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Nationally, more than 75% of individuals who are credentialed to teach are prepared in traditional college- or university-based teacher education programs (TEPs). But the college and employment pathways that prospective teachers take to TEP enrollment and completion have not been comprehensively examined. A better understanding of how credentialed individuals find their way into TEPs helps us understand the sources of new teacher supply early in the prospective teacher pipeline. With that in mind, we analyze pathways into and through TEPs using historical postsecondary and unemployment insurance data from Washington State. We find that the pathways are quite varied, with around 40% of bachelor's-level TEP completers spending at least some time in community colleges and fewer than 40% enrolling and finishing at the same university directly after high school. Pathways to master's TEP completion are even more varied, with almost half of the completers having prior employment experience. For researchers, this varied landscape raises important questions about the relationship between pathways, candidate persistence, and eventual job performance. For policymakers, the results suggest that efforts to recruit the next generation of teachers need to look beyond the pool of students already enrolled at a 4-year university to include students at 2-year colleges or in the labor force who might be interested in entering a TEP.

Postgraduate engagement in delivering outreach activities is more commonplace than it once was. However, the impact on postgraduate students (typically studying for a Ph.D. degree) of participating in the delivery of these outreach activities has rarely, if ever, been recorded. The Bristol ChemLabS Outreach program has been running for ca. 17 years, and in that time, many postgraduate students have been involved (approximately 500), with around 250 typically for up to 3 years. We sought to investigate the impact of outreach engagement on postgraduate alumni who were involved in the program for over 3 years (32) and how the experiences and training of the outreach program had impacted on their careers postgraduation. Thirty of the 32 postgraduates engaged and ~70% reported that their outreach experience had influenced their decision making on future careers. Many respondents reported that the skills and experiences gained through outreach participation had contributed to success in applying for and interviewing at their future employers. All respondents reported that outreach had helped them to develop key skills that were valued in the workplace, specifically, communication, teamwork, organizational skills, time planning, event planning, and event management. Rather than a pleasant distraction or an opportunity to supplement income, all participants noted that they felt there were many additional benefits and that this was time well spent. Outreach should not be viewed as a distraction to science research but rather an important enhancement to it provided that the program is well constructed and seeks to develop those delivering the outreach activities.

Aims: While cementless fixation offers potential advantages over cemented fixation, such as a shorter operating time, concerns linger over its higher cost and increased risk of periprosthetic fractures. If the risk of fracture can be forecasted, it would aid the shared decision-making process related to cementless stems. Our study aimed to develop and validate predictive models of periprosthetic femoral fracture (PPFF) necessitating revision and reoperation after elective total hip arthroplasty (THA). Methods: We included 154,519 primary elective THAs from the Swedish Arthroplasty Register (SAR), encompassing 21 patient-, surgical-, and implant-specific features, for model derivation and validation in predicting 30-day, 60-day, 90-day, and one-year revision and reoperation due to PPFF. Model performance was tested using the area under the curve (AUC), and feature importance was identified in the best-performing algorithm. Results: The Lasso regression excelled in predicting 30-day revisions (area under the receiver operating characteristic curve (AUC) = 0.85), while the Gradient Boosting Machine (GBM) model outperformed other models by a slight margin for all remaining endpoints (AUC range: 0.79 to 0.86). Predictive factors for revision and reoperation were identified, with patient features such as increasing age, higher American Society of Anesthesiologists grade (> III), and World Health Organization obesity classes II to III associated with elevated risks. A preoperative diagnosis of idiopathic necrosis increased revision risk. Concerning implant design, factors such as cementless femoral fixation, reverse-hybrid fixation, hip resurfacing, and small (< 35 mm) or large (> 52 mm) femoral heads increased both revision and reoperation risks. Conclusion: This is the first study to develop machine-learning models to forecast the risk of PPFF necessitating secondary surgery. Future studies are required to externally validate our algorithm and assess its applicability in clinical practice. Cite this article: Bone Joint Res 2025;14(1):46–57.

Objective: The short-term safety of methylphenidate (MPH) has been widely demonstrated; however the long-term safety is less clear. The aim of this study was to investigate the safety of MPH in relation to pubertal maturation and to explore the monitoring of bone age. Method: Participants from ADDUCE, a two-year observational longitudinal study with three parallel cohorts (MPH group, no-MPH group, and a non-ADHD control group), were compared with respect to Tanner staging. An Italian subsample of medicated-ADHD was further assessed by the monitoring of bone age. Results: The medicated and unmedicated ADHD groups did not differ in Tanner stages indicating no higher risk of sexual maturational delay in the MPH-treated patients. The medicated subsample monitored for bone age showed a slight acceleration of the bone maturation after 24 months, however their predicted adult height remained stable. Conclusion: Our results do not suggest safety concerns on long-term treatment with MPH in relation to pubertal maturation and growth.

Objective: Short-term RCTs have demonstrated that MPH-treatment significantly reduces ADHD-symptoms, but is also associated with adverse events, including sleep problems. However, data on long-term effects of MPH on sleep remain limited. Methods: We performed a 2-year naturalistic prospective pharmacovigilance multicentre study. Participants were recruited into three groups: ADHD patients intending to start MPH-treatment (MPH-group), those not intending to use ADHD-medication (no-MPH-group), and a non-ADHD control-group. Sleep problems were assessed with the Children's-Sleep-Habits-Questionnaire (CSHQ). Results: 1,410 participants were enrolled. Baseline mean CSHQ-total-sleep-scores could be considered clinically significant for the MPH-group and the no-MPH-group, but not for controls. The only group to show a significant increase in any aspect of sleep from baseline to 24-months was the control-group. Comparing the MPH- to the no-MPH-group no differences in total-sleep-score changes were found. Conclusion: Our findings support that sleep-problems are common in ADHD, but don't suggest significant negative long-term effects of MPH on sleep.

Despite numerous female contraceptive options, nearly half of all pregnancies are unintended. Family planning choices for men are currently limited to unreliable condoms and invasive vasectomies with questionable reversibility. Here, we report the development of an oral contraceptive approach based on transcriptional disruption of cyclical gene expression patterns during spermatogenesis. Spermatogenesis involves a continuous series of self-renewal and differentiation programs of spermatogonial stem cells (SSCs) that is regulated by retinoic acid (RA)-dependent activation of receptors (RARs), which control target gene expression through association with corepressor proteins. We have found that the interaction between RAR and the corepressor silencing mediator of retinoid and thyroid hormone receptors (SMRT) is essential for spermatogenesis. In a genetically engineered mouse model that negates SMRT-RAR binding (SMRTmRID mice), the synchronized, cyclic expression of RAR-dependent genes along the seminiferous tubules is disrupted. Notably, the presence of an RA-resistant SSC population that survives RAR de-repression suggests that the infertility attributed to the loss of SMRT-mediated repression is reversible. Supporting this notion, we show that inhibiting the action of the SMRT complex with chronic, low-dose oral administration of a histone deacetylase inhibitor reversibly blocks spermatogenesis and fertility without affecting libido. This demonstration validates pharmacologic targeting of the SMRT repressor complex for non-hormonal male contraception.

Mitochondrial dysfunction is a characteristic trait of human and rodent obesity, insulin resistance and fatty liver disease. Here we show that high-fat diet (HFD) feeding causes mitochondrial fragmentation in inguinal white adipocytes from male mice, leading to reduced oxidative capacity by a process dependent on the small GTPase RalA. RalA expression and activity are increased in white adipocytes after HFD. Targeted deletion of RalA in white adipocytes prevents fragmentation of mitochondria and diminishes HFD-induced weight gain by increasing fatty acid oxidation. Mechanistically, RalA increases fission in adipocytes by reversing the inhibitory Ser637 phosphorylation of the fission protein Drp1, leading to more mitochondrial fragmentation. Adipose tissue expression of the human homolog of Drp1, DNM1L, is positively correlated with obesity and insulin resistance. Thus, chronic activation of RalA plays a key role in repressing energy expenditure in obese adipose tissue by shifting the balance of mitochondrial dynamics toward excessive fission, contributing to weight gain and metabolic dysfunction.

Bile acids (BAs) affect the intestinal environment by ensuring barrier integrity, maintaining microbiota balance, regulating epithelium turnover, and modulating the immune system. As a master regulator of BA homeostasis, farnesoid X receptor (FXR) is severely compromised in patients with inflammatory bowel disease (IBD) and colitis-associated colorectal cancer (CAC). At the front line, gut macrophages react to the microbiota and metabolites that breach the epithelium. We aim to study the role of the BA/FXR axis in macrophages. This study demonstrates that inflammation-induced epithelial abnormalities compromised FXR signaling and altered BAs' profile in a mouse CAC model. Further, gut macrophage-intrinsic FXR sensed aberrant BAs, leading to pro-inflammatory cytokines' secretion, which promoted intestinal stem cell proliferation. Mechanistically, activation of FXR ameliorated intestinal inflammation and inhibited colitis-associated tumor growth, by regulating gut macrophages' recruitment, polarization, and crosstalk with Th17 cells. However, deletion of FXR in bone marrow or gut macrophages escalated the intestinal inflammation. In summary, our study reveals a distinctive regulatory role of FXR in gut macrophages, suggesting its potential as a therapeutic target for addressing IBD and CAC.

Oncogenic lesions in pancreatic ductal adenocarcinoma (PDAC) hijack the epigenetic machinery in stromal components to establish a desmoplastic and therapeutic resistant tumor microenvironment (TME). Here we identify Class I histone deacetylases (HDACs) as key epigenetic factors facilitating the induction of pro-desmoplastic and pro-tumorigenic transcriptional programs in pancreatic stromal fibroblasts. Mechanistically, HDAC-mediated changes in chromatin architecture enable the activation of pro-desmoplastic programs directed by serum response factor (SRF) and forkhead box M1 (FOXM1). HDACs also coordinate fibroblast pro-inflammatory programs inducing leukemia inhibitory factor (LIF) expression, supporting paracrine pro-tumorigenic crosstalk. HDAC depletion in cancer-associated fibroblasts (CAFs) and treatment with the HDAC inhibitor entinostat (Ent) in PDAC mouse models reduce stromal activation and curb tumor progression. Notably, HDAC inhibition (HDACi) enriches a lipogenic fibroblast subpopulation, a potential precursor for myofibroblasts in the PDAC stroma. Overall, our study reveals the stromal targeting potential of HDACi, highlighting the utility of this epigenetic modulating approach in PDAC therapeutics.

This article reflects on findings from a qualitative evaluation of the Narnian Virtues Character Education English Curriculum (NV) in the context of critical engagement with the field of character education. We recognise many people argue for or against character education based on ideological positions. This article will reflect on how those positions relate to our data, recognising in practice dominant neoliberal and deficit narratives influence the operationalising of the curriculum. It is then argued that character education has the potential to promote the wellbeing of young people where there exists robust conceptualisions of character and young people, whilst also making an overt effort to resist and challenge dominant ideologies.

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 ten 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.

Background Transcranial magnetic stimulation may lead to short-term improvement in depression symptoms. Pilot work suggested that personalised magnetic resonance imaging connectivity-guided intermittent theta burst stimulation might lead to sustained improvement in depression symptoms in treatment-resistant depression. Objectives To determine the efficacy, acceptability, and cost-effectiveness of connectivity-guided intermittent theta burst stimulation over 8, 16 and 26 weeks on depression symptoms (Hamilton Rating Scale for Depression-17) compared with repetitive transcranial magnetic stimulation. To explore the mechanism of action of transcranial magnetic stimulation through effective and functional connectivity, and gamma-aminobutyric acid and glutamate+glutamine in the prefrontal cortex, subgenual anterior cingulate cortex and right anterior insula. Design A multicentre parallel group, double-blind, randomised controlled trial, to test the efficacy of connectivity-guided intermittent theta burst stimulation versus repetitive transcranial magnetic stimulation without connectivity guidance, in patients with moderate to severe treatment-resistant major depressive disorder (treatment-resistant depression). Setting Secondary care mental health services across five study sites. Participants Aged 18 years or over with major depressive disorder, Massachusetts General Hospital Treatment Resistant Depression staging score ≥ 2, and Hamilton Rating Scale for Depression-17 score ≥ 16. Exclusions: bipolar disorder, secondary depression, suicidality, current substance abuse or dependence, neurological conditions, prior brain surgery, major unstable medical illness, standard contraindications to magnetic resonance imaging, change in prescribed medication or benzodiazepines or hypnotics ≥ 5 mgdiazepam equivalents daily in 2 weeks before baseline. Trial interventions In total 3000 pulses were delivered in each 37.5-minute repetitive transcranial magnetic stimulation or connectivity-guided intermittent theta burst stimulation session for 20 sessions over 4–6 weeks. Personalised transcranial magnetic stimulation stimulation targets were identified from magnetic resonance imaging (F3 site for repetitive transcranial magnetic stimulation, maximum effective connectivity from right anterior insula to left dorsolateral prefrontal cortex for connectivity-guided intermittent theta burst stimulation) using neuronavigation to deliver transcranial magnetic stimulation. Main outcome measures The primary outcome measure was mean change in depression symptoms from baseline and at 8, 16 and 26 weeks using the Grid version of the Hamilton Rating Scale for Depression-17. Secondary outcomes were response, remission, sustained response, self-rated depression (Patient Health Questionnaire-9, Beck Depression Inventory-II), generalised anxiety-7, function (Work and Social Adjustment Scale), quality of life (Euroqol five-dimension five line), overall improvement (Euroqol five-dimension five-line scale), acceptability, with cognition (THINC-it battery), resting state functional magnetic resonance imaging and magnetic resonance spectroscopy (baseline and 16 weeks) and costs from health and society perspectives. Results A total of 255 participants were randomised (128 connectivity-guided intermittent theta burst stimulation, 127 repetitive transcranial magnetic stimulation). There were no significant differences between repetitive transcranial magnetic stimulation and connectivity-guided intermittent theta burst stimulation in the Hamilton Rating Scale for Depression-17 score [intention-to-treat adjusted mean −0.31 (95% confidence interval −1.87 to 1.24)] nor on any secondary outcome. Sustained response rates at 26 weeks were 22/127 (17.3%) repetitive transcranial magnetic stimulation, and 29/128 (22.7%) connectivity-guided intermittent theta burst stimulation. Connectivity-guided intermittent theta burst stimulation was dominant over repetitive transcranial magnetic stimulation in cost-effectiveness (0.009 greater quality-adjusted life-year gain and £180 greater cost saving to health services per individual), albeit overlapping 95% confidence interval between treatment groups demonstrates uncertainties. One serious adverse event in each group (mania, psychosis) was attributable to transcranial magnetic stimulation. Both treatments were equally acceptable. Clinical improvement was associated with measures of effective or functional connectivity between left dorsolateral prefrontal cortex and right anterior insula, subgenual anterior cingulate cortex and left dorsomedial prefrontal cortex, and spectroscopy baseline gamma-aminobutyric acid. Limitations Participants may have benefited from > 20 transcranial magnetic stimulation sessions. There was no sham control group. Conclusion Connectivity-guided intermittent TBS was not superior in efficacy to standard repetitive transcranial magnetic stimulation. Magnetic resonance imaging neuronavigation personalised repetitive transcranial magnetic stimulation or intermittent theta burst stimulation are acceptable methods to reduce depression symptoms over 26 weeks in treatment-resistant depression alongside other reasons for improvement. Study registration Current Controlled Trials ISRCTN19674644. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme (NIHR award ref: 16/44/22) and is published in full in Efficacy and Mechanism Evaluation; Vol. 12, No. 2. See the NIHR Funding and Awards website for further award information. Plain language summary Transcranial magnetic stimulation delivers magnetic bursts of energy to the skull. It is recommended for use in the National Health Service in the United Kingdom by the National Institute for Health and Care Excellence as a treatment for treatment-resistant depression. Treatment-resistant depression is depression that has not improved with at least two different courses of treatment. In this trial, we randomly allocated (like a toss of a coin) 255 individuals with treatment-resistant depression to either the usual repetitive transcranial magnetic stimulation delivered to a standard brain region, or to an alternative patterned form of transcranial magnetic stimulation delivered to an individually personalised site called connectivity-guided intermittent theta burst stimulation. We used the participants’ magnetic resonance brain imaging scans to choose the site. All participants in the trial received 20 transcranial magnetic stimulation sessions over 4–6 weeks. We measured depression, anxiety, functioning, thinking, memory, acceptability, side effects, quality of life, and costs of both treatments at baseline and at 8, 16 and 26 weeks after they were randomised. We used brain imaging techniques before and 16 weeks after they were randomised to measure brain connectivity (how parts of the brain interact with each other) and chemical changes in the brain that may change with depression symptoms. Contrary to what we predicted, connectivity-guided intermittent theta burst stimulation was not more effective than repetitive transcranial magnetic stimulation on any of the outcomes except it might have cost a little less and slightly improved quality of life. About 20% of both groups showed a response lasting 26 weeks. Both treatment protocols were safe but often produced mild temporary side effects. Both treatments were acceptable. There were some associations between chemicals in the brain and improvement with treatments. There were similar changes in the way some parts of the brain interacted with each other when depression symptoms improved with transcranial magnetic stimulation. We concluded that both transcranial magnetic stimulation treatments produce lasting improvements for some people with treatment-resistant depression. However, there were reasons other than transcranial magnetic stimulation why some of these people might have improved. Scientific summary Background Major depressive disorder (MDD) is estimated by the World Health Organization in 2017 to be the leading cause of disability and suicide. About a third of MDD managed in specialist mental health services and 22% in primary care is treatment-resistant depression (TRD) that does not respond to two or more attempts to treat it. Alternative treatment approaches are required in addition to antidepressants and psychological treatments. Transcranial magnetic stimulation (TMS) was approved by the National Institute for Care Excellence for the management of depression and TRD because there is robust evidence of the effectiveness of active repetitive transcranial magnetic stimulation (rTMS) over sham rTMS. A recent large randomised controlled trial found that intermittent theta burst stimulation (iTBS) was non-inferior to rTMS in TRD but more cost-effective. However, there are concerns that rTMS and iTBS may be short-lived in effectiveness. Pilot work suggested that precise personalised iTBS stimulation using MRI measurement of effective connectivity between the right anterior insula (rAI) and left dorsolateral prefrontal cortex (lDLPFC) and neuronavigation might lead to longer duration of improvement in depression symptoms in TRD. Moreover, improvements in depression symptoms over 12 weeks were correlated with reductions in functional connectivity (FC) between the lDLPFC and the left dorsomedial prefrontal cortex (lDMPFC) and increases in gamma-aminobutyric acid (GABA) levels in the lDLPFC with connectivity-guided intermittent theta burst stimulation (cgiTBS) and MRI-neuronavigated rTMS. We propose that personalising iTBS through measuring effective connectivity between the rAI and lDLPFC may increase the duration of improvement in depression symptoms compared to standard rTMS. Objectives To determine the efficacy, that is the superiority, of personalised neuronavigated connectivity-guided intermittent theta burst stimulation (cgiTBS) over 8, 16 and 26 weeks on objective depression symptoms measured by the Hamilton Rating Scale for Depression-17 (HDRS-17) compared with personalised neuronavigated rTMS. To explore secondary clinical outcomes namely subjective depression, anxiety, cognition, social function, quality of life and overall clinical improvement over 8, 16 and 26 weeks. To examine cost-effectiveness of cgiTBS versus rTMS in a UK NHS population. To examine the patient’s acceptability and experience of cgiTBS and rTMS. To explore baseline effective connectivity (EC) from rAI to lDLPFC and changes in EC between baseline and 16 weeks from rAI to lDLPFC, and clinical improvement in depression symptoms. To explore change in FC between the IDLPFC-DMPFC, and clinical improvement in depression symptoms. To explore the relationship of baseline FC between IDLPFC and subgenual anterior cingulate cortex (sgACC), and changes in FC between the IDLPFC and sgACC with clinical improvement in depression symptoms. To explore baseline GABA, change in GABA from baseline to 16 weeks, and clinical improvement in depression symptoms. To explore change in Glx (glutamate + glutamine) and GABA/Glx ratio from baseline to 16 weeks and clinical improvement in depression symptoms. Methods Design This study was a multicentre parallel group, double-blind, randomised controlled trial, to test the efficacy of cgiTBS versus neuronavigated rTMS without connectivity guidance, in patients with a primary diagnosis of moderate to severe MDD, which was treatment resistant in their current episode. Setting This study was carried out at five sites across the UK NHS: Nottingham, Camden and Islington, Newcastle, Northampton and Oldham. Participants were recruited through secondary care services across the five study sites, self-referrals, and patient identification centres compromising primary care services and secondary care services at neighbouring NHS trusts near the main study sites. Inclusion criteria Adults ≥ 18 years. Diagnosis of current MDD (defined according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition), that is treatment resistant defined as scoring 2 or more on the Massachusetts General Hospital Treatment Resistant Depression Staging Score (MGH-S). Have an HDRS-17 score of 16 or more (moderate to severe depression). Capacity to provide informed consent before any trial-related activities. Exclusion criteria History of bipolar disorder (due to risk of mania) or depression secondary to other mental disorder. Neurological conditions, for example brain neoplasm, cerebrovascular events, epilepsy, neurodegenerative disorders and prior brain surgery. Standard contraindications to MRI, that is irremovable metal objects in and around the body (e.g. a cardiac pacemaker or implanted medication pump) and pregnancy (any doubt was resolved by a pregnancy test, with women of childbearing age taking precautions against pregnancy) This included other potential complicated factors such as red tattoos, which consist of iron on the head, neck, and back, and claustrophobia. Major unstable medical illness requiring further investigation or treatment. Change in prescribed medication 2 weeks before baseline assessment. Prescription of lamotrigine, gabapentin, or pregabalin in the 2 weeks prior to baseline assessment. Daily prescription of benzodiazepine above 5 mg diazepam equivalents, zopiclone above 7.5 mg, zolpidem above 10 mg or zaleplon above 10 mg. These drugs should not be used intermittently in the 2 weeks before baseline assessment. Current substance abuse or dependence [defined by Diagnostic and Statistical Manual of Mental Disorder version 5 (DSM-5) criteria). At risk of suicidality. Potential complicated factors relating to the TMS treatment, such as hairstyles that would impair magnetic transmission and piercings. Participants would be excluded only if they chose to not make the changes required to ensure effective treatment. Involved with any other clinical trial at the time of consent or 6 months prior. Unable to read or understand English. Randomisation Participants were randomly assigned in a 1 : 1 ratio into the rTMS and cgiTBS arms. Randomisation was stratified by study site and minimised on severity of depression (HDRS-17 score 16–23 moderate or ≥ 24 severe) and degree of treatment resistance [low 2–3.5, medium 4–6, high (≥ 6.5) as assessed at baseline]. Blinding to trial arm Participants, referring clinical teams, and the outcomes assessors were kept blinded with respect to the assigned treatment until after the participants’ final follow-up assessment. Any unintended unblinding of outcome assessors were recorded, with other assessors completing all further assessments for that participant. At each follow-up assessment, the outcomes assessor was asked to guess the participants’ treatment allocation. Trial interventions A total of 3000 pulses were delivered in each rTMS or cgiTBS session, with 20 TMS sessions delivered over a 4–6-week period. Each session for both cgiTBS (80% motor threshold) and rTMS (120% motor threshold) lasted approximately 37.5 minutes in total for the purposes of blinding participants and assessors of outcome. Multimodal magnetic resonance imaging (MRI) was acquired for each participant at baseline (before TMS treatment) with T1-weighted (structural MRI) and resting state (task-free) functional MRI (rsfMRI). Personalised TMS stimulation targets were identified from MRI (F3 site for rTMS, maximum EC from rAI to lDLPFC for cgiTBS) and the site was delivered via neuronavigation. Primary outcome The primary outcome measure was mean change in depression symptoms from baseline over 26 weeks using the 17-item Grid version of the HDRS-17 assessed at baseline and at 8, 16 and 26 weeks. Secondary outcomes Secondary outcomes were response (50% drop from baseline HDRS-17 score) and remission (

Summary: Background: Large-scale multicentre studies are needed to understand complex relationships between the gut microbiota, health and disease. Interrogating the mucosal microbiota may identify important biology not captured by stool analysis. Gold standard tissue cryopreservation (‘flash freezing’) limits large-scale study feasibility. We aimed to compare gut microbiota in gold standard and pragmatic mucosal biopsy storage conditions. Methods: We collected endoscopic recto-sigmoid biopsies from 20 adults with inflammatory bowel disease. Biopsies were preserved using three methods: (i) flash freezing (most proximal and distal biopsy sites); (ii) nucleic acid preservative reagents (QIAGEN Allprotect®, Invitrogen RNAlater™, and Zymo DNA/RNA Shield™); and (iii) formalin fixation with paraffin embedding (FFPE), which is used to preserve tissue for clinical histopathology within healthcare settings. Microbiota were sequenced on the MiSeq platform (V4 region, 16S rRNA gene). Findings: Tissue microbiota were consistent between most proximal and distal tissue suggesting any within-patient variation observed reflected storage condition, not biopsy location. There was no significant difference in alpha-diversity or microbial community profiles of reagent-preserved versus gold standard tissue. FFPE community structure was significantly dissimilar to other tissue samples, driven by differential relative abundance of obligate gut anaerobes; Faecalibacterium, Anaerostipes and Lachnospiraceae. Despite these differences, tissue microbiota grouped by participant regardless of preservation and storage conditions. Interpretation: Preservative reagents offer a convenient alternative to flash freezing tissue in prospective large-scale mucosal microbiota studies. Whilst less comparable, FFPE provides potential for retrospective microbiota studies using historical samples. Funding: Medical Research Council (MR/T032162/1) and The Leona M. and Harry B. Helmsley Charitable Trust (G-2002-04255).

Two recent papers identified a number of countries that have sustained reductions in carbon emissions. We first take a closer look at per capita emissions trends to settle on 24 ‘peak and decline’ carbon emissions countries. Then, we use a set of methods drawn from both economics and the larger energy/climate literature (i) to determine which of those countries have decoupled emissions from GDP, such that emissions and GDP are negatively associated/correlated, and (ii) to uncover how those decoupling countries achieved such a state. Only 15 countries actually have decoupled carbon emissions from GDP. They have done so by both reducing their energy consumption and decarbonizing their energy systems. And these decoupling countries have decarbonized largely by increasing both the share of energy services that are delivered via electricity and the share of nonfossil fuels used to generate that electricity. We conclude that sustaining declining carbon emissions will depend mainly on additional decarbonization, which itself will require further electrification of energy services.

As part of Ham Radio Science Citizen Investigation (HamSCI) Personal Space Weather Station (PSWS) project, a low-cost, commercial off-the-shelf magnetometer has been developed to provide quantitative and qualitative measurements of the geospace environment from the ground for both scientific and operational purposes at a cost that will allow for crowd-sourced data contributions. The PSWS magnetometers employ a magneto-inductive sensor technology to record three-axis magnetic field variations with a field resolution of ∼3 nT at a 1 Hz sample rate. The measurement range of the sensor is ±1.1×106 nT) and is valid over a temperature range of −40 °C to +85 °C. Data from the PSWS network will combine these magnetometer measurements with high frequency (HF, 3–30 MHz) radio observations to monitor large-scale current systems and ionospheric disturbances due to drivers from both space and the atmosphere. A densely-spaced magnetometer array, once established, will demonstrate their space weather monitoring capability to an unprecedented spatial extent. Magnetic field data obtained by the magnetometers installed at various locations in the US are presented and compared with the existing magnetometers nearby, demonstrating that the performance is very adequate for scientific investigations.

Colorectal cancer (CRC) is driven by genomic alterations in concert with dietary influences, with the gut microbiome implicated as an effector in disease development and progression. While meta-analyses have provided mechanistic insight into patients with CRC, study heterogeneity has limited causal associations. Using multi-omics studies on genetically controlled cohorts of mice, we identify diet as the major driver of microbial and metabolomic differences, with reductions in α diversity and widespread changes in cecal metabolites seen in high-fat diet (HFD)-fed mice. In addition, non-classic amino acid conjugation of the bile acid cholic acid (AA-CA) increased with HFD. We show that AA-CAs impact intestinal stem cell growth and demonstrate that Ileibacterium valens and Ruminococcus gnavus are able to synthesize these AA-CAs. This multi-omics dataset implicates diet-induced shifts in the microbiome and the metabolome in disease progression and has potential utility in future diagnostic and therapeutic developments.

We study the effect of magnification in the Dark Energy Survey Year 3 analysis of galaxy clustering and galaxy-galaxy lensing, using two different lens samples: a sample of luminous red galaxies, redMaGiC, and a sample with a redshift-dependent magnitude limit, MagLim. We account for the effect of magnification on both the flux and size selection of galaxies, accounting for systematic effects using the Balrog image simulations. We estimate the impact of magnification on the galaxy clustering and galaxy-galaxy lensing cosmology analysis, finding it to be a significant systematic for the MagLim sample. We show cosmological constraints from the galaxy clustering autocorrelation and galaxy-galaxy lensing signal with different magnifications priors, finding broad consistency in cosmological parameters in ΛCDM and wCDM. However, when magnification bias amplitude is allowed to be free, we find the two-point correlation functions prefer a different amplitude to the fiducial input derived from the image simulations. We validate the magnification analysis by comparing the cross-clustering between lens bins with the prediction from the baseline analysis, which uses only the autocorrelation of the lens bins, indicating that systematics other than magnification may be the cause of the discrepancy. We show that adding the cross-clustering between lens redshift bins to the fit significantly improves the constraints on lens magnification parameters and allows uninformative priors to be used on magnification coefficients, without any loss of constraining power or prior volume concerns.

Recent cosmological analyses rely on the ability to accurately sample from high-dimensional posterior distributions. A variety of algorithms have been applied in the field, but justification of the particular sampler choice and settings is often lacking. Here, we investigate three such samplers to motivate and validate the algorithm and settings used for the Dark Energy Survey (DES) analyses of the first 3 yr (Y3) of data from combined measurements of weak lensing and galaxy clustering. We employ the full DES Year 1 likelihood alongside a much faster approximate likelihood, which enables us to assess the outcomes from each sampler choice and demonstrate the robustness of our full results. We find that the ellipsoidal nested sampling algorithm MULTINEST reports inconsistent estimates of the Bayesian evidence and somewhat narrower parameter credible intervals than the sliced nested sampling implemented in POLYCHORD. We compare the findings from MULTINEST and POLYCHORD with parameter inference from the Metropolis–Hastings algorithm, finding good agreement. We determine that POLYCHORD provides a good balance of speed and robustness for posterior and evidence estimation, and recommend different settings for testing purposes and final chains for analyses with DES Y3 data. Our methodology can readily be reproduced to obtain suitable sampler settings for future surveys.