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Purpose of Review Describe the application of implementation science to improve the detection and management of familial hypercholesterolaemia. Recent Findings Gaps between evidence and practice, such as underutilization of genetic testing, family cascade testing, failure to achieve LDL-cholesterol goals and low levels of knowledge and awareness, have been identified through clinical registry analyses and clinician surveys. Implementation science theories, models and frameworks have been applied to assess barriers and enablers in the literature specific to local contextual factors (e.g. stages of life). The effect of implementation strategies to overcome these factors has been evaluated; for example, automated identification of individuals with FH or training and education to improve statin adherence. Clinical registries were identified as a key infrastructure to monitor, evaluate and sustain improvements in care. Summary The expansion in evidence supporting the care of familial hypercholesterolaemia requires a similar expansion of efforts to translate new knowledge into clinical practice.

While linear ubiquitin plays critical roles in multiple cell signaling pathways, few substrates have been identified. Global profiling of linear ubiquitin substrates represents a significant challenge because of the low endogenous level of linear ubiquitination and the background interference arising from highly abundant ubiquitin linkages (e.g. K48- and K63-) and from the non-specific attachment of interfering proteins to the linear polyubiquitin chain. We developed a bio-orthogonal linear ubiquitin probe by site-specific encoding of a norbornene amino acid on ubiquitin (NAEK-Ub). This probe facilitates covalent labeling of linear ubiquitin substrates in live cells and enables selective enrichment and identification of linear ubiquitin-modified proteins. Given the fact that the frequent overexpression of the linear linkage-specific deubiquitinase OTULIN correlates with poor prognosis in glioblastoma, we demonstrated the feasibility of the NAEK-Ub strategy by identifying and validating substrates of linear ubiquitination in patient-derived glioblastoma stem-like cells (GSCs). We identified STAT3 as a bona fide substrate of linear ubiquitin, and showed that linear ubiquitination negatively regulates STAT3 activity by recruitment of the phosphatase TC-PTP to STAT3. Furthermore, we demonstrated that preferential expression of OTULIN in GSCs restricts linear ubiquitination on STAT3 and drives persistent STAT3 signaling, and thereby maintains the stemness and self-renewal of GSCs.

Objective To observe the impact of mind-regulating acupuncture plus donepezil on the cognitive ability, mean cerebral blood flow velocity, event-related potential P300, and activities of daily living (ADL) in the aged patients with Alzheimer disease (AD). Methods Sixty senile AD patients were divided into a treatment group and a control group following the envelope method for random allocation, with 30 cases in each group. Based on the conventional treatment of the internal medicine, the control group received oral donepezil, and the treatment group received oral donepezil plus mind-regulating acupuncture. After 4-week treatment, the two groups were evaluated by the mini-mental state examination (MMSE), Alzheimer disease assessment scale-cognitive part (ADAS-Cog), and ADL; changes in P300 and the mean cerebral blood flow velocity were also observed. Results Before treatment, there were no significant differences in the scores of MMSE, ADAS-Cog, or ADL between the two groups (P>0.05). The MMSE score increased after treatment in both groups and was notably higher in the treatment group than in the control group, showing intra-group and inter-group statistical significance (PPPPPP Conclusion Mind-regulating acupuncture plus donepezil can regulate the latency and amplitude of P300, increase cerebral blood flow, and improve the learning and memory abilities of AD patients.

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.

ImportanceThe Netherlands is one of the few countries that has a long-term history of active screening for familial hypercholesterolemia (FH), enabling health-economic analyses.ObjectiveTo investigate cost-effectiveness and the return on investment (ROI) of a nationwide cascade case-finding and preventive treatment program starting with identification of FH in children and treatment, from both a societal and health care perspective.Design, Setting, and ParticipantsCascade case-finding and early preventive treatment were modeled to simulate the progression of disease and costs of 10-year-olds suspected of having heterozygous FH over a lifetime. The model consisted of 3 health states: alive without coronary heart disease (CHD), alive with CHD, and deceased. Mendelian randomization analysis was used to quantify the risk of a first CHD event as a function of age and total lifetime exposure to low-density lipoprotein cholesterol. Cost-effectiveness was defined as €20 000 ($21 800) per QALYs (quality-adjusted life-years) gained, using incremental cost-effectiveness ratios (ICERs). All future benefits and costs were discounted annually by 1.5% and 4%, respectively.InterventionsThe study compared 2 strategies: (1) cascade screening and initiation of treatment with statins in children (mean age, 10 years) and (2) no screening, later detection, and treatment.Main Outcomes and MeasuresOutcome of interest included cost, detection, and successful treatment of FH in terms of life-years gained and QALYs. The clinical and cost outputs for each model in the 2 scenarios (early detection and treatment and later detection and treatment) were totaled to determine the overall cost-effectiveness and ROI attributed to implementation of the Dutch FH program.ResultsIn this model constructed to simulate the progression of FH in 1000 hypothetical 10-year-olds, from a health care perspective, the program would gain 2.53 QALYs per person, at an additional cost of €23 365 ($25 468) (both discounted). These equated to an ICER of €9220 ($10 050) per QALY gained. From the societal perspective, the detection and treatment program were cost saving over a lifetime compared with no cascade screening for FH. The ROI for the detection and treatment program for FH in children was €8.37 ($9.12).Conclusions and RelevanceThe findings of this study suggest that the early detection and treatment program for FH in children may offer a good value for investment, being both health and cost saving. The findings and interpretations are conditional on assumptions inherent in the health economic model.

With the continuous spread of drug-resistant tuberculosis, there is an urgent need for new antituberculosis drugs with new mechanisms. The ability of Mtb to resist oxidative stress is extremely important for maintaining redox homeostasis and survival in the host.

Background: Heterozygous familial hypercholesterolemia (HeFH) is under-detected and undertreated. A general practitioner-led screening and care program for HeFH effectively identified and managed patients with HeFH. We evaluated the cost-effectiveness and the return on investment of an enhanced-care strategy for HeFH in primary care in Australia. Methods: We developed a multistate Markov model to estimate the outcomes and costs of a general practitioner-led detection and management strategy for HeFH in primary care compared with the standard of care in Australia. The population comprised individuals aged 50 to 80 years, of which 44% had prior cardiovascular disease. Cardiovascular risk, HeFH prevalence, treatment effects, and acute and chronic health care costs were derived from published sources. The study involved screening for HeFH using a validated data-extraction tool (TARB-Ex), followed by a consultation to improve care. The detection rate of HeFH was 16%, and 74% of the patients achieved target LDL-C (low-density lipoprotein cholesterol). Quality-adjusted life years, health care costs, productivity losses, incremental cost-effectiveness ratio, and return on investment ratio were evaluated, outcomes discounted by 5% annually, adopting a health care and a societal perspective. Results: Over the lifetime horizon, the model estimated a gain of 870 years of life lived and 1033 quality-adjusted life years when the general practitioner-led program was employed compared with standard of care. This resulted in an incremental cost-effectiveness ratio of AU$14 664/quality-adjusted life year gained from a health care perspective. From a societal perspective, this strategy, compared with standard of care was cost-saving, with a return on investment of AU$5.64 per dollar invested. Conclusions: An enhanced general practitioner-led model of care for HeFH is likely to be cost-effective.

Oil peony is an important oil crop, which has high quality and oil content. In order to improve the cutting quality and harvest efficiency of oil peony, the cutting equipment of the pruning machine and harvester is a key component. Also, the accurate prediction of cutting force of oil peony stalk is one of the essential processes for the design of the cutting equipment. In this article, to accurately predicted the cutting force of the stalk, the physical property parameters and chemical components were considered as influencing factors, which were used to establish the model of mechanical property parameter of oil peony stalk. The physical property parameters of oil peony stalk included the stalk diameter, internode distance, fresh weight, dry weight, relative moisture content, volume, fresh density, and dry density. The chemical components of the stalk were cellulose, hemicellulose, and lignin. Besides, the modeling methods, which were the partial least squares regression (PLSR), principal component analysis (PCA) couple with multiple linear regression (MLR), and grey relational analysis (GRA) couple with MLR, were used to optimize the multiple parameters (physical property parameters and chemical components). The results showed that the internode distance and relative moisture content had significant effects on the cutting force of oil peony stalk. The R c 2 and R p 2 values of the GRA (0.5) + MLR method were 0.801 and 0.820, and RMSEC and RMSEP values were 2.862N and 4.715N, respectively. Consequently, the GRA + MLR method could be used to predict the cutting force of oil peony stalk, which was an important basis for the design of precision cutting equipment.

Shone's complex is a rare syndrome characterized by congenital left heart defects that can differ among the patients.To use echocardiography in the diagnosis of Shone's complex and analyze the causes of missed diagnosis and misdiagnosis.This was a retrospective study of patients who underwent echocardiography and repair surgery from February 14, 2008, to November 22, 2019. The patients were followed once a year at the outpatient clinic after surgery.Sixty-six patients were included. The patients were 2.7 (0.8-5.6) years of age, and 54.5% were male. Ten (15.2%) had a history of heart surgery. The most common heart defect was the Annulo-Leaflet mitral ring (ALMR) (50/66, 75.8%), followed by coarctation of the aorta (CoA) (43/66, 65.2%). The patients had a variety of combinations of defects. Only two (3.0%) patients had all four defects. None of the patients had a family history of congenital heart disease. The preoperative echocardiographic findings were examined against the intraoperative findings. Echocardiography missed an ALMR in 31 patients (47.0%), a parachute mitral valve (PMV) in one patient (1.5%), subaortic stenosis in one patient (1.5%), and CoA in two patients (3.0%).Echocardiography is an effective method to diagnose the Shone's complex. Due to this disease's complexity and interindividual variability, Improving the understanding of the disease can reduce misdiagnosis and missed diagnosis.

In this paper, we point out that Lin’s general neighborhood systems-based rough set model is an extension of Qian’s optimistic rough set model, and thus called optimistic general neighborhood systmes-based rough set model. Then we present a new rough set model based on general neighborhood systems, and prove that it is an extension of Qian’s pessimistic rough set model. Later, we study the basic properties of the proposed pessimistic rough sets, and define the serial, reflexive, symmetric, transitive and Euclidean conditions for general neighborhood systems, and explore the further properties of related rough sets. Furthermore, we apply the pessimistic general neighborhood systems-based rough set model in the research of incomplete information system, and build a three-way decision model based on it. A simple practical example to show the effectiveness of our model is also presented.

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.

This study clarifies the heat generation and release of a 57.5 Ah HED (266.9 W h kg−1) Li-ion cell with a nickel-rich cathode and SiOx/graphite anode. Significant heat accumulation and delayed heat release effects in large-format cells are uncovered.

In this article, various exact solutions of the fifth-order variable coefficient KdV equation with higher-order dispersion term are studied. Because of the complexity of the exact solution of the variable coefficient t, it has a certain influence on the tension waves at the fluid interface on the gravity surface. First, the bilinear KdV equation is derived by using the Hirota bilinear method, and four mixed solutions consisting of positive quartic function, quadratic function, exponential function, and hyperbolic function are constructed. Second, the linear superposition principle is used to obtain the resonance multisoliton solution, and two cases are taken as examples to illustrate the study of resonance multi soliton solution. In addition, 3D images and contour images are drawn by mathematical symbol calculation and appropriate parameters, and the process of tension fluctuation is vividly explained by physical phenomena. The results obtained greatly expand the exact solution of the KdV equation in the existing literature and enable us to understand nonlinear dynamical systems more deeply.

Substitution of the six cysteine residues resulted in changes in Mtb CYP142A1 structure, binding ability, thermal stability and oxidation efficiency.

Background Lipoprotein(a) [Lp(a)] is a risk factor for cardiovascular disease. The burden of thrombus in ST-segment elevation myocardial infarction (STEMI) has implications on treatment and outcomes. However, the association between Lp(a) and atherothrombosis in STEMI remains unclear. Objectives Determine the association between Lp(a) and culprit artery thrombus burden in younger patients with STEMI. Methods Single-centre study of 83 patients aged 30 mg/dL. Multivariate analysis was performed adjusting for cardiovascular risk factors. Results The mean age was 48.08.4 years and 78.3% were male. Thirteen (16%), 9 (11%) and 61 (73%) patients had small, moderate, or large thrombus burden, respectively, and 34 (41%) had elevated Lp(a). Elevated Lp(a) was associated with greater thrombus burden compared to normal Lp(a) (large burden 85% versus 65%; P=0.024). Elevated Lp(a) was associated with moderate or large thrombus in univariate [OR 10.70 (95% CI 1.32-86.82); P=0.026] and multivariate analysis [OR 10.33 (95% CI 1.19-89.52); P=0.034]. Lp(a) was not associated with culprit artery or stenosis location according to culprit artery. Conclusions Elevated Lp(a) is associated with greater thrombus burden in younger patients with STEMI. The finding of this observational study accords with the thrombotic and anti-fibrinolytic properties of Lp(a). A causal relationship requires verification.

Lanthanide metal-organic frameworks (Ln-MOFs) are promising for luminescence detection of volatile organic compound (VOC) vapors, but usually suffer from the silent or quenched Ln3+ emission. Herein, we report a new dual-emissive Eu-MOF composed of the coordinatively unsaturated Eu9 clusters that afford abundant open metal sites to form a confined "binding pocket" to facilitate the preconcentration and recognition of VOCs. Single-crystal structural analyses reveal that specific analytes can replace the OH oscillators in the first coordination sphere of Eu3+ and form a unique hydrogen-bonding second-sphere adduct tying adjacent Eu9 clusters together to minimize their nonradiative vibrational decay. With the promoted Eu3+ luminescence, the MOF realizes real-time in situ visual sensing of THF vapor (1 s) and shows a quantitative ratiometric response to the vapor pressure with a limit of detection down to 17.33 Pa. Also, it represents a top-performing ratiometric luminescent thermometer.

A nonlinear oscillator with zero initial conditions is considered, which makes some effective methods, for example, the variational iteration method and the homotopy perturbation method, invalid. To solve the bottleneck, this paper suggests a simple transform to convert the problem into a traditional case so that He’s frequency formulation can be effectively used to solve its approximate solution. An microelectromechanical system (MEMS) oscillator is used as example to show the solution process, and a good result is obtained.

Antimicrobial resistance has been an increasingly serious threat to global public health. Anti-virulence strategies are being developed to manage antibiotic resistance because they apply a lower selective pressure for antimicrobial-resistant pathogens than that created using traditional bactericides. We aimed to discover novel small molecules that can reduce the production of virulence factors in Pseudomonas aeruginosa and determine the mechanism of action underlying these effects. A clinical compound library was screened, and ostarine was identified as a potential anti-virulence agent. The effects of ostarine were studied via antimicrobial susceptibility testing, bacterial growth assays, pyocyanin quantitation assays, transcriptomic analysis, quorum sensing signal molecule quantification, and real-time PCR assays. Ostarine treatment significantly decreased the synthesis of pyocyanin without any bactericidal action. Besides, ostarine treatment did not affect the relative growth rate and cell morphology of bacteria. Treatment with ostarine interfered with quorum sensing by decreasing the transcription of genes associated with quorum sensing systems and the production of signalling molecules. The inhibition of ostarine on pyocyanin production and gene expression can be alleviated when signalling molecules were supplemented externally. Overall, ostarine may act as a novel anti-virulence agent that can attenuate P. aeruginosa pyocyanin by interfering with quorum sensing systems.

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.

Emerging drug resistance is generating an urgent need for novel and effective antibiotics. A promising target that has not yet been addressed by approved antibiotics is the bacterial DNA gyrase subunit B (GyrB), and GyrB inhibitors could be effective against drug-resistant bacteria, such as methicillin-resistant

Accurate pretreatment assessment of histological differentiation grade of head and neck squamous cell carcinoma (HNSCC) is crucial for prognosis evaluation. This study aimed to construct and validate a contrast-enhanced computed tomography (CECT)-based deep learning radiomics nomogram (DLRN) to predict histological differentiation grades of HNSCC.A total of 204 patients with HNSCC who underwent CECT scans were enrolled in this study. The participants recruited from two hospitals were split into a training set (n=124, 74 well/moderately differentiated and 50 poorly differentiated) of patients from one hospital and an external test set of patients from the other hospital (n=80, 49 well/moderately differentiated and 31 poorly differentiated). CECT-based manually-extracted radiomics (MER) features and deep learning (DL) features were extracted and selected. The selected MER features and DL features were then combined to construct a DLRN via multivariate logistic regression. The predictive performance of the DLRN was assessed using ROCs and decision curve analysis (DCA).Three MER features and seven DL features were finally selected. The DLRN incorporating the selected MER and DL features showed good predictive value for the histological differentiation grades of HNSCC (well/moderately differentiated vs. poorly differentiated) in both the training (AUC, 0.878) and test (AUC, 0.822) sets. DCA demonstrated that the DLRN was clinically useful for predicting histological differentiation grades of HNSCC.A CECT-based DLRN was constructed to predict histological differentiation grades of HNSCC. The DLRN showed good predictive efficacy and might be useful for prognostic evaluation of patients with HNSCC.

Mitochondrial dysfunction in heart triggers an integrated stress response (ISR) through phosphorylation of eIF2α and subsequent ATF4 activation. DAP3 Binding Cell Death Enhancer 1 (DELE1) is a mitochondrial protein recently found to be critical for mediating mitochondrial stress-triggered ISR (MSR)-induced eIF2α-ATF4 pathway activation. However, the specific role of DELE1 in heart at baseline or in response to mitochondrial stress remains largely unknown. In this study, we report that DELE1 is dispensable for cardiac development and function under baseline conditions. Conversely, DELE1 is essential for mediating an adaptive response to mitochondrial dysfunction-triggered stress in the heart, playing a protective role in mitochondrial cardiomyopathy.

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.