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Abstract Background 2022 survey data showed 29% of Veterans utilized Veterans Affairs (VA) paid health care at a non-VA facility, 6% higher than in 2021. Despite an increase in the number of Veterans accessing care in the community via the MISSION Act Community Care Program (CCP), there is limited information on the quality of mental health care delivered to Veterans in these settings. Further, Veterans report barriers to quality care, including poor communication between CCP and VA providers, which can result in negative patient outcomes. We aimed to evaluate the feasibility and acceptability of using electronic screening, eScreening, as part of a process involving remote symptom screening, symptom monitoring, and clinically driven communication from VA to CCP providers, for Veterans accessing mental health treatment in CCP settings. Methods Veterans (n = 150) diagnosed with major depressive disorder, an anxiety disorder, post-traumatic stress disorder, and/or an adjustment disorder referred to mental health care in CCP between August-November 2021 were eligible to participate. Veterans received an eScreening link to complete an initial web-based assessment and three follow-up assessments spaced 4–6 weeks apart over the course of their treatment. Quantitative assessment data was largely characterized using descriptive statistics and included patient-reported outcome (PRO) measures (PTSD and depression), health-related quality of life/functioning, community care information (e.g., number of sessions attended), and satisfaction with the eScreening technology. Qualitative interview data was also collected from participating Veterans and CCP providers to better understand experiences with eScreening. Results Findings support the feasibility and acceptability of using eScreening to administer and monitor PROs for Veterans accessing mental health treatment in CCP. Of the Veterans who provided eScreening satisfaction ratings (Ns = 45–55), 89% had no technical difficulties; 78% felt comfortable entering personal information; and 83% were neutral or positive about ease of use. Focus group interviews revealed strong support from Veterans, who stated the software was easy to use; they felt comfortable completing PRO measures; and they appreciated having their symptoms monitored. Similarly, providers indicated eScreening had a positive impact on communication, collaboration of care, and transparency. Conclusions Technologies like eScreening represent a promising tool to support the mental health care Veterans receive when they access CCP.

Abstract GT103 is a first-in-class, fully human, IgG3 monoclonal antibody targeting complement factor H that kills tumor cells and promotes anti-cancer immunity in preclinical models. We conducted a first-in-human phase 1b study dose escalation trial of GT103 in refractory non-small cell lung cancer to assess the safety of GT103 (NCT04314089). Dose escalation was performed using a “3 + 3” schema with primary objectives of determining safety, tolerability, PK profile and maximum tolerated dose (MTD) of GT103. Secondary objectives included describing objective response rate, progression-free survival and overall survival. Dose escalation cohorts included GT103 given intravenously at 0.3, 1, 3, 10, and 15 mg/kg every 3 weeks, and 10 mg/kg every 2 weeks. Thirty one patients were enrolled across 3 institutions. Two dose-limiting adverse events were reported: grade 3 acute kidney injury (0.3 mg/kg) and grade 2 colitis (1 mg/kg). No dose-limiting toxicities were noted at the highest dose levels and the MTD was not reached. No objective responses were seen. Stable disease occurred in 9 patients (29%) and the median overall survival was 25.7 weeks (95% confidence interval [CI], 19.1–30.6). Pharmacokinetic analysis confirmed an estimated half life of 6.5 days. The recommended phase 2 dose of GT103 was 10 mg/kg every 3 weeks, however further dose optimization is needed given the absence of an MTD. The study achieved its primary objective of demonstrating safety and tolerability of GT103 in refractory NSCLC.

Abstract Plant genebanks contain large numbers of germplasm accessions that likely harbor useful alleles or genes absent in commercial plant breeding programs. Broadening the genetic base of commercial alfalfa germplasm with these valuable genetic variations can be achieved by screening the extensive genetic diversity in germplasm collections and enabling maximal recombination among selected genotypes. In this study, we assessed the genetic diversity and differentiation of germplasm pools selected in northern U.S. latitudes (USDA Plant Hardiness Zone 7 or below) originating from Eurasian germplasm. The germplasm evaluated included four BASE populations (C0) from different geographical origins (Central Asia, Northeastern Europe, Balkans-Turkey-Black Sea, and Siberia/Mongolia), 20 cycle-one populations (C1) derived from each of the four BASE populations selected across five locations in the U.S. and Canada, and four commercial cultivars. Using a panel of 3,000 Diversity Array Technologies (DArTag) marker loci, we retrieved 2,994 target SNPs and approximately 12,000 microhaplotypes. Microhaplotypes exhibited higher genetic diversity values than target SNPs. Principal component analysis and discriminant analysis of principal components revealed significant population structure among the alfalfa populations based on geographical origin, while the check cultivars formed a central cluster. Inbreeding coefficients (FIS) ranged from − 0.1 to 0.006, with 27 out of 28 populations showing negative FIS values, indicating an excess of heterozygotes. Interpopulation genetic distances were calculated using Rho pairwise distances (FST adapted for autotetraploid species) and analysis of molecular variance (AMOVA) parameters. All BASE populations showed lower Rho values compared to C1 populations and check cultivars. AMOVA revealed that most of the genetic diversity was among individuals within populations, especially in BASE populations (92.7%). This study demonstrates that individual plants in BASE populations possess high genetic diversity, low interpopulation distances, and minimal inbreeding, characteristics that are essential for base-broadening selection. The populations developed in this project serve as valuable sources of novel alleles for North American alfalfa breeding programs, offering breeders access to diverse, regionally adapted pools for improving various alfalfa traits.

Abstract Cardiac wall motion abnormalities (WMA) are strong predictors of mortality, but current screening methods using Q waves from electrocardiograms (ECGs) have limited accuracy and vary across racial and ethnic groups. This study aimed to identify novel ECG features using deep learning to enhance WMA detection, referencing echocardiography as the gold standard. We collected ECG and echocardiogram data from 35,210 patients in California and labeled WMA using unstructured language parsing of echocardiographic reports. A deep neural network (ECG-WMA-Net) was trained and outperformed both expert ECG interpretation and Q-wave indices, achieving an AUROC of 0.781 (CI: 0.762–0.799). The model was externally validated in a diverse cohort from Georgia (n = 2338), with an AUC of 0.723 (CI: 0.685–0.757). Explainability analysis revealed significant contributions from QRS and T-wave regions. This deep learning approach improves WMA screening accuracy, potentially addressing physiological differences not captured by standard ECG-based methods.

Abstract Background The American College of Cardiology, American Heart Association, and Centers for Medicare and Medicaid Services recommend shared decision-making (SDM) for patients with severe aortic stenosis choosing between transcatheter aortic valve replacement (TAVR) and surgical aortic valve replacement (SAVR). Although tools such as patient decision aids (DAs) and training in SDM have been shown to improve SDM, implementation of SDM and DAs is limited. The IMproving treatment decisions for Patients with AortiC stenosis Through Shared Decision Making (IMPACT SDM) study aims to (1) determine the effectiveness of the interventions (a DA and clinician SDM training) in achieving SDM (primary outcome) and improving the quality of decisions about aortic valve replacement, (2) determine the reach of the DAs and adoption of training, and (3) explore potential mechanisms of effectiveness and implementation at the patient-, clinician-, and clinic-level. Methods The study is a hybrid type II effectiveness-implementation study using a cluster randomized batched stepped wedge trial with 8 sites across the USA. Eligible patients will be surveyed before and after visits with the heart valve team; clinicians will be surveyed after visits. Reach of DAs and adoption of training will be tracked. Clinicians will be interviewed regarding barriers and facilitators to implementation. Discussion The IMPACT SDM Study seeks to provide evidence of the ability of the interventions to improve SDM and decision quality, and also to shed light on barriers and facilitators to SDM implementation to promote future implementation efforts. Trial registration ClinicalTrials.gov NCT06171737. Registered on December 15, 2023.

Abstract Background California’s relatively low smoking rate (10.1% in 2019–2020) (About CHIS, UCLA Center for Health Policy Research, 2024) masks deep disparities among low-income populations, where smoking rates are nearly double that of their middle- to upper-income peers. Low-income smokers report a similar desire to quit and similar rates of recent quit attempts as smokers from other groups; yet, they often face barriers in accessing effective resources to facilitate successful cessation. Methods Our team will conduct a pragmatic stepped-wedge cluster, randomized controlled trial of Enhanced Multicomponent Proactive Navigator-Assisted Cessation of Tobacco Use (EMPACT-Us), a suite of tobacco cessation services supported by patient navigators, designed in close partnership with patients, providers, and community stakeholders. The study will take place at Family Health Centers of San Diego (FHCSD), the largest federally qualified health center (FQHC) in San Diego. Eight primary care clinics are included, where 70% (n = 13,496) of smokers at FHCSD receive care. Discussion We hypothesize that multiple points of engagement and integration of navigation services into the workflow of existing staff will improve utilization and cessation success. This study will examine if the enhanced suite of services offers insights on how to best integrate evidence-based tobacco treatment services into usual care. Trial registration ClinicalTrials.gov, NCT05750537, Registered on March 1, 2023. https://clinicaltrials.gov/study/NCT05750537 .

Abstract The concept of spatiotemporal correlation, initially rooted in the domain of physics, has increasingly become of interest to scholars across various fields. This burgeoning interest is especially noted within the realm of human dynamics, where the examination of human behavior’s spatiotemporal aspects is emerging. The exploration into the nuanced ways in which human actions intertwine with geographical contexts is paramount. This paper delves into the Time-Space Characteristic Correlation of Human Behavior (TSCH) model, a pioneering framework that melds the intricacies of human behavior with geographic considerations through a micro-dynamic approach to population strategy, employing the mean-field limit method. This study scrutinizes the spatiotemporal dynamics of individual travel behaviors, focusing on specific traits such as sudden increases in activity (paroxysm B), behavioral memory (M), and the radius of gyration (Rg). The stability of these behavioral waves is evaluated through the application of the “db4” wavelet basis function, revealing stable fluctuations in population travel patterns that resonate deeply with regional characteristics. The model enables the computation of the overall cost burden of area visits for local residents, uncovering a power-law correlation between this cost and the spatial attractiveness of urban centers when analyzed at a collective level. Our findings underscore a profound linkage between the temporal and spatial patterns of human behavior at the urban scale. Furthermore, the TSCH model’s advancement facilitates a nuanced understanding of complex social issues, including urban development, public health management, and transportation systems optimization, offering valuable insights for sociological inquiry and practical application in addressing contemporary societal challenges.

Background and purpose: Lom-Am-Ma-Pruek (LAMP) remedy has been used in Thai traditional medicine to relieve pain associated with the inflammatory process. The anti-inflammatory activity and bioactivity of LAMP in an animal model have not been previously investigated. We evaluated the in-vitro and in-vivo anti-inflammatory activity of LAMP ethanol extract. Experimental approach: The anti-inflammatory activity of LAMP and its plant ingredients were investigated on lipopolysaccharide-stimulated NO, PGE2, and TNF-α release from RAW264.7 cells. Furthermore, the stability of LAMP under biological and chemical accelerated conditions was evaluated using the Griess reaction assay and HPLC. Lastly, rat models with ethyl phenylpropionate (EPP)-induced ear edema and carrageenan-induced paw edema were utilized to assess anti-inflammatory activity. Findings/Results: LAMP possessed potent inhibitory effects on NO, PGE2, and TNF-α production with IC50 values of 24.90 ± 0.86, 4.77 ± 0.03, and 35.01 ± 2.61 µg/mL, respectively. In addition, LAMP extract demonstrated stable biological activity, anti-inflammatory effects, and phytochemical content stability under stress conditions. Additionally, 0.5%, 1%, and 2% w/v LAMP significantly inhibited EPP-induced rat ear edema over time equivalent to 5% w/v phenylbutazone. LAMP at 180, 375, and 750 mg/kg also considerably reduced carrageenan-induced rat paw edema 2 h after carrageenan administration compared to phenylbutazone at 250 mg/kg. Conclusion and implications: LAMP has anti-inflammatory activity by inhibiting PGE2 formation. These findings are consistent with the efficacy and traditional use of the LAMP remedy in treating inflammatory diseases.

Objective: The superior transseptal approach to mitral valve surgery offers improved exposure compared with left atriotomy; however, concerns remain regarding postoperative arrhythmias and pacemaker placement. This study investigates intraoperative parameters and postoperative outcomes in these approaches. Methods: Retrospective review of 259 adults undergoing isolated mitral valve repair or replacement over a 10-year period was performed. Exclusion criteria included previous history of permanent pacemaker placement and concomitant cardiac procedures. The primary outcome evaluated was postoperative permanent pacemaker placement. Secondary outcomes included postoperative new-onset atrial fibrillation, new-onset arrhythmias, major adverse cardiovascular events, length of stay, and mortality. Results: Of 259 surgeries, 116 were performed via left atriotomy and 143 via superior transseptal approach. The overall incidence of postoperative permanent pacemaker placement was 3.0%, with similar rates (left atriotomy 1.7% vs superior transseptal 4.2%, P = .30). The incidence of new-onset atrial fibrillation (31.0% vs 42.7%, P = .055) and arrhythmias in general (37.1% vs 49.0%, P = .06) was similar. Rates of other secondary outcomes, such as major adverse cardiovascular events and mortality, were similar between cohorts. In addition, cardiopulmonary bypass and aortic crossclamp times did not differ. Interestingly, intensive care unit (55 vs 73 hours, P = .04) and postoperative length of stay (6.8 vs 9.0 days, P = .002) were shorter after left atriotomy. Conclusions: The superior transseptal approach provides optimal exposure while preserving similarly low rates of postoperative morbidity and mortality to left atriotomy. There is no difference in the incidence of postoperative permanent pacemaker placement and new-onset arrhythmias.

Abstract Aims LMNA‐related dilated cardiomyopathy (DCM) is a rare disease with an incompletely defined phenotype. The phase 3 REALM‐DCM trial evaluated a potential disease‐modifying therapy for LMNA‐related DCM but was terminated due to futility without safety concern. This study utilized pooled data from REALM‐DCM to descriptively characterize the phenotype and progression of LMNA‐related DCM in a contemporary cohort of patients using common heart failure (HF) measures. Methods REALM‐DCM enrolled patients with stable LMNA‐related DCM, an implanted cardioverter defibrillator or cardiac resynchronization therapy defibrillator, and New York Heart Association (NYHA) Class II/III HF symptoms. Results Between 2018 and 2022, 77 patients took part in REALM‐DCM. The median patient age was 53 years (range: 23–72), and 57% were male. Overall, 88% of patients had a pathogenic or likely pathogenic LMNA variant, and 12% had a variant of uncertain significance with a concordant phenotype. Among patients with confirmed sequencing, 55% had a missense variant. Atrial fibrillation was present in 60% of patients; 79% of all patients had NYHA Class II and 21% had NYHA Class III HF symptoms at baseline. Median (range) left ventricular ejection fraction (LVEF), 6 min walk test (6MWT) distance, Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ‐OS) score and N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) concentration at baseline were 42% (23–62), 403 m (173–481), 67 (18–97) and 866 pg/mL (57–5248), respectively. LVEF, 6MWT distance and KCCQ‐OS score were numerically lower in patients who had NYHA Class III versus II symptoms at baseline (LVEF: 38% vs. 43%; 6MWT distance: 326 vs. 413 m; and KCCQ‐OS score: 43 vs. 70), whereas NT‐proBNP concentration was higher (1216 vs. 799 pg/mL). Median follow‐up was 73 weeks (range: 0.4–218; 73 in NYHA Class II and 75 in NYHA Class III). Patients displayed variable change from baseline in 6MWT, KCCQ‐OS and NT‐proBNP values during follow‐up. Overall, 25% of patients experienced ventricular tachycardia, and 8% had ventricular fibrillation. Ten (13%) patients met the composite endpoint of worsening HF (adjudicated HF‐related hospitalization or urgent care visit) or all‐cause death; six had NYHA Class II and four had NYHA Class III at baseline. All‐cause mortality occurred in 6 (8%) patients; three had NYHA Class II and three had NYHA Class III symptoms at baseline. Conclusions Findings confirm the significant morbidity and mortality associated with LMNA‐related DCM despite the standard of care management. Typical measures of HF, including 6MWT distance, KCCQ‐OS score and NT‐proBNP concentration, were variable but correlated with NYHA class. An unmet treatment need remains among patients with LMNA‐related DCM. NCT03439514.

Background: Tirbanibulin is approved for actinic keratosis (AK) field treatment up to 25 cm2. However, AK often affects larger areas; thus, AK treatments for larger fields are needed. Objective: Evaluate the safety and tolerability of tirbanibulin when applied to a field of approximately 100 cm2. Methods: Phase 3, multicenter, open-label, single-arm study among adult patients having a treatment field on the face or balding scalp of approximately 100 cm2 with 4-12 AKs. Patients received tirbanibulin to cover the treatment field once daily (5 consecutive days). Safety was assessed by evaluating treatment emergent adverse events and tolerability by composite score of 6 local tolerability signs (LTS). Results: A total of 105 patients were included. The most common LTS were erythema (96.1%) and flaking/scaling (84.4%), being mostly mild-to-moderate severity, and resolved/returned to or close to baseline by Day 29. The only severe LTS were erythema (5.8%) and flaking/scaling (8.7%). Most frequent treatment emergent adverse events were application site pruritus (10.5%) and application site pain (8.6%). Mean total number of AKs decreased from 7.7 AKs at baseline to 1.8 AKs at Day 57. Mean percent of change (reduction) from baseline in lesion count was 77.8% at Day 57. Limitations: No control group. No long-term follow-up. Conclusion: Safety and tolerability profiles in patients treated with tirbanibulin up to 100 cm2 were consistent with those previously reported over smaller field. Tirbanibulin could be used on a larger field (>25 cm2).

Abstract Background This systematic review investigates the relationship between malaria incidence, climate variables, and deforestation in Colombia, Latin America, and the Caribbean from 2000 to 2020. Malaria, a significant public health issue in these regions, is influenced by ecological factors including climatic conditions and environmental changes, such as deforestation. Methods The review employs a comprehensive search strategy across PubMed, Web of Science, Embase, Scopus, Cochrane, and Scielo databases. It applies strict inclusion and exclusion criteria to ensure the relevance and quality of selected studies, focusing on analysing the relationship between climate variables, deforestation, and malaria incidence. Results Twenty-four articles were included in this review, fourteen of which assessed the relationship between climatic variables and malaria and ten between deforestation and malaria. The analysis reveals a nuanced understanding of malaria dynamics. A significant finding is the seasonal effect of climatic variables on malaria incidence. The study notes that increased rainfall is positively correlated with malaria incidence. Similarly, warmer temperatures are associated with increased malaria risks, and malaria rates can change by 10% to 80% for every degree of temperature increase, after adjusting for altitude. The impact of deforestation on malaria is complex, with positive and negative correlations observed, depending on the remaining forest cover. Conclusions The review highlights the multifaceted nature of malaria transmission, emphasizing the need for integrated approaches that consider both environmental and health perspectives. It underscores the importance of understanding the complex relationships between malaria incidence, climate variables, and deforestation.

Abstract Ethical issues arise in the context of implementation science that may differ from those encountered in other research settings. This report, developed out of a workshop convened by the Center for Translation Research and Implementation Science within the United States National Heart, Lung, and Blood Institute, identifies six key themes that are important to the assessment of ethical dimensions of implementation science. First, addressing ethical challenges in implementation science does not require new ethical principles, commitments, or regulations. However, it does require understanding of the specific contexts arising in implementation research related to both study design and the intervention being implemented. Second, implementation research involves many different types of people in research, including patients, clinicians, administrators, the social networks of any of these, and the general population. These individuals play different roles that may entail different ethical considerations, obligations, and vulnerabilities. Third, the appropriateness of and need for informed consent in implementation research is connected to the role of the subject/participant, the nature of the intervention, and the design of the study. Even where traditional “full” consent processes are unnecessary or inappropriate, communication and engagement are critical. Similarly, even when research is exempt and informed consent unnecessary, Data Safety and Monitoring Board oversight of implementation studies may be advisable to ensure quality, address unexpected consequences, and identify overwhelming evidence of benefit. Fourth, implementation science is often explicitly designed to encourage specific behaviors and discourage others. There is a need for clarity regarding when efforts at behavioral change enhance or threaten autonomy and how to protect participants whose autonomy is threatened. Fifth, there is significant overlap between implementation science and quality improvement, and the ideal regulatory oversight structure for implementation science remains unclear. It is critical to encourage learning and growth while assuring appropriate protections. Sixth, implementation research takes place across a range of social and cultural contexts. Engagement and collaboration with stakeholders in designing and executing implementation trials and studies- especially when vulnerabilities exist- is essential. Attention to these themes will help ensure that implementation science fulfills its goal of advancing the practice of health care within a sound ethical framework.

Abstract Background A low-fat vegan diet, supplemented with soybeans, has been shown effective in reducing postmenopausal hot flashes. This secondary analysis assessed the association of a plant-based index (PDI), healthful (hPDI), and unhealthful (uPDI), with changes in hot flashes in postmenopausal women. Methods Participants (n = 84) were randomly assigned to a low-fat vegan diet supplemented with soybeans (n = 42) or a control group (n = 42) for 12 weeks. Three-day dietary records were analyzed and PDI indices were calculated. A repeated measures analysis of variance (ANOVA) was used for statistical analysis. Results All three scores increased in the vegan group, compared with no change in the control group; the effect sizes were: PDI + 9.8 (95% CI + 5.8 to + 13.8; p

Abstract Introduction Resentment towards the Chinese population was perceived during the first months of the pandemic because the pandemic/disease started in that country. Objective To determine the factors associated with the perception of resentment towards the Chinese in Latin America during the first wave of the COVID-19 pandemic. Methodology Analytical cross-sectional study conducted during the second semester of the pandemic in more than a dozen countries. Four questions were asked about the perception of resentment towards the Chinese (Cronbach's Alpha: 0.88); those with the highest scores on the sum of the four questions were considered to have "more resentment towards the Chinese," and descriptive and analytical statistics were obtained. Results Of the 7721 respondents, in the multivariate analysis, it was found that there was a difference according to the country; compared to Peru, those who had more resentment towards the Chinese were those residing in Paraguay (aPR: 1.29; 95%CI: 1.17–1.42; p-value

Abstract Background We previously reported in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) treated with immune checkpoint inhibitors (ICIs), pretreatment higher lactate dehydrogenase (LDH) and absolute (abx) neutrophils as well as lower percent (%) lymphocytes correlated with worse overall survival (OS). In this study we aimed to develop a prognostic signature for HNSCC treated with ICIs using these peripheral blood biomarkers (PBBMs). Methods Adults with R/M HNSCC treated with ICIs at our institution from 08/2012 to 03/2021 with pretreatment PBBMs were included. Follow-up continued until 02/15/2022. The cohort (n = 151) was randomly split into training (n = 100) and testing (n = 51) datasets. A prognostic score incorporating LDH, % lymphocytes, and abx neutrophils was developed from the training dataset using Cox proportional hazards regression. In the training dataset, a grid search identified the optimal cutpoints classifying patients into high, medium, and low-risk groups (trichotomized signature) as well as high vs. low-risk groups (dichotomized signature). The prognostic score, dichotomized and trichotomized signatures were then validated in the testing dataset. Results Training and testing datasets showed no clinically meaningful differences in clinicodemographic characteristics or PBBMs. An OS prognostic model was developed from the training dataset: Risk score = 1.24*log10(LDH) − 1.95*log10(% lymphocytes) + 0.47*log10(abx neutrophils). Optimal risk score cutpoints for the dichotomized and trichotomized signatures were defined in the training dataset, and Kaplan-Meier curves for both dichotomized and trichotomized signatures showed good separation between risk groups. Risk scores were calculated in the testing dataset, where the trichotomized signature demonstrated overlap between low and medium-risk groups but good separation from the high-risk group while the dichotomized signature showed clear separation between low and high-risk groups. Higher risk score correlated with worse OS (HR 2.08, [95%CI 1.17–3.68], p = 0.012). Progression-free survival Kaplan-Meier curves likewise showed excellent separation between dichotomized risk groups in the training and testing datasets. Conclusions We developed a prognostic signature for OS based on 3 previously identified PBBMs for HNSCC treated with ICIs and identified a high-risk group of patients least likely to have survival benefit from ICIs. This signature may improve ICI patient selection and warrants validation in an independent cohort as well as correlation with CPS.

Abstract Zero-shot relation extraction (ZSRE) is essential for improving the understanding of natural language relations and enhancing the accuracy and efficiency of natural language processing methods in practical applications. However, the existing ZSRE models ignore the importance of semantic information fusion and possess limitations when used for zero-shot relation extraction tasks. Thus, this paper proposes a dual contrastive learning framework and a cross-attention network module for ZSRE. First, our model designs a dual contrastive learning framework to compare the input sentences and relation descriptions from different perspectives; this process aims to achieve better separation between different relation categories in the representation space. Moreover, the cross-attention network of our model is introduced from the computer vision field to enhance the attention paid by the input instance to the relevant information of the relation description. The experimental results obtained on the Wiki-ZSL and FewRel datasets fully demonstrate the effectiveness of our approach.

Endovascular stenting of the pulmonary artery treats arterial stenosis from pulmonary hypertension, congenital heart defects, or post-transplant stricture. Patients with malignant extrinsic pulmonary arterial compression, secondary to large mediastinal or pulmonary masses, often present with dyspnea, hypoxemia, and right ventricular failure. Conventional therapies like surgery, chemotherapy, and radiation are often slow and fail to promptly resolve acute symptoms.Balloon angioplasty and stenting have been explored as a rapid treatment to alleviate symptoms of external pulmonary artery compression. Despite its potential, the adoption of this procedure is limited due to risks like stent misplacement, migration, cardiac arrhythmias, and arterial rupture.This paper presents 3 cases of pulmonary angiography and stenting performed for malignant extrinsic pulmonary artery compression. These cases aim to demonstrate the feasibility of pulmonary artery stenting, encouraging its consideration as a palliative option for symptomatic patients with this condition.

Cholangiocarcinoma (CCA) is a malignancy that originates from the epithelial cells of the biliary system. Despite advancements in medical diagnostic techniques, CCAs remain a challenge to detect due to their silent clinical progression, making it difficult to diagnose these diseases. There are several well-established risk factors for CCA, including biliary tract infection and inflammation. However, there is also growing evidence that community and occupational exposures play a significant role in the development of bile duct cancers. This review examines the geographical distribution of these risk factors and the importance of surveillance in individuals exposed to these toxins who are more prone to developing CCA.

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

Abstract Aims The viability of cardiac resynchronization therapy (CRT) in inotrope‐dependent heart failure (HF) has been a matter of debate. Methods and results We searched Medline, EMBASE, Scopus, and the Cochrane Library until 31 December 2022. Studies were included if (i) HF patients required inotropic support at CRT implantation; (ii) patients were ≥18 years old; and (iii) they provided a clear definition of ‘inotrope dependence’ or ‘inability to wean’. A meta‐analysis was performed in R (Version 3.5.1). Nineteen studies comprising 386 inotrope‐dependent HF patients who received CRT (mean age 64.4 years, 76.9% male) were included. A large majority survived until discharge at 91.1% [95% confidence interval (CI): 81.2% to 97.6%], 89.3% were weaned off inotropes (95% CI: 77.6% to 97.0%), and mean discharge time post‐CRT was 7.8 days (95% CI: 3.9 to 11.7). After 1 year of follow‐up, 69.7% survived (95% CI: 58.4% to 79.8%). During follow‐up, the mean number of HF hospitalizations was reduced by 1.87 (95% CI: 1.04 to 2.70, P

Abstract Background Several adversity-focused treatment trials have reported improvements to adversity sequelae (e.g., PTSD symptoms) and decreases in psychotic symptoms among individuals with psychotic disorders. Yet, no trials have examined the impact of adversity-focused treatment on substance use or examined the outcomes among an early phase psychosis population. These gaps in both the research literature and clinical practice have resulted in less knowledge about the outcomes of adversity-focused treatment at this stage of illness, including the impact on substance use. Methods The outcomes of an adapted prolonged exposure protocol (PE+) among an early phase psychosis population were examined using a multiple-baseline design. Nineteen adults with a psychotic disorder, current substance misuse, and a history of adversity were recruited from an early psychosis program. Participants were randomized to treatment start time and participated in a 15-session course of PE + therapy. Ten assessments were completed focusing on primary outcomes (i.e., adversity sequelae, negative psychotic symptoms, substance misuse) and secondary outcomes (i.e., functioning, hopelessness, experiential avoidance). The Reliable Change Index (RCI) was used to establish whether there were clinically significant changes to primary or secondary outcomes. Results Half or more of treatment completers experienced clinically significant changes to most domains of adversity sequelae, no participants experienced improvements in negative psychotic symptoms, and substance misuse increased for several participants. In terms of secondary outcomes, functioning and experiential avoidance were improved for a number of participants, while hopelessness decreased for only one participant. Participants reported high satisfaction with the PE + treatment, and exposure and coping skills were rated as the most helpful elements of treatment. Conclusions Reductions in adversity sequelae were observed following PE + treatment, suggesting that adversity-focused treatment may be beneficial for an early psychosis population. Yet, few positive changes to psychotic symptoms or substance use were observed. Further integrating treatment strategies for psychosis and substance use into PE + may be required to effectively treat the links between psychosis, adversity sequelae, and substance use. Future studies should make efforts to integrate substance use strategies into adversity treatment trials for people with psychotic disorders. Trial registration Clinicaltrials.gov, NCT04546178; registration posted 11/09/2020, https://clinicaltrials.gov/ct2/show/NCT04546178?term=NCT04546178&draw=2&rank=1 .

Abstract Synthetic data promise privacy-preserving data sharing for healthcare research and development. Compared with other privacy-enhancing approaches—such as federated learning—analyses performed on synthetic data can be applied downstream without modification, such that synthetic data can act in place of real data for a wide range of use cases. However, the role that synthetic data might play in all aspects of clinical model development remains unknown. In this work, we used state-of-the-art generators explicitly designed for privacy preservation to create a synthetic version of ever-smokers in the UK Biobank before building prognostic models for lung cancer under several data release assumptions. We demonstrate that synthetic data can be effectively used throughout the medical prognostic modeling pipeline even without eventual access to the real data. Furthermore, we show the implications of different data release approaches on how synthetic biobank data could be deployed within the healthcare system.

Abstract The development of artificial cells has led to fundamental insights into the functional processes of living cells while simultaneously paving the way for transformative applications in biotechnology and medicine. A common method of generating artificial cells is to encapsulate protein expression systems within lipid vesicles. However, to communicate with the external environment, protein translocation across lipid membranes must take place. In living cells, protein transport across membranes is achieved with the aid of complex translocase systems which are difficult to reconstitute into artificial cells. Thus, there is need for simple mechanisms by which proteins can be encoded and expressed inside synthetic compartments yet still be externally displayed. Here we present a genetically encodable membrane functionalization system based on mutants of pore-forming proteins. We modify the membrane translocating loop of α-hemolysin to translocate functional peptides up to 52 amino acids across lipid membranes. Full membrane translocation occurs in the absence of any translocase machinery and the translocated peptides are recognized by specific peptide-binding ligands on the opposing membrane side. Engineered hemolysins can be used for genetically programming artificial cells to display interacting peptide pairs, enabling their assembly into artificial tissue-like structures.

Abstract Seabird colonies with long-term monitoring records, i.e., > 50 years, are rare. The population data for northern gannets (Morus bassanus) in Cape St. Mary’s (CSM) Ecological Reserve (Newfoundland and Labrador, Canada) is robust, extending back to 1883 when the colony was presumed established. We inferred the colony’s historical population shifts by measuring ornithogenic proxies in a dated sediment record collected from a nearby pond. Our record extended to the early eighteenth century, but the proxy data only began to show significant signs of seabird presence between ca. 1832 and 1910, aligning with the period gannets were first observed at CSM. Through the twentieth century, we observed significant increases in δ15N, P, Zn, Cd, and chlorophyll a, coeval with a shift in the dominant diatom species, indicating rapid colony growth. The proxies were overall highest in ca. 2005, corresponding to the reported historical maximum of the gannet colony in 2009. Our results validate that paleo-reconstructions using ornithogenic proxies can accurately reflect population trends and provide a stronger understanding of the colony’s establishment and growth. This study highlights the value of applying paleolimnological methods in seabird population studies to frame the history of a colony’s dynamics and inform conservation efforts.

Abstract Background Mandibular second premolar agenesis is a common problem in orthodontics and is often treated in conjunction with maxillary counterbalancing extractions. However, in cases without maxillary crowding or dental protrusion, space closure may pose challenges leading to compromised occlusal results or patient profile. Multiple techniques have been described to treat these patients; nevertheless, there is a paucity of data comparing effectiveness of space closure utilizing various anchorage techniques. The goal of this study is to assess the effectiveness of the Herbst device during mandibular molar protraction and compare it to the use of temporary anchorage device (TADs) in patients with mandibular second premolar agenesis. Materials and methods This retrospective study included 33 patients with mandibular premolar agenesis treated without maxillary extractions. Of these patients, 21 were treated with protraction Herbst devices and 12 with TADs. Changes in molar and incisor positions, skeletal base positions and occlusal plane angulations were assessed on pretreatment (T0) and post-treatment (T1) lateral cephalograms. Scans/photographs at T0 and T1 were used to evaluate canine relationship changes representing anchorage control. Space closure and breakage/failure rates were also compared. Data was analyzed with paired and unpaired t-tests at the significance level of 0.05. Results Within the Herbst group, changes in mandibular central incisor uprighting and mandibular molar crown angulations were statistically significant. However, no significant differences were noted between the Herbst and TAD groups. Protraction rates as well as overall treatment times were comparable (0.77 mm/month vs. 0.55 mm/month and 3.02 years vs. 2.67 years, respectively). Canine relationships were maintained or improved toward a class I in 82.85% of the Herbst sample, compared to in 66.7% of the TAD sample. Emergency visits occurred in 80.1% of the Herbst group, with cementation failures or appliance breakages as the most common reasons. Conclusion The Herbst device could be a viable modality in cases with missing mandibular premolars where maximum anterior anchorage is desired, or if patients/parents are resistant to TADs. Furthermore, they could be beneficial in skeletal class II patients with mandibular deficiency who also need molar protraction. However, the increased incidence of emergency visits must be considered when treatment is planned.

ABSTRACT: Objectives: We report the use of IV dalbavancin in Canadian patients using data captured by the national CLEAR registry. Methods: The CLEAR registry uses the web-based data management program, REDCap™ (online survey https://rcsurvey.radyfhs.umanitoba.ca/surveys/?s=TPMWJX98HL) to facilitate clinicians entering details associated with their clinical experiences using IV dalbavancin. Results: Data were available for 40 patients. The most common infections treated were acute bacterial skin and skin structure infection (ABSSSI) (62.5% of patients), bone/joint infection (22.5%), bloodstream/vascular infection (7.5%) and endocarditis (5.0%). Dalbavancin was used as directed (75.0%) and empiric therapy (25.0%). MRSA was the most common identified pathogen (70.0%). Dalbavancin was used both in outpatient (e.g., emergency department) (65.0%), and inpatient treatment settings (e.g., hospital ward) (35.0%). Dalbavancin was used due to the convenience of a single dose treatment (77.5%) as well as to facilitate hospital discharge (7.5%). Dalbavancin was primarily used alone (90.0%), and most commonly using a single 1500 mg dose (77.5%). Microbiological success (pathogen eradicated or presumed eradicated) occurred in 88.2% of known cases, while clinical success (cure and/or improvement) occurred in 93.3% of known cases. No adverse events were reported. Conclusions: In Canada, IV dalbavancin is used as both directed and empiric therapy to treat ABSSSI as well as off-label (bone/joint, bacteremia/vascular, endocarditis, device-related) infections. It is used in both outpatient and inpatient settings due primarily to its convenience as a single-dose treatment regimen and to facilitate early hospital discharge. Dalbavancin use is associated with high microbiological and clinical cure rates along with an excellent safety profile.

Background: Pelvic reirradiation of de novo rectal or anal cancer after prior prostate cancer RT poses a significant risk of urinary and rectal fistula. In this report we describe the use of a rectal spacer to improve dosimetry and reduce this risk. Methods: Patients undergoing anorectal radiotherapy (RT) after prior prostate RT who had a rectal spacer placed prior to RT were identified in a prospective database. Patient, disease, and treatment characteristics were collected for these patients. Survival data were calculated from the end of RT. Radiation was delivered with intensity-modulated radiation therapy (IMRT) or proton beam therapy (PBT) following rectal spacer placement. Results: Rectal spacer placement with hydrogel injected transperineally under transrectal ultrasound guidance was successful in all five patients. MR/CT simulation 1–2 weeks post-spacer placement and IMRT or PBT delivered to a dose of 36–50 Gy in 24–30 fractions once or twice daily were tolerated well by all patients. The V100% of the PTV ranged from 62–100% and mean rectal and bladder dose ranged from 39–46 Gy and 16–40 Gy, respectively. At the last follow-up, three patients were alive and without evidence of disease up to 48 months out from treatment. There were no acute or late grade 3 or higher toxicities observed, but acute grade 2 proctitis was observed in all patients. Conclusions: The use of a rectal spacer placement to improve dosimetry of IMRT and PBT after prior prostate RT is safe and feasible in appropriately selected anorectal cancer patients.

Abstract Single-cell RNA sequencing (scRNA-seq) is a key technology for investigating cell development and analysing cell diversity across various diseases. However, the high dimensionality and extreme sparsity of scRNA-seq data pose great challenges for accurate cell type annotation. To address this, we developed a new cell-type annotation model called scGAA (general gated axial-attention model for accurate cell-type annotation of scRNA-seq). Based on the transformer framework, the model decomposes the traditional self-attention mechanism into horizontal and vertical attention, considerably improving computational efficiency. This axial attention mechanism can process high-dimensional data more efficiently while maintaining reasonable model complexity. Additionally, the gated unit was integrated into the model to enhance the capture of relationships between genes, which is crucial for achieving an accurate cell type annotation. The results revealed that our improved transformer model is a promising tool for practical applications. This theoretical innovation increased the model performance and provided new insights into analytical tools for scRNA-seq data.

Background: Limited data exist on the long-term impact of beta-blocker therapy after percutaneous coronary intervention (PCI) in patients with stable coronary artery disease (CAD) and preserved left ventricular ejection fraction (LVEF). Objectives: The aim of the study was to evaluate the effects of early beta-blocker initiation vs no initiation following PCI in patients with stable CAD and preserved LVEF. Methods: This retrospective cohort study employed target trial emulation and incident user design, utilizing the TriNetx database (2009-2024). Early beta-blocker initiation (within days 1 and 7) was compared with no initiation using 1:1 greedy propensity score matching. The outcomes included all-cause mortality, hospitalization for myocardial infarction, heart failure, atrial fibrillation/flutter, stroke, and safety endpoints. Hospitalization for bone fracture and acute appendicitis served as falsification endpoints. In the intention-to-treat analysis, outcomes were analyzed over 5 years using Cox-proportional hazards. Results: Out of 11,681 matched patients per group, beta-blocker therapy was associated with increased all-cause mortality (HR: 1.11 [95% CI: 1.09-1.18]). No significant differences were found in hospitalization for myocardial infarction (HR: 1.03 [95% CI: 0.97-1.09]), stroke (HR: 0.98 [95% CI: 0.91-1.05]), heart failure (HR: 0.99 [95% CI: 0.95-1.03]), and atrial fibrillation/flutter (HR: 0.97 [95% CI: 0.93-1.01]). Hospitalization for hypotension was higher with beta-blockers (HR: 1.10 [95% CI: 1.06-1.14]). Hospitalization for bone fracture (HR: 1.02 [95% CI: 0.85-1.22]) and acute appendicitis (HR: 1.17 [95% CI: 0.95-1.45]) showed no significant associations. Several sensitivity analyses showed consistent results. Conclusions: Early beta-blocker initiation after PCI for stable CAD with preserved LVEF was associated with higher mortality, with no impact on cardiovascular events.

IntroductionPost-Traumatic Stress Disorder (PTSD) entails behavioral changes with increased risk of suicide, and there is no consensus on the preferred antidepressants for treatment of those PTSD patients who are at elevated risk for suicide.MethodsWe conducted a clinical trial emulation study comparing suicide-related events (SREs) among those patients’ initiating antidepressants within 60 days after a qualifying SRE. Patients were followed from initiation of antidepressant until any of the following: treatment cessation, switching, death, or loss to follow-up. The outcome is a new onset of an SRE.ResultsCitalopram exhibited a significantly fewer case with new SREs compared to other most used antidepressants such as venlafaxine, duloxetine, and mirtazapine–even after adjusting for multiple comparisons and other covariants.DiscussionFindings suggest potential risks associated with certain antidepressants in the PTSD population, emphasizing cautious prescription considerations.

As a key determinant of how efficiently lionfish (Pterois sp.) locate and capture prey, swimming speed plays a crucial role in shaping the predator-prey interactions and broader ecological dynamics within the invaded ecosystems. Swimming speed on a small temporal and spatial scale is difficult to measure because of the need for precise measurements of both distance and duration of the behavior. Using photogrammetry by way of stereo-camera setups is ideal for analyzing the minutiae of lionfish behaviors because it can include the benefits of remote video traps coupled with precise measurements of movements in three-dimensional space and time. The primary objective of this study was to identify and characterize lionfish behavior associated with different movement speeds, and then to quantify small-scale swimming speeds of lionfish associated with those behaviors. Swimming speeds were classified under three different observed behaviors: relaxed swimming, traverse swimming, and striking at prey. The differences between these behaviors were primarily distinguished based on body and fin positioning, as well as the apparent intent of the motion if any was evident. The mean lionfish swimming speed from stereoscopic camera footage was 44.75 mm s−1 for relaxed swimming, 138.99 mm s−1 for traverse swimming, and 625.44 mm s−1 for striking at prey. Swimming speed can be used to quantify how much habitat area a lionfish may cover in a day, and therefore the amount of prey that may be encountered by a predator. Lionfish feeding success under different environmental conditions could be an important factor in understanding their survival and growth in areas where they are found.

BackgroundMost longitudinal studies of COVID-19 incidence have used unlinked samples. The city of Manaus, Brazil, has a blood donation program which allows sample linkage, and was struck by two large COVID-19 epidemic waves between mid-2020 and early 2021.MethodsWe estimated the changing force of infection, i.e. incidence in susceptible individuals. Seroconversion was inferred by a mixture model for serial values from the Abbott Architect SARS-CoV-2 nucleocapsid (N) IgG assay. We estimated the number of suspected COVID-19 hospitalizations arising from each infection over calendar time.ResultsWhole blood donations between April 2020 and March 2021 were included from 6734 people, 2747 with two or more donations. The inferred criterion for seroconversion, and thus an incident infection, was a 6.07 fold increase in N IgG reactivity. The overall force of infection was 1.19 per person year (95% confidence interval 1.14-1.24) during the two main waves. The estimated number of suspected hospitalizations per infection, was approximately 4.1 times higher in the second wave than in the first.ConclusionsSerial values from this assay can be used to infer seroconversion over time, and in Manaus show a higher number of suspected COVID-19 hospitalizations per infection in the second wave relative to the first.

Electronic health records and patient portals are increasingly utilized to enhance research recruitment efficiency, yet response patterns across patient groups remain unclear. We examined 10 studies at Emory Healthcare that used these tools to identify and recruit 24,000 patients over 1 year. Response rates were lower among males and Black individuals, though study interest was higher among respondents. Interest was also greater among those with frequent healthcare interactions and lower comorbidity. In a large academic health system, portal-based recruitment offered a streamlined approach to research recruitment and patient engagement, with minor variations across patient characteristics warranting continued study.

Data collection systems are vital in implementation of interventions within patient care as they allow us to better understand and improve the care given. This is equally true in the field of psychiatric rehabilitation, which has been steadily growing in the medical world for the past 20 years. It has recently been a focus of psychiatric medicine in Kenya with the Kenya Mental Health Action Plan 2021-2025 calling for improvement of care in the field. With psychiatric rehabilitation growing in low- and middle-income countries in recent years studies have come out showing the effects of newly employed programs and stressing the need for data collection practices that can be used to encourage best practices in local communities. This paper describes the implementation of data systems for the Moi Teaching and Referral Hospital Nawiri Skills and Recovery Centre (Nawiri) in Eldoret, Kenya. The goals of the data systems were 1) To collect and organize information for continuous quality improvement of services at Nawiri, 2) To collect information for reporting to MTRH leadership, Ministry of Health as well as private funders, 3) To provide data to assess outcomes of people who receive services at Nawiri to create evidence for effective interventions to help create policy to make psychiatric rehabilitation more available to people living with Severe mental illness in Kenya. Lessons learned from data systems implementation included insights into ease of data collection, adaptability of data instruments to fit facility needs, and ability to reproduce RedCap data collection in other settings.

Background Achilles tendinopathy (AT) management can be difficult, given the paucity of effective treatment options and the degenerative nature of the condition. Innovative therapies for Achilles tendinopathy are therefore direly needed. New therapeutic developments predominantly begin with preclinical animal and in vitro studies to understand the effects at the molecular level and to evaluate toxicity. Despite the publication of many preclinical studies, a comprehensive, quality-assessed review of the basic molecular mechanisms in Achilles tendinopathy is lacking. Objectives This scoping review aims to summarize the literature regarding in vitro and in vivo animal studies examining AT treatments and evaluate their effect on tendon properties. Also, a quality assessment of the included animal studies is done. We provide a comprehensive insight into the current state of preclinical AT treatment research which may guide preclinical researchers in future research. Eligibility criteria Treatment options of Achilles tendinopathy in chemically or mechanically induced in vivo or in vitro Achilles tendinopathy models, reporting biomechanical, histological, and/or biochemical outcomes were included. Sources of evidence A systematically conducted scoping review was performed in PubMed, Embase.com, Clarivate Analytics/Web of Science, and the Wiley/Cochrane Library. Studies up to May 4, 2023 were included. Charting Methods Data from the included articles were extracted and categorized inductively in tables by one reviewer. The risk-of-bias quality assessment of the included animal studies is done with Systematic Review Centre for Laboratory Animal Experimentation risk-of-bias tool. Results A total of 98 studies is included, which investigated 65 different treatment options. 80% of studies reported significant improvement in the Achilles tendon characteristics after treatment. The main results were; maximum load and stiffness improvement; fibre structure recovered and less inflammation was observed; collagen I fibrils increased, collagen III fibrils decreased, and fewer inflammatory cells were observed after treatment. However, 65.4% to 92.5% of the studies had an uncertain to high risk of bias according to the risk-of-bias tool of the Systematic Review Centre for Laboratory Animal Experimentation. Conclusions Despite promising preclinical treatment outcomes, translation to clinical practice lags behind. This may be due to the poor face validity of animal models, heterogeneity in Achilles tendinopathy induction, and low quality of the included studies. Preclinical treatments that improved the biomechanical, histological, and biochemical tendon properties may be interesting for clinical trial investigation. Future efforts should focus on developing standardized preclinical Achilles tendinopathy models, improving reporting standards to minimize risk of bias, and facilitating translation to clinical practice.

Purpose: Oral mucositis (OM) is a debilitating side effect of cisplatin and intensity-modulated radiation therapy (IMRT) in patients with head and neck cancer. The phase 3 ROMAN trial showed avasopasem manganese (AVA) significantly decreased individual endpoints of incidence and duration of severe oral mucositis (SOM, World Health Organization [WHO] grade 3-4), with nominal decrease in severity (WHO grade 4) and significant increase in the delay in onset of SOM. We sought to determine the Net Treatment Benefit (NTB) of AVA versus placebo (PBO) using the generalized pairwise comparisons (GPC) method. Methods and Materials: GPC is a statistical method that permits simultaneous analysis of several prioritized outcomes, comparing all possible pairs of a patient in the active (ie, AVA) group and a patient from the control (ie, PBO) group. NTB is the net benefit across all the outcomes for AVA compared to PBO. Key clinically relevant outcomes from ROMAN were prioritized: (1) WHO grade 4 OM incidence; (2) SOM incidence; (3) days of SOM; (4) days to SOM onset, with 7 days difference defined as the clinical relevance threshold for SOM days and SOM onset. Results: GPC analysis of 407 patients (AVA = 241, placebo = 166) stratified by cisplatin schedule and treatment setting resulted in 13,969 pairwise comparisons. AVA showed statistically significant net benefit on all 4 key outcomes with a 53.9% probability that AVA would benefit patients versus a 35.0% probability that PBO would; the difference between these probabilities was a NTB of 18.9% (P = .0012), translating to an AVA number needed to treat of 5.3 patients. All outcomes contributed to NTB, reflecting improvements in SOM incidence, onset and duration, and in grade 4 OM incidence seen in the original ROMAN analysis. Conclusions: This GPC analysis shows compelling evidence from the ROMAN trial of AVA's clinical benefit across key parameters of SOM burden.

TRF2 is an essential and conserved double-strand telomere binding protein that stabilizes chromosome ends by suppressing DNA damage response and aberrant DNA repair. Herein we investigated the mechanisms and functions of the Trf2 ortholog in the basidiomycete fungus Ustilago maydis, which manifests strong resemblances to metazoans with regards to the telomere and DNA repair machinery. We showed that UmTrf2 binds to Blm in vitro and inhibits Blm-mediated unwinding of telomeric DNA substrates. Consistent with a similar inhibitory activity in vivo, over-expression of Trf2 induces telomere shortening, just like deletion of blm, which is required for efficient telomere replication. While the loss of Trf2 engenders growth arrest and multiple telomere aberrations, these defects are fully suppressed by the concurrent deletion of blm or mre11 (but not other DNA repair factors). Over-expression of Blm alone triggers aberrant telomere recombination and the accumulation of aberrant telomere structures, which are blocked by concurrent Trf2 over-expression. Together, these findings highlight the suppression of Blm as a key protective mechanism of Trf2. Notably, U. maydis harbors another double-strand telomere-binding protein (Tay1), which promotes Blm activity to ensure efficient replication. We found that deletion of tay1 partially suppresses the telomere aberration of Trf2-depleted cells. Our results thus point to opposing regulation of Blm helicase by telomere proteins as a strategy for optimizing both telomere maintenance and protection. We also show that aberrant transcription of both telomere G- and C-strand is a recurrent phenotype of telomere mutants, underscoring another potential similarity between double strand breaks and de-protected telomeres.

BackgroundNontraumatic painful upper-extremity conditions (NPUCs) are largely age-related degenerations that affect the majority of adults. Most patients with NPUCs do not seek medical care and adjust on their own. Among those who do seek care, approximately 20% report risky substance use, defined as a consumption pattern that increases the risk of harm to physical or psychosocial health. In the context of NPUC, risky substance use is associated with more intense pain, emotional distress, disability, and opioid or other substance misuse (ie, cross-tolerance). Consequently, risky substance use is a significant modifiable risk factor for the progression and maintenance of chronic pain-related disability and comorbid psychopathology among patients with NPUCs. ObjectiveThis study aims to develop, adapt, and test the feasibility of the Web-Based Toolkit for Resilient Life Beyond Pain and Substance Use (Web-TIRELESS), a novel, asynchronous, and web-based mind-body intervention aimed at modifying maladaptive pain-coping behaviors in patients with NPUC and comorbid risky substance use. This study illustrates the proposed study design, methodology, and intervention content. MethodsIn aim 1, we will conduct live video qualitative interviews (n=20) with care-seeking adult patients with NPUC and comorbid risky substance use to inform the development and refinement of Web-TIRELESS and study procedures. In aim 2, we propose an open pilot study (n=12) of Web-TIRELESS with exit interviews and pre- and postintervention assessments to evaluate the feasibility, credibility, and acceptability of Web-TIRELESS and refine study procedures. Aim 3 consists of a pilot feasibility randomized controlled trial of Web-TIRELESS versus minimally enhanced usual care (n=50), both of which follow a web-based modality, to demonstrate the feasibility of recruitment procedures and data collection, as well as the feasibility, credibility, and acceptability of Web-TIRELESS and the control condition (adherence, retention, fidelity, and satisfaction), following prespecified benchmarks. ResultsPatient interviews (aim 1) concluded in May 2024 and qualitative analysis is expected to be completed in September 2024. Completion of aim 2 (data collection and analysis) is expected by June 2025. The completion of aim 3 and other study-related operations is anticipated by June 2027. ConclusionsWe will develop and test Web-TIRELESS, the first asynchronous mind-body intervention specifically adapted to enhance resilience in response to chronic pain among individuals with NPUCs and comorbid risky substance use. Results from this 3-aim study (feasibility, acceptability, and satisfaction of Web-TIRELESS) will be leveraged to inform a future efficacy randomized controlled trial of Web-TIRELESS versus the minimally enhanced usual care. Trial RegistrationClinicalTrials.gov NCT06366633; https://clinicaltrials.gov/study/NCT06366633 International Registered Report Identifier (IRRID)DERR1-10.2196/64547

Abstract We consider maximal estimates associated with fermionic systems. Firstly, we establish maximal estimates with respect to the spatial variable. These estimates are certain boundary cases of the many‐body Strichartz estimates pioneered by Frank, Lewin, Lieb and Seiringer. We also prove new maximal‐in‐time estimates, thereby significantly extending work of Lee, Nakamura and the first author on Carleson's pointwise convergence problem for fermionic systems.

Summary: Background: Apomorphine is a dopaminergic candidate therapy to improve recovery in patients with prolonged disorders of consciousness (PDoC). Behavioural improvements were previously described in non-controlled case series, but its efficacy and neural mechanisms remain largely unknown. This open-label controlled study using multimodal outcome measures investigates the action of apomorphine in severely brain-injured patients. Methods: Thirteen PDoC patients received 30-day subcutaneous apomorphine treatment (n = 6) or standard care (control group, n = 7) in a neurological rehabilitation centre between February 2018 and January 2021. The apomorphine group was monitored 30 days before treatment initiation, during treatment and one year after treatment. Primary outcome measure was defined as changes in behavioural diagnosis using the Coma Recovery Scale—Revised (CRS-R). CRS-R index, recovery of new conscious behaviours, DoC-feeling scores, high-density electroencephalography, and fluorodeoxyglucose positron emission tomography were employed as secondary outcome measures. The control group was monitored with repeated CRS-R only. Registration: EudraCT 2018-003144-23; Clinicaltrials.gov NCT03623828. Findings: Groups (apomorphine vs. control: odds ratio 8.9, 95% CI 3.3–17.8) and study phase (treatment vs. baseline, apomorphine group only: odds ratio 3.9, 95% CI 1.5–10.1) significantly influenced positive changes in behavioural diagnosis. At one-year post-injury, 4/6 patients in the apomorphine group and 1/7 patients in the control group had improved their diagnosis. Similarly, CRS-R index was significantly influenced by study phase (treatment vs. baseline). All items on the DoC-feeling score were rated higher after treatment than before by both family and medical staff. Patients in the apomorphine group recovered more conscious behaviours than control patients. Alpha-band whole-brain connectivity and participation coefficient, as well as alpha-band parieto-temporal connectivity and frontal participation coefficient were higher after treatment than at baseline. Whole-brain metabolism increased by a relative mean of 13.8% after treatment compared to baseline, with a significant effect of timing (pre-vs. post-treatment scans) on regional SUV. Interpretation: Long-lasting consciousness improvements were observed in patients treated with apomorphine, compared to controls and compared to baseline. Changes in brain connectivity and metabolism were observed after treatment, providing insights into possible neurophysiological mechanisms and target areas. This open-label study confirmed the feasibility and safety of apomorphine treatment, which may represent a key therapeutic option for PDoC. Funding: University and University Hospital of Liege, Belgian National Funds for Scientific Research, Fund Generet of the King Baudouin Foundation, AstraZeneca Foundation, Leon Fredericq Foundation and NeuroHealing Pharmaceuticals Inc.

The current study evaluated factors that explain green entrepreneurship intention (GEI) among 407 university students in Chile, who were presented with an online questionnaire. Thirty-nine questions evaluated their GEI, and the data was analysed using multivariate techniques. Results showed thatconcept development support (CDS), business development support (BDS) and academic training support (ATS) had a positive effect on institutional support (IS). Country support (CS) had a positive effect on self-efficacy (SE). IS did not have a positive effect on SE. Finally, SE had a positive effect on GEI. The model explained 25.3% of GEI. Bootstrapping led support to these results. The effects of CDS, BDS, ATS, CS and SE were positive and significant. Recognizing which factors have a significant effect can be useful to devise university programs aiming to enhance GEI among university students. The results of this paper may provide useful indications about future entrepreneurship and possibly suggest ways in which students’ participation in private companies may create successful green products and services.

Background Tildrakizumab is an anti-interleukin-23 p19 monoclonal antibody approved for the treatment of moderate-to-severe plaque psoriasis. This report describes final primary results of a 64-week real-world study of the effect of tildrakizumab on patients’ health-related quality of life (HRQoL).Materials and methods In this open-label phase 4 study (NCT03718299), patients with moderate-to-severe plaque psoriasis received tildrakizumab 100 mg at week 0, week 4, and every 12 weeks thereafter through week 52. The primary endpoint was improvement from baseline in HRQoL measured by Psychological General Well-Being Index (PGWBI) total score at weeks 28 and 52. Secondary HRQoL endpoints included change from baseline in Dermatology Life Quality Index (DLQI) score through week 64. Missing data were not imputed.Results Of 55 patients enrolled, 45 were assessed at week 64. Mean ± standard deviation (SD) total PGWBI score improved from 78.1 ± 14.1 at baseline to 85.2 ± 12.0 at week 52 (p

Groundwater extracted from coal seams may be a resource for irrigation of land in areas with low rainfall, but the effect of this water on soil properties needs to be established. A lysimeter study was conducted using intact soil cores (0.75 m diameter, 1.4 m deep) of four different soil types (Sodic Vertisol, Calcic Solonetz, Haplic Solonetz and Xanthic Lixisol) from southern Queensland, Australia, to study changes in soil physical and chemical properties under accelerated rates of irrigation with coal seam (CS) water (electrical conductivity (ECw) of 3 dS/m, pH of 8.8, and a sodium adsorption ratio (SAR) of 100). Cores were also alternately irrigated with deionised water to simulate rainfall, and either lucerne (Medicago sativa L) or Rhodes grass (Chloris gayana Kunth.) where grown in the lysimeters. The soil surface was treated with stoichiometric rates of elemental sulfur (1.4 t/ha) and gypsum (2.5 t/ha) prior to every 450 mm CS water irrigation to minimise changes in SAR and pH. Three of the soils (Vertisol, both Solonetz) had low leaching fractions (≤ 0.1 %) due to their clay texture and were initially saline in the subsoil (ECse 1.4–4.4 dS/m). Irrigation with CS water resulted in a gradual increase in salt content (EC) and SAR throughout the soil profile, but pH was not increased due to surface-applied elemental sulfur. The Lixisol had a higher hydraulic conductivity and leaching fraction (6.7 %) due to is loamy texture – in this soil, accumulated salts could be leached and no increase in salinity or pH were measured. Despite an increase in SAR for this loamy soil, no structural degradation was observed, and it could be sustainably irrigated with up to 3200 mm CS water (with cumulative irrigation volume of 5400 mm). Hence, leaching fractions rather than soil chemistry are good indicators to identify soils suitable for irrigation with CS water that is saline, alkaline, and sodic.

Mobile Manipulators (MoMa) is a category of mobile robots designed to assist people with motor disabilities to perform object retrieval tasks using a webcam-based gaze control system. Using off-the-shelf components such as reproducible acrylic and 3D-printed plates, and a webcam for eye tracking, MoMa serves as an inexpensive, open-source, and customizable solution in assistive robotics. The robotic system consists of a mobile base that can move forward and backward, as well as turn in place; and a 2-axis cartesian arm equipped with a claw gripper that opens and closes. The simple movement of the robot also allows for a simple control method and graphical user interface (GUI). The user receives information about what is in front of the robot through a mounted camera, and, by looking at parts of the screen that correspond to controls, has their gaze predicted by a convolutional neural network and sends commands wirelessly. The performance of the entire system has been validated through testing of the gaze prediction model, the integration of the control system, as well as its task completion capabilities. All the design, construction and software files are freely available online under the CC BY 4.0 license at https://doi.org/10.17632/k7yfn6wdv7.2.

Abstract. Introduction:. Central neuropathic pain (CNP) commonly develops in patients after spinal cord injury (SCI), causing debilitating symptoms and sensory abnormalities to mechanical and thermal stimuli. The biological variability of pain phenotypes in individuals has limited the number of positive outcomes. Thus, it is necessary to investigate the physiological processes contributing to sensory changes that develop over time. Objective:. To investigate the physiological processes contributing to neuropathic pain sensory changes and locomotor impairments with sensory phenotypes that develop over time. Methods:. Using the tail flick and von Frey tests, we performed hierarchical clustering to determine the subpopulation of rats that developed thermal and mechanical sensory abnormalities. To measure inflammation as a potential mediator of CNP phenotypes, we used flow cytometry and immunohistochemistry. Finally, to assess the secondary effects on locomotor recovery, up to 8 weeks after injury, we used the CatWalk test to assess multiple parameters of gait. Results:. The von Frey test showed a subpopulation of SCI rats that were hyposensitive to mechanical stimuli from 6 to 8 weeks after injury. The tail flick test showed a subpopulation of SCI rats that were hypersensitive to thermal stimuli at 1 week and 3 to 8 weeks after injury. Although there were no differences in inflammatory cells between subpopulations, we did see significant changes in locomotor recovery between rats with and without sensory abnormalities. Conclusion:. The myeloid cell population at large is not affected by mechanical or thermal phenotypes of pain in this model; however, locomotor recovery is impaired depending on the pain phenotype present. Further investigation into acute inflammatory cells may be insightful for predicting the development of pain phenotypes.