Do Existing MRI Definitions of Knee Osteoarthritis Identify Knees That Will Develop Clinically Significant Disease Over Up To 11 Years of Follow-Up?

OBJECTIVES: In individuals without radiographic knee osteoarthritis (KOA), we investigated whether MRI-defined KOA at baseline was associated with incident radiographic and symptomatic disease during up to 11 years of follow-up. METHODS: Osteoarthritis Initiative participants without tibiofemoral radiographic KOA at baseline were assessed for MRI-based tibiofemoral cartilage damage, osteophyte presence, bone marrow lesions, and meniscal damage/extrusion. We defined MRI KOA using alternative, reported definitions (Def A and Def B). Kellgren-Lawrence (KL) grade, joint space narrowing (JSN), and frequent knee symptoms (Sx) were assessed at baseline, 1-, 2-, 3-, 4-, 6-, 8-, and 10/11-year follow-up visits. Incident tibiofemoral radiographic KOA (outcome) was defined as (1) KL ≥ 2, (2) KL ≥ 2 and JSN, or (3) KL ≥ 2 and Sx. Adjusted Cox proportional hazards regression models examined associations of baseline MRI-defined KOA (Def A and Def B) with incident outcomes during up to 11 years of follow-up. RESULTS: Among 1621 participants [mean age=58.8 (SD=9.0) years, mean BMI=27.2 (4.5) kg/m2, 59.5% women], 17% had MRI-defined KOA by Def A and 24% by Def B. Baseline MRI-defined KOA was associated with incident KL ≥ 2 [odds ratio=2.94 (95% CI=2.34-3.68) for Def A and 2.44 (95% CI=1.97-3.03) for Def B]. However, a substantial proportion of individuals with baseline MRI-defined KOA did not develop incident KL ≥ 2 during follow-up (59% for Def A and 64% for Def B). Findings were similar for the other two outcomes. CONCLUSIONS: Current MRI definitions of KOA do not adequately identify knees that will develop radiographic and symptomatic disease.

Asundexian versus Apixaban in Patients with Atrial Fibrillation.

BACKGROUND: Stroke prevention with direct-acting oral anticoagulant agents in patients with atrial fibrillation confers a risk of bleeding and limits their use. Asundexian, an activated factor XI (XIa) inhibitor, is an oral anticoagulant that may prevent strokes with less bleeding. METHODS: In a phase 3, international, double-blind trial, we randomly assigned high-risk patients with atrial fibrillation in a 1:1 ratio to receive asundexian at a dose of 50 mg once daily or standard-dose apixaban. The primary efficacy objective was to determine whether asundexian is at least noninferior to apixaban for the prevention of stroke or systemic embolism. The primary safety objective was to determine whether asundexian is superior to apixaban with respect to major bleeding events. RESULTS: A total of 14,810 randomly assigned patients were included in the intention-to-treat population. The mean (±SD) age of the patients was 73.9±7.7 years, 35.2% were women, 18.6% had chronic kidney disease, 18.2% had a previous stroke or transient ischemic attack, 16.8% had received oral anticoagulants for no more than 6 weeks, and the mean CHA2DS2-VASc score (range, 0 to 9, with higher scores indicating a greater risk of stroke) was 4.3±1.3. The trial was stopped prematurely at the recommendation of the independent data monitoring committee. Stroke or systemic embolism occurred in 98 patients (1.3%) assigned to receive asundexian and in 26 (0.4%) assigned to receive apixaban (hazard ratio, 3.79; 95% confidence interval [CI], 2.46 to 5.83). Major bleeding occurred in 17 patients (0.2%) who received asundexian and in 53 (0.7%) who received apixaban (hazard ratio, 0.32; 95% CI, 0.18 to 0.55). The incidence of any adverse event appeared to be similar in the two groups. CONCLUSIONS: Among patients with atrial fibrillation at risk for stroke, treatment with asundexian at a dose of 50 mg once daily was associated with a higher incidence of stroke or systemic embolism than treatment with apixaban in the period before the trial was stopped prematurely. There were fewer major bleeding events with asundexian than with apixaban during this time. (Funded by Bayer; OCEANIC-AF ClinicalTrials.gov number, NCT05643573; EudraCT number, 2022-000758-28.).

The mode of delivery after operative fixation of pelvic ring fractures-a retrospective observational study.

PURPOSE: The purpose of this study is to investigate whether retained hardware after surgical treatment for a pelvic fracture prior to pregnancy affects the choice of delivery method. The study aims to provide insights into the rates of vaginal delivery and caesarean sections, understanding whether the mode of delivery was influenced by patient preference or the recommendations of obstetricians or surgeons, and examining the rate of complications during delivery and postpartum. METHODS: All women of childbearing age who underwent surgical fixation for a pelvic ring fracture between 1994 and 2021 were identified. A questionnaire was sent about their possible pregnancies and deliveries. Of the included patients, surgical data were collected and the fracture patterns were retrospectively classified. Follow-up was a minimum of 36 months. RESULTS: A total of 168 women with a pelvic fracture were identified, of whom 13 had a pregnancy after surgical stabilization. Eleven women had combined anterior and posterior fracture patterns and two had isolated sacral fractures. Four women underwent combined anterior and posterior fixation, the others either anterior or posterior fixation. Seven women had a total of 11 vaginal deliveries, and 6 women had 6 caesarean sections. The decision for vaginal delivery was often the wish of the mother (n = 4, 57%) while the decision to opt for caesarean section was made by the surgeon or obstetrician (n = 5, 83%). One woman in the vaginal delivery group suffered a postpartum complication possibly related to her retained pelvic hardware. CONCLUSION: Women with retained hardware after pelvic ring fixation can have successful vaginal deliveries. Complications during labor or postpartum are rare. The rate of primary caesarean sections is high (46%) and is probably influenced by physician bias. Future research should focus on tools that can predict labor outcomes in this specific population, and larger multicenter studies are needed. LEVEL OF EVIDENCE: Level III.

Precious2GPT: the combination of multiomics pretrained transformer and conditional diffusion for artificial multi-omics multi-species multi-tissue sample generation.

Synthetic data generation in omics mimics real-world biological data, providing alternatives for training and evaluation of genomic analysis tools, controlling differential expression, and exploring data architecture. We previously developed Precious1GPT, a multimodal transformer trained on transcriptomic and methylation data, along with metadata, for predicting biological age and identifying dual-purpose therapeutic targets potentially implicated in aging and age-associated diseases. In this study, we introduce Precious2GPT, a multimodal architecture that integrates Conditional Diffusion (CDiffusion) and decoder-only Multi-omics Pretrained Transformer (MoPT) models trained on gene expression and DNA methylation data. Precious2GPT excels in synthetic data generation, outperforming Conditional Generative Adversarial Networks (CGANs), CDiffusion, and MoPT. We demonstrate that Precious2GPT is capable of generating representative synthetic data that captures tissue- and age-specific information from real transcriptomics and methylomics data. Notably, Precious2GPT surpasses other models in age prediction accuracy using the generated data, and it can generate data beyond 120 years of age. Furthermore, we showcase the potential of using this model in identifying gene signatures and potential therapeutic targets in a colorectal cancer case study.

Effect of game-based teaching on the oral health of children: a systematic review of randomised control trials.

Poor oral health during childhood can lead to various oral diseases and have long-term implications for dental health. Innovative and engaging oral health educational approaches such as game-based teaching have emerged as a promising modality for health education. This systematic review examined the effectiveness of game-based teaching methods on the oral health of children (4-12 yrs). Scopus, Medline and Web of Science databases were searched according to specific inclusion and exclusion criteria. Inclusion criteria included randomised trials that compared traditional methods of oral health education with game-based interventions in preschoolers and school-age children. The quality of the data was determined using Cochrane risk-of-bias tool for randomized trials (ROB-2). A total of seven studies that examined 1097 children (4-12 yrs) were included in this systematic review with the association of game-based teaching of oral health. The findings indicated that the utilization of game-based methods significantly improved children's oral health outcomes when compared to traditional teaching approaches. Specifically, the game-based interventions demonstrated positive effects on various aspects of oral health, including enhanced oral health knowledge, improved oral hygiene scores, and reductions in debris and plaque scores. The game-based interventions were found to be more effective in promoting oral health when compared to conventional methods of teaching, such as verbal instructions or educational posters. Based on the limited evidence available, game-based teaching appears to be an effective approach for promoting oral health among children, consistently demonstrating positive outcomes, including improved oral health knowledge, enhanced oral hygiene scores, and reductions in debris and plaque scores. Further well-designed trials adhering to reporting guidelines and using objective measures are necessary before outlining universal guidelines for best practice.

The revised Clinician-Administered PTSD scale for DSM-5 (CAPS-5-R): Initial psychometric evaluation in a trauma-exposed community sample.

The Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) is a widely used, well-validated structured interview for posttraumatic stress disorder (PTSD). It was recently revised to improve various aspects of administration and scoring. We conducted a psychometric evaluation of the revised version, known as the CAPS-5-R. Participants were 73 community residents with mixed trauma exposure (e.g., sexual assault, physical assault, transportation accident, the unnatural death of a loved one). CAPS-5-R PTSD diagnosis demonstrated good test-retest reliability, кs = .73-.79; excellent interrater reliability, кs = .86-.93; and good-to-excellent alternate forms reliability with the CAPS-5, кs = .79-.93. In addition, the CAPS-5-R total PTSD severity score demonstrated excellent test-retest reliability, intraclass correlation coefficient (ICC) = .86; interrater reliability, ICC = .98; and alternate forms reliability with the CAPS-5, r = .95. Further, the CAPS-5-R demonstrated good convergent validity with other measures of PTSD and good discriminant validity with measures of other constructs (e.g., depression, anxiety, alcohol problems, somatic concerns, mania). Given its strong psychometric performance in this study, as well as its improvements in administration and scoring, the CAPS-5-R appears to be a valuable update of the current CAPS-5.

Differential patch-leaving behavior during probabilistic foraging in humans and gerbils.

Foraging confronts animals, including humans, with the need to balance exploration and exploitation: exploiting a resource until it depletes and then deciding when to move to a new location for more resources. Research across various species has identified rules for when to leave a depleting patch, influenced by environmental factors like patch quality. Here we compare human and gerbil patch-leaving behavior through two analogous tasks: a visual search for humans and a physical foraging task for gerbils, both involving patches with randomly varying initial rewards that decreased exponentially. Patch-leaving decisions of humans but not gerbils follow an incremental mechanism based on reward encounters that is considered optimal for maximizing reward yields in variable foraging environments. The two species also differ in their giving-up times, and some human subjects tend to overharvest. However, gerbils and individual humans who do not overharvest are equally sensitive to declining collection rates in accordance with the marginal value theorem. Altogether this study introduces a paradigm for a between-species comparison on how to resolve the exploitation-exploration dilemma.

Online Mendelian Inheritance in Animals (OMIA): a genetic resource for vertebrate animals.

Online Mendelian Inheritance in Animals (OMIA) is a freely available curated knowledgebase that contains information and facilitates research on inherited traits and diseases in animals. For the past 29 years, OMIA has been used by animal geneticists, breeders, and veterinarians worldwide as a definitive source of information. Recent increases in curation capacity and funding for software engineering support have resulted in software upgrades and commencement of several initiatives, which include the enhancement of variant information and links to human data resources, and the introduction of ontology-based breed information and categories. We provide an overview of current information and recent enhancements to OMIA and discuss how we are expanding the integration of OMIA into other resources and databases via the use of ontologies and the adaptation of tools used in human genetics.

From d8 to d1: Iron(0) and Iron(I) Complexes Complete the Series of Eight Fe Oxidation States within the TIMMNMes Ligand Framework.

Reduction of the ferrous precursor [(TIMMNMes)Fe(Cl)]+ (1) (TIMMNMes = tris-[(3-mesitylimidazol-2-ylidene)methyl]amine) to the low-valent iron(0) complex [(TIMMNMes)Fe(CO)3] (2) is presented, where the tris(N-heterocyclic carbene) (NHC) ligand framework remains intact, yet the coordination mode changed from 3-fold to 2-fold coordination of the carbene arms. Further, the corresponding iron(I) complexes [(TIMMNMes)Fe(L)]+ (L = free site, η1-N2, CO, py) (3) are synthesized and fully characterized. Complexes 1-3 demonstrate the notable steric and electronic flexibility of the TIMMNMes ligand framework by variation of the Fe-N anchor and Fe-carbene distances and the variable size of the axial cavity occupation. This is further underpinned by the oxidation of 3-N2 in a reaction with benzophenone to yield the corresponding, charge-separated iron(II) radical complex [(TIMMNMes)Fe(OCPh2)]+ (4). We found rather surprising similarities in the reactivity behavior when going to low- or high-valent oxidation states of the central iron ion. This is demonstrated by the closely related reactivity of 3-N2, where H atom abstraction with TEMPO triggers the formation of the metallacycle [(TIMMNMes*)Fe(py)]+ (5), and the reactivity of the highly unstable Fe(VII) nitride complex [(TIMMNMes)Fe(N)(F)]3+ to give the metallacyclic Fe(V) imido complex [(TIMMNMesN)Fe(NMes)(MeCN)]3+ (6) upon warming. Thus, the employed tris(carbene) chelate is not only capable of stabilizing the superoxidized Fe(VI) and Fe(VII) nitrides but equally supports the iron center in its low oxidation states 0 and +1. Isolation and characterization of these zero- and monovalent iron complexes demonstrate the extraordinary capability of the tris(carbene) chelate TIMMN to support iron in eight different oxidation states within the very same ligand platform.

Systematic review of barriers, facilitators, and tools to promote shared decision making in the emergency department.

OBJECTIVE: The objective was to systematically review all studies focusing on barriers, facilitators, and tools currently available for shared decision making (SDM) in emergency departments (EDs). BACKGROUND: Implementing SDM in EDs seems particularly challenging, considering the fast-paced environment and sometimes life-threatening situations. Over 10 years ago, a previous review revealed only a few patient decision aids (PtDAs) available for EDs. METHODS: Literature searches were conducted in MEDLINE, Embase, and Cochrane library, up to November 2023. Observational and interventional studies were included to address barriers or facilitators for SDM or to investigate effects of PtDAs on the level of SDM for patients visiting an ED. RESULTS: We screened 1946 studies for eligibility, of which 33 were included. PtDAs studied in EDs address chest pain, syncope, analgesics usage, lumbar puncture, ureterolithiasis, vascular access, concussion/brain bleeding, head-CT choice, coaching for elderly people, and activation of patients with appendicitis. Only the primary outcome was meta-analyzed, showing that PtDAs significantly increased the level of SDM (18.8 on the 100-point OPTION scale; 95% CI 12.5-25.0). PtDAs also tended to increase patient knowledge, decrease decisional conflict and decrease health care services usage, with no obvious effect on overall patient satisfaction. Barriers and facilitators were identified on three levels: (1) patient level-emotions, health literacy, and their own proactivity; (2) clinician level-fear of medicolegal consequences, lack of SDM skills or knowledge, and their ideas about treatment superiority; and (3) system level-time constraints, institutional guidelines, and availability of PtDAs. CONCLUSIONS: Circumstances in EDs are generally less favorable for SDM. However, PtDAs for conditions seen in EDs are helpful in overcoming barriers to SDM and are welcomed by patients. Even in EDs, SDM is feasible and supported by an increasing number of tools for patients and physicians.

Role of national regime ideology for predicting biodiversity outcomes.

The rapid decline of global biodiversity has engendered renewed debate about the social, economic, and political factors contributing to it. Specifically, there is little understanding of the role that political ideology within a country (e.g., nationalism, conservatism, socialism) plays in determining biodiversity outcomes. We used negative binomial generalized linear models to investigate the importance of national regime ideology in predicting threatened animal species and protected area establishment compared with other factors that affect biodiversity outcomes, such as gross domestic product, inequality, and democracy. For threatened animals, the model with the highest Akaike weight suggested adverse biodiversity outcomes arose from larger gross domestic product (ß = 0.120, p < 0.001). However, nationalism (ß = 0.371, p < 0.01) and socialism (ß = 0.293, p < 0.05) were also significantly associated with increased proportions of threatened species. For protected areas, the model with the highest Akaike weight suggested increases in democracy (ß = 0.880, p < 0.001) led to a rise in relative protected area estate. Conservative regime ideology was also associated with greater protected area estate, although this did not increase the weight of evidence in support of the best models. These findings highlight the relevance of political ideology for predicting biodiversity outcomes at a national scale and illustrate opportunities to tailor policies and advocacy to promote biodiversity conservation more effectively. By targeting appropriate messaging and political advocacy, conservationists can improve the likelihood that politicians and their nations will participate in positive biodiversity actions.

El papel de la ideología del régimen nacional para la predicción de resultados de biodiversidad Resumen El rápido declive de la biodiversidad mundial ha suscitado un renovado debate sobre los factores sociales, económicos y políticos que contribuyen a él. En concreto, se conoce poco el papel que desempeña la ideología política dentro de un país (por ejemplo, el nacionalismo, el conservadurismo o el socialismo) a la hora de determinar los resultados en materia de biodiversidad. Utilizamos modelos lineales generalizados binomiales negativos para investigar la importancia de la ideología del régimen nacional a la hora de predecir las especies animales amenazadas y el establecimiento de áreas protegidas en comparación con otros factores que afectan a los resultados de la biodiversidad, como el producto interno bruto, la desigualdad y la democracia. En el caso de los animales amenazados, el modelo con la mayor ponderación de Akaike sugirió que los resultados adversos para la biodiversidad se debían a un mayor producto interno bruto (ß = 0,120, p < 0,001). Sin embargo, el nacionalismo (ß = 0,371, p < 0,01) y el socialismo (ß = 0,293, p < 0,05) también se asociaron significativamente con una mayor proporción de especies amenazadas. En el caso de las áreas protegidas, el modelo con la mayor ponderación de Akaike sugirió que el aumento de la democracia (ß = 0,880, p < 0,001) conducía a un aumento de la extensión relativa de las áreas protegidas. La ideología conservadora del régimen también se asoció con una mayor superficie de áreas protegidas, aunque no aumentó el peso de la evidencia en apoyo de los mejores modelos. Estos resultados resaltan la importancia de la ideología política para predecir los resultados de la biodiversidad a escala nacional e ilustran las oportunidades de adaptar las políticas y la defensa para promover la conservación de la biodiversidad de manera más eficaz. Si se orientan los mensajes y la promoción política de forma adecuada, los conservacionistas pueden mejorar la probabilidad de que los políticos y sus naciones participen en acciones positivas para la biodiversidad.

Non- or minimally displaced distal radius fractures in adult patients < 50 years of age : Three weeks of cast immobilisation versus one week of brace immobilisation: study protocol for a multicentre randomised controlled trial.

BACKGROUND: Currently, non- or minimally displaced distal radius fractures are treated by 3 to 5 weeks of cast immobilisation. Many patients with a distal radius fracture suffer from long-term functional restrictions, which might be related to stiffness due to cast immobilisation. Current literature indicates that 1 week of immobilisation might be safe; however, no level 1 evidence is available. This trial aims to compare 1 week of brace immobilisation with 3 weeks of cast immobilisation in patients with distal radius fractures that do not need reduction. METHODS: The aim of this trial is to evaluate the non-inferiority of 1 week of brace immobilisation in patients with non- or minimally displaced distal radius fractures. A two-armed single blinded multicentre randomised clinical trial will be conducted in three hospitals. Adult patients, between 18 and 50 years old, independent for activities of daily living, with a non- or minimally displaced distal radius fracture can be included in this study. The intervention group is treated with 1 week of brace immobilisation, and the control group with 3 weeks of cast immobilisation. Primary outcome is the patient-reported outcome measured by the Patient-Related Wrist Evaluation score (PRWE) at 6 months. Secondary outcomes are patient-reported outcome measured by the Quick Disabilities of the Arm, Shoulder and Hand score at 6 weeks and 6 months, PRWE at 6 weeks, range of motion, patient-reported pain score measured by VAS score, radiological outcome (dorsal/volar tilt, radial height, ulnar variance, presence of intra-articular step off), complications and cost-effectiveness measured by the EuroQol 5 Dimension questionnaire, Medical Consumption Questionnaire and Productivity Cost Questionnaire. DISCUSSION: This study will provide evidence on the optimal period of immobilisation in non-operatively treated displaced and reduced distal radius fractures. Both treatment options are accepted treatment protocols and both treatment options have a low risk of complications. Follow-up will be according to the current treatment protocol. This study will provide level 1 evidence on the optimal period and way of immobilisation for non- or minimally displaced distal radius fractures in adult patients. TRIAL REGISTRATION: ABR 81638 | NL81638.029.22 | www.toetsingonline.nl . 18th of October 2023.

Does regional implementation of a clinical pathway for older adult patients with pelvic fragility fractures after low-energy trauma improve patient outcomes (PELVIC): a multicentre, stepped-wedge, randomised controlled trial.

INTRODUCTION: Patients with pelvic fragility fractures suffer from high morbidity and mortality rates. Despite the high incidence, there is currently no regional or nationwide treatment protocol which results in a wide variety of clinical practices. Recently, there have been new insights into treatment strategies, such as early diagnosis and minimally invasive operative treatment. The aim of this study is to implement an evidence-based and experience-based treatment clinical pathway to improve outcomes in this fragile patient population. METHODS AND ANALYSIS: This study will be a regional stepped-wedge cluster randomised controlled trial. All older adult patients (≥50 years old) who suffered a pelvic fragility fracture after low-energetic trauma are eligible for inclusion. The pathway aims to optimise the diagnostic process, to guide the decision-making process for further treatment (eg, operative or conservative), to structure the follow-up and to provide guidelines on pain management, weight-bearing and osteoporosis workup. The primary outcome is mobility, measured by the Parker Mobility Score. Secondary outcomes are mobility measured by the Elderly Mobility Scale, functional performance, quality of life, return to home rate, level of pain, type and dosage of analgesic medications, the number of falls after treatment, the number of (fracture-related) complications, 1-year and 2-year mortality. Every 6 weeks, a cluster will switch from current practice to the clinical pathway. The aim is a total of 393 inclusions, which provides an 80% statistical power for an improvement in mobility of 10%, measured by the Parker mobility score. ETHICS AND DISSEMINATION: The Medical Research Ethics Committee of Academic Medical Center has exempted the PELVIC study from the Medical Research Involving Human Subjects Act (WMO). Informed consent will be obtained using the opt-out method and research data will be stored in a database and handled confidentially. The final study report will be shared via publication without restrictions from funding parties and regardless of the outcome. TRIAL REGISTRATION NUMBER: NCT06054165. PROTOCOL VERSION: V.1.0, 19 July 2022.

Semaglutide Improves Myocardial Perfusion and Performance in a Large Animal Model of Coronary Artery Disease.

Objective: Coronary artery disease (CAD) is the leading cause of death worldwide. It imposes an enormous symptomatic burden on patients, leaving many with residual disease despite optimal procedural therapy, and up to 1/3 with debilitating angina amenable neither to procedures, nor to current pharmacologic options. Semaglutide, a glucagon-like peptide 1 agonist originally approved for management of diabetes, has garnered substantial attention for its capacity to attenuate cardiovascular risk. Although subgroup analyses in patients indicate promise, studies explicitly designed to isolate the impact of semaglutide on the sequelae of CAD, independently of comorbid diabetes or obesity, are lacking. Approach and Results: Yorkshire swine (n=17) underwent placement of an ameroid constrictor around the left circumflex coronary artery to induce CAD. Oral semaglutide was initiated postoperatively at 1.5 mg and scaled up in 2 weeks to 3 mg in treatment animals (SEM, n=8) for a total of 5 weeks, while control animals (CON, n=9) received no drug. All then underwent myocardial harvest with acquisition of perfusion and functional data using microsphere injection and pressure-volume loop catheterization. Immunoblotting, immunohistochemistry, and immunofluorescence were performed on the most ischemic myocardial segments for mechanistic elucidation. SEM animals exhibited improved left ventricular ejection fraction, both at rest and during rapid myocardial pacing (both p<0.03), accompanied by increased perfusion to the most ischemic myocardial region at rest and during rapid pacing (both p<0.03); reduced perivascular and interstitial fibrosis (both p <0.03); and apoptosis (p=0.008). These changes were associated with increased activation of the endothelial-protective AMPK pathway (p=0.005), coupled with downstream increases in endothelial nitric oxide synthase (p=0.014). Conclusion: This study is the first to reveal the capacity of oral semaglutide to augment cardiac function in the chronically ischemic heart in a highly translational large animal model, likely through AMPK-mediated improvement in endothelial function and perfusion to the ischemic myocardium.

Successes and Challenges in Clinical Trial Recruitment: The Experience of a New Study Team.

Participant recruitment is one of the most challenging aspects of a clinical trial, directly impacting both the study's duration and the quality of its results. Therefore, reporting successful recruitment strategies is crucial. This study aimed to document the recruitment tactics and experiences of a research team during a university-based randomized clinical trial, conducted as part of a clinical research immersion program. Recruitment took place from October 2021 to October 2022. Before the study commenced, study team members received formal training in clinical trial participant recruitment from the Principal Investigator. The recruitment strategies were integrated into initial study design, which was approved by the Institutional Review Board. A multimodal approach was employed, incorporating both direct and indirect recruitment methods. These strategies successfully met the enrollment target within the twelve-month period. Throughout the process, team members acquired valuable knowledge in recruitment design and implementation, along with transferable interpersonal and networking skills. In-person recruitment was the most efficient and cost-effective strategy, followed by personal referrals. The primary challenge was accommodating participants' availability. Other study teams should consider these recruitment strategies during their study designs. Additionally, the knowledge and skills gained by this study team underscore the value of experiential learning in research education.

Cooperative spin crossover leading to bistable and multi-inert system states in an iron(III) complex.

Cooperativity among spin centres has long been the royal road in spin crossover (SCO) research to impose magnetic bistability in terms of thermal hysteresis. In this work we access magnetic multi-inert states of the iron(III) compound {FeL2[B(Ph)4]} ≡ FeB at low temperature, in addition to thermal bistability. The packing of the low-spin and high-spin forms of crystalline FeB differs only marginally what ultimately leads to structural conservatism. This indicates that the SCO-immanent breathing of the complex cation is almost fully compensated by the anion matrix. The unique cooling rate dependence of the residual low-temperature magnetisation in FeB unveils continuous switching between the trapped high-spin (ON) and the relaxed low-spin state (OFF). The macroscopic ratio of the spin states (ON:OFF) can be adjusted as a simple function of the cooling rate. That is, cooperative spin crossover can be the source of bistable and multi-inert system states in the very same material.

Comparative effects of canagliflozin and sitagliptin in chronically ischemic myocardium.

Aim: Recent studies demonstrate that sodium-glucose cotransporter 2 inhibitors (SGLT2i) and dipeptidyl peptidase-4 inhibitors (DPP4i), two classes of antidiabetic drugs, are cardioprotective. However, the mechanisms of these benefits and their comparative efficacy remain unclear. We aimed to compare the effects of these antidiabetic agents on cardiac function, perfusion, and microvascular density using a swine model of chronic myocardial ischemia. Methods: Chronic myocardial ischemia was induced in Yorkshire swine by ameroid constrictor placement to the left circumflex artery. Two weeks later, pigs were administered vehicle ("CON", 8 pigs), 300 mg SGLT2i canagliflozin, ("CANA", 8 pigs), or 100 mg DPP4i sitagliptin ("SIT", 5 pigs) daily. Five weeks later, pigs were euthanized. Cardiac function, perfusion, collateralization, and protein expression were determined by pressure-volume catheter, microsphere analysis, immunofluorescence, and immunoblotting, respectively. Results: Compared with SIT, CANA was associated with improved stroke volume and cardiac output, with a trend towards reduced left ventricular stiffness. Both CANA and SIT trended towards improved perfusion compared to CON, but there were no differences between the two treatment groups. SIT was associated with improved capillary density with a trend towards improved arteriolar density compared to CANA. Both CANA and SIT were associated with increased expression of vascular endothelial cadherin compared to CON, without differences in treatment groups. SIT pigs had decreased 5' adenosine monophosphate-activated protein kinase activation compared to CON and CANA. There was a trend towards increased endothelial nitric oxide synthase activation in the SIT group compared to CON. There were no differences in activation of extracellular signal-regulated kinase 1/2 across groups. Conclusions: In the setting of chronic myocardial ischemia, canagliflozin is associated with improved cardiac function compared to sitagliptin, with similar effects on perfusion despite differences in microvascular collateralization.

Strategies to attenuate maladaptive inflammatory response associated with cardiopulmonary bypass.

Cardiopulmonary bypass (CPB) initiates an intense inflammatory response due to various factors: conversion from pulsatile to laminar flow, cold cardioplegia, surgical trauma, endotoxemia, ischemia-reperfusion injury, oxidative stress, hypothermia, and contact activation of cells by the extracorporeal circuit. Redundant and overlapping inflammatory cascades amplify the initial response to produce a systemic inflammatory response, heightened by coincident activation of coagulation and fibrinolytic pathways. When unchecked, this inflammatory response can become maladaptive and lead to serious postoperative complications. Concerted research efforts have been made to identify technical refinements and pharmacologic interventions that appropriately attenuate the inflammatory response and ultimately translate to improved clinical outcomes. Surface modification of the extracorporeal circuit to increase biocompatibility, miniaturized circuits with sheer resistance, filtration techniques, and minimally invasive approaches have improved clinical outcomes in specific populations. Pharmacologic adjuncts, including aprotinin, steroids, monoclonal antibodies, and free radical scavengers, show real promise. A multimodal approach incorporating technical, circuit-specific, and pharmacologic strategies will likely yield maximal clinical benefit.

The impact of heparin and direct thrombin inhibitors on cell-penetrating polymer siRNA transfection.

Gene therapy using siRNA has become a promising strategy to achieve targeted gene knockdown for treatment of cardiovascular pathologies. However, efficient siRNA transfection often relies on cationic delivery vectors such as synthetic cell-penetrating polymers which are susceptible to interference by negatively charged molecules. Anticoagulants such as heparin, which is negatively charged and widely used in cardiovascular applications, may pose a significant barrier to effective siRNA delivery. We therefore conducted in vitro studies utilizing human smooth muscle and endothelial cells transfected with glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and ß2-microglobulin (B2M) siRNA in the presence of heparin, argatroban, and bivalirudin in order to determine which anticoagulant therapy is most compatible for siRNA delivery. We observed that while heparin, at clinical doses, decreases the efficiency of siRNA targeted mRNA knockdown, mRNA knockdown is not inhibited in the presence of either argatroban or bivalirudin. Our data suggests that heparin should be avoided during siRNA therapy with cationic transfection agents, and argatroban and bivalirudin should be used in its stead.