Clinical, socio-demographic, and parental correlates of early autism traits in a community cohort of toddlers.

Identifying factors linked to autism traits in the general population may improve our understanding of the mechanisms underlying divergent neurodevelopment. In this study we assess whether factors increasing the likelihood of childhood autism are related to early autistic trait emergence, or if other exposures are more important. We used data from 536 toddlers from London (UK), collected at birth (gestational age at birth, sex, maternal body mass index, age, parental education, parental language, parental history of neurodevelopmental conditions) and at 18 months (parents cohabiting, measures of socio-economic deprivation, measures of maternal parenting style, and a measure of maternal depression). Autism traits were assessed using the Quantitative Checklist for Autism in Toddlers (Q-CHAT) at 18 months. A multivariable model explained 20% of Q-CHAT variance, with four individually significant variables (two measures of parenting style and two measures of socio-economic deprivation). In order to address variable collinearity we used principal component analysis, finding that a component which was positively correlated with Q-CHAT was also correlated to measures of parenting style and socio-economic deprivation. Our results show that parenting style and socio-economic deprivation correlate with the emergence of autism traits at age 18 months as measured with the Q-CHAT in a community sample.

Neonatal brain dynamic functional connectivity in term and preterm infants and its association with early childhood neurodevelopment.

Brain dynamic functional connectivity characterises transient connections between brain regions. Features of brain dynamics have been linked to emotion and cognition in adult individuals, and atypical patterns have been associated with neurodevelopmental conditions such as autism. Although reliable functional brain networks have been consistently identified in neonates, little is known about the early development of dynamic functional connectivity. In this study we characterise dynamic functional connectivity with functional magnetic resonance imaging (fMRI) in the first few weeks of postnatal life in term-born (n = 324) and preterm-born (n = 66) individuals. We show that a dynamic landscape of brain connectivity is already established by the time of birth in the human brain, characterised by six transient states of neonatal functional connectivity with changing dynamics through the neonatal period. The pattern of dynamic connectivity is atypical in preterm-born infants, and associated with atypical social, sensory, and repetitive behaviours measured by the Quantitative Checklist for Autism in Toddlers (Q-CHAT) scores at 18 months of age.

Telepsychiatry: what clinicians need to know about digital mental healthcare.

The COVID-19 pandemic has rapidly accelerated the use of online and remote mental healthcare provision. The immediate need to transform services has not allowed for thorough examination of the literature supporting remote delivery of psychiatric care. In this article we review the history of telepsychiatry, the rationale for continuing to offer services remotely and the limitations of psychiatry without in-person care. Focusing on randomised controlled trials we find that evidence for the efficacy of remotely delivered psychiatric care compared with in-person treatment is of low quality and limited scope but does not demonstrate clear superiority of one care delivery method over the other.

Prenatal exposure to air pollution is associated with structural changes in the neonatal brain.

BACKGROUND: Prenatal exposure to air pollution is associated with adverse neurologic consequences in childhood. However, the relationship between in utero exposure to air pollution and neonatal brain development is unclear. METHODS: We modelled maternal exposure to nitrogen dioxide (NO2) and particulate matter (PM2.5 and PM10) at postcode level between date of conception to date of birth and studied the effect of prenatal air pollution exposure on neonatal brain morphology in 469 (207 male) healthy neonates, with gestational age of ≥36 weeks. Infants underwent MR neuroimaging at 3 Tesla at 41.29 (36.71-45.14) weeks post-menstrual age (PMA) as part of the developing human connectome project (dHCP). Single pollutant linear regression and canonical correlation analysis (CCA) were performed to assess the relationship between air pollution and brain morphology, adjusting for confounders and correcting for false discovery rate. RESULTS: Higher exposure to PM10 and lower exposure to NO2 was strongly canonically correlated to a larger relative ventricular volume, and moderately associated with larger relative size of the cerebellum. Modest associations were detected with higher exposure to PM10 and lower exposure to NO2 and smaller relative cortical grey matter and amygdala and hippocampus, and larger relaive brainstem and extracerebral CSF volume. No associations were found with white matter or deep grey nuclei volume. CONCLUSIONS: Our findings show that prenatal exposure to air pollution is associated with altered brain morphometry in the neonatal period, albeit with opposing results for NO2 and PM10. This finding provides further evidence that reducing levels of maternal exposure to particulate matter during pregnancy should be a public health priority and highlights the importance of understanding the impacts of air pollution on this critical development window.

Parsing brain-behavior heterogeneity in very preterm born children using integrated similarity networks.

Very preterm birth (VPT; ≤32 weeks' gestation) is associated with altered brain development and cognitive and behavioral difficulties across the lifespan. However, heterogeneity in outcomes among individuals born VPT makes it challenging to identify those most vulnerable to neurodevelopmental sequelae. Here, we aimed to stratify VPT children into distinct behavioral subgroups and explore between-subgroup differences in neonatal brain structure and function. 198 VPT children (98 females) previously enrolled in the Evaluation of Preterm Imaging Study (EudraCT 2009-011602-42) underwent Magnetic Resonance Imaging at term-equivalent age and neuropsychological assessments at 4-7 years. Using an integrative clustering approach, we combined neonatal socio-demographic, clinical factors and childhood socio-emotional and executive function outcomes, to identify distinct subgroups of children based on their similarity profiles in a multidimensional space. We characterized resultant subgroups using domain-specific outcomes (temperament, psychopathology, IQ and cognitively stimulating home environment) and explored between-subgroup differences in neonatal brain volumes (voxel-wise Tensor-Based-Morphometry), functional connectivity (voxel-wise degree centrality) and structural connectivity (Tract-Based-Spatial-Statistics). Results showed two- and three-cluster data-driven solutions. The two-cluster solution comprised a 'resilient' subgroup (lower psychopathology and higher IQ, executive function and socio-emotional scores) and an 'at-risk' subgroup (poorer behavioral and cognitive outcomes). No neuroimaging differences between the resilient and at-risk subgroups were found. The three-cluster solution showed an additional third 'intermediate' subgroup, displaying behavioral and cognitive outcomes intermediate between the resilient and at-risk subgroups. The resilient subgroup had the most cognitively stimulating home environment and the at-risk subgroup showed the highest neonatal clinical risk, while the intermediate subgroup showed the lowest clinical, but the highest socio-demographic risk. Compared to the intermediate subgroup, the resilient subgroup displayed larger neonatal insular and orbitofrontal volumes and stronger orbitofrontal functional connectivity, while the at-risk group showed widespread white matter microstructural alterations. These findings suggest that risk stratification following VPT birth is feasible and could be used translationally to guide personalized interventions aimed at promoting children's resilience.

Development of neonatal brain functional centrality and alterations associated with preterm birth.

Formation of the functional connectome in early life underpins future learning and behavior. However, our understanding of how the functional organization of brain regions into interconnected hubs (centrality) matures in the early postnatal period is limited, especially in response to factors associated with adverse neurodevelopmental outcomes such as preterm birth. We characterized voxel-wise functional centrality (weighted degree) in 366 neonates from the Developing Human Connectome Project. We tested the hypothesis that functional centrality matures with age at scan in term-born babies and is disrupted by preterm birth. Finally, we asked whether neonatal functional centrality predicts general neurodevelopmental outcomes at 18 months. We report an age-related increase in functional centrality predominantly within visual regions and a decrease within the motor and auditory regions in term-born infants. Preterm-born infants scanned at term equivalent age had higher functional centrality predominantly within visual regions and lower measures in motor regions. Functional centrality was not related to outcome at 18 months old. Thus, preterm birth appears to affect functional centrality in regions undergoing substantial development during the perinatal period. Our work raises the question of whether these alterations are adaptive or disruptive and whether they predict neurodevelopmental characteristics that are more subtle or emerge later in life.

Predicting age and clinical risk from the neonatal connectome.

The development of perinatal brain connectivity underpins motor, cognitive and behavioural abilities in later life. Diffusion MRI allows the characterisation of subtle inter-individual differences in structural brain connectivity. Individual brain connectivity maps (connectomes) are by nature high in dimensionality and complex to interpret. Machine learning methods are a powerful tool to uncover properties of the connectome which are not readily visible and can give us clues as to how and why individual developmental trajectories differ. In this manuscript we used Deep Neural Networks and Random Forests to predict demographic and neurodevelopmental characteristics from neonatal structural connectomes in a large sample of babies (n = 524) from the developing Human Connectome Project. We achieved an accurate prediction of post menstrual age (PMA) at scan in term-born infants (mean absolute error (MAE) = 0.72 weeks, r = 0.83 and p < 0.001). We also achieved good accuracy when predicting gestational age at birth in a cohort of term and preterm babies scanned at term equivalent age (MAE = 2.21 weeks, r = 0.82, p < 0.001). We subsequently used sensitivity analysis to obtain feature relevance from our prediction models, with the most important connections for prediction of PMA and GA found to predominantly involve frontal and temporal regions, thalami, and basal ganglia. From our models of PMA at scan for infants born at term, we computed a brain maturation index (predicted age minus actual age) of individual preterm neonates and found a significant correlation between this index and motor outcome at 18 months corrected age. Our results demonstrate the applicability of machine learning techniques in analyses of the neonatal connectome and suggest that a neural substrate of brain maturation with implications for future neurodevelopment is detectable at term equivalent age from the neonatal connectome.

Effects of gestational age at birth on perinatal structural brain development in healthy term-born babies.

Infants born in early term (37-38 weeks gestation) experience slower neurodevelopment than those born at full term (40-41 weeks gestation). While this could be due to higher perinatal morbidity, gestational age at birth may also have a direct effect on the brain. Here we characterise brain volume and white matter correlates of gestational age at birth in healthy term-born neonates and their relationship to later neurodevelopmental outcome using T2 and diffusion weighted MRI acquired in the neonatal period from a cohort (n = 454) of healthy babies born at term age (>37 weeks gestation) and scanned between 1 and 41 days after birth. Images were analysed using tensor-based morphometry and tract-based spatial statistics. Neurodevelopment was assessed at age 18 months using the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III). Infants born earlier had higher relative ventricular volume and lower relative brain volume in the deep grey matter, cerebellum and brainstem. Earlier birth was also associated with lower fractional anisotropy, higher mean, axial, and radial diffusivity in major white matter tracts. Gestational age at birth was positively associated with all Bayley-III subscales at age 18 months. Regression models predicting outcome from gestational age at birth were significantly improved after adding neuroimaging features associated with gestational age at birth. This work adds to the body of evidence of the impact of early term birth and highlights the importance of considering the effect of gestational age at birth in future neuroimaging studies including term-born babies.

Diagnostic stability and outcome after first episode psychosis.

BACKGROUND: Individuals diagnosed with schizophrenia are often assigned other psychiatric diagnoses during their lives. The significance of changing diagnosis has not been widely studied. AIMS: Our aim was to examine the association between diagnostic change and later outcome. METHODS: Individuals' diagnostic history, clinical and social outcomes were extracted from the AESOP-10 study, a 10-year follow-up of first episode psychosis cases. The association between outcome and different patterns of diagnosis over time were assessed using linear or logistic regression. RESULTS: Individuals always diagnosed with schizophrenia (n = 136) had worse clinical and social outcomes at follow-up than those never diagnosed with schizophrenia (n = 163), being more likely to be symptomatic, unemployed, single, and socially isolated. There was no difference in outcome between individuals always diagnosed with schizophrenia and those changing to a diagnosis of schizophrenia (n = 60), and no difference in outcome between individuals never diagnosed with schizophrenia, and those changing from a diagnosis of schizophrenia (n = 44). CONCLUSIONS: Individuals always and never diagnosed with schizophrenia had different outcomes. In cases of diagnostic instability participants had similar outcomes to those always assigned the diagnosis they changed to irrespective of initial diagnosis.

Parental age effects on neonatal white matter development.

OBJECTIVE: Advanced paternal age is associated with poor offspring developmental outcome. Though an increase in paternal age-related germline mutations may affect offspring white matter development, outcome differences could also be due to psychosocial factors. Here we investigate possible cerebral changes prior to strong environmental influences using brain MRI in a cohort of healthy term-born neonates. METHODS: We used structural and diffusion MRI images acquired soon after birth from a cohort (n = 275) of healthy term-born neonates. Images were analysed using a customised tract based spatial statistics (TBSS) processing pipeline. Neurodevelopmental assessment using the Bayley-III scales was offered to all participants at age 18 months. For statistical analysis neonates were compared in two groups, representing the upper quartile (paternal age ≥38 years) and lower three quartiles. The same method was used to assess associations with maternal age. RESULTS: In infants with older fathers (≥38 years), fractional anisotropy, a marker of white matter organisation, was significantly reduced in three early maturing anatomical locations (the corticospinal tract, the corpus callosum, and the optic radiation). Fractional anisotropy in these locations correlated positively with Bayley-III cognitive composite score at 18 months in the advanced paternal age group. A small but significant reduction in total brain volume was also observed in in the infants of older fathers. No significant associations were found between advanced maternal age and neonatal imaging. CONCLUSIONS: The epidemiological association between advanced paternal age and offspring outcome is extremely robust. We have for the first time demonstrated a neuroimaging phenotype of advanced paternal age before sustained parental interaction that correlates with later outcome.

Use of Prescribed Psychotropic Medications in an Opioid Substitution Therapy Cohort.

Objective: Comorbid mental illness is extremely common in individuals receiving opioid substitution therapy. The use of common psychiatric medications is complex in this cohort with increased risks of drug-drug interaction, overdose, and diversion or abuse of prescribed medication. We have therefore investigated rates of co-prescribing and psychiatric comorbidity in a cohort of individuals receiving therapeutic methadone or buprenorphine. Methods: Comprehensive electronic medical records were accessed for a cohort of individuals (n = 698) receiving opioid substitution therapy at a single center in London, United Kingdom. The following was collected for each individual: demographic data, current prescribed medications (including opioid substitution therapy agents), duration of prescription, indication for each prescription, and psychiatric diagnoses. Results: A total of 610 individuals were included in the final analysis. High rates of psychotropic co-prescribing were observed, with 36.7% of individuals receiving a psychotropic medication in addition to their opioid substitution drug, including 35.4% receiving an antidepressant, 9.2% an antipsychotic, 8.6% a benzodiazepine, and 4.5% a gabapentinoid, rates that are far in excess of the local population prescription frequency; 75.5% of antipsychotic prescriptions and 47.7% of benzodiazepine prescriptions were for an unlicensed indication. Conclusions: This highlights the need for evidence-based treatment of comorbid mental illness for individuals receiving opioid substitution therapy.

Single-center results of a series of prosthetic axillary-axillary arteriovenous access grafts for hemodialysis.

OBJECTIVE: Prosthetic infraclavicular axillary-axillary arteriovenous access grafts are one of a number of complex dialysis access options in patients when all of the usual upper limb possibilities have been exhausted. We present a follow-up of 35 patients who received this access graft during a 9-year period. METHODS: Patients were identified from our own operation records. Follow-up data were gathered from their locally held electronic medical records. Primary and secondary patency were calculated using the Kaplan-Meier estimate. RESULTS: During the study period, 15 of the 35 patients in our cohort underwent one or more revision operations. Primary patency was estimated at 88% at 6 months, and the secondary patency rate estimate was 54% at 48 months. Twelve patients died during the study period; the grafts in 17 of the 23 remaining patients were in use at the conclusion of the study. CONCLUSIONS: Although this is a small cohort, our results suggest that prosthetic axillary-axillary arteriovenous access should be at least considered as a viable long-term option for hemodialysis patients.

Early access ligation resolves presumed ischaemic monomelic neuropathy in a patient with recurrence of central venous occlusion.

PURPOSE: Ischaemic monomelic neuropathy (IMN) is a rare but serious complication of haemodialysis access procedures, with a highly variable clinical presentation. We present a case of presumed IMN managed with ligation of the prosthetic brachial-axillary access, leading to recovery of neurological function. METHODS: A 75-year-old male who underwent placement of a left prosthetic brachial-axillary access developed a swollen left upper limb following surgery and underwent interventional management for central venous occlusion. RESULTS: Eleven weeks following placement of the access, he presented with gross swelling and loss of function in the left arm. Ultrasonography excluded nerve compression. The brachial-axillary access was urgently ligated, leading to recovery of function in the arm. Electromyography (EMG) studies confirmed an ischaemic cause. CONCLUSIONS: The pathophysiology of IMN is poorly understood. This case is atypical in that the patient suffered from central venous stenosis prior to the development of IMN. This raises the possibility that the gross swelling secondary to recurrent central venous occlusion may have led to an ischaemic neuropathy by altering nerve perfusion. Early management led to a functional recovery of the affected limb, suggesting that an urgent approach in patients with suspected IMN might be associated with the best outcomes.

Mental health-related stigma in health care and mental health-care settings.

This Review considers the evidence for mental-health-related stigma in health-care and mental-health-care settings. Do mental-health-care and other health-care professionals stigmatise people using their services? If so, what are the effects on quality of mental and physical health care? How can stigma and discrimination in the context of health care be reduced? We show that the contact mental-health-care professionals have with people with mental illness is associated with positive attitudes about civil rights, but does not reduce stigma as does social contact such as with friends or family members with mental illness. Some evidence suggests educational interventions are effective in decreasing stigma especially for general health-care professionals with little or no formal mental health training. Intervention studies are needed to underpin policy; for instance, to decrease disparity in mortality associated with poor access to physical health care for people with mental illness compared with people without mental illness.

Developing ideas of professionalism.

BACKGROUND: Professionalism is widely acknowledged as being central to medical practice, and is taught at most UK medical schools. The impact of this teaching in the context of competing influences on a student's developing view of themselves as professional is, however, unclear. We explored the understanding of professionalism in third-year medical students who have recently completed this element of their formal teaching, and related this understanding to previously unexplored wider influences placed upon them during their development. METHODS: A questionnaire consisting of two closed questions and two open questions was distributed via e-mail to third-year students at Imperial College School of Medicine, London. The closed questions explored both beliefs about what constitutes medical professionalism and preferences for the teaching of professionalism. The open questions explored the contexts within which students believed their understanding of professionalism was derived. Content analysis of text-based questions was performed. RESULTS AND DISCUSSION: The most commonly cited aspects of professionalism by students in this study were confidentiality, good medical knowledge and practical skill. Students also cited promptness, hygiene and appearance as being important, although these factors are rarely cited in the literature. Students cited role models, the media and parents as the three most important influences on their view of professionalism. These merit further consideration in future research and course design. Most students agreed that professionalism should be taught at medical school, but that this would be best achieved within a clinical setting. The favoured model for acquisition of views on professionalism was observation of doctors rather than formal teaching.

Model IgG monoclonal autoantibody-anti-idiotype pair for dissecting the humoral immune response to oxidized low density lipoprotein.

Increasing evidence implicates IgG autoantibodies against oxidized forms of low density lipoprotein (oxLDL) in the pathophysiology of atherosclerotic arterial disease. However, insufficient knowledge of their structure and function is a key gap. Using an elderly LDL receptor-deficient atherosclerotic mouse, we isolated a novel IgG3k against oxLDL (designated MAb LO1). LO1 reacts with copper-oxidized LDL, but minimally with native LDL. Further analysis showed that MAb LO1 also reacts in vitro with malondialdehyde-conjugated LDL (MDA-LDL), a known key epitope in copper-oxidized LDL preparations. By screening a phage library expressing single chain variable region antibodies (scFv), we selected an anti-idiotype scFv (designated H3) that neutralizes MAb LO1 binding to MDA-LDL. Amino acid substitutions between H3 and an irrelevant control scFv C12 showed that residues in the H3 CDRH2, CDRH3, and CDRL2 are all critical for MAb LO1 binding, consistent with a conformational epitope on H3 involving both heavy and light chains. Comparison of amino acids in H3 CDRH2 and CDRL2 with apoB, the major LDL protein, showed homologous sequences, suggesting H3 has structural similarities to the MAb LO1 binding site on MDA-LDL. Immunocytochemical staining showed that MAb LO1 binds epitopes in mouse and human atherosclerotic lesions. The MAb LO1-H3 combination therefore provides a very promising model for analyzing the structure and function of an individual IgG autoantibody in relation to atherosclerosis.