Insilico generation of novel ligands for the inhibition of SARS-CoV-2 main protease (3CLpro) using deep learning

The recent emergence of novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing the coronavirus disease (COVID-19) has become a global public health crisis, and a crucial need exists for rapid identification and development of novel therapeutic interventions. In this study, a recurrent neural network (RNN) is trained and optimized to produce novel ligands that could serve as potential inhibitors to the SARS-CoV-2 viral protease: 3 chymotrypsin-like protease (3CLpro). Structure-based virtual screening was performed through molecular docking, ADMET profiling, and predictions of various molecular properties were done to evaluate the toxicity and drug-likeness of the generated novel ligands. The properties of the generated ligands were also compared with current drugs under various phases of clinical trials to assess the efficacy of the novel ligands. Twenty novel ligands were selected that exhibited good drug-likeness properties, with most ligands conforming to Lipinski’s rule of 5, high binding affinity (highest binding affinity: −9.4 kcal/mol), and promising ADMET profile. Additionally, the generated ligands complexed with 3CLpro were found to be stable based on the results of molecular dynamics simulation studies conducted over a 100 ns period. Overall, the findings offer a promising avenue for the rapid identification and development of effective therapeutic interventions to treat COVID-19

Global, regional, and national under-5 mortality, adult mortality, age-specific mortality, and life expectancy, 1970–2016: a systematic analysis for the Global Burden of Disease Study 2016

BACKGROUND: Detailed assessments of mortality patterns, particularly age-specific mortality, represent a crucial input that enables health systems to target interventions to specific populations. Understanding how all-cause mortality has changed with respect to development status can identify exemplars for best practice. To accomplish this, the Global Burden of Diseases, Injuries, and Risk Factors Study 2016 (GBD 2016) estimated age-specific and sex-specific all-cause mortality between 1970 and 2016 for 195 countries and territories and at the subnational level for the five countries with a population greater than 200 million in 2016. METHODS: We have evaluated how well civil registration systems captured deaths using a set of demographic methods called death distribution methods for adults and from consideration of survey and census data for children younger than 5 years. We generated an overall assessment of completeness of registration of deaths by dividing registered deaths in each location-year by our estimate of all-age deaths generated from our overall estimation process. For 163 locations, including subnational units in countries with a population greater than 200 million with complete vital registration (VR) systems, our estimates were largely driven by the observed data, with corrections for small fluctuations in numbers and estimation for recent years where there were lags in data reporting (lags were variable by location, generally between 1 year and 6 years). For other locations, we took advantage of different data sources available to measure under-5 mortality rates (U5MR) using complete birth histories, summary birth histories, and incomplete VR with adjustments; we measured adult mortality rate (the probability of death in individuals aged 15-60 years) using adjusted incomplete VR, sibling histories, and household death recall. We used the U5MR and adult mortality rate, together with crude death rate due to HIV in the GBD model life table system, to estimate age-specific and sex-specific death rates for each location-year. Using various international databases, we identified fatal discontinuities, which we defined as increases in the death rate of more than one death per million, resulting from conflict and terrorism, natural disasters, major transport or technological accidents, and a subset of epidemic infectious diseases; these were added to estimates in the relevant years. In 47 countries with an identified peak adult prevalence for HIV/AIDS of more than 0·5% and where VR systems were less than 65% complete, we informed our estimates of age-sex-specific mortality using the Estimation and Projection Package (EPP)-Spectrum model fitted to national HIV/AIDS prevalence surveys and antenatal clinic serosurveillance systems. We estimated stillbirths, early neonatal, late neonatal, and childhood mortality using both survey and VR data in spatiotemporal Gaussian process regression models. We estimated abridged life tables for all location-years using age-specific death rates. We grouped locations into development quintiles based on the Socio-demographic Index (SDI) and analysed mortality trends by quintile. Using spline regression, we estimated the expected mortality rate for each age-sex group as a function of SDI. We identified countries with higher life expectancy than expected by comparing observed life expectancy to anticipated life expectancy on the basis of development status alone. FINDINGS: Completeness in the registration of deaths increased from 28% in 1970 to a peak of 45% in 2013; completeness was lower after 2013 because of lags in reporting. Total deaths in children younger than 5 years decreased from 1970 to 2016, and slower decreases occurred at ages 5-24 years. By contrast, numbers of adult deaths increased in each 5-year age bracket above the age of 25 years. The distribution of annualised rates of change in age-specific mortality rate differed over the period 2000 to 2016 compared with earlier decades: increasing annualised rates of change were less frequent, although rising annualised rates of change still occurred in some locations, particularly for adolescent and younger adult age groups. Rates of stillbirths and under-5 mortality both decreased globally from 1970. Evidence for global convergence of death rates was mixed; although the absolute difference between age-standardised death rates narrowed between countries at the lowest and highest levels of SDI, the ratio of these death rates-a measure of relative inequality-increased slightly. There was a strong shift between 1970 and 2016 toward higher life expectancy, most noticeably at higher levels of SDI. Among countries with populations greater than 1 million in 2016, life expectancy at birth was highest for women in Japan, at 86·9 years (95% UI 86·7-87·2), and for men in Singapore, at 81·3 years (78·8-83·7) in 2016. Male life expectancy was generally lower than female life expectancy between 1970 and 2016, an

Phyto-assisted synthesis of zinc oxide nanoparticles using Cassia alata and its antibacterial activity against Escherichia coli

Zinc oxide, an established inorganic metal oxide in nanoparticles form exhibits tremendous anti-bacterial activity. The present study focuses on determining the anti-bacterial activity of green synthesized zinc oxide nanoparticles (ZnO NPs). Results clearly validate the effective synthesis of spherical shaped nanoparticles with average size range of 60–80 nm. SEM and EDAX data buttresses the results obtained by XRD pattern in terms of size and purity. ZnO NPs exhibited dose-dependent anti-bacterial activity against Escherichia coli (E. coli) and the IC50 value was calculated to be around 20 μg/mL. Growth kinetics study was conducted in the presence of nanoparticles which demonstrated the bacteriostatic effect of ZnO NPs. The study recommends the potential use of ZnO NPs in industries like food, pharmaceutical, agriculture, cosmetic industries for its anti-bacterial activity. Keywords: Green synthesis, Zinc oxide nanoparticles, Anti-bacterial activity, E. coli, Growth kinetic

Depressive symptoms and human immunodeficiency virus risk behavior among men who have sex with men in Chennai, India

Men who have sex with men (MSM) in India are a hidden population, facing unique environmental stressors and cultural pressures that place them at risk for depression. Depression may affect HIV risk behavior in MSM, and may affect the degree to which MSM may benefit from HIV prevention interventions. Depression in MSM in India, however, has largely been understudied. Two hundred ten MSM in Chennai completed an interviewer-administered behavioral assessment battery, which included the 20-item Center for Epidemiologic Studies Depression Scale (CES-D), demographics, sexual risk and identity, and other psychosocial variables. Over half (55%) of the sample exceeded the cutoff (CESD � 16) to screen in for clinically significant depressive symptoms; this was associated with having had unprotected anal sex (OR ¼ 1.97; 95% CI: 1.01–3.87) and higher number of male partners (OR ¼ 1.04; 95% CI: 1.01–1.07). Statistically significant bivariate predictors of meeting the screen in for depressive symptoms included sexual identity (Kothi 4 Panthi; OR ¼ 4.90; 95% CI: 2.30– 10.54), not being married (OR ¼ 3.40; 95% CI: 1.72–6.81), not having a child (OR ¼ 4.40; 95% CI: 2.07–9.39), family not knowing about one’s MSM identity (OR ¼ 2.30; 95% CI: 1.18–4.90), having been paid for sex (OR ¼ 5.10; p 95% CI: 2.87–9.47), and perceiving that one is at risk for acquiring HIV (OR ¼ 1.10; 95% CI: 1.02–1.17; continuous). In a multivariable logistic-regression model, unique predictors of screening in for depressive symptoms included not being married (AOR ¼ 3.10; 95% CI: 1.23–7.65), having been paid for sex (AOR 3.80; 95% CI: 1.87–7.99) and the perception of increased risk for HIV (AOR ¼ 1.10; 95% CI: 1.03–1.21; continuous); unprotected anal sex in the 3 months prior to study enrollment approached statistical significance (AOR 2.00; 95% CI: 0.91–4.48). Depression among MSM in Chennai is of concern and should be considered while developing HIV prevention interventions with this population. MSM who are not married, sex workers, and those who perceive they are at risk for acquiring HIV may be of higher risk for symptoms of depression

Unseen and unheard: predictors of sexual risk behavior and HIV infection among men who have sex with men in Chennai, India

In India men who have sex with men (MSM) are stigmatized, understudied, and at high risk for HIV. Understanding the impact of psychosocial issues on HIV risk behavior and HIV infection can help shape culturally relevant HIV prevention interventions. Peer outreach workers recruited 210 MSM in Chennai who completed an interviewer-administered psychosocial assessment battery and underwent HIV testing and counseling. More than one fifth (46/210) reported unprotected anal intercourse in the past 3 months, 8% tested positive for HIV, and 26% had previously participated in an HIV prevention intervention. In a multivariable logistic-regression model controlling for age, MSM subpopulation (kothi, panthi, or double-decker), marital status, and religion, significant predictors of any unprotected anal intercourse were being less educated (adjusted odds ratio [AOR] = .54; p = .009), not having previously participated in an HIV prevention program (AOR = 3.75; p = .05), having clinically significant depression symptoms (AOR = 2.8; p = .02), and lower self-efficacy (AOR = .40; p < .0001). Significant predictors of testing positive for HIV infection were: being less educated (AOR = .53; .05) and not currently living with parent(s) (AOR = 3.71; p = .05). Given the prevalence of HIV among MSM, efforts to reach hidden subpopulations of MSM in India are still needed. Such programs for MSM in India may need to address culturally-relevant commonly cooccurring psychosocial problems to maximize chances of reducing risk for infection

HIV Prevention Interventions in Chennai, India: Are Men Who Have Sex with Men Being Reached?

India has the greatest number of HIV infections in Asia and the third highest total number of infected persons globally. Men who have sex with men (MSM) are considered by the Government of India’s National AIDS Control Organization (NACO) a ‘‘core risk group’’ for HIV in need of HIV prevention efforts. However there is a dearth of information on the frequency of participation in HIV prevention interventions and subsequent HIV risk and other correlates amongMSMin India. Recruited through peer outreach workers, word of mouth and snowball sampling techniques, 210 MSM in Chennai completed an interviewer-administered assessment, including questions about participating in any HIV prevention interventions in the past year, sexual risk taking, demographics, MSM identities, and other psychosocial variables. Bivariate and multivariable logistic regression procedures were used to examine behavioral and demographic correlates with HIV prevention intervention participation. More than a quarter (26%) of the sample reported participating in an HIV prevention intervention in the year prior to study participation. Participants who reported engaging in unprotected anal sex (UAS; odds ratio [OR]¼0.28; p¼0.01) in the 3 months prior to study enrollment were less likely to have participated in an HIV prevention programin the past year. MSM who were older (OR¼1.04; p¼0.05), kothis (feminine acting=appearing and predominantly receptive partners in anal sex) compared to panthis (masculine appearing, predominantly insertive partners; OR¼5.52, p¼0.0004), those with higher educational attainment (OR¼1.48, p¼0.01), being ‘‘out’’ about having sex with other men (OR¼4.03, p¼0.0001), and MSM who reported ever having been paid in exchange for sex (OR¼2.92, p¼0.001) were more likely to have reported participation in an HIV prevention intervention in the preceding year. In a multivariable model, MSM reporting UAS in the prior 3 months were less likely to have participated in an HIV prevention intervention (AOR¼0.34, p¼0.04). MSM who were older (AOR¼1.05, p¼0.05), those with higher educational attainment (AOR¼1.92, p¼0.0009), and MSM who were ‘‘out’’ about having sex with other men (AOR¼2.71, p¼0.04) were more likely to have reported participating in an HIV prevention program. Findings suggest that exposure to HIV prevention interventions may be protective against engaging in UAS for some MSM in India. Understanding predictors of participation in an HIV prevention intervention is helpful for identifying Indian MSM who might have had no exposure to HIV prevention information and skills building, hence allowing researchers and prevention workers to focus efforts on individuals at greatest need

Global, regional, and national under-5 mortality, adult mortality, age-specific mortality, and life expectancy, 1970-2016 : a systematic analysis for the Global Burden of Disease Study 2016

Background Detailed assessments of mortality patterns, particularly age-specific mortality, represent a crucial input that enables health systems to target interventions to specific populations. Understanding how all-cause mortality has changed with respect to development status can identify exemplars for best practice. To accomplish this, the Global Burden of Diseases, Injuries, and Risk Factors Study 2016 (GBD 2016) estimated age-specific and sex-specific all-cause mortality between 1970 and 2016 for 195 countries and territories and at the subnational level for the five countries with a population greater than 200 million in 2016. Methods We have evaluated how well civil registration systems captured deaths using a set of demographic methods called death distribution methods for adults and from consideration of survey and census data for children younger than 5 years. We generated an overall assessment of completeness of registration of deaths by dividing registered deaths in each location-year by our estimate of all-age deaths generated from our overall estimation process. For 163 locations, including subnational units in countries with a population greater than 200 million with complete vital registration (VR) systems, our estimates were largely driven by the observed data, with corrections for small fluctuations in numbers and estimation for recent years where there were lags in data reporting (lags were variable by location, generally between 1 year and 6 years). For other locations, we took advantage of different data sources available to measure under-5 mortality rates (U5MR) using complete birth histories, summary birth histories, and incomplete VR with adjustments; we measured adult mortality rate (the probability of death in individuals aged 15-60 years) using adjusted incomplete VR, sibling histories, and household death recall. We used the U5MR and adult mortality rate, together with crude death rate due to HIV in the GBD model life table system, to estimate age-specific and sex-specific death rates for each location-year. Using various international databases, we identified fatal discontinuities, which we defined as increases in the death rate of more than one death per million, resulting from conflict and terrorism, natural disasters, major transport or technological accidents, and a subset of epidemic infectious diseases; these were added to estimates in the relevant years. In 47 countries with an identified peak adult prevalence for HIV/AIDS of more than 0.5% and where VR systems were less than 65% complete, we informed our estimates of age-sex-specific mortality using the Estimation and Projection Package (EPP)-Spectrum model fitted to national HIV/AIDS prevalence surveys and antenatal clinic serosurveillance systems. We estimated stillbirths, early neonatal, late neonatal, and childhood mortality using both survey and VR data in spatiotemporal Gaussian process regression models. We estimated abridged life tables for all location-years using age-specific death rates. We grouped locations into development quintiles based on the Sociodemographic Index (SDI) and analysed mortality trends by quintile. Using spline regression, we estimated the expected mortality rate for each age-sex group as a function of SDI. We identified countries with higher life expectancy than expected by comparing observed life expectancy to anticipated life expectancy on the basis of development status alone. Findings Completeness in the registration of deaths increased from 28% in 1970 to a peak of 45% in 2013; completeness was lower after 2013 because of lags in reporting. Total deaths in children younger than 5 years decreased from 1970 to 2016, and slower decreases occurred at ages 5-24 years. By contrast, numbers of adult deaths increased in each 5-year age bracket above the age of 25 years. The distribution of annualised rates of change in age-specific mortality rate differed over the period 2000 to 2016 compared with earlier decades: increasing annualised rates of change were less frequent, although rising annualised rates of change still occurred in some locations, particularly for adolescent and younger adult age groups. Rates of stillbirths and under-5 mortality both decreased globally from 1970. Evidence for global convergence of death rates was mixed; although the absolute difference between age-standardised death rates narrowed between countries at the lowest and highest levels of SDI, the ratio of these death rates-a measure of relative inequality-increased slightly. There was a strong shift between 1970 and 2016 toward higher life expectancy, most noticeably at higher levels of SDI. Among countries with populations greater than 1 million in 2016, life expectancy at birth was highest for women in Japan, at 86.9 years (95% UI 86.7-87.2), and for men in Singapore, at 81.3 years (78.8-83.7) in 2016. Male life expectancy was generally lower than female life expectancy between 1970 and 2016, and the gap between male and female life expectancy increased with progression to higher levels of SDI. Some countries with exceptional health performance in 1990 in terms of the difference in observed to expected life expectancy at birth had slower progress on the same measure in 2016. Interpretation Globally, mortality rates have decreased across all age groups over the past five decades, with the largest improvements occurring among children younger than 5 years. However, at the national level, considerable heterogeneity remains in terms of both level and rate of changes in age-specific mortality; increases in mortality for certain age groups occurred in some locations. We found evidence that the absolute gap between countries in age-specific death rates has declined, although the relative gap for some age-sex groups increased. Countries that now lead in terms of having higher observed life expectancy than that expected on the basis of development alone, or locations that have either increased this advantage or rapidly decreased the deficit from expected levels, could provide insight into the means to accelerate progress in nations where progress has stalled. Copyright (C) The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.Peer reviewe