Search

Abstract Glioblastoma (GBM) remains the most malignant primary brain tumor, with a median survival rarely exceeding 2 years. Tumor heterogeneity and an immunosuppressive microenvironment are key factors contributing to the poor response rates of current therapeutic approaches. GBM‐associated macrophages (GAMs) often exhibit immunosuppressive features that promote tumor progression. However, their dynamic interactions with GBM tumor cells remain poorly understood. Here, we used patient‐derived GBM stem cell cultures and combined single‐cell RNA sequencing of GAM‐GBM co‐cultures and real‐time in vivo monitoring of GAM‐GBM interactions in orthotopic zebrafish xenograft models to provide insight into the cellular, molecular, and spatial heterogeneity. Our analyses revealed substantial heterogeneity across GBM patients in GBM‐induced GAM polarization and the ability to attract and activate GAMs—features that correlated with patient survival. Differential gene expression analysis, immunohistochemistry on original tumor samples, and knock‐out experiments in zebrafish subsequently identified LGALS1 as a primary regulator of immunosuppression. Overall, our work highlights that GAM‐GBM interactions can be studied in a clinically relevant way using co‐cultures and avatar models, while offering new opportunities to identify promising immune‐modulating targets.

For the past two decades, cisplatin-based adjuvant chemoradiotherapy (CRT) has remained the standard of care for patients with resected, locally advanced squamous cell carcinoma of the head and neck (LA SCCHN) who are at high risk of disease recurrence. However, many patients are deemed ineligible for cisplatin-based CRT because of poor performance status, advanced age, poor renal function, or hearing loss. Outcomes with radiotherapy alone remain poor, so patients at high risk of disease recurrence who are ineligible to receive cisplatin represent a population with a significant unmet medical need. Although clinical guidelines and consensus documents have provided definitions for cisplatin ineligibility, there are still areas of debate, including thresholds for age and renal impairment as well as criteria for hearing loss. Treatment selection for patients with resected, high-risk LA SCCHN who are deemed ineligible to receive cisplatin is often based on clinical judgment, as treatment options are not clearly specified in international guidelines. Therefore, there is an urgent need to develop alternative systemic treatments to be used in combination with radiotherapy. In this podcast, we share our clinical experience and provide our perspectives related to cisplatin ineligibility in patients with LA SCCHN, discuss the limited clinical evidence for adjuvant treatment of patients with resected, high-risk disease, and highlight ongoing clinical trials that have the potential to provide new treatment options in this setting. [ABSTRACT FROM AUTHOR]

Objective: To understand the CD8+ tumour infiltrating lymphocyte (TIL) compartment of oesophageal adenocarcinoma (OAC) with regards to markers of lymphocyte exhaustion, tissue residency and to identify possible reasons behind differential responses to therapy. Design: Tumour samples from 44 patients undergoing curative resection for OAC were assessed by flow cytometry for presence of antigen-experienced TILs and markers of activation and exhaustion. Populations of PD-1 and CD39 positive OAC TILs were sorted, and bulk RNA sequencing undertaken using a modified SmartSeq2 protocol. Flow cytometric assessment of functionality was completed. Results: A higher proportion of antigen experienced CD8+ OAC TILs was associated with improved survival following surgery; while, high double positivity (DP) for PD-1 and CD39 among these TILs also correlated significantly with outcome. These DP TILs possess a minority population which is positive for the markers of exhaustion TIM3 and LAG3. Transcriptomic assessment of the PD-1 and CD39 DP TILs demonstrated enrichment for a tissue resident memory T lymphocyte (TRM) phenotype associated with improved survival in other cancers, reinforced by positivity for the canonical TRM marker CD103 by flow cytometry. This population demonstrated maintained functional capacity both in their transcriptomic profile, and on flow cytometric assessment, as well as preserved proliferative capacity. Conclusion: Resected OAC are variably infiltrated by PD-1 and CD39 DP TILs, an abundance of which among lymphocytes is associated with improved survival. This DP population has an increased, but still modest, frequency of TIM3 and LAG3 positivity compared to DN, and is in keeping with a functionally competent TRM phenotype. [ABSTRACT FROM AUTHOR]

Topological data analysis (TDA) is an active field of mathematics for quantifying shape in complex data. Standard methods in TDA such as persistent homology (PH) are typically focused on the analysis of data consisting of a single entity (e.g., cells or molecular species). However, state-of-the-art data collection techniques now generate exquisitely detailed multispecies data, prompting a need for methods that can examine and quantify the relations among them. Such heterogeneous data types arise in many contexts, ranging from biomedical imaging, geospatial analysis, to species ecology. Here, we propose two methods for encoding spatial relations among different data types that are based on Dowker complexes and Witness complexes. We apply the methods to synthetic multispecies data of a tumor microenvironment and analyze topological features that capture relations between different cell types, e.g., blood vessels, macrophages, tumor cells, and necrotic cells. We demonstrate that relational topological features can extract biological insight, including the dominant immune cell phenotype (an important predictor of patient prognosis) and the parameter regimes of a data-generating model. The methods provide a quantitative perspective on the relational analysis of multispecies spatial data, overcome the limits of traditional PH, and are readily computable. [ABSTRACT FROM AUTHOR]

Under the "One Health" concept, this paper aims to explore the occurrence of antimicrobial resistance in Enterobacterales (i.e., Escherichia coli and Salmonella enterica) among the South American Sea Lions on Argentina's northern Patagonian coast. From 177 fecal samples collected, conventional protocols were used to isolate E. coli and S. enterica. Antimicrobials classified as critically important by the WHO were evaluated by disk diffusion and agar spot (colistin) methods. Molecular tools were used to detect mcr genes as needed. A total of 176 antimicrobial-susceptible E. coli strains and 14 S. enterica strains were recovered. Twelve E. coli strains were colistin resistant (agar spot positive) but PCR negative for the mcr-1 to mcr-5 genes. Whole-genome sequencing revealed a chromosomal mutation, coding for Val161Gly change in PmrB protein, as the colistin resistance mechanism in one of these isolates. This study provides knowledge on AMR surveillance in wildlife associated with the marine environment in South America. [ABSTRACT FROM AUTHOR]

Background: Sarcomas are diverse neoplasms with highly variable histological appearances in which diagnosis is often challenging and management options for metastatic/unresectable disease limited. Many sarcomas have distinctive molecular alterations, but the range of alterations is large, variable in type and rapidly increasing, meaning that testing by limited panels is unable to capture the broad spectrum of clinically pertinent genomic drivers required. Paired whole genome sequencing (WGS) in contrast allows comprehensive assessment of small variants, copy number and structural variants along with mutational signature analysis and germline testing. Methods: Introduction of WGS as a diagnostic standard for all eligible patients with known or suspected soft tissue sarcoma over a 2-year period at a soft tissue sarcoma treatment centre. Results: WGS resulted in a refinement in the diagnosis in 37% of cases, identification of a target for personalised therapy in 33% of cases, and a germline alteration in 4% of cases. Conclusion: Introduction of WGS poses logistical and training challenges, but offers significant benefits to this group of patients. [ABSTRACT FROM AUTHOR]

The planned relocation of communities away from areas of climate-related risk has emerged as a critical strategy to adapt to the impacts of climate change. Empirical examples from around the world show, however, that such relocations often lead to poor outcomes for affected communities. To address this challenge, and contribute to developing guidelines for just and sustainable relocation processes, this paper calls attention to three fundamental tensions in planned relocation processes: (1) conceptualizations of risk and habitability; (2) community consultation and ownership; and (3) siloed policy frameworks and funding mechanisms. Drawing on the collective experience of 29 researchers, policymakers and practitioners from around the world working on planned relocations in the context of a changing climate, we provide strategies for collectively and collaboratively acknowledging and navigating these tensions among actors at all levels, to foster more equitable and sustainable relocation processes and outcomes. [ABSTRACT FROM AUTHOR]

Purpose: Metabolic health phenotypes exist across the body mass index spectrum. Diet may be an important modifiable risk factor, yet limited research exists on dietary patterns in this context. We investigated associations between dietary patterns, reflecting dietary quality, healthfulness and inflammatory potential, and metabolic health phenotypes in adults living with and without obesity. Methods: This cross-sectional study included 2,040 middle- to older-aged men and women randomly selected from a large primary care centre. The Dietary Approaches to Stop Hypertension score, Healthy Eating Index, Dietary Inflammatory Index, overall, healthful and unhealthful plant-based dietary indices and Nutri-Score were derived from validated food frequency questionnaires. Descriptive and logistic regression analyses were used to examine diet score relationships with metabolic health phenotypes (Metabolically Healthy/Unhealthy Obese (MHO/MUO) and Non-Obese (MHNO/MUNO)), defined using three separate metabolic health definitions, each capturing different aspects of metabolic health. Results: In fully adjusted models, higher unhealthful plant-based dietary scores were associated with a lower likelihood of MHO (OR = 0.96, 95% CI: 0.93–1.00, p = 0.038) and MHNO (OR = 0.97, 95% CI: 0.95–0.99, p = 0.006). Higher Nutri-Score values were associated with an increased likelihood of MHNO (OR = 1.06, 95% CI: 1.01–1.13, p = 0.033). Conclusion: These findings provide evidence that more unhealthful plant-based diets may be linked with unfavourable metabolic health status, irrespective of BMI. [ABSTRACT FROM AUTHOR]

Obesity is associated with an increased risk of incident heart failure with preserved ejection fraction (HFpEF) and, among patients with existing heart failure, is associated with worse quality of life, higher symptom burden, and more HF hospitalizations. Anti-obesity medication (AOM) semaglutide has been shown to be efficacious at both causing intentional weight loss and improving HF symptom burden, with some evidence to suggest that HF clinical events may also be reduced. Additional ongoing trials of AOM in patients with cardiovascular disease, including HFpEF, will further improve insight into the potential role of managing obesity to improve HF status among patients with HFpEF and obesity. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) is caused by an external mechanical force to the head, resulting in abnormal brain functioning and clinical manifestations. Antisecretory factor (AF16) is a potential therapeutic agent for TBI treatment due to its ability to inhibit fluid secretion and decrease inflammation, intracranial pressure, and interstitial fluid build-up, key hallmarks presented in TBI. Here, we investigated the effect of AF16 in an in vitro model of neuronal injury, as well as its impact on key components of the autophagy pathway and mitochondrial dynamics. N2Awt cells were treated with AF16, injured using a scratch assay, and analysed using confocal microscopy, correlative light and electron microscopy (CLEM), flow cytometry, and western blotting. Our results reveal that AF16 enhances autophagy activity, regulates mitochondrial dynamics, and provides protection as early as 6 h post-injury. Fluorescently labelled AF16 was observed to localise to lysosomes and the autophagy compartment, suggesting a role for autophagy and mitochondrial quality control in conferring AF16-associated neuronal protection. This study concludes that AF16 has potential as a therapeutic agent for TBI treatment through is regulation of autophagy and mitochondrial dynamics. [ABSTRACT FROM AUTHOR]

It is well known that elliptic estimates fail for the ∂ ¯ -Neumann problem. Instead, the best that one can hope for is that derivatives in every direction but one can be estimated by the associated Dirichlet form, and when this happens, we say that the ∂ ¯ -Neumann problem satisfies maximal estimates. In the pseudoconvex case, a necessary and sufficient geometric condition for maximal estimates has been derived by Derridj (for (0, 1)-forms) and Ben Moussa (for (0, q)-forms when q ≥ 1 ). In this paper, we explore necessary conditions and sufficient conditions for maximal estimates in the non-pseudoconvex case. We also discuss when the necessary conditions and sufficient conditions agree and provide examples. Our results subsume the earlier known results from the pseudoconvex case. [ABSTRACT FROM AUTHOR]

Background: Cancer rehabilitation navigation (CRNav) is a care delivery model that expedites identification and management of symptom-related functional morbidity for individuals undergoing cancer treatment. A CRNav program is unique in that it embeds a cancer rehabilitation professional in the cancer center for patient screening and assessment. The implementation of CRNav programs has not been studied and doing so could facilitate greater uptake of these programs. Methods: Using implementation science frameworks, we conducted a qualitative, post-implementation analysis of a CRNav program that was implemented in 2019. Semi-structured, 1:1 interviews were guided by the Consolidated Framework for Implementation Research (CFIR) and a combination of deductive and inductive analyses, using a priori established codes, was used to assess the implementation context, and identify emergent themes of barriers and facilitators to implementation. Participant described implementation strategies were characterized and defined using the Expert Consensus Recommendations for Implementing Change (ERIC) taxonomy. Results: Eleven stakeholders including physicians, administrators, clinical staff, and patients, involved with program development and the implementation effort, participated in interviews. Predominant barriers to implementation included developing the program infrastructure, and lack of awareness of rehabilitation services among oncology professionals, predominant facilitators of implementation included; physical co-location of the navigator in the cancer center, individual characteristics of the navigator, and unique characteristics of the program. Strategies described that supported implementation included developing stakeholder interrelationships, evaluating and iteratively adapting the program, creating infrastructure, training and education, and supporting clinicians. Conclusion: This analysis uses implementation science to methodically analyze and characterize factors that may contribute to successful implementation of a CRNav program. These findings could be used alongside a prospective context-specific analysis to tailor future implementation efforts. Implications for Cancer Survivors: Implementing a CRNav program expedites a patient's direct contact with a rehabilitation provider complementing the cancer care delivery team, and providing an additive and often missing service. [ABSTRACT FROM AUTHOR]

Spatial transcriptomics measures in situ gene expression at millions of locations within a tissue1, hitherto with some trade-off between transcriptome depth, spatial resolution and sample size2. Although integration of image-based segmentation has enabled impactful work in this context, it is limited by imaging quality and tissue heterogeneity. By contrast, recent array-based technologies offer the ability to measure the entire transcriptome at subcellular resolution across large samples3–6. Presently, there exist no approaches for cell type identification that directly leverage this information to annotate individual cells. Here we propose a multiscale approach to automatically classify cell types at this subcellular level, using both transcriptomic information and spatial context. We showcase this on both targeted and whole-transcriptome spatial platforms, improving cell classification and morphology for human kidney tissue and pinpointing individual sparsely distributed renal mouse immune cells without reliance on image data. By integrating these predictions into a topological pipeline based on multiparameter persistent homology7–9, we identify cell spatial relationships characteristic of a mouse model of lupus nephritis, which we validate experimentally by immunofluorescence. The proposed framework readily generalizes to new platforms, providing a comprehensive pipeline bridging different levels of biological organization from genes through to tissues.A method for topological automatic cell type classification across subcellular resolution spatial transcriptomic platforms is proposed, resolving cell type information and locating sparsely dispersed cells in human kidney and mouse kidney and brain. [ABSTRACT FROM AUTHOR]

Left ventricular outflow tract obstruction (LVOTO) remains a significant complication after primary repair of interrupted aortic arch with ventricular septal defect (IAA-VSD). Clinical and echocardiographic predictors for LVOTO reoperation are controversial and procedures to prophylactically prevent future LVOTO are not reliable. However, it is important to identify the patients at risk for future LVOTO intervention after repair of IAA-VSD. Patients who underwent single-stage IAA-VSD repair at our center 2006–2021 were retrospectively reviewed, excluding patients with associated cardiac lesions. Two-dimensional measurements, LVOT gradients, and 4-chamber (4C) and short-axis (SAXM) strain were obtained from preoperative and predischarge echocardiograms. Univariate risk analysis for LVOTO reoperation was performed using unpaired t-test. Thirty patients were included with 21 (70%) IAA subtype B and mean weight at surgery 3.0 kg. Repair included aortic arch patch augmentation in 20 patients and subaortic obstruction intervention in three patients. Seven (23%) required reoperations for LVOTO. Patient characteristics were similar between patients who required LVOT reoperation and those who did not. Patch augmentation was not associated with LVOTO reintervention. Patients requiring reintervention had significantly smaller LVOT AP diameter preoperatively and at discharge, and higher LVOT velocity, smaller AV annular diameter, and ascending aortic diameter at discharge. There was an association between LVOT-indexed cross-sectional area (CSAcm2/BSAm2) ≤ 0.7 and reintervention. There was no significant difference in 4C or SAXM strain in patients requiring reintervention. LVOTO reoperation was not associated with preoperative clinical or surgical variables but was associated with smaller LVOT on preoperative echo and smaller LVOT, smaller AV annular diameter, and increased LVOT velocity at discharge. [ABSTRACT FROM AUTHOR]

Purpose of Review: To review ongoing and planned clinical trials of weight loss among individuals with or at high risk of heart failure. Recent Findings: Intentional weight loss via semaglutide among persons with heart failure and preserved ejection fraction and obesity significantly improves weight loss and health status as assessed by the KCCQ-CSS score and is associated with improvements in 6-min walk test. Summary: Ongoing and planned trials will explore the role of intentional weight loss with treatments such as semaglutide or tirzepatide for individuals with heart failure across the entire ejection fraction spectrum. [ABSTRACT FROM AUTHOR]

Background: Smoking rates among people living with behavioral health conditions (BHC) range from 30 to 65% and are 2–4 times higher than rates found in the general population. Starting tobacco treatment during a hospital stay is effective for smoking cessation, but little is known regarding treatment response among inpatients with BHC. Objective: This study pooled data across multiple clinical trials to determine the relative success in quitting among participants with BHC compared to other study participants. Participants: Adults who smoke (≥ 18 years old) from five hospital-based smoking cessation randomized clinical trials. Design: A retrospective analysis using data from the electronic health record to identify participants with primary diagnoses related to BHC. Recruitment and data analysis were conducted from 2011 to 2016. We used propensity score matching to pair patients with BHC to those with similar characteristics and logistic regression to determine differences between groups. Measures: The main outcome was self-reported 30-day abstinence 6 months post-discharge. Results: Of 6612 participants, 798 patients had a BHC-related primary diagnosis. The matched sample included 642 pairs. Nearly 1 in 3 reported using tobacco medications after hospitalization, with no significant difference between patients with and without BHC (29.3% vs. 31.5%; OR (95% CI) = 0.90 (0.71, 1.14), p = 0.40). Nearly 1 in 5 patients with BHC reported abstinence at 6 months; however, their odds of abstinence were 30% lower than among people without BHC (OR (95% CI) = 0.70 (0.53,0.92), p = 0.01). Conclusion: When offered tobacco treatment, hospitalized patients with BHC were as likely as people without BHC to accept and engage in treatment. However, patients with BHC were less likely to report abstinence compared to those without BHC. Hospitals are a feasible and promising venue for tobacco treatment among inpatients with BHC. More studies are needed to identify treatment approaches that help people with BHC achieve long-term abstinence. [ABSTRACT FROM AUTHOR]

Introduction: Psoriatic arthritis (PsA) is a complex, progressive, and often debilitating disease. Despite recent advances in treatment, numerous unmet needs in patient care persist. Rheumacensus is a multistakeholder, pan-European initiative designed to identify ways to elevate the standard of care (SoC) and treatment ambition for patients with PsA, using the perspectives of three key stakeholder groups: patients, healthcare professionals (HCPs) and payors. Methods: Rheumacensus followed three phases: an insights-gathering workshop to identify current unmet needs in PsA and an area of focus for the project, a modified Delphi process to gain consensus on improvements within the agreed area of focus, and a Consensus Council (CC) meeting which used consensus statements as inspiration to generate 'Calls to Action' (CTA)—practical measures which, if implemented, could elevate the SoC for patients with PsA. Results: The Rheumacensus CC consisted of four patient representatives, four HCPs and four payors. All 12 members completed all three Delphi e-consultations. The shared area of focus that informed the Delphi process was "patient empowerment through education on the disease and treatment options available, to enable patient involvement in management". Four key themes emerged from the Delphi process: patient empowerment, patient knowledge and sources of education, patient–HCP consultations, and optimal initial treatment. Statements within these themes informed 12 overarching CTA, which focus on the need for a multistakeholder approach to implementing a paradigm shift towards patient-centred care and improved outcomes for patients with PsA. Conclusion: Rheumacensus has identified shortcomings in the current SoC for patients with PsA and provides a foundation for change through practical CTA. It is hoped that all stakeholders will now take practical steps towards implementing these CTA across Europe to elevate the SoC for patients with PsA. Plain Language Summary: Inequalities in the care patients with psoriatic arthritis (PsA) receive can be mainly explained by poorly coordinated management due to a lack of disease and treatment knowledge. This report is about a programme called Rheumacensus which has the overall aim of improving the standard of care (SoC) for patients with PsA. Rheumacensus brings together the points of view of three key groups involved in the care of people with PsA: patients, payors and healthcare professionals (HCPs) from across Europe. Together, these three groups agreed to focus on patient empowerment through education on the disease and treatment options as a way to raise the SoC. Through a series of exercises—to agree on the current SoC and what needs to be improved—and group discussions, four themes were established which were used by the groups to help them suggest 'Calls to action' (CTA). The CTAs were ideas of how improvements could be made or what needs to be done to improve the care patients receive. The four themes were (1) patient empowerment, (2) patient knowledge, (3) patient–HCP consultation and (4) optimal initial treatment. In total, 12 CTAs were developed across these themes that provide direction and practical next steps which patients, payors and HCPs could take to drive change and make a real difference to patients by improving their care. [ABSTRACT FROM AUTHOR]

Introduction: Several barriers to optimal care in axial spondyloarthritis (axSpA) exist, which is detrimental to patient outcomes. The Rheumacensus programme aimed to identify how the standard of care (SoC) and treatment ambition for patients with axSpA could be elevated, from the unique perspective of three key stakeholders from across Europe: patients, healthcare professionals (HCPs) and payors. Methods: Rheumacensus followed three phases: an insights-gathering workshop to identify current unmet needs in axSpA and an area of focus, a modified Delphi process to gain consensus on improvements within the agreed area of focus, and a Consensus Council (CC) meeting to generate 'Calls to Action' (CTA) to highlight the changes needed to elevate the SoC for patients with axSpA. Results: The Rheumacensus CC consisted of four patient representatives, four HCPs and four payors. All 12 members completed all three Delphi e-consultations. The shared area of focus that informed the Delphi process was patient empowerment through education on the disease and treatment options available, to enable patient involvement in management and ultimately increase treatment adherence. Four key themes emerged from the Delphi process: patient empowerment, patient knowledge, patient–HCP consultations and optimal initial treatment. These themes informed 11 overarching CTA, which demonstrate the need for a multistakeholder approach to implement a paradigm shift towards patient-centred care to elevate health outcomes in patients with axSpA. Conclusion: Rheumacensus identified CTA to help bridge the disparities observed in axSpA care. It is now imperative for all stakeholders to take practical steps towards addressing these CTA to elevate the SoC and treatment ambition in patients with axSpA. Plain Language Summary: Axial spondyloarthritis (axSpA) is a long-term inflammatory disease involving the spine and other joints of the body as well as where tendons and ligaments attach to bone. AxSpA is associated with a significant burden to patients which can be worsened by delays in diagnosis and poor disease management. This report is about a programme called Rheumacensus which has the overall aim of improving the standard of care (SoC) for patients with axSpA. Rheumacensus brings together the points of view of three key groups involved in the care of people with axSpA: patients, payors and healthcare professionals (HCPs) from across Europe. Together, these three groups agreed to focus on patient empowerment through education on the disease and treatment options to effectively enhance treatment adherence, as a way to raise the SoC. Through a series of exercises—to agree on the current SoC and what needs to be improved—and group discussions, four themes were established which were used by the groups to help them suggest 'Calls to action' (CTA). The CTAs were ideas of how improvements could be made or what needs to be done to improve the care patients receive. The four themes were (1) patient empowerment, (2) patient knowledge, (3) patient–HCP consultation and (4) optimal initial treatment. In total, 11 CTAs were developed across these themes that provide direction and practical next steps which patients, payors and HCPs could take to drive change and make a real difference to patients by improving their care. [ABSTRACT FROM AUTHOR]

Purpose: To estimate the combined effect of gabapentinoid and opioid therapy compared to opioid monotherapy on the risk of developing opioid-induced respiratory depression among breast cancer survivors with neuropathic pain. Method: A nested case–control study of Medicare female breast cancer survivors with neuropathic pain receiving both opioids and gabapentinoids, opioid monotherapy, gabapentinoid monotherapy, and none of these drugs was conducted using SEER-Medicare between 2007 and 2015. Cases were survivors with respiratory depression and were matched with controls on the event date (± 1 year), age at diagnosis (± 5 years), and stage at diagnosis. Exposure to opioids and gabapentinoids was assessed 120 days before the event date. Conditional logistic regression was used to assess the impact of exposure among cases and controls. Results: A total of 657 cases and 11,471 controls were identified. After matching, 656 cases and 5612 controls were retained, and cases were more likely to be diagnosed with mental health disorders (24.4% vs 10.5%, p < 0.0001) than controls. In the primary adjusted analysis, combined opioids and gabapentin use were associated with an increased risk of respiratory depression compared to opioid monotherapy (Adj. OR: 1.513; 95% CI: 1.473–2.350). Additionally, under secondary analysis, combined opioids and gabapentin use were associated with an increased risk of respiratory depression compared to receiving neither of these classes. (Adj. OR: 1.595; 95% CI: 1.050–2.421). Conclusion: There is a need for dose titration strategies of gabapentinoids and caution when co-prescribing opioids and gabapentinoids in older cancer survivors. [ABSTRACT FROM AUTHOR]

Copyright of European Journal of Pediatrics is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Purpose: Bariatric surgery is associated with a greater venous thromboembolism (VTE) risk in the weeks following surgery, but the long-term risk of VTE is incompletely characterized. We evaluated bariatric surgery in relation to long-term VTE risk. Materials and Methods: This population-based retrospective matched cohort study within three United States–based integrated health care systems included adults with body mass index (BMI) ≥ 35 kg/m2 who underwent bariatric surgery between January 2005 and September 2015 (n = 30,171), matched to nonsurgical patients on site, age, sex, BMI, diabetes, insulin use, race/ethnicity, comorbidity score, and health care utilization (n = 218,961). Follow-up for incident VTE ended September 2015 (median 9.3, max 10.7 years). Results: Our population included 30,171 bariatric surgery patients and 218,961 controls; we identified 4068 VTE events. At 30 days post-index date, bariatric surgery was associated with a fivefold greater VTE risk (HRadj = 5.01; 95% CI = 4.14, 6.05) and a nearly fourfold greater PE risk (HRadj = 3.93; 95% CI = 2.87, 5.38) than no bariatric surgery. At 1 year post-index date, bariatric surgery was associated with a 48% lower VTE risk and a 70% lower PE risk (HRadj = 0.52; 95% CI = 0.41, 0.66 and HRadj = 0.30; 95% CI = 0.21, 0.44, respectively). At 5 years post-index date, lower VTE risks persisted, with bariatric surgery associated with a 41% lower VTE risk and a 55% lower PE risk (HRadj = 0.59; 95% CI = 0.48, 0.73 and HRadj = 0.45; 95% CI = 0.32, 0.64, respectively). Conclusion: Although in the short-term bariatric surgery is associated with a greater VTE risk, in the long-term, it is associated with a substantially lower risk. [ABSTRACT FROM AUTHOR]

The article discusses the results of the Semaglutide Treatment Effect in People with Obesity and Heart Failure with Preserved Ejection Fraction and Diabetes Mellitus (STEP HFpEF DM) trial, which tested the use of semaglutide in patients with heart failure with preserved ejection fraction (HFpEF) and obesity who also had type 2 diabetes. The trial found that patients randomized to semaglutide lost more weight and experienced significant improvements in functional status and exercise capacity compared to those randomized to placebo. The article highlights the high prevalence of obesity and type 2 diabetes among patients with HFpEF and the limited treatment options available. It also discusses the need for further research to understand the impact of semaglutide on clinical outcomes for patients with HFpEF and obesity. [Extracted from the article]

Abstract Drugs that mobilise the immune system against cancer are dramatically improving care for many people. Dying cancer cells play an active role in inducing anti‐tumour immunity but not every form of death can elicit an immune response. Moreover, resistance to apoptosis is a major problem in cancer treatment and disease control. While the term “immunogenic cell death” is not fully defined, activation of receptor‐interacting serine/threonine‐protein kinase 1 (RIPK1) can induce a type of death that mobilises the immune system against cancer. However, no clinical treatment protocols have yet been established that would harness the immunogenic potential of RIPK1. Here, we report the first pre‐clinical application of an in vivo treatment protocol for soft‐tissue sarcoma that directly engages RIPK1‐mediated immunogenic cell death. We find that RIPK1‐mediated cell death significantly improves local disease control, increases activation of CD8+ T cells as well as NK cells, and enhances the survival benefit of immune checkpoint blockade. Our findings warrant a clinical trial to assess the survival benefit of RIPK1‐induced cell death in patients with advanced disease at limb extremities.

Entanglement and its propagation are central to understanding many physical properties of quantum systems1–3. Notably, within closed quantum many-body systems, entanglement is believed to yield emergent thermodynamic behaviour4–7. However, a universal understanding remains challenging owing to the non-integrability and computational intractability of most large-scale quantum systems. Quantum hardware platforms provide a means to study the formation and scaling of entanglement in interacting many-body systems8–14. Here we use a controllable 4 × 4 array of superconducting qubits to emulate a 2D hard-core Bose–Hubbard (HCBH) lattice. We generate superposition states by simultaneously driving all lattice sites and extract correlation lengths and entanglement entropy across its many-body energy spectrum. We observe volume-law entanglement scaling for states at the centre of the spectrum and a crossover to the onset of area-law scaling near its edges.By emulating a 2D hard-core Bose–Hubbard lattice using a controllable 4 × 4 array of superconducting qubits, volume-law entanglement scaling as well as area-law scaling at different locations in the energy spectrum are observed. [ABSTRACT FROM AUTHOR]

Low T C AlMn transition-edge sensors (TESs) have been developed as sensitive thermometers for the Q-Array, which will use superconducting targets to measure the coherent elastic neutrino nucleus scattering spectrum in the RICOCHET experiment. The TESs are made of manganese-doped aluminum with a titanium and gold antioxidation layer. A prototype TES thermometer consists of two TESs in parallel, an input gold pad in metallic contact with the TESs and an output gold pad and gold thermal link meanders, which are each designed to control the flow of heat through the TESs. We have fabricated and measured low T C AlMn TES chips with or without thermal flow control structures. We present T C measurements of the TESs after the initial fabrication and further T C tuning by re-heating and summarize the thermal property studies of the prototype TES thermometer by measuring I-V curves and complex impedance. [ABSTRACT FROM AUTHOR]

Coherent elastic neutrino-nucleus scattering (CEνNS) offers a valuable approach in searching for physics beyond the standard model. The Ricochet experiment aims to perform a precision measurement of the CEνNS spectrum at the Institut Laue–Langevin nuclear reactor with cryogenic solid-state detectors. The experiment plans to employ an array of cryogenic thermal detectors, each with a mass of around 30 g and an energy threshold of below 100 eV. The array includes nine detectors read out by transition-edge sensors (TES). These TES-based detectors will also serve as demonstrators for future neutrino experiments with thousands of detectors. In this article, we present an update on the characterization and modeling of a prototype TES detector. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to evaluate the effectiveness of an Artificial Intelligence‐Large Language Model (AI‐LLM) at improving the readability of knee radiology reports. Methods: Reports of 100 knee X‐rays, 100 knee computed tomography (CT) scans and 100 knee magnetic resonance imaging (MRI) scans were retrieved. The following prompt command was inserted into the AI‐LLM: 'Explain this radiology report to a patient in layman's terms in the second person:[Report Text]'. The Flesch–Kincaid reading level (FKRL) score, Flesch reading ease (FRE) score and report length were calculated for the original radiology report and the AI‐LLM generated report. Any 'hallucination' or inaccurate text produced by the AI‐LLM‐generated report was documented. Results: Statistically significant improvements in mean FKRL scores in the AI‐LLM generated X‐ray report (12.7 ± 1.0–7.2 ± 0.6), CT report (13.4 ± 1.0–7.5 ± 0.5) and MRI report (13.5 ± 0.9–7.5 ± 0.6) were observed. Statistically significant improvements in mean FRE scores in the AI‐LLM generated X‐ray report (39.5 ± 7.5–76.8 ± 5.1), CT report (27.3 ± 5.9–73.1 ± 5.6) and MRI report (26.8 ± 6.4–73.4 ± 5.0) were observed. Superior FKRL scores and FRE scores were observed in the AI‐LLM‐generated X‐ray report compared to the AI‐LLM‐generated CT report and MRI report, p < 0.001. The hallucination rates in the AI‐LLM generated X‐ray report, CT report and MRI report were 2%, 5% and 5%, respectively. Conclusions: This study highlights the promising use of AI‐LLMs as an innovative, patient‐centred strategy to improve the readability of knee radiology reports. The clinical relevance of this study is that an AI‐LLM‐generated knee radiology report may enhance patients' understanding of their imaging reports, potentially reducing the responder burden placed on the ordering physicians. However, due to the 'hallucinations' produced by the AI‐LLM‐generated report, the ordering physician must always engage in a collaborative discussion with the patient regarding both reports and the corresponding images. Level of Evidence: Level IV. [ABSTRACT FROM AUTHOR]

Purpose: Suicide risk is higher among violence-involved individuals. Intimate Partner Violence hotline workers are a critical source of support and can potentially be suicide prevention champions. Our primary goal was to examine the effectiveness of disseminating a free, online IPV—Suicide Prevention curriculum, via a randomized control trial, to hotline workers in ten states with the highest suicide and IPV homicide rates. Method: We divided the country into five regions and, based on criterion, chose two states in each region to randomize into the two arms of the study. We examined training participation and engagement between the two approaches: (1) 'dissemination as usual' (control) using a National Domestic Violence Hotline email and a postcard to state/county IPV directors, versus (2) 'enhanced dissemination' (intervention) using a four-point touch method (postcard, phone call, email, and letter) to 'drive' participation. Results: Participation increased in the intervention arm as approaches became more personal (i.e., email and phone calls vs. letters). Results indicate that traditional dissemination strategies such as email announcements and invitations are not as effective as varied and multiple touchpoints for IPV hotline staff. Conclusion: Successful dissemination strategies to promote digital training should consider the value added by personalized connection. Future research is needed to understand how to offer effective and efficient web-based training to those providing IPV and child abuse services. [ABSTRACT FROM AUTHOR]

Background: Selective biomarkers may improve outcomes in patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) treated with immune checkpoint inhibitor therapy. We investigated three independent biomarkers for association with efficacy in the randomized, phase III KESTREL study (NCT02551159) of first-line durvalumab monotherapy or durvalumab plus tremelimumab versus the EXTREME regimen: programmed cell death ligand-1 (PD-L1) immunohistochemistry, blood tumor mutational burden (bTMB) via circulating tumor DNA, and neutrophil-to-lymphocyte ratio (NLR). Methods: Tumor or blood samples from patients enrolled in the KESTREL study were analyzed for PD-L1, bTMB, and NLR. Associations with overall survival (OS) or objective response rates (ORRs) were evaluated based on prespecified cut-offs for PD-L1 (tumor cell [TC] ≥ 50%/immune cell ≥ 25% or TC ≥ 25%), bTMB (≥ 16 mutations [mut] per megabase [Mb]), and NLR (≤ 7). Ad hoc analyses of exploratory cut-offs were performed. Results: Prespecified or exploratory cut-offs for PD-L1 did not enrich for ORR or OS for durvalumab monotherapy or durvalumab plus tremelimumab versus EXTREME. In the bTMB ≥ 16 mut/Mb subgroup, OS hazard ratios (95% confidence interval) for durvalumab monotherapy and durvalumab plus tremelimumab versus EXTREME were 0.90 (0.48–1.72) and 0.69 (0.39–1.25), respectively. Complete response rates were 8.6% with durvalumab plus tremelimumab and 4.3% with EXTREME (≥ 16 mut/Mb subgroup). No improvement in OS was observed for durvalumab monotherapy or durvalumab plus tremelimumab versus EXTREME at prespecified or exploratory NLR cut-offs. Conclusions: bTMB demonstrated potential utility for selecting patients with R/M HNSCC who benefited from durvalumab with or without tremelimumab versus EXTREME. Trial registration ClinicalTrials.gov identifier NCT02551159. [ABSTRACT FROM AUTHOR]

Telomere Biology Disorders (TBDs) are a group of rare diseases characterized by the presence of short and/or dysfunctional telomeres. They comprise a group of bone marrow failure syndromes, idiopathic pulmonary fibrosis, and liver disease, among other diseases. Genetic alterations (variants) in the genes responsible for telomere homeostasis have been linked to TBDs. Despite the number of variants already identified as pathogenic, an even more significant number must be better understood. The study of TBDs is challenging since identifying these variants is difficult due to their rareness, it is hard to predict their impact on the disease onset, and there are not enough samples to study. Most of our knowledge about pathogenic variants comes from assessing telomerase activity from patients and their relatives affected by a TBD. However, we still lack a cell-based model to identify new variants and to study the long-term impact of such variants on the genes involved in TBDs. Herein, we present a cell-based model using CRISPR base editing to mutagenize the endogenous alleles of 21 genes involved in telomere biology. We identified key residues in the genes encoding 17 different proteins impacting cell growth. We provide functional evidence for variants of uncertain significance in patients with TBDs. We also identified variants resistant to telomerase inhibition that, similar to cells expressing wild-type telomerase, exhibited increased tumorigenic potential using an in vitro tumour growth assay. We believe that such cell-based approaches will significantly advance our understanding of the biology of TBDs and may contribute to the development of new therapies for this group of diseases. [ABSTRACT FROM AUTHOR]

Arkansas has a high cancer burden, and a pressing need exists for more medical students to pursue oncology as a career. The Partnership in Cancer Research (PCAR) program provides a summer research experience at the University of Arkansas for Medical Sciences for 12 medical students who have completed their first year of medical training. A majority of participants spend time pursuing cancer research in basic science, clinical, or community-based research. Students report on their research progress in an interactive "Live from the Lab!" series and assemble a final poster presentation describing their findings. Other activities include participation in a moderated, cancer-patient support group online, lecture series on cancer topics, medical simulations, palliative care clinic visit, "Death Over Dinner" event, and an entrepreneurship competition. Students completed surveys over PCAR's first 2 years in operation to evaluate all aspects of the program. Surveys reveal that students enthusiastically embraced the program in its entirety. This was especially true of the medical simulations which received the highest evaluations. Most significantly, surveys revealed that the program increased cancer knowledge and participant confidence to perform cancer research. [ABSTRACT FROM AUTHOR]

The generation of ultra-low-noise microwave and mmWave in miniaturized, chip-based platforms can transform communication, radar and sensing systems1–3. Optical frequency division that leverages optical references and optical frequency combs has emerged as a powerful technique to generate microwaves with superior spectral purity than any other approaches4–7. Here we demonstrate a miniaturized optical frequency division system that can potentially transfer the approach to a complementary metal-oxide-semiconductor-compatible integrated photonic platform. Phase stability is provided by a large mode volume, planar-waveguide-based optical reference coil cavity8,9 and is divided down from optical to mmWave frequency by using soliton microcombs generated in a waveguide-coupled microresonator10–12. Besides achieving record-low phase noise for integrated photonic mmWave oscillators, these devices can be heterogeneously integrated with semiconductor lasers, amplifiers and photodiodes, holding the potential of large-volume, low-cost manufacturing for fundamental and mass-market applications13.A miniaturized optical frequency division system that could transfer the generation of microwaves, with superior spectral purity, to a complementary metal-oxide-semiconductor-compatible integrated photonic platform is demonstrated showing potential for large-volume, low-cost manufacturing for many applications. [ABSTRACT FROM AUTHOR]

The accumulation of α-synuclein (α-Syn) into Lewy bodies is a hallmark of synucleinopathies, a group of neurological disorders that include Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). Small oligomers as well as larger fibrils of α-Syn have been suggested to induce cell toxicity leading to a degenerative loss of neurones. A richer understanding of α-Syn aggregation in disease, however, requires the identification of the different α-Syn species and the characterisation of their biochemical properties. We here aimed at a more in-depth characterisation of the α-Syn transgenic mice, Line 62 (L62), and examined the deposition pattern and solubility of human and murine α-Syn in these mice using immunohistochemical and biochemical methods. Application of multiple antibodies confirmed mAb syn204 as the most discriminatory antibody for human α-Syn in L62. Syn204 revealed an intense and widespread immunohistochemical α-Syn labelling in parietal cortex and hippocampus, and to a lower level in basal forebrain and hindbrain regions. The labelled α-Syn represented somatic inclusions as well as processes and synaptic endings. Biochemical analysis revealed a Triton-resistant human α-Syn pool of large oligomers, a second pool of small oligomers that was not resistant to solubilization with urea/Triton. A third SDS-soluble pool of intermediate sized aggregates containing a mixture of both, human and mouse α-Syn was also present. These data suggest that several pools of α-Syn can exist in neurones, most likely in different cellular compartments. Information about these different pools is important for the development of novel disease modifying therapies aimed at α-Syn. [ABSTRACT FROM AUTHOR]

Purpose of Review: Obesity is associated with cardiovascular (CV) conditions, including but not limited to atherosclerotic disease, heart failure, and atrial fibrillation. Despite this, the impact of intentional weight loss on CV outcomes for persons with obesity and established CV conditions remains poorly studied. New and emerging pharmacologic therapies for weight loss primarily targeting the incretin/nutrient sensing axes induce substantial and sustained weight loss. The glucagon-like-peptide 1 receptor agonists (GLP-1 RA) liraglutide and semaglutide have US FDA approval for the treatment of obesity, and the application for an obesity indication for the dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) receptor agonist tirzepatide is presently under FDA review. Extensive phase II and IIIa randomized controlled trials are underway evaluating permutations of combined GLP-1 RA, GIP receptor agonist, GIP receptor antagonist, and glucagon receptor agonists. Clinical outcome trials of these therapies in persons with obesity at high risk of established CV conditions should make it possible to estimate the role of intentional weight loss in managing CV risk via these medications. Recent Findings: High-dose once weekly injectable semaglutide (2.4 mg/week) use among persons with obesity and heart failure with preserved ejection fraction was effective at both reducing weight and improving health status; exercise capacity was also improved. Ongoing CV outcome trials of oral semaglutide and once weekly injectable tirzepatide will help to establish the role of these therapies among persons with other CV conditions. In addition to these two therapies targeting a CV claim or indication, many other new therapeutics for weight loss, as reviewed, are currently in development. Summary: The impact of pharmacologic-induced weight loss on CV conditions for persons with obesity and established CV conditions is currently under investigation for multiple agents. These therapies may offer new avenues to manage CV risk in persons with obesity and with established or at high risk for CV disease. [ABSTRACT FROM AUTHOR]

Purpose: Awareness of head and neck mucosal melanoma (HNMM) is important, as incorrect work-up can impact on the investigation and management of this rare and aggressive cancer. Following on from the 2020 HNMM UK guidelines, we set out the imaging recommendations and their rationale. To illustrate the key imaging characteristics, we also include a case series from our centre. Methods: All HNMM cases managed at our institution from January 2016 to January 2021 were identified, and the available imaging for each patient was reviewed. For each patient, the age, gender and location of primary tumour was recorded together with key staging and diagnostic imaging parameters. Results: A total of 14 patients were identified. The median age was 65 years with a female to male ratio of 1.33:1. Primary tumours were sinonasal in location in 93% of cases, with 7% of patients having metastatic neck nodes at presentation and 21% of cases having distant metastatic disease at presentation. Conclusion: This data set is in general concordance with other published series regarding the sinonasal origin of the vast majority of HNMM tumours along with the proportion of patients with metastatic neck nodes and distant metastases at presentation. We recommend dual-modality imaging with computed tomography (CT) and magnetic resonance imaging (MRI) of primary tumours whenever possible. In the systematic staging of HNMM, positron emission tomography (PET)-CT should be strongly considered, together with MRI of the brain. Pre-biopsy imaging of HNMM tumours is advisable whenever possible. [ABSTRACT FROM AUTHOR]

Background: Radiation-induced angiosarcoma (RIA) is an uncommon but morbid complication after radiotherapy for breast cancer. Methods: Retrospective analysis of breast RIA patients at Cambridge University Hospital (CUH), a regional treatment centre in the East of England. Results: 22 patients were identified between 2010 and 2022. Median age of diagnosis was 65 years (range 41–78). Median time from breast radiotherapy to RIA diagnosis was 6.5 years (range 2.4–16.0)—this interval has decreased over the last 24 years (r2 = 0.6601). 9% had metastasis at presentation. All patients underwent surgery (55% at CUH, 45% at local hospitals). 27% received peri-operative pegylated liposomal doxorubicin in the first-line setting. 62% relapsed following their primary curative-intent treatments after a median of 28 months. Metastases occurred in 36%, the commonest sites being lung (100%) and lymph node (50%). 2-year and 5-year overall survival (OS) rates for all patients were 73% and 60%, respectively. No correlation between progression-free survival (PFS) and OS was found with tumour size, margin, peri-operative chemotherapy, and whether surgery was performed at CUH. Patients with multifocal disease on their breasts had shorter PFS following surgery compared to single-lesion disease (median 10 vs 65 months; HR = 4.359 [95% CI 1.342–14.16]; P = 0.0143). Patients aged > 72 years had a median OS of 45 months vs 102 months for those ≤ 72 years (HR = 7.129 [95% CI 1.646–30.88]; P = 0.0086). Conclusion: RIA has high rates of recurrence and mortality and appears to be occurring sooner after breast radiotherapy. Further studies on its pathogenesis and effective treatment are warranted. [ABSTRACT FROM AUTHOR]

Background: Mandibular angle fractures (MAF) have a recognized complexity of treatment and an increased risk of incurring complications. Methods: This retrospective study included 45 consecutive patients who were diagnosed with an isolated MAF and no other facial fractures. The average age was 27.3 (SD = 7.7). Results: A comparatively low rate of complications (11.1%) and a low rate of reoperation (1.8%) are reported, along with a significant role of smoking in complications (p = 0.022). A non-significant association was noted between complications, male gender and assault as an aetiological factor. Conclusions: Review of the data from this study confirms that complication rates for patients attending the National Maxillofacial Unit are similar to or better than that of international studies. An overview of the aetiology of fracture complications is included. [ABSTRACT FROM AUTHOR]

Purpose: Renal transplantation (RT) is not recommended above BMI 40 kg/m2 as post-operative risks (delayed graft function, wound complications) are increased. Bariatric surgery (BS) results in sustained long-term weight loss. However, renal failure (RF) patients are theoretically higher risk candidates. We aim to investigate the safety of BS in patients with RF and the effect of BS on access to renal transplantation. Methods: We reviewed data from 31 patients with RF referred for BS between 2013 and 2021. We compared the outcomes of patients with RF who underwent BS to those who were referred but did not undergo BS. Controls matched for age/BMI/comorbidity (MC) but without RF were used for comparison. Results: Of 31 patients referred, 19 proceeded with BS (68% female, median age 52 years, BMI 46.2 ± 4.9 kg/m2) and 12 did not (58% female, median age 58, mean BMI 41.5 ± 4.1). Excess body weight loss (EBWL) was 71.2% ± 20.2% at 2 years in RF patients versus 66.0% ± 28.0% in MC patients. In the operated group, 11/19 (58%) patients reached their treatment target (six transplanted, five placed on waiting list) versus 3/12 (25%) in unoperated patients (three transplanted). There was no difference in perioperative complications between RF and MC groups. Long-term, there were seven deaths amongst RF patients (two operated, five unoperated), none amongst the MC group. Conclusion: BS in patients with RF increased access to RT and was safe and effective. We therefore recommend consideration of BS in patients with obesity and RF in specialised units. [ABSTRACT FROM AUTHOR]

Ammonia (NH3) is emerging as a potential favoured fuel for longer range decarbonised heavy transport, particularly in the marine sector, predominantly due to highly favourable characteristics as an effective hydrogen carrier. This is despite generally unfavourable combustion and toxicity attributes, restricting end use to applications where robust health and safety protocols can always be upheld. In the currently reported work, a spark ignited thermodynamic single cylinder research engine equipped with gasoline direct injection was upgraded to include gaseous ammonia port injection fuelling, with the aim of understanding maximum viable ammonia substitution ratios across the speed-load operating map. The work was conducted at varied effective compression ratios under overall stoichiometric conditions, with the spark timing re-optimised for maximum brake torque at all stable logged sites. The experiments included industry standard measurements of combustion, performance, and engine-out emissions (including NH3 "slip"). With a geometric compression ratio of 11.2:1, it was found possible to run the engine on pure ammonia at low engine speeds (1000-1800 rpm) and loads of 12 bar net IMEP. When progressively dropping down below this load limit an increasing amount of gasoline co-firing was required to avoid engine misfire. When operating at 1800 rpm and 12 bar net IMEP, all emissions of carbon (CO2, CO, unburned hydrocarbons) and NOx decreased considerably when switching to higher NH3 substitution ratios, with NOx reduced by ~ 45% at 1800 rpm/12 bar when switching from pure gasoline to pure NH3 (associated with longer and cooler combustion). By further increasing the geometric compression ratio to 12.4 and reducing the intake camshaft duration for maximum effective compression ratio, it was possible to operate the engine on pure ammonia at much lower loads in a fully warmed up state (e.g., linear low load limit line from 1000 rpm/6 bar net IMEP to 1800 rpm/9 bar net IMEP). Under all conditions, the indicated thermal efficiency of the engine was either equivalent to or slightly higher than that obtained using gasoline-only due to the favourable anti-knock rating of NH3. Ongoing work is concerned with detailed breakdown of individual NOx species together with measuring the impact of hydrogen enrichment across the operating map. [ABSTRACT FROM AUTHOR]

Early identification of atrial fibrillation (AF) can reduce the risk of stroke, heart failure, and other serious cardiovascular outcomes. However, paroxysmal AF may not be detected even after a two-week continuous monitoring period. We developed a model to quantify the risk of near-term AF in a two-week period, based on AF-free ECG intervals of up to 24 h from 459,889 patch-based ambulatory single-lead ECG (modified lead II) recordings of up to 14 days. A deep learning model was used to integrate ECG morphology data with demographic and heart rhythm features toward AF prediction. Observing a 1-day AF-free ECG recording, the model with deep learning features produced the most accurate prediction of near-term AF with an area under the curve AUC = 0.80 (95% confidence interval, CI = 0.79–0.81), significantly improving discrimination compared to demographic metrics alone (AUC 0.67; CI = 0.66–0.68). Our model was able to predict incident AF over a two-week time frame with high discrimination, based on AF-free single-lead ECG recordings of various lengths. Application of the model may enable a digital strategy for improving diagnostic capture of AF by risk stratifying individuals with AF-negative ambulatory monitoring for prolonged or recurrent monitoring, potentially leading to more rapid initiation of treatment. [ABSTRACT FROM AUTHOR]

Purpose: There is increasing interest in the health benefits of plant-based diets (PBDs). Evidence reports favourable associations with inflammatory profiles and reduced cardiovascular disease risk. However, limited studies have examined relationships between PBD indices (PDIs) and inflammatory biomarkers. We explored overall PDI, healthful PDI (hPDI) and unhealthful PDI (uPDI) associations with inflammatory biomarker profiles. Methods: This cross-sectional analysis included 1986 middle- to older-aged adults from the Mitchelstown Cohort. PDI scores were calculated using validated food frequency questionnaires. PDI score associations with inflammatory biomarkers were assessed via linear regression analysis, with adjustment for potential confounders. Results: Comparison of quintiles (Q5 vs Q1) revealed lower concentrations of C-reactive protein (CRP), interleukin 6 (IL-6), white blood cells (WBCs), neutrophils and monocytes, and the leptin-to-adiponectin ratio (PDI and hPDI P < 0.05); lower leptin (PDI, P < 0.05), and complement component 3 (C3), tumour necrosis factor alpha (TNF-α), plasminogen activator inhibitor 1, lymphocytes and eosinophils (hPDI, P < 0.05); and higher concentrations of adiponectin (PDI and hPDI, P < 0.05). Conversely, higher concentrations of C3, CRP, IL-6, TNF-α, resistin, WBCs, neutrophils, lymphocytes, monocytes and eosinophils, and the neutrophil-to-lymphocyte ratio, and lower adiponectin concentrations were observed comparing uPDI quintiles (P < 0.05). In fully adjusted regression models, higher hPDI scores were associated with lower concentrations of C3, TNF-α, WBCs, neutrophils and monocytes (all P < 0.01). Higher uPDI scores were associated with higher C3 and TNF-α concentrations (all P < 0.01). Conclusion: This study provides evidence that a more healthful PBD is associated with a more favourable inflammatory profile and that a more unhealthful PBD is associated with the reverse. [ABSTRACT FROM AUTHOR]

Networked service organisations are increasingly adopting a 'smarter networking' philosophy in their design of more agile and customer-focused supply models. Changing consumer behaviours and the emergence of transformative technologies—industry 4.0, artificial intelligence, big data analytics, the Internet of Things—are driving a series of innovations, in terms of 'products' and business models, with major implications for the industrial enterprise, in their design of more 'digitalised' supply chains. For B2B systems, emerging 'product-service' offerings are requiring greater visibility, alignment and integration across an increasingly complex network of multiple partners and collaborators, in order to deliver a better service and customer 'experience'. To support the design and operation of these multi-organisational service networks, we outline a concept of operations architecture here, underpinned by the literature and network theory, and demonstrate application using a series of exemplar case studies. Focusing on relational elements and the processes key to network integration within service supply networks, the cases inform a set of operating principles and protocols—applicable to all stakeholders 'cooperating', within a 'shared' environment. Equally critical is to understand how digital technologies may influence future operating philosophies. This article extends our theoretical understanding of network organisations, from a traditional 'product' perspective to that of 'services', and presents the case for developing a common, unified approach to designing diverse forms of multi-partner service networks. [ABSTRACT FROM AUTHOR]

Wave separation analysis (WSA) reveals the impact of forward- and backward-running waves on the arterial pressure pulse, but the calculations require a flow waveform. This study investigated (1) the variability of the ascending aortic flow waveform in children and adolescents with/without a childhood heart disease history (CHD); (2) the accuracy of WSA obtained with a representative flow waveform (RepFlow), compared with the triangulation method and published ultrasound-derived adult representative flow; (3) the impact of limitations in Doppler ultrasound on WSA; and (4) generalizability of results to adults with a history of CHD. Phase contrast MRI was performed in youth without (n = 45, Group 1, 10–19 years) and with CHD (n = 79, Group 2, 7–18 years), and adults with CHD history (n = 29, Group 3, 19–59 years). Segmented aortic cross-sectional area was used as a surrogate for the central pressure waveform in WSA. A subject-specific virtual Doppler ultrasound was performed on MRI data by extracting velocities from a sample volume. Time/amplitude-normalized ascending aortic flow waveforms were highly consistent amongst all groups. WSA with RepFlow therefore yielded errors < 10% in all groups for reflected wave magnitude and return time. Absolute errors were typically 1.5–3 times greater with other methods, including subject-specific (best-case/virtual) Doppler ultrasound, for which velocity profile skewing introduced waveform errors. Our data suggest that RepFlow is the optimal approach for pressure-only WSA in children and adolescents with/without CHD, as well as adults with CHD history, and may even be more accurate than subject-specific Doppler ultrasound in the ascending aorta. [ABSTRACT FROM AUTHOR]