Cost-effectiveness of fenofibrate versus standard care for reducing the progression of diabetic retinopathy: an economic evaluation based on data from the LENS trial

Aims: The LENS trial demonstrated that fenofibrate slowed progression of diabetic retinopathy compared to placebo in participants with early diabetic eye disease. We assessed its cost-effectiveness for reducing progression of diabetic retinopathy versus standard care from a UK National Health Service perspective. Methods: Resource use and outcome data were collected over follow-up for participants enrolled in LENS. Mean costs were compared at two years and per 6-months follow-up (median 4.0 years). Within trial cost-effectiveness was assessed in terms of incremental cost per case of referable disease averted. A microsimulation model, with inputs derived primarily from LENS trial data, was used to assess the incremental cost per quality adjusted life year (QALY). Results: Fenofibrate resulted in a mean (95% confidence interval) reduction in health service costs of -£254 (-1,062 to 624) at two years and -£101 (-243 to 42) per 6-months follow-up. This was accompanied by a 4.4% (1.3% to 8.0%) absolute reduction in any referable diabetic retinopathy or treatment thereof at two years, and a 27% (9%-42%) relative reduction over follow-up. Modelled over ten years, fenofibrate use cost an additional £6 per patient for an expected QALY gain of 0.02, costing £406 per QALY versus standard care under base case assumptions. The probability of cost-effectiveness varied from 70%-79% at a threshold of £20,000 per QALY, depending on the price discount applied to anti-VEGF drugs. Conclusions: Fenofibrate is likely to offer a cost-effective treatment for slowing progression of any diabetic retinopathy in people with early to moderate diabetic retinopathy or maculopathy

Working Memory Predicts Long‐Term Recognition of Auditory Sequences: Dissociation Between Confirmed Predictions and Prediction Errors

Memory is a crucial cognitive process involving several subsystems: sensory memory (SM), short‐term memory (STM), working memory (WM), and long‐term memory (LTM). While each has been extensively studied, the interaction between subsystems, particularly in relation to predicting temporal sequences, remains largely unexplored. This study investigates the association between WM and LTM, and how these relate to aging and musical training. Using three datasets with a total of 243 healthy volunteers across various age groups, we examined the impact of WM, age, and musical training on LTM recognition of novel and previously memorized musical sequences. Our results show that WM abilities are positively associated with the identification of novel sequences, but not with the recognition of memorized sequences. Additionally, musical training has a similar positive impact on the identification of novel sequences, while increasing age is associated with reduced memory performance. Different cognitive processes are involved in handling prediction errors compared to confirmatory predictions, and WM contributes to these processes differently. Future research should extend our investigation to populations with memory impairments and explore the underlying neural substrates

The role of the synovial microenvironment in Rheumatoid Arthritis

Rheumatoid Arthritis (RA) remains plagued by poor treatment responses and a lack of curative solutions despite a dense armamentarium. A deeper investigation into the tissue biology of the RA synovium, including its cells but also the remodelled extracellular matrix (ECM) that characterises it, represents a promising new approach in the quest for therapeutic tissue repair and inflammation resolution. Publicly available single cell RNA sequencing datasets were analysed to define the matrisomal gene expression landscape in RA. Distinct fibroblast subsets were found to express distinct matrisomal gene profiles, thereby defining the composition of specific subsynovial microarchitectures. Differential expression analysis identified common and unique matrix gene expression cassettes between fibroblast subsets, between osteoarthritis (OA) and RA, and between active RA and RA in remission. IGF signalling and basement membrane compositional dysregulation were identified as key features of RA pathology and investigated further at the protein level. A multiplexed immunofluorescence dataset was generated to look at the spatial distribution of IGFBP5, IGFBP7, COL4A1, and COL6A1 in human OA and RA synovium. COL6A1 was notably found to correlate positively with remission-associated MerTK+ macrophage abundance in tissue. Its deposition pattern was found to highlight specific areas devoid of collagen VI, termed dark zones, where immune cells localised. Despite the correlation with MerTK+ macrophages in tissue, collagen VI was unable to polarise monocyte derived macrophages towards this remission associated phenotype. Looking more closely into the dark zones however, all immune cell subsets apart from monocytes were tightly locally restricted to collagen VI dark zones. Monocyte ingress into collagen VI-rich regions was found to be associated with active collagen degradation, suggesting potential degradation-dependent migration. Preliminary data point to a direct role for collagen VI in preventing immune cell adhesion and thereby their migration through tissue. Fragments resulting from the cleavage of collagen by migrating monocytes were detectable specifically in human RA synovium. These data point to a novel mechanism of immune migration restriction by synovial stromal cells. Further investigation of this process may hold significant promise in the reestablishment of tissue homeostasis and the curtailing of immune cell infiltration in RA

Inefficient Melt Transport Across a Weakened Lithosphere Led to Anomalous Rift Architecture in the Turkana Depression

The Turkana Depression, located between the Ethiopian and East African plateaus, displays an anomalous rift architecture. It is missing the narrow, magma‐rich morphology observed in the Main Ethiopian Rift that cuts through the Ethiopian Plateau. Instead, diffuse faulting and isolated volcanic centers are widespread over several hundred kilometers. Turkana has also experienced less magmatism over the last 30 Myr than adjacent plateaus, despite having a thin crust and residing above a mantle that is inferred to be hot and partially molten. We hypothesize that lithospheric weakening has been the key control on magma transport across the lithosphere in the Turkana Depression and subsequent rift development. Using poro‐viscoelastic–viscoplastic models of melt transport, we show that magma extraction across a thin, weakened lithosphere is slower than across a thick, elastic lithosphere. Our results suggest that pre‐rift lithospheric strength can explain the magma‐poor character of Turkana for most of its tectonic history

Impact of sodium-glucose cotransporter-2 inhibitors on aging biomarkers and plasma ceramide levels in type 2 diabetes: beyond glycemic control

BackgroundAging is a complex biological process marked by the decline of physiological functions and heightened susceptibility to chronic illnesses, notably cardiometabolic disorders. Ceramides (Cer) are lipid derivatives linked to aging and metabolic diseases. Sodium-Glucose Cotransporter-2 inhibitors (SGLT2i), widely used in managing type 2 diabetes, have an unclear impact on aging biomarkers and Cer profiles.ObjectiveThis study explored the association between SGLT2i use, plasma Cer levels (CerC16:0, CerC18:0, CerC22:0, CerC24:0, and CerC24:1), and aging biomarkers-Human Insulin-Like Growth Factor 1 (IGF-1), mammalian target of rapamycin (mTOR), 5-Methylcytosine (5MC), and Human H2AFX (Histone H2AX) in patients with type 2 diabetes mellitus (T2DM).MethodsIn this retrospective study, 95 participants were divided into three groups: patients on SGLT2i (n = 34), patients on non-SGLT2i anti-diabetic treatments (n = 36), and healthy controls (n = 25). Plasma Cer and aging biomarkers were quantified using Liquid Chromatography with tandem mass spectrometry (LC-MS-MS) and ELISA, respectively. Principal component analysis (PCA) assessed group-based clustering, while ANCOVA evaluated group differences with confounder adjustment.ResultsSGLT2i-treated patients showed significantly lower CerC16:0, CerC22:0, and CerC24:1 levels (p p p ConclusionBeyond glucose control, SGLT2i may improve plasma Cer and aging markers in diabetic patients, supporting their broader therapeutic potential in aging and age-related diseases. Further large-scale studies are warranted to confirm these effects and underlying mechanisms

Investigating the consequences of replication fork collapse at protein-DNA barriers

The inadvertent stalling of replication forks (RFs) upon protein-DNA barrier collision may render them unable to continue DNA synthesis. Following fork collapse, DNA replication can be completed either by a canonical fork converging on the collapsed fork or by the collapsed fork restarting through a recombination-dependent process. Our knowledge of how recombination restarts collapsed forks and how fork convergence (FC) is conducted at replication fork barriers (RFBs) remains limited. Studies in Schizosaccharomyces pombe (S. pombe), using the unidirectional RFB RTS1 to induce site-specific RF collapse, have revealed some of the key factors that govern recombination-dependent replication (RDR) as well as characteristic features of the RDR process such as a propensity for the restarted replication to undergo template switching (TS) that can drive genome rearrangement. However, the list of factors that influence RDR remains incomplete. It also remains unclear whether the features of RDR that are triggered by RTS1 are similarly triggered by other RFBs. Studies using RTS1 have also provided insights into how FC at an RFB can provoke recombination that gives rise to different types of genome rearrangement. However, it remains unclear how exactly these genome rearrangements arise and what additional problems may be caused at bi-directional RFBs. In this study, the cellular response to two bi-directional site-specific protein-DNA RFBs, Tus-ter and MarBl, is investigated to explore whether key features of RDR and FC observed with RTS1 are induced by other RFBs. The findings show that Tus-ter and MarBl induce TS events but to a lesser extent than RTS1. Similar to RTS1, Tus-ter and MarBl also induce duplication-deletion (Dup-Del) rearrangements. This study investigates the genetic requirements for TS and putative Dup-Del events induced by Tus-ter. This study also investigates whether FC is likely responsible for the induction of high localised recombination rates at bi-directional RFBs. Lastly, efforts are presented to establish a new recombination reporter to facilitate the screening of a genome-wide S. pombe deletion library for genes that affect RTS1-induced recombination

The Oxford handbook of religion and education

The Oxford Handbook of Religion and Education offers a multi-disciplinary work of scholarship and research highlighting the global significance of a critical interface of cultural and social, political, and theological importance. Drawing on historical perspective and contemporary reflection, the collection provides a uniquely transformative analysis of why the interface of religion and education is of such critical significance. With contributions from some of the leading thinkers, the Handbook presents a cumulatively powerful argument to reassess the complexities of the intersection of religion and education. With ambitious and yet accessible intellectual engagements, the Handbook here furthers a central thesis: that the interface of religion and education is not merely a matter of arcane disputation about a domain of ancient origin or a rudimentary matter of formal educational process but a vibrant domain of critical contestation fundamental to knowing, understanding, and living in the modern world

A Systematic Search for Galaxies with Extended Emission Lines and Potential Outflows in JADES Medium-band Images

For the first time, we present a systematic search for galaxies with extended emission lines and potential outflow features using JWST medium-band images in the GOODS South field. This is done by comparing the morphology in medium-band images to adjacent continuum and UV bands. We look for galaxies that have a maximum extent 50% larger, an excess area 30% greater, or an axis ratio difference of more than 0.3 in the medium band compared to the reference bands. After visual inspection, we find 326 candidate galaxies at 1.4 < z < 8.4, with a peak in the population near cosmic noon, benefiting from the good coverage of the medium-band filters. By fitting their spectral energy distributions, we find that the candidate galaxies are at least 20% more bursty in their star-forming activity and have 50% more young stellar populations compared to a control sample selected based on the continuum band flux. Additionally, these candidates exhibit a significantly higher production rate of ionizing photons. We further find that candidates hosting known active galactic nuclei (AGN) produce extended emission that is more anisotropic compared to non-AGN candidates. A few of our candidates have been spectroscopically confirmed to have prominent outflow signatures through NIRSpec observations, showcasing the robustness of the photometric selection. Future spectroscopic follow-up will better help verify and characterize the kinematics and chemical properties of these systems

Assessment of soil impacts from lead release by lead-halide perovskite solar cells based on outdoor leaching tests

Perovskite solar cells represent a promising technology in the photovoltaic industry due to their high power conversion efficiency, potential for cost-effective manufacturing and versatile applications. The most stable and efficient perovskites to date rely on lead (Pb), raising concerns about leaching into the environment; however Pb release so far has only been quantified under laboratory conditions, and no field-based assessment under real outdoor expsosure has yet evaluated this risk. The present study quantified Pb leaching from various metal-halide perovskite compositions, device stacks and encapsulation approaches in a rooftop installation for up to 9 months. Pb leaching was low across all tested configurations, even in intentionally damaged materials. Glass–glass encapsulated tandem devices shattered by hail and plastic-encapsulated samples damaged by 100 µm pinholes released only 0.07% ± 0.01% and 0.15% ± 0.14% of their initial Pb, respectively, likely due to the slow diffusion of Pb cations in water. The highest leaching (4.81% ± 0.02%) occurred in unlaminated laboratory devices, demonstrating the importance of proper lamination. A self-developed freeware web tool was used to calculate predicted soil concentrations and evaluate potential impacts. Even for unlaminated devices, concentrations would only slightly exceed natural background levels (5.6 mg kg−1 increase), with negligible effects on soil fertility. A hypothetical worst-case scenario assuming a 1000 nm thick perovskite layer and complete Pb leaching onto a narrow strip of soil predicted a negative impact on soil fertility; however remediation would still not be required under Swiss environmental regulations. Overall, current industry-standard encapsulation limits Pb leaching to levels that almost completely mitigate negative impacts on soil health

Access to hypertension services and health-seeking experiences in rural Coastal Kenya: A qualitative study

Globally, hypertension causes 10.8 million deaths annually. However, in Kenya, like in other low-and middle-income countries, access to hypertension care remains limited and inequitable. Understanding patients’ journeys in accessing care along the care cascade is critical to inform patient-centred care and policy improvements. This study aimed to explore patient experiences in accessing primary care services for hypertension along the care cascade in rural Coastal Kenya―a setting with a high hypertension burden. We conducted a qualitative cross-sectional study and collected data using in-depth interviews (n = 24) and five focus group discussions (n = 30) with hypertension patients and their adult family caregivers in two purposively selected sub-counties in Kilifi County. We conducted and transcribed the interviews in Kiswahili and Giriama (local languages) and translated them into English. We used QSR NVivo 12 for data management. We analysed the data using a framework approach and interpreted our findings using Levesque’s access framework. Access to hypertension screening and diagnosis services was undermined by information barriers which led to inadequate awareness and lack of knowledge about hypertension and its causes. There were perceptions of inadequate health facility capacity to offer hypertension screening services, particularly to ‘healthy’ individuals thus presenting as a barrier to demand for screening services. Acceptability of care was undermined by inadequate patient counselling at diagnosis and perceived disrespectful treatment of patients. Access to treatment and diagnostic tests was undermined by unaffordable care, limited availability of medicines and equipment, long waiting times, and inaccessible health facilities. Having health insurance enabled access to care; however, most participants were uninsured. Participants adapted to these access barriers by reducing/skipping daily medication doses, resorting to alternative forms of care (e.g., herbal treatments and faith healing), and changing health facilities for routine clinic appointments. Access to care for older patients (i.e., ≥70 years) and those with complications was enabled by family caregivers who coordinated and navigated the health system on their behalf. Our findings show that people living with hypertension experience a combination of interacting individual, community, and health system-related barriers to accessing care. There is a need to systematically address identified barriers and ensure patient-centred responses that meet patients’ needs. Strengthening the health system’s capacity to ensure availability and affordability of treatment and diagnosis services, creation of community hypertension awareness, adequate patient counselling at screening and diagnosis, and involvement of family caregivers for older patients are examples of urgent interventions to improve access to hypertension care