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Abstract Background Coronary artery disease (CAD) is a global health crisis, responsible for nearly 20 million deaths annually worldwide and 12.6% of all deaths in the United States. Randomized controlled trials (RCTs) are critical for developing evidence-based clinical guidelines, but inconsistent outcome reporting across RCTs hinders evidence synthesis and comparability. In 2015, McNamara et al. introduced a CAD core outcome set (COS) to promote standardization in CAD trial outcomes. This study evaluates the uptake of the CAD COS in RCTs registered at ClinicalTrials.gov since its publication. Methods This trial registry analysis evaluated the uptake of the CAD COS in phase III/IV RCTs registered on ClinicalTrials.gov from May 2010 to June 2023. Trials were included if they assessed CAD interventions and excluded if the trials were non-randomized, focused on diagnostic tests, or were categorized as “not applicable” (e.g., behavioral interventions). COS adherence was measured as the proportion of reported outcomes among the 23 defined in the CAD COS. We analyzed changes in adherence over time, including pre- and post-COS publication periods, with secondary analyses examining continent, sponsor type, recruitment status, and enrollment number. Results Among 433 trials, procedural interventions (45.0%) and all-cause mortality (40.9%) were the most reported outcomes, while acute renal failure (2.1%) and dyspnea (2.8%) were the least. Pre-2015, trials reported an average of 11.5% of the COS-defined outcomes. Post-2015, trials initiated after the CAD COS publication reported a slightly higher proportion of COS-defined outcomes compared to earlier trials, reflecting a modest increase in the number of items reported. However, this increase was not statistically significant (p = 0.012). Recruitment status significantly influenced adherence (p

The effective training of law students, which demystifies technology, and the creation of cost effective, fit for purpose technology solutions are crucial to democratising legal technology and levelling the playing fields between "Big Law" and the legal services available to the bulk of South African citizens. A public/private partnership between the Nelson Mandela Faculty of Law, the university's Information and Communication Technology department and a consortium of legal practitioners (including Cliffe Dekker Hofmeyr and various industry players) has piloted HiveLaw, a SharePoint-based practice management solution custom designed to fit university law clinics' dual purpose of legal service delivery and practical legal education. This pilot serves as a case study firstly to investigate how legal technology can contribute to transformative teaching and learning and transformative legal practice at university law clinics, as it exposes staff and students to the benefits of digital and online activities. Secondly, the pilot illustrates how proficiency in the use of technology such as HiveLaw aids the staff and students to adapt to digital processes while improving access to justice for indigent communities. In this way staff and students make a difference in the working world by implementing their knowledge in legal practice, which is widely known for slowly adapting to digital processes, while being exposed to experiential learning and getting in touch with the demands of modern legal practice.

Abstract Dietary restriction has shown benefits in physiological, metabolic, and molecular signatures associated with aging but is a difficult lifestyle to maintain for most individuals. In mice, a less restrictive diet that allows for cyclical periods of reduced calories mitigates aging phenotypes, yet the effects of such an intervention in a genetically heterogenous, higher-order mammal has not been examined. Here, using middle-aged rhesus macaques matched for age and sex, we show that a regimen of 4 days of low-calorie intake followed by 10 days of ad libitum feeding (4:10 diet) performed in repeating cycles over 12 weeks led to significant loss of weight and fat percentage, despite the free access to food for most of the study duration. We show the 4-day restriction period is sufficient to drive alterations to the serum metabolome characterized by substantial differences in lipid classes. These phenotypes were paralleled by changes in the gut microbiome of restricted monkeys that highlight the involvement of a microbiome-metabolome axis. This regimen shows promising phenotypes, with some sex-dimorphic responses, including residual memory of the diet. As many calorie restriction interventions are difficult to sustain, we propose that this short-term diet may be easier to adhere to and have benefits directly relevant to human aging.

Stem cell heterogeneity is recognized as functionally relevant for tissue homeostasis and repair. The identity, context dependence, and regulation of skeletal muscle satellite cell (SC) subsets remains poorly understood. We identify a minor subset of Pax7+ SCs that is indelibly marked by an inducible Mx1-Cre transgene in vivo, is enriched for Pax3 expression, and has reduced ROS (reactive oxygen species) levels. Mx1+ SCs possess potent stem cell activity upon transplantation but minimally contribute to endogenous muscle repair, due to their relative low abundance. In contrast, a dramatic clonal expansion of Mx1+ SCs allows extensive contribution to muscle repair and niche repopulation upon selective pressure of radiation stress, consistent with reserve stem cell (RSC) properties. Loss of Pax3 in RSCs increased ROS content and diminished survival and stress tolerance. These observations demonstrate that the Pax7+ SC pool contains a discrete population of radiotolerant RSCs that undergo clonal expansion under severe stress.

The recently published article in Cell by the Sinclair lab and collaborators entitled “Loss of Epigenetic Information as a Cause of Mammalian Aging” [1] implicates heritable changes in gene expression as the basis for aging, a postulate consistent with the emerging information theory of aging. Sinclair’s group and colleagues induced epigenetic changes, i.e., DNA and histone modifications, via double-strand breaks (DSBs) catalyzed by the I-Pol endonuclease at specific genomic loci. The genomic DNA breaks, introduced without inducing insertion or deletion mutations (indels) in a mouse model, were targeted to 19 non-coding regions and one region in ribosomal DNA (rDNA), the latter shown to not have a significant effect on the function or transcription of rDNA [1]. With that experimental model in place, the authors present experimental evidence supporting a model that epigenetic changes drive aging via this inducible DNA break mechanism. After demonstrating the phenotypic alterations of this accelerated aging, they attempt to reverse selective phenotypes by resetting the altered epigenetic landscape. Establishing a causal relationship between epigenetic changes and aging, and how this connection might be manipulated to overturn cellular features of aging, is provocative and merits further study.

The tumour microenvironment has been shown to change the phenotypes and functionality of immune cells to enable tumour propagation. Here authors show that cancers can derail B cell development to give rise to macrophage-like cells, contributing to cancer progression and metastasis via disabling local T cell response.

Background: Coronary artery disease (CAD) is a global health crisis, responsible for nearly 20 million deaths annually worldwide and 12.6% of all deaths in the United States. Randomized controlled trials (RCTs) are critical for developing evidence-based clinical guidelines, but inconsistent outcome reporting across RCTs hinders evidence synthesis and comparability. In 2015, McNamara et al. introduced a CAD core outcome set (COS) to promote standardization in CAD trial outcomes. This study evaluates the uptake of the CAD COS in RCTs registered at ClinicalTrials.gov since its publication. Methods: This trial registry analysis evaluated the uptake of the CAD COS in phase III/IV RCTs registered on ClinicalTrials.gov from May 2010 to June 2023. Trials were included if they assessed CAD interventions and excluded if the trials were non-randomized, focused on diagnostic tests, or were categorized as "not applicable" (e.g., behavioral interventions). COS adherence was measured as the proportion of reported outcomes among the 23 defined in the CAD COS. We analyzed changes in adherence over time, including pre- and post-COS publication periods, with secondary analyses examining continent, sponsor type, recruitment status, and enrollment number. Results: Among 433 trials, procedural interventions (45.0%) and all-cause mortality (40.9%) were the most reported outcomes, while acute renal failure (2.1%) and dyspnea (2.8%) were the least. Pre-2015, trials reported an average of 11.5% of the COS-defined outcomes. Post-2015, trials initiated after the CAD COS publication reported a slightly higher proportion of COS-defined outcomes compared to earlier trials, reflecting a modest increase in the number of items reported. However, this increase was not statistically significant (p = 0.012). Recruitment status significantly influenced adherence (p < 0.001), while continent and sponsor type did not. A weak positive correlation was observed between enrollment number and adherence (r = 0.27, p < 0.001). Conclusions: Despite its publication in 2015, CAD COS uptake remains limited, with no significant changes in adherence over time. Barriers such as limited dissemination, lack of trialist awareness, and preferences for custom outcomes likely contribute to these findings. Greater emphasis on education, patient-centered outcomes, and COS tailored to specific CAD indications is needed to enhance uptake and comparability in CAD trials. [ABSTRACT FROM AUTHOR]

We present an exquisite 30 minute cadence Kepler (K2) light curve of the Type Ia supernova (SN Ia) 2018oh (ASASSN-18bt), starting weeks before explosion, covering the moment of explosion and the subsequent rise, and continuing past peak brightness. These data are supplemented by multi-color Panoramic Survey Telescope (Pan-STARRS1) and Rapid Response System 1 and Cerro Tololo Inter-American Observatory 4 m Dark Energy Camera (CTIO 4-m DECam) observations obtained within hours of explosion. The K2 light curve has an unusual two-component shape, where the flux rises with a steep linear gradient for the first few days, followed by a quadratic rise as seen for typical supernovae (SNe) Ia. This "flux excess" relative to canonical SN Ia behavior is confirmed in our i-band light curve, and furthermore, SN 2018oh is especially blue during the early epochs. The flux excess peaks 2.14 ± 0.04 days after explosion, has a FWHM of 3.12 ± 0.04 days, a blackbody temperature of K, a peak luminosity of , and a total integrated energy of . We compare SN 2018oh to several models that may provide additional heating at early times, including collision with a companion and a shallow concentration of radioactive nickel. While all of these models generally reproduce the early K2 light curve shape, we slightly favor a companion interaction, at a distance of ∼ based on our early color measurements, although the exact distance depends on the uncertain viewing angle. Additional confirmation of a companion interaction in future modeling and observations of SN 2018oh would provide strong support for a single-degenerate progenitor system.

# Background Iron deficiency anemia (IDA) remains one of the most common diet-related micronutrient deficiency disorders in the world. Although iron supplementation can effectively improve iron status, it is often a short-term solution to this endemic, chronic health problem. Lucky Iron Fish® (LIF) offers a novel, long-term approach to treat IDA that can be easily utilized in regions of the world where IDA is most prevalent. While the beneficial use of LIF for household preparation of meals has been demonstrated, its use in quantity food production has not been investigated. The purpose of this study was to develop methodology for large-scale iron fortification of cooking water and to assess changes in hemoglobin and hematocrit values in school-going children following 8 months of receiving iron-fortified school lunches prepared with LIF. # Methods Laboratory studies were conducted to develop the protocol to prepare iron fortification of cooking water using LIF. Study participants were school-going children from economically, disadvantaged families attending private schools in Jocotenango, Guatemala. Baseline measures (weight, height, hemoglobin, and hematocrit) were taken at the start and completion of the academic calendar. The sample was divided into quintiles based on pre-hemoglobin and hematocrit values where quintile 1 had the lowest baseline hemoglobin and hematocrit values and quintile 5 had the highest baseline hemoglobin and hematocrit values. Paired t-tests were used to determine if there were overall significant pre- and post-differences in iron status values by quintile groupings. # Results A total of 286 (77%) of children between the ages of 5 -- 16 (y) completed the study. Post- hemoglobin values were significantly higher than pre-hemoglobin values for those in quintile 1, whereas post-hematocrit values significantly increased for quintiles 1 and 2. # Conclusions Study results suggest that LIF can be used to prepare large quantities of food and that regular consumption of iron-fortified school lunches can improve iron status in children with marginal status. Equally important is the finding that iron-fortified meals do not negatively impact those with healthy iron values.

Many recognize that people who buy sexual services create a demand for services that can lead to exploitation and harms to individuals and communities involved, but little research in the Canadian context has been published to understand these buyers. The present research sought to understand the attitudes of people who buy sex towards people who provide sex services by analyzing comments posted by Toronto Escort Review Board members between April 1 and October 31, 2021. A set of 15 comments were randomly selected for each of 6 searchable characteristics: “young” (age), “spinner” (body type), “ebony” (race), “trans” (gender), “submissive” (disposition), and “greek” (activity). This research reveals an attitude of consumerism in people who buy sex that leverages online communities 1) to select almost any type of person for a sexual experience and 2) get the support of fellow members to help them pursue a desired sexual experience. However, analyzed comments also suggest that members who buy sex generally ignore, consciously or unconsciously, possible exploitation or the impact on the welfare of the individual in the short and long term. Ongoing collaborations between Canadian law makers, the criminal justice system, and health and education sectors are needed to reduce the demand in sex services. This research shows there is much more work to do to confront the consumeristic views of people who provide sex services held by people who buy sex and combat online cultures that promote the exploitation of others.

Abstract NAD+ supplementation has significant benefits in compromised settings, acting largely through improved mitochondrial function and DNA repair. Elevating NAD+ to physiological levels has been shown to improve the function of some adult stem cells, with implications that these changes will lead to sustained improvement of the tissue or system. Here, we examined the effect of elevating NAD+ levels in models with reduced hematopoietic stem cell (HSC) potential, ATM-deficient and aged WT mice, and showed that supplementation of nicotinamide riboside (NR), a NAD+ precursor, improved lymphoid lineage potential during supplementation. In aged mice, this improved lymphoid potential was maintained in competitive transplants and was associated with transcriptional repression of myeloid gene signatures in stem and lineage-committed progenitor cells after NR treatment. However, the altered transcriptional priming of the stem cells toward lymphoid lineages was not sustained in the aged mice after NR removal. These data characterize significant alterations to the lineage potential of functionally compromised HSCs after short-term exposure to NR treatment.

Cellular senescence, a state of persistent growth arrest, is closely associated with aging and age‐related diseases. Deciphering the heterogeneity within senescent cell populations and identifying therapeutic targets are paramount for mitigating senescence‐associated pathologies. In this study, proteins on the surface of cells rendered senescent by replicative exhaustion and by exposure to ionizing radiation (IR) were identified using mass spectrometry analysis, and a subset of them was further studied using single‐cell CITE‐seq (Cellular Indexing of Transcriptomes and Epitopes by Sequencing) analysis. Based on the presence of proteins on the cell surface, we identified two distinct IR‐induced senescent cell populations: one characterized by high levels of CD109 and CD112 (cluster 3), the other characterized by high levels of CD112, CD26, CD73, HLA‐ABC, CD54, CD49A, and CD44 (cluster 0). We further found that cluster 0 represented proliferating and senescent cells in the G1 phase of the division cycle, and CITE‐seq detection of cell surface proteins selectively discerned those in the senescence group. Our study highlights the heterogeneity of senescent cells and underscores the value of cell surface proteins as tools for distinguishing senescent cell programs and subclasses, paving the way for targeted therapeutic strategies in disorders exacerbated by senescence. [ABSTRACT FROM AUTHOR]