Management of neurological symptoms in Lesch-Nyhan disease: A systematic review.

Lesch-Nyhan Disease (LND) is an X-linked recessive genetic disorder arising from hypoxanthine phosphoribosyltransferase 1 gene mutations, leading to a complete deficiency. LND presents a complex neurological profile characterized by generalized dystonia, motor dysfunctions and self-injurious behavior, which management is challenging. We conducted a systematic review of studies assessing the efficacy of pharmacological and non-pharmacological interventions in management of neurological symptoms in LND (PROSPERO registration number:CRD42023446513). Among 34 reviewed full-text papers; 22 studies were rated as having a high risk of bias. Considerable heterogeneity was found in studies regarding the timing of treatment implementation, adjunctive treatments and outcome assessment. Single-patient studies and clinical trials often showed contradictory results, while therapeutic failures were underreported. S-Adenosylmethionine and Deep Brain Stimulation were the most studied treatment methods and require further research to address inconsistencies. The evidence from levodopa studies underlines that optimal timing of treatment implementation should be thoroughly investigated. Standardized study design and reducing publication bias are crucial to overcome current limitations of assessing intervention efficacy in LND.

Anthropometric and sociodemographic variables, but not preconception or prenatal maternal nutrition supplementation, predict neurodevelopment in offspring of the 'Women First' trial.

Multiple factors influence infant and child neurodevelopment in low resource settings. In offspring of participants in the preconception maternal nutrition trial, Women First (WF), we examined the impact of providing a preconception (Arm 1) or prenatal (Arm 2) nutrient supplement (compared to controls, Arm 3) on neurodevelopmental outcomes at 24 months; predictors of neurodevelopment scores; and associations of infant anthropometrics with neurodevelopmental scores. Follow-up visits for anthropometry were conducted at 6-, 12-, 18- and 24-month of age. At 24-months, in a randomized subset, the Bayley Scales of Infant Development, 3rd edition (BSID-III), including cognitive, motor and social-emotional subscales, and the Family Care Indicators (FCI) questionnaire, assessing family and home environment, were completed. Multiple covariates (intervention arm, site, maternal sociodemographic characteristics, FCI subscales, birthweight and 6-24 months' change in anthropometry z-scores, (e.g., ΔLAZ6-2 4) were evaluated by linear regression to predict BSID-III outcomes and to assess associations of anthropometric changes with BSID-III scores. The analysis consisted of 1386 infants (n = 441, 486, 459 for Arms 1, 2 and 3, respectively). None of the domain-specific BSID-III subscale scores differed by maternal intervention arm. Four covariates significantly predicted (p ≤ 0.01) all 3 BSID-III subscales: secondary maternal education, ΔLAZ6 - 24, birthweight >2500 g, and FCI play materials. Linear growth was associated with all domains of neurodevelopment. The results underscore the multi-dimensional aspects of child development represented by the nurturing care framework, including prenatal maternal nutrition, post-natal growth, maternal education for responsive caregiving and opportunities for early learning.

Perinatal intervention strategies providing food with micronutrients to pregnant and breastfeeding women in low- and middle-income countries: A scoping review.

In resource-constrained settings, pregnant and breastfeeding women and girls (PBW/G) are particularly vulnerable to undernutrition. Micronutrient-fortified balanced energy protein (BEP) supplementation may be provided to boost maternal nutritional status and improve birth and infant outcomes. We conducted a scoping review of the published literature to determine the impact of BEP and other related nutrition interventions that provided fortified food or cash along with a minimum of 3 micronutrients on maternal, birth, and infant/child outcomes in low- and middle-income countries. We conducted a PubMed search using pre-defined keywords and controlled vocabulary search terms. All titles and abstracts were reviewed for eligibility by two independent reviewers, and data were extracted according to outcome type. We identified 149 eligible research articles that reported on a total of 21 trials and/or programme evaluations which assessed the health impact of one or more products (fortified lipid-based nutrient supplement [LNS, n = 12], fortified blended flours [n = 5], milk-based beverages [n = 2], and local food/snacks [n = 3]) that provided 118-750 kcal/day and varying levels of protein and micronutrients. Only one of these programme evaluations assessed the impact of the provision of cash and fortified food. Effects on maternal outcomes such as gestational weight gain and duration of gestation were promising but inconsistent. Birth outcomes were reported in 15 studies, and the effects on birthweight and birth length were generally positive. Seven studies demonstrated sustained benefits on infant and child growth out of the 15 studies that reported at least one of these outcomes, although data were sparse. Additional research is needed to investigate issues of dose, cost-effectiveness, and incorporation into multi-component interventions.

Zinc Supplementation Initiated Prior to or During Pregnancy Modestly Impacted Maternal Status and High Prevalence of Hypozincemia in Pregnancy and Lactation: The Women First Preconception Maternal Nutrition Trial.

BACKGROUND: Data regarding effects of small-quantity-lipid-based nutrient supplements (SQ-LNS) on maternal serum zinc concentrations (SZC) in pregnancy and lactation are limited. OBJECTIVES: The objectives of this study were to evaluate the effect of preconception compared with prenatal zinc supplementation (compared with control) on maternal SZC and hypozincemia during pregnancy and early lactation in women in low-resource settings, and assess associations with birth anthropometry. METHODS: From ∼100 women/arm at each of 3 sites (Guatemala, India, and Pakistan) of the Women First Preconception Maternal Nutrition trial, we compared SZC at 12- and 34-wk gestation (n = 651 and 838, respectively) and 3-mo postpartum (n = 742) in women randomly assigned to daily SQ-LNS containing 15 mg zinc from ≥3 mo before conception (preconception, arm 1), from ∼12 wk gestation through delivery (early pregnancy, arm 2) or not at all (control, arm 3). Birth anthropometry was examined for newborns with ultrasound-determined gestational age. Statistical analyses were performed separately for each time point. RESULTS: At 12-wk gestation and 3-mo postpartum, no statistical differences in mean SZC were observed among arms. At 34-wk, mean SZC for arms 1 and 2 were significantly higher than for arm 3 (50.3, 50.8, 47.8 µg/dL, respectively; P = 0.005). Results were not impacted by correction for inflammation or albumin concentrations. Prevalence of hypozincemia at 12-wk (<56 µg/dL) was 23% in Guatemala, 26% in India, and 65% in Pakistan; at 34 wk (<50 µg/dL), 36% in Guatemala, 48% in India, and 74% in Pakistan; and at 3-mo postpartum (<66 µg/dL) 79% in Guatemala, 91% in India, and 92% in Pakistan. Maternal hypozincemia at 34-wk was associated with lower birth length-for-age Z-scores (all sites P = 0.013, Pakistan P = 0.008) and weight-for-age Z-scores (all sites P = 0.017, Pakistan P = 0.022). CONCLUSIONS: Despite daily zinc supplementation for ≥7 mo, high rates of maternal hypozincemia were observed. The association of hypozincemia with impaired fetal growth suggests widespread zinc deficiency in these settings. This trial is registered at clinicaltrials.gov as #NCT01883193.

The Cost and Cost-Effectiveness of an Integrated Wasting Prevention and Screening Intervention Package in Burkina Faso and Mali.

BACKGROUND: Little is known about costs and cost effectiveness of interventions that integrate wasting prevention into screening for child wasting. OBJECTIVES: This study's objective was to estimate the cost and cost-effectiveness of an intervention that integrated behavior change communication (BCC) and small-quantity lipid-based nutrient supplements (SQ-LNS) into platforms for wasting screening in Burkina Faso (a facility-based platform, where BCC was enhanced compared with standard care) and Mali (a community-based platform, with standard BCC). METHODS: Activity-based costing was used to estimate the cost per child-contact for the intervention and the comparison group, which did not receive the intervention. Costs were ascertained from accounting records, interviews, surveys, and observations. The number of child-contacts was calculated using population size estimates and average attendance rates for each service. Costs per disability-adjusted life year (DALY) averted were estimated using a Markov model populated with data from the parent trials on impact of wasting incidence and treatment coverage. RESULTS: In the intervention group in Burkina Faso, the cost per child-contact of facility-based screening was $0.85 of enhanced BCC was $4.28, and of SQ-LNS was $8.86. In Mali, the cost per child-contact of community-based screening was $0.57, standard BCC was $0.72, and SQ-LNS was $4.14. Although no SQ-LNS costs were incurred in the comparison groups (hence lower total costs), costs per child-contact for screening and BCC were higher because coverage of these services was lower. The intervention package cost $1073 per DALY averted in Burkina Faso and $747 in Mali. CONCLUSIONS: Integration of wasting prevention into screening for child wasting led to higher total costs but lower unit costs than standard screening due to increased coverage. Greater cost-effectiveness could be achieved if BCC were strengthened and led to improved caregiver health and nutrition practices and if screening triggered appropriate use of services and higher treatment coverage.

Factors associated with increased diagnostic yield of endobronchial ultrasound-guided transbronchial needle aspiration: an observational single center study.

Background: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is an innovative tool for diagnosing mediastinal diseases. We investigated the factors affecting the diagnostic yield of EBUS-TBNA and evaluated whether the effects of these factors (number of biopsies, core tissue acquisition rate, and diameter and volume of tissue) vary depending on computed tomography (CT) and/or positron emission tomography (PET)/CT results. Methods: We retrospectively analyzed lung cancer patients who underwent EBUS-TBNA at Korea University Ansan Hospital (January 2019-December 2022). Patients in whom EBUS-TBNA failed and those with missing diameter or volume data and no imaging data interpretation were excluded. Subgroup analysis was performed by dividing the patients into None (no cancer detected on CT or PET/CT), Either (cancer detected on either CT or PET/CT), and Both (cancer detected on both CT and PET/CT) groups. Results: In all, 228 patients were enrolled; 351 lymph node stations were analyzed. The median age of the patients was 69 years (male, 76.8%). Adenocarcinoma (28.5%) was the most common diagnosis. EBUS-TBNA was predominantly performed at station #4R (30.5%). Each examination involved two stations with a total procedure time of 30 minutes. An increased number of passes led to a higher diagnostic yield for EBUS-TBNA (P<0.001). Additionally, successful tissue sampling was associated with a large diameter (P=0.016) and volume (P=0.002) of the tissue. The effect of these factors was modified by imaging results. In the None and Either groups, an increase in the pass number was correlated with an increased diagnostic yield (adjusted P=0.003 and 0.007, respectively). However, in the Both group, it was not significant and remained at a suggestive level (P=0.304). The diameter and volume did not differ significantly across subgroups (adjusted P>0.05). Conclusions: Increasing the number of passes during EBUS-TBNA can maximize the diagnostic yield, especially when CT and/or PET/CT results are inconclusive.

Classification of superficial suspected lymph nodes: non-invasive radiomic model based on multiphase contrast-enhanced ultrasound for therapeutic options of lymphadenopathy.

Background: Accurate determination of the types of lymphadenopathy is of great importance in disease diagnosis and treatment and is usually confirmed by pathological findings. Radiomics is a non-invasive tool that can extract quantitative information from medical images. Our study was designed to develop a non-invasive radiomic approach based on multiphase contrast-enhanced ultrasound (CEUS) images for the classification of different types of lymphadenopathy. Methods: A total of 426 patients with superficial suspected lymph nodes (LNs) from three centres were grouped into a training cohort (n=190), an internal testing cohort (n=127), and an external testing cohort (n=109). The radiomic features were extracted from the prevascular phase, vascular phase, and postvascular phase of the CEUS images. Model 1 (the conventional feature model), model 2 (the multiphase radiomics model), and model 3 (the combined feature model) were established for lymphadenopathy classification. The area under the curve (AUC) and confusion matrix were used to evaluate the performance of the three models. The usefulness of the models was assessed in different threshold probabilities by decision curve analysis. Results: There were 139 patients (32.6%) with benign LNs, 110 patients (25.8%) with lymphoma, and 177 patients (41.5%) with metastatic LNs in our population. Finally, twenty features were selected to construct the radiomics models for these three types of lymphadenopathy. Model 2 integrating multiphase images of the CEUS yielded the AUCs of 0.838, 0.739, and 0.733 in the training cohort, internal testing cohort, and external testing cohort, respectively. After the combination of conventional features and radiomic features, the AUCs of model 3 improved to 0.943, 0.823 and 0.785 in the training cohort, internal testing cohort, and external testing cohort. Besides, model 3 had an accuracy of 81.05%, sensitivity of 80%, and specificity of 90.43% in the training cohort. Model performance was further confirmed in the internal testing cohort and external testing cohort. Conclusions: We constructed a combined feature model using a series of CEUS images for the classification of the lymphadenopathies. For patients with superficial suspected LNs, this model can help clinicians make a decision on the LN type noninvasively and choose appropriate treatments.

Nutrition supplementation plus standard of care versus standard of care alone or standard of care plus unconditional cash transfer in the prevention of chronic malnutrition in Southern Angola: study protocol for the MuCCUA study, a cluster randomized controlled trial.

BACKGROUND: Chronic malnutrition is a condition associated with negative impacts on physical and cognitive development. It is multi-causal and can start very early in life, already in utero, thus it is especially challenging to find appropriate interventions to tackle it. The government of Angola is implementing a standard of care program with potential to prevent it, and the provision of cash transfers and the supplementation with small quantity lipid-based nutrients (SQ-LNS) are also promising interventions. We aimed to evaluate the impact of the standard of care program alone and of the standard of care plus a cash transfer intervention in the lineal growth of children less than 2 years old and compare it to the effectiveness of a nutrition supplementation plus standard of care program in Southern Angola. METHODS/DESIGN: The three-arm parallel cluster randomised controlled trial is set in four communes of Huila and Cunene provinces. Clusters are villages or neighbourhoods with a population around 1075 people. A total of twelve clusters were selected per arm and forty pregnant women are expected to be recruited in each cluster. Pregnant women receive the standard of care alone, or the standard of care plus unconditional cash transfer or plus nutritional supplementation during the first 1000 days, from pregnancy to the child reaching 24 months. The primary outcome is the prevalence of stunting measured as height-for-age Z-score (HAZ) < -2 in children below 2 years. Impact will be assessed at 3, 6, 12, 18 and 24 months of children's age. Secondary outcomes include mortality, morbidity, caring, hygiene and nutrition behaviours and practices, and women and children's dietary diversity. Quantitative data are also collected on women's empowerment, household food security, expenditure and relevant clinical and social events at baseline, endline and intermediate time points. DISCUSSION: The results will provide valuable information on the impact of the standard of care intervention alone as well as combined with an unconditional cash transfer intervention compared to a nutrition supplementation plus standard of care intervention, carried out during the first 1000 days, in the children´s growth up to 2 years and related outcomes in Southern Angola. TRIAL REGISTRATION: Clinical Trials NCT05571280. Registered 7 October 2022.

Lipid-based Nutritional Supplement Impact on Energy Intake, Appetite, Glucose and Insulin Levels in Under-Weight Pregnant and Lactating Women with Preeclampsia.

OBJECTIVE: To investigate the response of nutritional supplement (LNS-PLW) on appetite score, energy intake, insulin and glucose levels in preeclamptic women. DESIGN & PARTICIPANTS: Sixty under-weight preeclamptic primigravida were divided into two groups randomly and provided LNS-PLW/Placebo in the fasted state. Blood samples were collected at fasting state, after 30mins of supplementation, "ad libitum buffet" breakfast and lunch for glucose and insulin levels. RESULTS: Total energy intake was higher significantly in the LNS-PLW group, although during breakfast it was significantly reduced. The insulin and glucose concentration was significantly increased after 30min of supplementation in the LNS-PLW group. CONCLUSION: Intake of the LNS-PLW by pre-eclamptic women had short-term suppression on subsequent meal but improved total energy intake during trial.

Seasonal Factors Are Associated with Activities of Enzymes Involved in High-Density Lipoprotein Metabolism among Pregnant Females in Ghana.

Background: Small-quantity lipid-based nutrient supplements (SQ-LNS) during pregnancy and postnatally were previously shown to improve high-density lipoprotein (HDL) cholesterol efflux capacity (CEC) and length in the children of supplemented mothers at 18 mo of age in the International Lipid-Based Nutrient Supplements (iLiNS) DYAD trial in Ghana. However, the effects of SQ-LNS on maternal HDL functionality during pregnancy are unknown. Objective: The goal of this cross-sectional, secondary outcome analysis was to compare HDL function in mothers supplemented with SQ-LNS vs. iron and folic acid (IFA) during gestation. Methods: HDL CEC and the activities of 3 HDL-associated enzymes were analyzed in archived plasma samples (N = 197) from a subsample of females at 36 weeks of gestation enrolled in the iLiNS-DYAD trial in Ghana. Correlations between HDL function and birth outcomes, inflammatory markers C-reactive protein (CRP) and alpha-1-acid glycoprotein (AGP), and the effects of season were explored to determine the influence of these factors on HDL function in this cohort of pregnant females. Results: There were no statistically significant differences in HDL CEC, plasma lecithin-cholesterol acyltransferase (LCAT) activity, cholesteryl ester transfer protein (CETP) activity, or phospholipid transfer protein (PLTP) activity between mothers supplemented with SQ-LNS compared with IFA control, and no statistically significant relationships between maternal HDL function and childbirth outcomes. LCAT activity was negatively correlated with plasma AGP (R = -0.19, P = 0.007) and CRP (R = -0.28, P < 0.001), CETP and LCAT activity were higher during the dry season compared to the wet season, and PLTP activity was higher in the wet season compared to the dry season. Conclusions: Mothers in Ghana supplemented with SQ-LNS compared with IFA during gestation did not have measurable differences in HDL functionality, and maternal HDL function was not associated with childbirth outcomes. However, seasonal factors and markers of inflammation were associated with HDL function, indicating that these factors had a stronger influence on HDL functionality than SQ-LNS supplementation during pregnancy. Clinical Trial Registry number: The study was registered as NCT00970866. https://clinicaltrials.gov/study/NCT00970866.

Comparative analysis of methodologies for predicting overall survival in patients with non-small cell lung cancer based on the number and rate of resected positive lymph nodes: A study based on the SEER database for 2010 through 2019.

BACKGROUND: Lymph node (LN) metastasis is crucial in non-small cell lung cancer (NSCLC) prognosis and treatment, but the TNM system lacks LN quantity consideration. Our goal is to investigate the role of positive LNs (nPLN) and positive LN rate (LNR) in overall survival (OS) and assess whether they offer higher value in prognostic assessment of NSCLC than N-stage. METHODS: Patients were stratified into four subgroups using X-Tile software. Statistical analysis was conducted using the Kaplan-Meier method, univariate analysis, and multivariate Cox regression analysis. Model performance was evaluated using the Harrell consistency index (C-index), Akaike information criterion (AIC), and Bayesian information criterion (BIC). The prognostic performance of the nodal classification was validated using overall survival as the endpoint. RESULTS: The survival curves demonstrate distinct disparities between each nPLN and LNR category. A pronounced trend toward deteriorating overall survival from N-PLN 1 to N-PLN 2+ was observed across all tumor size categories. However, the differences between each LNR category were only significant for tumors ≤3 cm and 5-7 cm. Notably, both nPLN and LNR classifications displayed a higher C-index, lower AIC, and lower BIC compared with the N staging. Furthermore, the LNR classification provided superior prognostic stratification when compared with the nPLN classification. CONCLUSIONS: Our results demonstrate that nPLN and LNR classifications may offer improved prognostic performance compared with the current N classification for LN-positive NSCLC patients. Nonetheless, more studies are needed to assess the feasibility of incorporating these classifications into the next TNM staging system.

LUNCRW: Prediction of potential lncRNA-disease associations based on unbalanced neighborhood constraint random walk.

Accumulating evidence suggests that long non-coding RNAs (lncRNAs) are associated with various complex human diseases. They can serve as disease biomarkers and hold considerable promise for the prevention and treatment of various diseases. The traditional random walk algorithms generally exclude the effect of non-neighboring nodes on random walking. In order to overcome the issue, the neighborhood constraint (NC) approach is proposed in this study for regulating the direction of the random walk by computing the effects of both neighboring nodes and non-neighboring nodes. Then the association matrix is updated by matrix multiplication for minimizing the effect of the false negative data. The heterogeneous lncRNA-disease network is finally analyzed using an unbalanced random walk method for predicting the potential lncRNA-disease associations. The LUNCRW model is therefore developed for predicting potential lncRNA-disease associations. The area under the curve (AUC) values of the LUNCRW model in leave-one-out cross-validation and five-fold cross-validation were 0.951 and 0.9486 ± 0.0011, respectively. Data from published case studies on three diseases, including squamous cell carcinoma, hepatocellular carcinoma, and renal cell carcinoma, confirmed the predictive potential of the LUNCRW model. Altogether, the findings indicated that the performance of the LUNCRW method is superior to that of existing methods in predicting potential lncRNA-disease associations.

Effectiveness of locally produced ready to use supplementary food on hemoglobin, anthropometrics, and plasma micronutrients concentrations of 6 to 23 months age children: a non-randomized community-based trial from Pakistan.

Background: Micronutrient deficiencies including vitamin A, vitamin D, and zinc are highly prevalent in children below 5 years of age in low and -middle-income countries. We aimed to evaluate the effectiveness of ready-to-use Lipid-based Nutrient Supplement-Medium Quantity (LNS-MQ) local name "Wawa-mum" on plasma micronutrient status, hemoglobin concentration and anthropometric measurements. Methods: A community-based non-randomized trial was conducted in the Kurram district of Khyber Pakhtunkhwa from January 2018 to June 2019. A total of 110 children aged 6 to 23 months old were recruited and allocated to the intervention and control arm of the study. A total of 57 children in the intervention arm received a daily ration of 50 g of Wawa-mum, for one year. To assess the impact of the intervention on primary outcome measures, i.e., serum vitamin A, D concentration, plasma zinc, and hemoglobin concentration. Blood samples were collected at baseline and after one year following the intervention. The vitamins concentration in serum were assessed using Enzyme-Linked Immunosorbent Assay (ELISA) and plasma zinc by atomic absorption spectrometry. The hemoglobin concentration was measured by an automated hematology analyzer. A 24-h dietary recall interview was used to assess the nutrient intake adequacy. Multivariate Linear regression models were used to analyze the outcomes while controlling for potential confounders. Results: In the intervention arm, children had on average 6.2 µg/dL (95% CI 3.0-9.3, value of p<0.001) increase in the serum vitamin A concentration, 8.1 ng/mL (95% CI 1.3-14.9, value of p 0.02) increase in serum vitamin D concentration and 49.0 µg/dL (95% CI 33.5-64.5, value of p<0.001) increase in the plasma zinc concentration, and 2.7 g/dL (95% CI 2.0-3.3, value of p<0.001) increase in hemoglobin concentration while adjusted for covariates. An addition, length-for-age z-score (LAZ), weight-for-length z-score (WLZ), weight-for-age z-score (WAZ), and prevalence of undernutrition including stunting, wasting, and underweight were calculated as a secondary outcome to investigate the impact of micronutrients on growth parameters, that has been improved significantly after receiving the Wawa-mum. Conclusion: Wawa-mum (LNS-MQ) is an effective intervention to improve the micronutrient status, hemoglobin concentration, and growth parameters in 6 to 23 months children, which can be scaled up in the existing health system to address the alarming rates of under nutrition in Pakistan and other developing countries. Clinical trial registration: https://doi.org/10.1186/ISRCTN94319790, ISRCTN94319790.

Treatment outcomes and associated factors for hospitalization of children treated for acute malnutrition under the OptiMA simplified protocol: a prospective observational cohort in rural Niger.

Introduction: Globally, access to treatment for severe and moderate acute malnutrition is very low, in part because different protocols and products are used in separate programs. New approaches, defining acute malnutrition (AM) as mid-upper arm circumference (MUAC) < 125 mm or oedema, are being investigated to compare effectiveness to current programs. Optimizing Malnutrition treatment (OptiMA) is one such strategy that treats AM with one product - ready-to-use therapeutic food, or RUTF - at reduced dosage as the child improves. Methods: This study aimed to determine whether OptiMA achieved effectiveness benchmarks established in the Nigerien National Nutrition protocol. A prospective cohort study of children in the rural Mirriah district evaluated outcomes among children 6-59 months with uncomplicated AM treated under OptiMA. In a parallel, unconnected program in one of the two trial sites, all non-malnourished children 6-23 months of age were provided small quantity lipid-based nutritional supplements (SQ-LNS). A multivariate logistic regression identified factors associated with hospitalization. Results: From July-December 2019, 1,105 children were included for analysis. Prior to treatment, 39.3% of children received SQ-LNS. Recovery, non-response, and mortality rates were 82.3%, 12.6%, and 0.7%, respectively, and the hospitalization rate was 15.1%. Children who received SQ-LNS before an episode of AM were 43% less likely to be hospitalized (ORa=0.57; 0.39-0.85, p = 0.004). Discussion: OptiMA had acceptable recovery compared to the Nigerien reference but non-response was high. Children who received SQ-LNS before treatment under OptiMA were less likely to be hospitalized, showing potential health benefits of combining simplified treatment protocols with food-based prevention in an area with a high burden of malnutrition such as rural Niger.

Effect of Milk Protein and Whey Permeate in Large-Quantity Lipid-Based Nutrient Supplement on Early Child Development among Children with Stunting: A Randomized 2 × 2 Factorial Trial in Uganda.

Stunting affects 22% children globally, putting them at risk of adverse outcomes including delayed development. We investigated the effect of milk protein (MP) vs. soy and whey permeate (WP) vs. maltodextrin in large-quantity, lipid-based nutrient supplement (LNS), and LNS itself vs. no supplementation, on child development and head circumference among stunted children aged 1-5 years. We conducted a randomized, double-blind, community-based 2 × 2 factorial trial in Uganda (ISRCTN1309319). We randomized 600 children to one of four LNS formulations (~535 kcal/d), with or without MP (n = 299 vs. n = 301) or WP (n = 301 vs. n = 299), for 12 weeks or to no supplementation (n = 150). Child development was assessed using the Malawi Development Assessment Tool. Data were analyzed using linear mixed-effects models. Children had a median [interquartile range] age of 30 [23; 41] months and mean ± standard deviation height-for-age z-score of -3.02 ± 0.74. There were no interactions between MP and WP for any of the outcomes. There was no effect of either MP or WP on any developmental domain. Although LNS itself had no impact on development, it resulted in 0.07 (95%CI: 0.004; 0.14) cm higher head circumference. Neither dairy in LNS, nor LNS in itself, had an effect on development among already stunted children.

Prenatal and postnatal small-quantity lipid-based nutrient supplements and children's social-emotional difficulties at ages 9-11 y in Ghana: follow-up of a randomized controlled trial.

BACKGROUND: Provision of small-quantity lipid-based nutrient supplements (SQ-LNSs) during early life improves growth and development. In the International Lipid-Based Nutrient Supplements DYAD-Ghana trial, prenatal and postnatal SQ-LNS reduced social-emotional difficulties at age 5 y, with greater effects among children in less-enriched home environments. OBJECTIVES: We aimed to investigate the effect of prenatal and postnatal SQ-LNS on children's social-emotional problems at age 9-11 y. METHODS: In 2009-2011, 1320 pregnant women ≤20 wk gestation were randomly assigned to receive the following daily until 6 mo postpartum: 1) iron and folic acid until delivery, then placebo, 2) multiple micronutrients (MMNs), or 3) SQ-LNS (20 g/d). Children in group 3 received SQ-LNS from 6 to 18 mo. In 2021, we evaluated children's social-emotional outcomes with 6 assessment tools that used caregiver, teacher, and/or self-report to measure socioemotional difficulties, conduct problems, temperament, mood, anxiety, and emotion management. RESULTS: We assessed outcomes in 966 children, comprising 79.4% of 1217 participants eligible for re-enrolment. No significant differences were found between the SQ-LNS and control (non-LNS groups combined) groups. Few children (<2%) experienced high parent-reported social-emotional difficulties at 9-11 y, in contrast to the high prevalence at age 5 in this cohort (25%). Among children in less-enriched early childhood home environments, the SQ-LNS group had 0.37 SD (-0.04 to 0.82) lower self-reported conduct problems than the control group (P-interaction = 0.047). CONCLUSIONS: Overall positive effects of SQ-LNS on social-emotional development previously found at age 5 y are not sustained to age 9-11 y; however, there is some evidence of positive effects among children in less-enriched environments. The lack of effects may be owing to low prevalence of social-emotional problems at preadolescence, resulting in little potential to benefit from early nutritional intervention at this age in this outcome domain. Follow-up during adolescence, when social-emotional problems more typically onset, may yield further insights. This trial was registered at clinicaltrials.gov as NCT00970866. https://clinicaltrials.gov/ct2/show/record/NCT00970866.

Nutritious Supplemental Foods for Pregnant Women from Food Insecure Settings: Types, Nutritional Composition, and Relationships to Health Outcomes.

There is growing evidence that the provision of nutritious supplemental foods to undernourished pregnant women can improve maternal and infant outcomes. However, comparing and synthesizing the evidence base is complicated by differences in interventions and products and the use of ambiguous terminology. We aimed to define 2 common types of nutritious supplemental foods used in pregnancy, balanced energy-protein (BEP) supplements and lipid-based nutrient supplements (LNS), and to review the evidence supporting each via a narrative review of systematic reviews and meta-analyses (SRMAs). Information about the nutritional composition of the food supplements and their effects on maternal and infant outcomes was abstracted. Five SRMAs (n = 20 trials) evaluated the effect of BEP compared with no BEP/control (comparison group commonly received iron and folic acid [IFA]). BEP foods/products ranged in calories (118-1017 kcals), protein (3-50 g), fat (6-57 g), and micronutrient content. Overall, maternal BEP improved birth weight and reduced the risk of stillbirth and small for gestational age when compared with no BEP/control in pregnancy. Three SRMAs (n = 5 trials) evaluated the effect of LNS compared with IFA or multiple micronutrients (MMNs). The LNS interventions comprised small- and large-quantity LNS that ranged in calories (118-746 kcals), protein (3-21 g), fat (10-53 g), and micronutrient content. LNS compared with IFA increased pregnancy duration, birth weight, and birth length and reduced the risk of small for gestational age and infant stunting; however, no beneficial effect of LNS was identified when compared with MMN. Despite heterogeneity in the nutritional composition of BEP supplements, the evidence suggests that in nutritionally at-risk populations, these products may improve birth outcomes in pregnant women. The evidence is limited but promising when LNS is compared with IFA in improving maternal and infant outcomes. Overall, BEP, compared with MMN or LNS, are key areas that have not been studied and deserve attention.

Therapeutic gene correction for Lesch-Nyhan syndrome using CRISPR-mediated base and prime editing.

Lesch-Nyhan syndrome (LNS) is inherited as an X-linked recessive genetic disorder caused by mutations in hypoxanthine-guanine phosphoribosyl transferase 1 (HPRT1). Patients with LNS show various clinical phenotypes, including hyperuricemia, gout, devastating behavioral abnormality, intellectual disability, and self-harm. Although uric acid overproduction can be modulated with the xanthine oxidase inhibitor allopurinol, there exists no treatment for behavioral and neurological manifestations of LNS. In the current study, CRISPR-mediated base editors (BEs) and prime editors (PEs) were utilized to generate LNS-associated disease models and correct the disease models for therapeutic approach. Cytosine BEs (CBEs) were used to induce c.430C>T and c.508C>T mutations in HAP1 cells, and then adenine BEs (ABEs) were used to correct these mutations without DNA cleavage. PEs induced a c.333_334ins(A) mutation, identified in a Korean patient with LNS, in HAP1 cells, which was corrected in turn by PEs. Furthermore, improved PEs corrected the same mutation in LNS patient-derived fibroblasts by up to 14% without any unwanted mutations. These results suggest that CRISPR-mediated BEs and PEs would be suggested as a potential therapeutic strategy of this extremely rare, devastating genetic disease.

Effects of Oral Lipid-Based nutritional supplements on appetite, energy intake, and lipid profile of moderately underweight children.

Oral lipid-based nutritional supplements (LNS) are designed to ensure dietary adequacy and to improve malnourishment in children. Therefore, this study investigated the effects of 4 weeks of LNS on appetite, energy intake, and lipid profile of moderately underweight children (5-10 years old) with BMI-Z score between -2 and - 3 SDS, recruited in a single-blind randomized control trial. In addition to the regular dietary intake, fasting blood samples, anthropometric measurements, energy intake, and appetite responses were obtained before and after 4 weeks of LNS (535 kcal) or PLACEBO (92 kcal). After 4 weeks of supplementation mean energy intake (kcal) (p < .001), body weight (kg) (p < .001), BMI (kg/m2) (p < .01), mid-upper arm circumference (cm) (p < .01), total cholesterol (mg/dl) (p < .01) and fasting glucose (mg/dl) (p < .01) were raised significantly in the LNS group as compared to the PLACEBO group. No significant changes were detected in appetite responses (p > 0.05). In conclusion, LNS increases the overall energy intake, but does not affect the appetite but may induce hyperglycemia and hyperlipidemia.

Moderators of metacognitive strategy training for executive functioning in early schizophrenia and psychosis risk.

Goal Management Training (GMT) improved self-reported executive functioning in a recent randomized, controlled trial in early intervention for psychosis participants. Little is known about the mechanism for this benefit, so this study investigates objectively measured executive function, the difference between subjective and objective executive function, independent living and employment status as potential moderators of efficacy of GMT. Baseline scores from 81 participants (GMT n = 39 vs Treatment-as-usual; TAU n = 42) were analyzed in a linear mixed model analysis for repeated measures as predictors of improvement on the self-reported Behavior Rating Inventory of Executive Function-Adult version (BRIEF-A) immediately and 30 weeks after GMT. Potential moderators were scores from objective measures of executive functioning, discrepancy between subjective and objective measures, independent living and employment status. Discrepancy was assessed by comparing four clusters of participants with differing patterns of scores. The effect of GMT remained significant regardless of initial objective executive functioning at baseline. Those with higher subjective complaints at baseline in two clusters with (i) both objective and subjective executive dysfunction, and (ii) mostly subjective executive dysfunction experienced greater change after treatment. Living arrangements or participation in education or work did not significantly moderate the effects of GMT. Poor performance on neuropsychological tasks is not an obstacle to making use of GMT, but further knowledge is needed about the benefits of strategy training for individuals with a combination of poor performance with few subjective complaints.