Residual Risk Research Articles

"Anti-inflammatory Therapies in Atherosclerosis - Where are we going?"

Inflammation has been commonly known for the past decade as a part of the pathophysiology of atherosclerosis, along with lipid accumulation. However, some patients with optimized lipid-lowering therapy still have elevated inflammatory biomarkers. Anti-inflammation therapies were developed to eradicate this residual risk. We summarized the primary inflammatory pathway and recent clinical trials in anti-inflammation therapies. Colchicine Cardiovascular Outcomes Trial (COLCOT) and LoDoCo2 (Colchicine Reduces Risk of Major Cardiovascular Events in Chronic Coronary Disease) found that low-dose colchicine significantly reduced cardiovascular death, myocardial infarction (MI), ischemic stroke and coronary revascularization in patients with recent MI within 30 days and chronic coronary disease respectively. The US Food and Drug Administration approved low-dose colchicine in 2023 for patients with established atherosclerotic cardiovascular disease (ASCVD). However, its use was limited for chronic kidney disease (CKD) patients. Reduction in Inflammation in Patients with Advanced Chronic Renal Disease Utilizing Antibody Mediated Interleukin-6 Inhibition (RESCUE) was conducted using Ziltivekimab, an IL-6 ligand monoclonal antibody and found that it significantly reduced high-sensitivity C-reactive protein, an inflammatory surrogate marker. There is an ongoing phase-3 clinical trial, Ziltivekimab Versus Placebo Cardiovascular Outcomes in Participants with Atherosclerotic Cardiovascular Disease, Chronic Kidney Disease, and Systemic Inflammation trial (ZEUS), which will be essential for further anti-inflammation therapy for patients with CKD. Numerous clinical trials have investigated anti-inflammation therapies. Colchicine is by far the only one that has the potential to be widely used due to its cost-effectiveness. Further research is needed on other novel anti-inflammation therapies and their real-world implementation.

Dynamic Residue Behavior and Risk Assessment of Thiamethoxam With Its Metabolite From Tea Production to Consumption

ABSTRACTThe entire fate of the widely used insecticide thiamethoxam from field cultivation, manufacturing to brewing were studied. A method to simultaneously detect thiamethoxam and its two metabolites, clothianidin and CGA265307, was developed. The field trial indicated a half‐life of thiamethoxam at 3.2 days on tea leaves, meanwhile, generation of clothianidin was observed with the maximum accumulation of 0.0152 mg/kg after 1 day of thiamethoxam application. The processing factors (PFs) during tea manufacturing ranged from 0.16 to 1.36 and 0.72 to 1.27 for thiamethoxam and clothianidin, respectively. Notably, PFs for thiamethoxam and clothianidin were higher during microwave deenzymed green tea manufacturing than pan deenzymed green tea and traditional black tea. Both thiamethoxam and clothianidin showed high infusion factors during tea brewing, whereas the risk quotient indicated an acceptable dietary risk of thiamethoxam with clothianidin through tea consumption. These findings could facilitate a more accurate assessment of safety risks and better protect the health of tea consumers.

Metabonomic Biomarkers of Plaque Burden and Instability in Patients With Coronary Atherosclerotic Disease After Moderate Lipid-Lowering Therapy.

Contemporary risk assessment in patients with coronary atherosclerotic disease (CAD) often relies on invasive angiography. However, we aimed to explore the potential of metabolomic biomarkers in reflecting residual risk in patients with CAD after moderate lipid-lowering therapy. We analyzed serum metabolomic profile among 2560 patients with newly diagnosed CAD undergoing moderate lipid-lowering therapy, through nuclear magnetic resonance spectroscopy and quantified 175 metabolites, predominantly lipoproteins and their components. CAD severity was evaluated using Gensini score for plaque burden and circulating cardiac troponin T levels for plaque instability. The association of metabolites with CAD severity was examined using multivariate linear regression, and the underlying potential causality was explored using a 2-sample Mendelian randomization approach. Two composite metabolomic indices were constructed to reflect CAD severity using least absolute shrinkage and selection operator linear regression, and their associations with risk of major adverse cardiac events during a median follow-up of 3.8 years were evaluated using Cox models. Our investigation revealed that triglycerides and apolipoprotein B in low-density lipoprotein particles displayed stronger associations with CAD severity compared with the clinically used low-density lipoprotein cholesterol marker. In large high-density lipoprotein, components like cholesterol, cholesterol esters, triglyceride, apolipoprotein A1/A2 showed inverse associations with CAD severity. Certain metabolites, including apolipoprotein B and dihydrothymine, showed a putative causal link with Gensini score. Notably, per standard deviation increase in Gensini score-based metabolomic index was associated with 14.8% higher major adverse cardiac event risk (hazard ratio, 1.148 [95% CI, 1.018-1.295]) independent of demographic factors, medication use, and disease status. Our findings highlight the potential of nuclear magnetic resonance-based metabolomics in identifying novel biomarkers of plaque burden and instability. Metabolites related to plaque burden may facilitate noninvasive assessment of CAD prognosis.

Environmental Fate and Sustainable Management of Pesticides in Soils: A Critical Review Focusing on Sustainable Agriculture

Pesticides are inevitable agrochemicals employed as plant protection agents and their application follows good agricultural practice (GAP). Although pesticides are primarily used for plant protection purposes, the residual pesticides may pose a threat to the next crops and/or off-target biota. Another important aspect of applied pesticides is the transformation into toxic metabolites. As a result, misuse or overuse of pesticides can lead to raised residual uncertainty, hidden risk of transformed metabolites, and potential risk to off-target biota. As per pesticide safety guidelines, regulations for the maximum limit of residual pesticides, addressing toxic metabolites derived from parent pesticides, and managing the potential risk of pesticides for off-targets are considered vital components. Despite the countable number of studies that have already been published on pesticide fate, residual risk, and metabolism in soils and plants, several vital research gaps remain untouched. In this study, the vital research gap of pesticide fate and transport is explored through vital keyword searches, followed by sorting of relevant articles using scholarly search engines. According to the study outcomes, residual uncertainty, secondary pollution, diversified fate and transport, and toxic metabolites, including their persistence, were detected as key research pitfalls. Thus, this paper critically addresses the current trends and research gaps and suggests specific recommendations for pesticide fate and potential risk studies.

The Effectiveness of Operational Residual Risk Assessment: The Case of General Aviation Organizations in Enhancing Flight Safety in Alignment with Sustainability

Operational risk management (ORM) is crucial for every aviation organization. The assessment of operational risk (OR) is a critical area of study, as organizations must continuously evaluate and mitigate potential risks to maintain high levels of performance and safety. The motivation for writing this paper was to address the cognitive gap identified through literature analysis. The aim of this paper is to assess the effectiveness of operational residual risk assessment in general aviation (GA) organizations, with a specific focus on its role within the decision-making process to enhance flight safety in line with sustainability. By addressing a cognitive gap identified in the literature, this study seeks to determine whether current risk management practices adequately assess and mitigate residual risks, especially in organizations where operational risk is inherently high. Based on a literature review, the authors present adopted concepts of ORM and OR. The survey methodology involved a questionnaire on OR assessment, consisting of 32 questions completed by respondents twice—before and after 63 series of flights. The survey was carried out across two groups with significantly varying levels of flying experience (students and instructor pilots), with a particular focus on the influence of human factors. The conclusions are based on a comparative analysis of the difference in the results obtained after and before the series of flights in both surveyed groups. The survey was conducted in three selected general aviation organizations in Poland using nonprobability convenience sampling. The results demonstrate an overall significant underestimation of OR in both student and instructor groups. Therefore, it can be concluded that operational risk assessment in the selected organizations was not sufficiently effective. Additionally, it was shown that staff experience affected the effectiveness of OR assessment. Moreover, this study identified specific aspects of operational risk that were most underestimated. By addressing the cognitive gap, this study enhances both the theoretical and practical understanding of residual risk management, particularly in relation to safety and efficient resource use in aviation. It also offers the Operational Residual Risk Underestimation Index (ORRUI) as an actionable parameter developed to quantify and standardize the level of underestimation of operational residual risks in civil aviation.

Variation in Lipoprotein(a) Response to Potent Lipid Lowering: The Role of Apolipoprotein (a) Isoform size

BackgroundLipoprotein(a) [Lp(a)] is a driver of residual cardiovascular risk. Proprotein Convertase Subtilisin/Kexin Type 9 inhibitors (PCSK9i) decrease Lp(a) with significant heterogeneity in response. We investigated contributors to the heterogeneous response. MethodsCHOlesterol Reduction and Residual Risk in Diabetes (CHORD) was a prospective study examining lipid lowering in participants with an LDL-C >100 mg/dl with and without diabetes (DM) on lipid lowering therapy (LLT) for 30-days with evolocumab 140 mg every 14 days combined with either atorvastatin 80 mg or ezetimibe 10 mg daily. Lp(a) level was measured by immunoturbidometry, and the apolipoprotein a [apo(a)] isoform size was measured by denaturing agarose gel electrophoresis and western blotting. We examined the change in Lp(a) levels from baseline to 30 days. ResultsAmong 150 participants (mean age 50 years, 58% female, 50% non-White, 17% Hispanic, 50% diabetes), median (IQR) Lp(a) was 27.5 (8-75) mg/dL at baseline and 23 (3-68) mg/dL at 30 days, leading to a 10% (0-36) median reduction (P<0.001). Among 73 (49%) participants with Lp(a) ≥30 mg/dL at baseline, there was a 15% (3-25) median reduction in Lp(a) (P<0.001). While baseline Lp(a) level was not correlated with change in Lp(a) (r=0.04, P=0.59), apo(a) size directly correlated with Lp(a) reduction (P<0.001). After adjustment for age, sex, race/ethnicity, DM, and type of LLT, apo(a) size remained positively associated with a reduction in Lp(a) (Beta 0.95, 95%CI, 0.93-0.97, p<0.001). ConclusionOur data demonstrate variation in Lp(a) reduction with potent LLT. Change in Lp(a) was strongly associated with apo(a) isoform size.

Cerium-based nanohydrolase for fast catalytic hydrolysis of β-lactam antibiotics in wastewater effluents

To defuse risks of antibiotic residues in effluent to achieve safe wastewater reuse, direct hydrolysis of the functional group responsible for the antibacterial activity, such as the of β-lactam ring in β-lactam antibiotics, has been recognized as an efficient and cost-effective strategy. However, the instability of natural hydrolases limits their use in treating antibiotic-containing wastewater. Herein, inspired by the active site of natural hydrolase, a Ce-based nanohydrolase was created for rapid hydrolysis of β-lactam antibiotics. The typical β-lactam antibiotic, penicillin G (PG), could be totally removed by the nanohydrolase within 2min with a hydrolysis efficiency of 44%, and the hydrolysis efficiency could reach 98% within 10min. It revealed that Ce(IV) in the nanohydrolase adsorbed PG via Lewis acid-Lewis base interaction to activate the β-lactam ring, while the -OH on Ce(III) served as nucleophile to attack the β-lactam ring, thereby promoting the hydrolysis of PG. The Ce-based nanohydrolase also showed good catalytic hydrolysis performance towards other commonly used β-lactam antibiotics and structurally related chemicals, implying its substrate universality. In addition to having high hydrolytic activity similar to that of natural hydrolases, this nanohydrolase exhibited extraordinary reusability and potential for practical applications that natural hydrolases do not possess. This work offers an innovative strategy to eliminate the risks of hydrolysable micropollutants in wastewater effluents and also provides reference for designing better nanohydrolase.

Children’s orthopaedics

The December 2024 Children’s orthopaedics Roundup360 looks at: Establishing best practice for managing idiopathic toe walking in children: a UK consensus; Long-term outcomes of below-elbow casting in paediatric diaphyseal forearm fractures; Residual dysplasia risk persists in developmental dysplasia of the hip patients after Pavlik harness treatment; 3D printing in paediatricorthopaedics: enhancing surgical efficiency and patient outcomes; Pavlik harness treatment for hip dysplasia does not delay motor skill development in children; High prevalence of hip dysplasia found in adolescents with idiopathic scoliosis on routine spine radiographs; Minifragment plates as effective growth modulation for ulnar deformities of the distal radius in children; Long-term success of Chiari pelvic osteotomy in preserving hip function: 30-year follow-up study.

Residue analysis and risk assessment of cyflumetofen and its three metabolites from fresh tea leaf to tea infusion through purification with new nano adsorbents and determination by ultra-performance liquid chromatography-tandem mass spectrometry

Residue analysis and risk assessment of cyflumetofen and its three metabolites from fresh tea leaf to tea infusion through purification with new nano adsorbents and determination by ultra-performance liquid chromatography-tandem mass spectrometry

Atherogenic low-density lipoprotein and cardiovascular risk.

Despite reductions in low-density lipoprotein (LDL) cholesterol (LDLc), residual cardiovascular risk remains due to factors beyond lipoprotein levels, such as LDL particle count, size, electronegativity and modifications. Technological advances allow detailed profiling of LDL particles, offering potential biomarkers for diagnosis, prognosis, and treatment of cardiovascular disease (CVD). The aim of this review is to provide an updated overview of the state of knowledge in the field of LDL atherosclerotic role, which is evolving rapidly due to technological advances in biomarker measurement and applications. While small dense LDL has been linked to increased CVD risk, current approaches favor a comprehensive evaluation of all lipoprotein subtypes, as this is a more feasible and standardized method. The atherogenic potential of circulating oxidized LDL (oxLDL) may be the key factor in the onset and progression of atherosclerosis. Thus, elevated oxLDL levels are recognized as a marker of increased CVD risk in both general and high-risk populations, although further research is needed to clarify some conflicting findings. The oxidized LDL receptor 1 (LOX-1) has emerged as a promising target for immunotherapy and innovative drug delivery strategies to modulate atherosclerosis. A panel of biomarkers related to LDL atherogenicity may help predict future ischemic events. An atheroprotective diet and increased physical activity could improve LDL oxidation. OxLDL has become a target for immunomodulatory antiatherosclerosis therapy and delivering LDL-based nanocarriers holds promise for both imaging and therapeutics.

Implementasi Job Hazard Analysis (JHA) pada Pekerjaan Distribusi Air Minum di PT. XYZ

Drinking water distribution work at PT. XYZ as a supporting part of the construction industry, involves a series of processes that have the potential to be dangerous and have high risks for workers. To ensure worker safety and health, identifying potential hazards and risks is important. The Job Hazard Analysis (JHA) method is an effective solution for carrying out this identification. This study aims to carry out the process of identifying potential hazards and risks and their control in the work of delivering drinking water supplies at PT. XYZ, using the JHA method. This approach allows systematic analysis of each step of the work, so that potential hazards can be clearly identified and the level of risk can be evaluated in depth. The results of the JHA analysis can be used as a basis for formulating effective control strategies to prevent accidents and injuries in the work environment. Based on the study results, the level of risk obtained at each stage of work before implementing controls varies but ranges between H12 or M9. After implementing risk control the residual risk value obtained is reduced to range between L2 to M6. The lowest residual risk value, namely L2, was obtained for the danger of negligence when checking vehicle oil from the previous value of M9 and the highest residual risk value of M6 was obtained for the danger of slippery floors when washing the vehicle from the previous risk value of M9.

Human dimensions of climate change adaptation: Gaps and knowledge frontiers

Adaptation science has grown exponentially in the past two decades and has progressed conceptually. However, these advances remain siloed from adaptation practice. In this commentary, I make three arguments: (1) adaptation theory has grown but is often unfit-for-practical-purpose; (2) disciplines and methodologies to study adaptation remain conservative, and poorly understand adaptation limits and residual risks; and (3) behaviour change as a critical lever of individual and societal adaptation remains understudied. By charting the landscape of knowledge gaps, I suggest frontiers for adaptation researchers to focus on.

MASLD, At-Risk MASH and Increased Liver Stiffness Are Associated With Young Adulthood Obesity Without Residual Risk After Losing Obesity.

Obesity can result in persistent metabolic changes despite weight loss, which may affect liver health. We aimed to investigate associations between young adulthood obesity and metabolic dysfunction-associated steatotic liver disease (MASLD), at-risk steatohepatitis and increased liver stiffness measurement (LSM) in a general population setting. We studied NHANES 2017-2020 community-dwelling participants aged > 40 years with BMI ≥ 18.5 and no heart failure. Weight at age 25 was obtained through questionnaires and compared to current weight. Assessment included controlled attenuation parameter (CAP) and LSM. Associations between obesity status change with MASLD or at-risk metabolic dysfunction-associated steatohepatitis (MASH) and increased LSM were investigated and adjusted for demographics and metabolic health. The cohort comprised 4,580 participants (57% stable non-obesity, 33% gained obesity, 2% lost obesity and 8% stable obesity). Compared to stable no-obesity, stable obesity was strongly associated with MASLD (odds ratio [OR]: 5.47, 95% confidence interval [95%CI]: 3.97-7.66) as was gained obesity (OR: 4.68, 95% CI: 3.93-5.59), whereas no increased risk was demonstrated for lost obesity (OR: 1.26, 95% CI: 0.76-2.10). Similar associations for stable obesity and gained obesity with at-risk MASH and LSM ≥ 8 kPa were demonstrated. No residual risk was found for lost obesity (MASH-OR: 1.05 95% CI: 0.36-2.49; LSM ≥ 8 kPa-OR: 0.85, 95% CI: 0.29-1.97). Results were consistent in sensitivity analysis where obesity change was calculated over the past 10 years and weight change was stratified in normal weight/overweight/obesity. Young adulthood obesity is an important risk factor for MASLD, at-risk MASH and increased LSM among the general population aged 40-80 years. Losing obesity resulted in normalisation of odds for MASLD, at-risk MASH and increased LSM. These findings underline the importance of preventing and treating young adulthood obesity to maintain liver health.

The impact of initial vascular morphology on outcomes in patients with intracranial vertebral artery dissection presenting with isolated headache.

The prognosis of isolated headache intracranial vertebral artery dissection (iVAD) without subarachnoid hemorrhage (SAH) or stroke is unknown. The authors of this study aimed to evaluate isolated headache iVAD prognosis. This is a single-center retrospective study of consecutive patients who presented with headache as their main complaint and underwent MRI between November 2016 and August 2022; those with acute isolated headache iVAD who were followed up for vascular morphological stability were eligible for study inclusion. The patients were divided into three groups based on the vascular morphology at initial diagnosis: aneurysm dilatation without stenosis (group 1), aneurysm dilatation with stenosis (group 2), and no aneurysm dilatation (group 3). Prognosis, time to radiological stability, and final vascular morphology were compared among the groups. One hundred five patients with isolated headache iVAD were included in the study. During a median follow-up of 478 (IQR 143-1094) days, none of the patients developed SAH or stroke, but 3/41 (7%) patients in group 1 underwent endovascular intervention for aneurysm enlargement. Patients in group 1 required significantly more long-term follow-up for morphological stability (p = 0.013), primarily due to aneurysm enlargement (p < 0.001), and were more likely to require surgical intervention (p = 0.043) than those in the other two groups. Residual aneurysm risk was significantly associated with initial vascular morphology in group 1 (OR 7.28, 95% CI 2.30-23.1, p < 0.001). Most patients with isolated headache iVAD had a favorable prognosis. However, patients with aneurysm dilatation without stenosis required the most careful follow-up, as this group had the highest aneurysm enlargement risk from early disease onset through the chronic phase. In such cases, patients may require surgical intervention to prevent critical conditions.

Attenuation of Hypertension and protection of vascular inflammation in hyperaldosteronism: GPER1 as potential therapeutic candidate when MR antagonist is less satisfying?

Hyperaldosteronism is an endocrine disorder leading to persistent and severe hypertension. G protein-coupled estrogen receptor 1(GPER1) is regarded as a potential receptor of aldosterone (ALDO). This study aimed to investigate the effects of GPER1 on aldosterone (ALDO)-induced hypertension and inflammation in mice. GPER1-knockout (KO) and wild-type (WT) C57BL/6j mice were divided into control (CON, normal saline treatment), ALDO (subcutaneous injections of 600 g/kg/d ALDO), and ALDO + eplerenone (EPL) (subcutaneous injections of 600 g/kg/d ALDO and 100 mg/kg/d EPL) groups (n = 5 per group). Fourteen days after drug administration, the heart rate and tail blood pressure of the mice in the different groups were measured. S100A8 and IL-1β protein expression in arterial tissues were detected by western blotting, NLRP3 expression was assessed using immunofluorescence, and CD68 expression was investigated using immunohistochemistry. GPER1 deficiency alleviated ALDO-induced diastolic blood pressure (P< 0.05). In addition, the protein expression levels of IL-1β, S100A8, and CD68 showed significant decreases in the arterial tissues of GPER1-KO mice after combination treatment with ALDO and EPL (all P < 0.05). We discovered attenuation of hypertension and vascular inflammation of GPER1 KO mice only on the basis of mineralocorticoid receptor (MR) blocking. Collectively, our study indicates that GPER1 might become a therapeutic target of hyperaldosteronism in controlling the residual risk of cardiovascular disease when MR antagonist alone is not satisfying.

Anonymize or synthesize? Privacy-preserving methods for heart failure score analytics

Abstract Aims Data availability remains a critical challenge in modern, data-driven medical research. Due to the sensitive nature of patient health records, they are rightfully subject to stringent privacy protection measures. One way to overcome these restrictions is to preserve patient privacy by using anonymization and synthetization strategies. In this work, we investigate the effectiveness of these methods for protecting patient privacy using real-world cardiology health records. Methods and results We implemented anonymization and synthetization techniques for a structure data set, which was collected during the HiGHmed Use Case Cardiology study. We employed the data anonymization tool ARX and the data synthetization framework ASyH individually and in combination. We evaluated the utility and shortcomings of the different approaches by statistical analyses and privacy risk assessments. Data utility was assessed by computing two heart failure risk scores on the protected data sets. We observed only minimal deviations to scores from the original data set. Additionally, we performed a re-identification risk analysis and found only minor residual risks for common types of privacy threats. Conclusion We could demonstrate that anonymization and synthetization methods protect privacy while retaining data utility for heart failure risk assessment. Both approaches and a combination thereof introduce only minimal deviations from the original data set over all features. While data synthesis techniques produce any number of new records, data anonymization techniques offer more formal privacy guarantees. Consequently, data synthesis on anonymized data further enhances privacy protection with little impacting data utility. We share all generated data sets with the scientific community through a use and access agreement.

Effect of Body Size on Plasma and Tissue Pharmacokinetics of Danofloxacin in Rainbow Trout (Oncorhynchus mykiss).

Danofloxacin is a fluoroquinolone antibiotic approved for use in fish. It can be used for bacterial infections in fish of all body sizes. However, physiological differences in fish depending on size may change the pharmacokinetics of danofloxacin and therefore its therapeutic efficacy. In this study, the change in the pharmacokinetics of danofloxacin in rainbow trout of various body sizes was revealed for the first time. The objective of this investigation was to compare the plasma and tissue pharmacokinetics of danofloxacin in rainbow trout of different body sizes. The study was conducted at 14 ± 0.5 °C in fish of small, medium, and large body size and danofloxacin was administered orally at a dose of 10 mg/kg. Concentrations of this antimicrobial in tissues and plasma were quantified by high performance liquid chromatography with ultraviolet detector. The plasma elimination half-life (t1/2ʎz), volume of distribution (Vdarea/F), total clearance (CL/F), peak concentration (Cmax), and area under the plasma concentration-time curve (AUC0-last) were 27.42 h, 4.65 L/kg, 0.12 L/h/kg, 2.53 µg/mL, and 82.46 h·µg/mL, respectively. Plasma t1/2ʎz, AUC0-last and Cmax increased concomitantly with trout growth, whereas CL/F and Vdarea/F decreased. Concentrations in liver, kidney, and muscle tissues were higher than in plasma. Cmax and AUC0-last were significantly higher in large sizes compared to small and medium sizes in all tissues. The scaling factor in small, medium, and large fish was 1.0 for bacteria with MIC thresholds of 0.57, 0.79, and 1.01 µg/mL, respectively. These results show that therapeutic efficacy increases with body size. However, since increases in danofloxacin concentration in tissues of large fish may affect withdrawal time, attention should be paid to the risk of tissue residue.

Detailed Lipid Profiles and Lipid-related Residual Risk after 12-week 10 mg Rosuvastatin Treatment for Acute Myocardial Infarction.

Objective We aimed to reveal detailed on-treatment lipid profiles, lipid-related surrogate markers, and factors predicting failure to achieve the guideline-recommended lipid management goal following guideline-recommended statin treatment in Japanese patients with acute myocardial infarction (AMI). Methods and Results Sixty AMI patients who underwent coronary intervention and had received rosuvastatin 10 mg/day since the start of their hospitalization were assessed for on-treatment lipid-related profiles, including high-sensitivity C-reactive protein, small dense low-density lipoprotein cholesterol (sd LDL-C), and lipoprotein (a), at the 12-week follow-up. Patients who failed to achieve the guideline-recommended lipid management at 12 weeks were defined as the "unachieved group." Univariate and multivariate logistic regression analyses were performed to evaluate the predictors of inclusion in the unachieved group after high-dose statin treatment. Despite the use of high-dose rosuvastatin, 61.7% of the enrolled AMI patients were included in the unachieved group. In addition, the unachieved group had higher sd LDL-C and lipoprotein (a) levels than the achieved group. Logistic regression analyses demonstrated that low baseline high-density lipoprotein cholesterol (HDL-C) levels and the absence of diabetes were predictors of inclusion in the unachieved group. Conclusion More than half of the Japanese AMI patients treated with rosuvastatin 10 mg/day did not achieve the guideline-recommended goal of lipid management and still had lipid-related residual risk at 12 weeks. Particular attention should be paid to patients with low baseline HDL-C levels and those without diabetes with regard to their on-treatment lipid profiles.

Abstract 4134911: Coronary Artery Calcium Predicts Cardiovascular Events in Individuals with Controlled Atherosclerotic Risk Factors: A Multi-Cohort Study

Background: There is residual risk of atherosclerotic cardiovascular disease (ASCVD) that remains despite adequate risk factor (RF) control. Coronary artery calcium (CAC) has demonstrated value in ASCVD risk stratification. We evaluated the value of CAC in identifying residual risk of ASCVD events among those with traditional RF control. Methods: Participants without clinical ASCVD were pooled from the Multi-Ethnic Study of Atherosclerosis, Heinz Nixdorf Recall Study, Framingham Heart Study, and Jackson Heart Study. RF control was classified as “guideline-concordant” and “optimal” (Figure 1). Participants were stratified by the number of controlled RFs at baseline and CAC score (CAC = 0, 1-99, ≥100). Cox proportional hazards models examined the association between CAC and incident ASCVD events. Results: The study included 14,780 individuals (mean age 58 years (SD: 11), 54% female, 59% White, 27% Black, 50% CAC = 0). Over a median follow-up of 14.6 years, there were 1,441 incident ASCVD events. The distribution of CAC and ASCVD event incidence is shown in Panel A; 10% of those with 3 optimal RFs and 19% of those with 3 guideline-concordant RFs controlled had CAC &gt; 100. The rate of ASCVD events decreased with more RFs controlled and increased with higher CAC. Overall, optimal RF control was associated with lower ASCVD event rates compared to guideline-concordant control. At every level of RF control, CAC &gt; 100 was associated with increased HRs for incident ASCVD (Panel B). Those with CAC ≥ 100 and controlled RFs experienced ASCVD rates numerically comparable to or exceeding those with uncontrolled RFs but CAC = 0 (Panel A). Adjusted HR (95% CI) for ASCVD events with CAC &gt; 100 compared to CAC = 0 was 5.0 (2.0, 12.9) in optimal RF control and 3.7 (2.6, 5.4) in guideline-concordant RF control. Conclusion: There is significant heterogeneity in residual ASCVD risk among those with optimal or guideline-concordant traditional RF control and CAC can help identify this risk. Irrespective of RF control, a higher CAC burden was associated with increased ASCVD risk. Future studies could use CAC testing to identify those with higher residual ASCVD risk despite effective traditional RF control to target for novel therapies.

Abstract 4115645: NLRP3 Inflammasome Inhibition With Dapansutrile in Type 2 Diabetes and Elevated Systemic Inflammation: Rationale and Design of the DAPAN-DIA study

Background: Monoclonal antibodies against IL-1β decrease inflammation, improve insulin secretion and glycaemia, and reduce residual CV risk, but must be injected and are associated with higher incidence of fatal infection. There remains an unmet need for an oral treatment for T2D patients at risk for cardiometabolic complications to safely reduce IL-1β-mediated inflammation chronically&amp;with low risk of immunosuppression. In an initial dose-range finding study in heart failure patients with T2D, we reported evidence of anti-hyperglycaemic efficacy and improvement in LVEF with dapansutrile an oral specific inhibitor of the NLRP3 inflammasome. Objectives: To investigate the potential of preventing the transition to organ complications, The EU funded consortium INTERCEPT-T2D in collaboration with US based biotech Olatec Therapeutics has launched a clinical trial of anti-inflammatory therapy with dapansutrile targeting T2D patients with low-grade inflammation. Methods: Dapansutrile in Diabetes and Complications (DAPAN-DIA, NCT06047262) aims to determine whether NLRP3 inhibition with dapansutrile has the potential to not only improve glycaemia but also reduce micro- and macro-vascular risk and complications from diabetes. DAPAN-DIA is a multicenter, pbo-controlled, prospective, randomized, double-blind trial conducted in Switzerland, France, Belgium and Germany. A total of 300 patients with T2D, HbA1c &gt;7.5% and hsCRP&gt;1.5 mg/L are being randomized to either dapansutrile 1000 mg BID or matching PBO tablets for 6 months (2:1 ratio dapansutrile: pbo). The primary endpoint is change from baseline HbA1c. Secondary endpoints include biomarkers associated with diabetic complications, progression of MASLD as well as chronic inflammation (IL-1 β, IL-6 and hsCRP). A subject-assessed QoL questionnaire is also collected. To detect an absolute difference of 0.5% in HbA1c between groups, approximately 300 subjects will be randomized 2:1 ratio to achieve 80% power, assuming a standard deviation of 1.2% in change from baseline in HbA1c at week 26. Results: The trial has launched and currently is enrolling subjects. Conclusions: DAPAN-DIA is the first placebo-controlled, adequately powered, large, multi-center study with an oral NLRP3-specific Inhibitor, dapansutrile. The trial will generate important data on a new clinically relevant dimension in T2D care where consideration at diagnosis of inflammatory parameters are of importance for the transition to T2D-related complications.