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Michal Mauda-Havakuk,1,2 Natalie M Hawken,1 Joshua W Owen,1 Andrew S Mikhail,1 Matthew F Starost,3 Baktiar Karim,4 Paul G Wakim,5 Olga L Franco-Mahecha,1 Andrew L Lewis,6 William F Pritchard,1 John W Karanian,1 Bradford J Wood7 1Center for Interventional Oncology, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, MD, USA; 2Interventional Radiology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel; 3Division of Veterinary Resources, National Institutes of Health, Bethesda, MD, USA; 4National Cancer Institute, National Institutes of Health, Frederick, MD, USA; 5Biostatistics and Clinical Epidemiology Service, National Institutes of Health Clinical Center, Bethesda, MD, USA; 6Alchemed Bioscience Consulting Ltd, Stable Cottage, Monkton Lane, Farnham, Surrey, UK; 7Center for Interventional Oncology, Radiology and Imaging Sciences, Clinical Center, National Institute of Biomedical Imaging and Bioengineering and National Cancer Institute Center for Cancer Research; National Institutes of Health, Bethesda, MD, USACorrespondence: Michal Mauda-Havakuk, Email michal.mh@gmail.comObjectives: Local and systemic immune responses evoked by locoregional therapies such as cryoablation are incompletely understood. The aim of this study was to characterize cryoablation-related immune response and the capacity of immune drugs to augment immunity upon cryoablation for the treatment of hepatocellular carcinoma (HCC) using a woodchuck hepatocellular carcinoma model.Materials and Methods: Twelve woodchucks chronically infected with woodchuck hepatitis virus and with hepatocellular carcinoma underwent imaging with contrast-enhanced CT. Partial cryoablation of tumors in three woodchucks was performed. Fourteen days after cryoablation, liver tissues were harvested and stained with H&E and TUNEL, and immune infiltrates were quantified. Peripheral blood mononuclear cells (PBMC) were collected from ablated and nonablated woodchucks, labeled with carboxyfluorescein succinimidyl ester (CFSE) and cultured with immune-modulating drugs, including a small PD-L1 antagonist molecule (BMS-202) and three TLR7/8 agonists (DSR 6434, GS-9620, gardiquimod). After incubation, cell replication and immune cell populations were analyzed by flow cytometry.Results: Local immune response in tumors was characterized by an increased number of CD3+ T lymphocytes and natural killer cells in the cryolesion margin compared to other tumor regions. T regulatory cells were found in higher numbers in distant tumors within the liver compared to untreated or control tumors. Cryoablation also augmented the systemic immune response as demonstrated by higher numbers of PBMC responses upon immune drug stimulation in the cryoablation group.Conclusions: Partial cryoablation augmented immune effects in both treated and remote untreated tumor microenvironments, as well as systemically, in woodchucks with HCC. Characterization of these mechanisms may enhance development of novel drug-device combinations for treatment of HCC.Plain Language Summary: The tumor microenvironment (TME) incorporates complex immune cell milieus. Tumor ablation can evoke an immune response in the tumor as well as systemically. Most reports, however, demonstrate modest immune activation.Better elucidation of the tumor microenvironment immune response to ablation was needed in order to promote an effective anti-tumoral response.In this study, the TME post ablation was analyzed in a multicompartmental fashion to better understand local immune response.In ablation margins, an abundance of anti-tumoral immune cells could be found. Distant tumors in ablated animals however had an increased number of regulatory immune cells.More effective response of peripheral blood mononuclear cells to stimulation of immune drugs was demonstrated post ablation.Strategies to augment more robust anti-tumoral immune responses might include targeting ablation margins with immune-stimulating agents and mitigating regulatory immune effects away from the ablation zone.Keywords: cryoablation, woodchuck, hepatocellular carcinoma, immune effect, tumor microenvironment, hepatitis B virus

Michal Mauda-Havakuk,1 Andrew S Mikhail,1 Matthew F Starost,2 Elizabeth C Jones,3 Baktiar Karim,4 David E Kleiner,5 Ari Partanen,1 Juan A Esparza-Trujillo,1 Ivane Bakhutashvili,1 Paul G Wakim,6 Michael T Kassin,1 Andrew L Lewis,7 John W Karanian,1 Bradford J Wood,8 William F Pritchard1 1Center for Interventional Oncology, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, MD, USA; 2Division of Veterinary Resources, National Institutes of Health, Bethesda, MD, USA; 3Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, MD, USA; 4National Cancer Institute, National Institutes of Health, Frederick, MD, USA; 5Center for Cancer Research, Clinical Center, National Cancer Institute, Bethesda, MD, USA; 6Biostatistics and Clinical Epidemiology Service, National Institutes of Health Clinical Center, Bethesda, MD, USA; 7Biocompatibles UK Ltd (a BTG International Group Company), Camberley, UK; 8Center for Interventional Oncology, Radiology and Imaging Sciences, Clinical Center, National Institute of Biomedical Imaging and Bioengineering and National Cancer Institute Center for Cancer Research, National Institutes of Health, Bethesda, MD, USACorrespondence: William F PritchardCenter for Interventional Oncology, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, 10 Center Drive, Room 3N320B, MSC 1182, Bethesda, MD, 20892, USATel +1 240-760-0153Fax +1 301-496-9933Email william.pritchard@nih.govBackground: Woodchucks chronically infected with woodchuck hepatitis virus (WHV), which resembles human hepatitis B virus, develop spontaneous hepatic tumors and may be an important biological and immunological model for human HCC. Nonetheless, this model requires further validation to fully realize its translational potential.Methods: Woodchucks infected at birth with WHV that had developed HCC (n=12) were studied. Computed tomography, ultrasound, and magnetic resonance imaging were performed under anesthesia. LI-RADS scoring and correlative histologic analysis of sectioned tissues were performed. For immune characterization of tumors, CD3 (T cells), CD4 (T helpers), NCAM (Natural killers), FOXP3 (T-regulatory), PDL-1 (inhibitory checkpoint protein), and the human hepatocellular carcinoma (HCC) biomarker alpha-fetoprotein (AFP) immunohistochemical stains were performed.Results: Forty tumors were identified on imaging of which 29 were confirmed to be HCC with 26 categorized as LR-4 or 5. The remainder of the tumors had benign histology including basophilic foci, adenoma, and lipidosis as well as pre-malignant dysplastic foci. LR-4 and LR-5 lesions showed high sensitivity (90%) and specificity (100%) for malignant and pre-malignant tumors. Natural killers count was found to be 2– 5 times lower in tumors relative to normal parenchyma while other immune cells were located in the periphery of tumors. Tumors expressed AFP and did not express PD-L1.Conclusion: Woodchucks chronically infected with WHV developed diverse hepatic tumor types with diagnostic imaging, pathology, and immune patterns comparable to that in humans. This unique animal model may provide a valuable tool for translation and validation of novel image-guided and immune-therapeutic investigations.Keywords: carcinoma, hepatocellular, radiology, interventional oncology, immunotherapy, models, animal, tumor microenvironment

Wild birds play a major role in the evolution, maintenance, and spread of avian influenza viruses. However, surveillance for these viruses in wild birds is sporadic, geographically biased, and often limited to the last outbreak virus. To identify opportunities to optimize wild bird surveillance for understanding viral diversity, we reviewed responses to a World Organisation for Animal Health–administered survey, government reports to this organization, articles on Web of Knowledge, and the Influenza Research Database. At least 119 countries conducted avian influenza virus surveillance in wild birds during 2008–2013, but coordination and standardization was lacking among surveillance efforts, and most focused on limited subsets of influenza viruses. Given high financial and public health burdens of recent avian influenza outbreaks, we call for sustained, cost-effective investments in locations with high avian influenza diversity in wild birds and efforts to promote standardized sampling, testing, and reporting methods, including full-genome sequencing and sharing of isolates with the scientific community.

Wild birds play a major role in the evolution, maintenance, and spread of avian influenza viruses. However, surveillance for these viruses in wild birds is sporadic, geographically biased, and often limited to the last outbreak virus. To identify opportunities to optimize wild bird surveillance for understanding viral diversity, we reviewed responses to a World Organisation for Animal Health-administered survey, government reports to this organization, articles on Web of Knowledge, and the Influenza Research Database. At least 119 countries conducted avian influenza virus surveillance in wild birds during 2008-2013, but coordination and standardization was lacking among surveillance efforts, and most focused on limited subsets of influenza viruses. Given high financial and public health burdens of recent avian influenza outbreaks, we call for sustained, cost-effective investments in locations with high avian influenza diversity in wild birds and efforts to promote standardized sampling, testing, and reporting methods, including full-genome sequencing and sharing of isolates with the scientific community.

Abstract The last decade has seen significant improvements in our understanding of skyrmions current induced dynamics, along with their room temperature stabilization, however, the impact of local material inhomogeneities still remains an issue that impedes reaching the regime of steady state motion of these spin textures. Here, we study the spin-torque driven motion of skyrmions in synthetic ferrimagnetic multilayers with the aim of achieving high mobility and reduced skyrmion Hall effect. We consider Pt|Co|Tb multilayers of various thicknesses with antiferromagnetic coupling between the Co and Tb magnetization. The increase of Tb thickness in the multilayers reduces the total magnetic moment and increases the spin-orbit torques allowing to reach velocities up to 400 ms−1 for skyrmions with diameters of about 160 nm. We demonstrate that due to reduced skyrmion Hall effect combined with the edge repulsion of the magnetic track, the skyrmions move along the track without any transverse deflection. Further, by comparing the field-induced domain wall motion and current-induced skyrmion motion, we demonstrate that the skyrmions at the largest current densities present all the characteristics of a dynamical flow regime.

Abstract A novel series of 2-cyano-3-(pyrazol-4-yl)-N-(thiazol-2-yl)acrylamide derivatives (3a–f) were synthesized using Knoevenagel condensation and characterized using various spectral tools. The weak nuclease activity of compounds (3a–f) against pBR322 plasmid DNA was greatly enhanced by irradiation at 365 nm. Compounds 3b and 3c, incorporating thienyl and pyridyl moieties, respectively, exhibited the utmost nuclease activity in degrading pBR322 plasmid DNA through singlet oxygen and superoxide free radicals’ species. Furthermore, compounds 3b and 3c affinities towards calf thymus DNA (CT-DNA) and bovine serum albumin (BSA) were investigated using UV–Vis and fluorescence spectroscopic analysis. They revealed good binding characteristics towards CT-DNA with Kb values of 6.68 × 104 M−1 and 1.19 × 104 M−1 for 3b and 3c, respectively. In addition, compounds 3b and 3c ability to release free radicals on radiation were targeted to be used as cytotoxic compounds in vitro for colon (HCT116) and breast cancer (MDA-MB-231) cells. A significant reduction in the cell viability on illumination at 365 nm was observed, with IC50 values of 23 and 25 µM against HCT116 cells, and 30 and 9 µM against MDA-MB-231 cells for compounds 3b and 3c, respectively. In conclusion, compounds 3b and 3c exhibited remarkable DNA cleavage and cytotoxic activity on illumination at 365 nm which might be associated with free radicals’ production in addition to having a good affinity for interacting with CT-DNA and BSA. Graphical Abstract

This experimental study focuses on exploiting laser Doppler velocimetry (LDV), a non-intrusive technique, for rheological characterization based on analyzing flows of Carbopol solutions at two distinct concentrations and two different temperatures within a pipe. The velocity profiles obtained using LDV and the pressure drops associated with each flow rate were exploited to establish the behavioral law of aqueous Carbopol solutions. Two approaches were used: the first was an analytical velocity model to fit the experimental profile, and the second used the first derivative of the experimental velocity profile and the pressure drops to reconstruct the flow curve. In addition, a third reference characterization was carried out using a rotary rheometer equipped with a vane geometry. This study’s three rheological characterization methods showed excellent agreement concerning the Herschel–Bulkley model. Finally, all the laws resulting from these three methods were validated using an empirical law relating to Darcy’s coefficient of friction.

Abstract Background Mining the vast pool of biomedical literature to extract accurate responses and relevant references is challenging due to the domain's interdisciplinary nature, specialized jargon, and continuous evolution. Early natural language processing (NLP) approaches often led to incorrect answers as they failed to comprehend the nuances of natural language. However, transformer models have significantly advanced the field by enabling the creation of large language models (LLMs), enhancing question-answering (QA) tasks. Despite these advances, current LLM-based solutions for specialized domains like biology and biomedicine still struggle to generate up-to-date responses while avoiding “hallucination” or generating plausible but factually incorrect responses. Results Our work focuses on enhancing prompts using a retrieval-augmented architecture to guide LLMs in generating meaningful responses for biomedical QA tasks. We evaluated two approaches: one relying on text embedding and vector similarity in a high-dimensional space, and our proposed method, which uses explicit signals in user queries to extract meaningful contexts. For robust evaluation, we tested these methods on 50 specific and challenging questions from diverse biomedical topics, comparing their performance against a baseline model, BM25. Retrieval performance of our method was significantly better than others, achieving a median Precision@10 of 0.95, which indicates the fraction of the top 10 retrieved chunks that are relevant. We used GPT-4, OpenAI's most advanced LLM to maximize the answer quality and manually accessed LLM-generated responses. Our method achieved a median answer quality score of 2.5, surpassing both the baseline model and the text embedding-based approach. We developed a QA bot, WeiseEule ( https://github.com/wasimaftab/WeiseEule-LocalHost ), which utilizes these methods for comparative analysis and also offers advanced features for review writing and identifying relevant articles for citation. Conclusions Our findings highlight the importance of prompt enhancement methods that utilize explicit signals in user queries over traditional text embedding-based approaches to improve LLM-generated responses for specialized queries in specialized domains such as biology and biomedicine. By providing users complete control over the information fed into the LLM, our approach addresses some of the major drawbacks of existing web-based chatbots and LLM-based QA systems, including hallucinations and the generation of irrelevant or outdated responses.

Abstract Background Trauma induced coagulopathy remains to be an important cause of high transfusion requirements and mortality and shock induced endotheliopathy (SHINE) has been implicated. Methods European multicenter observational study of adult trauma patients with injury severity score ≥ 16 arriving within 2 h from injury to the trauma centers. Admission blood samples obtained were used for analysis of the SHINE biomarkers (syndecan-1, soluble thrombomodulin, adrenaline) and extensive analysis of coagulation, -and fibrinolytic factors together with collection of clinical data. Hierarchical clustering of the SHINE biomarkers was used to identify the SHINE phenotypes. Results The 313 patients clustered into four SHINE phenotypes. Phenotype 2, having the highest glycocalyx shedding, encompassing 22% of the whole cohort, had severe coagulopathy with lower levels of prothrombin, FV, IX, X, XI and severe hyperfibrinolysis with higher plasmin – alpha 2-antiplasmin (PAP) – and tPA levels and lower alpha2 – antiplasmin levels. This phenotype had significantly higher transfusion requirements and higher mortality (39% vs. 23%, 15% and 14%) but similar injury severity score (ISS) compared to the others phenotypes. Conclusions Hierarchical clustering identified four SHINE phenotype in a cohort of trauma patients. Trauma induced coagulopathy was confined to only one of the SHINE phenotypes, encompassing 22% of the total cohort. This phenotype was characterized by severe hypocoagulability and hyperfibrinolysis, which translated to significantly higher transfusion requirements and higher mortality compared to the other SHINE phenotypes with similar injury severity, warranting further investigation.

Abstract We present a set of example models in which the Standard Model (SM) symmetry group is extended by a new abelian symmetry. This additional symmetry appears anomalous in the effective low-energy theory; however, the anomalies cancel out when massive chiral fermions not present in the effective low-energy theory are taken into account. These chiral fermions under the new abelian gauge group, are chosen to be vector-like under the SM symmetries, and reside in the same representations as quarks and leptons. This allows us to quantitatively determine the magnitude of tree-level interactions between three vector bosons induced in low-energy effective field theory by the integration of chiral heavy fermions. We also examine the perturbativity constraints of the theory and the ultraviolet cut-off. We conclude by highlighting possible extensions of our work.

Abstract Significant progress has been made in the field of plant genomics, as demonstrated by the increased use of high-throughput methodologies that enable the characterization of multiple genome-wide molecular phenotypes. These findings have provided valuable insights into plant traits and their underlying genetic mechanisms, particularly in model plant species. Nonetheless, effectively leveraging them to make accurate predictions represents a critical step in crop genomic improvement. We present AgroNT, a foundational large language model trained on genomes from 48 plant species with a predominant focus on crop species. We show that AgroNT can obtain state-of-the-art predictions for regulatory annotations, promoter/terminator strength, tissue-specific gene expression, and prioritize functional variants. We conduct a large-scale in silico saturation mutagenesis analysis on cassava to evaluate the regulatory impact of over 10 million mutations and provide their predicted effects as a resource for variant characterization. Finally, we propose the use of the diverse datasets compiled here as the Plants Genomic Benchmark (PGB), providing a comprehensive benchmark for deep learning-based methods in plant genomic research. The pre-trained AgroNT model is publicly available on HuggingFace at https://huggingface.co/InstaDeepAI/agro-nucleotide-transformer-1b for future research purposes.

Abstract Aims Predicting mortality in severe AL cardiac amyloidosis is challenging due to elevated biomarker levels and limited thresholds for stratifying severe cardiac damage. Methods and results This prospective, observational, cohort study included de novo, confirmed cardiac AL amyloidosis patients at the Henri Mondor National Reference Centre. The goal was to identify predictors of mortality to enhance prognostic stratification and improve informed decision‐making regarding therapy. Over the 12‐year study period, among the 233 patients included, 133 were NYHA III‐IV and 179 Mayo 2004 III. The independent predictors for mortality identified were hsTnT, NT‐proBNP, cardiac output, and conjugated bilirubin. A novel prognostic, conditional stratification, Mondor amyloidosis cardiac staging (MACS) was developed with biomarker cut‐off values for Stage 1: hsTnT ≤ 107 ng/L and NT‐proBNP ≤ 3867 ng/L (n = 77; 33%); for stage 2 NT‐proBNP > 3867 ng/L (n = 72; 30%). For stage 3, if troponin >107 ng/L, regardless of NT‐proBNP then CB 4 μmol/L, was added (n = 41; 17.5%) and stage 4: CB > 4 μmol/L (n = 43; 18.5%). The median overall survival was 8 months 95% CI [2–24]. At 1 year, 102 (44%) patients died and the Kaplan–Meier median survival with MACS Stage 1 was not reached, while stage 2 was 15.2 months (95% CI [11–18]) and stage 3, 6.6 months (95% CI [1–13]). Notably, among European stage II patients, 17.1%, n = 8 were MACS stage 3 and European stage IIIb 21.4% (n = 23) were MACS stage 4. Importantly, among European stage IIIb patients 42.2% (n = 29) were classified MACS stage 4 and 12.5% n = 9 were only MACS stage 2. Conclusions The Mondor prognostic staging system, including conjugate bilirubin may significantly improve prognostic stratification for patients with severe cardiac amyloidosis.

Not available.

Elbow joint rehabilitation presents a formidable challenge, underscored by the joint’s complex biomechanics and high vulnerability to injuries and degenerative conditions. Despite the advancements in rehabilitative technology, current solutions such as rigid exoskeletons often fall short in providing the precision, flexibility, and customization needed for effective treatment. Although traditional robotic aids, such as rigid exoskeletons, help recover, they lack in providing sufficient flexibility, comfort, and easy customization with no need for complicated calculation and complex design considerations. The introduction of soft pneumatic muscles marks a significant development in the rehabilitation technologies field, offering distinct advantages and unique challenges when compared to conventional rigid systems. These flexible actuators closely mimic the elasticity of biological tissues, improving safety and interaction between humans and machines. Designed for individualized therapy, its versatility allows application in various rehabilitation scenarios, from clinical settings to home settings. The novelty of this approach lies in the development of biomechanically-compliant soft pneumatic muscles optimized for precise rotational control of the elbow joint, coupled with an advanced deep learning-based motion tracking system. This design overcomes limitations in force control, stability, and pressure requirements found in existing pneumatic-based systems, improving the safety and efficacy of elbow rehabilitation. In this study, the design, fabrication and systematic evaluation of a soft pneumatic muscle for elbow rehabilitation are presented. The device is designed to closely simulate the complex biomechanical movements of the elbow, with a primary focus on the rotational motions that are essential for controlling flexion and extension, as well as positioning the wrist during grasping tasks. Through the integration of precise geometric parameters, the actuator is capable of controlled flexion and extension, reflecting the natural kinematics of the elbow. Employing a rigorous methodology, the research integrates finite element analysis with empirical testing to refine the actuator’s performance. Under varying air pressures, the soft muscle demonstrated remarkable deformation along the X-axis (10–150 mm) and the Y-axis, indicative of its symmetrical rotational behavior, while maintaining minimal elongation along the Z-axis (0.003 mm max), and proper lifiting force under a maximum wight of 470 gm. highlighting the stability and targeted response of the device to pneumatic actuation. A specialized experimental apparatus comprising a 3D environment, a pneumatic circuit, a LabVIEW-based control system, and a deep learning algorithm was developed for accurate position estimation. The algorithm achieved a high predictive accuracy of 99.8% in spatial coordination tracking, indicating the precision of the system in monitoring and controlling the actuator’s motion.

Abstract Piezoceramics have been the common choice for sensing applications, however their integration with other electronics is limited due to their large size. Also, environmental concerns have been limiting the use of ceramics due to their lead content, toxic for humans. Piezoelectric crystalline thin films have arisen as alternative materials offering compatibility with miniaturization and integrated processes, though their piezoelectric properties are low (d33 < 15 pC N−1) compared to ceramics (d33 > 300 pC N−1), hindering their applicability. Several methods have been studied aiming to improve the piezoelectric output of thin films, including doping or the less investigated inclusion of porosity. However, they all require complex techniques that increase the cost. In this work, a giant electromechanical d33 coefficient of 115.6 pC N−1 has been obtained inducing porosity in inclined ZnO thin films via oblique angle deposition, which is beyond record values reported for doped ZnO thin films and an order of magnitude higher than standard ZnO thin films (11.6 pC N−1). Morphology, composition, crystal structure, porosity, and piezoelectricity are reported for standard and inclined films. Finite element simulations have been carried out to investigate the performance of the piezoelectric‐enhanced thin films in an ultrasonic pulse‐echo setup.

Background:. Residency programs have developed monetary initiatives for students underrepresented in medicine (URiM). Our team sought to provide a centralized resource for URiM students seeking plastic surgery subinternships with funded opportunities. Methods:. A cross sectional analysis of URiM scholarships offered by US integrated plastic surgery programs (n = 91) between July and September 2023. The study used residency program web domains. Investigators collected information on the monetary value of scholarship, eligibility criteria, and required application documents. Inferential analyses were conducted to investigate whether programs’ geographic region or Doximity ranking played a role in likelihood of scholarship existence. Results:. The study found that approximately 52.7% (n = 48) of programs have in place monetary support for underrepresented visiting medical students (eg, stipend or reimbursement). The average monetary support was $1670. A univariate test demonstrated that programs with lower rankings in both reputation and research were less likely to have a scholarship available than higher ranking programs (P = 0.002; P = 0.02, respectively). Programs located in the Midwest regions were 3.5 times more likely to have a diversity scholarship available (P = 0.034). In our multivariate analysis, reputation ranking and geographic region remained significant. A Pearson chi square test showed the greatest proportions of scholarships among geographically similar programs to be in the Midwest (70%), however, not statistically significant. Conclusions:. This study provides a centralized resource for URiM students interested in completing away rotations. Further investigation into development of these scholarship opportunities would be of much benefit and could guide other programs in the funding their own diversity scholarships.

Background The most common cause of preventable death after injury is haemorrhage. Resuscitative endovascular balloon occlusion of the aorta is intended to provide earlier, temporary haemorrhage control, to facilitate transfer to an operating theatre or interventional radiology suite for definitive haemostasis. Objective To compare standard care plus resuscitative endovascular balloon occlusion of the aorta versus standard care in patients with exsanguinating haemorrhage in the emergency department. Design Pragmatic, multicentre, Bayesian, group-sequential, registry-enabled, open-label, parallel-group randomised controlled trial to determine the clinical and cost-effectiveness of standard care plus resuscitative endovascular balloon occlusion of the aorta, compared to standard care alone. Setting United Kingdom Major Trauma Centres. Participants Trauma patients aged 16 years or older with confirmed or suspected life-threatening torso haemorrhage deemed amenable to adjunctive treatment with resuscitative endovascular balloon occlusion of the aorta. Interventions Participants were randomly assigned 1 : 1 to: standard care, as expected in a major trauma centre standard care plus resuscitative endovascular balloon occlusion of the aorta. Main outcome measures Primary: Mortality at 90 days. Secondary: Mortality at 6 months, while in hospital, and within 24, 6 and 3 hours; need for haemorrhage control procedures, time to commencement of haemorrhage procedure, complications, length of stay (hospital and intensive care unit-free days), blood product use. Health economic: Expected United Kingdom National Health Service perspective costs, life-years and quality-adjusted life-years, modelled over a lifetime horizon. Data sources Case report forms, Trauma Audit and Research Network registry, NHS Digital (Hospital Episode Statistics and Office of National Statistics data). Results Ninety patients were enrolled: 46 were randomised to standard care plus resuscitative endovascular balloon occlusion of the aorta and 44 to standard care. Mortality at 90 days was higher in the standard care plus resuscitative endovascular balloon occlusion of the aorta group (54%) compared to the standard care group (42%). The odds ratio was 1.58 (95% credible interval 0.72 to 3.52). The posterior probability of an odds ratio > 1 (indicating increased odds of death with resuscitative endovascular balloon occlusion of the aorta) was 86.9%. The overall effect did not change when an enthusiastic prior was used or when the estimate was adjusted for baseline characteristics. For the secondary outcomes (3, 6 and 24 hours mortality), the posterior probability that standard care plus resuscitative endovascular balloon occlusion of the aorta was harmful was higher than for the primary outcome. Additional analyses to account for intercurrent events did not change the direction of the estimate for mortality at any time point. Death due to haemorrhage was more common in the standard care plus resuscitative endovascular balloon occlusion of the aorta group than in the standard care group. There were no serious adverse device effects. Resuscitative endovascular balloon occlusion of the aorta is less costly (probability 99%), due to the competing mortality risk but also substantially less effective in terms of lifetime quality-adjusted life-years (probability 91%). Limitations The size of the study reflects the relative infrequency of exsanguinating traumatic haemorrhage in the United Kingdom. There were some baseline imbalances between groups, but adjusted analyses had little effect on the estimates. Conclusions This is the first randomised trial of the addition of resuscitative endovascular balloon occlusion of the aorta to standard care in the management of exsanguinating haemorrhage. All the analyses suggest that a strategy of standard care plus resuscitative endovascular balloon occlusion of the aorta is potentially harmful. Future work The role (if any) of resuscitative endovascular balloon occlusion of the aorta in the pre-hospital setting remains unclear. Further research to clarify its potential (or not) may be required. Trial registration This trial is registered as ISRCTN16184981. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 14/199/09) and is published in full in Health Technology Assessment; Vol. 28, No. 54. See the NIHR Funding and Awards website for further award information. Plain language summary Trauma (physical injury) is a major cause of death and disability. The most common cause of preventable death after injury is uncontrolled bleeding. Resuscitative endovascular balloon occlusion of the aorta is a technique whereby a small balloon is inflated in the aorta (main blood vessel) which aims to limit blood loss until an operation can be done to stop the bleeding. In this study, which is the first randomised trial in the world of this technique, we investigated whether adding resuscitative endovascular balloon occlusion of the aorta to the standard care received in a major trauma centre reduced the risk of death in trauma patients who had life-threatening uncontrolled bleeding. The study took place in 16 major trauma centres in the United Kingdom. Ninety adult trauma patients with confirmed or suspected uncontrolled bleeding took part and were randomly divided into two groups: (1) those who received standard care and (2) those who received standard care plus resuscitative endovascular balloon occlusion of the aorta. We followed participants for 6 months using routinely collected data from the National Health Service and from the Trauma Audit Research Network registry. We also contacted surviving patients at 6 months to ask about their quality of life. In the standard care group, 42% of participants died within 90 days of their injury compared to 54% of participants in the standard care plus resuscitative endovascular balloon occlusion of the aorta group. Risk of death was also higher in the standard care plus resuscitative endovascular balloon occlusion of the aorta group at all other time points (3, 6 and 24 hours, in hospital and at 6 months). Overall, the study showed that the use of resuscitative endovascular balloon occlusion of the aorta in hospital increased the risk of death. Scientific summary Background Trauma is a major cause of death and disability. Trauma (physical injury) disproportionately affects the young, killing those who might otherwise have lived long and productive lives. The most common cause of preventable death after injury is haemorrhage. The addition of resuscitative endovascular balloon occlusion of the aorta (REBOA) to current standard care is intended to provide earlier, temporary haemorrhage control, to facilitate transfer to an operating theatre or interventional radiology suite, for definitive haemostasis. Objectives The UK-REBOA trial was a pragmatic, multicentre, Bayesian, open-label, group-sequential, parallel-group randomised controlled trial comparing standard care plus REBOA versus standard care in patients with exsanguinating haemorrhage in the emergency room. The study included an elicitation exercise, an embedded mixed-methods process evaluation and a health economic evaluation. The primary clinical outcome was 90-day mortality (defined as death within 90 days of injury, before or after discharge from hospital). Secondary clinical outcomes included 3-, 6- and 24-hour mortality, in-hospital mortality, 6-month mortality, length of stay (in hospital and intensive care unit), 24-hour blood product use, need for haemorrhage control procedures (operation or angioembolisation), time to commencement of haemorrhage control procedure, complications/safety data and functional outcome [measured using the extended Glasgow Outcome Scale (GOS-E)] at discharge. Economic outcomes were 6-month (within trial) and lifetime (modelled) UK NHS perspective costs, life-years and quality-adjusted life-years (QALYs) [calculated using EuroQol Group’s 5-dimension health status 5-level questionnaire (EQ-5D-5L)], 6-month quality of life (measured using EQ-5D-5L). Methods Trauma patients were recruited in 16 UK major trauma centres. Trauma patients aged (or believed to be aged) 16 years or older, with confirmed or suspected life-threatening torso haemorrhage thought to be amenable to adjunctive treatment with REBOA were eligible. Women known (or thought to be) pregnant and those with injuries deemed unsurvivable were excluded. The trauma team leader assessed the patients for eligibility. Patients who were eligible for inclusion in the trial were incapacitated and unable to give consent at the time of eligibility assessment and randomisation. There was also not sufficient time to consult a surrogate decision-maker, or even an independent medical practitioner, for advice about including the patient. Enrolment therefore took place without prior consent following Research Ethics Committee approval for this approach. Consent for continuing participation (i.e. data collection) was sought by a member of the UK-REBOA trial team once patients were no longer in a critical condition (defined as being cared for in a ward area rather than an intensive care unit or high-dependency unit) or from a personal (or nominated professional) consultee. The trauma team leader enrolled the participant using a dedicated, secure website, available on a handheld device (smartphone, tablet) or desktop computer which is linked directly to the 24-hour randomisation system at the Centre for Healthcare Randomised Trials, based in the Health Services Research Unit, University of Aberdeen. Patients were randomised into one of the two intervention arms, in a 1 : 1 allocation ratio, in randomly generated blocks of two or four. Standard care: Patients allocated to the control group received ‘standard care’, as expected in a specialist major trauma centre. Such treatment typically included intubation, blood transfusion including blood products in a 1 : 1 : 1 ratio, interventions such as tourniquet application, and early operative or endovascular haemorrhage control. Treatment could also have included open aortic occlusion of the thoracic or abdominal aorta. Standard care plus REBOA: Patients allocated to this arm of the trial additionally received the technique of endovascular aortic occlusion, for the purpose of resuscitation, as part of an overall treatment strategy. The addition of REBOA to current standard care was intended to provide earlier, temporary haemorrhage control, to facilitate transfer to an operating theatre or interventional radiology suite for definitive haemostasis. The trial sought to evaluate the technique of REBOA rather than a specific brand of device, and therefore permitted the use of any licensed occlusion balloon, and did not prescribe or mandate a particular product. The trial had an integrated training programme to ensure familiarity with the REBOA procedure. In patients who had been randomised to the standard care plus REBOA arm of the trial, clinicians could decide not to insert the balloon occlusion device if: the patient’s haemodynamic status improved (as a result of other resuscitative measures), if they were deemed to no longer have life-threatening torso haemorrhage requiring adjunctive treatment with REBOA; they deteriorated (to the point of imminent death); or there was technical difficulty in obtaining arterial access, and it was felt that operative control of haemorrhage could be obtained more quickly. The data collection strategy for the UK-REBOA trial was designed to minimise the burden on participants and clinicians, and for the avoidance of duplication. The randomisation system collected balloon inflation/deflation times. The trial drew on routinely collected data, primarily from the Trauma Audit and Research Network (TARN) registry which includes demographic, injury, treatment and outcome data (including the GOS-E and EQ-5D-5L). Mortality and hospital resource use data were also sought from NHS Digital. The main analysis was based on the intention-to-treat principle. There were two planned interim analyses of survival and a final analysis of all outcomes after follow-up was complete. Baseline and follow-up data were summarised using descriptive statistics and graphical summaries. Treatment effects are presented with 95% credible intervals for the primary and secondary outcomes. Elicitation exercise An elicitation exercise involving 20 subject matter experts (12 emergency medicine physicians, 3 pre-hospital care doctors, 4 surgeons and 1 intensivist) was undertaken to derive prior probability distributions to help contextualise the interpretation for the primary and secondary outcomes of the trial. Subject matter experts, on average, estimated in-hospital and 90-day mortality in this patient group, without the use of REBOA, to be in excess of 50%. Mortality at earlier time points (6 and 24 hours) was estimated to be closer to 25%. The elicited data, and the resulting prior probability distributions, indicate that the experts, on average, had a favourable opinion of REBOA, that is they expect the addition of REBOA to standard care to improve mortality at all time points. Clinical results Sixteen recruitment sites were opened in a staggered manner. Recruitment commenced in October 2017, was halted in March 2020 due to COVID-19, and restarted in July 2020. The second interim analysis (including 80 participants) triggered one of the pre-specified stopping rules, and recruitment closed in March 2022, by which time 90 participants had been recruited. Forty-four participants were randomised to standard care (2 of whom did receive REBOA) and 46 were randomised to standard care plus REBOA (19 of whom had the catheter inserted and balloon inserted and the remaining 27 progressed to different time points along this pathway). The groups were well-matched in terms of age, gender, comorbidities, mechanism of injury and injury severity. In the standard care arm, the median age was 39 years (interquartile range 30–56 years) and 77% were male. In the standard care plus REBOA arm, the median age was 46 years (interquartile range 33–62) and 61% were male. The median Injury Severity Score in both arms was 41 (interquartile range 29–50), with the majority classed as having very severe injury. Of the 46 patients allocated to standard care plus REBOA treatment, 25 (54%) died within 90 days. Of the 43 standard care patients for whom primary outcome data are available, 18 (42%) died within 90 days. Using the minimally informative prior, the odds of 90-day mortality were 1.58 for patients allocated to the standard care plus REBOA arm (95% credible interval 0.72 to 3.52). The posterior probability of an odds ratio > 1 (i.e. that REBOA was harmful) was 86.9%. The direction of the estimate did not change when an enthusiastic (the elicited) prior was used or when the estimate was adjusted for baseline characteristics. For the secondary outcomes (3-, 6- and 24-hour mortality), the posterior probability that REBOA was harmful was higher than for the primary outcome. Additional analyses to account for intercurrent events did not change the direction of the estimate for mortality at 3, 6 and 24 hours, at 90 days or 6 months, or in-hospital mortality. Death due to haemorrhage was more common in the standard care plus REBOA group than in the standard care group. The mean number of days spent in intensive care and in hospital were lower in the standard care plus REBOA group compared to the standard care group, partly because of the higher number of earlier deaths in the standard care plus REBOA arm. There were no serious adverse device effects. Health economics We costed individual components of resources and summed these to generate a total cost for the whole initial hospitalisation admission period. Total NHS resource use for the index hospitalisation was obtained from patient-level data in TARN and the key resource use variables for costing included time of arrival, time of emergency department departure, time of first operation, time of death/discharge, number and type of operative procedures and volume of blood transfusions that were required. Secondary care contacts and episodes of care that were commenced between the date of discharge from the index hospitalisation through 6 months post randomisation were sourced, where available, through linkage of patient records to the Hospital Episode Statistics database. All costs are reported from a UK NHS perspective in Great British pounds (GBP) (year 2020-1). Quality of life was measured using the EQ-5D-5L prior to patient’s discharge from their index hospitalisation and at 6 months post admission. EQ-5D-5L asks respondents to report any problems on a given day across five dimensions of mobility, self-care, usual activities, anxiety/depression and pain. The data were available from TARN and supplemented with data collected by the local trial teams. EQ-5D-5L data were cross-walked to the 3L version and valued using UK general population preference tariffs. Baseline utility was set equal to the unconscious state (−0.402) and utility following death was set to 0. QALYs were calculated using an area under the curve approach assuming linear extrapolation between time points. From the within-trial health economic analysis, participants in the standard care plus REBOA arm of the study incurred lower costs {index hospital admission: mean cost £57,384 [standard deviation (SD) £62,863]} compared to those in standard care [mean cost £116,064 (SD £128,957)]. Lower costs in the standard care plus REBOA arm of the study were mainly due to lower use of hospital resources (length of stay, etc.) due to the competing risk of death (i.e. a higher number of deaths in the REBOA plus standard care group). Similarly, life-years accrued and QALYs over 6 months post randomisation were also lower in standard care plus REBOA compared to standard care due to a greater proportion of trial participants dying, with mortality also occurring earlier in the follow-up period for the REBOA arm. The mean life-years gained in the standard care plus REBOA arm was 0.232 (SD 0.247) compared to 0.305 (SD 0.236) in the standard care arm. When modelled over a full lifetime horizon, standard care plus REBOA is less costly (probability 99%), due to the competing risk of mortality but is also substantially less effective in terms of QALYs accrued over a lifetime horizon (probability 91%). The findings are robust to a range of scenario analyses undertaken, with the probability of standard care being the optimal treatment strategy ranging from 66% to 81% at a threshold value of a QALY = £50,000. Process evaluation The process evaluation was conducted in two phases; both phases involved interviews with clinical and research staff based at recruitment sites. Phase 1 was designed to identify barriers during trial initial and set-up; Phase 2 focused on exploring barriers and facilitators of recruitment into the trial and intervention delivery. A behavioural framework was used in Phase 2 to direct analysis and generate solutions designed to enhance trial practices, which included regular online meetings between the principal investigators from each site, updates to training materials and delivery, and e-mail/Twitter feedback on recruitment activity. Conclusions This is the first randomised trial ever to be conducted examining the potential clinical effectiveness of REBOA for the management of exsanguinating haemorrhage. All the analyses conducted suggest with high probability that a strategy of standard care plus REBOA is harmful. Implications for health care: The continuing use of REBOA, at least in the UK in-hospital setting, should be re-evaluated. Implications for research: The role (if any) of REBOA in the pre-hospital setting remains unclear. Further research to clarify its potential (or not) may be required. Trial registration This trial is registered as ISRCTN16184981. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 14/199/09) and will be published in full in Health Technology Assessment; Vol. 28, No. 54. See the NIHR Funding and Awards website for further award information.

RationaleTranexamic acid (TXA) is a strong and specific plasminogen activator inhibitor with inhibitory effects on the matrix metalloproteases involved in the pathophysiology of osteoarthritis (OA) through targeting of the fibrinolysis pathway. In this study, we evaluated the analgesic and chondroprotective effects of a HA-tranexamic acid (HA/TXA) conjugate, compared to HA alone and placebo, in an animal model of knee OA.MethodsKnee OA was induced in 15 C57 b l/6J mice by IA injection of 0.75 mg of Monosodium IodoAcetate (MIA). At day 28, the mice received 1 IA injection of 10 µL of saline (control-group), or of HA or of HA/TXA. Tactile sensitivity was assessed using von Frey filaments. Stimulations started at 1 g and increased until a response was obtained (up to 4 g). A response to the stimulus was counted if the animal withdrew its paw. If the animal responded to the 1 g stimulation, stimulation was reduced until the lack of response was observed (up to 0.2 g). At day 56, mice were euthanized for knee histological assessment. Cartilage degradation was assessed using the OARSI score. Statistical analysis was performed on GraphPad Prism 8.0.2 software. Kruskal–Wallis or Mann-Whitney tests were performed as appropriate.ResultsJust before treatment administration, no intergroup difference in paw withdrawal threshold was observed. Throughout the experiment animals given saline and HA had a lower paw withdrawal threshold than those treated with HA/TXA (p < 0.01). In the control group OARSI score was 5.5 ± 0.6. In HA and HA + TXA treated mice the OARSI score was 3.2 ± 0.8 and 3.1 ± 0.5 (p < 0.01) showing that both treatments were able to reduce OA progression.ConclusionIn this animal model of MIA induced KOA, a single IA injection of a HA/TXA conjugate resulted in a greater efficacy on pain than both saline and HA. HA and HA/TXA exhibited chondroprotective effects compared to placebo.

The establishment of a quantitative gait analysis system holds paramount importance, particularly in the context of functional rehabilitation of the lower limbs. Clinicians emphasize the imperative for sensors to be portable, compact, integrated, and non-intrusive, crucial characteristics in the rehabilitation field to facilitate their use and ensure optimal integration into care protocols. This study investigates an innovative approach aimed at reducing the reliance on body-fixed sensors by harnessing their data within a neural network, thus concentrating on the joint kinematics of the lower limbs. The primary objective is to estimate the flexion-extension angles of the hip, knee, and ankle during walking, utilizing data collected by two sensors positioned on the subject's legs. Initially, the neural network undergoes training with calculated data (leg tilt angles and angular velocities) sourced from the OpenSim database, followed by further refinement with experimental data obtained from a subject walking on a treadmill, wherein leg tilt angles and angular velocities are measured. The significance of this research is underscored by the demonstrated capability, through conducted tests, of the implemented networks to efficiently fuse data from a minimal set of sensors. Consequently, the proposed approach emerges as both practical and minimally intrusive, facilitating a robust evaluation of gait kinematic parameters.

Objectives: Daratumumab-treated myeloma patients may face increased seasonal influenza risk due to weakened postvaccination immune responses, especially with daratumumab treatment. We aimed to assess humoral responses to boosted influenza vaccination in daratumumab-treated or -untreated patients. Methods: In a single-center study, we evaluated humoral responses (hemagglutination-inhibition assay) one month following a two-injection (4-weeks apart) influenza vaccination (standard dose) in 84 patients with multiple myeloma (40 with daratumumab in the past year). Results: Seroprotection rates (titer ≥1/40) after the second vaccine injection were low across vaccinal subtypes (except for A-H3N2): 71.3% (A-H3N2), 19.7% (A-H1N1pdm09), 9.9% (B-Victoria), 11.3% (B-Yamagata). Only A-H3N2 seroprotection rates significantly increased with the booster in daratumumab-treated patients (30% (12/40) after one injection vs 55% (22/40) after the boost; P = 0.01).After propensity score weighting, daratumumab was not significantly associated with a reduced likelihood of seroprotection against at least one vaccine strain (OR 0.65 [95% CI: 0.22-1.88]). Conclusion: While daratumumab treatment did not lead to a significant reduction in seroprotection rates following influenza vaccination, a booster vaccine injection demonstrated potential benefit for specific strains (A-H3N2) in patients undergoing daratumumab treatment. Nevertheless, the overall low response rates in patients with multiple myeloma necessitates the development of alternative vaccination and prophylaxis strategies.

Abstract Background Oncologic surgical resection is the standard of care for extremity and truncal soft tissue sarcoma (STS), often accompanied by the addition of pre- or postoperative radiation therapy (RT). Preoperative RT may decrease the risk of joint stiffness and fibrosis at the cost of higher rates of wound complications. Hypofractionated, preoperative RT has been shown to provide acceptable outcomes in prospective trials. Proton beam therapy (PBT) provides the means to decrease dose to surrounding organs at risk, such as the skin, bone, soft tissues, and adjacent joint(s), and has not yet been studied in patients with extremity and truncal sarcoma. Methods Our study titled “PROspective phase II trial of preoperative hypofractionated protoN therapy for extremity and Truncal soft tissue sarcOma (PRONTO)” is a non-randomized, prospective phase II trial evaluating the safety and efficacy of preoperative, hypofractionated PBT for patients with STS of the extremity and trunk planned for surgical resection. Adult patients with Eastern Cooperative Group Performance Status ≤ 2 with resectable extremity and truncal STS will be included, with the aim to accrue 40 patients. Treatment will consist of 30 Gy radiobiological equivalent of PBT in 5 fractions delivered every other day, followed by surgical resection 2–12 weeks later. The primary outcome is rate of major wound complications as defined according to the National Cancer Institute of Canada Sarcoma2 (NCIC-SR2) Multicenter Trial. Secondary objectives include rate of late grade ≥ 2 toxicity, local recurrence-free survival and distant metastasis-free survival at 1- and 2-years, functional outcomes, quality of life, and pathologic response. Discussion PRONTO represents the first trial evaluating the use of hypofractionated PBT for STS. We aim to prove the safety and efficacy of this approach and to compare our results to historical outcomes established by previous trials. Given the low number of proton centers and limited availability, the short course of PBT may provide the opportunity to treat patients who would otherwise be limited when treating with daily RT over several weeks. We hope that this trial will lead to increased referral patterns, offer benefits towards patient convenience and clinic workflow efficiency, and provide evidence supporting the use of PBT in this setting. Trial registration: NCT05917301 (registered 23/6/2023).

Abstract Background Active targeting by surface-modified nanoplatforms enables a more precise and elevated accumulation of nanoparticles within the tumor, thereby enhancing drug delivery and efficacy for a successful cancer treatment. However, surface functionalization involves complex procedures that increase costs and timelines, presenting challenges for clinical implementation. Biomimetic nanoparticles (BNPs) have emerged as unique drug delivery platforms that overcome the limitations of actively targeted nanoparticles. Nevertheless, BNPs coated with unmodified cells show reduced functionalities such as specific tumor targeting, decreasing the therapeutic efficacy. Those challenges can be overcome by engineering non-patient-derived cells for BNP coating, but these are complex and cost-effective approaches that hinder their wider clinical application. Here we present an immune-driven strategy to improve nanotherapeutic delivery to tumors. Our unique perspective harnesses T-cell exhaustion and tumor immune evasion to develop a groundbreaking new class of BNPs crafted from exhausted T-cells (NExT) of triple-negative breast cancer (TNBC) patients by specific culture methods without sophisticated engineering. Methods NExT were generated by coating PLGA (poly(lactic-co-glycolic acid)) nanoparticles with TNBC-derived T-cells exhausted in vitro by acute activation. Physicochemical characterization of NExT was made by dynamic light scattering, electrophoretic light scattering and transmission electron microscopy, and preservation and orientation of immune checkpoint receptors by flow cytometry. The efficacy of chemotherapy-loaded NExT was assessed in TNBC cell lines in vitro. In vivo toxicity was made in CD1 mice. Biodistribution and therapeutic activity of NExT were determined in cell-line- and autologous patient-derived xenografts in immunodeficient mice. Results We report a cost-effective approach with a good performance that provides NExT naturally endowed with immune checkpoint receptors (PD1, LAG3, TIM3), augmenting specific tumor targeting by engaging cognate ligands, enhancing the therapeutic efficacy of chemotherapy, and disrupting the PD1/PDL1 axis in an immunotherapy-like way. Autologous patient-derived NExT revealed exceptional intratumor accumulation, heightened chemotherapeutic index and efficiency, and targeted the tumor stroma in a PDL1+ patient-derived xenograft model of triple-negative breast cancer. Conclusions These advantages underline the potential of autologous patient-derived NExT to revolutionize tailored adoptive cancer nanotherapy and chemoimmunotherapy, which endorses their widespread clinical application of autologous patient-derived NExT.

Background: There is no definitive evidence of the prognosis impact of histological variants (HVs) in patients who undergo surgical resection of a nonmetastatic renal cell carcinoma (nm-RCC) with venous tumor thrombus (TT). Objective: To investigate the impact of HVs on the prognosis of patients with nm-RCC with TT after radical surgery. Design, setting, and participants: Patients who underwent radical nephrectomy with the removal of the venous TT for an nm-RCC were included in a retrospective study. Outcome measurements and statistical analysis: Three groups were identified: clear cell (ccRCC), papillary (pRCC), and chromophobe (chRCC) RCC. The primary outcome measures (disease-free and overall survival [OS]) were assessed using the Kaplan-Meier method and compared using the log-rank test. Univariate and multivariate Cox proportional hazard models were used to study the impact of HVs on survival. Results and limitations: A total of 873 patients were included. The histological subtypes were distributed as follows: ccRCC in 780 cases, pRCC in 58 cases, and chRCC in 35 cases. At the time of data analysis, 612 patients were recurrence free and 228 had died. A survival analysis revealed significant differences in both OS and recurrence-free survival across histological subtypes, with the poorest outcomes observed in pRCC patients (p

Abstract This paper presents the composite drought indicator (CDI) that Jordanian, Lebanese, Moroccan, and Tunisian government agencies now produce monthly to support operational drought management decision making, and it describes their iterative co-development processes. The CDI is primarily intended to monitor agricultural and ecological drought on a seasonal time scale. It uses remote sensing and modelled data inputs, and it reflects anomalies in precipitation, vegetation, soil moisture, and evapotranspiration. Following quantitative and qualitative validation assessments, engagements with policymakers, and consideration of agencies’ technical and institutional capabilities and constraints, we made changes to CDI input data, modelling procedures, and integration to tailor the system for each national context. We summarize validation results, drought modelling challenges and how we overcame them through CDI improvements, and we describe the monthly CDI production process and outputs. Finally, we synthesize procedural and technical aspects of CDI development and reflect on the constraints we faced as well as trade-offs made to optimize the CDI for operational monitoring to support policy decision-making—including aspects of salience, credibility, and legitimacy—within each national context.

Abstract As CMOS technologies face challenges in dimensional and voltage scaling, the demand for novel logic devices has never been greater, with spin-based devices offering scaling potential, at the cost of significantly high switching energies. Alternatively, magnetoelectric materials are predicted to enable low-power magnetization control, a solution with limited device-level results. Here, we demonstrate voltage-based magnetization switching and reading in nanodevices at room temperature, enabled by exchange coupling between multiferroic BiFeO3 and ferromagnetic CoFe, for writing, and spin-to-charge current conversion between CoFe and Pt, for reading. We show that, upon the electrical switching of the BiFeO3, the magnetization of the CoFe can be reversed, giving rise to different voltage outputs. Through additional microscopy techniques, magnetization reversal is linked with the polarization state and antiferromagnetic cycloid propagation direction in the BiFeO3. This study constitutes the building block for magnetoelectric spin-orbit logic, opening a new avenue for low-power beyond-CMOS technologies.

In this paper, we study weak solutions for a class of parabolic problems with dynamical boundary condition. We establish the existence of a weak solution to the corresponding Dynamical problem. Moreover, we will show that the existence time T of solution is finite when the initial energy satisfies certain condition. [ABSTRACT FROM AUTHOR]

The photosensitivity of the chemical bath deposited zinc selenide (ZnSe) thin film of bandgap 2.8 eV air annealed at different temperatures has been studied under sub-band gap optical illuminations of photon energies 1.77, 1.91, and 2.07 eV, respectively. The study reveals significant and systematic changes in the photocurrent even when the photon energy is restricted well below the band gap energy of the material. In addition, the photocurrent decreases more or less exponentially with the annealing temperature, although the absorption coefficients of the annealed samples in the sub-band gap region are seen to be enhanced compared to the as-deposited sample. The XRD measurements show the cubic phase of ZnSe, accompanying additionally the orthorhombic ZnSeO3 crystallites in the deposited film. The study further reveals comparatively stronger crystalline improvement of the ZnSeO3 crystals than the cubic ZnSe crystals upon annealing. The observed photosensitivity of the film is compared to that of the cadmium sulphide film deposited by a chemical bath deposition technique and found to be sharply contrasting in behavior. We attribute the unusual photosensitivity of the ZnSe film to ZnSeO3 crystallites which act simultaneously as self generators and absorbers of photoelectrons in the ZnSe crystals, without effectively contributing to the overall photoconductivity of the material. [ABSTRACT FROM AUTHOR]

Objective: To determine the frequency and etiology of Early Return Visits within 3 days of discharge to the Emergency Department. Study Design: Prospective longitudinal study. Place and Duration of Study: Emergency Department of Combined Military Hospital, Rawalpindi Pakistan, from Jan to Jun 2022. Methodology: All patients visiting the Emergency Department within the defined 6-month period were included in this study, which came to 101’113. To determine overall incidence of Early Return Visits, total number of patients revisiting within 72 hours of Emergency Department discharge was used. To find out the possible factors responsible for ERVs, a sample size of 80 patients revisiting the Emergency Department was calculated through World Health Organization calculator and selected through random sampling technique. Factors responsible for unscheduled Early Return Visits were divided into three broad categories: Doctor-associated, Disease-associated, and Patient-associated. Results: The total number of patients revisiting Emergency Department within 72 hours was 2,880 (2.9%). Out of these 52.5% patients reported back to the Emergency Department due to disease-associated reasons, 27.5% due to doctor-related reasons, and 20% revisited for patient-related reasons. Conclusion: Two-point nine percent patients made ERVs to the Emergency Department within 72 hours. The most common causes of Early Return Visits in this study are disease-related issues followed by doctor-related issues.

Abstract Introduction - L’objectif de cette étude est d’évaluer l’apport d’un accompagnementinfirmier codifié dans l’amélioration du contrôle du diabète chez des adolescentsen déséquilibre métabolique persistant.Patients et méthodes - Cette étude randomisée contrôlée a comparé 2 groupesd’adolescents âgés de 12 à 17 ans, atteints de DT1, ayant un taux d’HbA1c ? 9% et< 15%. Le groupe « A » a bénéficié des appels téléphoniques, toutes les 4 semainespar une infirmière, en alternance avec des visites mensuelles supervisées médicalement.Le groupe « B » a bénéficié des consultations toutes les 4 semaines.Résultats - Nous avons étudié 58 adolescents. A la fin de l’intervention de 5 mois,il y a eu une baisse de 3,41 points d’HbA1c pour le groupe A, de 2,96 points pour legroupe B (p=0,32) ; le pourcentage de patient avec un taux d’HbA1c au-dessous de7,5% était de 62,07% dans le groupe A et de 37,93% dans le groupe B (p=0,06). Aprèsl’intervention, il y a ré-ascension de l’HbA1c pour les 2 groupes.Conclusion - La prise en charge intensive à forte implication paramédicale faited’entretiens éducatifs et téléphoniques en complément des visites médicales habituelleschez des adolescents en déséquilibre persistant a entraîné l’amélioration del’équilibre glycémique à moyen terme. AbstractIntroduction - The objective of this study is to evaluate the contribution of codified nursing support in improving the diabetes control of adolescents with persistent me-tabolic imbalance.Patients and methods - This randomized controlled trial compared 2 groups of 12-17 year old adolescents with T1D, with HbA1c ≥ 9% and

Abstract Introduction /objectifs - Les regroupements éducatifs pour adolescents atteints dediabète type 1 ont pour but, d’une part, d’offrir une détente à ces jeunes, de leurpermettre de se rencontrer et de partager leurs expériences et, d’autre part, defaire de l’éducation thérapeutique (ETP) de groupe dans le cadre des programmescontinus d’éducation.L’objectif de ce travail était d’évaluer l’efficacité de cette forme d’éducation thérapeutiquecontinue.Patients et méthodes - Soixante-dix-sept adolescents ont été évalués, avant etaprès chaque regroupement éducatif de 5 jours, sur l’hémoglobine glyquée (HbA1c),la connaissance du DT1, la qualité de vie, le vécu de la maladie, l’adhésion et l’autonomiethérapeutiques, et la perception de l’état de santé.Résultats - Les adolescents étaient âgés de 13,57±1,46 ans et scolarisés à 97%.L’HbA1c passe de 8,64±2,44% à l’inclusion avec 36,36% de valeurs au seuil ciblede 7,5% à 8,09±2,28% (p

Abstract Introduction - Le diabète chez l’enfant subit une mutation profonde en termes de fréquence et de recul de l’âge de début depuis une vingtaine d’années au niveau mondial. L’Algérie est particulièrement impactée par l’épidémie au point de figurer depuis 2016 dans le ‘top 10’ des pays à très forte incidence de diabète de type 1 (DT1). Notre étude a pour but de présenter l’évolution épidémiologique du DT1 de l’enfant à travers le registre de la wilaya d’Oran. Matériels et méthodes - La population de référence est celle de la wilaya d’Oran. Les nouveaux cas de DT1 proviennent des unités de première ligne et des services de pédiatrie. L’enregistrement était centralisé au niveau du service de pédiatrie «C» du CHU d’Oran depuis 1973 avec une exhaustivité proche de 100%. Résultats - Du 1er janvier 1973 au 31 décembre 2017, 2358 nouveaux cas de DT1 de moins de 15 ans au diagnostic du DT1 ont été enregistrés. L’incidence annuelle moyenne des moins de 15 ans des cinq dernières années 2013-2017 s’établit à 31,12± 3,60 cas pour 100 000 avec une évolution annuelle moyenne de 12,78% sur les 25 dernières années. Les évolutions annuelles moyennes des classes d’âge pédiatriques de [0-4], [5-9] ans et [10-14] ans sont de 15,03, 15,50 et de 9,10%, respectivement. L’incidence pour 1000 naissances vivantes des années 1998-2002 montre un risque de contracter un DT1 dans les 15 premières années de vie de 3,5 p. 1000. La prévalence était de 207 pour 100.000, soit 1 DT1 pour 482 enfants de moins de 15 ans, au 31 décembre 2017. Le sex-ratio s’établit à 0,99 pour l’ensemble des cas, mais subit des variations cycliques significatives avec des extrêmes de 0,80 et 1,14 (p=0,02). La saisonnalité hiver/été, significative de 1973 à 2014 en faveur des mois d’hiver, ne l’est plus à partir de 2015. Conclusion - L’augmentation persistante de l’incidence et le rajeunissement marqué de l’âge d’apparition du DT1 de l’enfant de la wilaya d’Oran sont une réalité depuis une vingtaine d’années. Cette évolution, liée essentiellement à l’environnement, ne va pas sans poser de nouvelles difficultés aux familles et aux équipes en charge. Abstract Introduction - Diabetes in children is undergoing a profound change in terms of fre-quency and decrease in age in the last twenty years worldwide. Algeria is particularly impacted by the epidemic to the point of appearing in the ‘top 10’ 2016 of countries with very high incidence of type 1 diabetes (T1D). Our study aims to present the epidemiological evolution of T1D in children through a recruitment of 45 years in the register of the department of Oran. Materials and Methods - The reference population is that of the department of Oran. New cases of T1D are children under 15 years old coming from front-line units and pediatric departments. Registration was centralized at the level of the «C» pediatric unit of Oran University Hospital since 1973 with an assessment close to 100%. Results - From January 1st, 1973 to December 31st, 2017, 2358 T1D new cases aged less than 15 years at T1D diagnosis have been registered. The average annual inci-dence under 15 years old for the last 5 years 2013-2017 is 31.12± 3.60 cases per 100 000 with an annual evolution average of 12.78% in the last 25 years. The annual evo-lution average of pediatric age groups are 15.03, 15.50 and 9.10%, respectively for children of [0-4], [5-9] and [10-14] years old. The incidence per 1 000 live births shows a risk of contracting T1D in the first 15 years of life of around 3.5. At December 31, 2017, the prevalence was 207 for 100 000 equivalent to 1 T1D for 482 children under 15,. The sex-ratio for all cases is 0.99 (1175 boys / 1183 girls), but undergoes cyclical variations with extremes of 0.80 and 1.14 between the periods 1978-1997 and 1998-2007 (p= 0.02). The winter/summer seasonality, significant from 1973 to 2014 in favor of winter months is no longer available starting from 2015. Conclusion - In agreement with other teams, we confirm the outsized increase in the incidence of T1D and the rejuvenation of the age at onset in children under 15 in our country. This evolution, mainly related to environmental problems poses new difficul-ties to families and teams in charge of the disease.

Abstract Introduction / objectifs - Dans le diabète de type 1, la rémission partielle a uneffet bénéfique sur les complications aigues et chroniques. Notre objectif était dedécrire la rémission partielle et d’identifier ses facteurs prédictifs dans une cohorted’enfants et d’adolescents atteints de cette maladie.Patients et méthodes - Les enfants et adolescents âgés de moins de 15 ans, admisentre juin 2013 et juillet 2014, ayant débuté l’insulinothérapie moins d’un moisavant leur admission ont été inclus dans l’étude.Résultats - Cent-dix-sept (117) nouveaux cas ont été étudiés avec un sex-ratio de0,86, ont été analysés. A l’admission, l’âge moyen était de 8,2± 4,3 ans. L’acidocétoseinaugurale était présente dans 26 % des cas. La rémission (moins de 0,5 U/Kg/j d’insuline et HbA1c? 7,5%) a été obtenue chez 21 enfants, soit dans 17,95 %des cas avec une durée moyenne de 5,2 ± 4,2 mois (min. 3-max. 15). La rémissionétait significativement plus fréquente chez les enfants qui n’avaient pas présentéd’acidocétose inaugurale (p< 0,01), chez ceux qui n’avaient pas de germains atteintsde DT1 (p< 0,05) et chez les filles (p< 0,02). Il n’y avait pas de relation significativeavec le taux d’HbA1c à l’admission, le niveau d’instruction ou d’occupationmaternelle, l’origine géographique et l’âge.Conclusions - L’acidocétose au diagnostic est un facteur prédictif négatif de rémissionpartielle. L’absence de DT1 chez les germains et le sexe féminin sont desfacteurs prédictifs de rémission propres à notre contexte de travail. AbstractIntroduction /objectives - Partial remission, in type 1 diabetes, has beneficial ef-fects on acute and chronic complications. The aim of the study was to describe par-tial remission and identify its predictive factors in a cohort of children and adoles-cents with type 1 diabetes.Methods - Children and adolescents under 15 years, admitted between June 2013 and July 2014, having started insulin treatment within a month before admission were studied.Results - One hundred and seventeen new consecutive cases were analyzed. At ad-mission, sex ratio was 0.86, age was 8.2 ± 4.3 years (27%

Abstract A second autologous stem‐cell transplantation (ASCT2) is considered for relapsed multiple myeloma (RMM) patients showing prolonged response after a first ASCT. However, given breakthrough treatments like anti‐CD38 and immunotherapy, its role remains debated. We conducted a real‐life study in 10 French centers (1996–2017) involving 267 RMM patients receiving ASCT2. The median age was 61 years, with 49% females. Most patients received melphalan 200 mg/m² before ASCT2, with low early mortality (1%). Very good partial response or better (VGPR+) rate post ASCT2 was 78%. Post ASCT2, 48% received consolidation therapy and 40% maintenance therapy. Median event‐free survival (EFS) after ASCT2 was 2.6 years (95% confidence interval [CI]: 2.3–2.8), and 2‐year EFS estimate was 63% (95% CI: 57–70). Median overall survival (OS) was 8.1 years (95% CI: 5.9–NA), and 2‐year OS estimate was 92% (95% CI: 88–95). Multivariate analysis revealed that VGPR+ status and maintenance therapy post ASCT2 were associated with better EFS (hazard ratio [HR]: 0.6; 95% CI: 0.3–0.9, p = 0.012 and HR: 0.4; 95% CI: 0.3–0.6, p

Background & Aims: Tacrolimus has been associated with recurrence of primary biliary cholangitis (PBC) after liver transplantation (LT), which in turn may reduce survival. This study aimed to assess the association between the type of calcineurin inhibitor used and long-term outcomes following LT in patients with PBC. Methods: Survival analyses were used to assess the association between immunosuppressive drugs and graft or patient survival among adult patients with PBC in the European Liver Transplant Registry. Patients who received a donation after brain death graft between 1990 and 2021 with at least 1 year of event-free follow-up were included. Results: In total, 3,175 patients with PBC were followed for a median duration of 11.4 years (IQR 5.9–17.9) after LT. Tacrolimus (Tac) was registered in 2,056 (64.8%) and cyclosporin in 819 (25.8%) patients. Following adjustment for recipient age, recipient sex, donor age, and year of LT, Tac was not associated with higher risk of graft loss (adjusted hazard ratio [aHR] 1.07, 95% CI 0.92-1.25, p = 0.402) or death (aHR 1.06, 95% CI 0.90-1.24, p = 0.473) over cyclosporin. In this model, maintenance mycophenolate mofetil (MMF) was associated with a lower risk of graft loss (aHR 0.72, 95% CI 0.60-0.87, p

Nearly 50 years after the ground-breaking isolation of the primary Comptonia peregrina microsymbiont under axenic conditions, efforts to isolate a substantial number of Protofrankia and Frankia strains continue with enduring challenges and complexities. This study aimed to streamline genomic insights through comparative and predictive tools to extract traits crucial for isolating specific Frankia in axenic conditions. Pangenome analysis unveiled significant genetic diversity, suggesting untapped potential for cultivation strategies. Shared metabolic strategies in cellular components, central metabolic pathways, and resource acquisition traits offered promising avenues for cultivation. Ecological trait extraction indicated that most uncultured strains exhibit no apparent barriers to axenic growth. Despite ongoing challenges, potential caveats, and errors that could bias predictive analyses, this study provides a nuanced perspective. It highlights potential breakthroughs and guides refined cultivation strategies for these yet-uncultured strains. We advocate for tailored media formulations enriched with simple carbon sources in aerobic environments, with atmospheric nitrogen optionally sufficient to minimize contamination risks. Temperature adjustments should align with strain preferences—28–29°C for Frankia and 32–35°C for Protofrankia—while maintaining an alkaline pH. Given potential extended incubation periods (predicted doubling times ranging from 3.26 to 9.60 days, possibly up to 21.98 days), patience and rigorous contamination monitoring are crucial for optimizing cultivation conditions.

Objective: In external radiotherapy, dose boluses and compensators are used for treatment of irregular facial topography surfaces. In such cases, skewed isodose curves need to be addressed using a bolus that gives the deep dose distribution a shape adapted to the anatomical structures to be protected or irradiated. The combination of 3D modeling and printing technologies is a promising alternative to the conventional inaccurate and uncomfortable bolus fabrication technique. In this work, the proposed technologies will be used in the design and fabrication of high-performance and high-accuracy boluses that respond to the main constraints on metrology, adhesion to the patient's surface, comfort, and dose delivery. Methods: As a first phase in the implementation of the proposed solution, 3D printing materials, to be used in the fabrication of radiotherapy boluses, were selected and characterized to check how they respond to the required criteria on functionality, safety, and quality. Results: The obtained results show that among the studied materials, thermoplastic polyurethane (TPU) was found to be slightly more suitable than polylactic acid (PLA) for the fabrication of 3D printing boluses but for some kinds of treatments, PLA may be preferred despite its relative rigidity. Conclusion: In this work, procedures for dose bolus fabrication were proposed, and necessary data were obtained for some available 3D printing materials (TPU and PLA) that can be used for targeted applications. This achievement is a major step toward the final implementation of 3D modeling and printing technologies for the efficient fabrication of radiotherapy dose boluses.