Cardiovascular outcomes with intravitreal anti-vascular endothelial growth factor therapy in patients with diabetes: a real-world data analysis

Background: Anti-vascular endothelial growth factor (anti-VEGF) therapy is commonly used intravitreally for diabetic proliferative retinopathy, but when used systemically for treating cancers, an excess of cardiovascular disease (CVD) events has been noted. The latter is of concern for people with diabetes, who are at higher risk of CVD. This study aims to explore the relationship between incident CVD and intravitreal anti-VEGF therapy in patients with diabetes, compared to other therapies, using a large real-world global federated dataset. Methods: Data were analysed using TriNetX, a global electronic medical real-world ecosystem. The study included adults with diabetes and excluded those with a history of CVD prior to the time window of data extraction. Patients were categorised into two cohorts: anti-VEGF therapy or control cohort (laser or steroid therapies). The cohorts were 1:1 propensity score-matched for age, sex, ethnicity, body mass index, systolic blood pressure, HbA1c, and cardiovascular medications (n=1822). Outcomes analysed at 1, 6 and 12 months were: 1) mortality; 2) acute myocardial infarction (MI); 3) cerebral infarction; and 4) heart failure. Relative risk analyses were performed using the built-in R statistical computing platform on TriNetX. Results: In patients with diabetes (n=2205; mean age 58.8±15.8, SD 0.05; 56% male), anti-VEGF therapy was associated with a numerical but non-statistically significant increased CVD risk over 1, 6, and 12 months: Mortality over 1 month (RR 1; 95% CI 0.42,2.40), 6 months (RR 1.46; 95%CI 0.72,2.95) and 12 months (RR 1.41; 95%CI 0.88,2.27). There was no excess of acute MI over 1 (RR n/a: not applicable; 0/0: 0 events in the anti-VEGF group/0 events in the control group), 6 and 12 months (RR n/a; 0/10 events); cerebral infarction over 1, 6 months (RR n/a; 0/0 events), and 12 months (RR n/a; 0/10); and heart failure over 1 month (RR n/a; 0/0 events), 6 months (RR 1; 95%CI 0.42,2.40) and 12 months (RR 1; 95%CI 0.42,2.34). Conclusion: There was no statistically significant risk of cardiovascular-related events in the short or medium term in patients with diabetes who received intravitreal anti-VEGF therapy, despite a small increase in the number of CVD events. Our study supports the real-world safety of intravitreal anti-VEGF therapy in patients with diabetes free of baseline CVD.  <br/

A Process-Aware Framework to Support Process Mining from Blockchain Application

Several studies were conducted to demonstrate the application of Process Mining (PM) techniques to Ethereum-compatible application event data. However, the availability of event data is constrained by the application’s process awareness, which is under-reported in the literature. Based on domain analysis, which identified several challenges to mining the business process from blockchain applications, a framework was designed, instantiated, and tested in this study. The framework supports identification of appropriate cases for PM and automates the generation of event logs from blockchain data. It consists of two modules, the Process Awareness Recognizer (PAR) and the Event Log Generator (ELG). PAR is a rule-based classifier to assess the process awareness of a given application. ELG is an automated batch processing model consisting of three methods: (1) Extractor: to retrieve event data from blockchains; (2) Decoder: to transform the extracted data to a human-readable format; and (3) Formatter: to produce event log files in a format compatible with PM tools. It was validated by implementing a proof-of-concept application with an input set of 201 real-world applications. The results prove the framework’s feasibility and applicability

Geographic inequalities in need and provision of social prescribing link workers

BackgroundLong-term health conditions are major challenges for care systems. Social prescribing link workers have been introduced via Primary Care Networks (PCNs) across England since 2019 to address the wider determinants of health by connecting individuals to activities, groups, or services within their local community.Aim To assess whether the rollout of social prescribing link workers was in areas with the highest need.Design and Setting A retrospective study of social prescribing link workers in England from 2019 to 2023.MethodWe combined workforce, population, survey, and area-level data at the PCN-level from April 2020 to October 2023. We measured population need prior to the rollout of link workers using reported lack of support from local services in the 2019 GP Patient Survey. To assess if rollout reflected need, we used linear regression to relate provision of link workers (measured by full-time equivalent (FTE) per 10,000 patients) in each quarter to population need for support.Results Populations in urban, more deprived areas and with higher proportions of minority ethnicities had the highest reported lack of support. Geographically these were in the North West and London. Initially, there was no association between need and provision; then from July 2022, this became negative and significant. By October 2023, a 10-percentage point higher need for support was associated with a 0.035 (95%CI(-0.634 to -0.066)) lower FTE per 10,000 patients. ConclusionRollout of link workers has not been sufficiently targeted at areas with the highest need. Future deployments should be targeted at those areas. <br/

How 2D Nanoflakes Improve Transport in Mixed Matrix Membranes: Insights from a Simple Lattice Model and Dynamic Mean Field Theory

Mixed matrix membranes (MMMs), incorporating graphene and graphene oxide structural fragments, have emerged as promising materials for challenging gas separation processes. What remains unclear is the actual molecular mechanism responsible for the enhanced permeability and perm-selectivity of these materials. With the fully atomistic models still unable to handle the required time and length scales, here, we employ a simple qualitative model based on the lattice representation of the physical system and dynamic mean field theory. We demonstrate that the performance enhancement results from the flux-regularization impact of the 2D nanoflakes and that this effect sensitively depends on the orientation of the nanoflakes and the properties of the interface between the nanoflakes and the polymer

Contrasting responses of plant, soil fungal and above-ground arthropod communities to plant invasion across latitudes

1. The proliferation of alien species that can suppress resident species via biotic interactions represents a growing concern worldwide. Yet, how above- and below-ground communities simultaneously respond to plant invasion, particularly across large spatial scales, remains poorly explored. We hypothesized plant invasion has a greater impact on recipient above- and below-ground communities at lower than higher latitudes given that biotic interactions play a more significant role in shaping communities in more favorable, lower latitude environments. 2. To test this hypothesis, we conducted a comprehensive field survey of 124 sites spanning a 1700 km latitudinal gradient in China, to explore the effects of invasion of Alternanthera philoxeroides, a globally widespread invasive plant, on plant, soil fungal and above-ground arthropod communities. 3. Invasion of A. philoxeroides had divergent effects on beta diversity (i.e., variation in taxa composition among sites) of plants, above-ground arthropods, and soil saprotrophic fungi, with negative, neutral, and positive responses, respectively. Notably, the compositional dissimilarity of plant and arthropod communities between adjacent invaded and non-invaded sites remained constant across latitudes. In contrast, the compositional dissimilarity of the entire and pathogenic fungal communities between adjacent invaded and non-invaded sites increased with latitude. This resulted in a decreasing difference in invasion effects on the composition of plant and fungal communities with increasing latitude.4. Synthesis. Our study provides novel insights into the complexities of invasion effects by revealing contrasting responses of above- and below-ground communities to plant invasion across latitudes. The contrasting responses could weaken or reshape above- and below-ground interactions, and, in turn, affect future species invasions and the functioning of terrestrial ecosystems.<br/

Crowd-sourced benchmarking of single-sample tumor subclonal reconstruction

Subclonal reconstruction algorithms use bulk DNA sequencing data to quantify parameters of tumor evolution, allowing an assessment of how cancers initiate, progress and respond to selective pressures. We launched the ICGC-TCGA (International Cancer Genome Consortium-The Cancer Genome Atlas) DREAM Somatic Mutation Calling Tumor Heterogeneity and Evolution Challenge to benchmark existing subclonal reconstruction algorithms. This 7-year community effort used cloud computing to benchmark 31 subclonal reconstruction algorithms on 51 simulated tumors. Algorithms were scored on seven independent tasks, leading to 12,061 total runs. Algorithm choice influenced performance substantially more than tumor features but purity-adjusted read depth, copy-number state and read mappability were associated with the performance of most algorithms on most tasks. No single algorithm was a top performer for all seven tasks and existing ensemble strategies were unable to outperform the best individual methods, highlighting a key research need. All containerized methods, evaluation code and datasets are available to support further assessment of the determinants of subclonal reconstruction accuracy and development of improved methods to understand tumor evolution.</p

Evidence for biexponential glutamate T2 relaxation in human visual cortex at 3T: A functional MRS study

Functional magnetic resonance spectroscopy (fMRS) measures dynamic changes inmetabolite concentration in response to neural stimulation. The biophysical basis ofthese changes remains unclear. One hypothesis suggests that an increase or decreasein the glutamate signal detected by fMRS could be due to neurotransmitter move-ments between cellular compartments with different T 2 relaxation times. Previousstudies reporting glutamate (Glu) T 2 values have generally sampled at echo times(TEs) within the range of 30–450 ms, which is not adequate to observe a componentwith short T 2 (&lt;20 ms). Here, we acquire MRS measurements for Glu, (t) total crea-tine (tCr) and total N-acetylaspartate (tNAA) from the visual cortex in 14 healthy par-ticipants at a range of TE values between 9.3–280 ms during short blocks (64 s) offlickering checkerboards and rest to examine both the short- and long-T 2 compo-nents of the curve. We fit monoexponential and biexponential Glu, tCr and tNAA T 2relaxation curves for rest and stimulation and use Akaike information criterion toassess best model fit. We also include power calculations for detection of a 2% shiftof Glu between compartments for each TE. Using pooled data over all participants atrest, we observed a short Glu T 2-component with T 2 = 10 ms and volume fraction of0.35, a short tCr T 2-component with T 2 = 26 ms and volume fraction of 0.25 and ashort tNAA T 2-component around 15 ms with volume fraction of 0.34. No statisti-cally significant change in Glu, tCr and tNAA signal during stimulation was detectedat any TE. The volume fractions of short-T 2 component between rest and active con-ditions were not statistically different. This study provides evidence for a short T 2-component for Glu, tCr and tNAA but no evidence to support the hypothesis of task-related changes in glutamate distribution between short and long T 2 compartment

Folding a Molecular Strand into a Trefoil Knot of Single Handedness with Co(II)/Co(III) Chaperones

We report the synthesis of a right-handed (Δ-stereochemistry of strand crossings) trefoil knot from a single molecular strand containing three pyrazine-2,5-dicarboxamide units adjacent to point-chiral centers and six pyridine moieties. The oligomeric ligand strand folds into an overhand (open-trefoil) knot through the assistance of coordinatively dynamic Co(II) “chaperones” that drive the formation of a three-metal-ion circular helicate. The entangled structure is kinetically locked by oxidation to Co(III) and covalently captured by ring-closing olefin metathesis to generate a trefoil knot of single topological handedness. The stereochemistry of the strand crossings in the metal-coordinated overhand knot is governed by the stereochemistry of the point-chiral carbon centers in the ligand strand. The overhand and trefoil knots were characterized by NMR spectroscopy, mass spectrometry, and X-ray crystallography. Removal of the metal ions from the knot, followed by hydrogenation of the alkene, yielded the wholly organic trefoil knot. The metal-free knot and parent ligand were investigated by circular dichroism (CD) spectroscopy. The CD spectra indicate that the topological stereochemistry of the knot has a greater effect on the asymmetry of the chromophore environment than do the point-chiral centers of the strand

The role of lipid-modified proteins in cell wall synthesis and signaling

The plant cell wall is a complex and dynamic extracellular matrix. Plant primary cell walls are the first line of defense against pathogens and regulate cell expansion. Specialized cells deposit a secondary cell wall that provides support and permits water transport. The composition and organization of the cell wall varies between cell types and species, contributing to the extensibility, stiffness, and hydrophobicity required for its proper function. Recently, many of the proteins involved in the biosynthesis, maintenance, and remodeling of the cell wall have been identified as being post-translationally modified with lipids. These modifications exhibit diverse structures and attach to proteins at different sites, which defines the specific role played by each lipid modification. The introduction of relatively hydrophobic lipid moieties promotes the interaction of proteins with membranes and can act as sorting signals, allowing targeted delivery to the plasma membrane regions and secretion into the apoplast. Disruption of lipid modification results in aberrant deposition of cell wall components and defective cell wall remodeling in response to stresses, demonstrating the essential nature of these modifications. Although much is known about which proteins bear lipid modifications, many questions remain regarding the contribution of lipid-driven membrane domain localization and lipid heterogeneity to protein function in cell wall metabolism. In this update, we highlight the contribution of lipid modifications to proteins involved in the formation and maintenance of plant cell walls, with a focus on the addition of glycosylphosphatidylinositol anchors, N-myristoylation, prenylation, and S-acylation.</p

Computational methods for investigating organic radical species

Computational analysis of organic radical species presents significant challenges. This study compares the efficacy of various DFT and wavefunction methods in predicting radical stabilisation energies, bond dissociation energies, and redox potentials for organic radicals. The hybrid meta-GGA M062X-D3(0), and the range-separated hybrids ωB97M-V and ωB97M-D3(BJ) emerged as the most reliable functionals, consistently providing accurate predictions across different basis sets including 6-311G**, cc-pVTZ, and def2-TZVP.</p