Sex chromosomes and hormones independently influence healthy brain development but act similarly after cranial radiation.

The course of normal development and response to pathology are strongly influenced by biological sex. For instance, female childhood cancer survivors who have undergone cranial radiation therapy (CRT) tend to display more pronounced cognitive deficits than their male counterparts. Sex effects can be the result of sex chromosome complement (XX vs. XY) and/or gonadal hormone influence. The contributions of each can be separated using the four-core genotype mouse model (FCG), where sex chromosome complement and gonadal sex are decoupled. While studies of FCG mice have evaluated brain differences in adulthood, it is still unclear how sex chromosome and sex hormone effects emerge through development in both healthy and pathological contexts. Our study utilizes longitudinal MRI with the FCG model to investigate sex effects in healthy development and after CRT in wildtype and immune-modified Ccl2-knockout mice. Our findings in normally developing mice reveal a relatively prominent chromosome effect prepubertally, compared to sex hormone effects which largely emerge later. Spatially, sex chromosome and hormone influences were independent of one another. After CRT in Ccl2-knockout mice, both male chromosomes and male hormones similarly improved brain outcomes but did so more separately than in combination. Our findings highlight the crucial role of sex chromosomes in early development and identify roles for sex chromosomes and hormones after CRT-induced inflammation, highlighting the influences of biological sex in both normal brain development and pathology.

An audit and feedback-based intervention to improve diabetes management in the year after transfer to adult type 1 diabetes care: A multi-center quasi-experimental study.

AIM: To test whether an audit and feedback-based intervention improved HbA1c 12 months after transfer to type 1 diabetes adult care. METHODS: Multi-centre, quasi-experimental pre-post study of an AF-based intervention targeting paediatric diabetes teams, which encouraged the implementation of an evidence-informed structured transition process at five paediatric diabetes centres in Ontario, Canada. Participants entered the study at their final paediatric visit. A parallel control cohort was ascertained using population-based administrative datasets. The primary outcome was HbA1c 12 months after transfer. The main exposure was the study period: pre-implementation (June 2018-May 2019); early-implementation (June 2019-September 2020); and late-implementation (October 2020-September 2021). Multivariable linear regression models were fit separately in each cohort. RESULTS: There were 449 and 2844 individuals in the intervention and control cohorts, respectively. Twelve months after transfer, participants in the late-implementation intervention cohort had an HbA1c that was, on average, 0.41% lower than participants in the pre-implementation period (p = 0.016). Among the control cohort, there was no significant difference in the HbA1c 12 months after transfer between study periods. CONCLUSIONS: We found an effect of the intervention on glycaemic management one year following transfer to adult care. Future work will focus on refining and testing the effectiveness of the intervention in an expanded number of study sites and in collaboration with adult diabetes care providers.

Gender diversity is correlated with dimensional neurodivergent traits but not categorical neurodevelopmental diagnoses in children.

BACKGROUND: Gender clinic and single-item questionnaire-based data report increased co-occurrence of gender diversity and neurodevelopmental conditions. The nuances of these associations are under-studied. We used a transdiagnostic approach, combining categorical and dimensional characterization of neurodiversity, to further the understanding of its associations with gender diversity in identity and expression in children. METHODS: Data from 291 children (Autism N = 104, ADHD N = 104, Autism + ADHD N = 17, neurotypical N = 66) aged 4-12 years enrolled in the Province of Ontario Neurodevelopmental Network were analyzed. Gender diversity was measured multi-dimensionally using a well-validated parent-report instrument, the Gender Identity Questionnaire for Children (GIQC). We used gamma regression models to determine the significant correlates of gender diversity among age, puberty, sex-assigned-at-birth, categorical neurodevelopmental diagnoses, and dimensional neurodivergent traits (using the Social Communication Questionnaire and the Strengths and Weaknesses of ADHD Symptoms and Normal Behavior Rating Scales). Internalizing and externalizing problems were included as covariates. RESULTS: Neither a categorical diagnosis of autism nor ADHD significantly correlated with current GIQC-derived scores. Instead, higher early-childhood dimensional autistic social-communication traits correlated with higher current overall gender incongruence (as defined by GIQC-14 score). This correlation was potentially moderated by sex-assigned-at-birth: greater early-childhood autistic social-communication traits were associated with higher current overall gender incongruence in assigned-males-at-birth, but not assigned-females-at-birth. For fine-grained gender diversity domains, greater autistic restricted-repetitive behavior traits were associated with greater diversity in gender identity across sexes-assigned-at-birth; greater autistic social-communication traits were associated with lower stereotypical male expression across sexes-assigned-at-birth. CONCLUSIONS: Dimensional autistic traits, rather than ADHD traits or categorical neurodevelopmental diagnoses, were associated with gender diversity domains across neurodivergent and neurotypical children. The association between early-childhood autistic social-communication traits and overall current gender diversity was most evident in assigned-males-at-birth. Nuanced interrelationships between neurodivergence and gender diversity should be better understood to clarify developmental links and to offer tailored support for neurodivergent and gender-diverse populations.

Mouse models of immune dysfunction: their neuroanatomical differences reflect their anxiety-behavioural phenotype.

Extensive evidence supports the role of the immune system in modulating brain function and behaviour. However, past studies have revealed striking heterogeneity in behavioural phenotypes produced from immune system dysfunction. Using magnetic resonance imaging, we studied the neuroanatomical differences among 11 distinct genetically modified mouse lines (n = 371), each deficient in a different element of the immune system. We found a significant and heterogeneous effect of immune dysfunction on the brains of both male and female mice. However, by imaging the whole brain and using Bayesian hierarchical modelling, we were able to identify patterns within the heterogeneous phenotype. Certain structures-such as the corpus callosum, midbrain, and thalamus-were more likely to be affected by immune dysfunction. A notable brain-behaviour relationship was identified with neuroanatomy endophenotypes across mouse models clustering according to anxiety-like behaviour phenotypes reported in literature, such as altered volume in brains regions associated with promoting fear response (e.g., the lateral septum and cerebellum). Interestingly, genes with preferential spatial expression in the most commonly affected regions are also associated with multiple sclerosis and other immune-mediated diseases. In total, our data suggest that the immune system modulates anxiety behaviour through well-established brain networks.

Cohort profile update: The Canadian Maternal-Infant Research on Environmental Chemicals Child Development study (MIREC-CD PLUS).

BACKGROUND: The pan-Canadian Maternal-Infant Research on Environmental Chemicals (MIREC) study was established to determine whether maternal environmental chemical exposures were associated with adverse pregnancy outcomes in 2001 pregnant women. OBJECTIVES: The MIREC-Child Development (CD PLUS) study followed this cohort with the goal of assessing the potential effects of prenatal exposures on anthropometry and neurodevelopment in early childhood. POPULATION: MIREC families with children between the ages of 15 months and 5 years who had agreed to be contacted for future research (n = 1459) were invited to participate in MIREC-CD PLUS which combines data collected from an online Maternal Self-Administered Questionnaire with biomonitoring and neurodevelopment data collected from two in-person visits. PRELIMINARY RESULTS: Between April 2013 and March 2015, 803 children participated in the Biomonitoring visit where we collected anthropometric measures, blood, and urine from the children. The Behavioural Assessment System for Children-2, Behaviour Rating Inventory of Executive Function, MacArthur-Bates Communicative Development Inventories and the Communication subscale of the Adaptive Behaviour Scale from the Bayley Scales of Infant and Toddler Development-III are available on close to 900 children. There were 610 singleton children who completed in-person visits for neurodevelopment assessments including the Social Responsiveness Scale, Wechsler Preschool Primary Scale of Intelligence-III and NEuroPSYchological assessments (NEPSY). Currently, we are following the cohort into early adolescence to measure the impact of early life exposures on endocrine and metabolic function (MIREC-ENDO). CONCLUSIONS: Data collection for the MIREC-CD PLUS study is complete and analysis of the data continues. We are now extending the follow-up of the cohort into adolescence to measure the impact of early life exposures on endocrine and metabolic function (MIREC-ENDO). MIREC-CD PLUS is limited by loss to follow-up and the fact that mothers are predominately of higher socioeconomic status and 'White' ethnicity, which limits our generalizability. However, the depth of biomonitoring and clinical measures in MIREC provides a platform to examine associations of prenatal, infancy and childhood exposures with child growth and development.

Routine T4 No More? Reducing Excess Thyroid Hormone Testing at a Pediatric Tertiary Care Hospital.

OBJECTIVES: To promote resource stewardship in thyroid hormone testing at a pediatric tertiary care hospital. STUDY DESIGN: Quality improvement approaches generated 3 change ideas that were implemented simultaneously in the hospital electronic medical record: (1) a reflex free thyroxine (fT4), whereby fT4 is automatically reported if the thyroid-stimulating hormone is outside the normal range; (2) a forced-function for thyroid hormone ordering, whereby a provider must select an appropriate indication for ordering fT4 or triiodothyronine (T3); and (3) a clinical decision support message displayed at the time of ordering thyroid function tests. Laboratory data were audited to determine the mean number of fT4 and T3 tests performed per week as well as indications for testing. RESULTS: The mean number of fT4 and T3 tests processed per week decreased from 154 ± 21 and 11 ± 7, respectively, in the preintervention period, to 107 ± 12 (30% reduction) and 4 ± 3 (66% reduction) postintervention. These reductions were sustained for the full 20-week assessment period. Process and balancing measures revealed no unintended adverse consequences. Approximate cost savings were $43 000 per year. CONCLUSIONS: We describe the successful implementation of electronic medical record-based interventions (reflex fT4, forced-function selection of indication, decision support text) leading to sustained improvements in healthcare use, with significant associated cost-savings.

Gene expression profiling of puberty-associated genes reveals abundant tissue and sex-specific changes across postnatal development.

The timing of human puberty is highly variable, sexually dimorphic, and associated with adverse health outcomes. Over 20 genes carrying rare mutations have been identified in known pubertal disorders, many of which encode critical components of the hypothalamic-pituitary-gonadal (HPG) axis. Recent genome-wide association studies (GWAS) have identified more than 100 candidate genes at loci associated with age at menarche or voice breaking in males. We know little about the spatial, temporal or postnatal expression patterns of the majority of these puberty-associated genes. Using a high-throughput and sensitive microfluidic quantitative PCR strategy, we profiled the gene expression patterns of the mouse orthologs of 178 puberty-associated genes in male and female mouse HPG axis tissues, the pineal gland, and the liver at five postnatal ages spanning the pubertal transition. The most dynamic gene expression changes were observed prior to puberty in all tissues. We detected known and novel tissue-enhanced gene expression patterns, with the hypothalamus expressing the largest number of the puberty-associated genes. Notably, over 40 puberty-associated genes in the pituitary gland showed sex-biased gene expression, most of which occurred peri-puberty. These sex-biased genes included the orthologs of candidate genes at GWAS loci that show sex-discordant effects on pubertal timing. Our findings provide new insight into the expression of puberty-associated genes and support the possibility that the pituitary plays a role in determining sex differences in the timing of puberty.

Testing an audit and feedback-based intervention to improve glycemic control after transfer to adult diabetes care: protocol for a quasi-experimental pre-post design with a control group.

BACKGROUND: When young adults transfer from pediatric to adult diabetes care they are at risk for deterioration of glycemic control, putting them at an increased risk of developing both acute and chronic complications. Despite increased awareness of these risks, there are gaps in care delivery during this vulnerable time and variability in the implementation of recommended transition practice. Audit and feedback (AF) interventions have a positive but variable effect on implementation of best practices. An expert group identified specific suggestions for optimizing the effectiveness of AF interventions. We aim to test an AF-based intervention incorporating these specific suggestions to improve transition practices and glycemic control in the first year after transfer from pediatric to adult diabetes care. METHODS: This is a pragmatic quasi-experimental study; a series of three cohort studies (pre-implementation, early-implementation, and post-implementation) to compare the baseline adjusted hemoglobin A1c (HbA1c) in the 12 months after the final pediatric visit in five pediatric diabetes centres within the Ontario Pediatric Diabetes Network in Ontario, Canada. The intervention includes three components: 1) centre-level feedback reports compiling data from chart abstraction, linked provincial administrative datasets, and patient-reported experience measures; 2) webinars for facilitated conversations/coaching about the feedback; and 3) online repository of curated transition resources for providers. The primary outcome will be analyzed using a multivariable linear regression model. We will conduct a qualitative process evaluation to understand intervention fidelity and to provide insight into the mechanisms of action of our results. DISCUSSION: There is a need to develop an innovative system-level approach to improve outcomes and the quality of care for young adults with type 1 diabetes during the vulnerable time when they transfer to adult care. Our research team, a collaboration of health services, implementation science, and quality improvement researchers, are designing, implementing, and evaluating an AF-based intervention using recommendations about how to optimize effectiveness. This knowledge will be generalizable to other care networks that aim to deliver uniformly high-quality care in diverse care settings. TRIAL REGISTRATION: ClinicalTrials.gov NCT03781973. Registered 13 December 2018. Date of enrolment of the first participant to the trial: June 1, 2019.

Seeing Clearly: Effects of Initiatives to Improve Diabetic Retinopathy Screening at a Pediatric Center.

IN BRIEF "Quality Improvement Success Stories" are published by the American Diabetes Association in collaboration with the American College of Physicians, Inc. (ACP), and the National Diabetes Education Program. This series is intended to highlight best practices and strategies from programs and clinics that have successfully improved the quality of care for people with diabetes or related conditions. Each article in the series is reviewed and follows a standard format developed by the editors of Clinical Diabetes. The following article describes an initiative to improve retinopathy screening rates at the pediatric diabetes clinic of a large academic teaching hospital in Canada.

Impact of X/Y genes and sex hormones on mouse neuroanatomy.

Biological sex influences brain anatomy across many species. Sex differences in brain anatomy have classically been attributed to differences in sex chromosome complement (XX versus XY) and/or in levels of gonadal sex steroids released from ovaries and testes. Using the four core genotype (4CG) mouse model in which gonadal sex and sex chromosome complement are decoupled, we previously found that sex hormones and chromosomes influence the volume of distinct brain regions. However, recent studies suggest there may be more complex interactions between hormones and chromosomes, and that circulating steroids can compensate for and/or mask underlying chromosomal effects. Moreover, the impact of pre vs post-pubertal sex hormone exposure on this sex hormone/sex chromosome interplay is not well understood. Thus, we used whole brain high-resolution ex-vivo MRI of intact and pre-pubertally gonadectomized 4CG mice to investigate two questions: 1) Do circulating steroids mask sex differences in brain anatomy driven by sex chromosome complement? And 2) What is the contribution of pre- versus post-pubertal hormones to sex-hormone-dependent differences in brain anatomy? We found evidence of both cooperative and compensatory interactions between sex chromosomes and sex hormones in several brain regions, but the interaction effects were of low magnitude. Additionally, most brain regions affected by sex hormones were sensitive to both pre- and post-pubertal hormones. This data provides further insight into the biological origins of sex differences in brain anatomy.

Targets and teamwork: Understanding differences in pediatric diabetes centers treatment outcomes.

OBJECTIVE: The reason for center differences in metabolic control of childhood diabetes is still unknown. We sought to determine to what extent the targets, expectations, and goals that diabetes care professionals have for their patients is a determinant of center differences in metabolic outcomes. RESEARCH DESIGN AND METHODS: Children, under the age of 11 with type 1 diabetes and their parents treated at the study centers participated. Clinical, medical, and demographic data were obtained, along with blood sample for centralized assay. Parents and all members of the diabetes care team completed questionnaires on treatment targets for hemoglobin A1c (HbA1c) and recommended frequency of blood glucose monitoring. RESULTS: Totally 1113 (53% male) children (mean age 8.0 ± 2.1 years) from 18 centers in 17 countries, along with parents and 113 health-care professionals, participated. There were substantial differences in mean HbA1c between centers ranging from 7.3 ± 0.8% (53 mmol/mol ± 8.7) to 8.9 ± 1.1% (74 mmol/mol ± 12.0). Centers with lower mean HbA1c had (1) parents who reported lower targets for their children, (2) health-care professionals that reported lower targets and more frequent testing, and (3) teams with less disagreement about recommended targets. Multiple regression analysis indicated that teams reporting higher HbA1c targets and more target disagreement had parents reporting higher treatment targets. This seemed to partially account for center differences in Hb1Ac. CONCLUSIONS: The diabetes care teams' cohesiveness and perspectives on treatment targets, expectations, and recommendations have an influence on parental targets, contributing to the differences in pediatric diabetes center outcomes.

Use of Tc-99 m thyroid scans in borderline congenital hypothyroidism.

BACKGROUND: Mild or borderline congenital hypothyroidism [often referred to as mild neonatal hyperthyrotropinemia (MNH)] is characterized by an abnormal newborn screen (NBS), followed by mildly elevated TSH and normal FT4 on confirmatory testing. This condition is increasingly observed, but data regarding optimal management are limited. OBJECTIVE: Examine the use of routine technetium thyroid scanning (TS) in the management of MNH. METHODS: Retrospective study of infants with MNH between 2000 and 2011. We assessed the clinical course of infants with MNH according to TS results; as a comparator, infants with classic congenital hypothyroidism (CH) were analysed in parallel. RESULTS: We identified 69 infants (52% boys) with MNH and 164 (34% boys) with classic CH. TS results were divided into four subgroups: no uptake in 7% of MNH vs 24% of classic CH (P < 0·01), decreased uptake/anatomical abnormalities in 39% vs 46% (p = NS), increased uptake in 35% vs 26% (p = NS) and normal uptake in 19% vs 4% (P < 0·01). In MNH, neither NBS-TSH, confirmatory TSH and FT4, mean LT-4 treatment doses and number of dose escalations, nor post-treatment FT4 and TSH differed among the four subgroups. In contrast, clinical features in infants with classic CH differed among the subgroups. Among MNH infants who reached 3 years of age, trial-off treatment was successful in 6 of 11 (55%) with no apparent difference in success rates among TS subgroups. CONCLUSIONS: The information provided by TS during evaluation of MNH does not predict clinical course; obtaining these scans in infants with MNH may not be an effective use of healthcare resources.

Epigenetics: a new player in the regulation of mammalian puberty.

All reproductively competent adults have gone through puberty. While key genes and signaling pathways that lead to the onset of sexual maturation are known, the molecular mechanisms that determine when an individual enters puberty are only beginning to be understood. Both genetic and environmental factors determine the timing of puberty. New advances in understanding how environmentally sensitive, yet highly heritable developmental processes are regulated have come from the field of epigenetics. Of note, studies investigating the epigenetic control of the onset of puberty suggest that epigenetic repression of key inhibitory loci may play a fundamental role in the initiation of puberty. Current technologies that not only read out the DNA sequence, but also determine how the DNA is modified in response to the environment, promise new insight into how puberty is regulated, including the identification and understanding of gene regulatory networks that control the biological pathways affecting pubertal timing. Here we review the findings to date and discuss how epigenetic investigation can further our understanding of this fundamental aspect of human development.

Characteristics of Youth Presenting for Gender Care Compared to Background Populations: Examination of Social Determinants of Health.

Purpose: Transgender and gender diverse (TGD) youth in North American clinical reports are predominantly White with relatively high socioeconomic status suggesting that access to gender-affirming care is inequitable. This study examined whether socioeconomic and social determinant of health discrepancies exist between a clinical population of TGD youth and surrounding communities. Methods: Patient postal codes were used to link the Ontario Marginalization Index (ON-MARG) to a clinic-based TGD youth cohort (n = 298). Using ON-MARG, each patient was assigned a quintile score from 1 (least marginalized) to 5 (most marginalized) on four marginalization measures. Mean quintile scores were compared to background populations. Census-based Toronto neighborhood-level data on ethnic diversity and educational status were also examined. Neighborhoods were categorized as highly represented, less represented, or unrepresented based on representation in the clinic cohort. One-way analysis of covariance was used to determine associations between neighborhood-level variables and the degree of neighborhood representation. Results: ON-MARG data demonstrated that clinic patients hailed from areas with more individuals having paid employment. Patients from Toronto and surrounding areas came, in general, from communities with fewer recent immigrants and visible minorities. Highly represented Toronto neighborhoods had smaller proportions of visible minorities and immigrants compared with less and unrepresented neighborhoods. Educational status, represented by adults with bachelor's degrees, was lower among unrepresented neighborhoods. Conclusion: TGD youth seen in clinic, particularly those from Toronto, are disproportionally White and socioeconomically advantaged. Further research is needed to better understand the underrepresentation of racialized and low-socioeconomic status youth and to inform strategies to improve access to care.

Gender diversity among adolescents with obesity in a weight management programme.

Gender dysphoria (GD) and obesity share commonalities, including associations with mental health comorbidities, disordered eating, body dissatisfaction and may intensify with physical and developmental changes during adolescence. While associations of obesity and gender diversity have been identified, rates of gender diversity among adolescents with obesity remain unclear. The aim was to examine gender diversity among adolescents with obesity in a weight management programme. A single-centre cross-sectional questionnaire study was conducted. Eligible adolescents received the Gender Identity/GD Questionnaire for Adolescents and Adults (GIDYQ-AA), a validated instrument measuring gender diversity and GD. Gender identities, sexual orientations, questionnaire scores, and frequency of GD (GIDYQ-AA score <3) were determined. The relationship of GIDYQ-AA scores and BMI Z-score (BMIz) was assessed. Of 72 consenting youth, 29 assigned females (AF) and 17 assigned males (AM) completed GIDYQ-AA and demographic questions. Seventeen (59%) AF reported non-heterosexual orientations, and 6 (21%) reported non-cisgender identities. One (6%) AM reported non-cisgender identity. Two (4%) AF individuals had GD based on GIDYQ-AA scores. GIDYQ-AA scores did not correlate with BMIz. In conclusion, adolescents with obesity, particularly AF with non-heterosexual orientation, reported high rates of non-cisgender identity and GD. Routine screening for gender-related concerns in weight management settings may be warranted.

Contributions of common genetic variants to constitutional delay of puberty and idiopathic hypogonadotropic hypogonadism.

CONTEXT: Constitutional delay of puberty (CDP) is highly heritable, but the genetic basis for CDP is largely unknown. Idiopathic hypogonadotropic hypogonadism (IHH) can be caused by rare genetic variants, but in about half of cases, no rare-variant cause is found. OBJECTIVE: To determine whether common genetic variants that influence pubertal timing contribute to CDP and IHH. DESIGN: Case-control study. PARTICIPANTS: 80 individuals with CDP; 301 with normosmic IHH, and 348 with Kallmann syndrome; control genotyping data from unrelated studies. MAIN OUTCOME MEASURES: Polygenic scores (PGS) based on genome-wide association studies for timing of male pubertal hallmarks and age at menarche (AAM). RESULTS: The CDP cohort had higher PGS for male pubertal hallmarks and for AAM compared to controls (for male hallmarks, Cohen's d = 0.85, p = 1 × 10-16; for AAM, d = 0.67, p = 1 × 10-10). The normosmic IHH cohort also had higher PGS for male hallmarks compared to controls, but the difference was smaller (male hallmarks d = 0.20, p = 0.003; AAM d = 0.10, p = 0.055). No differences were seen for the KS cohort compared to controls (male hallmarks d = 0.04, p = 0.45; AAM d = -0.03, p = 0.86). CONCLUSIONS: Common genetic variants that influence pubertal timing in the general population contribute strongly to the genetics of CDP, weakly to normosmic IHH, and potentially not at all to KS. These findings demonstrate that the common-variant genetics of CDP and normosmic IHH are largely but not entirely distinct.

Age, sex, and cell type-resolved hypothalamic gene expression across the pubertal transition in mice.

BACKGROUND: The hypothalamus plays a central role in regulating puberty. However, our knowledge of the postnatal gene regulatory networks that control the pubertal transition in males and females is incomplete. Here, we investigate the age-, sex- and cell-type-specific gene regulation in the hypothalamus across the pubertal transition. METHODS: We used RNA-seq to profile hypothalamic gene expression in male and female mice at five time points spanning the onset of puberty (postnatal days (PD) 12, 22, 27, 32, and 37). By combining this data with hypothalamic single nuclei RNA-seq data from pre- and postpubertal mice, we assigned gene expression changes to their most likely cell types of origin. In our colony, pubertal onset occurs earlier in male mice, allowing us to focus on genes whose expression is dynamic across ages and offset between sexes, and to explore the bases of sex effects. RESULTS: Our age-by-sex pattern of expression enriched for biological pathways involved hormone production, neuronal activation, and glial maturation. Additionally, we inferred a robust expansion of oligodendrocytes precursor cells into mature oligodendrocytes spanning the prepubertal (PD12) to peri-pubertal (PD27) timepoints. Using spatial transcriptomic data from postpubertal mice, we observed the lateral hypothalamic area and zona incerta were the most oligodendrocyte-rich regions and that these cells expressed genes known to be involved in pubertal regulation. CONCLUSION: Together, by incorporating multiple biological timepoints and using sex as a variable, we identified gene and cell-type changes that may participate in orchestrating the pubertal transition and provided a resource for future studies of postnatal hypothalamic gene regulation.

High resolution whole brain imaging of anatomical variation in XO, XX, and XY mice.

The capacity of sex to modify behavior in health and illness may stem from biological differences between males and females. One such difference--fundamental to the biological definition of sex--is inequality of X chromosome dosage. Studies of Turner Syndrome (TS) suggest that X-monosomy profoundly alters mammalian brain development. However, use of TS as a model for X chromosome haploinsufficiency is complicated by karyotypic mosaicism, background genetic heterogeneity and ovarian dysgenesis. Therefore, to better isolate X chromosome effects on brain development and identify how these overlap with normative sex differences, we used whole-brain structural imaging to study X-monosomic mice (free of mosaicism and ovarian dysgenesis) alongside their karyotypical normal male and female littermates. We demonstrate that murine X-monosomy (XO) causes (i) accentuation of XX vs XY differences in a set of sexually dimorphic structures including classical foci of sex-hormone action, such as the bed nucleus of the stria terminal and medial amygdala, (ii) parietal and striatal abnormalities that recapitulate those reported TS, and (iii) abnormal development of brain systems relevant for domains of altered cognition and emotion in both murine and human X-monosomy. Our findings suggest an unexpected role for X-linked genes in shaping sexually dimorphic brain development, and an evolutionarily conserved influence of X-linked genes on both cortical and subcortical development in mammals. Furthermore, our murine findings highlight the bed nucleus of the stria terminalis and periaqueductal gray matter as novel neuroanatomical candidates for closer study in TS. Integration of these data with existing genomic knowledge generates a set of novel, testable hypotheses regarding candidate mechanisms for each observed pattern of anatomical variation across XO, XX and XY groups.

Hippocampal volumes differ across the mouse estrous cycle, can change within 24 hours, and associate with cognitive strategies.

Recent human and rodent brain imaging studies have shown that the shape of the brain can be changed by experience. These mesoscopic alterations in neuroanatomy are hypothesized to be driven by changes at the level of neuronal processes. To examine whether the shape of the brain changes rapidly, we used MRI to examine changes in the volume of the hippocampus across the 4-6 day estrous cycle in the female mouse. It is well known that changing steroid levels across the cycle influence dendritic spine maturation and alter synapse density in the hippocampus; our results show that the estrous cycle is associated with approximately 2-3% changes in hippocampal volume as seen by high-resolution ex-vivo MRI. Changes in hippocampal volume are, moreover, associated with a switch between hippocampal and striatal based navigation strategies in solving the dual choice T-maze in the same mice. A second experiment, using in-vivo MRI, suggests that these changes in hippocampal volume can occur over a 24 hour period. In summary, we show that the brain is highly plastic at a mesoscopic level of resolution detectable by MRI, that volumetric increases and decreases in hippocampal volume follow previously established patterns of changes in neuropil, and that these changes in volume predict changes in cognition.

Mild neonatal hyperthyrotrophinaemia: 10-year experience suggests the condition is increasingly common but often transient.

OBJECTIVE: To examine a large population of infants with mild neonatal hyperthyrotrophinaemia (MNH) and determine prevalence, clinical characteristics and treatment history. METHODS: Retrospective study of infants with MNH followed at The Hospital for Sick Children between 2000 and 2011. MNH was defined by an abnormal newborn screen followed by thyroid-stimulating hormone (TSH) between 5 and 30 mU/l and normal free T4 (FT4) on confirmatory tests. RESULTS: Mild neonatal hyperthyrotrophinaemia represented 22·3% of patients (103/462; 60 boys, 43 girls) within our clinic. Incidence increased from two of 20 in 2000 to 31 of 74 cases in 2010. Seventy eight percent of patients started L-thyroxine (initial dose: 8·3 ± 2·5 mcg/kg). The treated group had higher confirmatory TSH levels (P = 0·001) and had undergone thyroid scintigraphy more often (P = 0·0001) compared with the nontreated group. Evidence of overtreatment was detected in 45% of thyroid function tests obtained during treatment. Among the treated infants who had reached 3 years of age, 45% (N = 14) underwent a trial-off medication. Compared with those not trialled-off therapy, these infants were less likely to have had dose escalations during treatment (P = 0·001). The trial-off treatment was successful in 50% of cases. In the subset of infants with confirmatory TSH >10 mU/l, trial-off therapy was successful in 40%. None of the assessed variables predicted success of trial-off therapy. CONCLUSIONS: Mild neonatal hyperthyrotrophinaemia is an increasingly common diagnosis. It is more common in males and is often transient, but predictors of success of trial-off therapy were not identified. Further studies are needed to determine optimum L-thyroxine dosing and to determine whether treatment improves neurocognitive outcomes.