Correlation of severity & clinical outcomes of COVID-19 with virus variants: A prospective, multicentre hospital network study.

BACKGROUND OBJECTIVES: The clinical course of COVID-19 and its prognosis are influenced by both viral and host factors. The objectives of this study were to develop a nationwide platform to investigate the molecular epidemiology of SARS-CoV-2 (Severe acute respiratory syndrome Corona virus 2) and correlate the severity and clinical outcomes of COVID-19 with virus variants. METHODS: A nationwide, longitudinal, prospective cohort study was conducted from September 2021 to December 2022 at 14 hospitals across the country that were linked to a viral sequencing laboratory under the Indian SARS-CoV-2 Genomics Consortium. All participants (18 yr and above) who attended the hospital with a suspicion of SARS-CoV-2 infection and tested positive by the reverse transcription-PCR method were included. The participant population consisted of both hospitalized as well as outpatients. Their clinical course and outcomes were studied prospectively. Nasopharyngeal samples collected were subjected to whole genome sequencing to detect SARS-CoV-2 variants. RESULTS: Of the 4972 participants enrolled, 3397 provided samples for viral sequencing and 2723 samples were successfully sequenced. From this, the evolution of virus variants of concern including Omicron subvariants which emerged over time was observed and the same reported here. The mean age of the study participants was 41 yr and overall 49.3 per cent were female. The common symptoms were fever and cough and 32.5 per cent had comorbidities. Infection with the Delta variant evidently increased the risk of severe COVID-19 (adjusted odds ratio: 2.53, 95% confidence interval: 1.52, 4.2), while Omicron was milder independent of vaccination status. The independent risk factors for mortality were age >65 yr, presence of comorbidities and no vaccination. INTERPRETATION CONCLUSIONS: The authors believe that this is a first-of-its-kind study in the country that provides real-time data of virus evolution from a pan-India network of hospitals closely linked to the genome sequencing laboratories. The severity of COVID-19 could be correlated with virus variants with Omicron being the milder variant.

Statistical Characterisation of Fetal Anatomy in Simple Obstetric Ultrasound Video Sweeps.

OBJECTIVE: We present a statistical characterisation of fetal anatomies in obstetric ultrasound video sweeps where the transducer follows a fixed trajectory on the maternal abdomen. METHODS: Large-scale, frame-level manual annotations of fetal anatomies (head, spine, abdomen, pelvis, femur) were used to compute common frame-level anatomy detection patterns expected for breech, cephalic, and transverse fetal presentations, with respect to video sweep paths. The patterns, termed statistical heatmaps, quantify the expected anatomies seen in a simple obstetric ultrasound video sweep protocol. In this study, a total of 760 unique manual annotations from 365 unique pregnancies were used. RESULTS: We provide a qualitative interpretation of the heatmaps assessing the transducer sweep paths with respect to different fetal presentations and suggest ways in which the heatmaps can be applied in computational research (e.g., as a machine learning prior). CONCLUSION: The heatmap parameters are freely available to other researchers (https://github.com/agleed/calopus_statistical_heatmaps).

Development and external validation of Indian population-specific Garbhini-GA2 model for estimating gestational age in second and third trimesters.

Background: A large proportion of pregnant women in lower and middle-income countries (LMIC) seek their first antenatal care after 14 weeks of gestation. While the last menstrual period (LMP) is still the most prevalent method of determining gestational age (GA), ultrasound-based foetal biometry is considered more accurate in the second and third trimesters. In LMIC settings, the Hadlock formula, originally developed using data from a small Caucasian population, is widely used for estimating GA and foetal weight worldwide as the pre-programmed formula in ultrasound machines. This approach can lead to inaccuracies when estimating GA in a diverse population. Therefore, this study aimed to develop a population-specific model for estimating GA in the late trimesters that was as accurate as the GA estimation in the first trimester, using data from GARBH-Ini, a pregnancy cohort in a North Indian district hospital, and subsequently validate the model in an independent cohort in South India. Methods: Data obtained by longitudinal ultrasonography across all trimesters of pregnancy was used to develop and validate GA models for the second and third trimesters. The gold standard for GA estimation in the first trimester was determined using ultrasonography. The Garbhini-GA2, a polynomial regression model, was developed using the genetic algorithm-based method, showcasing the best performance among the models considered. This model incorporated three of the five routinely measured ultrasonographic parameters during the second and third trimesters. To assess its performance, the Garbhini-GA2 model was compared against the Hadlock and INTERGROWTH-21st models using both the TEST set (N = 1493) from the GARBH-Ini cohort and an independent VALIDATION dataset (N = 948) from the Christian Medical College (CMC), Vellore cohort. Evaluation metrics, including root-mean-squared error, bias, and preterm birth (PTB) rates, were utilised to comprehensively assess the model's accuracy and reliability. Findings: With first trimester GA dating as the baseline, Garbhini-GA2 reduced the GA estimation median error by more than three times compared to the Hadlock formula. Further, the PTB rate estimated using Garbhini-GA2 was more accurate when compared to the INTERGROWTH-21st and Hadlock formulae, which overestimated the rate by 22.47% and 58.91%, respectively. Interpretation: The Garbhini-GA2 is the first late-trimester GA estimation model to be developed and validated using Indian population data. Its higher accuracy in GA estimation, comparable to GA estimation in the first trimester and PTB classification, underscores the significance of deploying population-specific GA formulae to enhance antenatal care. Funding: The GARBH-Ini cohort study was funded by the Department of Biotechnology, Government of India (BT/PR9983/MED/97/194/2013). The ultrasound repository was partly supported by the Grand Challenges India-All Children Thriving Program, Biotechnology Industry Research Assistance Council, Department of Biotechnology, Government of India (BIRAC/GCI/0115/03/14-ACT). The research reported in this publication was made possible by a grant (BT/kiData0394/06/18) from the Grand Challenges India at Biotechnology Industry Research Assistance Council (BIRAC), an operating division jointly supported by DBT-BMGF-BIRAC. The external validation study at CMC Vellore was partly supported by a grant (BT/kiData0394/06/18) from the Grand Challenges India at Biotechnology Industry Research Assistance Council (BIRAC), an operating division jointly supported by DBT-BMGF-BIRAC and by Exploratory Research Grant (SB/20-21/0602/BT/RBCX/008481) from Robert Bosch Centre for Data Science and Artificial Intelligence (RBCDSAI), IIT Madras. An alum endowment from Prakash Arunachalam (BIO/18-19/304/ALUM/KARH) partly funded this study at the Centre for Integrative Biology and Systems Medicine, IIT Madras.

Post-natal gestational age assessment using targeted metabolites of neonatal heel prick and umbilical cord blood: A GARBH-Ini cohort study from North India.

Background: Accurate assessment of gestational age (GA) and identification of preterm birth (PTB) at delivery is essential to guide appropriate post-natal clinical care. Undoubtedly, dating ultrasound sonography (USG) is the gold standard to ascertain GA, but is not accessible to the majority of pregnant women in low- and middle-income countries (LMICs), particularly in rural areas and small secondary care hospitals. Conventional methods of post-natal GA assessment are not reliable at delivery and are further compounded by a lack of trained personnel to conduct them. We aimed to develop a population-specific GA model using integrated clinical and biochemical variables measured at delivery. Methods: We acquired metabolic profiles on paired neonatal heel prick (nHP) and umbilical cord blood (uCB) dried blood spot (DBS) samples (n = 1278). The master data set consists of 31 predictors from nHP and 24 from uCB after feature selection. These selected predictors including biochemical analytes, birth weight, and placental weight were considered for the development of population-specific GA estimation and birth outcome classification models using eXtreme Gradient Boosting (XGBoost) algorithm. Results: The nHP and uCB full model revealed root mean square error (RMSE) of 1.14 (95% confidence interval (CI) = 0.82-1.18) and of 1.26 (95% CI = 0.88-1.32) to estimate the GA as compared to actual GA, respectively. In addition, these models correctly estimated 87.9 to 92.5% of the infants within ±2 weeks of the actual GA. The classification models also performed as the best fit to discriminate the PTB from term birth (TB) infants with an area under curve (AUC) of 0.89 (95% CI = 0.84-0.94) for nHP and an AUC of 0.89 (95% CI = 0.85-0.95) for uCB. Conclusion: The biochemical analytes along with clinical variables in the nHP and uCB data sets provide higher accuracy in predicting GA. These models also performed as the best fit to identify PTB infants at delivery.

A quest for universal anti-SARS-CoV-2 T cell assay: systematic review, meta-analysis, and experimental validation.

Measuring SARS-CoV-2-specific T cell responses is crucial to understanding an individual's immunity to COVID-19. However, high inter- and intra-assay variability make it difficult to define T cells as a correlate of protection against COVID-19. To address this, we performed systematic review and meta-analysis of 495 datasets from 94 original articles evaluating SARS-CoV-2-specific T cell responses using three assays - Activation Induced Marker (AIM), Intracellular Cytokine Staining (ICS), and Enzyme-Linked Immunospot (ELISPOT), and defined each assay's quantitative range. We validated these ranges using samples from 193 SARS-CoV-2-exposed individuals. Although IFNγ ELISPOT was the preferred assay, our experimental validation suggested that it under-represented the SARS-CoV-2-specific T cell repertoire. Our data indicate that a combination of AIM and ICS or FluoroSpot assay would better represent the frequency, polyfunctionality, and compartmentalization of the antigen-specific T cell responses. Taken together, our results contribute to defining the ranges of antigen-specific T cell assays and propose a choice of assay that can be employed to better understand the cellular immune response against viral diseases.

Incidence of and risk factors for small vulnerable newborns in north India: a secondary analysis of a prospective pregnancy cohort.

BACKGROUND: Globally, recent estimates have shown there have been 3·6 million stillbirths and neonatal deaths in 2022, with nearly 60% occurring in low-income and middle-income countries. The Small Vulnerable Newborn Consortium has proposed a framework combining preterm birth (<37 weeks of gestation), small for gestational age (SGA) by INTERGROWTH-21st standard, and low birthweight (<2500 g) under the category small vulnerable newborns (SVN). Reliable data on SVN from sub-Saharan Africa, central Asia, and south Asia are sparse. We aimed to estimate the incidence of SVN and its types, and quantify risk factors, both overall and trimester-specific, from a pregnancy cohort in north India. METHODS: In the GARBH-Ini (Interdisciplinary Group for Advanced Research on Birth Outcomes-DBT India Initiative) pregnancy cohort, 8000 participants were enrolled with less than 20 weeks' gestation between May 11, 2015, and Aug 8, 2020, at a secondary-care hospital in north India. The cohort was followed up across the antenatal period for a detailed study on preterm birth. We conducted a secondary analysis of cohort data for the outcome of SVN, classified into its types: preterm-SGA, preterm-nonSGA, and term-SGA. We estimated the relative risk and population attributable fraction of candidate risk factors for SVN (modified Poisson regression) and its types (multinomial regression). FINDINGS: 7183 (89·9%) of 7990 participants completed the study. Among 6206 newborns included for analysis, the incidence of SVN was 48·4% (35·1% term-SGA newborns [n=2179], 9·7% preterm-nonSGA newborns [n=605], and 3·6% preterm-SGA newborns [n=222]). Compared with term-nonSGA newborns, proportions of stillbirths and neonatal deaths within 72 h of birth among SVN were three times and 2·5 times higher, respectively. Preterm-SGA newborns had the highest incidence of stillbirth (15 [6·8%] of 222) and neonatal deaths (six [4·2%] of 142). Low body-mass index (BMI <18·5 kg/m2) of participants at the start of pregnancy was associated with higher risk for preterm-SGA (adjusted relative risk [RR] 1·61 [95% CI 1·17-2·22]), preterm-nonSGA (1·35 [1·09-1·68]), and term-SGA (1·44 [1·27- 1·64]), with population attributable fraction ranging from 8·7% to 13·8%. Pre-eclampsia (adjusted RR 1·48 [95% CI 1·30-1·71]), short cervical length (1·15 [1·04-1·26]), and bacterial vaginosis (1·13 [0·88-1·45]) were other important antenatal risk factors. INTERPRETATION: In a comprehensive analysis of SVN and its types from north India, we identified risk factors to guide prioritisation of interventions. Complemented with risk-stratification tools, this focused approach will enhance antenatal care, and accelerate achievement of Sustainable Development Goals-namely, to end preventable deaths of newborns and children younger than 5 years by 2030 (target 3·2). FUNDING: Department of Biotechnology, Government of India and Grand Challenges India-Biotechnology Industry Research Assistance Council, Government of India. TRANSLATION: For the Hindi translation of the abstract see Supplementary Materials section.