Near-Term Quantum Classification Algorithms Applied to Antimalarial Drug Discovery.

Computational approaches are widely applied in drug discovery to explore properties related to bioactivity, physiochemistry, and toxicology. Over at least the last 20 years, the exploitation of machine learning on molecular data sets has been used to understand the structure-activity relationships that exist between biomolecules and druggable targets. More recently, these methods have also seen application for phenotypic screening data for neglected diseases such as tuberculosis and malaria. Herein, we apply machine learning to build quantum Quantitative Structure Activity Relationship models from antimalarial data sets. There is a continual need for new antimalarials to address drug resistance, and the readily available in vitro data sets could be utilized with newer machine learning approaches as these develop. Furthermore, quantum machine learning is a relatively new method that uses a quantum computer to perform the calculations. First, we present a classical-quantum hybrid computational approach by building a Latent Bernoulli Autoencoder machine learning model for compressing bit-vector descriptors to a size that can be adapted to quantum computers for classification tasks with limited loss of embedded information. Second, we apply our method for feature map compression to quantum classification algorithms, including a completely novel machine learning algorithm with no analogy in classical computers: the Quantum Fourier Transform Classifier. We apply both these approaches to build quantum machine learning models for small-molecule antimalarials with quantum simulation software and then benchmark these quantum models against classical machine learning approaches. While there are many challenges currently facing the development of reliable quantum computers, our results demonstrate that there is potential for the use of this technology in the field of drug discovery.

The anti-tubercular callyaerins target the Mycobacterium tuberculosis-specific non-essential membrane protein Rv2113.

Spread of antimicrobial resistances urges a need for new drugs against Mycobacterium tuberculosis (Mtb) with mechanisms differing from current antibiotics. Previously, callyaerins were identified as promising anti-tubercular agents, representing a class of hydrophobic cyclopeptides with an unusual (Z)-2,3-di-aminoacrylamide unit. Here, we investigated the molecular mechanisms underlying their antimycobacterial properties. Structure-activity relationship studies enabled the identification of structural determinants relevant for antibacterial activity. Callyaerins are bacteriostatics selectively active against Mtb, including extensively drug-resistant strains, with minimal cytotoxicity against human cells and promising intracellular activity. By combining mutant screens and various chemical proteomics approaches, we showed that callyaerins target the non-essential, Mtb-specific membrane protein Rv2113, triggering a complex dysregulation of the proteome, characterized by global downregulation of lipid biosynthesis, cell division, DNA repair, and replication. Our study thus identifies Rv2113 as a previously undescribed Mtb-specific drug target and demonstrates that also non-essential proteins may represent efficacious targets for antimycobacterial drugs.

Assessing expert reliability in determining intracranial EEG channel quality and introducing the Automated Bad Channel Detection algorithm.

OBJECTIVES: To evaluate the inter- and intra-rater reliability for the identification of bad channels among neurologists, EEG Technologists, and naïve research personnel, and to compare their performance with the automated bad channel detection (ABCD) algorithm for detecting bad channels. Methods: Six Neurologists, ten EEG Technologists, and six naïve research personnel (22 raters in total) were asked to rate 1440 real intracranial EEG channels as good or bad. Intra- and interrater kappa statistics were calculated for each group. We then compared each group to the ABCD algorithm which uses spectral and temporal domain features to classify channels as good or bad. Results: Analysis of channel ratings from our participants revealed variable intra-rater reliability within each group, with no significant differences across groups. Inter-rater reliability was moderate among neurologists and EEG Technologists but minimal among naïve participants. Neurologists demonstrated a slightly higher consistency in ratings than EEG Technologists. Both groups occasionally misclassified flat channels, and participants generally focused on low-frequency content for their assessments. The ABCD algorithm, in contrast, relied more on high-frequency content. A logistic regression model showed a linear relationship between the algorithm's ratings and user responses for predominantly good channels, but less so for channels rated as bad. Sensitivity and specificity analyses further highlighted differences in rating patterns among the groups, with neurologists showing higher sensitivity and naïve personnel higher specificity. Significance: Our study reveals the bias in human assessments of iEEG data quality and the tendency of even experienced professionals to overlook certain bad channels, highlighting the need for standardized, unbiased methods. The ABCD algorithm, outperforming human raters, suggests the potential of automated solutions for more reliable iEEG interpretation and seizure characterization, offering a reliable approach free from human biases. .

The Effect of Duration on Performance and Perceived Fatigability During Acute High-Intensity Interval Exercise in Young, Healthy Males and Females.

Few studies have explored the kinetics of performance and perceived fatigability during high-intensity interval training, despite its popularity. We aimed to characterize the kinetics of fatigability and recovery during an 8 × 4-min HIIT protocol, hypothesizing that most muscle function impairment would occur during the initial four intervals. Fifteen healthy males and females (mean ± standard deviation; age = 26 ± 5 years, V̇O2max = 46.8 ± 6.1 mL·kg-1·min-1) completed eight, 4-min intervals at 105% of critical power with 3 min of rest. Maximal voluntary knee extension contractions (MVCs) coupled with electrical nerve stimulation were performed at baseline and after the first, fourth, and eighth intervals. MVC, potentiated twitch force (Pt), and Db10:100 ratio all declined throughout HIIT (p < 0.05). MVC sharply declined after interval 1 (-15 ± 9% relative to baseline; p < 0.05) and had only further declined after interval 8 (-26 ± 11%; p < 0.05), but not interval 4 (-19 ± 13%; p > 0.05). Pt and Db10:100 also sharply declined after interval 1 (Pt: -18 ± 13%, Db10:100: -14 ± 20%; p < 0.05) and further declined after interval 4 (Pt: -35 ± 19%, Db10:100: -30 ± 20%; p < 0.05) but not interval 8 (Pt: -41 ± 19%; Db10:100: -32 ± 18%; p > 0.05). Voluntary activation did not significantly change across the HIIT protocol (p > 0.05). Evoked force recovery was significantly blunted as more intervals were completed: after interval 1, Pt recovered by 7 ± 11% compared to -6 ± 7% recovery after interval 8 (p < 0.05). Ratings of perceived effort, fatigue, and leg pain rose throughout the session (p < 0.05 for each) and were greater (effort and fatigue) for females (p < 0.05). Otherwise, males and females exhibited similar performance fatigability kinetics, with contractile function declines blunted in response to additional intervals.

Effects of strain and stocking density on leg health, activity, and use of enrichments in conventional broiler chicken production.

Conventional broiler production needs to evolve towards more animal-friendly production systems in order to meet increasing consumer concerns regarding animal welfare. Genetics and stocking density are 2 of the most promising leads to make this change possible. In this study, 6 strains with different growth rates (42-61 g/d) were reared at contrasting densities: 37 kg/m² (HD) and 29 kg/m² (LD). At the same body weight of 1.80-1.95 kg, we evaluated how growth rate and stocking density influenced broiler behaviors (general activity, interactions with enrichments), broiler health (mortality, leg problems, cleanliness and plumage growth) and litter quality. Density did not affect body weight, mortality or behaviors. For all strains, LD was associated with a lower prevalence of hock burns, a better gait score, and improved litter quality and broiler cleanliness. For the 3 strains most affected by pododermatitis, a lower prevalence was observed in LD than in HD pens. Fewer birds were inactive and more birds were standing and interacting with the enrichments (as proposed in the experiment) as soon as the growth rate was lower than that of the control strain (Ross 308). Others welfare indicators such as gait score, plumage growth improved as well. Litter humidity decreased with growth rate, contributing to better leg conditions and cleaner breasts. The prevalence of hock burns and certain behaviors (i.e., the proportion of birds grooming or walking/running) were not affected by growth rate. The proportion of birds foraging was higher at a lower growth rate. These results suggest that reducing growth rate as a preliminary measure, and reducing density as a supplementary one, would improve conventional broiler welfare.

Cystic fibrosis-related metabolic defects: crosstalk between ion channels and organs.

Cystic fibrosis is a debilitating disease characterized by a poor medical prognosis due to devastating lung injury. Recent medical advances targeting the major genetic mutation ΔF508 of the cystic fibrosis transmembrane conductance regulator (CFTR) protein have dramatically increased the lifespan of patients with this mutation. This development has led to major changes in the field and has pushed research beyond the ion transport nature of cystic fibrosis and toward multiorgan physiological reprogramming. In this issue of the JCI, Bae, Kim, and colleagues utilized a large animal pig model prior to the onset of disease. They revealed metabolic reprogramming and organ crosstalk that occurred prior to disease progression. These findings provide paradigm-shifting insight into this complex disease.

Residual Popliteal Aneurysm Perfusion Leading to Embolic Complications: A Case Report.

Introduction: Surgical management of popliteal artery aneurysms has been described for half a century. Long term development of the excluded aneurysm sac in the popliteal segment however remains widely unknown, with only a few small series describing outcomes. Residual aneurysm perfusion has the potential to lead to serious complications. Report: A 63 year old man presents with skin and soft tissue necrosis of the right calf two years after proximal and distal aneurysm ligation and great saphenous vein bypass for a popliteal artery aneurysm. Computed tomography and magnetic resonance angiography show perfusion of the excluded aneurysm as well as extensive necrosis of the gastrocnemius muscle. Direct angiography of the aneurysm demonstrated retrograde aneurysm perfusion due to insufficient distal ligation with recurrent micro-embolisation to the calf via geniculate arteries. Coiling of the geniculate arteries was performed, plugging the connection to the tibiofibular trunk and embolisation of the aneurysm sac. After the intervention, no flow was seen in the aneurysm sac and the patient made full recovery. Discussion: Residual aneurysm sac perfusion can lead to complications long after successful aneurysm exclusion. Follow-up after surgery of popliteal aneurysms should include observation of the excluded aneurysm sac with control of residual blood flow. For persistent sac perfusion, aneurysm enlargement or symptoms, further treatment should be considered. Surgical aspects such as complete transection of the artery after aneurysm ligation or end to end anastomosis of the bypass may be considered, to prevent such complications.

Interactive H5P content for increased student engagement in a dental hygiene program.

Background: Presently, dental hygiene education is primarily divided into classroom lectures, simulation labs, and clinical experiences. Although the recent surge of curriculum renovation in dental and medical schools centres around enhancing student engagement and active learning, classroom teaching remains teacher-focussed, involving students mainly as passive learners. H5P is an open platform for creating and sharing interactive HTML5 learning content. A large set of H5P content was created and provided to students through the learning management system as supplementary material for an oral biology course in the dental hygiene program at a Canadian university. This study was conducted to evaluate the impact of this interactive H5P content on the students' learning experiences. Methods: The third-year dental hygiene students enrolled in the oral biology course were invited to participate in the study. Anonymised student performance data from the summative exam were analysed, and a survey regarding the student experience with the supplementary H5P content was administered. Results: Students performed better on questions for which H5P supplements were provided. The results from the survey showed satisfaction and perceived benefit of using H5P as supplementary content in didactic lectures. Discussion: The H5P content allowed students to apply knowledge and reproduce understanding, promoting active learning in the didactic oral biology course. Students appreciated the content's interactive nature and expressed willingness to have similar experiences in other courses. Conclusion: Using H5P, interactive learning content can promote self-directed and personalized learning. This open learning platform has the potential to redefine didactic teaching by fostering an active learning environment.

Contexte: À l'heure actuelle, la formation en hygiène dentaire s'appuie principalement sur des exposés en classe, des simulations en laboratoire et des expériences cliniques. Bien que la récente vague de révision des programmes d'études des écoles dentaires et de médecine soit axée sur le renforcement de l'engagement des étudiants et de l'apprentissage actif, le travail en classe reste axé sur l'enseignement par un enseignant : dans ce contexte, les étudiants sont principalement des apprenants passifs. H5P est une plateforme ouverte pour la création et le partage de contenu d'apprentissage interactif au format HTML5. Un vaste ensemble de contenu H5P a été créé et fourni aux étudiants, par l'entremise du système de gestion de l'apprentissage, à titre de matériel supplémentaire pour un cours de biologie buccale dans le cadre du programme d'hygiène dentaire d'une université canadienne. Cette étude a été effectuée pour évaluer les effets de ce contenu H5P interactif sur les expériences d'apprentissage des étudiants. Méthodes: Les étudiants en hygiène dentaire de troisième année inscrits au cours de biologie buccale ont été invités à participer à l'étude. Des données anonymisées sur le rendement des étudiants provenant de l'examen sommatif ont été analysées, et un sondage sur l'expérience des étudiants avec le contenu H5P supplémentaire a été mené. Résultats: Les résultats des étudiants étaient meilleurs pour les questions pour lesquelles du contenu H5P supplémentaire a été fourni. Les résultats de l'enquête ont révélé les avantages perçus de l'utilisation du contenu H5P supplémentaire dans les cours didactiques, ainsi que la satisfaction en la matière. Discussion: Le contenu H5P a permis aux étudiants d'appliquer les connaissances et de reproduire la compréhension, favorisant ainsi l'apprentissage actif dans le cadre des cours didactiques de biologie buccale. Les étudiants ont apprécié la nature interactive du contenu et se sont dits prêts à répéter l'expérience dans le cadre d'autres cours. Conclusion: Grâce à H5P, le contenu d'apprentissage interactif peut favoriser l'apprentissage autodirigé et personnalisé. Cette plateforme d'apprentissage ouverte a le potentiel de redéfinir l'enseignement didactique en favorisant un environnement d'apprentissage actif.

Comparative transcriptomic analysis of soybean cyst nematode inbred populations non-adapted or adapted on soybean rhg1-a/Rhg4-mediated resistance.

Soybean cyst nematode (SCN, Heterodera glycines) is most effectively managed through planting resistant soybean cultivars, but the repeated use of the same resistance sources has led to a widespread emergence of virulent SCN populations that can overcome soybean resistance. Resistance to SCN HG type 0 (Race 3) in soybean cultivar Forrest is mediated by an epistatic interaction between the soybean resistance genes rhg1-a and Rhg4. We previously developed two SCN inbred populations by mass-selecting SCN HG type 0 (Race 3) on susceptible and resistant recombinant inbred lines, derived from a cross between Forrest and the SCN-susceptible cultivar Essex, which differ for Rhg4. To identify SCN genes potentially involved in overcoming rhg1-a/Rhg4-mediated resistance, we conducted RNA-sequencing on early parasitic juveniles of these two SCN inbred populations infecting their respective hosts, only to discover a handful of differentially expressed genes (DEGs). However, in a comparison to early parasitic juveniles of an avirulent SCN inbred population infecting a resistant host, we discovered 59 and 171 DEGs uniquely up- or down-regulated in virulent parasitic juveniles adapted on the resistant host. Interestingly, the proteins coded by these 59 DEGs included vitamin B-associated proteins (reduced folate carrier, biotin synthase, and thiamine transporter) and nematode effectors known to play roles in plant defense suppression, suggesting that virulent SCN may exert a heightened transcriptional response to cope with enhanced plant defenses and an altered nutritional status of a resistant soybean host.

Symptomatic intracerebral hemorrhage in proximal and distal medium middle cerebral artery occlusion patients treated with mechanical thrombectomy.

BACKGROUND: Acute ischemic stroke (AIS) caused by distal medium vessel occlusions (DMVOs) represents a significant proportion of overall stroke cases. While intravenous thrombolysis (IVT) has been a primary treatment, advancements in endovascular procedures have led to increased use of mechanical thrombectomy (MT) in DMVO stroke patients. However, symptomatic intracerebral hemorrhage (sICH) remains a critical complication of AIS, particularly after undergoing intervention. This study aims to identify factors associated with sICH in DMVO stroke patients undergoing MT. METHODS: This retrospective analysis utilized data from the Multicenter Analysis of Distal Medium Vessel Occlusions: Effect of Mechanical Thrombectomy (MAD-MT) registry, involving 37 centers across North America, Asia, and Europe. Middle cerebral artery (MCA) DMVO stroke patients were included. The primary outcome measured was sICH, as defined per the Heidelberg Bleeding Classification. Univariable and multivariable logistic regression were used to identify factors independently associated with sICH. RESULTS: Among 1708 DMVO stroke patients, 148 (8.7%) developed sICH. Factors associated with sICH in DMVO patients treated with MT included older age (adjusted odds ratio (aOR) 1.01, 95% confidence interval (95% CI) 1.00 to 1.03, P=0.048), distal occlusion site (M3, M4) compared with medium occlusions (M2) (aOR 1.71, 95% CI 1.07 to 2.74, P=0.026), prior use of antiplatelet drugs (aOR 2.06, 95% CI 1.41 to 2.99, P<0.001), lower Alberta Stroke Program Early CT Scores (ASPECTS) (aOR 0.75, 95% CI 0.66 to 0.84, P<0.001), higher preoperative blood glucose level (aOR 1.00, 95% CI 1.00 to 1.01, P=0.012), number of passes (aOR 1.27, 95% CI 1.15 to 1.39, P<0.001), and successful recanalization (Thrombolysis In Cerebral Infarction (TICI) 2b-3) (aOR 0.43, 95% CI 0.28 to 0.66, P<0.001). CONCLUSION: This study provides novel insight into factors associated with sICH in patients undergoing MT for DMVO, emphasizing the importance of age, distal occlusion site, prior use of antiplatelet drugs, lower ASPECTS, higher preoperative blood glucose level, and procedural factors such as the number of passes and successful recanalization. Pending confirmation, consideration of these factors may improve personalized treatment strategies.

Use and Cost of Low-Value Services Among Veterans Dually Enrolled in VA and Medicare.

BACKGROUND: Over half of veterans enrolled in the Veterans Health Administration (VA) are also enrolled in Medicare, potentially increasing their opportunity to receive low-value health services within and outside VA. OBJECTIVES: To characterize the use and cost of low-value services delivered to dually enrolled veterans from VA and Medicare. DESIGN: Retrospective cross-sectional. PARTICIPANTS: Veterans enrolled in VA and fee-for-service Medicare (FY 2017-2018). MAIN MEASURES: We used VA and Medicare administrative data to identify 29 low-value services across 6 established domains: cancer screening, diagnostic/preventive testing, preoperative testing, imaging, cardiovascular testing, and surgery. We determined the count of low-value services per 100 veterans delivered in VA and Medicare in FY 2018 overall, by domain, and by individual service. We applied standardized estimates to determine each service's cost. KEY RESULTS: Among 1.6 million dually enrolled veterans, the mean age was 73, 97% were men, and 77% were non-Hispanic White. Overall, 63.2 low-value services per 100 veterans were delivered, affecting 32% of veterans; 22.9 services per 100 veterans were delivered in VA and 40.3 services per 100 veterans were delivered in Medicare. The total cost was $226.3 million (M), of which $62.6 M was spent in VA and $163.7 M in Medicare. The most common low-value service was prostate-specific antigen testing at 17.3 per 100 veterans (VA 55.9%, Medicare 44.1%). The costliest low-value service was percutaneous coronary intervention (VA $10.1 M, Medicare $32.8 M). CONCLUSIONS: Nearly 1 in 3 dually enrolled veterans received a low-value service in FY18, with twice as many low-value services delivered in Medicare vs VA. Interventions to reduce low-value services for veterans should consider their substantial use of such services in Medicare.

Sonothrombolysis before and after percutaneous coronary intervention provides the largest myocardial salvage in ST-segment Elevation Myocardial Infarction.

BACKGROUND: Sonothrombolysis is a therapeutic application of ultrasound with ultrasound contrast for patients with ST elevation Myocardial Infarction (STEMI). Recent trials demonstrated that sonothrombolysis, delivered before and after primary percutaneous coronary intervention (pPCI), increase infarct vessel patency, improve microvascular flow, reduce infarct size, and improve ejection fraction. However, it is unclear whether pre-pPCI sonothrombolysis is essential for therapeutic benefit. We designed a parallel three-arm sham-controlled randomised controlled trial to address this. METHODS: Patients presenting with first STEMI undergoing pPCI within six hours of symptom onset were randomised 1:1:1 into three arms: sonothrombolysis pre/post pPCI (Group 1), Sham pre & sonothrombolysis post pPCI (Group 2), and Sham pre/post pPCI (Group 3). Our primary endpoint was infarct size (% LV mass) assessed by Cardiac MRI at day 4±2. Secondary endpoints included myocardial salvage index (MSI) and echocardiographic parameters at Day 4±2 and six months. RESULTS: Our trial was ceased early due to the COVID pandemic. From 122 patients screened between September 2020 and June 2021, 51 patients (Age 60, male 82%) were included post randomisation. Median sonothrombolysis took 5 minutes pre pPCI and 15 minutes post, without significant door-to-balloon delay. There was a trend towards reduction in median infarct size between Group 1 (8%[IQR 4,11]), Group 2 (11%[7,19]) or Group 3 (15%[9,22]). Similarly there was a trend towards improved MSI in Group 1 (79%[64,85]) compared to Groups 2 (51%[45,70]) and 3 (48%[37,73]) No major adverse cardiac events occurred during hospitalization. CONCLUSION: Pre-pPCI sonothrombolysis may be key to improving MSI in STEMI. Multicentre trials and health economic analyses are required before clinical translation.

Why are continent catheterizable channels continent? A stomal pressure profilometry feasibility study.

INTRODUCTION: A continent catheterizable channel (CCC) may be a solution for patients with impaired bladder emptying and difficult transurethral access. Leakage of the CCC is a common complication. To prevent leakage, the pressure in the CCC has to be higher than the reservoir (bladder/pouch) pressure in at least one location. It has not been clearly defined through which mechanism(s) the CCC achieves continence. In this feasibility study, we measured the CCC pressure profile in adult patients with various types of CCC's with and without stomal leakage. METHODS: Adult patients with a CCC on a (augmented) bladder or pouch who underwent a urodynamic investigation between January and March 2023 were included. Next to the standard urodynamic investigation, a continuous stomal pressure measurement (CSP) and stomal pressure profilometry with empty bladder (SPP-1) and with filled bladder (SPP-2) of the CCC were performed. RESULTS: A total of 17 patients were included. It was technically possible to perform SPP-1 and SPP-2 in all patients, and to measure the CSP in 16/17 patients. The median maximum stomal pressures in SPP-1 and SPP-2 were 112 (interquartile range [IQR], 76-140) cmH2O and 120 (IQR, 92-140) cmH2O, respectively. Nine patients had stomal leakage during the urodynamic investigation. In five patients, the detrusor leak point pressure (dLPP) was low (<20 cmH2O). A pressure peak at the beginning of SPP-2 was absent in all patients with stomal leakage at low dLPP. CONCLUSION: SPP and CSP measurement in CCCs are feasible. We found differences in SPP-2 between patients with and without leakage at low dLPP, indicative of a role of the intravesical tunnel in continence or high dLPP. The results of this study may improve our understanding of the physiology and dynamics of CCCs as well as the management of CCC-related complications.

Liver-specific Mettl14 deletion induces nuclear heterotypia and dysregulates RNA export machinery.

Modification of RNA with N6-methyladenosine (m6A) has gained attention in recent years as a general mechanism of gene regulation. In the liver, m6A, along with its associated machinery, has been studied as a potential biomarker of disease and cancer, with impacts on metabolism, cell cycle regulation, and pro-cancer state signaling. However these observational data have yet to be causally examined in vivo. For example, neither perturbation of the key m6A writers Mettl3 and Mettl14, nor the m6A readers Ythdf1 and Ythdf2 have been thoroughly mechanistically characterized in vivo as they have been in vitro. To understand the functions of these machineries, we developed mouse models and found that deleting Mettl14 led to progressive liver injury characterized by nuclear heterotypia, with changes in mRNA splicing, processing and export leading to increases in mRNA surveillance and recycling.

TRIM7 ubiquitinates SARS-CoV-2 membrane protein to limit apoptosis and viral replication.

SARS-CoV-2 is a highly transmissible virus that causes COVID-19 disease. Mechanisms of viral pathogenesis include excessive inflammation and viral-induced cell death, resulting in tissue damage. We identified the host E3-ubiquitin ligase TRIM7 as an inhibitor of apoptosis and SARS-CoV-2 replication via ubiquitination of the viral membrane (M) protein. Trim7 -/- mice exhibited increased pathology and virus titers associated with epithelial apoptosis and dysregulated immune responses. Mechanistically, TRIM7 ubiquitinates M on K14, which protects cells from cell death. Longitudinal SARS-CoV-2 sequence analysis from infected patients revealed that mutations on M-K14 appeared in circulating variants during the pandemic. The relevance of these mutations was tested in a mouse model. A recombinant M-K14/K15R virus showed reduced viral replication, consistent with the role of K15 in virus assembly, and increased levels of apoptosis associated with the loss of ubiquitination on K14. TRIM7 antiviral activity requires caspase-6 inhibition, linking apoptosis with viral replication and pathology.

Sonothrombolysis in patients with ST-elevation myocardial infarction with electrocardiographic no-reflow after percutaneous coronary intervention: a randomized controlled trial.

BACKGROUND AND AIMS: Approximately 50% of patients with ST-elevation myocardial infarction (STEMI) treated with percutaneous coronary intervention (PCI) suffer from microvascular no-reflow. Pre- and post-PCI sonothrombolysis has shown to decrease infarct size and improve left ventricular (LV) systolic function in STEMI patients receiving urgent PCI. The aim of this study was to investigate whether post-PCI sonothrombolysis alone in STEMI patients with persistent ST-elevation could reduce no-reflow and infarct size. METHODS: STEMI patients with symptoms <12 hours, who had persistent ST-elevation (≤70% ST-resolution) after primary PCI. were randomized to sonothrombolysis or control. The primary endpoint was summed (Σ) ST-elevation 60 minutes after study intervention. Secondary endpoints included infarct size, myocardial perfusion score, LV ejection fraction on cardiovascular magnetic resonance (CMR) imaging at two months follow up, and clinical outcome at six months follow up. RESULTS: 67 STEMI patients with persistent ST-elevation after PCI were randomized (49 left anterior descending, 18 right coronary/left circumflex artery). No difference was observed in Σ ST-elevation 60 minutes after study intervention (mean difference: 0.6mm, 95% CI: -1.1 - 2.2, p=0.50). Complete ST-resolution occurred in 14 (40%) of patients treated with sonothrombolysis compared to six (19%) of controls (p=0.16). Myocardial perfusion score index (1.5 ±0.3 vs. 1.5 ±0.3, p=0.93), infarct size (18.0±10% vs. 16.8±11%; p=0.29) or LV ejection fraction on CMR (46±8% vs.47±11% in the control group; p=0.86) were comparable. Incidence of all-cause death, acute coronary syndrome and hospital admission for heart failure at six months follow up was similar between the groups (sonothrombolysis: 2, control: 5). CONCLUSION: In STEMI patients with persistent ST-elevation after PCI, post-PCI sonothrombolysis did not result in more ST-resolution or smaller infarct size compared to control subjects. The incidence of the combined clinical endpoints was remarkably low in this high-risk patient population.

A most aggressive bear: Safari videos document sloth bear defense against tiger predation.

Sloth bears are non-carnivorous yet they attack more people than any other bear. They often stand up and charge explosively if a person mistakenly gets too close. Here, we argue that their aggression toward humans is an extension of their behavior toward tigers, which are their only natural predator. Interactions between sloth bears and tigers have not previously been studied because scientists have rarely observed such events. We collected and examined 43 videos or photo documentations of sloth bear-tiger interactions posted on the internet or social media from 2011 to 2023, mainly by tourists visiting tiger parks in India. We observed that sloth bears were most likely to stand up and charge if they first became aware of the tiger at close range (<3 m away). This aggressive-defensive strategy, intended to dissuade the tiger from attacking, appeared to be successful, in that 86% of interactions ended with no contact, whereas four (9%) culminated in the bear's death. We propose that a myrmecophagous diet led to this species' aggressive behavior: (1) their long, blunt front claws, well adapted for digging termites and ants, hamper their ability to climb trees for escape, and (2) they walk with their head down focused on scents underground, and make considerable noise digging and blowing soil, enabling tigers to approach quite closely without being detected. Sloth bears have coexisted with tigers or other (now extinct) large felid predators for their entire evolutionary history. Whereas their aggressive behavior has served them well for millions of years, more recently, people's fear of and retaliation against sloth bears represents a major threat to their survival. Understanding how sloth bears react to tigers provides guidance for reducing attacks on humans, thereby contributing to sloth bear conservation. Our investigation was made possible by passive citizen scientists, who unknowingly collected valuable data.

Renalase Peptides Reduce Pancreatitis Severity in Mice.

Acute pancreatitis, an acute inflammatory injury of the pancreas, lacks a specific treatment. The circulatory protein renalase is produced by the kidney and other tissues and has potent anti-inflammatory and prosurvival properties. Recombinant renalase can reduce the severity of mild cerulein pancreatitis; the activity is contained in a conserved 20 aa renalase site (RP220). Here we investigated the therapeutic effects of renalase on pancreatitis using two clinically relevant models of acute pancreatitis. The ability of peptides containing the RP220 site to reduce injury in a one-day post-ERCP and a two-day severe cerulein-induced in mice was examined. The initial dose of renalase peptides was given either prophylactically (before) or therapeutically (after) the initiation of the disease. Samples were collected to determine early pancreatitis responses (tissue edema, plasma amylase, active zymogens) and later histologic tissue injury and inflammatory changes. In both preclinical models, renalase peptides significantly reduced histologic damage associated with pancreatitis, especially inflammation, necrosis, and overall injury. Quantifying inflammation using specific immunohistochemical markers demonstrated that renalase peptides significantly reduced overall bone marrow-derived inflammation and neutrophils and macrophage populations in both models. In the severe cerulein model, administering a renalase peptide with or without pretreatment significantly reduced injury. Pancreatitis and renalase peptide effects appeared to be the same in female and male mice. These studies suggest renalase peptides that retain the anti-inflammatory and prosurvival properties of recombinant renalase and can reduce the severity of acute pancreatitis and might be attractive candidates for therapeutic development.