Positional cloning of hereditary deafness genes is a direct approach to identify molecules and mechanisms underlying auditory function. Here we report a locus for dominant deafness, DFNA36, which maps to human chromosome 9q13-21 in a region overlapping the DFNB7/B11 locus for recessive deafness. We identified eight mutations in a new gene, transmembrane cochlear-expressed gene 1 (TMC1), in a DFNA36 family and eleven DFNB7/B11 families. We detected a 1.6-kb genomic deletion encompassing exon 14 of Tmc1 in the recessive deafness (dn) mouse mutant, which lacks auditory responses and has hair-cell degeneration. TMC1 and TMC2 on chromosome 20p13 are members of a gene family predicted to encode transmembrane proteins. Tmc1 mRNA is expressed in hair cells of the postnatal mouse cochlea and vestibular end organs and is required for normal function of cochlear hair cells.

Objective In this study, we examine the validity of criteria for indiscriminately social/disinhibited and emotionally withdrawn/inhibited RAD. Methods As part of a longitudinal intervention trial of previously institutionalized children, caregiver interviews and direct observational measures provided continuous and categorical data used to examine the internal consistency, criterion validity, construct validity, convergent and discriminant validity, association with functional impairment, and the stability of these disorders over time. Results Our findings, like those in other studies, show distinctions between the two types of RAD. Evidence-derived criteria for both types of RAD showed acceptable internal consistency and criterion validity. In this study, rates of the indiscriminately social/disinhibited RAD at baseline, 30 months, 42 months, and 54 months were 41/129 (31.8 %), 22/122 (17.9%), 22/122 (18.0%), and 22/125 (17.6%), respectively. Signs of indiscriminately social/disinhibited RAD showed little association with caregiving quality. Nearly half of children with indiscriminately social/disinhibited RAD had organized attachment classifications. Signs of indiscriminately social/disinhibited RAD were associated with signs of activity/impulsivity and of ADHD and modestly to inhibitory control, but were distinct from the diagnosis of ADHD. At baseline, 30, 42, and 54 months, 6/130 (4.6%), 4/123 (3.3%), 2/125(1.6%), and 5/122 (4.1%) of children met criteria for emotionally withdrawn/inhibited RAD. Emotionally withdrawn/inhibited RAD was moderately associated with caregiving at the first three time points and strongly associated with attachment security. Signs of this type of RAD were associated with depressive symptoms, although two of the five children with this type of RAD at 54 months did not meet criteria for major depressive disorder. Signs of both types of RAD contributed independently to functional impairment and were stable over time. Conclusions Evidence-derived criteria for indiscriminately social/disinhibited and emotionally withdrawn/inhibited RAD define two statistically and clinically cohesive syndromes that are distinct from each other, shows stability over 2 years, have predictable associations with risk factors and attachment, can be distinguished from other psychiatric disorders, and cause functional impairment.

Accelerated telomere length attrition has been associated with psychological stress and early adversity in adults; however, no studies have examined whether telomere length in childhood is associated with early experiences. The Bucharest Early Intervention Project is a unique randomized controlled trial of foster care placement compared with continued care in institutions. As a result of the study design, participants were exposed to a quantified range of time in institutional care, and represented an ideal population in which to examine the association between a specific early adversity, institutional care and telomere length. We examined the association between average relative telomere length, telomere repeat copy number to single gene copy number (T/S) ratio and exposure to institutional care quantified as the percent of time at baseline (mean age 22 months) and at 54 months of age that each child lived in the institution. A significant negative correlation between T/S ratio and percentage of time was observed. Children with greater exposure to institutional care had significantly shorter relative telomere length in middle childhood. Gender modified this main effect. The percentage of time in institutional care at baseline significantly predicted telomere length in females, whereas the percentage of institutional care at 54 months was strongly predictive of telomere length in males. This is the first study to demonstrate an association between telomere length and institutionalization, the first study to find an association between adversity and telomere length in children, and contributes to the growing literature linking telomere length and early adversity.

Summary Background Early social deprivation can negatively affect domains of functioning. We examined psychopathology at age 12 years in a cohort of Romanian children who had been abandoned at birth and placed into institutional care, then assigned either to be placed in foster care or to care as usual. Methods We used follow-up data from the Bucharest Early Intervention Project (BEIP), a randomised controlled trial of abandoned children in all six institutions for young children in Bucharest, Romania. In the initial trial, 136 children, enrolled between ages 6–31 months, were randomly assigned to either care as usual or placement in foster care. In this study we followed up these children at age 12 years to assess psychiatric symptoms using the Diagnostic Interview Schedule for Children (4th edition; DISC-IV). We also recruited Romanian children who had never been placed in an institution from paediatric clinics and schools in Bucharest as a comparator group who had never been placed in an institution. The primary outcome measure was symptom counts assessed through DISC-IV scores for three domains of psychopathology: internalising symptoms, externalising symptoms, and attention-deficit hyperactivity disorder (ADHD). We compared mean DISC-IV scores between trial participants and comparators who had never been placed in an institution, and those assigned to care as usual or foster care. Analyses were done by modified intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00747396. Findings We followed up 110 children from the BEIP trial between Jan 27, 2011, and April 11, 2014, and 49 children as comparators who had never been placed in an institution. The 110 children who had ever been placed in an institution had higher symptom counts for internalising disorders (mean 0.93 [SD 1.68] vs 0.45 [0.84], difference 0.48 [95% CI 0.14–0.82]; p=0.0127), externalising disorders (2.31 [2.86] vs 0.65 [1.33], difference 1.66 [1.06–2.25]; p<0.0001), and ADHD (4.00 [5.01] vs 0.71 [1.85], difference 3.29 [95% CI 2.39–4.18]; p<0.0001) than did children who had never been placed in an institution. Compared with 55 children randomly assigned to receive care as usual, the 55 children in the foster-care group had fewer externalising symptoms (mean 2.89 [SD 3.00] for care as usual vs 1.73 [2.61] for foster care, difference 1.16 [95% CI 0.11 to 2.22]; p=0.0255), but symptom counts for internalising disorders (mean 1.00 [1.59] for care as usual vs 0.85 [1.78] for foster care, difference 0.15 [−0.35 to 0.65]; p=0.5681) and ADHD (mean 3.76 [4.61] for care as usual vs 4.24 [5.41] for foster care, difference −0.47 [−2.15 to 1.20; p=0.5790) did not differ. In further analyses, symptom scores substantially differed by stability of foster-care placement. Interpretation Early foster care slightly reduced the risk of psychopathology in children who had been living in institutions, but long-term stability of foster-care placements is an important predictor of psychopathology in early adolescence. Funding Nation...

Reducing health disparities requires an understanding of the mechanisms that generate disparities. Life course approaches to health disparities leverage theories that explain how socially patterned physical, environmental, and socioeconomic exposures at different stages of human development shape health within and across generations and can therefore offer substantial insight into the etiology of health disparities. Life course approaches are informed by developmental and structural perspectives. Developmental perspectives emphasize how socially patterned exposures to risk factors during sensitive life stages shift health trajectories, whereas structural perspectives emphasize how social identity and position within socially patterned environments disproportionately allocate risk factors and resources, resulting in altered health trajectories. We conclude that the science of health disparities will be advanced by integrating life course approaches into etiologic and intervention research on health disparities. The following 4 strategies are offered to guide in this process: (1) advance the understanding of multiple exposures and their interactions, (2) integrate life course approaches into the understanding of biological mechanisms, (3) explore transgenerational transmission of health disparities, and (4) integrate life course approaches into health disparities interventions.

Our objective was to explore the utility of salivary telomere length (sTL) as an early indicator of neighborhood level social environmental risk during child development. We therefore tested the hypothesis that sTL would be associated with markers of social stress exposure in children. Children age 4–14 from 87 neighborhoods were recruited through five urban schools in New Orleans, Louisiana, U.S. Data were collected at the level of the child, family/household, and neighborhood. DNA was obtained from saliva using commercially available kits and sTL was determined for 104 children using quantitative PCR. Analysis was performed on 99 children who had complete data including sTL, social environmental stress, and additional covariates. The mean sTL value was 7.4 T/S (telomere signal/single copy signal) ratio units (± 2.4, range=2.5–18.0), and 4.7% of the variance in sTL was attributed to differences across neighborhoods. Children living in neighborhoods characterized by high disorder had an sTL value 3.2 units lower than children not living in high disordered environments (p<0.05) and their odds of having low relative sTL (defined as < 1 standard deviation below standardized z score mean) values was 3.43 times that of children not living in high disorder environments (adjusted OR=3.43, 95% CI=1.22, 9.62). Our findings are consistent with previous studies in adults demonstrating a strong link between psychosocial stress and sTL obtained from peripheral blood, consistent with previous studies in youth demonstrating an association between early life stress and sTL obtained from buccal cell DNA and offer increased support for the hypothesis that sTL represents a non-invasive biological indicator of psychosocial stress exposure (i.e., neighborhood disorder) able to reflect differences in stress exposure levels even in young children.

Children raised in institutions, considered an extreme example of social deprivation, are one group through which we can better understand the impact of neglect on child health and development. The Bucharest Early Intervention Project (BEIP) is the first randomized, controlled trial of foster care as an intervention for institutionalized children. In this review we describe the mental health outcomes from the BEIP. Specifically, we report findings on attachment styles, attachment disorders, emotional reactivity, and psychiatric symptomatology for children in the BEIP. We describe the impact of the foster care intervention on these outcomes and also describe how outcomes differ by gender and by length of time spent in the institution. In addition, we explore the influence of genetic variation on individual outcomes and recovery from early severe social deprivation, as well as the role of differences in brain development in mediating later psychiatric morbidity. The results from the BEIP confirm and extend the previous findings on the negative sequelae of early institutional care on mental health. The results also underscore the benefit of early family placement for children living in institutions.

The authors examined the impact of cumulative neighborhood risk of psychosocial stress on allostatic load (AL) among adolescents as a mechanism through which life stress, including neighborhood conditions, may affect health and health inequities. They conducted multilevel analyses, weighted for sampling and propensity score-matched, among adolescents aged 12-20 years in the National Health and Nutrition Examination Survey (1999-2006). Individuals (first level, n = 11,886) were nested within families/households (second level, n = 6,696) and then census tracts (third level, n = 2,191) for examination of the contextual effect of cumulative neighborhood risk environment on AL. Approximately 35% of adolescents had 2 or more biomarkers of AL. A significant amount of variance in AL was explained at the neighborhood level. The likelihood of having a high AL was approximately 10% higher for adolescents living in medium-cumulative-risk neighborhoods (adjusted odds ratio (OR) = 1.09, 95% confidence interval (CI): 1.08, 1.09), 28% higher for those living in high-risk neighborhoods (adjusted OR = 1.28, 95% CI: 1.27, 1.30), and 69% higher for those living in very-high-risk neighborhoods (adjusted OR = 1.69, 95% CI: 1.68, 1.70) as compared with adolescents living in low-risk areas. Effect modification was observed by both individual- and neighborhood-level sociodemographic factors. These findings offer support for the hypothesis that neighborhood risks may culminate in a range of biologically mediated negative health outcomes detectable in adolescents.