Life course predictors of child emotional distress during the COVID-19 pandemic: Findings from a prospective intergenerational cohort study.

BACKGROUND: We examine precursors of child emotional distress during the COVID-19 pandemic in a prospective intergenerational Australian cohort study. METHODS: Parents (N = 549, 60% mothers) of 934 1-9-year-old children completed a COVID-19 specific module in 2020 and/or 2021. Decades prior, a broad range of individual, relational and contextual factors were assessed during parents' own childhood, adolescence and young adulthood (7-8 to 27-28 years old; 1990-2010) and again when their children were 1 year old (2012-2019). RESULTS: After controlling for pre-pandemic socio-emotional behaviour problems, COVID-19 child emotional distress was associated with a range of pre-pandemic parental life course factors including internalising difficulties, lower conscientiousness, social skills problems, poorer relational health and lower trust and tolerance. Additionally, in the postpartum period, pre-pandemic parental internalising difficulties, lower parental warmth, lower cooperation and fewer behavioural competencies predicted child COVID-19 emotional distress. CONCLUSIONS: Findings highlight the importance of taking a larger, intergenerational perspective to better equip young populations for future adversities. This involves not only investing in child, adolescent, and young adult emotional and relational health, but also in parents raising young families.

Diurnal variation in variables related to cognitive performance: a systematic review.

PURPOSE: The aim of this review was to assess current evidence regarding changes in cognitive function according to time-of-day (TOD) and assess the key components of research design related to manuscripts of chronobiological nature. METHODS: An English-language literature search revealed 523 articles through primary database searches, and 1868 via organization searches/citation searching. The inclusion criteria were met by eleven articles which were included in the review. The inclusion criteria set were healthy adult males, a minimum of two timepoints including morning and evening, cognitive measures of performance, and peer-reviewed academic paper. RESULTS: It was established that cognitive performance varies with TOD and the degree of difference is highly dependent on the type of cognitive task with differences ranging from 9.0 to 34.2% for reaction time, 7.3% for alertness, and 7.8 to 40.3% for attention. The type of cognitive function was a determining factor as to whether the performance was better in the morning, evening, or afternoon. CONCLUSION: Although some studies did not establish TOD differences, reaction time and levels of accuracy were highest in the evening. This implies that cognitive processes are complex, and existing research is contradictory. Some studies or cognitive variables did not show any measurable TOD effects, which may be due to differences in methodology, subjects involved, testing protocols, and confounding factors. No studies met all requirements related to chronobiological research, highlighting the issues around methodology. Therefore, future research must use a rigorous, approach, minimizing confounding factors that are specific to examinations of TOD.

Control of backbone chemistry and chirality boost oligonucleotide splice switching activity.

Although recent regulatory approval of splice-switching oligonucleotides (SSOs) for the treatment of neuromuscular disease such as Duchenne muscular dystrophy has been an advance for the splice-switching field, current SSO chemistries have shown limited clinical benefit due to poor pharmacology. To overcome limitations of existing technologies, we engineered chimeric stereopure oligonucleotides with phosphorothioate (PS) and phosphoryl guanidine-containing (PN) backbones. We demonstrate that these chimeric stereopure oligonucleotides have markedly improved pharmacology and efficacy compared with PS-modified oligonucleotides, preventing premature death and improving median survival from 49 days to at least 280 days in a dystrophic mouse model with an aggressive phenotype. These data demonstrate that chemical optimization alone can profoundly impact oligonucleotide pharmacology and highlight the potential for continued innovation around the oligonucleotide backbone. More specifically, we conclude that chimeric stereopure oligonucleotides are a promising splice-switching modality with potential for the treatment of neuromuscular and other genetic diseases impacting difficult to reach tissues such as the skeletal muscle and heart.

Factor structure of the Mini-Maternal Behavior Q-Sort and associations with infant attachment: Informing precision in research and intervention.

We examined the factor structure of parental sensitivity to infants as assessed by the Mini-Maternal Behavior Q-Sort (Mini-MBQS), a 25-item short-form of the original 90-item MBQS. We aimed to: (1) identify latent factors of the Mini-MBQS; and (2) validate each factor by testing associations with infant attachment classifications. Data on parent-infant dyads (n = 313; 222 mothers with 281 children, 29 fathers with 32 children) were drawn from a three-generation Australian cohort study. Exploratory Factor Analysis and Exploratory Structural Equation Modelling examined the structure of the Mini-MBQS. Two latent Mini-MBQS factors were identified, requiring 8 of 25 original items: (1) Attention and Responsiveness and (2) Contingency in Interactions. Infants with insecure attachment classifications had parents with lower sensitivity across both factors relative to infants classified secure. In particular, infants with resistant attachment classifications had parents with notably low Contingency in Interactions scores. Infants with disorganised attachment classifications had parents with the lowest relative sensitivity across both factors, and in these dyads Attention and Responsiveness scores were especially low. Results provide an empirically derived factor structure for the Mini-MBQS. Two subscales, each with significant infant attachment associations, may improve precision in clinical intervention and research translation.

Inequalities in the distribution of COVID-19-related financial difficulties for Australian families with young children.

BACKGROUND: We examine (1) the frequency of financial difficulties in Australian families with young children (0-8 years) in the early and later phases of the pandemic; (2) the extent to which parents' pre-pandemic socio-economic disadvantage (SED) predicted financial difficulties; and (3) whether grandparent intergenerational SED further amplified this risk. METHOD: Data: Australian Temperament Project (ATP; established 1983, N = 2443) and ATP Generation 3 study (ATPG3; established 2012; N = 702), of which 74% (N = 553) completed a COVID-specific module in the early (May-September 2020) and/or later (October-December 2021) phases of the pandemic. OUTCOMES: Parent-reported loss of employment/reduced income, difficulty paying for essentials, and financial strain. EXPOSURES: Pre-pandemic parent and grandparent education and occupation. ANALYSIS: Logistic regressions, estimated via generalized estimating equations, were used to examine associations between the pre-pandemic SED of parents and grandparents and their interaction with financial difficulties, adjusting for potential confounders. RESULTS: At both pandemic time points, a third of parents reported adverse financial impacts (early: 34%, 95% confidence interval [CI] = 30-38; later: 32%, 95% CI = 28-36). Each standard deviation increase in the parents' pre-pandemic SED was associated with a 36% increase in the odds of reporting multiple financial difficulties (odds ratio [OR] = 1.36, 95% CI = 1.04-1.78). There was little evidence of an interaction between the SED of parents and grandparents. CONCLUSIONS: Financial impacts related to the COVID-19 pandemic were common and, irrespective of grandparent SED, disproportionately borne by parents with higher pre-pandemic SED. Given the well-established relationship between disadvantage and child health and development, sustained and well-targeted government supports will be critical to minimizing adverse impacts in years to come.

Diet quality trajectories and cardiovascular phenotypes/metabolic syndrome risk by 11-12 years.

OBJECTIVE: To investigate associations between early-life diet trajectories and preclinical cardiovascular phenotypes and metabolic risk by age 12 years. METHODS: Participants were 1861 children (51% male) from the Longitudinal Study of Australian Children. At five biennial waves from 2-3 to 10-11 years: Every 2 years from 2006 to 2014, diet quality scores were collected from brief 24-h parent/self-reported dietary recalls and then classified using group-based trajectory modeling as 'never healthy' (7%), 'becoming less healthy' (17%), 'moderately healthy' (21%), and 'always healthy' (56%). At 11-12 years: During children's physical health Child Health CheckPoint (2015-2016), we measured cardiovascular functional (resting heart rate, blood pressure, pulse wave velocity, carotid elasticity/distensibility) and structural (carotid intima-media thickness, retinal microvasculature) phenotypes, and metabolic risk score (composite of body mass index z-score, systolic blood pressure, high-density lipoproteins cholesterol, triglycerides, and glucose). Associations were estimated using linear regression models (n = 1100-1800) adjusted for age, sex, and socioeconomic position. RESULTS: Compared to 'always healthy', the 'never healthy' trajectory had higher resting heart rate (2.6 bpm, 95% CI 0.4, 4.7) and metabolic risk score (0.23, 95% CI 0.01, 0.45), and lower arterial elasticity (-0.3% per 10 mmHg, 95% CI -0.6, -0.1) and distensibility (-1.2%, 95% CI -1.9, -0.5) (all effect sizes 0.3-0.4). Heart rate, distensibility, and diastolic blood pressure were progressively poorer for less healthy diet trajectories (linear trends p ≤ 0.02). Effects for systolic blood pressure, pulse wave velocity, and structural phenotypes were less evident. CONCLUSIONS: Children following the least healthy diet trajectory had poorer functional cardiovascular phenotypes and metabolic syndrome risk, including higher resting heart rate, one of the strongest precursors of all-cause mortality. Structural phenotypes were not associated with diet trajectories, suggesting the window to prevent permanent changes remains open to at least late childhood.

Prolonged grief in refugees, parenting behaviour and children's mental health.

BACKGROUND: Many refugees experience bereavement, and as a result they suffer elevated rates of prolonged grief disorder. Evidence also indicates that elevated rates of psychological disturbance in refugee children can be associated with parental mental health. This study examined the extent to which prolonged grief disorder in refugees is associated with their parenting behaviour and in turn with their children's mental health. METHODS: This study recruited participants from the Building a New Life in Australia prospective cohort study of refugees admitted to Australia between October 2013 and February 2014. The current data were collected in 2015-2016 and comprised 1799 adults, as well as 411 children of the adult respondents. Adult refugees were assessed for trauma history, post-migration difficulties, harsh and warm parenting, probable prolonged grief disorder and posttraumatic stress disorder. Children were administered the Strengths and Difficulties Questionnaire. The current analyses on bereaved refugees comprise 110 caregivers and 178 children. RESULTS: In this cohort, 37% of bereaved refugees reported probable prolonged grief disorder. Path analysis indicated that caregivers' grief was directly associated with children's emotional difficulties. Caregiver warmth was associated with reduced emotional problems in children of refugees with minimal grief but associated with more emotional problems in caregivers with more severe grief. More harsh parenting was associated with children's conduct problems, and this was more evident in those with less severe grief. CONCLUSION: Severity of prolonged grief disorder is directly linked to refugee children's mental health. The association between parenting style, grief severity and children's mental health highlights that managing grief reactions in refugees can benefit both refugees and their children.

Insights into adolescent well-being from computerised analysis of written language.

AIM: To examine associations between patterns of language use and early adolescent well-being. METHODS: Participants were 1763 Australian 11- to 12-year-olds in the Child Health CheckPoint. Six patterns of language use were identified from a writing activity using Linguistic Inquiry and Word Count and factor analysis: Acting in the present and future, Positive emotion, Gender and relationships, Self-aware, Inquisitive and time focused, and Confident. Well-being measures represented a spectrum from negatively to positively framed psychosocial health. Associations between language use and well-being were estimated using linear regression adjusted for age, sex and social disadvantage. RESULTS: Positive emotion (high emotional tone, positive emotion) was associated with better general well-being (standardised regression coefficient (SRC) 0.05; 95% confidence interval 0.00 to 0.11; p = 0.04), life satisfaction (0.06; 0.01 to 0.11; p = 0.03), psychosocial health (0.07; 0.02 to 0.12; p = 0.01) and quality of life (QoL) (0.06; 0.01 to 0.11; p = 0.02). Similarly, Self-aware (high first person singular pronouns, authentic, low clout) was associated with better general well-being, life satisfaction and psychosocial health (SRC 0.05, 0.09, 0.08), but Confident (high clout, first person plural pronouns, affiliation) was associated with worse life satisfaction, psychosocial health and QoL (SRC -0.06, -0.09, -0.06). CONCLUSION: If replicated in 'real-world' settings (e.g., social media), language patterns could provide naturalistic insights into early adolescents' well-being.

Reliability of Protein Abundance and Synthesis Measurements in Human Skeletal Muscle.

The repeatability of dynamic proteome profiling (DPP), which is a novel technique for measuring the relative abundance (ABD) and fractional synthesis rate (FSR) of proteins in humans, is investigated. LC-MS analysis is performed on muscle samples taken from male participants (n = 4) that consumed 4 × 50 mL doses of deuterium oxide (2 H2 O) per day for 14 days. ABD is measured by label-free quantitation and FSR is calculated from time-dependent changes in peptide mass isotopomer abundances. One-hundred one proteins have at least one unique peptide and are used in the assessment of protein ABD. Fifty-four of these proteins meet more stringent criteria and are used in the assessment of FSR data. The median (M), lower-, (Q1 ) and upper-quartile (Q3 ) values for protein FSR (%/d) are M = 1.63, Q1  = 1.07, and Q3  = 3.24, respectively. The technical CV of ABD data has a median value of 3.6% (Q1 1.7% to Q3 6.7%), whereas the median CV of FSR data is 10.1% (Q1 3.5% to Q3 16.5%). These values compare favorably against other assessments of technical repeatability of proteomics data, which often set a CV of 20% as the upper bound of acceptability.

From diagnosis to therapy in Duchenne muscular dystrophy.

Genetic approaches for the diagnosis and treatment of inherited muscle diseases have advanced rapidly in recent years. Many of the advances have occurred in the treatment of Duchenne muscular dystrophy (DMD), a muscle wasting disease where affected boys are typically wheelchair bound by age 12 years and generally die in their twenties from respiratory failure or cardiomyopathy. Dystrophin is a 421 kD protein which links F-actin to the extracellular matrix via the dystrophin-associated protein complex (DAPC) at the muscle membrane. In the absence of dystrophin, the DAPC is lost, making the muscle membrane more susceptible to contraction-induced injury. The identification of the gene causing DMD in 1986 resulted in improved diagnosis of the disease and the identification of hotspots for mutation. There is currently no effective treatment. However, there are several promising genetic therapeutic approaches at the preclinical stage or in clinical trials including read-through of stop codons, exon skipping, delivery of dystrophin minigenes and the modulation of expression of the dystrophin related protein, utrophin. In spite of significant progress, the problem of targeting all muscles, including diaphragm and heart at sufficiently high levels, remains a challenge. Any therapy also needs to consider the immune response and some treatments are mutation specific and therefore limited to a subgroup of patients. This short review provides a summary of the current status of DMD therapy with a particular focus on those genetic strategies that have been taken to the clinic.