Metformin Promotes Antitumor Immunity via Endoplasmic-Reticulum-Associated Degradation of PD-L1.

Metformin has been reported to possess antitumor activity and maintain high cytotoxic T lymphocyte (CTL) immune surveillance. However, the functions and detailed mechanisms of metformin's role in cancer immunity are not fully understood. Here, we show that metformin increases CTL activity by reducing the stability and membrane localization of programmed death ligand-1 (PD-L1). Furthermore, we discover that AMP-activated protein kinase (AMPK) activated by metformin directly phosphorylates S195 of PD-L1. S195 phosphorylation induces abnormal PD-L1 glycosylation, resulting in its ER accumulation and ER-associated protein degradation (ERAD). Consistently, tumor tissues from metformin-treated breast cancer patients exhibit reduced PD-L1 levels with AMPK activation. Blocking the inhibitory signal of PD-L1 by metformin enhances CTL activity against cancer cells. Our findings identify a new regulatory mechanism of PD-L1 expression through the ERAD pathway and suggest that the metformin-CTLA4 blockade combination has the potential to increase the efficacy of immunotherapy.

Multigenerational adversity impacts on human gut microbiome composition and socioemotional functioning in early childhood.

Adversity exposures in the prenatal and postnatal period are associated with an increased risk for psychopathology, which can be perpetuated across generations. Nonhuman animal research highlights the gut microbiome as a putative biological mechanism underlying such generational risks. In a sample of 450 mother-child dyads living in Singapore, we examined associations between three distinct adversity exposures experienced across two generations-maternal childhood maltreatment, maternal prenatal anxiety, and second-generation children's exposure to stressful life events-and the gut microbiome composition of second-generation children at 2 y of age. We found distinct differences in gut microbiome profiles linked to each adversity exposure, as well as some nonaffected microbiome features (e.g., beta diversity). Remarkably, some of the microbial taxa associated with concurrent and prospective child socioemotional functioning shared overlapping putative functions with those affected by adversity, suggesting that the intergenerational transmission of adversity may have a lasting impact on children's mental health via alterations to gut microbiome functions. Our findings open up a new avenue of research into the underlying mechanisms of intergenerational transmission of mental health risks and the potential of the gut microbiome as a target for intervention.

Trajectories of lifestyle patterns from 2 to 8 years of age and cardiometabolic risk in children: the GUSTO study.

BACKGROUND: Tracking combinations of lifestyle behaviours during childhood ("lifestyle pattern trajectories") can identify subgroups of children that might benefit from lifestyle interventions aiming to improve health outcomes later in life. However, studies on the critical transition period from early to middle childhood are limited. We aimed to describe lifestyle patterns trajectories in children from 2 to 8 years of age and evaluated their associations with cardiometabolic risk markers at age 8 years in a multi-ethnic Asian cohort. METHODS: Twelve lifestyle behaviours related to child's diet, physical activity, screen use, and sleep were ascertained using questionnaires at ages 2, 5, and 8 years. Age-specific lifestyle patterns were derived using principal component analysis and trajectories were determined using group-based multi-trajectory modelling. Child cardiometabolic risk markers were assessed at age 8 years, and associations with trajectories examined using multiple regression, adjusted for confounders. RESULTS: Among 546 children, two lifestyle patterns "healthy" and "unhealthy" were observed at ages 2, 5, and 8 years separately. Three trajectory groups from 2 to 8 years were identified: consistently healthy (11%), consistently unhealthy (18%), and mixed pattern (71%). Children in the consistently unhealthy group (vs. mixed pattern) had increased odds of pre-hypertension (OR = 2.96 [95% CI 1.18-7.41]) and higher levels of diastolic blood pressure (ß = 1.91 [0.27-3.55] mmHg), homeostasis model assessment of insulin resistance (ß = 0.43 [0.13-0.74]), triglycerides (ß = 0.11 [0.00-0.22] mmol/L), and metabolic syndrome score (ß = 0.85 [0.20-1.49]), but not with BMI z-score or any anthropometric measurements. The consistently healthy group showed no differences in cardiometabolic outcomes compared to the mixed pattern group. CONCLUSION: Three distinct lifestyle pattern trajectories were identified from early to middle childhood. Children in the consistently unhealthy lifestyle group did not have a raised BMI but was associated with several elevated cardiometabolic risk markers. These findings suggest the potential benefits of initiating holistic lifestyle interventions to improve children's health and well-being from an early age. TRIAL REGISTRATION: Trial registration number: NCT01174875. Name of registry: ClinicalTrials.gov. URL of registry: https://classic. CLINICALTRIALS: gov/ct2/show/NCT01174875 . Date of registration: August 4, 2010. Date of enrolment of the first participant to the trial: June 2009.

Efficacy and Safety of Avapritinib in Treating Unresectable or Metastatic Gastrointestinal Stromal Tumors: A Phase I/II, Open-Label, Multicenter Study.

BACKGROUND: Avapritinib is a type 1 kinase inhibitor designed to potently and selectively inhibit oncogenic KIT/PDGFRA mutants by targeting the kinase active conformation. This multicenter, single-arm, open-label, phase I/II bridging study of NAVIGATOR in Chinese patients evaluated the safety and the antineoplastic activity of avapritinib in Chinese patients with unresectable/metastatic gastrointestinal stromal tumors (GIST). METHODS: Phase I comprised dose escalation for safety and phase II dose determination. Phase II comprised dose expansion for safety/efficacy evaluations in patients with PDGFRA D842V mutations or patients having received at least 3 lines of therapy without PDGFRA D842V mutations. The primary endpoints were recommended phase II dose, safety, and Independent Radiology Review Committee (IRRC)-assessed objective response rate (ORR). RESULTS: No dose-limiting toxicities occurred (n = 10); the recommended phase II dose was avapritinib 300 mg once daily orally. Fifty-nine patients initially received avapritinib 300 mg. Common grade ≥3 treatment-related adverse events were anemia, decreased white blood cell count, increased blood bilirubin levels, and decreased neutrophil count. In patients with PDGFRA D842V mutations, IRRC- and investigator-assessed ORRs were 75% and 79%, respectively; clinical benefit rates were both 86%. Median duration of response/progression-free survival were not reached. IRCC- and investigator-assessed ORRs in patients in the fourth- or later-line setting were 22% and 35%, respectively. Median progression-free survivals were 5.6 months for both. Overall survival data were immature and not calculated. CONCLUSION: Avapritinib was generally well tolerated and showed marked anti-tumor activity in Chinese patients with GIST bearing PDGFRA D842V mutations and notable efficacy as fourth- or later-line monotherapy (ClinicalTrials.gov Identifier: NCT04254939).

ALKBH5-mediated CHAC1 depletion promotes malignant progression and decreases cisplatin-induced oxidative stress in gastric cancer.

The m6a demethyltransferase ALKBH5 dynamically modulates gene expression and intracellular metabolic molecules by modifying RNA m6a in cancer cells. However, ALKBH5's function in gastric cancer (GC) has remained controversial. This study demonstrates that ALKBH5 is highly expressed in GC. Silencing ALKBH5 hampers proliferation, and metastatic potential, and induces cell death in GC cells. Through a comprehensive analysis of the transcriptome and m6A sequencing, alterations in certain ALKBH5 target genes, including CHAC1, were identified. ALKBH5's demethylation effect regulates CHAC1 RNA stability, leading to reduced CHAC1 expression. Moreover, CHAC1 modulates intracellular ROS levels, influencing the chemotherapy sensitivity of gastric cancer. In summary, our study unveils the pivotal role of the ALKBH5-CHAC1-ROS axis and highlights the significance of m6A methylation in gastric cancer.

Mid-pregnancy and postpartum maternal mental health and infant sleep in the first year of life.

Perinatal depression and anxiety are common and associated with sleep problems in the offspring. Depression and anxiety are commonly comorbid, yet often studied independently. Our study used an integrative measure of anxiety and depressive symptoms to examine the associations of maternal mental health (mid-pregnancy and postnatal) with infant sleep during the first year of life. A total of 797 mother-child dyads from the 'Growing Up in Singapore Towards healthy Outcome' cohort study provided infant sleep data at 3, 6, 9 and 12 months of age, using the caregiver reported Brief Infant Sleep Questionnaire. Maternal mental health was assessed at 26-28 weeks gestation and 3 months postpartum using the Edinburgh Postnatal Depression Scale, Beck Depression Inventory and State-Trait Anxiety Inventory. Bifactor modelling with the individual questionnaire items produced a general affect factor score that provided an integrated measure of anxiety and depressive symptoms. Linear mixed models were used to model the sleep outcomes, with adjustment for maternal age, education, parity, ethnicity, sex of the child and maternal sleep quality concurrent with maternal mental health assessment. We found that poorer mid-pregnancy, but not postpartum, maternal mental health was associated with longer wake after sleep onset duration across the first year of life (ß = 49, 95% confidence interval 13-85 min). Poor maternal mental health during mid-pregnancy is linked to longer period of night awakening in the offspring during infancy. Interventions that aim to improve maternal antenatal mental health should examine infant sleep outcomes.

Nutrient trajectories during infancy and their associations with childhood neurodevelopment.

PURPOSE: To examine the associations between infants' dietary nutrient trajectories and subsequent neurodevelopment during childhood in the Growing Up in Singapore Towards healthy Outcomes study. METHODS: One-day food records were collected at ages 6, 9 and 12 months, whilst Bayley Scales of Infant and Toddler Development-III and Kaufman Brief Intelligence Test-2 were conducted at ages 24 and 54 months respectively. Nutrient trajectories were constructed using multi-level mixed modelling and associations with neurodevelopment (24 months: n = 484; 54 months: n = 444) were examined using adjusted multivariable linear regression. RESULTS: At age 24 months, higher protein intake (at 6 months) and increasing rate of intake (from 6 to 12 months) were associated with higher fine motor score [ß = 0.17 SD (95% CI 0.03, 0.31) and 0.62 SD (0.10, 1.14) respectively]. Higher fat intake was associated with higher receptive language score [0.04 SD (0.003, 0.07)], but increasing rate of intake was associated with lower expressive language [- 0.20 SD (- 0.39, - 0.01)] and fine motor [- 0.29 SD (- 0.48, - 0.10)] scores. Higher carbohydrate intake was associated with lower gross motor score [- 0.07 SD (- 0.14, - 0.005)], but increasing rate of intake was associated with higher receptive language [0.44 SD (0.08, 0.81)] and fine motor [0.56 SD (0.18, 0.93)] scores. Increasing rate of dietary fibre intake was associated with higher fine motor scores [0.63 SD (0.16, 1.10)]. No significant associations were observed with neurodevelopment at 54 months. CONCLUSION: Our findings provide greater understanding of how nutrition over time could have varying effects on child neurodevelopment.

Single-cell RNA-seq dissecting heterogeneity of tumor cells and comprehensive dynamics in tumor microenvironment during lymph nodes metastasis in gastric cancer.

Lymph node metastasis is the common metastasis route of gastric cancer. However, until now, heterogeneities of tumor cells and tumor microenvironment in primary tumors (PT) and metastatic lymph nodes (MLN) of gastric cancer (GC) remains uncharacterized. In our study, single cell RNA sequencing was performed on tissues from PT and MLN of gastric cancer. Trajectory analysis and function enrichment analyses were conducted to decode the underlying mechanisms contributing to LN metastasis of gastric cancer. Heterogeneous composition of immune cells and distinct intercellular interactions in PT and MLN were analyzed. Based on the generated single cell transcriptome profiles, dynamics of gene expressions in cancer cells between PT and MLN were characterized. Moreover, we reconstructed the developmental trajectory of GC cells' metastasis to LN and identified two subtypes of GC cells with distinct potentials of having malignant biological behaviors. We characterized the repression of neutrophil polarization associated genes, like LCN2, which would contribute to LN metastasis, and histochemistry experiments validated our findings. Additionally, heterogeneity in neutrophils, rather than macrophages, was characterized. Immune checkpoint associated interaction of SPP1 was found active in MLN. In conclusion, we decode the dynamics of tumor cells during LN metastasis in GC and to identify a subtype of GC cells with potentials of LN metastasis. Our data indicated that the disordering the neutrophils polarization and maturation and the activation of immune checkpoint SPP1 might contribute to LN metastasis in GC, providing a novel insight on the mechanism and potential therapeutic targets of LN metastasis in GC.

Family-focused contextual factors associated with lifestyle patterns in young children from two mother-offspring cohorts: GUSTO and EDEN.

BACKGROUND: Integrated patterns of energy balance-related behaviours of preschool children in Asia are sparse, with few comparative analyses. PURPOSE: Using cohorts in Singapore (GUSTO) and France (EDEN), we characterized lifestyle patterns of children and investigated their associations with family-focused contextual factors. METHODS: Ten behavioural variables related to child's diet, walking, outdoor play and screen time were ascertained by parental questionnaires at age 5-6 years. Using principal component analysis, sex-specific lifestyle patterns were derived independently for 630 GUSTO and 989 EDEN children. Contextual variables were organised into distal (family socio-economics, demographics), intermediate (parental health, lifestyle habits) and proximal (parent-child interaction factors) levels of influence and analysed with hierarchical linear regression. RESULTS: Three broadly similar lifestyle patterns were identified in both cohorts: "discretionary consumption and high screen time", "fruit, vegetables, and low screen time" and "high outdoor playtime and walking". The latter two patterns showed small differences between cohorts and sexes. The "discretionary consumption and high screen time" pattern was consistently similar in both cohorts; distal associated factors were lower maternal education (EDEN boys), no younger siblings (GUSTO boys) and Malay/Indian ethnicity (GUSTO), while intermediate and proximal associated factors in both cohorts and sexes were poor maternal diets during pregnancy, parents allowing high child control over food intake, snacking between meals and having television on while eating. CONCLUSIONS: Three similar lifestyle patterns were observed among preschool children in Singapore and France. There were more common associated proximal factors than distal ones. Cohort specific family-focused contextual factors likely reflect differences in social and cultural settings. Findings will aid development of strategies to improve child health.

The longitudinal association between early-life screen viewing and abdominal adiposity-findings from a multiethnic birth cohort study.

IMPORTANCE: Screen viewing in adults has been associated with greater abdominal adiposity, with the magnitude of associations varying by sex and ethnicity, but the evidence is lacking at younger ages. We aimed to investigate sex- and ethnic-specific associations of screen-viewing time at ages 2 and 3 years with abdominal adiposity measured by magnetic resonance imaging at age 4.5 years. METHODS: The Growing Up in Singapore Towards healthy Outcomes is an ongoing prospective mother-offspring cohort study. Parents/caregivers reported the time their child spent viewing television, handheld devices, and computer screens at ages 2 and 3 years. Superficial and deep subcutaneous and visceral abdominal adipose tissue volumes were quantified from magnetic resonance images acquired at age 4.5 years. Associations between screen-viewing time and abdominal adipose tissue volumes were examined by multivariable linear regression adjusting for confounding factors. RESULTS: In the overall sample (n = 307), greater total screen-viewing time and handheld device times were associated with higher superficial and deep subcutaneous adipose tissue volumes, but not with visceral adipose tissue volumes. Interactions with child sex were found, with significant associations with superficial and deep subcutaneous and visceral adipose tissue volumes in boys, but not in girls. Among boys, the increases in mean (95% CI) superficial and deep subcutaneous and visceral adipose tissue volumes were 24.3 (9.9, 38.7), 17.6 (7.4, 27.8), and 7.8 (2.1, 13.6) mL per hour increase in daily total screen-viewing time, respectively. Ethnicity-specific analyses showed associations of total screen-viewing time with abdominal adiposity only in Malay children. Television viewing time was not associated with abdominal adiposity. CONCLUSION: Greater total screen-viewing time (and in particular, handheld device viewing time) was associated with higher abdominal adiposity in boys and Malay children. Additional studies are necessary to confirm these associations and to examine screen-viewing interventions for preventing excessive abdominal adiposity and its adverse cardiometabolic consequences.

Severity of nausea and vomiting in pregnancy and early childhood neurobehavioural outcomes: The Growing Up in Singapore Towards Healthy Outcomes study.

BACKGROUND: Nausea and vomiting of pregnancy (NVP) affects 50 to 80 per cent of women. The existing literature has examined NVP from the perspective of the mother, and relatively less is known about offspring outcomes. OBJECTIVES: To study the relationships of NVP with social-emotional, behavioural, and cognitive outcomes of the offspring in a multi-ethnic Asian cohort. METHODS: In the Growing Up in Singapore Towards Healthy Outcomes prospective mother-offspring cohort study, mothers responded to a structured NVP questionnaire at 26-28 weeks' gestation (n = 1172) and participants with severe NVP were confirmed using medical records. Children underwent multiple neurodevelopmental assessments throughout childhood. We conducted multivariable regressions with post-estimation predictive margins to understand the associations of NVP with offspring neurobehavioural outcomes, which included 1-year Infant-Toddler Social and Emotional Assessment, 1.5-year Quantitative Checklist for Autism in Toddlers, 2-year Bayley Scales of Infant and Toddler Development, 2- and 4-year Child Behavior Checklist, and 4.5-year Kaufman Brief Intelligence Test. Analyses were adjusted for household income, birth variables, maternal mental health, and other relevant medical variables. Cohen's d effect sizes were calculated using standardised mean differences (µd ). RESULTS: Mothers were categorised into no (n = 296, 25.3%), mild-moderate (n = 686, 58.5%), and severe NVP (n = 190, 16.2%), of whom 67 (5.7%) required admission. Compared to children of mothers who had no or mild-moderate NVP, children with exposure to severe NVP exhibited more externalising behaviours (µd 2.0, 95% CI 0.3, 3.6; Cohen's d = 0.33) and social communication difficulties before 2 years (µd 4.1, 95% Cl 0.1, 8.0; Cohen's d = 0.38), both externalising (µd 1.5, 95% CI 0.4, 2.6; Cohen's d = 0.43) and internalising behaviours at 2 years (µd 1.2, 95% CI 0.1, 2.2; Cohen's d = 0.35), and only internalising behaviours after 2 years (µd 1.1, 95% CI 0.4, 2.0; Cohen's d = 0.37). CONCLUSIONS: Severe NVP is highly prevalent in this Asian cohort and may be adversely associated with multiple offspring neurobehavioural outcomes.

Higher maternal plasma ß-cryptoxanthin concentration is associated with better cognitive and motor development in offspring at 2 years of age.

PURPOSE: Current literature on the roles of α-, ß-carotene and ß-cryptoxanthin in neurocognitive function has largely focused on preventing cognitive decline in older people, and less on neuro-development in children. We examined the relations of maternal plasma carotenoids concentrations with offspring cognitive development up to age 4.5 years in the Growing Up in Singapore Towards healthy Outcomes mother-offspring cohort study. METHODS: Maternal plasma α-, ß-carotene and ß-cryptoxanthin concentrations at delivery were determined by ultra-performance liquid chromatography. Children's cognition was assessed at ages 2 (Bayley Scales of Infant and Toddler Development) and 4.5 (Kaufman Brief Intelligence Test) years. Associations were examined in 419 mother-offspring pairs using linear regressions adjusting for key confounders. RESULTS: Median and interquartile range of maternal plasma concentrations (mg/L) were: α-carotene 0.052 (0.032, 0.081), ß-carotene 0.189 (0.134, 0.286), and ß-cryptoxanthin 0.199 (0.123, 0.304). In 2 years old children, higher maternal carotenoids [per standard deviation (SD) log-concentration] were positively associated with neurocognitive functions: ß-cryptoxanthin with higher scores in cognitive [ß = 0.18, (0.08, 0.28) SD], receptive language [ß = 0.17 (0.07, 0.27) SD], fine motor [ß = 0.16 (0.05, 0.26) SD], and gross motor [ß = 0.16 (0.06, 0.27) SD] scales; ß-carotene with higher cognitive score [ß = 0.17 (0.05, 0.29) SD]. No significant associations were observed with neurocognitive functions at age 4.5 years. CONCLUSION: Our study provides novel data suggesting a potential role of prenatal carotenoids, particularly ß-cryptoxanthin, on early offspring cognitive and motor development. Whether the prenatal influences sustain beyond early childhood requires further investigation in longer term studies.

Associations of maternal zinc and magnesium with offspring learning abilities and cognitive development at 4 years in GUSTO.

Objectives: Minerals deficiencies during pregnancy have been shown to be associated with poorer cognitive outcomes in offspring. This study aimed to investigate associations of maternal plasma zinc and magnesium concentrations with cognitive development in 4-year old children from the Growing Up in Singapore Towards healthy Outcome cohort.Methods: Maternal plasma zinc and magnesium concentrations were measured at 26-28 weeks' gestation. The Lollipop test of school readiness, tests of working memory, number knowledge, receptive vocabulary, and phonological awareness were performed in children at 4 years. Associations were examined in 715 mother-offspring pairs using linear regressions adjusted for key confounders.Results: Maternal plasma zinc and magnesium concentrations were 812 ± 144 µg/L and 19.9 ± 1.8 mg/L (mean±SD); 19% and 71% of mothers were zinc deficient and magnesium insufficient, respectively. After adjustment for multiple testing, higher maternal zinc concentrations (per SD increment) were associated with 0.35 higher scores in Lollipop subtest 2 of picture description and spatial identification (95% CI: 0.13, 0.58); higher maternal magnesium concentrations (per SD increment) were associated with 0.65 higher scores in Lollipop subtest 4 of letters and writing identification (95% CI: 0.23, 1.07).Discussion: No significant associations were observed for other tests, suggesting little long term influences of maternal zinc and magnesium on child's cognitive development.

Correlations between imatinib plasma trough concentration and adverse reactions in Chinese patients with gastrointestinal stromal tumors.

BACKGROUND: Imatinib is the standard treatment for patients with gastrointestinal stromal tumors (GISTs), but there is significant variation in imatinib plasma trough concentrations (Cmin ) among patients. The imatinib Cmin distribution at different doses and the correlation of adverse reactions with Cmin in Chinese patients with GIST from a high-volume center were evaluated. METHODS: From July 1, 2017 to December 31, 2018, patients who were receiving imatinib treatment for GIST were prospectively enrolled. Steady-state blood samples were obtained from patients who had received same-dose imatinib treatment for ≥1 month with good compliance. Adverse reactions were recorded during regular follow-up, and blood samples were collected 24 ± 2 hours after dosing. Liquid chromatography-tandem mass spectrometry was used to measure drug concentrations. RESULTS: In total, 307 patients who received 367 dose levels were investigated. The imatinib Cmin was 1315 ± 716 ng/mL, 2117 ± 597 ng/mL, and 3844 ± 987 ng/mL in patients who were receiving imatinib 400 mg, 600 mg, and 800 mg daily, respectively. The Cmin was significantly correlated with periorbital and limb edema (P < .001), anemia (P < .001), and rash (P = .037). Nausea and vomiting, diarrhea, and conjunctival hemorrhage also were correlated, but not significantly. A much higher Cmin was observed with severe adverse reactions. There was no correlation between the imatinib Cmin and leukopenia, muscle cramps, or hepatobiliary dysfunction. CONCLUSIONS: In Chinese patients with GIST, the imatinib Cmin was higher than that reported for Western populations, especially at higher doses. The Cmin was correlated with periorbital and limb edema, anemia, and rash, suggesting that monitoring the imatinib Cmin should be considered when patients develop severe adverse reactions caused by excessive imatinib plasma concentrations.

Do intrinsic brain functional networks predict working memory from childhood to adulthood?

Working memory (WM) is defined as the ability to maintain a representation online to guide goal-directed behavior. Its capacity in early childhood predicts academic achievements in late childhood and its deficits are found in various neurodevelopmental disorders. We employed resting-state fMRI (rs-fMRI) of 468 participants aged from 4 to 55 years and connectome-based predictive modeling (CPM) to explore the potential predictive power of intrinsic functional networks to WM in preschoolers, early and late school-age children, adolescents, and adults. We defined intrinsic functional networks among brain regions identified by activation likelihood estimation (ALE) meta-analysis on existing WM functional studies (ALE-based intrinsic functional networks) and intrinsic functional networks generated based on the whole brain (whole-brain intrinsic functional networks). We employed the CPM on these networks to predict WM in each age group. The CPM using the ALE-based and whole-brain intrinsic functional networks predicted WM of individual adults, while the prediction power of the ALE-based intrinsic functional networks was superior to that of the whole-brain intrinsic functional networks. Nevertheless, the CPM using the whole-brain but not the ALE-based intrinsic functional networks predicted WM in adolescents. And, the CPM using neither the ALE-based nor whole-brain networks predicted WM in any of the children groups. Our findings showed the trend of the prediction power of the intrinsic functional networks to cognition in individuals from early childhood to adulthood.

Nutrients or nursing? Understanding how breast milk feeding affects child cognition.

PURPOSE: To explore the associations between type of milk feeding (the "nutrients") and mode of breast milk feeding (the "nursing") with child cognition. METHODS: Healthy children from the GUSTO (Growing Up in Singapore Toward healthy Outcomes) cohort participated in repeated neurodevelopmental assessments between 6 and 54 months. For "nutrients", we compared children exclusively bottle-fed according to type of milk received: formula only (n = 296) vs some/all breast milk (n = 73). For "nursing", we included only children who were fully fed breast milk, comparing those fed directly at the breast (n = 59) vs those fed partially/completely by bottle (n = 63). RESULTS: Compared to infants fed formula only, those who were bottle-fed breast milk demonstrated significantly better cognitive performance on both the Bayley Scales of Infant and Toddler Development (Third Edition) at 2 years [adjusted mean difference (95% CI) 1.36 (0.32, 2.40)], and on the Kaufman Brief Intelligence Test (Second Edition) at 4.5 years [7.59 (1.20, 13.99)]. Children bottle-fed breast milk also demonstrated better gross motor skills at 2 years than those fed formula [1.60 (0.09, 3.10)]. Among infants fully fed breast milk, those fed directly at the breast scored higher on several memory tasks compared to children bottle-fed breast milk, including the deferred imitation task at 6 months [0.67 (0.02, 1.32)] and relational binding tasks at 6 [0.41 (0.07, 0.74)], 41 [0.67 (0.04, 1.29)] and 54 [0.12 (0.01, 0.22)] months. CONCLUSIONS: Our findings suggest that nutrients in breast milk may improve general child cognition, while nursing infants directly at the breast may influence memory.

Multiple modifiable lifestyle factors and the risk of perinatal depression during pregnancy: Findings from the GUSTO cohort.

BACKGROUND: Studies have identified lifestyle risk factors for perinatal depression, but none have examined the cumulative effect of these risk factors in pregnant women. METHODS: We considered the following six factors during pregnancy: poor diet quality (Healthy eating index for Singapore pregnant women 5), physical inactivity (<600 MET-minutes/week), vitamin D insufficiency (<50 nmol/l), smoking before or during pregnancy, and the perceived need for social support. Probable depression was assessed using the Edinburgh postnatal depression scale during pregnancy (>15) and at three months postpartum (≥13). Prevalence risk ratios were calculated with Poisson regressions while adjusting for potential confounders. RESULTS: Of 535 pregnant women, 207 (39%) had zero or one risk factor, 146 (27%) had two, 119 (22%) had three, 48 (9%) had four, and 15 (3%) had ≥5 risk factors at 26-28 weeks' gestation. These six lifestyle habits contributed to 32% of the variance in depressive symptoms during pregnancy. The prevalence of being probably depressed was 6.4 (95% CI 2.1, 19.8; ptrend < 0.001) for expecting women who had ≥4 risk factors compared to women who had ≤1 risk factor. No association was observed between the number of risk factors and depressive symptoms at 3 months postpartum (ptrend = 0.746). CONCLUSION: Pregnant women with ≥4 lifestyle risk factors showed a higher prevalence of depression during pregnancy, while no associations were observed for postpartum depression. CLINICAL TRIAL REGISTRATION: This cohort is registered under the Clinical Trials identifier NCT01174875; http://www.clinicaltrials.gov/ct2/show/NCT01174875?term=GUSTO&rank=2.

The Monocyte-to-Lymphocyte Ratio at Hospital Admission Is a Novel Predictor for Acute Traumatic Intraparenchymal Hemorrhage Expansion after Cerebral Contusion.

PURPOSE: To explore the potential of monocyte-to-lymphocyte ratio (MLR) at hospital admission for predicting acute traumatic intraparenchymal hematoma (tICH) expansion in patients with cerebral contusion. Patients and Methods. This multicenter, observational study included patients with available at-hospital admission (baseline) and follow-up computed tomography for volumetric analysis (retrospective development cohort: 1146 patients; prospective validation cohort: 207 patients). Semiautomated software assessed tICH expansion (defined as ≥33% or 5 mL absolute growth). MLR was acquired from routine blood tests upon admission. We constructed two predictive models: basic combined model of clinical and imaging variables and MLR combined model of both MLR and other variables in the basic model. Receiver operating characteristic (ROC) analysis and decision curve analysis (DCA) were used to estimate the performance of MLR for predicting acute tICH expansion. RESULTS: MLR was significantly larger in patients with acute tICH expansion compared to those without acute tICH expansion (mean [SD], 1.08 [1.05] vs. 0.59 [0.37], P < 0.001). A nonlinear positive relationship between MLR and the incidence of acute tICH expansion was observed. Multivariate logistic regression indicated MLR as an independent risk factor for acute tICH expansion (odds ratio (OR), 5.88; 95% confidence interval (CI), 4.02-8.61). The power of the multivariate model for predicting acute tICH expansion was substantially improved with the inclusion of MLR (AUC 0.86 vs. AUC 0.74, P < 0.001), as was also observed in an external validation cohort (AUC 0.83 vs. AUC 0.71, P < 0.001). The net benefit of MLR model was higher between threshold probabilities of 20-100% in DCA. For clinical application, a nomogram derived from the multivariate model with MLR was introduced. In addition, MLR was positively associated with 6-month unfavorable outcome. CONCLUSION: MLR is a novel predictor for traumatic parenchymatous hematoma expansion. A nomogram derived from the MLR model may provide an easy-to-use tool for predicting acute tICH expansion and promoting the individualized treatment of patients with hemorrhagic cerebral contusion. MLR is associated with long-term outcome after cerebral contusion.

Sex-specific longitudinal associations of screen viewing time in children at 2-3 years with adiposity at 3-5 years.

OBJECTIVES: Screen-viewing in late childhood has been associated with adiposity and blood pressure (BP), but evidence is lacking at younger ages. To investigate the prospective associations of total and device-specific screen-viewing at age 2-3 years with BMI, sum of skinfold thicknesses and BP among Singaporean children at age 3-5 years. METHODS: As part of the Growing Up in Singapore Towards healthy Outcomes (GUSTO) cohort, mothers/caregivers reported the time per day their 2 and 3-year-old children watched/used television, handheld devices and computers. Average screen-viewing time (total, television and handheld-devices) at ages 2 and 3 years was used in the analyses. Height; weight; triceps, biceps and subscapular skinfold thicknesses; and systolic and diastolic BP were measured at ages 3, 4 and 5. Associations of screen-viewing with BMI, sum of skinfold thicknesses and BP in 956 children were investigated using repeated-measures linear regression models. Analyses were further stratified by sex as we found significant interaction. RESULTS: Among boys and girls combined, screen-viewing was positively associated with sum of skinfold thicknesses, but not with BMI or BP. Sex-specific analyses showed significant associations with both BMI and sum of skinfold thicknesses in boys, but not in girls. Screen-viewing was not associated with BP in boys or girls. The increases in mean (95% CI) BMI per hour increase in daily total, television and handheld-devices screen-viewing among boys were 0.12 (0.03, 0.21), 0.18 (0.06, 0.30) and 0.11 (-0.07, 0.29) kg/m2, respectively. The corresponding increases in mean sum of skinfold thicknesses were 0.68 (0.29, 1.07), 0.79 (0.26, 1.32) and 1.18 (0.38, 1.99) mm. CONCLUSIONS: Greater screen-viewing at age 2-3 years was associated with later adiposity at 3-5 years in boys, but not in girls. In light of the increasing use of screen devices and cardiometabolic risk in young children, these findings may have important public health implications.