The Sec1-Munc18 protein VPS33B forms a uniquely bidirectional complex with VPS16B.

Loss-of-function variants of vacuolar protein sorting proteins VPS33B and VPS16B (VIPAS39) are causative for arthrogryposis, renal dysfunction, and cholestasis syndrome, where early lethality of patients indicates that VPS33B and VPS16B play essential cellular roles. VPS33B is a member of the Sec1-Munc18 protein family and thought to facilitate vesicular fusion via interaction with soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complexes, like its paralog VPS33A in the homotypic fusion and vacuole sorting complex. VPS33B and VPS16B are known to associate, but little is known about the composition, structure, or function of the VPS33B-VPS16B complex. We show here that human VPS33B-VPS16B is a high molecular weight complex, which we expressed in yeast to perform structural, composition, and stability analysis. Circular dichroism data indicate VPS33B-VPS16B has a well-folded α-helical secondary structure, and size-exclusion chromatography-multiangle light scattering revealed a molecular weight of ∼315 kDa. Quantitative immunoblotting indicated a VPS33B:VPS16B ratio of 2:3. Expression of arthrogryposis, renal dysfunction, and cholestasis syndrome-causing VPS33B missense variants showed L30P disrupts complex formation but not S243F or H344D. Truncated VPS16B (amino acids 143 to 316) was sufficient to form a complex with VPS33B. Small-angle X-ray scattering and negative-staining EM revealed a two-lobed shape for VPS33B-VPS16B. Avidin tagging indicated that each lobe contains a VPS33B molecule, and they are oriented in opposite directions. We propose a structure for VPS33B-VPS16B that allows the VPS33B at each end to interact with separate SNARE bundles and/or SNAREpins, plus associated membrane components. These observations reveal the only known potentially bidirectional Sec1-Munc18 protein complex.

The antidepressant effect of whole-body hyperthermia is associated with the classical interleukin-6 signaling pathway.

There is urgent need for novel antidepressant treatments that confer therapeutic benefits via engagement with identified mechanistic targets. The objective of the study was to determine whether activation of the classical anti-inflammatory interleukin-6 signaling pathways is associated with the antidepressant effects of whole-body hyperthermia. A 6-week, randomized, double-blind study compared whole-body hyperthermia with a sham condition in a university-based medical center. Medically healthy participants aged 18-65 years who met criteria for major depressive disorder, were free of psychotropic medication use, and had a baseline 17-item Hamilton Depression Rating Scale score ≥ 16 were randomized with 1-to-1 allocation in blocks of 6 to receive whole-body hyperthermia or sham. Of 338 individuals screened, 34 were randomized, 30 received interventions and 26 had ≥ 2 blood draws and depressive symptom assessments. Secondary data analysis examined change in the ratio of IL-6:soluble IL-6 receptor pre-intervention, post-intervention, and at weeks 1 and 4. Hierarchical linear modeling tested whether increased IL-6:soluble IL-6 receptor ratio post-intervention was associated with decreased depressive symptom at weeks 1, 2, 4 and 6 for those randomized to whole-body hyperthermia. Twenty-six individuals were randomized to whole-body hyperthermia [n = 12; 75 % female; age = 37.9 years (SD = 15.3) or sham [n = 14; 57.1 % female; age = 41.1 years (SD = 12.5). When compared to the sham condition, active whole-body hyperthermia only increased the IL-6:soluble IL-6 receptor ratio post-treatment [F(3,72) = 11.73,p < .001], but not pre-intervention or at weeks 1 and 4. Using hierarchical linear modeling, increased IL-6:sIL-6R ratio following whole-body hyperthermia moderated depressive symptoms at weeks 1, 2, 4 and 6, such that increases in the IL-6:soluble IL-6 receptor ratio were associated with decreased depressive symptoms at weeks 1, 2, 4 and 6 for those receiving the active whole-body hyperthermia compared to sham treatment (B = -229.44, t = -3.82,p < .001). Acute activation of classical intereukin-6 signaling might emerge as a heretofore unrecognized novel mechanism that could be harnessed to expand the antidepressant armamentarium.

Machine Learning Diagnosis of Small-Bowel Crohn Disease Using T2-Weighted MRI Radiomic and Clinical Data.

BACKGROUND. Radiologists have variable diagnostic performance and considerable interreader variability when interpreting MR enterography (MRE) examinations for suspected Crohn disease (CD). OBJECTIVE. The purposes of this study were to develop a machine learning method for predicting ileal CD by use of radiomic features of ileal wall and mesenteric fat from noncontrast T2-weighted MRI and to compare the performance of the method with that of expert radiologists. METHODS. This single-institution study included retrospectively identified patients who underwent MRE for suspected ileal CD from January 1, 2020, to January 31, 2021, and prospectively enrolled participants (patients with newly diagnosed ileal CD or healthy control participants) from December 2018 to October 2021. Using axial T2-weighted SSFSE images, a radiologist selected two slices showing greatest terminal ileal wall thickening. Four ROIs were segmented, and radiomic features were extracted from each ROI. After feature selection, support-vector machine models were trained to classify the presence of ileal CD. Three fellowship-trained pediatric abdominal radiologists independently classified the presence of ileal CD on SSFSE images. The reference standard was clinical diagnosis of ileal CD based on endoscopy and biopsy results. Radiomic-only, clinical-only, and radiomic-clinical ensemble models were trained and evaluated by nested cross-validation. RESULTS. The study included 135 participants (67 female, 68 male; mean age, 15.2 ± 3.2 years); 70 were diagnosed with ileal CD. The three radiologists had accuracies of 83.7% (113/135), 88.1% (119/135), and 86.7% (117/135) for diagnosing CD; consensus accuracy was 88.1%. Interradiologist agreement was substantial (κ = 0.78). The best-performing ROI was bowel core (AUC, 0.95; accuracy, 89.6%); other ROIs had worse performance (whole-bowel AUC, 0.86; fat-core AUC, 0.70; whole-fat AUC, 0.73). For the clinical-only model, AUC was 0.85 and accuracy was 80.0%. The ensemble model combining bowel-core radiomic and clinical models had AUC of 0.98 and accuracy of 93.5%. The bowel-core radiomic-only model had significantly greater accuracy than radiologist 1 (p = .009) and radiologist 2 (p = .02) but not radiologist 3 (p > .99) or the radiologists in consensus (p = .05). The ensemble model had greater accuracy than the radiologists in consensus (p = .02). CONCLUSION. A radiomic machine learning model predicted CD diagnosis with better performance than two of three expert radiologists. Model performance improved when radiomic data were ensembled with clinical data. CLINICAL IMPACT. Deployment of a radiomic-based model including T2-weighted MRI data could decrease interradiologist variability and increase diagnostic accuracy for pediatric CD.

Prospective Relations between Life Stress, Emotional Clarity, and Suicidal Ideation in an Adolescent Clinical Sample.

OBJECTIVE: Although life stress has been linked to adolescent suicidal ideation, most past research has been cross-sectional, and potential processes characterizing this relation remain unclear. One possibility may be a lack of emotional clarity. Informed by stress generation, the current study examined prospective relations between episodic life stress, lack of emotional clarity, and suicidal ideation in an adolescent clinical sample. METHODS: The sample consisted of 180 youths (Mage = 14.89; SD = 1.35; 71.7% female; 78.9% White; 43.0% sexual minority) recruited from a psychiatric inpatient facility. Suicidal ideation severity was assessed at baseline and 18-month follow-up. Lack of emotional clarity and life stress were assessed at baseline, as well as 6-, and 12-month follow-ups. Two random-intercepts cross-lagged panel models were created to estimate within-person relations for variables of interest. RESULTS: At the within-person level, lack of emotional clarity at baseline predicted greater 6-month impact of interpersonal dependent stressors (b = 0.29, p = .012, 95% CI [0.07, 0.52]), which subsequently predicted a greater 12-month lack of emotional clarity (b = 0.41, p = .005, 95% CI [0.12, 0.70]). Next, a 12-month lack of emotional clarity but not interpersonal dependent stress, predicted greater 18-month suicidal ideation (b = 0.81, p = .006, 95% CI [0.23, 1.30]; R2 = .24, p < .001). No significant relations were found for the lack of emotional clarity and independent stress. CONCLUSIONS: Results support the stress generation hypothesis and suggest that future research should be conducted evaluating whether bolstering youth's understanding of their emotional experiences may reduce subsequent suicidal ideation.

Rectified Latent Variable Model-Based EMG Factorization of Inhibitory Muscle Synergy Components Related to Aging, Expertise and Force-Tempo Variations.

Muscle synergy has been widely acknowledged as a possible strategy of neuromotor control, but current research has ignored the potential inhibitory components in muscle synergies. Our study aims to identify and characterize the inhibitory components within motor modules derived from electromyography (EMG), investigate the impact of aging and motor expertise on these components, and better understand the nervous system's adaptions to varying task demands. We utilized a rectified latent variable model (RLVM) to factorize motor modules with inhibitory components from EMG signals recorded from ten expert pianists when they played scales and pieces at different tempo-force combinations. We found that older participants showed a higher proportion of inhibitory components compared with the younger group. Senior experts had a higher proportion of inhibitory components on the left hand, and most inhibitory components became less negative with increased tempo or decreased force. Our results demonstrated that the inhibitory components in muscle synergies could be shaped by aging and expertise, and also took part in motor control for adapting to different conditions in complex tasks.

Reversible CO2 Capture and On-Demand Release by an Acidity-Matched Organic Photoswitch.

Separation of carbon dioxide (CO2) from point sources or directly from the atmosphere can contribute crucially to climate change mitigation plans in the coming decades. A fundamental practical limitation for the current strategies is the considerable energy cost required to regenerate the sorbent and release the captured CO2 for storage or utilization. A directly photochemically driven system that demonstrates efficient passive capture and on-demand CO2 release triggered by sunlight as the sole external stimulus would provide an attractive alternative. However, little is known about the thermodynamic requirements for such a process or mechanisms for modulating the stability of CO2-derived dissolved species by using photoinduced metastable states. Here, we show that an organic photoswitchable molecule of precisely tuned effective acidity can repeatedly capture and release a near-stoichiometric quantity of CO2 according to dark-light cycles. The CO2-derived species rests as a solvent-separated ion pair, and key aspects of its excited-state dynamics that regulate the photorelease efficiency are characterized by transient absorption spectroscopy. The thermodynamic and kinetic concepts established herein will serve as guiding principles for the development of viable solar-powered negative emission technologies.

Untargeted metabolomics of perfusate and their association with hypothermic machine perfusion and allograft failure.

Although hypothermic machine perfusion (HMP) is associated with improved kidney graft viability and function, the underlying biological mechanisms are unknown. Untargeted metabolomic profiling may identify potential metabolites and pathways that can help assess allograft viability and contribute to organ preservation. Therefore, in this multicenter study, we measured all detectable metabolites in perfusate collected at the beginning and end of deceased-donor kidney perfusion and evaluated their associations with graft failure. In our cohort of 190 kidney transplants, 33 (17%) had death-censored graft failure over a median follow-up of 5.0 years (IQR 3.0-6.1 years). We identified 553 known metabolites in perfusate and characterized their experimental and biological consistency through duplicate samples and unsupervised clustering. After perfusion-time adjustment and false discovery correction, six metabolites in post-HMP perfusate were significantly associated with death-censored graft failure, including alpha-ketoglutarate, 3-carboxy-4-methyl-5-propyl-2-furanpropanoate, 1-carboxyethylphenylalanine, and three glycerol-phosphatidylcholines. All six metabolites were associated with an increased risk of graft failure (Hazard Ratio per median absolute deviation range 1.04-1.45). Four of six metabolites also demonstrated significant interaction with donation after cardiac death with notably greater risk in the donation after cardiac death group (Hazard Ratios up to 1.69). Discarded kidneys did not have significantly different levels of any death-censored graft failure-associated metabolites. On interrogation of pathway analysis, production of reactive oxygen species and increased metabolism of fatty acids were upregulated in kidneys that subsequently developed death-censored graft failure. Thus, further understanding the role of these metabolites may inform the HMP process and help improve the objective evaluation of allograft offers, thereby reducing the discard of potentially viable organs.

Vimentin tunes cell migration on collagen by controlling ß1 integrin activation and clustering.

Vimentin is a structural protein that is required for mesenchymal cell migration and directly interacts with actin, ß1 integrin and paxillin. We examined how these interactions enable vimentin to regulate cell migration on collagen. In fibroblasts, depletion of vimentin increased talin-dependent activation of ß1 integrin by more than 2-fold. Loss of vimentin was associated with reduction of ß1 integrin clustering by 50% and inhibition of paxillin recruitment to focal adhesions by more than 60%, which was restored by vimentin expression. This reduction of paxillin was associated with 65% lower Cdc42 activation, a 60% reduction of cell extension formation and a greater than 35% decrease in cell migration on collagen. The activation of PAK1, a downstream effector of Cdc42, was required for vimentin phosphorylation and filament maturation. We propose that vimentin tunes cell migration through collagen by acting as an adaptor protein for focal adhesion proteins, thereby regulating ß1 integrin activation, resulting in well-organized, mature integrin clusters.This article has an associated First Person interview with the first author of the paper.

The epidemiology of non-suicidal self-injury: lifetime prevalence, sociodemographic and clinical correlates, and treatment use in a nationally representative sample of adults in England.

BACKGROUND: Although the clinical importance of non-suicidal self-injury (NSSI) has received increasing recognition, relatively little is known about its epidemiology. The objective of this study was to estimate the lifetime prevalence of NSSI in adults and its association with sociodemographic characteristics, psychiatric disorders, and lifetime treatment for NSSI. METHODS: A nationally representative face-to-face survey was conducted with 7192 adults aged ≥18 years in England. Respondents were interviewed about engagement in NSSI, psychiatric illness, suicidal thoughts and behavior, and treatment history for this behavior. RESULTS: The estimated lifetime prevalence rate of NSSI was 4.86%. Younger age, growing up without biological parents in the household, being unmarried, and impoverished backgrounds were associated with NSSI. The majority of respondents with lifetime NSSI (63.82%) had at least one current psychiatric disorder. Most psychiatric conditions were associated with greater odds of lifetime NSSI in multivariate models. NSSI was strongly associated with suicidal ideation and suicide attempts, respectively, even after accounting for psychiatric disorders and sociodemographic covariates. A substantial proportion of respondents with NSSI history (30.92%) have engaged in medically severe self-harm, as indexed by requiring medical attention for this behavior. The majority of respondents with NSSI (56.20%) had not received psychiatric care for this behavior. CONCLUSIONS: NSSI is prevalent in the general population and associated with considerable psychiatric comorbidity. A high rate of unmet treatment needs is evident among those with this behavior. Those at the greatest lifetime risk for NSSI may also be particularly limited in their resources to cope with this behavior.

Prevalence, predictors, and treatment of eating disorders in children: a national study.

BACKGROUND: Although the prevalence rates of preadolescent eating disorders (EDs) are on the rise, considerably less is known about the correlates and treatment of EDs in this age group. Clarifying the epidemiology of EDs in preadolescent children is a necessary first step to understand the nature and scope of this problem in this age group. METHODS: Analysis of data collected in the ABCD Study release 2.0.1. The ABCD cohort was a population-based sample that consisted of 11 721 children ages 9-10 years. Measures included reports of a lifetime and current mental disorders determined using a diagnostic interview for DSM-5 disorders, sociodemographic factors, and psychiatric treatment utilization. RESULTS: The lifetime prevalence of EDs was 0.95%. Being Black, multiracial, having unmarried parents, and family economic insecurity were significant predictors for developing an ED. Among psychiatric conditions, the major depressive disorder was most robustly associated with EDs in both cross-sectional and temporal analyses. Only 47.40% of children who had a lifetime ED received some type of psychiatric treatment. EDs were not a significant predictor of psychiatric treatment utilization after accounting for sex, sexual orientation, parent marital status, economic insecurity, and all other psychiatric diagnoses. CONCLUSIONS: Despite increasing prevalence rates of preadolescent EDs, the current findings suggest that the majority of children with these disorders remain untreated. Devoting increased attention and resources to reaching families of children with EDs with the least means for receiving care, and screening for EDs in children with depression, may be important steps for reducing this unmet need.

Lessons learned from examination of Canadian medico-legal cases related to interventional therapies for chronic pain management.

PURPOSE: Chronic pain is a common condition affecting almost one in five Canadians. One of the methods used to treat chronic pain is injection therapies. While they are considered relatively safe procedures, they do carry inherent risk that can result in adverse events. Our goal was to investigate these patient safety events to identify themes that could be used to shape practice guidelines and standards and improve patient safety. METHODS: We looked at closed civil legal actions and regulatory college complaints associated with injection therapies for chronic pain in the Canadian Medical Protection Association database from 2015 to 2019. Injury was defined as that arising from, or associated with, plans or actions taken during the provision of health care, rather than an underlying disease or injury. RESULTS: Of the 91 cases identified, the most common reported complications were neurologic-related symptoms, injury, and infection. Fifty-eight percent (53/91) of patients experienced health care-related harm that had a negative effect on their health or quality of life. Peer experts were critical of the clinical care provided in 74% (67/91) of the cases. Provider-related (60%, 40/67), team-related (75%, 50/67), and system-related factors (21%, 14/67) were identified as contributing factors in these cases. Common examples of provider-related factors were deficiencies in clinical decision-making (48%, 19/40), failure to follow established procedures (43%, 17/40), and situational awareness (38%, 15/40). Common examples of team-related factors were deficiencies in medical record keeping (80%, 40/50) and communication breakdowns (56%, 28/50). All system-related factors were related to inadequate office procedures. CONCLUSION: We recommend that clinicians conduct appropriate physical examinations, keep up-to-date with clinical standards, and ensure their documentation reflects their assessment, the patient's condition, and the treatment rationale.

RéSUMé: OBJECTIF: La douleur chronique est une affection courante qui touche près d'une personne sur cinq au Canada. Les traitements par injections constituent l'une des méthodes utilisées pour traiter la douleur chronique. Bien que ces thérapies soient considérées comme des interventions relativement sécuritaires, elles comportent des risques inhérents qui peuvent entraîner des événements indésirables. Notre objectif était d'examiner ces événements liés à la sécurité des patient·es afin de cerner les thèmes qui pourraient être utilisés pour façonner les lignes directrices et les normes de pratique et améliorer la sécurité des patient·es. MéTHODE: Nous avons examiné les poursuites civiles fermées et les plaintes aux ordres de réglementation associées aux traitements par injection pour la douleur chronique dans la base de données de l'Association canadienne de protection médicale entre 2015 et 2019. Était considérée comme blessure toute lésion découlant de ou associée à des plans mis en place ou des mesures prises pendant la prestation de soins de santé, plutôt que comme une maladie ou une blessure sous-jacente. RéSULTATS: Sur les 91 cas identifiés, les complications les plus fréquemment signalées étaient des symptômes, des blessures et des infections neurologiques. Cinquante-huit pour cent (53/91) des patient·es ont subi des préjudices liés aux soins de santé qui ont eu un effet négatif sur leur santé ou leur qualité de vie. Les expert·es ont critiqué les soins cliniques fournis dans 74 % (67/91) des cas. Les facteurs liés aux prestataires (60 %, 40/67), à l'équipe (75 %, 50/67) et au système (21 %, 14/67) ont été identifiés comme des facteurs contributifs dans ces cas. Les exemples courants de facteurs liés aux prestataires comportaient les lacunes dans la prise de décision clinique (48 %, 19/40), le non-respect des procédures établies (43 %, 17/40) et la conscience situationnelle (38 %, 15/40). Les lacunes dans la tenue des dossiers médicaux (80 %, 40/50) et les problèmes de communication (56 %, 28/50) comptaient parmi les exemples courants de facteurs liés à l'équipe. Tous les facteurs identifiés comme étant systémiques étaient liés à des procédures administratives inadéquates. CONCLUSION: Nous recommandons aux cliniciennes et cliniciens de réaliser des examens physiques appropriés, de se tenir au courant des normes cliniques et de s'assurer que leur documentation reflète leur évaluation, l'état du/de la patient·e et la justification du traitement.

Temporal and Spatial Patterns of Inflammation and Tissue Injury in Patients with Postoperative Respiratory Failure after Lung Resection Surgery: A Nested Case-Control Study.

Thoracic surgeries involving resection of lung tissue pose a risk of severe postoperative pulmonary complications, including acute respiratory distress syndrome (ARDS) and respiratory failure. Lung resections require one-lung ventilation (OLV) and, thus, are at higher risk of ventilator-induced lung injury (VILI) attributable to barotrauma and volutrauma in the one ventilated lung, as well as hypoxemia and reperfusion injury on the operated lung. Further, we also aimed to assess the differences in localized and systemic markers of tissue injury/inflammation in those who developed respiratory failure after lung surgery versus matched controls who did not develop respiratory failure. We aimed to assess the different inflammatory/injury marker patterns induced in the operated and ventilated lung and how this compared to the systemic circulating inflammatory/injury marker pattern. A case-control study nested within a prospective cohort study was performed. Patients with postoperative respiratory failure after lung surgery (n = 5) were matched with control patients (n = 6) who did not develop postoperative respiratory failure. Biospecimens (arterial plasma, bronchoalveolar lavage separately from ventilated and operated lungs) were obtained from patients undergoing lung surgery at two timepoints: (1) just prior to initiation of OLV and (2) after lung resection was completed and OLV stopped. Multiplex electrochemiluminescent immunoassays were performed for these biospecimen. We quantified 50 protein biomarkers of inflammation and tissue injury and identified significant differences between those who did and did not develop postoperative respiratory failure. The three biospecimen types also display unique biomarker patterns.

Does an inflammatory diet affect mental well-being in late childhood and mid-life? A cross-sectional study.

Inflammatory diets are increasingly recognised as a modifiable determinant of mental illness. However, there is a dearth of studies in early life and across the full mental well-being spectrum (mental illness to positive well-being) at the population level. This is a critical gap given that inflammatory diet patterns and mental well-being trajectories typically establish by adolescence. We examined the associations of inflammatory diet scores with mental well-being in 11-12-year-olds and mid-life adults. Throughout Australia, 1759 11-12-year-olds (49 % girls) and 1812 parents (88 % mothers) contributed cross-sectional population-based data. Alternate inflammatory diet scores were calculated from a twenty-six-item FFQ, based on the prior literature and prediction of inflammatory markers. Participants reported negatively and positively framed mental well-being via psychosocial health, quality of life and life satisfaction surveys. We used causal inference modelling techniques via generalised linear regression models (mean differences and risk ratios (RR)) to examine how inflammatory diets might influence mental well-being. In children and adults, respectively, a 1 sd higher literature-derived inflammatory diet score conferred between a 44 % (RR 95 % CI 1·2, 1·8) to 57 % (RR 95 % CI 1·3, 2·0) and 54 % (95 % CI 1·2, 2·0) to 86 % (RR 95 % CI 1·4, 2·4) higher risk of being in the worst mental well-being category (i.e. <16th percentile) across outcome measures. Results for inflammation-derived scores were similar. BMI mediated effects (21-39 %) in adults. Inflammatory diet patterns were cross-sectionally associated with mental well-being at age 11-12 years, with similar effects observed in mid-adulthood. Reducing inflammatory dietary components in childhood could improve population-level mental well-being across the life course.

Thwarted Belongingness Mediates Interpersonal Stress and Suicidal Thoughts: An Intensive Longitudinal Study with High-risk Adolescents.

OBJECTIVE: Interpersonal negative life events (NLEs) have been linked to risk for suicidal thoughts and behaviors. However, little is known about how this risk is conferred over the short term and the mechanisms linking interpersonal NLEs to suicide risk, particularly in adolescents. This study used an intensive longitudinal design to examine thwarted belongingness with family and friends as potential mechanisms linking interpersonal NLEs to suicidal thoughts. METHOD: Forty-eight adolescents (Mage = 14.96 years; 64.6% female, 77.1% White), who recently received acute psychiatric care for suicide risk, were followed intensely for 28 days after discharge. Smartphone-based ecological momentary assessment was used to measure presence of interpersonal NLEs at the day level, fluctuations in thwarted belongingness with family and friends (separately) within day, and fluctuations in suicidal thoughts within day. A multi-level structural equation model was utilized to examine family thwarted belongingness and friend thwarted belongingness as parallel mediators in the relationship between interpersonal NLEs and next-day suicidal thoughts. RESULTS: Significant direct effects were observed between interpersonal NLEs and family thwarted belongingness, family thwarted belongingness and suicidal thoughts, and friend thwarted belongingness and suicidal thoughts. In addition, family, but not friend, thwarted belongingness significantly mediated the association between interpersonal NLEs and next-day suicidal thoughts. CONCLUSIONS: Interpersonal NLEs predicted greater suicidal thoughts over the short term (next day) in high-risk adolescents. Findings suggest how interpersonal NLEs may confer risk for suicidal thoughts - by reducing feelings of family belongingness. Future research is needed to examine how modifying belongingness may reduce suicide risk in adolescents.

Electrocatalytic Isoxazoline-Nanocarbon Metal Complexes.

We report the synthesis of new carbon-nanomaterial-based metal chelates that enable effective electronic coupling to electrocatalytic transition metals. In particular, multiwalled carbon nanotubes (MWCNTs) and few-layered graphene (FLG) were covalently functionalized by a microwave-assisted cycloaddition with nitrile oxides to form metal-binding isoxazoline functional groups with high densities. The covalent attachment was evidenced by Raman spectroscopy, and the chemical identity of the surface functional groups was confirmed by X-ray photoelectron spectroscopy (XPS) and time-of-flight secondary ion mass spectrometry (ToF-SIMS). The functional carbon nanomaterials effectively chelate precious metals Ir(III), Pt(II), and Ru(III), as well as earth-abundant metals such as Ni(II), to afford materials with metal contents as high as 3.0 atom %. The molecularly dispersed nature of the catalysts was confirmed by X-ray absorption spectroscopy (XAS) and energy-dispersive X-ray spectroscopy (STEM-EDS) elemental mapping. The interplay between the chelate structure on the graphene surface and its metal binding ability has also been investigated by a combination of experimental and computational studies. The defined ligands on the graphene surfaces enable the formation of structurally precise heterogeneous molecular catalysts. The direct attachment of the isoxazoline functional group on the graphene surfaces provides strong electronic coupling between the chelated metal species and the conductive carbon nanomaterial support. We demonstrate that the metal-chelated carbon nanomaterials are effective heterogeneous catalysts in the oxygen evolution reaction with low overpotentials and tunable catalytic activity.

Diet quality trajectories and cardiovascular phenotypes/metabolic syndrome risk by 11-12 years.

OBJECTIVE: To investigate associations between early-life diet trajectories and preclinical cardiovascular phenotypes and metabolic risk by age 12 years. METHODS: Participants were 1861 children (51% male) from the Longitudinal Study of Australian Children. At five biennial waves from 2-3 to 10-11 years: Every 2 years from 2006 to 2014, diet quality scores were collected from brief 24-h parent/self-reported dietary recalls and then classified using group-based trajectory modeling as 'never healthy' (7%), 'becoming less healthy' (17%), 'moderately healthy' (21%), and 'always healthy' (56%). At 11-12 years: During children's physical health Child Health CheckPoint (2015-2016), we measured cardiovascular functional (resting heart rate, blood pressure, pulse wave velocity, carotid elasticity/distensibility) and structural (carotid intima-media thickness, retinal microvasculature) phenotypes, and metabolic risk score (composite of body mass index z-score, systolic blood pressure, high-density lipoproteins cholesterol, triglycerides, and glucose). Associations were estimated using linear regression models (n = 1100-1800) adjusted for age, sex, and socioeconomic position. RESULTS: Compared to 'always healthy', the 'never healthy' trajectory had higher resting heart rate (2.6 bpm, 95% CI 0.4, 4.7) and metabolic risk score (0.23, 95% CI 0.01, 0.45), and lower arterial elasticity (-0.3% per 10 mmHg, 95% CI -0.6, -0.1) and distensibility (-1.2%, 95% CI -1.9, -0.5) (all effect sizes 0.3-0.4). Heart rate, distensibility, and diastolic blood pressure were progressively poorer for less healthy diet trajectories (linear trends p ≤ 0.02). Effects for systolic blood pressure, pulse wave velocity, and structural phenotypes were less evident. CONCLUSIONS: Children following the least healthy diet trajectory had poorer functional cardiovascular phenotypes and metabolic syndrome risk, including higher resting heart rate, one of the strongest precursors of all-cause mortality. Structural phenotypes were not associated with diet trajectories, suggesting the window to prevent permanent changes remains open to at least late childhood.

CuH-Catalyzed Olefin Functionalization: From Hydroamination to Carbonyl Addition.

In organic synthesis, ligand-modified copper(I) hydride (CuH) complexes have become well-known reagents and catalysts for selective reduction, particularly toward Michael acceptors and carbonyl compounds. Recently, our group and others have found that these hydride complexes undergo migratory insertion (hydrocupration) with relatively unactivated and electronically unpolarized olefins, producing alkylcopper intermediates that can be leveraged to forge a variety of useful bonds. The resulting formal hydrofunctionalization reactions have formed the basis for a resurgence of research in CuH catalysis. This Account chronicles the development of this concept in our research group, highlighting its origin in the context of asymmetric hydroamination, evolution to more general C-X bond-forming reactions, and applications in the addition of olefin-derived nucleophiles to carbonyl derivatives.Hydroamination, the formal insertion of an olefin into the N-H bond of an amine, is a process of significant academic and industrial interest, due to its potential to transform widely available alkenes and alkynes into valuable complex amines. We developed a polarity-reversed strategy for catalytic enantioselective hydroamination relying on the reaction of olefins with CuH to generate chiral organocopper intermediates, which are intercepted by electrophilic amine reagents. By engineering the auxiliary ligand, amine electrophile, and reaction conditions, the scope of this method has since been extended to include many types of olefins, including challenging internal olefins. Further, the scope of amine reagents has been expanded to enable the synthesis of primary, secondary, and tertiary amines as well as amides, N-alkylated heterocycles, and anilines. All of these reactions exhibit high regio- and stereoselectivity and, due to the mild conditions required, excellent tolerance for heterocycles and polar functional groups.Though the generation of alkylcopper species from olefins was originally devised as a means to solve the hydroamination problem, we soon found that these intermediates could react efficiently with an unexpectedly broad range of electrophiles, including alkyl halides, silicon reagents, arylpalladium species, heterocycles, and carbonyl derivatives. The general ability of olefins to function as precursors for nucleophilic intermediates has proved particularly advantageous in carbonyl addition reactions because it overcomes many of the disadvantages associated with traditional organometallic reagents. By removing the need for pregeneration of the nucleophile in a separate operation, CuH-catalyzed addition reactions of olefin-derived nucleophiles feature improved step economy, enhanced functional group tolerance, and the potential for catalyst control over regio- and stereoselectivity. Following this paradigm, feedstock olefins such as allene, butadiene, and styrene have been employed as reagents for asymmetric alkylation of ketones, imines, and aldehydes.

History of Depression, Elevated Body Mass Index, and Waist-to-Height Ratio in Preadolescent Children.

OBJECTIVE: This study aimed to evaluate whether a history of depression or self-injurious thoughts and behaviors predict elevated body mass index (BMI) and elevated waist-to-height ratio in preadolescents. METHODS: Baseline data were evaluated from a large, nationally representative cohort study of 9- and 10-year-old children (unweighted n = 11,875), the Adolescent Brain and Cognitive Development study. RESULTS: In the weighted sample, 10.6% of children had a history of depression, 7.0% had engaged in nonsuicidal self-injury, 13.1% had experienced suicidal ideation in their lifetime, and 1.1% had a history of attempted suicide. Among the children, 34.1% had an elevated BMI in the overweight or obese range and 31.9% had a waist-to-height ratio >0.5. In multivariate analyses, history of depression was associated with elevated BMI and waist-to-height ratio. Furthermore, interactions with sex were found; girls with a history of depression were more likely to have an elevated BMI (odds ratio = 1.47, 95% confidence interval = 1.24-1.74) and elevated waist-to-height ratio (odds ratio = 1.48, 95% confidence interval = 1.18-1.86) than girls without a history of depression, but no differences were observed between boys with and without a history of depression. Self-injurious thoughts and behaviors were not associated with elevated BMI or elevated waist-to-height. CONCLUSIONS: In this study, 9- and 10-year-old girls with a history of depression were more likely to have an elevated BMI and elevated waist-to-height ratio than girls with no history of depression. These results provide important clinical context in caring for preadolescents with a history of depression.

Suicidal thoughts and behaviors in preadolescents: Findings and replication in two population-based samples.

INTRODUCTION: Given increasing concern in suicide in preadolescent children, this study aimed to characterize and identify potential indicators of risk for suicidal ideation (SI) and suicide attempts (SAs) in this population. METHODS: Data were drawn from two population-based samples of preadolescents: the 2007 and 2010 Minnesota Student Survey and analyses were restricted to 11- and 12-year-olds. Sociodemographic characteristics, childhood maltreatment, parental relations, peer relations, and school climate were examined in relation to past-year SI and SA. To examine correlates of SI, unconfounded by risk for SA, individuals with a history of SA were excluded from SI analyses. Correlates of SA were examined among individuals with past-year SI. Logistic regression analyses were conducted with past-year SI and SA as criterion variables. RESULTS: Results from the 2007 and 2010 data sets were highly consistent. The prevalence of past-year SI was 9.28% and 9.25% in 2007 and 2010, respectively. Of the total sample, 1.90% and 1.87% reported a past-year SA (17.00% and 16.78% of those with past-year SI). Overall, effect sizes were generally modest to medium. The strongest effects were observed for sexual and physical abuse, parental support, and perceived safety at school (ps < .001). In multivariate analyses of SI and SA, sexual and physical abuse had the largest effect sizes (ORSI = 2.18 [95% CI = 1.90-2.51] to 2.96 [95% CI = 2.69-3.26]; ORSA = 1.55 [95% CI = 1.29-1.86] to 2.26 [95% CI = 1.82-2.80]). CONCLUSIONS: SI and SA occur at a concerning rate among preadolescent children. Screening for childhood sexual and physical abuse may be important for identifying those at risk for these clinical outcomes.

Waddell (Nonorganic) Signs and Their Association With Interventional Treatment Outcomes for Low Back Pain.

BACKGROUND: The rising use of injections to treat low back pain (LBP) has led to efforts to improve selection. Nonorganic (Waddell) signs have been shown to portend treatment failure for surgery and other therapies but have not been studied for minimally invasive interventions. METHODS: We prospectively evaluated the association between Waddell signs and treatment outcome in 3 cohorts: epidural steroid injections (ESI) for leg pain and sacroiliac joint (SIJ) injections and facet interventions for LBP. Categories of Waddell signs included nonanatomic tenderness, pain during sham stimulation, discrepancy in physical examination, overreaction, and regional disturbances divulging from neuroanatomy. The primary outcome was change in patient-reported "average" numerical rating scale for pain intensity (average NRS-PI), modeled as a function of the number of Waddell signs using simple linear regression. Secondary outcomes included a binary indicator of treatment response. We conducted secondary and sensitivity analyses to account for potential confounders. RESULTS: We enrolled 318 patients: 152 in the ESI cohort, 102 in the facet cohort, and 64 in the SIJ cohort, having sufficient data for primary analysis on 308 patients. Among these, 62% (n = 192) had no Waddell signs, 18% (n = 54) had 1 sign, 11% (n = 33) had 2, 5% (n = 16) had 3, 2% (n = 7) had 4, and about 2% (n = 6) had all 5 signs. The mean change in average NRS-PI in each of these 6 groups was -1.6 ± 2.6, -1.1 ± 2.7, -1.5 ± 2.5, -1.6 ± 2.6, -1 ± 1.5, and 0.7 ± 2.1, respectively, and their corresponding treatment failure rates were 54% (102 of 192), 67% (36 of 54), 70% (23 of 33), 75% (12 of 16), 71% (5 of 7), and 83% (5 of 6). In the primary analysis, an increasing number of Waddell signs were not associated with a significant decrease in average NRS-PI (coefficient [Coef] = 0.19; 95% confidence interval [CI], -0.43 to 0.05; P = .12). A higher number of Waddell signs were associated with treatment failure, with a 1.35 increased odds of treatment failure per cumulative number of signs (P = .008). CONCLUSIONS: Whereas this study found no consistent relationship between Waddell signs and decreased mean pain scores, a significant relationship between the number of Waddell signs and treatment failure was observed.