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The combination of metformin and the peroxisome proliferator-activated receptors (PPAR) agonists offers a promising avenue for managing type 2 diabetes (T2D) through their potential complementary mechanisms of action. The results from randomized controlled trials (RCT) assessing the efficacy of PPAR agonists plus metformin versus metformin alone in T2D are inconsistent, which prompted the conduct of the systematic review and meta-analysis. We searched MEDLINE and EMBASE from inception (1966) to March 2023 to identify all RCTs comparing any PPAR agonists plus metformin versus metformin alone in T2D. Categorical variables were summarized as relative risk along with 95% confidence interval (CI). Twenty RCTs enrolling a total of 6058 patients met the inclusion criteria. The certainty of evidence ranged from moderate to very low. Pooled results show that using PPAR agonist plus metformin, as compared to metformin alone, results in lower concentrations of fasting glucose [MD = - 22.07 mg/dl (95% CI - 27.17, - 16.97), HbA1c [MD = - 0.53% (95% CI - 0.67, - 0.38)], HOMA-IR [MD = - 1.26 (95% CI - 2.16, - 0.37)], and fasting insulin [MD = - 19.83 pmol/L (95% CI - 29.54, - 10.13)] without significant increase in any adverse events. Thus, synthesized evidence from RCTs demonstrates the beneficial effects of PPAR agonist add-on treatment versus metformin alone in T2D patients. In particular, novel dual PPARα/γ agonist (tesaglitazar) demonstrate efficacy in improving glycaemic and lipid concentrations, so further RCTs should be performed to elucidate the long-term outcomes and safety profile of these novel combined and personalized therapeutic strategies in the management of T2D.PROSPERO registration no. CRD42023412603., (© 2024. The Author(s).)

Background: Educational mobility at the macro-level is a common measure of social inequality. Nonetheless, the correlates of mobility of education at the individual level are less well studied. We evaluated whether educational mobility of the second generation (compared to the first generation level) predicts differences in parenting practices of the second generation and school achievement and intelligence in the third generation., Methods: Data from a population-based cohort of children in the Netherlands (N = 3547; 49.4% boys) were analyzed. Maternal, grandparental education and family routines, a parenting practice, were reported by the mother. Child school achievement at the end of primary school (∼12 years, with the national Dutch academic test score) and child intelligence (∼6 and 13 years) were measured in a standardized manner. Also, a child genome-wide polygenic score of academic attainment was calculated. To estimate the effect of educational mobility, inverse probability-weighted linear models and Diagonal Reference Models (DRM) were used., Results: Upward maternal educational mobility was associated with better offspring school achievement, higher intelligence, and more family routines if compared to offspring of mothers with no upward mobility. However, mothers did not implement the same level of family routines as similarly educated mothers and grandfathers who already had achieved this educational level. Likewise, children of mothers with upward educational mobility had lower school achievement and intelligence than children of similarly educated mothers with no mobility. Child's genetic potential for education followed a similar association pattern with higher potential in children of upward mobile mothers., Conclusion: Policymakers might overlook social inequalities when focused on parental socioeconomic status. Grandparental socioeconomic status, which independently predicts child school achievement, intelligence, and parental family routines, should also be assessed. The child's genetic endowment reflects the propensity for education across generations that partly underlies mobility and some of its effect on the offspring., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Developmental disorders (DDs), such as autism spectrum disorder (ASD), incorporate various conditions; once identified, further diagnostics are necessary to specify their type and severity. The aim of this exploratory study was to identify genetic variants that can help differentiate ASD early from other DDs. We selected 36 children (mean age 60.1 months) with DDs using Developmental Behavioral Scales (DBS) through "EDUS-Education for All", an organization providing services for children with developmental disorders in Bosnia and Herzegovina. We further rated children's autistic traits with the preschool version of the Childhood Autism Rating Scale, second edition (CARS-II). We defined ASD if scores were >25.5 and other DDs if scores were <25.5. Diagnosis of ASD and DD were independently confirmed by child psychiatrists. Whole exome sequencing (WES) was performed by Veritas Genetics, USA, using Illumina NovaSeq 6000 (Illumina Inc., San Diego, CA, USA) next-generation sequencing (NGS) apparatus. We tested genetic association by applying SKAT-O, which optimally combines the standard Sequence Kernel Association Test (SKAT) and burden tests to identify rare variants associated with complex traits in samples of limited power. The analysis yielded seven genes (DSE, COL10A1, DLK2, CSMD1, FAM47E, PPIA, PYDC2) to potentially differentiate observed phenotypic characteristics between our cohort participants with ASD and other DDs. Our exploratory study in a small sample of participants with ASD and other DDs contributed to gene discovery in differentiating ASD from DDs. A replication study is needed in a larger sample to confirm our results.

Objective: Depression and obesity are 2 highly prevalent and often comorbid conditions. Exposure to early-life stress (ELS) has been associated with both depression and obesity in adulthood, as well as their preclinical manifestations during development. However, it remains unclear whether (1) associations differ depending on the timing of stress exposure (prenatal vs postnatal), and whether (2) ELS is a shared risk factor underlying the comorbidity between the 2 conditions., Method: Leveraging data from 2 large population-based birth cohorts (ALSPAC: n = 8,428 [52% male participants]; Generation R: n = 4,268 [48% male participants]), we constructed comprehensive cumulative measures of prenatal (in utero) and postnatal (from birth to 10 years) ELS. At age 13.5 years, we assessed the following: internalizing symptoms (using maternal reports); fat mass percentage (using dual-energy X-ray absorptiometry); and their comorbidity, defined as the co-occurrence of high internalizing and high adiposity., Results: Both prenatal (total effect [95% CI] = 0.20 [0.16; 0.22]) and postnatal stress (β [95%CI] = 0.22 [0.17; 0.25]) were associated with higher internalizing symptoms, with evidence of a more prominent role of postnatal stress. A weaker association (driven primarily by prenatal stress) was observed between stress and adiposity (prenatal: 0.07 [0.05; 0.09]; postnatal: 0.04 [0.01; 0.07]). Both prenatal (odds ratio [95%CI] = 1.70 [1.47; 1.97]) and postnatal (1.87 [1.61; 2.17]) stress were associated with an increased risk of developing comorbidity., Conclusion: We found evidence of timing and shared causal effects of ELS on psycho-cardiometabolic health in adolescence; however, future research is warranted to clarify how these associations may unfold over time., Diversity & Inclusion Statement: We worked to ensure sex and gender balance in the recruitment of human participants. We worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. We worked to ensure that the study questionnaires were prepared in an inclusive way. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented racial and/or ethnic groups in science. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented sexual and/or gender groups in science. We actively worked to promote sex and gender balance in our author group., (Copyright © 2023 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Lower fine motor performance in childhood has been associated with poorer cognitive development and neurodevelopmental conditions such as autism spectrum disorder, yet, biological underpinnings remain unclear. DNA methylation (DNAm), an essential process for healthy neurodevelopment, is a key molecular system of interest. In this study, we conducted the first epigenome-wide association study of neonatal DNAm with childhood fine motor ability and further examined the replicability of epigenetic markers in an independent cohort. The discovery study was embedded in Generation R, a large population-based prospective cohort, including a subsample of 924 ~ 1026 European-ancestry singletons with available data on DNAm in cord blood and fine motor ability at a mean (SD) age of 9.8 (0.4) years. Fine motor ability was measured using a finger-tapping test (3 subtests including left-, right-hand and bimanual), one of the most frequently used neuropsychological instruments of fine motor function. The replication study comprised 326 children with a mean (SD) age of 6.8 (0.4) years from an independent cohort, the INfancia Medio Ambiente (INMA) study. Four CpG sites at birth were prospectively associated with childhood fine motor ability after genome-wide correction. Of these, one CpG (cg07783800 in GNG4) was replicated in INMA, showing that lower levels of methylation at this site were associated with lower fine motor performance in both cohorts. GNG4 is highly expressed in the brain and has been implicated in cognitive decline. Our findings support a prospective, reproducible association between DNAm at birth and fine motor ability in childhood, pointing to GNG4 methylation at birth as a potential biomarker of fine motor ability.

Background: Lifestyle changes and dietary intervention, including the use of probiotics, can modulate dysbiosis of gut microbiome and contribute to the management of type 2 diabetes mellitus (T2DM). This systematic review and meta-analysis aim to assess the efficacy of metformin plus probiotics versus metformin alone on outcomes in patients with T2DM., Methods: We searched MEDLINE and EMBASE from inception to February 2023 to identify all randomized controlled trials (RCTs), which compared the use of metformin plus probiotics versus metformin alone in adult patients with T2DM. Data were summarized as mean differences (MD) with 95 % confidence interval (CI) and pooled under the random effects model., Findings: Fourteen RCTs (17 comparisons, 1009 patients) were included in this systematic review. Pooled results show a significant decrease in fasting glucose (FG) (MD = -0.64, 95 % CI = -1.06, -0.22) and HbA1c (MD = -0.29, 95 % CI = -0.47, -0.10) levels in patients with T2DM treated with metformin plus probiotics versus metformin alone. The addition of probiotics to metformin resulted in lower odds of gastrointestinal adverse events (Odds ratio = 0.18, 95 % CI = 0.09, 0.3.8; I 2  = 0 %)., Conclusions: The addition of probiotics to metformin therapy is associated with improvement in T2DM outcomes. However, high-quality and adequately reported RCTs are needed in the future to confirm our findings., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: Excessive crying in infancy has been associated with increased risk of later behavioral problems. To identify individuals at risk for behavioral problems and to understand the mechanisms underlying excessive crying and irritability in infancy, research into the neurobiology of excessive crying is needed. We examined whether excessive crying and irritability in infancy are associated with behavioral problems and amygdala volume among children and adolescents., Method: This study included 4,751 singleton children from the prospective population-based Generation R Study cohort, born in the Netherlands in 2002 to 2006. Excessive crying (>3 hours on at least 1 day/wk) and irritability (Mother and Baby Scales questionnaire) were parent-rated at 3 months. Amygdala volume was measured at 10 years using magnetic resonance imaging, and internalizing and externalizing were parent-rated at 1.5, 3, 6, 10, and 14 years and self-rated at 14 years. Covariates included child age, sex, national origin, gestational age, and maternal age, psychopathology score, parity, education, relationship status, and family income., Results: Children who cried excessively in infancy had higher parent-rated internalizing (effect estimate = 0.20 SD-units, 95% CI = 0.14, 0.27) and externalizing (0.17 SD-units, 95% CI = 0.10, 0.24) throughout childhood (linear mixed models), and smaller amygdala volume at 10 years (-0.19 SD-units, 95% CI = -0.32, -0.06) (linear regression model). The pattern of associations for both behavioral problems and amygdala volume was similar for irritability., Conclusion: Excessive crying and irritability in infancy may reflect an early vulnerability to behavioral problems and may be linked with neurobiological differences in the development of the amygdala., (Copyright © 2023 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Parental education is one of the best predictors of child school achievement. Higher parental education is not only associated with higher child intelligence, but children from highly educated parents also perform better in school due to other family related factors. This study evaluates the relation between parental education, child non-verbal intelligence and parenting practices with child school achievement., Methods: Longitudinal data from a large population-based, multi-ethnic cohort of children in the Netherlands (63% Dutch origin) followed from birth to age 13 years (3547 children; 52.3% girls) were analyzed. School achievement was measured at the end of primary school (12 years of age) with a national Dutch academic test score. Parental education was assessed at age 3 years. The non-verbal intelligence of the child was measured at age 6 years and a full intelligence was measured at age 13 years. Maternal and paternal family routines, harsh parenting and corporal punishment were assessed in early and mid-childhood. Mediation analysis was performed with the G-formula and Structural Equation Models., Results: Child intelligence partially mediated [B indirect effect =0.54 95% CI (0.46, 0.62) P < 0.001] the association between parental education and child school achievement. Independent of intelligence, family routines [B indirect effect =0.04 95% CI (0.01, 0.07) P < 0.01], but not harsh parenting mediated this association., Conclusions: Higher parental education was associated with better school achievement through two independent mechanisms, through higher intelligence of the child and parenting practices., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Public Health Association.)