 {26.5%)} for blaOXA48-like gene only, and six {12.2%} for both). The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of mCIM were found to be 77.6%, 100%, 100%, and 78.9%, respectively. Statistically significant differences were found in the AST pattern between the isolates with two genes. Increased MIC levels of colistin were observed, though they lay in the sensitive range. Mortality occurred in all six patients who were infected with CRKP harboring both the genes though no significant difference was observed in NDM and OXA-48 producing CRKP isolates.Conclusion: Surveillance of carbapenemase genes in a hospital setting is essential. The possible reasons for the low diagnostic accuracy of mCIM and differences in AST patterns are discussed.