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Objective To investigate the associations between neonatal unit admission (NNU) and subsequent emotional and behavioural difficulties during childhood and adolescence.Design Longitudinal general population cohort study.Setting The Millennium Cohort Study: nationally representative UK-based cohort.Participants All children with exposure, outcome and confounding data.Exposure NNU admission was identified at 9 months by asking parents whether their baby was ‘taken to special care or neonatal or intensive care unit after birth’.Main outcome measures Emotional and behavioural problems were assessed using the Strengths and Difficulties Questionnaire when children were 3, 5, 7, 11, 14 and 17 years. We explored the association between NNU admission and trajectories of emotional and behavioural problems using multilevel models with growth curves for outcome data between 3–17 years and adjusted for a broad range of confounders.Results 14 013 participants (48.9% female, 13.7% ethnic minority) were included in the analytical sample. In the sample, mean gestational age was 275.81 (SD): 13.80) days, and mean birth weight was 3.36 kg (SD=0.58). 1273 (9.1%) participants had an NNU admission. The latter was associated with increased emotional difficulties (mean difference (MD) 0.13, 95% CI 0.045 to 0.22, p=0.003) and peer problems (MD 0.11, 95% CI 0.026 to 0.19, p=0.010) during childhood in fully adjusted models. There was no evidence that NNU admission was associated with conduct problems (MD 0.013, 95% CI −0.062 to 0.088, p=0.732) or hyperactivity symptoms (MD 0.042, 95% CI −0.070 to 0.15, p=0.452).Conclusions Children admitted to NNUs at birth are more likely to experience emotional difficulties and peer problems during childhood. These differences are apparent from early childhood continuing into adolescence and strengthen the case for a calm NNU environment with parental visits and mental health support, and early interventions for children admitted to NNUs.

Aims Irritability is common and easily identified in childhood. It is transdiagnostic and a common reason for referral to mental health services. Irritability which does not decrease during early childhood is associated with adolescent depression. We hypothesised that irritability would be associated with increased risk-taking overall but reduced risk-taking in response to loss. Methods We used data from the Millennium Cohort Study, a population-based cohort of 18,552 children born in 2000–02. We examined whether irritability at 3, 5 and 7 years is associated with risk-taking on the CGT using multilevel mixed effect generalised linear models (MEGLMs). We also calculated the change in irritability between 3–7 years for each participant using multilevel mixed models. We then examined the association between this change measure and risk-taking on the CGT using MEGLMs. Analyses were adjusted for a broad range of confounders. Results We found that children whose irritability did not decrease as would be expected from 3 to 7 years were more likely to stake a higher number of points per trial on the CGT at 11 years. This increase was most evident when the previous trial had been won. Irritability at 7 years was associated with staking a higher number of points per trial on the CGT (coefficient 0.52, 95%CI −0.04–1.08, p = 0.067) in fully adjusted model, whereas irritability at 3 and 5 years were not (3 years – coefficient 0.02, 95%CI -0.62–0.65, p = 0.961; 5 years – coefficient 0.14, 95%CI −0.45–0.73, p = 0.641). There was evidence of an interaction between irritability at seven years and whether the previous trial was won (p = 0.014). Childhood irritability which did not decrease between 3–7 years was associated with staking a higher number of points per trial on the CGT (coefficient 1.36, 95%CI 0.44–2.28, p = 0.004); there was evidence of an interaction between change in irritability and whether the previous trial was won (p = 0.056). Conclusion This is the first longitudinal population-based study examining the relationship between changes in irritability during early childhood and risk-taking behaviour measured by the CGT. Our findings illustrate that irritability in children is characterised by an increase in risk-taking at age 11 years, reflecting differences in how children behave in relation to rewards and losses based on prior irritability. Further understanding of how the processes such as risk-taking which link childhood phenotypes such as irritability, relate to future mental health, may enable the development of new interventions focussing on reactions to rewards and losses.

Summary: Background: GBP510 vaccine contains self-assembling, recombinant nanoparticles displaying SARS-CoV-2 spike receptor-binding domains. We report interim phase 3 immunogenicity results for GBP510 adjuvanted with AS03 (GBP510/AS03) compared with ChAdOx1-S (Vaxzevria, AstraZeneca) in healthy adults aged ≥18 years, up to 6 months after the second dose. Methods: This was a randomised, active-controlled, observer-blinded, parallel group, phase 3 study, conducted at 38 sites across six countries (South Korea, Philippines, Thailand, Vietnam, Ukraine and New Zealand). Cohort 1 (no history of SARS-CoV-2 infection/COVID-19 vaccination) was randomised 2:1 to receive two doses of GBP510/AS03 or ChAdOx1-S (immunogenicity and safety), while Cohort 2 (regardless of baseline serostatus) was randomised 5:1 (safety). Primary objectives were to demonstrate superiority in geometric mean titre (GMT) and non-inferiority in seroconversion rate (SCR; ≥4-fold rise from baseline) of GBP510/AS03 vs. ChAdOx1-S for neutralising antibodies against the ancestral strain by live-virus neutralisation assay. Secondary objectives included assessment of safety and reactogenicity (long-term 6 months cut-off date: 09 August 2022). This study was registered on ClinicalTrials.gov (NCT05007951). Findings: Between 30 August 2021 and 11 January 2022, a total of 4913 participants were screened and 4036 participants (1956 in Cohort 1 and 2080 in Cohort 2) who met eligibility criteria were enrolled and randomised to receive 2 doses of GBP510/AS03 (n = 3039) or ChAdOx1-S (n = 997). Most participants were Southeast Asian (81.5%) and aged 18–64 years (94.7%). The primary objectives assessed in per-protocol set included 877 participants in GBP510/AS03 and 441 in ChAdOx1-S group: at 2 weeks after the second vaccination, the GMT ratio (GBP510/AS03/ChAdOx1-S) in per-protocol set was 2.93 (95% CI 2.63–3.27), demonstrating superiority (95% CI lower limit >1) of GBP510/AS03; the between-group SCR difference of 10.8% (95% CI 7.68–14.32) also satisfied the non-inferiority criterion (95% CI lower limit > −5%). Neutralizing antibody titres sustained higher for the GBP510/AS03 group compared to the ChAdOx1-S group through 6 months after the second vaccination. In Safety analysis (Cohort 1 & 2), the proportion of participants with adverse events (AEs) after any vaccination was higher with GBP510/AS03 vs. ChAdOx1-S for solicited local AEs (56.7% vs. 49.2%), but was similar for solicited systemic AEs (51.2% vs. 53.5%) and unsolicited AEs (13.3% vs. 14.6%) up to 28 days after the second vaccination. No safety concerns were identified during follow-up for 6 months after the second vaccination. Interpretation: Our interim findings suggested that GBP510/AS03 met the superiority criterion for neutralising antibodies and non-inferiority criterion for SCR compared with ChAdOx1-S, and showed a clinically acceptable safety profile. Funding: This work was supported, in whole or in part, by funding from CEPI and the Bill & Melinda Gates Foundation Investments INV-010680 and INV-006462. The Bill & Melinda Gates Foundation supported this project for the generation of IND-enabling data and CEPI supported this clinical study.

Abstract Background Young adults and especially those with pre-existing mental health conditions, such as disordered eating and self-harm, appear to be at greater risk of developing metal health problems during the COVID-19 pandemic. However, it is unclear whether this increased risk is affected by any changes in lockdown restrictions, and whether any lifestyle changes could moderate this increased risk. Methods In a longitudinal UK-based birth cohort (The Avon Longitudinal Study of Parents and Children, ALSPAC) we assessed the relationship between pre-pandemic measures of disordered eating and self-harm and mental health during the COVID-19 pandemic in 2657 young adults. Regression models examined the relationship between self-reported disordered eating, self-harm, and both disordered eating and self-harm at age 25 years and depressive symptoms, anxiety symptoms and mental wellbeing during a period of eased restrictions in the COVID-19 pandemic (May–July 2020) when participants were aged 27–29 years. Analyses were adjusted for sex, questionnaire completion date, pre-pandemic socioeconomic disadvantage and pre-pandemic mental health and wellbeing. We also examined whether lifestyle changes (sleep, exercise, alcohol, visiting green space, eating, talking with family/friends, hobbies, relaxation) in the initial UK lockdown (April–May 2020) moderated these associations. Results Pre-existing disordered eating, self-harm and comorbid disordered eating and self-harm were all associated with the reporting of a higher frequency of depressive symptoms and anxiety symptoms, and poorer mental wellbeing during the pandemic compared to individuals without disordered eating and self-harm. Associations remained when adjusting for pre-pandemic mental health measures. There was little evidence that interactions between disordered eating and self-harm exposures and lifestyle change moderators affected pandemic mental health and wellbeing. Conclusions Young adults with pre-pandemic disordered eating, self-harm and comorbid disordered eating and self-harm were at increased risk for developing symptoms of depression, anxiety and poor mental wellbeing during the COVID-19 pandemic, even when accounting for pre-pandemic mental health. Lifestyle changes during the pandemic do not appear to alter this risk. A greater focus on rapid and responsive service provision is essential to reduce the impact of the pandemic on the mental health of these already vulnerable individuals. Plain English summary The aim of this project was to explore the mental health of young adults with disordered eating behaviours (such as fasting, vomiting/taking laxatives, binge-eating and excessive exercise) and self-harm during the COVID-19 pandemic. We analysed data from an established study that has followed children from birth (in 1991 and 1992) up to present day, including during the pandemic when participants were 28 years old. We looked at the relationship between disordered eating and/or self-harm behaviours from before the pandemic and mental health problems (symptoms of depression and anxiety) and mental wellbeing during the pandemic. We also explored whether there were any lifestyle changes (such as changes in sleep, exercise, visiting green space) that might be linked to better mental health and wellbeing in young adults with disordered eating and self-harm. We found that young adults with prior disordered eating and/or self-harm had more symptoms of depression and anxiety, and worse mental wellbeing than individuals without prior disordered eating or self-harm. However, lifestyle changes did not appear to affect mental health and wellbeing in these young adults. Our findings suggest that people with a history of disordered eating and/or self-harm were at high risk for developing mental health problems during the pandemic, and they will need help from mental health services.

Summary: Background: Vaccination has helped to mitigate the COVID-19 pandemic. Ten traditional and novel vaccines have been listed by the World Health Organization for emergency use. Additional alternative approaches may better address ongoing vaccination globally, where there remains an inequity in vaccine distribution. GBP510 is a recombinant protein vaccine, which consists of self-assembling, two-component nanoparticles, displaying the receptor-binding domain (RBD) in a highly immunogenic array. Methods: This randomised, placebo-controlled, observer-blinded phase 1/2 study was conducted to evaluate the safety and immunogenicity of GBP510 (2-doses at a 28-day interval) adjuvanted with or without AS03 in adults aged 19–85 years at 14 hospital sites in Korea. This study was consisted of two stages (stage I, healthy adults aged 19–55 years; stage II, 240 healthy adults aged 19–85 years). Healthy participants who did not previously receive any vaccine within 4 weeks (2 weeks for flu vaccine) prior to the study, no history of COVID-19 vaccination/medication, and were naïve to SARS-CoV-2 infection at screening were eligible for the study enrollment. Participants were block-randomized in a 2:2:1 ratio to receive 2 doses of 10 µg GBP510 adjuvanted with AS03 (group 1), 10 µg unadjuvanted GBP510 (group 2) or placebo intramuscularly in stage I, while they were block-randomized in a 2:2:1:1 ratio to receive 10 µg GBP510 adjuvanted with AS03 (group 1), 25 µg GBP510 adjuvanted with AS03 (group 3), 25 µg unadjuvanted GBP510 (group 4) or placebo in stage II. The primary safety outcomes were solicited and unsolicited adverse events, while primary immunogenicity outcomes included anti-SARS-CoV-2 RBD IgG antibodies; neutralizing antibody responses; and T-cell immune responses. Safety assessment included all participants who received at least 1 dose of study intervention (safety set). Immunogenicity assessment included all participants who completed the vaccination schedule and had valid immunogenicity assessment results without any major protocol deviations (per-protocol set). This study was registered with ClinicalTrials.gov (NCT04750343). Findings: Of 328 participants who were enrolled between February 1 and May 28, 2021, 327 participants received at least 1 dose of vaccine. Each received either 10 µg GBP510 adjuvanted with AS03 (Group 1, n = 101), 10 µg unadjuvanted GBP510 (Group 2, n = 10), 25 µg GBP510 adjuvanted with AS03 (Group 3, n = 104), 25 µg unadjuvanted GBP510 (Group 4, n = 51), or placebo (n = 61). Higher reactogenicity was observed in the GBP510 adjuvanted with AS03 groups compared to the non-adjuvanted and placebo groups. The most frequently reported solicited local adverse event (AE) was injection site pain after any vaccination: (88·1% in group 1; 50·0% in group 2; 92·3% in group 3; 66·7% in group 4). Fatigue and myalgia were two most frequently reported systemic AEs and more frequently reported in GBP510 adjuvanted with AS03 recipients (79·2% and 78·2% in group 1; 75·0% and 79·8% in group 3, respectively) than in the unadjuvanted vaccine recipients (40·0% and of 40·0% in group 2; 60·8% and 47·1% in group 4) after any vaccination. Reactogenicity was higher post-dose 2 compared to post-dose 1, particularly for systemic AEs. The geometric mean concentrations of anti-SARS-CoV-2-RBD IgG antibody reached 2163·6/2599·2 BAU/mL in GBP510 adjuvanted with AS03 recipients (10 µg/25 µg) by 14 days after the second dose. Two-dose vaccination of 10 µg or 25 µg GBP510 adjuvanted with AS03 induced high titres of neutralizing antibody via pseudovirus (1369·0/1431·5 IU/mL) and wild-type virus (949·8/861·0 IU/mL) assay. Interpretation: GBP510 adjuvanted with AS03 was well tolerated and highly immunogenic. These results support further development of the vaccine candidate, which is currently being evaluated in Phase 3. Funding: This work was supported, in whole or in part, by funding from CEPI and the Bill & Melinda Gates Foundation Investment ID OPP1148601. The Bill & Melinda Gates Foundation supported this project for the generation of IND-enabling data and CEPI supported this clinical study.

Abstract Background To date, it is unclear if consumer wearable activity trackers (CWATs), with or without behaviour multi-component strategies, effectively improve adherence to physical activity and health outcomes under free living conditions in populations with chronic diseases. Therefore, we systematically evaluated the efficacy of CWAT-based interventions to promote physical activity levels and cardiometabolic health in populations with chronic diseases. Methods Randomised controlled trials were collected from five bibliographic databases (PubMed, Embase, Web of Science, The Cochrane Central Register of Controlled Trials and CINAHL). Studies were eligible for inclusion if they evaluated a CWAT-based counselling intervention versus control intervention among patients with chronic respiratory diseases, type 2 diabetes mellitus, cardiovascular diseases, overweight/obesity, cognitive disorders, or sedentary older adults. Data were pooled using a random-effects model. Results After deduplication 8147 were identified of which 35 studies met inclusion criteria (chronic respiratory diseases: 7, type 2 diabetes mellitus: 12, cardiovascular diseases: 6, overweight/obesity: 3, cognitive disorders: 1, sedentary older adults: 6). Compared to control groups, CWAT-based interventions significantly increased physical activity by 2123 steps per day (95% confidence interval [CI], [1605–2641]; p

The development of dentition in dogs has been associated with several problems including tooth over-crowding, missing permanent dentition, and persistent deciduous teeth (PDT). Information on dentition development in different breeds is lacking. This study of 61 Yorkshire terriers aimed to determine the (i) average age at deciduous tooth exfoliation, (ii) average age at permanent tooth eruption, (iii) PDT incidence, and influencing factors such as body weight. The ages of exfoliation of deciduous teeth and eruption of permanent dentition were influenced by body weight and tooth type. These dentition changes tended to occur later in dogs ≤ 3 kg versus dogs > 5 kg. Generally, incisors were exfoliated first, followed by premolars and then canines. At a body weight of 4.5 kg, the middle of the data range, the estimated age at loss of deciduous teeth (with 95% confidence intervals) was 21.9 (21.1, 22.9) weeks for incisors, 26.1 (24.9, 27.4) weeks for canines, and 23.9 (22.9, 24.9) weeks for premolar. The estimated age at eruption of permanent dentition was 22.3 (21.6, 23.0) weeks for incisors, 23.8 (23.0, 24.6) weeks for canines, 24.7 (24.0, 25.5) weeks for premolars, and 26.4 (25.5, 27.3) for molar teeth. However, this sequence was disrupted in dogs ≤ 3 kg. Yorkshire terriers had a high incidence of PDT. At a body weight of 4.5 kg, the estimated proportion of PDT was: incisors 0.86% (0.32, 2.31), canines 15.62% (7.62, 29.37) and premolars 3.57% (1.62, 7.66). Canines constituted the most frequently retained tooth type, with 89.1% retained in dogs ≤ 3 kg compared to 12.0% in dogs > 5 kg. This information will enable veterinarians to provide personalised advice regarding the oral care requirements for Yorkshire terriers and highlights the need to regularly monitor this breed between the ages of two and seven months, during the active phases of tooth development.

Introduction Disruptive behaviour disorders, including oppositional defiant disorder and conduct disorder, are a common set of diagnoses in childhood and adolescence, with global estimates of 5.7%, 3.6% and 2.1% for any disruptive disorder, oppositional defiant disorder and conduct disorder, respectively. There are high economic and social costs associated with disruptive behaviours and the prevalence of these disorders has increased in recent years. As such, disruptive behaviours represent an escalating major public health concern and it is important to understand what factors may influence the risk of these behaviours. Such research would inform interventions that aim to prevent the development of disruptive behaviours. The current review will identify the most stringent evidence of putative risk factors for disruptive behaviour from quasi-experimental studies, which enable stronger causal inference.Methods and analysis The review will be carried out according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. An electronic search of references published between 1 January 1980 and 1 March 2020 will be conducted using Medline, Embase, PsycINFO and Web of Science. Initial abstract and title screening, full-text screening and data extraction will be completed independently by two reviewers using Evidence for Policy and Practice Information (EPPI)-Reviewer 4 software. Quasi-experimental studies in the English language examining the association between any putative risk factor and a clearly defined measure of disruptive behaviour (eg, a validated questionnaire measure) will be included. We will conduct meta-analyses if we can pool a minimum of three similar studies with the same or similar exposures and outcomes.Ethics and dissemination The proposed review does not require ethical approval. The results will help to identify risk factors for which there is strong evidence of causal effects on disruptive behaviours and also highlight potential risk factors that require further research. The findings will be disseminated via publication in a peer-reviewed scientific journal and through presentations at international meetings and conferences.PROSPERO registration number CRD42020169313.

Abstract Background Women who have an overweight or obese BMI are more likely to experience pregnancy complications. However, little is known on the cost of childbirth in this group and no studies have been undertaken in England to date. The aim of this paper is therefore to investigate whether women with overweight and obese pre-pregnancy body mass index (BMI) incur higher average hospital costs of childbirth. Methods We employed data from 7564 women in the first wave of data collection of the Millennium Cohort Study. Using interval regression, we investigated the association between hospital costs of childbirth and pre-pregnancy BMI, fitting four models, progressively adjusting for additional potential confounders and mediators. Model 1 was a univariate model; model 2 adjusted for maternal age, education, marital status, ethnicity, income, and region; model 3 additionally included number of previous children, number of babies delivered, whether birth was at term, and type of delivery; model 4 also included length of hospital stay. Results Childbirth costs incurred by women who were overweight, obese class I and obese class II and III were £22, £82 and £126 higher than those incurred by women whose BMI was in the normal range (p ≤ 0.05). Delivery method, pre-term delivery, and length of hospital stay accounted for the observed difference. Conclusions Women with elevated pre-pregnancy BMI make greater use of services resulting in higher hospital costs. Interventions promoting healthy BMI in pre-pregnancy among women of child-bearing age have the potential to reduce pregnancy complications and be cost-effective.

Background: Bowel cancer screening reduces cancer-specific mortality. There is a socioeconomic gradient in the uptake of the English NHS Bowel Cancer Screening Programme (BCSP), which may lead to inequalities in cancer outcomes. Objective: To reduce socioeconomic inequalities in uptake of the NHS BCSP’s guaiac faecal occult blood test (gFOBt) without compromising uptake in any socioeconomic group. Design: Workstream 1 explored psychosocial determinants of non-uptake of gFOBt in focus groups and interviews. Workstream 2 developed and tested four theoretically based interventions: (1) ‘gist’ information, (2) a ‘narrative’ leaflet, (3) ‘general practice endorsement’ (GPE) and (4) an ‘enhanced reminder’ (ER). Workstream 3 comprised four national cluster randomised controlled trials (RCTs) of the cost-effectiveness of each intervention. Methods: Interventions were co-designed with user panels, user tested using interviews and focus groups, and piloted with postal questionnaires. RCTs compared ‘usual care’ (existing NHS BCSP invitations) with usual care plus each intervention. The four trials tested: (1) ‘gist’ leaflet (n = 163,525), (2) ‘narrative’ leaflet (n = 150,417), (3) GPE on the invitation letter (n = 265,434) and (4) ER (n = 168,480). Randomisation was based on day of mailing of the screening invitation. The Index of Multiple Deprivation (IMD) score associated with each individual’s home address was used as the marker of socioeconomic circumstances (SECs). Change in the socioeconomic gradient in uptake (interaction between treatment group and IMD quintile) was the primary outcome. Screening uptake was defined as the return of a gFOBt kit within 18 weeks of the invitation that led to a ‘definitive’ test result of either ‘normal’ (i.e. no further investigation required) or ‘abnormal’ (i.e. requiring referral for further testing). Difference in overall uptake was the secondary outcome. Results: The gist and narrative trials showed no effect on the SECs gradient or overall uptake (57.6% and 56.7%, respectively, compared with 57.3% and 58.5%, respectively, for usual care; all p-values > 0.05). GPE showed no effect on the gradient (p = 0.5) but increased overall uptake [58.2% vs. 57.5% in usual care, odds ratio (OR) = 1.07, 95% confidence interval (CI) 1.04 to 1.10; p

BACKGROUND:Programmes have had limited success in improving guideline adherence for chronic disease. Use of theory is recommended but is often absent in programmes conducted in 'real-world' rather than research settings. MATERIALS AND METHODS:This mixed-methods study tested a retrospective theory-based approach to evaluate a 'real-world' programme in primary care to improve adherence to national guidelines for chronic obstructive pulmonary disease (COPD). Qualitative data, comprising analysis of documents generated throughout the programme (n>300), in-depth interviews with planners (clinicians, managers and improvement experts involved in devising, planning, and implementing the programme, n = 14) and providers (practice clinicians, n = 14) were used to construct programme theories, experiences of implementation and contextual factors influencing care. Quantitative analyses comprised controlled before-and-after analyses to test 'early' and evolved' programme theories with comparators grounded in each theory. 'Early' theory predicted the programme would reduce emergency hospital admissions (EHA). It was tested using national analysis of standardized borough-level EHA rates between programme and comparator boroughs. 'Evolved' theory predicted practices with higher programme participation would increase guideline adherence and reduce EHA and costs. It was tested using a difference-in-differences analysis with linked primary and secondary care data to compare changes in diagnosis, management, EHA and costs, over time and by programme participation. RESULTS:Contrary to programme planners' predictions in 'early' and 'evolved' programme theories, admissions did not change following the programme. However, consistent with 'evolved' theory, higher guideline adoption occurred in practices with greater programme participation. CONCLUSIONS:Retrospectively constructing theories based on the ideas of programme planners can enable evaluators to address some limitations encountered when evaluating programmes without a theoretical base. Prospectively articulating theory aided by existing models and mid-range implementation theories may strengthen guideline adoption efforts by prompting planners to scrutinise implementation methods. Benefits of deriving programme theory, with or without the aid of mid-range implementation theories, however, may be limited when the evidence underpinning guidelines is flawed.