Association of antenatal or neonatal SARS-COV-2 exposure with developmental and respiratory outcomes, and healthcare usage in early childhood: a national prospective cohort study.

Background: Perinatal exposure to SARS-CoV-2 may affect neurodevelopment before 12 months of age, but longer-term outcomes remain unknown. We examined whether antenatal or neonatal SARS-CoV-2 exposure compared with non-exposure is associated with neurodevelopment, respiratory symptoms, and health care usage in early childhood. Methods: This prospective national population-based cohort study was conducted in England and Wales, United Kingdom. We enrolled term-born children (≥37 weeks' gestation) with and without antenatal or neonatal exposure to SARS-CoV-2 infection by approaching parents of eligible children who were cared for in 87 NHS hospitals. Potential participants were identified through the national active surveillance studies of pregnant women and newborn infants hospitalised with confirmed SARS-CoV-2 infection conducted through the UK Obstetric Surveillance System and the British Paediatric Surveillance Unit. We defined antenatal and neonatal SARS-CoV-2 exposure as infants born to mothers hospitalised with confirmed SARS-CoV-2 infection between 14 + 0 and 36 + 6 weeks gestation and infants admitted to hospital with confirmed SARS-CoV-2 infection within the first 28 days after birth. Children born preterm or with major congenital anomaly or who were not residing in the UK were excluded. We assessed children's development (Ages and Stages Questionnaire 3rd Edition (ASQ-3); Ages and Stages Questionnaire Social-Emotional 2nd Edition (ASQ:SE-2)), respiratory symptoms (Liverpool Respiratory Symptom Questionnaire (LRSQ)) and health care usage (parent-completed questionnaire) at 21-32 months of age. Primary outcome: total ASQ-3 score, converted to z-scores. Secondary outcomes: ASQ:SE-2 z-scores; risk of delay in ASQ-3 domains; total LRSQ scores, converted to z-scores. Analyses were adjusted for children's age, sex, maternal ethnicity, parental education, and index of multiple deprivation. Findings: Between October 20, 2021 and January 27, 2023, we approached 668 and 1877 families out of 712 and 1917 potentially eligible participants in the exposed and comparison cohort. Of the 125 and 306 participants who were enrolled to the exposed and comparison cohort 121 and 301 participants completed the questionnaires and 96 and 243 participants were included in the analysis. In the age adjusted analysis, the mean total ASQ-3 z-score was lower in the exposed than the comparison cohort (-0.3, 95% CI: -0.6 to -0.05), however, when adjusted for sex, parental education, ethnicity and IMD quintile, there was no significant difference (difference in mean z-score = -0.2 95% CI: -0.5 to 0.03). SARS-CoV-2 exposure was associated with increased risk of delayed personal-social skills (odds ratio = 3.81; 95% CI: 1.07-13.66), higher ASQ:SE-2 total z-scores (difference in mean z-score = 0.4; 95% CI: 0.2-0.6) and increased risk of delayed social-emotional development (OR = 3.58, 95% CI: 1.30-9.83), after adjusting for sex, age at assessment, parental education, ethnicity and IMD quintile. The exposed cohort had a higher mean total LRSQ z-score than the comparison cohort (0.3 95% CI: 0-0.6) and higher inpatient (38% vs. 21%, p = 0.0001), outpatient (38% vs. 30%, p = 0.0090), and General Practitioner appointments (60% vs. 50%, p = 0.021) than the comparison cohort, after adjusting for sex, age at assessment, parental education, ethnicity and IMD quintile. No differences in other secondary outcomes between the exposed and comparison cohorts were found. Interpretation: Although the exposed cohort did not differ from the comparison cohort on the primary outcome, total ASQ-3 score, the exposed cohort were at greater risk of delayed social-emotional development, had a greater prevalence of respiratory symptoms and increased health care usage relative to the comparison cohort. The study is limited by the smaller sample size due to the low response rate and lack of clinical developmental assessments. Given the association of poor social-emotional development with antenatal or neonatal SARS-CoV-2 exposure, developmental screening, and follow-up of children with confirmed antenatal or neonatal SARS-CoV-2 infection may be warranted to identify those in need of early intervention. Funding: Action Medical Research for Children.

Antenatal and neonatal exposure to SARS-CoV-2 and children's development: a systematic review and meta-analysis.

OBJECTIVES: To conduct a systematic review of the impact of antenatal and neonatal exposure to SARS-CoV-2 on developmental outcomes in preterm and term-born infants. METHODS: We searched Embase, Emcare, MEDLINE, PsycINFO, Web of Science and grey literature on May 27, 2022 and updated on May 8, 2023. Studies defining exposure with a positive SARS-CoV-2 protein or genetic material, used a contemporaneous non-exposed cohort, and reported developmental outcomes up to 2 years of age were included. RESULTS: Four out of 828 screened studies were included. Meta-analysis included 815 infants screened for developmental delay (n = 306 exposed; n = 509 non-exposed) between 3- and 11-months of age. Among term-born infants, we did not find an increased risk of delay in communication (odd's ratio: 0.73 (95% CI: 0.24-2.24)), gross motor (1.50 (0.62, 3.62)), fine motor (2.90 (0.58, 14.43)), problem-solving (1.19 (0.54, 2.66)) or personal-social development (1.93 (0.78, 4.75)) in exposed infants. The number of preterm-born infants in the exposed (n = 37) and comparison cohorts (n = 41) were too few to report meaningful comparisons. CONCLUSION: Evidence regarding the potential impact of antenatal or neonatal exposure to SARS-CoV-2 infection on developmental outcomes in early infancy is limited and inconsistent. Larger cohorts with outcomes beyond the first year of life are needed. IMPACT: The current evidence examining associations between SARS-CoV-2 exposure during the neonatal period and developmental outcomes in infancy is limited by there being few studies with extremely small sample sizes. Based on sparse data there was no consistent association between antenatal or neonatal exposure to SARS-CoV-2 infection and an adverse impact on developmental outcomes below 12 months of age for babies born preterm or at term. This study highlights that larger cohorts with outcomes assessed beyond the first year are needed to determine the potential longer-term impact of SARS-CoV-2 infection exposure on child development.

Slower rates of prism adaptation but intact aftereffects in patients with early to mid-stage Parkinson's disease.

There is currently mixed evidence on the effect of Parkinson's disease on motor adaptation. Some studies report that patients display adaptation comparable to age-matched controls, while others report a complete inability to adapt to novel sensory perturbations. Here, early to mid-stage Parkinson's patients were recruited to perform a prism adaptation task. When compared to controls, patients showed slower rates of initial adaptation but intact aftereffects. These results support the suggestion that patients with early to mid-stage Parkinson's disease display intact adaptation driven by sensory prediction errors, as shown by the intact aftereffect. But impaired facilitation of performance through cognitive strategies informed by task error, as shown by the impaired initial adaptation. These results support recent studies that suggest that patients with Parkinson's disease retain the ability to perform visuomotor adaptation, but display altered use of cognitive strategies to aid performance and generalises these previous findings to the classical prism adaptation task.

Factors associated with MRI success in children cooled for neonatal encephalopathy and controls.

OBJECTIVE: To investigate if an association exists between motion artefacts on brain MRI and comprehension, co-ordination, or hyperactivity scores in children aged 6-8 years, cooled for neonatal encephalopathy (cases) and controls. METHODS: Case children (n = 50) without cerebral palsy were matched with 43 controls for age, sex, and socioeconomic status. Children underwent T1-weighted (T1w), diffusion-weighted image (DWI) brain MRI and cognitive, behavioural, and motor skills assessment. Stepwise multivariable logistic regression assessed associations between unsuccessful MRI and comprehension (including Weschler Intelligence Scale for Children (WISC-IV) verbal comprehension, working memory, processing speed and full-scale IQ), co-ordination (including Movement Assessment Battery for Children (MABC-2) balance, manual dexterity, aiming and catching, and total scores) and hyperactivity (including Strengths and Difficulties Questionnaire (SDQ) hyperactivity and total difficulties scores). RESULTS: Cases had lower odds of completing both T1w and DWIs (OR: 0.31, 95% CI 0.11-0.89). After adjusting for case-status and sex, lower MABC-2 balance score predicted unsuccessful T1w MRI (OR: 0.81, 95% CI 0.67-0.97, p = 0.022). Processing speed was negatively correlated with relative motion on DWI (r = -0.25, p = 0.026) and SDQ total difficulties score was lower for children with successful MRIs (p = 0.049). CONCLUSIONS: Motion artefacts on brain MRI in early school-age children are related to the developmental profile. IMPACT: Children who had moderate/severe neonatal encephalopathy are less likely to have successful MRI scans than matched controls. Motion artefact on MRI is associated with lower MABC-2 balance scores in both children who received therapeutic hypothermia for neonatal encephalopathy and matched controls, after controlling for case-status and sex. Exclusion of children with motion artefacts on brain MRI can introduce sampling bias, which impacts the utility of neuroimaging to understand the brain-behaviour relationship in children with functional impairments.

Cerebello-Thalamo-Cortical Network Dynamics in the Harmaline Rodent Model of Essential Tremor.

Essential Tremor (ET) is a common movement disorder, characterised by a posture or movement-related tremor of the upper limbs. Abnormalities within cerebellar circuits are thought to underlie the pathogenesis of ET, resulting in aberrant synchronous oscillatory activity within the thalamo-cortical network leading to tremors. Harmaline produces pathological oscillations within the cerebellum, and a tremor that phenotypically resembles ET. However, the neural network dynamics in cerebellar-thalamo-cortical circuits in harmaline-induced tremor remains unclear, including the way circuit interactions may be influenced by behavioural state. Here, we examined the effect of harmaline on cerebello-thalamo-cortical oscillations during rest and movement. EEG recordings from the sensorimotor cortex and local field potentials (LFP) from thalamic and medial cerebellar nuclei were simultaneously recorded in awake behaving rats, alongside measures of tremor using EMG and accelerometery. Analyses compared neural oscillations before and after systemic administration of harmaline (10 mg/kg, I.P), and coherence across periods when rats were resting vs. moving. During movement, harmaline increased the 9-15 Hz behavioural tremor amplitude and increased thalamic LFP coherence with tremor. Medial cerebellar nuclei and cerebellar vermis LFP coherence with tremor however remained unchanged from rest. These findings suggest harmaline-induced cerebellar oscillations are independent of behavioural state and associated changes in tremor amplitude. By contrast, thalamic oscillations are dependent on behavioural state and related changes in tremor amplitude. This study provides new insights into the role of cerebello-thalamo-cortical network interactions in tremor, whereby neural oscillations in thalamocortical, but not cerebellar circuits can be influenced by movement and/or behavioural tremor amplitude in the harmaline model.

Effect of SARS-CoV-2 infection in neonates or in pregnancy on developmental outcomes at 21-24 months (SINEPOST): study protocol for a prospective cohort study.

INTRODUCTION: Exposure to SARS-CoV-2 during pregnancy or in the neonatal period may impact fetal or neonatal brain development either through direct central nervous system infection or indirectly through the adverse effects of viral infection-related inflammation in the mother or newborn infant. This study aims to determine whether there are early neurodevelopmental effects of SARS-CoV-2 infection. METHODS AND ANALYSIS: We will conduct a prospective national population-based cohort study of children aged 21-24 months who were born at term (≥37 weeks' gestation) between 1 March 2020 and 28 February 2021 and were either antenatally exposed, neonatally exposed or unexposed (comparison cohort) to SARS-CoV-2. Nationally, hospitals will identify and approach parents of children eligible for inclusion in the antenatally and neonatally exposed cohorts using information from the UK Obstetric Surveillance System (UKOSS) and British Paediatric Surveillance Unit (BPSU) national surveillance studies and will identify and approach eligible children for the comparison cohort through routine birth records. Parents will be asked to complete questionnaires to assess their child's development at 21-24 months of age. Outcome measures comprise the Ages and Stages Questionnaire, Third Edition (ASQ-3), Ages and Stages Questionnaire Social-Emotional, Second Edition (ASQ-SE-2), Liverpool respiratory symptoms questionnaire and questionnaire items to elicit information about healthcare usage. With parental consent, study data will be linked to routine health and education records for future follow-up. Regression models will compare ASQ-3 and ASQ-SE-2 scores and proportions, frequency of respiratory symptoms and healthcare usage between the exposed and comparison cohorts, adjusting for potential confounders. ETHICS AND DISSEMINATION: Ethics approval was obtained from the London-Westminster Research Ethics Committee. Findings will be disseminated in scientific conference presentations and peer-reviewed publications. ISRCTN REGISTRATION NUMBER: ISRCTN99910769.

The Montana model: integrated primary care and behavioral health in a family practice residency program.

To address the local health care needs of both patients and primary care providers in Montana, an integrated primary care and behavioral health family practice clinic was developed. In this paper we describe our experience with integrating mental health and substance abuse services into a primary care setting (a community health center) while simultaneously teaching family practice physicians to take the lead in providing these services. The Deering Community Health Center in Billings, Montana, is a Federally Qualified Health Center serving a largely low-income patient population. The medical care at the clinic is provided primarily by the faculty and residents of the Montana Family Medicine Residency. The teaching model was founded on the belief that improved care will result when physicians have increased comfort with, and are able to enjoy the challenges of, patients with mental illnesses. The enhanced longitudinal curriculum incorporates mental health across the 3 years of the family practice residency. Unique characteristics of this model include staffing and the concurrent delivery of a high volume mental health service while teaching family practice resident physicians and the faculty to integrate this competency into their primary care practices.