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Oral rotavirus vaccines have consistently proven to be less immunogenic among infants in developing countries. Discrepancies in the intestinal microbiota, including a greater burden of enteropathogens and an altered commensal community composition, may contribute to this trend by inhibiting the replication of vaccine viruses. To test this possibility, we performed a nested case–control study in Vellore, India, in which we compared the intestinal microbiota of infants who responded serologically or not after two doses of Rotarix delivered at 6 and 10 weeks of age as part of a clinical trial (CTRI/2012/05/002677). The prevalence of 40 bacterial, viral, and eukaryotic pathogen targets was assessed in pre-vaccination stool samples from 325 infants using singleplex real-time PCR on a Taqman array card (TAC). In a subset of 170 infants, we assessed bacterial microbiota composition by sequencing the 16S rRNA gene V4 region. Contrary to expectations, responders were more likely than non-responders to harbor ≥1 bacterial enteropathogen at dose 1 (26% [40/156] vs 13% [21/157] of infants with TAC results who completed the study per protocol; χ2, P = .006), although this was not apparent at dose 2 (24% [38/158] vs 23% [36/158]; P = .790). Rotavirus shedding after dose 1 was negatively correlated with the replication of co-administered oral poliovirus vaccine (OPV). We observed no consistent differences in composition or diversity of the 16S bacterial microbiota according to serological response, although rotavirus shedding was associated with slightly more bacterial taxa pre-vaccination. Overall, our findings demonstrate an inhibitory effect of co-administered OPV on the first dose of Rotarix, consistent with previous studies, but in the context of OPV co-administration we did not find a strong association between other components of the intestinal microbiota at the time of vaccination and Rotarix immunogenicity.

•Oral rotavirus vaccines are less immunogenic and effective in low-income settings.•Infant gut microbiota and micronutrient status may contribute to this phenomenon.•We did a randomised controlled trial of probiotic and zinc supplementation in India.•Probiotic was associated with a modest (7.5%) improvement in vaccine immunogenicity.•Zinc supplementation (5mg/day) did not alter zinc status or vaccine immunogenicity. Strategies are needed to improve oral rotavirus vaccine (RV), which provides suboptimal protection in developing countries. Probiotics and zinc supplementation could improve RV immunogenicity by altering the intestinal microbiota and immune function. Infants 5weeks old living in urban Vellore, India were enrolled in a randomized, double-blind, placebo-controlled trial with a 4-arm factorial design to assess the effects of daily zinc (5mg), probiotic (1010Lactobacillus rhamnosus GG) or placebo on the immunogenicity of two doses of RV (Rotarix®, GlaxoSmithKline Biologicals) given at 6 and 10weeks of age. Infants were eligible for participation if healthy, available for the study duration and without prior receipt of RV or oral poliovirus vaccine other than the birth dose. The primary outcome was seroconversion to rotavirus at 14weeks of age based on detection of VP6-specific IgA at ≥20U/ml in previously seronegative infants or a fourfold rise in concentration. The study took place during July 2012 to February 2013. 620 infants were randomized equally between study arms and 551 (88.9%) completed per protocol. Seroconversion was recorded in 54/137 (39.4%), 42/136 (30.9%), 40/143 (28.0%), and 37/135 (27.4%) infants receiving (1) probiotic and zinc, (2) probiotic and placebo, (3) placebo and zinc, (4) two placebos. Seroconversion showed a modest improvement among infants receiving probiotic (difference between groups 1, 2 and 3, 4 was 7.5% (97.5% Confidence Interval (CI): −1.4%, 16.2%), p=0.066) but not zinc (difference between groups 1, 3 and 2, 4 was 4.4% (97.5% CI: −4.4%, 13.2%), p=0.272). 16 serious adverse events were recorded, none related to study interventions. Zinc or probiotic supplementation did not significantly improve the low immunogenicity of rotavirus vaccine given to infants in a poor urban community in India. A modest effect of combined supplementation deserves further investigation. The trial was registered in India (CTRI/2012/05/002677).

Interference from transplacental and breast milk antibodies may impede the performance of oral live vaccines. The effect of breastfeeding on the immunogenicity of Rotarix®, a two-dose oral monovalent rotavirus vaccine, was examined in a community-based trial in New Delhi, India. Four hundred mother–infant pairs were randomized into two equal groups. Infants were aged 6–7 weeks at enrollment. Mothers were encouraged to either breastfeed or to withhold breastfeeding during the 30min prior to and after each vaccine dose was administered. We collected blood specimens from infants at enrollment and 4 weeks after the second vaccine dose. Blood and breast milk specimens were obtained from mothers at baseline and breast milk specimens were collected at the time of the second vaccine dose. Seroconversion was defined as infant serum anti-VP6 IgA antibody level of ≥20IU/mL 4 weeks after the second vaccine dose and a ≥4-fold rise from baseline. There was no difference in the proportion who seroconverted between the two groups (26% vs 27%; p=0.92). The levels of infant serum IgA, maternal serum and breast milk IgA and IgG anti-rotavirus antibodies predicted the anti-rotavirus IgA level in infants at end-study and explained approximately 10% of the variability of the immune response (r2=0.10, p<0.001). In this population, the immune response to Rotarix® was not enhanced by withholding breastfeeding around the time of vaccination. Maternal anti-rotavirus antibodies explained little of the variability in the immune response to the vaccine. Factors other than maternal anti-rotavirus antibodies probably explain why infants in low-and middle-income settings respond poorly to live oral rotavirus vaccines.

Background. Cryptosporidium is a leading cause of moderate to severe childhood diarrhea in resource-poor settings. Understanding the natural history of cryptosporidiosis and the correlates of protection are essential to develop effective and sustainable approaches to disease control and prevention. Methods. Children (N = 497) were recruited at birth in semiurban slums in Vellore, India, and followed for 3 years with twice-weekly home visits. Stool samples were collected every 2 weeks and during diarrheal episodes were tested for Cryptosporidium species by polymerase chain reaction (PCR). Serum samples obtained every 6 months were evaluated for seroconversion, defined as a 4-fold increase in immunoglobulin G directed against Cryptosporidium gp15 and/or Cp23 antigens between consecutive sera. Results. Of 410 children completing follow-up, 397 (97%) acquired cryptosporidiosis by 3 years of age. PCR identified 1053 episodes of cryptosporidiosis, with an overall incidence of 0.86 infections per child-year by stool and serology. The median age for the first infection was 9 (interquartile range, 4–17) months, indicating early exposure. Although infections were mainly asymptomatic (693 [66%]), Cryptosporidium was identified in 9.4% of diarrheal episodes. The proportion of reinfected children was high (81%) and there was clustering of asymptomatic and symptomatic infections (P < .0001 for both). Protection against infection increased with the order of infection but was only 69% after 4 infections. Cryptosporidium hominis (73.3%) was the predominant Cryptosporidium species, and there was no species-specific protection. Conclusions. There is a high burden of endemic cryptosporidiosis in southern India. Clustering of infection is suggestive of host susceptibility. Multiple reinfections conferred some protection against subsequent infection.

Background Poor growth in early childhood has been considered irreversible after 2–3 years of age and has been associated with morbidity and mortality over the short-term and with poor economic and cognitive outcomes over the long-term. The MAL-ED cohort study was performed in eight low-income settings with the goal of evaluating relationships between the child’s environment and experience (dietary, illness, and pathogen exposure, among others) and their growth and development. The goal of this analysis is to determine whether there are differences in the factors associated with growth from 24 to 60 months using two different metrics. Methods Across six MAL-ED sites, 942 children had anthropometry data at 24 and 60 months, as well as information about socioeconomic status, maternal height, gut permeability (lactulose-mannitol z-score (LMZ)), dietary intake from 9 to 24 months, and micronutrient status. Anthropometric changes were in height- or weight-for-age z-score (HAZ, WAZ), their absolute difference from the growth standard median (HAD (cm), WAD (kg)), as well as recovery from stunting/underweight. Outcomes were modeled using multivariate regression. Results At 24 months, almost half of the cohort was stunted (45%) and 21% were underweight. Among those who were stunted at 24 months ( n  = 426), 185 (43%) were no longer stunted at 60 months. Most children increased their HAZ from 24 to 60 months (81%), whereas fewer (33%) had positive changes in their HAD. Linear regression models indicate that girls improved less than boys from 24 to 60 months (HAZ: -0.21 (95% CI -0.27, -0.15); HAD: -0.75 (-1.07, -0.43)). Greater intestinal permeability (higher LMZ) at 0–24 months was associated with lower relative and absolute changes from 24 to 60 months (HAZ: -0.10 (-0.16, -0.04); HAD: -0.47 (-0.73, -0.21)). Maternal height (per 10 cm) was positively associated with changes (HAZ: 0.09 (0.03, 0.15); HAD: 0.45 (0.15, 0.75)). Similar relationships were identified for changes in WAZ and WAD. Conclusions The study children demonstrated improved growth from 24 to 60 months of age, but only a subset had positive changes in HAD and WAD. The same environmental factors were associated with growth from 24 to 60 months regardless of metric used (change in HAZ or HAD, or WAZ and WAD).

The purpose of this systematic review was to examine the evidence for the use of the Iowa Oral Performance Instrument (IOPI) to measure strength and endurance of the tongue and hand in healthy populations and those with medical conditions. A systematic search of the scientific literature published since 1991 yielded 38 studies that addressed this purpose. The IOPI was used primarily for tongue strength (38 studies) and endurance (15 studies) measurement; relatively few studies measured hand strength (9 studies) or endurance (6 studies). The majority of the studies identified used the IOPI as an evaluation tool, although four used it as an intervention tool. Half the studies were conducted in healthy people, primarily adults. Most of the other participants had disorders with dysphagia, primarily Parkinson’s disease or head or neck cancer. Age and gender, as well as a number of medical conditions, influence the values of tongue and hand strength. There is sufficient evidence to support the use of the IOPI as a suitable tool for measuring tongue strength and endurance and as an assessment tool for intervention studies, and there is growing support for its use to assess hand strength and endurance in healthy and clinical populations.

The assessment of asthma control is pivotal to the evaluation of treatment response in individuals and in clinical trials. Previously, asthma control, severity, and exacerbations were defined and assessed in many different ways. The Task Force was established to provide recommendations about standardization of outcomes relating to asthma control, severity, and exacerbations in clinical trials and clinical practice, for adults and children aged 6 years or older. A narrative literature review was conducted to evaluate the measurement properties and strengths/weaknesses of outcome measures relevant to asthma control and exacerbations. The review focused on diary variables, physiologic measurements, composite scores, biomarkers, quality of life questionnaires, and indirect measures. The Task Force developed new definitions for asthma control, severity, and exacerbations, based on current treatment principles and clinical and research relevance. In view of current knowledge about the multiple domains of asthma and asthma control, no single outcome measure can adequately assess asthma control. Its assessment in clinical trials and in clinical practice should include components relevant to both of the goals of asthma treatment, namely achievement of best possible clinical control and reduction of future risk of adverse outcomes. Recommendations are provided for the assessment of asthma control in clinical trials and clinical practice, both at baseline and in the assessment of treatment response. The Task Force recommendations provide a basis for a multicomponent assessment of asthma by clinicians, researchers, and other relevant groups in the design, conduct, and evaluation of clinical trials, and in clinical practice.

Schistosomiasis is endemic to Malawi, where preventive chemotherapy by mass drug administration (MDA) has been the foundational public health strategy for over a decade. Despite ongoing control, our understanding of the contemporary epidemiology of schistosomiasis in rural Malawi is limited to infrequent school-based surveys, typically lacking evidence from community-based surveys particularly within non-lakeshore upland communities who may be perceived to be at lower risk. Between July and August 2022, we conducted a cross-sectional parasitological survey amongst a community-representative sub-sample of boys aged 10-15 years who had been randomly selected and recruited to the DeWorm3 endline survey in Namwera, Mangochi District. A total of 306 participants from 38 communities were assessed for S. mansoni by duplicate Kato-Katz thick smears. Of these, 243 (79.4%) subsequently provided a urine sample to be assessed by filtration for S. haematobium and 238 (77.8%) responded to a risk-factor questionnaire. A parallel malacological survey of eight locally important water contact sites was conducted. The overall prevalence of egg-patent schistosomiasis was 50.6% (95% CI 44.2-57.1). The prevalence of S. haematobium was 47.7% (95% CI 41.3-54.2), of which 37.9% (n=44) were heavy intensity infections whereas the prevalence of S. mansoni was 6.5% (95% CI 4.0-9.9), with one moderate intensity infection (0.3%). There was strong evidence of a positive association between detected S. haematobium infection and reporting \"red urine\" (p<0.001) and 'bilharzia' (p=0.005). Biomphalaria spp. were found at two sites while Bulinus spp. were found at five sites. Despite multiple years of MDA at reportedly high coverage, we observed a high egg-patent prevalence with high prevalence of heavy intensity infections amongst boys aged 10-15 years. This evidences engrained and ongoing transmission requiring additional efforts to gain and sustain effective control. Our findings highlight the importance of epidemiological monitoring alongside a schistosomiasis control programme, particularly in areas historically perceived to be at lower risk.

Mixia osmundae (Basidiomycota, Pucciniomycotina) represents a monotypic class containing an unusual fern pathogen with incompletely understood biology. We sequenced and analyzed the genome of M. osmundae, focusing on genes that may provide some insight into its mode of pathogenicity and reproductive biology. Mixia osmundae has the smallest plant pathogenic basidiomycete genome sequenced to date, at 13.6 Mb, with very few repeats, high gene density, and relatively few significant gene family gains. The genome shows that the yeast state of M. osmundae is haploid and the lack of segregation of mating genes suggests that the spores produced on Osmunda spp. fronds are probably asexual. However, our finding of a complete complement of mating and meiosis genes suggests the capacity to undergo sexual reproduction. Analyses of carbohydrate active enzymes suggest that this fungus is a biotroph with the ability to break down several plant cell wall components. Analyses of publicly available sequence data show that other Mixia members may exist on other plant hosts and with a broader distribution than previously known.