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.

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.

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

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 6mg 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 40µm [range -3 to 89.5] (P=0.0007). 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.

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 double switch operation (DSO) after pulmonary arterial band (PAB) placement involves cardiac MRI (cMRI) to measure LV ejection fraction (EF) and mass and cardiac catheterization (cath) to assess LV:RV pressure ratio (LV:RVp). We described the relationships between echocardiographic and cath/cMRI measures of readiness for DSO, and developed risk factors for LV dysfunction after DSO based on echocardiographic measures of ventricular arterial coupling (VAC). METHODS: We reviewed patients with ccTGA undergoing LV retraining at a DSO referral center. We compared EF measured by echo to cMRI, and LV:RVp measured by echo to cath with Bland-Altman (BA) analysis. We analyzed the relationship between preoperative VAC markers and postoperative echocardiogram using end-systolic elastance (EES), and a novel marker consisting of the product of EF and the LV:RVp (EFPR). RESULTS: We included 31 patients with 56 evaluations for DSO, 24 of which underwent DSO. Echo EF correlated well with cMRI (r= 0.79), and BA slightly overestimated cMRI (mean difference +3%). Echo EF had moderate ability to identify normal cMRI EF (AUC of 0.80) and at optimal cutpoint of echo EF threshold of 61%, there was 71% sensitivity and 76% specificity to detect cMRI LVEF >=55%. Echo LV:RVp correlated well with cath (r=0.77) and slightly underestimated cath (mean difference of -0.11). Echo LV:RVp had good ability to identify adequate LV:RVp by cath (AUC=0.95) and at optimal echo cutpoint of 0.75 had 100% Sensitivity and 85% specificity to detect a catheterization LV:RVp above 0.9. Echo-based criteria for DSO readiness (echo EF 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 EF of 55% and cath LV:RVp of 0.9). EES and EFPR correlated with post DSO EF (rho= 0.72 and 0.60). EFPR of 0.51 demonstrated 78% sensitivity and 100% specificity for post DSO LV dysfunction (EF < 55%). Age at first PAB also strongly correlated with post DSO EF (rho=0.75). No patient with first PAB under age 1 years exhibited post DSO LV dysfunction. CONCLUSIONS: Echocardiographic measures of EF and LV:RVp are reliable indicators of reference standard modalities, and can guide management during retraining. Preoperative VAC markers EES and EFPR may be useful markers of post-DSO LV dysfunction. Echo LV:RVp > 0.75 are likely to meet pressure-generation criteria for DSO and should be considered for referral for cath and cMRI evaluation for DSO. PAB placement before 1 year of life may optimize LV outcomes in patients considered for DSO.

Durability of Aortic Homografts in Pulmonary Atresia and Major Aortopulmonary Collateral Arteries.

Objectives: It is well-known that right ventricle-to-pulmonary artery homograft conduit durability is worse for smaller conduits and smaller/younger patients. However, there is limited literature on age and conduit-size specific outcomes, or on the role of conduit oversizing. Methods: Patients diagnosed with tetralogy of Fallot and major aortopulmonary collateral arteries undergoing right ventricular outflow tract (RVOT) reconstruction with a valved aortic homograft conduit from November 2001 through March 2023, at our institution were included. Conduits were grouped and evaluated by diameter, diameter Z-score, and patient age at implant. The primary time-related outcome was freedom from RVOT reintervention. Factors associated with freedom from time-related outcomes were assessed with univariable Cox regression analysis. Results: A total of 863 RVOT conduits were implanted in 722 patients. On multivariable analysis, younger age, male sex, Alagille syndrome, smaller diameter of the conduit, and smaller Z-score were associated with shorter freedom from reintervention. Among patients with smaller diameter conduits, larger Z-scores were associated with longer freedom from conduit reintervention (P < .001). Transcatheter interventions were commonly used to extend conduit lifespan across ages and conduit sizes. Conclusions: Larger conduit diameter, older age, and higher conduit Z-score were associated with longer freedom from reintervention in patients undergoing RVOT reconstruction in this cohort. Oversizing of conduits, even beyond a Z-score of 4, is generally appropriate.

Integrative proteomics identifies a conserved Aß amyloid responsome, novel plaque proteins, and pathology modifiers in Alzheimer's disease.

Alzheimer's disease (AD) is a complex neurodegenerative disorder that develops over decades. AD brain proteomics reveals vast alterations in protein levels and numerous altered biologic pathways. Here, we compare AD brain proteome and network changes with the brain proteomes of amyloid ß (Aß)-depositing mice to identify conserved and divergent protein networks with the conserved networks identifying an Aß amyloid responsome. Proteins in the most conserved network (M42) accumulate in plaques, cerebrovascular amyloid (CAA), and/or dystrophic neuronal processes, and overexpression of two M42 proteins, midkine (Mdk) and pleiotrophin (PTN), increases the accumulation of Aß in plaques and CAA. M42 proteins bind amyloid fibrils in vitro, and MDK and PTN co-accumulate with cardiac transthyretin amyloid. M42 proteins appear intimately linked to amyloid deposition and can regulate amyloid deposition, suggesting that they are pathology modifiers and thus putative therapeutic targets. We posit that amyloid-scaffolded accumulation of numerous M42+ proteins is a central mechanism mediating downstream pathophysiology in AD.

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.

Cyclical Etidronate Reduces the Progression of Arterial Calcifications in Patients with Pseudoxanthoma Elasticum: A 6-Year Prospective Observational Study.

Background: Pseudoxanthoma elasticum (PXE), a rare genetic disorder presenting with slowly progressing calcification of various tissues, including the arteries, is caused by mutations in the ABCC6 gene that lead to the reduction of pyrophosphate, a natural inhibitor of calcification. We showed that, compared to a placebo, the cyclical administration of etidronate, a stable pyrophosphate analog, significantly reduced arterial calcification assessed by low-dose CT scans after one year. The aim of the present prospective, single center, observational cohort study was the assessment of the efficacy and safety of cyclical etidronate in patients treated for periods longer than one year. Methods: Seventy-three patients were followed for a median of 3.6 years without etidronate and 2.8 years with etidronate, and each patient served as their own control. Results: The median absolute yearly progression of total calcification volume during the period with etidronate (388 [83-838] µL) was significantly lower than that without etidronate (761 [362-1415] µL; p < 0.001). The rates of the relative progression of arterial calcification were 11.7% (95% CI: 9.6-13.9) without etidronate compared to 5.3% (95% CI: 3.7-7.0) with etidronate, after adjustment for confounders. Conclusions: The cyclical administration of etidronate for nearly 3 years significantly reduced the progression rate of arterial calcification in patients with PXE with pre-existing calcifications without any serious adverse effects.

Estimating uncertainty when providing individual cardiovascular risk predictions: a Bayesian survival analysis.

BACKGROUND: Cardiovascular disease (CVD) risk scores provide point estimates of individual risk without uncertainty quantification. The objective of the current study was to demonstrate the feasibility and clinical utility of calculating uncertainty surrounding individual CVD-risk predictions using Bayesian methods. STUDY DESIGN AND SETTING: Individuals with established atherosclerotic CVD were included from the Utrecht Cardiovascular Cohort-Secondary Manifestations of ARTerial disease (UCC-SMART). In 8,355 individuals, followed for median of 8.2 years (IQR 4.2-12.5), a Bayesian Weibull model was derived to predict the 10-year risk of recurrent CVD events. RESULTS: Model coefficients and individual predictions from the Bayesian model were very similar to that of a traditional ('frequentist') model but the Bayesian model also predicted 95% credible intervals (CIs) surrounding individual risk estimates. The median width of the individual 95%CrI was 5.3% (IQR 3.6-6.5) and 17% of the population had a 95%CrI width of 10% or greater. The uncertainty decreased with increasing sample size used for derivation of the model. Combining the Bayesian Weibull model with sampled hazard ratios based on trial reports may be used to estimate individual estimates of absolute risk reduction with uncertainty measures and the probability that a treatment option will result in a clinically relevant risk reduction. CONCLUSION: Estimating uncertainty surrounding individual CVD risk predictions using Bayesian methods is feasible. The uncertainty regarding individual risk predictions could have several applications in clinical practice, like the comparison of different treatment options or by calculating the probability of the individual risk being below a certain treatment threshold. However, as the individual uncertainty measures only reflect sampling error and no biases in risk prediction, physicians should be familiar with the interpretation before widespread clinical adaption.

Cryptococcosis Associated With Biologic Therapy: A Narrative Review.

Cryptococcus is an opportunistic fungal pathogen that can cause disseminated infection with predominant central nervous system involvement in patients with compromised immunity. Biologics are increasingly used in the treatment of neoplasms and autoimmune/inflammatory conditions and the prevention of transplant rejection, which may affect human defense mechanisms against cryptococcosis. In this review, we comprehensively investigate the association between cryptococcosis and various biologics, highlighting their risks of infection, clinical manifestations, and clinical outcomes. Clinicians should remain vigilant for the risk of cryptococcosis in patients receiving biologics that affect the Th1/macrophage activation pathways, such as tumor necrosis factor α antagonists, Bruton tyrosine kinase inhibitors, fingolimod, JAK/STAT inhibitors (Janus kinase/signal transducer and activator of transcription), and monoclonal antibody against CD52. Other risk factors-such as age, underlying condition, and concurrent immunosuppressants, especially corticosteroids-should also be taken into account during risk stratification.

Effects of Different Cow-Milk Beta-Caseins on the Gut-Brain Axis: A Narrative Review of Preclinical, Animal, and Human Studies.

The gut and brain communicate through bidirectional neural, endocrine, and immune signals to coordinate central nervous system activity with gastrointestinal function. Dysregulated inflammation can promote immune cell activation and increase entero-endocrine signaling and intestinal permeability; hence, a functional gut-brain axis is necessary for a healthy digestive system. The consumption of milk products can lead to gut discomfort via effects on gastrointestinal tract function and the inflammatory state, which, in turn, affect the brain. A1 ß-casein and A2 ß-casein are major components of bovine-milk protein, and their digestion may result in different physiological effects following the consumption of milk products. Peptides derived from A1 ß-casein, such as ß-casomorphins, may increase gut dysfunction and inflammation, thereby modulating the availability of bioactive metabolites in the bloodstream and contribute to changes in cognitive function. This narrative review examines the functional interrelationships between the consumption of cow-milk-derived ß-caseins and their effect on the brain, immune system, and the gut, which together comprise the gut-brain axis.

Policy Iteration-Based Learning Design for Linear Continuous-Time Systems Under Initial Stabilizing OPFB Policy.

Policy iteration (PI), an iterative method in reinforcement learning, has the merit of interactions with a little-known environment to learn a decision law through policy evaluation and improvement. However, the existing PI-based results for output-feedback (OPFB) continuous-time systems relied heavily on an initial stabilizing full state-feedback (FSFB) policy. It thus raises the question of violating the OPFB principle. This article addresses such a question and establishes the PI under an initial stabilizing OPFB policy. We prove that an off-policy Bellman equation can transform any OPFB policy into an FSFB policy. Based on this transformation property, we revise the traditional PI by appending an additional iteration, which turns out to be efficient in approximating the optimal control under the initial OPFB policy. We show the effectiveness of the proposed learning methods through theoretical analysis and a case study.