On SU(3)FSU(3)_{F} Breaking through Final State Interactions and CP Asymmetries in D→PPD\to P P Decays

We analyse $D$ decays to two pseudoscalars $(\pi,K)$ assuming the dominant source of $\mathrm{SU}(3)_F$ breaking lies in final state interactions. We obtain an excellent agreement with experimental data and are able to predict CP violation in several channels based on current data on branching ratios and $\Delta \mathrm{A_{CP}}$. We also make predictions for $\delta_{K\pi}$ and the branching fraction for the decay $D_s^+\to K^+K_L$.Comment: 21 pages. Updated with the 2019 measurement of $\Delta \mathrm{A_{CP}}$ from LHC

Atmospheric Neutrino Octant from Flavour Symmetry

The binary tetrahedral group ($T^{'}$) has provided the most successful flavour symmetry in understanding simultaneously the three mixing angles both for quarks in the CKM matrix and for neutrinos in the PMNS matrix. One prediction, invariant under leptonic CP violation, relates the atmospheric and reactor neutrino mixings $\theta_{23}$ and $\theta_{13}$ respectively. We study sedulously this relation using the latest neutrino data. It is natural to focus on the frustrating experimental octant ambiguity of $\theta_{23}$. We conclude that the flavour symmetry requires that $\theta_{23}$ is in the second octant $\theta > 45^0$, not in the first one $\theta_{23}<45^0$, and eagerly await experimental confirmation of this prediction.Comment: 6 pages LaTe

Reliability and Validity of the Early Years Physical Activity Questionnaire (EY-PAQ).

Measuring physical activity (PA) and sedentary time (ST) in young children (<5 years) is complex. Objective measures have high validity but require specialist expertise, are expensive, and can be burdensome for participants. A proxy-report instrument for young children that accurately measures PA and ST is needed. The aim of this study was to assess the reliability and validity of the Early Years Physical Activity Questionnaire (EY-PAQ). In a setting where English and Urdu are the predominant languages spoken by parents of young children, a sample of 196 parents and their young children (mean age 3.2 ± 0.8 years) from Bradford, UK took part in the study. A total of 156 (79.6%) questionnaires were completed in English and 40 (20.4%) were completed in transliterated Urdu. A total of 109 parents took part in the reliability aspect of the study, which involved completion of the EY-PAQ on two occasions (7.2 days apart; standard deviation (SD) = 1.1). All 196 participants took part in the validity aspect which involved comparison of EY-PAQ scores against accelerometry. Validty anaylsis used all data and data falling with specific MVPA and ST boundaries. Reliability was assessed using intra-class correlations (ICC) and validity by Bland⁻Altman plots and rank correlation coefficients. The test re-test reliability of the EY-PAQ was moderate for ST (ICC = 0.47) and fair for moderate-to-vigorous physical activity (MVPA)(ICC = 0.35). The EY-PAQ had poor agreement with accelerometer-determined ST (mean difference = -87.5 min·day-1) and good agreement for MVPA (mean difference = 7.1 min·day-1) limits of agreement were wide for all variables. The rank correlation coefficient was non-significant for ST (rho = 0.19) and significant for MVPA (rho = 0.30). The EY-PAQ has comparable validity and reliability to other PA self-report tools and is a promising population-based measure of young children's habitual MVPA but not ST. In situations when objective methods are not possible for measurement of young children's MVPA, the EY-PAQ may be a suitable alternative but only if boundaries are applied

Is small size at birth associated with early childhood morbidity in white British and Pakistani origin UK children aged 0-3? Findings from the born in Bradford cohort study

Abstract Background Low birthweight is associated with increased infant morbidity, poorer developmental outcomes and risk of adult disease and its prevention remains a public health priority. South Asian children are more likely to be born small and there is some debate around whether this is a normal phenomenon within this population or whether they have a greater risk of morbidity. We examined the association between small size at birth and morbidity in White British and Pakistani origin children aged 0–3 participating in the Born in Bradford cohort study. Methods We included 4119 White British and 4731 Pakistani origin children and examined health service use (General Practitioner (GP) consultations, the most common prescribing categories (analgesics, antibiotics, bronchodilators), emergency and elective hospital episodes) as markers of morbidity, in children born small defined as: (i) low birthweight (< 2500 g) (ii) small for gestational age (SGA) using customised birth charts. We used negative binomial regression models to predict the adjusted incidence of morbidity markers. Results 8.7% of Pakistani and 5% of White British children were born with a low birthweight (< 2500 g). Using customised charts, these proportions were 15.3 and 6.2% respectively. Children born small in both groups irrespective of the criteria used, generally had a higher rate of episodes for morbidity markers compared to normal weight children. Incidence of GP consultations (IRR 1.48 (95% CI 1.27, 1.73) to 1.55 (95% CI 1.36, 1.76) depending on birthweight category), analgesic (IRR 1.76 (95% CI 1.37, 2.25) to 2.31 (95% CI 2.19, 2.45) and antibiotic prescriptions (IRR 1.13 (95% CI 0.08, 1.46) to 1.38 (95% CI 1.30, 1.48) and emergency hospital episodes (IRR 1.20 (95% CI 1.06, 1.36) to 1.46 (95% CI 0.92, 2.32), was higher in Pakistani origin children with either a low or normal birthweight. Conclusion Being born small is associated with greater morbidity estimated by use of health services, in both White British and Pakistani origin children underlining the importance of public health policy to reduce low birthweight. Pakistani origin children access health services more frequently than White British children irrespective of birthweight and this has implications for health service planning in areas with South Asian populations

Reliability and validity of the early years physical activity questionnaire (EY-PAQ)

Measuring physical activity (PA) and sedentary time (ST) in young children (<5 years) is complex. Objective measures have high validity but require specialist expertise, are expensive, and can be burdensome for participants. A proxy-report instrument for young children that accurately measures PA and ST is needed. The aim of this study was to assess the reliability and validity of the Early Years Physical Activity Questionnaire (EY-PAQ). In a setting where English and Urdu are the predominant languages spoken by parents of young children, a sample of 196 parents and their young children (mean age 3.2 ± 0.8 years) from Bradford, UK took part in the study. A total of 156 (79.6%) questionnaires were completed in English and 40 (20.4%) were completed in transliterated Urdu. A total of 109 parents took part in the reliability aspect of the study, which involved completion of the EY-PAQ on two occasions (7.2 days apart; standard deviation (SD) = 1.1). All 196 participants took part in the validity aspect which involved comparison of EY-PAQ scores against accelerometry. Validty anaylsis used all data and data falling with specific MVPA and ST boundaries. Reliability was assessed using intra-class correlations (ICC) and validity by Bland–Altman plots and rank correlation coefficients. The test re-test reliability of the EY-PAQ was moderate for ST (ICC = 0.47) and fair for moderate-to-vigorous physical activity (MVPA)(ICC = 0.35). The EY-PAQ had poor agreement with accelerometer-determined ST (mean difference = −87.5 min·day−1) and good agreement for MVPA (mean difference = 7.1 min·day−1) limits of agreement were wide for all variables. The rank correlation coefficient was non-significant for ST (rho = 0.19) and significant for MVPA (rho = 0.30). The EY-PAQ has comparable validity and reliability to other PA self-report tools and is a promising population-based measure of young children’s habitual MVPA but not ST. In situations when objective methods are not possible for measurement of young children’s MVPA, the EY-PAQ may be a suitable alternative but only if boundaries are applied

ActEarly: a City Collaboratory approach to early promotion of good health and wellbeing.

Economic, physical, built, cultural, learning, social and service environments have a profound effect on lifelong health. However, policy thinking about health research is dominated by the 'biomedical model' which promotes medicalisation and an emphasis on diagnosis and treatment at the expense of prevention. Prevention research has tended to focus on 'downstream' interventions that rely on individual behaviour change, frequently increasing inequalities. Preventive strategies often focus on isolated leverage points and are scattered across different settings. This paper describes a major new prevention research programme that aims to create City Collaboratory testbeds to support the identification, implementation and evaluation of upstream interventions within a whole system city setting. Prevention of physical and mental ill-health will come from the cumulative effect of multiple system-wide interventions. Rather than scatter these interventions across many settings and evaluate single outcomes, we will test their collective impact across multiple outcomes with the goal of achieving a tipping point for better health. Our focus is on early life (ActEarly) in recognition of childhood and adolescence being such critical periods for influencing lifelong health and wellbeing

PPAR-gamma agonist pioglitazone recovers mitochondrial quality control in fibroblasts from PITRM1-deficient patients

Introduction: Biallelic variants in PITRM1 are associated with a slowly progressive syndrome characterized by intellectual disability, spinocerebellar ataxia, cognitive decline and psychosis. The pitrilysin metallopeptidase 1 (PITRM1) is a mitochondrial matrix enzyme, which digests diverse oligopeptides, including the mitochondrial targeting sequences (MTS) that are cleaved from proteins imported across the inner mitochondrial membrane by the mitochondrial processing peptidase (MPP). Mitochondrial peptidases also play a role in the maturation of Frataxin, the protein affected in Friedreich’s ataxia. Recent studies in yeast indicated that the mitochondrial matrix protease Ste23, which is a homologue of the human insulin-degrading enzyme (IDE), cooperates with Cym1 (homologue of PITRM1) to ensure the proper functioning of the preprotein processing machinery. In humans, IDE could be upregulated by Peroxisome Proliferator-Activated Receptor Gamma (PPARG) agonists.Methods: We investigated preprotein processing, mitochondrial membrane potential and MTS degradation in control and patients’, and we evaluated the pharmacological effect of the PPARG agonist Pioglitazone on mitochondrial proteostasis.Results: We discovered that PITRM1 dysfunction results in the accumulation of MTS, leading to the disruption and dissipation of the mitochondrial membrane potential. This triggers a feedback inhibition of MPP activity, consequently impairing the processing and maturation of Frataxin. Furthermore, we found that the pharmacological stimulation of PPARG by Pioglitazone upregulates IDE and also PITRM1 protein levels restoring the presequence processing machinery and improving Frataxin maturation and mitochondrial function.Discussion: Our findings provide mechanistic insights and suggest a potential pharmacological strategy for this rare neurodegenerative mitochondrial disease

Maternal iodine status, intrauterine growth, birth outcomes and congenital anomalies in a UK birth cohort.

BACKGROUND: Severe iodine insufficiency in pregnancy has significant consequences, but there is inadequate evidence to indicate what constitutes mild or moderate insufficiency, in terms of observed detrimental effects on pregnancy or birth outcomes. A limited number of studies have examined iodine status and birth outcomes, finding inconsistent evidence for specific outcomes. METHODS: Maternal iodine status was estimated from spot urine samples collected at 26-28 weeks' gestation from 6971 mothers in the Born in Bradford birth cohort. Associations with outcomes were examined for both urinary iodine concentration (UIC) and iodine-to-creatinine ratio (I:Cr). Outcomes assessed included customised birthweight (primary outcome), birthweight, small for gestational age (SGA), low birthweight, head circumference and APGAR score. RESULTS: There was a small positive association between I:Cr and birthweight in adjusted analyses. For a typical participant, the predicted birthweight centile at the 25th percentile of I:Cr (59 μg/g) was 2.7 percentage points lower than that at the 75th percentile of I:Cr (121 μg/g) (99% confidence interval (CI) 0.8 to 4.6), birthweight was predicted to be 41 g lower (99% CI 13 to 69) and the predicted probability of SGA was 1.9 percentage points higher (99% CI 0.0 to 3.7). There was no evidence of associations using UIC or other birth outcomes, including stillbirth, preterm birth, ultrasound growth measures or congenital anomalies. CONCLUSION: Lower maternal iodine status was associated with lower birthweight and greater probability of SGA. Whilst small, the effect size for lower iodine on birthweight is comparable to environmental tobacco smoke exposure. Iodine insufficiency is avoidable, and strategies to avoid deficiency in women of reproductive age should be considered. TRIAL REGISTRATION: ClinicalTrials.gov NCT03552341. Registered on June 11, 2018

Meta-analysis of epigenome-wide association studies in newborns and children show widespread sex differences in blood DNA methylation

Publisher Copyright: © 2022 The AuthorsBackground: Among children, sex-specific differences in disease prevalence, age of onset, and susceptibility have been observed in health conditions including asthma, immune response, metabolic health, some pediatric and adult cancers, and psychiatric disorders. Epigenetic modifications such as DNA methylation may play a role in the sexual differences observed in diseases and other physiological traits. Methods: We performed a meta-analysis of the association of sex and cord blood DNA methylation at over 450,000 CpG sites in 8438 newborns from 17 cohorts participating in the Pregnancy And Childhood Epigenetics (PACE) Consortium. We also examined associations of child sex with DNA methylation in older children ages 5.5–10 years from 8 cohorts (n = 4268). Results: In newborn blood, sex was associated at Bonferroni level significance with differences in DNA methylation at 46,979 autosomal CpG sites (p < 1.3 × 10−7) after adjusting for white blood cell proportions and batch. Most of those sites had lower methylation levels in males than in females. Of the differentially methylated CpG sites identified in newborn blood, 68% (31,727) met look-up level significance (p < 1.1 × 10−6) in older children and had methylation differences in the same direction. Conclusions: This is a large-scale meta-analysis examining sex differences in DNA methylation in newborns and older children. Expanding upon previous studies, we replicated previous findings and identified additional autosomal sites with sex-specific differences in DNA methylation. Differentially methylated sites were enriched in genes involved in cancer, psychiatric disorders, and cardiovascular phenotypes.Peer reviewe

Maternal iodine status, intrauterine growth, birth outcomes and congenital anomalies in a UK birth cohort

Abstract: Background: Severe iodine insufficiency in pregnancy has significant consequences, but there is inadequate evidence to indicate what constitutes mild or moderate insufficiency, in terms of observed detrimental effects on pregnancy or birth outcomes. A limited number of studies have examined iodine status and birth outcomes, finding inconsistent evidence for specific outcomes. Methods: Maternal iodine status was estimated from spot urine samples collected at 26–28 weeks’ gestation from 6971 mothers in the Born in Bradford birth cohort. Associations with outcomes were examined for both urinary iodine concentration (UIC) and iodine-to-creatinine ratio (I:Cr). Outcomes assessed included customised birthweight (primary outcome), birthweight, small for gestational age (SGA), low birthweight, head circumference and APGAR score. Results: There was a small positive association between I:Cr and birthweight in adjusted analyses. For a typical participant, the predicted birthweight centile at the 25th percentile of I:Cr (59 μg/g) was 2.7 percentage points lower than that at the 75th percentile of I:Cr (121 μg/g) (99% confidence interval (CI) 0.8 to 4.6), birthweight was predicted to be 41 g lower (99% CI 13 to 69) and the predicted probability of SGA was 1.9 percentage points higher (99% CI 0.0 to 3.7). There was no evidence of associations using UIC or other birth outcomes, including stillbirth, preterm birth, ultrasound growth measures or congenital anomalies. Conclusion: Lower maternal iodine status was associated with lower birthweight and greater probability of SGA. Whilst small, the effect size for lower iodine on birthweight is comparable to environmental tobacco smoke exposure. Iodine insufficiency is avoidable, and strategies to avoid deficiency in women of reproductive age should be considered. Trial registration: ClinicalTrials.gov NCT03552341. Registered on June 11, 2018