Role of central endpoint adjudication and challenges in trials on neonatal sepsis-a case of ProSPoNS trial.

Despite progress in reducing the infant mortality in India, the neonatal mortality decline has been slower, necessitating concerted efforts to achieve Sustainable Development Goal-3. A promising strategy aiming to prevent neonatal sepsis in high-risk, vulnerable, low birth weight neonates through an innovative intervention includes probiotic supplementation. This article communicates the decision by the ProSPoNS trial investigators to establish a Central Endpoint Adjudication Committee (CEAC) as an addendum to the protocol published in Trials in 2021 for the purpose of clarifying the primary outcome. In the published protocol, the study hypothesis and primary objective are based on "sepsis," the primary outcome has been specified as sepsis/PSBI, whereas the sample size estimation was performed based on the "physician diagnosed sepsis." To align all the three above, the investigators meeting, held on 17th-18th August 2023, at MGIMS Sevagram, Wardha, deliberated and unanimously agreed that "physician diagnosed sepsis" is the primary study outcome which includes sepsis/PSBI. The CEAC, chaired by an external subject expert and members including trial statistician, a microbiologist, and all site principal investigators will employ four criteria to determine "physician diagnosed sepsis": (1) blood culture status, (2) sepsis screen status, (3) PSBI/non-PSBI signs and symptoms, and (4) the clinical course for each sickness event. Importantly, this clarification maintains consistency with the approved study protocol (Protocol No. 5/7/915/2012 version 3.1 dated 14 Feb 2020), emphasizing the commitment to methodological transparency and adherence to predefined standards. The decision to utilize the guidance of a CEAC is recommended as the gold standard in multicentric complex clinical trials to achieve consistency and accuracy in assessment of outcomes.Trial registrationClinical Trial Registry of India (CTRI) CTRI/2019/05/019197. Registered on 16 May 2019.

Methodology for adapting a co-created early childhood development intervention and implementation strategies for use by frontline workers in India and Guatemala: a systematic application of the FRAME-IS framework.

There is little evidence on optimizing the effectiveness and implementation of evidence-based early childhood development (ECD) interventions when task-shifted to frontline workers. In this Methods Forum paper, we describe our adaptation of the International Guide for Monitoring Child Development (GMCD) for task-shifting to frontline workers in Guatemala and India. In 2021-2022, implementers, trainers, frontline workers, caregivers, and international GMCD experts collaborated to adapt the GMCD for a task shifted implementation by frontline workers. We used an eight-step co-creating process: assembling a multidisciplinary team, training on the existing package, working groups to begin modifications, revision of draft modifications, tailoring of visual materials and language, train-the-trainers activities, pilot frontline worker trainings, final review and feedback. Preliminary effectiveness of adaptations was evaluated through narrative notes and group-based qualitative feedback following pilot trainings with 16 frontline workers in India and 6 in Guatemala. Final adaptations included: refining training techniques to match skill levels and learning styles of frontline workers; tailoring all visual materials to local languages and contexts; design of job aids for providing developmental support messages; modification of referral and triage processes for children in need of enhanced support and speciality referral; and creation of post-training support procedures. Feedback from pilot trainings included: (1) group consensus that training improved ECD skills and knowledge across multiple domains; and (2) feedback on ongoing needed adjustments to pacing, use of video-based vs. role-playing materials, and time allocated to small group work. We use the Framework for Reporting Adaptations and Modifications to Evidence-based Implementation Strategies (FRAME-IS) framework to document our adaptations. The co-creating approach we use, as well as systematic documentation of adaptation decisions will be of use to other community-based early childhood interventions and implementation strategies.

Main findings: The International Guide for Monitoring Child Development, an early childhood development support and monitoring tool, was successfully adapted for use by frontline workers in rural India and Guatemala.Added knowledge: Our Methods Forum paper uses a detailed framework to document the collaborative, co-creating process used and the adaptive decisions taken.Global health impact for policy and action: Evidence on how best to adapt and optimize early childhood interventions for frontline workers will be useful or scaling up support for children globally.

Evaluating Maternal Health Services Within the Reproductive, Maternal, Newborn, Child Health and Adolescents (RMNCH+A) Framework Amidst the COVID-19 Pandemic in Rural India: A Comprehensive Mixed-Methods Analysis.

Background Around half of the pregnant women in India do not receive full antenatal care. During the year 2020, routine health services were further affected by COVID-19. This study was conducted to assess the effect of the pandemic on the delivery/utilization of reproductive, maternal, newborn, child health, and adolescent (RMNCH+A) services. Methodology The study, conducted in Wardha district, Maharashtra, from July to December 2020, aimed to assess maternal health. In Wardha block, 200 pregnant and postnatal women were surveyed using a multistage sampling approach. Adequate knowledge was gauged through Mother and Child Protection Card comprehension. Health system data for April to December 2020 was compared with 2019 district-wide. In-depth interviews were conducted with beneficiaries, including pregnant and post-natal women and healthcare workers. The qualitative inquiries involved medical officers, supervisory staff, community health officers, an auxiliary nurse and midwife (ANMs), Taluka Health Officers, and focus group discussions with accredited social health activists (ASHA), Anganwadi workers (AWW), and Village Health Nutrition and Sanitation Committee members. Results Essential services were delivered to both antenatal and postpartum women, though family planning services and health education were the worst affected. Among the survey respondents, 75% of the post-partum women were not using any contraceptives. District-wide coverage of post-abortion/MTP contraception fell by around 90% as compared to the previous year. The most common difficulties faced by the respondents in availing of the services were related to finances and arranging transport to visit health facilities. Conclusion Learning from the current pandemic for system strengthening, adequate manpower, and planning to prevent disruption of essential services and promoting e-health and m-health initiatives may prevent such catastrophic events in the future from affecting the delivery of routine services.

Cluster-in-Cluster Approach for Computing MP2-Level Vibrational Infrared Spectra of Large Molecular Clusters.

Constructing the Hessian matrix (HM) for large molecules demands huge computational resources. Here, we report a cluster-in-cluster (CIC) procedure for efficiently evaluating HM and dipole derivatives for large molecular clusters by employing the second-order Møller-Plesset perturbation (MP2) theory. The highlight of the proposal is the separation of the estimations of Hartree-Fock (HF) and post-HF components. The parent cluster with n molecules is divided (virtually) into n subclusters centering each monomer and accommodating its near neighbors decided by a distance cutoff. The HF-level HM is obtained by doing full calculation (FC), while the correlation part is approximated by the respective subclusters. A software automating the procedure [followed by calculating infrared (IR) frequencies and intensities] is applied to deduce the IR spectrum for a variety of molecular clusters, particularly water clusters of various sizes, containing up to ∼2000 basis functions. The accuracy of the IR spectrum constructed using CIC is remarkable, with a substantial time advantage (with respect to its FC counterpart). The reduced computational resources and the tractability of the computations are other major benefits of the procedure.

Magnitude and determinants of psychological morbidities among pregnant women: Results from a pregnancy cohort in rural Central India.

Background: Psychological morbidities are one of the emerging global health problems. It affects a considerable number of ante-natal women leading to consequences during the postnatal period as well. We conducted this research to study the magnitude and determinants of psychological morbidities during pregnancy. Methods: In this study, we included 650 pregnant women from an established cohort of 2500 pregnant women and assessed the psychological morbidities among them using the GMHAT/PC tool. Results: The overall prevalence of psychological morbidities during pregnancy was 14.6%, with anxiety and depression being the leading ones. Low education levels, lower socio-economic status, unintended pregnancy, complicated previous pregnancy, lack of family and social support, and domestic violence increased the odds of psychological morbidity. On Multivariate logistic regression, Low education levels increased the odds to more than twice [illiterate/primary schooling OR: 4.00, p = 0.026; secondary schooling OR: 2.64, p = 0.034; high school OR: 2.60, p = 0.033] unintended pregnancy [OR: 1.91, p = 0.043] and lack of family support [OR: 7.19, p < 0.001] increased the odds of psychological morbidity among pregnant women. Conclusion: Bringing these issues to the mainstream and addressing them by developing interventions to address them during the lifecycle of a female will help to prevent episodes of psychological stress and morbidity among pregnant females.

Compensation in Neonatal Clinical Trials: A Perspective.

Well conducted clinical trials are the mainstay for generating evidence on preferred treatments. In order to adequately protect the interests of the trial participants, the Central Licensing Authority of India has formulated guidelines to determine the quantum of compensation in cases of regulatory clinical trial related injury or death. However, these guidelines do not address the nuances of trials recruiting children aged under 16 years, within which, neonates are the most vulnerable population. Thus, there is a need for addressing this lacuna in the current guidelines. This article examines the challenges in determining the quantum of compensation in neonatal clinical trials using the current formula, which is a corollary to the challenges faced by the authors in procuring clinical trial insurance for the Probiotic supplementation for Prevention of Neonatal Sepsis (ProSPoNS) trial. Further, it suggests a template for a differential formula using birthweight of infants, which is one of the many important factors impacting neonatal mortality.

Effect of Inclusive Early Childhood Development (IECD) on Growth and Development of Children in the Rural Part of the Central India: A Cohort Study.

OBJECTIVES: To compare the difference between the growth and developmental status of the children who were residing in the area where Inclusive Early Childhood Development (IECD) project was being implemented and who had received interventions through trained Anganwadi workers (Frontline workers) under Integrated Child Development Services (ICDS) scheme with the children who had not received the Inclusive ECD project interventions. METHODS: It was a mixed method cohort study, nested in an ongoing project in a medical college in which Inclusive ECD was used as an intervention through International Guide for Monitoring Child Development (GMCD) which is a tool for both monitoring and assessment with the help of existing government structures and personnel such as Anganwadi workers, Anganwadi supervisors and their contact points with communities. A sample of 200 children was selected; 100 each from intervention group (IECD cohort) and comparison group (Usual care cohort) and were followed till the child became 2 y of age. RESULTS: IECD intervention showed statistically significant effect on weight (p = 0.04) and height (p = 0.03) of the IECD cohort. Overall developmental assessment showed that the identified developmental issues (Concerns + Delays) were approximately half in IECD cohort (9.67% + 5.37% = 15.04%) as compared to usual care cohort (17.20% + 11.82% = 29.02%). The results from binomial logistic regression performed for developmental outcomes were statistically significant (p = 0.04) suggesting that children with IECD intervention have lower odds of developing developmental issues. CONCLUSIONS: The study indicates that it is possible to implement IECD interventions through frontline workers, which significantly improves the growth and development of the children.

Hydrogen bond energy estimation (H-BEE) in large molecular clusters: A Python program for quantum chemical investigations.

A procedure, derived from the fragmentation-based molecular tailoring approach (MTA), has been proposed and extensively applied by Deshmukh and Gadre for directly estimating the individual hydrogen bond (HB) energies and cooperativity contributions in molecular clusters. However, the manual fragmentation and high computational cost of correlated quantum chemical methods make the application of this method to large molecular clusters quite formidable. In this article, we report an in-house developed software for automated hydrogen bond energy estimation (H-BEE) in large molecular clusters. This user-friendly software is essentially written in Python and executed on a Linux platform with the Gaussian package at the backend. Two approximations to the MTA-based procedure, viz. the first spherical shell (SS1) and the Fragments-in-Fragments (Frags-in-Frags), enabling cost-effective, automated evaluation of HB energies and cooperativity contributions, are also implemented in this software. The software has been extensively tested on a variety of molecular clusters and is expected to be of immense use, especially in conjunction with correlated methods such as MP2, CCSD(T), and so forth.

REAlgo: Rapid and efficient algorithm for estimating MP2/CCSD energy gradients for large molecular clusters.

This work reports the development of an algorithm for rapid and efficient evaluation of energy gradients for large molecular clusters employing correlated methods viz. second-order Møller-Plesset perturbation theory (MP2) theory and couple cluster singles and doubles (CCSD). The procedure segregates the estimation of Hartree-Fock (HF) and correlation components. The HF energy and gradients are obtained by performing a full calculation. The correlation energy is approximated as the corresponding two-body interaction energy. Correlation gradients for each monomer are approximated from the respective monomer-centric fragments comprising its immediate neighbours. The programmed algorithm is explored for the geometry optimization of large molecular clusters using the BERNY optimizer as implemented in the Gaussian suite of software. The accuracy and efficacy of the method are critically probed for a variety of large molecular clusters containing up to 3000 basis functions, in particular large water clusters. The CCSD level geometry optimization of molecular clusters containing ∼800 basis functions employing a modest hardware is also reported.

Vitalizing Community for Health Promotion Against Modifiable Risk Factors of Noncommunicable Diseases (V-CaN) in Rural Central India: Protocol for a Hybrid Type II Implementation Effectiveness Trial.

BACKGROUND: Low- and middle-income countries are facing the emerging burden of chronic noncommunicable diseases (NCDs). Apart from loss of human lives and premature deaths, NCDs result in huge costs for treatment to individuals and the health system. Although NCDs develop in later life, the risk factors begin at an early age. The key to the control of the global epidemic of NCDs is primary prevention based on comprehensive community-based programs. OBJECTIVE: This study aims to develop, implement, and evaluate the effect of a participatory health promotion initiative utilizing the existing mechanisms of Village Health Nutrition and Sanitation Committees (VHNSCs), women's self-help groups (SHGs), and schools on modifiable risk factors for NCDs among young people aged 10-30 years. METHODS: The proposed type II hybrid effectiveness implementation cluster randomized field trial will be conducted in the catchment area of 4 primary health centers (PHCs) in Wardha district, India, comprising 100 villages with a population of 144,000. Each PHC will be randomly allocated to one of the 3 intervention arms or the control arm. The 3-intervention arm PHCs will utilize a unique strategy with either VHNSC or SHG members or school students as change agents for health action against common modifiable NCD risk factors. This study will be implemented in 3 phases from January 2022 to December 2024. First, the preparatory phase for baseline assessments includes anthropometry, behavioral and biochemical risk factors for NCDs, and participatory development of the health promotion intervention modules. Second, the implementation phase will focus on capacity building of the change agents and implementation of the participatory health promotion initiative. The implementation will include organization of community-based events, 6-monthly participatory assessment of change, and preparation of a sustainability and exit plan toward the end of this phase. Third, the evaluation phase will consist of studying the effectiveness of each intervention strategy in the reduction of risk factor prevalence at the population level. RESULTS: We will assess 12,000 (3000 in each arm) randomly selected individuals for behavioral risk factors and 1600 (400 in each arm) individuals for biochemical risk factors during baseline as well as endline assessments. Difference in differences, ANOVA or multivariate analysis of covariance, and regression analysis will be performed to assess the effectiveness of the interventions. Qualitative methods such as focus group discussions and stories of change will be documented and analyzed using thematic framework analysis. The implementation outcomes will be reported using the PRISM (Practical Robust Implementation and Sustainability Model) RE-AIM (Reach, Effectiveness, Adoption, Implementation, Maintenance) framework. The results are expected to be published by mid-2025. CONCLUSIONS: This study will show the magnitude of risk factors for NCDs, its determinants, feasibility, effectiveness of community-based interventions, and health promotion models for NCD prevention. TRIAL REGISTRATION: Clinical Trials Registration India CTRI/2020/10/028700; https://ctri.nic.in/Clinicaltrials/showallp.php?mid1=47597&EncHid=&userName=V-CaN. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/42450.

School Health Services in India: Status, Challenges and the Way Forward.

Schools provide a crucial platform for health and well-being interventions targeting children and adolescents. Early promotive and preventive initiatives are vital for enabling children and adolescents to reach their optimal potential, thereby adding to the country's social return-on-investment, creating a favourable demographic dividend. This review analyses the evolution of school health initiatives in India, including the current curriculum proposed under the Ayushman Bharat program. The manuscript highlights the challenges, and gaps in implementation of the current school health programs and proposes potential pathways for bridging these gaps for promotion of adolescent well-being. The review also discusses the concept of Health Promoting Schools and suggests adaptations and key recommendations to Indian context regarding 'how' to translate it into on-field reality based on the appraisal of successful case studies from other countries. Though India started school health services more than 100 y ago, the school health programmes in most Indian states are weak and fragmented, with piecemeal health screening with minimal focus on health promotion and well-being. The recently launched School Health and Wellness initiative under the Ayushman Bharat program has lots of promise. However, it needs to be translated into effective implementation to prevent it from meeting the fate of its forerunner programs. The school health program needs to move beyond the screening centric approach and be aspirational and holistic in nature focusing upon the overall well-being of the adolescents. Concerted efforts through intersectoral convergence are needed to optimally utilise the platforms of schools for promotion of adolescent well-being.

Combining fragmentation method and high-performance computing: Geometry optimization and vibrational spectra of proteins.

Exploring the structures and spectral features of proteins with advanced quantum chemical methods is an uphill task. In this work, a fragment-based molecular tailoring approach (MTA) is appraised for the CAM-B3LYP/aug-cc-pVDZ-level geometry optimization and vibrational infrared (IR) spectra calculation of ten real proteins containing up to 407 atoms and 6617 basis functions. The use of MTA and the inherently parallel nature of the fragment calculations enables a rapid and accurate calculation of the IR spectrum. The applicability of MTA to optimize the protein geometry and evaluate its IR spectrum employing a polarizable continuum model with water as a solvent is also showcased. The typical errors in the total energy and IR frequencies computed by MTA vis-à-vis their full calculation (FC) counterparts for the studied protein are 5-10 millihartrees and 5 cm-1, respectively. Moreover, due to the independent execution of the fragments, large-scale parallelization can also be achieved. With increasing size and level of theory, MTA shows an appreciable advantage in computer time as well as memory and disk space requirement over the corresponding FCs. The present study suggests that the geometry optimization and IR computations on the biomolecules containing ∼1000 atoms and/or ∼15 000 basis functions using MTA and HPC facility can be clearly envisioned in the near future.

A Literature Review on Perceptions and Practices Related to Healthcare and Nutrition Amongst the Residents of Urban Slums Across India.

Urban regions are home to more than a billion people worldwide; by 2030, more than half of the world's population is projected to reside there. Many rural residents relocate to urban regions in pursuit of employment, better living conditions, and access to healthcare facilities. The study's primary objective is to collate the findings related to perceptions, knowledge, attitude, and practices from studies across the urban slums in India related to healthcare and nutrition. A systematic search of articles was conducted on the National Library of Medicine PubMed Portal Google Scholar, and J-Stor databases for published studies across the indexed journals. Academic social media sites like Academia.edu and Researchgate.org were also searched for grey literature. The inclusion criteria include studies conducted in Urban slums from 2010 to 2022, conducted amongst the Indian population within the Indian Geography, and focusing on documenting perceptions, knowledge, attitude, and practices. Exclusion criteria were cross-sectional surveys with quantitative questionnaires focusing on the prevalence of diseases and the burden of risk factors, literature reviews, systematic reviews, frameworks for implementation of specific interventions, and experimental study designs. A total of 18 qualitative observational studies were included in the review and the findings related to knowledge, attitudes, and practices identified from the literature were summarized. The literature indicated adequate knowledge about nutrition and healthcare, and the barriers towards transitioning knowledge to practice were related to lack of resources, priorities around employment and income, and the attitudes towards change-making were usually based on convenience to access cost of service and availability of the services. The review recommends further investment in research to understand the perceptions, patterns of nutrition, and health-seeking behaviours. Also, there is a pressing need to use the evidence for developing policies in line with the expectations of poor urban communities.

Ring-Polymer Instanton Tunneling Splittings of Tropolone and Isotopomers using a Δ-Machine Learned CCSD(T) Potential: Theory and Experiment Shake Hands.

Tropolone, a 15-atom cyclic molecule, has received much interest both experimentally and theoretically due to its H-transfer tunneling dynamics. An accurate theoretical description is challenging owing to the need to develop a high-level potential energy surface (PES) and then to simulate quantum-mechanical tunneling on this PES in full dimensionality. Here, we tackle both aspects of this challenge and make detailed comparisons with experiments for numerous isotopomers. The PES, of near CCSD(T)-quality, is obtained using a Δ-machine learning approach starting from a pre-existing low-level DFT PES and corrected by a small number of approximate CCSD(T) energies obtained using the fragmentation-based molecular tailoring approach. The resulting PES is benchmarked against DF-FNO-CCSD(T) and CCSD(T)-F12 calculations. Ring-polymer instanton calculations of the splittings, obtained with the Δ-corrected PES are in good agreement with previously reported experiments and a significant improvement over those obtained using the low-level DFT PES. The instanton path includes heavy-atom tunneling effects and cuts the corner, thereby avoiding passing through the conventional saddle-point transition state. This is in contradistinction with typical approaches based on the minimum-energy reaction path. Finally, the subtle changes in the splittings for some of the heavy-atom isotopomers seen experimentally are reproduced and explained.

Constructing Potential Energy Surface with Correlated Theory for Dipeptides Using Molecular Tailoring Approach.

We demonstrate a cost-effective alternative employing the fragment-based molecular tailoring approach (MTA) for building the potential energy surface (PES) for two dipeptides viz. alanine-alanine and alanine-proline employing correlated theory, with augmented Dunning basis sets. About 1369 geometries are generated for each test dipeptide by systematically varying the dihedral angles Φ ${{\rm{\Phi }}}$ and Ψ ${{{\Psi }}}$ . These conformational geometries are partially optimized by relaxing all the other Z-matrix parameters, fixing the values of Φ ${{\rm{\Phi }}}$ and Ψ ${{{\Psi }}}$ . The MP2 level PES is constructed from the MTA-energies of chemically intact geometries using minimal hardware. The fidelity of MP2/aug-cc-pVDZ level PES is brought out by comparing it with its full calculation counterpart. Further, we bring out the power of the method by reporting the MTA-based CCSD/aug-cc-pVDZ level PES for these two dipeptides containing 498 and 562 basis functions respectively.

Development and testing of an algorithm for efficient MP2/CCSD(T) energy estimation of molecular clusters with the 2-body approach.

This work reports the development and testing of an automated algorithm for estimating the energies of weakly bound molecular clusters employing correlated theory. Firstly, the monomers and dimers of (homo/hetero) clusters are identified, and the sum of one-body and two-body contributions to correlation energy is calculated. The addition of this contribution to the Hartree-Fock full calculation (FC) energies provides a good estimate of the total energies at Møller-Plesset second-order perturbation theory (MP2)/coupled-cluster method with singles and doubles (CCSD) (T)-level theory using augmented Dunning basis sets. The estimated energies for several test clusters show an excellent agreement with their FC counterparts, with a substantial wall-clock time saving employing off-the-shelf hardware. Furthermore, the complete basis set (CBS) limit for MP2 energy computed using the two-body approach also agrees with its CBS energy with its FC counterpart.

Early mobilisation in critically ill children: Does routine patient screening reduce time to commencing mobilisation?

OBJECTIVE: The objective of this study was to investigate the impact of daily screening for medical readiness to participate in early mobilisation in the paediatric intensive care unit (PICU), on reducing time to mobilisation and to explore the safety-, feasibility-, and patient-level barriers to the practice. METHODS: An interventional study with a historical control group was conducted in a PICU in a tertiary teaching hospital in Australia. The Early Mobilisation Screening Checklist was applied at 24-48 h of PICU stay with the aim to reduce time to commencing mobilisation. All patients aged term to 18 years admitted to the PICU for >48 h were included in this study. Data on time to mobilisation and patient characteristics were collected by an unblinded case note audit of children admitted to the PICU over 5 months in 2018 for the baseline group and over a corresponding period in 2019 for the intervention group. MEASUREMENTS AND MAIN RESULTS: A total of 71 children were enrolled. Survival analysis was used to compare time to mobilisation between groups, and a cox regression model found that children in the intervention group were 1.26 times more likely to participate in mobility, but this was not statistically significant (P = 0.391, log rank test for equality of survival functions). Early mobilisation was safe, with no adverse events reported in 177 participant mobilisation days. Feasibility was demonstrated by 62% of participants mobilising within 72 h of admission. Mechanical ventilation during stay (P = 0.043) and days receiving sedation infusion (% of days) (P = 0.042) were associated with a decreased likelihood of participating in mobility. CONCLUSIONS: Implementation of routine screening alone does not significantly reduce time to commencing mobility in the PICU. Early mobilisation in the PICU is safe and feasible and resulted in no adverse events during mobilisation. Patient characteristics influencing participation in mobility warrant further exploration.

Enabling Rapid and Accurate Construction of CCSD(T)-Level Potential Energy Surface of Large Molecules Using Molecular Tailoring Approach.

The construction of a potential energy surface (PES) of even a medium-sized molecule employing correlated theory, such as CCSD(T), is arduous due to the high computational cost involved. The present study reports the possibility of efficiently constructing such a PES of molecules containing up to 15 atoms and 550 basis functions by employing the fragment-based molecular tailoring approach (MTA) on off-the-shelf hardware. The MTA energies at the CCSD(T)/aug-cc-pVTZ level for several geometries of three test molecules, viz., acetylacetone, N-methylacetamide, and tropolone, are reported. These energies are in excellent agreement with their full calculation counterparts with a time advantage factor of 3-5. The energy barrier from the ground to transition state is also accurately captured. Further, we demonstrate the accuracy and efficiency of MTA for estimating the energy gradients at the CCSD(T) level. As a further application of our MTA methodology, the energies of acetylacetone at ∼430 geometries are computed at the CCSD(T)/aug-cc-pVTZ level and used for generating a Δ-machine learning (Δ-ML) PES. This leads to the H-transfer barrier of 3.02 kcal/mol, well in agreement with the benchmarked barrier of 3.19 kcal/mol. The fidelity of this Δ-ML PES is examined by geometry optimization and normal mode frequency calculations of global minima and saddle point geometries. We trust that the present work is a major development for the rapid and accurate construction of PES at the CCSD(T) level for molecules containing up to 20 atoms and 600 basis functions using off-the-shelf hardware.

Perceived burden, causes and consequences of adolescent pregnancy in the rural Maharashtra: a cultural domain analysis.

OBJECTIVES: The existing level of the early age pregnancy necessitates in-depth discussions and study. The objective of this study is to explore the perception of rural population regarding adolescent pregnancy with reference to the perceived burden, causes and consequences. METHODS: A cross-sectional study through cultural domain analysis using free listing and participatory learning and action (PLA) tool of ten seed analysis was used for exploring the perceptions of the community. Cognitive salience was estimated using the Sutrop (Su) index. RESULTS: The perceived burden of adolescent pregnancy was around 18%. Early marriage (Su index = 0.274), love/relationship (Su index = 0.246), pre-marital sex (Su index = 0.215), rape/incest (Su index = 0.162), and poor educational status (Su index = 0.152) were the salient causes of adolescent pregnancy. The salient consequences identified were weak baby (Su index = 0.170), social stigma (Su index = 0.124), excessive bleeding during delivery (Su index = 0.114), mother may die (Su index = 0.112) and abortion (Su index = 0.109). CONCLUSIONS: Teenage pregnancy is perceived as a problem by the community. The causes of teenage pregnancy in this setting are multi-dimensional and are deeply embedded in the system of local values, beliefs and practices.

Evaluating the efficacy of a multistrain probiotic supplementation for prevention of neonatal sepsis in 0-2-month-old low birth weight infants in India-the "ProSPoNS" Study protocol for a phase III, multicentric, randomized, double-blind, placebo-controlled trial.

BACKGROUND: Progress has been made in the reduction of under-five mortality in India; however, neonatal mortality is reducing at a slower rate. Efforts are required to bring down neonatal mortality in order to attain the Sustainable Development Goal-3. Prevention of sepsis among the high-risk, vulnerable low birth weight neonates by a newer intervention with probiotic supplementation is promising. METHODS: A phase III, multicenter, randomized, double-blind, placebo-controlled study is being conducted at six sites in India. A total of 6144 healthy low birth weight (LBW) infants fulfilling the eligibility criteria would be enrolled within the first week of life, after obtaining written informed consent from the parents of the infant. Randomization in 1:1 ratio, stratified by site, sex, and birth weight, would be done through an interactive web response system (IWRS) using a standard web browser and email service. Vivomixx®, a probiotic containing a mix of 8 strains of bacteria, in a suspension form standardized to deliver 10 billion CFU/ml, or an organoleptically similar placebo would be fed to enrolled infants in a 1-ml/day dose for 30 days. The follow-up of enrolled infants for 60 days would take place as per a pre-specified schedule for recording morbidities and outcome assessments at the six participating sites. Screening for morbidities would be conducted by trained field workers in the community, and sick infants would be referred to designated clinics/hospitals. A physician would examine the referred infants presenting with complaints and clinical signs, and blood samples would be collected from sick infants for diagnosis of neonatal sepsis by performing sepsis screen and blood culture. Appropriate treatment would be provided as per hospital protocol. The study would be implemented as per the MRC guideline for the management of Global Health Trials in accordance with ICH-GCP and Indian Regulatory guidelines. A contract research organization would be engaged for comprehensive monitoring and quality assurance. The final analysis would be conducted in a blinded manner as per the statistical analysis plan (SAP) to estimate the primary outcomes of sepsis, possible serious bacterial infection (PSBI), and secondary outcomes. The codes will be broken after DMC permission. The protocol has been reviewed by the Research Ethics Committee of the Liverpool School of Tropical Medicine (REC-LSTM), from Research Ethics Committees of the six subject recruitment participating sites. DISCUSSION: This adequately powered and well-designed trial would conclusively answer the question whether probiotics can prevent neonatal sepsis in the high-risk group of low birth weight infants as indicated by a pilot study in 1340 LBW infants, evidence from systematic reviews of hospital-based studies, and a primary study on healthy newborns in Orissa. Results of the study would be generalizable to India and other low-middle-income countries. TRIAL REGISTRATION: Clinical Trial Registry of India (CTRI) CTRI/2019/05/019197 . Registered on 16 May 2019.