A pathogen effector co-opts a host RabGAP protein to remodel pathogen interface and subvert defense-related secretion.

Pathogens have evolved sophisticated mechanisms to manipulate host cell membrane dynamics, a crucial adaptation to survive in hostile environments shaped by innate immune responses. Plant-derived membrane interfaces, engulfing invasive hyphal projections of fungal and oomycete pathogens, are prominent junctures dictating infection outcomes. Understanding how pathogens transform these host-pathogen interfaces to their advantage remains a key biological question. Here, we identified a conserved effector, secreted by plant pathogenic oomycetes, that co-opts a host Rab GTPase-activating protein (RabGAP), TOPGAP, to remodel the host-pathogen interface. The effector, PiE354, hijacks TOPGAP as a susceptibility factor to usurp its GAP activity on Rab8a, a key Rab GTPase crucial for defense-related secretion. By hijacking TOPGAP, PiE354 purges Rab8a from the plasma membrane, diverting Rab8a-mediated immune trafficking away from the pathogen interface. This mechanism signifies an uncanny evolutionary adaptation of a pathogen effector in co-opting a host regulatory component to subvert defense-related secretion, thereby providing unprecedented mechanistic insights into the reprogramming of host membrane dynamics by pathogens.

A randomized trial of aerobic exercise in colorectal cancer: Rationale, design, recruitment, and exercise adherence results.

BACKGROUND: Physical activity is associated with improved disease-free survival in colorectal cancer survivors. This report describes the purpose, design, recruitment, and exercise adherence results of the National Cancer Institute (NCI)-sponsored Exercise and Colorectal Cancer Treatment (EXACT) trial. METHODS: The primary objective of the EXACT trial is to determine if randomization to 150 min per week of moderate-intensity aerobic exercise reduces systemic inflammation among stage I-III colorectal cancer survivors compared with a waitlist control group over 12 weeks. Participants were provided with an in-home treadmill and heart rate monitor. Characteristics associated with randomization were identified using χ2 or Fisher's exact test for categorical variables and t-tests or analysis of covariance (ANCOVA). Exercise adherence was calculated as the total minutes exercised by total minutes prescribed. RESULTS: Between August 2019 and February 2023, 3082 colorectal cancer survivors were invited to participate, 89 were screened, and 60 were randomized to the study protocol. Younger age (P = 0.02), female sex (P = 0.002), white race (P = 0.01), proximal time since tumor resection (P = 0.02), and regional tumor stage (P < 0.001) were associated with study participation. Average exercise adherence was 92.2 % (95 % CI: 85.5, 98.8) and all study participants achieved ≥80 % exercise adherence. Endpoint data collection was completed for all participants in May 2023. CONCLUSION: The results from the EXACT trial will characterize the changes that occur from exercise to advance our understanding of the biological mechanisms by which exercise may prevent tumor recurrence and death in colorectal cancer survivors.

From starvation to time-restricted eating: a review of fasting physiology.

We have long known that subjects with obesity who fast for several weeks survive. Calculations that assume the brain can only use glucose indicated that all carbohydrate and protein sources would be consumed by the brain within several weeks yet subjects with obesity who fasted for several weeks survived. This anomaly led to the determination of the metabolic role of ketone bodies. Subsequent studies transformed our understanding of ketone bodies and illustrated the value of challenging the norm and adapting theory to evidence. Although prolonged fasting is no longer a treatment for obesity, the early studies of starvation provided valuable insights about macronutrient metabolism and ketone body adaptations that fasting elicits. Intermittent fasting and its variants such as time-restricted eating are fasting models that are far less regimented than starvation and severe calorie restriction; yet they produce metabolic benefits. The mechanisms that produce the metabolic changes that intermittent fasting elicits are relatively unknown. In this article, we review the physiology of starvation, starvation adaptation diets, diet-induced ketosis, and intermittent fasting. Understanding the premise and physiology that these regimens induce is necessary to draw parallels and provoke thoughts on the mechanisms underlying the metabolic benefits of intermittent fasting and its variants.

Damping excessive viral-induced IFN-γ rescues the impaired anti-Aspergillus host immune response in influenza-associated pulmonary aspergillosis.

BACKGROUND: Influenza-associated pulmonary aspergillosis (IAPA) is a severe fungal superinfection in critically ill influenza patients that is of incompletely understood pathogenesis. Despite the use of contemporary therapies with antifungal and antivirals, mortality rates remain unacceptably high. We aimed to unravel the IAPA immunopathogenesis as a means to develop adjunctive immunomodulatory therapies. METHODS: We used a murine model of IAPA to investigate how influenza predisposes to the development of invasive pulmonary aspergillosis. Immunocompetent mice were challenged with an intranasal instillation of influenza on day 0 followed by an orotracheal inoculation with Aspergillus 4 days later. Mice were monitored daily for overall health status, lung pathology with micro-computed tomography (µCT) and fungal burden with bioluminescence imaging (BLI). At endpoint, high parameter immunophenotyping, spatial transcriptomics, histopathology, dynamic phagosome biogenesis assays with live imaging, immunofluorescence staining, specialized functional phagocytosis and killing assays were performed. FINDINGS: We uncovered an early exuberant influenza-induced interferon-gamma (IFN-γ) production as the major driver of immunopathology in IAPA and delineated the molecular mechanisms. Specifically, excessive IFN-γ production resulted in a defective Th17-immune response, depletion of macrophages, and impaired killing of Aspergillus conidia by macrophages due to the inhibition of NADPH oxidase-dependent activation of LC3-associated phagocytosis (LAP). Markedly, mice with partial or complete genetic ablation of IFN-γ had a restored Th17-immune response, LAP-dependent mechanism of killing and were fully protected from invasive fungal infection. INTERPRETATION: Together, these results identify exuberant viral induced IFN-γ production as a major driver of immune dysfunction in IAPA, paving the way to explore the use of excessive viral-induced IFN-γ as a biomarker and new immunotherapeutic target in IAPA. FUNDING: This research was funded by the Research Foundation Flanders (FWO), project funding under Grant G053121N to JW, SHB and GVV; G057721N, G0G4820N to GVV; 1506114 N to KL and GVV; KU Leuven internal funds (C24/17/061) to GVV, clinical research funding to JW, Research Foundation Flanders (FWO) aspirant mandate under Grant 1186121N/1186123 N to LS, 11B5520N to FS, 1SF2222N to EV and 11M6922N/11M6924N to SF, travel grants V428023N, K103723N, K217722N to LS. FLvdV was supported by a Vidi grant of the Netherlands Association for Scientific Research. FLvdV, JW, AC and GC were supported by the Europeans Union's Horizon 2020 research and innovation program under grant agreement no 847507 HDM-FUN. AC was also supported by the Fundação para a Ciência e a Tecnologia (FCT), with the references UIDB/50026/2020, UIDP/50026/2020, PTDC/MED-OUT/1112/2021 (https://doi.org/10.54499/PTDC/MED-OUT/1112/2021), and 2022.06674.PTDC (http://doi.org/10.54499/2022.06674.PTDC); and the "la Caixa" Foundation under the agreement LCF/PR/HR22/52420003 (MICROFUN).

Regulation of plasma soluble receptors of TNF and IL-1 in patients with COVID-19 differs from that observed in sepsis.

OBJECTIVES: IL-1α/ß and TNF are closely linked to the pathology of severe COVID-19 and sepsis. The soluble forms of their receptors, functioning as decoy receptors, exhibit inhibitory effects. However, little is known about their regulation in severe bacterial and viral infections, which we aimed to investigate in this study. METHODS: The circulating soluble receptors of TNF (sTNFR1 and sTNFR2) and IL-1α/ß (sIL-1R1, sIL-1R2) were evaluated in the plasma of patients with COVID-19, severe bacterial infections, and sepsis and compared with healthy controls. Additionally, IL1R1, IL1R2, TNFRSF1A, and TNFRSF1B expression was evaluated at the single cell level in PBMCs derived from COVID-19 or sepsis patients. RESULTS: Plasma concentrations of sIL-1R1, sTNFR1, and sTNFR2 were significantly higher in COVID-19 patients compared to healthy subjects. Notably, sIL-1R1 levels were particularly elevated in ICU COVID-19 patients, and transcriptome analysis indicated heightened IL1R1 expression in PBMCs from severe COVID-19 patients. In severe bacterial infections, only sTNFR1 and sTNFR2 exhibited increased levels compared to healthy controls. Sepsis patients had decreased sIL-1R1 plasma concentrations but elevated sIL-1R2, sTNFR1, and sTNFR2 levels compared to healthy individuals, reflecting the heightened expression due to the increased numbers of monocytes present in sepsis. Finally, elevated concentrations of sIL-1R2, sTNFR1, and sTNFR2 were moderately associated with reduced 28-day survival in sepsis patients. CONCLUSION: Our study reveals distinct regulation of plasma concentrations of soluble IL-1 receptors in COVID-19 and sepsis. Moreover, soluble TNF receptors 1 and 2 consistently rise in all conditions and show a positive correlation with disease severity in sepsis.

Testicular large B-cell lymphoma is genetically similar to PCNSL and distinct from nodal DLBCL.

Testicular large B-cell lymphoma (TLBCL) is an infrequent and aggressive lymphoma arising in an immune-privileged site and has recently been recognized as a distinct entity from diffuse large B-cell lymphoma (DLBCL). We describe the genetic features of TLBCL and compare them with published series of nodal DLBCL and primary large B-cell lymphomas of the CNS (PCNSL). We collected 61 patients with TLBCL. We performed targeted next-generation sequencing, copy number arrays, and fluorescent in situ hybridization to assess chromosomal rearrangements in 40 cases with available material. Seventy percent of the cases showed localized stages. BCL6 rearrangements were detected in 36% of cases, and no concomitant BCL2 and MYC rearrangements were found. TLBCL had fewer copy number alterations (p < 0.04) but more somatic variants (p < 0.02) than nodal DLBCL and had more frequent 18q21.32-q23 (BCL2) gains and 6q and 9p21.3 (CDKN2A/B) deletions. PIM1, MYD88 L265P , CD79B, TBL1XR1, MEF2B, CIITA, EP300, and ETV6 mutations were more frequent in TLBCL, and BCL10 mutations in nodal DLBCL. There were no major genetic differences between TLBCL and PCNSL. Localized or disseminated TLBCL displayed similar genomic profiles. Using LymphGen, the majority of cases were classified as MCD. However, we observed a subgroup of patients classified as BN2, both in localized and disseminated TLBCL, suggesting a degree of genetic heterogeneity in the TLBCL genetic profile. TLBCL has a distinctive genetic profile similar to PCNSL, supporting its recognition as a separate entity from DLBCL and might provide information to devise targeted therapeutic approaches.

Preventing Inappropriate Signals Pre- and Post-Ligand Perception by a Toggle-Switch Mechanism of ERECTA.

Dynamic control of signaling events requires swift regulation of receptors at an active state. By focusing on Arabidopsis ERECTA (ER) receptor kinase, which perceives peptide ligands to control multiple developmental processes, we report a mechanism preventing inappropriate receptor activity. The ER C-terminal tail (ER_CT) functions as an autoinhibitory domain: its removal confers higher kinase activity and hyperactivity during inflorescence and stomatal development. ER_CT is required for the binding of a receptor kinase inhibitor, BKI1, and two U-box E3 ligases PUB30 and PUB31 that inactivate activated ER. We further identify ER_CT as a phosphodomain transphosphorylated by the co-receptor BAK1. The phosphorylation impacts the tail structure, likely releasing from autoinhibition. The phosphonull version enhances BKI1 association, whereas the phosphomimetic version promotes PUB30/31 association. Thus, ER_CT acts as an off-on-off toggle switch, facilitating the release of BKI1 inhibition, enabling signal activation, and swiftly turning over the receptors afterwards. Our results elucidate a mechanism fine-tuning receptor signaling via a phosphoswitch module, keeping the receptor at a low basal state and ensuring the robust yet transient activation upon ligand perception.

Robust self-propulsion in sand using simply controlled vibrating cubes.

Much of the Earth and many surfaces of extraterrestrial bodies are composed of non-cohesive particulate matter. Locomoting on such granular terrain is challenging for common robotic devices, either wheeled or legged. In this work, we discover a robust alternative locomotion mechanism on granular media-generating movement via self-vibration. To demonstrate the effectiveness of this locomotion mechanism, we develop a cube-shaped robot with an embedded vibratory motor and conduct systematic experiments on granular terrains of various particle properties and slopes. We investigate how locomotion changes as a function of vibration frequency/intensity on such granular terrains. Compared to hard surfaces, we find such a vibratory locomotion mechanism enables the robot to move faster, and more stably on granular surfaces, facilitated by the interaction between the body and surrounding grains. We develop a numerical simulation of a vibrating single cube on granular media, enabling us to justify our hypothesis that the cube achieves locomotion through the oscillations excited at a distance from the cube's center of mass. The simplicity in structural design and controls of this robotic system indicates that vibratory locomotion can be a valuable alternative way to produce robust locomotion on granular terrains. We further demonstrate that such cube-shaped robots can be used as modular units for vibratory robots with capabilities of maneuverable forward and turning motions, showing potential practical scenarios for robotic systems.

Echocardiographic Predictors of Readiness for Double Switch Operation and Postoperative Ejection Fraction in Patients With Congenitally Corrected Transposition of the Great Arteries Undergoing Left Ventricular Retraining.

BACKGROUND: In patients with congenitally corrected transposition of the great arteries (ccTGA), assessment of readiness for the double switch operation (DSO) after pulmonary arterial band (PAB) placement involves cardiac magnetic resonance imaging (cMRI) to measure left ventricular ejection fraction (LVEF) and mass and cardiac catheterization (catheterization) to assess the ratio of left ventricular to right ventricular pressure (LV:RVp). The aims of this study were to describe the relationships between echocardiographic and catheterization and cMRI measures of readiness for DSO and to develop risk factors for left ventricular (LV) dysfunction after DSO on the basis of echocardiographic measures of ventricular-arterial coupling (VAC). METHODS: Patients with ccTGA undergoing LV retraining at a DSO referral center were reviewed. LVEF measured by echocardiography was compared with that measured by cMRI, and LV:RVp measured by echocardiography was compared with that measured by catheterization using Bland-Altman analysis. The relationship between preoperative VAC markers and postoperative echocardiography was analyzed using ventricular end-systolic elastance (EES) and a novel marker consisting of the product of LVEF and LV:RVp (EFPR). RESULTS: Thirty-one patients with 56 evaluations for DSO were included, 24 of whom underwent DSO. Echocardiographic LVEF correlated well with cMRI LVEF (r = 0.79), and Bland-Altman analysis slightly overestimated cMRI LVEF (mean difference, +3%). Echocardiographic LVEF had a moderate ability to identify normal cMRI LVEF (area under the curve, 0.80) and at an optimal cut point of echocardiographic LVEF threshold of 61%, there was 71% sensitivity and 76% specificity to detect cMRI LVEF ≥ 55%. Echocardiographic LV:RVp correlated well with LV/RVp by catheterization (r = 0.77) and slightly underestimated the catheterization value (mean difference, -0.11). Echocardiographic LV:RVp had a good ability to identify adequate LV:RVp by catheterization (area under the curve, 0.95) and at an optimal echocardiography cut point of 0.75 had 100% sensitivity and 85% specificity to detect a catheterization LV:RVp >0.9. Echocardiography-based criteria for DSO readiness (echocardiographic LVEF of 61% and LV:RVp of 0.75) demonstrated specificity of 97% and positive predictive value of 96% for published criteria of DSO readiness (cMRI LVEF of 55% and catheterization LV:RVp of 0.9). EES and EFPR correlated with post-DSO LVEF (ρ = 0.72 and ρ = 0.60, respectively). EFPR of 0.51 demonstrated 78% sensitivity and 100% specificity for post-DSO LV dysfunction (LVEF < 55%). Age at first PAB also strongly correlated with post-DSO LVEF (ρ = 0.75). No patient with first PAB at <1 year of age exhibited post-DSO LV dysfunction. CONCLUSIONS: Echocardiographic measures of LVEF and LV:RVp are reliable indicators of reference standard modalities and can guide management during retraining. The preoperative VAC markers EES and EFPR may be useful markers of post-DSO LV dysfunction. Values of echocardiographic LV:RVp >0.75 are likely to meet pressure-generation criteria for DSO and should be considered for referral to catheterization and cMRI evaluation for DSO. PAB placement before 1 year of life may optimize LV outcomes in patients considered for DSO.

Reinforcement Learning for Synchronization of Heterogeneous Multiagent Systems by Improved Q -Functions.

This article dedicates to investigating a methodology for enhancing adaptability to environmental changes of reinforcement learning (RL) techniques with data efficiency, by which a joint control protocol is learned using only data for multiagent systems (MASs). Thus, all followers are able to synchronize themselves with the leader and minimize their individual performance. To this end, an optimal synchronization problem of heterogeneous MASs is first formulated, and then an arbitration RL mechanism is developed for well addressing key challenges faced by the current RL techniques, that is, insufficient data and environmental changes. In the developed mechanism, an improved Q -function with an arbitration factor is designed for accommodating the fact that control protocols tend to be made by historic experiences and instinctive decision-making, such that the degree of control over agents' behaviors can be adaptively allocated by on-policy and off-policy RL techniques for the optimal multiagent synchronization problem. Finally, an arbitration RL algorithm with critic-only neural networks is proposed, and theoretical analysis and proofs of synchronization and performance optimality are provided. Simulation results verify the effectiveness of the proposed method.

Prediction of Severe Baseline Asymptomatic Carotid Stenosis and Subsequent Risk of Stroke and Cardiovascular Disease.

BACKGROUND: Risk models to identify patients at high risk of asymptomatic carotid artery stenosis (ACAS) can help in selecting patients for screening, but long-term outcomes in these patients are unknown. We assessed the diagnostic and prognostic value of the previously published Prevalence of ACAS (PACAS) risk model to detect ACAS at baseline and to predict subsequent risk of stroke and cardiovascular disease (CVD) during follow-up. METHODS: We validated the discrimination and calibration of the PACAS risk model to detect severe (≥70% narrowing) ACAS with patients from the Reduction of Atherothrombosis for Continued Health registry. We subsequently calculated the incidence rates of stroke and CVD (fatal and nonfatal stroke or myocardial infarction or vascular death) during follow-up in 4 risk groups (low, medium, high, and very high, corresponding to sum scores of ≤9, 10-13, 14-17, and ≥18, respectively). RESULTS: Among 26 384 patients, aged between 45 and 80 years, without prior carotid procedures, 1662 (6.3%) had severe baseline ACAS. During ≈70 000 patient-years of follow-up, 1124 strokes and 2484 CVD events occurred. Discrimination of the PACAS model was 0.67 (95% CI, 0.65-0.68), and calibration showed adequate concordance between predicted and observed risks of severe baseline ACAS after recalibration. Significantly higher incidence rates of stroke (Ptrend<0.011) and CVD (Ptrend<0.0001) during follow-up were found with increasing PACAS risk groups. Among patients with high PACAS sum score of ≥14 (corresponding to 27.7% of all patients), severe baseline ACAS prevalence was 11.4%. In addition, 56.6% of incident strokes and 64.9% of incident CVD events occurred in this group. CONCLUSIONS: The PACAS risk model can reliably identify patients at high risk of severe baseline ACAS. Incidence rates of stroke and CVD during follow-up were significantly higher in patients with high PACAS sum scores. Selective screening of patients with high PACAS sum scores may help to prevent future stroke or CVD.

Glucagon-like peptide-1 receptor agonist-based agents and weight loss composition: Filling the gaps.

Excess adiposity is at the root of type 2 diabetes (T2D). Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as first-line treatments for T2D based on significant weight loss results. The composition of weight loss using most diets consists of <25% fat-free mass (FFM) loss, with the remainder from fat stores. Higher amounts of weight loss (achieved with metabolic bariatric surgery) result in greater reductions in FFM. Our aim was to assess the impact that GLP-1RA-based treatments have on FFM. We analysed studies that reported changes in FFM with the following agents: exenatide, liraglutide, semaglutide, and the dual incretin receptor agonist tirzepatide. We performed an analysis of various weight loss interventions to provide a reference for expected changes in FFM. We evaluated studies using dual-energy X-ray absorptiometry (DXA) for measuring FFM (a crude surrogate for skeletal muscle). In evaluating the composition of weight loss, the percentage lost as fat-free mass (%FFML) was equal to ΔFFM/total weight change. The %FFML using GLP-1RA-based agents was between 20% and 40%. In the 28 clinical trials evaluated, the proportion of FFM loss was highly variable, but the majority reported %FFML exceeding 25%. Our review was limited to small substudies and the use of DXA, which does not measure skeletal muscle mass directly. Since FFM contains a variable amount of muscle (approximately 55%), this indirect measure may explain the heterogeneity in the data. Assessing quantity and quality of skeletal muscle using advanced imaging (magnetic resonance imaging) with functional testing will help fill the gaps in our current understanding.

Targeting the Tie-2 Receptor With Faricimab in Central Serous Chorioretinopathy: A Case Series Motivated by a Genetic Finding.

PURPOSE: To investigate the effects of faricimab, a bispecific antibody targeting VEGF and Ang-2 (thus increasing Tie-2 activity), in patients with CSC based on a recent genetic study that implicated Tie-2 signaling in CSC pathophysiology. DESIGN: A retrospective interventional multicenter case series. METHODS: We included patients with chronic CSC (persistent or recurrent SRF for ≥6 months) who received at least one faricimab 6 mg injection between January 1 2022, and April 1 2024,. Study sites included Massachusetts Eye and Ear and University of California San Francisco. Patients with evidence of a choroidal neovascular membrane on color photos, optical coherence tomography (OCT) and/or fluorescein angiography were excluded. 16 eyes (15 patients) met the inclusion criteria. The median central macular thickness at each visit from 52 weeks before to 52 weeks after the first faricimab injection was calculated using automated Heidelberg Spectralis ETDRS subfield measurements. RESULTS: Prior to treatment with faricimab, CSC had been diagnosed a median of 4.1 years (range 0.9-8) earlier and SRF (and intraretinal fluid [IRF] in a subset) had been continuously present for a median of 30 weeks (range 9-257). Decreases in macular thickness were observed in 14/16 eyes after the first faricimab injection and in 14/16 eyes in the full follow-up period compared with prior, 10 of which experienced complete resolution of SRF following the start of the first series of injections at a median of 4 weeks (range 2-25). One eye worsened after the second injection. The median improvement in macular thickness was 40 µm [range -3 to 89.5] (P = .0007). Upon review of OCT images, reductions in macular thickness were consistent with reductions in SRF and/or IRF. Visual acuity improved by 2 lines or more in 6/16 eyes. CONCLUSIONS: In a retrospective case series of patients with chronic CSC and longstanding SRF, we observed improvement in macular thickness after intravitreal faricimab. While the small number of patients and variable natural history of CSC preclude definitive conclusions, a randomized controlled trial seems warranted.

Addressing residual risk beyond statin therapy: New targets in the management of dyslipidaemias-A report from the European Society of Cardiology Cardiovascular Round Table.

Cardiovascular (CV) disease is the most common cause of death in Europe. Despite proven benefits, use of lipid-lowering therapy remains suboptimal. Treatment goals are often not achieved, even in patients at high risk with atherosclerotic CV disease (ASCVD). The occurrence of CV events in patients on lipid-lowering drugs is defined as "residual risk", and can result from inadequate control of plasma lipids or blood pressure, inflammation, diabetes, and environmental hazards. Assessment of CV risk factors and vascular imaging can aid in the evaluation and management decisions for individual patients. Lifestyle measures remain the primary intervention for lowering CV risk. Where drug therapies are required to reach lipid treatment targets, their effectiveness increases when they are combined with lifestyle measures delivered through formal programs. However, lipid drug dosage and poor adherence to treatment remain major obstacles to event-free survival. This article discusses guideline-supported treatment algorithms beyond statin therapy that can help reduce residual risk in specific patient profiles while also likely resulting in substantial healthcare savings through better patient management and treatment adherence.

Adding ethnicity to cardiovascular risk prediction: External validation and model updating of SCORE2 using data from the HELIUS population cohort.

BACKGROUND: Current prediction models for mainland Europe do not include ethnicity, despite ethnic disparities in cardiovascular disease (CVD) risk. SCORE2 performance was evaluated across the largest ethnic groups in the Netherlands and ethnic backgrounds were added to the model. METHODS: 11,614 participants, aged between 40 and 70 years without CVD, from the population-based multi-ethnic HELIUS study were included. Fine and Gray models were used to calculate sub-distribution hazard ratios (SHR) for South-Asian Surinamese, African Surinamese, Ghanaian, Turkish and Moroccan origin groups, representing their CVD risk relative to the Dutch group, on top of individual SCORE2 risk predictions. Model performance was evaluated by discrimination, calibration and net reclassification index (NRI). RESULTS: Overall, 274 fatal and non-fatal CVD events, and 146 non-cardiovascular deaths were observed during a median of 7.8 years follow-up (IQR 6.8-8.8). SHRs for CVD events were 1.86 (95 % CI 1.31-2.65) for the South-Asian Surinamese, 1.09 (95 % CI 0.76-1.56) for the African-Surinamese, 1.48 (95 % CI 0.94-2.31) for the Ghanaian, 1.63 (95 % CI 1.09-2.44) for the Turkish, and 0.67 (95 % CI 0.39-1.18) for the Moroccan origin groups. Adding ethnicity to SCORE2 yielded comparable calibration and discrimination [0.764 (95 % CI 0.735-0.792) vs. 0.769 (95 % CI 0.740-0.797)]. The NRI for adding ethnicity to SCORE2 was 0.24 (95 % CI 0.18-0.31) for events and - 0.12 (95 % CI -0.13-0.12) for non-events. CONCLUSIONS: Adding ethnicity to the SCORE2 risk prediction model in a middle-aged, multi-ethnic Dutch population did not improve overall discrimination but improved risk classification, potentially helping to address CVD disparities through timely treatment.

Course of the effects of LDL-cholesterol reduction on cardiovascular risk over time: A meta-analysis of 60 randomized controlled trials.

BACKGROUND AND AIMS: Individuals with or at high risk of cardiovascular disease (CVD) often receive long-term treatment with low-density lipoprotein cholesterol (LDL-C) lowering therapies, but whether the effects of LDL-C reduction remain stable over time is uncertain. This study aimed to establish the course of the effects of LDL-C reduction on cardiovascular risk over time. METHODS: Randomized controlled trials (RCTs) of LDL-C lowering therapies were identified through a search in MEDLINE and EMBASE (1966-January 2023). The primary analyses were restricted to statins, ezetimibe, and proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors, with other therapies included in sensitivity analyses. Random-effects meta-analyses were performed to establish the hazard ratio (HR) for major vascular events (cardiovascular death, myocardial infarction, unstable angina, coronary revascularization, or stroke) per 1 mmol/L LDL-C reduction. Course of the effects over time was assessed using random-effects meta-regression analyses for the association between follow-up duration, age, and the HR for major vascular events per 1 mmol/L LDL-C reduction. Additionally, treatment-by-time interactions were evaluated in an individual participant data meta-analysis of six atorvastatin trials. RESULTS: A total of 60 RCTs were identified (408,959 participants, 51,425 major vascular events). The HR for major vascular events per 1 mmol/L LDL-C reduction was 0.78 (95 % confidence interval [CI] 0.75-0.81). Follow-up duration was not associated with a change in the HR for major vascular events (HR for change per year 0.994; 95 % CI 0.970-1.020; p = 0.66). The HR attenuated with increasing age in primary prevention (HR for change per 5 years 1.097; 95 % CI 1.031-1.168; p = 0.003), but not secondary prevention (HR for change per 5 years 0.987; 95 % CI 0.936-1.040; p = 0.63). Consistent results were found for statin trials only, and all trials combined. In the individual participant data meta-analysis (31,310 participants, 6734 major vascular events), the HR for major vascular events did not significantly change over follow-up time (HR for change per year 0.983; 95 % CI 0.943-1.025; p = 0.42), or age (HR for change per 5 years 1.022; 95 % CI 0.990-1.055; p = 0.18). CONCLUSIONS: Based on available RCT data with limited follow-up duration, the relative treatment effects of LDL-C reduction are stable over time in secondary prevention, but may attenuate with higher age in primary prevention.

A critical literature review highlighting the methodological differences within epidemiological studies: Pedal Amputations in England.

INTRODUCTION: There is an absence in the application of standardised epidemiological principles when calculating and reporting on lower extremity amputation (LEA) rates [1]. The rates of minor LEAs in the diabetic population range from 1.2-362.9 per 100,000 and in the population without diabetes 0.9-109.4 per 100,000. The reported rates of major lower limb amputations vary from 5.6-600 per 100,000 in the diabetic population and 3.6-58.7 per 100,000 in the total population [1]. The variation in methodology does not facilitate comparison across populations and time. All studies published using the population from England, UK, describing minor amputations were systematically reviewed and rates and methodologies compared. METHOD: A systematic search was carried out using (PRISMA) guidelines [2] to reveal primary data of minor lower extremity amputation rates in England between 1988-2018. This was carried out using electronic databases, grey literature and reference list searching. The search yielded eleven studies that were eligible for review. RESULTS: Significant variation in the reporting of minor lower extremity amputation rates across regional and gender groups in England was found. Rates in the diabetic and non-diabetic population varied from 1.2 to 362.9 per 100,000 and 0.9 to 109.4 per 100,000 respectively. This was predominately a result of poorly describing numerator and denominator populations and defining minor amputations differently. As a result, there was an inability to confidently establish regional, gender and time trends. CONCLUSION: The inconsistent nature of reporting minor amputations makes drawing conclusions on temporal and population change difficult. Future studies should describe and present basic numerator and denominator population characteristics e.g. number, age and sex and use the standard definition of minor amputation as one that is at or below the ankle.

The Revalorization of Fishery By-Products: Types, Bioactive Compounds, and Food Applications.

Recently, fish consumption has been increasing; subsequently, the number of by-products has also increased. However, generated residues are frequently discarded, and an appropriate management is necessary to properly use all fish by-products. Fishery by-products are well known for their content of bioactive compounds, such as unsaturated fatty acids, amino acids, minerals, peptides, enzymes, gelatin, collagen, and chitin. Several studies have reported that fishery by-products could provide significant properties, including antioxidant, antihypertensive, antimicrobial, anti-inflammatory, and antiobesity. Consequently, fish discards are of considerable interest to different industrial sectors, including food, nutraceuticals, medical, and pharmacology. In the food industry, the interest in using fishery by-products is focused on hydrolysates as food additives, collagen and gelatin as protein sources, chitin and chitosan to form edible films to protect food during storage, and oils as a source of Omega-3 and useful as antioxidants. Although different studies reported good results with the use of these by-products, identifying new applications in the food sector, as well as industrial applications, remains necessary.