Nicotinamide for Skin-Cancer Chemoprevention in Transplant Recipients.

BACKGROUND: Immunosuppressed organ-transplant recipients have an increased incidence of, and mortality from, skin cancer. Nicotinamide (vitamin B3) enhances the repair of ultraviolet (UV) radiation-induced DNA damage, reduces the cutaneous immunosuppressive effects of UV radiation, and reduces the incidence of keratinocyte cancers (including squamous-cell and basal-cell carcinomas) and actinic keratoses among high-risk immunocompetent patients. Whether oral nicotinamide is useful for skin-cancer chemoprevention in organ-transplant recipients is unclear. METHODS: In this phase 3 trial, we randomly assigned, in a 1:1 ratio, organ-transplant recipients who had had at least two keratinocyte cancers in the past 5 years to receive 500 mg of nicotinamide or placebo twice daily for 12 months. Participants were examined for skin lesions by dermatologists at 3-month intervals for 12 months. The primary end point was the number of new keratinocyte cancers during the 12-month intervention period. Secondary end points included the numbers of squamous-cell and basal-cell carcinomas during the 12-month intervention period, the number of actinic keratoses until 6 months after randomization, safety, and quality of life. RESULTS: A total of 158 participants were enrolled, with 79 assigned to the nicotinamide group and 79 to the placebo group. The trial was stopped early owing to poor recruitment. At 12 months, there were 207 new keratinocyte cancers in the nicotinamide group and 210 in the placebo group (rate ratio, 1.0; 95% confidence interval, 0.8 to 1.3; P = 0.96). No significant between-group differences in squamous-cell and basal-cell carcinoma counts, actinic keratosis counts, or quality-of-life scores were observed. Adverse events and changes in blood or urine laboratory variables were similar in the two groups. CONCLUSIONS: In this 12-month, placebo-controlled trial, oral nicotinamide therapy did not lead to lower numbers of keratinocyte cancers or actinic keratoses in immunosuppressed solid-organ transplant recipients. (Funded by the National Health and Medical Research Council; ONTRANS Australian New Zealand Clinical Trials Registry number, ACTRN12617000599370.).

PIP2 depletion and altered endocytosis caused by expression of Alzheimer's disease-protective variant PLCγ2 R522.

Variants identified in genome-wide association studies have implicated immune pathways in the development of Alzheimer's disease (AD). Here, we investigated the mechanistic basis for protection from AD associated with PLCγ2 R522, a rare coding variant of the PLCG2 gene. We studied the variant's role in macrophages and microglia of newly generated PLCG2-R522-expressing human induced pluripotent cell lines (hiPSC) and knockin mice, which exhibit normal endogenous PLCG2 expression. In all models, cells expressing the R522 mutation show a consistent non-redundant hyperfunctionality in the context of normal expression of other PLC isoforms. This manifests as enhanced release of cellular calcium ion stores in response to physiologically relevant stimuli like Fc-receptor ligation or exposure to Aß oligomers. Expression of the PLCγ2-R522 variant resulted in increased stimulus-dependent PIP2 depletion and reduced basal PIP2 levels in vivo. Furthermore, it was associated with impaired phagocytosis and enhanced endocytosis. PLCγ2 acts downstream of other AD-related factors, such as TREM2 and CSF1R, and alterations in its activity directly impact cell function. The inherent druggability of enzymes such as PLCγ2 raises the prospect of PLCγ2 manipulation as a future therapeutic approach in AD.

The synthetic TRPML1 agonist ML-SA1 rescues Alzheimer-related alterations of the endosomal-autophagic-lysosomal system.

Abnormalities in the endosomal-autophagic-lysosomal (EAL) system are an early event in Alzheimer's disease (AD) pathogenesis. However, the mechanisms underlying these abnormalities are unclear. The transient receptor potential channel mucolipin 1(TRPML1, also known as MCOLN1), a vital endosomal-lysosomal Ca2+ channel whose loss of function leads to neurodegeneration, has not been investigated with respect to EAL pathogenesis in late-onset AD (LOAD). Here, we identify pathological hallmarks of TRPML1 dysregulation in LOAD neurons, including increased perinuclear clustering and vacuolation of endolysosomes. We reveal that induced pluripotent stem cell (iPSC)-derived human cortical neurons expressing APOE ε4, the strongest genetic risk factor for LOAD, have significantly diminished TRPML1-induced endolysosomal Ca2+ release. Furthermore, we found that blocking TRPML1 function in primary neurons by depleting the TRPML1 agonist PI(3,5)P2 via PIKfyve inhibition, recreated multiple features of EAL neuropathology evident in LOAD. This included increased endolysosomal Ca2+ content, enlargement and perinuclear clustering of endolysosomes, autophagic vesicle accumulation and early endosomal enlargement. Strikingly, these AD-like neuronal EAL defects were rescued by TRPML1 reactivation using its synthetic agonist ML-SA1. These findings implicate defects in TRPML1 in LOAD EAL pathogenesis and present TRPML1 as a potential therapeutic target.

Towards a youth mental health paradigm: a perspective and roadmap.

Most mental disorders have a typical onset between 12 and 25 years of age, highlighting the importance of this period for the pathogenesis, diagnosis, and treatment of mental ill-health. This perspective addresses interactions between risk and protective factors and brain development as key pillars accounting for the emergence of psychopathology in youth. Moreover, we propose that novel approaches towards early diagnosis and interventions are required that reflect the evolution of emerging psychopathology, the importance of novel service models, and knowledge exchange between science and practitioners. Taken together, we propose a transformative early intervention paradigm for research and clinical care that could significantly enhance mental health in young people and initiate a shift towards the prevention of severe mental disorders.

Testing the interpersonal theory of suicide in adolescents: A multi-wave longitudinal study.

BACKGROUND: Suicide is a major public health crisis among youth. Several prominent theories, including the Interpersonal Theory of Suicide (IPTS), aim to characterize the factors leading from suicide ideation to action. These theories are largely based on findings in adults and require testing and elaboration in adolescents. METHODS: Data were examined from high-risk 13-18-year-old adolescents (N = 167) participating in a multi-wave, longitudinal study; 63% of the sample exhibited current suicidal thoughts or recent behaviors (n = 105). The study included a 6-month follow-up period with clinical interviews and self-report measures at each of the four assessments as well as weekly smartphone-based assessments of suicidal thoughts and behaviors. Regression and structural equation models were used to probe hypotheses related to the core tenets of the IPTS. RESULTS: Feelings of perceived burdensomeness were associated with more severe self-reported suicidal ideation (b = 0.58, t(158) = 7.64, p < .001). Similarly, burdensomeness was associated with more frequent ideation based on weekly smartphone ratings (b = 0.11, t(1460) = 3.41, p < .001). Contrary to IPTS hypotheses, neither feelings of thwarted belongingness, nor interactions between burdensomeness and thwarted belongingness were significantly associated with ideation (ps > .05). Only elevated depression severity was associated with greater odds of suicide events (i.e., suicide attempts, psychiatric hospitalizations, and/or emergency department visits for suicide concerns) during the follow-up period (OR = 1.83, t(158) = 2.44, p = .01). No effect of acquired capability was found. CONCLUSIONS: Perceptions of burdensomeness to others reflect a critical risk factor for suicidal ideation among high-risk adolescents. Null findings with other IPTS constructs may suggest a need to adopt more developmentally sensitive models or measures of interpersonal and acquired capability risk factors for youth. Refining methods and theoretical models of suicide risk may help improve the identification of high-risk cases and inform clinical intervention.

Detecting adolescent depression through passive monitoring of linguistic markers in smartphone communication.

BACKGROUND: Cross sectional studies have identified linguistic correlates of major depressive disorder (MDD) in smartphone communication. However, it is unclear whether monitoring these linguistic characteristics can detect when an individual is experiencing MDD, which would facilitate timely intervention. METHODS: Approximately 1.2 million messages typed into smartphone social communication apps (e.g. texting, social media) were passively collected from 90 adolescents with a range of depression severity over a 12-month period. Sentiment (i.e. positive vs. negative valence of text), proportions of first-person singular pronouns (e.g. 'I'), and proportions of absolutist words (e.g. 'all') were computed for each message and converted to weekly aggregates temporally aligned with weekly MDD statuses obtained from retrospective interviews. Idiographic, multilevel logistic regression models tested whether within-person deviations in these linguistic features were associated with the probability of concurrently meeting threshold for MDD. RESULTS: Using more first-person singular pronouns in smartphone communication relative to one's own average was associated with higher odds of meeting threshold for MDD in the concurrent week (OR = 1.29; p = .007). Sentiment (OR = 1.07; p = .54) and use of absolutist words (OR = 0.99; p = .90) were not related to weekly MDD. CONCLUSIONS: Passively monitoring use of first-person singular pronouns in adolescents' smartphone communication may help detect MDD, providing novel opportunities for early intervention.

The emerging spectrum of fetal acetylcholine receptor antibody-related disorders (FARAD).

In utero exposure to maternal antibodies targeting the fetal acetylcholine receptor isoform (fAChR) can impair fetal movement, leading to arthrogryposis multiplex congenita (AMC). Fetal AChR antibodies have also been implicated in apparently rare, milder myopathic presentations termed fetal acetylcholine receptor inactivation syndrome (FARIS). The full spectrum associated with fAChR antibodies is still poorly understood. Moreover, since some mothers have no myasthenic symptoms, the condition is likely underreported, resulting in failure to implement effective preventive strategies. Here we report clinical and immunological data from a multicentre cohort (n = 46 cases) associated with maternal fAChR antibodies, including 29 novel and 17 previously reported with novel follow-up data. Remarkably, in 50% of mothers there was no previously established myasthenia gravis (MG) diagnosis. All mothers (n = 30) had AChR antibodies and, when tested, binding to fAChR was often much greater than that to the adult AChR isoform. Offspring death occurred in 11/46 (23.9%) cases, mainly antenatally due to termination of pregnancy prompted by severe AMC (7/46, 15.2%), or during early infancy, mainly from respiratory failure (4/46, 8.7%). Weakness, contractures, bulbar and respiratory involvement were prominent early in life, but improved gradually over time. Facial (25/34; 73.5%) and variable peripheral weakness (14/32; 43.8%), velopharyngeal insufficiency (18/24; 75%) and feeding difficulties (16/36; 44.4%) were the most common sequelae in long-term survivors. Other unexpected features included hearing loss (12/32; 37.5%), diaphragmatic paresis (5/35; 14.3%), CNS involvement (7/40; 17.5%) and pyloric stenosis (3/37; 8.1%). Oral salbutamol used empirically in 16/37 (43.2%) offspring resulted in symptom improvement in 13/16 (81.3%). Combining our series with all previously published cases, we identified 21/85 mothers treated with variable combinations of immunotherapies (corticosteroids/intravenous immunoglobulin/plasmapheresis) during pregnancy either for maternal MG symptom control (12/21 cases) or for fetal protection (9/21 cases). Compared to untreated pregnancies (64/85), maternal treatment resulted in a significant reduction in offspring deaths (P < 0.05) and other complications, with treatment approaches involving intravenous immunoglobulin/ plasmapheresis administered early in pregnancy most effective. We conclude that presentations due to in utero exposure to maternal (fetal) AChR antibodies are more common than currently recognized and may mimic a wide range of neuromuscular disorders. Considering the wide clinical spectrum and likely diversity of underlying mechanisms, we propose 'fetal acetylcholine receptor antibody-related disorders' (FARAD) as the most accurate term for these presentations. FARAD is vitally important to recognize, to institute appropriate management strategies for affected offspring and to improve outcomes in future pregnancies. Oral salbutamol is a symptomatic treatment option in survivors.

The 2017 and 2022 ILAE epilepsy classification systems identify needs and opportunities in care: A paediatric hospital-based study.

OBJECTIVES: There is a paucity of studies reporting the epilepsy spectrum using the 2017 and 2022 ILAE classification systems in everyday clinical practice. To identify gaps and opportunities in care we evaluated a hospital-based cohort applying these epilepsy classification systems, including aetiology and co-morbidity, and the utility of molecular genetic diagnosis to identify available precision therapies. METHODS: Cross sectional retrospective study of all children with epilepsy (≤16 years) attending University Hospital Galway (2017-2022). Data collection and analysis of each case was standardised to ensure a systematic approach and application of the recent ILAE categorisation and terminology (2017 and 2022). Ethics approval was obtained. RESULTS: Among 356 children, epilepsy was classified as focal (46.1 %), generalised (38.8 %), combined (6.2 %), and unknown (9 %). Epilepsy syndrome was determined in 145/356 (40.7 %), comprising 24 different syndromes, most commonly SeLECTS (9 %), CAE (7 %), JAE (6.2 %) and IESS (5.9 %). New aetiology-specific syndromes were identified (e.g. CDKL5-DEE). Molecular diagnosis was confirmed in 19.9 % (n = 71) which encompassed monogenic (13.8 %) and chromosomopathy/CNV (6.2 %). There was an additional 35.7 % (n = 127) of patients who had a presumed genetic aetiology of epilepsy. Remaining aetiology included structural (18.8 %, n = 67), infectious (2 %, n = 7), metabolic (1.7 %, n = 6) and unknown (30.3 %, n = 108). Encephalopathy categorisation was determined in 182 patients (DE in 38.8 %; DEE in a further 11.8 %) associated with a range of co-morbidities categorised as global delay (29.2 %, n = 104), severe neurological impairment (16.3 %, n = 58), and ASD (14.6 %, n = 52). Molecular-based "precision therapy" was deemed available in 21/356 (5.9 %) patients, with "molecular precision" approach utilised in 13/356 (3.7 %), and some benefit noted in 6/356 (1.7 %) of overall cohort or 6/71 (8.5 %) of the molecular cohort. CONCLUSION: Applying the latest ILAE epilepsy classification systems allow comparison across settings and identifies a major neuro-developmental co-morbidity rate and a large genetic aetiology. We identified very few meaningful molecular-based disease modifying "precision therapies". There is a monumental gap between aetiological identification, and impact of meaningful therapies, thus the new 2017/2022 classification clearly identifies the major challenges in the provision of routine epilepsy care.

Importance of investing in adolescence from a developmental science perspective.

This review summarizes the case for investing in adolescence as a period of rapid growth, learning, adaptation, and formational neurobiological development. Adolescence is a dynamic maturational period during which young lives can pivot rapidly-in both negative and positive directions. Scientific progress in understanding adolescent development provides actionable insights into windows of opportunity during which policies can have a positive impact on developmental trajectories relating to health, education, and social and economic success. Given current global changes and challenges that affect adolescents, there is a compelling need to leverage these advances in developmental science to inform strategic investments in adolescent health.

Soluble mutant huntingtin drives early human pathogenesis in Huntington's disease.

Huntington's disease (HD) is an incurable inherited brain disorder characterised by massive degeneration of striatal neurons, which correlates with abnormal accumulation of misfolded mutant huntingtin (mHTT) protein. Research on HD has been hampered by the inability to study early dysfunction and progressive degeneration of human striatal neurons in vivo. To investigate human pathogenesis in a physiologically relevant context, we transplanted human pluripotent stem cell-derived neural progenitor cells (hNPCs) from control and HD patients into the striatum of new-born mice. Most hNPCs differentiated into striatal neurons that projected to their target areas and established synaptic connexions within the host basal ganglia circuitry. Remarkably, HD human striatal neurons first developed soluble forms of mHTT, which primarily targeted endoplasmic reticulum, mitochondria and nuclear membrane to cause structural alterations. Furthermore, HD human cells secreted extracellular vesicles containing mHTT monomers and oligomers, which were internalised by non-mutated mouse striatal neurons triggering cell death. We conclude that interaction of mHTT soluble forms with key cellular organelles initially drives disease progression in HD patients and their transmission through exosomes contributes to spread the disease in a non-cell autonomous manner.

Early mortality in STXBP1-related disorders.

INTRODUCTION: Pathogenic variants in STXBP1 cause a spectrum of disorders mainly consisting of developmental and epileptic encephalopathy (DEE), often featuring drug-resistant epilepsy. An increased mortality risk occurs in individuals with drug-resistant epilepsy and DEE, with sudden unexpected death in epilepsy (SUDEP) often the major cause of death. This study aimed to identify the rate and causes of mortality in STXBP1-related disorders. METHODS: Through an international call, we analyzed data on individuals with STXBP1 pathogenic variants, who passed away from causes related to their disease. RESULTS: We estimated a mortality rate of 3.2% (31/966), based on the STXBP1 Foundation and the STXBP1 Global Connect registry. In total, we analyzed data on 40 individuals (23 males) harboring pathogenic STXBP1 variants, collected from different centers worldwide. They died at a median age of 13 years (range: 11 months-46 years). The most common cause of death was SUDEP (36%), followed by pulmonary infections and respiratory complications (33%). The incidence of SUDEP peaked in mid-childhood, while non-SUDEP causes were more frequent in early childhood or adulthood (p = 0.006). In the most severe phenotypes, death was related to non-SUDEP causes (p = 0.018). CONCLUSION: We found a mortality rate in STXBP1-related disorders similar to other DEEs, with an early age at death and SUDEP as well as pulmonary infections as the main cause of death. These findings assist in prognostic evaluation and genetic counseling for the families. They help to define the mortality risk of STXBP1-related disorders and implement preventative strategies.

Complement receptor 1 is expressed on brain cells and in the human brain.

Genome wide association studies (GWAS) have highlighted the importance of the complement cascade in pathogenesis of Alzheimer's disease (AD). Complement receptor 1 (CR1; CD35) is among the top GWAS hits. The long variant of CR1 is associated with increased risk for AD; however, roles of CR1 in brain health and disease are poorly understood. A critical confounder is that brain expression of CR1 is controversial; failure to demonstrate brain expression has provoked the suggestion that peripherally expressed CR1 influences AD risk. We took a multi-pronged approach to establish whether CR1 is expressed in brain. Expression of CR1 at the protein and mRNA level was assessed in human microglial lines, induced pluripotent stem cell (iPSC)-derived microglia from two sources and brain tissue from AD and control donors. CR1 protein was detected in microglial lines and iPSC-derived microglia expressing different CR1 variants when immunostained with a validated panel of CR1-specific antibodies; cell extracts were positive for CR1 protein and mRNA. CR1 protein was detected in control and AD brains, co-localizing with astrocytes and microglia, and expression was significantly increased in AD compared to controls. CR1 mRNA expression was detected in all AD and control brain samples tested; expression was significantly increased in AD. The data unequivocally demonstrate that the CR1 transcript and protein are expressed in human microglia ex vivo and on microglia and astrocytes in situ in the human brain; the findings support the hypothesis that CR1 variants affect AD risk by directly impacting glial functions.

Brain volumes in alcohol use disorder: Do females and males differ? A whole-brain magnetic resonance imaging mega-analysis.

Emerging evidence suggests distinct neurobiological correlates of alcohol use disorder (AUD) between sexes, which however remain largely unexplored. This work from ENIGMA Addiction Working Group aimed to characterize the sex differences in gray matter (GM) and white matter (WM) correlates of AUD using a whole-brain, voxel-based, multi-tissue mega-analytic approach, thereby extending our recent surface-based region of interest findings on a nearly matching sample using a complementary methodological approach. T1-weighted magnetic resonance imaging (MRI) data from 653 people with AUD and 326 controls was analyzed using voxel-based morphometry. The effects of group, sex, group-by-sex, and substance use severity in AUD on brain volumes were assessed using General Linear Models. Individuals with AUD relative to controls had lower GM volume in striatal, thalamic, cerebellar, and widespread cortical clusters. Group-by-sex effects were found in cerebellar GM and WM volumes, which were more affected by AUD in females than males. Smaller group-by-sex effects were also found in frontotemporal WM tracts, which were more affected in AUD females, and in temporo-occipital and midcingulate GM volumes, which were more affected in AUD males. AUD females but not males showed a negative association between monthly drinks and precentral GM volume. Our results suggest that AUD is associated with both shared and distinct widespread effects on GM and WM volumes in females and males. This evidence advances our previous region of interest knowledge, supporting the usefulness of adopting an exploratory perspective and the need to include sex as a relevant moderator variable in AUD.

Longitudinal changes in within-salience network functional connectivity mediate the relationship between childhood abuse and neglect, and mental health during adolescence.

BACKGROUND: Understanding the neurobiological underpinnings of childhood maltreatment is vital given consistent links with poor mental health. Dimensional models of adversity purport that different types of adversity likely have distinct neurobiological consequences. Adolescence is a key developmental period, during which deviations from normative neurodevelopment may have particular relevance for mental health. However, longitudinal work examining links between different forms of maltreatment, neurodevelopment, and mental health is limited. METHODS: In the present study, we explored associations between abuse, neglect, and longitudinal development of within-network functional connectivity of the salience (SN), default mode (DMN), and executive control network in 142 community residing adolescents. Resting-state fMRI data were acquired at age 16 (T1; M = 16.46 years, s.d. = 0.52, 66F) and 19 (T2; mean follow-up period: 2.35 years). Mental health data were also collected at T1 and T2. Childhood maltreatment history was assessed prior to T1. RESULTS: Abuse and neglect were both found to be associated with increases in within-SN functional connectivity from age 16 to 19. Further, there were sex differences in the association between neglect and changes in within-DMN connectivity. Finally, increases in within-SN connectivity were found to mediate the association between abuse/neglect and lower problematic substance use and higher depressive symptoms at age 19. CONCLUSIONS: Our findings suggest that childhood maltreatment is associated with altered neurodevelopmental trajectories, and that changes in salience processing may be linked with risk and resilience for the development of depression and substance use problems during adolescence, respectively. Further work is needed to understand the distinct neurodevelopmental and mental health outcomes of abuse and neglect.

Development of morning-eveningness in adolescence: implications for brain development and psychopathology.

BACKGROUND: Morning-evening preference is defined as an individual's preference for a morning- or evening-oriented rhythm. Across adolescence, a preference for eveningness becomes more predominant. Although eveningness is cross-sectionally associated with internalizing and externalizing psychopathology, few studies have examined developmental changes in eveningness and its potential biological substrates. Here, we investigated the longitudinal relationships among the trajectory of eveningness preference, internalizing and externalizing psychopathology and white matter development, across adolescence. METHODS: Two-hundred and nine adolescents (49% male) were assessed longitudinally at four separate time points between 12 and 19 years of age. Morning-evening preference and internalizing and externalizing symptoms were assessed at each time point. Diffusion-weighted images were acquired on a subset of participants at the final two time points to estimate changes in global mean fractional anisotropy (FA). Linear mixed models were performed to estimate the change in eveningness over time. A series of linear regression models assessed the influence of change in eveningness on psychopathology and white matter development at age 19. RESULTS: Across the sample, a preference for eveningness became more predominant by 19 years of age. Greater individual-level change towards eveningness significantly predicted greater severity in externalizing, but not internalizing, symptoms at 19 years of age. In contrast, change in psychopathology from 12 to 19 years of age was not associated with morning-eveningness at age 19. A change towards eveningness predicted an attenuated increase in FA between 17 and 19 years of age. CONCLUSIONS: This study suggests that developmental changes in morning-evening preference may predict both neurodevelopmental and psychological outcomes in adolescents.

Ultra-low current electrospray ionization of chloroform solution for the analysis of perfluorinated sulfonic acids.

RATIONALE: Femtoamp and picoamp electrospray ionization (ESI) characteristics of a nonpolar solvent were explored. The direct ESI mass spectrometry analysis of chloroform extract solution enabled rapid analysis of perfluorinated sulfonic acid analytes in drinking water. METHODS: Neat chloroform solvent and extracts were directly used in a typical wire-in ESI setup using micrometer emitter tips. Ionization currents were measured with femtoamp sensitivity while ramping the spray voltage from 0 to -5000 V. Methanol was used as a comparison to illustrate the characteristics of electrospraying chloroform. The effects of spray voltage and inlet temperature were studied. A liquid-liquid extraction workflow was developed to analyze perfluorooctanoate sulfonate (PFOS) in drinking water using an ion-trap mass spectrometer. RESULTS: The ionization onset of chloroform solution was 41 ± 17 fA at 300 V. The ionization current gradually increased with voltage while remaining below 100 pA when using voltages up to -5000 V. The ion signal of PFOS was significantly enhanced to improve the limit of detection (LoD) to 25 ppt in chloroform. Coupled with a liquid-liquid extraction workflow, LoD of 0.38-5.1 ppt and a quantitation range of 5-400 ppt were achieved for perfluorinated sulfonic compounds in 1-ml water samples. CONCLUSIONS: Femtoamp and picoamp modes expand the solvent compatibility range of ESI and can enable quantitative analysis in parts per trillion (ppt) concentrations.

Effects of concurrent exercise training on body composition, systemic inflammation, and components of metabolic syndrome in inactive academics: a randomised controlled trial.

PURPOSE: Low physical activity in the academic workplace may increase the risk of cardiometabolic disease. This randomised controlled trial investigated the effect of 14 weeks of concurrent exercise training (CT) on components of metabolic syndrome, body composition, insulin resistance, and markers of systemic inflammation in inactive academics. METHODS: 59 inactive academics were randomised into a CT (n = 29) or wait-list control group (n = 30). CT performed supervised training at an onsite facility 3 times per week for 14 weeks and cardiometabolic health was assessed pre- and post-intervention. Aerobic capacity was measured via a metabolic cart. Dual-Energy X-ray Absorptiometry measured fat mass, lean mass, and central adiposity. Fasting blood samples were analysed for interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), glucose, and lipid profile. RESULTS: Following the intervention, there was a decrease in fat mass (mean ± SD; - 1.3 ± 1.4%), android fat mass (median (IQR); - 0.06 (0.27) kg), and visceral adipose tissue (median (IQR); - 66 (110) cm3) in CT, but not control. Lean mass (median (IQR); 1.35 (1.86) kg) and aerobic capacity (mean ± SD; 4.0 ± 3.1 mL/kg/min) increased in CT, but not in control. There were no changes in IL-6, TNF-a, HOMA-IR, glucose, or lipid profile in response to the intervention (P > 0.05). Changes in insulin resistance were positively associated with IL-6 in the control group only (coefficients [95%CI]; 5.957 [2.961, 8.953]). CONCLUSION: Implementing combined aerobic and resistance exercise training programs in academic institutions may be an appropriate intervention to increase physical activity and reduce risk factors associated with cardiometabolic disease. TRIAL REGISTRATION: The study was registered with the Australian New Zealand Clinical Trials Registry on the 23rd of April, 2019 (ACTRN12619000608167).

Maternal depression, parental attributions, and adolescent psychopathology: An evaluation using observational and video-mediated recall methods.

Parenting styles associated with maternal depression are a risk factor for adolescent psychopathology, and maternal attributional styles may be a key mechanism in this relationship. Mother-adolescent dyads (N = 180; 96 male; ages 10-15) completed in-person interactions and then the mothers participated in a video-mediated recall procedure to assess maternal attributions. Maternal depression was associated with negative attributions. Negative attributions were associated with low parental acceptance, aggressive parenting, and low positive parenting. Positive maternal attributions were associated with less aggressive parenting, and more positive parenting during one interaction task. Adolescent externalizing behaviors were associated with negative attributions. Future research should evaluate whether maternal attributions mediate the association between maternal depression and both parenting behaviors and adolescent mental health.

The Impact of Time and State Opioid Legislation on Opioid Prescription Filling in Total Ankle Arthroplasty.

Total ankle arthroplasty (TAA) is an increasingly utilized treatment for ankle arthritis, and opioids are commonly used as part of perioperative pain control. However, many states have enacted opioid-limiting legislation to reduce perioperative opioid prescribing. The aim of this study was to evaluate the impact of time and state legislation on perioperative opioid prescribing in TAA. This study is a retrospective, observational review of 90-day perioperative opioid prescribing in 1,829 patients undergoing TAA throughout the United States using a large insurance database. Initial and cumulative volumes and rates of opioid prescription filling were recorded along with baseline patient and operative characteristics. Dates of state legislation enactment were also recorded. Student t-tests, analysis of variance, and multivariable linear and logistic regression were utilized to analyze the impact of time and state legislation on opioid prescription filling. In the 90-day perioperative time period, initial and cumulative opioid prescription filling in oxycodone 5-mg equivalents has decreased significantly from 2010 (63.8 initial and 163.3 cumulative) to 2019 (41.1 initial and 67.2 cumulative). States with opioid-limiting legislation saw larger and more significant reductions in initial and cumulative opioid prescription filling preact to postact (63.3-50.6 with legislation vs 61.4-51.9 without legislation initial and 146.4-93.3 with legislation vs 125.1-108.6 without legislation cumulative). This study demonstrates that foot and ankle surgeons in states with opioid-limiting legislation have responded by significantly reducing 90-day perioperative opioid prescribing in TAA. These results encourage states without legislation to enact opioid-specific laws to reduce opioid prescribing.

Selective activation and down-regulation of Trk receptors by neurotrophins in human neurons co-expressing TrkB and TrkC.

In the central nervous system, most neurons co-express TrkB and TrkC, the tyrosine kinase receptors for brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT3). As NT3 can also activate TrkB, it has been difficult to understand how NT3 and TrkC can exert unique roles in the assembly of neuronal circuits. Using neurons differentiated from human embryonic stem cells expressing both TrkB and TrkC, we compared Trk activation by BDNF and NT3. To avoid the complications resulting from TrkB activation by NT3, we also generated neurons from stem cells engineered to lack TrkB. We found that NT3 activates TrkC at concentrations lower than those of BDNF needed to activate TrkB. Downstream of Trk activation, the changes in gene expression caused by TrkC activation were found to be similar to those resulting from TrkB activation by BDNF, including a number of genes involved in synaptic plasticity. At high NT3 concentrations, receptor selectivity was lost as a result of TrkB activation. In addition, TrkC was down-regulated, as was also the case with TrkB at high BDNF concentrations. By contrast, receptor selectivity as well as reactivation were preserved when neurons were exposed to low neurotrophin concentrations. These results indicate that the selectivity of NT3/TrkC signalling can be explained by the ability of NT3 to activate TrkC at concentrations lower than those needed to activate TrkB. They also suggest that in a therapeutic perspective, the dosage of Trk receptor agonists will need to be taken into account if prolonged receptor activation is to be achieved.