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Objectif : Les manifestations neurologiques et psychiatriques comptent parmi les atteintes viscérales les plus sévères et sont regroupées sous le terme général de « neurolupus ». Nous rapportons le cas d’un patient ayant présenté un accès psychotique aigue révélant un neurolupus. Observation : Patient de 21 ans, sans antécédents psychiatriques personnels ni familiaux connus suivi depuis janvier 2022 pour un LES hospitalisé à quelques reprises dans le service de rhumatologie dont la dernière remonte en juillet 2022. Il fut traité par de l’hydroxychloroquine et une corticothérapie à faible dose. Deux mois après sa dernière hospitalisation le patient a présenté des troubles cognitifs, un refus de s’alimenter et un ralentissement psychomoteur. L’examen psychiatrique notait une humeur labile, un mutisme, une insomnie de maintien, un syndrome confusionnel fait d’amimie, de regard figé, d’écholalie et de désorientation temporo-spatiale. L’exploration de la pensée a révélé un cours continu marqué par un délire passionnel à mécanisme hallucinatoire. Ces hallucinations étaient auditives et visuelles en dehors de toute période confusionnelle « il y a des gens qui jouent et qui me demandent de danser et de chanter ». L’examen neurologique était sans particularité. L’imagerie par résonance magnétique cérébrale a objectivé une atrophie cortico sous corticale sévère. Le patient a bénéficié d’un bolus de corticoïdes pendant trois jours puis relayé par voie orale et de l’hydroxychloroquine. Sur le plan psychiatrique, le patient fut traité par du rispéridone comprimé. Conclusion : Le neurolupus chez les sujets jeunes de sexe masculin sont extrêmement rares posant véritablement problème de diagnostic différentiel dans notre contexte. Il doit être recherché systématiquement même en absence de signes neurologiques afin d’améliorer la prise en charge.

ABSTRACT This study evaluated the substitution of commercial antibiotics with phytotherapeutics and probiotics in Japanese quail diets during the rearing phase, and their effects on performance, serum metabolites, organ weight and size, and egg quality in the initial laying phase. Conducted over 42 days with 300 quails, starting at 21 days of age and an average weight of 87 ± 3.5 g, the quails were divided into five groups: negative control (no additives), commercial antibiotics, probiotics (BS Gold®), essential oils (Phyto 100®), and natural pollen. The experiment was analyzed using variance analysis and Tukey’s test with a 5% significance level. Feed conversion differed significantly in the periods between 28-35 and 35-42 days. Egg quality showed variations, with higher albumen height in the probiotic group, better yolk height and luminosity with pollen, increased luminosity in the control group, and a larger yolk diameter with phytotherapeutics. The findings indicated that essential oils, probiotics, and pollen effectively replaced antibiotics without negatively affecting zootechnical performance, serum metabolites, or organ weight and size. Additionally, egg performance and quality were maintained during the initial laying phase.

Jennifer Dine,1 Yanfen Guan,2 Mirline Milien,1 Claire Ervin,1 Dana D Byrne,2 Michelle L Brown,2 Carisa De Anda,2 Josephine M Norquist2 1RTI Health Solutions, Research Triangle Park, Durham, NC, USA; 2Merck & Co., Inc., Rahway, NJ, USACorrespondence: Jennifer Dine, Patient-Centered Outcomes Assessment, RTI Health Solutions, 3040 E Cornwallis Road, Research Triangle Park, Durham, NC, 27709, USA, Email jdine@rti.orgIntroduction: The COVID-19 Symptoms Daily Diary (CSDD) is a patient-reported outcome measure designed to assess the severity of core COVID-19 symptoms in clinical trials. The preliminary version of the CSDD was developed based on regulatory guidance and the hallmark COVID-19 symptoms identified by the CDC. This study aimed to evaluate CSDD content validity, to determine whether it is fit for the purpose of supporting efficacy endpoints in clinical trials of treatments for COVID-19. This research also sought to evaluate the appropriateness of a newly developed Pre–COVID-19 Symptoms Questionnaire.Methods: A targeted literature review was completed to evaluate the relevance of concepts included in the diary and to identify any important symptoms that may have been missing. Hybrid (concept elicitation and cognitive debriefing) semistructured qualitative interviews were then conducted across 3 iterative rounds with 30 adults in the United States recently diagnosed with COVID-19.Results: The CSDD included concepts that were most frequently reported by interview participants, including those identified as most bothersome and most important to treat. During cognitive debriefing, participants described the diary concepts as salient and reported the instructions, recall period, and response options as clear and appropriate. Only 2 of 15 CSDD items were modified across 3 interview rounds; specifically, definitions for the vomiting and diarrhea frequency items were clarified for consistent interpretation and response. Interview participants also reported general ease in understanding and responding to the Pre–COVID-19 questionnaire, with feedback resulting in only minor changes to the reference period and instructions.Conclusion: The findings of the current study provide strong evidence for the content validity of the CSDD and the appropriateness of each of the items assessed. This rigorous evaluation (aligned with regulatory guidance) indicates that the CSDD is fit for the purpose of supporting efficacy endpoints in planned clinical trials evaluating medications for COVID-19 treatment.Keywords: patient-reported outcome measures, COVID-19, qualitative, symptom burden

Exposure to alcohol during pregnancy produces Fetal Alcohol Spectrum Disorders, which in its most severe form is characterized by physical dysmorphology and neurobehavioral alterations. Moderate prenatal alcohol exposure (mPAE) is known to produce deficits in discrimination of spatial locations in adulthood. However, the impact of mPAE on higher-order sensory representations, such as discrimination of perceptually similar stimuli, is currently unknown. In the present study, we tested the hypothesis that mPAE would disrupt performance on hippocampal-sensitive tasks that require discrimination between perceptually similar objects or discrimination between spatial locations in a radial arm maze. Here we report that male mPAE rats exhibited intact performance on three types of object discrimination tasks: one in which rats discriminated between distinct toy objects, a second in which discrimination was made between distinct and similar LEGO objects, and a mnemonic similarity task in which rats discriminated between randomly presented LEGO objects that varied in similarity with a learned object. Although adult male mPAE rats performed similarly to control rats on all three object discrimination tasks, they showed deficits when tested in a radial arm maze spatial discrimination task. Specifically, male mPAE rats expressed a significantly higher number of working memory errors (returns to previously visited arms) and were more likely to use non-spatial strategies during training. Together, the findings of the present study support the conclusion that mPAE produces specific deficits in the online processing of spatial information and executing spatial navigation strategies, but spares the ability to discriminate between perceptually similar stimuli., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Stress is a known contributor to psychosocial pathological conditions and reduction of well-being. The literature has highlighted the role of emotional schemas and psychological flexibility as psychological processes underlying this relationship in the short term. This two-wave longitudinal study analyses the mediating role of psychological flexibility and emotional schemas in the relationship between stress responses to COVID-19-related events and mental health 6 months later. Two hundred and seventy-six individuals were included in this study, completing measures of stress responses, emotional schemas, psychological flexibility and positive and negative mental health. Negative evaluation of emotions was a significant mediator in the longitudinal relationship between stress responses and negative mental health. Valued action and openness to experience mediate the longitudinal relationship between stress responses and positive mental health. This study underscores the importance of the different dimensions of psychological processes, suggesting that over time, more maladaptive psychological processes play a significant role in elucidating the relationship between stress responses and negative mental health. Similarly, it suggests that more adaptive processes may help explain the relationship between stress responses and positive mental health. This contributes to a better understanding of the stability of these processes, which is important for determining which intervention targets should be prioritised., (© 2024 The Author(s). Applied Psychology: Health and Well‐Being published by John Wiley & Sons Ltd on behalf of International Association of Applied Psychology.)

Study Design: A retrospective chart review was conducted at a single institution., Objective: The purpose of this study was to investigate the clinical outcomes of cervical disc arthroplasty (CDA) used for the treatment of symptomatic adjacent segment disease (ASD) developed after anterior cervical discectomy and fusion (ACDF)., Background: A major clinical concern following ACDF is the development of ASD. ASD after ACDF is often treated with an additional fusion, but risks include pseudoarthrosis and further ASD. CDA is a motion-preserving alternative that addresses these concerns, and therefore, has been proposed as an alternative treatment for ASD after ACDF., Materials and Methods: Patients who underwent CDA at level(s) adjacent to a prior ACDF (n = 120) were identified from a consecutive series of patients who underwent CDA at one institution. Pre-CDA to post-CDA patient-reported outcome measures were compared using the paired Wilcoxon signed-rank test., Results: A total of 142 devices were implanted-98 patients underwent a 1-level CDA, and 22 patients underwent a 2-level CDA. The mean follow-up duration after CDA was 32.11 months. Neck pain, arm pain, and Neck Disability Index scores significantly improved from the preoperative to postoperative time point (respectively: 6.14-3.02, 4.42-1.61, 44.28-28.62, all P < 0.001). In total, 7 patients underwent reoperation (5.83%). One of these patients underwent reoperation for pseudarthrosis at the level of ACDF following a hybrid procedure. The indications for index level reoperations (n = 3) were foraminal stenosis, osteolysis, and postoperative hematoma. All patients with an adjacent level reoperation (n = 3) received surgery at levels adjacent to the prior fusion, not the more recent CDA., Conclusion: The results of this study found that CDA was effective for the treatment of ASD following ACDF. CDA appears to be a viable treatment option for ASD after ACDF in appropriately selected patients., Competing Interests: No funding was received in support of this study. A.M.S. royalties and consulting for DeGen Medical, stock and scientific advisory board for AGADA. R.D.G. speaking/teaching and consulting for Globus and Centinel Spine. S.L.B. consulting for Globus, Centinel Spine, Degen Medical, and Neo Spine. J.E.Z. consulting for Spineway, Globus, Centinel Spine, and Orthofix, royalties for ZimVie, scientific advisory board for Safe Orthopedics. J.L.S. consulting and speaking/teaching for Globus, consulting for Centinel Spine, SeaSpine, Axis Spine, and ZimVie/Highridge. P.B.D. speaking/teaching with joimax, Arthrex, Degen Medical, and Accelus, royalties from Accelus and DeGen Medical, stock ownership with Goldfinch Health, consulting for joimax, Accelus, and DeGen Medical. The remaining authors report no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

RBCs deformability plays a crucial role in maintaining proper blood flow and oxygen delivery throughout the body. Conventional ektacytometry fails to differentiate between variations in deformability of RBC subpopulations as the averaging measurement process obscures these differences. In this study, we introduced an approach that integrates label-free optics-based techniques (flow cytometry, phase-contrast, and two-photon excitation fluorescent microscopy) with ektacytometry to evaluate subpopulations that exhibit decreased RBCs deformability upon an in vitro oxidation using 0.5 mM TBHP, as a low-level oxidative agent. We found that flow cytometry can easily detect rigidified and oxidized subpopulations based on FSC/SSC light distribution, as well as RBCs fluorescence intensity and peak area likely originating from hemoglobin photo and/or degradation products. Two-photon excitation fluorescence microscopy proved altered morphology and spatial location of fluorescence intensity signal near the membrane of oxidized RBCs, when compared to control RBCs, indicating a link with the reduced deformability. The proposed label-free optics-based methodology, which combines established techniques with more sophisticated microscopy, emerges as a promising tool for detecting mechano-biological changes in different RBC subpopulations induced by oxidative stress. The findings suggest potential applications in clinical practice for monitoring pathological conditions influenced by physical or environmental stress and as a quality control measure for stored RBCs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Antimicrobial resistance is currently one of the biggest challenges in controlling infectious diseases and was listed among the top 10 threats to global health by the World Health Organization (WHO) in 2023. The antibiotics misuse has led to the widespread emergence of antimicrobial resistance, marking the beginning of the alarming increase in antibiotic resistance. In this context, Antimicrobial Photodynamic Therapy (aPDT) has garnered significant attention from the scientific community due to its potential to effectively eliminate multidrug-resistant pathogenic bacteria and its low propensity to induce drug resistance, which bacteria can quickly develop against traditional antibiotic treatments. However, some efflux pumps can expel diverse substrates from inside the cell, including photosensitizers used in aPDT, contributing to multidrug-resistance mechanisms. Efflux Pump Inhibitors are potential solutions to combat resistance mediated by these pumps and can play a crucial role in enhancing aPDT's effectiveness against multidrug-resistant bacteria. Therefore, combining efflux pumps inhibitors with photosensitizers can possible to eliminate the pathogen more efficiently. This review summarizes the mechanisms in which bacteria resist conventional antibiotic treatment, with a particular emphasis on efflux pump-mediated resistance, and present aPDT as a promising strategy to combat antibiotic resistance. Additionally, we highlighted several molecules of photosensitizer associated with efflux pump inhibitors as potential strategies to optimize aPDT, aiming to offer a perspective on future research directions on aPDT for overcoming the limitations of antibiotic resistance., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Obesity is a complex disease marked by increased adiposity and impaired metabolic function. While diet and lifestyle are primary causes, endocrine-disrupting chemicals (EDCs), such as bisphenol A (BPA), significantly contribute to obesity. BPA, found in plastic consumer products, accumulates in the hypothalamus and dysregulates energy homeostasis by disrupting the neuropeptide Y (NPY)/agouti-related peptide (AgRP) and pro-opiomelanocortin (POMC) neurons. However, the precise molecular mechanisms of how BPA disrupts neuropeptide expression remains unclear. We hypothesized that microRNAs (miRNAs), which regulate approximately 60% of the human protein-coding genome and are crucial for hypothalamic energy regulation, may mediate the effects of BPA on Agrp. Using the TargetScanMouse 8.0 and DIANA microT bioinformatics tools, we identified miR-501-5p as a potential miRNA that directly regulates Agrp and the miR-34 family as miRNAs that indirectly regulate Agrp through its transcription factor krüppel-like factor 4 (KLF4). We found that in an immortalized NPY/AgRP-expressing cell line, mHypoE-41, miR-501-5p unexpectedly upregulated Agrp, while miR-34a-5p reduced Klf4 and Agrp mRNA levels. Serum starvation reduced miR-34a-5p levels and elevated Agrp mRNA levels, suggesting a potential role in AgRP regulation. Inhibiting the miR-34a-5p interaction with the Klf4 3'UTR using a specific target site blocker prevented the downregulation of both Klf4 and Agrp, suggesting miR-34a-5p alters Agrp mRNA levels via regulation of KLF4. BPA treatment increased Agrp and Klf4 expression while simultaneously decreasing miR-34a-5p levels, indicating miR-34a-5p may play a role in BPA-mediated dysregulation of Agrp. Overall, this study highlights indirect miRNA-based regulation of Agrp, which can also be dysregulated by obesogens, such as BPA., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objective: To investigate the efficacy of dual kidney transplantation (DKT) from adult donors. Methods: Clinical data of adult DKT donors and recipients in the Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology from March 2015 to June 2024 were retrospectively analyzed. The patients were followed up until September 2024. The clinical data of donor and recipient, donor kidney, surgical techniques, complications, and follow-up were collected. Transplant renal function and recipient/graft survival rates within 5 years were analyzed. Results: A total of 102 pairs of DKT donors and recipients were included. Among the donors, 83 were male and 19 were female, with age of (57.8±11.1) years and body mass index (BMI) of (23.1±3.2) kg/m². Among the recipients, 95 were male and 7 were female, with age of (42.0±11.0) years and BMI of (22.1±3.1) kg/m². The postoperative hospitalization and follow-up duration [ M ( Q 1 , Q 3 )] for recipients were [20.0 (15.0, 27.0)] days and [30.0 (12.5, 49.0)] months, respectively. China Class Ⅱ donation accounted for 64.7% (66/102) of donor categories. The pre-procurement serum creatinine (Scr) level of donors was [97.0 (66.5, 144.5)] μmol/L, and the hypothermic machine perfusion utilization rate was 52% (53/102). The warm ischemia time was (5.5±1.7) minutes, and the mean cold ischemia time was (8.7±3.8) hours. The Remuzzi scores for the left and right kidneys before transplantation were (4.8±1.3) and (5.1±1.4) scores, respectively. The glomerulosclerosis rates for the left and right kidneys were 34.0%±16.2% and 35.3%±16.7%, respectively. The primary nephropathy was unknown in 80.3% (82/102) of recipients, and IgA nephropathy was diagnosed in 8.8% (9/102) of the recipients. Bilateral kidneys were implanted ipsilaterally in 94.1% (96/102) of recipients, with operative time of (5.3±1.4) hours. Lymphocyte-depleting induction therapy was administered to 74.5% (76/102) of recipients. One recipient experienced primary graft non-function after surgery. The incidences of delayed graft function and rejection were 30.4% (31/102) and 9.8% (10/102), respectively. The overall incidence of surgical complications was 10.8% (11/102). The 1, 3, and 5-year recipient survival rates were 100.0%, 98.3%, and 98.3%, respectively. The 1, 3, and 6-month and 1, 3, and 5-year graft survival rates were 97.1%, 96.1%, 95.0%, and 94.0%, 89.3%, 85.6%, respectively. The recipient's kidney function remains stable for 5 years after transplantation. At 5 years, the recipient median Scr level and mean estimated glomerular filtration rate (eGFR) were 153.0 (120.0, 232.0) μmol/L and (42.1±17.1) ml -1 ·min -1 ·(1.73 m²) -1 , respectively. Conclusion: Adult donor DKT demonstrates favorable short-term and 5-year clinical efficacy.

BACKGROUND: On-pitch rehabilitation is a crucial part of returning to sport after injury in elite soccer. The control-chaos continuum ( CCC ) initially offered a framework for practitioners to plan on-pitch rehabilitation, focusing on physical preparation and sport specificity. However, our experiences with the CCC , combined with recent research in injury neurophysiology, point to a need for an updated model that integrates practice design and physical-cognitive interactions. CLINICAL QUESTION: What are the insights from injury neurophysiology, soccer performance, and coaching science needed to update the CCC and improve the planning, delivery, and progression of on-pitch rehabilitation in elite soccer? KEY RESULTS: Drawing on extensive experience in elite sport, we explain how recent research on neurophysiological recovery from injury, game models, and practice design has been applied to update the CCC and evolve the existing framework. CLINICAL APPLICATION: The evolution of the CCC expands on the original model to enhance planning, delivery, and progression of on-pitch rehabilitation. The updated framework incorporates elements of visual cognition, attentional challenges, decision-making, and progressive representation of the game model to enhance sport-specific preparation for returning to sport. J Orthop Sports Phys Ther 2025;55(2):1-11. Epub 3 January 2025. doi:10.2519/jospt.2025.13158 .

A CT-based method for objectively assessing fracture severity was previously developed and validated to address poor reliability in existing subjective fracture classification systems. The method involved quantifying the energy involved in creating a fracture. However, clinical utility of the method was hindered by reliance upon an intact contralateral CT and lengthy analysis time (8-10 h). Significant methodological improvements detailed here enable the assessment of fracture severity in any joints and bones, while obviating the need for an intact contralateral CT scan. Analysis time was reduced to <2 h per case. Fracture energies computed using the new methods showed strong agreement (R 2  = 0.95, p < 0.001) with prior results in analyzing twenty tibial pilon fractures. New metrics, articular fracture edge length and subchondral energy, were developed to better describe joint injuries by incorporating knowledge of preferential chondrocyte death along fracture edges. Based on two-year radiographic grading for these pilon fractures, fracture energy, articular fracture edge length, and subchondral energy were all significantly different (p < 0.01) between cases that did or did not develop post-traumatic osteoarthritis. These developments enable measurement of fracture severity in larger populations and in more clinically relevant timeframes with articular fractures involving a variety of joints and bones. This generalized assessment method offers opportunity to change the way severity is considered in fracture treatment algorithms. Studies involving larger cohorts are anticipated to yield insights into the impact of fracture severity on PTOA risk and serve as a foundation for evaluating new treatment strategies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Background: Talabostat, an oral small molecule inhibitor of dipeptidyl peptidases (DPP4 and DPP8/9), has shown synergistic activity with immune checkpoint inhibitors in preclinical studies. This open label, phase 2 basket trial assessed the antitumor activity of combining talabostat and pembrolizumab (anti-programmed death-1 antibody) in advanced solid tumor patients., Methods: The primary objective was assessment of dose-limiting toxicity (DLT) rates in the first six patients (lead-in stage) and response rate (efficacy stage; included cohort A [checkpoint inhibitor (ICI) naive] and cohort B [ICI pretreated]) for the study treatment using the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and immune RECIST (iRECIST). Efficacy was assessed using a Bayesian optimal phase 2 design., Results: A total of 31 patients enrolled in this trial (14 in cohort A, 17 in cohort B). The median age was 61 years; 17 (55%) patients were male and 21 (68%) patients were White. Among 19 (61%) patients evaluable for response, the best response was stable disease in nine patients, unconfirmed progressive disease in seven patients, and clinical progressive disease in three patients based on iRECIST. Disease control rate was 47%. One patient with programmed death-ligand 1 negative, microsatellite stable endometrial cancer had unconfirmed partial response. Median progression-free survival was 2.7 months; median overall survival was 20.5 months. One patient (cohort A) experienced a grade 4 hypotension as a DLT and treatment discontinuation. The most common toxicities were hypotension (22.6%), fatigue (9.7%), diarrhea, rash, thrombocytopenia, vomiting, syncope, general disorders and administration site conditions-other, and skin and subcutaneous tissue disorders-other, each in 6.5% of patients., Conclusions: This study of the combination of talabostat and pembrolizumab in patients with advanced solid tumors demonstrated predictable adverse events and limited activity. The combination was shown to be safe. Efficacy data shows immune stable disease in nine of 19 evaluable patients, and an unconfirmed immune partial response in a patient with endometrial cancer., (© 2025 American Cancer Society.)

The occurrence and development of tumor is mediated by a wide range of complex mechanisms. Subsequent to nitric oxide and carbon monoxide, hydrogen sulfide (H 2 S) holds the distinction of being the third identified gasotransmitter. Alternation of H 2 S level has been widely demonstrated to induce an array of disturbances in important cancer cell signaling pathways. As a result, the effects of H 2 S-catalyzing enzymes in cancers also attract widspread attention. 3-mercaptopyruvate sulfurtransferase (3-MST) is privileged to be one of them. In fact, 3-MST is overexpressed in many tumors including human colon cancer, lung adenocarcinoma, and bladder urothelial carcinoma. But it is also lowly expressed in hepatocellular carcinoma. In this review, we focus on the generation of endogenous H 2 S and polysulfides, facilitated by 3-MST. Additionally, we delve deeply into the potential role of 3-MST in tumorigenesis and development. The impact of 3-MST inhibition on the development of tumors and its potential for tumor therapy are also highlighted., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025. Published by Elsevier Inc.)

Background: Ex-vivo lung perfusion (EVLP) has potential to expand donor lung utilization, evaluate allograft viability, and mitigate ischemia-reperfusion injury. However, trends in EVLP use and recipient outcomes are unknown on a national scale. We examined trends in EVLP use and recipient outcomes in the United States., Methods: Adult patients undergoing lung transplant between 2013 and 2023 were identified in the Standard Transplant Analysis and Research-Organ Procurement and Transplantation Network database. Effects of EVLP use on center volume changes were assessed using difference-in-difference analysis. Multivariable logistic regression was used to evaluate associations between EVLP use and recipient 30-day mortality, post-operative length of stay, grade 3 primary graft dysfunction (PGD), and need for mechanical ventilation at 72 hours., Results: Of 23,807 lung transplants during the study period, 813 utilized EVLP. While transplant volume increased over time, this was not attributable to EVLP use. Recipients in the EVLP cohort demonstrated increased 30-day mortality [3.8% vs 2.4%; OR 1.57 (1.02-2.41); p = 0.040], mechanical ventilation at 72 hours [40.2% vs 31.2%; OR 1.58 (1.33-1.87); p < 0.001], and longer postoperative length of stay (35.8 vs 30.0 days; IRR 1.19 (1.18-1.21); p < 0.001) compared to the non-EVLP cohort. No difference in grade 3 PGD was found between groups [14.5% vs 14.1%; OR 1.04 (0.80-1.34); p = 0.791]., Conclusions: Although annual transplant volume has increased, the upward trend cannot yet be attributed to EVLP use. In the largest study to date, our results suggest outcome differences between EVLP and non-EVLP recipient cohorts. This motivates future work to characterize how patient selection and institutional factors influence outcomes with EVLP use., (Copyright © 2024 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Colorectal cancers (CRCs) from people with biallelic germline likely pathogenic/pathogenic variants in MUTYH or NTHL1 exhibit specific single base substitution (SBS) mutational signatures, namely combined SBS18 and SBS36 (SBS18+SBS36), and SBS30, respectively. The aim was to determine if adenomas from biallelic cases demonstrated these mutational signatures at diagnostic levels., Methods: Whole-exome sequencing of FFPE tissue and matched blood-derived DNA was performed on 9 adenomas and 15 CRCs from 13 biallelic MUTYH cases, on 7 adenomas and 2 CRCs from 5 biallelic NTHL1 cases and on 27 adenomas and 26 CRCs from 46 non-hereditary (sporadic) participants. All samples were assessed for COSMIC v3.2 SBS mutational signatures., Results: In biallelic MUTYH cases, SBS18+SBS36 signature proportions in adenomas (mean±standard deviation, 65.6 %±29.6 %) were not significantly different to those observed in CRCs (76.2 % ± 20.5 %, p-value=0.37), but were significantly higher compared with non-hereditary adenomas (7.6 % ± 7.0 %, p-value=3.4 × 10 -4 ). Similarly, in biallelic NTHL1 cases, SBS30 signature proportions in adenomas (74.5 %±9.4 %) were similar to those in CRCs (78.8 % ± 2.4 %) but significantly higher compared with non-hereditary adenomas (2.8 % ± 3.6 %, p-value=5.1 × 10 -7 ). Additionally, a compound heterozygote with the c.1187G>A p.(Gly396Asp) pathogenic variant and the c.533G>C p.(Gly178Ala) variant of unknown significance (VUS) in MUTYH demonstrated high levels of SBS18+SBS36 in four adenomas and one CRC, providing evidence for reclassification of the VUS to pathogenic., Conclusions: SBS18+SBS36 and SBS30 were enriched in adenomas at comparable proportions to those observed in CRCs from biallelic MUTYH and biallelic NTHL1 cases, respectively. Therefore, testing adenomas may improve the identification of biallelic cases and facilitate variant classification, ultimately enabling opportunities for CRC prevention., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Robert C. Grant received a scholarship from Pfizer and provided consulting or advisory roles for Astrazeneca, Tempus, Eisai, Incyte, Knight Therapeutics, Guardant Health, and Ipsen. All other authors have no relevant financial or non-financial interests to disclose., (Copyright © 2024. Published by Elsevier Inc.)

Background and Objective: Lymph node dissection (LND) has been standard in cancer surgery for more than a century, yet evidence from randomized trials showing a benefit is scarce. We conducted a clinically integrated randomized trial comparing limited versus extended pelvic LND (PLND) during radical prostatectomy and previously reported comparable biochemical recurrence (BCR) rates. We report updated BCR rates and compare rates of metastasis between the study arms., Methods: Between October 2011 and March 2017, 1432 patients undergoing radical prostatectomy were enrolled at a single center. Surgeons were cluster randomized to perform limited (external iliac nodes) or extended PLND (external iliac, obturator, and hypogastric nodes) with crossover for 3-mo periods. Cox proportional-hazards regression with robust standard errors clustered by surgeon was used to assess whether the PLND template affected BCR or distant or locoregional metastasis., Key Findings and Limitations: There were 452 BCR events at median follow-up of 4.2 yr for participants who did not develop BCR. The results confirm our previous finding of comparable BCR rates between the arms (hazard ratio [HR] 1.05, 95% confidence interval [CI] 0.97-1.13; p = 0.3). However, with 123 metastasis events and median follow-up of 5.4 yr for patients without metastasis, we found a clinically and statistically significant protective effect of extended PLND against metastasis (any metastasis: HR 0.82, 95% CI 0.71-0.93; p = 0.003; distant metastasis: HR 0.75, 95% CI 0.64-0.88; p < 0.001)., Conclusions and Clinical Implications: Patients undergoing radical prostatectomy should receive extended PLND that includes the external iliac, obturator, and hypogastric nodes. Further research should examine biological mechanisms regarding the anatomic location of affected nodes. Trials of LND for other cancers are warranted and should consider our clinically integrated design. This trial is registered on ClinicalTrials.gov as NCT01407263., (Copyright © 2024. Published by Elsevier B.V.)

Aims: Obesity always leads to profound perturbation of metabolome. Metabolome studies enrich the knowledge on associations between endogenous metabolites and obesity, potentially providing innovative strategies for the development of novel anti-obesity pharmacotherapy. This study aims to identify an endogenous metabolite that regulates energy expenditure and to explore its application for obesity treatment., Materials and Methods: C57BL/6 mice were fed with a high-fat and high-cholesterol (HFC) diet, comprising 60% fat and 1.2% cholesterol, for 12 weeks to induce obesity. Significant metabolites were identified in the livers of both health and obese mice through comparative hepatic metabolomics analysis. Correlation between serum or adipose L-aspartate level and body weight in obese mice, as well as human body mass index (BMI), was evaluated. In addition, saline or 200 mg/kg L-aspartate was orally administrated to HFC diet mice and HFC diet-induced obese mice for 6-7 weeks. Body weight, adipose tissue weight, glucose tolerance and liver damage were assessed to evaluate the effect on obesity prevention and treatment. Comprehensive lab animal monitoring system (CLAMS) and seahorse assay were employed to investigate the regulatory effect of L-aspartate on energy metabolism in vivo and in vitro, respectively. 3T3-L1 preadipocytes and murine white adipose tissue (WAT) were utilized to examine the impact of L-aspartate on adipocyte adipogenesis and lipogenesis and cellular signalling pathway in vitro and in vivo., Results: L-aspartate, an approved drug for liver injury and chronic fatigue, was identified as an endogenous inducer of energy expenditure. Serum or adipose L-aspartate levels were found to be negatively correlated with the severity of obesity in both humans and mice. Administration of L-aspartate to HFC diet mice led to a significant reduction in body weight, with decreases of 14.5% in HFC diet mice and 8.5% in HFC diet-induced obese mice, respectively. In addition, the treatment improved related metabolic syndrome (Figure 2 and Figure S3). These therapeutics were associated with enhancements in whole-body energy expenditure and suppression of adipocyte adipogenesis along with activation of Adenosine 5'-monophosphate-activated protein kinase (AMPK) signalling pathway., Conclusion: L-aspartate may serve as a novel endogenous inducer of energy expenditure and suppressor of adipogenesis and lipogenesis along with activation of AMPK, thereby offering a promising therapeutic strategy for obesity prevention and treatment., (© 2024 John Wiley & Sons Ltd.)

A current challenge in the rational design of biomolecular sensors is the ability to custom design binding affinities and detection mode in silico. To this end, we re-engineered a previously reported computationally-designed fluorescent maltooligosaccharide (MOS)-detecting biosensor to both alter its ligand-binding affinity and to analyse the underlying sensing mechanism. The dynamic range of the biosensor was expanded through the computer aided introduction of a series of amino acid substitutions in the starting protein scaffold (MalX from Streptococcus pneumoniae), which generated a biosensor set with binding affinities spanning over five orders of magnitude. The impact of the introduced substitutions on the underlying mode of signal generation was assessed in silico using our previously reported Computational Identification of Non-disruptive Conjugation sites (CINC) pipeline. CINC utilizes molecular dynamics simulations and an in-house developed algorithm to examine and exploit the structural dynamics of a protein at amino acid-level resolution. Using CINC, we demonstrate that re-engineering of the MOS-detecting biosensor set resulted in sensors with two distinct output modes which differed based on local conformational changes at the fluorescently modified reporter position. These output modes were classified as "ligand-sensing"-type biosensors (readout based on the tool sensing a unique conformation in the ligand-bound state), and "apo-sensing"-type biosensors (readout based on the tool sensing a unique conformation in the apo state). Together, these results demonstrate that structural dynamics at the individual amino acid residue level can be used as an engineer-able feature to rationally alter the fluorescence reporting properties of a biosensing device. Moving forward, the CINC workflow can also be adapted for the rational design of protein dynamic properties maximizing its utility as an in silico design platform for custom biomolecular tools., Competing Interests: Declaration of competing interest DDS, DWA, and HJW are Joint Inventors on International PCT Patent Application No. CA2021/05/01/10 (Filed January 30, 2021) which describes the CINC biosensor design process., (Crown Copyright © 2025. Published by Elsevier Inc. All rights reserved.)

Cystic fibrosis (CF) respiratory outcomes are heavily influenced by complications of infection. Pseudomonas aeruginosa and Staphylococcus aureus are the most common colonizers of the cystic fibrosis lung, and frequently overlap to cause chronic and persistent coinfections associated with severe disease. However, the dynamics of P. aeruginosa and S. aureus coinfection and its impacts on the development of CF lung structural damage are poorly understood. Additionally, small colony variants (SCVs) of S. aureus have been associated with P. aeruginosa infections in people with CF, but their role in disease progression is largely unknown. In this work, the CF rat was used to model chronic lung coinfection with P. aeruginosa and S. aureus, using clinically and laboratory-derived normal colony and SCV strains of S. aureus to evaluate the impact of phenotype on clinical outcomes. Rats coinfected with clinically derived S. aureus of both phenotypes experienced increased inflammation in the lung. However, only the combination of P. aeruginosa and clinically normal colony S. aureus led to lung structural decline, including mucus obstruction and bronchiectasis. Regression analyses showed that the damage was associated with a higher burden of P. aeruginosa. These data indicate that chronic coinfection with normal colony S. aureus and P. aeruginosa may support the progression CF lung decline driven by P. aeruginosa, which might be avoided when coinfecting S. aureus exhibits the SCV phenotype., Competing Interests: Disclosure Statement None declared., (Copyright © 2025 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Stroke leaves a great economic burden due to its high morbidity and mortality. Rapid revascularization of targeted vessel(s) is the effective treatment for ischemic stroke, but subsequent ischemia-reperfusion (I/R) injury is a common complication following revascularization, leading to microcirculation dysfunction and infarct volume increase. Thrombo-inflammation, the interaction between thrombosis and inflammation, plays a critical role in the pathophysiology of ischemic stroke. In the context of I/R injury, thrombo-inflammation consists of platelet activation, endothelial injury, and inflammatory cell infiltration. Numerous studies are devoted to exploring methods of regulating thrombo-inflammation to mitigate I/R injury post-stroke, including blocking activations of platelets and neutrophils. Drugs such as antiplatelet medications, anticoagulants, and glucocorticoids have been confirmed to have the potential to regulate thrombo-inflammation. Furthermore, several recently developed drugs have also shown promises in relieving I/R injury by manipulating thrombo-inflammation. However, the majority of these studies are still in the preclinical stage. Herein, in this review, we will address the mechanisms of thrombo-inflammation in ischemic stroke, related research advances, and particularly the clinical feasibility of thrombo-inflammation as a therapeutic strategy against I/R injury., Competing Interests: Declarations. Conflict of Interest: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Risk difference is a valuable measure of association in epidemiology and healthcare which has the potential to be used in medical and clinical variable selection., Objective: In this study, an attribute ranking algorithm, called AttributeRank, was developed to facilitate variable selection from clinical data sets., Methods: The algorithm computes the risk difference between a predictor and the response variable to determine the level of importance of a predictor. The performance of the algorithm was compared with some existing variable selection algorithms using five clinical data sets on neonatal birthweight, bacterial survival after treatment, myocardial infarction, breast cancer, and diabetes., Results: The variable subsets selected by AttributeRank yielded the highest average classification accuracy across the data sets, compared to Fisher score, Pearson's correlation, variable importance function, and Chi-Square., Conclusion: AttributeRank proved to be more valuable in attribute ranking of clinical data sets compared to the existing algorithms and should be implemented in a user-friendly application in future research., (© 2024 The Author(s). Journal of Evaluation in Clinical Practice published by John Wiley & Sons Ltd.)

The promise of injection of extracellular matrix (ECM) from animal hearts as a treatment of myocardial ischemia has been limited by immune reactions and harsh ECM-damaging extraction procedures. We developed a novel method to produce lab-grown human three-dimensional (3-D) acellular ECM particles from human mesenchymal stem cells (MSCs) to mitigate product variability, immunogenicity, and preserve ECM architecture. We hypothesized that intramyocardial injection (I/M) of this novel ECM (dia ∼ 200 microns) would improve cardiac function in a postmyocardial infarction (MI) murine model. WT mice aged 8-10 wk underwent ligation of the left anterior descending coronary (LAD) artery and I/M injection of 10 μL ECM or normal saline ( n = 10/group). Compared with control, ECM-treated hearts showed significant reduction in infarct size ( P = 0.04), increased capillary density in ischemic myocardium ( P = 0.01), and increased fractional shortening (FS) ( P < 0.05) on postoperative days (POD) 14 , 21 , and 28 by echocardiography. There were no significant differences in immunogenic response as determined by TNFα, IL6, CD86, or CD163 levels ( P > 0.05 for all) in the hearts. Biodistribution of fluorophore-conjugated ECM demonstrated localized epifluorescence in the heart after I/M injection, without significant peripheral end organ epifluorescence. Proteomic analysis of ischemic and perfused myocardium from control and ECM-treated hearts using LC-MS/MS ( n = 3/group) detected significant changes in proteins involved in cardiomyocyte contractility and fatty acid metabolism. These findings suggest that 3-D ECM particles induce recovery of ischemic myocardium, by upregulating protein networks involved in cellular contractility and metabolism. Taken together, 3-D ECM particles represent a promising therapy for MI and warrant confirmatory studies in a high-fidelity large animal model. NEW & NOTEWORTHY Our novel lab-grown, human 3-D extracellular matrix (ECM) represents a novel therapeutic approach to prevent pathological remodeling and heart failure in an animal model of heart attack. This novel finding may help develop nonsurgical therapeutic modalities aimed at reducing the global burden of cardiovascular disease.

The "one-pot" cascade process involves multiple catalytic conversions followed by a single workup stage. This method has the capability to optimize catalytic efficiency by reducing chemical processes. The key to achieving cascade reactions lies in designing cascade catalysts with well-dispersed, stably immobilized, and accessible noble metal nanoparticles for multiple catalytic conversions. This work presents a strategy for creating long-lasting cascade catalysts by encapsulating Ru and Pd nanoparticles within multi-shell spongy-core porous microspheres (MS-SC-PMs). This cascade catalyst strategy enables the continuous hydrogenation of nitrobenzene to aniline and further to cyclohexylamine, demonstrating both high selectivity and conversion rates. Notably, this approach overcomes the typical challenges associated with noble metal nanoparticles, such as poor stability and recyclability, as it maintains its performance over ten consecutive cycles. Additionally, the MS-SC-PMs have the versatility to encapsulate various metal nanoparticles, providing catalytic versatility, scalability, and a promising avenue for designing long-lasting catalysts loaded with nanoparticles., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Delay discounting refers to the devaluation of an outcome as temporal delay increases. Steep discounting is characterized by preferring a smaller, immediate outcome over a larger, delayed outcome and is associated with maladaptive behaviors such as tobacco use. Previous studies have compared delay discounting outcomes between combustible cigarette (CC) smokers and nonusers using various discounting tasks. With the growing use of electronic cigarettes (e-cigarettes [EC]) and various delay discounting tasks available to researchers, we extended previous work in delay discounting and EC use in two ways. The present study assessed delay discounting in a web-based sample of 259 participants to (a) establish convergent validity across four different delay discounting tasks and (b) compare the outcomes between four subgroups: dual users, exclusive EC users, exclusive CC users, and nonusers. The four delay discounting tasks (Monetary Choice Questionnaire, 5-Trial Adjusting Delay Discounting Task [ADT-5], Temporal Discounting Questionnaire, and Brief Intertemporal Choice Task [BRIC Task]) showed moderate to strong convergent validity ( p < .001). Further, findings indicated significant differences between all four subgroups across the four different delay discounting tasks ( p < .048) with small effect sizes. Pairwise comparisons showed that exclusive EC users exhibited significantly steeper discounting than nonusers in ADT-5 ( p = .043) and BRIC Task ( p = .029) and dual users exhibited significantly steeper discounting than nonusers on ADT-5 ( p = .043) and BRIC Task ( p = .030). Our findings replicate previous findings and suggest the potential role of delay discounting in explaining the behavioral mechanism underlying e-cigarette use. (PsycInfo Database Record (c) 2025 APA, all rights reserved).

Robot-assisted physical rehabilitation offers promising benefits for patients, yet its adoption among therapists remains a complex challenge. This study investigates the acceptance of robot-assisted physical rehabilitation technology among therapists in Vietnam, a middle-income country with a growing demand for rehabilitation services. Drawing on the Technology Acceptance Model 2 (TAM2) and the Theory of Planned Behaviour (TPB), an online survey and semi-structured interviews were conducted to explore therapists' attitudes and intentions towards using this technology. The results show that Vietnamese therapists recognised its potential benefits and expressed a willingness to use it. Although having similar acceptance patterns compared to developed regions, they demonstrated significantly higher levels of agreement across acceptance constructs. This may be attributed to factors such as the novelty effect, cultural perceptions of robots, and the high workload of therapists in Vietnam. Gender and location were found to influence two acceptance constructs-subjective norms and image, respectively-highlighting the need for tailored strategies in technology implementation. The study underscores the importance of considering socio-cultural factors in the adoption of technology and provides insights for enhancing the acceptance and effectiveness of robot-assisted physical rehabilitation in Vietnam. This contributes to the global understanding of therapist acceptance of technology in this field.

Background and Aims: Alcohol use is prevalent among hepatology clinic patients with chronic liver disease (CLD). We explored factors associated with the importance and confidence dimensions of motivation to reduce drinking., Methods: Participants (N = 121) with unhealthy alcohol use (i.e., over NIH guidelines) receiving care in hepatology clinics from a safety-net hospital (SN, N = 54) and two Veterans Affairs Healthcare Systems (VA, N = 67) were enrolled in an alcohol intervention trial from March 2022 through October 2023. Baseline assessments included Generalised Anxiety Disorder (GAD-7), Patient Health Questionnaire (PHQ-8), Alcohol Use Disorders Identification Test (AUDIT), COVID-19 stress; and measures of importance and confidence to decrease alcohol use (readiness rulers, scales of 1-10). Liver disease aetiology and severity were extracted from electronic health records. We performed multivariable linear regression models with forward selection to assess pre-specified variables' associations with importance and confidence., Results: The sample was 84% male, 40% Latino, 31% White, 18% Black and 11% other races; median age was 61 years. Median (Q1-Q3) AUDIT score was 16 (12-24), importance was 9 (6-10) and confidence was 8 (5-9). On multivariable analysis, VA site (vs. SN) participants had a 0.97-point lower importance score (p = 0.02); higher symptoms of depression (PHQ-8 score ≥ 10 vs. < 10) and AUDIT scores (for each point increase) were associated with higher importance score (estimates 1.2 and 0.08, p < 0.05, respectively). Liver disease aetiology and severity were not significantly associated with outcomes., Conclusions: Depression, alcohol problem severity and treatment site may influence motivation to reduce alcohol use and could inform future hepatology-based interventions., (© 2024 John Wiley & Sons Ltd.)

Prenatal alcohol exposure can produce disruptions in a wide range of cognitive functions, but it is especially detrimental to spatial navigation. In open environments, rodents organize their spatial behaviors around centralized locations, termed home bases, from which they make circuitous and slow locomotor trips (progressions) into the rest of the environment. Open-field behaviors are organized even under darkened test conditions, suggesting a role for self-motion cues (vestibular, motor, etc.). The impact of moderate prenatal alcohol exposure (mPAE) on the organization of spontaneous open-field behaviors under darkened conditions has not been investigated. Here we tested adult female and male rats with mPAE or saccharin control exposure in a circular open field for 30 min in a testing room that was made completely dark. While general locomotion, as measured by reductions in travel distance and increased stop duration, decreased across the test session, the organization of these behaviors, as measured by stop duration, home base establishment, home base stability, progression accuracy, and scaling of peak speeds with progression length, did not differ between mPAE and saccharin control rats. Together, the findings strongly suggest that spontaneous movement organization in relation to self-motion cues remains intact in adult mPAE rats. (PsycInfo Database Record (c) 2025 APA, all rights reserved).

Background: The win ratio (WR) is an emerging alternative for reporting composite outcomes, prioritizing clinically significant events such as mortality while incorporating surrogate measures. However, its benefits should be weighed against limitations, particularly the influence of lower hierarchical outcomes. This secondary analysis of the PARAGLIDE-HF trial performed a WR sensitivity analysis using a modified hierarchical composite outcome to assess the utility of WR sensitivity analysis and the efficacy of sacubitril/valsartan versus valsartan., Methods: PARAGLIDE-HF compared sacubitril/valsartan with valsartan in heart failure (HF) patients with ejection fraction >40% (N = 466). A hierarchical outcome in the primary analysis included cardiovascular death, HF hospitalizations, urgent HF visits, and change in N-terminal pro-B-type natriuretic peptide (NT-proBNP), with a 25% decrease considered a win. In the prespecified subgroup with ejection fraction ≤60% (N = 357), sacubitril/valsartan showed a treatment effect on the hierarchical outcome (WR, 1.46; 95% CI, 1.08-1.97). Sensitivity analyses for this subgroup included: (1) excluding NT-proBNP change, (2) substituting the 25% proportion change of NT-proBNP with 10% or 50%, and (3) including renal outcomes within the hierarchical outcome. In addition to the WR, the win odds (WO), in which 50% of the ties are allocated to both the numerator and denominator of the WR-a potentially more suitable modification of the WR that accounts for the presence of ties-were presented., Results: Excluding NT-proBNP (WR, 1.49; 95% CI, 1.00-2.22; WO, 1.12; 95% CI, 1.00-1.26), adjusting the NT-proBNP threshold from 25% to 10% or 50% (WR, 1.41; 95% CI, 1.06-1.89; WO, 1.27; 95% CI, 1.04-1.56 for 10%; and WR, 1.54; 95% CI, 1.11-2.12; WO, 1.25; 95% CI, 1.06-1.48 for 50%), and incorporating renal outcomes (WR, 1.44; 95% CI, 1.07-1.94; WO, 1.28; 95% CI, 1.05-1.56) consistently favored sacubitril/valsartan., Conclusions: Multiple WR sensitivity analyses support a consistent treatment benefit of sacubitril/valsartan versus valsartan in patients with ejection fraction >40% to 60%. Future studies could consider prespecifying WR sensitivity analysis for comprehensive assessment of treatment effects., Trial Registration: PARAGLIDE-HF; ClinicalTrials.gov ID, NCT03988634 (https://clinicaltrials.gov/study/NCT03988634)., Competing Interests: Conflict of interest Dr Hernandez has received research grants from American Regent, Amgen, AstraZeneca, Bayer, Bayer, Boehringer Ingelheim, Cytokinetics, Merck, Novartis, Somologic, and Verily; and has served as a consultant for Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Boston Scientific, Cytokinetics, Merck, Novartis, and Novo Nordisk. Dr Velazquez has received grants from Novartis and the National Heart, Lung, and Blood Institute/National Institutes of HealthNHLBI and serves on advisory committees for REDVIA, ABIOMED and CardioMech. Drs Ward, Williamson, and Sarwat are employees of Novartis. Dr Starling serves on the steering committee for the PARAGLIDE trial sponsored by Novartis. Dr Desai has received research grants (to BWH) from Abbott, Alnylam, AstraZeneca, Bayer, and Novartis; and has received personal consulting fees from Abbott, Alnylam, AstraZeneca, Avidity Bio- pharma, Axon Therapeutics, Bayer, Biofourmis, Cytokinetics, Glax- oSmithKline, Medpace, Merck, New Amsterdam, Novartis, Parexel, Regeneron, River2Renal, Roche, Verily, and Veristat. Dr Zieroth received research grant support, served on advisory boards for, or speaker engagements with Abbott, AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Cytokinetics, Eli Lilly, GSK, Medtronic, Merck, Novartis, Novo-Nordisk, Pfizer and Vifor Pharma; and serves on a clinical trial committee or as a national lead for studies sponsored by AstraZeneca, Boehringer Ingelheim, Merck, Novartis, Pfizer, Salubris Bio. Nonindustry: Canadian Medical and Surgical KT Group, CCS, CHFS, Charite, EOCI, Liv, Medscape, Ology, PACE-CME, Radcliffe, Reach MD, Translational Medicine Academy. Dr Solomon has received research grants from Alnylam, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Cytokinetics, Eidos, GlaxoSmithKline, Ionis, Lilly, MyoKardia, National Institutes of Health/National Heart, Lung, and Blood Institute, Novartis, Novo Nordisk, Respicardia, Sanofi Pasteur, Theracos, Actelion, Amgen, Bellerophon, Celladon, Gilead, Mesoblast, Neurotronik, and lure 11 and has consulted for Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GlaxoSmithKline, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, Akros, and Valo. Dr Mentz has received research support and/or honoraria from Novartis, Abbott, American Regent, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cytokinetics, Fast BioMedical, Gilead, Innolife, Eli Lilly, Medtronic, Medable, Merck, Novo Nordisk, Pharmacosmos, Relypsa, Respicardia, Roche, Sanofi, Vifor, Windtree Therapeutics, and Zoll., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The main phenolic derivatives and antioxidant capacity of ninety-three yellow maize varieties were investigated, together with their color parameters. Sixteen phenolics were identified in the free extract by UPLC-ESI-MS/MS, N', N″-diferuloyl putrescine and N', N″-dicoumaryl spermidine were the major phenolic derivatives. Fourteen phenolic compounds were found in the bound extract, with trans-p-coumaric acid, trans- and cis-ferulic acid being the predominant phenolic acids. The orange-yellow maize varieties presented the highest total phenolic content (TPC) and total flavonoid content (TFC), along with significantly higher antioxidant potential. Correlation analysis showed that b* value (corresponding to yellow degree) was positively correlated with the total carotenoid content (TCC), phenolic content, and antioxidant capacity (p < 0.05). Through Hierarchical Clustering Analysis (HCA), the 93 maize varieties could be divided into three categories according to b* value and antioxidant activity. The heatmap visualization further underscored the component differences across various varieties, unveiling the intricate phytochemical profiles of these maize varieties., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Aims: We aim to determine if our previously validated, diagnostic artificial intelligence (AI) electrocardiogram (ECG) model is prognostic for survival among patients with cardiac amyloidosis (CA)., Methods: A total of 2533 patients with CA (1834 with light chain amyloidosis (AL), 530 with wild-type transthyretin amyloid protein (ATTRwt) and 169 with hereditary transthyretin amyloid (ATTRv)] were included. An amyloid AI ECG (A2E) score was calculated for each patient reflecting the likelihood of CA. CA stage was calculated using the European modification of the Mayo 2004 criteria for AL and Mayo stage for transthyretin amyloid (ATTR). Risk of death was modelled using Cox proportional hazards, and Kaplan-Meier was used to estimate survival., Results: Median age of the cohort was 67 [inter-quartile ratio (IQR) 59, 74], and 71.6% were male. The median overall survival for the cohort was 35.6 months [95% confidence interval (CI) 32.3, 39.5]. For AL, ATTRwt and ATTRv, respectively, median survival was 22.9 (95% CI 19.2, 28.2), 47.2 (95% CI 43.4, 52.3) and 61.4 (95% CI 48.7, 75.9) months. On univariate analysis, an increasing A2E score was associated with more than a two-fold risk of all-cause death. On multivariable analysis, the A2E score retained its importance with a risk ratio of 2.0 (95% CI 1.58, 2.55) in the AL group and 2.7 (95% CI 1.81, 4.24) in the ATTR group., Conclusions: Among patients with AL and ATTR amyloidosis, the A2E model helps to stratify risk of CA and adds another dimension of prognostication., (© 2024 The Author(s). ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Microenvironmental contributions to soft tissue sarcoma progression are relatively undefined, particularly during sarcoma onset. Use of animal models to reveal these contributions is impeded by difficulties in discriminating between microenvironmental, precancerous, and cancer cells, and challenges in defining a precancerous microenvironment. We developed a zebrafish model that allows segregation of microenvironmental, precancerous, and cancerous cell populations by fluorescence-activated cell sorting. This model has high predilection for malignant peripheral nerve sheath tumor (MPNST), a type of soft tissue sarcoma that exhibits rapid, aggressive growth. Using RNA-seq, we profiled the transcriptomes of microenvironmental, precancerous, and cancer cells from our zebrafish MPNST model. We show broad activation of inflammation/immune-associated signaling networks, describe gene expression patterns that uniquely characterize the transition from precancerous to cancer ME, and identify macrophages as potential contributors to microenvironmental phenotypes. We identify conserved gene expression changes and candidate genes of interest by comparative genomics analysis of MPNST versus benign lesions in both humans and zebrafish. Finally, we functionally validate a candidate extracellular matrix protein, periostin (POSTN), in human MPNST. This work provides insight into how the microenvironment may regulate MPNST initiation and progression., Competing Interests: Competing interests: The authors declare no competing interests. Ethics approval and consent to Participate: All methods were performed in accordance with the relevant guidelines and regulations. All animal studies were approved by the Institutional Animal Care and Use Committee, North Carolina State University, Raleigh, NC (Animal Use Protocol 17-067-B) and by the Institutional Care and Use Committee, The Ohio State University, Columbus, OH (Animal Use Protocol 2019A00000097). Animal studies were performed in accordance with approved protocols and complied with ARRIVE guidelines. Human specimens used in this study were exempt from Institutional Review Board review and informed consent was not required., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Objective: Investigational cell therapies have been developed as disease-modifying agents for the treatment of osteoarthritis (OA), including those that inducibly respond to inflammatory factors driving OA progression. However, dysregulated inflammatory cascades do not specifically signify the presence of OA. Here, we deploy a synthetic receptor platform that regulates cell behaviors in an arthritis-specific fashion to confine transgene expression to sites of cartilage degeneration., Design: A single-chain variable fragment specific for type II collagen (CII) that is exposed in damaged cartilage was used to produce a synthetic Notch (synNotch) receptor that enables "CII-synNotch" mesenchymal stromal cells (MSCs) to recognize degraded cartilage. Artificial signaling induced by both CII-treated culture surfaces and primary tissues was measured via fluorescence and luminescence assays. Separate studies measured the ability of CII-synNotch to govern cartilage anabolic activity of MSCs. Finally, a co-culture with ATDC5 chondrocytes was used to determine whether CII-synNotch MSCs can protect chondrocytes against deleterious effects of pro-inflammatory interleukin-1 in a CII-dependent manner., Results: CII-synNotch MSCs are highly and selectively responsive to CII, but not type I collagen, as measured by luminescence assays, fluorescence microscopy, and concentrations of secreted transgene products in culture media. CII-synNotch cells exhibit the capacity to distinguish between healthy and damaged cartilage tissue and constrain transgene expression to regions of exposed CII fibers. Receptor-regulated production of cartilage anabolic and anti-inflammatory transgenes was effective to mediate cartilage regenerative functions., Conclusion: This work demonstrates proof-of-concept that the synNotch platform guides MSCs for spatially regulated, disease-dependent delivery of OA-relevant biologic drugs., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Black, Indigenous, and People of Color (BIPOC) racial/ethnic groups, sexual minorities (SM), and men have higher odds of smoking, less access to smoking cessation education and services, and lower smoking cessation rates than their white, heterosexual, and women counterparts. The purpose of this study is to examine the experiences of BIPOC gay men in accessing smoking cessation counseling from their healthcare providers and understand the facilitators and barriers to smoking cessation., Methods: This study analyzed data from BIPOC gay men who smoke daily via social media and organizational listservs throughout the United States and conducted semi-structured individual qualitative interviews. Two trained coders used thematic analysis to analyze the data., Results: Findings identified three overarching themes: 1) Sources of Information, 2) Facilitators and Barriers, and 3) Areas of Improvement for Smoking Cessation Counseling. Participants reported trusting advice from community members over healthcare providers regarding smoking cessation counseling. They also felt that the smoking cessation advice received from healthcare providers was, at times, confusing and inadequate. Identity concordance between patient and healthcare provider helped participants feel seen by their provider, which motivated them to engage in smoking cessation counseling. Finally, participants suggested improvements for smoking cessation counseling for BIPOC gay men such as integrating mental health support in smoking cessation services, accountability for patients, and providing harm reduction alternatives instead of smoking cessation only., Conclusion: BIPOC gay men who smoke daily value the importance of receiving culturally adaptive and gender-affirming care from healthcare providers who share their identities when receiving smoking cessation and harm reduction counseling., Competing Interests: Declaration of competing interest Dr. Ahluwalia received sponsored funds for travel expenses as a speaker for the 2021, 2022, and 2023 annual GTNF conference. Dr. Ahluwalia also serves as a consultant and has equity in a start-up company, Qnovia. Qnovia is a start-up company that is developing a nicotine replacement therapy prescription product. Preclinical work has been completed and the plan is to begin Phase I clinical trial work. The rest of the authors have no competing interests to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

LGBTQ+ individuals face discrimination in healthcare settings. Magnet hospitals have been associated with positive patient outcomes, yet it remains uncertain whether Magnet designation is associated with hospitals' LGBTQ+ inclusivity in policies and practices. This study examined 801 American hospitals across 47 states that participated in the Healthcare Equality Index (HEI) in 2021. Multilevel modeling was utilized to investigate the association between Magnet status and HEI scores, adjusting for hospital type and state-level covariates, including LGBTQ+ inclusiveness in laws, political climate, racial/ethnic minority population, and Medicaid expansion status. Among the 801 hospitals, 32.1% (257 hospitals) held Magnet status. Magnet hospitals demonstrated higher HEI scores compared to non-Magnet hospitals (γ = 2.13, p = 0.022), despite significant variations across states (intraclass correlation = 0.22). No significant cross-level interactions were found. Overall, Magnet designation is independently associated with improved LGBTQ+ inclusivity in hospitals regardless of the state in which the hospital is located. Policymakers and healthcare leaders should consider leveraging the Magnet Recognition Program as a benchmark for promoting LGBTQ+ inclusivity within hospitals. Additionally, all healthcare institutions should prioritize comprehensive evaluations and improvements to their policies and practices to ensure inclusivity for LGBTQ+ patients., (© 2024 The Author(s). Research in Nursing & Health published by Wiley Periodicals LLC.)

Background: Ewing's family sarcoma (EFS) is an aggressive malignancy with a peak incidence in adolescents. Multimodal treatment involves surgery and/or radiotherapy, and chemotherapy typically with VDC/IE (vincristine, doxorubicin, and cyclophosphamide alternating with ifosfamide and etoposide). There is a paucity of data for the treatment of adults, with protocols extrapolated from the pediatric setting. This study aimed to assess patterns of care, chemotherapy tolerability across age groups, and outcomes from four Australian sarcoma centers., Methods: ANZSA ACCORD sarcoma database and medical records were used to identify and collect data of patients aged ≥ 10 years with EFS who received VDC/IE between 2010 and 2020. Survival outcomes were analyzed based on chemotherapy received dose intensity (RDI). Clinical predictors of RDI were explored using logistic regression., Results: Of 146 patients with EFS, 76 received VDC/IE. The majority had localized disease (65%). Seventy-one percent completed scheduled chemotherapy, with some requiring dose reduction (29%), delay > 7 days (65%), or cycle omission (4%). Hematological toxicity was the main reason for dose reduction/delay. Fifty-seven percent patients achieved an acceptable RDI ≥85%. Compared to those aged 10-19, the odds ratio for acceptable RDI aged 40-59 was 0.20 (95% CI 0.04-0.86, p = 0.04). RDI was an independent prognostic factor for overall survival, after accounting for age, gender, Ewing's type, primary site, and stage (adjusted HR 0.25 [95% CI 0.10-0.63], p = 0.004)., Conclusion: Survival outcomes in EFS were associated with chemotherapy RDI. Older adults more commonly required dose reduction or early cessation of treatment due to toxicity. VDC/IE chemotherapy should be carefully tailored in adults > 40 years., (© 2023 The Authors. Asia‐Pacific Journal of Clinical Oncology published by John Wiley & Sons Australia, Ltd.)

Hydrogen sulfide (H 2 S) is a potent redox-active signaling molecule commonly dysregulated in disease states. The production of H 2 S and its involvement in various pathological conditions associated with mitochondrial dysfunction have extensively documented. During stress, cystathionine gamma-lyase and cystathionine beta-synthase in cytosol are copiously translocated into the mitochondria to boost H 2 S production, confirming its pivotal role in mitochondrial activities. However, little study has been done on H 2 S levels in tissues, cells and organelles, mainly due to the absence of precise and accurate detection tools. Thus, there is an urgent need to determine and monitor the levels of H 2 S in these important organelles. Fluorescent probes are efficient tools for detecting and monitoring various important biomolecules including biological thiols. The development of fluorescent probes is a multi-pronged approach which involves coupling fluorophores with responsive sites. The use of fluorescent probes for monitoring mitochondrial H 2 S levels has recently received widespread attention, resulting in numerous publications depicting their synthesis, mechanism of action, application, and potential challenges. Fluorescent probes offer precise and timely results, high sensitivity and selectivity, low biotoxicity, and minimal background interference. In this review, we aim to report designs of such probes, reaction mechanisms and their application in detecting mitochondrial H 2 S levels. Fluorescent probes can help uncover physio/pathological levels of H 2 S in essential organelles, its interactions with various biomarkers and associated consequences in biological systems., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)