Longitudinal study of the effect of a 5-year exercise intervention on structural brain complexity in older adults. A Generation 100 substudy

Physical inactivity has been identified as an important risk factor for dementia. High levels of cardiorespiratory fitness (CRF) have been shown to reduce the risk of dementia. However, the mechanism by which exercise affects brain health is still debated. Fractal dimension (FD) is an index that quantifies the structural complexity of the brain. The purpose of this study was to investigate the effects of a 5-year exercise intervention on the structural complexity of the brain, measured through the FD, in a subset of 105 healthy older adults participating in the randomized controlled trial Generation 100 Study. The subjects were randomized into control, moderate intensity continuous training, and high intensity interval training groups. Both brain MRI and CRF were acquired at baseline and at 1-, 3- and 5-years follow-ups. Cortical thickness and volume data were extracted with FreeSurfer, and FD of the cortical lobes, cerebral and cerebellar gray and white matter were computed. CRF was measured as peak oxygen uptake (VO2peak) using ergospirometry during graded maximal exercise testing. Linear mixed models were used to investigate exercise group differences and possible CRF effects on the brain's structural complexity. Associations between change over time in CRF and FD were performed if there was a significant association between CRF and FD. There were no effects of group membership on the structural complexity. However, we found a positive association between CRF and the cerebral gray matter FD (p < 0.001) and the temporal lobe gray matter FD (p < 0.001). This effect was not present for cortical thickness, suggesting that FD is a more sensitive index of structural changes. The change over time in CRF was associated with the change in temporal lobe gray matter FD from baseline to 5-year follow-up (p < 0.05). No association of the change was found between CRF and cerebral gray matter FD. These results demonstrated that entering old age with high and preserved CRF levels protected against loss of structural complexity in areas sensitive to aging and age-related pathology

Separating parental and treatment contributions to perinatal health after fresh and frozen embryo transfer in assisted reproduction : A cohort study with within-sibship analysis

Background Compared to naturally conceived children, adverse perinatal outcomes are more common among children born after assisted reproductive technology with fresh embryo transfer (fresh-ET) or frozen embryo transfer (frozen-ET). However, most previous studies could not adequately control for family confounding factors such as subfertility. We compared birth size and duration of pregnancy among infants born after fresh-ET or frozen-ET versus natural conception, using a within-sibship design to account for confounding by maternal factors. Methods and findings This registry-based cohort study with nationwide data from Denmark (1994-2014), Norway (1988-2015), and Sweden (1988-2015) consisted of 4,510,790 live-born singletons, 4,414,703 from natural conception, 78,095 from fresh-ET, and 17,990 from frozen-ET. We identified 33,056 offspring sibling groups with the same mother, conceived by at least 2 different conception methods. Outcomes were mean birthweight, small and large for gestational age, mean gestational age, preterm (= 37), and very preterm birth (= 32). Singletons born after fresh-ET had lower mean birthweight (- 51 g, 95% CI - 58 to - 45, p < 0.001) and increased odds of small for gestational age (odds ratio [OR] 1.20, 95% CI 1.08 to 1.34, p < 0.001), while those born after frozen-ET had higher mean birthweight (82 g, 95% CI 70 to 94, p < 0.001) and increased odds of large for gestational age (OR 1.84, 95% CI 1.56 to 2.17, p < 0.001), compared to naturally conceived siblings. Conventional population analyses gave similar results. Compared to naturally conceived siblings, mean gestational age was lower after fresh-ET (-1.0 days, 95% CI - 1.2 to -0.8AU : Here; andinTable2; in 1:0days; 95%CI 1:2to 0:84; Ichanged 0:84to, p < 0.001), but not after frozen-ET (0.3 days, 95% CI 0.0 to 0.6, p = 0.028). There: were; so that related values are all given to the same decimal place: were increased odds of preterm birth after fresh-ET (OR 1.27, 95% CI 1.17 to 1.37, p < 0.001), and in most models after frozen-ET, versus naturally conceived siblings, with somewhat stronger associations in population analyses. For very preterm birth, population analyses showed increased odds for both fresh-ET (OR 2.03, 95% CI 1.90 to 2.12, p < 0.001) and frozen-ET (OR 1.66, 95% CI 1.42 to 1.94, p < 0.001) compared with natural conception, but results were notably attenuated within siblings (OR 1.18, 95% CI 1.0 to 1.41, p = 0.059, and OR 0.92, 95% CI 0.67 to 1.27, p = 0.6, for fresh-ET and frozen-ET, respectively). Sensitivity analyses in full siblings, in siblings born within 3-year interval, by birth order, and restricting to single embryo transfers and blastocyst transfers were consistent with the main analyses. Main limitations were high proportions of missing data on maternal body mass index and smoking. Conclusions We found that infants conceived by fresh-ET had lower birthweight and increased odds of small for gestational age, and those conceived by frozen-ET had higher birthweight and increased odds of large for gestational age. Conception by either fresh-ET or frozen-ET was associated with increased odds of preterm birth. That these findings were observed within siblings, as well as in conventional multivariable population analyses, reduces the likelihood that they are explained by confounding or selection bias.Peer reviewe

A prospective cohort study comparing the reactogenicity of trivalent influenza vaccine in pregnant and non-pregnant women

Background: Influenza vaccination during pregnancy can prevent serious illness in expectant mothers and provide protection to newborns; however, historically uptake has been limited due to a number of factors, including safety concerns. Symptomatic complaints are common during pregnancy and may be mistakenly associated with reactions to trivalent influenza vaccine (TIV). To investigate this, we compared post-vaccination events self-reported by pregnant women to events reported by non-pregnant women receiving TIV. Methods: A prospective cohort of 1,086 pregnant women and 314 non-pregnant female healthcare workers (HCWs) who received TIV between March-May 2014 were followed-up seven days post-vaccination to assess local and systemic adverse events following immunisation (AEFIs). Women were surveyed by text message regarding perceived reactions to TIV. Those reporting an AEFI completed an interview by telephone or mobile phone to ascertain details. Logistic regression models adjusting for age and residence were used to compare reactions reported by pregnant women and non-pregnant HCWs. Results: Similar proportions of pregnant women and non-pregnant, female HCWs reported ≥1 reaction following vaccination with TIV (13.0% and 17.3%, respectively; OR = 1.2 [95% CI: 0.8-1.8]). Non-pregnant, female HCWs were more likely to report fever or headache compared to pregnant women (OR: 4.6 [95% CI 2.1-10.3] and OR: 2.2 [95% CI 1.0-4.6], respectively). No other significant differences in reported symptoms were observed. No serious vaccine-associated adverse events were reported, and less than 2% of each group sought medical advice for a reaction. Conclusions: We found no evidence suggesting pregnant women are more likely to report adverse events following influenza vaccination when compared to non-pregnant female HCWs of similar age, and in some cases, pregnant women reported significantly fewer adverse events. These results further support the safety of TIV administered in pregnant women

Investigating causal relations between sleep duration and risks of adverse pregnancy and perinatal outcomes:linear and nonlinear Mendelian randomization analyses

BACKGROUND: Observational studies have reported maternal short/long sleep duration to be associated with adverse pregnancy and perinatal outcomes. However, it remains unclear whether there are nonlinear causal effects. Our aim was to use Mendelian randomization (MR) and multivariable regression to examine nonlinear effects of sleep duration on stillbirth (MR only), miscarriage (MR only), gestational diabetes, hypertensive disorders of pregnancy, perinatal depression, preterm birth and low/high offspring birthweight. METHODS: We used data from European women in UK Biobank (N=176,897), FinnGen (N=~123,579), Avon Longitudinal Study of Parents and Children (N=6826), Born in Bradford (N=2940) and Norwegian Mother, Father and Child Cohort Study (MoBa, N=14,584). We used 78 previously identified genetic variants as instruments for sleep duration and investigated its effects using two-sample, and one-sample nonlinear (UK Biobank only), MR. We compared MR findings with multivariable regression in MoBa (N=76,669), where maternal sleep duration was measured at 30 weeks. RESULTS: In UK Biobank, MR provided evidence of nonlinear effects of sleep duration on stillbirth, perinatal depression and low offspring birthweight. Shorter and longer duration increased stillbirth and low offspring birthweight; shorter duration increased perinatal depression. For example, longer sleep duration was related to lower risk of low offspring birthweight (odds ratio 0.79 per 1 h/day (95% confidence interval: 0.67, 0.93)) in the shortest duration group and higher risk (odds ratio 1.40 (95% confidence interval: 1.06, 1.84)) in the longest duration group, suggesting shorter and longer duration increased the risk. These were supported by the lack of evidence of a linear effect of sleep duration on any outcome using two-sample MR. In multivariable regression, risks of all outcomes were higher in the women reporting <5 and ≥10 h/day sleep compared with the reference category of 8–9 h/day, despite some wide confidence intervals. Nonlinear models fitted the data better than linear models for most outcomes (likelihood ratio P-value=0.02 to 3.2×10(−52)), except for gestational diabetes. CONCLUSIONS: Our results show shorter and longer sleep duration potentially causing higher risks of stillbirth, perinatal depression and low offspring birthweight. Larger studies with more cases are needed to detect potential nonlinear effects on hypertensive disorders of pregnancy, preterm birth and high offspring birthweight. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12916-022-02494-y

Household Tobacco Smoke and Admission Weight Predict Severe Bronchiolitis in Infants Independent of Deprivation: Prospective Cohort Study

To examine demographic, environmental and clinical factors associated with severe bronchiolitis in infants admitted to hospital and quantify the independent effects of these factors

Long-term cardiometabolic health in people born after assisted reproductive technology: a multi-cohort analysis

Aims To examine associations of assisted reproductive technology (ART) conception (vs. natural conception: NC) with offspring cardiometabolic health outcomes and whether these differ with age. Methods and results Differences in systolic (SBP) and diastolic blood pressure (DBP), heart rate (HR), lipids, and hyperglycaemic/insulin resistance markers were examined using multiple linear regression models in 14 population-based birth cohorts in Europe, Australia, and Singapore, and results were combined using meta-analysis. Change in cardiometabolic outcomes from 2 to 26 years was examined using trajectory modelling of four cohorts with repeated measures. 35 938 (654 ART) offspring were included in the meta-analysis. Mean age ranged from 13 months to 27.4 years but was <10 years in 11/14 cohorts. Meta-analysis found no statistical difference (ART minus NC) in SBP (-0.53 mmHg; 95% CI:-1.59 to 0.53), DBP (-0.24 mmHg; -0.83 to 0.35), or HR (0.02 beat/min; -0.91 to 0.94). Total cholesterol (2.59%; 0.10-5.07), HDL cholesterol (4.16%; 2.52-5.81), LDL cholesterol (4.95%; 0.47-9.43) were statistically significantly higher in ART-conceived vs. NC offspring. No statistical difference was seen for triglycerides (TG), glucose, insulin, and glycated haemoglobin. Long-term follow-up of 17 244 (244 ART) births identified statistically significant associations between ART and lower predicted SBP/DBP in childhood, and subtle trajectories to higher SBP and TG in young adulthood; however, most differences were not statistically significant. Conclusion These findings of small and statistically non-significant differences in offspring cardiometabolic outcomes should reassure people receiving ART. Longer-term follow-up is warranted to investigate changes over adulthood in the risks of hypertension, dyslipidaemia, and preclinical and clinical cardiovascular disease.Acknowledgements We thank all cohort members and researchers who participated in the study. Cohort-specific acknowledgments can be found in Supplementary material online, Text S2. Data used in this study are available to bone fide researchers upon request to each cohort. Details of how to access the data are provided in Supplementary material online, Text S2. Please contact Professor Deborah Lawlor ([email protected]) and Dr Ahmed Elhakeem ([email protected]) if you have relevant data and would like to join the ART-Health Cohort Collaboration and contribute to future collaborations

Hypertensive Disorders of Pregnancy and DNA Methylation in Newborns Findings From the Pregnancy and Childhood Epigenetics Consortium

Hypertensive disorders of pregnancy (HDP) are associated with low birth weight, shorter gestational age, and increased risk of maternal and offspring cardiovascular diseases later in life. The mechanisms involved are poorly understood, but epigenetic regulation of gene expression may play a part. We performed meta-analyses in the Pregnancy and Childhood Epigenetics Consortium to test the association between either maternal HDP (10 cohorts; n=5242 [cases=476]) or preeclampsia (3 cohorts; n=2219 [cases=135]) and epigenome-wide DNA methylation in cord blood using the Illumina HumanMethylation450 BeadChip. In models adjusted for confounders, and with Bonferroni correction, HDP and preeclampsia were associated with DNA methylation at 43 and 26 CpG sites, respectively. HDP was associated with higher methylation at 27 (63%) of the 43 sites, and across all 43 sites, the mean absolute difference in methylation was between 0.6% and 2.6%. Epigenome-wide associations of HDP with offspring DNA methylation were modestly consistent with the equivalent epigenome-wide associations of preeclampsia with offspring DNA methylation (R-2=0.26). In longitudinal analyses conducted in 1 study (n=108 HDP cases; 550 controls), there were similar changes in DNA methylation in offspring of those with and without HDP up to adolescence. Pathway analysis suggested that genes located at/near HDP-associated sites may be involved in developmental, embryogenesis, or neurological pathways. HDP is associated with offspring DNA methylation with potential relevance to development.Peer reviewe

Purinergic Receptor Stimulation Reduces Cytotoxic Edema and Brain Infarcts in Mouse Induced by Photothrombosis by Energizing Glial Mitochondria

Treatments to improve the neurological outcome of edema and cerebral ischemic stroke are severely limited. Here, we present the first in vivo single cell images of cortical mouse astrocytes documenting the impact of single vessel photothrombosis on cytotoxic edema and cerebral infarcts. The volume of astrocytes expressing green fluorescent protein (GFP) increased by over 600% within 3 hours of ischemia. The subsequent growth of cerebral infarcts was easily followed as the loss of GFP fluorescence as astrocytes lysed. Cytotoxic edema and the magnitude of ischemic lesions were significantly reduced by treatment with the purinergic ligand 2-methylthioladenosine 5′ diphosphate (2-MeSADP), an agonist with high specificity for the purinergic receptor type 1 isoform (P2Y1R). At 24 hours, cytotoxic edema in astrocytes was still apparent at the penumbra and preceded the cell lysis that defined the infarct. Delayed 2MeSADP treatment, 24 hours after the initial thrombosis, also significantly reduced cytotoxic edema and the continued growth of the brain infarction. Pharmacological and genetic evidence are presented indicating that 2MeSADP protection is mediated by enhanced astrocyte mitochondrial metabolism via increased inositol trisphosphate (IP3)-dependent Ca2+ release. We suggest that mitochondria play a critical role in astrocyte energy metabolism in the penumbra of ischemic lesions, where low ATP levels are widely accepted to be responsible for cytotoxic edema. Enhancement of this energy source could have similar protective benefits for a wide range of brain injuries