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Incidence Rates of Autoimmune Diseases in European Healthcare Databases: A Contribution of the ADVANCE Project
Get PDFIntroduction: The public–private ADVANCE collaboration developed and tested a system to generate evidence on vaccine benefits and risks using European electronic healthcare databases. In the safety of vaccines, background incidence rates are key to allow proper monitoring and assessment. The goals of this study were to compute age-, sex-, and calendar-year stratified incidence rates of nine autoimmune diseases in seven European healthcare databases from four countries and to assess validity by comparing with published data. Methods: Event rates were calculated for the following outcomes: acute disseminated encephalomyelitis, Bell’s palsy, Guillain–Barré syndrome, immune thrombocytopenia purpura, Kawasaki disease, optic neuritis, narcolepsy, systemic lupus erythematosus, and transverse myelitis. Cases were identified by diagnosis codes. Participating organizations/databases originated from Denmark, Italy, Spain, and the UK. The source population comprised all persons registered, with at least 1 year of data prior to the study start, or follow-up from birth. Stratified incidence rates were computed per database over the period 2003 to 2014. Results: Between 2003 and 2014, 148,947 incident cases of nine autoimmune diseases were identified. Crude incidence rates were highest for Bell’s palsy [23.8/100,000 person-years (PYs), 95% confidence interval (CI) 23.6–24.1] and lowest for Kawasaki disease (0.7/100,000 PYs, 95% CI 0.6–0.7). Specific patterns were observed by sex, age, calendar time, and data sources. Rates were comparable with published estimates. Conclusion: A range of autoimmune events could be identified in the ADVANCE system. Estimation of rates indicated consistency across selected European healthcare databases, as well as consistency with US published data
Associations of maternal dietary inflammatory potential and quality with offspring birth outcomes: An individual participant data pooled analysis of 7 European cohorts in the ALPHABET consortium
Get PDFBACKGROUND: Adverse birth outcomes are major causes of morbidity and mortality during childhood and associate with a higher risk of noncommunicable diseases in adult life. Maternal periconception and antenatal nutrition, mostly focusing on single nutrients or foods, has been shown to influence infant birth outcomes. However, evidence on whole diet that considers complex nutrient and food interaction is rare and conflicting. We aim to elucidate the influence of whole-diet maternal dietary inflammatory potential and quality during periconceptional and antenatal periods on birth outcomes. METHODS AND FINDINGS: We harmonized and pooled individual participant data (IPD) from up to 24,861 mother-child pairs in 7 European mother-offspring cohorts [cohort name, country (recruitment dates): ALSPAC, UK (1 April 1991 to 31 December 1992); EDEN, France (27 January 2003 to 6 March 2006); Generation R, the Netherlands (1 April 2002 to 31 January 2006); Lifeways, Ireland (2 October 2001 to 4 April 2003); REPRO_PL, Poland (18 September 2007 to 16 December 2011); ROLO, Ireland (1 January 2007 to 1 January 2011); SWS, United Kingdom (6 April 1998 to 17 December 2002)]. Maternal diets were assessed preconceptionally (n = 2 cohorts) and antenatally (n = 7 cohorts). Maternal dietary inflammatory potential and quality were ranked using the energy-adjusted Dietary Inflammatory Index (E-DII) and Dietary Approaches to Stop Hypertension (DASH) index, respectively. Primary outcomes were birth weight and gestational age at birth. Adverse birth outcomes, i.e., low birth weight (LBW), macrosomia, small-for-gestational-age (SGA), large-for-gestational-age (LGA), preterm and postterm births were defined according to standard clinical cutoffs. Associations of maternal E-DII and DASH scores with infant birth outcomes were assessed using cohort-specific multivariable regression analyses (adjusted for confounders including maternal education, ethnicity, prepregnancy body mass index (BMI), maternal height, parity, cigarettes smoking, and alcohol consumption), with subsequent random-effects meta-analyses. Overall, the study mothers had a mean ± SD age of 29.5 ± 4.9 y at delivery and a mean BMI of 23.3 ± 4.2 kg/m2. Higher pregnancy DASH score (higher dietary quality) was associated with higher birth weight [β(95% CI) = 18.5(5.7, 31.3) g per 1-SD higher DASH score; P value = 0.005] and head circumference [0.03(0.01, 0.06) cm; P value = 0.004], longer birth length [0.05(0.01, 0.10) cm; P value = 0.010], and lower risk of delivering LBW [odds ratio (OR) (95% CI) = 0.89(0.82, 0.95); P value = 0.001] and SGA [0.87(0.82, 0.94); P value < 0.001] infants. Higher maternal prepregnancy E-DII score (more pro-inflammatory diet) was associated with lower birth weight [β(95% CI) = -18.7(-34.8, -2.6) g per 1-SD higher E-DII score; P value = 0.023] and shorter birth length [-0.07(-0.14, -0.01) cm; P value = 0.031], whereas higher pregnancy E-DII score was associated with a shorter birth length [-0.06(-0.10, -0.01) cm; P value = 0.026] and higher risk of SGA [OR(95% CI) = 1.18(1.11, 1.26); P value < 0.001]. In male, but not female, infants higher maternal prepregnancy E-DII was associated with lower birth weight and head circumference, shorter birth length, and higher risk of SGA (P-for-sex-interaction = 0.029, 0.059, 0.104, and 0.075, respectively). No consistent associations were observed for maternal E-DII and DASH scores with gestational age, preterm and postterm birth, or macrosomia and LGA. Limitations of this study were that self-reported dietary data might have increased nondifferential measurement error and that causality cannot be claimed definitely with observational design. CONCLUSIONS: In this cohort study, we observed that maternal diet that is of low quality and high inflammatory potential is associated with lower offspring birth size and higher risk of offspring being born SGA in this multicenter meta-analysis using harmonized IPD. Improving overall maternal dietary pattern based on predefined criteria may optimize fetal growth and avert substantial healthcare burden associated with adverse birth outcomes
Shielding SNS content from parents: a survey investigating perspectives of emerging adults who have recently left the parental home
Get PDFEmerging adults are increasingly “unfriending” their parents on Social Networking Sites (SNS). A survey among 300 emerging adults who recently moved out of the parental home investigated whether family communication patterns were related to shielding of SNS content from parents and whether perceived undesirability of privacy invasion mediated this relation. Structural equation modeling analyses showed that emerging adults from high conformity-oriented families reported higher perceived undesirability of privacy invasion, which related to higher shielding of SNS content. In contrast, emerging adults from high conversation-oriented families reported lower perceived undesirability of privacy invasion, which related to lower shielding of SNS content
Exploring label dynamics of velocity-selective arterial spin labeling in the kidney
Get PDFPurpose: Velocity-selective arterial spin labeling (VSASL) has been proposed for renal perfusion imaging to mitigate planning challenges and effects of arterial transit time (ATT) uncertainties. In VSASL, label generation may shift in the vascular tree as a function of cutoff velocity. Here, we investigate label dynamics and especially the ATT of renal VSASL and compared it with a spatially selective pulsed arterial spin labeling technique, flow alternating inversion recovery (FAIR). Methods: Arterial spin labeling data were acquired in 7 subjects, using free-breathing dual VSASL and FAIR with five postlabeling delays: 400, 800, 1200, 2000, and 2600 ms. The VSASL measurements were acquired with cutoff velocities of 5, 10, and 15 cm/s, with anterior–posterior velocity-encoding direction. Cortical perfusion-weighted signal, temporal SNR, quantified renal blood flow, and arterial transit time were reported. Results: In contrast to FAIR, renal VSASL already showed fairly high signal at the earliest postlabeling delays, for all cutoff velocities. The highest VSASL signal and temporal SNR was obtained with a cutoff velocity of 10 cm/s at postlabeling delay = 800 ms, which was earlier than for FAIR at 1200 ms. Fitted ATT on VSASL was ≤ 0 ms, indicating ATT insensitivity, which was shorter than for FAIR (189 ± 79 ms, P .05) with good correlations on subject level. Conclusion: Velocity-selective arterial spin labeling in the kidney reduces ATT sensitivity compared with the recommended pulsed arterial spin labeling method, as well as if cutoff velocity is increased to reduce spurious labeling due to motion. Thus, VSASL has potential as a method for time-efficient, single-time-point, free-breathing renal perfusion measurements, despite lower tSNR than FAIR
G3BPs tether the TSC complex to lysosomes and suppress mTORC1 signaling
Get PDFDistinct from their contributions to stress granules, G3BPs regulate mTORC1 activity through spatial control of the TSC complex.Ras GTPase-activating protein-binding proteins 1 and 2 (G3BP1 and G3BP2, respectively) are widely recognized as core components of stress granules (SGs). We report that G3BPs reside at the cytoplasmic surface of lysosomes. They act in a non-redundant manner to anchor the tuberous sclerosis complex (TSC) protein complex to lysosomes and suppress activation of the metabolic master regulator mechanistic target of rapamycin complex 1 (mTORC1) by amino acids and insulin. Like the TSC complex, G3BP1 deficiency elicits phenotypes related to mTORC1 hyperactivity. In the context of tumors, low G3BP1 levels enhance mTORC1-driven breast cancer cell motility and correlate with adverse outcomes in patients. Furthermore, G3bp1 inhibition in zebrafish disturbs neuronal development and function, leading to white matter heterotopia and neuronal hyperactivity. Thus, G3BPs are not only core components of SGs but also a key element of lysosomal TSC-mTORC1 signaling
Variation in the SERPINA6/SERPINA1 locus alters morning plasma cortisol, hepatic corticosteroid binding globulin expression, gene expression in peripheral tissues, and risk of cardiovascular disease
Get PDFThe stress hormone cortisol modulates fuel metabolism, cardiovascular homoeostasis, mood, inflammation and cognition. The CORtisol NETwork (CORNET) consortium previously identified a single locus associated with morning plasma cortisol. Identifying additional genetic variants that explain more of the variance in cortisol could provide new insights into cortisol biology and provide statistical power to test the causative role of cortisol in common diseases. The CORNET consortium extended its genome-wide association meta-analysis for morning plasma cortisol from 12,597 to 25,314 subjects and from ~2.2 M to ~7 M SNPs, in 17 population-based cohorts of European ancestries. We confirmed the genetic association with SERPINA6/SERPINA1. This locus contains genes encoding corticosteroid binding globulin (CBG) and α1-antitrypsin. Expression quantitative trait loci (eQTL) analyses undertaken in the STARNET cohort of 600 individuals showed that specific genetic variants within the SERPINA6/SERPINA1 locus influence expression of SERPINA6 rather than SERPINA1 in the liver. Moreover, trans-eQTL analysis demonstrated effects on adipose tissue gene expression, suggesting that variations in CBG levels have an effect on delivery of cortisol to peripheral tissues. Two-sample Mendelian randomisation analyses provided evidence that each genetically-determined standard deviation (SD) increase in morning plasma cortisol was associated with increased odds of chronic ischaemic heart disease (0.32, 95% CI 0.06–0.59) and myocardial infarction (0.21, 95% CI 0.00–0.43) in UK Biobank and similarly in CARDIoGRAMplusC4D. These findings reveal a causative pathway for CBG in determining cortisol action in peripheral tissues and thereby contributing to the aetiology of cardiovascular disease
Comprehensive study of 28 individuals with SIN3A-related disorder underscoring the associated mild cognitive and distinctive facial phenotype
Get PDFWitteveen-Kolk syndrome (OMIM 613406) is a recently defined neurodevelopmental syndrome caused by heterozygous loss-of-function variants in SIN3A. We define the clinical and neurodevelopmental phenotypes related to SIN3A-haploinsufficiency in 28 unreported patients. Patients with SIN3A variants adversely affecting protein function have mild intellectual disability, growth and feeding difficulties. Involvement of a multidisciplinary team including a geneticist, paediatrician and neurologist should be considered in managing these patients. Patients described here were identified through a combination of clinical evaluation and gene matching strategies (GeneMatcher and Decipher). All patients consented to participate in this study. Mean age of this cohort was 8.2 years (17 males, 11 females). Out of 16 patients ≥ 8 years old assessed, eight (50%) had mild intellectual disability (ID), four had moderate ID (22%), and one had severe ID (6%). Four (25%) did not have any cognitive impairment. Other neurological symptoms such as seizures (4/28) and hypotonia (12/28) were common. Behaviour problems were reported in a minority. In patients ≥2 years, three were diagnosed with Autism Spectrum Disorder (ASD) and four with Attention Deficit Hyperactivity Disorder (ADHD). We report 27 novel variants and one previously reported variant. 24 were truncating variants; three were missense variants and one large in-frame gain including exons 10–12
The use of lower or higher than recommended doses of folic acid supplements during pregnancy is associated with child attentional dysfunction at 4–5 years of age in the inma project
Get PDFWe assessed the association between the use of lower-and higher-than-recommended doses of folic acid supplements (FAs) during pregnancy and attentional function in boys and girls at age of 4–5. We analyzed data from 1329 mother-child pairs from the mother-child cohort INfancia y Medio Ambiente Project (INMA) study. Information on FAs use during pregnancy was collected in personal interviews at weeks 12 and 30, and categorized in <400, 400–999 (recommended dose), and ≥1000 µg/day. Child attentional function was assessed by Conners’ Kiddie Continuous Performance Test. Multivariable regression analyses were used to estimate incidence rate ratios (IRR) and beta coefficients with 95% confidence intervals (CI). Compared to recommended FAs doses, the periconceptional use of <400 and ≥1000 µg/day was associated with higher risk of omission errors—IRR = 1.14 (95% CI: 1.01; 1.29) and IRR = 1.16 (95% CI: 1.02; 1.33), respectively. The use of FAs < 400 µg/day and ≥1000 µg/day was significantly associated with deficits of attentional function only in boys. FAs use < 400 µg/day was associated with higher omission errors with IRR = 1.22 and increased hit reaction time (HRT) β = 34.36, and FAs use ≥ 1000 µg/day was associated with increased HRT β = 33.18 and HRT standard error β = 3.31. The periconceptional use of FAs below or above the recommended doses is associated with deficits of attentional function in children at age of 4–5, particularly in boys
Longitudinal Patterns of Ethical Organisational Culture as a Context for Leaders’ Well-Being: Cumulative Effects Over 6 Years
Get PDFThe aim of this longitudinal study was to investigate the temporal dynamics of ethical organisational culture and how it associates with well-being at work when potential changes in ethical culture are measured over an extended period of 6 years. We used a person-centred study design, which allowed us to detect both typical and atypical patterns of ethical culture stability as well as change among a sample of leaders. Based on latent profile analysis and hierarchical linear modelling we found longitudinal, concurrent relations and cumulative gain and loss cycles between different ethical culture patterns and leaders’ well-being. Leaders in the strongest ethical culture pattern experienced the highest level of work engagement and a decreasing level of ethical dilemmas and stress. Leaders who gave the lowest ratings on ethical culture which also decreased over time reported the highest level of ethical dilemmas, stress, and burnout. They also showed a continuous increase in these negative outcomes over time. Thus, ethical culture has significant cumulative effects on well-being, and these longitudinal effects can be both negative and positive, depending on the experienced strength of the culture’s ethicality
Greening monetary policy
Get PDFWhile there is increasing interest in decarbonizing or greening monetary policy, central banks are keen to maintain market neutrality. However, there is evidence that the market has a bias towards carbon-intensive companies. The paper develops a method to tilt the European Central Bank’s (ECB) asset and collateral framework towards low-carbon assets. We find that a medium tilting approach reduces carbon emissions in the ECB’s corporate and bank bond portfolio by over 50%. We show that a low carbon allocation can be done without undue interference with the transmission mechanism of monetary policy. Key policy insights The ECB’s asset and collateral portfolio for monetary policy operations is overweight in high carbon companies. A medium tilting approach towards low-carbon companies reduces carbon emissions by 55% in the ECB's portfolio. It also reduces the cost of capital for low carbon companies. This is an incentive for high carbon companies to reform and adopt low carbon technologies