Key Messages Research Articles

CD155 promotes the advancement of hepatocellular carcinoma by suppressing the p53-mediated ferroptosis via interacting with CD96.

This work researched the influence and mechanism of CD155 on hepatocellular carcinoma advancement. CD155 expression and its effect on survival of hepatocellular carcinoma patients were analyzed based on the GEPIA2 database. String software predicted the interacting between CD155 and CD96, which was further verified by co-immunoprecipitation experiment. The function of CD155 and CD96 on the proliferation, migration, and invasion of hepatocellular carcinoma cells (HCC) was explored by colony formation, wound healing, and transwell assays. To research the effect of CD155 and CD96 on ferroptosis, ferroptosis-related factors in HCC were investigated. CD155 and p53 were both silenced in HCC to explore whether CD155 regulates hepatocellular carcinoma progression by acting on p53. Xenograft tumor study was conducted to examine the impact of CD155 on the in vivo growth of HCC. It was discovered that, CD155 up-regulation predicted poor survival of hepatocellular carcinoma patients. CD155 could be interacted with CD96. The proliferation, migration, and invasion of HCC were heightened by CD155. However, ferroptosis was suppressed by CD155, as CD155 decreased p53 and iron but increased SLC7A11, GPX4 and GSH in HCC. In fact, CD96 silencing abolished these effects of CD155. The suppressed malignant behaviors and the enhanced ferroptosis in HCC induced by CD155 silencing were abrogated by p53 silencing. In vivo, CD155 silencing suppressed growth and enhanced ferroptosis of hepatocellular carcinoma, which were counteracted by p53 silencing. Thus, CD155 might facilitate hepatocellular carcinoma advancement through blocking the p53-mediated ferroptosis via interacting with CD96. CD155 might be a promising target for treating hepatocellular carcinoma. KEY MESSAGES: CD155 was up-regulated in hepatocellular carcinoma, predicting poor survival. CD155 protein could be interacted with CD96 protein. Proliferation and invasion of liver cancer cells were facilitated by CD155. Proliferation and invasion of liver cancer cells were decreased by CD96 loss. CD155 promoted liver cancer by suppressing p53-mediated ferroptosis via CD96.

Kat7 accelerates osteoarthritis disease progression through the TLR4/NF-κB signaling pathway.

Osteoarthritis (OA) is a common degenerative bone and joint disease with an unclear pathogenesis. Our study identified that the histone acetyltransferase encoded by Kat7 is upregulated in the affected articular cartilage of OA patients and in a mice model of medial meniscal instability-induced OA. Chondrocyte-specific knockdown of Kat7 expression exhibited a protective effect on articular cartilage integrity. In vitro experiments demonstrated that KAT7 promotes cartilage catabolism, inhibits cartilage anabolism, and induces chondrocyte senescence and apoptosis. Conversely, knocking down Kat7 was shown to protect chondrocyte function. Corresponding in vivo results indicated that silencing Kat7 effectively enhances cartilage anabolism, prevents articular cartilage damage, and significantly slows OA progression. Mechanistically, KAT7 activates the TLR4/NF-κB signaling pathway, and inhibition of this pathway reverses the catabolic effects and restores anabolic activity in the presence of Kat7 overexpression. Collectively, these findings confirm the critical role of KAT7 in the pathogenesis of OA and suggest that Kat7 represents a potential therapeutic target for OA treatment. KEY MESSAGES: There is a lack of clinically effective drugs for the treatment of osteoarthritis (OA). Kat7 plays a key role in the development of OA. Knocking down Kat7 expression can alleviate the progression of OA. Kat7 accelerates the progression of OA by activating the TLR4/NF-KB signaling pathway.

AI and machine learning for detection and management of delirium in care home residents

Background Presently, diagnosing delirium in older people is a challenge. Diagnostic support tools such as the Confusion Assessment Method and 4AT provide structure but require specialist training, resources, and implementation support, while some subjectivity persists in diagnosis. This is particularly the case in people who live with dementia who often experience rapid fluctuation in cognitive abilities and behaviours. This leads to variation in diagnosis between settings and care providers, with consequent harmful impact on those experiencing delirium. These challenges become greater in care homes where dementia is prevalent, daily fluctuation is the norm and where the majority of staff are not trained healthcare professionals. Summary Here we outline the potential for AI-based Human Activity Recognition (HAR) approaches to identify and flag deviations from normal behaviour that may be precursors of a delirium state, enabling earlier detection and management, and better outcomes. We outline how Statistical Process Control (SPC) approaches could form the basis of diagnostic algorithms and the steps required to test the feasibility of this approach in the care home setting. Key Messages Delirium detection and diagnosis, difficult in any setting, is more difficult in care homes because of resident, staff and organisational factors. Artificial intelligence, machine learning and human activity recognition have potential to make diagnosis more reliable because of their ability to recognise changes from normal patterns of behaviour at an individual level.

Neurological deterioration after acute ischemic stroke: A common phenomenon with important implications.

Background：Neurological deterioration following acute ischemic stroke (AIS) is a common clinical phenomenon associated with poor clinical outcomes. However, neurological deterioration can be attributed to diverse mechanisms in different clinical contexts. Further, there is still a lack of standard and well-recognized definitions of neurological deterioration, which compounds the complexities and challenges of its early identification and management of neurological deterioration. As AIS becomes increasingly common, the need to address neurological deterioration after AIS in clinical practice and further improve functional outcomes is becoming more urgent. Summary: To facilitate earlier recognition and more precise interventions, in this review, we comprehensively outline the evolution of the definition of neurological deterioration, its incidence in various patient groups, and the potential underlying causes rooted in multiple pathophysiological mechanisms. We further highlight the diverse risk factors associated with neurological deterioration and provide an overview of the scientific basis and practical applications of preventative and therapeutic strategies. Key messages: Early identification and management of neurological deterioration in AIS patients is crucial but challenging due to lack of unified assessment criteria and diverse mechanisms. Standardizing definitions and developing targeted strategies based on pathological mechanisms and pharmacological profiles are needed to improve outcomes.

Effect of optimized food-based recommendations on nutrient intakes, hemoglobin levels, and memory performance of adolescent girls in East Java, Indonesia

BackgroundFAO/WHO introduced food-based dietary guidelines (FBDG) to promote healthy dietary habits. To translate the FBDG, optimized food-based recommendations (FBR) can be developed using linear programming (LP) to address problem nutrients. Despite the importance of local-specific FBR for anemia prevention, no study has reported the effect of nutrition education which promoted FBR in adolescent girls. Therefore, this study aimed to investigate the effect of optimized FBR in adolescent girls in improving dietary and nutrient intakes, hemoglobin levels, and memory performance.MethodsThe intervention study was carried out in Malang District, Indonesia amongst 14–18 year adolescent girls. The study’s Indonesian slogan was Remaja which meant Active, Healthy, Smart, and Creative adolescents. The optimized FBR was developed using LP and translated into six key messages. Twenty-week nutrition education was integrated into the weekly school’s system.ResultsAfter 20 weeks, a significant increase in dietary practices (animal protein, liver, plant protein, vegetables), nutrient intakes (protein, fat, iron), and memory performance (digit span forward and backward) were found in the intervention group. In contrast, there was decreases in the control group’s intakes of animal and plant protein.ConclusionsThis finding shows that nutrition education with optimized FBR increased intakes of nutrient-dense food, protein, fat, iron, and memory performance (concentration). Nutrition education with optimized FBR should be integrated into the school system together with weekly iron supplementation for anemia prevention among these adolescent girls.Trial registrationThe study was registered on ClinicalTrials.gov (ID No: NCT03946475).

Drosophila modeling to identify causative genes and reveal the underlying molecular mechanisms for primary ovarian insufficiency.

Primary ovarian insufficiency (POI) is a disease defined as a reduction in ovarian function under the age of 40 and represents the main cause of female infertility. In recent years, many genetic mutations associated with POI have been identified using high-throughput sequencing technology. However, one big challenge today is to determine the disease-causing gene associations through functional assessment. Here, we develop a Drosophila model to study the POI-associated genes and provide in vivo functional evidence to validate the POI-causing genes. We use two different Gal4 drivers, in combination with RNAi transgene, and systematically knockdown 51 genes associated with POI. We show that 22 and 17 genes are required for female fertility and ovarian development in somatic and germline cells, respectively. Moreover, we also focus on AlaRS-m, the Drosophila ortholog of the human AARS2 gene, for further functional characterization. Depletion of AlaRS-m in ovarian somatic cells leads to decreased female fertility and a reduction in ovary size, as well as egg chamber degeneration. We also provide evidence that AlaRS-m deficiency causes mitochondrial dysfunction, overproduction of ROS, and apoptotic cell death. Our findings demonstrate that Drosophila can be used as a platform to assess the functional significance of POI-associated genes identified in genomic studies and illustrate the molecular mechanism underlying the pathogenesis of POI. KEY MESSAGES: • One hundred fourteen genes associated with POI are identified, and 76 of them have Drosophila orthologs. • Twenty-two genes and 17 genes are required for female fertility when knocked down in the Drosophila ovarian somatic cells and germline cells, respectively. • AlaRS-m/AARS2 deficiency causes female fertility defects with egg chamber degeneration.

A multimodal approach to reduce the incidence of peripheral venous cannula bacteraemias and improve patient safety.

Incidence of peripheral venous cannula (PVC) bacteraemia have been rising in a trust in the south-west of England, with a 267% increase noted over the 2022/23 financial year compared with the previous year. To use a multimodal approach to reduce the incidence of PVC bacteraemia and improve patient safety. The initiative consisted of an educational poster highlighting the severity of infection associated with PVCs alongside key prevention messages rooted in Trust policy. Teaching sessions, complementing the poster, were delivered by the infection prevention and control team to each clinical area. The data showed that the provision of further educational resources and wider support resulted in a 54.5% decrease in the incidence of PVC bacteraemia in 2023/24 compared with the previous year. An audit undertaken in the fourth quarter of 2023/24 (January-March) found zero cases of PVC bacteraemia for the first time in 2 years. Dedication and collaborative working are vital for securing the success of quality improvement projects. PVC-related bacteraemias and the severity of infection remain an under-acknowledged and under-recognised topic within health care, with further research required.

Sodium-Glucose Cotransporter-2 Inhibitors in Diabetic Kidney Disease and Beyond

Background Sodium-glucose co-transporter 2 inhibitors (SGLT2is) have significantly impacted the management of diabetic kidney disease (DKD) and heart failure (HF), providing benefits beyond glycemic control. This review examines the mechanisms through which SGLT2is provide renal and cardiovascular protection and assesses their clinical efficacy. Summary By inducing glucosuria and natriuresis, SGLT2is alleviate multiple complications induced by chronic hyperglycemia. Moreover, SGLT2is reduce albuminuria, improve tubular function, and modulate erythropoiesis. Additionally, they mitigate inflammation and fibrosis by decreasing oxidative stress and downregulating pro-inflammatory pathways. Clinical trials have demonstrated significant reductions in renal and cardiovascular events among patients with type 2 diabetes mellitus. A comprehensive review of the literature was conducted through PUBMED, highlighting the effects of SGLT2is and the results of major clinical trials involving SGLT2is. Key messages SGLT2is play a crucial role in the management of DKD and HF by addressing multiple pathogenic pathways. Currently, SGLT2is are included in clinical guidelines for DKD and HF management, and their benefits extend to non-diabetic populations. Further research is needed to explore SGLT2is’ multifaceted mechanisms and potential applications across diverse patient populations and different disease etiologies.

Hereditary non-spherocytic hemolytic anemia with GPI mutations successfully treated with allogeneic hematopoietic stem cell transplantation: a first report of two cases.

Glucose phosphate isomerase (GPI) deficiency caused by GPI gene mutations is a rare heterogenous condition that causes hereditary non-spherocytic hemolytic anemia (HNSHA). Patients who suffer from severe anemia may need more effective treatment. Here, clinical data and genetic testing results of two cases of HNSHA with GPI mutations treated with allogeneic hematopoietic stem cell transplantation (allo-HSCT) were retrospectively analyzed. Specifically, two unrelated 6-year-old male patients with severe hemolytic anemia had hemoglobin (Hb) below the normal range despite frequent blood transfusions. Two novel missense mutations in the GPI gene were detected in them, respectively. They underwent peripheral blood stem cell (PBSC) transplantation successfully, and there was no anemia post-transplantation. In conclusion, HNSHA caused by mutations of the GPI gene is inherited in an autosomal recessive (AR) manner. Allo-HSCT offers an acceptable therapeutic efficacy and improvement of quality of life in HNSHA patients with GPI mutations. Our study expands the genetic spectrum of GPI deficiency. KEY MESSAGES: We reported for the first time that two cases of hereditary non-spherocytic hemolytic anemia with GPI mutations successfully treated with allogeneic hematopoietic stem cell transplantation (allo-HSCT). Two novel missense mutations in GPI gene were detected in each of the two cases, respectively, which were predicted to be pathogenic or damaging. Our study expands the genetic spectrum of GPI deficiency. Allo-HSCT offers an acceptable therapeutic efficacy and improvement of quality of life in HNSHA patients with GPI mutations.

Primary versus Secondary Immune Thrombocytopenia (ITP): A Meeting Report from the 2023 McMaster ITP Summit.

The McMaster Immune Thrombocytopenia (ITP) Summit, held on October 27, 2023, was an educational seminar from leading experts in immune thrombocytopenia and related disorders geared toward hematologists, internists, immunologists, and clinical and translational scientists. The focus of the Summit was to review the mechanisms, diagnosis, and treatment of primary versus secondary ITP. Specific objectives were to describe the unique features of secondary ITP, and to review its mechanisms in the context of autoimmune disease and infection. The key messages in this Summit were: (1) ITP is a heterogeneous disease, and genetic and immunologic insights may help classify patient subtypes; (2) exploring the autoimmune mechanisms and their association with hypogammaglobulinemia in patients with secondary ITP could improve our understanding of ITP and its subtypes; (3) investigating the mechanisms of ITP in the context of infections caused by viruses such as CMV, HIV, dengue, and hepatitis C, or bacteria such as H. pylori, or vaccinations could provide insight into the causes of ITP. A better understanding of secondary ITP could help elucidate the pathogenesis of ITP.

The Sir Ludwig Guttmann lecture 2023: psychosocial factors and adjustment dynamics after spinal cord injury.

Narrative review OBJECTIVES: Sir Ludwig Guttmann realised spinal cord injury (SCI) rehabilitation should incorporate more than a biomedical approach if SCI patients were to adjust to their injury and achieve productive social re-integration. He introduced components into rehabilitation he believed would assist his patients build physical strength as well as psychological resilience that would help them re-engage with their communities. We pay tribute to Sir Ludwig by presenting research that has focussed on psychosocial factors that contribute to adjustment dynamics after SCI. Not applicable. Five factors with a psychosocial source will be examined, featured in my research, namely psychological distress, cognitive impairment, pain catastrophizing, sleep disorder and fatigue. A multifactorial model of adjustment will be examined. Evidence shows these factors can be significant barriers to adjustment and reciprocally related to self-efficacy and life decisions. A theoretical rehabilitation framework/model is presented called the SCI Adjustment Model (SCIAM), that explains the process of adjustment dynamics. It describes how multifactorial factors contribute to adjustment in a non-linear process over time. Key clinical messages include: (i) adjustment dynamics will be enhanced if viewed through the lens of a multifactorial model that clarifies how multiple psychosocial factors can combine and act as barriers or facilitators to adjustment; (ii) judiciously using this information, assess and then strategize to reduce the influence of barriers or strengthen facilitators during SCI rehabilitation and beyond, and (iii) integrate psychosocial guidelines and a person-centred approach into SCI rehabilitation to achieve treatment goals.

Designing supports for family and friends: outcomes from an Australian lived experience of suicide workshop.

This study addresses the pivotal role of family and friends in supporting individuals experiencing suicidal distress. The research draws insights from a workshop at an Australian Lived Experience of Suicide Summit (2023) to explore how information and peer support should be presented and used in support programs and resources for family and friends supporting someone experiencing suicidal distress. The study engaged 52 delegates in an interactive workshop, comprising individuals with a lived experience of suicidal distress (30%), those bereaved by suicide (27%), family members or friends supporting someone with a lived experience of suicide (20%), sector representatives (16%) and others (7%). The workshop involved discussions on language, images, multimedia resources, key messages for programs and the integration of peer support. Content analysis categorized responses, and themes were ranked by popularity. Consensus emerged on preferred language referring to family and friends and those receiving support. Participants highlighted the importance of diversity in language, multimedia and images used in programs. This work helps to provide an understanding of family and friends' preferences for language, media, imagery and messaging when considering developing programs for family and friends supporting someone in suicidal distress. Peer support was also acknowledged as valuable for family and friends, but further understanding of the format and implementation of peer support is needed. Adapting program content based on end-users' advice is crucial for safety and engagement.

Nourishment of nerves and innervation: A novel approach for the treatment of myocardial infarction.

Autonomic innervation of the heart plays a pivotal role not only in regulating the heart rate but also in modulating the cardiac cell microenvironment via cell-cell interactions and influencing the heart's repair capabilities. Currently, the primary clinical approach for treating myocardial infarction (MI) is percutaneous coronary intervention. However, the myocardial salvage rate remains low for patients with advanced disease. MI is recognized as an autonomic nervous system disorder, marked by sympathetic hyperactivity and the loss of parasympathetic nerves. Following MI, ventricular sympathetic nerve sprouting occurs, leading to an increase in ventricular sympathetic innervation and, consequently, an increased risk of ventricular arrhythmia, which is the primary cause of sudden cardiac death in patients with a history of MI. The vagus nerve positively regulates cardiomyocyte proliferation and regeneration, enhancing ventricular remodeling and cardiac function post-MI. This process is highly significant in the treatment and rehabilitation of MI. Cardiac autonomic nerves are influenced by factors such as inflammation, immunity, intercellular communication, metabolism, genetics, epigenetics, and cytokine secretion related to cardiac mesenchymal nerves. In recent years, significant advancements have been made regarding treatment for MI, specifically in the fields of autonomic nervous system therapies, stem cell and extracellular vesicle treatments, traditional Chinese medicine acupuncture and moxibustion, and peripheral electrophysiological stimulation and bioengineering materials. The balance of dominance between the sympathetic and parasympathetic nervous systems in the heart affects tissue regeneration and cardiac remodeling after MI. The secretion of neurons regulates the microenvironment of cardiac repair. The neural therapy of MI involves multiple fields such as traditional Chinese medicine, biomaterials, stem cell therapy, and drug research and development, and has broad development prospects Key Messages: The regulation exerted by the cardiac autonomic nervous system on the heart significantly influences the prognosis of MI. This involves nervous system modulation of inflammation and heart rate and complex interactions between neurons and cardiomyocytes, immune cells, fibroblasts, adipocytes, stem cells, and other cellular components. Genetic and epigenetic modifications, as well as shifts in energy metabolism, also play crucial roles.

The central control of energy metabolism; hypothalamic obesity is not one disease.

Background The hypothalamus, a neuro-endocrine gland located centrally in the brain, weighs only on average 4 grams but is the captain on the ship of our energy balance. In the hypothalamus, signals of the satiety and hunger hormones are integrated and individuals with a dysfunctional hypothalamus develop obesity. The hypothalamus, however, integrates much more than the satiety and hunger hormones and hypothalamic obesity may be the result of a combination of factors. Summary The consequences of hypothalamic dysfunction can be categorized in six different domains. By systematically evaluating each domain, the underlying cause for obesity may be better understood and doors for successful management can be opened. The different domains are; pituitary gland dysfunction, behavioral problems, disturbance of the circadian rhythm, hyperphagia, low resting energy expenditure and temperature dysregulation. All of these domains may contribute to the development of obesity and may be more or less present in the individual patient. Key Messages Hypothalamic obesity is not one disease, but different underlying contributing factors may be present. Consequently, hypothalamic obesity management is not one-size-fits-all but needs to be personalized. In this paper, the current state of the art for both the diagnostics and approach of acquired hypothalamic obesity is reviewed.

Global Trends and Collaborative Models in Manipulative Therapy for Low Back Pain: A Bibliometric and Academic Network Analysis.

Background Low back pain (LBP) is a prevalent condition that significantly affects work productivity and quality of life. Despite advancements in treatment, LBP continues to pose a global health challenge, with increasing research on manipulative therapy as a non-invasive treatment option. This study aims to provide a comprehensive bibliometric analysis of global research trends in manipulative therapy for LBP. Summary This study utilized the Web of Science Core Collection database to analyze global research dynamics on manipulative therapy for LBP from 1998 to 2023. A total of 2,879 articles were identified and analyzed using CiteSpace software, revealing key research trends, leading countries, and influential contributors. The analysis demonstrated that research on manipulative therapy for LBP has been steadily increasing, particularly between 2019 and 2021. The United States, the Netherlands, and Denmark were among the leading countries in this field. Core research concepts identified through keyword co-occurrence analysis include "low back pain," "manipulative therapy," and "spinal manipulation." Key Messages Manipulative therapy for LBP is a growing field with increasing global interest, particularly between 2019 and 2021. The United States, Netherlands, and Denmark are leading contributors to the research, with notable academic collaborations. Future research should focus on comparative treatment effectiveness, safety assessments, and mechanistic analyses to further validate the role of manipulative therapy in LBP management.

A prospective multi-site study to evaluate the performance and usability of an oral fluid-based HIV self-test in Canada

BackgroundBlood and oral fluid-based HIV self-tests are important for reaching the undiagnosed living with HIV. The study objectives were to evaluate the oral fluid-based OraQuick® HIV Self-Test (HIV-ST) performance in comparison to laboratory reference testing; determine if laypersons can correctly perform the HIV-ST; document if intended users can successfully interpret pre-made contrived positive, negative, and invalid results; and document if intended users can understand the key messages in the product labeling.MethodsThis prospective study enrolled consenting adult intended users of HIV self-testing from six community health centres in four Canadian provinces between June 2022 and January 2024. Positive and negative agreement was determined by comparing the results of the HIV self-tests with the results of the laboratory-based “gold standard” Abbott Alinity HIV Antigen/Antibody Combo test. Descriptive statistics were used to summarize usability self-test procedure steps.ResultsOverall, 951 participants were recruited and consented with 911 available for all analyses. With respect to sociodemographics: 84% of participants were between 18–45 years of age, 73% had at least a college education, 48% were Cis-male, 45% were employed; and 26% identified as White, 23% as African, Caribbean or Black, 5% as Indigenous [First Nations, Métis or Inuit], 33% as Asian, and 6% as LatinX. Primary efficacy analysis on the 911 who completed HIV-ST revealed a single confirmed positive participant and a negative percent agreement of 100% (880/880, 95% CI: 99.9–100%) with the comparator method. For usability determination, the average success rate for “critical” steps for completing the test was 94.1%. Approximately 97% of participants found the instructions easy to follow and 98% of participants reported they would use the test again. Of the 465 participants who interpreted the strong positive, weak positive, negative, and invalid pre-made contrived results, the average of correct interpretations ranged from 59–97%ConclusionsA licensed oral fluid-based HIV self-test in Canada can present an accurate, easy-to-use, and less invasive alternative to blood-based HIV testing. The addition of an oral-fluid self-test along with the current licensed blood-based HIV self-test could help reach the undiagnosed with HIV in Canada and positively impact HIV testing rates overall by offering individuals a choice of self-testing devices.

Stroke Epidemiology in Asia.

Background Stroke is a major cause of death and disability globally, with different stroke burdens in different regions. This paper reviews the epidemiology of stroke in Asia. Summary There is a wide range in age and sex-standardised stroke incidence, highest in China, lowest in Bhutan. Geographically, incidence is highest in East Asia, lowest in South Asia. Stroke mortality is highest in Papua New Guinea, lowest in Singapore. There are variations in mortality within regions - in East Asia, it is higher in Mongolia and North Korea, lowest in Japan; in South Asia, it is higher in Bangladesh and Pakistan, lowest in Sri Lanka; in South-East Asia, it is higher in Papua New Guinea and Indonesia, lowest in Singapore. Stroke Disability Adjusted Life-Years lost (DALYs) is highest in Papua New Guinea, lowest in Singapore. There is intra-regional variation - in East Asia, it is higher in Mongolia and North Korea, lowest in Japan; in South Asia, higher in Bangladesh and Pakistan, lowest in Sri Lanka; in South-East Asia, it is highest in Papua New Guinea, lowest in Singapore. Among the stroke subtypes, ischaemic stroke (IS) has the highest incidence, intracerebral haemorrhage (ICH) second, subarachnoid haemorrhage (SAH) third. IS incidence is highest in China, lowest in Bhutan. The burden due to ICH is highest in Mongolia; ICH incidence is lowest in Sri Lanka, mortality and DALYs are lowest in Japan. SAH has a high incidence in Japan, Singapore, Brunei and Republic of Korea. In hospital-based registries, the frequency of ICH was highest in Myanmar, low in Mongolia. Among IS, based on the Trial of Org 10,172 in Acute Stroke Treatment classification, large artery atherosclerosis (LAA) is more frequent in some countries (eg China, India, Indonesia, Pakistan, Republic of Korea), but small artery occlusion (SAO) in most others (Bangladesh, Japan, Nepal, Singapore, Sri Lanka, Taiwan, Thailand, Vietnam); cardioembolism is third. Of the stroke risk factors, hypertension is the most frequent, diabetes mellitus (DM) is usually second, with varying positions for hyperlipidaemia, smoking and prior stroke or transient ischaemic attacks, obesity and insufficient physical activity. Key Messages Asis carries a particularly heavy burden of stroke, higher in some countries. IS is the most common subtype. Among IS, the more common mechanisms are LAA and SAO. Hypertension and DM are the more common risk factors. A greater understanding of stroke epidemiology and risk factors will help in healthcare planning for the prevention and management of stroke.

The molecular and cellular landscape of hypertrophic cardiomyopathy phenotypes: transition from obstructive to end-stage heart failure.

Hypertrophic cardiomyopathy (HCM) is a myocardial disorder which commonly presents as an obstructive or end-stage disease. This study aims to investigate the transcriptomic changes related to cardiac cell-specific expression profiles that underpin the molecular transition between the HCM phenotypes. This study utilizes bioinformatics meta-analysis to integrate independent datasets to generate a comprehensive gene expression profile of obstructive HCM and end-stage HCM phenotypes compared to donor hearts. Gene set enrichment and cellular deconvolution were applied to identify ontologies and pathways related to each phenotype and to enumerate cell abundances. The intersection between cell lineage genes and meta-genes was identified to explore the cellular contribution to the phenotypic molecular signatures. Meta-analysis revealed, enhanced muscle function and myocardial remodeling, alongside impaired immune and inflammatory processes in obstructive HCM. In contrast, enriched tissue matrix remodeling pathways and altered metabolic and signaling cascades were identified in end-stage HCM, indicating a shift towards cellular dysfunction and loss of homeostasis. These molecular profiles were associated with an altered cellular landscape, with increased cardiomyocytes and lower immune cell populations in obstructive samples but increased fibroblasts and smooth muscle cells in end-stage HCM, implicating extensive tissue remodeling. This study provides novel insights into the cellular contributions of contractile, immune, homeostatic, and vascular alterations underpinning each of the HCM phenotypes. KEY MESSAGES: HCM phenotypes are characterized by distinct molecular and cellular profiles. Obstructive HCM has an enriched contractile profile underpinned by an expanded cardiomyocyte population. End-stage HCM shifts the cellular profile towards extracellular and vascular remodeling.

VSMC-specific TRPC1 deletion attenuates angiotensin II-induced hypertension and cardiovascular remodeling.

Transient receptor potential canonical 1 (TRPC1) channel, a Ca2+-permeable ion channel widely expressed in vasculature, has been reported to be involved in various cardiovascular disorders. However, the pathophysiological function of vascular smooth muscle cell (VSMC)-derived TRPC1 in hypertension and hypertensive cardiovascular remodeling remains to be defined. In this study, we found increased TRPC1 expression in both angiotensin II (AngII)-treated VSMCs and aortas from AngII-infused mice. VSMC-specific TRPC1 deficiency strikingly attenuated AngII-induced vasoconstriction, hypertension, vascular remodeling, and cardiac hypertrophy. Mechanistically, AngII activated enhancer of zeste homolog 2 (EZH2) to stimulate TRPC1 expression, induced calcium influx and phosphorylation of mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK-ERK), which in turn triggered VSMC proliferation and migration and exacerbated hypertension and cardiovascular remodeling. Treatment with EZH2 inhibitor reduced VSMC proliferation and migration and alleviated vasoconstriction and hypertension in AngII-infused mice. Together, we revealed the pathogenic role of the EZH2-TRPC1-MEK/ERK pathway in AngII-induced hypertension and cardiovascular damage. TRPC1 or EZH2 inhibition may represent a desirable therapeutic target for the treatment of hypertension. KEY MESSAGES: AngII activates AT1R-EZH2-TRPC1 pathway in VSMCs and aortas of hypertensive mice. TRPC1 promotes VSMC proliferation and migration via MEK/ERK signaling. Inhibition of TRPC1 or EZH2 alleviates hypertension and cardiovascular remodeling.

Repetition in Robert F. Kennedy and Martin Luther King Jr.’s Selected Speeches Against Social Injustice: A Contrastive Critical Discourse Analysis

This paper conducts a contrastive critical discourse analysis to examine the role of repetition in selected speeches delivered by Robert F. Kennedy (RFK) and Martin Luther King Jr. (MLK) against social injustice. The study aims to examine repetition as a rhetorical and linguistic device through a contrastive lens, presenting its divergent usage and impact on framing these significant speeches. Along with this, the study tries to highlight the underpinning ideologies through the used types of repetition. By adopting Cockcroft and Cockcroft’s (2014) framework and by following a mixed method of research analysis, the study has found that RFK’s speeches employ certain types of repetition, namely, random repletion, initial repetition, stop-and-start, and full circle so that to emphasise key points, ideas, actions in order to make the speeches memorable and give them variety as well as to impact emotions. Concerning MLK’s speeches, the study has found that repetition, through its various types, is used to emphasise and to ensure key messages about social injustice and allow the audience to reinforce these messages. The study has also revealed that types of repetition are interrelated and could be used interchangeably; thus, a repeated phrase of initial repetition could be repeated in random, stop-and-start, full-circle types. It has been identified that repetition is a powerful device in uncovering ideology, by repeating certain words, phrases, ideologies become apparent. Accordingly, RFK’s ideologies are: social justice, liberalism and democracy, resistance and humanitarianism, while, MLK’s ideologies are: progress and change, non-violence and justice, civil rights and racial equality.