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Summary: We utilized scRNA-seq to delineate the diversity of cell types in the zebrafish heart. Transcriptome profiling of over 50,000 cells at 48 and 72 hpf defined at least 18 discrete cell lineages of the developing heart. Utilizing well-established gene signatures, we identified a population of cells likely to be the primary pacemaker and characterized the transcriptome profile defining this critical cell type. Two previously uncharacterized genes, atp1b3b and colec10, were found to be enriched in the sinoatrial cardiomyocytes. CRISPR/Cas9-mediated knockout of these two genes significantly reduced heart rate, implicating their role in cardiac development and conduction. Additionally, we describe other cardiac cell lineages, including the endothelial and neural cells, providing their expression profiles as a resource. Our results established a detailed atlas of the developing heart, providing valuable insights into cellular and molecular mechanisms, and pinpointed potential new players in heart rhythm regulation.

ABSTRACT Large breasts may increase the likelihood of thoracic vertebral fractures by increasing the mechanical loading of the spine. We examined breast size as a factor associated with prevalent thoracic vertebral fractures, also considering its relationship with thoracic kyphosis and upper back extensor muscle endurance. Using a cross‐sectional study, the design measurements collected were thoracic vertebral fractures (≥20% loss in vertebral body height on lateral radiograph), breast size (bra size converted to an ordinal breast size score), BMD (g/cm2 averaged femoral neck, DXA), upper back extensor muscle endurance (isometric chest raise test), body composition (DXA), thoracic kyphosis (radiograph), and upper back pain (numerical rating scale). Correlations and multivariable logistic regression examined relationships between characteristics and their association with vertebral fracture. Participants were 117 healthy postmenopausal women. The 17 (15%) women with ≥1 thoracic vertebral fracture had larger breast size (mean difference [MD]: 2.2 sizes; 95% CI, 0.6 to 3.8 sizes), less upper back extensor muscle endurance (MD: −38.6 s; 95% CI, −62.9 to −14.3 s), and greater thoracic kyphosis (MD: 7.3°; 95% CI, 1.7° to 12.8°) than those without vertebral fracture. There were no between group differences in age, height, weight, and BMD. Breast size (r = −0.233, p = 0.012) and thoracic kyphosis (r = −0.241, p = 0.009) correlated negatively with upper back extensor muscle endurance. Breast size was unrelated to thoracic kyphosis (r = 0.057, p = 0.542). A (final) multivariable model containing breast size (OR 1.85; 95% CI, 1.10 to 3.10) and thoracic kyphosis (OR 2.04; 95%CI, 1.12 to 3.70) explained 18% of the variance in vertebral fracture. Breast size had a significant, but weak relationship with vertebral fracture (R2 = 0.10), which was independent of BMD and unrelated to thoracic kyphosis. Further work is needed to confirm larger breast size as a risk factor for vertebral fracture. © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

Spigelian hernia (SH) is a rare entity accounting for 1â2% of ventral abdominal wall hernias. Elusive clinical signs and symptoms pose a diagnostic challenge and a consequent risk of strangulation. We present an emergent case of a Spigelian hernia involving the appendix. Keywords: Spigelian hernia, Appendix, Ultrasound, Computed tomography

OBJECTIVES:To evaluate the utility of preoperative multiparametric magnetic resonance imaging (MP-MRI) in predicting biochemical recurrence (BCR) following radical prostatectomy (RP). MATERIALS/METHODS:From March 2007 to January 2015, 421 consecutive patients with prostate cancer (PCa) underwent preoperative MP-MRI and RP. BCR-free survival rates were estimated using the Kaplan-Meier method. Cox proportional hazards models were used to identify clinical and imaging variables predictive of BCR. Logistic regression was performed to generate a nomogram to predict three-year BCR probability. RESULTS:Of the total cohort, 370 patients met inclusion criteria with 39 (10.5%) patients experiencing BCR. On multivariate analysis, preoperative prostate-specific antigen (PSA) (p = 0.01), biopsy Gleason score (p = 0.0008), MP-MRI suspicion score (p = 0.03), and extracapsular extension on MP-MRI (p = 0.03) were significantly associated with time to BCR. A nomogram integrating these factors to predict BCR at three years after RP demonstrated a c-index of 0.84, outperforming the predictive value of Gleason score and PSA alone (c-index 0.74, p = 0.02). CONCLUSION:The addition of MP-MRI to standard clinical factors significantly improves prediction of BCR in a post-prostatectomy PCa cohort. This could serve as a valuable tool to support clinical decision-making in patients with moderate and high-risk cancers.

Several cytogenetic abnormalities identified in patients with childhood acute lymphocytic leukemia (ALL) have been associated with a poor prognosis. There are several case reports in the literature describing t(17;19) in children with ALL. This translocation has been associated with hypercalcemia, coagulopathy, and poor outcome. We present three cases of ALL with t(17;19) treated at our institution and review the outcome of children reported in the medical literature.

Abstract Aims Interatrial shunts are under evaluation as a treatment for heart failure (HF); however, their in vivo flow performance has not been quantitatively studied. We aimed to investigate the fluid dynamics properties of the 0.51 cm orifice diameter Ventura shunt and assess its lumen integrity with serial transesophageal echocardiography (TEE). Methods and results Computational fluid dynamics (CFD) and bench flow tests were used to establish the flow‐pressure relationship of the shunt. Open‐label patients from the RELIEVE‐HF trial underwent TEE at shunt implant and at 6 and 12 month follow‐up. Shunt effective diameter (Deff) was derived from the vena contracta, and flow was determined by the continuity equation. CFD and bench studies independently validated that the shunt's discharge coefficient was 0.88 to 0.89. The device was successfully implanted in all 97 enrolled patients; mean age was 70 ± 11 years, 97% were NYHA class III, and 51% had LVEF ≤40%. Patency was confirmed in all instances, except for one stenotic shunt at 6 months. Deff remained unchanged from baseline at 12 months (0.47 ± 0.01 cm, P = 0.376), as did the trans‐shunt mean pressure gradient (5.1 ± 3.9 mmHg, P = 0.316) and flow (1137 ± 463 mL/min, P = 0.384). TEE measured flow versus pressure closely correlated (R2 ≥ 0.98) with a fluid dynamics model. At 12 months, the pulmonary/systemic flow Qp/Qs ratio was 1.22 ± 0.12. Conclusions When implanted in patients with advanced HF, this small interatrial shunt demonstrated predictable and durable patency and performance.

Abstract Background Rheumatoid arthritis (RA) is associated with a high concentration of extracellular DNA (ecDNA). This could be a consequence of the inflammation, but the ecDNA could also be involved in the unknown etiopathogenesis of RA. Clearance of ecDNA is hypothesized to prevent the development of RA. This study aimed to analyze the effects of exogenous deoxyribonuclease I (DNase I) administration in an animal model of RA. Methods The collagen antibody-induced arthritis (CAIA) model of RA was induced in adult female DBA/1J mice. CAIA mice were treated with saline or DNase I (10 mg/kg) every 12 h for the whole duration of the experiment. Arthritic scores were assessed. Paw volume and temperature were assessed using a plethysmometer and a thermal camera, respectively. Plasma ecDNA and its subcellular origin were analyzed using fluorometry and real-time PCR. DNase activity was quantified with single radial enzyme diffusion method. Results The CAIA model was successfully induced as proved by a higher volume, temperature and the overall arthritis score in comparison to controls. The administration of DNase I resulted in a nearly two-fold increase in serum DNase activity. Still, it did affect neither plasma ecDNA, nor the arthritis score or other measures of joint inflammation. Conclusion Our results suggest that exogenous DNase I does not prevent the development of CAIA in mice. Whether this is true for other animal models of arthritis or clinical RA requires further research. EcDNA does not seem to be involved in the pathogenesis of CAIA. Additional studies are also needed to elucidate the role of ecDNA in the development of RA, focusing especially on its origin and inhibition of ecDNA release.

Abstract Multiple myeloma (MM) is an incurable malignancy of plasma cells. Epidemiological studies indicate a substantial heritable component, but the underlying mechanisms remain unclear. Here, in a genome-wide association study totaling 10,906 cases and 366,221 controls, we identify 35 MM risk loci, 12 of which are novel. Through functional fine-mapping and Mendelian randomization, we uncover two causal mechanisms for inherited MM risk: longer telomeres; and elevated levels of B-cell maturation antigen (BCMA) and interleukin-5 receptor alpha (IL5RA) in plasma. The largest increase in BCMA and IL5RA levels is mediated by the risk variant rs34562254-A at TNFRSF13B. While individuals with loss-of-function variants in TNFRSF13B develop B-cell immunodeficiency, rs34562254-A exerts a gain-of-function effect, increasing MM risk through amplified B-cell responses. Our results represent an analysis of genetic MM predisposition, highlighting causal mechanisms contributing to MM development.

Abstract During an examination of 3299 cheeses imported into the United Arab Emirates (UAE) from 2017 to 2021 for compliance with regulations regarding moisture and fat content, microbial quality, acidity, the presence of quinoline (a non-permitted colorant), sorbic acid, and the presence of rust discoloration, it was found that 91% of cheeses were compliant with UAE legislation. However, 9% were in violation of one or more of the mandated quality parameters, suggesting that adulteration had occurred. Within product categories the greatest level of non-conformity at 13% was noted for processed cheese, primarily due to violations caused by high moisture and low-fat content. This is important because moisture levels in processed cheese can influence its texture and shelf life. The microbial assessment of cheese showed that 85.7% of semi-hard and 77.5% of soft cheeses had non-compliant levels of E. coli. It was notable that 21.8% of non-compliant products originated from Turkey. Cheeses from Germany had the lowest level of non-conformity at 0.6%. This study illustrates the need for border scrutiny to include physicochemical examinations of cheese samples. The current initiative aims to promote the need for equity in global trade and to prevent the marketing of adulterated food items. Graphical Abstract

Abstract Background Smoking continues to be the single largest cause of preventable disease and death and a major contributor to health inequalities. Dental professionals are well placed to offer behavioural support in combination with pharmacotherapy to increase smoking cessation rates across the population. We aimed to assess the trends and socioeconomic inequalities in the dental attendance of adult smokers in Scotland from 2009 to 2019 and examine the potential population reach of dental settings for smoking cessation interventions. Methods A secondary analysis was conducted of combined Scottish Health Surveys (SHeS) from 2009/11, 2013/15 and 2017/19. ‘Recent’ dental attendance (within the past two years) was the focus and descriptive analysis examined attendance of self-reported smokers compared to non-smokers and stratified by the area-based Scottish Index of Multiple Deprivation (SIMD) and individual socioeconomic measures (income, education, and occupation). Generalised linear models were used to model recent attendance in non-smokers relative to smokers adjusted by the socioeconomic measures, for each of the survey cohorts separately. Absolute differences and risk ratios were calculated with 95% Confidence Intervals (CI). Results Recent dental attendance was generally high and increased in both smokers (70–76%) and non-smokers (84–87%) from 2009/11 to 2017/19 and increased across all SIMD groups. After adjustment for sociodemographic variables, the adjusted Risk Difference (aRD) for recent attendance between non-smokers and smokers was 8.9% (95% CI 4.6%, 13.2%) by 2017/19. Within smokers, recent attendance was 7–9% lower in those living in the most deprived areas compared to those living in the least deprived areas over the three surveys. Conclusions SHeS data from 2009 to 2019 demonstrated that a high and increasing proportion of smokers in the population attend the dentist, albeit slightly less frequently than non-smokers. There were large inequalities in the dental attendance of smokers, to a lesser extent in non-smokers, and these persisted over time. Dental settings provide a good potential opportunity to deliver population-level smoking cessation interventions, but smokers in the most deprived groups and older age groups may be harder to reach. Consideration should be given to ensure that these groups are given appropriate proportionate support to take up preventive interventions.

Abstract Background Ticks are obligate hematophagous ectoparasites involved in transmitting viruses of public health importance. The objective of this work was to identify the Jingmen tick virus in hard ticks from the Colombian Caribbean, an arbovirus of importance for public health. Methods Ticks were collected in rural areas of Córdoba and Cesar, Colombia. Taxonomic identification of ticks was carried out, and pools of 13 individuals were formed. RNA extraction was performed. Library preparation was performed with the MGIEasy kit, and next-generation sequencing (NGS) with MGI equipment. Bioinformatic analyses and taxonomic assignments were performed using the Galaxy platform, and phylogenetic analyses were done using IQ-TREE2. Results A total of 766 ticks were collected, of which 87.33% (669/766) were Rhipicephalus microplus, 5.4% (42/766) Dermacentor nitens, 4.2% (32/766) Rhipicephalus linnaei, and 3.0% (23/766) Amblyomma dissimile. Complete and partial segments 1, 2, 3, and 4 of Jingmen tick virus (JMTV) were detected in the metatranscriptome of the species R. microplus, D. nitens, and A. dissimile. The JMTVs detected are phylogenetically related to JMTVs detected in Aedes albopictus in France, JMTVs detected in R. microplus in Trinidad and Tobago, JMTVs in R. microplus and A. variegatum in the French Antilles, and JMTVs detected in R. microplus in Colombia. Interestingly, our sequences clustered closely with JMTV detected in humans from Kosovo. Conclusions JMTV was detected in R. microplus, D. nitens, and A. dissimile. JMTV could pose a risk to humans. Therefore, it is vital to establish epidemiological surveillance measures to better understand the possible role of JMTV in tropical diseases. Graphical Abstract

Daylight is essential for ecosystems and for the physical and mental well-being of people. In densely populated cities, only a small proportion of total daylight is available to support urban greenery and most people have little daily exposure to natural daylight. Despite this, many cities have followed a strategy of densification as a way of preventing urban sprawl and reducing energy consumption. In this article, we review the biological importance of daylight and show that urban densification leads to a reduction in the daylight available for both people and nature. We conclude that daylight in cities should be treated as a limiting resource that needs to be planned and managed carefully, much like water or energy. We suggest elements for a policy framework aimed at optimizing urban daylight, including how to determine daylight needs, how to determine the maximum viable urban density, and policy options for built and unbuilt areas.

Abstract Background Article 14 of the WHO ‘Framework Convention on Tobacco Control’ recommends, that all oral healthcare providers provide support for tobacco cessation, to all patients. Despite evidence on the effectiveness of tobacco cessation interventions in dental settings, implementation remains low in most high-burden countries like Pakistan. A pragmatic pilot trial of a dentist-delivered behavioural support intervention for smokeless tobacco (ST) cessation, was conducted in dental hospitals in Pakistan. This paper presents the findings of the process evaluation of the trial. Methods A mixed-method process evaluation of a multi-centre randomised control pilot trial of dentist-delivered behavioural support intervention ST cessation was conducted. The intervention included three sessions namely: pre-quit, quit and post-quit sessions. The process evaluation involved: semi-structured interviews with trial participants (n = 26, of which dental patients were n = 13 and participating dentists were n = 13 conducted from June-August 2022); and fidelity assessment of audio recordings of the intervention sessions (n = 29). The framework approach was used to thematically analyse the interview data. Results Overall the trial procedures were well accepted, however, young patients expressed uneasiness over revealing their ST use status. The intervention was received positively by dentists and patients. Dentists identified some challenges in delivering behavioural support to their patients. Of these, some were related to the contents of the intervention whereas, others were related to the logistics of delivering the intervention in a clinical setting (such as workload and space). Acceptability of the intervention resources was overall low amongst young patients as they did not take the intervention resources home due to fear of their family members finding out about their ST use. The intervention was successful in achieving the intended impact (in those who engaged with the intervention), i.e., change in the patients’ ST use behaviour. Giving up ST with the aid of behavioural support also had an unintended negative effect i.e., the use of harmful substances (cannabis, cigarettes) to give up ST use. Patients’ satisfaction with their dental treatment seemed to influence the intervention outcome. Conclusion While there are many variables to consider, but for the participants of this study, behavioural support for abstinence delivered through dentists during routine dental care, appears to be an acceptable and practical approach in helping patients give up ST use, in a country like Pakistan, where negligible support is offered to ST users.

The aim of this research was to evaluate the effect of the strain hardening of a homogeneous metallic material on the size and shape of hydrostatic and plastic zones forming in the indentation process with a spherical indenter. Precise measurements and finite element calculations (FEM) were performed for indentations and the results were compared with those of the expanding cavity model (ECM). We concluded that in the range of d/D (impression diameter/indenter diameter) = 0.42–0.5 there is a good agreement between the measured and FEM-calculated hardness results if the strain hardening effect is properly taken into account. The results show that the ECM model underestimates the size of the hydrostatic zone and overestimates that of the plastic deformation region. We have also proved that the hydrostatic and plastic zones have a more complex shape than a hemisphere. In the investigated cases, the ratio of the plastic and hydrostatic volumes beneath the indenter is nearly independent of the d/D ratio in the range of 0.42–0.5, and its value is around 6. In these cases, the calculated geometry and size of the hydrostatic and plastic zones can be assumed to be close to their actual values. These results demonstrate that the reliability of hardness measurement performed by spherical indenter is highest when the d/D ratio of 0.42–0.5 is fulfilled, within the d/D range of 0.24–0.6 allowed by the standard. In this paper, we provided a well-defined and reproducible way to define the boundary between the hydrostatic core and the plastic zone (for a homogeneous structure with a spherical indenter) taking into account strain hardening.

IntroductionVolumetric modulated arc therapy (VMAT) total body irradiation (TBI) allows for greater organ sparing with improved target coverage compared to 2D-TBI. However, there is limited evidence of whether improved organ sparing translates to decreases in toxicities and how its toxicities compare to those of the 2D technique. We aimed to compare differences in toxicities among patients treated with TBI utilizing VMAT and 2D techniques.Methods/materialsA matched-pair single-institution retrospective analysis of 200 patients treated with TBI from 2014 to 2023 was performed. Overall survival (OS) and progression-free survival (PFS) were analyzed using the Kaplan–Meier method and compared using log-rank tests. Differences in characteristics and toxicities between the VMAT and 2D cohorts were compared using Fisher’s exact test.ResultsOf the 200 patients analyzed, 100 underwent VMAT-TBI, and 100 underwent 2D-TBI. The median age for VMAT-TBI and 2D-TBI patients was 13.7 years and 16.2 years, respectively (p = 0.25). In each cohort, 53 patients were treated with myeloablative regimens (8–13.76 Gy), and 47 were treated with non-myeloablative regimens (2–4 Gy). For the entire VMAT-TBI cohort, lung Dmean, kidney Dmean, and lens Dmax were spared to 60.6% ± 5.0%, 71.0% ± 8.5%, and 90.1% ± 3.5% of prescription, respectively. For the non-myeloablative VMAT-TBI cohort, testis/ovary Dmax, brain, and thyroid Dmean were spared to 33.4% ± 7.3%, 75.4% ± 7.0%, and 76.1% ± 10.5%, respectively. For 2D-TBI, lungs were spared using partial-transmission lung blocks for myeloablative regimens. The VMAT-TBI cohort experienced significantly lower rates of any grade of pneumonitis (2% vs. 12%), nephrotoxicity (7% vs. 34%), nausea (68% vs. 81%), skin (16% vs. 35%), and graft versus host disease (GVHD) (42% vs. 62%) compared to 2D-TBI patients. For myeloablative regimen patients, rates of pneumonitis (0% vs. 17%) and nephrotoxicity (9% vs. 36%) were significantly lower with VMAT-TBI versus 2D-TBI (p < 0.01). Median follow-up was 14.3 months, and neither median OS nor PFS for the entire cohort was reached. In the VMAT versus 2D-TBI cohort, the 1-year OS was 86.0% versus 83.0% (p = 0.26), and the 1-year PFS was 86.6% and 80.0% (p = 0.36), respectively.ConclusionNormal tissue sparing with VMAT-TBI compared to the 2D-TBI translated to significantly lower rates of pneumonitis, renal toxicity, nausea, skin toxicity, and GVHD in patients, while maintaining excellent disease control.

The demographics of environmental and Earth scientists are not representative of the UK’s multicultural society. We sought to widen diversity and engage equitably through two related engaged research projects, “Walking the Walk” and “Landscape Stories.” This paper offers a critically reflexive account, based on the methodology of duoethnography, of how we co-constructed a “third space” with and for minoritized community groups and environmental scientists. We sought to create the conditions for inclusive leadership informed by connectedness, respect, humility and intentionality. We argue that for environmental and Earth science research to be more equitable and inclusive, members of project teams should be engaged and more representative of wider society. Following this, collective work to create third spaces requires: respect for diversity and different forms of expertise, knowledge starting points, power dynamics and esteem; a willingness to make connections across disciplines and sub-cultures, actively listening and (un)learning from different (knowledge) cultures; and a commitment to be respectful of hidden and manifest difference, exploring purpose and gaps in knowledge in more holistic ways.

Background This research concerns improving the National Health Service health services trans adults need. These include the national specialist Gender Identity Clinics that support people making a medical transition. Not all trans people need to make a medical transition, and transition can take many different paths. Waits to be seen by Gender Identity Clinics are, however, several years long, and there may be significant problems of co-ordination between different aspects of transition-related care, and between transition-related care and general health care. Objectives The main objectives were to understand: Which factors make services more or less accessible and acceptable to the variety of trans adults? How initiatives for providing more person-centred and integrated care can be successfully implemented and further improved? Design, data sources and participants An online and paper screening survey was used to gather data on demographics and service use of trans people across the United Kingdom, with 2056 responses. Researchers used survey data to construct five purposive subsamples for individual qualitative interviews, identifying groups of people more likely to experience social exclusion or stigma. There were 65 online interviews. In addition, 23 trans Black people and people of colour attended focus groups. Six case studies were completed: four on initiatives to improve care and two on experiences of particular trans populations. Fifty-five service provider staff and 45 service users were interviewed. Results The following undermine person-centred co-ordinated care and can lead to experiences of harm: lack of respectful treatment of trans people by general practitioner practices; inadequate funding of services; lack of support during waiting; the extended and challenging nature of Gender Identity Clinic diagnostic assessments, sometimes experienced as adversarial; breakdowns in collaboration between Gender Identity Clinics and general practitioner practices over hormone therapy; lack of National Health Service psychological support for trans people. Case studies indicated ways to improve care, although each has significant unresolved issues: training in trans health care for general practitioners; third-sector peer-support workers for trans people who come to National Health Services; gender services taking a collaborative approach to assessing what people need, clarifying treatment options, benefits and risks; regional general practitioner-led hormone therapy clinics, bringing trans health care into the mainstream; psychology services that support trans people rather than assess them. Limitations Some contexts of care and experiences of particular groups of trans people were not addressed sufficiently within the scope of the project. While efforts were made to recruit people subject to multiple forms of stigma, there remained gaps in representation. Conclusions and future work The findings have significant implications for commissioners and providers of existing National Health Services gender services, including recently established pilot services in primary care. In particular they point to the need for assessments for access to transition care to be more collaborative and culturally aware, implying the value of exploring informed consent models for accessing transition-related care. Further research is needed to investigate how far the findings apply with particular subpopulations. Study registration This study is registered as Research Registry, no. 5235. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health and Social Care Delivery Research programme (NIHR award ref: 17/51/08) and is published in full in Health and Social Care Delivery Research; Vol. 12, No. 28. See the NIHR Funding and Awards website for further award information. Plain language summary This research concerns improving the range of National Health Service health services that trans adults need. Trans people have a different gender from that assigned at birth or in early childhood. Not all need to make a medical transition to express their gender, and transition can take many different forms, including hormone therapy, various kinds of surgery, and other procedures such as hair removal. At the time of writing, trans people over 17 who need to make a medical transition can seek care at one of the United Kingdom’s 10 specialist National Health Service Gender Identity Clinics. However, people must wait a very long time before they are seen. Through 110 in-depth interviews, as well as focus groups attended by 23 people, this research explored recent experiences of trans people receiving various kinds of health care. A further 55 interviews investigated the views of National Health Service and voluntary-sector staff involved in delivering trans health care. All of this has led to insights about how services can be improved, and the development of online courses for healthcare staff and for people who use services or support those who use services. The research indicates what can lead to experiences of poor care that is not ‘joined up’: lack of respectful treatment of trans people by general practitioner practices; inadequate funding of services; lack of support while waiting; the extended and difficult nature of Gender Identity Clinic diagnostic assessments; breakdowns in collaboration between Gender Identity Clinics and general practitioner practices over hormone therapy; lack of National Health Service psychological support for trans people. The research indicates some important ways to improve care: training in trans health care for general practitioners; third-sector peer-support workers for trans people who come to National Health Service services; gender services taking a collaborative approach to assessing what people need, clarifying treatment options, benefits and risks; regional general practitioner-led hormone therapy clinics, bringing trans health care into the mainstream; psychology services that support trans people rather than assessing them. Scientific summary Background Throughout this report we use the term trans to refer to the diverse people whose gender identities do not correspond to how they were assigned at birth or in early life. The term includes non-binary people. This research concerns improving the range of NHS health services that trans adults need. These include services intended to support people in making a medical transition, and many other services relevant to wider aspects of physical and mental health and well-being. Not all trans people need to make a medical transition, and transition can take many different paths, including hormone therapy, various types of surgery and other procedures such as hair removal. At the time of writing, trans people over 17 years of age who need to make a medical transition can seek care at one of the UK’s 10 specialist NHS Gender Identity Clinics (GICs), sometimes also known as Gender Identity Services (GIS). In recent years, people encounter very long waiting times before they are seen. Further, issues of co-ordination arise between different aspects of transition-related care and also between transition-related care and general health care. Because of the barriers to accessing NHS care they need within an acceptable timescale, many trans people in the UK, who can afford to, turn to private providers of hormone therapy and gender-related surgery, both within the UK and abroad. Many also access private provision of procedures that are important to their transition which are not offered by the NHS, such as facial feminisation surgery. This research has sought to build on initiatives to improve care and its integration, including those involving third-sector lesbian, gay, bisexual, transgender, queer and intersex, plus (LGBTQI+) organisations working in partnership with primary care organisations or with GICs. It has also explored how lessons about the effective integration of trans health care can best be implemented in the context of an NHS that is still coping with the impact and consequences of the coronavirus disease discovered in 2019 (COVID-19) pandemic. Research questions The research addresses the following questions: What is the range of models recently used in the UK for providing integrated care for meeting the specific health and well-being needs of trans people? Which factors make services more or less accessible and acceptable to the variety of trans adults who need them? In the different integrated service models, how effective are the different aspects of services and their interaction in meeting the needs of people at different stages of their gender transition and at different ages? What lessons emerge as to how models for providing integrated care can be successfully implemented and further improved in meeting the needs of trans people, within limited resources and continuing constraints resulting from the COVID-19 pandemic? Research design and methods The overall research design is a multicomponent and mixed-methods study of current realities and initiatives to improve health care for trans people, leading to the identification of areas for improvement and the production of educational materials. The research took place over a period of 2.5 years, from March 2019 to September 2021, with a 6-month pause during the initial phases of the COVID-19 pandemic, from March to October 2020. The educational materials stemming from the research take the form of open-access online learning materials. There are separate sets of learning materials for general practitioners (GPs), for mental health professionals and for members of the public. These are available from late 2023. The research plan involved the extensive involvement of the Improving Care for Trans Adults (ICTA) patient and public involvement (PPI) group, of trans people. They were consulted about the content of the research instruments and participant information sheets, as well as on sampling priorities. They were involved in commenting on the analysis and draft reports throughout the project. The whole project was focused on health inequalities and equality, diversity and inclusion (EDI). The PPI group played an important role in keeping such concerns foregrounded. The research design consisted of the following main elements: Desk research on current arrangements across the UK for providing transition-related care and for recognising the distinctive needs of trans people within general health care. This addressed RQ1. It also informed the selection of initiatives to improve care studied. An investigation of factors associated with service use and non-use. This addressed RQ2. An initial online and paper screening survey was used to gather data on demographics and service use across the UK, and received over 2056 responses, compared to a target of 500. It was promoted widely by the project partners and through LGBTQI+ networks and organisations. Response options included offering to be interviewed, with over 800 people putting themselves forward. Researchers used data on demographics and service use to construct five purposive subsamples, to be invited for individual qualitative interviews. The underlying rationale was to identify groups who were more likely to experience social exclusion or stigma in everyday life, and who were also more likely to experience difficulties in accessing and receiving health care. The experience of these groups would be an indication of the priorities for improving services to make them more inclusive and more effective in addressing health inequalities. In discussion with the PPI group, the following five groups were identified as priorities for subsamples of trans service users: older people and trans ‘elders’ (e.g. historic transitioners); disabled or chronically ill people; people with a low income or low educational qualifications; people living in rural areas; Black people and people of colour. This gave rise to 65 interviews, most lasting between 1 and 3 hours, and all carried out online. An initiative to recruit more trans Black people and people of colour (TBPoC) resulted in a further 23 people attending focus groups to cover the same topics as in interviews. All of the interviews and focus groups were audio-recorded and transcribed, and then the transcriptions were anonymised. Case studies of service experiences and initiatives to improve integration of care. This was to address RQ3 and contribute to answering RQ4. Six case studies were undertaken: Case Study 1: third-sector gender-outreach workers attached to a GIC Case Study 2: primary care liaison and psychology services within a GIC Case Study 3: primary care training and accreditation for trans health care Case Study 4: the Welsh Gender Service Case Study 5: trans healthcare experiences in Northern Ireland Case Study 6: healthcare experiences of trans people with mental health concerns or conditions Fifty-five staff and 45 service users were interviewed across these case studies. The staff were invited to participate because of their role and experience relevant to the initiative being studied. The service users were invited to participate based on their having participated in the national screening survey of trans adults’ healthcare experiences described above and indicated that they both had experience of the services being studied and were willing to be interviewed. Interviews were audio-recorded and transcribed, and then the transcriptions were anonymised. Thematic analysis was used to analyse accounts of experiences of using services, and accounts of practices in delivering and improving them, the achievements and benefits resulting, and the issues or challenges encountered. This included the analyses and comparison of the six case studies and the five purposive subsamples. A 1-day online workshop attended by all project partners, an Advisory Group of NHS clinicians, third-sector organisations and representatives of trans communities, the PPI group and study steering group members was held in July 2021 to review the emerging findings. Research findings The analysis of the purposively sampled qualitative interviews and focus groups with trans service users revealed a significant body of experience of poor care, although there were also more positive experiences. Regardless of the extent to which these experiences represent those of the total UK population of service users, they allowed the identification of factors which undermine person-centred, co-ordinated care, make it difficult for trans people to access care, or which lead to problematic, unacceptable and even harmful experiences of care. Poor experiences of care included: lack of understanding within GP practices of trans identities and respectful treatment of trans people, their health concerns and of the referral routes for transition-related care; waiting times of several years for GIC appointments once referrals have been made; the extended nature of GIC diagnostic assessments, which can seem to doubt that trans people know their own minds and be experienced as infantilising; breakdowns in collaboration between GICs and GP practices over the management of hormone therapy; difficulties of receiving psychological support within a GIC system that is experienced as seeing a mental health condition as a reason for delaying gender-affirming treatment; general mental health services that appear unwilling to treat trans people apparently simply because they are trans. When experienced either separately or in combination, these factors can cause iatrogenic harm; that is, harm from the healthcare system itself. Analysis of the initiatives to improve the integration of care revealed both benefits and unresolved issues. Training in trans health care for GPs can lead to trans people feeling welcomed and respected, to less stressful experiences of obtaining a GIC referral and more effective management of hormone therapy, when recommended by a GIC or, if needed prior to this, for harm reduction. However, the impact of training across the staff within a GP practice can be variable, often resulting in an uncertain quality of care. Third-sector peer-support workers attached to a gender service can deliver effective practical and emotional support to people awaiting assessment and also play an important role once gender-affirming treatment has begun. However, the long wait to access transition-related care remains the key issue for service users, over which peer workers have little or no influence. They must navigate a stressful ‘dual belonging’ to trans communities and a gender service. There is also a risk that relatively low-paid trans peer workers are expected to make up for gaps or shortages within the provision of other NHS services, such as mental health services. Gender service clinicians who pursue a collaborative approach to assessment for gender-affirming treatment, with the emphasis on clarifying the treatment options, potential benefits and risks, can lead to quicker, less stressful assessment experiences for service users. The practice of clinicians extending assessments for some people raises issues as to the most appropriate criteria to apply here, in order to avoid the danger of subjecting more stigmatised groups to a more extended process. Linking regional GP-led hormone therapy clinics to a gender service allows more rapid initiation of hormone therapy following assessment, with GP prescribers able to co-ordinate transition-related and general healthcare needs. There are, however, issues in finding an approach to electronic patient records that fully supports collaboration between a gender service, regional primary care hormone clinics and a trans person’s own GP practice. Further problems persist in terms of the willingness of GP practices to take over hormone prescribing even after a period of stabilisation with the regional clinic. A psychologist team attached to a gender service, delivering individual and group sessions, can support trans people in working through problematic aspects of social transition or emotional reactions to their medical transition, as well as addressing experiences of isolation. However, tensions may exist between a therapeutic ethos and the role of a gender service in assessing people for access to gender-affirming treatment. Conclusions Learning from the national sample of interviews and the case studies of initiatives for improving care has implications for improving care within the established model of trans people accessing transition care through a tertiary GIC service. It also provides insight into how to improve the primary care gender services that were recently established by NHS England (NHSE). The findings suggest that a primary care gender service has great potential for integrating different aspects of transition-related care with each other and with other aspects of health care that a trans person needs. Key directions for future practice include: mandatory trans healthcare standards and training for primary care, as well as for NHS services in general; peer support attached to gender services, with peer workers included within the professional team, able to answer questions from the service users on behalf of the service; psychological support made available to people using gender services, with the separation of therapeutic support from diagnostic assessment; further development of collaborative forms of assessment, including revisiting of the existing diagnostic guidelines in the light of how some areas of questioning can be experienced; fundamental reconsideration of the level of funding of trans health care, to address the egregiously long, damaging waiting times that trans people experience. Increased funding should, however, take account of the findings about effective models for delivering person-centred, co-ordinated care; greater involvement of trans staff in healthcare delivery, and of representatives of trans communities in the management and shaping of gender services and health services more generally. Interviews with trans service users further indicated a widespread view that gender services should move, in the longer term, towards an informed consent model (ICM), which would dispense with the requirement for a psychological or psychiatric diagnosis before gender-affirming treatments can be accessed. Research on ICMs in the USA and Australia suggests ICMs have the potential to combine a person-centred focus on the goals of care with medical diligence and the authorisation of treatment. The findings from our case studies suggest the benefits of care practices consistent with an ICM, as well as issues that would need to be resolved in order to implement one. These potential benefits and issues require further exploration by policy-makers and clinicians, working together with trans communities. Limitations and further research Drawing on over 160 qualitative interviews, this research sought to understand the dynamics underlying experiences of poor and better care. These findings are of broader relevance to helping a wide range of health services to improve the care they provide for trans people. However, some contexts of care and needs of particular groups of trans people could not be addressed sufficiently. There were some gaps in representation of people who are subjected to multiple forms of social stigma. In particular, further research is needed regarding: The experiences of trans people at clinics that have adopted ICMs, using a similar level of qualitative detail as we were able to pursue during our ICTA interviews. What forms of assessment are appropriate for groups of trans people whom clinicians may regard as having an impaired ability to understand and consent to specific treatments, such as those with mental health conditions, those with learning difficulties, and some autistic people. These are groups who typically experience multiple forms of stigma across many settings, including health care. Research should also seek to explore what kinds of additional social and psychological support should be provided to accompany gender-affirming medical care for such groups. Study registration This study is registered as Research Registry, no. 5235. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health and Social Care Delivery Research programme (NIHR award ref: 17/51/08) and is published in full in Health and Social Care Delivery Research; Vol. 12, No. 28. See the NIHR Funding and Awards website for further award information.

ObjectiveEvidence suggests that changes in dietary advanced glycation end-products (AGEs) may influence body weight, but the effects of different dietary patterns remain to be explored.The aim of this study was to compare the effects of a Mediterranean and a low-fat vegan diet on dietary AGEs and test their association with body weight.Materials and methodsIn this randomized cross-over trial, 62 overweight adults were assigned to a Mediterranean or a low-fat vegan diet for 16-week periods in random order, separated by a 4-week washout. Body weight was the primary outcome. Three-day diet records were analyzed using the Nutrition Data System for Research software and dietary AGEs were estimated, using an established database. Statistical approaches appropriate for crossover trials were implemented.ResultsDietary AGEs decreased by 73%, that is, by 9,413 kilounits AGE/day (95% −10,869 to −7,957); p < 0.001, compared with no change on the Mediterranean diet (treatment effect −10,303 kilounits AGE/day [95% CI −13,090 to −7,516]; p < 0.001). The participants lost 6.0 kg on average on the vegan diet, compared with no change on the Mediterranean diet (treatment effect −6.0 kg [95% CI −7.5 to −4.5]; p < 0.001). Changes in dietary AGEs correlated with changes in body weight (r = +0.47; p < 0.001) and remained significant after adjustment for total energy intake (r = +0.39; p = 0.003).ConclusionDietary AGEs did not change on the Mediterranean diet but decreased on a low-fat vegan diet, and this decrease was associated with changes in body weight, independent of energy intake.Clinical trial registrationhttps://clinicaltrials.gov/, identifier NCT03698955

Abstract. Introduction: We explored trajectories of pain intensity and depressive symptoms over the first 24 months of the pandemic in people with low back pain. Methods: This longitudinal study was conducted alongside the Quebec Low Back Pain Study. Starting in April 2020 and every 3 months until July 2022, 291 participants completed an online survey. Group-based trajectory modeling was used to identify patterns of pain intensity and depressive symptoms. Onset outbreak characteristics were then put in relation with trajectory groups using multivariate logistic regression. Results: The analysis revealed 5 trajectories of pain intensity and depressive symptoms, respectively. The pain trajectories were stable mild (n = 17, 5.8%); stable moderate (n = 103, 35.4%); stable severe (n = 81, 27.8%); U-shape (n = 24, 8.3%), and inverted U-shape (n = 66, 22.7%). The trajectories of depressive symptoms were stable none (n = 58, 19.9%); stable very mild (n = 61, 21.0%); stable mild (n = 85, 29.2%); stable moderate (n = 59, 21.7%); and severe slightly improving (n = 24, 8.3%). Pre-COVID everyday/nearly everyday pain, average pain intensity, and widespread bodily pain were predictive of pain trajectory groups. Higher pre-COVID depression, acute stress disorder, and lockdown measures-related stress were associated with moderate/severe depressive trajectories. Discussion: Our findings indicated relative stability of pain and depressive symptoms among participants during the COVID-19 pandemic but also highlighted subgroups of people who experienced temporary deterioration or improvement over the first months of the pandemic that then reverted back to baseline levels. Modifiable risk factors were identified before the onset of the pandemic, which could give preventive measures in targeted populations.

Abstract For many cancers there are only a few well-established risk factors. Here, we use summary data from genome-wide association studies (GWAS) in a Mendelian randomisation (MR) phenome-wide association study (PheWAS) to identify potentially causal relationships for over 3,000 traits. Our outcome datasets comprise 378,142 cases across breast, prostate, colorectal, lung, endometrial, oesophageal, renal, and ovarian cancers, as well as 485,715 controls. We complement this analysis by systematically mining the literature space for supporting evidence. In addition to providing supporting evidence for well-established risk factors (smoking, alcohol, obesity, lack of physical activity), we also find sex steroid hormones, plasma lipids, and telomere length as determinants of cancer risk. A number of the molecular factors we identify may prove to be potential biomarkers. Our analysis, which highlights aetiological similarities and differences in common cancers, should aid public health prevention strategies to reduce cancer burden. We provide a R/Shiny app to visualise findings.

Abstract Developing X-ray scintillators that are water-dispersible, compatible with polymeric matrices, and processable to flexible substrates is an important challenge. Herein, Tb3+-doped Na5Lu9F32 is introduced as an X-ray scintillating material with steady-state X-ray light yields of 15,800 photons MeV−1, which is generated as nanocrystals on halloysite nanotubes. The obtained product exhibits good water-dispersibility and highly sensitive luminescence to X-rays. It is deposited onto a polyurethane foam to afford a composite foam material with dose-dependent radioluminescence. Moreover, the product is dispersed into polymer matrixes in aqueous solution to prepare rigid or flexible scintillator screen for X-ray imaging. As a third example, it is incorporated multilayer hydrogels for information camouflage and multilevel encryption. Encrypted information can be recognized only by X-ray irradiation, while the false information is read out under UV light. Altogether, we demonstrate that the water-dispersible scintillators are highly promising for aqueous processing of radioluminescent, X-ray imaging, and information encrypting materials.

Recently, there has been a growing interest among researchers in enhancing the efficacy of learning through the utilization of diverse machine learning models within the field of artificial intelligence. However, imbalanced data distributions in educational datasets present a significant challenge to machine learning algorithms. This imbalance can result in biased models, untrustworthy outcomes, and poor performance. Data was gathered from a sample of 2176 first-year novice programming students in this study. Due to an alarming 76% failure rate, the imbalanced dataset was preprocessed before being oversampled with techniques such as SMOTE, SMOTE Borderline, SMOTE-ENN, and ADASYN. The proposed non-redundant synthetic data cooperation approach, named Equi-Fused-Data-based SMOTE, seeks to capitalize on the diversity of the obtained data by combining oversampled datasets. The balanced bagging model was then applied to the combined dataset to demonstrate the robustness of this approach. The promising results demonstrate the effectiveness of the Equi-Fused-Data-based SMOTE model, which achieved a higher Accuracy of 93.85%, a Precision, Recall and F1-score of 92,86%, and an AUC of 98.08%.

BackgroundGlobally, there are marked inconsistencies in how immunosuppression is characterized and subdivided into clinical risk groups. This is detrimental to the precision and comparability of disease surveillance efforts—which has negative implications for the care of those who are immunosuppressed and their health outcomes. This was particularly apparent during the COVID-19 pandemic; despite collective motivation to protect these patients, conflicting clinical definitions created international rifts in how those who were immunosuppressed were monitored and managed during this period. We propose that international clinical consensus be built around the conditions that lead to immunosuppression and their gradations of severity concerning COVID-19. Such information can then be formalized into a digital phenotype to enhance disease surveillance and provide much-needed intelligence on risk-prioritizing these patients. ObjectiveWe aim to demonstrate how electronic Delphi objectives, methodology, and statistical approaches will help address this lack of consensus internationally and deliver a COVID-19 risk-stratified phenotype for “adult immunosuppression.” MethodsLeveraging existing evidence for heterogeneous COVID-19 outcomes in adults who are immunosuppressed, this work will recruit over 50 world-leading clinical, research, or policy experts in the area of immunology or clinical risk prioritization. After 2 rounds of clinical consensus building and 1 round of concluding debate, these panelists will confirm the medical conditions that should be classed as immunosuppressed and their differential vulnerability to COVID-19. Consensus statements on the time and dose dependencies of these risks will also be presented. This work will be conducted iteratively, with opportunities for panelists to ask clarifying questions between rounds and provide ongoing feedback to improve questionnaire items. Statistical analysis will focus on levels of agreement between responses. ResultsThis protocol outlines a robust method for improving consensus on the definition and meaningful subdivision of adult immunosuppression concerning COVID-19. Panelist recruitment took place between April and May of 2024; the target set for over 50 panelists was achieved. The study launched at the end of May and data collection is projected to end in July 2024. ConclusionsThis protocol, if fully implemented, will deliver a universally acceptable, clinically relevant, and electronic health record–compatible phenotype for adult immunosuppression. As well as having immediate value for COVID-19 resource prioritization, this exercise and its output hold prospective value for clinical decision-making across all diseases that disproportionately affect those who are immunosuppressed. International Registered Report Identifier (IRRID)PRR1-10.2196/56271

Background Asthma remains a common cause of hospital admissions across the life course. We estimated the contribution of key risk factors to asthma-related hospital and intensive care unit (ICU) admissions in children, adolescents and adults.Methods This was a UK-based cohort study using linked primary care (Clinical Practice Research Datalink Aurum) and secondary care (Hospital Episode Statistics Admitted Patient Care) data. Patients were eligible if they were aged 5 years and older and had been diagnosed with asthma. This included 90 989 children aged 5–11 years, 114 927 adolescents aged 12–17 years and 1 179 410 adults aged 18 years or older. The primary outcome was asthma-related hospital admissions from 1 January 2017 to 31 December 2019. The secondary outcome was asthma-related ICU admissions. Incidence rate ratios adjusted for demographic and clinical risk factors were estimated using negative binomial models. Population attributable fraction (PAF) was estimated for modifiable risk factors.Results Younger age groups, females and those from ethnic minority and lower socioeconomic backgrounds had an increased risk of asthma-related hospital admissions. Increasing medication burden, including excessive use of short-acting bronchodilators, was also strongly associated with the primary outcome. Similar risk factors were observed for asthma-related ICU admissions. The key potentially modifiable or treatable risk factors were smoking in adolescents and adults (PAF 6.8%, 95% CI 0.9% to 12.3% and 4.3%, 95% CI 3.0% to 5.7%, respectively), and obesity (PAF 23.3%, 95% CI 20.5% to 26.1%), depression (11.1%, 95% CI 9.1% to 13.1%), gastro-oesophageal reflux disease (2.3%, 95% CI 1.2% to 3.4%), anxiety (2.0%, 95% CI 0.5% to 3.6%) and chronic rhinosinusitis (0.8%, 95% CI 0.3% to 1.3%) in adults.Conclusions There are significant sociodemographic inequalities in the rates of asthma-related hospital and ICU admissions. Treating age-specific modifiable risk factors should be considered an integral part of asthma management, which could potentially reduce the rate of avoidable hospital admissions.

ABSTRACT: The aim of this study was to investigate the antimicrobial effect of marination, natural antimicrobials, and packaging on the microbial population of chicken tawook during storage at 4°C. Chicken meat was cut into 10 g cubes and marinated. The chicken was then mixed individually with 0.5% or 1% (w/v) vanillin (VA), β-resorcylic acid (BR), or eugenol (EU), and stored under aerobic (AP) or vacuum (VP) packing at 4°C for 7 d. The marinade decreased microbial growth as monitored by total plate count, yeast and mold, lactic acid bacteria, and Pseudomonas spp. by about 1 log cfu/g under AP. The combination of marinade and antimicrobials under AP and VP decreased growth of spoilage-causing microorganisms by 1.5 to 4.8 and 2.3 to 4.6 log cfu/g, respectively. Change in pH in VP meat was less than 0.5 in all treated samples including the control. Marination decreased the lightness of the meat (L*) and significantly (p < 0.05) increased the redness (A*) and yellowness (B*). Overall acceptability was highest for marinated samples with 0.5% BR.

BackgroundInnovation in seasonal influenza vaccine development has resulted in a wider range of formulations becoming available. Understanding vaccine coverage across populations including the timing of administration is important when evaluating vaccine benefits and risks. ObjectiveThis study aims to report the representativeness, uptake of influenza vaccines, different formulations of influenza vaccines, and timing of administration within the English Primary Care Sentinel Cohort (PCSC). MethodsWe used the PCSC of the Oxford-Royal College of General Practitioners Research and Surveillance Centre. We included patients of all ages registered with PCSC member general practices, reporting influenza vaccine coverage between September 1, 2019, and January 29, 2020. We identified influenza vaccination recipients and characterized them by age, clinical risk groups, and vaccine type. We reported the date of influenza vaccination within the PCSC by International Standard Organization (ISO) week. The representativeness of the PCSC population was compared with population data provided by the Office for National Statistics. PCSC influenza vaccine coverage was compared with published UK Health Security Agency’s national data. We used paired t tests to compare populations, reported with 95% CI. ResultsThe PCSC comprised 7,010,627 people from 693 general practices. The study population included a greater proportion of people aged 18-49 years (2,982,390/7,010,627, 42.5%; 95% CI 42.5%-42.6%) compared with the Office for National Statistics 2019 midyear population estimates (23,219,730/56,286,961, 41.3%; 95% CI 4.12%-41.3%; P

Abstract We propose an experiment based on a Bose–Einstein condensate interferometer for strongly constraining fifth-force models. Additional scalar fields from modified gravity or higher dimensional theories may account for dark energy and the accelerating expansion of the Universe. These theories have led to proposed screening mechanisms to fit within the tight experimental bounds on fifth-force searches. We show that our proposed experiment would greatly improve the existing constraints on these screening models by many orders of magnitude.

Abstract We evaluated biochemical changes in skeletal muscle of women with breast cancer initiating aromatase inhibitors (AI), including oxidation of ryanodine receptor RyR1 and loss of stabilizing protein calstabin1, and detailed measures of muscle function. Fifteen postmenopausal women with stage I–III breast cancer planning to initiate AI enrolled. Quadriceps muscle biopsy, dual-energy x-ray absorptiometry, isokinetic dynamometry, Short Physical Performance Battery, grip strength, 6-min walk, patient-reported outcomes, and serologic measures of bone turnover were assessed before and after 6 months of AI. Post-AI exposure, oxidation of RyR1 significantly increased (0.23 ± 0.37 vs. 0.88 ± 0.80, p

Abstract Background The findings from multi-centre trials are central to the practice of evidence-based medicine, enabling the development and implementation of new treatments. The time it takes to commence clinical trials at sites can be long, and ethics and governance approvals are key steps on the pathway to site activation. The goal of this study was to explore factors influencing the times to ethics approval, governance approval and site activation for multi-centre clinical trials. Methods This paper assessed the associations of trial characteristics (disease area and trial phase), site characteristics (government or private ownership, country) and characteristics of the ethics and governance processes (scope guidelines, mutual acceptance requirements and triage of projects by risk) with times to approvals and activation. Median times were compared between site initiations that were and were not exposed to each characteristic using non-parametric tests in univariable and multivariable regressions. Results There were data from 150 site activations done across 91 sites, 16 trials and 5 countries from November 2013 to November 2021. The overall median time to activation was 234 days (range 74 to 657), with ethics approval taking a median of 48 days (0 to 369) and governance approval a median of 34 days (0 to 489). Both the univariable and multivariable analyses identified associations of disease area, particularly oncology (p univariable = 0.012, p multivariable = 0.044), use of scope guidelines (p 0.054). The only factors associated with reduced overall time to site activation in both univariable and multivariable analyses were the early trial phase (p

Abstract Establishing a dosing regimen that maximizes clinical benefit and minimizes adverse effects for novel therapeutics is a key objective for drug developers. Finding an optimal dose and schedule can be particularly challenging for compounds with a narrow therapeutic window such as in oncology. Modeling and simulation tools can be valuable to conduct in silico evaluations of various dosing scenarios with the goal to identify those that could minimize toxicities, avoid unscheduled dose interruptions, or minimize premature discontinuations, which all could limit the potential for therapeutic benefit. In this tutorial, we present a stepwise development of an adaptive dose simulation framework that can be used for dose optimization simulations. The tutorial first describes the general workflow, followed by a technical description with basic to advanced practical examples of its implementation in mrgsolve and is concluded with examples on how to use this in decision‐making around dose and schedule optimization. The adaptive simulation framework is built with pharmacokinetic, pharmacodynamic (i.e., biomarkers, activity markers, target engagement markers, efficacy markers), and safety models that include evaluations of unexplained interindividual and intraindividual variability and covariate impact, which can be replaced and expanded (e.g., combination setting, comparator setting) with user‐defined models. Subsequent adaptive simulations allow investigation of the impact of starting dose, dosing intervals, and event‐driven (exposure or effect) dose modifications on any end point. The resulting simulation‐derived insights can be used in quantitatively proposing dose and regimens that better balance benefit and adverse effects for further evaluation, aiding dose selection discussions, and designing dose modification recommendations, among others.

Over 200 health journals call on the United Nations, political leaders, and health professionals to recognise that climate change and biodiversity loss are one indivisible crisis and must be tackled together to preserve health and avoid catastrophe. This overall environmental crisis is now so severe as to be a global health emergency. The world is currently responding to the climate crisis and the nature crisis as if they were separate challenges. This is a dangerous mistake. The 28th Conference of the Parties (COP) on climate change is about to be held in Dubai while the 16th COP on biodiversity is due to be held in Turkey in 2024. The research communities that provide the evidence for the two COPs are unfortunately largely separate, but they were brought together for a workshop in 2020 when they concluded that: “Only by considering climate and biodiversity as parts of the same complex problem…can solutions be developed that avoid maladaptation and maximize the beneficial outcomes” .

This study proposes a new, doubly re-entrant auxetic unit-cell design that is based on the widely used auxetic honeycomb structure. Our objective was to develop a structure that preserves and enhances the advantages of the auxetic honeycomb while eliminating all negative aspects. The doubly re-entrant geometry design aims to enhance the mechanical properties, while eliminating the buckling deformation characteristic of the re-entrant deformation mechanism. The effects of the geometric modification are described and evaluated using two parameters, offset and deg. A series of experiments were conducted on a wide range of parameters based on these two parameters. Specimens were printed via the vat photopolymerization process and were subjected to a compression test. Our aim was to investigate the mechanical properties (energy absorption and compressive force) and the deformation behaviour of these specimens in relation to the relevant parameters. The novel geometry achieved the intended properties, outperforming the original auxetic honeycomb structure. Increasing the offset and deg parameters results in increasing the energy absorption capability (up to 767%) and the maximum compressive force (up to 17 times). The right parameter choice eliminates buckling and results in continuous auxetic behaviour. Finally, the parameter dependency of the deformation behaviour was predicted by analytical approximation as well.

Pigs try to separate their lying area from the dunging area. However, due to several factors such as pen design, increasing ambient temperatures, or lack of space, pigs often lie in the dunging area or defaecate in the lying area, resulting in increased pen and animal soiling. Besides poor hygienic conditions, this may also lead to increased ammonia emissions. Thus, proper changes to support the structure of conventional pens may help facilitate better elimination behaviour of pigs and establish and maintain their functional areas, including dunging areas. In this study, we investigated the effect of measures to help pigs use pre-defined functional areas. The study was done on a conventional farm in pens with fully slatted floors. Pen and animal soiling was recorded by a scoring scheme in a total of 37 pens during two fattening periods. In the first fattening period (baseline period), the pen design remained unchanged to evaluate the status quo. In the second fattening period (treatment period), certain changes in 16 test pens were done to structure the pen into a designated dunging and a resting area. The remaining 21 pens served as control pens. Changes included installation of LED spotlights, partly open pen partitions, and re-arrangement of nipple drinkers and hay racks. To compare the soiling of pens, the difference in pen soiling was calculated both between the baseline and the treatment periods and the control and test pens. As a first step, the difference in pen soiling between the control and test pens within both fattening periods was compared. Additionally, to control for changes in pen soiling over time, the differences between the pen soiling of the control pens during the baseline period and the treatment period were compared. The same comparison was done for the test pens. In the treatment period, no significant difference in the pen soiling between the control pens and test pens was found. However, over time, i.e., comparing the soiling of test pens and control pens between the baseline and the treatment periods, pigs soiled the designated dunging areas more in the treatment period. The fattening pigs in both the test and the control pens were very clean during both fattening periods. Our pen modification treatment that combined changes in LED spotlights, drinker locations, roughage locations, and partly open pen partitions did not result in clear effects. However, we can not rule out that these features can help to structure the pens in a positive way.

Summary: The brain can generate actions, such as reaching to a target, using different movement strategies. We investigate how such strategies are learned in a task where perched head-fixed mice learn to reach to an invisible target area from a set start position using a joystick. This can be achieved by learning to move in a specific direction or to a specific endpoint location. As mice learn to reach the target, they refine their variable joystick trajectories into controlled reaches, which depend on the sensorimotor cortex. We show that individual mice learned strategies biased to either direction- or endpoint-based movements. This endpoint/direction bias correlates with spatial directional variability with which the workspace was explored during training. Model-free reinforcement learning agents can generate both strategies with similar correlation between variability during training and learning bias. These results provide evidence that reinforcement of individual exploratory behavior during training biases the reaching strategies that mice learn.

This study details the novel self-assembly of sodium titanate converted Ti-based microspheres into hierarchical porous 3D constructs, with macro-, micro-, and nanoporosity, for the first time. Ti6Al4V microspheres were suspended into 5 M NaOH (60 °C/24 h) solutions, with extensive variations in microsphere:solution ratios to modify microsphere interaction and initiate self-assembly through proximity merging of titanate surface dendritic growth. The formed structures, which either produced 1) unbonded, sodium titanate-converted microspheres; 2) flat (non-macroporous) scaffolds; or 3) open, hierarchically porous scaffolds, were then assessed in terms of their formation mechanism, chemical composition, porosity, as well as the effect of post-heat treatments on compressive mechanical properties. It was found that specific microsphere:solution ratios tended to form certain structures (3 flat non-macroporous, >8 powder) due to a combination of microsphere freedom of movement, H2 gas bubble formation, and exposed surface reactivity. This promising discovery highlights the potential for lower temperature, simplistic production of 3D constructs with modifiable chemical properties due to the ion-exchange potential of titanate structures, with clear applications in a wide-range of fields, from medical materials to catalysts.

Abstract Genome‐wide introgression and substitution lines have been developed in many plant species, enhancing mapping precision, gene discovery, and the identification and exploitation of variation from wild relatives. Created over multiple generations of crossing and/or backcrossing accompanied by marker‐assisted selection, the resulting introgression lines are a fixed genetic resource. In this study we report the development of spring wheat (Triticum aestivum L.) chromosome segment substitution lines (CSSLs) generated to systematically capture genetic variation from tetraploid (T. turgidum ssp. dicoccoides) and diploid (Aegilops tauschii) progenitor species. Generated in a common genetic background over four generations of backcrossing, this is a base resource for the mapping and characterization of wheat progenitor variation. To facilitate further exploitation the final population was genetically characterized using a high‐density genotyping array and a range of agronomic and grain traits assessed to demonstrate the potential use of the populations for trait localization in wheat.

INTRODUCTION The UN General Assembly in September 2021 will bring countries together at a critical time for marshalling collective action to tackle the global environmental crisis. They will meet again at the biodiversity summit in Kunming, China and the climate conference (COP26) in Glasgow, UK. Ahead of these pivotal meetings, we – the editors of health journals worldwide – call for urgent action to keep average global temperature increases below 1.5°C, halt the destruction of nature, and protect health. Health is already being harmed by global temperature increases and the destruction of the natural world, a state of affairs health professionals have been bringing attention to for decades.1 The science is unequivocal; a global increase of 1.5°C above the pre-industrial average and the continued loss of biodiversity risk catastrophic harm to health pulmonary morbidity and mortality.5,6 Harms disproportionately affect the most vulnerable, including among children, older populations, ethnic minorities, poorer communities and those with underlying health problems.2,4 Global heating is also contributing to the decline in global yield potential for major crops, falling by 1.8-5.6% since 1981; this, together with the effects of extreme weather and soil depletion, is hampering efforts to reduce undernutrition.4 Thriving ecosystems are essential to human health, and the widespread destruction of nature, including habitats and species, is eroding water and food security and increasing the chance of pandemics.3,7,8 The consequences of the environmental crisis fall disproportionately on those countries and communities that have contributed least to the problem and are least able to mitigate the harms. Yet no country, no matter how wealthy, can shield itself from these impacts. Allowing the consequences to fall disproportionately on the most vulnerable will breed more conflict, food insecurity, forced displacement and zoonotic disease – with severe implications for all countries and communities. As with the covid-19 pandemic, we are globally as strong as our weakest member. Rises above 1.5°C increase the chance of reaching tipping points in natural systems that could lock the world into an acutely unstable state. This would critically impair our ability to mitigate harms and to prevent catastrophic, runaway environmental change.9,10

ABSTRACT: Chicken liver is considered a delicacy in the Middle East where pomegranate molass is commonly used as a salad dressing and in marinade recipes. Marinated chicken liver is a common entrée and represents a value-added product compared to the otherwise unmarinated liver which commands a lower price. The aim of this study was to investigate the inhibitory effects of a pomegranate-based marinade alone or following the addition of cinnamaldehyde or β-resorcylic acid on the spoilage microorganisms present in chicken liver during storage for 14 d at 4°C or under mild temperature abuse conditions (10°C). The pH and microbial populations of total plate count (TPC), lactic acid bacteria (LAB), Pseudomonas spp. (PS), yeast and mold (YM), and Enterobacteriaceae (EN) were tested during the storage period and the shelf life was determined (defined as 107 log cfu/g). Sensory analysis was also conducted. The pH increased by a greater extent in unmarinated samples as compared to marinated samples (with or without antimicrobials) upon storage. The initial TPC, LAB, PS, YM, and EN microbial populations in the chicken liver were 3.85 ± 0.79, 3.73 ± 0.85, 3.85 ± 0.79, 3.73 ± 0.87, and 3.69 ± 0.23 log cfu/g, respectively. The marinade decreased the microbial populations by 2 to 4 log cfu/g. The marinade and antimicrobial mixture decreased the microbial populations by 3 to 4 log cfu/g. Except for 1 sample, none of the marinated chicken liver samples with or without antimicrobials reached the end of shelf life even up to 14 d of storage at both 4°C and 10°C. The overall sensory score was rated around 6/9 for the treated samples.

Over 200 health journals call on the United Nations, political leaders, and health professionals to recognise that climate change and biodiversity loss are one indivisible crisis and must be tackled together to preserve health and avoid catastrophe. This overall environmental crisis is now so severe as to be a global health emergency.

Summary: Background: Tumour-promoting inflammation is a “hallmark” of cancer and conventional epidemiological studies have reported links between various inflammatory markers and cancer risk. The causal nature of these relationships and, thus, the suitability of these markers as intervention targets for cancer prevention is unclear. Methods: We meta-analysed 6 genome-wide association studies of circulating inflammatory markers comprising 59,969 participants of European ancestry. We then used combined cis-Mendelian randomization and colocalisation analysis to evaluate the causal role of 66 circulating inflammatory markers in risk of 30 adult cancers in 338,294 cancer cases and up to 1,238,345 controls. Genetic instruments for inflammatory markers were constructed using genome-wide significant (P 70% was employed to indicate support for shared causal variants across inflammatory markers and cancer outcomes. Findings were replicated in the FinnGen study and then pooled using meta-analysis. Findings: We found strong evidence to support an association of genetically-proxied circulating pro-adrenomedullin concentrations with increased breast cancer risk (OR: 1.19, 95% CI: 1.10–1.29, q-value = 0.033, PPH4 = 84.3%) and suggestive evidence to support associations of interleukin-23 receptor concentrations with increased pancreatic cancer risk (OR: 1.42, 95% CI: 1.20–1.69, q-value = 0.055, PPH4 = 73.9%), prothrombin concentrations with decreased basal cell carcinoma risk (OR: 0.66, 95% CI: 0.53–0.81, q-value = 0.067, PPH4 = 81.8%), and interleukin-1 receptor-like 1 concentrations with decreased triple-negative breast cancer risk (OR: 0.92, 95% CI: 0.88–0.97, q-value = 0.15, PPH4 = 85.6%). These findings were replicated in pooled analyses with the FinnGen study. Though suggestive evidence was found to support an association of macrophage migration inhibitory factor concentrations with increased bladder cancer risk (OR: 2.46, 95% CI: 1.48–4.10, q-value = 0.072, PPH4 = 76.1%), this finding was not replicated when pooled with the FinnGen study. For 22 of 30 cancer outcomes examined, there was little evidence (q-value ≥0.20) that any of the 66 circulating inflammatory markers examined were associated with cancer risk. Interpretation: Our comprehensive joint Mendelian randomization and colocalisation analysis of the role of circulating inflammatory markers in cancer risk identified potential roles for 4 circulating inflammatory markers in risk of 4 site-specific cancers. Contrary to reports from some prior conventional epidemiological studies, we found little evidence of association of circulating inflammatory markers with the majority of site-specific cancers evaluated. Funding: Cancer Research UK (C68933/A28534, C18281/A29019, PPRCPJT∖100005), World Cancer Research Fund (IIG_FULL_2020_022), National Institute for Health Research (NIHR202411, BRC-1215-20011), Medical Research Council (MC_UU_00011/1, MC_UU_00011/3, MC_UU_00011/6, and MC_UU_00011/4), Academy of Finland Project 326291, European Union's Horizon 2020 grant agreement no. 848158 (EarlyCause), French National Cancer Institute (INCa SHSESP20, 2020-076), Versus Arthritis (21173, 21754, 21755), National Institutes of Health (U19 CA203654), National Cancer Institute (U19CA203654).

Over 200 health journals call on the United Nations, political leaders, and health professionals to recognise that climate change and biodiversity loss are one indivisible crisis and must be tackled together to preserve health and avoid catastrophe. This overall environmental crisis is now so severe as to be a global health emergency. The world is currently responding to the climate crisis and the nature crisis as if they were separate challenges. This is a dangerous mistake. The 28th Conference of the Parties (COP) on climate change is about to be held in Dubai while the 16th COP on biodiversity is due to be held in Turkey in 2024. The research communities that provide the evidence for the two COPs are unfortunately largely separate, but they were brought together for a workshop in 2020 when they concluded that: "Only by considering climate and biodiversity as parts of the same complex problem…can solutions be developed that avoid maladaptation and maximize the beneficial outcomes

Applications of artificial intelligence (AI) and machine learning (ML) have become pervasive in our everyday lives. These applications range from the mundane (asking ChatGPT to write a thank you note) to high-end science (predicting future weather patterns in the face of climate change), but, because they rely on human-generated or mediated data, they also have the potential to perpetuate systemic oppression and racism. For museums and other cultural heritage institutions, there is great interest in automating the kinds of applications at which AI and ML can excel, for example, tasks in computer vision including image segmentation, object recognition (labelling or identifying objects in an image) and natural language processing (e.g. named-entity recognition, topic modelling, generation of word and sentence embeddings) in order to make digital collections and archives discoverable, searchable and appropriately tagged.A coalition of staff, Fellows and interns working in digital spaces at the Smithsonian Institution, who are either engaged with research using AI or ML tools or working closely with digital data in other ways, came together to discuss the promise and potential perils of applying AI and ML at scale and this work results from those conversations. Here, we present the process that has led to the development of an AI Values Statement and an implementation plan, including the release of datasets with accompanying documentation to enable these data to be used with improved context and reproducibility (dataset cards). We plan to continue releasing dataset cards and for AI and ML applications, model cards, in order to enable informed usage of Smithsonian data and research products.