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Familial hypercholesterolemia (FH) is the most common monogenic disorder. Due to the marked elevation of cardiovascular risk, the early detection, diagnosis, and proper management of this disorder are critical. Herein, the 2022 Korean guidance on this disease is presented. Clinical features include severely elevated low-density lipoprotein cholesterol (LDL-C) levels, tendon xanthomas, and premature coronary artery disease. Clinical diagnostic criteria include clinical findings, family history, or pathogenic mutations in the LDLR, APOB, or PCSK9. Proper suspicion of individuals with typical characteristics is essential for screening. Cascade screening is known to be the most efficient diagnostic approach. Early initiation of lipid-lowering therapy and the control of other risk factors are important. The first-line pharmacological treatment is statins, followed by ezetimibe, and PCSK9 inhibitors as required. The ideal treatment targets are 50% reduction and < 70 or < 55 mg/dL (in the presence of vascular disease) of LDL-C, although less strict targets are frequently used. Homozygous FH is characterized by untreated LDL-C > 500 mg/dL, xanthoma since childhood, and family history. In children, the diagnosis is made with criteria, including items largely similar to those of adults. In women, lipid-lowering agents need to be discontinued before conception.

Aims Familial hypercholesterolemia (FH) is currently a worldwide health issue. Understanding the characteristics of patients is important for proper diagnosis and treatment. This study aimed to analyze the phenotypic and genetic features, including threshold cholesterol levels, of Korean patients with FH. Methods A total of 296 patients enrolled in the Korean FH registry were included, according to the following criteria: low-density lipoprotein-cholesterol (LDL-C) ＞190 mg/dL with tendon xanthoma or family history compatible with FH, or LDL-C ＞225 mg/dL. DNA sequences of three FH-associated genes were obtained using whole-exome or target exome sequencing. Threshold cholesterol levels for differentiating patients with FH/pathogenic variant (PV) carriers and predictors of PVs were identified. Results Of the 296 patients, 104 had PVs and showed more obvious clinical findings, including higher cholesterol levels. PV rates ranged from 30% to 64% when patients were categorized by possible or definite type according to the Simon Broome criteria. Frequent PV types included missense variants and copy number variations (CNVs), while the most frequent location of PVs was p.P685L in LDLR. The threshold LDL-C levels for patient differentiation and PV prediction were 177 and 225 mg/dL, respectively. Younger age, tendon xanthoma, and higher LDL-C levels were identified as independent predictors of PVs, while traditional cardiovascular risk factors were predictors of coronary artery disease. Conclusions Korean patients with FH had variable PV rates depending on diagnostic criteria and distinctive PV locations. The reported threshold LDL-C levels pave the way for efficient patient care in this population.

Aims Mismatches between the risk status of a patient and coronary imaging data can lead to conflicting strategies to prevent a cardiovascular event. We evaluated whether statin use was associated with cardiovascular benefit in high-risk individuals whose coronary computed tomography angiography (CCTA) results showed normal coronary arteries. Methods Among asymptomatic individuals whose CCTA showed normal or near normal coronary arteries, 3,389 persons with high- or very-high-risk status were included in this retrospective study. After 1:2 propensity score matching, 906 individuals (302 new statin users and 604 controls; mean age 61 years; male 58%) were analysed. The primary outcome variable was major adverse cardiovascular and cerebrovascular events (MACCEs) that consisted of cardiovascular death, nonfatal myocardial infarction, coronary revascularisation, and nonfatal ischemic stroke. Results At a median follow-up of 5.8 years, 20 statin users and 17 controls (7.4 and 5.6 events/1,000 person-year, respectively; hazard ratio [HR) 1.04; p=0.92) experienced MACCE. Kaplan-Meier curves showed similar MACCE rates in both groups (p=0.91). In separate analyses for persons with normal (p=0.29) or near normal coronary arteries (p=0.67), MACCE rates did not differ between the groups. Age (HR 1.04; p=0.044), male sex (HR 3.06, p=0.018), and smoking (HR 2.87, p=0.019) were independently associated with MACCEs. In subgroup analyses, no significant factors affected the relationship between statin use and MACCEs. Conclusions Statin use was not associated with cardiovascular risk reduction in high-risk persons with normal or near normal coronary arteries. More individualised lipid-lowering therapy may benefit this population.

Protein phase separation in biological systems has captured the attention of scientists in the last decade; however, the main mechanism underlying protein phase separation in cells remains unclear. Biologists, physicists, and chemists have all tried to understand this important biological phenomenon, each using their own unique techniques and language. Each subject has its advantages in explaining protein phase separation; however, in this study, we find that the chemical language of molecular structure is the key to explaining the mechanism underlying protein phase separation. Using fluroescence microscopy and molecular dynamics, this study identifies small multivalently charged biomolecules, such as nucleoside triphosphate (negatively charged) and polyamine (positively charged), as important drivers of phase separation of highly charged proteins in cells.

Although there are many genetic loci in noncoding regions associated with vascular disease, studies on long noncoding RNAs (lncRNAs) discovered from human plaques that affect atherosclerosis have been highly limited. We aimed to identify and functionally validate a lncRNA using human atherosclerotic plaques. Human aortic samples were obtained from patients who underwent aortic surgery, and tissues were classified according to atherosclerotic plaques. RNA was extracted and analyzed for differentially expressed lncRNAs in plaques. Human aortic smooth muscle cells (HASMCs) were stimulated with oxidized low-density lipoprotein (oxLDL) to evaluate the effect of the identified lncRNA on the inflammatory transition of the cells. Among 380 RNAs differentially expressed between the plaque and control tissues, lncRNA HSPA7 was selected and confirmed to show upregulated expression upon oxLDL treatment. HSPA7 knockdown inhibited the migration of HASMCs and the secretion and expression of IL-1β and IL-6; however, HSPA7 knockdown recovered the oxLDL-induced reduction in the expression of contractile markers. Although miR-223 inhibition promoted the activity of Nf-κB and the secretion of inflammatory proteins such as IL-1β and IL-6, HSPA7 knockdown diminished these effects. The effects of miR-223 inhibition and HSPA7 knockdown were also found in THP-1 cell-derived macrophages. The impact of HSPA7 on miR-223 was mediated in an AGO2-dependent manner. HSPA7 is differentially increased in human atheroma and promotes the inflammatory transition of vascular smooth muscle cells by sponging miR-223. For the first time, this study elucidated the molecular mechanism of action of HSPA7, a lncRNA of previously unknown function, in humans., Atherosclerosis: Identifying noncoding RNA effect A long non-coding RNA (lncRNA) called HSPA7 promotes the development of atherosclerosis, plaque in arteries. Many atherosclerosis-related genetic loci are in noncoding regions of genome, but there has been an incomplete understanding of them. Sang-Hak Lee at Yonsei University College of Medicine, Seoul, South Korea, and co-workers set out to identify a lncRNA involved in atherosclerosis and investigate its mode of action. Comparison of aortic tissues allowed them to identify lncRNAs more abundant in atherosclerotic tissue but less in healthy tissue. Of the 380 lncRNAs identified, only HSPA7 reliably increased when aortic cells were treated with a trigger of atherosclerosis. Inhibiting HSPA7 restored normal function in vascular cells, decreasing migration and inflammation. Further investigation showed that HSPA7 blocks the activity of miR-223, a microRNA that suppresses inflammation. These results identify a potential therapeutic target for atherosclerosis.

PURPOSE Residual cardiovascular risk reduction by fenofibrate in patients with high serum triglyceride (TG) levels despite previous statin monotherapy is not well characterized. The purpose of this study was to evaluate the efficacy and safety of a combination of choline fenofibrate and statin in patients with inadequately controlled TG levels despite previous statin monotherapy. METHODS This prospective, multicenter, randomized, double-blind study was conducted in Korea. A total of 133 patients with controlled LDL-C but elevated TG levels, already receiving statin monotherapy, were enrolled in the study, which was conducted from July 2018 to December 2019. Patients were randomly assigned to receive combination therapy with choline fenofibrate and statin or statin monotherapy in a 1:1 ratio. After 8 weeks of treatment, the lipid profiles and safety parameters of the patients in the 2 groups were compared. FINDINGS The study included 127 patients (64 in the combination group and 63 in the control group) older than 19 years. After 8 weeks of therapy, mean serum TG levels significantly decreased from 269.8 to 145.5 mg/dL (P < 0.0001) in the combination therapy group, whereas no significant changes occurred in the statin monotherapy group (from 271.1 to 280.5 mg/dL). Contrarily, the mean serum HDLC levels significantly increased from 45.0 to 50.4 mg/dL (P = 0.0004) in the combination therapy group, whereas there were no significant changes in the monotherapy group (from 44.3 to 44.7 mg/dL). There were no additional serious adverse events in the combination therapy group compared with the statin monotherapy group. IMPLICATIONS The combination therapy using choline fenofibrate and statin was found to be effective in serum TG control and likely tolerable in patients with high TG levels despite statin monotherapy. A larger study, conducted for a longer duration, is needed to evaluate the effectiveness of this combination in reducing cardiovascular risk. ClinicalTrials.gov identifier: NCT03874260.

Background This study aimed to assess the efficacy of tranexamic acid (TXA) mixed in a periarticular multimodal cocktail (PAMC) as a topical administration and to determine whether combined use of intravenous and topical administration is more effective than a single administration of TXA. Methods A total of 240 patients who underwent primary total knee arthroplasty (TKA) was enrolled for this prospective randomized controlled study. Patients were divided into three groups of 80 patients each. Baseline data were comparable for all groups. Average follow-up was 18.7 months. Group 1 consisted of patients who received intravenous (IV) TXA, Group 2 patients were those who received TXA in a PAMC injection for topical administration, and Group 3 consisted of patients who received a combination of both intravenous and topical administration of TXA. Primary outcomes were postoperative hemoglobin drop and amount of suction drainage. Secondary outcomes were estimated blood loss (EBL), postoperative transfusion rate, and complications. Results The mean postoperative hemoglobin drop was significantly lower in Group 3 (2.13 ± 0.77 g/dL, p=0.004), and there was no difference between Group 1 and Group 2 (2.56 ± 1.07 g/dL vs 2.55 ± 0.86 g/dL, p=0.999). The mean drainage amount was significantly lower in Group 3 (326.58 ± 57.55 ml, p Conclusion TXA mixed in a PAMC injection showed a similar effect to IV administration of TXA following TKA. Furthermore, combined use of both IV and PAMC injection provided better perioperative bleeding control with similar safety in patients without relevant comorbidities. Trial registration WHO ICTRP identifier KCT0005703. Retrospectively registered: 12/24/2020

Sacubitril/valsartan is superior to enalapril in reducing the risks of cardiovascular death and preventing hospitalization in patients with heart failure and reduced ejection fraction (HFrEF). However, patients often do not receive sacubitril/valsartan because of concerns about hypotension. We examined the feasibility of initiating sacubitril/valsartan at a very low dose (VLD) in potentially intolerant patients with HFrEF and subsequent dose up-titration, treatment persistence and outcomes. We analyzed 206 patients with HFrEF grouped according to starting sacubitril/valsartan dose. The VLD group (n = 106) commenced 25 mg twice daily, and the standard-dose (SD) group (n = 100) started on ≥ 50 mg twice daily. Baseline systolic blood pressure was 103 ± 12 mmHg vs. 119 ± 14 mmHg in the SD group (P

Background: Although biomechanical and clinical studies have reported adverse effects on the patellofemoral joint after medial open-wedge high tibial osteotomy (MOWHTO), there is a paucity of literature that describes outcomes longer than midterm follow-up. Purpose: We aimed to evaluate the mid- to long-term radiologic and clinical outcomes of the patellofemoral joint after MOWHTO and to assess whether radiologic deterioration of the patellofemoral joint affected clinical outcomes or survivorship after MOWHTO. Study Design: Case series; Level of evidence, 4. Methods: We retrospectively reviewed 170 knees that underwent MOWHTO and had a minimum 5-year follow-up. In radiologic evaluation, serial postoperative changes in the patellofemoral joint compared with the preoperative status were evaluated on the Merchant view according to the Kellgren-Lawrence grade. The American Knee Society (AKS) score, Knee injury and Osteoarthritis Outcome Score (KOOS), Kujala score, incidence of anterior knee pain, and survivorship were used to assess clinical outcomes. Using radiologic assessment of the patellofemoral joint, we divided the patients into a radiologic progression group and a radiologic nonprogression group to evaluate whether radiologic progression of patellofemoral arthritis affected long-term clinical outcomes and survivorship after MOWHTO. Results: The mean follow-up period was 96.3 months (range, 60-163 months). Arthritic progression of the patellofemoral joint on the Merchant view was observed in 44.9%, 56.3%, 66.0%, and 84.0% of the cases at 5, 7, 9, and 11 years, respectively. Clinical outcomes such as AKS scores and KOOS significantly improved after MOWHTO ( P < .001) at the latest follow-up. The incidence of anterior knee pain was 5.3% (9/170 knees). One knee (0.6%) underwent conversion to TKA due to progressive medial osteoarthritis, so the survival rate was 99.4% at a mean follow-up of 96.3 months. Despite patellofemoral degeneration over time, there were no significant differences in clinical outcomes or survivorship between patients with and without radiologic progression at the latest follow-up. Conclusion: Although degeneration of the patellofemoral joint was observed with time after MOWHTO, the related symptoms were minimal and arthritic changes in the patellofemoral joint did not affect the clinical outcomes or survivorship after MOWHTO over a mid- to long-term follow-up.

Genetic and medical insights from studies on cardioprotective phenotypes aid the development of novel therapeutics. This study identified genetic variants associated with supernormal coronary arteries using genome-wide association study data and the corresponding genes based on expression quantitative trait loci (eQTL).Study participants were selected from two Korean cohorts according to inclusion criteria that included males with high cardiovascular risk (Framingham risk score ≥ 14, 10-year risk ≥ 16%) but with normal coronary arteries (supernormal group) or coronary artery disease (control group). After screening 12,309 individuals, males meeting the supernormal phenotype (n=72) and age-matched controls (n=94) were enrolled. Genetic variants associated with the supernormal phenotype were identified using Firth's logistic regression, and eQTL was used to evaluate whether the identified variants influence the expression of particular genes in human tissues.Approximately 5 million autosomal variants were tested for association with the supernormal phenotype, and 10 independent loci suggestive of supernormal coronary arteries (p＜5.0 ×10This study identified genetic variants and eQTL genes associated with supernormal coronary arteries. These results suggest candidate genes representing potential therapeutic targets for coronary artery disease.

We found that electron attachment to the van der Waals complex (O2···CO2) turns the weak intermolecular bond into a pseudochemical bond of significant strength. The resulting monomeric molecular anion (O2-CO2)- may be a form of CO4-, the gaseous anionic species suspected to be present in Earth's ionosphere whose chemical characteristics have not been comprehensively identified since its existence was first predicted by Conway in 1962. The measured vertical detachment energy of CO4- is very large (4.56 ± 0.05 eV), while the known electron affinity of its component species is much smaller (0.448 eV, O2) or even negative (-0.6 eV, CO2). These characteristics are correctly borne out by theoretical calculations that show that electron attachment transforms the van der Waals complex to a single contiguous molecular anion, with the formation of a pseudochemical bond between O2 and CO2 through an extended π-orbital system.

Single-molecule localization has been a helpful tool to identify the position of a single-molecule emitter. Capturing a single fluorophore with the camera pinpoints the molecule with great precision (∼1 nm), which is the main concept of single-molecule localization. Hence, we devised an optical system to demonstrate the light diffraction of materials with 2D as well as helical structures. Our optical configuration determined the positions of diffracted spots with a precision of several hundred nanometers (∼200–300 nm). This demonstration is very useful to elucidate the concept of light diffraction and single-molecule localization to undergraduate-level and high school students in physical chemistry or physics laboratories.

Given the immense challenge of excessive accumulation of carbon dioxide (CO2) in the earth's atmosphere, an extensive search is under way to convert atmospheric CO2 to compounds of more utility. With CO2 being thermodynamically extremely stable, activation of CO2 is the first and most important step toward its chemical conversion. Building upon our earlier model for the anionic activation of CO2 with azabenzene and inspired by the work of others on metal atom-CO2 complexes, we investigated the possibility of anionic activation of CO2 on small anionic metal clusters, which would have implications for catalytic conversion of CO2 on metal surfaces with atomic-scale structural irregularities. We carried out theoretical calculations using density functional theory to examine small anionic metal clusters of Cu, Ag, and Au to check whether they form a complex with CO2, with the sign of CO2 being chemically activated. We found that a class of anionic metal clusters Mn- with 1, 2, and 6 atoms consistently produced the activated complex (Mn-CO2)- for all three metals. There exists a strong interaction between the CO2 moiety and Mn- via a partially covalent M-C bond with a full delocalization of the electronic charge, as a result of electron transfer from the HOMO of Mn- to the LUMO of CO2 as in metal-CO2 π-backbonding. We examined the interaction of frontier orbitals from the viewpoints of the orbital geometry and orbital energetics and found that the above magic numbers are consistent with both aspects.

To determine the risk factors for lateral meniscus and root tears in patients with acute anterior cruciate ligament (ACL) injuries. A total of 226 patients undergoing acute ACL reconstruction were included in the study sample. Exclusion criteria were revisions, fractures, chronic cases, and multiple ligament injuries, with the exception of medial collateral ligament (MCL) injuries. The patients were divided into groups based on the presence of lateral meniscus and root tears by arthroscopy. Binary logistic regression was used to analyze risk factors including age, sex, body mass index (BMI), injury mechanism (contact/non-contact), Segond fracture, side-to-side laxity, location of bone contusion, medial and lateral tibial and meniscal slope, mechanical axis angle, and grade of pivot shift. Overall lateral meniscus (LM) tears were identified in 97 patients (42.9%), and LM root tears were found in 22 patients (9.7%). The risk of an LM tear in ACL-injured knees increased with bone contusion on LTP (odds ratio [OR], 3.5; 95% confidence interval [CI] 1.419–8.634; P = 0.007), steeper lateral tibial slope (OR, 1.133; 95% CI 1.003–1.28; P = 0.045), MCL injury (OR, 2.618; 95% CI 1.444–4.746; P = 0.002), and non-contact injury mechanism (OR, 3.132; 95% CI 1.446–6.785; P = 0.004) in logistic regression analysis. The risk of LM root tear in ACL-injured knees increased with high-grade pivot shift (OR, 9.127; 95% CI 2.821–29.525; P = 0.000) and steeper lateral tibial slope (OR, 1.293; 95% CI 1.061–1.576; P = 0.011). The increased risk of LM lesions in acute ACL-injured knees should be considered if significant risk factors including bone contusion on lateral compartments, MCL injury, and a steeper lateral tibial slope are present. Moreover, high-grade rotational injury with steeper lateral tibial slope are also significant risk factors for LM root tears, and therefore care should be taken by clinicians not to miss such lesions. III.

Nitrogen-containing polycyclic aromatic hydrocarbon (PAH) is the single basic moiety in N-doped graphene, the only metal-free catalyst reported to date to successfully produce the oxygen reduction reaction. N-doped graphene is quite promising as a material to increase the efficiency of oxygen reduction. In addition, it is known that when carbon dioxide is added to aza-benzene, there will be an associative chemical reaction upon electron attachment between the anionic nitrogen atoms in the aza-benzene and the carbon atom in the carbon dioxide; however, it has previously been reported that when there are more nitrogen atoms in the small aza-benzene moiety, the associative reaction does not always occur. In this study, we carried out a theoretical simulation to determine whether more electrons increase the CO2 reductive reactivity of the aza-naphthalene as a model system of a nitrogen-containing polycyclic aromatic hydrocarbon. We found that even though an associative chemical reaction between nitrogen atoms in the N-PAH and carbon atoms in carbon dioxide did not occur in anionic complexes of aza-naphthalene and carbon dioxide, chemical reactions did occur in all the nitrogen atoms of these complexes when we added an extra excess electron. Therefore, we conclude that the efficiency of CO2 reduction will be increased in nitrogen atoms when more electrons are added to increase their anionic properties.

Background No previous studies have compared the position and size of the remaining discoid lateral meniscus (DLM) with that of a normal lateral meniscus. This study aimed to evaluate the postoperative position and size of DLM compared with that of normal controls using magnetic resonance imaging (MRI). Methods This retrospective study involved 52 symptomatic complete type DLMs (discoid group) who underwent arthroscopic surgery and 50 normal controls (control group). Pre- and postoperative MRI evaluations, height, width, and relative percentage of extrusion (RPE) were assessed. Sagittal position parameters, including distances from articular cartilage center to anterior meniscus (CAMD) and from anterior articular cartilage margin to anterior horn (ACMD), were also assessed. Logistic regression analysis was performed to find factors with extrusion of remaining DLM. Results The height of the discoid group was significantly lower than that of the control group (P = 0.000). RPE in the discoid group was significantly larger than in the control group (P = 0.005). Only CAMD and ACMD in the discoid group were different (positioned more anteriorly) from the control group (P = 0.000). Preoperative meniscal shift (odds ratio (OR): 12.448; P = 0.003) and operative technique, especially partial meniscectomy with repair (OR: 19.125; P = 0.000), were the major factors associated with extrusion. Conclusion The width of remaining DLM was comparable to that of normal controls, but the position was found to be more anterior and lateral than that of normal controls. Preoperative meniscal shift and combined meniscus repair were the major factors for smaller width and greater extrusion; thus, surgeons should address and counsel these factors before surgery.

Background The factors affecting cardioprotective collateral circulation are still incompletely understood. Recently, characteristics, such as CpG methylation of cell-free DNA (cfDNA), have been reported as markers with clinical utility. The aim of this study was to evaluate whether cfDNA methylation patterns are associated with the grade of coronary collateral circulation (CCC). Result In this case–control study, clinical and angiographic data were obtained from 143 patients (mean age, 58 years, male 71%) with chronic total coronary occlusion. Enzymatic methyl-sequencing (EM-seq) libraries were prepared using the cfDNA extracted from the plasma. Data were processed to obtain the average methylation fraction (AMF) tables of genomic regions from which blacklisted regions were removed. Unsupervised analysis of the obtained AMF values showed that some of the changes in methylation were due to CCC. Through random forest preparation process, 256 differentially methylated region (DMR) candidates showing strong association with CCC were selected. A random forest classifier was then constructed, and the area under the curve of the receiver operating characteristic curve indicated an appropriate predictive function for CCC. Finally, 20 DMRs were identified to have significantly different AMF values between the good and poor CCC groups. Particularly, the good CCC group exhibited hypomethylated DMRs. Pathway analysis revealed five pathways, including TGF-beta signaling, to be associated with good CCC. Conclusion These data have demonstrated that differential hypomethylation was identified in dozens of cfDNA regions in patients with good CCC. Our results support the clinical utility of noninvasively obtained epigenetic signatures for predicting collateral circulation in patients with vascular diseases.

Some individuals exhibit discrepancies between risk classifications assessed using clinical factors and those obtained by vascular imaging. We aimed to evaluate whether statins provide clinical outcome benefits in patients classified as having low to moderate cardiovascular risk but with carotid plaque.This was a retrospective propensity score matching study. A total of 12,158 consecutive patients undergoing carotid ultrasound between January 2012 to February 2020 were screened. Individuals with low to moderate cardiovascular risk who were not currently recommended for statin therapy but had carotid plaques were included. Among 1,611 enrolled individuals, 806 (statin group: 403, control group: 403) were analyzed. The primary outcomes were major adverse cardiovascular and cerebrovascular events (MACCEs: cardiovascular death, myocardial infarction, coronary revascularization, and ischemic stroke or transient ischemic attack) and all-cause mortality.During the median follow-up of 6.0 years, the incidence of MACCEs did not differ between the groups (6.1 and 5.7/1,000 person-years in the control and statin groups, respectively; adjusted hazard ratio [HR], 0.95; p=0.90). The incidence of all-cause mortality did not differ (3.9 and 3.9/1,000 person-years, respectively; adjusted HR, 1.02; p=0.97). Kaplan-Meier curves revealed similar rates of MACCEs (log-rank p=0.72) and all-cause mortality (log-rank p=0.99) in the 2 groups. Age and smoking were independent predictors of MACCEs. Subgroups exhibited no differences in clinical outcomes with statin use.Benefit of statin therapy was likely to be limited in low to moderate risk patients with carotid plaques. These results could guide physicians in clinical decision-making regarding cardiovascular prevention.