A combination of potently neutralizing monoclonal antibodies isolated from an Indian convalescent donor protects against the SARS-CoV-2 Delta variant.

Although efficacious vaccines have significantly reduced the morbidity and mortality of COVID-19, there remains an unmet medical need for treatment options, which monoclonal antibodies (mAbs) can potentially fill. This unmet need is exacerbated by the emergence and spread of SARS-CoV-2 variants of concern (VOCs) that have shown some resistance to vaccine responses. Here we report the isolation of five neutralizing mAbs from an Indian convalescent donor, out of which two (THSC20.HVTR04 and THSC20.HVTR26) showed potent neutralization of SARS-CoV-2 VOCs at picomolar concentrations, including the Delta variant (B.1.617.2). One of these (THSC20.HVTR26) also retained activity against the Omicron variant. These two mAbs target non-overlapping epitopes on the receptor-binding domain (RBD) of the spike protein and prevent virus attachment to its host receptor, human angiotensin converting enzyme-2 (hACE2). Furthermore, the mAb cocktail demonstrated protection against the Delta variant at low antibody doses when passively administered in the K18 hACE2 transgenic mice model, highlighting their potential as a cocktail for prophylactic and therapeutic applications. Developing the capacity to rapidly discover and develop mAbs effective against highly transmissible pathogens like coronaviruses at a local level, especially in a low- and middle-income country (LMIC) such as India, will enable prompt responses to future pandemics as an important component of global pandemic preparedness.

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.

Trends of humoral immune responses to heterologous antigenic exposure due to vaccination & omicron SARS-CoV-2 infection: Implications for boosting.

Background & objectives: Vaccination and natural infection can both augment the immune responses against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but how omicron infection has affected the vaccine-induced and hybrid immunity is not well studied in Indian population. The present study was aimed to assess the durability and change in responses of humoral immunity with age, prior natural infection, vaccine type and duration with a minimum gap of six months post-two doses with either ChAdOx1 nCov-19 or BBV152 prior- and post-emergence of the omicron variant. Methods: A total of 1300 participants were included in this observational study between November 2021 and May 2022. Participants had completed at least six months after vaccination (2 doses) with either ChAdOx1 nCoV-19 or an inactivated whole virus vaccine BBV152. They were grouped according to their age (≤ or ≥60 yr) and prior exposure of SARS-CoV-2 infection. Five hundred and sixteen of these participants were followed up after emergence of the Omicron variant. The main outcome was durability and augmentation of the humoral immune response as determined by anti-receptor-binding domain (RBD) immunoglobulin G (IgG) concentrations, anti-nucleocapsid antibodies and anti-omicron RBD antibodies. Live virus neutralization assay was conducted for neutralizing antibodies against four variants - ancestral, delta and omicron and omicron sublineage BA.5. Results: Before the omicron surge, serum anti-RBD IgG antibodies were detected in 87 per cent participants after a median gap of eight months from the second vaccine dose, with a median titre of 114 [interquartile range (IQR) 32, 302] BAU/ml. The levels increased to 594 (252, 1230) BAU/ml post-omicron surge (P<0.001) with 97 per cent participants having detectable antibodies, although only 40 had symptomatic infection during the omicron surge irrespective of vaccine type and previous history of infection. Those with prior natural infection and vaccination had higher anti-RBD IgG titre at baseline, which increased further [352 (IQR 131, 869) to 816 (IQR 383, 2001) BAU/ml] (P<0.001). The antibody levels remained elevated after a mean time gap of 10 months, although there was a decline of 41 per cent. The geometric mean titre was 452.54, 172.80, 83.1 and 76.99 against the ancestral, delta, omicron and omicron BA.5 variants in the live virus neutralization assay. Interpretation & conclusions: Anti-RBD IgG antibodies were detected in 85 per cent of participants after a median gap of eight months following the second vaccine dose. Omicron infection probably resulted in a substantial proportion of asymptomatic infection in the first four months in our study population and boosted the vaccine-induced humoral immune response, which declined but still remained durable over 10 months.

Studying the post-COVID-19 condition: research challenges, strategies, and importance of Core Outcome Set development.

BACKGROUND: A substantial portion of people with COVID-19 subsequently experience lasting symptoms including fatigue, shortness of breath, and neurological complaints such as cognitive dysfunction many months after acute infection. Emerging evidence suggests that this condition, commonly referred to as long COVID but also known as post-acute sequelae of SARS-CoV-2 infection (PASC) or post-COVID-19 condition, could become a significant global health burden. MAIN TEXT: While the number of studies investigating the post-COVID-19 condition is increasing, there is no agreement on how this new disease should be defined and diagnosed in clinical practice and what relevant outcomes to measure. There is an urgent need to optimise and standardise outcome measures for this important patient group both for clinical services and for research and to allow comparing and pooling of data. CONCLUSIONS: A Core Outcome Set for post-COVID-19 condition should be developed in the shortest time frame possible, for improvement in data quality, harmonisation, and comparability between different geographical locations. We call for a global initiative, involving all relevant partners, including, but not limited to, healthcare professionals, researchers, methodologists, patients, and caregivers. We urge coordinated actions aiming to develop a Core Outcome Set (COS) for post-COVID-19 condition in both the adult and paediatric populations.

Dynamic Alteration in the Vaginal Secretory Proteome across the Early and Mid-Trimesters of Pregnancy.

Pregnancy is characterized by intense physiological and structural alterations in the vagina, cervix, and overlying fetal membranes. High vaginal fluid (HVF) is a proximal fluid that covers the lower part of the female reproductive system and the severity of vaginal pathology often adversely affects pregnancy outcomes. To identify the correlation of vaginal fluid proteome dynamics and physiological changes during the progression of pregnancy, a longitudinal study was performed on 20 pregnant women who delivered a baby in >37 weeks without any complications. SWATH-MS-based label-free quantitative proteomics was performed to profile the HVF proteome at three time points defined as V1 (7-12 weeks), V2 (18-20 weeks), and V3 (26-28 weeks). Linear mixed-effect models were used to estimate protein abundance as a function of the period of gestational age. In this study, we identified 1015 HVF proteins and 61 of them were significantly altered until late second trimester. Our result demonstrates that the HVF proteins reveal gestational age-specific expression patterns and the function of these proteins is associated with tissue remodeling, organ development, and microbial defense. Our study provides an opportunity to monitor the underlying physiology of pregnancy that may be further probed for the biomarker identification in pregnancy-related adverse outcomes. Data are available via ProteomeXchange with identifiers PXD014846 and PXD021811.

Comparison of first trimester dating methods for gestational age estimation and their implication on preterm birth classification in a North Indian cohort.

BACKGROUND: Different formulae have been developed globally to estimate gestational age (GA) by ultrasonography in the first trimester of pregnancy. In this study, we develop an Indian population-specific dating formula and compare its performance with published formulae. Finally, we evaluate the implications of the choice of dating method on preterm birth (PTB) rate. This study's data was from GARBH-Ini, an ongoing pregnancy cohort of North Indian women to study PTB. METHODS: Comparisons between ultrasonography-Hadlock and last menstrual period (LMP) based dating methods were made by studying the distribution of their differences by Bland-Altman analysis. Using data-driven approaches, we removed data outliers more efficiently than by applying clinical parameters. We applied advanced machine learning algorithms to identify relevant features for GA estimation and developed an Indian population-specific formula (Garbhini-GA1) for the first trimester. PTB rates of Garbhini-GA1 and other formulae were compared by estimating sensitivity and accuracy. RESULTS: Performance of Garbhini-GA1 formula, a non-linear function of crown-rump length (CRL), was equivalent to published formulae for estimation of first trimester GA (LoA, - 0.46,0.96 weeks). We found that CRL was the most crucial parameter in estimating GA and no other clinical or socioeconomic covariates contributed to GA estimation. The estimated PTB rate across all the formulae including LMP ranged 11.27-16.50% with Garbhini-GA1 estimating the least rate with highest sensitivity and accuracy. While the LMP-based method overestimated GA by 3 days compared to USG-Hadlock formula; at an individual level, these methods had less than 50% agreement in the classification of PTB. CONCLUSIONS: An accurate estimation of GA is crucial for the management of PTB. Garbhini-GA1, the first such formula developed in an Indian setting, estimates PTB rates with higher accuracy, especially when compared to commonly used Hadlock formula. Our results reinforce the need to develop population-specific gestational age formulae.

Vaginal Microbiome of Pregnant Indian Women: Insights into the Genome of Dominant Lactobacillus Species.

The trillions of microorganisms residing in the human body display varying degrees of compositional and functional diversities within and between individuals and contribute significantly to host physiology and susceptibility to disease. Microbial species present in the vaginal milieu of reproductive age women showed a large personal component and varies widely in different ethnic groups at the taxonomic, genomic, and functional levels. Lactobacillus iners, L. crispatus, L. gasseri, L. jensenii, and L. johnsonii are most frequently detected bacterial species in the vaginal milieu of reproductive age women. However, we currently lack (i) an understanding of the baseline vaginal microbiota of reproductive age Indian women, (ii) the extent of taxonomic and functional variations of vaginal microbiota between individuals and (iii) the genomic repertoires of the dominant vaginal microbiota associated with the Indian subjects. In our study, we analyzed the metagenome of high vaginal swab (HVS) samples collected from 40 pregnant Indian women enrolled in the GARBH-Ini cohort. Composition and abundance of bacterial species was characterized by pyrosequencing 16S rRNA gene. We identified 3067 OTUs with ≥ 10 reads from four different bacterial phyla. Several species of lactobacilli were clustered into three community state types (CSTs). L. iners, L. crispatus, L. gasseri, and L. jensenii are the most frequently detected Lactobacillus species in the vaginal environment of Indian women. Other than Lactobacillus, several species of Halomonas were also identified in the vaginal environment of most of the women sampled. To gain genomic and functional insights, we isolated several Lactobacillus species from the HVS samples and explored their whole genome sequences by shotgun sequencing. We analyzed the genome of dominant Lactobacillus species, L. iners, L. crispatus, L. gasseri, and L. paragesseri to represent the CSTs and identify functions that may influence the composition of complex vaginal microbial ecology. This study reports for the first time the vaginal microbial ecology of Indian women and genomic insights into L. iners, L. crispatus, L. gasseri, and L. paragesseri commonly found in the genital tract of reproductive age women.

EFFECT OF GLUTEN-FREE DIET ON METABOLIC CONTROL AND ANTHROPOMETRIC PARAMETERS IN TYPE 1 DIABETES WITH SUBCLINICAL CELIAC DISEASE: A RANDOMIZED CONTROLLED TRIAL.

Objective: It is unclear whether the institution of gluten-free diet (GFD) is beneficial in patients with type 1 diabetes (T1DM) and subclinical celiac disease (CD). Our primary objective was to evaluate the effect of GFD on the frequency of hypoglycemia, in patients with T1DM and subclinical CD. Our secondary objective was to investigate the effect of GFD on height, weight, glycosylated hemoglobin (HbA1c), insulin dose requirement, and bone mineral homeostasis. Methods: We carried out a prospective open label randomized controlled trial (RCT). Patients with T1DM and subclinical CD were randomized to receive GFD or a normal diet for 1 year. The primary outcome was the frequency of hypoglycemic episodes (blood glucose <70 mg/dL) measured by self-monitoring of blood glucose (SMBG) at the sixth month of the study in the 2 groups. Results: Screening for CD was carried out in 320 T1DM patients. Thirty eligible patients were randomized to receive GFD (n = 15) or a normal diet (n = 15). The mean number of hypoglycemic episodes/month recorded by SMBG and the mean time spent in hypoglycemia measured by CGM (minutes) in the GFD group versus the non-GFD group at six months was 2.3 minutes versus 3.4 minutes (P = .5) and 124.1 minutes versus 356.9 minutes (P = .1), respectively. The mean number of hypoglycemic episodes/month significantly declined in the GFD group (3.5 episodes at baseline versus 2.3 episodes at the sixth month; P = .03). The mean HbA1c declined by 0.73% in the GFD group and rose by 0.99% in non-GFD group at study completion. Conclusion: This is the first RCT to assess the effect of GFD in T1DM and subclinical CD. A trend towards a decrease in hypoglycemic episodes and better glycemic control was seen in patients receiving GFD. Abbreviations: BMC = bone mineral content; BMI = body mass index; CD = celiac disease; CGM = continuous glucose monitoring; GFD = gluten-free diet; Hb = hemoglobin; HbA1c = glycosylated hemoglobin; iPTH = intact parathyroid hormone; RCT = randomized controlled trial; SMBG = self-monitoring of blood glucose; T1DM = type 1 diabetes mellitus; tTG-IgA = tissue transglutaminase immunoglobulin A.

A Pregnancy Cohort to Study Multidimensional Correlates of Preterm Birth in India: Study Design, Implementation, and Baseline Characteristics of the Participants.

Globally, preterm birth is a major public health problem. In India, 3.6 million of the 27 million infants born annually are preterm. Risk stratification of women based on multidimensional risk factors assessed during pregnancy is critical for prevention of preterm birth. A cohort study of pregnant women was initiated in May 2015 at the civil hospital in Gurugram, Haryana, India. Women are enrolled within 20 weeks of gestation and are followed until delivery and once postpartum. The objectives are to identify clinical, epidemiologic, genomic, epigenomic, proteomic, and microbial correlates; discover molecular-risk markers by using an integrative -omics approach; and generate a risk-prediction algorithm for preterm birth. We describe here the longitudinal study design, methodology of data collection, and the repositories of data, biospecimens, and ultrasound images being created. A total of 4,326 pregnant women, with documented evidence of recruitment before 20 weeks of gestation, have been enrolled through March 2018. We report baseline characteristics and outcomes of the first 2,000 enrolled participants. A high frequency of preterm births (14.9% among 1,662 live births) is noteworthy. The cohort database and the repositories will become global resources to answer critical questions on preterm birth and other birth outcomes.

Characterization of a Novel POU1F1 Mutation Identified on Screening 160 Growth Hormone Deficiency Patients.

The objective of the study is the functional characterization of a novel POU1F1 c.605delC mutation in combined pituitary hormone deficiency (CPHD) and to report the clinical and genetic details of 160 growth hormone deficiency patients. Screening of GH1, GHRHR, POU1F1, PROP1, and HESX1 genes by Sanger sequencing was carried out in 160 trios and 100 controls followed by characterization of the POU1F1 c.605delC mutation by expression studies including site directed mutagenesis, co-transfection, protein degradation, and luciferase assays to compare the wild type and mutant POU1F1. In vitro studies showed that the POU1F1 c.605delC mutation codes for a truncated protein with reduced transactivation capacity on its downstream effectors, viz., growth hormone (GH) and prolactin (PRL) causing severe CPHD. Experiments using different protease inhibitors reveal rescue of the protein upon blockage of the lysosomal pathway that might be useful in novel drug designing using targeted approach thereby maintaining the milieu and preventing/delaying the disease. The study provides an insight into the disease causing mechanism of POU1F1 c.605delC mutation identified in a CPHD child with severe short stature and failure to thrive. It also shows mutation effect on the expression, function and turnover of protein and highlights mechanistic details by which these potent regulators may operate.

Predictors of death in infants with probable serious bacterial infection.

BackgroundBacterial infections account for a significant proportion of neonatal and infant mortality globally. We aimed to identify predictors of death in infants with probable serious bacterial infection (PSBI) defined as signs/symptoms of possible serious bacterial infection along with baseline C-reactive protein (CRP) ≥12 mg/l.MethodsWe did a secondary analysis using the data collected from 700 infants with PSBI who participated in a randomized controlled trial in India in which zinc or placebo was given in addition to the standard antibiotics. Logistic regression was used to estimate the associations between relevant variables and death within 21 days.ResultsThose infants who were fed cow's milk or formula before the illness episode had 3.7-fold (95% confidence interval (CI) 1.5-9.3) and 5.3-fold (95% CI 2.0-13.6) higher odds of death, respectively. Lethargy (odds ratio (OR) 2.4, 95% CI 1.1-5.4) and CRP (OR 1.9, 95% CI 1.1-3.3) were also independent predictors of death. In the model including only clinical features, female gender (OR 2.25, 95% CI 1.0-5.0), abdominal distention (3.7, 95% CI 1.1-12.3), and bulging fontanelle (5.8, 95% CI 1.1-30.5) were also independent predictors for death.ConclusionFormula or cow milk feeding prior to the illness, lethargy at the time of presentation, and high serum CRP levels predicted death in infants with PSBI.

Interaction of CD80 with Neph1: a potential mechanism of podocyte injury.

BACKGROUND: The induction of CD80 on podocytes has been shown in animal models of podocyte injury and in certain cases of nephrotic syndrome. In a lipopolysaccharide (LPS)-induced mouse model of albuminuria, we have recently shown a signalling axis of LPS-myeloid cell activation-TNFα production-podocyte CD80 induction-albuminuria. Therefore, in this report, we investigated the cellular and molecular consequences of TNFα addition and CD80 expression on cultured podocytes. METHODS: A murine podocyte cell line was used for TNFα treatment and for over-expressing CD80. Expression and localization of various podocyte proteins was analysed by reverse transcriptase-polymerase chain reaction, western blotting and immunofluorescence. HEK293 cells were used to biochemically characterize interactions. RESULTS: Podocytes treated with LPS in vitro did not cause CD80 upregulation but TNFα treatment was associated with an increase in CD80 levels, actin derangement and poor wound healing. Podocytes stably expressing CD80 showed actin derangement and co-localization with Neph1. CD80 and Neph1 interaction was confirmed by pull down assays of CD80 and Neph1 transfected in HEK293 cells. CONCLUSION: Addition of TNFα to podocytes causes CD80 upregulation, actin reorganization and podocyte injury. Overexpressed CD80 and Neph1 interact via their extracellular domain. This interaction implies a mechanism of slit diaphragm disruption and possible use of small molecules that disrupt CD80-Neph1 interaction as a potential for treatment of nephrotic syndrome associated with CD80 upregulation.

Efficacy of Oral Zinc Supplementation in Radiologically Confirmed Pneumonia: Secondary Analysis of a Randomized Controlled Trial.

Objective: To evaluate the effect of zinc as an adjuvant therapy in radiologically confirmed pneumonia in children 2-24 months of age. Patients and Methods: We analyzed data of 212 children with pneumonia for whom chest X-ray films were available at enrollment and at least two radiologists agreed on the diagnosis of pneumonia. We compared the time to recovery in the two groups (n = 121, zinc group and n = 91, placebo group) using a Cox proportional hazards regression model. Results: Time to recovery was similar in both groups [median interquartile range: zinc, 84 h (64, 140 h); placebo, 85 h (65, 140 h)]. The absolute risk reduction for treatment failure was 5.2% (95% confidence interval: -4.8, 15.1) with zinc supplementation. Conclusion: There was no significant beneficial effect of zinc on the duration of recovery or risk of treatment failure in children with radiologically confirmed pneumonia.

Direct Detection of Rifampin and Isoniazid Resistance in Sputum Samples from Tuberculosis Patients by High-Resolution Melt Curve Analysis.

Drug-resistant tuberculosis (TB) is a major threat to TB control worldwide. Globally, only 40% of the 340,000 notified TB patients estimated to have multidrug-resistant-TB (MDR-TB) were detected in 2015. This study was carried out to evaluate the utility of high-resolution melt curve analysis (HRM) for the rapid and direct detection of MDR-TB in Mycobacterium tuberculosis in sputum samples. A reference plasmid library was first generated of the most frequently observed mutations in the resistance-determining regions of rpoB, katG, and an inhA promoter and used as positive controls in HRM. The assay was first validated in 25 MDR M. tuberculosis clinical isolates. The assay was evaluated on DNA isolated from 99 M. tuberculosis culture-positive sputum samples that included 84 smear-negative sputum samples, using DNA sequencing as gold standard. Mutants were discriminated from the wild type by comparing melting-curve patterns with those of control plasmids using HRM software. Rifampin (RIF) and isoniazid (INH) monoresistance were detected in 11 and 21 specimens, respectively, by HRM. Six samples were classified as MDR-TB by sequencing, one of which was missed by HRM. The HRM-RIF, INH-katG, and INH-inhA assays had 89% (95% confidence interval [CI], 52, 100%), 85% (95% CI, 62, 97%), and 100% (95% CI, 74, 100%) sensitivity, respectively, in smear-negative samples, while all assays had 100% sensitivity in smear-positive samples. All assays had 100% specificity. Concordance of 97% to 100% (κ value, 0.9 to 1) was noted between sequencing and HRM. Heteroresistance was observed in 5 of 99 samples by sequencing. In conclusion, the HRM assay was a cost-effective (Indian rupee [INR]400/US$6), rapid, and closed-tube method for the direct detection of MDR-TB in sputum, especially for direct smear-negative cases.

Development and evaluation of molecular methods for detection of Cryptosporidium spp. in human clinical samples.

Cryptosporidiosis is predominantly a gastrointestinal disease of humans and other animals, caused by various species of protozoan parasites representing the genus Cryptosporidium. Detection of Cryptosporidium spp. in human clinical samples is central to the prevention, surveillance and control of cryptosporidiosis, particularly given that there is presently no broadly applicable treatment regimen for this disease. A non-radioactive, genus specific DNA dot blot hybridization assay was developed using Digoxigenin (DIG) labelled probes to detect Cryptosporidium DNA in human clinical samples. Four hundred fifty (n = 450) clinical samples were subjected to microscopic examination, Polymerase Chain Reaction assay (PCR), Dot blot hybridization assay and Real Time PCR assay. A total of forty-one (n = 41) samples were positive by microscopy, forty-two (n = 42) by both PCR assay and dot blot hybridization assay and forty-three (n = 43) by Real Time PCR assay. Dot blot hybridization assay with a sensitivity of 95.5% and specificity of 99.75% could be an ideal choice for routine investigation of a large number of samples in a clinical setting as well as field.

Efficacy of stem cell in improvement of left ventricular function in acute myocardial infarction--MI3 Trial.

BACKGROUND & OBJECTIVES: Acute myocardial infarction (AMI) is characterized by irreparable and irreversible loss of cardiac myocytes. Despite major advances in the management of AMI, a large number of patients are left with reduced left ventricular ejection fraction (LVEF), which is a major determinant of short and long term morbidity and mortality. A review of 33 randomized control trials has shown varying improvement in left ventricular (LV) function in patients receiving stem cells compared to standard medical therapy. Most trials had small sample size and were underpowered. This phase III prospective, open labelled, randomized multicenteric trial was undertaken to evaluate the efficacy in improving the LVEF over a period of six months, after injecting a predefined dose of 5-10 × 10 [8] autologous mononuclear cells (MNC) by intra-coronary route, in patients, one to three weeks post ST elevation AMI, in addition to the standard medical therapy. METHODS: In this phase III prospective, multicentric trial 250 patients with AMI were included and randomized into stem cell therapy (SCT) and non SCT groups. All patients were followed up for six months. Patients with AMI having left ventricular ejection fraction (LVEF) of 20-50 per cent were included and were randomized to receive intracoronary stem cell infusion after successfully completing percutaneous coronary intervention (PCI). RESULTS: On intention-to-treat analysis the infusion of MNCs had no positive impact on LVEF improvement of ≥ 5 per cent. The improvement in LVEF after six months was 5.17 ± 8.90 per cent in non SCT group and 4.82 ± 10.32 per cent in SCT group. The adverse effects were comparable in both the groups. On post hoc analysis it was noted that the cell dose had a positive impact when infused in the dose of ≥ 5 X 10 [8] (n=71). This benefit was noted upto three weeks post AMI. There were 38 trial deviates in the SCT group which was a limitation of the study. INTERPRETATION & CONCLUSIONS: Infusion of stem cells was found to have no benefit in ST elevation AMI. However, the procedure was safe. A possible benefit was seen when the predefined cell dose was administered which was noted upto three weeks post AMI, but this was not significant and needs confirmation by larger trials.

Oral zinc supplements are ineffective for treating acute dehydrating diarrhoea in 5-12-year-olds.

AIM: Many countries have guidelines recommending the use of oral zinc in acute dehydrating diarrhoea in children aged 2 months to 5 years of age, but no guidelines exist for older children. This study tested how effective existing recommendations are in children from 5 to 12 years of age. METHODS: Children hospitalised with acute dehydrating diarrhoea (n = 134) were randomised to receive 40 mg of oral zinc sulphate tablets or a placebo for 14 days. The primary outcome variable was the time taken for diarrhoea to stop. Secondary outcome variables included time taken for rehydration, duration of hospitalisation and recurrence of diarrhoea in the next 3 months. RESULTS: The median time for resolution of diarrhoea was 60 h in both groups. The zinc group was marginally better, but not statistically significant, for resolution (hazard ratio = 0.89, 95% CI 0.63-1.24), rehydration (hazard ratio = 0.93, 95% CI 0.66-1.32) and hospitalisation (hazard ratio = 0.94, 95% CI 0.67-1.34). The risk ratio of recurrence for zinc versus placebo (95% CI) was 0.65 [0.37-1.23] [p = 0.11]. CONCLUSION: Daily zinc supplements (40 mg for 14 days) in children aged 5-12 years with acute dehydrating diarrhoea did not shorten the duration of diarrhoea or reduce subsequent episodes. Further adequately sized, community-based trials are needed.

Intravenous autologous bone marrow mononuclear stem cell therapy for ischemic stroke: a multicentric, randomized trial.

BACKGROUND AND PURPOSE: Pilot studies have suggested benefit from intravenous administration of bone marrow mononuclear stem cells (BMSCs) in stroke. We explored the efficacy and safety of autologous BMSCs in subacute ischemic stroke. METHODS: This was a phase II, multicenter, parallel group, randomized trial with blinded outcome assessment that included 120 patients. Patients with subacute ischemic stroke were randomly assigned to the arm that received intravenous infusion of autologous BMSCs or to control arm. Coprimary clinical efficacy outcomes were Barthel Index score and modified Rankin scale at day 180. Secondary outcomes were change in infarct volume, National Institute of Health Stroke Scale (NIHSS) at day 90 and 180. Main safety outcomes were adverse events, any new area of (18)fluorodeoxyglucose positron emission tomography uptake in any body part over 365 days. RESULTS: Fifty-eight patients received a mean of 280.75 million BMSCs at median of 18.5 days after stroke onset. There was no significant difference between BMSCs arm and control arm in the Barthel Index score (63.1 versus 63.6; P=0.92), modified Rankin scale shift analysis (P=0.53) or score >3 (47.5% versus 49.2%; P=0.85), NIHSS score (6.3 versus 7.0; P=0.53), change in infarct volume (-11.1 versus -7.36; P=0.63) at day 180. Adverse events were also similar in the 2 arms, and no patient showed any new area of (18)fluorodeoxyglucose uptake. CONCLUSIONS: With the methods used, results of this hitherto first randomized controlled trial indicate that intravenous infusion of BMSCs is safe, but there is no beneficial effect of treatment on stroke outcome. CLINICAL TRIAL REGISTRATION: URLs: http://ctri.nic.in/Clinicaltrials and http://www.clinicaltrials.gov. Unique identifiers: CTRI-ROVCTRI/2008/091/0004 and NCT0150177.

Vitamin D levels in Indian children with intrathoracic tuberculosis.

BACKGROUND & OBJECTIVES: Deficiency of vitamin D, an immunomodulator agent, is associated with increased susceptibility to tuberculosis in adults, but only limited studies are available in the paediatric age group, especially regarding association of vitamin D with type and outcome of tuberculosis. We conducted this study to determine the baseline 25-hydroxy vitamin D levels in children suffering from intrathoracic tuberculosis and its association with type and outcome of tuberculosis. METHODS: Children with intrathoracic tuberculosis, diagnosed on the basis of clinico-radiological criteria, were enrolled as part of a randomized controlled trial on micronutrient supplementation in paediatric tuberculosis patients. Levels of 25-hydroxy vitamin D were measured in serum samples collected prior to starting antitubercular therapy by chemiluminescent immunoassay technology. RESULTS: Two hundred sixty six children (mean age of 106.9 ± 43.7 months; 57.1% girls) were enrolled. Chest X-ray was suggestive of primary pulmonary complex, progressive disease and pleural effusion in 81 (30.5%), 149 (56%) and 36 (13.5%) subjects, respectively. Median serum 25-hydroxy vitamin D level was 8 ng/ml (IQR 5, 12). One hundred and eighty six (69.9%) children were vitamin D deficient (serum 25-hydroxy vitamin D <12 ng/ml), 55 (20.7%) were insufficient (12 to <20 ng/ml) and 25 (9.4%) were vitamin D sufficient (≥ 20 ng/ml). Levels of 25-hydroxy vitamin D were similar in all three types of intrathoracic tuberculosis, and in microbiologically confirmed and probable cases. Levels of 25-hydroxy vitamin D did not significantly affect outcome of the disease. Children who were deficient or insufficient were less likely to convert (become smear/culture negative) at two months as compared to those who were 25-hydroxy vitamin D sufficient ( p <0.05). INTERPRETATION & CONCLUSIONS: Majority of Indian children with newly diagnosed intrathoracic tuberculosis were deficient in vitamin D. Type of disease or outcome was not affected by 25-hydroxy vitamin D levels in these children. However, children who did not demonstrate sputum conversion after intensive phase of antitubercular therapy had lower baseline 25-hydroxy vitamin D levels as compared to those who did.

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).