Child Neurodevelopment After Multidomain Interventions From Preconception Through Early Childhood: The WINGS Randomized Clinical Trial.

Importance: Multidomain interventions in pregnancy and early childhood have improved child neurodevelopment, but little is known about the effects of additional preconception interventions. Objective: To evaluate the effect of a multifaceted approach including health; nutrition; water, sanitation, and hygiene (WASH); and psychosocial support interventions delivered during the preconception period and/or during pregnancy and early childhood on child neurodevelopment. Design, Setting, and Participants: In this randomized trial involving low- and middle-income neighborhoods in Delhi, India, 13 500 participants were assigned to preconception interventions or routine care for the primary outcome of preterm births and childhood growth. Participants who became pregnant were randomized to pregnancy and early childhood interventions or routine care. Neurodevelopmental assessments, the trial's secondary outcome reported herein, were conducted in a subsample of children at age 24 months, including 509 with preconception, pregnancy, and early childhood interventions; 473 with preconception interventions alone; 380 with pregnancy and early childhood interventions alone; and 350 with routine care. This study was conducted from November 1, 2000, through February 25, 2022. Interventions: Health, nutrition, psychosocial care and support, and WASH interventions delivered during preconception, pregnancy, and early childhood periods. Main Outcomes and Measures: Cognitive, motor, language, and socioemotional performance at age 24 months, assessed using the Bayley Scales of Infant and Toddler Development 3 tool. Results: The mean age of participants at enrollment was 23.8 years (SD, 3.0 years). Compared with the controls at age 24 months, children in the preconception intervention groups had higher cognitive scores (mean difference [MD], 1.16; 98.3% CI, 0.18-2.13) but had similar language, motor, and socioemotional scores as controls. Those receiving pregnancy and early childhood interventions had higher cognitive (MD, 1.48; 98.3% CI, 0.49-2.46), language (MD, 2.29; 98.3% CI, 1.07-3.50), motor (MD, 1.53; 98.3% CI, 0.65-2.42), and socioemotional scores (MD, 4.15; 98.3% CI, 2.18-6.13) than did controls. The pregnancy and early childhood group also had lower incidence rate ratios (RRs) of moderate to severe delay in cognitive (incidence RR, 0.62; 98.3% CI, 0.40-0.96), language (incidence RR, 0.73; 98.3% CI, 0.57-0.93), and socioemotional (incidence RR, 0.49; 98.3% CI, 0.24-0.97) development than did those in the control group. Children in the preconception, pregnancy, and early childhood intervention group had higher cognitive (MD, 2.60; 98.3% CI, 1.08-4.12), language (MD, 3.46; 98.3% CI, 1.65-5.27), motor (MD, 2.31; 98.3% CI, 0.93-3.69), and socioemotional (MD, 5.55; 98.3% CI, 2.66-8.43) scores than did those in the control group. Conclusions and Relevance: Multidomain interventions during preconception, pregnancy and early childhood led to modest improvements in child neurodevelopment at 24 months. Such interventions for enhancing children's development warrant further evaluation. Trial Registration: Clinical Trials Registry-India CTRI/2017/06/008908.

Impact of a package of health, nutrition, psychosocial support, and WaSH interventions delivered during preconception, pregnancy, and early childhood periods on birth outcomes and on linear growth at 24 months of age: factorial, individually randomised controlled trial.

OBJECTIVE: To determine the effect of integrated and concurrent delivery of health, nutrition, water, sanitation and hygiene (WaSH), and psychosocial care interventions during the preconception period alone, during pregnancy and early childhood, and throughout preconception, pregnancy, and early childhood on birth outcomes and linear growth at 24 months of age compared with routine care. DESIGN: Individually randomised factorial trial. SETTING: Low and middle income neighbourhoods of Delhi, India. PARTICIPANTS: 13 500 women were randomised to receive preconception interventions (n=6722) or routine care (n=6778). 2652 and 2269 pregnant women were randomised again to receive pregnancy and early childhood interventions or routine care. The analysis of birth outcomes included 1290 live births for the preconception, pregnancy, and early childhood interventions (group A), 1276 for the preconception intervention (group B), 1093 for the pregnancy and early childhood interventions (group C), and 1093 for the control (group D). Children aged 24 months by 30 June 2021 were included in the 24 month outcome analysis (453 in group A, 439 in B, 293 in C, and 271 in D). INTERVENTIONS: Health, nutrition, psychosocial care and support, and WaSH interventions were delivered during preconception, pregnancy, and early childhood periods. MAIN OUTCOME MEASURES: The primary outcomes were low birth weight, small for gestational age, preterm, and mean birth weight. At 24 months, the outcomes were mean length-for-age z scores and proportion stunted. Three prespecified comparisons were made: preconception intervention groups (A+B) versus no preconception intervention groups (C+D); pregnancy and early childhood intervention groups (A+C) versus routine care during pregnancy and early childhood (B+D) and preconception, pregnancy, and early childhood interventions groups (A) versus control group (D). RESULTS: The proportion with low birth weight was lower in the preconception intervention groups (506/2235) than in the no preconception intervention groups (502/1889; incidence rate ratio 0.85, 98.3% confidence interval 0.75 to 0.97; absolute risk reduction -3.80%, 98.3% confidence interval -6.99% to -0.60%). The proportion with low birth weight was lower in the pregnancy intervention groups (502/2096) than in the no pregnancy intervention groups (506/2028) but the upper limit of the confidence interval crossed null effect (0.87, 0.76 to 1.01; -1.71%, -4.96% to 1.54%). There was a larger effect on proportion with low birth weight in the group that received interventions in the preconception and pregnancy periods (267/1141) compared with the control group (267/934; 0.76, 0.62 to 0.91; -5.59%, -10.32% to -0.85%). The proportion stunted at 24 months of age was substantially lower in the pregnancy and early childhood intervention groups (79/746) compared with the groups that did not receive these interventions (136/710; 0.51, 0.38 to 0.70; -8.32%, -12.31% to -4.32%), and in the group that received preconception, pregnancy, and early childhood interventions (47/453) compared with the control group (51/271; 0.49, 0.32 to 0.75; -7.98%, -14.24% to -1.71%). No effect on stunting at 24 months was observed in the preconception intervention groups (132/892) compared with the no preconception intervention groups (83/564). CONCLUSIONS: An intervention package delivered during preconception, pregnancy, and early childhood substantially reduced low birth weight and stunting at 24 months. Pregnancy and early childhood interventions alone had lower but important effects on birth outcomes and 24 month outcomes. Preconception interventions alone had an important effect on birth outcomes but not on 24 month outcomes. TRIAL REGISTRATION: Clinical Trial Registry-India CTRI/2017/06/008908.

Mid upper arm circumference as a predictor of risk of mortality in children in a low resource setting in India.

OBJECTIVE: In this secondary analysis of data from an intervention trial, we assessed the performance of Mid Upper Arm Circumference (MUAC) as a predictor of mortality in children aged 6-59 months from Delhi, India, one year after their initial MUAC measurements were taken. Additionally, we assessed MUAC as an absolute value and MUAC z-scores as predictors of risk of mortality. METHODS: In the trial, children were screened using MUAC prior to referral to the study clinic. These children were revisited a year later to ascertain their vital status. Baseline MUAC and MUAC z-scores were used to categorize children as severely (MUAC <115 mm, MUAC z-score <-3SD) or moderately (MUAC 115 to <125 mm, MUAC z-score <-2SD) malnourished. The proportion of malnutrition, risk of mortality, relative risk estimates, positive predictive value and area under the curve (AUC) by MUAC and MUAC z-scores were calculated. RESULTS: In the resurvey, the first 36159 children of the 48635 in the initial survey were contacted. Of these, vital status of 34060 (94.2%) was available. The proportion of severe malnutrition by MUAC (<115 mm) was 0.5% with an associated mortality of 4.7% over a one year period and an attributable mortality of 13% while the proportion of the severe malnutrition by MUAC z-score (<-3SDwas 0.9% with an associated mortality of 2.2%. CONCLUSIONS: MUAC is a significant predictor of subsequent mortality in under-five children. In settings where height measurement is not feasible, MUAC can be used as a screening tool for identifying severely malnourished children for management.

International network of cancer genome projects.

The International Cancer Genome Consortium (ICGC) was launched to coordinate large-scale cancer genome studies in tumours from 50 different cancer types and/or subtypes that are of clinical and societal importance across the globe. Systematic studies of more than 25,000 cancer genomes at the genomic, epigenomic and transcriptomic levels will reveal the repertoire of oncogenic mutations, uncover traces of the mutagenic influences, define clinically relevant subtypes for prognosis and therapeutic management, and enable the development of new cancer therapies.

Comparison of Ready-to-Use Therapeutic Food with cereal legume-based khichri among malnourished children.

OBJECTIVE: To compare the acceptability and energy intake of Ready-to-Use Therapeutic Food (RUTF) with cereal legume based khichri among malnourished children. DESIGN: An acceptability trial with cross-over design. SETTING: Urban low to middle socioeconomic neighbor-hoods in Delhi. SUBJECTS: 31 children aged > or =6 to < or =36 months with malnutrition, defined as Weight for height (WHZ) < -2 to > or = -3 SD, with no clinical signs of infection or edema. INTERVENTION: Children were offered weighed amounts of RUTF and khichri in unlimited amounts for 2 days, one meal of each on both days. Water was fed on demand. Caregivers interviews and observations were conducted on the second day. OUTCOME MEASURES: Acceptability of RUTF compared to khichri based on direct observation and energy intake for test and control meals. RESULTS: The proportion of children who accepted RUTF eagerly was 58% as against 77% for khichri. 42% children on RUTF and 23% on khichri accepted the meal but not eagerly. The median (IQR) energy intake over the two day period in children aged 6 to 36 months from RUTF was 305 (153, 534) kcal, and from khichri was 242 (150, 320) kcal (P=0.02). CONCLUSION: RUTF and khichri were both well accepted by study children. The energy intake from RUTF was higher due to its extra energy density.

Emergence of G12 rotavirus strains in Delhi, India, in 2000 to 2007.

The prospect that rotavirus diarrhea in children may soon be prevented by vaccines has placed a new priority on understanding the diversity of rotavirus strains and the mechanism by which these strains evolve over time. We have characterized a total of 465 rotavirus strains collected in North India from 2000 to 2007 for G and P types by reverse transcription-PCR and sequencing. The novel G12 rotavirus strains recently detected in other countries were first detected in India in 2001 and have emerged as the predominant strains in Delhi, India, during 2005 to 2007. While the VP7 sequence was highly homologous among G12 strains isolated in Delhi, suggesting recent emergence from a common ancestor, the strains had a diverse constellation of other gene segments, demonstrating substantial reassortment. For the entire period, the common rotavirus G types G1 (26%), G2 (25%), and G9 (14%) comprised 65% of the strains, and common P types, P[4] (19%), P[6] (22%), and P[8] (35%), comprised 76% of the total P types. Of note, we detected a high percentage of unusual (17%) strains and fecal specimens with mixed (12% G and 15% P) rotavirus infections having a variety of genomic constellations. For the first time, we identified two novel rotavirus strains with unusual G/P combinations, G2P[11] and G3P[11], in patients with diarrhea. The study highlights the great diversity among rotaviruses isolated from Indian children, the opportunity for genetic reassortment between strains, and the emergence of a novel G12 strain in our country. Due to the demonstrated effect of antigenic diversity on rotavirus vaccines, it will be important to continue careful monitoring of these strains as rotavirus vaccine programs are implemented in India.

First detection of G12 rotaviruses in newborns with neonatal rotavirus infection at all India Institute of Medical Sciences, New Delhi, India.

Rotavirus genotype G12 strains were detected for the first time among newborns with asymptomatic rotavirus infection (74% of 39 rotavirus strains isolated from the infected infants were genotype G12) in the nursery of the All India Institute of Medical Sciences during a period from 2005 to 2006. Sequence analysis of the VP7 genes from these neonatal strains indicated a high level of homology to other G12 strains reported worldwide, suggesting the recent emergence of these strains in humans. Such nosocomial infections of newborns represent a potential source of introduction of novel rotavirus serotypes into the community.

Polymorphism in L-selectin, E-selectin and ICAM-1 genes in Asian Indian pediatric patients with celiac disease.

Celiac disease (CD) follows an autoimmune course in which both genetic and environmental factors contribute to its development. A strong association with HLA class II molecules, predominantly HLA-DQ2, has been reported in most ethnic groups with CD. The aim of this study was to determine if genetic polymorphisms in L-selectin, E-selectin, and intercellular adhesion molecule-1 (ICAM-1) have any correlation with CD. We investigated 5 mutations, namely F206L in L-selectin, S128R and L554F in E-selectin, and G241R and K469E in ICAM-1, in 37 North Indian pediatric patients with CD. A significant increase in allele frequencies of 128R of E-selectin and the associated genotype SR was observed in patients. No significant differences were observed in the F206L polymorphism of L-selectin, or the G241R and E469K polymorphisms in the ICAM-1 gene in CD. This study illustrates that selectin gene polymorphism might contribute to the genetic background of CD and invites further investigation relevant to understanding the mechanisms underlying the immunopathogenesis of this autoimmune disease.

Quantitative evaluation of rotaviral antigenemia in children with acute rotaviral diarrhea.

BACKGROUND: Rotaviral antigen and RNA have recently been identified in the serum of patients with rotaviral gastroenteritis, but the roles they play in disease remains undetermined. METHODS: Rotaviral antigen and RNA were quantified by enzyme-linked immunosorbant assay and by quantitative reverse-transcription polymerase chain reaction in stool and serum specimens from children with rotaviral diarrhea (n=102), children with nonrotaviral diarrhea (n=40), and nondiarrheal control children (n=30). RESULTS: Rotaviral antigenemia was detected in 64%, 3%, and 0% of the children with rotaviral diarrhea, the children with nonrotaviral diarrhea, and the nondiarrheal control children, respectively. The level of rotaviral antigen in serum was approximately 2x10(2) -fold lower than that in stool, and a moderate correlation was observed between the 2 levels. Rotaviral RNA was detected in 93% of the antigen-positive serum specimens. The median number of RNA copies in serum was approximately 1 x 10(5) -fold lower than that in stool, and no correlation was observed between the 2 levels. Serum levels of both antigen and RNA were inversely associated with baseline titers of rotaviral serum immunoglobulin G (P<.01). Antigenemia was also associated with G1 serotype. CONCLUSIONS: Rotaviral antigenemia and viremia were common in children with rotaviral diarrhea, but antigen and RNA levels in serum were substantially lower than those in stool. Antigenemia was associated with infection with G1 strains and with low baseline titers of rotaviral serum antibody.

Safety and immunogenicity of two live attenuated human rotavirus vaccine candidates, 116E and I321, in infants: results of a randomised controlled trial.

We evaluated safety and immunogenicity of two orally administered human rotavirus vaccine candidates 116E and I321. Ninety healthy infants aged 8 weeks received a single dose of 116E (10(5)FFu (florescence focus units)), I321 (10(5)FFu) or placebo. There were no significant differences in the number of adverse events. Fever was reported by 6/30, 1/30 and 5/30 in the 116E, I321 and placebo groups; the corresponding figures for diarrhoea were 5/30, 8/29 and 3/30. Serum IgA seroconversion rates were 73%, 39% and 20% in the 116E, I321 and placebo groups, respectively. Vaccine virus was shed on days 3, 7 or 28 in 11/30 infants of the 116E and none in the other two groups. The 116E strain is attenuated, clinically safe and highly immunogenic with a single dose.

Typhoid and paratyphoid fever.

Typhoid fever is estimated to have caused 21.6 million illnesses and 216,500 deaths globally in 2000, affecting all ages. There is also one case of paratyphoid fever for every four of typhoid. The global emergence of multidrug-resistant strains and of strains with reduced susceptibility to fluoroquinolones is of great concern. We discuss the occurrence of poor clinical response to fluoroquinolones despite disc sensitivity. Developments are being made in our understanding of the molecular pathogenesis, and genomic and proteomic studies reveal the possibility of new targets for diagnosis and treatment. Further, we review guidelines for use of diagnostic tests and for selection of antimicrobials in varying clinical situations. The importance of safe water, sanitation, and immunisation in the presence of increasing antibiotic resistance is paramount. Routine immunisation of school-age children with Vi or Ty21a vaccine is recommended for countries endemic for typhoid. Vi vaccine should be used for 2-5 year-old children in highly endemic settings.

Incidence of severe rotavirus diarrhea in New Delhi, India, and G and P types of the infecting rotavirus strains.

A total of 62,475 children <5 years old from a defined population of approximately 500,000 children and adults from slums in New Delhi, India, were assessed for 1 year by means of passive surveillance, to identify children who were hospitalized for diarrhea. The incidence of severe rotavirus diarrhea was estimated, and the G and P types of the infecting rotavirus strains were determined and were correlated with the clinical severity of diarrhea. Of 584 children who were hospitalized with diarrhea, 137 (23.5%) had rotavirus detected in stool specimens (incidence of rotavirus diarrhea-associated hospitalizations, 337 hospitalizations/100,000 children <5 years of age). Most cases of diarrhea (98%) occurred during the first 2 years of life, peaking at 9-11 months of age. Rotavirus-associated diarrhea occurred year-round but was predominant in winter. Among the strains that could be G-typed, G1 was the most common serotype, followed by G9 and G2; 10% of cases of diarrhea were due to mixed G-type infections. Common strains identified in the present surveillance study were P[8]G1, P[4]G2, P[8]G9, P[6]G1, P[6]G9, and P[6]G3. Children infected with G1 strains had a greater risk of developing more-severe cases of diarrhea than did children infected with other rotavirus strains (odds ratio, 2.95; 95% confidence interval, 1.3-6.67).

Variability pattern and correlation studies in Silybum marianum Gaertn.

Phenotypic and genotypic coefficient of variability, heritability in broad sense and genetic advance were determined investigating the characters of 15 accessions of Silybum marianum. Seed yield/plant and number of capsules/plant had highest estimates of genotypic variation, heritability and genetic advance which suggest that direct selection for these traits is suitable for the improvement of this crop. Number of capsules/plant had a significant positive correlation with the number of branches/plant and leaf length (r=0.3398, 0.7547), whereas seed yield/plant had a positive significant correlation with leaf length, stem diameter, capsule diameter and silymarin content (r=0.6830, 0.3140, 0.3484, 0.2925).

Diffuse intra-abdominal fibromatosis-report of a new entity with review of literature.

Fibromatosis, arare non-neoplastic spindle cell proliferation of unknown aetiology, can occur anywhere in the body. Though extra-abdominal sites are commonly involved, intra-abdominal fibromatosis has also been described. Described herein is an unusual case of diffuse intra-abdominal fibromatosis in a 9-year-old boy, who could not be salvaged despite extensive medical management.

Possible role of neonatal infection with the asymptomatic reassortant rotavirus (RV) strain I321 in the decrease in hospital admissions for RV diarrhea, Bangalore, India, 1988-1999.

We sought to determine the proportion of rotavirus (RV) infections among children with severe diarrhea in Bangalore, India, and to determine the role of neonatal infection with the asymptomatic RV strain I321 in protection against subsequent RV diarrhea. At 2 major hospitals, there was a >42% decrease in diarrhea-specific admissions during the study period. At 6 hospitals, asymptomatic infections were found in 25%-50% of neonates, when screening was performed randomly, and in >58% of neonates, when screening was performed daily, with the majority of infections occurring within the first 7 days of life. All the RVs found in asymptomatic neonates were strain I321. A 24-month follow-up of a cohort of 44 children who had been neonatally infected with strain I321 and 28 children who had not (control group) revealed comparable rates of RV detection but a marked decrease in the number of RV diarrhea episodes in the strain I321-infected group (2.3%), compared with the control group (39.3%) (P<.0001). This preliminary study suggests a possible association between neonatal infection with strain I321 and protection against subsequent RV illness.

Zinc supplementation for four months does not affect plasma copper concentration in infants.

AIM: The aim of the present study, which was undertaken as a sub-study within a randomized controlled trial of zinc supplementation, was to evaluate the effect of prolonged zinc supplementation on copper status as assessed by hematological markers. METHODS: Plasma copper and zinc were estimated at baseline and after 120 d of supplementation in a randomly selected infant subset (115) of the children. Of these, 61 children were in a zinc group (Z) getting 10 mg of elemental zinc, and 54 were in a control group (C) getting supplement without zinc. RESULTS: Baseline plasma zinc was comparable in the two groups; post-supplementation zinc was significantly higher (Z 93.0 +/- 3.6 vs C 60.6 +/- 8.0) in the zinc supplementation group. There was no significant difference in the mean/median copper levels between the zinc and control groups. The percentage of children with plasma copper <100 microg/dl was also not significantly different between groups (baseline Z 14.8%, C 11.1%; post-supplementation Z 18.0%, C 11.1%). There were no differences between the zinc and control groups after 120 d of supplementation in hemoglobin (Hgb), mean corpuscular volume (MCV), mean corpuscular hemoglobin concentration (MCHC), or number of lymphocytes or granulocytes. CONCLUSION: Zinc supplementation of 10 mg/d for 4 mo in this study did not affect copper status, as assessed by plasma copper concentration and hematological parameters, diagnostics of copper deficiency.

Bacteriuria and urinary tract infections in malnourished children.

We prospectively examined the incidence of bacteriuria in malnourished patients between 6 months and 5 years of age. For each patient, a normally nourished control matched for age, sex, and presence of fever and diarrhea was included. Of 112 patients (65 boys), 55 had moderate and 57 had severe malnutrition; 43 had diarrhea and 35 had fever. Clean-catch and suprapubic urine specimens were examined microscopically and cultured. Significant bacteriuria was found in 17 (15.2%) malnourished and 2 (1.8%) control subjects ( P<0.01). The incidence of bacteriuria in malnourished and normally nourished subjects with fever was 28.6% and 5.7%, respectively ( P<0.05). The risk of bacteriuria increased significantly with the severity of malnutrition and in patients with diarrhea. Bacteriuria was associated with symptoms (70.6%) and elevated levels of acute-phase reactants (88.2%), indicating the presence of urinary tract infections (UTI) rather than asymptomatic colonization. Our observations show that malnourished children, particularly those with fever, are at risk for UTI. Urinalysis is useful for screening for UTI in these subjects. Urine culture should be performed in patients showing an abnormal urinalysis, and if the likelihood of detecting bacteriuria is high (as in patients with fever or diarrhea). Significant bacteriuria in malnourished subjects should be treated with appropriate antimicrobials.