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BACKGROUND: Methylphenidate is the most frequently prescribed medication for the treatment of ADHD in children and adolescents in many countries. Although many randomised controlled trials support short-term efficacy, tolerability, and safety, data on long-term safety and tolerability are scarce. The aim of this study was to investigate the safety of methylphenidate over a 2-year period in relation to growth and development, psychiatric health, neurological health, and cardiovascular function in children and adolescents. METHODS: We conducted a naturalistic, longitudinal, controlled study as part of the ADDUCE research programme in 27 European child and adolescent mental health centres in the UK, Germany, Switzerland, Italy, and Hungary. Participants aged 6-17 years were recruited into three cohorts: medication-naive ADHD patients who intended to start methylphenidate treatment (methylphenidate group), medication-naive ADHD patients who did not intend to start any ADHD medication (no-methylphenidate group), and a control group without ADHD. Children with ADHD diagnosed by a qualified clinician according to the DSM-IV criteria and, in the control group, children who scored less than 1·5 on average on the Swanson, Nolan, and Pelham IV rating scale for ADHD items, and whose hyperactivity score on the parent-rated Strengths and Difficulties Questionnaire was within the normal range (

We use the small scales of the Dark Energy Survey (DES) Year-3 cosmic shear measurements, which are excluded from the DES Year-3 cosmological analysis, to constrain the baryonic feedback. To model the baryonic feedback, we adopt a baryonic correction model and use the numerical package \texttt{Baccoemu} to accelerate the evaluation of the baryonic nonlinear matter power spectrum. We design our analysis pipeline to focus on the constraints of the baryonic suppression effects, utilizing the implication given by a principal component analysis on the Fisher forecasts. Our constraint on the baryonic effects can then be used to better model and ameliorate the effects of baryons in producing cosmological constraints from the next generation large-scale structure surveys. We detect the baryonic suppression on the cosmic shear measurements with a $\sim 2 \sigma$ significance. The characteristic halo mass for which half of the gas is ejected by baryonic feedback is constrained to be $M_c > 10^{13.2} h^{-1} M_{\odot}$ (95\% C.L.). The best-fit baryonic suppression is $\sim 5\%$ at $k=1.0 {\rm Mpc}\ h^{-1}$ and $\sim 15\%$ at $k=5.0 {\rm Mpc} \ h^{-1}$. Our findings are robust with respect to the assumptions about the cosmological parameters, specifics of the baryonic model, and intrinsic alignments., Comment: 20 pages, 10 figures. DES Collaboration, Year-3 analysis

European neuropsychopharmacology : ENP 64, 63-71 (2022). doi:10.1016/j.euroneuro.2022.09.001, Published by Elsevier, Amsterdam

Among other responsibilities, youth sport coaches are positioned to monitor and address the mental health needs of their athletes. Despite this, there are limited interventions aimed at improving coaches’ mental health literacy. Using a mixed-methods design, the aim of this pilot study was to evaluate the feasibility, acceptability, and mental health literacy outcomes associated with a brief (75 min) workshop for youth sport coaches. Fourteen coaches (13 males, one female) completed pre- and postworkshop surveys measuring indices of mental health literacy, and 10 of these same participants engaged in a semistructured interview 1-month later. Overall, coaches who participated in the pilot workshop reported significant improvements in depression literacy, intentions to seek self-help for oneself and their athletes, and knowledge and confidence to provide help. In addition, coaches reported positive impressions of the workshop during the follow-up interviews and provided concrete examples of program content application. An important suggestion made by coaches was the need to align the workshop content to governing policy. Taken together, this pilot mental health literacy workshop for youth sport coaches shows strong promise and is ready for large-scale dissemination.

The Goldacre review, published in April, 2022, 1 is a landmark evaluation of the use, availability, and safety of National Health Service (NHS) data across all four nations of the UK. The review underscores the necessary role of data in driving health-care improvement and innovation, and the potential risks inherent in using data routinely contributed by health service users. The review recommends a radical overhaul in NHS data curation, access, and analysis, and, crucially, argues that substantial new resources must be marshalled to make this aspiration a reality.

The salt metathesis reactions of the yttrium methanediide iodide complex [Y(BIPM)(I)(THF)2] (BIPM = {C(PPh2NSiMe3)2}) with the group 1 silanide ligand transfer agents MSiR3 (M = Na, R3 = tBu2Me or tBu3; M = K, R3 = (SiMe3)3) gave the yttrium methanediide silanide complexes [Y(BIPM)(SitBu2Me)(THF)] (1), [Y(BIPM)(SitBu3)(THF)] (2) and [Y(BIPM){Si(SiMe3)3}(THF)] (3). Complexes 1-3 provide rare examples of structurally authenticated rare earth metal-silicon bonds, and were characterized by single crystal X-ray diffraction, multinuclear NMR and ATR-IR spectroscopy, and elemental analysis. Density functional theory calculations were performed on 1-3 to probe their electronic structures further to reveal predominantly ionic Y–Si bonding. The computed Y–Si bonds show lower covalency than Y=C bonds, which are in turn best represented by Y+–C– dipolar forms due to the strong σ-donor properties of the silanide ligands investigated; these observations are in accord with experimentally-obtained 13C{1H} and 29Si{1H} NMR data for 1-3 and related Y(III) BIPM alkyl complexes in the literature. Preliminary reactivity studies were performed, with complex 1 treated separately with benzophenone, azobenzene and N,N′-dicyclohexyl-carbodiimide. 29Si{1H} and 31P{1H} NMR spectra of these reaction mixtures indicated that 1,2-migratory insertion of the unsaturated substrate into the Y–Si bond is favored, whilst for the latter substrate a [2 + 2] cycloaddition reaction also occurs at the Y=C bond to afford [Y{C(PPh2NSiMe3)2[C(NCy)2]-κ4C,N,N′,N′}{C(NCy)2(SitBu2Me)-κ2N,N′}] (4); these reactivity profiles complement and contrast with those of Y(III) BIPM alkyl complexes.

Prior work on teacher candidates in Washington State has shown that about two thirds of individuals who trained to become teachers between 2005 and 2015 and received a teaching credential did not enter the state's public teaching workforce immediately after graduation, while about one third never entered a public teaching job in the state at all. In this analysis, we link data on these teacher candidates to unemployment insurance data in the state to provide a descriptive portrait of the future earnings and wages of these individuals inside and outside of public schools. Candidates who initially became public school teachers earned considerably more, on average, than candidates who were initially employed either in other education positions or in other sectors of the state's workforce. These differences persisted 10 years into the average career and across transitions into and out of teaching. There is therefore little evidence that teacher candidates who did not become teachers were lured into other professions by higher compensation. Instead, the patterns are consistent with demand-side constraints on teacher hiring during this time period that resulted in individuals who wanted to become teachers taking positions that offered lower wages but could lead to future teaching positions.

Abstract Aberrant resting-state connectivity within and between the Default Mode Network, the Executive Control Network, and the Salience Network is well-established in schizophrenia. Meta-analyses have identified that bilateral lingual gyrus is as the only region showing hyperactivity in schizophrenia and there are reports of increased connectivity between the lingual gyrus and other brain regions in schizophrenia. It is not clear whether these abnormalities represent state or trait markers of the illness, i.e., if they are only present during the acute phase of the illness (state) or if they reflect a predisposition to schizophrenia (trait). In this study, we used a seed-based functional connectivity analysis to investigate brain networks in schizophrenia patients who are in the stable phase of their illness and assess functional connectivity using seeds in the lingual gyrus, the posterior cingulate, the right dorsolateral prefrontal cortex (dlPFC), the right anterior insula (rAI) and the right orbital frontoinsula. Twenty patients with schizophrenia in a stable phase of their illness (as defined by the course of illness and Signs and Symptoms of Psychotic Illness (SSPI) scores) and 20 age and sex-matched healthy controls underwent resting-state functional Magnetic Resonance Imaging (rs-fMRI). Data was analysed using the Data Processing Assistant for Resting-State fMRI Advanced Edition (DPARSFA) V3.1 (http://rfmri.org/DPARSF) and the statistical parametric mapping software 8 (SPM8). Compared with healthy controls, patients with schizophrenia showed increased connectivity between the left lingual gyrus and the middle frontal gyrus, and the cingulate cortex. Lingual gyrus hyper-connectivity may be a stable trait neuroimaging marker for schizophrenia. Our findings suggest that aberrant connectivity in major resting-state networks may not be present after the acute illness has stabilised.

Objectives This conceptual review aims to integrate findings from published qualitative studies focusing on individual experiences of people living with dementia to generate a better understanding and conceptualisation of anxiety in dementia, including its subclinical manifestations. The review aims to inform the clinical practice to facilitate the development of targeted psychological interventions and provision of holistic support to people living with dementia. Design The review was conducted according to the guide for reporting meta-ethnographic qualitative syntheses eMERGe and the PRISMA guidelines. Results The search yielded a total of 2947 studies, out of which 13 were included in the final qualitative synthesis. The interpretive synthesis identified common experiences of people living with mild to moderate dementia, characterised by clusters of themes around worry, emotional experiences, and behavioural reactions in response to the diagnosis of dementia and its symptoms. These represent the components of a conceptual framework of anxiety in mild to moderate dementia, where anxiety is triggered by negative appraisals of living with an irreversible neurodegenerative disease. Stemming from these appraisals of dementia progression and its impact on the person’s overall future, the content of worrisome thoughts and concerns include the loss of self and identity, losing independence and the ability to perform previous activities, concerns about being a burden to loved ones, and worry about the impact on interpersonal relationships. Conclusion This conceptualisation of anxiety in dementia, including its subclinical manifestations facilitates the development of psychological interventions and provision of holistic support to people living with dementia.

Introduction: Acute coronary syndrome in pediatric patients with graft-versus-host disease is rare. Case Report: We present an 18-year-old male with graft-versus-host disease referred for chest pain, electrocardiogram abnormalities, and troponin leak. Additional risk factors for acute coronary syndrome included chronic steroid use, elevated triglyceride/low-density lipoprotein (LDL) levels and cannabis use. A catheterization revealed >90% occlusion of the left coronary artery and he underwent successful percutaneous intervention. Conclusion: Given the overall rarity of acute coronary syndrome in pediatric patients, it may go unrecognized and underappreciated as a significant cause of morbidity in those with graft-versus-host disease.

We undertook a qualitative assessment of aged care technology needs from the perspective of consumers and providers using a cross-sectional survey that assumed a largely open-response format. We recruited a convenience sample of individuals aged 18 years or older, lived in Australia, and self-identified as either an older adult ( n = 133), an informal caregiver of an older adult ( n = 27), and/or clinician, healthcare practitioner, and aged care provider ( n = 148). Survey responses were analyzed using a descriptive qualitative content analysis approach to interpret meaning from written survey responses. We identified seven themes reporting that technologies used in aged care do not appear to be meeting end-user needs. Supporting the Technology Acceptance Model, consumers and providers perceive usefulness of the technology and its actual ease of use as drivers of acceptance toward gerontechnology. Ten recommendations are proposed to support technology use and the quality of aged care.

Background Asthma affects approximately 10% of Australian children. Electronic medical record (EMR) systems and clinical decision support initiatives have been shown to improve the delivery of asthma care. Our institution implemented an EMR-based asthma “hub,” which collates asthma-related information to a central location within a patient's record, provides a template to collect relevant clinical information, allows clinicians to evaluate a patient's history and presentation in a systematic manner and prompts relevant actions. Objective The aim of the study is to measure year-on-year improvement in asthma-related documentation and provide a key gold-standard aspects of asthma management after the introduction of an EMR asthma “hub” tool in the outpatient setting. Methods The asthma “hub” was introduced in November 2020. A chart review was conducted of all patients who attended the Complex Asthma Clinic between January-April 2020 and January-April 2021. The provision and presence of documentation of core aspects of asthma care were described in percentages and comparisons of pre- and post-introduction of the asthma “hub” were assessed. Results There was a significant increase in the documentation of asthma triggers, including smoking/smoker exposure, (47.5–92.6%, p Conclusion An evidence-based EMR intervention improved the documentation and provision of aspects of asthma care in an outpatient clinic setting at a tertiary pediatric hospital, suggesting replication in the inpatient and emergency settings would be worthwhile. Further research is required to understand the tool's impact on clinical outcomes and on clinical efficiency and workflow.

BACKGROUND & AIMS: Mitochondrial dysfunction disrupts the synthesis and secretion of digestive enzymes in pancreatic acinar cells and plays a primary role in the etiology of exocrine pancreas disorders. However, the transcriptional mechanisms that regulate mitochondrial function to support acinar cell physiology are poorly understood. Here, we aim to elucidate the function of estrogen-related receptor γ (ERRγ) in pancreatic acinar cell mitochondrial homeostasis and energy production. METHODS: Two models of ERRγ inhibition, GSK5182-treated wild-type mice and ERRγ conditional knock-out (cKO) mice, were established to investigate ERRγ function in the exocrine pancreas. To identify the functional role of ERRγ in pancreatic acinar cells, we performed histological and transcriptome analysis with the pancreas isolated from ERRγ cKO mice. To determine the relevance of these findings for human disease, we analyzed transcriptome data from multiple independent human cohorts and conducted genetic association studies for ESRRG variants in two distinct human pancreatitis cohorts. RESULTS: Blocking ERRγ function in mice by genetic deletion or inverse agonist treatment results in striking pancreatitis-like phenotypes accompanied by inflammation, fibrosis, and cell death. Mechanistically, loss-of-ERRγ in primary acini abrogates mRNA expression and protein levels of mitochondrial oxidative phosphorylation (OXPHOS) complex genes, resulting in defective acinar cell energetics. Mitochondrial dysfunction due to ERRγ deletion further triggers autophagy dysfunction, ER stress, and production of reactive oxygen species, ultimately leading to cell death. Interestingly, ERRγ-deficient acinar cells that escape cell death acquire ductal cell characteristics indicating a role for ERRγ in acinar-to-ductal metaplasia. Consistent with our findings in ERRγ cKO mice, ERRγ expression was significantly reduced in patients with chronic pancreatitis compared to normal subjects. Furthermore, candidate locus region genetic association studies revealed multiple single nucleotide variants (SNVs) for ERRγ that associated with chronic pancreatitis. CONCLUSIONS: Collectively, our findings highlight an essential role for ERRγ in maintaining the transcriptional program that supports acinar cell mitochondrial function and organellar homeostasis and provide a novel molecular link between ERRγ and exocrine pancreas disorders.

Background There is emerging evidence for abnormal beta oscillations in psychosis. Beta oscillations are likely to play a key role in the coordination of sensorimotor information that is crucial to healthy mental function. Growing evidence suggests that beta oscillations typically manifest as transient beta bursts that increase in probability following a motor response, observable as post-movement beta rebound. Evidence indicates that post-movement beta rebound is attenuated in psychosis, with greater attenuation associated with greater symptom severity and impairment. Delineating the functional role of beta bursts therefore may be key to understanding the mechanisms underlying persistent psychotic illness. Methods We used concurrent electroencephalography and functional magnetic resonance imaging to identify blood oxygen level–dependent correlates of beta bursts during the n-back working memory task and intervening rest periods in healthy participants (n = 30) and patients with psychosis (n = 48). Results During both task blocks and intervening rest periods, beta bursts phasically activated regions implicated in task-relevant content while suppressing currently tonically active regions. Patients showed attenuated post-movement beta rebound that was associated with persisting disorganization symptoms as well as impairments in cognition and role function. Patients also showed greater task-related reductions in overall beta burst rate and showed greater, more extensive, beta burst–related blood oxygen level–dependent activation. Conclusions Our evidence supports a model in which beta bursts reactivate latently maintained sensorimotor information and are dysregulated and inefficient in psychosis. We propose that abnormalities in the mechanisms by which beta bursts coordinate reactivation of contextually appropriate content can manifest as disorganization, working memory deficits, and inaccurate forward models and may underlie a core deficit associated with persisting symptoms and impairment.

Modelling clinical pathways from Electronic Health Records (EHRs) can optimize resources and improve patient care, but current methods for generating pathway models using clustering have limitations including scalability and fidelity of the clusters. We propose a novel pathway modelling approach using Maximum Likelihood (ML) data clustering on Markov chain representations of clinical pathways. Our method is calibrated to produce clusters with low inter-cluster variability across the pathways. We use machine learning with Stochastic Radial Basis Functions (SRBF) kernels for surrogate optimization to handle non-convexity and propose an incremental optimization method to improve scalability. We also define a methodology based on novel replayability scores to help analysts compare the fidelity of alternative clustering results. Results show that our ML method produces clusters that have higher fidelity in terms of replayability scores than k-means based clustering and in capturing queueing contention, which is important for bottleneck identification in healthcare.

Corticosteroids act on the glucocorticoid receptor (GR; NR3C1) to resolve inflammation and are routinely prescribed to breast cancer patients undergoing chemotherapy treatment to alleviate side effects. Triple negative breast cancers (TNBCs) account for 15-20% of diagnoses and lack expression of estrogen and progesterone receptors as well as amplified HER2, but often express high GR levels. GR is a mediator of TNBC progression to advanced metastatic disease, however the mechanisms underpinning this transition to more aggressive behavior remain elusive. We previously showed that tissue/cellular stress (hypoxia, chemotherapies) as well as factors in the tumor microenvironment (TGFβ, HGF) activate p38 MAPK, which phosphorylates GR on Ser134. In the absence of ligand, p-Ser134-GR further upregulates genes important for responses to cellular stress, including key components of the p38 MAPK pathway. Herein, we show that p-Ser134-GR is required for TNBC metastatic colonization to the lungs of female mice. To understand the mechanisms of p-Ser134-GR action in the presence of GR agonists, we examined glucocorticoid-driven transcriptomes in CRISPR knock-in models of TNBC cells expressing wild-type or phospho-mutant (S134A) GR. We identified dexamethasone- and p-Ser134-GR-dependent regulation of specific gene sets controlling TNBC migration (NEDD9, CSF1, RUNX3) and metabolic adaptation (PDK4, PGK1, PFKFB4). TNBC cells harboring S134A-GR displayed metabolic reprogramming that was phenocopied by PDK4 knockdown. PDK4 knockdown or chemical inhibition also blocked cancer cell migration. Our results reveal a convergence of GR agonists (i.e., host stress) with cellular stress signaling whereby pSer134-GR critically regulates TNBC metabolism, an exploitable target for the treatment of this deadly disease.

• Background Anxiety is commonly experienced by people living with mild cognitive impairment (MCI) and dementia. Whilst there is strong evidence for late-life anxiety treatment using Cognitive Behavioural Therapy (CBT) and delivery via telehealth, there is little evidence for the remote delivery of psychological treatment for anxiety in people living with MCI and dementia. This paper reports the protocol for the Tech-CBT study which aims to investigate the efficacy, cost-effectiveness, usability and acceptability of a technology-assisted and remotely delivered CBT intervention to enhance delivery of anxiety treatment for people living with MCI and dementia of any aetiology. • Methods A hybrid II single-blind, parallel-group randomised trial of a Tech-CBT intervention (n = 35) versus usual care (n = 35), with in-built mixed methods process and economic evaluations to inform future scale-up and implementation into clinical practice. The intervention (i) consists of six weekly sessions delivered by postgraduate psychology trainees via telehealth video-conferencing, (ii) incorporates voice assistant app technology for home-based practice, and (iii) utilises a purpose-built digital platform, My Anxiety Care. The primary outcome is change in anxiety as measured by the Rating Anxiety in Dementia scale. Secondary outcomes include change in quality of life and depression, and outcomes for carers. The process evaluation will be guided by evaluation frameworks. Qualitative interviews will be conducted with a purposive sample of participants (n = 10) and carers (n = 10), to evaluate acceptability and feasibility, as well as factors influencing participation and adherence. Interviews will also be conducted with therapists (n = 18) and wider stakeholders (n = 18), to explore contextual factors and barriers/facilitators to future implementation and scalability. A cost-utility analysis will be undertaken to determine the cost-effectiveness of Tech-CBT compared to usual care. • Discussion This is the first trial to evaluate a novel technology-assisted CBT intervention to reduce anxiety in people living with MCI and dementia. Other potential benefits include improved quality of life for people with cognitive impairment and their care partners, improved access to psychological treatment regardless of geographical location, and upskilling of the psychological workforce in anxiety treatment for people living with MCI and dementia. Trial registration: This trial has been prospectively registered with ClinicalTrials.gov: NCT05528302 [September 2, 2022].

Cholecystokinin receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on CCK receptors [90]) are activated by the endogenous peptides cholecystokinin-8 (CCK-8), CCK-33, CCK-58 and gastrin (gastrin-17). There are only two distinct subtypes of CCK receptors, CCK1 and CCK2 receptors [64, 124], with some alternatively spliced forms most often identified in neoplastic cells. The CCK receptor subtypes are distinguished by their peptide selectivity, with the CCK1 receptor requiring the carboxyl-terminal heptapeptide-amide that includes a sulfated tyrosine for high affinity and potency, while the CCK2 receptor requires only the carboxyl-terminal tetrapeptide shared by each CCK and gastrin peptides. These receptors have characteristic and distinct distributions, with both present in both the central nervous system and peripheral tissues.

COG-UK is supported by funding from the MRC part of UK Research & Innovation, the National Institute of Health Research (Grant code MC_PC_19027), and Genome Research Limited, operating as the Welcome Sanger Institute. Background The first epidemic wave of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in Scotland resulted in high case numbers and mortality in care homes. In Lothian, over one-third of care homes reported an outbreak, while there was limited testing of hospital patients discharged to care homes. Aim To investigate patients discharged from hospitals as a source of SARS-CoV-2 introduction into care homes during the first epidemic wave. Methods A clinical review was performed for all patients discharges from hospitals to care homes from 1st March 2020 to 31st May 2020. Episodes were ruled out based on coronavirus disease 2019 (COVID-19) test history, clinical assessment at discharge, whole-genome sequencing (WGS) data and an infectious period of 14 days. Clinical samples were processed for WGS, and consensus genomes generated were used for analysis using Cluster Investigation and Virus Epidemiological Tool software. Patient timelines were obtained using electronic hospital records. Findings In total, 787 patients discharged from hospitals to care homes were identified. Of these, 776 (99%) were ruled out for subsequent introduction of SARS-CoV-2 into care homes. However, for 10 episodes, the results were inconclusive as there was low genomic diversity in consensus genomes or no sequencing data were available. Only one discharge episode had a genomic, time and location link to positive cases during hospital admission, leading to 10 positive cases in their care home. Conclusion The majority of patients discharged from hospitals were ruled out for introduction of SARS-CoV-2 into care homes, highlighting the importance of screening all new admissions when faced with a novel emerging virus and no available vaccine. Publisher PDF

Background The COVID-19 pandemic increased the use of telehealth consultations by telephone and video around the world. While telehealth can improve access to primary health care, there are significant gaps in our understanding about how, when and to what extent telehealth should be used. This paper explores the perspectives of health care staff on the key elements relating to the effective use of telehealth for patients living in remote Australia. Methods Between February 2020 and October 2021, interviews and discussion groups were conducted with 248 clinic staff from 20 different remote communities across northern Australia. Interview coding followed an inductive approach. Thematic analysis was used to group codes into common themes. Results Reduced need to travel for telehealth consultations was perceived to benefit both health providers and patients. Telehealth functioned best when there was a pre-established relationship between the patient and the health care provider and with patients who had good knowledge of their personal health, spoke English and had access to and familiarity with digital technology. On the other hand, telehealth was thought to be resource intensive, increasing remote clinic staff workload as most patients needed clinic staff to facilitate the telehealth session and complete background administrative work to support the consultation and an interpreter for translation services. Clinic staff universally emphasised that telehealth is a useful supplementary tool, and not a stand-alone service model replacing face-to-face interactions. Conclusion Telehealth has the potential to improve access to healthcare in remote areas if complemented with adequate face-to-face services. Careful workforce planning is required while introducing telehealth into clinics that already face high staff shortages. Digital infrastructure with reliable internet connections with sufficient speed and latency need to be available at affordable prices in remote communities to make full use of telehealth consultations. Training and employment of local Aboriginal staff as digital navigators could ensure a culturally safe clinical environment for telehealth consultations and promote the effective use of telehealth services among community members.

Supplemental Figure 2. Calcipotriol does not alter LRP6 expression in Low-BAR/Low-VDR cell lines. (A) Western blot for LRP6 or tubulin (loading control) following treatment with vehicle or 10 μM calcipotriol. Representative experiments from 2-3 biologic replicates are shown.

AMP-activated protein kinase (AMPK) regulates lipid, cholesterol, and glucose metabolism in specialized metabolic tissues, such as muscle, liver, and adipose tissue. Agents that activate AMPK, such as metformin and 5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside (AICAR), have beneficial effects on liver glucose and lipid metabolism. In addition, AMPK activation in proliferating hepatic stellate cells (HSC) induces growth arrest and inhibits hepatic fibrosis. As metformin and AICAR act in different ways to achieve their effects, our aim was to examine the effects of AMPK activation in quiescent HSCs with these two agents on HSC function. We found that phospho-AMPK levels were markedly upregulated by both AICAR and metformin in quiescent HSCs. However, although AICAR treatment induced cell death, cells treated with metformin did not differ from untreated controls. AICAR-mediated HSC cell death was paralleled by loss of expression of the TGF-β decoy receptor Bambi, whereas metformin increased Bambi expression. Transfection of siRNA-Bambi into HSCs also induced cell death, mimicking the effects of AICAR, whereas overexpression of Bambi partially rescued AICAR-treated cells. As Bambi has previously been shown to promote cell survival through Wnt/β-catenin signaling, a reporter incorporating binding sites for a downstream target of this pathway was transfected into HSCs and was induced. We conclude that although AICAR and metformin both activate AMPK in quiescent HSCs, AICAR rapidly induced cell death, whereas metformin-treated cells remained viable. The finding that metformin increases Bambi expression and activates Wnt/β-catenin signaling provides a possible mechanistic explanation for this observation. These results suggest that AICAR and metformin may confer disease-specific therapeutic benefits. Cancer Prev Res; 5(4); 553–61. ©2012 AACR.

Supplemental Figure 1. Calcipotriol does not inhibit Wnt signaling through VDR sequestration of β-catenin or induction of DKK1. (A) AsPC-1 cells were treated with 100 nM calcipotriol for 4 hours. Whole cell lysates were collected and immunoprecipitated with anti- β-catenin or isotype control antibodies followed by western blots for β-catenin, E-cadherin or VDR. (B) Western blot for DKK-1 and tubulin (loading control) and (C) BAR reporter activity for indicated conditions. AsPC-1 cells were transfected with control or DKK1 siRNA for 48 hours and treated with vehicle or 100 nM calcipotriol for an additional 24 hours. BAR was normalized to vehicle and siRNA control and is reported as mean {plus minus} SD, with one representative experiment of 3 biological repeats shown.

Supplemental Figure 3. Calcipotriol reduces VDR message while paradoxically increasing VDR protein levels. (A) VDR expression in AsPC-1 by qPCR after treatments described in Figure 3E. (B) Western blots for VDR or tubulin (loading control) for AsPC-1 lysates at indicated timepoints after calcipotriol treatment. Arrowhead indicates specific band representing VDR protein. qPCR reported as mean {plus minus} SEM. Representative experiments from 2-3 biologic replicates are shown. **P

Supplemental Table 1. QPCR PRIMERS

Supplemental Table 2. RNA-Seq analysis showing significant gene expression changes following 6 hour calcipotriol treatment of AsPC-1 cell line

Endogenous programs in avian reproductive seasonal life history transitions have been known for over 30 years. Attempts to identify the neural and molecular substrates of photoperiodic time measurement have, to date, focussed on blunt changes in light exposure during a restricted period of photoinducibility. Here we report mediobasal hypothalamus (MBH) and pituitary gland specific transcript expression cascades associated with photoperiod-induced seasonal life history transitions. We identified multiple waves of transcript expression that were not synchronized across brain regions. Follicle-stimulating hormone-β (FSHβ) expression increased during the simulated vernal equinox, prior to photoinduced increases in prolactin, thyrotropin-stimulating hormone-β and testicular growth. Analyses showed sustained elevated levels of daily FSHβ expression in the pituitary under conditions of the vernal, compared to autumnal equinox, short (12L) photoperiods. FSHβ expression increased in Quail held in non-stimulatory photoperiod, indicative of an endogenous programmed change in transcription. These data identify that FSHβ provides an endogenous program for the photoperiod-dependent external coincidence timing for seasonal transitions in reproduction. FSHβ may prime the pituitary for subsequent stimulation by triiodothyronine-mediated changes in tanycytes during the photoinducible phase. Overall, the data indicate a multi-cellular, multi-neural interval timing mechanism resides in the brain to control seasonal life-history transitions in birds.

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Background Cultural competency is often promoted as a strategy to address health inequities; however, there is little evidence linking cultural competency with improved patient outcomes. This article describes the characteristics of recent educational interventions designed to improve cultural competency in healthcare workers for First Nations peoples of Australia, New Zealand, Canada and the USA. Methods In total, 13 electronic databases and 14 websites for the period from January 2015 to May 2021 were searched. Information on the characteristics and methodological quality of included studies was extracted using standardised assessment tools. Results Thirteen published evaluations were identified; 10 for Australian Aboriginal and Torres Strait Islander peoples. The main positive outcomes reported were improvements in health professionals’ attitudes and knowledge, and improved confidence in working with First Nations patients. The methodological quality of evaluations and the reporting of methodological criteria were moderate. Conclusions Cultural competency education programs can improve knowledge, attitudes and confidence of healthcare workers to improve the health of First Nations peoples. Providing culturally safe health care should be routine practice, particularly in places where there are concentrations of First Nations peoples, yet there is relatively little research in this area. There remains limited evidence of the effectiveness of cultural education programs alone on community or patient outcomes.

Proper mitochondrial function and adequate cellular ATP are necessary for normal pancreatic protein synthesis and sorting, maintenance of intracellular organelles and enzyme secretion. Inorganic phosphate is required for generating ATP and its limited availability may lead to reduced ATP production causing impaired Ca(2+) handling, defective autophagy, zymogen activation, and necrosis, which are all features of acute pancreatitis. We hypothesized that reduced dietary phosphate leads to hypophosphatemia and exacerbates pancreatitis severity of multiple causes. We observed that mice fed a low-phosphate diet before the induction of pancreatitis by either repeated caerulein administration or pancreatic duct injection as a model of pressure-induced pancreatitis developed hypophosphatemia and exhibited more severe pancreatitis than normophosphatemic mice. Pancreatitis severity was significantly reduced in mice treated with phosphate. In vitro modeling of secretagogue- and pressure-induced pancreatic injury was evaluated in isolated pancreatic acini using cholecystokinin and the mechanoreceptor Piezo1 agonist, Yoda1, under low and normal phosphate conditions. Isolated pancreatic acini were more sensitive to cholecystokinin- and Yoda1-induced acinar cell damage and mitochondrial dysfunction under low-phosphate conditions and improved following phosphate supplementation. Importantly, even mice on a normal phosphate diet exhibited less severe pancreatitis when treated with supplemental phosphate. Thus, hypophosphatemia sensitizes animals to pancreatitis and phosphate supplementation reduces pancreatitis severity. These appear to be direct effects of phosphate on acinar cells through restoration of mitochondrial function. We propose that phosphate administration may be useful in the treatment of acute pancreatitis. NEW & NOTEWORTHY Impaired ATP synthesis disrupts acinar cell homeostasis and is an early step in pancreatitis. We report that reduced phosphate availability impairs mitochondrial function and worsens pancreatic injury. Phosphate supplementation improves mitochondrial function and protects against experimental pancreatitis, raising the possibility that phosphate supplementation may be useful in treating pancreatitis.

We report the synthesis and characterization of uranium(IV) and thorium(IV) mesoionic carbene complexes [An{N(SiMe

This retrospective non-experimental study examined the short-term (2-year) and longer-term (5-year and 8-year) sustainment of 137 programs in Europe and North America implementing a single evidence-based practice (EBP), Multidimensional Family Therapy (MDFT). MDFT implementation and sustainment is based on the Stages of Implementation (SIC) model outlined by Saldana and colleagues. The study had two primary objectives: (1) to examine short-term and longer-term sustainment rates of MDFT in Europe and North America, and (2) to explore potential factors that may be associated with sustainment of MDFT in particular, and the potential implications for behavioral health EBPs more generally. Results show that 90% of MDFT programs were sustained for at least 2 years, 87% of the programs sustained for at least 5 years, and 70% for at least 8 years. These findings compare favorably with the previous research on implementing and sustaining evidence-based practices. The findings support the growing consensus that not only start-up funding but also ongoing financing either through governments or third-party payors may be essential for longer-term sustainability of EBPs in both Europe and North America. This study also highlights the potential value of multi-site program networks. Future research directions are suggested, such as examination of the potential importance of the quality and nature of the EBP itself, adaptability to different organizations and clients, and providing high-quality structured and empowering training and quality assurance to sustain evidence-based behavioral health interventions. These programmatic and clinician-level factors are critical areas for further investigation into the sustainment of EBPs.

Aims This study investigates the use of the metabolic equivalent of task (MET) score in a young hip arthroplasty population, and its ability to capture additional benefit beyond the ceiling effect of conventional patient-reported outcome measures. Methods From our electronic database of 751 hip arthroplasty procedures, 221 patients were included. Patients were excluded if they had revision surgery, an alternative hip procedure, or incomplete data either preoperatively or at one-year follow-up. Included patients had a mean age of 59.4 years (SD 11.3) and 54.3% were male, incorporating 117 primary total hip and 104 hip resurfacing arthroplasty operations. Oxford Hip Score (OHS), EuroQol five-dimension questionnaire (EQ-5D), and the MET were recorded preoperatively and at one-year follow-up. The distribution was examined reporting the presence of ceiling and floor effects. Validity was assessed correlating the MET with the other scores using Spearman’s rank correlation coefficient and determining responsiveness. A subgroup of 92 patients scoring 48/48 on the OHS were analyzed by age, sex, BMI, and preoperative MET using the other metrics to determine if differences could be established despite scoring identically on the OHS. Results Postoperatively the OHS and EQ-5D demonstrate considerable negatively skewed distributions with ceiling effects of 41.6% and 53.8%, respectively. The MET was normally distributed postoperatively with no relevant ceiling effect. Weak-to-moderate significant correlations were found between the MET and the other two metrics. In the 48/48 subgroup, no differences were found comparing groups with the EQ-5D, however significantly higher mean MET scores were demonstrated for patients aged < 60 years (12.7 (SD 4.7) vs 10.6 (SD 2.4), p = 0.008), male patients (12.5 (SD 4.5) vs 10.8 (SD 2.8), p = 0.024), and those with preoperative MET scores > 6 (12.6 (SD 4.2) vs 11.0 (SD 3.3), p = 0.040). Conclusion The MET is normally distributed in patients following hip arthroplasty, recording levels of activity which are undetectable using the OHS. Cite this article: Bone Joint Res 2022;11(5):317–326.

DES Collaboration: V. Wetzell et al., We measure the velocity dispersions of clusters of galaxies selected by the red-sequence Matched-filter Probabilistic Percolation (redMaPPer) algorithm in the first three years of data from the Dark Energy Survey (DES), allowing us to probe cluster selection and richness estimation, λ, in light of cluster dynamics. Our sample consists of 126 clusters with sufficient spectroscopy for individual velocity dispersion estimates. We examine the correlations between cluster velocity dispersion, richness, X-ray temperature, and luminosity, as well as central galaxy velocity offsets. The velocity dispersion–richness relation exhibits a bimodal distribution. The majority of clusters follow scaling relations between velocity dispersion, richness, and X-ray properties similar to those found for previous samples; however, there is a significant population of clusters with velocity dispersions that are high for their richness. These clusters account for roughly 22 per cent of the λ < 70 systems in our sample, but more than half (55 per cent) of λ < 70 clusters at z > 0.5. A couple of these systems are hot and X-ray bright as expected for massive clusters with richnesses that appear to have been underestimated, but most appear to have high velocity dispersions for their X-ray properties likely due to line-of-sight structure. These results suggest that projection effects contribute significantly to redMaPPer selection, particularly at higher redshifts and lower richnesses. The redMaPPer determined richnesses for the velocity dispersion outliers are consistent with their X-ray properties, but several are X-ray undetected and deeper data are needed to understand their nature., This work was supported by the U.S. Department of Energy, Office of Science, Office of High Energy Physics, under Award Numbers DE-SC0010107 and A00-1465-001. AS is supported by the ERC-StG ‘ClustersXCosmo’ grant agreement 716762, by the FARE-MIUR grant ’ClustersXEuclid’ R165SBKTMA, and by INFN InDark Grant. PTPV was supported by Fundação para a Ciência e a Tecnologia (FCT) through research grants UIDB/04434/2020andUIDP/04434/2020. Funding for the DES Projects has been provided by the U.S. Department of Energy, the U.S. National Science Foundation, the Ministry of Science and Education of Spain, the Science and Technology Facilities Council of the United Kingdom, the Higher Education Funding Council for England, the University of Illinois at Urbana-Champaign - National Center for Supercomputing Applications, the Kavli Institute of Cosmological Physics at the University of Chicago, the Center for Cosmology and Astro-Particle Physics at the Ohio State University, the Mitchell Institute for Fundamental Physics and Astronomy at Texas A&M University, Financiadora de Estudos e Projetos, Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro, Conselho Nacional de Desenvolvimento Científico e Tecnológico and the Ministério da Ciência, Tecnologia e Inovação, the Deutsche Forschungsgemeinschaft, and the Collaborating Institutions in the Dark Energy Survey. The Collaborating Institutions are Argonne National Laboratory, the University of California, Santa Cruz, the University of Cambridge, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas – Madrid, the University of Chicago, University College London, the DES-Brazil Consortium, the University of Edinburgh, the Eidgenössische Technische Hochschule Zürich, Fermi National Accelerator Laboratory, the University of Illinois at Urbana-Champaign, the Institut de Ciències de l’Espai (IEEC/CSIC), the Institut de Física d’Altes Energies, Lawrence Berkeley National Laboratory, the Ludwig-Maximilians-Universität München and the associated Excellence Cluster Universe, the University of Michigan, NFS’s NOIRLab, the University of Nottingham, The Ohio State University, the University of Pennsylvania, the University of Portsmouth, SLAC National Accelerator Laboratory, Stanford University, the University of Sussex, Texas A&M University, and the OzDES Membership Consortium. This study is based in part on observations at Cerro Tololo Inter-American Observatory at NSF’s NOIRLab (NOIRLab Prop. ID 2012B-0001; PI: J. Frieman), which is managed by the Association of Universities for Research in Astronomy (AURA) under a cooperative agreement with the National Science Foundation. The DES data management system is supported by the National Science Foundation under grant numbers AST-1138766 and AST-1536171. The DES participants from Spanish institutions are partially supported by MICINN under grants ESP2017-89838, PGC2018-094773, PGC2018-102021, SEV-2016-0588, SEV-2016-0597, and MDM-2015-0509, some of which include ERDF funds from the European Union. IFAE is partially funded by the CERCA program of the Generalitat de Catalunya. Research leading to these results has received funding from the European Research Council under the EU Seventh Framework Programme (FP7/2007-2013) including ERC grant agreements 240672, 291329, and 306478. We acknowledge support from the Brazilian Instituto Nacional de Ciência e Tecnologia (INCT) do e-Universo (CNPq grant 465376/2014-2). This paper has been authored by Fermi Research Alliance, LLC under contract no. DE-AC02-07CH11359 with the U.S. Department of Energy, Office of Science, Office of High Energy Physics.

We use data on over 14,000 teacher candidates in Washington state, merged with employment data from the state’s public schools and Unemployment Insurance system, to investigate the career paths of recently certified teacher candidates in the state. About two thirds of these candidates are observed as public school teachers at some point within 5 years after completing student teaching, many of whom transition from nonteaching education positions into public school teaching positions within a few years of student teaching. We also find that candidates with STEM endorsements and candidates who graduated after the Great Recession are far more likely to be employed in public K–12 teaching positions within the first several years after student teaching.

Aims Unicompartmental and total knee arthroplasty (UKA and TKA) are successful treatments for osteoarthritis, but the solid metal implants disrupt the natural distribution of stress and strain which can lead to bone loss over time. This generates problems if the implant needs to be revised. This study investigates whether titanium lattice UKA and TKA implants can maintain natural load transfer in the proximal tibia. Methods In a cadaveric model, UKA and TKA procedures were performed on eight fresh-frozen knee specimens, using conventional (solid) and titanium lattice tibial implants. Stress at the bone-implant interfaces were measured and compared to the native knee. Results Titanium lattice implants were able to restore the mechanical environment of the native tibia for both UKA and TKA designs. Maximum stress at the bone-implant interface ranged from 1.2 MPa to 3.3 MPa compared with 1.3 MPa to 2.7 MPa for the native tibia. The conventional solid UKA and TKA implants reduced the maximum stress in the bone by a factor of 10 and caused > 70% of bone surface area to be underloaded compared to the native tibia. Conclusion Titanium lattice implants maintained the natural mechanical loading in the proximal tibia after UKA and TKA, but conventional solid implants did not. This is an exciting first step towards implants that maintain bone health, but such implants also have to meet fatigue and micromotion criteria to be clinically viable. Cite this article: Bone Joint Res 2022;11(2):91–101.

open access article Covid-19 has led to renewed public support for public services. Frontline workers symbolise a renewed ideal of public service ethos (PSE), though little attention has been paid to how the public managers delivering vital services interpret and mobilise PSE. We show how PSE is implemented by public managers reflecting their local contexts. We examine the theoretical roots of PSE and challenges by newer theories of public management before illustrating its contemporary manifestations through three case studies of local government responses to Covid-19 in England, showing how PSE has been adapted in current contexts and continues to inform public management practice.

Treatment of [U IV(N 3)(Tren TIPS)] (1, Tren TIPS = {N(CH 2CH 2NSiPr i 3) 3} 3−) with excess Li resulted in the isolation of [{U IV(μ-NLi 2)(Tren TIPS)} 2] (2), which exhibits a diuranium(iv) ‘diamond-core’ dinitride motif. Over-reduction of 1 produces [U III(Tren TIPS)] (3), and together with known [{U V(μ-NLi)(Tren TIPS)} 2] (4) an overall reduction sequence 1 → 4 → 2 → 3 is proposed. Attempts to produce an odd-electron nitride from 2 resulted in the formation of [{U IV(Tren TIPS)} 2(μ-NH)(μ-NLi 2)Li] (5). Use of heavier alkali metals did not result in the formation of analogues of 2, emphasising the role of the high charge-to-radius-ratio of lithium stabilising the charge build up at the nitride. Variable-temperature magnetic data for 2 and 5 reveal large low-temperature magnetic moments, suggesting doubly degenerate ground states, where the effective symmetry of the strong crystal field of the nitride dominates over the spin-orbit coupled nature of the ground multiplet of uranium(iv). Spin Hamiltonian modelling of the magnetic data for 2 and 5 suggest U⋯U anti-ferromagnetic coupling of −4.1 and −3.4 cm −1, respectively. The nature of the U⋯U electronic communication was probed computationally, revealing a borderline case where the prospect of direct uranium-uranium bonding was raised, but in-depth computational analysis reveals that if any uranium-uranium bonding is present it is weak, and instead the nitride centres dominate the mediation of U⋯U electronic communication. This highlights the importance of obtaining high-level ab initio insight when probing potential actinide-actinide electronic communication and bonding in weakly coupled systems. The computational analysis highlights analogies between the ‘diamond-core’ dinitride of 2 and matrix-isolated binary U 2N 2

Since its inception nearly 40 years ago [Kallenbach, et al., Nature, 1983, 305, 829; N. C. Seeman, J. Theoretical Biology, 1982, 99, 237], Nucleic Acid Nanotechnology (NAN) has matured and is beginning to find commercial applications.