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Introduction: Acute encephalitis syndrome (AES) is one of the important causes of mortality among children in India. Active management of the cases, followed by addressing the cause of AES, is the key strategy for preventing mortality. Lack of laboratory facility and difficulty of sampling blood and cerebrospinal fluid (CSF) for assessing causes is one of the important barriers to early initiation of treatment. The main objective of the study is to validate the Scrub Typhus Encephalitis Assessment Tool (SEAT) for the management of AES. Methods: The study is a continuation of a study conducted in a tertiary care hospital in Eastern Uttar Pradesh. A machine learning (LightGBM) model was built to predict the probability of scrub typhus diagnosis among patients with acute encephalitis. Three models were built: one with sociodemographic characters, the second with Model 1 variables and blood parameters, and the third with Model 2 variables and CSF parameters. Results: The sensitivity of diagnosing the scrub typhus case was 71%, 77.5%, and 83% in Model 1, Model 2, and Model 3, respectively, and specificity was 61.5%, 75.5%, and 76.3%, respectively, in the models. In Model 1 fever duration, in Models 2 and 3, neutrophil/lymphocyte ratio was the most important predictor for differentiating the scrub and nonscrub cases. Conclusion: With the available sensitivity and specificity of the tool, the SEAT can be a valuable tool for the prediction of scrub typhus as a cause of AES cases in remote areas.

Background: In the present scenario, ayurvedic drugs and their formulations need standardization to understand their pharmacokinetics and to prevent any safety issues. Shadanga Paniya (SP) is a classical ayurvedic formulation composed of six herbs and most of the constituent herbs have been shown the presence of alkaloids, flavonoids, and total phenolic contents (TPC). Materials and Methods: Preliminary qualitative estimations of alkaloids, flavonoids, and TPC in SP formulation and its constituent herbs were done using Dragendroff's method, sodium hydroxide solution, and ferric chloride solution. The quantitative estimations were done using bromocresol green, aluminum chloride colorimetric method, and Folin–Ciocalteu's phenol reagent method. Statistical Analysis Used: All the qualitative and quantitative analyses were replicated in three independent assays, and the results were reported as a mean ± standard deviation. Results and Conclusion: The results revealed that constituent herbs of SP formulation have the presence of flavonoids and total phenolic acid, whereas alkaloid was only found in Vetiveria zizanioides herb. The quantitative estimation of alkaloids, total flavonoids, and total phenolic acid contents of SP formulation was found as 86.105 ± 6.4 mgAE/g, 87.8 ± 4.0 mgRE/g, and 105.8 ± 3.8 mgGAE/g, respectively. This is the first report on the phytochemical estimation of SP formulation.

SARS-CoV-2 has mutated rapidly since its first case report in Wuhan, China, leading to the emergence of an indefinite number of variants. India has witnessed three waves of the COVID-19 pandemic. The country saw its first wave of SARS-CoV-2 illness from late January 2020 to February 2021. With a peak surge of cases in mid-September 2020, India recorded more than 11 million cases and a death toll of more than 0.165 million at this time. India faced a brutal second wave driven by the emergence of highly infectious SARS-CoV-2 variants B.1.617.2 (Delta variant) and the third wave with the leading cause of BA.2 (Omicron variant), which has led to an unprecedented rise in COVID-19 cases in the country. On September 14, 2022, India recorded a cumulative 44.51 million cases of COVID-19 with more than 0.528 million deaths. The discovery of common circulating mutants is facilitated by genome sequencing. The changes in the Spike surface glycoprotein recombinant binding domains served as the critical alterations, resulting in enhanced infectivity and transmissibility, with severe clinical effects. Further, the predominant mutation in the SARS-CoV-2 spike protein; the D614G strains served as a model for vaccine development. The mutation of the Wuhan strain to the Variant of Concern led to a significant increase in SARS-CoV-2 infections. In addition, there was a shift in the age group affected by SARS-CoV-2 variant infection. The current review summarized the COVID-19 pandemic's Variant of Concern and the advent of SARS-CoV-2 in India.

Despite the significant success of India's COVID-19 vaccination program, a sizeable proportion of the adult population remains unvaccinated or has received a single dose of the vaccine. Despite the recommendations of the Government of India for the two doses of the COVID-19 vaccine and the precautionary booster dose, many people were still hesitant towards the COVID-19 full vaccination. Hence, this study aimed to identify the primary behavioral and psychological factors contributing to vaccine hesitancy. Cross-sectional data was collected via a multi-stage sampling design by using a scheduled sample survey in the Gorakhpur district of Uttar Pradesh, India, between 15 July 2022 to 30 September 2022. This study has utilized three health behavior models-the Health Belief Model (HBM), the Theory of Planned Behavior (TPB), and the 5C Psychological Antecedents of vaccination, and employed bivariate and multivariable binary logistic regression model to assess the level of vaccine hesitancy and predictive health behavior of the respondents. Results indicate that among the constructs of the HBM and 5C Antecedents models, "perceived benefits", "confidence" and "collective responsibility" showed a lesser likelihood of COVID-19 vaccine hesitancy. However, in the TPB model constructs, a 'negative attitude towards the vaccine' showed a four times higher likelihood of COVID-19 vaccine hesitancy. From the future policy perspective, this study suggested that addressing the issue of 'negative attitudes towards the vaccine' and increasing the trust or confidence for the vaccine through increasing awareness about the benefits of the vaccination in India may reduce vaccine hesitancy.

IntroductionIndia launched the COVID-19 vaccination drive on 16th January 2021 by vaccinating the adult population above 18 years of age. This was followed by the introduction of an additional precaution dose. As on 18th October 2022, 1,02,66,96,808 (1.02 Billion) first dose and 94, 95, 39,516 (949 Million) second doses of COVID-19 vaccine were administered. However, when compared to the uptake of the primary doses, the precaution dose uptake lagged behind with only 21,75, 12,721 (217 million) doses administered. Even though, the uptake of the primary doses remained optimal, irrespective of different interventions by the Government of India, the uptake of the precaution dose remained poor. In this context, the Ministry of Health & Family Welfare wanted to understand the facilitators and Barriers for precaution dose uptake among adults so that future immunization campaigns could address these issues.MethodsAn exploratory qualitative study was conducted to assess the facilitators and barriers for COVID-19 precaution dose uptake at community level across 6 different states in India. From each of the states, two districts with the highest and lowest rates of COVID-19 vaccine precaution dose uptake were selected. In each of these districts, 2 block Primary Healthcare Centres (PHCs), one with high and one with low uptake were identified. Within these block PHCs, a PHC field area with high and low precaution dose uptakes was identified. From the identified sites a minimum of four IDIs, four FGDs were conducted among the community members. KIIs of the State Immunization Officers, District Immunisation Officers, PHC Medical Officers, healthcare workers like Accredited Social Health Activist/Auxiliary Nurse Midwife were also conducted. The data was audio recorded and it was transcribed, translated and analysed using framework approach.ResultsIt was observed that rise in COVID-19 cases prompted the community to take the precaution dose, this along with the cost of hospitalization and the number of productive days being lost as a result of being infected resulted in vaccine uptake. The fear of non-availability of COVID-19 vaccines latter on also prompted people for vaccine uptake. While the barriers were, poor accessibility to vaccination centers, long hours of travel, poor road connectivity and lack of transportation facilities. However, the most prominent barriers observed across all study sites was that a sense of pandemic fatigue and complacency had developed both among the providers as well as the beneficiaries. Other barriers include differences in vaccination schedules and longer duration between the primary doses of some vaccines. Media was identified to be both a barrier and facilitator for Covid-19 Precaution dose uptake. Even though media played an important role in disseminating information in the beginning of the campaign, it was soon followed by the circulation of both misinformation and disinformation.DiscussionThe study identified that dissemination of accurate information and community involvement at each stage of planning and implementation are crucial for the success of any campaign. Efforts should be constantly made to address and re-invent strategies that will be most suitable for the needs of the community. Therefore, in order to ensure successful vaccination campaigns, it is crucial that along with political will it is also important to have a decentralized approach with inter-sectoral coordination with different stakeholders such as healthcare workers, community members and the different departments such as the local self-governments, education department, law & order department etc. These lessons learnt from COVID-19 vaccination campaigns must not be forgotten and must be applied in future vaccination campaigns and while framing public health policies.

ABSTRACTWild non-human primates carry many types of RNA viruses, including simian immunodeficiency virus (SIV), simian foamy virus, simian T-cell leukemia virus, and hepatitis C virus. These viruses can also infect humans via zoonotic transmission through handling and consumption of primate bushmeat. Characterizing viral prevalence and shedding in natural hosts is critical to understand infection and transmission risks within and between primate species. Here, we sought to identify a robust “field-friendly” method (i.e., without freezing or refrigeration) for preserving viral RNA, specifically SIV, in primate fecal samples. Fecal samples were collected from a mantled guereza colobus (Colobus guereza) housed at the Columbus Zoo and Aquarium. Samples were homogenized and inoculated with three concentrations (low, medium, and high) of inactivated SIV and preserved in four different storage buffers (DNA/RNA Shield, RNAlater, 95% Ethanol, and Viral Transport Medium). SIV viral RNA was then extracted from samples at four time points (1 week, 4 weeks, 8 weeks, and 12 weeks) to determine the efficacy of each buffer for preserving SIV RNA. Quantitative reverse transcriptase polymerase chain reaction (RT-PCR) was used for the detection and quantification of viral RNA. At all concentrations, DNA/RNA Shield yielded the highest average SIV virion concentrations. We then successfully validated this approach using fecal samples from known SIV-positive and SIV-negative sooty mangabeys (Cercocebus atys) housed at Emory National Primate Research Center. Our results indicate that DNA/RNA Shield is an optimal “field-friendly” buffer for preserving SIV RNA in fecal samples over time and may also be effective for preserving other RNA viruses in feces.IMPORTANCESimian immunodeficiency virus (SIV), which originated in African monkeys, crossed the species barrier into humans and ultimately gave rise to HIV and the global HIV/AIDS epidemic. While SIV infects over 40 primate species in sub-Saharan Africa, testing for RNA viruses in wild primate populations can be challenging. Optimizing field-friendly methods for assessing viral presence/abundance in non-invasively collected biological samples facilitates the study of viruses, including potentially zoonotic viruses, in wild primate populations. This study compares SIV RNA preservation and recovery from non-human primate feces stored in four different buffers. Our results will inform future fieldwork and facilitate improved approaches to characterizing prevalence, shedding, and transmission of RNA viruses like SIV in natural hosts including wild-living non-human primates.

Puccinia spp. causing rust diseases in wheat and other cereals secrete several specialized effector proteins into host cells. Characterization of these proteins and their interaction with host’s R proteins could greatly help to limit crop losses due to diseases. Prediction of effector proteins by combining the transcriptome analysis and multiple in-silico approaches is gaining importance in revealing the pathogenic mechanism. The present study involved identification of 13 Puccinia triticina (Pt) coding sequences (CDSs), through transcriptome analysis, that were differentially expressed during wheat-leaf rust interaction; and prediction of their effector like features using different in-silico tools. NCBI-BLAST and pathogen-host interaction BLAST (PHI-BLAST) tools were used to annotate and classify these sequences based on their most closely matched counterpart in both the databases. Homology between CDSs and the annotated sequences in the NCBI database ranged from 79 to 94% and with putative effectors of other plant pathogens in PHI-BLAST from 24.46 to 54.35%. Nine of the 13 CDSs had effector-like features according to EffectorP 3.0 (≥0.546 probability of these sequences to be effector). The qRT-PCR expression analysis revealed that the relative expression of all CDSs in compatible interaction (HD2329) was maximum at 11 days post inoculation (dpi) and that in incompatible interactions (HD2329 + Lr28) was maximum at 3 dpi in seven and 9 dpi in five CDSs. These results suggest that six CDSs (>0.8 effector probability as per EffectorP 3.0) could be considered as putative Pt effectors. The molecular docking and MD simulation analysis of these six CDSs suggested that candidate Lr28 protein binds more strongly to candidate effector c14094_g1_i1 to form more stable complex than the remaining five. Further functional characterization of these six candidate effectors should prove useful for a better understanding of wheat-leaf rust interaction. In turn, this should facilitate effector-based leaf rust resistance breeding in wheat.

Objective: India has a tribal population of 8.6%. Health concerns of the high-altitude tribal population in India play a vital role in overall socio-economic development and health transformation of the country. Therefore, the aim of this study was to determine the current health problems among the tribal population of Lahaul and Spiti district of Himachal Pradesh. Material and Methods: The study area encompasses one regional hospital (RH) in Keylong (the district headquarters), three community health centers (CHCs), and 16 primary health care centers (PHCs). In addition, the district has 37 sub-centers (SCs) and 21 Ayurveda dispensaries to serve the district. The data for this study were gathered over a 4-year period from records of daily out-patient department registration from the various health centers (RH, CHCs, and PHCs) from 2017 to 2020. Results: In terms of communicable diseases, the population in the concerned region was more likely to have acute respiratory infection, enteric fever, tuberculosis, and typhoid. Hypertension, asthma, bronchitis, and diabetes mellitus type II were determined to be the most common non-communicable diseases. Conclusion: Acute respiratory disease, hypertension, diarrhea, accidental injuries, and eye problems were shown to be prevalent in the study area. The population's position in relation to these five diseases indicates the community's sensitivity to a variety of common conditions. There is a need to review the needs and priorities of the concerned population and create goals and targets to meet those needs using validated public health measures.

Wheat stripe rust caused by Puccinia striiformis Westend. f.sp. tritici (Pst) is a global threat to wheat production. Genetic modification of defense-responsive factors in wheat rust interactions could help devise strategies to control stripe rust on wheat. This experiment studied the interaction between Pst pathotype 78S84 in PBW343 and FLW-3 by evaluating the quantitative temporal transcription profiles of defense-related genes at different time points. This is the first attempt to exhibit inter-connections among different proteins and depict a hypothetical model for the mechanism of R gene-mediated resistance. Transcript levels of LTP, AQP1, PR1, PR2, PR4, and PR10 were relatively higher under compatible interaction, while under incompatible interaction, transcript levels of COMT1, PRA2, WCAB, and PR9 were significantly high. This study projected the role of defense-responsive genes, inter-networking of proteins, and R gene-mediated resistance between wheat and stripe rust.

Pseudomonas aeruginosa (P.a.) infection accounts for nearly 20% of all cases of hospital acquired pneumonia with mortality rates >30%. P.a. infection induces a robust inflammatory response, which ideally enhances bacterial clearance. Unfortunately, excessive inflammation can also have negative effects, and often leads to cardiac dysfunction with associated morbidity and mortality. However, it remains unclear how P.a. lung infection causes cardiac dysfunction. Using a murine pneumonia model, we found that P.a. infection of the lungs led to severe cardiac left ventricular dysfunction and electrical abnormalities. More specifically, we found that neutrophil recruitment and release of S100A8/A9 in the lungs activates the TLR4/RAGE signaling pathways, which in turn enhance systemic inflammation and subsequent cardiac dysfunction. Paradoxically, global deletion of S100A8/A9 did not improve but aggravated cardiac dysfunction and mortality likely due to uncontrolled bacterial burden in the lungs and heart. Our results indicate that P.a. infection induced release of S100A8/9 is double-edged, providing increased risk for cardiac dysfunction yet limiting P.a. growth.

HIV-infected patients are at higher risk of developing oral mucosal infection and Epstein–Barr virus (EBV)-associated B cell malignancies. However, the potential role of oral immunity in the pathogenesis of oral lesions is unknown. Tonsils are oral-pharyngeal mucosal-associated lymphoid tissues that play an important role in oral mucosal immunity. In this study, we investigated the changes of innate and adaptive immune cells in macaque tonsils during chronic SIV infection. We found significantly higher frequencies of classical monocytes, CD3+CD56+ (NKT-like) cells, CD3+CD4+CD8+ (DP), and CD161+ CD4 T cells in tonsils from chronic infected compared to naïve animals. On the contrary, intermediate monocytes and CD3+CD4-CD8- (DN) cells were lower in chronic SIV-infected macaques. We further confirmed a recently described small B-cell subset, NKB cells, were higher during chronic infection. Furthermore, both adaptive and innate cells showed significantly higher TNF-α and cytotoxic marker CD107a, while IL-22 production was significantly reduced in innate and adaptive immune cells in chronic SIV-infected animals. A dramatic reduction of IFN-γ production by innate immune cells might indicate enhanced susceptibility to EBV infection and potential transformation of B cells in the tonsils. In summary, our observation shows that the SIV-associated immune responses are distinct in the tonsils compared to other mucosal tissues. Our data extends our understanding of the oral innate immune system during SIV infection and could aid future studies in evaluating the role of tonsillar immune cells during HIV-associated oral mucosal infections.

Objectives: To highlight and assess the impact of intervention tools used by Indian Council of Medical Research (ICMR) against COVID19 associated infodemic in the world's largest democratic country, India. Study design: It is a retrospective cross sectional study. The impact of ICMR's multi-pronged strategy to address the infodemic during pandemic has been assessed through analysis of print media reportage and social media engagements. Methods: The impact of the interventions was assessed using cloud media mappers like MediaCloud and Meltwater using keywords. The data was analysed in terms of reportage, theme of reportage. A sub-section of media reportage (Feb 2020–June 2020) was analysed in details from 4 major dailies to understand the coverage and tonality of media reports. The data on COVID 19 related tweets, posts and uploads were taken from social media platforms of Indian Council of Medical Research (ICMR) particularly twitter, instagram, facebook and youtube and estimate of pre and post pandemic changes in followers or users were collected for analysis. The data was curated and analysed using MS excel. Results: There was a surge of 3800% reportage in media during pandemic as compared to same time frame in pre-pandemic times. A surge of followers on twitter from 26,823 on Feb 2020 (before pandemic) to 3,36,098 at March 2022 (after pandemic) was observed. A drastic increase in monthly followers was observed after start of Pandemic (after Feb 2020) in comparison to before pandemic (Before Feb 2020). Similar trends were observed on other social media platforms of ICMR. Conclusions: The Communications Unit at ICMR geared up with more robust plans and designed several interventions to mitigate the infodemic which helped in evidence based decision making towards outbreak response and action. This highlights the importance of evidence based, crisp, timely and effective communication during the epidemics/pandemics to buid trust and confidence in the community.

Orientia tsutsugamushi is responsible for causing scrub typhus (ST) and is the leading cause of acute encephalitis syndrome (AES) in AES patients. A rapid and sensitive method to detect scrub typhus on-site is essential for the timely deployment of control measures. In the current study, we developed a rapid, sensitive, and instrument-free lateral flow assay (LFA) detection method based on CRISPR/Cas12a technology for diagnosing ST (named LoCIST). The method is completed in three steps: first, harnessing the ability of recombinase polymerase for isothermal amplification of the target gene; second, CRISPR/Cas12a-based recognition of the target; and third, end-point detection by LFA. The detection limit of LoCIST was found to be one gene copy of ST genomic DNA per reaction, and the process was complete within an hour. In 81 clinical samples, the assay showed no cross-reactivity with other rickettsial DNA and was 100% consistent with PCR detection of ST. LoCIST demonstrated 97.6% sensitivity and 100% specificity. Overall, the LoCIST offers a novel alternative for the portable, simple, sensitive, and specific detection of ST, and it may help prevent and control AES outbreaks due to ST. In conclusion, LoCIST does not require specialized equipment and poses a potential for future applications as a point-of-care diagnostic.

Abstract The vaccine Mycobacterium bovis Bacillus Calmette-Guérin (BCG) elicits an immune response that is protective against certain forms of tuberculosis (TB); however, because BCG efficacy is limited it is important to identify alternative TB vaccine candidates. Recently, the BCG deletion mutant and vaccine candidate BCGΔBCG1419c was demonstrated to survive longer in intravenously infected BALB/c mice due to enhanced biofilm formation, and better protected both BALB/c and C57BL/6 mice against TB-induced lung pathology during chronic stages of infection, relative to BCG controls. BCGΔBCG1419c-elicited protection also associated with lower levels of proinflammatory cytokines (i.e. IL6, TNFα) at the site of infection in C57BL/6 mice. Given the distinct immune profiles of BCG- and BCGΔBCG1419c-immunized mice during chronic TB, we set out to determine if there are early immunological events which distinguish these two groups, using multi-dimensional flow cytometric analysis of the lungs and other tissues soon after immunization. Our results demonstrate a number of innate and adaptive response differences between BCG- and BCGΔBCG1419c-immunized mice which are consistent with the latter being longer lasting and potentially less inflammatory, including lower frequencies of exhausted CD4+ T helper (TH) cells and higher frequencies of IL10-producing T cells, respectively. These studies suggest the use of BCGΔBCG1419c may be advantageous as an alternative TB vaccine candidate.

Abstract Background Molecular mechanisms underlying inflammation-associated breast tumor growth are poorly studied. S100A7, a pro-inflammatory molecule has been shown to enhance breast cancer growth and metastasis. However, the S100A7-mediated molecular mechanisms in enhancing tumor growth and metastasis are unclear. Methods Human breast cancer tissue and plasma samples were used to analyze the expression of S100A7, cPLA2, and PGE2. S100A7-overexpressing or downregulated human metastatic breast cancer cells were used to evaluate the S100A7-mediated downstream signaling mechanisms. Bi-transgenic mS100a7a15 overexpression, TNBC C3 (1)/Tag transgenic, and humanized patient-derived xenograft mouse models and cPLA2 inhibitor (AACOCF3) were used to investigate the role of S100A7/cPLA2/PGE2 signaling in tumor growth and metastasis. Additionally, CODEX, a highly advanced multiplexed imaging was employed to delineate the effects of S100A7/cPLA2 inhibition on the recruitment of various immune cells. Results In this study, we found that S100A7 and cPLA2 are highly expressed and correlate with decreased overall survival in breast cancer patients. Further mechanistic studies revealed that S100A7/RAGE signaling promotes the expression of cPLA2 to mediate its oncogenic effects. Pharmacological inhibition of cPLA2 suppressed S100A7-mediated tumor growth and metastasis in multiple pre-clinical models including transgenic and humanized patient-derived xenograft (PDX) mouse models. The attenuation of cPLA2 signaling reduced S100A7-mediated recruitment of immune-suppressive myeloid cells in the tumor microenvironment (TME). Interestingly, we discovered that the S100A7/cPLA2 axis enhances the immunosuppressive microenvironment by increasing prostaglandin E2 (PGE2). Furthermore, CO-Detection by indEXing (CODEX) imaging-based analyses revealed that cPLA2 inhibition increased the infiltration of activated and proliferating CD4+ and CD8+ T cells in the TME. In addition, CD163+ tumor associated-macrophages were positively associated with S100A7 and cPLA2 expression in malignant breast cancer patients. Conclusions Our study provides new mechanistic insights on the cross-talk between S100A7/cPLA2 in enhancing breast tumor growth and metastasis by generating an immunosuppressive TME that inhibits the infiltration of cytotoxic T cells. Furthermore, our studies indicate that S100A7/cPLA2 could be used as novel prognostic marker and cPLA2 inhibitors as promising drugs against S100A7-overexpressing aggressive breast cancer.

Dengue fever is an endemic disease in India, transmitted by an infected mosquito bite. In India, the number of concurrent infections and the circulation of multiple dengue virus (DENV) serotypes has increased in recent decades. Molecular surveillance among the DENV serotype is important to keep track of the circulating serotypes, evolutionary changes, and key mutations that can alter the diagnostics. The current study included patients admitted for dengue in the Eastern Uttar Pradesh (E-UP) region during 2018–2019. The genetic characterization of the circulating DENV was accomplished through partial CprM (511 bp) gene amplification via reverse transcriptase polymerase chain reaction and sequencing. Phylogenetic analysis revealed the circulation of all four DENV1-4 serotypes. DENV-2 was the most abundant serotype (44%, 27/61), followed by DENV-3 (32%, 20/61). DENV-1 had a 16% (10/61) predominance, while DENV-4 (6%, 4/61) was found to be the least abundant serotype. DENV-2 genotypes were distributed among lineages I (7.4%), II (85%) and III (7.4%) of genotype IV, DENV-3 to lineage III of genotype III, DENV-1 to genotype III; DENV-2 to lineage B (75%) and C (25%) of genotype I. This primary report on the co-circulation of DENV1-4 serotypes from the E-UP region highlights the requirement of continuous molecular surveillance for monitoring circulating DENV serotypes.

BackgroundRecent studies on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reveal that Omicron variant BA.1 and sub-lineages have revived the concern over resistance to antiviral drugs and vaccine-induced immunity. The present study aims to analyze the clinical profile and genome characterization of the SARS-CoV-2 variant in eastern Uttar Pradesh (UP), North India.MethodsWhole-genome sequencing (WGS) was conducted for 146 SARS-CoV-2 samples obtained from individuals who tested coronavirus disease 2019 (COVID-19) positive between the period of 1 January 2022 and 24 February 2022, from three districts of eastern UP. The details regarding clinical and hospitalized status were captured through telephonic interviews after obtaining verbal informed consent. A maximum-likelihood phylogenetic tree was created for evolutionary analysis using MEGA7.ResultsThe mean age of study participants was 33.9 ± 13.1 years, with 73.5% accounting for male patients. Of the 98 cases contacted by telephone, 30 (30.6%) had a travel history (domestic/international), 16 (16.3%) reported having been infected with COVID-19 in past, 79 (80.6%) had symptoms, and seven had at least one comorbidity. Most of the sequences belonged to the Omicron variant, with BA.1 (6.2%), BA.1.1 (2.7%), BA.1.1.1 (0.7%), BA.1.1.7 (5.5%), BA.1.17.2 (0.7%), BA.1.18 (0.7%), BA.2 (30.8%), BA.2.10 (50.7%), BA.2.12 (0.7%), and B.1.617.2 (1.3%) lineages. BA.1 and BA.1.1 strains possess signature spike mutations S:A67V, S:T95I, S:R346K, S:S371L, S:G446S, S:G496S, S:T547K, S:N856K, and S:L981F, and BA.2 contains S:V213G, S:T376A, and S:D405N. Notably, ins214EPE (S1- N-Terminal domain) mutation was found in a significant number of Omicron BA.1 and sub-lineages. The overall Omicron BA.2 lineage was observed in 79.5% of women and 83.2% of men.ConclusionThe current study showed a predominance of the Omicron BA.2 variant outcompeting the BA.1 over a period in eastern UP. Most of the cases had a breakthrough infection following the recommended two doses of vaccine with four in five cases being symptomatic. There is a need to further explore the immune evasion properties of the Omicron variant.

Objective To determine the Japanese encephalitis (JE)-associated long-term functional and neurological outcomes, the extent of reduced social participation and predictors of poor outcomes among paediatric JE survivors.Design A retrospective cohort study.Setting Laboratory-confirmed JE-positive paediatric cases (

CD3-epsilon(CD3e) immunotoxins (IT), a promising precision reagent for various clinical conditions requiring effective depletion of T cells, often shows limited treatment efficacy for largely unknown reasons. Tissue-resident T cells that persist in peripheral tissues have been shown to play pivotal roles in local and systemic immunity, as well as transplant rejection, autoimmunity and cancers. The impact of CD3e-IT treatment on these local cells, however, remains poorly understood. Here, using a new murine testing model, we demonstrate a substantial enrichment of tissue-resident Foxp3+ Tregs following CD3e-IT treatment. Differential surface expression of CD3e among T-cell subsets appears to be a main driver of Treg enrichment in CD3e-IT treatment. The surviving Tregs in CD3e-IT-treated mice were mostly the CD3edimCD62Llo effector phenotype, but the levels of this phenotype markedly varied among different lymphoid and nonlymphoid organs. We also found notable variations in surface CD3e levels among tissue-resident T cells of different organs, and these variations drive CD3e-IT to uniquely reshape T-cell compositions in local organs. The functions of organs and anatomic locations (lymph nodes) also affected the efficacy of CD3e-IT. The multi-organ pharmacodynamics of CD3e-IT and potential treatment resistance mechanisms identified in this study may generate new opportunities to further improve this promising treatment.

ObjectiveTo assess factors associated with COVID-19 stigmatizing attitudes in the community and stigma experiences of COVID-19 recovered individuals during first wave of COVID-19 pandemic in India.MethodsA cross-sectional study was conducted in 18 districts located in 7 States in India during September 2020 to January 2021 among adults > 18 years of age selected through systematic random sampling. Data on socio demographic and COVID-19 knowledge were collected from 303 COVID-19 recovered and 1,976 non-COVID-19 infected individuals from community using a survey questionnaire. Stigma was assessed using COVID-19 Stigma Scale and Community COVID-19 Stigma Scale developed for the study. Informed consent was sought from the participants. Univariate and multivariate binary logistic regression analysis were conducted.ResultsHalf of the participants (51.3%) from the community reported prevalence of severe stigmatizing attitudes toward COVID-19 infected while 38.6% of COVID-19 recovered participants reported experiencing severe stigma. Participants from the community were more likely to report stigmatizing attitudes toward COVID-19 infected if they were residents of high prevalent COVID-19 zone (AOR: 1.5; CI: 1.2–1.9), staying in rural areas (AOR: 1.5; CI:1.1–1.9), belonged to the age group of 18–30 years (AOR: 1.6; CI 1.2–2.0), were male (AOR: 1.6; CI: 1.3–1.9), illiterate (AOR: 2.7; CI: 1.8–4.2), or living in Maharashtra (AOR: 7.4; CI: 4.8–11.3). COVID-19 recovered participants had higher odds of experiencing stigma if they had poor knowledge about COVID-19 transmission (AOR: 2.8; CI: 1.3–6.3), were staying for 6–15 years (AOR: 3.24; CI: 1.1–9.4) in the current place of residence or belonged to Delhi (AOR: 5.3; CI: 1.04–26.7).ConclusionFindings indicated presence of stigmatizing attitudes in the community as well as experienced stigma among COVID-19 recovered across selected study sites in India during the first wave of COVID-19 pandemic. Study recommends timely dissemination of factual information to populations vulnerable to misinformation and psychosocial interventions for individuals affected by stigma.

Background: Earlier serosurveys in India revealed seroprevalence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) of 0.73% in May–June 2020 and 7.1% in August–September 2020. A third serosurvey was conducted between December 2020 and January 2021 to estimate the seroprevalence of SARS-CoV-2 infection among the general population and healthcare workers (HCWs) in India. Methods: The third serosurvey was conducted in the same 70 districts as the first and second serosurveys. For each district, at least 400 individuals aged ≥10 years from the general population and 100 HCWs from subdistrict-level health facilities were enrolled. Serum samples from the general population were tested for the presence of immunoglobulin G (IgG) antibodies against the nucleocapsid (N) and spike (S1-RBD) proteins of SARS-CoV-2, whereas serum samples from HCWs were tested for anti-S1-RBD. Weighted seroprevalence adjusted for assay characteristics was estimated. Results: Of the 28,598 serum samples from the general population, 4585 (16%) had IgG antibodies against the N protein, 6647 (23.2%) had IgG antibodies against the S1-RBD protein, and 7436 (26%) had IgG antibodies against either the N protein or the S1-RBD protein. Weighted and assay-characteristic-adjusted seroprevalence against either of the antibodies was 24.1% [95% confidence interval (CI) 23.0–25.3%]. Among 7385 HCWs, the seroprevalence of anti-S1-RBD IgG antibodies was 25.6% (95% CI 23.5–27.8%). Conclusions: Nearly one in four individuals aged ≥10 years from the general population as well as HCWs in India had been exposed to SARS-CoV-2 by December 2020.

Background: Worldwide, more than 1.2 billion population is adolescents. Nutrition, physical activity, psychological health, and sanitations are few areas that affect adolescents, making them more vulnerable to diseases and contributing in disease burden. The present study was part of the Indian Council of Medical Research’s (ICMR) school based health program Mission SHAKTTI which focused, and reported on adolescents’ awareness and health literacy about nutrition, physical activity, and sanitation in Delhi. Methods: A cross-sectional qualitative study was conducted with students (aged 11-19 years), and the Mission SHAKTTI program was devised using the pillars of Gandhi’s teachings for good health. Data were collected using a pre-tested open ended questionnaire (n=1796). For data analysis, deductive approach was adopted, and thematic content analysis was done with 95% confidence intervals (CI). Results: The study showed that students were somewhat aware of various health-related issues pertaining to Mahatma Gandhi’s ideology of health, with 49.5% (CI: 46.72-51.39) reported that Gandhiji’s mantra for staying healthy was simply a clean environment and proper sanitation. A gap between their understanding and perceptions of a balanced diet was observed, since many felt that merely eating enough food could labelled as balanced diet (36.46%; CI: 34.24-38.74). Conclusions: Findings may be useful in developing a suitable health-based educational program to inculcate knowledge about healthy practices among school-aged children through Gandhian health ideology. This may also help in forging a stronger and more aware foundation of nation leading to prevention of numerous diseases in the near future.

Nontuberculous mycobacteria (NTM) are an increasingly common cause of respiratory infection in people with cystic fibrosis (PwCF). Relative to those with no history of NTM infection (CF-NTMNEG), PwCF and a history of NTM infection (CF-NTMPOS) are more likely to develop severe lung disease and experience complications over the course of treatment. In other mycobacterial infections (e.g., tuberculosis), an overexuberant immune response causes pathology and compromises organ function; however, since the immune profiles of CF-NTMPOS and CF-NTMNEG airways are largely unexplored, it is unknown which, if any, immune responses distinguish these cohorts or concentrate in damaged tissues. Here, we evaluated lung lobe–specific immune profiles of 3 cohorts (CF-NTMPOS, CF-NTMNEG, and non-CF adults) and found that CF-NTMPOS airways are distinguished by a hyperinflammatory cytokine profile. Importantly, the CF-NTMPOS airway immune profile was dominated by B cells, classical macrophages, and the cytokines that support their accumulation. These and other immunological differences between cohorts, including the near absence of NK cells and complement pathway members, were enriched in the most damaged lung lobes. The implications of these findings for our understanding of lung disease in PwCF are discussed, as are how they may inform the development of host-directed therapies to improve NTM disease treatment.

Stem rust caused by Puccinia graminis f. sp. tritici (Pgt) is a devastating disease of wheat worldwide since time immemorial. Several wheat stem rust outbreaks have been reported worldwide including India. Approximately 7 mha wheat area in central and peninsular India is highly vulnerable to stem rust epidemics. In this study, a repository of 29 single genotype uredospore pathotypes, representing five geographical regions, was characterized by investigating their virulence phenotype and simple sequence repeat (SSR) genotypes using 37 reproducible polymorphic SSR markers, 32 of which had ≥ 0.50 polymorphic information content (PIC) value. Virulence phenotypes were used to evaluate the virulence frequency (VF) and construct a hypothetical evolutionary hierarchy of these pathotypes. We projected seven lineages to explain the evolutionary pattern of the Pgt population. The VF of these pathotypes ranged between 0% and 100%. The virulence-based neighbor-joining (NJ) cluster analysis grouped Pgt pathotypes into five virulence groups. Likewise, five molecular groups were categorized using molecular genotypes. The molecular grouping was supported by principal coordinate analysis (PCoA), which revealed 25% of the cumulative variance contributed by the first two axes. Analysis of molecular variance (AMOVA) revealed 8 and 92% of the variation among and within the populations, respectively. The Mantel test confirmed a positive but weak correlation (R2 = 0.15) between virulence phenotypes and SSR genotypes. The highest and lowest values of different genetic diversity parameters (Na, Ne, I, He, uHe, and %P) revealed maximum and minimum variability in the Pgt population from Maharashtra and Uttar Pradesh, respectively. The population structure analysis clustered 29 Pgt pathotypes into two subpopulations and an admixture. Our results demonstrated that there was significant genetic diversity among Pgt pathotypes resulting from their long-distance dispersal ability complemented by gene flow. These findings provide insights into the virulence patterns, genetic variations, and possible evolution of Pgt pathotypes, which would support strategic stem rust resistance breeding.

BackgroundNoncommunicable disease (NCD) multimorbidity throws a unique challenge to healthcare systems globally in terms of not only management of disease, but also familial, social, and economic implications associated with it.ObjectiveTo assess the prevalence of NCD multimorbidity and its associated risk factors along with health expenditures among adults (≥18 years) living in a rural area.MethodsA secondary data analysis of the first-round survey done as part of the Gorakhpur Health and Demographic Surveillance Site (GHDSS) was done. Information related to self-reported morbidity and other variables related to sociodemographics and out-of-pocket expenditure (OOPE) was captured using a pretested questionnaire. Multivariable cluster adjusted binomial regression analysis was done to identify factors associated with multimorbidity.ResultsThe overall prevalence of NCD multimorbidity was found to be 1.8% (95% CI: 1.7–1.9%). The prevalence of NCD multimorbidity was highest among elderly (≥60 years) [6.0% (95% CI: 5.5–6.5%)] and among women [2.4% (95% CI: 2.3–2.6%)]. Sociodemographic factors, such as age, gender, occupation, education, marital status, religion, caste, and household wealth, were all found to be independently associated with NCD multimorbidity. The median annual OOPE was found to be significantly higher among those with NCD multimorbidity (INR 20,000) compared with those with no NCD (INR 5,000) or having only one NCD (INR 8,000).ConclusionAmong the adults in GHDSS, about 13 in every 100 were suffering from at least one NCD and around two in 100 were having NCD multimorbidity. Those with NCD multimorbidity spent almost four times higher annual OOPE compared with those without NCDs.

IntroductionAcute encephalitis syndrome (AES) is a major public health enigma in India and the world. Uttar Pradesh (UP) is witnessing recurrent and extensive seasonal AES outbreaks since 1978. Government of India and UP state government have devised various mitigation measures to reduce AES burden and AES associated mortality, morbidity and disability in Uttar Pradesh. The aim of this study was to describe the public health measures taken in order to control seasonal outbreaks of AES in UP between 1978 and 2020.MethodsWe used literature review as a method of analysis, including the Indian government policy documents. This review utilized search engines such as PubMed, Google Scholar, Research Gate, Cochrane, Medline to retrieve articles and information using strategic keywords related to Acute Encephalitis Syndrome. Data was also collected from progress reports of government schemes and websites of Indian Council of Medical Research (ICMR), National Vector Borne Disease Control Programme (NVBDCP) and Integrated Disease Surveillance Programmes (IDSP).ResultsThe incidence of AES cases in UP have declined from 18.2 per million population during 2005-2009 to 15 per million population during 2015-2019 [CI 12.6–20.6, P-value < 0.001] and case fatality rate (CFR) reduced from 33% during 1980-1984 to 12.6% during 2015-2019 [CI 17.4–30.98, P-value < 0.001]. AES incidence was 9 (2019) and 7 (2020) cases per million populations respectively and CFR was 5.8% (2019) and 5% (2020). This decline was likely due to active surveillance programs identifying aetiological agents and risk factors of AES cases. The identified etiologies of AES include Japanese encephalitis virus (5–20%), Enterovirus (0.1–33%), Orientia tsutsugamushi (45–60%) and other viral (0.2–4.2%), bacterial (0–5%) and Rickettsial (0.5–2%) causes. The aggressive immunization programs against Japanese encephalitis with vaccination coverage of 72.3% in UP helped in declining of JE cases in the region. The presumptive treatment of febrile cases with empirical Doxycycline and Azithromycin (EDA) caused decline in Scrub Typhus-AES cases. Decrease in incidence of vector borne diseases (Malaria, Dengue, Japanese Encephalitis and Kala Azar) i.e., 39.6/100,000 population in 2010 to 18/100,000 population in 2017 is highlighting the impact of vector control interventions. Strengthening healthcare infrastructure in BRD medical college and establishment of Encephalitis Treatment Centre (ETC) at peripheral health centres and emergency ambulance services (Dial 108) reduced the referral time and helped in early treatment and management of AES cases. The AES admissions increased at ETC centres to 60% and overall case fatality rate of AES declined to 3%. Under clean India mission and Jal Jeevan mission, proportion of population with clean drinking water increased from 74.3% in 1992 to 98.7% in 2020. The proportion of household having toilet facilities increased from 22.9% in 1992 to 67.4% in 2020. Provisions for better nutritional status under state and national nutrition mission helped in reducing the burden of stunting (52%) and wasting (53.4%) among under five children in 1992 to 38.8% (stunting) and 36.8% (wasting) in year 2018. These factors have all likely contributed to steady AES decline observed in UP.ConclusionThere is a recent steady decline in AES incidence and CFR since implementation of intensive AES surveillance system and JE immunization campaigns which is highlighting the success of interventions made by central and state government to control seasonal AES outbreaks in UP. Currently, AES incidence is 9 cases per million population (in year 2019) and mortality is 5.8%.

ABSTRACT Infection of rhesus macaques with simian-human immunodeficiency viruses (SHIVs) is the preferred model system for vaccine development because SHIVs encode human immunodeficiency virus type 1 (HIV-1) envelope glycoproteins (Envs)—a key target of HIV-1 neutralizing antibodies. Since the goal of vaccines is to prevent new infections, SHIVs encoding circulating HIV-1 Env are desired as challenge viruses. Development of such biologically relevant SHIVs has been challenging, as they fail to infect rhesus macaques, mainly because most circulating HIV-1 Envs do not use rhesus CD4 (rhCD4) receptor for viral entry. Most primary HIV-1 Envs exist in a closed conformation and occasionally transit to a downstream, open conformation through an obligate intermediate conformation. Here, we provide genetic evidence that open Env conformations can overcome the rhCD4 entry barrier and increase replication of SHIVs in rhesus lymphocytes. Consistent with prior studies, we found that circulating HIV-1 Envs do not use rhCD4 efficiently for viral entry. However, by using HIV-1 Envs with single amino acid substitutions that alter their conformational state, we found that transitions to intermediate and open Env conformations allow usage of physiological levels of rhCD4 for viral entry. We engineered these single amino acid substitutions in the transmitted/founder HIV-1BG505 Envs encoded by SHIV-BG505 and found that open Env conformation enhances SHIV replication in rhesus lymphocytes. Lastly, CD4-mediated SHIV pulldown, sensitivity to soluble CD4, and fusogenicity assays indicated that open Env conformation promotes efficient rhCD4 binding and viral-host membrane fusion. These findings identify the conformational state of HIV-1 Env as a major determinant for rhCD4 usage, viral fusion, and SHIV replication. IMPORTANCE Rhesus macaques are a critical animal model for preclinical testing of HIV-1 vaccine and prevention approaches. However, HIV-1 does not replicate in rhesus macaques, and thus, chimeric simian-human immunodeficiency viruses (SHIVs), which encode HIV-1 envelope glycoproteins (Envs), are used as surrogate challenge viruses to infect rhesus macaques for modeling HIV-1 infection. Development of SHIVs encoding Envs from clinically relevant, circulating HIV-1 variants has been extremely challenging, as such SHIVs replicate poorly, if at all, in rhesus lymphocytes. This is most probably because many circulating HIV-1 Envs do not use rhesus CD4 efficiently for viral entry. In this study, we identified conformational state of HIV-1 envelope as a key determinant for rhesus CD4 usage, viral-host membrane fusion, and SHIV replication in rhesus lymphocytes.

Uttar Pradesh is the densely populated state of India and is the sixth highest COVID-19 affected state with 22,904 deaths recorded on November 12, 2021. Whole-genome sequencing (WGS) is being used as a potential approach to investigate genomic evolution of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. In this study, a total of 87 SARS-CoV-2 genomes−49 genomes from the first wave (March 2020 to February 2021) and 38 genomes from the second wave (March 2021 to July 2021) from Eastern Uttar Pradesh (E-UP) were sequenced and analyzed to understand its evolutionary pattern and variants against publicaly available sequences. The complete genome analysis of SARS-CoV-2 during the first wave in E-UP largely reported transmission of G, GR, and GH clades with specific mutations. In contrast, variants of concerns (VOCs) such as Delta (71.0%) followed by Delta AY.1 (21.05%) and Kappa (7.9%) lineages belong to G clade with prominent signature amino acids were introduced in the second wave. Signature substitution at positions S:L452R, S:P681R, and S:D614G were commonly detected in the Delta, Delta AY.1, and Kappa variants whereas S:T19R and S:T478K were confined to Delta and Delta AY.1 variants only. Vaccine breakthrough infections showed unique mutational changes at position S:D574Y in the case of the Delta variant, whereas position S:T95 was conserved among Kappa variants compared to the Wuhan isolate. During the transition from the first to second waves, a shift in the predominant clade from GH to G clade was observed. The identified spike protein mutations in the SARS-CoV-2 genome could be used as the potential target for vaccine and drug development to combat the effects of the COVID-19 disease.

Organic compounds have constantly proved to be a proficient candidate for nonlinear optical (NLO) applications. In this respect an organic amino acid compound i.e. l-Prolinium Trichloroacetate single crystal has been synthesized and grown through slow evaporation solution growth technique. The lattice parameters obtained from single crystal X-ray diffraction were comparable with reported one. The diffraction pattern along the strain present inside the crystal was measured through powder X-ray diffraction technique. Its photoconductivity has also been observed, in which the traits of dark and photon current were recorded over a range of applied voltage. Further, birefringence was performed for the sample in which it was found that the crystal is having negative optical homogeneity character. The thermal transport parameters were calculated through photo-pyroelectric technique. Its resistance toward the laser beam was examined using laser damage threshold technique. The mechanical characteristics of the single crystal were determined on nanoscale using Oliver–Pharr method. Keywords: X-ray diffraction, Crystal growth, Photoluminescence, Thermal conductivity, Specific heat, Thermal diffusivity

We explored the antibacterial potential (alone and combination) against multidrug resistant (MDR) Pseudomonas aeruginosa isolates KG-P2 using synthesized thieno[3,2-c]pyran-2-ones in combination with different antibiotics. Out of 14 compounds, two compounds (3g and 3l) abridged the MIC of tetracycline (TET) by 16 folds. Compounds was killing the KG-P2 cells, in time dependent manner, lengthened post-antibiotic effect (PAE) of TET and found decreased the mutant prevention concentration (MPC) of TET. In ethidium bromide efflux experiment, two compounds repressed the drug transporter (efflux pumps) which is further supported by molecular docking of these compounds with efflux complex MexAB-OprM. In another study, these compounds inhibited the synthesis of biofilm.

Summary: Background: The association of air pollution with multiple adverse health outcomes is becoming well established, but its negative economic impact is less well appreciated. It is important to elucidate this impact for the states of India. Methods: We estimated exposure to ambient particulate matter pollution, household air pollution, and ambient ozone pollution, and their attributable deaths and disability-adjusted life-years in every state of India as part of the Global Burden of Disease Study (GBD) 2019. We estimated the economic impact of air pollution as the cost of lost output due to premature deaths and morbidity attributable to air pollution for every state of India, using the cost-of-illness method. Findings: 1·67 million (95% uncertainty interval 1·42–1·92) deaths were attributable to air pollution in India in 2019, accounting for 17·8% (15·8–19·5) of the total deaths in the country. The majority of these deaths were from ambient particulate matter pollution (0·98 million [0·77–1·19]) and household air pollution (0·61 million [0·39–0·86]). The death rate due to household air pollution decreased by 64·2% (52·2–74·2) from 1990 to 2019, while that due to ambient particulate matter pollution increased by 115·3% (28·3–344·4) and that due to ambient ozone pollution increased by 139·2% (96·5–195·8). Lost output from premature deaths and morbidity attributable to air pollution accounted for economic losses of US$28·8 billion (21·4–37·4) and $8·0 billion (5·9–10·3), respectively, in India in 2019. This total loss of $36·8 billion (27·4–47·7) was 1·36% of India's gross domestic product (GDP). The economic loss as a proportion of the state GDP varied 3·2 times between the states, ranging from 0·67% (0·47–0·91) to 2·15% (1·60–2·77), and was highest in the low per-capita GDP states of Uttar Pradesh, Bihar, Rajasthan, Madhya Pradesh, and Chhattisgarh. Delhi had the highest per-capita economic loss due to air pollution, followed by Haryana in 2019, with 5·4 times variation across all states. Interpretation: The high burden of death and disease due to air pollution and its associated substantial adverse economic impact from loss of output could impede India's aspiration to be a $5 trillion economy by 2024. Successful reduction of air pollution in India through state-specific strategies would lead to substantial benefits for both the health of the population and the economy. Funding: UN Environment Programme; Bill & Melinda Gates Foundation; and Indian Council of Medical Research, Department of Health Research, Ministry of Health and Family Welfare, Government of India.

Anti-CD3-epsilon (CD3e) monoclonal antibodies (mAbs) and CD3e immunotoxins (ITs) are promising targeted therapy options for various T-cell disorders. Despite significant advances in mAb and IT engineering, vascular leakage syndrome (VLS) remains a major dose-limiting toxicity for ITs and has been poorly characterized for recent “engineered” mAbs. This study undertakes a direct comparison of non-mitogenic CD3e-mAb (145-2C11 with Fc-silentTM murine IgG1: S-CD3e-mAb) and a new murine-version CD3e-IT (saporin–streptavidin (sZAP) conjugated with S-CD3e-mAb: S-CD3e-IT) and identifies their distinct toxicity profiles in mice. As expected, the two agents showed different modes of action on T cells, with S-CD3e-mAb inducing nearly complete modulation of CD3e on the cell surface, while S-CD3e-IT depleted the cells. S-CD3e-IT significantly increased the infiltration of polymorphonuclear leukocytes (PMNs) into the tissue parenchyma of the spleen and lungs, a sign of increased vascular permeability. By contrast, S-CD3e-mAbs-treated mice showed no notable signs of vascular leakage. Treatment with control ITs (sZAP conjugated with Fc-silent isotype antibodies) induced significant vascular leakage without causing T-cell deaths. These results demonstrate that the toxin portion of S-CD3e-IT, not the CD3e-binding portion (S-CD3e-mAb), is the main driver of vascular leakage, thus clarifying the molecular target for improving safety profiles in CD3e-IT therapy.

The early management, diagnosis, and treatment of emerging and re-emerging infections and the rising burden of non-communicable diseases (NCDs) are necessary. The Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-Cas system has recently acquired popularity as a diagnostic tool due to its ability to target specific genes. It uses Cas enzymes and a guide RNA (gRNA) to cleave target DNA or RNA. The discovery of collateral cleavage in CRISPR-Cas effectors such as Cas12a and Cas13a was intensively repurposed for the development of instrument-free, sensitive, precise and rapid point-of-care diagnostics. CRISPR/Cas demonstrated proficiency in detecting non-nucleic acid targets including protein, analyte, and hormones other than nucleic acid. CRISPR/Cas effectors can provide multiple detections simultaneously. The present review highlights the technical challenges of integrating CRISPR/Cas technology into the onsite assessment of clinical and other specimens, along with current improvements in CRISPR bio-sensing for nucleic acid and non-nucleic acid targets. It also highlights the current applications of CRISPR/Cas technologies.

Background: The healthcare infrastructure of a country determines the health-seeking behaviour of the population. In developing countries such as India, there is a great disparity in the distribution of healthcare institutions across urban and rural areas with disadvantages for people living in rural areas. Objectives: Our objectives were to study the health-seeking behavior and factors associated with the use of formal healthcare among the Gorakhpur Health and Demographic Surveillance System (GHDSS) cohort of North India. Methods: The study was conducted in 28 villages from two rural blocks in the Gorakhpur district of eastern Uttar Pradesh, North India. Structured questionnaires were used to collect the data with regard to demographics, health-seeking behaviour and healthcare utilization. An adjusted odds ratio with 95% confidence interval was used to report the factors associated with the utilization of healthcare. Results: Out of 120,306 individuals surveyed, 19,240 (16%) individuals reported having any health problem in the last 15 days. Of them, 90% sought healthcare for their health needs. The formal healthcare utilization was 79%. The use of public health facilities was very low (37%) with most of the people seeking treatment from private healthcare (63%). Females, people with a higher level of education (graduate and above), and those belonging to rich and middle tercile were more likely to use formal healthcare services. Among different ailments, respiratory problems, gastrointestinal problems, and musculoskeletal problems were associated with decreased use of formal healthcare. Conclusion: About four in five individuals surveyed who had health problems sought treatments from formal healthcare with three in five preferring private institutions to public healthcare facilities due to a perceived higher level of treatment quality and nearby availability. There is an urgent need to re-establish community trust among public healthcare facilities with a focus on delivering on-site health care and enhancing the quality of services offered by public healthcare institutions.

Non-alcoholic fatty liver disease (NAFLD) is currently the most frequently occurring liver disorder in the world. However, a specific drug for the treatment of patients with NAFLD is not available. Therefore, the discovery of novel compounds for the treatment of NAFLD and elucidation of the underlying mechanisms of therapeutic drugs that can be used to treat this disease are urgently needed. 1,2,3,4,6 penta-O-galloyl-β-d-glucose (PGG) is known to exert anti-inflammatory, antidiabetic, and hepatoprotective effects. However, little is known about the therapeutic potential of PGG in NAFLD. In this study, we investigated the effects of PGG on a high-fat diet (HFD)-induced mouse model of NAFLD. PGG was co-administered along with an HFD to C57BL/6 mice. After eight weeks of treatment, serum biochemistry, liver steatosis, and lipid metabolism-related genes were examined. The results showed that PGG treatment significantly reduced HFD-induced gain in body weight, liver steatosis, and leukocyte infiltration in a dose-dependent manner. Furthermore, PGG treatment markedly reduced serum triglyceride and glucose levels in HFD mice. Moreover, alterations in the mRNA expression of genes involved in lipid metabolism, including Hmgcr, Acc1, Abca1, Mttp, and Cd36, observed in the livers of HFD-treated mice were significantly reversed by PGG treatment. PGG significantly reduced HFD-induced protein expression of CD36, which is associated with fatty acid uptake, insulin resistance, hyperinsulinemia, and increased hepatic steatosis, in the liver of HFD mice. These results suggest that PGG inhibits HFD-induced hepatic steatosis and reverses HFD-induced alterations of gene expression in lipid metabolism. PGG has been shown to be well tolerated; therefore, it has potential uses in NAFLD treatment.

The new pandemic virus SARS-CoV-2 emerged in China and spread around the world in

Background: To inform actions at the district level under the National Nutrition Mission (NNM), we assessed the prevalence trends of child growth failure (CGF) indicators for all districts in India and inequality between districts within the states. Methods: We assessed the trends of CGF indicators (stunting, wasting and underweight) from 2000 to 2017 across the districts of India, aggregated from 5 × 5 km grid estimates, using all accessible data from various surveys with subnational geographical information. The states were categorised into three groups using their Socio-demographic Index (SDI) levels calculated as part of the Global Burden of Disease Study based on per capita income, mean education and fertility rate in women younger than 25 years. Inequality between districts within the states was assessed using coefficient of variation (CV). We projected the prevalence of CGF indicators for the districts up to 2030 based on the trends from 2000 to 2017 to compare with the NNM 2022 targets for stunting and underweight, and the WHO/UNICEF 2030 targets for stunting and wasting. We assessed Pearson correlation coefficient between two major national surveys for district-level estimates of CGF indicators in the states. Findings: The prevalence of stunting ranged 3.8-fold from 16.4% (95% UI 15.2–17.8) to 62.8% (95% UI 61.5–64.0) among the 723 districts of India in 2017, wasting ranged 5.4-fold from 5.5% (95% UI 5.1–6.1) to 30.0% (95% UI 28.2–31.8), and underweight ranged 4.6-fold from 11.0% (95% UI 10.5–11.9) to 51.0% (95% UI 49.9–52.1). 36.1% of the districts in India had stunting prevalence 40% or more, with 67.0% districts in the low SDI states group and only 1.1% districts in the high SDI states with this level of stunting. The prevalence of stunting declined significantly from 2010 to 2017 in 98.5% of the districts with a maximum decline of 41.2% (95% UI 40.3–42.5), wasting in 61.3% with a maximum decline of 44.0% (95% UI 42.3–46.7), and underweight in 95.0% with a maximum decline of 53.9% (95% UI 52.8–55.4). The CV varied 7.4-fold for stunting, 12.2-fold for wasting, and 8.6-fold for underweight between the states in 2017; the CV increased for stunting in 28 out of 31 states, for wasting in 16 states, and for underweight in 20 states from 2000 to 2017. In order to reach the NNM 2022 targets for stunting and underweight individually, 82.6% and 98.5% of the districts in India would need a rate of improvement higher than they had up to 2017, respectively. To achieve the WHO/UNICEF 2030 target for wasting, all districts in India would need a rate of improvement higher than they had up to 2017. The correlation between the two national surveys for district-level estimates was poor, with Pearson correlation coefficient of 0.7 only in Odisha and four small north-eastern states out of the 27 states covered by these surveys. Interpretation: CGF indicators have improved in India, but there are substantial variations between the districts in their magnitude and rate of decline, and the inequality between districts has increased in a large proportion of the states. The poor correlation between the national surveys for CGF estimates highlights the need to standardise collection of anthropometric data in India. The district-level trends in this report provide a useful reference for targeting the efforts under NNM to reduce CGF across India and meet the Indian and global targets.

Background and Objectives: Activation of NRF2, a key transcription factor of cytoprotectant against oxidative stress, and its target genes are associated with aggressive tumor progression, metastasis and poor survival. In addition, NRF2 signaling mediates cancer stem cell (CSC)-like properties in hepatocellular carcinoma (HCC) cells. Moreover, CSCs have been associated with HCC onset and unfavorable prognosis. Transcatheter arterial embolization (TAE) and/or transcatheter arterial chemoembolization (TACE), which attempt to restrict blood supply to diminish tumor growth, can create a hypoxic environment. However, its effect on NRF2 signaling and CSC marker CD133 in the context of prognosis of HCCs have not been investigated. Therefore, we studied the possible role of the expressions of NRF2, its target genes and CSC markers CD133 and EpCAM on the survival of HCC patients after TAE/TACE. Materials and Methods: RT-qPCR was performed with 120 tumor (T) and adjacent tumor (N) tissue pairs. Expression of a single marker or combination was assessed for associations with survival of HCC patients after TAE/TACE. Results: The result of multivariate Cox regression showed that vascular invasion (HR, 1.821; p = 0.015), metastasis (HR, 2.033; p = 0.049) and CD133 overexpression (HR, 2.013; p = 0.006) were associated with poor survival. In a Kaplan–Meier survival analysis, patients with high expression of CD133 had shorter overall survival (OS) than those with low expression of CD133 in post-TAE/TACE HCC (p < 0.001). In contrast, neither NRF2 nor components of its signaling pathway correlated with survival. Combination marker analysis showed that co-expression of NQO1 and CD133 was associated with poor outcome. Conclusions: This study suggests that analyzing the expression status of CD133 alone and co-expression of NQO1 and CD133 may have additional value in predicting the outcome of TAE/TACE-treated HCC patients.

Bacteria employ numerous resistance mechanisms against structurally distinct drugs by the process of multidrug resistance. A study was planned to discover the antibacterial potential of a graphene oxide nanosheet (GO), a graphene oxide–zinc oxide nanocomposite (GO/ZnO), a graphene oxide-chitosan nanocomposite (GO–CS), a zinc oxide decorated graphene oxide–chitosan nanocomposite (GO–CS/ZnO), and zinc oxide nanoparticles (ZnO) alone and in a blend with antibiotics against a PS-2 isolate of Pseudomonas aeruginosa. These nanocomposites reduced the MIC of tetracycline (TET) from 16 folds to 64 folds against a multidrug-resistant clinical isolate. Efflux pumps were interfered, as evident by an ethidium bromide synergy study with nanocomposites, as well as inhibiting biofilm synthesis. These nanoparticles/nanocomposites also decreased the mutant prevention concentration (MPC) of TET. To the best of our knowledge, this is the first report on nanomaterials as a synergistic agent via inhibition of efflux and biofilm synthesis.

The asymmetric unit of the title compound, C8H15N3S, contains two independent molecules. In both molecules, the seven-membered cycloheptane ring adopts a chair conformation. An intramolecular N—H...N hydrogen bond is observed in both molecules, forming S(5) graph-set motifs. In the crystal, the two independent molecules are connected through N—H...S hydrogen bonds, forming dimers which are in turn further connected by N—H...S hydrogen bonds into chains along [010].

Summary: Background: Air pollution is a major planetary health risk, with India estimated to have some of the worst levels globally. To inform action at subnational levels in India, we estimated the exposure to air pollution and its impact on deaths, disease burden, and life expectancy in every state of India in 2017. Methods: We estimated exposure to air pollution, including ambient particulate matter pollution, defined as the annual average gridded concentration of PM2.5, and household air pollution, defined as percentage of households using solid cooking fuels and the corresponding exposure to PM2.5, across the states of India using accessible data from multiple sources as part of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017. The states were categorised into three Socio-demographic Index (SDI) levels as calculated by GBD 2017 on the basis of lag-distributed per-capita income, mean education in people aged 15 years or older, and total fertility rate in people younger than 25 years. We estimated deaths and disability-adjusted life-years (DALYs) attributable to air pollution exposure, on the basis of exposure–response relationships from the published literature, as assessed in GBD 2017; the proportion of total global air pollution DALYs in India; and what the life expectancy would have been in each state of India if air pollution levels had been less than the minimum level causing health loss. Findings: The annual population-weighted mean exposure to ambient particulate matter PM2·5 in India was 89·9 μg/m3 (95% uncertainty interval [UI] 67·0–112·0) in 2017. Most states, and 76·8% of the population of India, were exposed to annual population-weighted mean PM2·5 greater than 40 μg/m3, which is the limit recommended by the National Ambient Air Quality Standards in India. Delhi had the highest annual population-weighted mean PM2·5 in 2017, followed by Uttar Pradesh, Bihar, and Haryana in north India, all with mean values greater than 125 μg/m3. The proportion of population using solid fuels in India was 55·5% (54·8–56·2) in 2017, which exceeded 75% in the low SDI states of Bihar, Jharkhand, and Odisha. 1·24 million (1·09–1·39) deaths in India in 2017, which were 12·5% of the total deaths, were attributable to air pollution, including 0·67 million (0·55–0·79) from ambient particulate matter pollution and 0·48 million (0·39–0·58) from household air pollution. Of these deaths attributable to air pollution, 51·4% were in people younger than 70 years. India contributed 18·1% of the global population but had 26·2% of the global air pollution DALYs in 2017. The ambient particulate matter pollution DALY rate was highest in the north Indian states of Uttar Pradesh, Haryana, Delhi, Punjab, and Rajasthan, spread across the three SDI state groups, and the household air pollution DALY rate was highest in the low SDI states of Chhattisgarh, Rajasthan, Madhya Pradesh, and Assam in north and northeast India. We estimated that if the air pollution level in India were less than the minimum causing health loss, the average life expectancy in 2017 would have been higher by 1·7 years (1·6–1·9), with this increase exceeding 2 years in the north Indian states of Rajasthan, Uttar Pradesh, and Haryana. Interpretation: India has disproportionately high mortality and disease burden due to air pollution. This burden is generally highest in the low SDI states of north India. Reducing the substantial avoidable deaths and disease burden from this major environmental risk is dependent on rapid deployment of effective multisectoral policies throughout India that are commensurate with the magnitude of air pollution in each state. Funding: Bill & Melinda Gates Foundation; and Indian Council of Medical Research, Department of Health Research, Ministry of Health and Family Welfare, Government of India.

In the title compound, C11H8Cl2N2O3, the plane of the pyrrolidine ring (r.m.s. deviation = 0.065 Å) makes a dihedral angle of 52.9 (2)° with the plane of the benzene ring. The least-squares plane of the central amide fragment makes dihedral angles of 49.3 (7) and 77.9 (7)° with those of the benzene and pyrrolidine rings, respectively. In the crystal, molecules are linked via N—H...O hydrogen bonds, forming chains along the b-axis direction. π–π interactions link these chains into a two-dimensional network parallel to (100).