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Purpose: The majority of pediatric antibiotic prescribing occurs in the outpatient setting and inappropriate use contributes to antimicrobial resistance. There are regional variations in outpatient antibiotic use with the highest rates occurring in the Southern states, including in Appalachia. The purpose of this study was to describe the rates and risk factors for inappropriate antibiotic prescription among pediatric patients enrolled in North Carolina (NC) Medicaid., Methods: We used Medicaid prescription claims data from 2013 to 2019 to describe patterns of pediatric antibiotic prescription in NC. We assessed patient and provider factors to identify variations in prescribing., Findings: Children who were less than 2 years of age, non-Hispanic White, and living in a rural area had the highest overall rates of antibiotic prescription. Compared to pediatricians, the risk of inappropriate antibiotic prescription was highest among other specialists and general practioners and lowest among nurse practitioners. Rural areas of NC had the highest rates of inappropriate antibiotic prescribing, and the risk for non-Hispanic Black children compared to children of other races/ethnicities was compounded by rurality., Conclusions: Prescribing practices in NC differ compared to neighboring states with a lower overall risk of inappropriate prescription in Appalachian regions; however, disparities by race and rurality exist. Outpatient stewardship efforts in NC should focus on ensuring health equity by appreciating racial and geographic variations in prescribing patterns and providing education to all health care providers., (© 2024 National Rural Health Association.)

Antibiotic resistance is a global threat driven primarily by antibiotic use. We evaluated the effects of antibiotic exposures on the gut microbiomes and resistomes of children at high risk of colonization by antibiotic-resistant bacteria. We performed shotgun metagenomic sequencing of 691 serially collected fecal samples from 80 children (<18 years) undergoing hematopoietic cell transplantation. We evaluated the effects of aerobic (cefepime, vancomycin, fluoroquinolones, aminoglycosides, macrolides, and trimethoprim-sulfamethoxazole) and anaerobic (piperacillin-tazobactam, carbapenems, metronidazole, and clindamycin) antibiotic exposures on the diversity and composition of the gut microbiome and resistome. We identified 372 unique antibiotic resistance genes (ARGs); the most frequent ARGs identified encode resistance to tetracyclines ( n  = 88), beta-lactams ( n  = 84), and fluoroquinolones ( n  = 79). Both aerobic and anaerobic antibiotic exposures were associated with a decrease in the number of bacterial species (aerobic, β = 0.71, 95% CI: 0.64, 0.79; anaerobic, β = 0.66, 95% CI: 0.53, 0.82) and the number of unique ARGs (aerobic, β = 0.81, 95% CI: 0.74, 0.90; anaerobic, β = 0.73, 95% CI: 0.61, 0.88) within the gut metagenome. However, only antibiotic regimens that included anaerobic activity were associated with an increase in acquisition of new ARGs (anaerobic, β = 1.50; 95% CI: 1.12, 2.01) and an increase in the relative abundance of ARGs in the gut resistome (anaerobic, β = 1.62; 95% CI: 1.15, 2.27). Specific antibiotic exposures were associated with distinct changes in the number and abundance of ARGs for individual antibiotic classes. Our findings detail the impact of antibiotics on the gut microbiome and resistome and demonstrate that anaerobic antibiotics are particularly likely to promote acquisition and expansion of antibiotic-resistant bacteria.

The use of error-corrected Next Generation Sequencing (ecNG) to determine mutagenicity has been a subject of growing interest and potentially a disruptive technology that could supplement, and in time, replace current testing paradigms in preclinical safety assessment. Considering this, a Next Generation Sequencing Workshop was held at the Royal Society of Medicine in London in May 2022, supported by the United Kingdom Environmental Mutagen Society (UKEMS) and TwinStrand Biosciences (WA, USA), to discuss progress and future applications of this technology. In this meeting report, the invited speakers provide an overview of the Workshop topics covered and identify future directions for research. In the area of somatic mutagenesis, several speakers reviewed recent progress made with correlating ecNGS to classic in vivo transgenic rodent mutation assays as well as exploring the use of this technology directly in humans and animals, and in complex organoid models. Additionally, ecNGS has been used for detecting off-target effects of gene editing tools and emerging data suggest ecNGS potential to measure clonal expansion of cells carrying mutations in cancer driver genes as an early marker of carcinogenic potential and for direct human biomonitoring. As such, the workshop demonstrated the importance of raising awareness and support for advancing the science of ecNGS for mutagenesis, gene editing, and carcinogenesis research. Furthermore, the potential of this new technology to contribute to advances in drug and product development and improve safety assessment was extensively explored., (© The Author(s) 2023. Published by Oxford University Press on behalf of the UK Environmental Mutagen Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The pace of US Food and Drug Administration-approved medical devices that incorporate artificial intelligence (AI) or machine learning as part of the device is accelerating. As of September 2021, 350 such devices have been approved for commercial sale in the United States. As much as AI has become ubiquitous in our lives-keeping our cars between the lines on the highway, converting speech to text on the fly, recommending movies, books, or restaurants, and so much more, AI also appears destined to become a routine aspect in daily spine surgery. Neural network types of AI programs have achieved extraordinary pattern recognition and predictive abilities-far surpassing human capabilities-and thus appears well suited to back pain and spine surgery diagnostic and treatment pattern recognition and prediction tasks. These AI programs are also data hungry. As luck would have it, surgery generates an estimated 80 MB per patient per day collected in a variety of datasets. When aggregated, this represents a 200+ billion patient record data ocean of diagnostic and treatment patterns. Such Big Data, when combined with a new generation of convolutional neural network (CNN) AI, set the stage for a cognitive revolution in spine surgery. However, there are important issues and concerns. Spine surgery is a mission-critical task. Because AI programs lack explainability and are absolutely reliant on correlative, not causative, data relationships, the emerging role of AI and Big Data in spine surgery will likely come first in productivity tools and later in narrowly defined spine surgery tasks. The purpose of this article is to review the emergence of AI in spine surgery applications and examine spine surgery heuristics and "expert" decision models within the context of AI and Big Data., Competing Interests: Declaration of Conflicting Interests : The authors report no conflicts of interest in this work., (This manuscript is generously published free of charge by ISASS, the International Society for the Advancement of Spine Surgery. Copyright © 2023 ISASS. To see more or order reprints or permissions, see http://ijssurgery.com.)

Background: Racial inequities influence health outcomes in the United States, but their impact on sepsis outcomes among children is understudied. We aimed to evaluate for racial inequities in sepsis mortality using a nationally representative sample of pediatric hospitalizations., Methods: This population-based, retrospective cohort study used the 2006, 2009, 2012 and 2016 Kids' Inpatient Database. Eligible children 1 month to 17 years old were identified using sepsis-related International Classification of Diseases, Ninth Revision or International Classification of Diseases, Tenth Revision codes. We used modified Poisson regression to evaluate the association between patient race and in-hospital mortality, clustering by hospital and adjusting for age, sex and year. We used Wald tests to assess for modification of associations between race and mortality by sociodemographic factors, geographic region and insurance status., Results: Among 38,234 children with sepsis, 2555 (6.7%) died in-hospital. Compared with White children, mortality was higher among Hispanic (adjusted relative risk: 1.09; 95% confidence interval: 1.05-1.14), Asian/Pacific Islander (1.17, 1.08-1.27) and children from other racial minority groups (1.27, 1.19-1.35). Black children had similar mortality to White children overall (1.02, 0.96-1.07), but higher mortality in the South (7.3% vs. 6.4%; P < 0.0001). Hispanic children had higher mortality than White children in the Midwest (6.9% vs. 5.4%; P < 0.0001), while Asian/Pacific Islander children had higher mortality than all other racial categories in the Midwest (12.6%) and South (12.0%). Mortality was higher among uninsured children than among privately insured children (1.24, 1.17-1.31)., Conclusions: Risk of in-hospital mortality among children with sepsis in the United States differs by patient race, geographic region and insurance status., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

The OECD Test Guideline 488 (TG 488) for the Transgenic Rodent Gene Mutation Assay has undergone several revisions to update the recommended design for studying mutations in somatic tissues and male germ cells. The recently revised TG recommends a single sampling time of 28 days following 28 days of exposure (i.e., 28 + 28 days) for all tissues, irrespective of proliferation rates. An alternative design (i.e., 28 + 3 days) is appropriate when germ cell data is not required, nor considered. While the 28 + 28 days design is clearly preferable for slowly proliferating somatic tissues and germ cells, there is still uncertainty about the impact of extending the sampling time to 28 days for rapidly somatic tissues. Here, we searched the available literature for evidence supporting the applicability and utility of the 28 + 28 days design for rapidly proliferating tissues. A total of 79 tests were identified. When directly comparing results from both designs in the same study, there was no evidence that the 28 + 28 days regimen resulted in a qualitatively different outcome from the 28 + 3 days design. Studies with a diverse range of agents that employed only a 28 + 28 days protocol provide further evidence that this design is appropriate for rapidly proliferating tissues. Benchmark dose analyses demonstrate high quantitative concordance between the 28 + 3 and 28 + 28 days designs for rapidly proliferating tissues. Accordingly, our review confirms that the 28 + 28 days design is appropriate to assess mutagenicity in both slowly and rapidly proliferating somatic tissues, and germ cells, and provides further support for the recommended design in the recently adopted TG 488., (© 2022 His Majesty the King in Right of Canada. Environmental and Molecular Mutagenesis published by Wiley Periodicals LLC on behalf of Environmental Mutagen Society. Reproduced with the permission of the Minister of Health Canada.)

Background: Pediatric solid organ transplant (SOT) recipients commonly have Epstein-Barr virus (EBV) DNAemia and are at risk of developing post-transplant lymphoproliferative disorder (PTLD). EBV DNAemia has not been analyzed on a continuous scale in this population., Methods: All children ≤ 18 years of age who underwent SOT at a single center between January 1, 2007 and July 31, 2018 were included in this retrospective study. Transplant episodes in which PTLD occurred were compared to transplant episodes without PTLD. Multivariable logistic regression was used to identify factors associated with the development of EBV DNAemia and maximum height of EBV DNAemia. A Cox proportional hazards model was used to calculate hazard ratios for time to PTLD., Results: Of 275 total transplant recipients and 294 transplant episodes, there were 14 episodes of PTLD. Intestinal and multivisceral transplant were strongly associated with PTLD (p = 0.002). Risk factors for the development of EBV DNAemia include donor and recipient positive EBV serologies (p = 0.001) and older age (p = 0.001). Maximum level of EBV DNAemia was significantly associated with development of PTLD (p<0.0001). Every one log (log10) increase in the maximum level of EBV DNAemia was associated with a more than doubling of the hazard on developing PTLD (HR: 2.18, 95% CI 1.19-3.99)., Conclusions: Transplant type was strongly associated with development of PTLD in pediatric SOT recipients. EBV serologies and age were associated with the development of EBV DNAemia and height of DNAemia. High levels of EBV DNAemia were strongly associated with an increased hazard for PTLD., Competing Interests: The authors have declared that no competing interests exist.

We describe the frequency of pediatric healthcare-associated infections (HAIs) identified through prospective surveillance in community hospitals participating in an infection control network. Over a 6-year period, 84 HAIs were identified. Of these 51 (61%) were pediatric central-line-associated bloodstream infections, and they often occurred in children <1 year of age.

Background: AR is a targetable pathway with AR modulation inhibiting estrogen- and androgen-mediated cell proliferation. Orteronel is an oral, selective, nonsteroidal inhibitor of 17, 20-lyase, a key enzyme in androgen biosynthesis. This study evaluated single-agent orteronel in AR+ metastatic breast cancer (MBC)., Methods: Male/female patients with AR+ MBC were grouped in Cohort 1: AR+ TNBC with l-3 prior chemotherapy regimens or Cohort 2: AR+ HR+ (estrogen [ER+]/ progesterone receptor [PR+] positive) HER2+/- with 1 to 3 prior hormonal and at least 1 prior chemotherapy regimen. Patients with HER2+ MBC must have received at least 2 lines of HER2-targeted therapy. Orteronel was administered at 300 mg BID; response rate was the primary endpoint., Results: Seventy patients were enrolled (Cohort 1, n = 26 and Cohort 2, n = 44). Median treatment duration was 7.1 weeks. Seven patients were on treatment for ≥6 months. One of the 21 evaluated patients in Cohort 1 (4.8%) had an objective response. In Cohort 2, none of the first 23 patients to be evaluated had a response and accrual was stopped. Median progression-free and overall survival were 1.8 and 8.3 months, respectively. Toxicities were predominantly Grade 1 or 2 nausea/vomiting (36%) and fatigue (31%). Grade 3 or 4 events in ≥5% of patients included increased amylase/lipase (10%) and hypertension (6%)., Conclusions: Orteronel demonstrated limited clinical activity in heavily pre-treated AR+ MBC. Further development of orteronel in MBC is not recommended. Further efforts to validate the AR as a therapeutic target should focus on identifying new markers predictive of sensitivity to AR-targeted agents., (Copyright © 2021. Published by Elsevier Inc.)

Streptococcus pneumoniae (pneumococcus) is a leading cause of severe infections among children and adults. Interactions between commensal microbes in the upper respiratory tract and S. pneumoniae are poorly described. In this study, we sought to identify interspecies interactions that modify the risk of S. pneumoniae colonization during infancy and to describe development of the upper respiratory microbiome during infancy in a sub-Saharan African setting. We collected nasopharyngeal swabs monthly (0-6 months of age) or bimonthly (6-12 months of age) from 179 mother-infant dyads in Botswana. We used 16S ribosomal RNA gene sequencing to characterize the nasopharyngeal microbiome and identified S. pneumoniae colonization using a species-specific PCR assay. We detect S. pneumoniae colonization in 144 (80%) infants at a median age of 71 days and identify a strong negative association between the relative abundance of the bacterial genera Corynebacterium within the infant nasopharyngeal microbiome and the risk of S. pneumoniae colonization. Using in vitro cultivation experiments, we demonstrate growth inhibition of S. pneumoniae by secreted factors from strains of several Corynebacterium species isolated from these infants. Finally, we demonstrate that antibiotic exposures and the winter season are associated with a decline in the relative abundance of Corynebacterium within the nasopharyngeal microbiome, while breastfeeding is associated with an increase in the Corynebacterium relative abundance. Our findings provide novel insights into the interspecies interactions that contribute to colonization resistance to S. pneumoniae and suggest that the nasopharyngeal microbiome may be a previously unrecognized mechanism by which environmental factors influence the risk of pneumococcal infections during childhood. Moreover, this work lays the foundation for future studies seeking to use targeted manipulation of the nasopharyngeal microbiome to prevent infections caused by S. pneumoniae., (© 2021. The Author(s), under exclusive licence to International Society for Microbial Ecology.)

Pneumococcal conjugate vaccines reduce the burden of invasive pneumococcal disease, but the sustained effect of these vaccines can be diminished by an increase in disease caused by non-vaccine serotypes. To describe pneumococcal serotype epidemiology in Botswana following introduction of 13-valent pneumococcal conjugate vaccine (PCV-13) in July 2012, we performed molecular serotyping of 268 pneumococcal strains isolated from 221 children between 2012 and 2017. The median (interquartile range) age of the children included in this analysis was 6 (3,12) months. Fifty-nine percent of the children had received at least one dose of PCV-13 and 35% were fully vaccinated with PCV-13. While colonization by vaccine serotypes steadily declined following PCV-13 introduction, 25% of strains isolated more than 3 years after vaccine introduction were PCV-13 serotypes. We also observed an increase in colonization by non-vaccine serotypes 21 and 23B, which have been associated with invasive pneumococcal disease and antibiotic resistance in other settings., Competing Interests: The authors have declared that no competing interests exist.

Background: Cytomegalovirus (CMV) causes substantial morbidity and mortality after hematopoietic stem cell transplantation (HSCT). There are limited data on risk factors for CMV viremia and the safety of antiviral medications used to treat CMV in children., Methods: We conducted a single-center retrospective study of children who underwent HSCT between 2000 and 2016. We used log-logistic regression to evaluate associations between clinical characteristics and CMV-free survival at 100 days after HSCT. We compared the incidences of laboratory-defined adverse events (AEs) during treatment with ganciclovir and foscarnet., Results: Among 969 children, the median (interquartile range) age was 6.5 (3.1-11.5) years, and 80% underwent allogeneic HSCT. Two hundred forty-four (25%) children developed CMV viremia. Older age (odds ratio [OR], 0.95; 95% CI, 0.92-0.98), male sex (OR, 0.71; 95% CI, 0.51-0.99), non-Black, non-White race (OR, 0.56; 95% CI, 0.36-0.87), umbilical cord blood donor source (OR, 0.28; 95% CI, 0.08-0.97), and CMV seropositivity (R-/D+: OR, 0.17; 95% CI, 0.07-0.41; R+/D-: OR, 0.14; 95% CI, 0.09-0.21; R+/D+: OR, 0.08; 95% CI, 0.04-0.15) were associated with lower odds of 100-day CMV-free survival. Compared with foscarnet, ganciclovir was associated with lower incidences of thrombocytopenia (incidence rate ratio [IRR], 0.38; 95% CI, 0.15-0.97), electrolyte AEs (IRR, 0.42; 95% CI, 0.24-0.75), endocrine AEs (IRR, 0.52; 95% CI, 0.34-0.79), and renal AEs (IRR, 0.36; 95% CI, 0.19-0.65)., Conclusions: CMV viremia occurred commonly among children after HSCT, and ganciclovir and foscarnet were associated with distinct toxicity profiles among children with CMV infection. These findings should be considered when developing CMV prevention and treatment strategies for children after HSCT., (© The Author(s) 2021. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Assessment of genotoxicity is a critical component of mode of action (MOA) analysis and carcinogen risk assessment due to its influence on quantitative risk extrapolation approaches. To date, clear guidance and expert consensus on the determination of a mutagenic MOA remains elusive, resulting in different estimates of carcinogenic risk for the same chemical among different stakeholders. Oral toxicity criteria for hexavalent chromium [Cr(VI)], for example, differ by orders of magnitude due largely to the interpretation of in vivo genotoxicity data. Herein, we review in vivo genotoxicity studies for Cr(VI) to inform the MOA for Cr(VI)-induced tumors observed in a two-year cancer bioassay in mice and rats exposed via drinking water. Overall, genotoxicity results in carcinogenic target tissues ( viz., oral cavity and duodenum) are negative. Results in the intestine are consistent with imaging data indicating little to no chromium present in the crypt compartment following oral exposure. Positive genotoxicity results in nontarget tissues have been reported at high doses mostly following nonphysiological routes of exposure. Given the negative genotoxicity results in carcinogenic target organs from oral exposure to Cr(VI), there is scientific justification to support the use of nonlinear low-dose extrapolation methods in the derivation of oral toxicity criteria for Cr(VI). These results highlight important differences between genotoxicity testing for hazard identification purposes and quantitative risk assessment.

Background: Globally, pneumonia is the leading cause of death among children. Few data exist regarding the effect of Haemophilus influenzae type b (Hib) vaccine and 13-valent pneumococcal conjugate vaccine (PCV-13) on the burden of childhood pneumonia in African settings., Methods: We collected data on children aged 1 to 59 months at 3 hospitals in Botswana. Hib vaccine and PCV-13 were introduced in Botswana in November 2010 and July 2012, respectively. We compared pneumonia hospitalizations and deaths prevaccine (January 2009 to October 2010) with postvaccine (January 2013 to December 2017) using seasonally adjusted, interrupted time-series analyses., Results: We identified 6943 pneumonia hospitalizations and 201 pneumonia deaths. In the prevaccine period, pneumonia hospitalizations and deaths increased by 24% (rate, 1.24; 95% CI, .94-1.64) and 59% (rate, 1.59; 95% CI, .87-2.90) per year, respectively. Vaccine introduction was associated with a 48% (95% CI, 29-62%) decrease in the number of pneumonia hospitalizations and a 50% (95% CI, 1-75%) decrease in the number of pneumonia deaths between the end of the prevaccine period (October 2010) and the beginning of the postvaccine period (January 2013). During the postvaccine period, pneumonia hospitalizations and deaths declined by 6% (rate, .94; 95% CI, .89-.99) and 22% (rate, .78; 95% CI, .67-.92) per year, respectively., Conclusions: Pneumonia hospitalizations and deaths among children declined sharply following introduction of Hib vaccine and PCV-13 in Botswana. This effect was sustained for more than 5 years after vaccine introduction, supporting the long-term effectiveness of these vaccines in preventing childhood pneumonia in Botswana., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: It is unknown whether prenatal lipid-based nutrient supplements (LNSs) affect blood pressure (BP). Associations between hypertension and birth outcomes using recently updated BP cutoffs are undetermined., Objectives: We aimed to assess the impact of LNSs on maternal hypertension and associations between hypertension and birth outcomes., Methods: Pregnant Ghanaian women at ≤20 weeks of gestation (n = 1320) were randomly assigned to receive daily 1) iron and folic acid (IFA), 2) multiple micronutrients (MMN), or 3) LNSs until delivery. BP was measured at enrollment and 36 weeks of gestation. We analyzed the effect of LNSs on BP using ANOVA and associations between hypertension [systolic BP (SBP) ≥130 mm Hg or diastolic BP (DBP) ≥80 mm Hg] and birth outcomes by linear and logistic regressions., Results: Mean ± SD SBP and DBP were 110 ± 11 and 63 ± 8 mm Hg at 36 weeks of gestation and did not differ by supplementation group (SBP, P > 0.05; DBP, P > 0.05). At enrollment, higher DBP was associated with lower birth weight and shorter gestation; women with high DBP had greater risk of low birth weight (LBW) [risk ratio (RR): 2.58; 95% CI: 1.09, 6.08] and preterm birth (PTB) (RR: 3.30; 95% CI: 1.47, 7.40). At 36 weeks of gestation, higher SBP was associated with lower birth weight, length, and head circumference and shorter gestation; higher DBP was associated with lower birth weight and length; and women with high DBP had greater risk of LBW (RR: 3.39; 95% CI: 1.32, 8.69). Neither high SBP nor hypertension were associated with birth outcomes at either time point., Conclusions: Daily provision of LNSs does not affect maternal hypertension, compared with IFA and MMN. Higher SBP and DBP are associated with a shorter gestation and smaller birth size; however, only high DBP is associated with LBW and PTB. The new BP cutoffs may help identify pregnancies at risk of adverse birth outcomes.This trial was registered at clinicaltrials.gov as NCT00970866., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

The ability to accurately measure mutations is critical for basic research and identifying potential drug and chemical carcinogens. Current methods for in vivo quantification of mutagenesis are limited because they rely on transgenic rodent systems that are low-throughput, expensive, prolonged, and do not fully represent other species such as humans. Next-generation sequencing (NGS) is a conceptually attractive alternative for detecting mutations in the DNA of any organism; however, the limit of resolution for standard NGS is poor. Technical error rates (∼1 × 10 -3 ) of NGS obscure the true abundance of somatic mutations, which can exist at per-nucleotide frequencies ≤1 × 10 -7 Using duplex sequencing, an extremely accurate error-corrected NGS (ecNGS) technology, we were able to detect mutations induced by three carcinogens in five tissues of two strains of mice within 31 d following exposure. We observed a strong correlation between mutation induction measured by duplex sequencing and the gold-standard transgenic rodent mutation assay. We identified exposure-specific mutation spectra of each compound through trinucleotide patterns of base substitution. We observed variation in mutation susceptibility by genomic region, as well as by DNA strand. We also identified a primordial marker of carcinogenesis in a cancer-predisposed strain of mice, as evidenced by clonal expansions of cells carrying an activated oncogene, less than a month after carcinogen exposure. These findings demonstrate that ecNGS is a powerful method for sensitively detecting and characterizing mutagenesis and the early clonal evolutionary hallmarks of carcinogenesis. Duplex sequencing can be broadly applied to basic mutational research, regulatory safety testing, and emerging clinical applications., Competing Interests: Competing interest statement: C.C.V., L.N.W., T.L., and J.J.S., are employees and equity holders at TwinStrand Biosciences Inc. and are authors on one or more duplex sequencing-related patents. R.R.Y. is an employee of MilliporeSigma. At the time the study was conducted, R.K. was an employee of MilliporeSigma but is now an employee of EMD Serono. MilliporeSigma and EMD Serono are independent business units of Merck KGaA, Darmstadt, Germany. S.M. is an employee of Amgen. M.R.F. was an employee of Amgen at the time of the study and is currently an employee of Expansion Therapeutics., (Copyright © 2020 the Author(s). Published by PNAS.)

Certain anaerobic bacteria are important for maintenance of gut barrier integrity and immune tolerance and may influence the risk of graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HSCT). We conducted a single-center retrospective cohort study of allogeneic HSCT recipients to evaluate associations between receipt of antibiotics with an anaerobic spectrum of activity and GVHD outcomes. We identified 1214 children and adults who developed febrile neutropenia between 7 days before and 28 days after HSCT and compared GVHD risk and mortality among patients who received anaerobic antibiotics (piperacillin-tazobactam or carbapenems; n = 491) to patients who received only antibiotics with minimal activity against anaerobes (aztreonam, cefepime, or ceftazidime; n = 723). We performed metagenomic sequencing of serial fecal samples from 36 pediatric patients to compare the effects of specific antibiotics on the gut metagenome. Receipt of anaerobic antibiotics was associated with higher hazards of acute gut/liver GVHD (hazard ratio [HR], 1.26; 95% confidence interval [CI], 1.03 to 1.54) and acute GVHD mortality (HR, 1.63; 95% CI, 1.08 to 2.46), but not chronic GVHD diagnosis (HR, 1.04; 95% CI: .84 to 1.28) or chronic GVHD mortality (HR, .88; 95% CI, .53 to 1.45). Anaerobic antibiotics resulted in decreased gut bacterial diversity, reduced abundances of Bifidobacteriales and Clostridiales, and loss of bacterial genes encoding butyrate biosynthesis enzymes from the gut metagenome. Acute gut/liver GVHD was preceded by a sharp decline in bacterial butyrate biosynthesis genes with antibiotic treatment. Our findings demonstrate that exposure to anaerobic antibiotics is associated with increased risks of acute gut/liver GVHD and acute GVHD mortality after allogeneic HSCT. Use of piperacillin-tazobactam or carbapenems should be reserved for febrile neutropenia cases in which anaerobic or multidrug-resistant infections are suspected., (Copyright © 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Background: Bloodstream infections (BSIs) occur frequently after hematopoietic stem cell transplantation (HSCT). We examined the microbiology of BSI in pediatric HSCT recipients over a 2-decade period at our institution to inform empirical antimicrobial prescribing and infection prevention strategies., Methods: We conducted a retrospective cohort study of children (<18 years) who underwent HSCT at Duke University between 1997 and 2015. We used recurrent-event gap-time Cox proportional hazards models to determine the hazards of all-cause and cause-specific BSI according to HSCT year. We compared the median time to BSI by causative organism type and evaluated for temporal trends in the prevalence of antibiotic resistance among causative organisms., Results: A total of 865 BSI occurred in 1311 children, including 412 (48%) Gram-positive bacterial, 196 (23%) Gram-negative bacterial, 56 (6%) fungal, 23 (3%) mycobacterial, and 178 (21%) polymicrobial BSI. The hazard of all BSIs did not change substantially over time during the study period, but the hazard of fungal BSIs declined over time during the study period ( P  = .04). Most fungal BSIs (82%) occurred in the first 100 days after HSCT, whereas mycobacterial BSIs occurred later after HSCT than BSIs caused by other organisms ( P  < .0001). The prevalence of vancomycin resistance among BSIs caused by Enterococcus faecium increased during the study period ( P  = .0007). The risk of 2-year mortality in children was increased with BSI ( P  = .02), Gram-negative bacterial BSI ( P  = .02), and fungal BSI ( P  < .0001)., Conclusions: Despite expanded practices for BSI prevention over the past several decades, the incidence of BSI remains high in pediatric HSCT recipients at our institution. Additional strategies are urgently needed to effectively prevent BSIs in this high-risk population., (© The Author(s) 2020. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

An unhealthy gut microbial community may act as a barrier to improvement in growth and health outcomes in response to nutritional interventions. The objective of this analysis was to determine whether the infant microbiota modified the effects of a randomized controlled trial of lipid-based nutrient supplements (LNS) in Malawi on growth and inflammation at 12 and 18 months, respectively. We characterized baseline microbiota composition of fecal samples at 6 months of age (n = 506, prior to infant supplementation, which extended to 18 months) using 16S rRNA gene sequencing of the V4 region. Features of the gut microbiota previously identified as being involved in fatty acid or micronutrient metabolism or in outcomes relating to growth and inflammation, especially in children, were investigated. Prior to correction for multiple hypothesis testing, the effects of LNS on growth appeared to be modified by Clostridium (p-for-interaction = 0.02), Ruminococcus (p-for-interaction = 0.007), and Firmicutes (p-for-interaction = 0.04) and effects on inflammation appeared to be modified by Faecalibacterium (p-for-interaction = 0.03) and Streptococcus (p-for-interaction = 0.004). However, after correction for multiple hypothesis testing these findings were not statistically significant, suggesting that the gut microbiota did not alter the effect of LNS on infant growth and inflammation in this cohort.

Dysregulation of the stress response can occur early in life and may be affected by nutrition. Our objective was to evaluate the long-term effect of nutritional supplementation during gestation and early childhood on child cortisol and buccal telomere length (a marker of cellular aging) at 4-6 years of age. We conducted a follow-up study of children born to women who participated in a nutritional supplementation trial in Ghana. In one group, a lipid-based nutrient supplement (LNS) was provided to women during gestation and the first 6 months postpartum and to their infants from age 6 to 18 months. The control groups received either iron and folic acid (IFA) during gestation or multiple micronutrients during gestation and the first 6 months postpartum, with no infant supplementation. At age 4-6 years, we measured hair cortisol, buccal telomere length, and salivary cortisol before and after a stressor. Salivary cortisol was available for 364 children across all three trial arms and hair cortisol and telomere length were available for a subset of children ( n  = 275 and 278, respectively) from the LNS and IFA groups. Telomere length, salivary cortisol, and hair cortisol did not differ by supplementation group. Overall, these findings suggest that nutritional supplementation given during gestation and early childhood does not have an effect on child stress response or chronic stress in children at 4-6 years. Trial registration: ClinicalTrials.gov Identifier NCT00970866.Lay SummaryThis study addressed a research gap about whether improved nutrition during pregnancy and early childhood impacts telomere length and cortisol in preschool children. There was no difference in child telomere length or cortisol between two trial arms of a nutritional supplementation trial that began during pregnancy. The research outcomes indicate lipid-based nutrient supplements, a relatively new form of supplementation, do not have an effect on markers of stress or cellular aging measured in later childhood.

Fecal samples collected for microbiome analyses are typically frozen to avoid postcollection changes in microbial composition. eNAT is a guanidine thiocyanate-based medium that stabilizes microbial DNA and allows safe specimen handling and shipping by inactivating microorganisms. We collected fecal samples (n = 50) from children undergoing hematopoietic stem cell transplantation. We divided samples into three aliquots: (a) stored in RNAlater and immediately transferred to -80°C; (b) stored in eNAT medium and immediately transferred to -80°C; and (c) stored in eNAT medium at ambient temperature (~20°C) for 30 days prior to transfer to -80°C. Mean (standard deviation) Shannon diversity and Chao1 indices in sample aliquots were 2.05 (0.62) and 23.8 (16.6), respectively. Comparing samples frozen immediately in RNAlater to samples frozen immediately in eNAT, there were no differences in Shannon diversity (p = .51), Chao1 richness (p = .66), and overall microbiome composition (p = .99). Comparing eNAT samples frozen immediately to samples stored at ambient temperature, we identified no differences in Shannon diversity (p = .65), Chao1 richness (p = .87), and overall microbiome composition (p = .99). Storage of fecal samples in eNAT at ambient temperature for 30 days did not alter microbiome richness, diversity, or composition. eNAT may be a useful medium for fecal microbiome studies, particularly when cold chain storage is unavailable., (© 2020 The Authors. MicrobiologyOpen published by John Wiley & Sons Ltd.)

Background: Therapies targeting estrogen receptor signaling are standard for patients with hormone receptor (HR)-positive (HR + ) metastatic breast cancer (MBC). Dysregulation of the phosphoinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway is associated with treatment resistance. Addition of the mTOR inhibitor, everolimus, to exemestane doubled progression-free survival (PFS) in HR + /HER2 - MBC patients whose disease had previously progressed during endocrine therapy. In this phase II study, we used everolimus in addition to the most recent endocrine therapy during which a patient's disease progressed, in an attempt to restore and extend the benefit of the antiestrogen therapy in patients with HR + /HER2 - MBC., Patients and Methods: Patients with HR + MBC who progressed on antiestrogen therapy received everolimus (10 mg orally daily) in combination with the antiestrogen therapy most recently administered. Treatment was administered in 4-week cycles and continued until disease progression or unacceptable toxicity. Blood and archival tumor specimens were collected for VeriStrat (Biodesix, Inc) and Foundation One (Foundation Medicine) assays, respectively. Accrual of 42 evaluable patients allowed detection of improvement in median PFS from 2.8 months (expected with hormonal treatment alone) to 5 months (power 80%, α = 5%)., Results: Forty-seven patients were enrolled and treated. After a median follow-up of 22.2 months, median PFS was 6.6 months. Secondary efficacy end points included: overall response rate, 6%; clinical benefit rate, 40%; and median overall survival, 21.1 months. No unexpected toxicity was observed. Efficacy could not be correlated with PI3K/AKT/mTOR alterations or VeriStrat (Biodesix, Inc) prognostic signatures., Conclusion: After progression during antiestrogen therapy, the addition of everolimus, without changing the hormonal therapy, resulted in a median PFS of 6.6 months, suggesting efficacy in patients with HR + /HER2 - MBC., (Copyright © 2019. Published by Elsevier Inc.)

Background: Children undergoing hematopoietic stem cell transplantation (HSCT) are at high risk for hospital-associated bloodstream infections (HA-BSIs). This study aimed to describe the incidence, microbiology, and risk factors for HA-BSI in pediatric HSCT recipients., Methods: We performed a single-center retrospective cohort study of children and adolescents (<18 years of age) who underwent HSCT over a 20-year period (1997-2016). We determined the incidence and case fatality rate of HA-BSI by causative organism. We used multivariable Poisson regression to identify risk factors for HA-BSI., Results: Of 1294 patients, the majority (86%) received an allogeneic HSCT, most commonly with umbilical cord blood (63%). During the initial HSCT hospitalization, 334 HA-BSIs occurred among 261 (20%) patients. These were classified as gram-positive bacterial (46%), gram-negative bacterial (24%), fungal (12%), mycobacterial (<1%), or polymicrobial (19%). During the study period, there was a decline in the cumulative incidence of HA-BSI ( P  = .021) and, specifically, fungal HA-BSIs ( P  = .002). In multivariable analyses, older age (incidence rate ratio [IRR], 1.03; 95% confidence interval [CI], 1.01-1.06), umbilical cord blood donor source (vs bone marrow; IRR, 1.69; 95% CI, 1.19-2.40), and nonmyeloablative conditioning (vs myeloablative; IRR, 1.85; 95% CI, 1.21-2.82) were associated with a higher risk of HA-BSIs. The case fatality rate was higher for fungal HA-BSI than other HA-BSI categories (21% vs 6%; P  = .002)., Conclusions: Over the past 2 decades, the incidence of HA-BSIs has declined among pediatric HSCT recipients at our institution. Older age, umbilical cord blood donor source, and nonmyeloablative conditioning regimens are independent risk factors for HA-BSI among children undergoing HSCT., (© The Author(s) 2020. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Adequate knowledge about the safety of consumption of small-quantity lipid-based nutrient supplements (SQ-LNSs) is needed., Objective: We aimed to test the hypothesis that SQ-LNS consumption is noninferior to control with respect to child morbidity., Methods: Women (n = 1320) ≤20 wk pregnant were assigned to iron and folic acid until delivery with no supplementation for offspring; or multiple micronutrient supplements until 6 mo postpartum with no supplementation for offspring; or SQ-LNSs until 6 mo postpartum, and SQ-LNSs for offspring (6 mg Fe/d) from 6 to 18 mo of age [the lipid-based nutrient supplement (LNS) group]. We assessed noninferiority (margin ≤20%) between any 2 groups during 0-6 mo of age, and between the non-LNS and LNS groups during 6-18 mo of age for caregiver-reported acute respiratory infection, diarrhea, gastroenteritis, fever/suspected malaria, poor appetite, and "other illnesses.", Results: During 0-6 mo of age, 1197 infants contributed 190,503 infant-days. For all morbidity combined, overall mean incidence (per 100 infant-days) was 3.3 episodes, overall mean prevalence (percentage of infant-days) was 19.3%, and the 95% CIs of the incidence rate ratio (IRR) and longitudinal prevalence rate ratio (LPRR) between any 2 groups were ≤1.20. During 6-18 mo, there were 240,097 infant-days for the non-LNS group and 118,698 for the LNS group. For all morbidity combined, group mean incidences were 4.3 and 4.3, respectively (IRR: 1.0; 95% CI: 1.0, 1.1), and mean prevalences were 28.2% and 29.3%, respectively (LPRR: 1.0; 95% CI: 1.0, 1.1). Noninferiority was inconclusive for diarrhea, fever/suspected malaria, and poor appetite., Conclusions: SQ-LNS consumption does not increase reported overall child morbidity in this population compared with the 2 other treatments.This trial was registered at clinicaltrials.gov as NCT00970866., (Copyright © American Society for Nutrition 2019.)

Objective: We aimed to identify factors (child diet, physical activity; maternal BMI) associated with body composition of Ghanaian pre-school children., Design: Longitudinal analysis of the International Lipid-Based Nutrient Supplements (iLiNS)-DYAD-Ghana randomized trial, which enrolled 1320 pregnant women at ≤20 weeks' gestation and followed them and their infants until 6 and 18 months postpartum, respectively. At follow-up, child age 4-6 years, we collected data on body composition (by 2H dilution), physical activity and diet, extracted dietary patterns using factor analysis, and examined the association of children's percentage body fat with maternal and child factors by regression analysis., Setting: Eastern Region, Ghana., Participants: Children 4-6 years of age., Results: The analysis included 889 children with percentage body fat and dietary data at follow-up. We identified two major dietary patterns, a snacking and a cooked foods pattern. Percentage body fat was positively associated (standardized β (se)) with maternal BMI at follow-up (0·10 (0·03); P = 0·003) and negatively associated with physical activity (-0·15 (0·05); P = 0·003, unadjusted for child gender), but not associated with the snacking (0·06 (0·03); P = 0·103) or cooked foods (-0·05 (0·07); P = 0·474) pattern. Boys were more active than girls (1470 v. 1314 mean vector magnitude counts/min; P < 0·0001) and had lower percentage body fat (13·8 v. 16·9 %; P < 0·0001)., Conclusions: In this population, maternal overweight and child physical activity, especially among girls, may be key factors for addressing child overweight/obesity. We did not demonstrate a relationship between the dietary patterns and body fatness, which may be related to limitations of the dietary data available.

Low gestational weight gain (GWG) and low mid-upper arm circumference (MUAC) are associated with adverse pregnancy outcomes. We aimed to assess the prevalence and determinants of low GWG and low MUAC among pregnant women in rural Zinder, Niger. A community-based survey was conducted among 1,384 pregnant women in the catchment areas of 18 integrated health centers in the region of Zinder, Niger. Weight and MUAC were measured during an in-home visit and again 1 month later, when haemoglobin concentration and micronutrient status were also assessed. The prevalence of low GWG was defined based on the 2009 United States Institute of Medicine (U.S. IOM) guidelines (<0.35 kg/week) and less than the third centile of the International Fetal and Newborn Growth Consortium for the 21st Century (INTERGROWTH-21st) standards. Factors associated with GWG and MUAC were identified using logistic regression models adjusting for season, village, and gestational age. The median (interquartile range) age was 25.0 (20.7, 30.0) years, and 16.4% were ≤19 years. The prevalence of low GWG were 62.9% and 27.5% according to 2009 IOM and less than the third INTERGROWTH-21st centile, respectively; 24.9% had low MUAC. Higher α-1-acid glycoprotein (OR = 1.7, 95% CI [1.1, 2.8]) and C-reactive protein (OR = 1.2, 95% CI [1.02, 1.50]) increased the odds of low GWG. Adolescents (OR = 2.7, 95% CI [1.8, 4.0]), housewives (OR = 1.97, 95% CI [1.36, 2.86]), and those who reported recent food assistance (OR = 1.80, 95% CI [1.04, 3.11]) had higher odds of low MUAC. Prevalence of low GWG and low MUAC was high among pregnant women. Determinants of GWG and MUAC included socio-economic, demographic, and biological factors, although only markers of inflammation were consistent predictors across different definitions of low GWG., (© 2019 The Authors. Maternal & Child Nutrition published by John Wiley & Sons, Ltd.)

Background: Anaemia is prevalent among pregnant women in rural Niger and antenatal care (ANC) attendance is suboptimal. We designed a programmatic intervention including community-based behaviour change communication, provision of essential drugs (including iron folic acid (IFA) supplements) and quality improvement activities at selected integrated health centres (IHCs)., Objective: To assess the impact of the programmatic intervention on: (1) utilisation of ANC, (2) adherence to daily IFA supplementation and (3) prevalence of adequate gestational weight gain (GWG) and anaemia among pregnant women in Zinder, Niger., Methods: Using a quasi-experimental study design comparing a cohort of women at baseline to another cohort of women at endline, 18 IHCs and surrounding villages were randomly assigned to time of enrolment over 1 year. A baseline survey was implemented among randomly selected pregnant women in 68 village clusters. Subsequently, the intervention was rolled out and an endline survey was implemented 6 months later in the same villages., Results: Mean age in the baseline (n=1385) and endline (n=922) surveys was 25.8±6.4 years. The percentage of pregnant women who reported attending any number of ANC and an adequate number of ANC for their gestational age, respectively, was not significantly different between the endline and the baseline surveys. Pregnant women in the endline survey were more likely to have received IFA (60.0% vs 45.8%, OR: 2.7 (1.2, 6.1)); and the proportion of pregnant women who reportedly consumed IFA daily in the previous 7 days was significantly higher in the endline than in the baseline survey (46.4% vs 32.8%, OR: 2.8 (1.2, 6.5)). There was no impact on the prevalence of adequate GWG or anaemia., Conclusions: The programmatic intervention resulted in a modest increase in the number of pregnant women who reported receiving and consuming IFA supplements as recommended, but did not affect ANC attendance and nutritional status., Competing Interests: Competing interests: BN works for Nutrition International., (© 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.)

Evidence on whether nutritional supplementation affects physical activity (PA) during early childhood is limited. We examined the long-term effects of lipid-based nutrient supplements (LNS) on total PA, moderate-to-vigorous PA (MVPA) and sedentary behaviour (SB) of children at 4-6 years using an accelerometer for 1 week. Their mothers were enrolled in the International Lipid-based Nutrient Supplement-DYAD randomised controlled trial in Ghana, assigned to daily LNS or multiple micronutrients (MMN) during pregnancy through 6 months postpartum or Fe and folic acid (IFA) during pregnancy and placebo for 6 months postpartum. From 6 to 18 months, children in the LNS group received LNS; the other two groups received no supplements. Analysis was done with intention to treat comparing two groups: LNS v. non-LNS (MMN+ IFA). Of the sub-sample of 375 children fitted with accelerometers, 353 provided sufficient data. Median vector magnitude (VM) count was 1374 (interquartile range (IQR) 309), and percentages of time in MVPA and SB were 4·8 (IQR 2) and 31 (IQR 8) %, respectively. The LNS group (n 129) had lower VM (difference in mean -73 (95 % CI -20, -126), P = 0·007) and spent more time in SB (LNS v. non-LNS: 32·3 v. 30·5 %, P = 0·020) than the non-LNS group (n 224) but did not differ in MVPA (4·4 v. 4·7 %, P = 0·198). Contrary to expectations, provision of LNS in early life slightly reduced the total PA and increased the time in SB but did not affect time in MVPA. Given reduced social-emotional difficulties in the LNS group previously reported, including hyperactivity, one possible explanation is less restless movement in the LNS group.

It is important to identify the periods during childhood when exposure to environmental risk factors results in long-term neurodevelopmental deficits. Stunting and anaemia may be sensitive indicators of exposure to such risks. In a prospective cohort enrolled before birth, we investigated the association of developmental scores at 4-6 years with (a) birth length and linear growth during three postnatal periods and (2) haemoglobin (Hb) concentration at three time points. Children were participants in a follow-up study of a randomized controlled trial of nutritional supplementation in Ghana. At 4-6 years, cognitive, motor, and social-emotional developments were assessed using standard tests adapted for this population. We estimated the associations of length-for-age z-score (LAZ) at birth and postnatal linear growth (n = 710) and Hb (n = 617) with developmental scores in regression models, using multistage least squares analysis to calculate uncorrelated residuals for postnatal growth. Cognitive development at 4-6 years was significantly associated with LAZ at birth (β = 0.12, 95% CI = 0.05, 0.19), ΔLAZ from 6 to 18 months (β = 0.16, 95% CI = 0.04, 0.28), and Hb at 18 months (β = 0.13, 95% CI = 0.06, 0.20), but not with ΔLAZ during 0-6 months, ΔLAZ from 18 months to 4-6 years, Hb at 6 months, or Hb at 4-6 years. No evidence of associations with motor or social-emotional development were found. These results suggest that in similar contexts, the earlier periods prior to birth and up to 18 months are more sensitive to risk factors for long-term cognitive development associated with LAZ and Hb compared with later childhood. This may inform the optimal timing of interventions targeting improved cognitive development., (© 2019 John Wiley & Sons Ltd.)

Background: Few studies have evaluated the long-term effects of nutritional supplementation during the first 1000 d of life. We previously reported that maternal and child lipid-based nutrient supplements (LNS) increased child length by 18 mo., Objective: The aim of this study was to examine the effects of LNS on later growth and body composition at 4-6 y of age., Design: This was a follow-up of children in the International Lipid-based Nutrient Supplements (iLiNS)-DYAD trial in Ghana. Women (n = 1320) at ≤20 weeks of gestation were randomly assigned to: 1) iron and folic acid during pregnancy and 200 mg calcium/d for 6 mo postpartum, 2) multiple micronutrients (1-2 RDA of 18 vitamins and minerals) during both periods, or 3) maternal LNS during both periods plus child LNS from 6 to 18 mo. At 4-6 y, we compared height, height-for-age z score (HAZ), and % body fat (deuterium dilution method) between the LNS group and the 2 non-LNS groups combined., Results: Data were available for 961 children (76.5% of live births). There were no significant differences between LNS compared with non-LNS groups in height [106.7 compared with 106.3 cm (mean difference, MD, 0.36; P = 0.226)], HAZ [-0.49 compared with -0.57 (MD = 0.08; P = 0.226)], stunting (< -2 SD) [6.5 compared with 6.3% (OR = 1.00; P = 0.993)], or % body fat [15.5 compared with 15.3% (MD = 0.16; P = 0.630)]. However, there was an interaction with maternal prepregnancy BMI (kg/m2) (P-interaction = 0.046 before correction for multiple testing): among children of women with BMI < 25 , LNS children were taller than non-LNS children (+1.1 cm, P = 0.017), whereas there was no difference among children of women with BMI ≥ 25 (+0.1 cm; P = 0.874)., Conclusions: There was no overall effect of LNS on height at 4-6 y in this cohort, which had a low stunting rate, but height was greater in the LNS group among children of nonoverweight/obese women. There was no adverse impact of LNS on body composition. This trial was registered at clinicaltrials.gov as NCT00970866., (Copyright © American Society for Nutrition 2019.)

Background: The impact of feeding a slightly sweet nutrient supplement early in life on later sweet taste preference is unknown., Objective: We tested the hypothesis that the level of sucrose most preferred by 4-6-y-old children exposed to a slightly sweet lipid-based nutrient supplement (LNS) early in life would not be higher than that of children never exposed to LNS., Design: We followed up children born to women (n = 1,320) who participated in a randomized trial in Ghana. In one group, LNS was provided to women on a daily basis during pregnancy and the first 6 mo postpartum and to their infants from age 6 to 18 mo (LNS group). The control groups received daily iron and folic acid or multiple micronutrients during pregnancy and the first 6 mo postpartum, with no infant supplementation (non-LNS group). At age 4-6 y, we randomly selected a subsample of children (n = 775) to assess the concentration of sucrose most preferred using the Monell 2-series, forced-choice, paired-comparison tracking procedure. We compared LNS with non-LNS group differences using a noninferiority margin of 5% weight/volume (wt/vol)., Results: Of the 624 children tested, most (61%) provided reliable responses. Among all children, the mean ± SD sucrose solution most preferred (% wt/vol) was 14.6 ± 8.6 (LNS group 14.9 ± 8.7; non-LNS group 14.2 ± 8.4). However, among children with reliable responses, it was 17.0 ± 10.2 (LNS group 17.5 ± 10.4; non-LNS group 16.5 ± 10.0). The upper level of the 95% CI of the difference between groups did not exceed the noninferiority margin in either the full sample or those with reliable responses, indicating that the LNS group did not have a higher sweet preference than the non-LNS group., Conclusion: Exposure to a slightly sweet nutrient supplement early in life did not increase the level of sweet taste most preferred during childhood. This trial was registered at clinicaltrials.gov as NCT00970866., (Copyright © American Society for Nutrition 2019.)

A child's endowment is a reflection of his/her genetic makeup and the conditions faced in early life. Parents build on their child's endowment by investing resources in their child, and together, a child's endowment and subsequent investments act as input into important later-life outcomes. A positive or negative shock to a child's endowment can have a direct biological effect on a child's long-term outcomes but may also affect parents' decisions about investments in the health and human capital of their children. Using follow-up data collected several years after a randomized trial in Ghana, we explored whether maternal and child supplementation with small-quantity lipid-based nutrient supplements (SQ-LNS) throughout much of the first 1,000 days influenced parental investments in the health and human capital of their children. Across the domains of family planning, breastfeeding, health, education, and paternal financial support, we found that, in general, the intervention did not affect investments in the treated child nor his/her untreated siblings. These results suggest that given production technologies, constraints, and preferences, the intervention either did not change parents' optimal investment strategies or that the effects of the intervention, namely increased birth size and attained length at 18 months of age, were too small for parents to perceive or to have any meaningful impact on parents' expectations about the returns to investments in their children., Competing Interests: The authors have declared that no competing interests exist.

Background: Whether consuming sweet foods early in life affects sweet food preferences and consumption later in childhood is unknown., Objective: We tested the hypothesis that exposure to a slightly sweet lipid-based nutrient supplement (LNS) early in life would not increase preference for or consumption of sweet items at preschool age., Methods: We followed up children who had participated in a randomized trial in Ghana in which LNS was provided to 1 group of women during pregnancy and 6 mo postpartum and to their infants from ages 6-18 mo (LNS group). The control group (non-LNS group) received iron and folic acid during pregnancy or multiple micronutrients during pregnancy and 6 mo postpartum, with no infant supplementation. At 4-6 y, we obtained data from caregivers on children's food and beverage preferences and consumption (n = 985). For a randomly selected subsample (n = 624), we assessed preference for sweet items using a photo game (range in potential scores, 0-15). For the photo game and reported consumption of sweet items, we examined group differences using predetermined noninferiority margins equivalent to an effect size of 0.2., Results: Median (quartile 1, quartile 3) reported consumption of sweet items (times in previous week) was 14 (8, 23) in the LNS group and 16 (9, 22) in the non-LNS group; in the photo game, the number of sweet items selected was 15 (11, 15) and 15 (11, 15), respectively. The upper level of the 95% CI of the mean difference between LNS and non-LNS groups did not exceed the noninferiority margins for these outcomes. Caregiver-reported preferences for sweet items also did not differ between groups (P = 0.9)., Conclusion: In this setting, where child consumption of sweet foods was common, exposure to a slightly sweet LNS early in life did not increase preference for or consumption of sweet foods and beverages at preschool age. This trial was registered at clinicaltrials.gov as NCT00970866., (© 2019 American Society for Nutrition.)

Background: In the International Lipid-Based Nutrient Supplements (iLiNS)-DYAD-Ghana trial, prenatal small-quantity lipid-based nutrient supplements (LNSs) had a positive effect on birth weight. Birth weight may be inversely related to blood pressure (BP) later in life., Objectives: We examined the effect of the intervention on BP at 4-6 y of age, and maternal and child factors related to BP., Methods: The iLiNS-DYAD-Ghana study was a partially double-blind, randomized controlled trial which assigned women (n = 1320) ≤20 weeks of gestation to daily supplementation with: 1) iron and folic acid during pregnancy and 200 mg Ca for 6 mo postpartum , 2) multiple micronutrients during pregnancy and postpartum, or 3) LNSs during pregnancy and postpartum plus LNSs for infants from 6 to 18 mo of age. At 4-6 y of age (n = 858, 70% of live births), we compared BP, a secondary outcome, between non-LNS and LNS groups and examined whether BP was related to several factors including maternal BP, child weight-for-age z score (WAZ), and physical activity., Results: Non-LNS and LNS groups did not differ in systolic (99.2 ± 0.4 compared with 98.5 ± 0.6 mm Hg; P = 0.317) or diastolic (60.1 ± 0.3 compared with 60.0 ± 0.4 mm Hg; P = 0.805) BP, or prevalence of high BP (systolic or diastolic BP ≥90th percentile of the US National Heart, Lung, and Blood Institute reference: 31% compared with 28%; P = 0.251). BP at 4-6 y of age was positively related to birth weight; this relation was largely mediated through concurrent WAZ in a path model. Concurrent WAZ and maternal BP were the factors most strongly related to child BP., Conclusions: Despite greater birth weight in the LNS group, there was no intervention group difference in BP at 4-6 y. In this preschool population at high risk of adult hypertension based on BP at 4-6 y, high maternal BP and child WAZ were key factors related to BP. This trial was registered at clinicaltrials.gov as NCT00970866., (© 2019 American Society for Nutrition.)

Background: Adequate nutrition is necessary for brain development during pregnancy and infancy. Few randomized controlled trials of supplementation during these periods have measured later developmental outcomes., Objective: Our objective was to investigate the effects of provision of prenatal and postnatal lipid-based nutrient supplements (LNS) on child development at preschool age., Methods: We conducted a follow-up study of 966 children aged 4-6 y in 2016, born to women who participated in the International Lipid-Based Nutrient Supplements-DYAD trial conducted in Ghana in 2009-2014, representing 79% of eligible children. Women ≤20 weeks of gestation were randomized to daily LNS or multiple micronutrient (MMN) capsules during pregnancy through 6 mo postpartum or iron and folic acid (IFA) capsules during pregnancy and calcium placebo capsules during 6 mo postpartum. Children in the LNS group received LNS from 6 to 18 mo. Primary outcomes of this follow-up study were (1) a cognitive factor score based on a test battery adapted from several standard tests, 2) fine motor score (9-hole pegboard test), and (3) social-emotional difficulties (Strengths and Difficulties Questionnaire; SDQ). Eight secondary outcomes were calculated in specific domains (e.g., language, SDQ prosocial). Analysis was by a complete case intention to treat in a 2-group comparison: LNS compared with non-LNS (MMN + IFA)., Results: Children in the LNS group had significantly lower social-emotional difficulties z-scores than children in the non-LNS group (adjusted for child age β = -0.12, 95% CI: -0.25, 0.02, P = 0.087; fully adjusted β = -0.16, 95% CI: -0.29, -0.03, P = 0.013). The effect of LNS on social-emotional difficulties score was larger among children living in households with lower home environment scores (P-interaction = 0.081). No other outcomes differed between the 2 intervention groups., Conclusions: Provision of LNS during the first 1000 d of development improved behavioral function, particularly for children from low nurturing and stimulation households, but did not affect cognition at preschool age in this setting. Trial Registration: clinicaltrials.gov, Identifier NCT00970866.