Stopping versus continuing metformin in patients with advanced CKD: A nationwide Scottish target trial emulation study

Rationale & Objective: Current guidance recommends against the use of metformin in people with advanced kidney impairment despite a lack of supporting evidence. The aim of this observational study was to compare outcomes of patients with type 2 diabetes who continued versus stopped metformin after developing stage 4 chronic kidney disease (CKD) (eGFR <30 ml/min/1.73m2). Study Design: Nationwide observational cohort study. Setting & Participants: All adults with type 2 diabetes and incident stage 4 CKD in Scotland who were treated with metformin between January 2010 and April 2019. Exposure: Stopping versus continuing metformin within six months following incident stage 4 CKD. Outcomes: Primary outcome was all-cause mortality. Secondary outcomes included major adverse cardiovascular events (MACE). Analytical Approach: Target trial emulation with clone-censor-weight design and marginal structural models fit for sensitivity analyses. Results: In a population of 371,742 Scottish residents with a diagnosis of type 2 diabetes before 30th April 2019, 4,278 were identified as prevalent metformin users with incident CKD stage 4. Within six months of developing CKD stage IV, 1,713 (40.1%) individuals discontinued metformin. Compared with continuing metformin, stopping metformin was associated with a lower 3-year survival (63.7%, 95% CI 60.9 to 66.6 versus 70.5%, 95% CI 68.0 to 73.0; HR=1.26, 95% CI 1.10 to 1.44), while the incidence of MACE was similar between both strategies (HR=1.05, 95% CI 0.88 to 1.26). Marginal structural models confirmed the higher risk of all-cause mortality and similar risk of MACE in patients who stopped versus continued metformin (all-cause mortality: HR=1.34, 95% CI 1.08 to 1.67; MACE: HR=1.04, 95% CI 0.81 to 1.33). Limitations: Residual confounding. Conclusions: The continued use of metformin may be appropriate when eGFR falls below 30 ml/min/1.73m2. Randomized controlled trials are needed to confirm these findings

Women Writers of the Second World War: Country House Fiction from Bowen to Compton-Burnett

The country house is one of the crucial sites in anglophone fiction published just before and after World War II. Each of my chapters converges on a different author – Elizabeth Bowen, Elizabeth Taylor, Ivy Compton-Burnett and Barbara Comyns – to explore how their novels represent species of spaces and class hierarchies in the ancestral mansion or Anglo-Irish ‘big house’. Why these four authors in particular? First, they read, admired and promoted one another’s work. In her regular ‘Book Reviews’ column for The Tatler magazine, Bowen discussed new novels by Taylor, Compton-Burnett and Comyns. Taylor’s attitude to Bowen’s fiction was one of ‘blinkered devotion’, according to Taylor’s biographer Nicola Beauman. Compton-Burnett and Taylor were also friends; their correspondence affords a fascinating glimpse into their narrative strategies and recreational reading habits. Crucially, all four novelists treat the country house as a ‘laboratory’ in which to probe governing systems, family tyrannies, subterfuge and secrets – what Bowen termed those dense ‘thickets of mystery between person and person’ – at precisely that historical moment when the National Trust sought to convert surviving aristocratic manors into ‘heritage’ venues open to the public

Nonlinear inertial amplifier liquid column dampers

Conventional Tuned Liquid Column Dampers effectively mitigate structural vibrations; however, their efficacy is limited by the need for supplementary static mass, which escalates costs and complicates adaptability. This work presents a novel solution: Nonlinear Inertial Amplifier Liquid Column Dampers, which improve vibration attenuation without augmenting static mass. The suggested system is implemented on a single-degree-of-freedom framework, with its governing equations determined by Newton's second law and Lagrange's approach. The optimal design parameters are derived using H2 and H∞ optimisation methods. Results indicate that nonlinear inertial amplifier liquid column dampers much exceed the performance of conventional tuned liquid column dampers and inerter-based tuned liquid column dampers, attaining a dynamic response reduction of up to 83.60% and 82.11%. The closed-form solutions and parametric analyses validate the efficacy of this method, establishing nonlinear inertial amplifier liquid column dampers as a potential technique for enhancing structural resilience in civil engineering applications

Measurement of top-quark pair production in association with charm quarks in proton–proton collisions at √s = 13 TeV with the ATLAS detector

Inclusive cross-sections for top-quark pair production in association with charm quarks are measured with proton–proton collision data at a center-of-mass energy of 13 TeV corresponding to an integrated luminosity of 140 fb−1, collected with the ATLAS experiment at the LHC between 2015 and 2018. The measurements are performed by requiring one or two charged leptons (electrons and muons), two b-tagged jets, and at least one additional jet in the final state. A custom flavor-tagging algorithm is employed for the simultaneous identification of b-jets and c-jets. In a fiducial phase space that replicates the acceptance of the ATLAS detector, the cross-sections for tt¯+≥2c and tt¯+1c production are measured to be 1.28−0.24+0.27pb and 6.4−0.9+1.0pb, respectively. The measurements are primarily limited by uncertainties in the modeling of inclusive tt¯ and tt¯+bb¯ production, in the calibration of the flavor-tagging algorithm, and by data statistics. Cross-section predictions from various tt¯ simulations are largely consistent with the measured cross-section values, though all underpredict the observed values by 0.5 to 2.0 standard deviations. In a phase-space volume without requirements on the tt¯ decay products and the jet multiplicity, the cross-section ratios of tt¯+≥2c and tt¯+1c to total tt¯+jets production are determined to be (1.23±0.25)% and (8.8±1.3)%

Non-Specific Pleuritis: an update

Purpose of Review: Non-Specific Pleuritis (NSP) is a common diagnosis following thoracoscopy and encompasses a broad range of aetiologies with heterogeneous outcomes. In this article, we review pathophysiology, associated syndromes, and current best practice in follow-up. Recent Findings: NSP typically runs a benign disease course; however, the biomechanical consequences of subsequent tissue re-modelling can be severe. A proportion of patients develop malignancy, notably pleural mesothelioma (PM), and clinicians currently lack the ability to stratify those at risk. Some may be harbouring occult malignancy with false-negative pleural biopsies. Alternatively, NSP may represent a true pre-PM precursor supported by the recent characterisation of mesothelioma-in-situ. Summary: Prospective surveillance of NSP patients could unlock the final biological milestone preceding PM evolution. Progress in this area would permit a more personalised patient stratification, whilst offering novel opportunities for translational research. The PREDICT-Meso International Accelerator Network has been established to focus on this goal

Hidden causes of variation in offspring reproductive value: negative effects of maternal breeding age on offspring telomere length persist undiminished across multiple generations

Offspring of older breeders frequently show reduced longevity, which has been linked to shorter offspring telomere length. It is currently unknown whether such telomere reduction persists beyond a single generation, as would be the case if germline trans�mission is involved. In a within-grandmother, multi-generational study using zebra finches, we show that the shorter telomeres observed in F1 offspring of older mothers are still present in the F2 generation even when the breeding age of their F1 mothers is young. The effect was substantial: 43% shorter telomeres in grandoffspring from the ‘grandmother old at breeding’ line com�pared with those from the ‘grandmother young at breeding’ line. Shorter telomeres at fledging in this species are associated with a reduction in lifespan. Our data demonstrate the need to look beyond a single generation to explain inter-individual variation in ageing rates and thereby variation in optimal allocation of age-specific reproductive effort

Bioremediation of multiple heavy metals through biostimulation of Microbial-Induced Calcite Precipitation at varying calcium-to-urea concentrations

Studies on heavy metal bioremediation through microbial-induced calcite precipitation (MICP) typically involve bioaugmentation approaches that use low calcium-to-urea ratios and target single contaminants. We present an investigation on the efficiency of soils’ autochthonous ureolytic bacteria to simultaneously remediate multiple heavy metals and sequester carbon through urea hydrolysis and MICP on an urban soil containing excess Pb, Zn, Mn, Sr, Ba and Al. Soils were treated at a fixed urea concentration of 333 mM and increasing calcium content of 0, 50 and 333 mM to provide a range of carbonation potential. Urea hydrolysis (Ca2+ = 0 mM) did not produce quantifiable soil carbonation and mobilised Mn into the exchangeable fraction. Ca2+ at 50 mM delayed soils’ autochthonous ureolytic activity and produced limited carbon and heavy metal mineralisation (CaCO3 = 0-0.7%). 333 mM of Ca2+ inhibited urea hydrolysis however, if applied following urea hydrolysis, both carbon (CaCO3 = 4-7%) and heavy metal (Pb, Zn, Mn, Sr and Ba) mineralisation were maximised. Urea hydrolysis and MICP were most successful in removing Pb and Zn from the exchangeable fraction (>85%). However, the higher pH induced by urea hydrolysis at Ca2+ = 0-50 mM (~9) compared to 333 mM (~8.5) favoured partition of Pb into the oxyhydroxide fraction. Instead, partition of Zn, Mn, Sr and Ba into the soil carbonate fraction increased with increasing calcium, whilst there was no evidence of Al carbonation. The results of this study evidence the feasibility of biostimulation approaches to remediate multiple contaminants simultaneously through MICP, provide insights into multiple element’s behaviour during urea hydrolysis and MICP and demonstrate carbon and element mineralisation are maximised at equimolar calcium-to-urea ratio of 333 mM

Expanding the genomic diversity of human anelloviruses

Anelloviruses are a group of small, circular, single-stranded DNA viruses that are found ubiquitously across mammalian hosts. Here, we explored a large number of publicly available human microbiome datasets and retrieved a total of 829 anellovirus genomes, substantially expanding the known diversity of these viruses. The majority of new genomes fall within the three major human anellovirus genera: Alphatorquevirus, Betatorquevirus and Gammatorquevirus, while we also present new genomes of the under-sampled Hetorquevirus, Memtorquevirus and Samektorquevirus genera. We performed recombination analysis and show evidence of extensive recombination across all human anelloviruses. Interestingly, more than 95% of the detected events are between members of the same genus and only 15 inter-genus recombination events were detected. The breakpoints of recombination cluster in hotspots at the ends and outside of the ORF1 gene, while a recombination coldspot was detected within the gene. Our analysis suggests that anellovirus evolution is governed by homologous recombination, however events between distant viruses or ones producing chimaeric ORF1s likely lead to non-viable recombinants. The large number of genomes further allowed us to examine how essential genomic features vary across anelloviruses. These include functional domains in the ORF1 protein and the nucleotide motif of the replication loop region, required for the viruses’ rolling-circle replication. A subset of the genomes assembled in both this, and previous studies are completely lacking these essential elements, opening up the possibility that anellovirus intracellular populations contain non-standard viral genomes (nsVGs). However, low read depth of the metagenomically assembled contigs may partly explain the lack of some features. Overall, our study highlights key features of anellovirus genomics and evolution, a largely understudied group of viruses whose potential in virus-based therapeutics is recently being explored

Comparison of survival after treatment of presumed intracranial meningioma by radiotherapy or surgery in 285 dogs

Background: The comparative effectiveness of radiotherapy and surgery for treating intracranial meningioma is unknown. Objectives: To compare survival after treatment of suspected intracranial meningioma by either surgery or radiotherapy. Animals: Two hundred eighty-five companion dogs with suspected intracranial meningiomas presenting to 11 specialty clinics in three countries. Methods: Parallel cohort comparison study on retrospective data. Dogs diagnosed with intracranial meningioma by board-certified veterinary neurologists or radiologists and treated by radiotherapy or surgery were identified through medical record searches and presenting and survival data extracted. Lesion site was classified as rostro- or caudotentorial and size was measured on contrast magnetic resonance images. Outcome was all-cause death. Analysis of survival by Cox proportional hazards, including selection for optimal multivariable model using lasso, counterfactual modeling including variables associated with treatment allocation and survival. Results: One hundred sixty-eight dogs received radiotherapy and 117 received surgery. All analyses indicated reduced survival associated with surgery compared to radiotherapy. There was a median survival after surgery of 297 (IQR: 99–768) days compared with 696 (IQR: 368–999) for dogs treated by radiation, associated with a univariable hazard ratio of 1.802 (95% CI: 1.357–2.394). Counterfactual modeling estimated a mean survival of 480 (95% CI: 395–564) days after surgery and 673 (95% CI: 565–782) days after radiotherapy, representing a decrease in survival of 29%. Location and size of the lesion were not associated with survival duration. Conclusions and Clinical Importance: Dogs with suspected intracranial meningioma have substantially superior survival after radiotherapy compared to surgery

Early versus delayed mobilisation for non-surgically treated proximal humerus fractures: a systematic review and meta-analysis of randomised trials

Background: Proximal humerus fractures (PHFs) are among the commonest bony injuries and the majority of them can be managed non-surgically. The aim of our systematic review and meta-analysis was to compare the effectiveness and safety of early versus delayed mobilisation in conservatively treated PHFs. Methods: A literature search was performed in Medline, EMBASE and clinicaltrials.gov in Januray 2025 aiming to identify all randomised controlled trials (RCTs) comparing early versus delayed (conventional) mobilisation as part of the non-surgical management of PHFs. Primary outcomes were patient-reported function and pain at short-term (3 months), mid-term (6 months) and long-term (12 months) follow-up, and secondary outcomes included secondary fracture displacement and total complications. Meta-analyses produced mean differences (MDs) or standardised MDs (SMDs) for continuous outcomes and odds ratios (ORs) for binary outcomes, with 95% confidence intervals (CI). Certainty of evidence was assessed using the GRADE tool. Recommendations for clinical practice were given only based on results of high or moderate certainty of evidence. Results: Six (6) RCTs were included that compared early mobilisation (EM; within one week from injury) to delayed mobilisation (DM; after 3 or 4 weeks of immobilisation) with a total of 470 patients with PHFs. There were no differences in patient-reported function (combined or Constant score) or pain between the EM and DM groups at any follow-up time points except for a significant difference in combined function scores favouring EM [SMD 0.4 CI (0.1,0.7), P = 0.006] at 3 months follow-up. There were no significant differences in the incidence of secondary fracture displacement and total complications in the two groups [OR 3.5 CI (0.7,18.2), P > 0.05, and OR 1.2 CI (0.5,2.9), P > 0.05, respectively]. All results were based on moderate or high strength of evidence. The most significant limitations of our study were the small number of pooled studies and inability to perform subgroup analyses for specific fracture types. Conclusions: Our meta-analysis of RCTs showed that commencement of mobilisation within one week from injury for non-surgically managed PHFs is safe and may confer short-term functional benefits compared to delayed mobilisation