Preoperative fasting in children. The evolution of recommendations and guidelines, and the underlying evidence.

This review discusses the evolution of preoperative fasting guidelines and examines the incidence of pulmonary aspiration of gastric contents and suggested treatments. Nine guidelines developed by professional societies and published in peer-reviewed journals since 1994 were identified. The recommendations on preoperative fasting for various categories have undergone only small adaptations in the following three decades in pediatric anesthesia. We found twelve published studies of the incidence of pulmonary aspiration, which ranges from 0.6 to 12 in 10,000 anesthetics in children. However, this variation reflects differences in the definition of aspiration as well as differences in study design. The main risk factors identified are emergency surgery, ASA physical status, and patient age. Several additional risk factors have been suggested, including non-compliance to fasting guidelines. The duration of clear fluid fasting is not associated with an increased risk of pulmonary aspiration which may be reflected in future guideline updates in pediatric anesthesia.

A systematic catalog of studies on fetal heart rate pattern and neonatal outcome variables.

OBJECTIVES: To study the methodology and results of studies assessing the relationship between fetal heart rate and specified neonatal outcomes including, heart rate, infection, necrotizing enterocolitis, intraventricular hemorrhage, hypoxic-ischemic encephalopathy, and seizure. METHODS: Embase, Medline ALL, Web of Science Core Collection, Cochrane Central Register of Controlled Trials, and CINAHL were searched from inception to October 5, 2023. RESULTS: Forty-two studies were included, encompassing 57,232 cases that underwent fetal monitoring and were evaluated for neonatal outcome. Heterogeneity was observed in the timing and duration of fetal heart rate assessment, classification guidelines used, number of assessors, and definition and timing of neonatal outcome assessment. Nonreassuring fetal heart rate was linked to lower neonatal heart rate variability. A significant increase in abnormal fetal heart rate patterns were reported in neonates with hypoxic-ischemic encephalopathy, but the predictive ability was found to be limited. Conflicting results were reported regarding sepsis, seizure and intraventricular hemorrhage. No association was found between necrotizing enterocolitis rate and fetal heart rate. CONCLUSIONS: There is great heterogeneity in the methodology used in studies evaluating the association between fetal heart rate and aforementioned neonatal outcomes. Hypoxic-ischemic encephalopathy was associated with increased abnormal fetal heart rate patterns, although the predictive ability was low. Further research on developing and evaluating an automated early warning system that integrates computerized cardiotocography with a perinatal health parameter database to provide objective alerts for patients at-risk is recommended.

Temporal trends in concordance between ICD-coded and cardiac biomarker-classified hospitalisation rates for acute coronary syndromes: a linked hospital and biomarker data study.

BACKGROUND: Since 2000, the definition of myocardial infarction (MI) has evolved with reliance on cardiac troponin (cTn) tests. The implications of this change on trends of acute coronary syndrome (ACS) subtypes obtained from routinely collected hospital morbidity data are unclear. Using person-linked hospitalisation data, we compared International Classification of Diseases (ICD)-coded data with biomarker-classified admission rates for ST-segment elevation MI (STEMI), non-STEMI (NSTEMI) and unstable angina (UA) in Western Australia (WA). METHODS: We used linked hospitalisation data from all WA tertiary hospitals to identify patients with a principal diagnosis of STEMI, NSTEMI or UA between 2002 and 2016. Linked biomarker results were classified as 'diagnostic' for MI according to established criteria. We calculated age-standardised and sex-standardised rates (ASSRs) for ICD-coded versus biomarker-classified admissions by ACS subtypes and estimated annual change in admissions using Poisson regression adjusting for age and sex. RESULTS: There were 37 272 ACS admissions in 30 683 patients (64.2% male), and 96% of cases had linked biomarker data, predominantly conventional cTn at the start and high-sensitive cTn from late 2013. Despite lower ASSRs, trends in MI classified with a diagnostic biomarker were concordant with ICD-coded admissions rates for both STEMI and NSTEMI. Between 2002 and 2010, STEMI rates declined by 4.1% (95% CI 5.0%, 3.1%) and 3.4% (95% CI 4.6%, 2.3%) in ICD-coded and biomarker-classified admissions, respectively, and both plateaued thereafter. For NSTEMI between 2002 and 2010, the ICD-coded and biomarker-classified rates increased 8.0% per year (95% CI 7.2%, 8.9%) and 8.0% (95% CI 7.0%, 9.0%), respectively, and both subsequently declined. For UA, both ICD-coded and biomarker-classified UA admission rates declined in a steady and concordant manner between 2002 and 2016. CONCLUSIONS: The present study supports the validity of using administrative data to monitor population trends in ACS subtypes as they appear to generally reflect the redefinition of MI in the troponin era.

Bruggeman homogenization of a particulate composite material comprising truncated spheres and spheroids.

Closed-form expressions were established for depolarization dyadics for a truncated sphere and a truncated spheroid, both electrically small, immersed in a uniaxial dielectric ambient medium. These depolarization dyadics were used to develop the Bruggeman homogenization formalism to predict the relative permittivity dyadic of a homogenized composite material (HCM) arising from a randomly distributed mixture of oriented particles shaped as truncated spheres and spheroids. Unlike other homogenization formalisms, most notably the Maxwell Garnett formalism, the Bruggeman formalism is not restricted to composites containing dilute volume fractions of constituent particles. Numerical investigations highlighted the anisotropy of the HCM and its relation to the shapes of its constituent particles and their volume fractions. Specifically, greater degrees of HCM anisotropy arise from constituent particles whose shapes deviate more from spherical, especially for mid-range volume fractions.

Harnessing the Reactivity of Nitroarene Radical Anions to Create Quinoline N-Oxides by Electrochemical Reductive Cyclization.

Electrochemical reduction of 2-allyl-substituted nitroarenes using a simple, undivided electrochemical cell with non-precious electrodes to generate nitroarene radical anions was developed. The nitroarene radical anion intermediates participate in 1,5-hydrogen atom transfer reactions to construct quinoline N-oxides bearing aryl-, heteroaryl-, alkenyl-, benzyl-, sulfonyl-, or carboxyl groups.

The relationships between age, sex and exercise intensity on cerebral artery haemodynamics during isometric handgrip exercise.

Age and sex may alter the cerebral blood flow (CBF) responses to acute isometric exercise, via associated elevations in mean arterial pressure (MAP) and sympathetic activation. Our aim was to determine the relationships between age, sex and exercise intensity on cerebrovascular responses to isometric handgrip exercise. In 78 healthy adults (18-80 years, N=42 female), cerebrovascular responses were assessed during two minute isometric exercise bouts at three intensities (15, 30, 45% maximal voluntary contraction). Intracranial responses of the middle cerebral artery (MCA) and posterior cerebral artery (PCA) velocity (v) were measured using transcranial Doppler ultrasound. Extracranial responses of the internal carotid artery (ICA) and vertebral artery (VA) were assessed using Duplex ultrasound. Cardiopulmonary haemodynamic and neural parameters were measured throughout, including muscle sympathetic nerve activity, end-tidal carbon dioxide, and MAP. There were significant positive relationships between exercise intensity and the cerebral responses of the MCAv (P<0.001) and PCAv (P=0.005). There were no effects of intensity on ICA and VA responses (P>0.05), despite intensity-dependent increases in MAP (P<0.001). The increased MCAv response to exercise was blunted with advancing age (P=0.01) with no influence of sex (P=0.86). The present study provides data on age, sex and intensity specific relationships with intracranial and extracranial cerebrovascular responses to isometric exercise. Despite similar ICA, VA, and PCA responses, MCAv responses were attenuated with advancing age during handgrip exercise with no sex dependent influence. Further, intracranial responses were intensity dependent, whereas extracranial blood flow, shear-stress and velocity responses were similarly increased at all intensities during handgrip exercise.

Middle cerebral artery blood velocity and end-tidal carbon dioxide responses to moderate intensity cycling in children, adolescents, and adults.

This study investigated the middle cerebral artery blood velocity (MCAv) response to constant work-rate moderate-intensity cycling exercise in 21 children (9.3 ± 0.8 yr), 17 adolescents (12.3 ± 0.4 yr), and 20 young adults (23.6 ± 2.4 yr). Participants completed an incremental ramp test to exhaustion on a cycle ergometer to determine maximal oxygen uptake and gas exchange threshold (GET) before completing three 6-min transitions at a moderate intensity (90% GET) on separate visits. On each visit, bilateral MCAv was measured by transcranial Doppler ultrasonography and breath-by-breath end-tidal carbon dioxide ([Formula: see text]) via a metabolic cart. Data were ensemble-averaged for each participant and analyzed using a monoexponential model. Absolute MCAv was significantly higher throughout exercise in children and adolescents compared with adults (P < 0.001). Children had a significantly lower relative increase in MCAv from baseline (∼12%) compared with adolescents (∼20%) and adults (∼18%, P < 0.040). All adolescents and adults had a monoexponential rise in MCAv and [Formula: see text], but this was observed in only eight children. Children and adolescents had a significantly faster MCAv time constant (τ, 12 ± 6 and 14 ± 8 s, respectively) compared with adults (27 ± 9 s, P < 0.001). MCAv τ was positively associated with faster [Formula: see text] τ in adolescents (r = 0.70, P = 0.002) but not in children (r = -0.20, P = 0.640). Time- and amplitude-based response parameters of MCAv kinetics were significantly associated with [Formula: see text] kinetics in adults (r = 0.50-0.74, P ≤ 0.025), but not in children (r = -0.19 to -0.48, P > 0.227). These findings suggest that the transition from childhood to adulthood impacts the MCAv response to exercise and the relationships between [Formula: see text] and MCAv kinetics during exercise.NEW & NOTEWORTHY This is the first study to find that children have smaller increases in Δ%MCAv (∼12%) during moderate-intensity exercise compared with adolescents and adults (∼18%-20%). Furthermore, MCAv kinetics were significantly faster in children and adolescents, compared with adults. MCAv kinetic responses were significantly and positively associated with [Formula: see text] kinetics in adults, but not in children. These novel data also suggest that the regulatory role of [Formula: see text] on MCAv during exercise begins to strengthen during adolescence.

A randomized phase 2b trial examined the effects of the glucagon-like peptide-1 and glucagon receptor agonist cotadutide on kidney outcomes in patients with diabetic kidney disease.

Cotadutide is a glucagon-like peptide-1 (GLP-1) and glucagon receptor agonist that may improve kidney function in patients with type 2 diabetes (T2D) and chronic kidney disease (CKD). In this phase 2b study, patients with T2D and CKD (estimated glomerular filtration rate [eGFR] of 20 or more and under 90 mL/min per 1.73 m2 and urinary albumin-to-creatinine ratio [UACR] over 50 mg/g) were randomized 1:1:1:1:1 to 26 weeks' treatment with standard of care plus subcutaneous cotadutide uptitrated to 100, 300, or 600 µg, or placebo daily (double-blind), or the GLP-1 agonist semaglutide 1 mg once weekly (open-label).The co-primary endpoints were absolute and percentage change versus placebo in UACR from baseline to the end of week 14. Among 248 randomized patients, mean age 67.1 years, 19% were female, mean eGFR was 55.3 mL/min per 1.73 m2, geometric mean was UACR 205.5 mg/g (coefficient of variation 270.0), and 46.8% were receiving concomitant sodium-glucose co-transporter 2 inhibitors. Cotadutide dose-dependently reduced UACR from baseline to the end of week 14, reaching significance at 300 µg (-43.9% [95% confidence interval -54.7 to -30.6]) and 600 µg (-49.9% [-59.3 to -38.4]) versus placebo; with effects sustained at week 26. Serious adverse events were balanced across arms. Safety and tolerability of cotadutide 600 µg were comparable to semaglutide. Thus, our study shows that in patients with T2D and CKD, cotadutide significantly reduced UACR on top of standard of care with an acceptable tolerability profile, suggesting kidney protective benefits that need confirmation in a larger study.

Influence of age and co-medication on dolutegravir glucuronidation in paediatric patients.

Dolutegravir (DTG) is primarily metabolized by uridine diphosphate glucuronosyltransferases, forming the pharmacologically inactive DTG glucuronide (DTG-gluc). We described the dolutegravir metabolic ratio (DTG-MR; DTG-gluc AUC0-24h divided by DTG AUC0-24h) in 85 children with HIV aged 3 months to 18 years receiving DTG in the CHAPAS-4 (ISRCTN22964075) and ODYSSEY (NCT02259127) trials. Additionally, we assessed the influence of age, body weight, nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) backbone, rifampicin use and kidney function on DTG-MR. The overall geometric mean (CV%) DTG-MR was 0.054 (52%). Rifampicin use was the only significant factor associated with DTG-MR (P < .001) in multiple linear regression. DTG-MR geometric mean ratio was 1.81 (95% CI: 1.57-2.08) for children while on vs. off rifampicin. This study showed that overall DTG-MR in children was similar to adults, unaffected by age or NRTI backbone, and increased with rifampicin co-administration. These findings support future paediatric pharmacokinetic modelling and extrapolation from adult data.

Endoscopic Management of Biliary and Pancreatic Pathologies in Roux-en-Y Gastric Bypass Patients: Development of a Treatment Algorithm Based on 9-Year Experience.

BACKGROUND: Management of biliopancreatic pathology in Roux-en-Y gastric bypass (RYGB) patients is challenging despite the availability of multiple approaches like single-balloon enteroscopy-assisted ERCP (SBE-ERCP), laparoscopy-assisted ERCP (LA-ERCP), and EUS-directed transgastric intervention (EDGI). We evaluated the outcomes of the interchangeable combination of endoscopic procedures to treat biliopancreatic pathology in RYGB patients. MATERIALS AND METHODS: This is a monocentric retrospective study of consecutive RYGB patients with biliopancreatic pathology between June 2014 and September 2023. Primary endpoints were technical success, adverse events (AE), and parameters of endoscopic procedures according to etiology. A clinically useful management algorithm was developed. RESULTS: A total of 102 patients with RYGB (73 women; mean age 55 ± 10 years) were included. A total of 113 SBE-ERCP (in 90 patients), 26 EDGI (in 23 patients), and 2 LA-ERCP (in 2 patients) were performed. Technical success of SBE-ERCP was lower compared to EDGI (74.4% vs 95.1%, p = 0.002). The AE rate was lower using SBE-ERCP compared to EDGI (12.4% vs 38.5%, p = 0.003). Two sub-groups based on etiology were identified as "common bile duct stone" (CBDS) and "Other." In the CBDS group, the mean number and time of procedures were lower in SBE-ERCP as the first-line technique compared to first-line EDGI (1.1 vs 2.7, p < 0.00 and 91 ± 20.7 min vs 161 ± 61.3 min, p < 0.00). CONCLUSION: A combination of endoscopic procedures can achieve high technical success in managing biliopancreatic pathology in RYGB patients with an acceptable AE rate. In the case of CBDS, SBE-ERCP appeared to be a good first-line single-step option. For other indications, EDGI should be proposed as the first line.

Germline-targeting HIV vaccination induces neutralizing antibodies to the CD4 binding site.

Eliciting potent and broadly neutralizing antibodies (bnAbs) is a major goal in HIV-1 vaccine development. Here, we describe how germline-targeting immunogen BG505 SOSIP germline trimer 1.1 (GT1.1), generated through structure-based design, engages a diverse range of VRC01-class bnAb precursors. A single immunization with GT1.1 expands CD4 binding site (CD4bs)-specific VRC01-class B cells in knock-in mice and drives VRC01-class maturation. In nonhuman primates (NHPs), GT1.1 primes CD4bs-specific neutralizing serum responses. Selected monoclonal antibodies (mAbs) isolated from GT1.1-immunized NHPs neutralize fully glycosylated BG505 virus. Two mAbs, 12C11 and 21N13, neutralize subsets of diverse heterologous neutralization-resistant viruses. High-resolution structures revealed that 21N13 targets the same conserved residues in the CD4bs as VRC01-class and CH235-class bnAbs despite its low sequence similarity (~40%), whereas mAb 12C11 binds predominantly through its heavy chain complementarity-determining region 3. These preclinical data underpin the ongoing evaluation of GT1.1 in a phase 1 clinical trial in healthy volunteers.

An in situ bioadhesive foam as a large intestinal delivery platform for antibody fragment to treat inflammatory bowel disease.

Biologics have been widely used as injectables in the treatment of inflammatory bowel disease (IBD). Different local treatment attempts have been developed in recent years. However, maintaining systemic levels of biologics is still crucial for achieving colitis remission. An equilibrium between systemic and local concentrations of biologics is therefore essential for treatment of colitis. Current formulations struggle to create optimal balance between drug concentrations in plasma and the colonic wall. Addressing this challenge, we developed a rectally delivered in situ foam that generates CO2via a reaction between potassium bicarbonate (PB) and citric acid (CA) without the aid of an external device. An anti-TNF-α antibody fragment (Fab) was loaded into the foam formulation, which promoted prolonged colon retention and improved Fab distribution up to proximal colon following rectal administration to mice. In addition, we observed increased plasma Fab concentrations in mice receiving the rectal Fab foam compared to a Fab solution. In a non-everted rat gut ex vivo model, a single exposure to the CO2-containing foam improved macromolecule transepithelial flux across colonic tissue by over ten-fold. Foam efficacy for Fab was investigated in a range of colitis mouse models, from acute to chronic. This non-invasive formulation platform demonstrates potential to overcome existing limitations in delivering biologics to inflamed colonic tissue.

Suicide and dementia: A systematic review and meta-analysis of prevalence and risk factors.

Dementia is a global health concern with increasing numbers of people living long enough to develop dementia. People with dementia (PwD) may be particularly vulnerable to suicidality. However, suicide in PwD has not been thoroughly explored. The objective of this review was to determine the prevalence and risk factors of suicide in PwD. Five databases were searched from inception to July 2023. Peer-reviewed publications reporting prevalence, risk factors or quantitative summary data for suicide outcomes in PwD were included. Random effects models were used to calculate the pooled prevalence and effect sizes. 54 studies met inclusion criteria. In PwD, the point prevalence of suicidal ideation was 10 % (95 %CI=6 %;16 %), 2-year period prevalence of suicide attempts was 0.8 % (95 %CI=0.3 %;2 %), 10-year period prevalence of suicide attempts was 8.7 % (95 %CI=6.0 %%;12.7 %) and the incidence of death by suicide 0.1 % (95 %CI=0.1 %;0.2 %). Compared to not having dementia, a diagnosis of dementia increased risk of suicidal ideation (OR=1.62[95 %CI=1.17;2.24]) but not risk of suicide attempt (OR=1.77 [95 %CI=0.85;3.69]) or death by suicide (OR=1.30 [95 %CI=0.81;2.10]). People with moderate dementia had significantly increased risk of suicidal ideation than those with mild dementia (OR=1.59[95 %CI=1.11;2.28]), younger PwD were at increased risk of dying by suicide (OR=2.82[95 %CI=2.16;3.68]) and men with dementia were more likely to attempt (OR=1.28[95 %CI=1.25;1.31]) and die by suicide (OR=2.88[95 %CI=1.54;5.39]) than women with dementia. This review emphasises the need for mental health support and suicide prevention in dementia care, emphasising tailored approaches based on age, symptoms, and being male.

The role of body image dissatisfaction in the relationship between body size and disordered eating and self-harm: complimentary Mendelian randomization and mediation analyses.

Disordered eating and self-harm commonly co-occur in young people suggesting potential for shared underlying causes. Body image dissatisfaction (BID) has been recognised as a psychological correlate of body size, associated with both disordered eating and self-harm. However, the investigation into etiological pathways early in the lifecourse to provide detail on how body size and BID may foster disordered eating and self-harm remains largely unexplored. Employing data from two large population-based cohorts, the UK Biobank and the Avon Longitudinal Study of Parents And Children (ALSPAC), we conducted bidirectional Mendelian randomization (MR) to determine the causal direction of effect between genetically predicted prepubertal body size and two measures of BID indicating (i) desire to be smaller, and (ii) desire to be larger. We then used multivariable regression followed by counterfactual mediation analyses. Bidirectional MR indicated robust evidence that increased genetically predicted prepubertal body size increased desire to be smaller and decreased desire to be larger. Evidence for the reverse causal direction was negligible. These findings remained very similar across sensitivity analyses. In females and males, multivariable regression analyses demonstrated that being overweight increased the risk of disordered eating (risk ratio (RR), 95% confidence interval (CI): 1.19, 1.01 to 1.40 and 1.98, 1.28 to 3.05, respectively) and self-harm (RR, 95% CI: 1.35, 1.04 to 1.77 and 1.55, 0.86 to 2.81, respectively), while being underweight was protective against disordered eating (RR, 95% CI: 0.57, 0.40 to 0.81 and 0.81, 0.38 to 1.73, respectively). There was weak evidence of an increase in the risk of self-harm among underweight individuals. Mediation analyses indicated that the relationship between being overweight and subsequent disordered eating was largely mediated by the desire to be smaller. Our research carries important public health implications, suggesting distinct risk profiles for self-harm and disordered eating in relation to weight and body image. In addition, a better understanding of genetically predicted prepubertal BID may be valuable in the prevention and treatment of disordered eating and self-harm in adolescence.

Exploring pleiotropy in Mendelian randomisation analyses: What are genetic variants associated with 'cigarette smoking initiation' really capturing?

Genetic variants used as instruments for exposures in Mendelian randomisation (MR) analyses may have horizontal pleiotropic effects (i.e., influence outcomes via pathways other than through the exposure), which can undermine the validity of results. We examined the extent of this using smoking behaviours as an example. We first ran a phenome-wide association study in UK Biobank, using a smoking initiation genetic instrument. From the most strongly associated phenotypes, we selected those we considered could either plausibly or not plausibly be caused by smoking. We examined associations between genetic instruments for smoking initiation, smoking heaviness and lifetime smoking and these phenotypes in UK Biobank and the Avon Longitudinal Study of Parents and Children (ALSPAC). We conducted negative control analyses among never smokers, including children. We found evidence that smoking-related genetic instruments were associated with phenotypes not plausibly caused by smoking in UK Biobank and (to a lesser extent) ALSPAC. We observed associations with phenotypes among never smokers. Our results demonstrate that smoking-related genetic risk scores are associated with unexpected phenotypes that are less plausibly downstream of smoking. This may reflect horizontal pleiotropy in these genetic risk scores, and we would encourage researchers to exercise caution this when using these and genetic risk scores for other complex behavioural exposures. We outline approaches that could be taken to consider this and overcome issues caused by potential horizontal pleiotropy, for example, in genetically informed causal inference analyses (e.g., MR) it is important to consider negative control outcomes and triangulation approaches, to avoid arriving at incorrect conclusions.

Cancer EV stimulate endothelial glycolysis to fuel protein synthesis via mTOR and AMPKα activation.

Hypoxia is a common feature of solid tumours and activates adaptation mechanisms in cancer cells that induce therapy resistance and has profound effects on cellular metabolism. As such, hypoxia is an important contributor to cancer progression and is associated with a poor prognosis. Metabolic alterations in cells within the tumour microenvironment support tumour growth via, amongst others, the suppression of immune reactions and the induction of angiogenesis. Recently, extracellular vesicles (EV) have emerged as important mediators of intercellular communication in support of cancer progression. Previously, we demonstrated the pro-angiogenic properties of hypoxic cancer cell derived EV. In this study, we investigate how (hypoxic) cancer cell derived EV mediate their effects. We demonstrate that cancer derived EV regulate cellular metabolism and protein synthesis in acceptor cells through increased activation of mTOR and AMPKα. Using metabolic tracer experiments, we demonstrate that EV stimulate glucose uptake in endothelial cells to fuel amino acid synthesis and stimulate amino acid uptake to increase protein synthesis. Despite alterations in cargo, we show that the effect of cancer derived EV on recipient cells is primarily determined by the EV producing cancer cell type rather than its oxygenation status.

Identifying the Origin of Thermal Modulation of Exchange Bias in MnPS3/Fe3GeTe2 van der Waals Heterostructures.

The exchange bias phenomenon, inherent in exchange-coupled ferromagnetic and antiferromagnetic systems, has intrigued researchers for decades. Van der Waals materials, with their layered structures, offer an ideal platform for exploring exchange bias. However, effectively manipulating exchange bias in van der Waals heterostructures remains challenging. This study investigates the origin of exchange bias in MnPS3/Fe3GeTe2 van der Waals heterostructures, demonstrating a method to modulate nearly 1000% variation in magnitude through simple thermal cycling. Despite the compensated interfacial spin configuration of MnPS3, a substantial 170 mT exchange bias is observed at 5 K, one of the largest observed in van der Waals heterostructures. This significant exchange bias is linked to anomalous weak ferromagnetic ordering in MnPS3 below 40 K. The tunability of exchange bias during thermal cycling is attributed to the amorphization and changes in the van der Waals gap during field cooling. The findings highlight a robust and adjustable exchange bias in van der Waals heterostructures, presenting a straightforward method to enhance other interface-related spintronic phenomena for practical applications. Detailed interface analysis reveals atom migration between layers, forming amorphous regions on either side of the van der Waals gap, emphasizing the importance of precise interface characterization in these heterostructures.

Childhood adiposity underlies numerous adult brain traits commonly attributed to midlife obesity.

Obese adults are often reported to have smaller brain volumes than their non-obese peers. Whether this represents evidence of accelerations in obesity-driven atrophy or is instead a legacy of developmental differences established earlier in the lifespan remains unclear. This study aimed to investigate whether early-life differences in adiposity explain differences in numerous adult brain traits commonly attributed to mid-life obesity. We utilised a two-sample lifecourse Mendelian randomization study in 37,501 adults recruited to UK Biobank (UKB) imaging centers from 2014, with secondary analyses in 6,996 children assessed in the Adolescent Brain Cognitive Development Study (ABCD) recruited from 2018. Exposures were genetic variants for childhood (266 variants) and adult (470 variants) adiposity derived from a GWAS of 407,741 UKB participants. Primary outcomes were adult total brain volume; grey matter volume, thickness, and surface area; white matter volume and hyperintensities; and hippocampus, amygdala, and thalamus volumes at mean age 55 in UKB. Secondary outcomes were equivalent childhood measures collected at mean age 10 in ABCD. In UKB, individuals who were genetically-predicted to have had higher levels of adiposity in childhood were found to have multiple smaller adult brain volumes relative to intracranial volume (e.g. z-score difference in normalised brain volume per category increase in adiposity [95%CI] = -0.20 [-0.28, -0.12]; p = 4 × 10-6). These effect sizes remained essentially unchanged after accounting for birthweight or current adult obesity in multivariable models, whereas most observed adult effects attenuated towards null (e.g. adult z-score [95%CI] for total volume = 0.06 [-0.05,0.17]; p = 0.3). Observational analyses in ABCD showed a similar pattern of changes already present in those with a high BMI by age 10 (z-score [95%CI] = -0.10 [-0.13, -0.07]; p = 8 × 10-13), with follow-up genetic risk score analyses providing some evidence for a causal effect already at this early age. Sensitivity analyses revealed that many of these effects were likely due to the persistence of larger head sizes established in those who gained excess weight in childhood (childhood z-score [95%CI] for intracranial volume = 0.14 [0.05,0.23]; p = 0.002), rather than smaller brain sizes per se. Our data suggest that persistence of early-life developmental differences across the lifecourse may underlie numerous neuroimaging traits commonly attributed to obesity-related atrophy in later life.