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Increased risk of coronary artery disease (CAD) in familial hypercholesterolaemia (FH) is modified by factors beyond defects in the low-density lipoprotein receptor pathway. The rs1250229-T single nucleotide polymorphism (SNP) in the FN1 gene is associated with CAD in genome-wide association studies and is in linkage disequilibrium with another SNP (rs1250259-T) in FN1 that is associated with decrease fibronectin secretion.We investigated whether rs1250229-T was also associated with prevalent CAD in patients with genetically confirmed FH.We collected clinical data from 256 patients with genetically confirmed FH. The FN1 rs1250229 SNP was genotyped on a SEQUENOM platform. The association between rs1250229-T and prevalent CAD was assessed using simple and multiple regression analyses.In patients with FH, the FN1 rs1250229-T (minor) allele was a significant negative predictor of prevalent CAD (odds ratio [OR] 0.353; 95% confidence interval [CI] 0.193 - 0.647; P = 0.001). FN1 rs1250229-T remained a significant predictor of prevalent CAD after adjusting for age, sex, obesity, hypertension, smoking status and lipoprotein(a) concentration (OR 0.200; 95% CI 0.091 - 0.441; P 0.001).The FN1 rs1250229-T allele is inversely associated with CAD in patients with genetically confirmed FH, independently of traditional risk factors. While this finding requires replication, it suggests that the biology of fibronectin may contribute to variation in the risk of CAD in FH.

This study aimed to investigate the performance of handmade tri-leaflet expanded polytetrafluoroethylene (ePTFE) conduits in the absence of a suitable homograft.Patients who underwent right ventricular outflow tract reconstruction with tri-leaflet ePTFE conduits or homografts between December 2016 and August 2020 were included. The primary endpoint was the incidence of moderate or severe conduit stenosis (≥ 36 mmHg) and/or moderate or severe insufficiency. The secondary endpoint was the incidence of severe conduit stenosis (≥ 64 mmHg) and/or severe insufficiency.There were 102 patients in the ePTFE group and 52 patients in the homograft group. The median age was younger [34.5 (interquartile range: 20.8-62.8) vs. 60.0 (interquartile range: 39.3-81.0) months, P = 0.001] and the median weight was lower [13.5 (10.0-19.0) vs. 17.8 (13.6-25.8) kg, P = 0.003] in the ePTFE group. The conduit size was smaller (17.9 ± 2.2 vs. 20.5 ± 3.0 mm, P 0.001) and the conduit Z score was lower (1.48 ± 1.04 vs. 1.83 ± 1.05, P = 0.048) in the ePTFE group. There was no significant difference in the primary endpoints (log rank, P = 0.33) and secondary endpoints (log rank, P = 0.35). Multivariate analysis identified lower weight at surgery [P = 0.01; hazard ratio: 0.75; 95% confidence interval (CI) 0.59-0.94] and homograft conduit use (P = 0.04; hazard ratio: 8.43; 95% CI 1.14-62.29) to be risk factors for moderate or severe conduit insufficiency. No risk factors were found for moderate or severe conduit stenosis or conduit dysfunction on multivariate analysis.Handmade tri-leaflet ePTFE conduits showed acceptable early and midterm outcomes in the absence of a suitable homograft, but a longer follow-up is needed.

Extrachromosomal circular DNA (eccDNA) refers to a type of circular DNA that originate from but are likely independent of chromosomes. Due to technological advancements, eccDNAs have recently emerged as multifunctional molecules with numerous characteristics. The unique topological structure and genetic characteristics of eccDNAs shed new light on the monitoring, early diagnosis, treatment, and prediction of cancer. EccDNAs are commonly observed in both normal and cancer cells and function via different mechanisms in the stress response to exogenous and endogenous stimuli, aging, and carcinogenesis and in drug resistance during cancer treatment. The structural diversity of eccDNAs contributes to the function and numerical diversity of eccDNAs and thereby endows eccDNAs with powerful roles in evolution and in cancer initiation and progression by driving genetic plasticity and heterogeneity from extrachromosomal sites, which has been an ignored function in evolution in recent decades. EccDNAs show great potential in cancer, and we summarize the features, biogenesis, evaluated functions, functional mechanisms, related methods, and clinical utility of eccDNAs with a focus on their role in evolution and cancer.

BackgroundGiant cell tumors of the mobile spine invasion of the adjacent vertebrae are an ignored imaging finding.MethodsNine patients with giant cell tumors of the mobile spine with invasion of the adjacent vertebrae confirmed by pathology were enrolled. Eight patients had pure giant cell tumors (GCTs), while one patient also had an aneurysmal bone cyst. All patients underwent conventional computed tomography, three-dimensional reconstruction, and conventional magnetic resonance imaging, while seven patients also underwent post-contrast magnetic resonance imaging.ResultsAll patients showed GCTs of the mobile spine that arose from the vertebral body and extended to the vertebral arch. The tumors showed soft-tissue attenuation with no evidence of a mineralized matrix. Pathological fracture was seen in five patients. The margin of the original tumor showed partial sclerosis in four patients and involved an adjacent vertebral body with a sclerotic rim in two patients. The tumors showed a homogeneous and similar signal intensity to the normal spinal cord on T1WI (T1-weighted image) in five patients. The cystic area of the tumors was hyperintense on T2WI in the remaining four patients, while one patient showed hemorrhage that was hyperintense on T1WI. The solid components of the GCTs show marked enhancement in all cases, while the cystic area of the tumors was observed without enhancement on contrast-enhanced images in four patients. Bone destruction of the adjacent vertebral body showed a homogeneous signal on T1WI and T2WI and marked enhancement on contrast-enhanced images.ConclusionsGiant cell tumors of the mobile spine with invasion into adjacent vertebrae are an unusual imaging finding. Radiologists should be familiar with this imaging characteristic.

General practitioners (GPs) are ideally placed to have a much larger role in detection and management of familial hypercholesterolaemia (FH) among their patients. The aim of this study was to seek the reflections of practice staff and newly diagnosed patients with FH on the implementation of an FH model of care in the general practice setting.Qualitative descriptive methodology was used. Interviews were conducted with 36 practice staff and 51 patients from 15 practices participating in the study.Data were analysed thematically and coded into themes - efficacy of GP training, screening for FH, model of care, patient awareness and cascade testing.Findings reflect the real-world clinical experience of Australian general practice and the acceptability of the model of care for both patients with FH and practice staff. Patient health literacy is a barrier to both management of FH and cascade testing. A systematic approach to cascade testing is required.

Studies exploring the association of tetrabromobisphenol A (TBBPA) with breast cancer and related mechanisms are limited. To investigate the relationship between TBBPA levels in breast adipose and breast cancer, we carried out case-control research. As well as further examine the mediating role of adipose metabolites between TBBPA and breast cancer using the metabolomics approach. In this study, the concentration of TBBPA was determined utilizing ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) after a solid phase extraction (SPE) pretreatment. High-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) was employed to analyze adipose metabolomics. Evaluation of metabolites linked to TBBPA exposure and breast cancer was performed utilizing mediation analysis. With an estimated OR (95%CI) of 1.153 (1.023, 1.299), TBBPA was firmly linked with breast cancer. We also used propensity score matching analysis and sensitivity analysis to reduce the effect of confounding factors on the results. Metabolomics of adipose suggested significant perturbation in the linoleic acid metabolism pathway. In addition, for PC (16:0/16:0) as phospholipids, a mediation effect on the associations of TBBPA exposure with breast cancer risks was observed (estimated mediation percentage: 56.58%). Understanding the relationship between TBBPA exposure and the risk of breast cancer may be facilitated by the findings, which point to potential mediation metabolites.

Familial hypercholesterolaemia (FH) can be effectively detected and managed in primary care, but the health economic evidence for this is scarce. The aim of this study was to examine management pathways and cost implications of FH screening and management in Australian general practice.Cost-effectiveness outcomes were projected using a life table model. Data was used from 133 patients in 15 Australian general practice clinics from an earlier screening and management study. Costing and mortality data were sourced from governmental sources and published literature.Most patients had a regular general practice consultation at baseline (82%), though the proportion seen under a chronic disease management item at follow-up increased to 23%. The median cost of management was $275 per annum in the first year of management. Managing patients with statins up to the age of 60 years yielded an increase of 248,954 life-years at a cost of $759 million, representing a cost per life-year gained of $3047.Screening and management of FH in general practice has the potential for substantial health benefits while requiring relatively modest investments from the health system.

Rationale and Objectives To evaluate the value of a radiomics nomogram for preoperative differentiating hepatocellular adenoma (HCA) from hepatocellular carcinoma (HCC) in the noncirrhotic liver. Materials and Methods One hundred and thirty-one patients with HCA (n = 46) and HCC (n = 85) were divided into a training set (n = 93) and a test set (n = 38). Clinical data and CT findings were analyzed. Radiomics features were extracted from the triphasic contrast CT images. A radiomics signature was constructed with the least absolute shrinkage and selection operator algorithm and a radiomics score was calculated. Combined with the radiomics score and independent clinical factors, a radiomics nomogram was developed by multivariate logistic regression analysis. The performance of the radiomics nomogram was assessed by calibration, discrimination and clinical usefulness. Results Gender, age, and enhancement pattern were the independent clinical factors. Three thousand seven hundred and sixty-eight features were extracted and reduced to 7 features as the optimal discriminators to build the radiomics signature. The radiomics nomogram (area under the curve [AUC], 0.96; 95% confidence interval [CI], 0.93–0.99) and the clinical factors model (AUC, 0.93; 95%CI, 0.88–0.99) showed better discrimination capability (p = 0.001 and 0.047) than the radiomics signature (AUC, 0.83; 95%CI, 0.74–0.92) in the training set. In the test set, the radiomics nomogram (AUC, 0.94; 95%CI, 0.87–1.00) performed better (p = 0.013) than the radiomics signature (AUC, 0.75; 95%CI, 0.59–0.91). Decision curve analysis showed the radiomics nomogram outperformed the clinical factors model and the radiomics signature in terms of clinical usefulness. Conclusion The CT-based radiomics nomogram has the potential to accurately differentiate HCA from HCC in the noncirrhotic liver.

Background Lipoprotein(a) (Lp[a]) is a causal risk factor for atherosclerotic cardiovascular disease (ASCVD). Proprotein convertase subtilisin/kexin‐9 monoclonal antibodies (PCSK9mAbs) can lower Lp(a) levels in clinical trials, but their effects in patients with elevated Lp(a) in clinical practice remain unclear. Aims To investigate the effectiveness and safety of PCSK9mAbs in lowering plasma Lp(a) in patients with elevated Lp(a) concentrations in a lipid clinic. Methods This was an open‐label study of 53 adult patients with elevated Lp(a) concentration (≥0.5 g/L). Clinical, biochemical, and safety data were collected before and on treatment with evolocumab or alirocumab over a mean period of 11 months. Results Treatment with a PCSK9mAb resulted in a significant reduction of 0.29 g/L (−22%) in plasma Lp(a) concentration (p.05 in all). 7.5% and 47% of the patients attained a target concentration of Lp(a)

Background: Guidelines on lipid disorders are constantly evolving. General practitioners regularly face critical decisions about the best treatment strategies for individual patients. Cardiovascular disease (CVD) is common, with most morbidity and mortality due to atherosclerosis. Raised low-density lipoprotein cholesterol (LDL-C) is the most atherogenic component - lowering it lowers the risk of future cardiovascular events. Objective: The aim of this article is to provide an evidence-informed summary of national guidelines and recent research to help clinicians reduce the risk of atherosclerotic CVD and improve health service delivery through improved lipid management strategies. Discussion: Elevated plasma lipids, especially LDL-C, increase the likelihood of a CVD event over time. Knowledge of family and personal histories plus other risk factors for CVD should alert clinicians to the need for treatment. The greater the overall burden of combined risk factors, the greater the lifetime risk. This update provides new information that informs future approaches for improving lipid management in Australian general practice.

Familial hypercholesterolaemia (FH) is a highly penetrant monogenic disorder present from birth that markedly elevates plasma low-density lipoprotein (LDL)-cholesterol (LDL-C) concentration and, if untreated, leads to premature atherosclerosis and coronary artery disease (CAD). At a prevalence of 1:250 individuals, with over 90% undiagnosed, recent estimates suggest that there are approximately 22 000 children and adolescents with FH in Australia and New Zealand. However, the overwhelming majority remain undetected and inadequately treated until adulthood or after their first cardiac event. The guidance in this paper aims to increase awareness about paediatric FH and provide practical advice for the diagnosis and management of FH in children and adolescents. Recommendations are given on the detection, diagnosis, assessment and management of FH in children and adolescents. Recommendations are also made on genetic testing, including counselling and the potential for universal screening programmes. Practical guidance on management includes treatment of non-cholesterol risk factors, and safe and appropriate use of LDL-C lowering therapies, including statins, ezetimibe, PCSK9 inhibitors and lipoprotein apheresis. Models of care for FH need to be adapted to local and regional health care needs and available resources. Targeting the detection of FH as a priority in children and young adults has the potential to alter the natural history of atherosclerotic cardiovascular disease and recognise the promise of early detection for improving long-term health outcomes. A comprehensive implementation strategy, informed by further research, including assessments of cost-benefit, will be required to ensure that this new guidance benefits all families with or at risk of FH.

With research progress on longevity, we have gradually recognized that cardiac aging causes changes in heart structure and function, including progressive myocardial remodeling, left ventricular hypertrophy, and decreases in systolic and diastolic function. Elucidating the regulatory mechanisms of cardiac aging is a great challenge for biologists and physicians worldwide. In this review, we discuss several key molecular mechanisms of cardiac aging and possible prevention and treatment methods developed in recent years. Insights into the process and mechanism of cardiac aging are necessary to protect against age-related diseases, extend lifespan, and reduce the increasing burden of cardiovascular disease in elderly individuals. We believe that research on cardiac aging is entering a new era of unique significance for the progress of clinical medicine and social welfare.

Pesticide residues have become a healthy threaten of human beings. Among the pesticides, many of them have neurotoxicity. Extracellular Regulated Protein Kinases (ERK) pathway is an important signaling pathway that regulates a variety of downstream progress. In this work, peach (PRUNUS persica) and cherry (PRUNUS cerasus) were sampled from over 300 plantations in China and assessed for the residue risk. In mechanism studies, high-risk pesticide Avermectin showed a high activity inhibiting three neurotoxicity models, SH-SY5Y, PC-12 and SK-N-SH cells. At protein levels, ERK pathway proteins and their downstream proteins were obviously down-regulated. Moreover, the effects of low-dose Avermectin can be accumulated at protein levels in the low-dose long-term chronic toxicology detection.

Cellular cholesterol efflux is a key step in reverse cholesterol transport that may impact on atherosclerotic cardiovascular risk. The process may be reliant on the availability of apolipoprotein (apo) B-100-containing lipoproteins to accept cholesterol from high-density lipoprotein. Evolocumab and atorvastatin are known to lower plasma apoB-100-containing lipoproteins that could impact on cholesterol efflux capacity (CEC).We conducted a 2-by-2 factorial trial of the effects of subcutaneous evolocumab (420 mg every 2 weeks) and atorvastatin (80 mg daily) for 8 weeks on CEC in 81 healthy, normolipidaemic men. The capacity of whole plasma and apoB-depleted plasma, including ATP-binding cassette transporter A1 (ABCA1)-mediated and passive diffusion, to efflux cholesterol, was measured.Evolocumab and atorvastatin independently decreased whole plasma CEC (main effect p .01 for both). However, there were no significant effects of evolocumab and atorvastatin on apoB-depleted plasma, ABCA1-mediated and passive diffusion-mediated CEC (p .05 in all). In the three intervention groups combined, the reduction in whole plasma CEC was significantly correlated with the corresponding reduction in plasma apoB-100 concentration (r = .339, p .01). In the evolocumab monotherapy group, the reduction in whole plasma CEC was also significantly correlated with the corresponding reduction in plasma lipoprotein(a) concentration (r = .487, p .05).In normolipidaemic men, evolocumab and atorvastatin decrease the capacity of whole plasma to efflux cellular cholesterol. These effects may be chiefly owing to a fall in the availability of apoB-100-containing lipoproteins. Reduction in circulating lipoprotein(a) may also contribute to the decrease in whole plasma cholesterol efflux with evolocumab monotherapy.

[Background]: Homozygous familial hypercholesterolaemia (HoFH) is a rare inherited disorder resulting in extremely elevated low-density lipoprotein cholesterol levels and premature atherosclerotic cardiovascular disease (ASCVD). Current guidance about its management and prognosis stems from small studies, mostly from high-income countries. The objective of this study was to assess the clinical and genetic characteristics, as well as the impact, of current practice on health outcomes of HoFH patients globally., [Methods]: The HoFH International Clinical Collaborators registry collected data on patients with a clinical, or genetic, or both, diagnosis of HoFH using a retrospective cohort study design. This trial is registered with ClinicalTrials.gov, NCT04815005., [Findings]: Overall, 751 patients from 38 countries were included, with 565 (75%) reporting biallelic pathogenic variants. The median age of diagnosis was 12∙0 years (IQR 5∙5–27∙0) years. Of the 751 patients, 389 (52%) were female and 362 (48%) were male. Race was reported for 527 patients; 338 (64%) patients were White, 121 (23%) were Asian, and 68 (13%) were Black or mixed race. The major manifestations of ASCVD or aortic stenosis were already present in 65 (9%) of patients at diagnosis of HoFH. Globally, pretreatment LDL cholesterol levels were 14∙7 mmol/L (IQR 11∙6–18∙4). Among patients with detailed therapeutic information, 491 (92%) of 534 received statins, 342 (64%) of 534 received ezetimibe, and 243 (39%) of 621 received lipoprotein apheresis. On-treatment LDL cholesterol levels were lower in high-income countries (3∙93 mmol/L, IQR 2∙6–5∙8) versus non-highincome countries (9∙3 mmol/L, 6∙7–12∙7), with greater use of three or more lipid-lowering therapies (LLT; highincome 66% vs non-high-income 24%) and consequently more patients attaining guideline-recommended LDL cholesterol goals (high-income 21% vs non-high-income 3%). A first major adverse cardiovascular event occurred a decade earlier in non-high-income countries, at a median age of 24∙5 years (IQR 17∙0–34∙5) versus 37∙0 years (29∙0–49∙0) in high-income countries (adjusted hazard ratio 1∙64, 95% CI 1∙13–2∙38)., [Interpretation]: Worldwide, patients with HoFH are diagnosed too late, undertreated, and at high premature ASCVD risk. Greater use of multi-LLT regimens is associated with lower LDL cholesterol levels and better outcomes. Significant global disparities exist in treatment regimens, control of LDL cholesterol levels, and cardiovascular event-free survival, which demands a critical re-evaluation of global health policy to reduce inequalities and improve outcomes for all patients with HoFH., Amsterdam University Medical Centers, Location Academic Medical Center; Perelman School of Medicine at the University of Pennsylvania; and European Atherosclerosis Society

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Inhibition of proprotein convertase subtilisin/kexin type 9 with alirocumab decreases plasma lipoprotein(a) [Lp(a)] levels. The kinetic mechanism for lowering Lp(a) by alirocumab may differ according to pre-treatment apolipoprotein(a) [apo(a)] levels.The effect of 12-week alirocumab (150 mg subcutaneously fortnightly) on the kinetics of apo(a) was compared in statin-treated patients with high (n = 10) and very high Lp(a) concentrations (n = 11).In patients with high apo(a) concentrations, alirocumab lowered plasma apo(a) pool size (-17%, p0.01) chiefly by increasing the fractional catabolic rate (FCR) of apo(a) (+27%, p0.001). By contrast in patients with very high apo(a) concentrations, alirocumab significantly lowered plasma apo(a) pool size (-32%, p0.001) by both increasing apo(a) FCR (+30%, p0.001) and lowering production rate (-11%, p0.05).In statin-treated patients with very high apo(a) concentrations, alirocumab lowers plasma Lp(a) concentration by a dual mode of action that increases the clearance and decreases the production of Lp(a) particles.

Hypertriglyceridemia (HTG) is a risk factor for atherosclerotic cardiovascular disease (ASCVD), aortic stenosis, hepatic steatosis and pancreatitis. We briefly review the aetiology and treatment of HTG and familial chylomicronemia syndrome (FCS), as well as the implementation of a clinical quality registry for improving care, the Australian Hypertriglyceridemia (AUSTRIG) Registry.There is a need to improve the detection of individuals with severe HTG and FCS, who could benefit from more intense and novel treatments to prevent end-organ damage. Patient registries provide valuable data for advancing care of individuals with severe HTG at high risk of acute pancreatitis, steatohepatitis and ASCVD. However, there is a paucity of registries of such patients. We outline the design and implementation of the AUSTRIG Registry.Clinical registries can be employed in many ways for improving outcomes for patients with HTG, through the collation and analysis of data for enabling health service planning, clinical trials and audits, and for better informing and empowering registrants.

Atherosclerosis (AS) is a chronic inflammatory disease involving endothelial dysfunction, and is one of the main causes of death from cardiovascular disease (CVD). Long non-coding RNA plasmacytoma variant translocation 1 (lncRNA PVT1) is overexpressed in the serum of CVD patients. However, the mechanism by which lncRNA PVT1 functions in AS remains unknown. Our research was designed to probe interactions involving lncRNA PVT1 and oxidized low-density lipoprotein (ox-LDL)-stimulated endothelial cell injury in AS. lncRNA PVT1 expression in the serum of AS patients and ox-LDL-stimulated human umbilical vein endothelial cells (HUVECs) was detected using reverse transcriptase quantitative polymerase chain reaction (RT-qPCR). Cell counting kit (CCK)-8 assays, flow cytometry (FCM), and enzyme-linked immunosorbent assay (ELISA) were used to determine cell proliferation, apoptosis, and levels of inflammatory cytokines, respectively. Moreover, the correlation between lncRNA PVT1 and miR-30 c-5p was predicted and verified using StarBase3.0, TargetScan, and luciferase reporter-gene assays. lncRNA PVT1 was overexpressed in the serum of AS patients and in ox-LDL-stimulated HUVECs relative to controls. Knockdown of lncRNA PVT1 facilitated proliferation, reduced apoptosis, and secretion of inflammatory factors in ox-LDL-treated HUVECs. Moreover, miR-30 c-5p was verified as a direct target of lncRNA PVT1. Furthermore, we observed that miR-30 c-5p expression was lower in AS patients than in controls. In addition, the influence of lncRNA PVT1 knockdown on ox-LDL-treated HUVECs was significantly reversed by downregulation of miR-30 c-5p. In conclusion, lncRNA PVT1 silencing inhibited HUVEC damage stimulated by ox-LDL via miR-30 c-5p regulation.

Background There are no studies that have specifically investigated the cost-effectiveness of cascade screening of children for heterozygous familial hypercholesterolemia (FH) and treatment of affected individuals with statins to prevent coronary heart disease (CHD). Purpose This study explores the cost-effectiveness of this strategy from the perspective of the Australian public healthcare system. Methods A lifetime Markov model with four health states (Alive without CHD, Alive with CHD, Dead from fatal CHD, and Dead from other causes) was developed to simulate the progression of ten- year-old children screened for FH and treated immediately with statins if found to have FH. The underlying prevalence of FH in this target population was assumed to be 56.8%, and the sensitivity and specificity of testing was 100%. The comparator was usual care, which assumed that subjects started statins spontaneously at a later point or when they experienced a cardiovascular event. The effect of reducing low-density lipoprotein cholesterol (LDL-C) on the risk of a first event at each age assumed that risk was proportional to total lifetime exposure and was implemented using Mendelian randomisation analysis data. Cost and other outcome data were sourced from published sources. Outcome of interests were costs in Australian dollars (AUD), life years gained (LYG) and quality-adjusted life years (QALYs) gained, as well as incremental cost-effectiveness ratios (ICERs) of costs per LYG and per QALY gained. All future costs and outcomes were discounted by 5% annually. Results Undiscounted results showed that compared with usual care, cascade screening of ten year-old children for FH and initiation of treatment of affected individuals saved 7.77 LYG and 7.53 QALYs per person over a lifetime. With 5% annual discounting, there were 0.97 LYG and 1.07 QALYs gained per person, at an additional cost of $3,244. These equated to ICERs of $3334 per LYG and $3023 per QALY gained. The equivalent ICERs in USD would be $5089 per LYG gained and $4615 per QALY gained. Sensitivity analysis showed the results to be robust. Conclusions Compared to usual care, cascade screening of ten year old children for FH and treating affected individuals is likely to be highly cost-effective. Table 1. Granular cost and benefit data Funding Acknowledgement Type of funding source: None

Familial hypercholesterolaemia (FH) is caused by a major genetic defect in the low-density lipoprotein (LDL) clearance pathway. Characterised by LDL-cholesterol elevation from birth, FH confers a significant risk for premature coronary artery disease (CAD) if overlooked and untreated. With risk exposure beginning at birth, early detection and intervention is crucial for the prevention of CAD. Lowering LDL-cholesterol with lifestyle and statin therapy can reduce the risk of CAD. However, most individuals with FH will not reach guideline recommended LDL-cholesterol targets. FH has an estimated prevalence of approximately 1:250 in the community. Multiple strategies are required for screening, diagnosing and treating FH. Recent publications on FH provide new data for developing models of care, including new therapies. This review provides an overview of FH and outlines some recent advances in the care of FH for the prevention of CAD in affected families. The future care of FH in Australia should be developed within the context of the National Health Genomics Policy Framework.

Familial hypercholesterolaemia (FH) is characterised by a high, but variable risk of premature coronary artery disease (CAD). Cardiac computed tomography angiography (CCTA) can be employed to assess subclinical coronary atherosclerosis. We investigated the features and distribution of coronary artery plaques in asymptomatic patients with and without genetically confirmed heterozygous FH.We undertook an aged-matched case-control study of asymptomatic phenotypic FH patients with (cases, M+) and without (controls, M-) an FH-causing mutation. Coronary atherosclerosis was assessed by CCTA and calcium scoring. Coronary segments were evaluated for global and vessel-level coronary plaques and degree of stenosis.We studied 104 cases and 104 controls (mean age 49.9 ± 10.4 years), who had a similar spectrum of non-cardiovascular risk factors. Pre-treatment plasma LDL-cholesterol was higher in the M+ than M- group (7.8 ± 2.1 vs 6.2 ± 1.2 mmol/L, p0.001). There was a greater proportion of patients with mixed and calcified plaque, as well as a higher coronary artery calcium score and segment stenosis score (all p0.05), in the M+ compared with the M- group. M+ patients also had a significantly higher frequency of coronary artery calcium in the left main and anterior descending and right coronary arteries (all p0.05), but not in the left circumflex.Among patients with phenotypic FH, those with a genetically confirmed diagnosis had a higher frequency and severity of coronary atherosclerotic plaques, and specifically more advanced calcified plaques.

Pancreatic ductal adenocarcinoma (PDAC) is radioresistant. Due to their strong X-ray absorption capacity, gold nanoparticles (AuNPs) have been used as radiosensitizers for cancer therapeutics. Herein, we describe a novel conjugate complex consisting of a peptide for targeting plectin-1 (PTP) specifically expressed on the PDAC cell membrane and AuNPs, termed AuNP-PTP, to be used for PDAC radiotherapy in vitro and in vivo. Previous studies revealed that compared with unmodified AuNPs, AuNP-PTP along with relevant low-energy X-ray irradiation of 6 MV at a dose of 2 Gy (RF) increased the targeting efficiency and induced apoptosis in treated PANC-1 cells and tumours. Importantly, extensive histopathological examination did not reveal evidence of acute or chronic injury in mice due to AuNPs or AuNP-PTP for up to six weeks despite the presence of X-ray exposure. The delicate AuNP-PTP hybrid provides a novel strategy to enhance radiotherapy efficiency in PDAC treatment.

BACKGROUND Diagnostic tools for familial hypercholesterolemia (FH) rely on estimation of LDL cholesterol concentration. However, routine measurement or calculation of LDL cholesterol concentration using the Friedewald equation contains a cholesterol contribution from lipoprotein(a) [Lp(a)]. We investigated whether Lp(a) influences the phenotypic diagnosis of FH by commonly used clinical criteria. METHODS A cohort of 907 adult index patients attending a clinic were studied. The Dutch Lipid Clinic Network (DLCN) and Simon Broome (SB) diagnostic criteria were estimated before and after adjusting LDL cholesterol concentration for the cholesterol content (30%) of Lp(a). Diagnostic reclassification rates and area under the ROC (AUROC) curves in predicting an FH mutation were also compared. RESULTS Seventy-four patients defined by DLCN criteria (8.2%) and 207 patients defined by SB criteria (22.8%) were reclassified to “unlikely” FH after adjusting LDL cholesterol for Lp(a) cholesterol. The proportion of FH patients defined by DLCN (probable/definite) and SB (possible/definite) criteria decreased significantly in patients with increased Lp(a) (>0.5 g/L; n = 330) after Lp(a) cholesterol adjustment (P < 0.01). The overall reclassification rate was significantly higher in patients with Lp(a) concentration >1.0 g/L (P < 0.001). The AUROC curve for LDL cholesterol concentration ≥191 mg/dL (≥5.0 mmol/L), DLCN criteria, and SB criteria in predicting an FH mutation increased significantly after adjustment (P < 0.001). There was no significant difference in AUROC curve before and after Lp(a) cholesterol adjustment at an LDL cholesterol concentration ≥251 mg/dL (≥6.5 mmol/L). CONCLUSIONS Adjusting LDL cholesterol concentration for Lp(a) cholesterol improves the diagnostic accuracy of DLCN and SB criteria, especially with Lp(a) >1.0 g/L and LDL cholesterol

Pituitary adrenocorticotropic hormone (ACTH)-secreting adenoma is a relatively intractable endocrine adenoma that can cause a range of severe metabolic disorders and pathological changes involving multiple systems. Previous studies have shown that celastrol has antitumor effects on a variety of tumor cells via the AKT/mTOR signaling. However, whether celastrol has pronounced antitumor effects on pituitary ACTH-secreting adenoma is unclear. This study aimed to identify a new effective therapeutic drug for pituitary ACTH-secreting adenoma.Mouse pituitary ACTH-secreting adenoma cells (AtT20 cells) were used as an experimental model in vitro and to establish a xenograft tumor model in mice. Cells and animals were administered doses of celastrol at various levels. The effects of celastrol on cell viability, migration, apoptosis and autophagy were then examined. Finally, the potential involvement of AKT/mTOR signaling in celastrol's mechanism was assessed.Celastrol inhibited the proliferation and migration of pituitary adenoma cells in a time- and concentration-dependent manner. It blocked AtT20 cells in the G0/G1 phase, and induced apoptosis and autophagy by downregulating the AKT/mTOR signaling pathway. Similar results were obtained in mice.Celastrol exerts potent antitumor effects on ACTH-secreting adenoma by downregulating the AKT/mTOR signaling in vitro and in vivo.

Comparisons between ticagrelor and clopidogrel for the secondary prevention of stroke inWe conducted a randomized, double-blind, placebo-controlled trial at 202 centers in China involving patients with a minor ischemic stroke or transient ischemic attack (TIA) who carriedA total of 11,255 patients were screened and 6412 patients were enrolled, with 3205 assigned to the ticagrelor group and 3207 to the clopidogrel group. The median age of the patients was 64.8 years, and 33.8% were women; 98.0% belonged to the Han Chinese ethnic group. Stroke occurred within 90 days in 191 patients (6.0%) in the ticagrelor group and 243 patients (7.6%) in the clopidogrel group (hazard ratio, 0.77; 95% confidence interval, 0.64 to 0.94; P = 0.008). Secondary outcomes were generally in the same direction as the primary outcome. Severe or moderate bleeding occurred in 9 patients (0.3%) in the ticagrelor group and in 11 patients (0.3%) in the clopidogrel group; any bleeding occurred in 170 patients (5.3%) and 80 patients (2.5%), respectively.Among Chinese patients with minor ischemic stroke or TIA who were carriers of

Background and aims Familial hypercholesterolaemia (FH) and elevated plasma lipoprotein(a) [Lp(a)] are inherited conditions independently associated with atherosclerotic cardiovascular disease. This study investigated the detection of new cases of elevated Lp(a) during cascade testing of relatives of probands with a definite diagnosis of FH and elevated Lp(a) (≥50 mg/dL). Methods Relatives from 62 adult probands were tested for FH genetically and for elevated Lp(a) using an immunoassay. The prevalence and yield of new cases of FH with or without elevated Lp(a) (≥50 mg/dL) among relatives and the association between the detection of elevated Lp(a) and the Lp(a) concentration of the probands were assessed. Results Among 162 relatives tested (136 adults and 26 children), the prevalence of FH and elevated Lp(a) was 60.5% and 41.4%, respectively: FH alone was detected in 31.5%, elevated Lp(a) alone in 12.3%, FH with elevated Lp(a) in 29.0%, and neither disorder in 27.2% of the relatives. Cascade testing detected a new case of FH, elevated Lp(a) and FH with elevated Lp(a) for every 1.5, 2.1 and 3.0 relatives tested, respectively. The proportion of relatives detected with elevated Lp(a) was significantly higher when tested from probands with Lp(a) ≥100 mg/dL compared with those from probands with Lp(a) between 50-99 mg/dL (53% vs 34%, p = 0.018). The concordance between the detection of FH and elevated Lp(a) was 56.2% (kappa statistic 0.154), indicating a poor agreement. Conclusions A dual approach to cascade testing families for FH and high Lp(a) from appropriate probands can effectively identify not only new cases of FH, but also new cases of elevated Lp(a) with or without FH. The findings accord with the co-dominant and independent heritability of FH and Lp(a).

Background and objectives: A lack of public and health professional awareness about familial hypercholesterolaemia (FH) leads to an estimated 90,000 Australians remaining undiagnosed. The aim of this study was to establish the level of knowledge and awareness of FH in Australian general practices. Method: A qualitative descriptive methodology was used to explore baseline knowledge and perceptions of practice staff about diagnosing and managing FH. Overall, 63 interviews were conducted with general practice staff at 15 practices taking part in a National Health and Medical Research Council partnership grant study (GNT1142883). Results: Data were analysed thematically and coded into themes - knowledge/awareness/recall, management, use of guidelines/referrals, and contacting family members. Most general practitioners treated the high cholesterol component as their primary focus. Guidelines and referrals were rarely used. Discussion: This research reflected a lack of knowledge, awareness and use of guidelines similar to that shown in other published studies. Improved primary care infrastructure, knowledge and awareness of FH need to be addressed.

ObjectiveGenetic variants that disrupt the function of the PCSK9 (proprotein convertase subtilisin kexin type 9) and APOB (apolipoprotein B)genes result in lower serum low-density lipoprotein cholesterol (LDL-C) levels and subsequently confer protection against coronary heart disease (CHD). The objective of this study was to measure the prevalence and selective advantage of such variants among healthy older individuals without a history of CHD.MethodsWe performed targeted sequencing of the PCSK9 and APOB genes in 13 131 healthy individuals without CHD aged 70 years or older enrolled into the ASPirin in Reducing Events in the Elderly trial. We detected variants in the PCSK9 and APOB genes with predicted loss-of-function. We associated variant carrier status with serum LDL-C and total cholesterol (TC) levels at the time of study enrolment, adjusting for statin use.ResultsWe detected 22 different rare PCSK9/APOB candidate variants with putative lipid-lowering effect, carried by 104 participants (carrier rate 1 in 126). Serum LDL-C and TC concentrations for rare PCSK9/APOB variant carriers were consistently lower than non-carriers. Rare variant carrier status was associated with 19.4 mg/dL (14.6%) lower LDL-C, compared with non-carriers (p≤0.001, adjusted for statin use). Statin prescriptions were less prevalent in rare variant carriers (16%) than non-carriers (35%). The more common PCSK9 R46L variant (rs11591147-T) was associated with 15.5 mg/dL (11.8%) lower LDL-C in heterozygotes, and 25.2 mg/dL (19.2%) lower LDL-C in homozygotes (both p≤0.001).ConclusionsLipid-lowering genetic variants are carried by healthy older individuals and contribute to CHD-free survival.Trial registration numberNCT01038583.

AIM Familial hypercholesterolaemia (FH) is a common and treatable cause of premature coronary artery disease. However, the majority of individuals with FH remain undiagnosed. This study investigated the feasibility, acceptability and cost-effectiveness of screening children aged 1-2 years for FH at the time of an immunisation. METHODS Children 1-2 years of age were offered screening for FH with a point-of-care total cholesterol (TC) test by capillary-collected blood sample at the time of an immunisation. An additional blood sample was taken to allow genetic testing if the TC level was above the 95th percentile (>5.3 mmol/L). Parents of children diagnosed with FH were offered testing. Following detection of the affected parent, cascade testing of their first-degree blood relatives was performed. RESULTS We screened 448 children with 32 (7.1%) having a TC ≥ 5.3 mmol/L. The FH diagnosis was confirmed in three children (1:150 screened). Reverse cascade testing of other family members identified a further five individuals with FH; hence, eight new cases of FH were diagnosed from screening 448 children (1:56 screened). Ninety-six percent of parents would screen future children for FH. The approach was cost-effective, at $3979 per quality-adjusted life year gained. CONCLUSION In Western Australia, universal screening of children aged 1-2 years for FH, undertaken at the time of an immunisation, was a feasible and effective approach to detect children, parents and other blood relatives with FH. The approach was acceptable to parents and is potentially a highly cost-effective detection strategy for families at risk of FH.

Prenatal diagnosis and planned peripartum care is an unexplored concept in China. This study aimed to evaluate the effects of the "prenatal diagnosis and postnatal treatment integrated model" for newborns with critical congenital heart disease.The medical records of neonates (≤ 28 days) admitted to Fuwai Hospital were reviewed retrospectively from January 2019 to December 2020. The patients were divided into "prenatal diagnosis and postnatal treatment integrated group" (n = 47) and "non-integrated group" (n = 69).The age of admission to the hospital and the age at surgery were earlier in the integrated group than in the non-integrated group (5.2 ± 7.2 days vs. 11.8 ± 8.0 days, P 0.001; 11.9 ± 7.0 days vs. 16.5 ± 7.7 days, P = 0.001, respectively). The weight at surgery also was lower in the integrated group than in the non-integrated group (3.3 ± 0.4 kg vs. 3.6 ± 0.6 kg, P = 0.010). Longer postoperative recovery time was needed in the integrated group, with a median mechanical ventilation time of 97 h (interquartile range 51-259 h) vs. 69 h (29-168 h) (P = 0.030) and with intensive care unit time of 13.0 days (8.0-21.0 days) vs. 9.0 days (4.5-16.0 days) (P = 0.048). No significant difference was observed in the all-cause mortality (2.1 vs. 8.7%, P = 0.238), but it was significantly lower in the integrated group for transposition of the great arteries (0 vs. 18.8%, log rank P = 0.032).The prenatal diagnosis and postnatal treatment integrated model could significantly shorten the diagnosis and hospitalization interval of newborns, and surgical intervention could be performed with a lower risk of death, especially for transposition of the great arteries.

Tubulin has been regarded as an attractive and successful molecular target in cancer therapy and drug discovery. Vicinal diaryl is a simple scaffold found in many colchicine site tubulin inhibitors, which is also an important pharmacophoric point of tubulin binding and anti-cancer activity. As the continuation of our research work on colchicine binding site tubulin inhibitors, we designed and synthesized a series of diarylamide N-containing heterocyclic derivatives by the combination of vicinal diaryl core and N-containing heterocyclic skeletons into one hybrid though proper linkers. Among of these compounds, compound 15b containing a 5-methoxyindole group exhibited the most potent inhibitory activity against the tested three human cancer cell lines (MGC-803, PC-3 and EC-109) with IC50 values of 1.56 μM, 3.56 μM and 14.5 μM, respectively. Besides, the SARs of these compounds were preliminarily studied and summarized. The most active compound 15b produced the inhibition of tubulin polymerization in a dose-dependent manner and caused microtubule network disruption in MGC-803 cells. Therefore, compound 15b was identified as a novel tubulin polymerization inhibitor targeting the colchicine binding site. In addition, the results of molecular docking also suggested compound 15b could tightly bind into the colchicine binding site of β-tubulin.

Bruton tyrosine kinase (BTK) is a key kinase in the B cell antigen receptor signal transduction pathway, which is involved in the regulation of the proliferation, differentiation and apoptosis of B cells. BTK has become a significant target for the treatment of hematological malignancies and autoimmune diseases. Ibrutinib, the first-generation BTK inhibitor, has made a great contribution to the treatment of B cell malignant tumors, but there are still some problems such as resistance or miss target of site mutation. Therefore, there is an imperative need to develop novel BTK inhibitors to overcome these problems. Besides, proteolysis targeting chimera (PROTAC) technology has been successfully applied to the development of BTK degradation agents, which has opened a fresh way for the BTK targeted treatment. This paper reviews the biological function of BTK, the discovery and development of BTK targeted drugs as a promising cancer therapy. It mainly reviews the binding sites and structural characteristics of BTK, structure-activity relationships, activity and drug resistance of BTK inhibitors, as well as potential treatment strategies to overcome the resistance of BTK, which provides a reference for the rational design and development of new powerful BTK inhibitors.

Aims The aim of this study was to assess the impact and cost-effectiveness of offering population genomic screening to all young adults in Australia to detect heterozygous familial hypercholesterolaemia (FH). Methods and results We designed a decision analytic Markov model to compare the current standard of care for heterozygous FH diagnosis in Australia (opportunistic cholesterol screening and genetic cascade testing) with the alternate strategy of population genomic screening of adults aged 18–40 years to detect pathogenic variants in the LDLR/APOB/PCSK9 genes. We used a validated cost-adaptation method to adapt findings to eight high-income countries. The model captured coronary heart disease (CHD) morbidity/mortality over a lifetime horizon, from healthcare and societal perspectives. Risk of CHD, treatment effects, prevalence, and healthcare costs were estimated from published studies. Outcomes included quality-adjusted life years (QALYs), costs and incremental cost-effectiveness ratio (ICER), discounted 5% annually. Sensitivity analyses were undertaken to explore the impact of key input parameters on the robustness of the model. Over the lifetime of the population (4 167 768 men; 4 129 961 women), the model estimated a gain of 33 488years of life lived and 51 790 QALYs due to CHD prevention. Population genomic screening for FH would be cost-effective from a healthcare perspective if the per-test cost was ≤AU$250, yielding an ICER of Conclusion Based on our model, offering population genomic screening to all young adults for FH could be cost-effective, at testing costs that are feasible.

Homozygous familial hypercholesterolemia (hoFH) is a rare inherited disorder characterized by extreme elevation of low-density lipoprotein (LDL) cholesterol, accelerated coronary artery disease, and premature death. Aggressive LDL-lowering therapies are important for survival, but these are not available worldwide.The aim of the study was to compare and contrast cardiovascular outcomes and mortality of hoFH patients in 2 countries with disparate use of lipoprotein apheresis (LA) and modern therapies for lowering LDL cholesterol.A retrospective study was undertaken comparing cardiovascular disease (CVD)-free survival and mortality in 44 hoFH patients who were treated with statins but not LA, from a center in Beijing, China, and 18 hoFH patients who were treated with LA and novel therapies from an early age, from a center in Rome, Italy.CVD-free survival and survival were significantly reduced in Chinese patients compared with the Italian patients after 30 years of follow-up (log-rank P .01). In a pooled analysis, cardiovascular survival was significantly increased with earlier age at treatment, longer duration of treatment, and lower on-treatment LDL cholesterol concentrations (P .05). In addition, the probability of a CVD event and death were increased in patients that carried a null mutation in the LDLR or had elevated lipoprotein(a).We show that coronary artery disease outcomes in patients with hoFH can be significantly improved with earlier and potent LDL cholesterol lowering with pharmacotherapies and LA. This has major implications for countries, such as China, where the models of care for hoFH remains underdeveloped.

BACKGROUND: There is a lack of information on the health care of familial hypercholesterolemia (FH).OBJECTIVE: The objective of this study was to compare the health care of FH in countries of the Asia-Pacific region and Southern Hemisphere.METHODS: A series of questionnaires were completed by key opinion leaders from selected specialist centers in 12 countries concerning aspects of the care of FH, including screening, diagnosis, risk assessment, treatment, teaching/training, and research; the United Kingdom (UK) was used as the international benchmark.RESULTS: The estimated percentage of patients diagnosed with the condition was low (overall

Familial hypercholesterolaemia (FH) is the commonest monogenic disorder that accelerates atherosclerotic cardiovascular disease. We compared and contrasted the characteristics of patients from three specialist centres in the southern hemisphere.Adult index-cases with molecularly diagnosed heterozygous FH attending specialist lipid centres in Cape Town, Perth and São Paulo were studied. Myocardial infarction, revascularisation, hypertension, diabetes, smoking and lipid-lowering treatment were recorded at the time of diagnosis and compared across the three centres.The spectrum of genetic variants causative of FH was significantly different in patients attending the centres in South Africa compared with Australia and Brazil. Hypertension and diabetes were more prevalent in Brazilian and Australian patients, than in South African patients, but the frequency of smoking was significantly greater in South Africa than the other two centres (p0.01). Age, male sex and smoking were significant independent predictors of coronary artery disease (CAD) in all three countries (p0.05).Patients with FH in three specialist centres in the southern hemisphere exhibit a high prevalence of non-cholesterol cardiovascular disease risk factors. Older age, male sex and smoking were more common among subjects with CAD. In all three countries, there should be vigorous programmes for the control of risk factors beyond good control of hypercholesterolaemia among patients with FH. Promotion of a healthy lifestyle, especially anti-smoking advice, is of paramount importance.

Background and aims Familial hypercholesterolaemia has not been previously described in the Vietnamese population. We aimed to describe the features of patients with homozygous familial hypercholesterolaemia (hoFH) in Vietnam and the outcomes of screening family members using genetic and cholesterol testing. Methods Mutation testing by massively parallel sequencing for genes causative of FH was undertaken in five index cases presenting to a single cardiac center with a presumptive diagnosis of hoFH. Cascade testing of all available family members was subsequently undertaken. The number of new cases of FH detected and commenced on lipid-lowering treatment was evaluated. Results All five index cases had true homozygous mutations in the LDL receptor gene (LDLR). Cascade screening was undertaken in four families. 107 relatives were screened and FH was identified in 56 relatives (52%), including 3 new cases of hoFH. Only 5 FH relatives (9%) were subsequently treated owing to the adverse perceptions and comparative high cost of drug treatment, and lack of awareness of FH among patients and local doctors. Conclusions HoFH due to LDLR mutations is a severe disorder in Vietnam that needs early detection and treatment with LDL-cholesterol lowering drugs. Cascade testing of families allows effective detection of new cases of FH that may also benefit from early treatment. However, convincing patients to commence statin treatment is a challenge. Extended education and awareness programs and treatment subsidies are imperative to improve the care of patients and families suffering from FH in Vietnam.

Familial hypercholesterolaemia (FH) is a common, heritable and preventable cause of premature coronary artery disease. New clinical practice recommendations are presented to assist practitioners in enhancing the care of all patients with FH. Core recommendations are made on the detection, diagnosis, assessment and management of adults, children and adolescents with FH. Management is under-pinned by the precepts of risk stratification, adherence to healthy lifestyles, treatment of non-cholesterol risk factors and appropriate use of low-density lipoprotein (LDL)-cholesterol-lowering therapies including statins, ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. The recommendations need to be utilised using judicious clinical judgement and shared decision-making with patients and families. New government-funded schemes for genetic testing and use of PCSK9 inhibitors, as well as the National Health Genomics Policy Framework, will enable adoption of the recommendations. However, a comprehensive implementation science and practice strategy is required to ensure that the guidance translates into benefit for all families with FH.

Background The European Atherosclerosis Society Familial Hypercholesterolaemia Studies Collaboration (FHSC) global registry provides a platform for the global surveillance of familial hypercholesterolaemia through harmonisation and pooling of multinational data. In this study, we aimed to characterise the adult population with heterozygous familial hypercholesterolaemia and described how it is detected and managed globally. Methods Using FHSC global registry data, we did a cross-sectional assessment of adults (aged 18 years or older) with a clinical or genetic diagnosis of probable or definite heterozygous familial hypercholesterolaemia at the time they were entered into the registries. Data were assessed overall and by WHO regions, sex, and index versus non-index cases. Findings Of the 61 612 individuals in the registry, 42 167 adults (21 999 [53.6%] women) from 56 countries were included in the study. Of these, 31 798 (75.4%) were diagnosed with the Dutch Lipid Clinic Network criteria, and 35 490 (84.2%) were from the WHO region of Europe. Median age of participants at entry in the registry was 46.2 years (IQR 34.3-58.0); median age at diagnosis of familial hypercholesterolaemia was 44.4 years (32.5-56.5), with 40.2% of participants younger than 40 years when diagnosed. Prevalence of cardiovascular risk factors increased progressively with age and varied by WHO region. Prevalence of coronary disease was 17.4% (2.1% for stroke and 5.2% for peripheral artery disease), increasing with concentrations of untreated LDL cholesterol, and was about two times lower in women than in men. Among patients receiving lipid-lowering medications, 16 803 (81.1%) were receiving statins and 3691 (21.2%) were on combination therapy, with greater use of more potent lipid-lowering medication in men than in women. Median LDL cholesterol was 5.43 mmol/L (IQR 4.32-6.72) among patients not taking lipid-lowering medications and 4.23 mmol/L (3.20-5.66) among those taking them. Among patients taking lipid-lowering medications, 2.7% had LDL cholesterol lower than 1.8 mmol/L; the use of combination therapy, particularly with three drugs and with proprotein convertase subtilisin-kexin type 9 inhibitors, was associated with a higher proportion and greater odds of having LDL cholesterol lower than 1.8 mmol/L. Compared with index cases, patients who were non-index cases were younger, with lower LDL cholesterol and lower prevalence of cardiovascular risk factors and cardiovascular diseases (all p, Pfizer Independent Grant for Learning Change [16157823]; Amgen; Merck Sharp Dohme; Sanofi-Aventis; Daiichi Sankyo; Regeneron; National Institute for Health Research (NIHR) Imperial Biomedical Research Centre, UK; NIHR; Czech Ministry of Health [NU20-02-00261]; Canadian Institutes of Health Research; Austrian Heart Foundation; Tyrolean Regional Government; Gulf Heart Association, The EAS FHSC is an academic initiative that has received funding from a Pfizer Independent Grant for Learning & Change 2014 (16157823) and from investigator-initiated research grants to the European Atherosclerosis Society-Imperial College London from Amgen, Merck Sharp & Dohme, Sanofi-Aventis, Daiichi Sankyo, and Regeneron. KKR acknowledges support from the National Institute for Health Research (NIHR) Imperial Biomedical Research Centre, UK. KID acknowledges support from a PhD Studentship from NIHR under the Applied Health Research programme for Northwest London, UK (the views expressed in this publication are those of the authors and not necessarily those of the National Health Service, the NIHR, or the Department of Health). TF was supported by a grant from the Czech Ministry of Health (NU20-02-00261). JG receives support from the Canadian Institutes of Health Research. The Austrian Familial Hypercholesterolaemia registry has been supported by funds from the Austrian Heart Foundation and the Tyrolean Regional Government. The Gulf Familial Hypercholesterolaemia registry was done under the auspices of the Gulf Heart Association.

Chalcone is a common scaffold found in many biologically active compounds. The chalcone scaffold was also frequently utilized to design novel anticancer agents with potent biological efficacy. Aiming to continue the research of effective chalcone derivatives to treat cancers with potent anticancer activity, fourteen amino chalcone derivatives were designed and synthesized. The antiproliferative activity of amino chalcone derivatives was studied in vitro and 5-Fu as a control group. Some of the compounds showed moderate to good activity against three human cancer cells (MGC-803, HCT-116 and MCF-7 cells) and compound 13e displayed the best antiproliferative activity against MGC-803 cells, HCT-116 cells and MCF-7 cells with IC50 values of 1.52 &mu, M (MGC-803), 1.83 &mu, M (HCT-116) and 2.54 &mu, M (MCF-7), respectively which was more potent than the positive control (5-Fu). Further mechanism studies were explored. The results of cell colony formatting assay suggested compound 10e inhibited the colony formation of MGC-803 cells. DAPI fluorescent staining and flow cytometry assay showed compound 13e induced MGC-803 cells apoptosis. Western blotting experiment indicated compound 13e induced cell apoptosis via the extrinsic/intrinsic apoptosis pathway in MGC-803 cells. Therefore, compound 13e might be a valuable lead compound as antiproliferative agents and amino chalcone derivatives worth further effort to improve amino chalcone derivatives&rsquo, potency.

Background Assessment of optic nerve sheath diameter (ONSD) is a non-invasive measure of intracranial pressure (ICP). However, it is not clear whether healthy individuals exhibit ONSD variation or whether factors other than ICP affect the ONSD. Purpose To investigate whether ONSD was correlated with age, sex, height, weight, eyeball transverse diameter (ETD), or body mass index (BMI), and to develop a new diagnostic model to increase the diagnostic accuracy of intracranial hypertension (IH). Material and Methods A total of 145 relatively healthy adults and 40 patients with acute IH who underwent high-resolution magnetic resonance imaging (MRI) were enrolled in this study. Linear regression analyses were used to determine the relationship between ONSD and these variables. If correlations were identified, an index ONSDΔ removing variables effects was calculated. ROC analysis was used to assess the IH predictive value of ONSDΔ in terms of sensitivity and specificity. Results In relatively healthy adults, there was a correlation between ONSD and BMI ( P = 0.002), which can be presented as an index ONSDΔ. The ONSDΔ model better predicted IH than the ONSD model ( P = 0.035), with a sensitivity of 70.00%, a specificity of 71.72%, and an AUC of 0.755. Conclusion A correlation between ONSD and body mass index (BMI) was found using high-resolution MRI. This result indicates that the effects of BMI should be considered along with the ONSD during ICP monitoring. Meanwhile, the index ONSDΔ was better than the ONSD in predicting IH and could be used to obtain a more precise estimation of ICP.

Background Infections caused by drug-resistant Staphylococcus aureus, especially vancomycin-intermediate Staphylococcus aureus (VISA), leave clinicians with limited therapeutic options for treatment. Persister cells is a leading cause of recalcitrant infection and antibiotic treatment failure, and there is no drug in clinical use that specifically targets persister cells currently. Here, we report a promising combination therapy of sodium new houttuyfonate (SNH) and berberine chloride (BBR) which is able to eradicate both growing and persistent drug-resistant Staphylococcus aureus. Results The susceptibility test showed SNH exhibited anti-MRSA activity with MIC90 at 64 μg/mL, while BBR showed weak anti-MRSA activity with MIC90 at 512 μg/mL. MICs of BBR in combination with 1/2 MIC SNH decreased by 4 to 64 folds compared with MICs of BBR alone. The results of time-killing assays revealed that the combined use of sub-MIC SNH and BBR offered an in vitro synergistic action against growing MRSA (including pathogenic MRSA) and VISA strains. More importantly, the combination of SNH and BBR was able to eradicate VISA Mu50 and pathogenic MRSA persister cells. The synergistic effect is likely related to the interruption of the cell membrane caused by SNH, which is confirmed by scanning electron microscope and membrane potential and permeability analysis. Conclusions Our study provide a promising clinical curative strategy for combating drug-resistant S. aureus infections, especially for recalcitrant infections caused by persister cells.

Familial hypercholesterolaemia (FH) is a dominant and highly penetrant monogenic disorder present from birth that markedly elevates plasma low-density lipoprotein (LDL)-cholesterol concentration and, if untreated, leads to premature atherosclerosis and coronary artery disease (CAD). There are approximately 100,000 people with FH in Australia. However, an overwhelming majority of those affected remain undetected and inadequately treated, consistent with FH being a leading challenge for public health genomics. To further address the unmet need, we provide an updated guidance, presented as a series of systematically collated recommendations, on the care of patients and families with FH. These recommendations have been informed by an exponential growth in published works and new evidence over the last 5 years and are compatible with a contemporary global call to action on FH. Recommendations are given on the detection, diagnosis, assessment and management of FH in adults and children. Recommendations are also made on genetic testing and risk notification of biological relatives who should undergo cascade testing for FH. Guidance on management is based on the concepts of risk re-stratification, adherence to heart healthy lifestyles, treatment of non-cholesterol risk factors, and safe and appropriate use of LDL-cholesterol lowering therapies, including statins, ezetimibe, proprotein convertase subtilisin/kexin type 9 inhibitors and lipoprotein apheresis. Broad recommendations are also provided for the organisation and development of health care services. Recommendations on best practice need to be underpinned by good clinical judgment and shared decision making with patients and families. Models of care for FH need to be adapted to local and regional health care needs and available resources. A comprehensive and realistic implementation strategy, informed by further research, including assessments of cost-benefit, will be required to ensure that this new guidance benefits all Australian families with or at risk of FH.

Purpose of Review Statins are first-line therapy for lowering low-density lipoprotein (LDL) cholesterol in familial hypercholesterolemia (FH), particularly in heterozygous patients. We review advances and new questions on the use of statins in FH. Recent Findings Cumulative evidence from registry data and sub-analyses of clinical trials mandates the value of statin therapy for prevention of atherosclerotic cardiovascular disease (ASCVD) in FH. Statins are safe in children and adolescents with FH, with longer term cardiovascular benefits. The potentially toxic effects of statins in pregnancy need to be considered, but no association has been reported in prospective cohort studies with birth defects. There is no rationale for discontinuation of statins in elderly FH unless indicated by adverse events. FH is undertreated, with > 80% of statin-treated FH patients failing to attain LDL cholesterol treatment targets. This may relate to adherence, tolerability, and genetic differences in statin responsiveness. Statin treatment from childhood may reduce the need for stringent cholesterol targets. Combination of statins with ezetimibe and PCSK9 inhibitors significantly improves the efficacy of treatment. Whether statin use could improve the clinical course of FH patients with COVID-19 and other respiratory infections remains an unsolved issue for future research. Summary Statins are the mainstay for primary and secondary prevention of ASCVD in FH. Sustained long-term optimal statin treatment from an early age can effectively prevent ASCVD over decades of life. Despite their widespread use, statins merit further investigation in FH.

Preoperative differentiation between benign parotid gland tumors (BPGT) and malignant parotid gland tumors (MPGT) is important for treatment decisions. The purpose of this study was to develop and validate an MRI-based radiomics nomogram for the preoperative differentiation of BPGT from MPGT. A total of 115 patients (80 in training set and 35 in external validation set) with BPGT (n = 60) or MPGT (n = 55) were enrolled. Radiomics features were extracted from T1-weighted and fat-saturated T2-weighted images. A radiomics signature model and a radiomics score (Rad-score) were constructed and calculated. A clinical-factors model was built based on demographics and MRI findings. A radiomics nomogram model combining the Rad-score and independent clinical factors was constructed using multivariate logistic regression analysis. The diagnostic performance of the three models was evaluated and validated using ROC curves on the training and validation datasets. Seventeen features from MR images were used to build the radiomics signature. The radiomics nomogram incorporating the clinical factors and radiomics signature had an AUC value of 0.952 in the training set and 0.938 in the validation set. Decision curve analysis showed that the nomogram outperformed the clinical-factors model in terms of clinical usefulness. The above-described radiomics nomogram performed well for differentiating BPGT from MPGT, and may help in the clinical decision-making process. • Differential diagnosis between BPGT and MPGT is rather difficult by conventional imaging modalities. • A radiomics nomogram integrated with the radiomics signature, clinical data, and MRI features facilitates differentiation of BPGT from MPGT with improved diagnostic efficacy.