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Insulin-like growth factor 1 (IGF1) is a regulator of human growth during infancy and childhood, known to promote bone and muscle growth as well as lipid accumulation. This study aimed to investigate the effects of formula milk with or without IGF1 supplementation (in the form of pure IGF1 or bovine colostrum) on growth and body composition in infant cynomolgus macaques during the first 6 months of life. Three groups of infants were nursery-reared and received formula milk with or without IGF1 or bovine colostrum supplementation for 4 months, and a fourth group consisting of breast-fed infants was included for comparison (n=6 for each group). Ranked-based analysis of covariance was used to detect differences between adjusted means for sex. No differences in weight, height, fat mass, and fat-free mass could be detected between groups. However, bone mineral density (BMD) was significantly different between groups at the end of formula feeding. Infants that received bovine colostrum supplementation displayed higher mean BMD than infants of all other groups, with no differences between the latter three groups. In conclusion, our results suggest that supplementation with bovine colostrum can enhance BMD in formula-fed infants, an effect that apparently does not depend on IGF1. Bovine colostrum supplementation could be beneficial for long-term bone health in infants with suboptimal bone growth. [ABSTRACT FROM PUBLISHER]

Numerical modelling is commonly used to design, analyse and optimise tube-in-tank phase change thermal energy storage systems with fins. A new simplified two dimensional mathematical model, based on the effectiveness-number of transfer units technique, has been developed to characterise tube-in-tank phase change material systems, with radial round fins. The model applies an empirically derived P factor which defines the proportion of the heat flow which is parallel and isothermal. This P factor was determined using a validated computational fluid dynamics model. This method can be used to design and optimise tube-in-tank salt based phase change thermal storage units with finned tubes. [ABSTRACT FROM AUTHOR]

In this work the aqueous phase physicochemical properties of some 3-substituted indazole derivatives were computed by using semiempirical methods and the obtained results were evaluated by searching a possible correlation with the previously obtained experimental properties.The aqueous phase geometries, relative stabilities, acidity constants, tautomerism, proton affinities and dipole moments for the tautomeric forms of some 3-substituted indazoles and their fixed forms (model compounds in which proton migration is eliminated by replacing the mobile hydrogen atom with a methyl group) were calculated with full geometry optimization using AM1, PM3, and MNDO methods.The results of aqueous phase semiempirical calculations indicate that 1H form of the studied molecules are more stable than that of 2H form as stated in the literature. [Copyright &y& Elsevier]

The protonation of six isomeric forms of bipyridine has been investigated by means of different quantum chemical methods (i.e. semi-empirical (PM5), DFT (B3LYP/6-31G(d)) and ab initio (HF/6-31G(d)). It is concluded that 2,2′-bipyridine exists as transoid isomer, 2,3′-bipyridine as cisoid isomer and 3,3′-bipyridine coexist in equal amount of cisoid and transoid isomeric forms. [ABSTRACT FROM AUTHOR]

Retinal arteriovenous malformations (AVMs) are rare congenital, nonhereditary vascular anomalies of the retina. We report the case of a 6-year-old child presenting with recurrent frontal headaches. Funduscopy examination revealed an AVM in the right eye, inferior to the optic nerve head. Optical coherence tomography and retinal imaging confirmed the presence of an AVM measuring 3 disk diameters. Magnetic resonance imaging of the head revealed a cavernous malformation in the right frontal subcortical region., (Copyright © 2024. Published by Elsevier Inc.)

Among marsupials, the endangered numbat (Myrmecobius fasciatus) is the only obligate myrmecophage with a diet comprised strictly of termites. Like many other specialised myrmecophagous mammals, numbats have a gracile and highly specialised skull morphology with an elongated rostrum and small braincase. Myrmecobiidae is one of four taxonomic families within the Australasian marsupial order Dasyuromorphia, and to date, the muscular anatomy of any member of this group is relatively poorly known. We utilised microdissection and contrast-enhanced microcomputed tomography scanning to provide the first comprehensive qualitative and quantitative descriptions of jaw muscle anatomy in numbats and quolls (Dasuyrus species). The arrangement of the jaw muscles across these species was conservative, both in gross anatomy and muscle proportions, corresponding to a 'generalised' mammalian pattern. In contrast to Dasyurus, the jaw muscles of the numbat were greatly reduced. Many aspects of the muscle anatomy of the numbat were similar to patterns reported in other myrmecophagous species, particularly a greatly reduced temporalis muscle. Unusually, the digastric muscle in the numbat was comprised of a single, large anterior belly while the posterior belly was absent. We propose that the enlarged anterior belly of the digastric may be linked to jaw stabilisation and coordination of tongue movements during feeding. The lateral insertion and fascial connection of the digastric to the tongue in numbats may also aid in distributing stress evenly across the jaw and minimise muscle fatigue. The muscle descriptions and three-dimensional models provided in this study will facilitate further analysis of musculoskeletal adaptation and evolution within the Dasyuromorphia., (© 2024 The Authors. Journal of Morphology published by Wiley Periodicals LLC.)

Background: Pathological myopia (PM) is a major cause of worldwide blindness and represents a serious threat to eye health globally. Artificial intelligence (AI)-based methods are gaining traction in ophthalmology as highly sensitive and specific tools for screening and diagnosis of many eye diseases. However, there is currently a lack of high-quality evidence for their use in the diagnosis of PM., Methods: A systematic review and meta-analysis of studies evaluating the diagnostic performance of AI-based tools in PM was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidance. Five electronic databases were searched, results were assessed against the inclusion criteria and a quality assessment was conducted for included studies. Model sensitivity and specificity were pooled using the DerSimonian and Laird (random-effects) model. Subgroup analysis and meta-regression were performed., Results: Of 1021 citations identified, 17 studies were included in the systematic review and 11 studies, evaluating 165,787 eyes, were included in the meta-analysis. The area under the summary receiver operator curve (SROC) was 0.9905. The pooled sensitivity was 95.9% [95.5%-96.2%], and the overall pooled specificity was 96.5% [96.3%-96.6%]. The pooled diagnostic odds ratio (DOR) for detection of PM was 841.26 [418.37-1691.61]., Conclusions: This systematic review and meta-analysis provides robust early evidence that AI-based, particularly deep-learning based, diagnostic tools are a highly specific and sensitive modality for the detection of PM. There is potential for such tools to be incorporated into ophthalmic public health screening programmes, particularly in resource-poor areas with a substantial prevalence of high myopia., (© 2023. The Author(s).)

Background: Negative life events (NLEs) increase the risk for externalizing behaviors (EBs) and internalizing behaviors (IBs) in adolescence and adult psychopathology. DNA methylation associated with behavioral problems may reflect this risk and long-lasting effects of NLEs., Methods: To identify consistent associations between blood DNA methylation and EBs or IBs across adolescence, we conducted longitudinal epigenome-wide association studies (EWASs) using data from the IMAGEN cohort, collected at ages 14 and 19 years (n = 506). Significant findings were validated in a separate subsample (n = 823). Methylation risk scores were generated by 10-fold cross-validation and further tested for their associations with gray matter volumes and NLEs., Results: No significant findings were obtained for the IB-EWAS. The EB-EWAS identified a genome-wide significant locus in a gene linked to attention-deficit/hyperactivity disorder (ADHD) (IQSEC1, cg01460382; p = 1.26 × 10 -8 ). Other most significant CpG sites were near ADHD-related genes and enriched for genes regulating tumor necrosis factor and interferon-γ signaling, highlighting the relevance of EB-EWAS findings for ADHD. Analyses with the EB methylation risk scores suggested that it partly reflected comorbidity with IBs in late adolescence. Specific to EBs, EB methylation risk scores correlated with smaller gray matter volumes in medial orbitofrontal and anterior/middle cingulate cortices, brain regions known to associate with ADHD and conduct problems. Longitudinal mediation analyses indicated that EB-related DNA methylation were more likely the outcomes of problematic behaviors accentuated by NLEs, and less likely the epigenetic bases of such behaviors., Conclusions: Our findings suggest that novel epigenetic mechanisms through which NLEs exert short and longer-term effects on behavior may contribute to ADHD., (Copyright © 2022. Published by Elsevier Inc.)

Alcohol use disorder (AUD) is a chronic and fatal disease. The main impediment of the AUD therapy is a high probability of relapse to alcohol abuse even after prolonged abstinence. The molecular mechanisms of cue-induced relapse are not well established, despite the fact that they may offer new targets for the treatment of AUD. Using a comprehensive animal model of AUD, virally-mediated and amygdala-targeted genetic manipulations by CRISPR/Cas9 technology and ex vivo electrophysiology, we identify a mechanism that selectively controls cue-induced alcohol relapse and AUD symptom severity. This mechanism is based on activity-regulated cytoskeleton-associated protein (Arc)/ARG3.1-dependent plasticity of the amygdala synapses. In humans, we identified single nucleotide polymorphisms in the ARC gene and their methylation predicting not only amygdala size, but also frequency of alcohol use, even at the onset of regular consumption. Targeting Arc during alcohol cue exposure may thus be a selective new mechanism for relapse prevention., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

This in vitro study evaluated the effects of the infiltration of F - and Ca 2+ ions into human enamel by electrokinetic flow (EKF) on the enamel microhardness and F - content. Sound human enamel ground sections of unerupted third molars were infiltrated with de-ionized water by EKF and with F - ion by EKF respectively. All samples were submitted to two successive transverse acid-etch biopsies (etching times of 30 s and 20 min) to quantify F - ion infiltrated deep into enamel. Remarkably, sound enamel showed a large increase in microhardness (MH) after infiltration of NaF (p < 0.00001) and CaCl 2 (p = 0.013) by EKF. Additionally, NaF-EKF increased the remineralization in the lesion body of artificial enamel caries lesions compared to controls (p < 0.01). With the enamel biopsy technique, at both etching times, more F - ions were found in the EKF-treated group than the control group (p << 0.05), and more fluoride was extracted from deeper biopsies in the NaF-EKF group. In conclusion, our results show that EKF treatment is superior in transporting Ca 2+ and F - ions into sound enamel when compared to molecular diffusion, enhancing both the mineralization of sound enamel and the remineralization of artificial enamel caries., (© 2023. The Author(s).)

Alcohol use, abuse, and addiction, and resulting health hazards are highly sex-dependent with unknown mechanisms. Previously, strong links between the SMPD3 gene and its coded protein neutral sphingomyelinase 2 (NSM) and alcohol abuse, emotional behavior, and bone defects were discovered and multiple mechanisms were identified for females. Here we report strong sex-dimorphisms for central, but not for peripheral mechanisms of NSM action in mouse models. Reduced NSM activity resulted in enhanced alcohol consumption in males, but delayed conditioned rewarding effects. It enhanced the acute dopamine response to alcohol, but decreased monoaminergic systems adaptations to chronic alcohol. Reduced NSM activity increased depression- and anxiety-like behavior, but was not involved in alcohol use for the self-management of the emotional state. Constitutively reduced NSM activity impaired structural development in the brain and enhanced lipidomic sensitivity to chronic alcohol. While the central effects were mostly opposite to NSM function in females, similar roles in bone-mediated osteocalcin release and its effects on alcohol drinking and emotional behavior were observed. These findings support the view that the NSM and multiple downstream mechanism may be a source of the sex-differences in alcohol use and emotional behavior., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Brain cancer and leukemia are the most common cancers diagnosed in the pediatric population and are often treated with lifesaving chemotherapy. However, chemotherapy causes severe adverse effects and chemotherapy-induced peripheral neuropathy (CIPN) is a major dose-limiting and debilitating side effect. CIPN can greatly impair quality of life and increases morbidity of pediatric patients with cancer, with the accompanying symptoms frequently remaining underdiagnosed. Little is known about the incidence of CIPN, its impact on the pediatric population, and the underlying pathophysiological mechanisms, as most existing information stems from studies in animal models or adult cancer patients. Herein, we aim to provide an understanding of CIPN in the pediatric population and focus on the 6 main substance groups that frequently cause CIPN, namely the vinca alkaloids (vincristine), platinum-based antineoplastics (cisplatin, carboplatin and oxaliplatin), taxanes (paclitaxel and docetaxel), epothilones (ixabepilone), proteasome inhibitors (bortezomib) and immunomodulatory drugs (thalidomide). We discuss the clinical manifestations, assessments and diagnostic tools, as well as risk factors, pathophysiological processes and current pharmacological and non-pharmacological approaches for the prevention and treatment of CIPN., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Tay, Laakso, Schweitzer, Endersby, Vetter and Starobova.)

To improve the storage and transport of clinical specimens for the diagnosis of Neisseria meningitidis (Nm) infections in resource-limited settings, we have evaluated the performance of dried blood spot (DBS) and dried cerebrospinal fluid spot (DCS) assays. DBS and DCS were prepared on filter paper from liquid specimens previously tested for Nm in the United Kingdom. Nm was detected and genogrouped by real-time PCR performed on crude genomic DNA extracted from the DBS (n = 226) and DCS (n = 226) specimens. Targeted whole-genome sequencing was performed on a subset of specimens, DBS (n = 4) and DCS (n = 6). The overall agreement between the analysis of liquid and dried specimens was (94.2%; 95% CI 90.8−96.7) for blood and (96.4%; 95% CI 93.5−98.0) for cerebrospinal fluid. Relative to liquid specimens as the reference, the DBS and DCS assays had sensitivities of (89.1%; 95% CI 82.7−93.8) and (94.2%; 95% CI 88.9−97.5), respectively, and both assays had specificities above 98%. A genogroup was identified by dried specimen analysis for 81.9% of the confirmed meningococcal infections. Near full-length Nm genome sequences (>86%) were obtained for all ten specimens tested which allowed determination of the sequence type, clonal complex, presence of antimicrobial resistance and other meningococcal genotyping. Dried blood and CSF filter spot assays offer a practical alternative to liquid specimens for the molecular and genomic characterisation of invasive meningococcal diseases in low-resource settings.

Background: Sex-related differences in psychopathology are known phenomena, with externalizing and internalizing symptoms typically more common in boys and girls, respectively. However, the neural correlates of these sex-by-psychopathology interactions are underinvestigated, particularly in adolescence., Methods: Participants were 14 years of age and part of the IMAGEN study, a large ( N = 1526) community-based sample. To test for sex-by-psychopathology interactions in structural grey matter volume (GMV), we used whole-brain, voxel-wise neuroimaging analyses based on robust non-parametric methods. Psychopathological symptom data were derived from the Strengths and Difficulties Questionnaire (SDQ)., Results: We found a sex-by-hyperactivity/inattention interaction in four brain clusters: right temporoparietal-opercular region ( p < 0.01, Cohen's d = -0.24), bilateral anterior and mid-cingulum ( p < 0.05, Cohen's d = -0.18), right cerebellum and fusiform ( p < 0.05, Cohen's d = -0.20) and left frontal superior and middle gyri ( p < 0.05, Cohen's d = -0.26). Higher symptoms of hyperactivity/inattention were associated with lower GMV in all four brain clusters in boys, and with higher GMV in the temporoparietal-opercular and cerebellar-fusiform clusters in girls., Conclusions: Using a large, sex-balanced and community-based sample, our study lends support to the idea that externalizing symptoms of hyperactivity/inattention may be associated with different neural structures in male and female adolescents. The brain regions we report have been associated with a myriad of important cognitive functions, in particular, attention, cognitive and motor control, and timing, that are potentially relevant to understand the behavioural manifestations of hyperactive and inattentive symptoms. This study highlights the importance of considering sex in our efforts to uncover mechanisms underlying psychopathology during adolescence.

In this study, novel 4-(5-((2/3/4-substituted benzyl)thio)-4-(4-substituted phenyl)-4 H -1,2,4-triazol-3-yl)-2-(pyridin-3/4-yl)thiazoles were synthesized following a multi-step synthetic procedure. All the compounds were screened with a panel of gram positive/negative bacteria, yeasts, and molds for antimicrobial activity using the disc diffusion method. Then, the minimum inhibitor concentration (MIC) and the minimum bactericidal concentration (MBC) values of active compounds were determined against Micrococcus luteus , Bacillus cereus , Listeria monocytogenes , and Staphylococcus aureus using the broth microdilution technique. These compounds were also screened for their inhibitory activities against S. aureus DNA gyrase by supercoiling assay. Furthermore, the crystal structure of S. aureus DNA gyrase B ATPase was subjected to a docking experiment to identify the possible interactions between the most active ligand and the active site. Lastly, the in silico technique was performed to analyze and predict the drug-likeness, molecular and ADME properties of the synthesized molecules., (© 2022 Walter de Gruyter GmbH, Berlin/Boston.)

Background: Asian representation in sport is increasing, yet there remains a lack of reference values for the Asian athlete's heart. Consequently, current guidelines for cardiovascular screening recommend using Caucasian athletes' norms to evaluate Asian athletes. This study aims to outline electrocardiographic and echocardiographic characteristics of the Asian athlete's heart using a Singaporean prospective registry of Southeast (SE) Asian athletes. Methods and Results: One hundred and fifty elite athletes, mean age of 26.1 ± 5.7 years (50% males, 88% Chinese), were evaluated using a questionnaire, 12-lead electrocardiogram (ECG) and transthoracic echocardiogram. All ECGs were analyzed using the 2017 International Recommendations. Echocardiographic data were presented by gender and sporting discipline. The prevalence of abnormal ECGs among SE Asian athletes was 6.7%-higher than reported figures for Caucasian athletes. The abnormal ECGs comprised mainly anterior T wave inversions (ATWI) beyond lead V2, predominantly in female athletes from mixed/endurance sport (9.3% prevalence amongst females). None had echocardiographic structural abnormalities. Male athletes had reduced global longitudinal strain compared to females (-18.7 ± 1.6 vs. -20.7 ± 2.1%, p < 0.001). Overall, SE Asian athletes had smaller left ventricular cavity sizes and wall thickness compared to non-Asian athletes. Conclusion: SE Asian athletes have higher abnormal ECG rates compared to Caucasian athletes, and also demonstrate structural differences that should be accounted for when interpreting their echocardiograms compared to athletes of other ethnicities., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Yeo, Wang, Grignani, McKinney, Koh, Tan, Chan, Tay, Chan, Lee, Oxborough, Malhotra, Sharma and Richards.)

Background: Eating disorders are common in adolescence and are devastating and strongly comorbid with other psychiatric disorders. Yet little is known about their etiology, knowing which would aid in developing effective preventive measures., Methods: Longitudinal assessments of disordered eating behaviors (DEBs)-binge-eating, purging, and dieting-and comorbid psychopathology were measured in 1386 adolescents from the IMAGEN study. Development of DEBs and associated mental health problems was investigated by comparing participants who reported symptoms at ages 16 or 19 years, but not at age 14 years, with asymptomatic control participants. Voxel-based morphometry and psychopathological differences at age 14 were investigated to identify risk factors for the development of DEBs and associated mental health problems., Results: DEBs and depressive symptoms developed together. Emotional and behavioral problems, including symptoms of attention-deficit/hyperactivity disorder and conduct disorder, predated their development. Alterations in frontostriatal brain areas also predated the development of DEBs and depressive symptoms. Specifically, development of binge-eating was predicted by higher gray matter volumes in the right putamen/globus pallidus at age 14. Conversely, development of purging and depressive symptoms was predicted by lower volumes in the medial orbitofrontal, dorsomedial, and dorsolateral prefrontal cortices. Lower gray matter volumes in the orbitofrontal and anterior cingulate cortices mediated the relationship between attention-deficit/hyperactivity disorder and conduct disorder symptoms and future purging and depressive symptoms., Conclusions: These findings suggest that alterations in frontal brain circuits are part of the shared etiology among eating disorders, attention-deficit/hyperactivity disorder, conduct disorder, and depression and highlight the importance of a transdiagnostic approach to treating these conditions., (Copyright © 2020 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Mental disorders are highly comorbid and occur together with physical diseases, which are often considered to arise from separate pathogenic pathways. We observed in alcohol-dependent patients increased serum activity of neutral sphingomyelinase. A genetic association analysis in 456,693 volunteers found associations of haplotypes of SMPD3 coding for NSM-2 (NSM) with alcohol consumption, but also with affective state, and bone mineralisation. Functional analysis in mice showed that NSM controls alcohol consumption, affective behaviour, and their interaction by regulating hippocampal volume, cortical connectivity, and monoaminergic responses. Furthermore, NSM controlled bone-brain communication by enhancing osteocalcin signalling, which can independently supress alcohol consumption and reduce depressive behaviour. Altogether, we identified a single gene source for multiple pathways originating in the brain and bone, which interlink disorders of a mental-physical co-morbidity trias of alcohol abuse-depression/anxiety-bone disorder. Targeting NSM and osteocalcin signalling may, thus, provide a new systems approach in the treatment of a mental-physical co-morbidity trias., (© 2021. The Author(s).)

Alcohol misuse is a major public health problem originating from genetic and environmental risk factors. Alterations in the brain epigenome may orchestrate changes in gene expression that lead to alcohol misuse and dependence. Through epigenome-wide association analysis of DNA methylation from human brain tissues, we identified a differentially methylated region, DMR-DLGAP2, associated with alcohol dependence. Methylation within DMR-DLGAP2 was found to be genotype-dependent, allele-specific and associated with reward processing in brain. Methylation at the DMR-DLGAP2 regulated expression of DLGAP2 in vitro, and Dlgap2-deficient mice showed reduced alcohol consumption compared with wild-type controls. These results suggest that DLGAP2 may be an interface for genetic and epigenetic factors controlling alcohol use and dependence., (© 2019. The Author(s), under exclusive licence to Springer Nature Limited.)

Background and Objective: Simulation enhances a physician's competency in procedural skills by accelerating ascent of the learning curve. Training programmes are moving away from the Halstedian model of 'see one, do one, teach one', also referred as medical apprenticeship. We aimed to determine if a 3-month structured bronchoscopy curriculum that incorporated simulator training could improve bronchoscopy competency among pulmonary medicine trainees., Methods: We prospectively recruited trainees from hospitals with accredited pulmonary medicine programmes. Trainees from hospitals (A, B and C) were assigned to control group (CG) where they received training by traditional apprenticeship while trainees from hospital D were assigned to intervention group (IG) where they underwent 3-month structured curriculum that incorporated training with the bronchoscopy simulator. Two patient bronchoscopy procedures per trainee were recorded on video and scored independently by two expert bronchoscopists using the modified Bronchoscopy Skills and Tasks Assessment Tool (BSTAT) forms. A 25 multiple choice questions (MCQ) test was administered to all participants at the end of 3 months., Results: Eighteen trainees participated; 10 in CG and eight in IG with equal female:male ratio. Competency assessed by modified BSTAT and MCQ tests was variable and not driven by volume as IG performed fewer patient bronchoscopies but demonstrated better BSTAT, airway anaesthesia and MCQ scores. Bronchoscopy simulator training was the only factor that correlated with better BSTAT (r = 0.80), MCQ (r = 0.85) and airway anaesthesia scores (r = 0.83), and accelerated the learning curve of IG trainees., Conclusion: An intensive 3-month structured bronchoscopy curriculum that incorporated simulator training led to improved cognitive and technical skill performance as compared with apprenticeship training., (© 2021 Asian Pacific Society of Respirology.)

Importance: Eating disorders are serious mental disorders with increasing prevalence. Without early identification and treatment, eating disorders may run a long-term course., Objective: To characterize any associations among disordered eating behaviors (DEBs) and other mental health disorders and to identify early associations with the development of symptoms over time., Design, Setting, and Participants: This multicenter, population-based, longitudinal cohort study used data from baseline (collected in 2010), follow-up 1 (collected in 2012), and follow-up 2 (collected in 2015) of the IMAGEN Study, which included adolescents recruited from 8 European sites. The present study assessed data from 1623 healthy adolescents, aged 14 years at baseline, recruited from high schools. Data analyses were performed from January 2018 to September 2019., Main Outcomes and Measures: Body mass index (BMI), mental health symptoms, substance use behaviors, and personality variables were investigated as time-varying associations of DEBs (dieting, binge eating, and purging) or change in BMI over time. Polygenic risk scores were calculated to investigate genetic contributions associated with BMI, attention-deficit/hyperactivity disorder (ADHD) and neuroticism to DEBs., Results: In this cohort study of 1623 adolescents (829 girls [51.1%]) recruited at a mean (SD) age of 14.5 (0.4) years and followed up at ages 16 and 19 years, 278 adolescents (17.1%) reported binge eating, 334 adolescents (20.6%) reported purging, and 356 adolescents (21.9%) reported dieting at 14, 16, or 19 years. Among the precursors of DEBs, high BMI was associated with future dieting (OR, 3.44; 95% CI, 2.09-5.65). High levels of neuroticism (OR, 1.04; 95% CI, 1.01-1.06), conduct problems (OR, 1.41; 95% CI, 1.17-1.69), and deliberate self-harm (OR, 2.18; 95% CI, 1.37-3.45) were associated with future binge eating. Low agreeableness (OR, 0.95; 95% CI, 0.92-0.97), deliberate self-harm (OR, 2.59; 95% CI, 1.69-3.95), conduct problems (OR, 1.42; 95% CI, 1.20-1.68), alcohol misuse (OR, 1.31; 95% CI, 1.10-1.54), and drug abuse (OR, 2.91; 95% CI, 1.78-4.74) were associated with future purging. Polygenetic risk scores for BMI were associated with dieting (at 14 years: OR, 1.27; lower bound 95% CI, 1.08; at 16 years: OR, 1.38; lower bound 95% CI, 1.17); ADHD, with purging (at 16 years: OR, 1.25; lower bound 95% CI, 1.08; at 19 years, OR, 1.23; lower bound 95% CI, 1.06); and neuroticism, with binge eating (at 14 years: OR, 1.32; lower bound 95% CI, 1.11; at 16 years: OR, 1.24; lower bound 95% CI, 1.06), highlighting distinct etiologic overlaps between these traits. The DEBs predated other mental health problems, with dieting at 14 years associated with future symptoms of depression (OR, 2.53; 95% CI, 1.56-4.10), generalized anxiety (OR, 2.27; 95% CI, 1.14-4.51), deliberate self-harm (OR, 2.10; 95% CI, 1.51-4.24), emotional problems (OR, 1.24; 95% CI, 1.08-1.43), and smoking (OR, 2.16; 95% CI, 1.36-3.48). Purging at 14 years was also associated with future depression (OR, 2.87; 95% CI, 1.69-5.01) and anxiety (OR, 2.48; 95% CI, 1.49-4.12) symptoms., Conclusions and Relevance: The findings of this study delineate temporal associations and shared etiologies among DEBs and other mental health disorders and emphasize the potential of genetic and phenotypical assessments of obesity, behavioral disorders, and neuroticism to improve early and differential diagnosis of eating disorders.

Tooth enamel has an important mechanical function for human dental health, yet characterizing its mechanical properties is not trivial due to its complex nanoporous structures. We examined the distribution of hardness and modulus across the lingual-buccal enamel cross-section by nanoindentation. At the occlusal surface, the hardness and modulus of enamel were found to be 5.00 ± 0.22 GPa and 97.12 ± 2.95 GPa, respectively. At the area close to the enamel-dentine-junction (EDJ), the hardness and modulus were 3.72 ± 0.35 GPa and 76.83 ± 5.71 GPa, respectively. At the middle region in between the EDJ and the outer enamel layer, the hardness and modulus were found to be 4.23 ± 0.18 GPa and 87.62 ± 2.50 GPa, respectively. The surface and area underneath the nanoindent were analyzed using the following microscopy tools: Scanning Electron Microscopy, Focused Ion Beam imaging, and Transmission Electron Microscopy. The deformation mechanisms of enamel were found to be location dependent and influenced by changes in the chemical composition within enamel. The EDJ forms the interface between enamel and dentin. The deformation behavior differed at the EDJ, due to the increased organic phase at the interface. Within the intermediate enamel region, intra-rod cracks were formed at the center of enamel rods and propagated into the neighboring inter-rod region at deviated directions along the orientation of the local crystallites. At the outer enamel layer, crack propagation was constrained by the rigid structure surrounding the indented site. Most of the cracks were formed close to the surface. A significant amount of material was also pushed upwards and delaminated from the enamel surface of the indentation area., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Reinforcement-related cognitive processes, such as reward processing, inhibitory control and social-emotional regulation are critical components of externalising and internalising behaviours. It is unclear to what extent the deficit in each of these processes contributes to individual behavioural symptoms, how their neural substrates give rise to distinct behavioural outcomes and whether neural activation profiles across different reinforcement-related processes might differentiate individual behaviours. We created a statistical framework that enabled us to directly compare functional brain activation during reward anticipation, motor inhibition and viewing emotional faces in the European IMAGEN cohort of 2,000 14-year-old adolescents. We observe significant correlations and modulation of reward anticipation and motor inhibition networks in hyperactivity, impulsivity, inattentive behaviour and conduct symptoms, and we describe neural signatures across cognitive tasks that differentiate these behaviours. We thus characterise shared and distinct functional brain activation patterns underling different externalising symptoms and identify neural stratification markers, while accounting for clinically observed comorbidity.

Importance: Alcohol abuse correlates with gray matter development in adolescents, but the directionality of this association remains unknown., Objective: To investigate the directionality of the association between gray matter development and increase in frequency of drunkenness among adolescents., Design, Setting, and Participants: This cohort study analyzed participants of IMAGEN, a multicenter brain imaging study of healthy adolescents in 8 European sites in Germany (Mannheim, Dresden, Berlin, and Hamburg), the United Kingdom (London and Nottingham), Ireland (Dublin), and France (Paris). Data from the second follow-up used in the present study were acquired from January 1, 2013, to December 31, 2016, and these data were analyzed from January 1, 2016, to March 31, 2018. Analyses were controlled for sex, site, socioeconomic status, family history of alcohol dependency, puberty score, negative life events, personality, cognition, and polygenic risk scores. Personality and frequency of drunkenness were assessed at age 14 years (baseline), 16 years (first follow-up), and 19 years (second follow-up). Structural brain imaging scans were acquired at baseline and second follow-up time points., Main Outcomes and Measures: Increases in drunkenness frequency were measured by latent growth modeling, a voxelwise hierarchical linear model was used to observe gray matter volume, and tensor-based morphometry was used for gray matter development. The hypotheses were formulated before the data analyses., Results: A total of 726 adolescents (mean [SD] age at baseline, 14.4 [0.38] years; 418 [58%] female) were included. The increase in drunkenness frequency was associated with accelerated gray matter atrophy in the left posterior temporal cortex (peak: t1,710 = -5.8; familywise error (FWE)-corrected P = 7.2 × 10-5; cluster: 6297 voxels; P = 2.7 × 10-5), right posterior temporal cortex (cluster: 2070 voxels; FWE-corrected P = .01), and left prefrontal cortex (peak: t1,710 = -5.2; FWE-corrected P = 2 × 10-3; cluster: 10 624 voxels; P = 1.9 × 10-7). According to causal bayesian network analyses, 73% of the networks showed directionality from gray matter development to drunkenness increase as confirmed by accelerated gray matter atrophy in late bingers compared with sober controls (n = 20 vs 60; β = 1.25; 95% CI, -2.15 to -0.46; t1,70 = 0.3; P = .004), the association of drunkenness increase with gray matter volume at age 14 years (β = 0.23; 95% CI, 0.01-0.46; t1,584 = 2; P = .04), the association between gray matter atrophy and alcohol drinking units (β = -0.0033; 95% CI, -6 × 10-3 to -5 × 10-4; t1,509 = -2.4; P = .02) and drunkenness frequency at age 23 years (β = -0.16; 95% CI, -0.28 to -0.03; t1,533 = -2.5; P = .01), and the linear exposure-response curve stratified by gray matter atrophy and not by increase in frequency of drunkenness., Conclusions and Relevance: This study found that gray matter development and impulsivity were associated with increased frequency of drunkenness by sex. These results suggest that neurotoxicity-related gray matter atrophy should be interpreted with caution.

Most psychopathological disorders develop in adolescence. The biological basis for this development is poorly understood. To enhance diagnostic characterization and develop improved targeted interventions, it is critical to identify behavioural symptom groups that share neural substrates. We ran analyses to find relationships between behavioural symptoms and neuroimaging measures of brain structure and function in adolescence. We found two symptom groups, consisting of anxiety/depression and executive dysfunction symptoms, respectively, that correlated with distinct sets of brain regions and inter-regional connections, measured by structural and functional neuroimaging modalities. We found that the neural correlates of these symptom groups were present before behavioural symptoms had developed. These neural correlates showed case-control differences in corresponding psychiatric disorders, depression and attention deficit hyperactivity disorder in independent clinical samples. By characterizing behavioural symptom groups based on shared neural mechanisms, our results provide a framework for developing a classification system for psychiatric illness that is based on quantitative neurobehavioural measures.