The egg-counter: a novel microfluidic platform for characterization of Caenorhabditis elegans egg-laying.

Reproduction is a fundamental process that shapes the demography of every living organism yet is often difficult to assess with high precision in animals that produce large numbers of offspring. Here, we present a novel microfluidic research platform for studying Caenorhabditis elegans' egg-laying. The platform provides higher throughput than traditional solid-media behavioral assays while providing a very high degree of temporal resolution. Additionally, the environmental control enabled by microfluidic animal husbandry allows for experimental perturbations difficult to achieve with solid-media assays. We demonstrate the platform's utility by characterizing C. elegans egg-laying behavior at two commonly used temperatures, 15 and 20 °C. As expected, we observed a delayed onset of egg-laying at 15 °C degrees, consistent with published temperature effects on development rate. Additionally, as seen in solid media studies, egg laying output was higher under the canonical 20 °C conditions. While we validated the Egg-Counter with a study of temperature effects in wild-type animals, the platform is highly adaptable to any nematode egg-laying research where throughput or environmental control needs to be maximized without sacrificing temporal resolution.

Implementation and Impact of Perinatal Food Is Medicine Programs: A Qualitative Research Study.

BACKGROUND: Improving social determinants of health, such as access to nutritious food, is crucial for achieving health equity. Nutrition insecurity, especially during pregnancy and postpartum, can lead to poor maternal and birth outcomes. Food is Medicine (FIM) programs, which integrate food into the health care system to prevent or manage disease, have the potential to improve nutrition insecurity, but research about perinatal FIM programs is limited. OBJECTIVE: The purpose of this study was to explore perceptions of public health impacts of perinatal FIM programs from the perspectives of both program implementers and program supporters and implementation strategies used to enhance program adoption, implementation, and maintenance. DESIGN: Qualitative data were collected through semi-structured interviews. The interview guide was based on the Reach, Effectiveness, Adoption, Implementation, Maintenance framework. PARTICIPANTS/SETTING: Program implementers (n = 16) and program supporters (n = 20) were recruited across the United States through purposive sampling in 2022 and 2023. ANALYSIS: Data were analyzed using deductive thematic analysis and an iterative feedback loop with the project partner. RESULTS: Interviews were completed with program implementers and program supporters and generated meaning units (n = 1,942), which were coded into themes aligned with each Reach, Effectiveness, Adoption, Implementation, Maintenance dimension. Perinatal FIM programs reached multiple priority populations who were mainly recruited through health care systems. Effectiveness measures typically included nutrition patterns and practices, as well as return on investment. Motivations for adopting programs primarily included partnerships and connections, financing, and policies and laws. Program components varied and were adapted to meet participants and setting needs. Policy, evidence, funding, and partnerships could lead to program maintenance. Implementation strategies applied by the program supporters included financial strategies and infrastructure changes. CONCLUSIONS: There is a need to identify the core functions and adaptable forms of perinatal FIM programs, which could lead to identification of standard evaluation metrics. This could result in greater uptake by potential delivery agents, increased funding and policy support, and enhanced benefits for perinatal population experiencing health disparities.

The Egg-Counter: A novel microfluidic platform for characterization of Caenorhabditis elegans egg-laying.

Reproduction is a fundamental process that shapes the demography of every living organism yet is often difficult to assess with high precision in animals that produce large numbers of offspring. Here, we present a novel microfluidic research platform for studying Caenorhabditis elegans' egg-laying. The platform provides higher throughput than traditional solid-media assays while providing a very high degree of temporal resolution. Additionally, the environmental control enabled by microfluidic animal husbandry allows for experimental perturbations difficult to achieve with solid-media assays. We demonstrate the platform's utility by characterizing C. elegans egg-laying behavior at two commonly used temperatures, 15 and 20°C. As expected, we observed a delayed onset of egg-laying at 15°C degrees, consistent with published temperature effects on development rate. Additionally, as seen in solid media studies, egg laying output was higher under the canonical 20°C conditions. While we validated the Egg-Counter with a study of temperature effects in wild-type animals, the platform is highly adaptable to any nematode egg-laying research where throughput or environmental control needs to be maximized without sacrificing temporal resolution.

Understanding the Liquid Structure in Mixtures of Ionic Liquids with Semiperfluoroalkyl or Alkyl Chains.

By mixing ionic liquids (ILs), it is possible to fine-tune their bulk and interfacial structure. This alters their physical properties and solvation behavior and is a simple way to prepare a collection of ILs whose properties can be tuned to optimize a specific application. In this study, mixtures of perfluorinated and alkylated ILs have been prepared, and links between composition, properties, and nanostructure have been investigated. These different classes of ILs vary substantially in the flexibility and polarizability of their chains. Thus, a range of useful structural and physical property variations are accessible through mixing that will expand the library of IL mixtures available in an area that to this point has received relatively little attention. In the experiments presented herein, the physical properties and bulk structure of mixtures of 1-methyl-3-octylimidazolium bis(trifluoromethylsulfonyl)imide [C8MIM][Tf2N] and 1-(1H,1H,2H,2H-perfluorooctyl)-3-methylimidazolium bis(trifluoromethylsulfonyl)imide [C8MIM-F13][Tf2N] have been prepared. The bulk liquid structure was investigated using a combination of small-angle X-ray and neutron scattering (SAXS and SANS, respectively) experiments in combination with atomistic molecular dynamics simulations and the measurement of density and viscosity. We observed that the addition of [C8MIM-F13][Tf2N] to [C8MIM][Tf2N] causes changes in the nanostructure of the IL mixtures that are dependent on composition so that variation in the characteristic short-range correlations is observed as a function of composition. Thus, while the length scales associated with the apolar regions (polar non-polar peak─PNPP) increase with the proportion of [C8MIM-F13][Tf2N] in the mixtures, perhaps surprisingly given the greater volume of the fluorocarbon chains, the length scale of the charge-ordering peak decreases. Interestingly, consideration of the contact peak shows that its origins are both in the direct anion···cation contact length scale and the nature (and hence volume) of the chains appended to the imidazolium cation.

Tissue-Specific Vulnerability to Apoptosis in Machado-Joseph Disease.

Machado-Joseph disease (MJD) is a dominant neurodegenerative disease caused by an expanded CAG repeat in the ATXN3 gene encoding the ataxin-3 protein. Several cellular processes, including transcription and apoptosis, are disrupted in MJD. To gain further insights into the extent of dysregulation of mitochondrial apoptosis in MJD and to evaluate if expression alterations of specific apoptosis genes/proteins can be used as transcriptional biomarkers of disease, the expression levels of BCL2, BAX and TP53 and the BCL2/BAX ratio (an indicator of susceptibility to apoptosis) were assessed in blood and post-mortem brain samples from MJD subjects and MJD transgenic mice and controls. While patients show reduced levels of blood BCL2 transcripts, this measurement displays low accuracy to discriminate patients from matched controls. However, increased levels of blood BAX transcripts and decreased BCL2/BAX ratio are associated with earlier onset of disease, indicating a possible association with MJD pathogenesis. Post-mortem MJD brains show increased BCL2/BAX transcript ratio in the dentate cerebellar nucleus (DCN) and increased BCL2/BAX insoluble protein ratio in the DCN and pons, suggesting that in these regions, severely affected by degeneration in MJD, cells show signs of apoptosis resistance. Interestingly, a follow-up study of 18 patients further shows that blood BCL2 and TP53 transcript levels increase over time in MJD patients. Furthermore, while the similar levels of blood BCL2, BAX, and TP53 transcripts observed in preclinical subjects and controls is mimicked by pre-symptomatic MJD mice, the expression profile of these genes in patient brains is partially replicated by symptomatic MJD mice. Globally, our findings indicate that there is tissue-specific vulnerability to apoptosis in MJD subjects and that this tissue-dependent behavior is partially replicated in a MJD mouse model.

Single-cell analysis reveals prognostic fibroblast subpopulations linked to molecular and immunological subtypes of lung cancer.

Fibroblasts are poorly characterised cells that variably impact tumour progression. Here, we use single cell RNA-sequencing, multiplexed immunohistochemistry and digital cytometry (CIBERSORTx) to identify and characterise three major fibroblast subpopulations in human non-small cell lung cancer: adventitial, alveolar and myofibroblasts. Alveolar and adventitial fibroblasts (enriched in control tissue samples) localise to discrete spatial niches in histologically normal lung tissue and indicate improved overall survival rates when present in lung adenocarcinomas (LUAD). Trajectory inference identifies three phases of control tissue fibroblast activation, leading to myofibroblast enrichment in tumour samples: initial upregulation of inflammatory cytokines, followed by stress-response signalling and ultimately increased expression of fibrillar collagens. Myofibroblasts correlate with poor overall survival rates in LUAD, associated with loss of epithelial differentiation, TP53 mutations, proximal molecular subtypes and myeloid cell recruitment. In squamous carcinomas myofibroblasts were not prognostic despite being transcriptomically equivalent. These findings have important implications for developing fibroblast-targeting strategies for cancer therapy.

What can we learn from 28 years of monitoring of fish tissue polychlorinated biphenyls in Michigan's rivers?

Polychlorinated biphenyls (PCBs) are an important part of chemical legacies in the Laurentian Great Lakes basin. Used in industrial products worldwide, PCBs are now extensively monitored because of their potential toxicity to humans. Fish consumption is a major pathway for exposure. Edible portion (i.e., fish fillet) data from Michigan's fish tissue PCB monitoring program were evaluated using regression statistics, principal component analysis, and t-tests to answer three questions: (1) How do fish tissue total PCB concentrations vary across Michigan's rivers? (2) Are the PCB congener patterns uniformly distributed among tested sites and species? (3) Do monitoring methods limit our ability to discern trends in fish tissue PCB concentrations? Our results indicate that although contaminated sites have been successfully identified, based on higher PCB concentrations in samples from Areas of Concern (AOCs) compared to non-AOC sites, 77% of fish samples from 2010 to 2015 exceeded the safe fish tissue PCB concentration for unrestricted consumption (97 g/day) by sensitive populations. The PCB congener profiles vary among species and locations. Results demonstrate that these data are not useful for supplementing ongoing spatial and temporal trend analysis. Only 15 of the 83 species + waterbody pairs had adequate data for evaluating temporal trends with more than three data points. In general, the trends at each location varied based on the analytical method. Conclusions from this work can inform revisions to existing monitoring programs and improve our ability to protect human health. Integr Environ Assess Manag 2023;19:152-162. © 2022 SETAC.

Lagging coverage for mental health services among children and adolescents through home and community-based Medicaid waivers.

PROBLEM: Many states cover mental health home and community-based services (HCBS) for youth through 1915(c) Medicaid HCBS waivers that allow states to waive certain Medicaid eligibility criteria and define high-risk populations based on age, medical condition(s), and disability status. We sought to evaluate how States are covering children and adolescents with mental health needs through 1915(c) waivers compared to other youth waiver populations. METHODS: Data elements were extracted from Medicaid 1915(c) approved waivers applications for all included waivers targeting any pediatric age range through October 31, 2018. Normalization criteria were developed and an aggregate overall coverage score and level of funding per person per waiver were calculated for each waiver. FINDINGS: One hundred and forty-two waivers across 45 states were included in this analysis. Even though there was uniformity in the Medicaid applications, there was great heterogeneity in how waiver eligibility, transition plans, services covered, and wait lists were defined across group classifications. Those with mental health needs (termed serious emotional disturbance) represented 5% of waivers with the least annual funding per person per waiver. CONCLUSIONS: We recommend greater links between public policy, infrastructure, health care providers, and a family-centered approach to extend coverage and scope of services for children and adolescents with mental health needs.

Blockades of effector T cell senescence and exhaustion synergistically enhance antitumor immunity and immunotherapy.

BACKGROUND: Current immunotherapies still have limited successful rates among cancers. It is now recognized that T cell functional state in the tumor microenvironment (TME) is a key determinant for effective antitumor immunity and immunotherapy. In addition to exhaustion, cellular senescence in tumor-infiltrating T cells (TILs) has recently been identified as an important T cell dysfunctional state induced by various malignant tumors. Therefore, a better understanding of the molecular mechanism responsible for T cell senescence in the TME and development of novel strategies to prevent effector T cell senescence are urgently needed for cancer immunotherapy. METHODS: Senescent T cell populations in the TMEs in mouse lung cancer, breast cancer, and melanoma tumor models were evaluated. Furthermore, T cell senescence induced by mouse tumor and regulatory T (Treg) cells in vitro was determined with multiple markers and assays, including real-time PCR, flow cytometry, and histochemistry staining. Loss-of-function strategies with pharmacological inhibitors and the knockout mouse model were used to identify the potential molecules and pathways involved in T cell senescence. In addition, melanoma mouse tumor immunotherapy models were performed to explore the synergistical efficacy of antitumor immunity via prevention of tumor-specific T cell senescence combined with anti-programmed death-ligand 1 (anti-PD-L1) checkpoint blockade therapy. RESULTS: We report that both mouse malignant tumor cells and Treg cells can induce responder T cell senescence, similar as shown in human Treg and tumor cells. Accumulated senescent T cells also exist in the TME in tumor models of lung cancer, breast cancer and melanoma. Induction of ataxia-telangiectasia mutated protein (ATM)-associated DNA damage is the cause for T cell senescence induced by both mouse tumor cells and Treg cells, which is also regulated by mitogen-activated protein kinase (MAPK) signaling. Furthermore, blockages of ATM-associated DNA damage and/or MAPK signaling pathways in T cells can prevent T cell senescence mediated by tumor cells and Treg cells in vitro and enhance antitumor immunity and immunotherapy in vivo in adoptive transfer T cell therapy melanoma models. Importantly, prevention of tumor-specific T cell senescence via ATM and/or MAPK signaling inhibition combined with anti-PD-L1 checkpoint blockade can synergistically enhance antitumor immunity and immunotherapy in vivo. CONCLUSIONS: These studies prove the novel concept that targeting both effector T cell senescence and exhaustion is an effective strategy and can synergistically enhance cancer immunotherapy.

Daily Inclusion of Resistant Starch-Containing Potatoes in a Dietary Guidelines for Americans Dietary Pattern Does Not Adversely Affect Cardiometabolic Risk or Intestinal Permeability in Adults with Metabolic Syndrome: A Randomized Controlled Trial.

Poor diet quality influences cardiometabolic risk. Although potatoes are suggested to adversely affect cardiometabolic health, controlled trials that can establish causality are limited. Consistent with potatoes being rich in micronutrients and resistant starch, we hypothesized that their inclusion in a Dietary Guidelines for Americans (DGA)-based dietary pattern would improve cardiometabolic and gut health in metabolic syndrome (MetS) persons. In a randomized cross-over trial, MetS persons (n = 27; 32.5 ± 1.3 year) consumed a DGA-based diet for 2 weeks containing potatoes (DGA + POTATO; 17.5 g/day resistant starch) or bagels (DGA + BAGEL; 0 g/day resistant starch) prior to completing oral glucose and gut permeability tests. Blood pressure, fasting glucose and insulin, and insulin resistance decreased (p < 0.05) from baseline regardless of treatment without any change in body mass. Oral glucose-induced changes in brachial artery flow-mediated dilation, nitric oxide homeostasis, and lipid peroxidation did not differ between treatment arms. Serum endotoxin AUC0−120 min and urinary lactulose/mannitol, but not urinary sucralose/erythritol, were lower in DGA + POTATO. Fecal microbiome showed limited between-treatment differences, but the proportion of acetate was higher in DGA + POTATO. Thus, short-term consumption of a DGA-based diet decreases cardiometabolic risk, and the incorporation of resistant starch-containing potatoes into a healthy diet reduces small intestinal permeability and postprandial endotoxemia.

Pre-existing polymerase-specific T cells expand in abortive seronegative SARS-CoV-2.

Individuals with potential exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) do not necessarily develop PCR or antibody positivity, suggesting that some individuals may clear subclinical infection before seroconversion. T cells can contribute to the rapid clearance of SARS-CoV-2 and other coronavirus infections1-3. Here we hypothesize that pre-existing memory T cell responses, with cross-protective potential against SARS-CoV-2 (refs. 4-11), would expand in vivo to support rapid viral control, aborting infection. We measured SARS-CoV-2-reactive T cells, including those against the early transcribed replication-transcription complex (RTC)12,13, in intensively monitored healthcare workers (HCWs) who tested repeatedly negative according to PCR, antibody binding and neutralization assays (seronegative HCWs (SN-HCWs)). SN-HCWs had stronger, more multispecific memory T cells compared with a cohort of unexposed individuals from before the pandemic (prepandemic cohort), and these cells were more frequently directed against the RTC than the structural-protein-dominated responses observed after detectable infection (matched concurrent cohort). SN-HCWs with the strongest RTC-specific T cells had an increase in IFI27, a robust early innate signature of SARS-CoV-2 (ref. 14), suggesting abortive infection. RNA polymerase within RTC was the largest region of high sequence conservation across human seasonal coronaviruses (HCoV) and SARS-CoV-2 clades. RNA polymerase was preferentially targeted (among the regions tested) by T cells from prepandemic cohorts and SN-HCWs. RTC-epitope-specific T cells that cross-recognized HCoV variants were identified in SN-HCWs. Enriched pre-existing RNA-polymerase-specific T cells expanded in vivo to preferentially accumulate in the memory response after putative abortive compared to overt SARS-CoV-2 infection. Our data highlight RTC-specific T cells as targets for vaccines against endemic and emerging Coronaviridae.

Alternative tissue fixation for combined histopathological and molecular analysis in a clinically representative setting.

Formalin is the principal tissue fixative used worldwide for clinical and research purposes. Despite optimal preservation of morphology, its preservation of DNA and RNA is poor. As clinical diagnostics increasingly incorporates molecular-based analysis, the requirement for maintaining nucleic acid quality is of increasing importance. Here we assess an alternative non-formalin-based tissue fixation method, PAXgene Tissue system, with the aim of better preserving nucleic acids, while maintaining the quality of the tissue to be used for vital existing diagnostic techniques. In this study, these criteria are assessed in a clinically representative setting. In total, 203 paired PAXgene Tissue and formalin-fixed samples were obtained. Blind-scored haematoxylin and eosin (H&E) sections showed comparable and acceptable staining. Immunohistochemistry (IHC) staining was suboptimal using existing protocols but improved with minor method adjustment and optimisation. Quality of DNA and RNA was significantly improved by PAXgene tissue fixation [RIN 2.8 versus 3.8 (p < 0.01), DIN 5.68 versus 6.77 (p < 0.001)], which translated into improved performance on qPCR assay. These results demonstrate the potential of PAXgene Tissue to be used routinely in place of formalin, maintaining adequate histological staining and significantly improving the preservation of biological molecules in the genomic era.

Large cell neuroendocrine lung carcinoma: consensus statement from The British Thoracic Oncology Group and the Association of Pulmonary Pathologists.

Over the past 10 years, lung cancer clinical and translational research has been characterised by exponential progress, exemplified by the introduction of molecularly targeted therapies, immunotherapy and chemo-immunotherapy combinations to stage III and IV non-small cell lung cancer. Along with squamous and small cell lung cancers, large cell neuroendocrine carcinoma (LCNEC) now represents an area of unmet need, particularly hampered by the lack of an encompassing pathological definition that can facilitate real-world and clinical trial progress. The steps we have proposed in this article represent an iterative and rational path forward towards clinical breakthroughs that can be modelled on success in other lung cancer pathologies.

Race, witness credibility, and jury deliberation in a simulated drug trafficking trial.

OBJECTIVE: The present study integrates several distinct lines of jury decision-making research by examining how the racial identities of the defendant and an informant witness interact in a federal drug conspiracy trial scenario and by assessing whether jurors' individual racial identity and jury group racial composition influence their judgments. HYPOTHESES: We predicted that jurors would be biased against the Black defendant and would be more likely to convict after exposure to a White informant, among other hypotheses. METHOD: We recruited 822 nonstudent jury-eligible participants assigned to 144 jury groups. Each group was assigned to one of four onditions where defendant race (Black or White) and informant race (Black or White) was manipulated. Each group watched a realistic audio-visual trial presentation, then deliberated as a group to render a verdict. RESULTS: Contrary to expectations, the conditions depicting a Black defendant yielded lower conviction rates compared to those with a White defendant-at both the predeliberation individual (odds ratio [OR] = 1.54) and postdeliberation group level (OR = 2.91)-while the informant race did not influence verdict outcomes. We also found that jurors rated the government witnesses as more credible when the defendant was White compared to when he was Black. Credibility ratings and verdict outcomes were also predicted by jurors' own race, although juror race did not interact with the race conditions when predicting verdicts. CONCLUSIONS: Jurors are sensitive to defendant race, and this sensitivity appears to strengthen after deliberation-but in a direction opposite to what was expected. One potential implication of our findings is that juries may operate as a check on system bias by applying greater scrutiny to law enforcement-derived evidence when the defendant is Black. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Prediction of severe neutropenia and diarrhoea in breast cancer patients treated with abemaciclib.

INTRODUCTION: Neutropenia and diarrhoea are common and potentially serious adverse events associated with abemaciclib in advanced breast cancer (ABC), and the risk factors have been minimally explored. The study aimed to develop clinical prediction tools that allow personalized predictions of neutropenia and diarrhoea following abemaciclib initiation. MATERIALS AND METHODS: Data was pooled from MONARCH 1, 2 and 3 trials investigating abemaciclib. Cox proportional hazard analysis was used to assess the association between pre-treatment clinicopathological data and grade ≥3 diarrhoea and neutropenia occurring within the first 365 days of abemaciclib use. RESULTS: Older age was associated with increased risk of grade ≥3 diarrhoea [HR [95%CI] for age > 70: 1.72 [1.14-2.58]; P = 0.009]. A clinical prediction tool for abemaciclib induced grade ≥3 neutropenia was optimally defined by race, ECOGPS and white blood cell count. Large discrimination between subgroups was observed; the highest risk subgroup had a 64% probability of grade ≥3 neutropenia within the first 365 days of abemaciclib (150 mg twice daily) + fulvestrant/NSAI, compared to 5% for the lowest risk subgroup. CONCLUSION: The study identified advanced age as significantly associated with an increased risk of abemaciclib induced grade ≥ 3 diarrhoea. A clinical prediction tool, defined by race, ECOGPS and pre-treatment white blood cell count, was able to discriminate subgroups with significantly different risks of grade ≥3 neutropenia following abemaciclib initiation. The tool may enable improved interpretation of personalized risks and the risk-benefit ratio of abemaciclib.

Persistent T Cell Repertoire Perturbation and T Cell Activation in HIV After Long Term Treatment.

Objective: In people living with HIV (PLHIV), we sought to test the hypothesis that long term anti-retroviral therapy restores the normal T cell repertoire, and investigate the functional relationship of residual repertoire abnormalities to persistent immune system dysregulation. Methods: We conducted a case-control study in PLHIV and HIV-negative volunteers, of circulating T cell receptor repertoires and whole blood transcriptomes by RNA sequencing, complemented by metadata from routinely collected health care records. Results: T cell receptor sequencing revealed persistent abnormalities in the clonal T cell repertoire of PLHIV, characterized by reduced repertoire diversity and oligoclonal T cell expansion correlated with elevated CD8 T cell counts. We found no evidence that these expansions were driven by cytomegalovirus or another common antigen. Increased frequency of long CDR3 sequences and reduced frequency of public sequences among the expanded clones implicated abnormal thymic selection as a contributing factor. These abnormalities in the repertoire correlated with systems level evidence of persistent T cell activation in genome-wide blood transcriptomes. Conclusions: The diversity of T cell receptor repertoires in PLHIV on long term anti-retroviral therapy remains significantly depleted, and skewed by idiosyncratic clones, partly attributable to altered thymic output and associated with T cell mediated chronic immune activation. Further investigation of thymic function and the antigenic drivers of T cell clonal selection in PLHIV are critical to efforts to fully re-establish normal immune function.

AMEE Consensus Statement: Planetary health and education for sustainable healthcare.

The purpose of this Consensus Statement is to provide a global, collaborative, representative and inclusive vision for educating an interprofessional healthcare workforce that can deliver sustainable healthcare and promote planetary health. It is intended to inform national and global accreditation standards, planning and action at the institutional level as well as highlight the role of individuals in transforming health professions education. Many countries have agreed to 'rapid, far-reaching and unprecedented changes' to reduce greenhouse gas emissions by 45% within 10 years and achieve carbon neutrality by 2050, including in healthcare. Currently, however, health professions graduates are not prepared for their roles in achieving these changes. Thus, to reduce emissions and meet the 2030 Sustainable Development Goals (SDGs), health professions education must equip undergraduates, and those already qualified, with the knowledge, skills, values, competence and confidence they need to sustainably promote the health, human rights and well-being of current and future generations, while protecting the health of the planet.The current imperative for action on environmental issues such as climate change requires health professionals to mobilize politically as they have before, becoming strong advocates for major environmental, social and economic change. A truly ethical relationship with people and the planet that we inhabit so precariously, and to guarantee a future for the generations which follow, demands nothing less of all health professionals.This Consensus Statement outlines the changes required in health professions education, approaches to achieve these changes and a timeline for action linked to the internationally agreed SDGs. It represents the collective vision of health professionals, educators and students from various health professions, geographic locations and cultures. 'Consensus' implies broad agreement amongst all individuals engaged in discussion on a specific issue, which in this instance, is agreement by all signatories of this Statement developed under the auspices of the Association for Medical Education in Europe (AMEE).To ensure a shared understanding and to accurately convey information, we outline key terms in a glossary which accompanies this Consensus Statement (Supplementary Appendix 1). We acknowledge, however, that terms evolve and that different terms resonate variably depending on factors such as setting and audience. We define education for sustainable healthcare as the process of equipping current and future health professionals with the knowledge, values, confidence and capacity to provide environmentally sustainable services through health professions education. We define a health professional as a person who has gained a professional qualification for work in the health system, whether in healthcare delivery, public health or a management or supporting role and education as 'the system comprising structures, curricula, faculty and activities contributing to a learning process'. This Statement is relevant to the full continuum of training - from undergraduate to postgraduate and continuing professional development.

Pan-AKT Inhibitor Capivasertib With Docetaxel and Prednisolone in Metastatic Castration-Resistant Prostate Cancer: A Randomized, Placebo-Controlled Phase II Trial (ProCAID).

PURPOSE: Capivasertib is a pan-AKT inhibitor. Preclinical data indicate activity in metastatic castration-resistant prostate cancer (mCRPC) and synergism with docetaxel. PATIENTS AND METHODS: ProCAID was a placebo controlled randomized phase II trial in mCRPC. Patients received up to ten 21-day cycles of docetaxel (75 mg/m2 intravenous, day 1) and prednisolone (5 mg twice daily, oral, day 1-21) and were randomly assigned (1:1) to oral capivasertib (320 mg twice daily, 4 days on/3 days off, from day 2 each cycle), or placebo, until disease progression. Treatment allocation used minimization factors: bone metastases; visceral metastases; investigational site; and prior abiraterone or enzalutamide. The primary objective, by intention to treat, determined if the addition of capivasertib prolonged a composite progression-free survival (cPFS) end point that included prostate-specific antigen progression events. cPFS and overall survival (OS) were also assessed by composite biomarker subgroup for PI3K/AKT/PTEN pathway activation status. RESULTS: One hundred and fifty patients were enrolled. Median cPFS was 7.03 (95% CI, 6.28 to 8.25) and 6.70 months (95% CI, 5.52 to 7.36) with capivasertib and placebo respectively (hazard ratio [HR], 0.92; 80% CI, 0.73 to 1.16; one-sided P = .32). Median OS was 31.15 (95% CI, 20.07 to not reached) and 20.27 months (95% CI, 17.51 to 24.18), respectively (HR, 0.54; 95% CI, 0.34 to 0.88; two-sided P = .01). cPFS and OS results were consistent irrespective of PI3K/AKT/PTEN pathway activation status. Grade III-IV adverse events were equivalent between arms (62.2%). The most common adverse events of any grade deemed related to capivasertib were diarrhea, fatigue, nausea, and rash. CONCLUSION: The addition of capivasertib to chemotherapy did not extend cPFS in mCRPC irrespective of PI3K/AKT/PTEN pathway activation status. The observed OS result (a secondary end point) will require prospective validation in future studies to address potential for bias.

Moderate Intensity Exercise in Pre-manifest Huntington's Disease: Results of a 6 months Trial.

BACKGROUND: While it has been shown that aerobic exercise interventions are well tolerated in participants with the Huntington disease (HD) gene mutation, no study to date has tested whether an aerobic exercise intervention benefits brain structure and function in pre-manifest HD. OBJECTIVE: In this study we utilized magnetic resonance (MR) imaging techniques to assess the efficacy of moderate-to-vigorous exercise treatment relative to active stretching and toning control. METHODS: Forty pre-manifest participants with confirmed HD gene expansion were recruited into a two-arm intervention study that included a moderate-to-vigorous intensity home-based walking exercise intervention (N=34) and an active stretching and toning control intervention (N=6). Participants were assessed at baseline and after 26 weeks in one of the two study arms. RESULTS: 25 of the 34 (74%) participants assigned to the moderate-to-vigorous intensity group completed the intervention while 4 of the 6 (67%) participants in the stretching and toning intervention completed the study. The primary analyses compared the two arms of the study and found no statistical differences between the groups. Both groups were found to have improved their cardiorespiratory fitness as assessed by maximal oxygen uptake (VO2max). A secondary analysis combined the two arms of the study and there was a significant relationship (p<0.05) between change in VO2max and change in brain structure. CONCLUSIONS: Though this study did not show efficacy for the exercise intervention, secondary results suggest that aerobic exercise interventions increasing cardiorespiratory fitness may be a potential way to slow progression in pre-manifest HD.

Tracheal leiomyoma mimicking asthma for over 20 years.

Benign tracheal tumours have an incidence of 1 in 1,000,000, of which leiomyomas represent only 1%. We report a case of tracheal leiomyoma masquerading as asthma for over 20 years. A 48-year-old man presented aged 26 years with asthma symptoms unresponsive to treatments and an obstructive spirometry pattern. Symptoms were not particularly troubling but suddenly exacerbated 22 years later. Flow-volume studies were consistent with upper airway obstruction. Computed tomography chest revealed a 2.3 cm mass arising from the posterior aspect of the trachea 2 cm above the carina. Bronchoscopic resection was performed using a Nd:YAG laser. Histology confirmed leiomyoma. Follow-up after 6 weeks revealed complete resolution of symptoms with normal spirometry. Tracheal masses should be considered in any patient with atypical asthma. A flow-volume loop may provide a clue to diagnosis and bronchoscopic laser resection is a minimally invasive treatment option.