The structure and mechanism of action of a distinct class of dicistrovirus intergenic region IRESs.

Internal ribosomal entry sites (IRESs) engage with the eukaryotic translation apparatus to promote end-independent initiation. We identified a conserved class of ∼150 nt long intergenic region (IGR) IRESs in dicistrovirus genomes derived from members of the phyla Arthropoda, Bryozoa, Cnidaria, Echinodermata, Entoprocta, Mollusca and Porifera. These IRESs, exemplified by Wenling picorna-like virus 2, resemble the canonical cricket paralysis virus (CrPV) IGR IRES in comprising two nested pseudoknots (PKII/PKIII) and a 3'-terminal pseudoknot (PKI) that mimics a tRNA anticodon stem-loop base-paired to mRNA. However, they are ∼50 nt shorter than CrPV-like IRESs, and PKIII is an H-type pseudoknot that lacks the SLIV and SLV stem-loops that are primarily responsible for the affinity of CrPV-like IRESs for the 40S ribosomal subunit and that restrict initial binding of PKI to its aminoacyl (A) site. Wenling-class IRESs bound strongly to 80S ribosomes but only weakly to 40S subunits. Whereas CrPV-like IRESs must be translocated from the A site to the peptidyl (P) site by elongation factor 2 for elongation to commence, Wenling-class IRESs bound directly to the P site of 80S ribosomes, and decoding begins without a prior translocation step. A chimeric CrPV clone containing a Wenling-class IRES was infectious, confirming that the IRES functioned in cells.

Platelet-rich fibrin as an apical barrier for MTA placement in the treatment of teeth with open apices: a pilot study.

OBJECTIVE: The aim of the present pilot study was to assess the effectiveness of the platelet-rich fibrin (PRF) apical barrier for the placement of MTA for the treatment of teeth with periapical lesions and open apices. METHODS: A total of thirty teeth on twenty-eight patients with open apices and periapical periodontitis were enrolled and divided into two groups in the present pilot study. In the PRF group (fourteen teeth in thirteen patients), nonsurgical endodontic treatment was performed using PRF as an apical matrix, after which the apical plug of the MTA was created. For the non-PRF group (fourteen teeth in fourteen patients), nonsurgical endodontic therapy was performed using only the MTA for an apical plug with no further periapical intervention. Clinical findings and periapical digital radiographs were used for evaluating the healing progress after periodic follow-ups of 1, 3, 6, and 9 months. The horizontal dimension of the periapical lesion was gauged, and the changes in the dimensions were recorded each time. The Friedman test, Dunn-Bonferroni post hoc correction, and Mann-Whitney U test were used for statistical analysis, with P < 0.05 serving as the threshold for determining statistical significance. RESULTS: All patients in both groups in the present pilot study had no clinical symptoms after 1 month, with a significant reduction in the periapical lesion after periodic appointments. The lesion width of the PRF group was significantly smaller than that of the non-PRF group in the sixth and ninth month after treatment. CONCLUSIONS: PRF is a promising apical barrier matrix when combined with MTA for the treatment of teeth with open apices and periapical periodontitis. Small number of study subjects and the short time of follow-up period limit the generalizability of these results. TRIAL REGISTRATION: TCTR, TCTR20221109006. Registered 09 November 2022 - Retrospectively registered, https://www.thaiclinicaltrials.org/show/TCTR20221109006 .

The relationship of preterm and small for gestational age with child cognition during school-age years.

BACKGROUND: Children born preterm and/or small for gestational age (SGA) are at increased risk of poor cognitive outcomes, particularly in low and middle-income countries (LMICs). OBJECTIVES: This study examined the cognitive and academic deficits during the school age years in children born preterm or SGA compared to term adequate for gestational age (AGA) in rural Vietnam. METHOD: Children born to women in a preconception micronutrient supplementation trial in Vietnam were classified into three groups: preterm AGA (n =138), term SGA (n =169) and term AGA (n= 1134). Cognitive abilities were assessed using the Wechsler Intelligence Scale for Children, measuring four domains (verbal comprehension -VCI, perceptual reasoning -PRI, working memory -WMI, and processing speed Index scores - PSI) and full-scale intelligence quotient (FSIQ) at 6-7y and 10-11y. Academic achievement was assessed with math and language tests. ANOVA and multiple regression models were used to analyze differences in cognitive function and academic achievement at 6-7y and 10-11y by birth phenotypes. RESULTS: Compared to term AGA children, those born SGA had lower cognitive scores at both 6-7y (-2.3 VCI, -3.7 PRI, -2.1 PSI and -2.9 FSIQ) and 10-11y (-3.7 VCI, -3.5 PRI, -2.7 WMI, -1.9 PSI and -3.9 FSIQ). Children born SGA also had poorer academic achievement with lower language (5.3) and math (2.5) scores. Adjustments for maternal factors and home environment attenuated the associations, but the differences in VCI, PRI, FSIQ and language at 10-11y remained significant. There were no differences in cognitive function and academic achievement between children born preterm and AGA. CONCLUSIONS: Our findings highlight the enduring association of birth phenotype on cognitive functioning and academic achievement during the school years, despite adjustments for maternal education and family environment. Further research is needed to implement effective interventions to improve birth outcomes and optimize child health and development in LMICs. CLINICAL TRIAL REGISTRY: The trial was registered at ClinicalTrials.Gov as NCT01665378, URL: https://clinicaltrials.gov/ct2/show/NCT01665378.

Preconception Micronutrient Supplementation Affects Maternal BMI and Body Composition Postpartum: A Randomized Controlled Trial in Vietnam.

BACKGROUND: Although there is growing evidence on the role of preconception nutrition for birth outcomes, limited evidence exists for its effects on maternal health. OBJECTIVES: This study evaluates the impact of preconception micronutrient supplementation on maternal BMI (kg/m2) and body composition at 6 to 7 y postpartum (PP). METHODS: We followed females who participated in a randomized controlled trial of preconception supplementation in Vietnam and delivered live offspring (n = 1599). Females received weekly supplements containing either 2800 µg folic acid (FA) only, 60 mg iron and 2800 µg FA (IFA), or multiple micronutrients (MMs) (15 micronutrients including IFA) from baseline until conception followed by daily prenatal IFA supplements until delivery. Height, weight, mid-upper arm circumference, triceps skinfold, and waist-hip circumference were measured at recruitment and at 1, 2, and 6 to 7 y PP. Body fat was assessed using bioelectric impedance at 6 to 7 y PP (n = 867). Group comparisons were made using analysis of variance or chi-square tests and general linear models for adjusted models. RESULTS: At 6 to 7 y PP, we found significant differences (P < 0.05) by treatment group for mean percent fat (MM: 29.2%; IFA: 27.6%; FA: 27.8%), absolute fat mass (MM: 15.1 kg; IFA: 14.0 kg; FA: 14.3 kg), and prevalence of underweight based on BMI < 18.5 (MM: 5.8%; IFA: 10.3%; FA: 14.3%). Mean BMI and triceps skinfold thickness were higher in the MM group, but these differences were not statistically significant; the differences in absolute fat mass were also attenuated after controlling for body weight. No differences were observed for fat-free mass, prevalence of overweight (BMI >23), or other anthropometric measurements. CONCLUSIONS: Preconception MM supplementation was associated with lower prevalence of underweight and higher percent fat when compared with IFA and/or FA only. Preconception micronutrient interventions may have long-term effects on maternal health and merit further examination. This trial was registered at clinicaltrials.gov as NCT01665378.

Reaching High Accuracy for Energetic Properties at Second-Order Perturbation Cost by Merging Self-Consistency and Spin-Opposite Scaling.

Quantum chemical methods dealing with challenging systems while retaining low computational costs have attracted attention. In particular, many efforts have been devoted to developing new methods based on second-order perturbation that may be the simplest correlated method beyond Hartree-Fock. We have recently developed a self-consistent perturbation theory named one-body Møller-Plesset second-order perturbation theory (OBMP2) and shown that it can resolve issues caused by the noniterative nature of standard perturbation theory. In this work, we extend the method by introducing spin-opposite scaling to the double-excitation amplitudes, resulting in the O2BMP2 method. We assess the O2BMP2 performance on the triple-bond N2 dissociation, singlet-triplet gaps, and ionization potentials. O2BMP2 performs much better than standard MP2 and reaches the accuracy of coupled-cluster methods in all cases considered in this work.

Investigation of Urinary Metabolites of Organophosphate Esters in Hanoi, Vietnam: Assessment Exposure and Estimated Daily Intake.

In recent years, organophosphate esters (OPEs) have become one of the most common additives in various consumer products worldwide, therefore the exposure and impact of OPEs on human health are drawing a lot of attention. In this study, three metabolites of OPEs including bis(1,3-dichloro-2-propyl) phosphate (BDCIPP), diphenyl phosphate (DPhP) and diethyl phosphate (DEP) were investigated in first-morning void urine samples taken from a population (age range: 3-76 years old) in Hanoi, Vietnam. The most dominant urinary OPE metabolite was DEP with the geometric mean of specific gravity adjust (SG-adjusted) concentration were 1960 ng mL-1 and detected frequency (DF) of 98%. Followed by DPhP (8.01 ng mL-1, DF: 100%) and BDCIPP (2.18 ng mL-1, DF: 51%). The results indicated that gender and age might have associations with the OPE metabolites variation in urine samples. The levels of OPE metabolites in urine samples from females were slightly higher than in males. An increase in age seems to have an association with a decrease in DPhP levels in urine. Exposure doses of parent OPEs were evaluated from the unadjusted urinary concentration of corresponding OPE metabolite. The estimated exposure doses of triethyl phosphate (TEP) (mean: 534,000 ng kg-1 d-1) were significantly higher than its corresponding reference dose, suggesting the high potential risk from the current exposure doses of TEP to human health. The results of this work provided the initial information on the occurrence of three OPE metabolites in urine from Hanoi, Vietnam and estimated exposure dose of corresponding parent OPEs.

Platelet rich fibrin and MTA in the treatment of teeth with open apices.

BACKGROUND: The present study aimed to evaluate the effectiveness of using platelet-rich fibrin (PRF) as the apical matrix for the placement of MTA in nonsurgical endodontic therapy for teeth with periapical lesions and open apices. METHODS: Twelve teeth from eleven patients with periapical periodontitis and open apices were enrolled in the study. Nonsurgical endodontic therapy was performed with the PRF used as an apical barrier and the MTA manipulated as an apical plug for further thermoplasticized gutta percha in the remaining part of the root canal. Clinical signs and periapical digital radiographs were recorded and analyzed to evaluate the curing progress after periodical follow-ups of 1, 3, and 6 months. The horizontal dimension of the periapical lesion was determined, and the changes in the dimensions were recorded each time. The Friedman test was used for statistical analysis, with P < .05 serving as the threshold for determining statistical significance. RESULTS: All patients had no clinical symptoms after the first month of treatment, with a significant reduction in the periapical lesion after periodical appointments. CONCLUSIONS: PRF is an effective barrier when combined with MTA for the treatment of teeth with periapical periodontitis and open apices.

The relationships between optimal infant feeding practices and child development and attained height at age 2 years and 6-7 years.

Limited evidence exists on the long-term effects of early feeding practices on child growth and development. We examined the relationships between infant feeding practices and child height and development at ages 2 and 6-7 years. We studied 885 mother-child dyads from a randomized controlled trial of preconception supplementation in Vietnam. Early initiation of breastfeeding (EIBF), exclusive breastfeeding (EBF), breastfeeding (BF) duration and minimum dietary diversity (MDD) were assessed using World Health Organization (WHO) guidelines. Child development was assessed by the Bayley Scales of Infant Development-III at 2 years and the Wechsler Intelligence Scale for Children® - IV at 6-7 years. Child height-for-age z-score (HAZ) was calculated from child height and age. Multivariable regression and structural equation models were used in analyses that controlled for confounding. EIBF and EBF at 6 months occurred in 52% and 62% of children, respectively. Mean breastfeeding duration was 18 months and 83% achieved MDD at 1 year. EIBF was associated with motor (ß = 0.13, 95% confidence interval [CI]: 0.00, 0.28) and cognitive development at 2 years (ß = 0.12, 95% CI: -0.01, 0.26), which in turn were positively associated with cognitive development at 6-7 years. EBF was directly associated with development at 6-7 years (ß = 0.21, 95% CI:0.08, 0.34) whereas motor and cognitive development at 2 years explained 41%-75% of the relationship between EIBF and development at 6-7 years. HAZ at 2 years also mediated 70% of the association between MDD at 1 year and HAZ at 6-7 years. BF duration was not associated with child development and HAZ. Early infant feeding practices, especially EIBF and EBF, have important long-term implications for optimizing child linear growth and cognition as they begin school.

Temporal Dietary Diversity Patterns Are Associated with Linear Growth but Not Ponderal Growth in Young Children in Rural Vietnam.

BACKGROUND: The first 2 y of life mark critical changes in children's diet from milk-based food to diverse food rich in taste and texture, but few studies in low-resource settings have explored the changes in diet quality during this period. OBJECTIVES: We examine temporal dietary diversity patterns between 6 and 25 mo of age and their associations with child growth outcomes in rural Vietnam. METHODS: We used data from a prospective cohort (PRECONCEPT) and included 781 children that had dietary diversity data for 4 age windows: 6-8, 11-13, 17-19, and 23-25 mo of age. The temporal dietary diversity patterns were constructed by tracking how minimum dietary diversity changed over the 4 age windows. Multivariate logistic and linear regressions were used to assess the associations of dietary patterns with stunting and wasting at the 23-25 mo window and with relative linear and ponderal growth between 6 and 25 mo, respectively. RESULTS: Two key aspects of diet quality (the introduction and the stability of diverse diet) were used to define 5 temporal dietary diversity patterns: timely-stable (30% of the sample), timely-unstable (27%), delayed-stable (16%), delayed-unstable (15%), and super-delayed (12%). Compared with timely-stable pattern (the most optimal pattern), timely-unstable and super-delayed patterns were associated with a higher risk of stunting (odds ratio [OR]: 1.78; 95% confidence interval [CI]: 1.05, 3.04 and OR: 1.98; 95% CI: 1.02, 3.80, respectively) and slower linear growth (ß: -0.24; 95% CI: -0.43, -0.06 and ß: -0.25; 95% CI: -0.49, -0.02, respectively). No associations were found for wasting and relative ponderal growth. CONCLUSIONS: Delayed introduction of a diverse diet and failure to maintain a diverse diet are associated with slower linear growth but not ponderal growth in the first 2 y of age. This trial was registered at clinicaltrials.gov as NCT01665378.

Long-Term Association Between Maternal Preconception Hemoglobin Concentration, Anemia, and Child Health and Development in Vietnam.

BACKGROUND: The long-term association between preconception maternal hemoglobin (Hb) concentrations and child health and development is unclear. OBJECTIVES: We examined associations between maternal preconception Hb concentrations and anemia with 1) birth outcomes (weight, length, preterm, gestational age, small for gestational age); 2) child Hb at 3 mo, 6 mo, 12 mo, and 24 mo; and 3) motor and mental development at 12 mo and 24 mo (Bayley scales for infant development) and cognitive functioning at 6-7 y (Wechsler Intelligence Scale for Children). METHODS: We used data from a randomized controlled trial (PRECONCEPT) conducted in Vietnam. Over 5000 women who were intending to conceive were recruited, and offspring were prospectively followed from birth (n = 1599) through 6-7 y (n = 1318). Multivariable linear and logistic regressions were used to assess the association between preconception Hb or anemia (Hb < 12g/dL) on child health and development outcomes, adjusted by supplementation group (tested for interactions) and confounding at maternal, child, and household levels. RESULTS: At preconception enrollment, 20% of the women were anemic. Maternal preconception Hb was positively associated with child Hb at 3 mo (0.06; 95% CI: 0.01, 0.12), 6 mo (0.08; 95% CI: 0.03, 0.13), 12 mo (0.10; 95% CI: 0.04, 0.15), and 24 mo (0.07; 95% CI: 0.02, 0.12). Likewise, maternal preconception Hb was associated with reduced risk of child anemia at 6 mo (0.89; 95% CI: 0.81, 0.98), 12 mo (0.81; 95% CI: 0.74, 0.89), and 24 mo (0.87; 95% CI: 0.79, 0.95). Maternal preconception anemia was negatively associated with cognition (-1.64; 95% CI: -3.09, -0.19) and language development (-1.61; 95% CI: -3.20, -0.03) at 24 mo. Preconception Hb was not associated with birth outcomes or cognitive outcomes at 6-7 y. CONCLUSIONS: Maternal preconception Hb was associated with child Hb across the first 1000 d of life. However, preconception Hb was not a significant predictor of birth outcomes or cognitive outcomes at 6-7 y in this cohort from Vietnam. CLINICAL TRIAL REGISTRATION: PRECONCEPT study (NCT: 01665378).

Validation of Mobile Artificial Intelligence Technology-Assisted Dietary Assessment Tool Against Weighed Records and 24-Hour Recall in Adolescent Females in Ghana.

BACKGROUND: Important gaps exist in the dietary intake of adolescents in low- and middle-income countries (LMICs), partly due to expensive assessment methods and inaccuracy in portion-size estimation. Dietary assessment tools leveraging mobile technologies exist but only a few have been validated in LMICs. OBJECTIVE: We validated Food Recognition Assistance and Nudging Insights (FRANI), a mobile artificial intelligence (AI) dietary assessment application in adolescent females aged 12-18 y (n = 36) in Ghana, against weighed records (WR), and multipass 24-hour recalls (24HR). METHODS: Dietary intake was assessed during 3 nonconsecutive days using FRANI, WRs, and 24HRs. Equivalence of nutrient intake was tested using mixed-effect models adjusted for repeated measures, by comparing ratios (FRANI/WR and 24HR/WR) with equivalence margins at 10%, 15%, and 20% error bounds. Agreement between methods was assessed using the concordance correlation coefficient (CCC). RESULTS: Equivalence for FRANI and WR was determined at the 10% bound for energy intake, 15% for 5 nutrients (iron, zinc, folate, niacin, and vitamin B6), and 20% for protein, calcium, riboflavin, and thiamine intakes. Comparisons between 24HR and WR estimated equivalence at the 20% bound for energy, carbohydrate, fiber, calcium, thiamine, and vitamin A intakes. The CCCs by nutrient between FRANI and WR ranged between 0.30 and 0.68, which was similar for CCC between 24HR and WR (ranging between 0.38 and 0.67). Comparisons of food consumption episodes from FRANI and WR found 31% omission and 16% intrusion errors. Omission and intrusion errors were lower when comparing 24HR with WR (21% and 13%, respectively). CONCLUSIONS: FRANI AI-assisted dietary assessment could accurately estimate nutrient intake in adolescent females compared with WR in urban Ghana. FRANI estimates were at least as accurate as those provided through 24HR. Further improvements in food recognition and portion estimation in FRANI could reduce errors and improve overall nutrient intake estimations.

Correlated Reference-Assisted Variational Quantum Eigensolver.

We propose an active-space approximation to reduce the quantum resources required for variational quantum eigensolver (VQE). Starting from the double exponential unitary coupled-cluster ansatz and employing the downfolding technique, we arrive at an effective Hamiltonian for active space composed of the bare Hamiltonian and a correlated potential caused by the internal-external interaction. The correlated potential is obtained from the one-body second-order Møller-Plesset perturbation theory (OBMP2), which is derived using the canonical transformation and cumulant approximation. Considering different systems with singlet and doublet ground states, we examine the accuracy in predicting both energy and density matrix (by evaluating dipole moment). We show that our approach can dramatically outperform the active-space VQE with an uncorrelated Hartree-Fock reference.

Home environment and nutritional status mitigate the wealth gap in child development: a longitudinal study in Vietnam.

BACKGROUND: Inequity in child development is found at early age, but limited evidence exists on whether these gaps change over time and what are the mediators. OBJECTIVE: We aim to (1) quantify wealth related gaps in cognitive and socio-emotional development in early and middle childhood; (2) examine how these gaps were mitigated by maternal, child factors and home environment. METHODS: We assessed the offspring of women who participated in a randomized controlled trial of preconception micronutrient supplementation in Vietnam (n = 1599). Child development was measured by the Bayley Scales of Infant Development-III (at 1-2y) and the Wechsler Intelligence Scale for Children®-IV (at 6-7y). We used multivariable regression to estimate the changes in wealth gaps for child development over time, adjusting for potential factors that potentially influence cognitive development. RESULTS: We found significant wealth gaps in cognitive development during early childhood (gaps between top and bottom quintiles: 0.5 SD); these gaps increased substantially in middle childhood (0.9 SD). Wealth disparity in social emotion did not change over time (0.26-0.28 SD). Maternal factors, quality of home environment, and child nutritional status mitigated the wealth gap in cognitive development (7-42%) in early childhood. The contribution of these mitigating factors was smaller in middle childhood (2- 15%). Wealth gap in social emotion reduced by 13% and 43% among children with better nutritional status at 2y and higher quality of home environment at 6-7y, respectively. CONCLUSION: Interventions focusing on improving quality of home environment, maternal education, wellbeing, and child nutrition status may help reduce developmental deficits associated with poverty.

Specificity Matters: Unpacking Impact Pathways of Individual Interventions within Bundled Packages Helps Interpret the Limited Impacts of a Maternal Nutrition Intervention in India.

BACKGROUND: To address gaps in coverage and quality of nutrition services, Alive & Thrive (A&T) strengthened the delivery of maternal nutrition interventions through government antenatal care (ANC) services in Uttar Pradesh, India. The impact evaluation of the A&T interventions compared intensive ANC (I-ANC) with standard ANC (S-ANC) areas and found modest impacts on micronutrient supplementation, dietary diversity, and weight-gain monitoring. OBJECTIVES: This study examined intervention-specific program impact pathways (PIPs) and identified reasons for limited impacts of the A&T maternal nutrition intervention package. METHODS: We used mixed methods: frontline worker (FLW) surveys (n = ∼500), counseling observations (n = 407), and qualitative in-depth interviews with FLWs, supervisors, and block-level staff (n = 59). We assessed 7 PIP domains: training and materials, knowledge, supportive supervision, supply chains, data use, service delivery, and counseling. RESULTS: Exposure to training improved in both I-ANC and S-ANC areas with more job aids used in I-ANC compared with S-ANC (90% compared with 70%), but gaps remained for training content and refresher trainings. FLWs' knowledge improvement was higher in I-ANC than S-ANC (22-36 percentage points), but knowledge of micronutrient supplement benefits and recommended foods was insufficient (<50%). Most FLWs received supervision (>90%), but supportive supervision was limited by staff vacancies and competing work priorities. Supplies of iron-folic acid and calcium supplements were low in both areas (30-50% stock-outs). Use of monitoring data during review meetings was higher in I-ANC than S-ANC (52% compared with 36%) but was constrained by time, understanding, and data quality. Service provision improved in both I-ANC and S-ANC areas, but counseling on supplement benefits and weight-gain monitoring was low (30-40%). CONCLUSIONS: Systems-strengthening efforts improved maternal nutrition interventions in ANC, but gaps remained. Taking an intervention-specific perspective to the PIP analysis in this package of services was critical to understand how common and specific barriers influenced overall program impact.

Implementation of Vancomycin Therapeutic Monitoring Guidelines: Focus on Bayesian Estimation Tools in Neonatal and Pediatric Patients.

BACKGROUND: The 2020 consensus guidelines for vancomycin therapeutic monitoring recommend using Bayesian estimation targeting the ratio of the area under the curve over 24 hours to minimum inhibitory concentration as an optimal approach to individualize therapy in pediatric patients. To support institutional guideline implementation in children, the objective of this study was to comprehensively assess and compare published population-based pharmacokinetic (PK) vancomycin models and available Bayesian estimation tools, specific to neonatal and pediatric patients. METHODS: PubMed and Embase databases were searched from January 1994 to December 2020 for studies in which a vancomycin population PK model was developed to determine clearance and volume of distribution in neonatal and pediatric populations. Available Bayesian software programs were identified and assessed from published articles, software program websites, and direct communication with the software company. In the present review, 14 neonatal and 20 pediatric models were included. Six programs (Adult and Pediatric Kinetics, BestDose, DoseMeRx, InsightRx, MwPharm++, and PrecisePK) were evaluated. RESULTS: Among neonatal models, Frymoyer et al and Capparelli et al used the largest PK samples to generate their models, which were externally validated. Among the pediatric models, Le et al used the largest sample size, with multiple external validations. Of the Bayesian programs, DoseMeRx, InsightRx, and PrecisePK used clinically validated neonatal and pediatric models. CONCLUSIONS: To optimize vancomycin use in neonatal and pediatric patients, clinicians should focus on selecting a model that best fits their patient population and use Bayesian estimation tools for therapeutic area under the -curve-targeted dosing and monitoring.

Can second-order perturbation theory accurately predict electron density of open-shell molecules? The importance of self-consistency.

Electron density plays an essential role in predicting molecular properties. It is also a simple observable from which machine-learning models for molecular electronic structure can be derived. In this work, we present the performance of the one-body Møller-Plesset second-order perturbation (OBMP2) theory, which we have recently developed, in predicting electron density and related properties. In OBMP2, an effective one-body Hamiltonian including dynamic correlation at the MP2 level is derived using the canonical transformation followed by the cumulant approximation. We diagonalize the effective one-body Hamiltonian to yield eigenvalues and eigenvectors corresponding to molecular orbitals and orbital energies that are then used to update the MP2 double-excitation amplitudes. We examine the OBMP2 performance by considering three different groups of open-shell systems: atomic systems, main-group radicals, and halogen-bonding dimers. We find that OBMP2 outperforms standard MP2 and density functional theory in all cases considered here, and its accuracy is comparable to coupled-cluster singles and doubles (CCSD), a higher-level method. OBMP2 is thus believed to be an effective method for predicting the accurate electron density of open-shell molecules.

Nanobodies for the Early Detection of Ovarian Cancer.

Ovarian cancer ranks fifth in cancer-related deaths among women. Since ovarian cancer patients are often asymptomatic, most patients are diagnosed only at an advanced stage of disease. This results in a 5-year survival rate below 50%, which is in strong contrast to a survival rate as high as 94% if detected and treated at an early stage. Monitoring serum biomarkers offers new possibilities to diagnose ovarian cancer at an early stage. In this study, nanobodies targeting the ovarian cancer biomarkers human epididymis protein 4 (HE4), secretory leukocyte protease inhibitor (SLPI), and progranulin (PGRN) were evaluated regarding their expression levels in bacterial systems, epitope binning, and antigen-binding affinity by enzyme-linked immunosorbent assay and surface plasmon resonance. The selected nanobodies possess strong binding affinities for their cognate antigens (KD~0.1-10 nM) and therefore have a pronounced potential to detect ovarian cancer at an early stage. Moreover, it is of utmost importance that the limits of detection (LOD) for these biomarkers are in the pM range, implying high specificity and sensitivity, as demonstrated by values in human serum of 37 pM for HE4, 163 pM for SLPI, and 195 pM for PGRN. These nanobody candidates could thus pave the way towards multiplexed biosensors.

A Phase 3 Trial of l-Glutamine in Sickle Cell Disease.

BACKGROUND: Oxidative stress contributes to the complex pathophysiology of sickle cell disease. Oral therapy with pharmaceutical-grade l-glutamine (USAN, glutamine) has been shown to increase the proportion of the reduced form of nicotinamide adenine dinucleotides in sickle cell erythrocytes, which probably reduces oxidative stress and could result in fewer episodes of sickle cell-related pain. METHODS: In a multicenter, randomized, placebo-controlled, double-blind, phase 3 trial, we tested the efficacy of pharmaceutical-grade l-glutamine (0.3 g per kilogram of body weight per dose) administered twice daily by mouth, as compared with placebo, in reducing the incidence of pain crises among patients with sickle cell anemia or sickle ß0-thalassemia and a history of two or more pain crises during the previous year. Patients who were receiving hydroxyurea at a dose that had been stable for at least 3 months before screening continued that therapy through the 48-week treatment period. RESULTS: A total of 230 patients (age range, 5 to 58 years; 53.9% female) were randomly assigned, in a 2:1 ratio, to receive l-glutamine (152 patients) or placebo (78 patients). The patients in the l-glutamine group had significantly fewer pain crises than those in the placebo group (P=0.005), with a median of 3.0 in the l-glutamine group and 4.0 in the placebo group. Fewer hospitalizations occurred in the l-glutamine group than in the placebo group (P=0.005), with a median of 2.0 in the l-glutamine group and 3.0 in the placebo group. Two thirds of the patients in both trial groups received concomitant hydroxyurea. Low-grade nausea, noncardiac chest pain, fatigue, and musculoskeletal pain occurred more frequently in the l-glutamine group than in the placebo group. CONCLUSIONS: Among children and adults with sickle cell anemia, the median number of pain crises over 48 weeks was lower among those who received oral therapy with l-glutamine, administered alone or with hydroxyurea, than among those who received placebo, with or without hydroxyurea. (Funded by Emmaus Medical; ClinicalTrials.gov number, NCT01179217 .).

Improved Automated Quantification Algorithm (AQuA) and Its Application to NMR-Based Metabolomics of EDTA-Containing Plasma.

We have recently presented an Automated Quantification Algorithm (AQuA) and demonstrated its utility for rapid and accurate absolute metabolite quantification in 1H NMR spectra in which positions and line widths of signals were predicted from a constant metabolite spectral library. The AQuA quantifies based on one preselected signal per metabolite and employs library spectra to model interferences from other metabolite signals. However, for some types of spectra, the interspectral deviations of signal positions and line widths can be pronounced; hence, interferences cannot be modeled using a constant spectral library. We here address this issue and present an improved AQuA that handles interspectral deviations. The improved AQuA monitors and characterizes the appearance of specific signals in each spectrum and automatically adjusts the spectral library to model interferences accordingly. The performance of the improved AQuA was tested on a large data set from plasma samples collected using ethylenediaminetetraacetic acid (EDTA) as an anticoagulant (n = 772). These spectra provided a suitable test system for the improved AQuA since EDTA signals (i) vary in intensity, position, and line width between spectra and (ii) interfere with many signals from plasma metabolites targeted for quantification (n = 54). Without the improvement, ca. 20 out of the 54 metabolites would have been overestimated. This included acetylcarnitine and ornithine, which are considered particularly difficult to quantify with 1H NMR in EDTA-containing plasma. Furthermore, the improved AQuA performed rapidly (<10 s for all spectra). We believe that the improved AQuA provides a basis for automated quantification in other data sets where specific signals show interspectral deviations.

Maternal Preconception Body Size and Early Childhood Growth during Prenatal and Postnatal Periods Are Positively Associated with Child-Attained Body Size at Age 6-7 Years: Results from a Follow-up of the PRECONCEPT Trial.

BACKGROUND: Growth faltering is associated with adverse consequences during childhood and later life. However, questions remain on the relative importance of preconception maternal nutritional status (PMNS) and child growth during the first 1000 d of life. OBJECTIVES: We examined associations between PMNS, gestational weight gain (GWG), and child growth during the first 1000 d with attained body size at age 6-7 y. METHODS: We used data from a follow-up of a double-blinded randomized controlled trial of preconception micronutrient supplementation in Vietnam (n = 5011 women). The outcomes included offspring height-for-age z score (HAZ), BMI-for-age z score (BMIZ), and prevalence of stunting and overweight/obese at age 6-7 y (n = 1579). We used multivariable linear and Poisson regression models to evaluate the relative contributions of PMNS (height and BMI), GWG, and conditional growth in 4 periods: fetal, 0-6 mo, 6-12 mo, and 12-24 mo. RESULTS: PMNS was positively associated with child-attained size at 6-7 y. For each 1-SD higher maternal height and BMI, offspring had 0.28-SD and 0.13-SD higher HAZ at 6-7 y, respectively. Higher maternal BMI and GWG were associated with larger child BMIZ (ß: 0.29 and 0.10, respectively). Faster linear growth, especially from 6 to 24 mo, had the strongest association with child HAZ at 6-7 y (ß: 0.39-0.42), whereas conditional weight measures in all periods were similarly associated with HAZ (ß: 0.10-0.15). For BMIZ at 6-7 y, the magnitude of association was larger and increased with child age for conditional weight gain (ß: 0.21-0.41) but smaller for conditional length gain. Faster growth in the first 2 y was associated with reduced risk of stunting and thinness but increased risk of overweight/obese at 6-7 y. CONCLUSIONS: Interventions aimed at improving child growth while minimizing the risk of overweight during the school age years should target both women of reproductive age prior to conception through delivery and their offspring during the first 1000 d. The trial was registered at clinicaltrials.gov as NCT01665378.