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Young people growing up in England from a poorer background are less likely to progress into higher education compared to their better off counterparts. This is especially true with respect to more selective universities. This study used government administrative data to gauge the effectiveness of the 'Realising Opportunities' programme, which provides a package of support to prospective university applicants from disadvantaged backgrounds to facilitate their progression to more selective universities. Data was gathered concerning 769 16 to 18-year-old students who took part in the programme--which is delivered by a consortium of selective universities--between 2015 and 2017. This data revealed participants' personal characteristics (e.g., gender, ethnicity and socioeconomic status), school attainment and eventual university destination (or lack thereof). Additionally, national administrative data was sourced from the Department for Education's National Pupil Database and the Higher Education Statistics Agency for the entire cohort of state school pupils in England who turned 16 in the 2014-2015 academic year. This national data was used to generate a statistical model that could predict the likelihood of a young person in England progressing to a selective university based on their school attainment and other personal characteristics. Data concerning the programme participants was fed through the model and it was observed that the number of participants who had in fact progressed to selective universities greatly exceeded that predicted. Participation in the Realising Opportunities programme therefore appeared to be positively associated with an increased likelihood of progression to a selective university.

Abstract Hydrogen, as an energy carrier, is attractive to many stakeholders based on the assumption that the extensive global network of natural gas infrastructure can be repurposed to transport hydrogen as part of a zero‐carbon energy future. Therefore, utility companies and governments are rapidly advancing efforts to pilot blending low‐carbon hydrogen into existing natural gas systems, many with the goal of eventually shifting to pure hydrogen. However, hydrogen has fundamentally different physical and chemical properties to natural gas, with major consequences for safety, energy supply, climate, and cost. We evaluate the suitability of using existing natural gas infrastructure for distribution of hydrogen. We summarize differences between hydrogen and natural gas, assess the latest science and engineering of each component of the natural gas value chain for hydrogen distribution, and discuss proposed solutions for building an effective hydrogen value chain. We find that every value chain component is challenged by reuse. Hydrogen blending can circumvent many challenges but offers only a small reduction in greenhouse gas emissions due to hydrogen's low volumetric energy density. Furthermore, a transition to pure hydrogen is not possible without significant retrofits and replacements. Even if technical and economic barriers are overcome, serious safety and environmental risks remain.

Abstract Background Limited data exists regarding gender-specific microbial alterations during gender-affirming hormonal therapy (GAHT) in transgender individuals. This study aimed to investigate the nuanced impact of sex steroids on gut microbiota taxonomy and function, addressing this gap. We prospectively analyzed gut metagenome changes associated with 12 weeks of GAHT in trans women and trans men, examining both taxonomic and functional shifts. Methods Thirty-six transgender individuals (17 trans women, 19 trans men) provided pre- and post-GAHT stool samples. Shotgun metagenomic sequencing was used to assess the changes in gut microbiota structure and potential function following GAHT. Results While alpha and beta diversity remained unchanged during transition, specific species, including Parabacteroides goldsteinii and Escherichia coli, exhibited significant abundance shifts aligned with affirmed gender. Overall functional metagenome analysis showed a statistically significant effect of gender and transition (R 2 = 4.1%, P = 0.0115), emphasizing transitions aligned with affirmed gender, particularly in fatty acid-related metabolism. Conclusions This study provides compelling evidence of distinct taxonomic and functional profiles in the gut microbiota between trans men and women. GAHT induces androgenization in trans men and feminization in trans women, potentially impacting physiological and health-related outcomes. Trial registration Clinicaltrials.gov NCT02185274.

Abstract Androgen insensitivity syndrome (AIS) is a difference of sex development (DSD) characterized by different degrees of undervirilization in individuals with a 46,XY karyotype despite normal to high gonadal testosterone production. Classically, AIS is explained by hemizygous mutations in the X-chromosomal androgen receptor (AR) gene. Nevertheless, the majority of individuals with clinically diagnosed AIS do not carry an AR gene mutation. Here, we present a patient with a 46,XY karyotype, born with undervirilized genitalia, age-appropriate testosterone levels and no uterus, characteristic for AIS. Diagnostic whole exome sequencing (WES) showed a maternally inherited LINE1 (L1) retrotransposon insertion in the 5′ untranslated region (5′UTR) of the AR gene. Long-read nanopore sequencing confirmed this as an insertion of a truncated L1 element of ≈ 2.7 kb and showed an increased DNA methylation at the L1 insertion site in patient-derived genital skin fibroblasts (GSFs) compared to healthy controls. The insertion coincided with reduced AR transcript and protein levels in patient-derived GSFs confirming the clinical diagnosis AIS. Our results underline the relevance of retrotransposons in human disease, and expand the growing list of human diseases associated with them.

Abstract Background Advanced Trauma Life Support (ATLS) is the gold standard of initial assessment of trauma patients and therefore a widely used training program for medical professionals. Practical application of the knowledge taught can be challenging for medical students and inexperienced clinicians. Simulation-based training, including virtual reality (VR), has proven to be a valuable adjunct to real-world experiences in trauma education. Previous studies have demonstrated the effectiveness of VR simulations for surgical and technical skills training. However, there is limited evidence on VR simulation training specifically for trauma education, particularly within the ATLS curriculum. The purpose of this pilot study is to evaluate the feasibility, effectiveness, and acceptance of using a fully immersive VR trauma simulation to prepare medical students for the ATLS course. Methods This was a prospective randomised controlled pilot study on a convenience sample of advanced medical students (n = 56; intervention group with adjunct training using a commercially available semi-automated trauma VR simulation, n = 28, vs control group, n = 28) taking part in the ATLS course of the Military Physician Officer School. Feasibility was assessed by evaluating factors related to technical factors of the VR training (e.g. rate of interruptions and premature termination). Objective and subjective effectiveness was assessed using confidence ratings at four pre-specified points in the curriculum, validated surveys, clinical scenario scores, multiple choice knowledge tests, and ATLS final clinical scenario and course pass rates. Acceptance was measured using validated instruments to assess variables of media use (Technology acceptance, usability, presence and immersion, workload, and user satisfaction). Results The feasibility assessment demonstrated that only one premature termination occurred and that all remaining participants in the intervention group correctly stabilised the patient. No significant differences between the two groups in terms of objective effectiveness were observed (p = 0.832 and p = 0.237 for the pretest and final knowledge test, respectively; p = 0.485 for the pass rates for the final clinical scenario on the first attempt; all participants passed the ATLS course). In terms of subjective effectiveness, the authors found significantly improved confidence post-VR intervention (p

Abstract Background Systematically screening published literature to determine the relevant publications to synthesize in a review is a time-consuming and difficult task. Large language models (LLMs) are an emerging technology with promising capabilities for the automation of language-related tasks that may be useful for such a purpose. Methods LLMs were used as part of an automated system to evaluate the relevance of publications to a certain topic based on defined criteria and based on the title and abstract of each publication. A Python script was created to generate structured prompts consisting of text strings for instruction, title, abstract, and relevant criteria to be provided to an LLM. The relevance of a publication was evaluated by the LLM on a Likert scale (low relevance to high relevance). By specifying a threshold, different classifiers for inclusion/exclusion of publications could then be defined. The approach was used with four different openly available LLMs on ten published data sets of biomedical literature reviews and on a newly human-created data set for a hypothetical new systematic literature review. Results The performance of the classifiers varied depending on the LLM being used and on the data set analyzed. Regarding sensitivity/specificity, the classifiers yielded 94.48%/31.78% for the FlanT5 model, 97.58%/19.12% for the OpenHermes-NeuralChat model, 81.93%/75.19% for the Mixtral model and 97.58%/38.34% for the Platypus 2 model on the ten published data sets. The same classifiers yielded 100% sensitivity at a specificity of 12.58%, 4.54%, 62.47%, and 24.74% on the newly created data set. Changing the standard settings of the approach (minor adaption of instruction prompt and/or changing the range of the Likert scale from 1–5 to 1–10) had a considerable impact on the performance. Conclusions LLMs can be used to evaluate the relevance of scientific publications to a certain review topic and classifiers based on such an approach show some promising results. To date, little is known about how well such systems would perform if used prospectively when conducting systematic literature reviews and what further implications this might have. However, it is likely that in the future researchers will increasingly use LLMs for evaluating and classifying scientific publications.

Cell division is fundamental to all healthy tissue growth, as well as being rate-limiting in the tissue repair response to wounding and during cancer progression. However, the role that cell divisions play in tissue growth is a collective one, requiring the integration of many individual cell division events. It is particularly difficult to accurately detect and quantify multiple features of large numbers of cell divisions (including their spatio-temporal synchronicity and orientation) over extended periods of time. It would thus be advantageous to perform such analyses in an automated fashion, which can naturally be enabled using deep learning. Hence, we develop a pipeline of deep learning models that accurately identify dividing cells in time-lapse movies of epithelial tissues in vivo. Our pipeline also determines their axis of division orientation, as well as their shape changes before and after division. This strategy enables us to analyse the dynamic profile of cell divisions within the Drosophila pupal wing epithelium, both as it undergoes developmental morphogenesis and as it repairs following laser wounding. We show that the division axis is biased according to lines of tissue tension and that wounding triggers a synchronised (but not oriented) burst of cell divisions back from the leading edge.

Insects can represent a valuable and cost effective source of animal feed in Africa. Recently, the interest in incorporating black-soldier fly larvae (BSFL) in animal feed has increased tremendously. However, many factors, including food neophobia and social and cultural context may affect consumers' perception of insect-technologies-derived food products. This study shed light on consumers' perception of the usage of BSFL as animal feed and consumption, buying, and commercialization of food from animals fed on BSFL in DR Congo, Mali, and Niger. We used data from 1560 consumers that were analyzed applying parametric and non-parametric tests and the generalized ordered logit model. Our findings show that about 87 % of respondents consider that consuming food from animals fed on BSFL is acceptable and 34 % accept buying eggs, fish, and meat from animals fed on BSFL. However, about 40 % of consumers recommend the label differentiation of BSF-technologies-derived food products and they also expect a lower price than conventional animal feed products. The analysis of factors driving consumers' readiness to buy BSF-derived food products have revealed that effective market penetration of BSF-technologies-derived food products could be achieved with great awareness creation, targeting farming households, married and literate heads. Furthermore, strategic communication and intensive sensitization through farmers' associations will be crucial. Finally, credit access and income diversification are also necessary to support consumers’ choices toward sustainable food habits built on bio-circular economy.

Chest radiography, computed tomography (CT) and positron emission tomography (PET)-CT are required for staging nonsmall cell lung cancers. Stage I cancers may be up to 4 cm in maximal diameter, with stage IA tumours being up to 3 cm and stage IB up to 4 cm. A lung cancer becomes stage II if the tumour is between 4 and ≤5 cm (stage IIA), or it spreads to ipsilateral peribronchial or hilar lymph nodes (stage IIB). Stage IA tumours should be surgically resected, ideally using minimally invasive methods. Lobectomy is usually performed, although some studies have shown good outcomes for sublobar resections. If surgery is not possible, stereotactic body radiotherapy is a good alternative. This involves delivering a few high-dose radiation treatments at very high precision. For stage IB to IIB disease, combinations of surgery, chemotherapy or immunotherapy and radiotherapy are used. There is evidence that neoadjuvant treatment (immunotherapy with nivolumab and chemotherapy for stage IB and II) optimises outcomes. Adjuvant chemotherapy with a platinum-based doublet (typically cisplatin+vinorelbine) should be offered for resected stage IIB tumours and considered for resected IIA tumours. Adjuvant pembrolizumab is used for stage IB–IIIA following resection and adjuvant platinum-based chemotherapy. Osimertinib may be used for resected stage IB to IIIA cancers which have relevant mutations (epidermal growth factor receptor exon 19 deletions or exon 21 (L858R) substitution). There are no fixed guidelines for follow-up, but most centres recommend 6-monthly CT scanning for the first 2–3 years after definitive treatment, followed by annual scans.

Abstract Myelofibrosis is a chronic myeloproliferative disorder characterized by bone marrow fibrosis, splenomegaly, anemia, and constitutional symptoms, with a median survival of ≈6 years from diagnosis. While currently approved Janus kinase (JAK) inhibitors (ruxolitinib, fedratinib) improve splenomegaly and symptoms, most can exacerbate myelofibrosis‐related anemia, a negative prognostic factor for survival. Momelotinib is a novel JAK1/JAK2/activin A receptor type 1 (ACVR1) inhibitor approved in the US, European Union, and the UK and is the first JAK inhibitor indicated specifically for patients with myelofibrosis with anemia. Momelotinib not only addresses the splenomegaly and symptoms associated with myelofibrosis by suppressing the hyperactive JAK–STAT (signal transducer and activator of transcription) pathway but also improves anemia and reduces transfusion dependency through ACVR1 inhibition. The recommended dose of momelotinib is 200 mg orally once daily, which was established after review of safety, efficacy, pharmacokinetic, and pharmacodynamic data. Momelotinib is metabolized primarily by CYP3A4 and excreted as metabolites in feces and urine. Steady‐state maximum concentration is 479 ng/mL (CV%, 61%), with a mean AUCtau of 3288 ng.h/mL (CV%, 60%); its major metabolite, M21, is active (≈40% of pharmacological activity of parent), with a metabolite‐to‐parent AUC ratio of 1.4–2.1. This review describes momelotinib's mechanism of action, detailing how the JAK–STAT pathway is involved in myelofibrosis pathogenesis and ACVR1 inhibition decreases hepcidin, leading to improved erythropoiesis. Additionally, it summarizes the pivotal studies and data that informed the recommended dosage and risk/benefit assessment.

To locate and fertilize the egg, sperm probe the varying microenvironment prevailing at different stages during their journey across the female genital tract. To this end, they are equipped with a unique repertoire of mostly sperm-specific proteins. In particular, the flagellar Ca2+ channel CatSper has come into focus as a polymodal sensor used by human sperm to register ligands released into the female genital tract. Here, we provide the first comprehensive study on the pharmacology of the sperm-specific human Slo3 channel, shedding light on its modulation by reproductive fluids and their constituents. We show that seminal fluid and contained prostaglandins and Zn2+ do not affect the channel, whereas human Slo3 is inhibited in a non-genomic fashion by diverse steroids as well as by albumin, which are released into the oviduct along with the egg. This indicates that not only CatSper but also Slo3 harbours promiscuous ligand-binding sites that can accommodate structurally diverse molecules, suggesting that Slo3 is involved in chemosensory signalling in human sperm.

Objectives: To evaluate effects of dose intensified salvage radiotherapy (sRT) on erectile function in biochemically recurrent prostate cancer (PC) after radical prostatectomy (RP). Materials and methods: Eligible patients had evidence of biochemical failure after RP and a PSA at randomization of ≤ 2 ng/ml. Erectile dysfunction (ED) was investigated as secondary endpoint within the multicentre randomized trial (February 2011 to April 2014) in patients receiving either 64 Gy or 70 Gy sRT. ED and quality of life (QoL) were assessed using CTCAE v4.0 and the EORTC QoL questionnaires C30 and PR25 at baseline and up to 5 years after sRT. Results: 344 patients were evaluable. After RP 197 (57.3 %) patients had G0-2 ED while G3 ED was recorded in 147 (42.7 %) patients. Subsequently, sexual activity and functioning was impaired. 5 years after sRT, 101 (29.4 %) patients noted G0-2 ED. During follow-up, 44.2 % of patients with baseline G3 ED showed any improvement and 61.4 % of patients with baseline G0-2 ED showed worsening. Shorter time interval between RP and start of sRT (p = 0.007) and older age at randomization (p = 0.005) were significant predictors to more baseline ED and low sexual activity in the long-term. Age (p = 0.010) and RT technique (p = 0.031) had a significant impact on occurrence of long-term ED grade 3 and worse sexual functioning. During follow-up, no differences were found in erectile function, sexual activity, and sexual functioning between the 64 Gy and 70 Gy arm. Conclusion: ED after RP is a known long-term side effect with significant impact on patients’ QoL. ED was further affected by sRT, but dose intensification of sRT showed no significant impact on erectile function recovery or prevalence of de novo ED after sRT. Age, tumor stage, prostatectomy and RT-techniques, nerve-sparing and observation time were associated with long-term erectile function outcome.ClinicalTrials.gov. Identifier: NCT01272050.

Introduction: Maxillary torus are rare, asymptomatic and slowly progressive benign bony exostoses. Their exaggerated growth could affect swallowing, phonetics and the making of removable prostheses. Objective: To present the clinical case of the surgical approach of a wide palatal torus. Clinical Case: A 40-year-old female patient came to the dentistry service to consult about the presence of an elevated area in the midline of the hard palate, with a firm consistency. On clinical evaluation she was asymptomatic. A cone beam computed tomography was requested and a diagnosis of palatal torus was made. A double Y-shaped incision was made and the torus was sectioned in 6 parts to later remove the fragments with a percussive chisel. It was sutured and a containment splint was placed to keep the flap fixed. The evolution of the case was favorable. Conclusion: Palatal torus can disrupt some oral functions and their presence and size can be of concern to patients. A correct diagnosis and tomographic analysis can indicate to the clinician an adequate surgical approach when the case requires it.

Abstract Functional enrichment analysis of genome-wide association study (GWAS)-summary statistics has suggested that CD4+ T-cells play an important role in asthma pathogenesis. Despite this, CD4+ T-cells are under-represented in asthma transcriptome studies. To fill the gap, 3'-RNA-Seq was used to generate gene expression data on CD4+ T-cells (isolated within 2 h from collection) from peripheral blood from participants with well-controlled asthma (n = 32) and healthy controls (n = 11). Weighted Gene Co-expression Network Analysis (WGCNA) was used to identify sets of co-expressed genes (modules) associated with the asthma phenotype. We identified three modules associated with asthma, which are strongly enriched for GWAS-identified asthma genes, antigen processing/presentation and immune response to viral infections. Through integration of publicly available eQTL and GWAS summary statistics (colocalisation), and protein–protein interaction (PPI) data, we identified PTPRC, a potential druggable target, as a putative master regulator of the asthma gene-expression profiles. Using a co-expression network approach, with integration of external genetic and PPI data, we showed that CD4+ T-cells from peripheral blood from asthmatics have different expression profiles, albeit small in magnitude, compared to healthy controls, for sets of genes involved in immune response to viral infections (upregulated) and antigen processing/presentation (downregulated).

Abstract Momelotinib—approved for treatment of myelofibrosis in adults with anemia—and its major active metabolite, M21, were assessed as drug–drug interaction (DDI) victims with a strong cytochrome P450 (CYP) 3A4 inhibitor (multiple‐dose ritonavir), an organic anion transporting polypeptide (OATP) 1B1/1B3 inhibitor (single‐dose rifampin), and a strong CYP3A4 inducer (multiple‐dose rifampin). Momelotinib DDI perpetrator potential (multiple‐dose) was evaluated with CYP3A4 and breast cancer resistance protein (BCRP) substrates (midazolam and rosuvastatin, respectively). DDI was assessed from changes in maximum plasma concentration (Cmax), area under the concentration–time curve (AUC), time to reach Cmax, and half‐life. The increase in momelotinib (23% Cmax, 14% AUC) or M21 (30% Cmax, 24% AUC) exposure with ritonavir coadministration was not clinically relevant. A moderate increase in momelotinib (40% Cmax, 57% AUC) and minimal change in M21 was observed with single‐dose rifampin. A moderate decrease in momelotinib (29% Cmax, 46% AUC) and increase in M21 (31% Cmax, 15% AUC) were observed with multiple‐dose rifampin compared with single‐dose rifampin. Due to potentially counteracting effects of OATP1B1/1B3 inhibition and CYP3A4 induction, multiple‐dose rifampin did not significantly change momelotinib pharmacokinetics compared with momelotinib alone (Cmax no change, 15% AUC decrease). Momelotinib did not alter the pharmacokinetics of midazolam (8% Cmax, 16% AUC decreases) or 1′‐hydroxymidazolam (14% Cmax, 16% AUC decreases) but increased rosuvastatin Cmax by 220% and AUC by 170%. Safety findings were mild in this short‐term study in healthy volunteers. This analysis suggests that momelotinib interactions with OATP1B1/1B3 inhibitors and BCRP substrates may warrant monitoring for adverse reactions or dose adjustments.

Purpose: Technological progress of machine learning and natural language processing has led to the development of large language models (LLMs), capable of producing well-formed text responses and providing natural language access to knowledge. Modern conversational LLMs such as ChatGPT have shown remarkable capabilities across a variety of fields, including medicine. These models may assess even highly specialized medical knowledge within specific disciplines, such as radiation therapy. We conducted an exploratory study to examine the capabilities of ChatGPT to answer questions in radiation therapy. Methods and Materials: A set of multiple-choice questions about clinical, physics, and biology general knowledge in radiation oncology as well as a set of open-ended questions were created. These were given as prompts to the LLM ChatGPT, and the answers were collected and analyzed. For the multiple-choice questions, it was checked how many of the answers of the model could be clearly assigned to one of the allowed multiple-choice-answers, and the proportion of correct answers was determined. For the open-ended questions, independent blinded radiation oncologists evaluated the quality of the answers regarding correctness and usefulness on a 5-point Likert scale. Furthermore, the evaluators were asked to provide suggestions for improving the quality of the answers. Results: For 70 multiple-choice questions, ChatGPT gave valid answers in 66 cases (94.3%). In 60.61% of the valid answers, the selected answer was correct (50.0% of clinical questions, 78.6% of physics questions, and 58.3% of biology questions). For 25 open-ended questions, 12 answers of ChatGPT were considered as “acceptable,” “good,” or “very good” regarding both correctness and helpfulness by all 6 participating radiation oncologists. Overall, the answers were considered “very good” in 29.3% and 28%, “good” in 28% and 29.3%, “acceptable” in 19.3% and 19.3%, “bad” in 9.3% and 9.3%, and “very bad” in 14% and 14% regarding correctness/helpfulness. Conclusions: Modern conversational LLMs such as ChatGPT can provide satisfying answers to many relevant questions in radiation therapy. As they still fall short of consistently providing correct information, it is problematic to use them for obtaining medical information. As LLMs will further improve in the future, they are expected to have an increasing impact not only on general society, but also on clinical practice, including radiation oncology.

Glucocorticoids represent a key element in the treatment of pediatric acute lymphoblastic leukemia (ALL) and lead to adrenal suppression. We aimed to ass ess the differential response profile of adrenal steroids in children with ALL during BFM (Berlin–Frankfurt– Münster) induction treatment. Therefore, we performed liquid chromatography tandem– mass spectrometry (LC–MS/MS)-based steroid profiling of up to se ven consecutive leftover morning serum samples derived from 11 patients (pts) with ALL before (day 0) and during induction therapy at days 1–5, 6–12, 13–26, 27–29, 30–35 and 36–40. 17-hydroxyprogesterone (17OHP), 11-deoxycortisol (11S), cortisol, 11-deoxycorticosterone (DOC), corticosterone and aldosterone were determined in parallel. Subsequently, steroid concentrations were normalized by multiples of median (MOM) to adequately consider pediatric age- and sex-specific reference ranges. MOM-cortisol a nd its precursors MOM– 11S and MOM–17OHP were significantly suppressed by glucocorticoi d treatment until day 29 (P < 8.06 × 10−10, P < 5.102 × 10−5, P < 0.0076, respectively). Cortisol recovered in one of four pts at days 27–29 and in two of five pts at days 36–40. Amo ng the mineralocorticoids, corticosterone was significantly suppressed (P < 3.115 × 10−6). Aldosterone and DOC showed no significant changes when comparing day 0 to the treatm ent time points. However, two ALL patients with ICU treatment due to the sepsis showed significantly lower MOM–DOC (P = 0.006436) during that time and almost always the lowest aldost erone compared to all other time points. Suppression of mineralocorticoid precursors under high-dose glucocorticoid therapy suggests a functional cross talk of central glucocorticoid regulation and adrenal mineralocorticoid synthesis. Our data should stimulate prospective investigation to assess potential clinical relevance.

Introducción: La displasia fibrosa es una condición benigna rara, en la que el hueso es reemplazado por tejido conectivo. La guía de corte y planificación virtual permiten obtener resultados más predecibles con mínima morbilidad. Objetivo: Proponer una nueva técnica quirúrgica conservadora para el tratamiento de la displasia fibrosa craneofacial. Caso clínico: Paciente de sexo masculino con diagnóstico de displasia fibrosa cigomaticomaxilar, acudió por aumento de volumen en la región cigomaticomaxilar derecha de 6 meses de evolución, asintomático y de consistencia dura. El principal motivo de consulta fue no estar conforme con su asimetría facial. Se realizó un contorneado óseo a través de la obtención de una guía de corte preformada sobre un modelo estereolitográfico. Conclusiones: La confección de una guía quirúrgica personalizada con mediciones de profundidad ofrece una solución a la dificultad del contorneado óseo convencional.

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).

Summary: Background: Methotrexate (MTX) is the gold-standard first-line disease-modifying anti-rheumatic drug for juvenile idiopathic arthritis (JIA), despite only being either effective or tolerated in half of children and young people (CYP). To facilitate stratified treatment of early JIA, novel methods in machine learning were used to i) identify clusters with distinct disease patterns following MTX initiation; ii) predict cluster membership; and iii) compare clusters to existing treatment response measures. Methods: Discovery and verification cohorts included CYP who first initiated MTX before January 2018 in one of four UK multicentre prospective cohorts of JIA within the CLUSTER consortium. JADAS components (active joint count, physician (PGA) and parental (PGE) global assessments, ESR) were recorded at MTX start and over the following year.Clusters of MTX ‘response’ were uncovered using multivariate group-based trajectory modelling separately in discovery and verification cohorts. Clusters were compared descriptively to ACR Pedi 30/90 scores, and multivariate logistic regression models predicted cluster-group assignment. Findings: The discovery cohorts included 657 CYP and verification cohorts 1241 CYP. Six clusters were identified: Fast improvers (11%), Slow Improvers (16%), Improve-Relapse (7%), Persistent Disease (44%), Persistent PGA (8%) and Persistent PGE (13%), the latter two characterised by improvement in all features except one. Factors associated with clusters included ethnicity, ILAR category, age, PGE, and ESR scores at MTX start, with predictive model area under the curve values of 0.65–0.71. Singular ACR Pedi 30/90 scores at 6 and 12 months could not capture speeds of improvement, relapsing courses or diverging disease patterns. Interpretation: Six distinct patterns following initiation of MTX have been identified using methods in artificial intelligence. These clusters demonstrate the limitations in traditional yes/no treatment response assessment (e.g., ACRPedi30) and can form the basis of a stratified medicine programme in early JIA. Funding: Medical Research Council, Versus Arthritis, Great Ormond Street Hospital Children's Charity, Olivia’s Vision, and the National Institute for Health Research.

Costs of hemophilia A treatment are increasing. Waste of clotting products should be avoided. To estimate the first-year waste of emicizumab prophylaxis for people with hemophilia A and inhibitors (PwHAi) who failed immune tolerance induction (ITI), in Brazil. We evaluated the manufacturer and the Brazilian Ministry of Health (MoH) protocol-recommended regimens in a budget impact model. The loading dose consisted of 3.0 mg/kg/Q1W for 4 weeks, for both recommendations. The manufacturer maintenance regimens comprised 1.5 mg/kg/Q1W, 3.0 mg/kg/Q2W, and 6.0 mg/kg/Q4W. The MoH protocol maintenance regimen encompassed a hybrid Q1W/Q2W administration, depending on the body weight. The Q4W regimen was not recommended by the MoH protocol. Analyses were performed to estimate waste given its expense based on the World Health Organization body weight range (percentiles [P] 15, 50, and 85). The first-year emicizumab waste was estimated individually and for the disclosed PwHAi who failed ITI (n = 114). The highest emicizumab waste was estimated for the lowest body weights and the Q1W regimen. The Q4W regimen resulted in the lowest emicizumab waste, followed by the MoH protocol regimen. The total reconstituted costs estimated for the PwHAi who failed ITI according to the hybrid MoH protocol ranged from US$32,858,777 (P15) to US$47,186,858 (P85), with emicizumab waste ranging from 7.9 % (US$2,594,515) to 3.7 % (US$1,738,750), respectively. Lost resources due to current protocols for emicizumab prophylaxis for PwHAi who failed ITI in Brazil are considerable. Waste was more pronounced due to lower body weight and shorter administration intervals.

Abstract Background/purpose Impaired healing is a feared complication with devastating outcomes for each patient. Most studies focus on geriatric fracture fixation and assess well known risk factors such as infections. However, risk factors, others than infections, and impaired healing of proximal femur fractures in non-geriatric adults are marginally assessed. Therefore, this study aimed to identify non-infection related risk factors for impaired fracture healing of proximal femur fractures in non-geriatric trauma patients. Methods This study included non-geriatric patients (aged 69 years and younger) who were treated between 2013 and 2020 at one academic Level 1 trauma center due to a proximal femur fracture (PFF). Patients were stratified according to AO/OTA classification. Delayed union was defined as failed callus formation on 3 out of 4 cortices after 3 to 6 months. Nonunion was defined as lack of callus-formation after 6 months, material breakage, or requirement of revision surgery. Patient follow up was 12 months. Results This study included 150 patients. Delayed union was observed in 32 (21.3%) patients and nonunion with subsequent revision surgery occurred in 14 (9.3%). With an increasing fracture classification (31 A1 up to 31 A3 type fractures), there was a significantly higher rate of delayed union. Additionally, open reduction and internal fixation (ORIF) (OR 6.17, (95% CI 1.54 to 24.70, p ≤ 0.01)) and diabetes mellitus type II (DM) (OR 5.74, (95% CI 1.39 to 23.72, p = 0.016)), were independent risk factors for delayed union. The rate of nonunion was independent of fracture morphology, patient’s characteristics or comorbidities. Conclusion Increasing fracture complexity, ORIF and diabetes were found to be associated with delayed union of intertrochanteric femur fractures in non-geriatric patients. However, these factors were not associated with the development of nonunion.