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Cellular senescence is associated with various age-related disorders and is assumed to play a major role in the pathogenesis of osteoarthritis (OA). Based on this, we tested a senolytic combination therapy using Dasatinib (D) and Quercetin (Q) on aged isolated human articular chondrocytes (hACs), as well as in OA-affected cartilage tissue (OARSI grade 1-2). Stimulation with D + Q selectively eliminated senescent cells in both, cartilage explants and isolated hAC. Furthermore, the therapy significantly promoted chondroanabolism, as demonstrated by increased gene expression levels of COL2A1, ACAN, and SOX9, as well as elevated collagen type II and glycosaminoglycan biosynthesis. Additionally, D + Q treatment significantly reduced the release of SASP factors (IL6, CXCL1). RNA sequencing analysis revealed an upregulation of the anabolic factors, inter alia, FGF18, IGF1, and TGFB2, as well as inhibitory effects on cytokines and the YAP-1 signaling pathway, explaining the underlying mechanism of the chondroanabolic promotion upon senolytic treatment. Accordingly, stimulation of untreated hAC with conditioned medium of D + Q-treated cells similarly induced the expression of chondrogenic markers. Detailed analyses demonstrated that chondroanabolic effects could be mainly attributed to Dasatinib, while monotherapeutical application of Quercetin or Navitoclax did not promote the chondroanabolism. Overall, D + Q therapy restored the chondrogenic phenotype in OA hAC most likely by creating a pro-chondroanabolic environment through the reduction of SASP factors and upregulation of growth factors. This senolytic approach could therefore be a promising candidate for further testing as a disease-modifying osteoarthritis drug., (© 2024 The Author(s). Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Understanding the mechanisms that underlie the adaptive response of ectotherms to rising temperatures is key to mitigate the effects of climate change. We assessed the molecular and physiological processes that differentiate between rainbow trout (Oncorhynchus mykiss) with high and low tolerance to acute thermal stress. To achieve our goal, we used a critical thermal maximum trial in two strains of rainbow trout to elicit loss of equilibrium responses to identify high and low tolerance fish. We then compared the hepatic transcriptome profiles of high and low tolerance fish relative to untreated controls common to both strains to uncover patterns of differential gene expression and to gain a broad perspective on the interacting gene pathways and functional processes involved. We observed some of the classic responses to increased temperature (e.g., induction of heat shock proteins) but these responses were not the defining factors that differentiated high and low tolerance fish. Instead, high tolerance fish appeared to suppress growth-related functions, enhance certain autophagy components, better regulate neurodegenerative processes, and enhance stress-related protein synthesis, specifically spliceosomal complex activities, mRNA regulation, and protein processing through post-translational processes, relative to low tolerance fish. In contrast, low tolerance fish had higher transcript diversity and demonstrated elevated developmental, cytoskeletal, and morphogenic, as well as lipid and carbohydrate metabolic processes, relative to high tolerance fish. Our results suggest that high tolerance fish engaged in processes that supported the prevention of further damage by enhancing repair pathways, whereas low tolerance fish were more focused on replacing damaged cells and their structures. [ABSTRACT FROM AUTHOR]

Background: Canada has the fourth highest per capita rate of opioid prescriptions in the world, contributing to the country's opioid crisis. Due to both their pain-relieving and euphoric properties, opioids can be highly addictive, leading to potential overdose and death. Deprescription is an endorsed and organized method of discontinuing a drug but very little is known about the barriers that Canadian physicians face when attempting to deprescribe opioids, particularly those who practice in rural areas (which have some of the highest rates of opioid users). Methods: This was an explorative, qualitative study describing rural family doctors' experiences and practices regarding opioid deprescription in primary care. A convenience sample of family doctors who had experience working with patients taking opioid medications was recruited from the professional networks of study team members. After consenting to participate, data was collected using semi-structured telephone interviews and analyzed by researchers experienced in applying the Theoretical Domains Framework to assess barriers and enablers of behavior change. Principal findings: 10 physicians participated in this study. Our analysis revealed four barriers and five enablers related to opioid deprescription in rural primary care. Barriers include a lack of knowledge and skills related to deprescribing, discomfort initiating deprescription, patient pressure to continue prescribing opioids, and a lack of foundational support required to deprescribe. Enablers include working with colleagues who share common views on overuse of opioids and deprescription; access to other healthcare providers, community-based resources, and clinical tools; using a systematic approach to deprescription; previous experience successfully deprescribing opioids; and practicing in a rural setting. Conclusions: Opioid dependence and over-prescription continue to be a problem for our health system. Deprescription is necessary but challenging for family physicians. Rural physicians are keenly aware of the importance of preserving the physician-patient therapeutic relationship and open and clear communication about opioid medications and deprescription but feel unprepared to manage this in the face of difficult issues surrounding deprescription. They also feel unprepared to deal with deprescription effectively without access to other resources, healthcare professionals, patient education materials and time. Rural physicians would benefit most from added foundational supports for deprescription. [ABSTRACT FROM AUTHOR]

The right to counsel for parents in administrative abuse and neglect cases, as well as for the children that are the subject of these matters, is a necessity that may not be obvious. This Article seeks to elucidate the fundamental interests that are at stake and justify why the sacrosanct protections of the landmark Gideon v. Wainwright right to counsel case should be extended to an administrative proceeding involving parents who are facing inclusion on a state child abuse and neglect registry. The Article also reveals an inconvenient truth-that communities of color are disproportionately impacted by the consequence of adverse child welfare actions. Part I expounds on the dilemma, including the current state of administrative proceedings and explaining the inequities resulting from current administrative practices. Part II will detail several narrative case studies to further elucidate the problematic outcomes under the status quo model. Parts III and IV will present a comparative analysis with other areas of the law where a right to counsel has strengthened outcomes for litigants, including the criminal and civil contexts, and draw parallels to justify the extension of the right to counsel to administrative abuse and neglect proceedings. Part V will examine a contemporary state precedent where the right to counsel has been extended to parents in the administrative context in abuse and neglect cases. The Article will conclude with a call to action for states and the federal government to implement a right to counsel and avert an injustice, thus strengthening the rule of law. [ABSTRACT FROM AUTHOR]

This article explores the new surgical population of gender affirming surgery, specifically vaginal surgeries for transgender and gender diverse people. There are established perioperative rehabilitation guidelines for nearly all other surgeries. A growing population of people is seeking gender affirming healthcare which includes vaginal surgery. This article reviews the guidelines set forth by the World Professional Association for Transgender Health Standards of Care (Version 8), explores the occupational needs of this population, as well as provides suggestions for future versions of official documents of the American Occupational Therapy Association to provide more inclusive language for the unique needs of this population following surgery. [ABSTRACT FROM AUTHOR]

Background: Young people with life-limiting conditions have unmet psycho-spiritual needs. Dignity Therapy is a psycho-therapeutic end-of-life intervention that addresses life review, meaning making and legacy leaving. Studies of Dignity Therapy including young people are limited. Aim: To co-design a digital Dignity Therapy-based intervention for young people with life-limiting conditions (DIGNISPACE). Design: A qualitative study including focus groups (n=5) with hospice-based healthcare professionals (n=23), semi-structured interviews with young people with life-limiting conditions (n=13) and family carers (n=12). Data were analyzed using framework analysis. Results: Three main themes were derived; intervention purpose, amendments to the Dignity Therapy question protocol and content for a digital application. Findings influenced the development of DIGNISPACE and a model of dignity in young people with life-limiting conditions. Conclusions: DIGNISPACE addresses the psycho-spiritual needs of young people with life-limiting conditions, including tenets of the model of dignity in young people with life-limiting conditions in its content and delivery. [ABSTRACT FROM AUTHOR]

Purpose: Patient-Reported Outcomes (PROs) are widely used in clinical trials, epidemiological research, quality of life (QOL) studies, routine clinical care, and medical surveillance. The Patient Reported Outcomes Measurement Information System (PROMIS) is a system of reliable and standardized measures of PROs developed with Item Response Theory (IRT) using latent scores. Power estimation is critical to clinical trials and research designs. However, in clinical trials with PROs as endpoints, observed scores are often used to calculate power rather than latent scores., Methods: In this paper, we conducted a series of simulations to compare the power obtained with IRT latent scores, including Bayesian IRT, Frequentist IRT, and observed scores, focusing on small sample size common in pilot studies and Phase I/II trials. Taking the PROMIS depression measures as an example, we simulated data and estimated power for two-armed clinical trials manipulating the following factors: sample size, effect size, and number of items. We also examined how misspecification of effect size affected power estimation., Results: Our results showed that the Bayesian IRT, which incorporated prior information into latent score estimation, yielded the highest power, especially when sample size was small. The effect of misspecification diminished as sample size increased., Conclusion: For power estimation in two-armed clinical trials with standardized PRO endpoints, if a medium effect size or larger is expected, we recommend BIRT simulation with well-grounded informative priors and a total sample size of at least 40., Competing Interests: Declarations. Conflict of interest: All authors declare that they have no conflict of interest. Ethical approval: This is a simulation study and does not involve the participation of human subjects., (© 2025. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Cells orchestrate their processes through complex interactions, precisely organizing biomolecules in space and time. Recent discoveries have highlighted the crucial role of biomolecular condensates-membrane-less assemblies formed through the condensation of proteins, nucleic acids, and other molecules-in driving efficient and dynamic cellular processes. These condensates are integral to various physiological functions, such as gene expression and intracellular signal transduction, enabling rapid and finely tuned cellular responses. Their ability to regulate cellular signaling pathways is particularly significant, as it requires a careful balance between flexibility and precision. Disruption of this balance can lead to pathological conditions, including neurodegenerative diseases, cancer, and viral infections. Consequently, biomolecular condensates have emerged as promising therapeutic targets, with the potential to offer novel approaches to disease treatment. In this review, we present the recent insights into the regulatory mechanisms by which biomolecular condensates influence intracellular signaling pathways, their roles in health and disease, and potential strategies for modulating condensate dynamics as a therapeutic approach. Understanding these emerging principles may provide valuable directions for developing effective treatments targeting the aberrant behavior of biomolecular condensates in various diseases., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Increased expression of the cyclin-dependent kinase inhibitor p16Ink4a (p16) is detected in neurons of human Alzheimer's disease (AD) brains and during normal aging. Importantly, selective eliminating p16-expressing cells in AD mouse models attenuates tau pathologies and improves cognition. But whether and how p16 contributes to AD pathogenesis remains unclear. To address this question, we tested whether induction of p16 expression in neurons exacerbates AD pathologies. We created a doxycycline-inducible system to trigger p16 up-regulation in human-induced pluripotent stem cells (iPSCs) and neurons differentiated from iPSCs. We demonstrated that up-regulated p16 expression in iPSCs reduces cell proliferation, down-regulates cell cycle genes, and up-regulates genes involved in focal adhesion, interferon α response and PI3K-Akt signaling. Our approach enables temporal control of p16 induction upon differentiation from iPSCs to neurons. In differentiated cortical neurons, we found that up-regulation of p16 increases tau phosphorylation at Ser202/Thr205 and Thr231 in a cell-autonomous manner, while amyloid beta secretion is not affected. These data suggest a critical role of p16 in regulating tau phosphorylation in neurons, and thereby contributing to pathological progression of AD. As pathological tau tangles have been shown to induce p16 expression, our studies suggest a positive feedback loop between p16 and tau to exacerbate tau pathologies., (© 2025 The Author(s). Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Virtual ligand libraries for ligand discovery have recently increased 10,000-fold. Whether this has improved hit rates and potencies has not been directly tested. Meanwhile, typically only dozens of docking hits are assayed, clouding hit-rate interpretation. Here we docked a 1.7 billion-molecule virtual library against β-lactamase, testing 1,521 new molecules and comparing the results to a 99 million-molecule screen where 44 molecules were tested. In a larger screen, hit rates improved twofold, more scaffolds were discovered and potency improved. Fifty-fold more inhibitors were found, supporting the idea that the large libraries harbor many more ligands than are being tested. In sampling smaller sets from the 1,521, hit rates only converged when several hundred molecules were tested. Hit rates and affinities improved steadily with docking score. It may be that as the scale of docking libraries and their testing grows, both ligands and our ability to rank them will improve., Competing Interests: Competing interests: B.K.S. is a founder of Epiodyne, Inc.; BlueDolphin, LLC; and Deep Apple Therapeutics, Inc., and serves on the SAB of Schrodinger LLC and of Vilya Therapeutics, and on the SRB of Genentech. J.J.I. cofounded Deep Apple Therapeutics, Inc., and BlueDolphin, LLC. J.S.F. is a consultant for, has equity in and receives research support from Relay Therapeutics. The other authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to Springer Nature America, Inc.)

The history of life's formation and the origin of its stereochemistry are nearly as multifaceted as the life itself. In this review, we focus on analyzing the step-by-step path leading to what we can define as "life" in parallel to what we know about the emergence of enantiomeric imbalance and subsequent transition to full homochirality. We start at the level of assembly of the building blocks of life from inorganic molecules and build up to the polymerization and formation of nucleic acids and peptides. We report and analyze different theories at various stages of this development and try to elucidate the most plausible theory., (© 2024 The Authors. Chemistry - An Asian Journal published by Wiley-VCH GmbH.)

Cardiovascular (CV) diseases caused 20.5 million deaths in 2021, making up nearly one-third of global mortality. This highlights the need for practical prognostic markers to better classify patients and guide treatment, especially in ischemic heart disease (IHD), which represents one of the leading causes of CV mortality. Transthoracic echocardiography (TTE) is a key, non-invasive imaging tool widely used in cardiology for diagnosing and managing a range of CV conditions. It is the first choice for diagnosing and monitoring patients with acute coronary syndrome (ACS). Alongside well-established echocardiographic measures, new techniques have proven useful for predicting adverse events in IHD patients, such as three-dimensional (3D) and tissue Doppler imaging (TDI), and speckle tracking technology. This review aims to explore the latest echocardiographic tools that could provide new prognostic markers for patients in the acute phase and during follow-up after an acute myocardial infarction (AMI). We focus on new imaging methods like TDI, myocardial work index (MWI), speckle-tracking strain, and 3D technologies using TTE, which are easy to use and widely available at all stages of coronary artery disease (CAD)., (© 2024 Wiley Periodicals LLC.)

Diabetes mellitus (DM) is a debilitating, life-limiting disease. According to recent estimates, 415 million adults currently suffer from the disease. This number is expected to rise to 642 million by 2040. Skin disorders can often predict the onset of this metabolic disorder. Uncontrolled hyperglycemia impairs the overall immunity of patients with DM, involving various mechanistic pathways, resulting in the diabetic skin being immunocompromised and prone to bacterial infections. Among others, diabetic foot infections are very common. In this article, we have focused on the association of DM with different types of bacterial skin infections and resistance patterns to antimicrobial agents commonly used in the treatment of diabetes-associated infections., Competing Interests: Einhaltung ethischer Richtlinien. Interessenkonflikt: E. Makrantonaki, S. Kostaras und C.C. Zouboulis geben an, dass kein Interessenkonflikt besteht. Für diesen Beitrag wurden von den Autor/-innen keine Studien an Menschen oder Tieren durchgeführt. Für die aufgeführten Studien gelten die jeweils dort angegebenen ethischen Richtlinien. Für Bildmaterial oder anderweitige Angaben innerhalb des Manuskripts, über die Patient/-innen zu identifizieren sind, liegt von ihnen und/oder ihren gesetzlichen Vertretern/Vertreterinnen eine schriftliche Einwilligung vor., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Introduction: There are few studies on the use medicinal herbs by pregnant women in Brazil, even though there is a wealth of knowledge about medicinal herbs among Brazilians of Indigenous, African, and European ancestry. The aim of this study was to assess the prevalence and type of herbs used by pregnant women living in the Amazon region. Methods: This was a cross-sectional study conducted with 811 pregnant women attending 10 public antenatal clinics in Manaus, Amazonas state, Brazil. The consumption of medicinal herbs was assessed through individual 24-hour dietary recall. Results: A total of 811 women in their second trimester (16 to 20 weeks) of pregnancy were included and 69 (8.5%) reported that they used herbs to make teas. There was a significant difference between users and non-users of medicinal teas, with a higher proportion of overweight women in the group that used teas (46.4% versus 31.9%; p=0.005). Nearly half (47.8%) of those who used medicinal teas consumed herbs with sedative effects, 23 percent consumed herbs for the relief of urinary tract symptoms, and 13 percent used herbs with digestive properties. Most women reported using natural herbs from their own gardens. Conclusions: Approximately 10 percent of Brazilian women in the Amazon region consumed medicinal herbs to alleviate common symptoms of pregnancy. The most frequently used plants had sedative, urinary tract, or gastrointestinal effects. Most plants were obtained in natura from local gardens. Many of these plants have known adverse effects and their use is contraindicated during pregnancy. [ABSTRACT FROM AUTHOR]

Introduction: Health technology assessment of medical devices often faces the challenge that approval studies have an insufficient study design. The European Medical Device Regulation (MDR), which has been in force since May 2021, places stricter requirements on clinical studies for high-risk medical devices. One important way of implementing the regulation is through guidance documents from the Medical Device Coordination Group (MDCG). Methods: Our objective was to systematically identify and analyze recommendations for the design of pivotal studies of high-risk therapeutic medical devices from the MDCG and other regulatory authorities of high-income countries. We systematically searched the websites of regulatory authorities and included both cross-device and device-specific recommendations on clinical trial design for cardiovascular, orthopedic, and diabetes related high-risk medical devices. We extracted and compared the recommendations according to the following seven topics: definitions of study types and level of evidence; need for clinical investigations; appropriate choice of study methodology; general aspects; statistical methods; consideration of context and learning curve; and reporting. Results: We included 30 documents from regulatory authorities. Eight documents from the European Union (EU) focused mainly on procedural issues and reporting. Guidance on appropriate levels of evidence and choice of study methodology for design and analysis of clinical investigations was missing. Eleven guidance documents were from the United States Food and Drug Administration, which provided detailed recommendations on almost all topics regarding study design as well as new methods. The remaining documents originated from four other countries and the International Medical Device Regulators Forum. A document from Australia included device-specific recommendations but hardly any general recommendations on clinical trials. Conclusions: The recommendations published to date in the EU are insufficient to support stakeholders in choosing or assessing appropriate study designs to implement the evidence requirements of the European MDR. Detailed guidance from the MDCG is needed to create a common understanding between manufacturers, notified bodies, MDR expert panels, and competent authorities regarding what sufficiency of clinical data means. [ABSTRACT FROM AUTHOR]