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Integration of insecticides and biological controls is an important tactic of Integrated Pest Management (IPM). Trichogramma chilonis is a promising natural enemy of many lepidopteran insect pests. However, this hymenopteran egg parasitoid is adversely affected by most insecticides. Contact toxicity of nineteen insecticides and three biopesticides on adults of T. chilonis was investigated by using dry film residue bioassays under laboratory conditions. Profenofos and chlorpyrifos were highly lethal to the adults even at sublethal doses followed by dimethoate, spinosad, indoxacarb and acephate + imidacloprid. Diafenthiuron, nimbecidine and flubendiamide were categorised as less toxic. The biopesticides viz., Metarhizium anisopliae, Beauveria bassiana and Metarhizium rileyi were found innocuous to T. chilonis. The study suggests that the insecticides with less toxicity and biopesticides with apparently no harmful effects on the parasitoid can be used in conjunction with parasitoids in IPM programmes. This will also advise plant protectionists in avoiding insecticides with detrimental effects on this hymenopteran wasp with appropriate timing of application that controls the pests without adversely affecting their natural enemies. [ABSTRACT FROM AUTHOR]

Anthracnose caused by Colletotrichum truncatum is a major soybean disease in India. Genetic resistance is the viable option to combat yield losses due to this disease. In the current study, 19 soybean genotypes were evaluated for anthracnose disease resistance at five locations (Medziphema, Palampur, Dharwad, Jabalpur and Indore) for three consecutive years (2017–2019) to identify stable and superior genotypes as resistant sources and to elucidate genotype (G) × environment (E) interactions. Genotype effect, environment effect and G × E interactions were found significant (P < 0.001) where G × E interactions contributed highest (42.44) to the total variation followed by environment (29.71) and genotype (18.84). Through Weighted Average of Absolute Scores (WAASB) stability analysis, PS 1611 (WAASB score = 0.33) was found to be most stable and through WAASBY superiority analysis NRC 128 (WAASBY score = 94.31) and PS 1611 (WAASBY score = 89.43) were found to be superior for mean performance and stability. These two genotypes could be candidate parents for breeding for durable and stable anthracnose resistance. Through principal component analysis, disease score was found to be positively associated with relative humidity, wind speed at 2 m above ground level, effect of temperature on radiation use efficiency and global solar radiation based on latitude and Julian day. Among the five locations, Indore was found to be highly discriminative with the highest mean disease incidence and could differentiate anthracnose-resistant and susceptible genotypes effectively, therefore can be considered an ideal location for breeding for field resistance against anthracnose disease. [ABSTRACT FROM AUTHOR]

The present study aimed to investigate the repellent proprieties of recommended insecticides targeted at the management of pigeon pea pod borer, Helicoverpa armigera along with the recuperation of three species of honey bees under field condition during 2018-19 and 2019-20 at Vijayapur and Bagalkot districts of Karnataka-India. The repellency studies of insecticides concerning honey bees in both locations and during both the years indicated that the recovery percentage of honey bees (Apis florea, Apis cerana and Apis dorsata) for the treated field had the fastest rate in the plots treated with Neem Seed Kernel Extract followed by chlorantraniliprole compared to other insecticides. Further, normal activity (100% recovery) of the bees was realized in the treatment with Neem seed kernel extract and chlorantraniliprole which took only 2 and 3 days as compared to more than 7 days for other insecticides. Among the bee species studied, A. dorsata resumed its normal activity sooner than A. cerana and A. florea. A. florea was the most sensitive species to insecticides in pigeon pea. The results indicate the faster recovery of bees which has augmented pollination services and has a greater relevance in enhancing the yield in pigeon pea, whenever the insecticides with less repellent activity were used in the IPM programmes. [ABSTRACT FROM AUTHOR]

Background: Public perception regarding the disease and concerns regarding safety and reliability of the new COVID 19 vaccine is the determining factor for acceptance of the vaccine. Objectives: To assess the risk perception of the health science students towards COVID 19 and COVID 19 vaccination. Methodology: A total of 701 health science students from Kasturba Medical College, Mangalore and Manipal College of Dental Sciences, Mangalore were included in this cross-sectional study. Institutional Ethics Committee permission was obtained prior to the commencement of the study. Risk perception towards COVID 19 and COVID 19 vaccination was assessed using Health belief model questionnaire. Data was analysed using IBM SPSS for windows version 25.0, Armonk, New York, 25.0. Results: Among the total participants, a higher proportion (57.6%) of the participants had a strong belief that COVID 19 can cause serious infection and 75.1% had strong belief that COVID 19 vaccine could provide protection against infection. Majority, 62% of the participants had received the 1st dose of vaccine, however, 37.6% had hesitancy. Conclusion: A lower percentage of the study participants had hesitancy towards COVID 19 vaccine. Major reasons for hesitancy were fear of side effects, history of allergic reactions, concern about safety and efficacy of the vaccine.

Ancient Indian texts such as Varahamihira's 'BrihathSamhitha', Chavundaraya's 'Lokopakara' and Sarangadhara's SarangadharaSamhitha', provide recommendations for an integrated approach to control crop pests and diseases by managing soil, seed, plant and environment. The seed treatment with cow dung, milk, juice of plants and cow ghee is also prescribed. As prophylactic measure for disease control, the incense of plant leaves and flowers, along with fish meat, turmeric, mustard, are mentioned. 'Panchagavya' to control plant diseases were found effective in managing soil-borne diseases of tomato and Panama wilt disease banana. [ABSTRACT FROM AUTHOR]

A 19-year-old male, right dominant, diagnosed with myotonic dystrophy (MD) Type I was referred to the rehabilitation services in a public hospital. The patient abstained from a job of shopkeeper for the past 3 months due to progressive hand function affectation. Functional evaluation revealed difficulty to release handheld objects and decreased grip strength. Hence, improving hand function was selected as therapeutic goal using client-centered approach. Six full-text articles were retrieved which could guide in planning disease-specific evaluation strategies and occupational therapy interventions. Purdue pegboard hand function test, grip strength using Jamar dynamometer, and pinch strength using pinchometer were performed pre- and post-4 weeks of intervention. Modified hand function training along with vocational counseling was selected as intervention strategy. Posttherapy, Purdue pegboard component scores on preferred hand, nonpreferred hand, and both hands and assembly scores showed 24%, 12%, 12%, and 8% improvement, respectively. Grip strength improved by 2 kg in the right and by 9 kg in the left hand on a dynamometer. Pinch strength improved by 1 kg bilaterally on pinchometer. Hence, Evidence-based clinical practice was found to be effective in the management of MD type I. [ABSTRACT FROM AUTHOR]

Background: Eyelid malignancies are completely treatable if detected early. The treatment depends on the invasiveness of the cancer which in turn depends on the type of malignancy. Aim: The aim of the study was to characterize the distribution of the types of eyelid malignancies in central India. Settings and Design: The study was conducted in the Department of Plastic and Maxillofacial Surgery at a tertiary care hospital. Materials and Methods: We report a series of 27 cases of eyelid malignancies. In the same case series, we also include a case of malignant hemangiopericytoma which is an extremely rare form of eyelid malignancy worldwide. Statistical Analysis: Depending on the underlying statistical distribution, either analysis of variance (ANOVA) or the Kruskal-Wallis (K-W) test was used to assess the differential distribution of these variables across the types of eyelid malignancies observed in this study. Results: We observed that sebaceous cell carcinoma (~37%) was almost as prevalent as basal cell carcinoma (~44%) in the study subjects and had an earlier age of occurrence and a more rapid clinical course. Conclusions: Sebaceous cell carcinoma of the eyelid is almost as common as basal cell carcinoma in a large tertiary care centre in central India.

During early lactation, dairy cows have a negative energy balance since their energy demands exceed their energy intake: in this study, we aimed to investigate the association between diet and plasma metabolomics profiles and how these relate to energy unbalance of course in the early-lactation stage. Holstein-Friesian cows were randomly assigned to a glucogenic ( n = 15) or lipogenic ( n = 15) diet in early lactation. Blood was collected in week 2 and week 4 after calving. Plasma metabolite profiles were detected using liquid chromatography-mass spectrometry (LC-MS), and a total of 39 metabolites were identified. Two plasma metabolomic profiles were available every week for each cow. Metabolite abundance and metabolite ratios were used for the analysis using the XGboost algorithm to discriminate between diet treatment and lactation week. Using metabolite ratios resulted in better discrimination performance compared with the metabolite abundances in assigning cows to a lipogenic diet or a glucogenic diet. The quality of the discrimination of performance of lipogenic diet and glucogenic diet effects improved from 0.606 to 0.753 and from 0.696 to 0.842 in week 2 and week 4 (as measured by area under the curve, AUC), when the metabolite abundance ratios were used instead of abundances. The top discriminating ratios for diet were the ratio of arginine to tyrosine and the ratio of aspartic acid to valine in week 2 and week 4, respectively. For cows fed the lipogenic diet, choline and the ratio of creatinine to tryptophan were top features to discriminate cows in week 2 vs. week 4. For cows fed the glucogenic diet, methionine and the ratio of 4-hydroxyproline to choline were top features to discriminate dietary effects in week 2 or week 4. This study shows the added value of using metabolite abundance ratios to discriminate between lipogenic and glucogenic diet and lactation weeks in early-lactation cows when using metabolomics data. The application of this research will help to accurately regulate the nutrition of lactating dairy cows and promote sustainable agricultural development.

In India, the incidence of mucormycosis reached high levels during 2021-2022, coinciding with the COVID-19 pandemic. In response to this, we established a multicentric ambispective cohort of patients hospitalised with mucormycosis across India. In this paper, we report their baseline profile, clinical characteristics and outcomes at discharge. Patients hospitalized for mucormycosis during March-July 2021 were included. Mucormycosis was diagnosed based on mycological confirmation on direct microscopy (KOH/Calcofluor white stain), culture, histopathology, or supportive evidence from endoscopy or imaging. After consent, trained data collectors used medical records and telephonic interviews to capture data in a pre-tested structured questionnaire. At baseline, we recruited 686 patients from 26 study hospitals, of whom 72.3% were males, 78% had a prior history of diabetes, 53.2% had a history of corticosteroid treatment, and 80% were associated with COVID-19. Pain, numbness or swelling of the face were the commonest symptoms (73.3%). Liposomal Amphotericin B was the commonest drug formulation used (67.1%), and endoscopic sinus surgery was the most common surgical procedure (73.6%). At discharge, the disease was stable in 43.3%, in regression for 29.9% but 9.6% died during hospitalization. Among survivors, commonly reported disabilities included facial disfigurement (18.4%) and difficulties in chewing/swallowing (17.8%). Though the risk of mortality was only 1 in 10, the disability due to the disease was very high. This cohort study could enhance our understanding of the disease's clinical progression and help frame standard treatment guidelines., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Background: Cancer is a leading cause of death globally and in the US, prompting research into medicinal plants with anticancer properties. Withania somnifera , or Ashwagandha, is one such plants, known for its diverse pharmacological effects. Withaferin A and Viscosalactone B are two compounds found in Ashwagandha with known anticancer activity. The protein NQO1, overexpressed in various cancers, was the focus of this study., Hypothesis and Aim: We hypothesize that specific phytochemicals in Withania somnifera can effectively interact with and inhibit the NQO1 protein, thereby exhibiting anticancer properties. This study aims to identify these interactions using in silico approaches., Methodology: CFDT was performed using the Gaussian 16 program package, followed by QSAR analysis of the compounds in the PASS online web server. The Schrodinger suite was used to carry out ligand and protein preparation, molecular docking, and molecular dynamic simulation to analyse the interaction of these compounds with NQO1 and ADME studies. Protox-II and SWISSADME tools were used to predict the toxicity and blood-brain barrier permeability of the phytochemicals., Results and Conclusion: CDFT and frontier molecular orbital analyses predicted the stability and reactivity of all the selected molecules. QSAR analysis predicted the biological activity and toxicity of the compounds. Withaferin A exhibited the highest glide gscore (-4.953 kcal/mol) and demonstrated 6 hydrogen bond interactions with NQO1, suggesting its potential as an anticancer agent. Conceptual density functional theory-based analysis suggested the strong electrophilicity of the ligands, further supporting their potential anticancer activities. Viscosalactone B, another phytochemical from Ashwagandha, also showed interactions involving 6 hydrogen bonds with NQO1, with a glide gscore of (-4.593 kcal/mol). Molecular dynamic simulations validated the stability of the Withaferin A-NQO1 complex. ADME-T properties predicted high oral absorption for the selected ligands, indicating that Withaferin A could be a viable orally administered drug., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Single-cell clonal selection is a critical procedure for generating a homogeneous population of human pluripotent stem cells. Here, we present a protocol that repurposes the STRIPPER Micropipetter, normally used for in vitro fertilization, to pick single stem cells. We describe steps for tool and reagent preparation, single-cell picking, and colony passaging. We then detail procedures for amplification and analysis. Our protocol does not require cell sorting and produces homogenous clonal cultures with more than 50% survival rate. For complete details on the use and execution of this protocol, please refer to Deng et al. 1 ., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: Early stages with streptococcal necrotizing soft tissue infections (NSTIs) are often difficult to discern from cellulitis. Increased insight into inflammatory responses in streptococcal disease may guide correct interventions and discovery of novel diagnostic targets., Methods: Plasma levels of 37 mediators, leucocytes and CRP from 102 patients with β-hemolytic streptococcal NSTI derived from a prospective Scandinavian multicentre study were compared to those of 23 cases of streptococcal cellulitis. Hierarchical cluster analyses were also performed., Results: Differences in mediator levels between NSTI and cellulitis cases were revealed, in particular for IL-1β, TNFα and CXCL8 (AUC >0.90). Across streptococcal NSTI etiologies, eight biomarkers separated cases with septic shock from those without, and four mediators predicted a severe outcome., Conclusion: Several inflammatory mediators and wider profiles were identified as potential biomarkers of NSTI. Associations of biomarker levels to type of infection and outcomes may be utilized to improve patient care and outcomes., Competing Interests: Declaration of Competing Interest All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and no potential conflicts are reported. Some of the data were presented at a lecture at the 21st Lancefield International Symposium for Streptococci and Streptococcal Diseases 2022, 7th - 10th June., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Nanoparticles provide a promising and alternative platform of eco-friendly technologies that encompasses better cost-resilient remedies against one of the most economically harnessing insect pests of cotton. The main goal of this research was to provide a better management strategy through biologically synthesizing (sunlight exposure method) green nanoparticles from leaf extracts of Azadirachta indica and Pongamia pinnata and proving their bioefficacy on H. armigera (2nd instar). Characterization of bio-synthesized silver nanoparticles was carried out using UV-Visible spectroscopy for confirming the formation of nanoparticles, a Particle Size Analyzer (PSA) for determining the size/distribution of particles, and a Scanning Electron Microscope (SEM) for analyzing the surface topology of nanoparticles. The results obtained from PSA analysis showed that A. indica and P. pinnata -based silver nanoparticles had an average diameter of 61.70 nm and 68.80, respectively. Topographical images obtained from SEM proved that most of the green synthesized silver nanoparticles were spherical in shape. A. indica-based silver nanoparticles were found to be comparatively more efficient and have higher insecticidal activity compared to P. pinnata -based nanoparticles. A. indica -based AgNPs recorded larval mortality of 60.00 to 93.33 percent at the concentrations of 500 to 2000 ppm, followed by P. pinnata -based nanoparticles, with 60.00 to 90.00 percent larval mortality. Shelf-life studies revealed that A. indica-based AgNPs had the maximum negative zeta potential of -58.96 mV and could be stored for three months without losing bioefficacy and up to six months with negligible reduction in bioefficacy. Symptoms caused by silver nanoparticles were leakage of body fluids, sluggishness, inactiveness, brittleness, etc.

The WHO Global Vaccine Safety Multi-Country Collaboration study on safety in pregnancy aims to estimate the minimum detectable risk for selected perinatal and neonatal outcomes and assess the applicability of standardized case definitions for study outcomes and maternal immunization in low- and middle-income countries (LMICs). This paper documents the operational lessons learned from the study. A prospective observational study was conducted across 21 hospitals in seven countries. All births occurring at sites were screened to identify select perinatal and neonatal outcomes from May 2019 to August 2020. Up to 100 cases per outcome were recruited to assess the applicability of standardized case definitions. A multi-pronged study quality assurance plan was implemented. The impact of the COVID-19 pandemic on site functioning and project implementation was also assessed. Multi-layered ethics and administrative approvals, limited clinical documentation, difficulty in identifying outcomes requiring in-hospital follow-up, and poor quality internet connectivity emerged as important barriers to study implementation. Use of electronic platforms, application of a rigorous quality assurance plan with frequent interaction between the central and site teams helped improve data quality. The COVID-19 pandemic disrupted data collection for up to 6 weeks in some sites. Our study succeeded in establishing an international hospital-based surveillance network for evaluating perinatal and neonatal outcomes using common study protocol and procedures in geographically diverse sites with differing levels of infrastructure, clinical and health-utilization practices. The enhanced surveillance capacity of participating sites shall help support future pharmacovigilance efforts for pregnancy interventions., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Author(s).)

Background: Most perinatal and neonatal deaths occur in low- and middle-income countries (LMICs), yet, quality data on burden of adverse outcomes of pregnancy is limited in such countries., Methods: A network of 21 maternity units, across seven countries, undertook surveillance for low birthweight, preterm birth, small for gestational age (SGA), stillbirths, congenital microcephaly, in-hospital neonatal deaths, and neonatal infections in a cohort of over 85,000 births from May 2019 - August 2020. For each outcome, site-specific rates per 1,000 livebirths (or per 1,000 total births for stillbirth) and 95% confidence intervals (CI) were calculated. Descriptive sensitivity analysis was conducted to gain insight regarding underreporting of four outcomes at 16 sites., Findings: Estimated rates varied across countries and sites, ranging between 43·3-329·5 and 21·4-276·6/1000 livebirths for low birthweight and preterm birth respectively and 11·8-81/1,000 livebirths for SGA. No cases of congenital microcephaly were reported by three sites while the highest estimated rate was 13/1,000 livebirths. Neonatal infection and neonatal death rates varied between 1·8-73 and 0-59·9/1000 livebirths respectively while stillbirth rates ranged between 0-57·1/1000 total births across study sites. Results from the sensitivity analysis confirmed the underreporting of congenital microcephaly and SGA in our study., Interpretation: Our study establishes site-specific baseline rates for important adverse perinatal and neonatal outcomes and addresses a critical evidence gap towards improved monitoring of benefits and risks of emerging pregnancy and neonatal interventions., Funding: The study was sponsored by the World Health Organization with funding from the Bill and Melinda Gates Foundation., Competing Interests: Margarita Riera-Montes (P95) & Christine Guillard Maure (WHO) declare that their institutions received funding support for this manuscript from the WHO and the Bill & Melinda Gates Foundation respectively. All the remaining authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 World Health Organization.)

Background: Necrotising soft tissue infections (NSTIs) are rapidly progressing bacterial infections usually caused by either several pathogens in unison (polymicrobial infections) or Streptococcus pyogenes (mono-microbial infection). These infections are rare and are associated with high mortality rates. However, the underlying pathogenic mechanisms in this heterogeneous group remain elusive., Methods: In this study, we built interactomes at both the population and individual levels consisting of host-pathogen interactions inferred from dual RNA-Seq gene transcriptomic profiles of the biopsies from NSTI patients., Results: NSTI type-specific responses in the host were uncovered. The S. pyogenes mono-microbial subnetwork was enriched with host genes annotated with involved in cytokine production and regulation of response to stress. The polymicrobial network consisted of several significant associations between different species (S. pyogenes, Porphyromonas asaccharolytica and Escherichia coli) and host genes. The host genes associated with S. pyogenes in this subnetwork were characterised by cellular response to cytokines. We further found several virulence factors including hyaluronan synthase, Sic1, Isp, SagF, SagG, ScfAB-operon, Fba and genes upstream and downstream of EndoS along with bacterial housekeeping genes interacting with the human stress and immune response in various subnetworks between host and pathogen., Conclusions: At the population level, we found aetiology-dependent responses showing the potential modes of entry and immune evasion strategies employed by S. pyogenes, congruent with general cellular processes such as differentiation and proliferation. After stratifying the patients based on the subject-specific networks to study the patient-specific response, we observed different patient groups with different collagens, cytoskeleton and actin monomers in association with virulence factors, immunogenic proteins and housekeeping genes which we utilised to postulate differing modes of entry and immune evasion for different bacteria in relationship to the patients' phenotype., (© 2022. The Author(s).)

Chromosomal instability (CIN) is associated with the initiation and progression of gastrointestinal (GI) tract cancers. Cancers of the GI tract are typically characterized by altered chromosome numbers. While the dynamics of CIN have been extensively characterized in 2D monolayer cell cultures derived from GI tumors, the tumor microenvironment and 3D tumor architecture also contribute to the progression of CIN, which is not captured in 2D cell culture systems. To overcome these limitations, self-organizing cellular structures that retain organ-specific 3D architecture, namely organoids, have been derived from various tissues of the GI tract. Organoids derived from normal tissue and patient tumors serve as a useful paradigm to study the crosstalk between tumor cells in the context of a tissue microenvironment and its impact on chromosomal stability. Such a paradigm, therefore, has a considerable advantage over 2D cell culture systems in drug screening and personalized medicine. Here, we review the importance of patient-derived tumor organoids (PDTOs) as a model to study CIN in cancers of the GI tract., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Standardized case definitions strengthen post-marketing safety surveillance of new vaccines by improving generated data, interpretation and comparability across surveillance systems. The Global Alignment of Immunization Safety Assessment in Pregnancy (GAIA) project developed standardized case definitions for 21 key obstetric and neonatal terms following the Brighton Collaboration (BC) methodology. In this prospective cohort study, we assessed the applicability of GAIA definitions for maternal immunization exposure and for low birth weight (LBW), preterm birth, small for gestational age (SGA), stillbirth, neonatal death, neonatal infection, and congenital microcephaly. We identified the missing data elements that prevented identified cases and exposures from meeting the case definition (level 1-3 of BC diagnostic certainty). Over a one-year period (2019-2020), all births occurring in 21 sites (mostly secondary and tertiary hospitals) in 6 Low Middle Income Countries and 1 High Income Country were recorded and the 7 perinatal and neonatal outcome cases were identified from routine medical records. Up to 100 cases per outcome were recruited sequentially from each site. Most cases recruited for LBW, preterm birth and neonatal death met the GAIA case definitions. Birth weight, a key parameter for all three outcomes, was routinely recorded at all sites. The definitions for SGA, stillbirth, neonatal infection (particularly meningitis and respiratory infection) and congenital microcephaly were found to be less applicable. The main barrier to obtaining higher levels of diagnostic certainty was the lack of sonographic documentation of gestational age in first or second trimester. The definition for maternal immunization exposure was applicable, however, the highest level of diagnostic certainty was only reached at two sites. Improved documentation of maternal immunization will be important for vaccine safety studies. Following the field-testing of these 8 GAIA definitions, several improvements are suggested that may lead to their easier implementation, increased standardization and hence comparison across studies., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Christine Guillard Maure reports financial support was provided by Bill & Melinda Gates Foundation., (© 2021 The Authors.)

BACKGROUNDNecrotizing soft-tissue infections (NSTIs) are rapidly progressing infections frequently complicated by septic shock and associated with high mortality. Early diagnosis is critical for patient outcome, but challenging due to vague initial symptoms. Here, we identified predictive biomarkers for NSTI clinical phenotypes and outcomes using a prospective multicenter NSTI patient cohort.METHODSLuminex multiplex assays were used to assess 36 soluble factors in plasma from NSTI patients with positive microbiological cultures (n = 251 and n = 60 in the discovery and validation cohorts, respectively). Control groups for comparative analyses included surgical controls (n = 20), non-NSTI controls (i.e., suspected NSTI with no necrosis detected upon exploratory surgery, n = 20), and sepsis patients (n = 24).RESULTSThrombomodulin was identified as a unique biomarker for detection of NSTI (AUC, 0.95). A distinct profile discriminating mono- (type II) versus polymicrobial (type I) NSTI types was identified based on differential expression of IL-2, IL-10, IL-22, CXCL10, Fas-ligand, and MMP9 (AUC >0.7). While each NSTI type displayed a distinct array of biomarkers predicting septic shock, granulocyte CSF (G-CSF), S100A8, and IL-6 were shared by both types (AUC >0.78). Finally, differential connectivity analysis revealed distinctive networks associated with specific clinical phenotypes.CONCLUSIONSThis study identifies predictive biomarkers for NSTI clinical phenotypes of potential value for diagnostic, prognostic, and therapeutic approaches in NSTIs.TRIAL REGISTRATIONClinicalTrials.gov NCT01790698.FUNDINGCenter for Innovative Medicine (CIMED); Region Stockholm; Swedish Research Council; European Union; Vinnova; Innovation Fund Denmark; Research Council of Norway; Netherlands Organisation for Health Research and Development; DLR Federal Ministry of Education and Research; and Swedish Children's Cancer Foundation.

Networks and network analyses are fundamental tools of systems biology. Networks are built by inferring pair-wise relationships among biological entities from a large number of samples such that subject-specific information is lost. The possibility of constructing these sample (individual)-specific networks from single molecular profiles might offer new insights in systems and personalized medicine and as a consequence is attracting more and more research interest. In this study, we evaluated and compared LIONESS (Linear Interpolation to Obtain Network Estimates for Single Samples) and ssPCC (single sample network based on Pearson correlation) in the metabolomics context of metabolite-metabolite association networks. We illustrated and explored the characteristics of these two methods on (i) simulated data, (ii) data generated from a dynamic metabolic model to simulate real-life observed metabolite concentration profiles, and (iii) 22 metabolomic data sets and (iv) we applied single sample network inference to a study case pertaining to the investigation of necrotizing soft tissue infections to show how these methods can be applied in metabolomics. We also proposed some adaptations of the methods that can be used for data exploration. Overall, despite some limitations, we found single sample networks to be a promising tool for the analysis of metabolomics data.

Twist1 is a basic helix-loop-helix transcription factor, essential during early development in mammals. While Twist1 induces epithelial-to-mesenchymal transition (EMT), here we show that Twist1 overexpression enhances nuclear and mitotic aberrations. This is accompanied by an increase in whole chromosomal copy number gains and losses, underscoring the role of Twist1 in inducing chromosomal instability (CIN) in colorectal cancer cells. Array comparative genomic hybridization (array CGH) analysis further shows sub-chromosomal deletions, consistent with an increased frequency of DNA double strand breaks (DSBs). Remarkably, Twist1 overexpression downmodulates key cell cycle checkpoint factors-Bub1, BubR1, Mad1 and Mad2-that regulate CIN. Mathematical simulations using the RACIPE tool show a negative correlation of Twist1 with E-cadherin and BubR1. Data analyses of gene expression profiles of patient samples from The Cancer Genome Atlas (TCGA) reveal a positive correlation between Twist1 and mesenchymal genes across cancers, whereas the correlation of TWIST1 with CIN and DSB genes is cancer subtype-specific. Taken together, these studies highlight the mechanistic involvement of Twist1 in the deregulation of factors that maintain genome stability during EMT in colorectal cancer cells. Twist1 overexpression enhances genome instability in the context of EMT that further contributes to cellular heterogeneity. In addition, these studies imply that Twist1 downmodulates nuclear lamins that further alter spatiotemporal organization of the cancer genome and epigenome. Notwithstanding their genetic background, colorectal cancer cells nevertheless maintain their overall ploidy, while the downstream effects of Twist1 enhance CIN and DNA damage enriching for sub-populations of aggressive cancer cells., (© The Author(s) 2020. Published by Oxford University Press.)

Metabolite differential connectivity analysis has been successful in investigating potential molecular mechanisms underlying different conditions in biological systems. Correlation and Mutual Information (MI) are two of the most common measures to quantify association and for building metabolite-metabolite association networks and to calculate differential connectivity. In this study, we investigated the performance of correlation and MI to identify significantly differentially connected metabolites. These association measures were compared on (i) 23 publicly available metabolomic data sets and 7 data sets from other fields, (ii) simulated data with known correlation structures, and (iii) data generated using a dynamic metabolic model to simulate real-life observed metabolite concentration profiles. In all cases, we found more differentially connected metabolites when using correlation indices as a measure for association than MI. We also observed that different MI estimation algorithms resulted in difference in performance when applied to data generated using a dynamic model. We concluded that there is no significant benefit in using MI as a replacement for standard Pearson's or Spearman's correlation when the application is to quantify and detect differentially connected metabolites.

Biological networks play a paramount role in our understanding of complex biological phenomena, and metabolite-metabolite association networks are now commonly used in metabolomics applications. In this study we evaluate the performance of several network inference algorithms (PCLRC, MRNET, GENIE3, TIGRESS, and modifications of the MRNET algorithm, together with standard Pearson's and Spearman's correlation) using as a test case data generated using a dynamic metabolic model describing the metabolism of arachidonic acid (consisting of 83 metabolites and 131 reactions) and simulation individual metabolic profiles of 550 subjects. The quality of the reconstructed metabolite-metabolite association networks was assessed against the original metabolic network taking into account different degrees of association among the metabolites and different sample sizes and noise levels. We found that inference algorithms based on resampling and bootstrapping perform better when correlations are used as indexes to measure the strength of metabolite-metabolite associations. We also advocate for the use of data generated using dynamic models to test the performance of algorithms for network inference since they produce correlation patterns that are more similar to those observed in real metabolomics data.

We would like to report 2 cases where we encountered a rare complication of hypertension without tachycardia after the administration of an interscalene block. We have tried to explain the same with the anatomical correlations.

Background & Objectives: The multiple drug resistance (MDR) is a serious health problem and major challenge to the global drug discovery programmes. Most of the genetic determinants that confer resistance to antibiotics are located on R-plasmids in bacteria. The present investigation was undertaken to investigate the ability of organic extract of the fruits of Helicteres isora to cure R-plasmids from certain clinical isolates., Methods: Active fractions demonstrating antibacterial and antiplasmid activities were isolated from the acetone extracts of shade dried fruits of H. isora by bioassay guided fractionation. Minimal inhibitory concentration (MIC) of antibiotics and organic extracts was determined by agar dilution method. Plasmid curing activity of organic fractions was determined by evaluating the ability of bacterial colonies (pre treated with organic fraction for 18 h) to grow in the presence of antibiotics. The physical loss of plasmid DNA in the cured derivatives was further confirmed by agarose gel electrophoresis., Results: The active fraction did not inhibit the growth of either the clinical isolates or the strains harbouring reference plasmids even at a concentration of 400 microg/ml. However, the same fraction could cure plasmids from Enterococcus faecalis, Escherichia coli, Bacillus cereus and E. coli (RP4) at curing efficiencies of 14, 26, 22 and 2 per cent respectively. The active fraction mediated plasmid curing resulted in the subsequent loss of antibiotic resistance encoded in the plasmids as revealed by antibiotic resistance profile of cured strains. The physical loss of plasmid was also confirmed by agarose gel electrophoresis., Interpretation & Conclusions: The active fraction of acetone extract of H. isora fruits cured R-plasmids from Gram-positive and Gram-negative clinical isolates as well as reference strains. Such plasmid loss reversed the multiple antibiotic resistance in cured derivatives making them sensitive to low concentrations of antibiotics. Acetone fractions of H. isora may be a source to develop antiplasmid agents of natural origin to contain the development and spread of plasmid borne multiple antibiotic resistance.

Bioassay-guided fractionation of an aqueous methanolic extract of Dioscorea bulbifera L. bulbs was performed using organic solvents. A novel plasmid-curing compound was identified as 8-epidiosbulbin E acetate (EEA) (norditerpene) on the basis of modern spectroscopic analysis and X-ray crystallography. EEA exhibited broad-spectrum plasmid-curing activity against multidrug-resistant (MDR) bacteria, including vancomycin-resistant enterococci. EEA cured antibiotic resistance plasmids (R-plasmids) from clinical isolates of Enterococcus faecalis, Escherichia coli, Shigella sonnei and Pseudomonas aeruginosa with 12-48% curing efficiency. The reference plasmids of Bacillus subtilis (pUB110), E. coli (RP4), P. aeruginosa (RIP64) and Salmonella typhi (R136) were cured with efficiency ranging from 16% to 64%. EEA-mediated R-plasmid curing decreased the minimal inhibitory concentration of antibiotics against MDR bacteria, thus making antibiotic treatment more effective. The antibiotic resistance pattern revealed that the compound was effective in the reversal of bacterial resistance to various antibiotics. In addition, the compound did not show any cytotoxicity against a broad range of human cancer cell lines, namely MCF-7 (breast cancer), SiHa (cervical cancer) and A431 (epidermal carcinoma), and hence has the potential to be used as a lead compound for drug discovery programmes.

Background and Aim: The pancreas is a retroperitoneal organ and has been classically considered to be immobile on respiration. Recent radiological studies assessing the mobility of the pancreas have challenged this traditional concept. The present study was conducted to assess the movement of pancreas with respiration using fluoroscopy, a simple and inexpensive method., Methods: Patients with chronic pancreatitis who had either pancreatic calcification evident on fluoroscopy or an indwelling pancreatic duct stent were studied. The movement of the pancreas was assessed under fluoroscopy by measuring the displacement of the stent or calcification in relationship to the spine in maximum inspiration followed by maximum expiration., Results: Twenty-two patients (mean age 35.45 + or - 11.29 years, 17 men) with chronic pancreatitis were included in the study. Ten patients had pancreatic calcification and 12 had an indwelling pancreatic duct stent (two in the dorsal duct, 10 in the ventral duct). In all patients, the pancreas moved downward in the craniocaudal direction on deep inspiration. Pancreatic excursion from maximum inspiration to maximum expiration ranged from 0.1 to 3.4 cm. In addition, a medial movement of the head of pancreas was also noted in most of the patients. On univariate analysis, no association was found between the range of movement and the age or sex of the patient, duration or etiology of disease, presence or absence of calcification, severity of ductal changes of chronic pancreatitis and the length or diameter of the pancreatic stent placed., Conclusion: The pancreas moves craniocaudally with respiration and the head moves medially on inspiration.

Wilson disease (WD) is an autosomal recessive disorder due to the defect in ATP7B gene characterized by excessive accumulation of copper in the liver with progressive hepatic damage and subsequent redistribution to various extrahepatic tissues including the brain, kidneys, and cornea. Strikingly, the total serum copper concentration is always low in WD, even though the non-ceruloplasmin copper level is still expected to be high. To assess the role of free radical reactions catalyzed by non-ceruloplasmin copper, we investigated erythrocyte metabolism and oxidative stress as a mechanism for hemolysis in eight WD patients during episodes of acute hemolysis and compared them with eight follow-up cases of WD on d-penicillamine therapy and eight healthy, age-matched children. Elevated levels of non-ceruloplasmin copper were found in all the WD patients during an episode of hemolytic anemia. There was marked inhibition in erythrocyte enzymes, namely, hexokinase, total adenosine triphosphatase (ATPase), and glucose-6-phosphate dehydrogenase (G-6-PD) from WD patients compared with patients on penicillamine and healthy children, indicating altered erythrocyte metabolism during a hemolytic crisis. Antioxidant status was also found to be compromised as is evident from decreased glutathione (GSH) levels, decreased antioxidant enzymes (namely, superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase), increased lipid peroxidation, and deranged plasma antioxidants. Uric acid showed maximum decrease followed by ascorbic acid. These findings suggest that the free radical production by elevated non-ceruloplasmin copper through transition metal catalyzed reactions leads to oxidative injury resulting in altered erythrocyte metabolism and severely compromised antioxidant status of WD patients during hemolytic anemia.

Background and Aims: Portal hypertensive gastropathy and colopathy are well described endoscopic abnormalities in patients with portal hypertension. Endoscopic abnormalities in the ileum in patients with portal hypertension have not been well described. The aim of the present study was to evaluate endoscopic abnormalities in the ileum of patients with portal hypertension., Methods: Patients with portal hypertension of various etiologies were included in the study. Upper gastrointestinal endoscopy was performed to record esophageal varices, gastric varices and portal hypertensive gastropathy. Colonoscopy with retrograde intubation of the ileum was performed and the presence of colorectal varices, colopathy and mucosal findings in the ileum were noted., Results: Forty-one patients (age 16-80 years, 33 men) were studied. Esophageal varices were present in all. Portal hypertensive gastropathy was present in 27/41 (66%) patients. Rectal varices were noted in 22/41 (54%) patients and 17/41 (42%) patients had features suggestive of colopathy. Ileum could be intubated in 38 patients (93%). Endoscopic abnormalities in the ileum were noted in 13/38 (34%) patients. Ileopathy as evident by endoscopic mucosal abnormalities was observed in 10/38 (26%) patients. Ileal varices were present in 8/38 (21%) patients. Three of these had ileal varices alone while the remaining five patients also had associated ileopathy The presence of ileopathy was significantly associated with the presence of portal hypertensive gastropathy and colopathy but not with esophageal, gastric or rectal varices., Conclusions: Ileopathy occurs in one-third of patients with portal hypertension and is significantly associated with the presence of portal hypertensive gastropathy and colopathy.