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Abstract Background Diarrhea is the third leading infectious cause of death worldwide and is estimated to be responsible for approximately 2 million deaths a year. While many infectious causes of diarrhea have been established, approximately 40% of all diarrhea cases are of unknown etiology. In an effort to identify novel viruses that may be causal agents of diarrhea, we used high throughput mass sequencing to analyze stool samples collected from patients with acute diarrhea. Results Sequences with limited similarity to known picornaviruses were detected in a stool sample collected in Australia from a child with acute diarrhea. Using a combination of mass sequencing, RT-PCR, 5' RACE and 3' RACE, a 6383 bp fragment of the viral genome was sequenced. Phylogenetic analysis demonstrated that this virus was highly divergent from, but most closely related to, members of the genus Kobuvirus. We have tentatively named this novel virus klassevirus 1. We also detected klassevirus 1 by RT-PCR in a diarrhea specimen collected from a patient in St. Louis, United States as well as in untreated sewage collected in Barcelona, Spain. Conclusion Klassevirus 1 is a previously undescribed picornavirus that is globally widespread and present on at least three continents. Further investigations to determine whether klassevirus 1 is a human pathogen are needed.

Abstract Diarrhea, the third leading infectious cause of death worldwide, causes approximately 2 million deaths a year. Approximately 40% of these cases are of unknown etiology. We previously developed a metagenomic strategy for identification of novel viruses from diarrhea samples. By applying mass sequencing to a stool sample collected in Melbourne, Australia from a child with acute diarrhea, one 395 bp sequence read was identified that possessed only limited identity to known picornaviruses. This initial fragment shared only 55% amino acid identity to its top BLAST hit, the VP3 protein of Theiler's-like virus, suggesting that a novel picornavirus might be present in this sample. By using a combination of mass sequencing, RT-PCR, 5' RACE and 3' RACE, 6562 bp of the viral genome was sequenced, which includes the entire putative polyprotein. The overall genomic organization of this virus was similar to known picornaviruses. Phylogenetic analysis of the polyprotein demonstrated that the virus was divergent from previously described picornaviruses and appears to belong to the newly proposed picornavirus genus, Cosavirus. Based on the analysis discussed here, we propose that this virus represents a new species in the Cosavirus genus, and it has tentatively been named Human Cosavirus E1 (HCoSV-E1).

Abstract Background Astroviruses infect a variety of mammals and birds and are causative agents of diarrhea in humans and other animal hosts. We have previously described the identification of several sequence fragments with limited sequence identity to known astroviruses in a stool specimen obtained from a child with acute diarrhea, suggesting that a novel virus was present. Results In this study, the complete genome of this novel virus isolate was sequenced and analyzed. The overall genome organization of this virus paralleled that of known astroviruses, with 3 open reading frames identified. Phylogenetic analysis of the ORFs indicated that this virus is highly divergent from all previously described animal and human astroviruses. Molecular features that are highly conserved in human serotypes 1–8, such as a 3'NTR stem-loop structure and conserved nucleotide motifs present in the 5'NTR and ORF1b/2 junction, were either absent or only partially conserved in this novel virus. Conclusion Based on the analyses described herein, we propose that this newly discovered virus represents a novel species in the family Astroviridae. It has tentatively been named Astrovirus MLB1.

Among 1316 rotavirus specimens collected during strain surveillance in the United States from 1996 to 1999, most strains (95%) belonged to the common types (G1 to G4 and G9), while 5% were mixed infections of common serotypes, rare strains, or not completely typeable. In this report, 2 rare (P[9],G3) and 2 partially typeable (P[6],G?; P[9],G?) strains from that study were further characterized. The P[6] strain was virtually indistinguishable by hybridization analysis in 10 of its 11 gene segments with recently isolated P2A[6],G9 strains (e.g., U.S.1205) from the United States, but had a distinct VP7 gene homologous (94.7% aa and 90.2% nt) to the cognate gene from P1B[4],G12 reference strain L26. Thus, this serotype P2A[6],G12 strain represents a previously unrecognized reassortant. Three P3[9] strains were homologous (97.8–98.2% aa) in the VP8 region of VP4 to the P3[9],G3 feline-like reference strain AU-1, but had a high level of genome homology to Italian bovine-like, P3[9],G3 and P3[9],G6 rotavirus strains. Two of the U.S. P3[9] strains were confirmed to be type G3 (97.2–98.2% VP7 aa homology with reference G3 strain AU-1), while the other was most similar to Italian bovine-like strain PA151 (P3[9],G6), sharing 99.0% aa homology in VP7. Cross-neutralization studies confirmed all serotype assignments and represented the first detection of these rotavirus serotypes in the United States. The NSP4 genes of all U.S. P3[9] strains and rotavirus PA151 were most closely related to the bovine and equine branch within the DS-1 lineage, consistent with an animal origin. These results demonstrate that rare strains with P and G serotypes distinct from those of experimental rotavirus vaccines circulate in the United States, making it important to understand whether current vaccine candidates protect against these strains. [Copyright &y& Elsevier]

Large-scale Randomised Controlled Trials (RCTs) are widely regarded as "the gold standard" for testing the causal effects of school-based interventions. RCTs typically present the statistical significance of the average treatment effect (ATE), which captures the effect an intervention has had on average for a given population. However, key decisions in child health and education are often about individuals who may be very different from those averages. One way to identify heterogeneous treatment effects across different individuals, not captured by the ATE, is to conduct subgroup analyses. For example, free school meal (FSM) pupils as required for projects funded by the Education Endowment Foundation (EEF) in England. These subgroup analyses, as we demonstrate in 48 EEF-funded RCTs involving over 200,000 students, are usually not standardised across studies and offer flexible degrees of freedom to researchers, potentially leading to mixed, if not misleading, results. Here, we develop and deploy an alternative to ATE and subgroup analysis, a machine-learning and regression-based framework to predict individualised treatment effects (ITEs). ITEs could show where an intervention worked, for which individuals, and to what extent. Our findings have implications for decision-makers in fields like education, healthcare, law, and clinical practices concerning children and adolescents., (© 2024. The Author(s).)

Purpose: Despite potential benefits of intravenous (i.v.) administration of acetaminophen (APAP), consistent outcome data are lacking. This, combined with the higher acquisition cost of the drug, has led to variation in i.v. APAP management strategies. This project evaluated the contemporary formulary status and restrictions of i.v. APAP in the perioperative setting. Methods: A survey focusing on i.v. APAP formulary restriction in the perioperative setting was developed by the Vizient Pharmacy Research Committee and distributed to Vizient Pharmacy Program participant listservs for Pharmacy Directors or Drug Information Pharmacists. The four survey domains included hospital characteristics, perioperative i.v. APAP formulary status and prescribing restrictions, perioperative i.v. APAP use, and perioperative i.v. APAP medication use evaluation (MUE) results. Responses were collected and summarized, and primary outcomes were evaluated using Fisher's exact test. Results: A total of 1195 surveys were distributed with a response rate of 19%. Respondents were equally distributed between academic medical centers (AMC) and non-academic medical centers (non-AMC). Two cohorts were examined: those with i.v. APAP on formulary and those without. The non-AMCs showed a larger proportion of hospitals with the medication on formulary ( P  = .041). Regarding formulary decision-making, the AMCs were more considerate of value. Several different practices were employed to limit or restrict i.v. APAP. Conclusion: A survey of directors of pharmacy and drug information specialists revealed that the majority of hospitals have i.v. APAP on formulary for perioperative use, but use is restricted. Differences in i.v. APAP formulary practices between AMCs and non-AMCs warrant further consideration., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2020.)

Competing Interests: JPB declares no competing interests. CK reports a patent Rv3 rotavirus vaccine issued (PCT/AU2013/000945).

Introduction: Rotavirus vaccines were introduced into the Australian National Immunisation Program in 2007. Despite this, Northern Territory Indigenous children continue to be hospitalised with rotavirus at a rate more than 20 times higher than non-Indigenous children in other Australian jurisdictions, with evidence of waning protection in the second year of life. We hypothesised that scheduling an additional (third) dose of oral human rotavirus vaccine (Rotarix, GlaxoSmithKline) for children aged 6 to <12 months would improve protection against clinically significant all-cause gastroenteritis., Methods and Analysis: This Bayesian adaptive clinical trial will investigate whether routinely scheduling an additional dose of Rotarix for Australian Indigenous children aged 6 to <12 months old confers significantly better protection against clinically important all-cause gastroenteritis than the current two-dose schedule at 2 and 4 months old. There are two coprimary endpoints: (1) seroconversion from baseline serum anti-rotavirus immunoglobulin A (IgA) titre <20 U/mL prior to an additional dose of Rotarix/placebo to serum anti-rotavirus IgA titre >20 U/mL following the administration of the additional dose of Rotarix/placebo and (2) time from randomisation to medical attendance (up to age 36 months old) for which the primary reason is acute gastroenteritis/diarrhoea. Secondary endpoints include the change in anti-rotavirus IgA log titre, time to hospitalisation for all-cause diarrhoea and for rotavirus-confirmed gastroenteritis/diarrhoea, and rotavirus notification. Analysis will be based on Bayesian inference with adaptive sample size., Ethics, Registration and Dissemination: Ethics approval has been granted by Central Australian Human Research Ethics Committee (HREC-16-426) and Human Research Ethics Committee of the Northern Territory Department of Health and Menzies School of Health Research (HREC-2016-2658). Study investigators will ensure the trial is conducted in accordance with the principles of the Declaration of Helsinki and with the ICH Guidelines for Good Clinical Practice. Individual participant consent will be obtained. Results will be disseminated via peer-reviewed publication. The trial is registered with Clinicaltrials.gov (NCT02941107) and important modifications to this protocol will be updated., Trial Registration Number: NCT02941107; Pre-results., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Rotavirus vaccines have been introduced into over 95 countries globally and demonstrate substantial impact in reducing diarrheal mortality and diarrheal hospitalizations in young children. The vaccines are also considered by WHO as "very cost effective" interventions for young children, particularly in countries with high diarrheal disease burden. Yet the full potential impact of rotavirus immunization is yet to be realized. Large countries with big birth cohorts and where disease burden is high in Africa and Asia have not yet implemented rotavirus vaccines at all or at scale. Significant advances have been made demonstrating the impact of the vaccines in low- and lower-middle income countries, yet the modest effectiveness of the vaccines in these settings is challenging. Current research highlights these challenges and considers alternative strategies to overcome them, including alternative immunization schedules and host factors that may inform us of new opportunities.

Background: Acute diarrhoeal disease caused by viral, bacterial and parasitic infections is a major global health problem; in low- and middle-income countries (LMICs) it is associated with substantial mortality and morbidity in children under 5. Some of these infections also impact large segments of populations in high-income countries (HICs), as well as individuals who travel overseas for work, business or pleasure., Aims: The aim of this review is to describe the current landscape of licensed enteric vaccines, potential new vaccines on the horizon, and the challenges of development and utilization of vaccines against enteric pathogens., Sources: Relevant data from the literature, as well as clinical trials described in European and US registries, were examined in the conduct of this review., Content: The review involves discussion of current licensed vaccines against rotavirus, cholera and typhoid, as well as potential second- and third-generation vaccines against these pathogens currently in the development pipeline. In addition, novel vaccines against enterotoxigenic Escherichia coli, shigellosis and norovirus in advanced development are described. Challenges to the development and utilization of global vaccines are discussed., Implications: Despite advances in population health, food security, improved sanitation and water quality, and the reduction in poverty, acute enteric infections continue to plague global populations. Advancing utilization of current enteric vaccines is of critical public health importance, as is the development of new vaccines, particularly for enteric pathogens where none currently exist., (Copyright © 2018. Published by Elsevier Ltd.)

Predictive mapping of indoor radon potential often requires the use of additional datasets. A range of geological, geochemical and geophysical data may be considered, either individually or in combination. The present work is an evaluation of how much of the indoor radon variation in south west England can be explained by four different datasets: a) the geology (G), b) the airborne gamma-ray spectroscopy (AGR), c) the geochemistry of topsoil (TSG) and d) the geochemistry of stream sediments (SSG). The study area was chosen since it provides a large (197,464) indoor radon dataset in association with the above information. Geology provides information on the distribution of the materials that may contribute to radon release while the latter three items provide more direct observations on the distributions of the radionuclide elements uranium (U), thorium (Th) and potassium (K). In addition, (c) and (d) provide multi-element assessments of geochemistry which are also included in this study. The effectiveness of datasets for predicting the existing indoor radon data is assessed through the level (the higher the better) of explained variation (% of variance or ANOVA) obtained from the tested models. A multiple linear regression using a compositional data (CODA) approach is carried out to obtain the required measure of determination for each analysis. Results show that, amongst the four tested datasets, the soil geochemistry (TSG, i.e. including all the available 41 elements, 10 major - Al, Ca, Fe, K, Mg, Mn, Na, P, Si, Ti - plus 31 trace) provides the highest explained variation of indoor radon (about 40%); more than double the value provided by U alone (ca. 15%), or the sub composition U, Th, K (ca. 16%) from the same TSG data. The remaining three datasets provide values ranging from about 27% to 32.5%. The enhanced prediction of the AGR model relative to the U, Th, K in soils suggests that the AGR signal captures more than just the U, Th and K content in the soil. The best result is obtained by including the soil geochemistry with geology and AGR (TSG + G + AGR, ca. 47%). However, adding G and AGR to the TSG model only slightly improves the prediction (ca. +7%), suggesting that the geochemistry of soils already contain most of the information given by geology and airborne datasets together, at least with regard to the explanation of indoor radon. From the present analysis performed in the SW of England, it may be concluded that each one of the four datasets is likely to be useful for radon mapping purposes, whether alone or in combination with others. The present work also suggest that the complete soil geochemistry dataset (TSG) is more effective for indoor radon modelling than using just the U (+Th, K) concentration in soil., (Copyright © 2016 Natural Environment Research Council. Published by Elsevier Ltd.. All rights reserved.)