Genome-wide cell-free DNA fragmentation in patients with cancer.

Cell-free DNA in the blood provides a non-invasive diagnostic avenue for patients with cancer1. However, characteristics of the origins and molecular features of cell-free DNA are poorly understood. Here we developed an approach to evaluate fragmentation patterns of cell-free DNA across the genome, and found that profiles of healthy individuals reflected nucleosomal patterns of white blood cells, whereas patients with cancer had altered fragmentation profiles. We used this method to analyse the fragmentation profiles of 236 patients with breast, colorectal, lung, ovarian, pancreatic, gastric or bile duct cancer and 245 healthy individuals. A machine learning model that incorporated genome-wide fragmentation features had sensitivities of detection ranging from 57% to more than 99% among the seven cancer types at 98% specificity, with an overall area under the curve value of 0.94. Fragmentation profiles could be used to identify the tissue of origin of the cancers to a limited number of sites in 75% of cases. Combining our approach with mutation-based cell-free DNA analyses detected 91% of patients with cancer. The results of these analyses highlight important properties of cell-free DNA and provide a proof-of-principle approach for the screening, early detection and monitoring of human cancer.

An adaptive teosinte mexicana introgression modulates phosphatidylcholine levels and is associated with maize flowering time.

Native Americans domesticated maize (Zea mays ssp. mays) from lowland teosinte parviglumis (Zea mays ssp. parviglumis) in the warm Mexican southwest and brought it to the highlands of Mexico and South America where it was exposed to lower temperatures that imposed strong selection on flowering time. Phospholipids are important metabolites in plant responses to low-temperature and phosphorus availability and have been suggested to influence flowering time. Here, we combined linkage mapping with genome scans to identify High PhosphatidylCholine 1 (HPC1), a gene that encodes a phospholipase A1 enzyme, as a major driver of phospholipid variation in highland maize. Common garden experiments demonstrated strong genotype-by-environment interactions associated with variation at HPC1, with the highland HPC1 allele leading to higher fitness in highlands, possibly by hastening flowering. The highland maize HPC1 variant resulted in impaired function of the encoded protein due to a polymorphism in a highly conserved sequence. A meta-analysis across HPC1 orthologs indicated a strong association between the identity of the amino acid at this position and optimal growth in prokaryotes. Mutagenesis of HPC1 via genome editing validated its role in regulating phospholipid metabolism. Finally, we showed that the highland HPC1 allele entered cultivated maize by introgression from the wild highland teosinte Zea mays ssp. mexicana and has been maintained in maize breeding lines from the Northern United States, Canada, and Europe. Thus, HPC1 introgressed from teosinte mexicana underlies a large metabolic QTL that modulates phosphatidylcholine levels and has an adaptive effect at least in part via induction of early flowering time.

Error-Corrected Deep Targeted Sequencing of Circulating Cell-Free DNA from Colorectal Cancer Patients for Sensitive Detection of Circulating Tumor DNA.

Circulating tumor DNA (ctDNA) is a promising biomarker, reflecting the presence of tumor cells. Sequencing-based detection of ctDNA at low tumor fractions is challenging due to the crude error rate of sequencing. To mitigate this challenge, we developed ultra-deep mutation-integrated sequencing (UMIseq), a fixed-panel deep targeted sequencing approach, which is universally applicable to all colorectal cancer (CRC) patients. UMIseq features UMI-mediated error correction, the exclusion of mutations related to clonal hematopoiesis, a panel of normal samples for error modeling, and signal integration from single-nucleotide variations, insertions, deletions, and phased mutations. UMIseq was trained and independently validated on pre-operative (pre-OP) plasma from CRC patients (n = 364) and healthy individuals (n = 61). UMIseq displayed an area under the curve surpassing 0.95 for allele frequencies (AFs) down to 0.05%. In the training cohort, the pre-OP detection rate reached 80% at 95% specificity, while it was 70% in the validation cohort. UMIseq enabled the detection of AFs down to 0.004%. To assess the potential for detection of residual disease, 26 post-operative plasma samples from stage III CRC patients were analyzed. From this we found that the detection of ctDNA was associated with recurrence. In conclusion, UMIseq demonstrated robust performance with high sensitivity and specificity, enabling the detection of ctDNA at low allele frequencies.

Low- versus standard- pneumoperitoneum in patients undergoing robot-assisted radical prostatectomy: a randomised, triple-blinded study.

OBJECTIVE: To investigate the effectiveness and impact of low-pressure pneumoperitoneum (Pnp) on postoperative quality of recovery (QoR) and surgical workspace (SWS) in patients with prostate cancer undergoing robot-assisted radical prostatectomy (RARP). PATIENTS AND METHODS: A randomised, triple-blinded trial was conducted in a single centre in Denmark from March 2021 to January 2022. A total of 98 patients with prostate cancer undergoing RARP were randomly assigned to either low-pressure Pnp (7 mmHg) or standard-pressure Pnp (12 mmHg). Co-primary outcomes were postoperative QoR measured via the QoR-15 questionnaire on postoperative Day 1 (POD1), POD3, POD14, and POD30, and SWS assessed intraoperatively by a blinded assessor (surgeon) via a validated SWS scale. Data analysis was performed according to the intention-to-treat principle. RESULTS: Patients who underwent RARP at low Pnp pressure demonstrated better postoperative QoR on POD1 (mean difference = 10, 95% confidence interval [CI] 4.4-15.5), but no significant differences were observed in the SWS (mean difference = 0.25, 95% CI -0.02 to 0.54). Patients allocated to low-pressure Pnp experienced statistically higher blood loss than those in the standard-pressure Pnp group (mean difference = 67 mL, P = 0.01). Domain analysis revealed significant improvements in pain (P = 0.001), physical comfort (P = 0.007), and emotional state (P = 0.006) for patients with low-pressure Pnp. This trial was registered at ClinicalTrials.gov, NCT04755452, on 16/02/2021. CONCLUSION: Performing RARP at low Pnp pressure is feasible without compromising the SWS and improves postoperative QoR, including pain, physical comfort, and emotional state, compared to the standard pressure.

Building a tRNA thermometer to estimate microbial adaptation to temperature.

Because ambient temperature affects biochemical reactions, organisms living in extreme temperature conditions adapt protein composition and structure to maintain biochemical functions. While it is not feasible to experimentally determine optimal growth temperature (OGT) for every known microbial species, organisms adapted to different temperatures have measurable differences in DNA, RNA and protein composition that allow OGT prediction from genome sequence alone. In this study, we built a 'tRNA thermometer' model using tRNA sequence to predict OGT. We used sequences from 100 archaea and 683 bacteria species as input to train two Convolutional Neural Network models. The first pairs individual tRNA sequences from different species to predict which comes from a more thermophilic organism, with accuracy ranging from 0.538 to 0.992. The second uses the complete set of tRNAs in a species to predict optimal growth temperature, achieving a maximum ${r^2}$ of 0.86; comparable with other prediction accuracies in the literature despite a significant reduction in the quantity of input data. This model improves on previous OGT prediction models by providing a model with minimum input data requirements, removing laborious feature extraction and data preprocessing steps and widening the scope of valid downstream analyses.

Age-stratified reference intervals unlock the clinical potential of circulating cell-free DNA as a biomarker of poor outcome for healthy individuals and patients with colorectal cancer.

Circulating cell-free DNA (cfDNA) has spurred much interest as a biomarker in oncology. However, inter- and intra-individual cfDNA levels vary greatly. Consequently, in order to base clinical decisions on cfDNA measurements, normal reference intervals are essential to avoid that ordinary variation is confused with clinically relevant change. The lack of reference intervals may potentially explain the ambiguous results reported in the field. Our study aimed to establish reference intervals and to evaluate the association between cfDNA and demographic and clinical variables, including colorectal cancer (CRC). Plasma samples and clinical data from 2817 subjects were collected including 1930 noncancer individuals and 887 CRC patients. cfDNA was measured using droplet digital polymerase chain reaction (PCR). The large cohort combined with robust cfDNA quantification enabled establishment of reference intervals (<67 years: 775-4860 copies/mL; ≥67 years: 807-6561 copies/mL). A cfDNA level above the age-stratified 90% percentile was prognostic of reduced survival in both noncancer individuals and CRC patients, with HR values of 2.56 and 2.01, respectively. Moreover, cfDNA levels increased significantly with age, elevated BMI and chronic diseases. In CRC, the cfDNA level was increased for Stage IV, but not Stage I to Stage III cancer. In summary, the use of reference intervals revealed that high cfDNA levels were predictive of shorter survival in both noncancer individuals and CRC patients, and that CRC development did not affect the cfDNA level until metastatic dissemination. Furthermore, cfDNA levels were impacted by age and chronic diseases. Conclusively, our study presents reference intervals that will help pave the way for clinical utilization of cfDNA.

Assessment of feasibility and utility of universal referral to specialty palliative care in a multidisciplinary amyotrophic lateral sclerosis clinic: A cohort study.

INTRODUCTION: Although the value of palliative care integration in multidisciplinary amyotrophic lateral sclerosis (ALS) clinics has been increasingly recognized, limited data are available demonstrating the feasibility and utility of a palliative care specialist embedded in an ALS clinic. The purpose of this study is to describe the feasibility and utility of a universal outpatient referral model for specialty palliative care for patients with amyotrophic lateral sclerosis. METHODS: This is a retrospective cohort study of initial patient visits with a palliative care physician in a multidisciplinary ALS clinic at an academic institution. All patients were referred to an embedded palliative care physician from January to December 2019. RESULTS: Within the study period, 52 of 69 (75%) patients with a confirmed diagnosis of ALS were seen by the palliative care physician. The most common reason patients were not seen by palliative care was a lack of insurance authorization (n = 5). At the visit, 94% of patients discussed at least one advance care planning or goals of care topic. The most common advance care planning topic discussed was code status (40%). The most common goals of care topic discussed was meaning and values (57%). Symptom management was discussed with 40 patients (77%). The most common symptom addressed was pain and/or muscle spasms (33%). DISCUSSION: These data support the feasibility and utility of universal, outpatient palliative care referral for patients with ALS. Further research is necessary to determine the long-term effect on outcomes for this population.

Intergenerational impacts of trauma and hardship through parenting.

BACKGROUND: Millions of people worldwide experience severe trauma in their lifetime. Trauma has immediate and long-term effects on emotional wellbeing. Moreover, the experiences of one generation may influence subsequent generations via social and biological pathways. Poor mental health and emotion dysregulation associated with trauma may affect parenting behaviours, which may have long-lasting effects on children's development. METHODS: We use longitudinal data from a unique sample of 732 caregivers of children aged 6-36 months living in extremely poor rural households in Rwanda to examine associations of caregiver lifetime trauma, recent daily hardships, mental health, and emotion dysregulation with parenting behaviours reflecting parental acceptance and rejection of their offspring. RESULTS: Cumulative trauma exposure (ß = .234, p < .001) and recent daily hardships (ß = .323, p < .001) are associated with higher levels of internalising symptoms. Trauma (ß = .257, p < .001) and daily hardships (ß = .323, p < 0.001) are also associated with post-traumatic stress disorder (PTSD) symptoms. Internalising symptoms predict more rejection (ß = .177, p = .001), but show no association with acceptance. Caregiver PTSD symptoms predict more rejection (ß = .277, p < .001) and less acceptance (ß = -.190, p = .003). Both internalising symptoms (ß = .557, p < .001) and PTSD symptoms (ß = .606, p < .001) are strongly associated with poor emotion regulation. Indirect effects suggest that caregiver trauma and hardships affect parenting indirectly via elevated caregiver internalising symptoms and PTSD and that some of these effects are accounted for by emotion dysregulation. CONCLUSIONS: Caregiver internalising and PTSD symptoms are important mechanisms through which caregiver trauma and hardship affect parenting behaviours. Emotion dysregulation is a shared mechanism linking caregivers' mental health problems with parenting behaviours that reflect acceptance and rejection of the child. Emotion regulation is indicated as a key target for prevention of adverse effects of caregiver trauma on mental health and child wellbeing.

Enhanced Performance of DNA Methylation Markers by Simultaneous Measurement of Sense and Antisense DNA Strands after Cytosine Conversion.

BACKGROUND: Most existing DNA methylation-based methods for detection of circulating tumor DNA (ctDNA) are based on conversion of unmethylated cytosines to uracil. After conversion, the 2 DNA strands are no longer complementary; therefore, targeting only 1 DNA strand merely utilizes half of the available input DNA. We investigated whether the sensitivity of methylation-based ctDNA detection strategies could be increased by targeting both DNA strands after bisulfite conversion. METHODS: Dual-strand digital PCR assays were designed for the 3 colorectal cancer (CRC)-specific methylation markers KCNQ5, C9orf50, and CLIP4 and compared with previously reported single-strand assays. Performance was tested in tumor and leukocyte DNA, and the ability to detect ctDNA was investigated in plasma from 43 patients with CRC stages I to IV and 42 colonoscopy-confirmed healthy controls. RESULTS: Dual-strand assays quantified close to 100% of methylated control DNA input, whereas single-strand assays quantified approximately 50%. Furthermore, dual-strand assays showed a 2-fold increase in the number of methylated DNA copies detected when applied to DNA purified from tumor tissue and plasma from CRC patients. When the results of the 3 DNA methylation markers were combined into a ctDNA detection test and applied to plasma, the dual-strand assay format detected 86% of the cancers compared with 74% for the single-strand assay format. The specificity was 100% for both the dual- and single-strand test formats. CONCLUSION: Dual-strand assays enabled more sensitive detection of methylated ctDNA than single-strand assays.

Group penalized generalized estimating equation for correlated event-related potentials and biomarker selection.

BACKGROUND: Event-related potentials (ERP) data are widely used in brain studies that measure brain responses to specific stimuli using electroencephalogram (EEG) with multiple electrodes. Previous ERP data analyses haven't accounted for the structured correlation among observations in ERP data from multiple electrodes, and therefore ignored the electrode-specific information and variation among the electrodes on the scalp. Our objective was to evaluate the impact of early adversity on brain connectivity by identifying risk factors and early-stage biomarkers associated with the ERP responses while properly accounting for structured correlation. METHODS: In this study, we extend a penalized generalized estimating equation (PGEE) method to accommodate structured correlation of ERPs that accounts for electrode-specific data and to enable group selection, such that grouped covariates can be evaluated together for their association with brain development in a birth cohort of urban-dwelling Bangladeshi children. The primary ERP responses of interest in our study are N290 amplitude and the difference in N290 amplitude. RESULTS: The selected early-stage biomarkers associated with the N290 responses are representatives of enteric inflammation (days of diarrhea, MIP1b, retinol binding protein (RBP), Zinc, myeloperoxidase (MPO), calprotectin, and neopterin), systemic inflammation (IL-5, IL-10, ferritin, C Reactive Protein (CRP)), socioeconomic status (household expenditure), maternal health (mother height) and sanitation (water treatment). CONCLUSIONS: Our proposed group penalized GEE estimator with structured correlation matrix can properly model the complex ERP data and simultaneously identify informative biomarkers associated with such brain connectivity. The selected early-stage biomarkers offer a potential explanation for the adversity of neurocognitive development in low-income countries and facilitate early identification of infants at risk, as well as potential pathways for intervention. TRIAL REGISTRATION: The related clinical study was retrospectively registered with https://doi.org/ClinicalTrials.gov , identifier NCT01375647, on June 3, 2011.

Promoting parent-child relationships and preventing violence via home-visiting: a pre-post cluster randomised trial among Rwandan families linked to social protection programmes.

BACKGROUND: Sugira Muryango is a father-engaged early child development and violence-prevention home-visiting programme delivered by trained lay workers. This cluster-randomised trial evaluates whether families living in extreme poverty (Ubudehe 1, the poorest category in the Government of Rwanda's wealth ranking) who receive Sugira Muryango in combination with a government-provided social protection programme demonstrate greater responsive, positive caregiving, nutrition, care seeking, hygiene, and father involvement compared with control families receiving usual care (UC). METHODS: Using detailed maps, we grouped closely spaced villages into 284 geographic clusters stratified by the type of social protection programmes operating in the village clusters; 198 clusters met all enrolment criteria. Sugira Muryango was delivered to n = 541 families in 100 treatment clusters with children aged 6-36 months living in extreme poverty. We assessed changes in outcomes in intervention and n = 508 UC control families using structured surveys and observation. Analyses were intent to treat using mixed models to accommodate clustering. RESULTS: Families receiving Sugira Muryango improved on core outcomes of parent-child relationships assessed using the Home Observation for Measurement of the Environment (Cohen's d = 0.87, 95% CI: 0.74, 0.99) and the Observation of Mother-Child Interaction (Cohen's d = 0.29, 95% CI: 0.17, 0.41). We also saw reductions in harsh discipline on items from the UNICEF MICS (OR = 0.30: 95% CI: 0.19, 0.47) and in violent victimisation of female caregivers by their partners (OR = 0.49, 95% CI: 0.24, 1.00) compared with UC. Moreover, children in families receiving SM had a 0.45 higher increase in food groups consumed in the past 24 h (Cohen's d = 0.35, 95% CI: 0.22, 0.47), increased care seeking for diarrhoea (OR = 4.43, 95% CI: 1.95, 10.10) and fever (OR = 3.28, 95% CI: 1.82, 5.89), and improved hygiene behaviours such as proper treatment of water (OR = 3.39, 95% CI: 2.16, 5.30) compared with UC. Finally, Sugira Muryango was associated with decreased caregiver depression and anxiety (OR = 0.58, 95% CI: 0.38, 0.88). CONCLUSIONS: Sugira Muryango led to improvements in caregiver behaviours linked to child development and health as well as reductions in violence. TRIAL REGISTRATION: ClinicalTrials.gov number NCT02510313.

A comparison study: Periodontal practice approach of dentists and dental hygienists.

OBJECTIVES: The aim of this study was to investigate periodontal practice methods of dentists and dental hygienists to compare their knowledge and treatment approach in managing periodontal disease. METHODS: An electronic survey was designed to assess and capture three aspects of data: (a) knowledge of periodontics; (b) practice approaches in non-surgical periodontal therapy; and (c) factors affecting clinical care. The survey was distributed to dentists and dental hygienists who graduated from the same dental school within 5 years (2012-2016). Results were analysed by chi-square test, Fisher's exact test and logistic regression model. RESULTS: Out of total 117 participants, 111 of them reported their profession (n = 77 in the dental programme, n = 34 in the dental hygiene programme). The results showed no statistical difference in basic periodontal knowledge between dentists and dental hygienists (P = .12). Only 13% of the surveyed population identified appropriate recall intervals for periodontal maintenance and more dental hygienists reported periodontal re-evaluations being performed within their offices compared with dentists (91% vs 70%, P = .02). Almost half of the participants who reportedly performed periodontal re-evaluations (46%) charged for the re-evaluation procedure, despite it not being covered by dental insurance. More hygienists reported being familiar with and performing adjunct therapy compared to dentists in the study (P < .01). CONCLUSION: In general, dentists and hygienists in the study were found to have similar periodontal knowledge and practice approaches. However, differences in performing periodontal re-evaluation and adjunct therapy were significant. Further studies are needed to investigate clinical barriers that impact evidence-based periodontal care.

Growth faltering is associated with altered brain functional connectivity and cognitive outcomes in urban Bangladeshi children exposed to early adversity.

BACKGROUND: Stunting affects more than 161 million children worldwide and can compromise cognitive development beginning early in childhood. There is a paucity of research using neuroimaging tools in conjunction with sensitive behavioral assays in low-income settings, which has hindered researchers' ability to explain how stunting impacts brain and behavioral development. We employed high-density EEG to examine associations among children's physical growth, brain functional connectivity (FC), and cognitive development. METHODS: We recruited participants from an urban impoverished neighborhood in Dhaka, Bangladesh. One infant cohort consisted of 92 infants whose height (length) was measured at 3, 4.5, and 6 months; EEG data were collected at 6 months; and cognitive outcomes were assessed using the Mullen Scales of Early Learning at 27 months. A second, older cohort consisted of 118 children whose height was measured at 24, 30, and 36 months; EEG data were collected at 36 months; and Intelligence Quotient (IQ) scores were assessed at 48 months. Height-for-age (HAZ) z-scores were calculated based on the World Health Organization standard. EEG FC in different frequency bands was calculated in the cortical source space. Linear regression and longitudinal path analysis were conducted to test the associations between variables, as well as the indirect effect of child growth on cognitive outcomes via brain FC. RESULTS: In the older cohort, we found that HAZ was negatively related to brain FC in the theta and beta frequency bands, which in turn was negatively related to children's IQ score at 48 months. Longitudinal path analysis showed an indirect effect of HAZ on children's IQ via brain FC in both the theta and beta bands. There were no associations between HAZ and brain FC or cognitive outcomes in the infant cohort. CONCLUSIONS: The association observed between child growth and brain FC may reflect a broad deleterious effect of malnutrition on children's brain development. The mediation effect of FC on the relation between child growth and later IQ provides the first evidence suggesting that brain FC may serve as a neural pathway by which biological adversity impacts cognitive development.

Breaking the curse of dimensionality to identify causal variants in Breeding 4.

In the past, plant breeding has undergone three major transformations and is currently transitioning to a new technological phase, Breeding 4. This phase is characterized by the development of methods for biological design of plant varieties, including transformation and gene editing techniques directed toward causal loci. The application of such technologies will require to reliably estimate the effect of loci in plant genomes by avoiding the situation where the number of loci assayed (p) surpasses the number of plant genotypes (n). Here, we discuss approaches to avoid this curse of dimensionality (n ≪ p), which will involve analyzing intermediate phenotypes such as molecular traits and component traits related to plant morphology or physiology. Because these approaches will rely on novel data types such as DNA sequences and high-throughput phenotyping images, Breeding 4 will call for analyses that are complementary to traditional quantitative genetic studies, being based on machine learning techniques which make efficient use of sequence and image data. In this article, we will present some of these techniques and their application for prioritizing causal loci and developing improved varieties in Breeding 4.

Cumulative psychosocial risk and early child development: validation and use of the Childhood Psychosocial Adversity Scale in global health research.

BACKGROUND: Evidence suggests that cumulative early psychosocial adversity can influence early child development (ECD). The Childhood Psychosocial Adversity Scale (CPAS) is a novel measure of cumulative risk designed for use in global ECD research. We describe its development and assess validity from its first application in Bangladesh, where it predicts cognitive development scores among young children. METHODS: Items were generated from literature review and qualitatively assessed for local relevance. Two-hundred and eighty-five mother-child dyads from an urban slum of Dhaka completed the CPAS at child ages 18, 24, 48, and/or 60 months. The CPAS was assessed for internal consistency, retest reliability, and convergent, incremental, and predictive validity. RESULTS: The CPAS includes subscales assessing child maltreatment, caregiver mental health, family conflict, domestic violence, and household/community psychosocial risks. In Bangladesh, subscales had good internal consistency (Cronbach's α > 0.70). Full-scale score had good 2-week test-retest reliability (intra-class correlation coefficient = 0.89; F(38,38) = 8.45, p < 0.001). Using multivariate regression, 48-month CPAS score significantly predicted 60-month intelligence quotient, accounting for more variance than socioeconomic status or malnutrition. CONCLUSIONS: The CPAS is a novel tool assessing cumulative childhood psychosocial risk. Evidence supports validity of its use in ECD research in Bangladesh, and ongoing work is applying it in additional countries.

Introduction to special issue on global child development studies.

As global child development research is taking off, this special issue provides a collection of recent research characterizing child development across the globe, validating behavioral and neuroimaging tools across diverse geographical setting and cultures, exploring relationships between risk and protective factors and diverse child outcomes, and testing novel avenues of innovative intervention. In particular, three prominent themes that emerge from this special issue are (a) research linking biology and behavior in the service of uncovering biological systems that are susceptible to experience and may mediate associations between experiences and long-term developmental outcomes in global child development research, (b) a movement towards inclusion of more detailed investigation of children's socio-emotional functions in global child development research, and (c) longitudinal studies of developmental outcomes across global settings. In this introduction we outline key themes and findings from the 25 articles included in the special issue.

Using functional near-infrared spectroscopy to assess social information processing in poor urban Bangladeshi infants and toddlers.

Children living in low-resource settings are at risk for failing to reach their developmental potential. While the behavioral outcomes of growing up in such settings are well-known, the neural mechanisms underpinning poor outcomes have not been well elucidated, particularly in the context of low- and middle-income countries. In this study, we measure brain metabolic responses to social and nonsocial stimuli in a cohort of 6- and 36-month-old Bangladeshi children. Study participants in both cohorts lived in an urban slum and were exposed to a broad range of adversity early in life including extreme poverty, malnutrition, recurrent infections, and low maternal education. We observed brain regions that responded selectively to social stimuli in both ages indicating that these specialized brain responses are online from an early age. We additionally show that the magnitude of the socially selective response is related to maternal education, maternal stress, and the caregiving environment. Ultimately our results suggest that a variety of psychosocial hazards have a measurable relationship with the developing social brain.

The relationship between biological and psychosocial risk factors and resting-state functional connectivity in 2-month-old Bangladeshi infants: A feasibility and pilot study.

Childhood poverty has been associated with structural and functional alterations in the developing brain. However, poverty does not alter brain development directly, but acts through associated biological or psychosocial risk factors (e.g. malnutrition, family conflict). Yet few studies have investigated risk factors in the context of infant neurodevelopment, and none have done so in low-resource settings such as Bangladesh, where children are exposed to multiple, severe biological and psychosocial hazards. In this feasibility and pilot study, usable resting-state fMRI data were acquired in infants from extremely poor (n = 16) and (relatively) more affluent (n = 16) families in Dhaka, Bangladesh. Whole-brain intrinsic functional connectivity (iFC) was estimated using bilateral seeds in the amygdala, where iFC has shown susceptibility to early life stress, and in sensory areas, which have exhibited less susceptibility to early life hazards. Biological and psychosocial risk factors were examined for associations with iFC. Three resting-state networks were identified in within-group brain maps: medial temporal/striatal, visual, and auditory networks. Infants from extremely poor families compared with those from more affluent families exhibited greater (i.e. less negative) iFC in precuneus for amygdala seeds; however, no group differences in iFC were observed for sensory area seeds. Height-for-age, a proxy for malnutrition/infection, was not associated with amygdala/precuneus iFC, whereas prenatal family conflict was positively correlated. Findings suggest that it is feasible to conduct infant fMRI studies in low-resource settings. Challenges and practical steps for successful implementations are discussed.

Associations between prenatal, childhood, and adolescent stress and variations in white-matter properties in young men.

OBJECTIVE: Previous studies have shown that both pre- and post-natal adversities, the latter including exposures to stress during childhood and adolescence, explain variation in structural properties of white matter (WM) in the brain. While previous studies have examined effects of independent stress exposures within one developmental period, such as childhood, we examine effects of stress across development using data from a prospective longitudinal study. More specifically, we ask how stressful events during prenatal development, childhood, and adolescence relate to variation in WM properties in early adulthood in young men recruited from a birth cohort. METHOD: Using data from 393 mother-son pairs from a community-based birth cohort from England (Avon Longitudinal Study of Parents and Children), we examined how stressful life events relate to variation in different structural properties of WM in the corpus callosum and across the whole brain in early adulthood in men aged 18-21 years. We distinguish between stress occurring during three developmental periods: a) prenatal maternal stress, b) postnatal stress within the first four years of life, c) stress during adolescence (age 12-16 years). To obtain a comprehensive quantification of variation in WM, we assess structural properties of WM using four different measures, namely fractional anisotropy (FA), mean diffusivity (MD), magnetization transfer ratio (MTR) and myelin water fraction (MWF). RESULTS: The developmental model shows that prenatal stress is associated with lower MTR and MWF in the genu and/or splenium of the corpus callosum, and with lower MTR in global (lobar) WM. Stress during early childhood is associated with higher MTR in the splenium, and stress during adolescence is associated with higher MTR in the genu and lower MD in the splenium. We see no associations between postnatal stress and variation in global (lobar) WM. CONCLUSIONS: The current study found evidence for independent effects of stress on WM properties during distinct neurodevelopmental periods. We speculate that these independent effects are due to differences in the developmental processes unfolding at different developmental time points. We suggest that associations between prenatal stress and WM properties may relate to abnormalities in neurogenesis, affecting the number and density of axons, while postnatal stress may interfere with processes related to myelination or radial growth of axons. Potential consequences of prenatal glucocorticoid exposure should be considered in obstetric care.

Inflammation-related epigenetic risk and child and adolescent mental health: A prospective study from pregnancy to middle adolescence.

In 785 mother-child (50% male) pairs from a longitudinal epidemiological birth cohort, we investigated associations between inflammation-related epigenetic polygenic risk scores (i-ePGS), environmental exposures, cognitive function, and child and adolescent internalizing and externalizing problems. We examined prenatal and postnatal effects. For externalizing problems, one prenatal effect was found: i-ePGS at birth associated with higher externalizing problems (ages 7-15) indirectly through lower cognitive function (age 7). For internalizing problems, we identified two effects. For a prenatal effect, i-ePGS at birth associated with higher internalizing symptoms via continuity in i-ePGS at age 7. For a postnatal effect, higher postnatal adversity exposure (birth through age 7) associated with higher internalizing problems (ages 7-15) via higher i-ePGS (age 7). Hence, externalizing problems were related mainly to prenatal effects involving lower cognitive function, whereas internalizing problems appeared related to both prenatal and postnatal effects. The present study supports a link between i-ePGS and child and adolescent mental health.