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 DDs 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) NGS sequencing 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, and 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.

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.

OBJECTIVE Depression and obesity are two 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: (i) associations differ depending on the timing of stress exposure (prenatal vs postnatal) and (ii) ELS is a shared risk factor underlying the comorbidity between the two conditions. METHOD Leveraging data from two large population-based birth cohorts (ALSPAC: n=8428 (52% male participants); Generation R: n=4268 (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: a) internalizing symptoms (using maternal reports); b) fat mass percentage (using dual-energy X-ray absorptiometry); c) 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 (primarily driven by prenatal stress) was observed between stress and adiposity (prenatal: 0.07 [0.05;0.09]; postnatal: 0.04 [0.01;0.07]). Both pre- (OR [95%CI] = 1.70 [1.47;1.97]) and postnatal stress (1.87 [1.61;2.17]) were associated with an increased risk of developing comorbidity. CONCLUSION We found evidence of (i) timing and (ii) shared causal effects of ELS on psycho-cardiometabolic health in adolescence, but future research is warranted to clarify how these associations may unfold over time.

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; I2=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.

ABSTRACT 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.

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 if 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 2002-2006. Excessive crying (>3h on at least 1 day/week) 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% confidence interval [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 be linked with neurobiological differences in the development of the amygdala.

Abstract 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.

Between March 5th and July 25th, 2020, the total number of SARS-CoV-2 confirmed cases in Bosnia and Herzegovina (BH) was 10,090, corresponding to a cumulative incidence rate of 285.7/100,000 population. Demographic and clinical information on all the cases along with exposure and contact information were collected using a standardized case report form. In suspected SARS-CoV-2 cases, respiratory specimens were collected and tested by real-time reverse-transcriptase polymerase chain reaction assay. The dynamic of the outbreak was summarized using epidemiological curves, instantaneous reproduction number Rt, and interactive choropleth maps for geographical distribution and spread. The rate of hospitalization was 14.0% (790/5646) in the Federation of Bosnia and Herzegovina (FBH) and 6.2% (267/4299) in the Republic of Srpska (RS). The death rate was 2.2% (122/5646) in FBH and 3.6% in the RS (155/4299). After the authorities lifted mandatory quarantine restrictions, the instantaneous reproduction number increased from 1.13 on May 20th to 1.72 on May 31st. The outbreak concerns both entities, FBH and RS, and it is more pronounced in those aged 20-44 years. It is important to develop the communication and emergency plan for the SARS-CoV-2 outbreak in BH, including the mechanisms to allow the ongoing notification and updates at the national level.

Recent evidence shows that COVID-19 patients with existing metabolic disorders, such as diabetes and metabolic syndrome, are exposed to a high risk of morbidity and mortality. At the same time, in order to manage the pandemic, the health authorities around the world are advising people to stay at home. This results in decreased physical activity and an increased consumption of an unhealthy diet, which often leads to an increase in body weight, risk for diabetes, insulin resistance, and metabolic syndrome, and thus, paradoxically, to a high risk of morbidity and mortality due to COVID-19 complications. Here we summarize the evidence demonstrating that the promotion of a healthy life style, including physical activity and a dietary intake of natural polyphenols present in coffee and tea, has the potential to improve the prevention and management of insulin resistance and diabetes in the time of COVID-19 pandemic. Particularly, it would be pertinent to evaluate further the potential positive effects of coffee beverages, rich in natural polyphenols, as an adjuvant therapy for COVID-19, which appear not to be studied sufficiently.

Recently, Leung et al. [1] proposed that α7-subtype nicotinic acetylcholine receptor (α7-nAChR) antagonists might decrease angiotensin-converting enzyme (ACE)2 receptor expression in respiratory epithelium and, hence, prevent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) invasion of pulmonary epithelial cells. Let us further theoretically evaluate this assertion and contribute to the quest for potential medications that might reduce virulence and pathogenicity of coronavirus disease 2019 (COVID-19). Smoking may be associated with progression and negative outcome of COVID-19 [1]. The receptor-binding domain of the S protein (spike) on the surface of SARS-CoV-2 interacts with the ACE2 receptor, which is an entry point of the virus into host respiratory cells [2]. Memantine, as an antagonist of α7-nAChR and NMDA receptors, may decrease ACE2 receptor expression and reduce oxidative stress and inflammation. Hence, memantine may potentially reduce SARS-CoV-2 virulence. https://bit.ly/2AZHiVg