An efficient privacy-preserving blockchain storage method for internet of things environment.

Blockchain is a key technology to realize decentralized trust management. In recent studies, sharding-based blockchain models are proposed and applied to the resource-constrained Internet of Things (IoT) scenario, and machine learning-based models are presented to improve the query efficiency of the sharding-based blockchains by classifying hot data and storing them locally. However, in some scenarios, these presented blockchain models cannot be deployed because the block features used as input in the learning method are privacy. In this paper, we propose an efficient privacy-preserving blockchain storage method for the IoT environment. The new method classifies hot blocks based on the federated extreme learning machine method and saves the hot blocks through one of the sharded blockchain models called ElasticChain. The features of hot blocks will not be read by other nodes in this method, and user privacy is effectively protected. Meanwhile, hot blocks are saved locally, and data query speed is improved. Furthermore, in order to comprehensively evaluate a hot block, five features of hot blocks are defined, including objective feature, historical popularity, potential popularity, storage requirements and training value. Finally, the experimental results on synthetic data demonstrate the accuracy and efficiency of the proposed blockchain storage model.

A relaxometry method that emphasizes practicality and availability.

PURPOSE: Although many methods have been proposed to quantitatively map the main MRI parameters (e.g., T1 , T2 , C × M0 ), these methods often involve special sequences not readily available on clinical scanners and/or may require long scan times. In contrast, the proposed method can readily run on most scanners, offer flexible tradeoffs between scan time and image quality, and map MRI parameters jointly to ensure spatial alignment. METHODS: The approach is based on the multi-shot spin-echo (SE) EPI sequence. The corresponding signal equation was derived and strategies for solving it were developed. As usual with multi-shot EPI, scan time can readily be traded-off against image quality by adjusting the echo train length. Validation was performed against reference relaxometry methods, in gel phantoms with varying concentrations of gadobutrol and gadoterate meglumine contrast agents. In vivo examples are further presented, from 3 neuroradiology patients. RESULTS: Bland-Altman analysis was performed: for T2 , as compared to 2D SE, bias was 0.29 ms and the 95% limits of agreement ranged from -1.15 to +1.73 ms. For T1 , compared to inversion-recovery SE (and MOLLI), bias was -20.2 ms (and -14.5 ms) and the limits of agreement ranged from -62.4 to +22.0 ms (and -53.8 to +24.9 ms). The mean relative T1 error between the proposed method and each of the 2 reference methods was similar to that of the reference methods among themselves. CONCLUSION: In the constellation of existing relaxometry methods, the proposed method is meant to stand out in terms of its practicality and availability.

The Prediction for COVID-19 Outbreak in China by using the Concept of Term Structure for the Turning Period.

This study aims to develop a general framework for predicting the duration of the Turning Period (or Turning Phase) for the COVID-19 outbreak in China that started in late December 2019 from Wuhan. A new concept called the Term Structure for Turning Period (instead of Turning Point) is used for this study, and the framework, implemented into an individual SEIR (iSEIR) model, has enabled a timely prediction of the turning period when applied to Wuhan's COVID-19 epidemic, and provided the opportunity for relevant authorities to take appropriate and timely actions to successfully control the epidemic. By using the observed daily COVID-19 cases in Wuhan from January 23, 2020 to February 6 (and February 10), 2020 as inputs to the framework it allowed us to generate the trajectory of COVID-19 dynamics and to predict that the Turning Period of COVID-19 outbreak in Wuhan would arrive within one week after February 14. This prediction turned out to be timely and accurate, which has provided adequate time for the government, hospitals and related sectors and services to meet peak demand and to prepare aftermath planning. We want to emphasize that emergency risk management entails the implementation of an emergency plan, where timing the Turning Period is key to express a clear timeline for effective actions. Our study confirms the observed effectiveness of Wuhan's Lockdown and Isolation control program imposed since January 23, 2020 to the middle of March, 2020 and resulted in swiftly flattened epidemic curve, and Wuhan's success offers an exemplary lesson for the world to learn in combating COVID-19 pandemic.

Accelerated Segmented Diffusion-Weighted Prostate Imaging for Higher Resolution, Higher Geometric Fidelity, and Multi-b Perfusion Estimation.

PURPOSE: The aim of this study was to improve the geometric fidelity and spatial resolution of multi-b diffusion-weighted magnetic resonance imaging of the prostate. MATERIALS AND METHODS: An accelerated segmented diffusion imaging sequence was developed and evaluated in 25 patients undergoing multiparametric magnetic resonance imaging examinations of the prostate. A reduced field of view was acquired using an endorectal coil. The number of sampled diffusion weightings, or b-factors, was increased to allow estimation of tissue perfusion based on the intravoxel incoherent motion (IVIM) model. Apparent diffusion coefficients measured with the proposed segmented method were compared with those obtained with conventional single-shot echo-planar imaging (EPI). RESULTS: Compared with single-shot EPI, the segmented method resulted in faster acquisition with 2-fold improvement in spatial resolution and a greater than 3-fold improvement in geometric fidelity. Apparent diffusion coefficient values measured with the novel sequence demonstrated excellent agreement with those obtained from the conventional scan (R = 0.91 for bmax = 500 s/mm and R = 0.89 for bmax = 1400 s/mm). The IVIM perfusion fraction was 4.0% ± 2.7% for normal peripheral zone, 6.6% ± 3.6% for normal transition zone, and 4.4% ± 2.9% for suspected tumor lesions. CONCLUSIONS: The proposed accelerated segmented prostate diffusion imaging sequence achieved improvements in both spatial resolution and geometric fidelity, along with concurrent quantification of IVIM perfusion.

Fast diffusion imaging with high angular resolution.

PURPOSE: High angular resolution diffusion imaging (HARDI) is a well-established method to help reveal the architecture of nerve bundles, but long scan times and geometric distortions inherent to echo planar imaging (EPI) have limited its integration into clinical protocols. METHODS: A fast imaging method is proposed here that combines accelerated multishot diffusion imaging (AMDI), multiplexed sensitivity encoding (MUSE), and crossing fiber angular resolution of intravoxel structure (CFARI) to reduce spatial distortions and reduce total scan time. A multishot EPI sequence was used to improve geometrical fidelity as compared to a single-shot EPI acquisition, and acceleration in both k-space and diffusion sampling enabled reductions in scan time. The method is regularized and self-navigated for motion correction. Seven volunteers were scanned in this study, including four with volumetric whole brain acquisitions. RESULTS: The average similarity of microstructural orientations between undersampled datasets and their fully sampled counterparts was above 85%, with scan times below 5 min for whole-brain acquisitions. Up to 2.7-fold scan time acceleration along with four-fold distortion reduction was achieved. CONCLUSION: The proposed imaging strategy can generate HARDI results with relatively good geometrical fidelity and low scan duration, which may help facilitate the transition of HARDI from a successful research tool to a practical clinical one. Magn Reson Med 77:696-706, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Hybrid MRI-Ultrasound acquisitions, and scannerless real-time imaging.

PURPOSE: To combine MRI, ultrasound, and computer science methodologies toward generating MRI contrast at the high frame rates of ultrasound, inside and even outside the MRI bore. METHODS: A small transducer, held onto the abdomen with an adhesive bandage, collected ultrasound signals during MRI. Based on these ultrasound signals and their correlations with MRI, a machine-learning algorithm created synthetic MR images at frame rates up to 100 per second. In one particular implementation, volunteers were taken out of the MRI bore with the ultrasound sensor still in place, and MR images were generated on the basis of ultrasound signal and learned correlations alone in a "scannerless" manner. RESULTS: Hybrid ultrasound-MRI data were acquired in eight separate imaging sessions. Locations of liver features, in synthetic images, were compared with those from acquired images: The mean error was 1.0 pixel (2.1 mm), with best case 0.4 and worst case 4.1 pixels (in the presence of heavy coughing). For results from outside the bore, qualitative validation involved optically tracked ultrasound imaging with/without coughing. CONCLUSION: The proposed setup can generate an accurate stream of high-speed MR images, up to 100 frames per second, inside or even outside the MR bore. Magn Reson Med 78:897-908, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

PSD-95 regulates CRFR1 localization, trafficking and ß-arrestin2 recruitment.

Corticotropin-releasing factor (CRF) is a neuropeptide commonly associated with the hypothalamic-pituitary adrenal axis stress response. Upon release, CRF activates two G protein-coupled receptors (GPCRs): CRF receptor 1 (CRFR1) and CRF receptor 2 (CRFR2). Although both receptors contribute to mood regulation, CRFR1 antagonists have demonstrated anxiolytic and antidepressant-like properties that may be exploited in the generation of new pharmacological interventions for mental illnesses. Previous studies have demonstrated CRFR1 capable of heterologously sensitizing serotonin 2A receptor (5-HT2AR) signaling: another GPCR implicated in psychiatric disease. Interestingly, this phenomenon was dependent on Postsynaptic density 95 (PSD-95)/Disc Large/Zona Occludens (PDZ) interactions on the distal carboxyl termini of both receptors. In the current study, we demonstrate that endogenous PSD-95 can be co-immunoprecipitated with CRFR1 from cortical brain homogenate, and this interaction appears to be primarily via the PDZ-binding motif. Additionally, PSD-95 colocalizes with CRFR1 within the dendritic projections of cultured mouse neurons in a PDZ-binding motif-dependent manner. In HEK 293 cells, PSD-95 overexpression inhibited CRFR1 endocytosis, whereas PSD-95 shRNA knockdown enhanced CRFR1 endocytosis. Although PSD-95 does not appear to play a significant role in CRF-mediated cAMP or ERK1/2 signaling, PSD-95 was demonstrated to suppress ß-arrestin2 recruitment: providing a potential mechanism for PSD-95's inhibition of endocytosis. In revisiting previously documented heterologous sensitization, PSD-95 shRNA knockdown did not prevent CRFR1-mediated enhancement of 5-HT2AR signaling. In conclusion, we have identified and characterized a novel functional relationship between CRFR1 and PSD-95 that may have implications in the design of new treatment strategies for mental illness.

On replacing the manual measurement of ACR phantom images performed by MRI technologists with an automated measurement approach.

PURPOSE: To assess whether measurements on American College of Radiology (ACR) phantom images performed by magnetic resonance imaging (MRI) technologists as part of a weekly quality control (QC) program could be performed exclusively using an automated system without compromising the integrity of the QC program. MATERIALS AND METHODS: ACR phantom images are acquired on 15 MRI scanners at a number of ACR-accredited sites to fulfill requirements of a weekly QC program. MRI technologists routinely perform several measurements on these images. Software routines are also used to perform the measurements. A set of geometry measurements made by technologists over a five week period and those made using software routines were compared to reference-standard measurements made by two MRI physicists. RESULTS: The geometry measurements performed by software routines had a very high positive correlation (0.92) with the reference-standard measurements. Technologist measurements also had a high positive correlation (0.63), although the correlation was less than for the automated measurements. Bland-Altman analysis revealed overall good agreement between the automated and reference-standard measurements, with the 95% limits of agreement being within ±0.62 mm. Agreement between the technologist and the reference-standard measurements was demonstratively poorer, with 95% limits of agreement being ±1.46 mm. Some of the technologist measurements differed from the reference standard by as much as 2 mm. CONCLUSION: The technologists' geometry measurements may be able to be replaced by automated measurement without compromising the weekly QC program required by the ACR.

Next generation multilocus sequence typing (NGMLST) and the analytical software program MLSTEZ enable efficient, cost-effective, high-throughput, multilocus sequencing typing.

Multilocus sequence typing (MLST) has become the preferred method for genotyping many biological species, and it is especially useful for analyzing haploid eukaryotes. MLST is rigorous, reproducible, and informative, and MLST genotyping has been shown to identify major phylogenetic clades, molecular groups, or subpopulations of a species, as well as individual strains or clones. MLST molecular types often correlate with important phenotypes. Conventional MLST involves the extraction of genomic DNA and the amplification by PCR of several conserved, unlinked gene sequences from a sample of isolates of the taxon under investigation. In some cases, as few as three loci are sufficient to yield definitive results. The amplicons are sequenced, aligned, and compared by phylogenetic methods to distinguish statistically significant differences among individuals and clades. Although MLST is simpler, faster, and less expensive than whole genome sequencing, it is more costly and time-consuming than less reliable genotyping methods (e.g. amplified fragment length polymorphisms). Here, we describe a new MLST method that uses next-generation sequencing, a multiplexing protocol, and appropriate analytical software to provide accurate, rapid, and economical MLST genotyping of 96 or more isolates in single assay. We demonstrate this methodology by genotyping isolates of the well-characterized, human pathogenic yeast Cryptococcus neoformans.

Hybrid Utrasound and MRI Acquisitions for High-Speed Imaging of Respiratory Organ Motion.

Magnetic Resonance (MR) imaging provides excellent image quality at a high cost and low frame rate. Ultrasound (US) provides poor image quality at a low cost and high frame rate. We propose an instance-based learning system to obtain the best of both worlds: high quality MR images at high frame rates from a low cost single-element US sensor. Concurrent US and MRI pairs are acquired during a relatively brief offine learning phase involving the US transducer and MR scanner. High frame rate, high quality MR imaging of respiratory organ motion is then predicted from US measurements, even after stopping MRI acquisition, using a probabilistic kernel regression framework. Experimental results show predicted MR images to be highly representative of actual MR images.

Role of SAP97 in the regulation of 5-HT2AR endocytosis and signaling.

Serotonin (5-HT) interacts with a wide variety of 5-HT receptors (5-HTR) of which 5-HT2AR plays an important target for antidepressant and atypical antipsychotic drugs. The carboxyl-terminal tail of 5-HT2AR encodes a motif that mediates interactions with PSD-95/disc large/zona occludens (PDZ) domain-containing proteins. In the present study, we found that 5-HT2AR interacts with synapse-associated protein 97 (SAP97; also known as DLG1) by coimmunoprecipitation in human embryonic 293 (HEK 293) cells and cortical brain lysates. We found that 5-HT2AR expression results in the recruitment of SAP97 from the cytosol to the plasma membrane and that this recruitment is dependent on an intact 5-HT2AR PDZ binding motif. We also show that 5-HT2AR interacts with SAP97 using bioluminescence energy transfer and that overexpression of SAP97 retards 5-HT2AR endocytosis, while single hairpin RNA knockdown facilitates 5-HT2AR internalization. The knockdown of SAP97 in HEK 293 cells results in a reduction in the maximum efficacy for 5-HT2AR-stimulated inositol phosphate formation and that the deletion of the 5-HT2AR PDZ motif also impairs 5-HT2AR signaling. Similarly to what has been observed for the corticotropin-releasing factor receptor 1 (CRFR1), SAP97 expression is essential for 5-HT2AR-stimulated extracellular-regulated protein kinase 1/2 (ERK1/2) phosphorylation by a PDZ interaction-independent mechanism. Moreover, we find that SAP97 is not responsible for CRFR1-mediated sensitization of 5-HT2AR signaling. Taken together, our studies show that SAP97 plays a conserved role in regulating 5-HT2AR endocytosis and ERK1/2 signaling, but plays a novel role in regulating 5-HT2AR G protein coupling.

Genomic mapping of phosphorothioates reveals partial modification of short consensus sequences.

Bacterial phosphorothioate (PT) DNA modifications are incorporated by Dnd proteins A-E and often function with DndF-H as a restriction-modification (R-M) system, as in Escherichia coli B7A. However, bacteria such as Vibrio cyclitrophicus FF75 lack dndF-H, which points to other PT functions. Here we report two novel, orthogonal technologies to map PTs across the genomes of B7A and FF75 with >90% agreement: single molecule, real-time sequencing and deep sequencing of iodine-induced cleavage at PT (ICDS). In B7A, we detect PT on both strands of GpsAAC/GpsTTC motifs, but with only 12% of 40,701 possible sites modified. In contrast, PT in FF75 occurs as a single-strand modification at CpsCA, again with only 14% of 160,541 sites modified. Single-molecule analysis indicates that modification could be partial at any particular genomic site even with active restriction by DndF-H, with direct interaction of modification proteins with GAAC/GTTC sites demonstrated with oligonucleotides. These results point to highly unusual target selection by PT-modification proteins and rule out known R-M mechanisms.

Complex interplay among DNA modification, noncoding RNA expression and protein-coding RNA expression in Salvia miltiorrhiza chloroplast genome.

Salvia miltiorrhiza is one of the most widely used medicinal plants. As a first step to develop a chloroplast-based genetic engineering method for the over-production of active components from S. miltiorrhiza, we have analyzed the genome, transcriptome, and base modifications of the S. miltiorrhiza chloroplast. Total genomic DNA and RNA were extracted from fresh leaves and then subjected to strand-specific RNA-Seq and Single-Molecule Real-Time (SMRT) sequencing analyses. Mapping the RNA-Seq reads to the genome assembly allowed us to determine the relative expression levels of 80 protein-coding genes. In addition, we identified 19 polycistronic transcription units and 136 putative antisense and intergenic noncoding RNA (ncRNA) genes. Comparison of the abundance of protein-coding transcripts (cRNA) with and without overlapping antisense ncRNAs (asRNA) suggest that the presence of asRNA is associated with increased cRNA abundance (p<0.05). Using the SMRT Portal software (v1.3.2), 2687 potential DNA modification sites and two potential DNA modification motifs were predicted. The two motifs include a TATA box-like motif (CPGDMM1, "TATANNNATNA"), and an unknown motif (CPGDMM2 "WNYANTGAW"). Specifically, 35 of the 97 CPGDMM1 motifs (36.1%) and 91 of the 369 CPGDMM2 motifs (24.7%) were found to be significantly modified (p<0.01). Analysis of genes downstream of the CPGDMM1 motif revealed the significantly increased abundance of ncRNA genes that are less than 400 bp away from the significantly modified CPGDMM1motif (p<0.01). Taking together, the present study revealed a complex interplay among DNA modifications, ncRNA and cRNA expression in chloroplast genome.

Fiber-optic bronchoscopy and volume-cycled mouthpiece ventilation for a patient with multiple sclerosis and ventilatory failure.

Fiber-optic bronchoscopy supported by continuous or bilevel positive airway pressure has helped patients with hypoxemic or hypercapnic respiratory failure avoid respiratory complications. The authors describe a case of a 57-yr-old man with multiple sclerosis with a vital capacity of 250 ml (5% of predicted normal) who was using continuous noninvasive intermittent positive pressure ventilatory support when he underwent bronchoscopy while receiving continuous noninvasive intermittent positive pressure ventilatory support via a 15-mm angled mouthpiece interface. He was switched from a nasal to a 15-mm angled mouthpiece interface for continuous noninvasive intermittent positive pressure ventilatory support for the procedure. Simple mouthpieces may be useful alternatives to other facial interfaces for ventilatory support during bronchoscopy because of patient comfort and operator convenience.

Accelerated multi-shot diffusion imaging.

PURPOSE: To reduce image distortion in MR diffusion imaging using an accelerated multi-shot method. METHODS: The proposed method exploits the fact that diffusion-encoded data tend to be sparse when represented in the kb-kd space, where kb and kd are the Fourier transform duals of b and d, the b-factor and the diffusion direction, respectively. Aliasing artifacts are displaced toward under-used regions of the kb-kd plane, allowing nonaliased signals to be recovered. A main characteristic of the proposed approach is how thoroughly the navigator information gets used during reconstruction: The phase of navigator images is used for motion correction, while the magnitude of the navigator signal in kb-kd space is used for regularization purposes. As opposed to most acceleration methods based on compressed sensing, the proposed method reduces the number of ky lines needed for each diffusion-encoded image, but not the total number of images required. Consequently, it tends to be most effective at reducing image distortion rather than reducing total scan time. RESULTS: Results are presented for three volunteers with acceleration factors ranging from 4 to 8, with and without the inclusion of parallel imaging. CONCLUSION: An accelerated motion-corrected diffusion imaging method was introduced that achieves good image quality at relatively high acceleration factors.

Genome reference and sequence variation in the large repetitive central exon of human MUC5AC.

Despite modern sequencing efforts, the difficulty in assembly of highly repetitive sequences has prevented resolution of human genome gaps, including some in the coding regions of genes with important biological functions. One such gene, MUC5AC, encodes a large, secreted mucin, which is one of the two major secreted mucins in human airways. The MUC5AC region contains a gap in the human genome reference (hg19) across the large, highly repetitive, and complex central exon. This exon is predicted to contain imperfect tandem repeat sequences and multiple conserved cysteine-rich (CysD) domains. To resolve the MUC5AC genomic gap, we used high-fidelity long PCR followed by single molecule real-time (SMRT) sequencing. This technology yielded long sequence reads and robust coverage that allowed for de novo sequence assembly spanning the entire repetitive region. Furthermore, we used SMRT sequencing of PCR amplicons covering the central exon to identify genetic variation in four individuals. The results demonstrated the presence of segmental duplications of CysD domains, insertions/deletions (indels) of tandem repeats, and single nucleotide variants. Additional studies demonstrated that one of the identified tandem repeat insertions is tagged by nonexonic single nucleotide polymorphisms. Taken together, these data illustrate the successful utility of SMRT sequencing long reads for de novo assembly of large repetitive sequences to fill the gaps in the human genome. Characterization of the MUC5AC gene and the sequence variation in the central exon will facilitate genetic and functional studies for this critical airway mucin.

Genetic forms of the cardiometabolic syndrome: what can they tell the clinician?

A well-worn medical aphorism states that "when you hear hoof beats, think of a horse and not a zebra." When applying this principle to the cardiometabolic syndrome (CMS), the horse would be represented by the prevalent CMS phenotype that affects approximately 30% of individuals in Westernized societies, while the zebra is represented by very rare conditions--such as lipodystrophy syndromes--that share some features with the more prevalent CMS. For instance, familial partial lipodystrophy types 2 and 3 result from heterozygous mutations in LMNA, encoding nuclear lamin A/C, and in PPARG, encoding peroxisome proliferator-activated receptor (PPAR)-gamma, respectively. Patients with either subtype of partial lipodystrophy exhibit an increased ratio of central to peripheral fat stores, dysglycemia, dyslipidemia, and hypertension, with predisposition for developing insulin-resistant diabetes and atherosclerosis end points. Sometimes, however, the zebra serves as a model that can help us understand the horse, so that the rare partial lipodystrophies might offer some insight into pathogenesis and treatment of the more prevalent CMS.

Hypertriglyceridemia: its etiology, effects and treatment.

Elevated plasma triglyceride concentration is a common biochemical finding, but the evidence for the benefit of treating this lipid disturbance remains less robust than that for treating elevated low-density lipoprotein-cholesterol. Part of the difficulty in the provision of specific recommendations has been the frequent coexistence of elevated triglycerides with other conditions that affect cardiovascular disease risk, such as depressed high-density lipoprotein-cholesterol, obesity, metabolic syndrome, proinflammatory and prothrombotic biomarkers, and type 2 diabetes. Recent investigations of outcomes of cardiovascular disease when medications are used to reduce triglyceride levels suggest that, although a net benefit probably exists, both relative and absolute risk reductions seem underwhelming when compared with the benefit of reducing low-density lipoprotein-cholesterol levels with treatment. However, the totality of evidence suggests that elevated triglyceride levels likely contribute independently to increased risk of cardiovascular disease, although there is no consensus about appropriate target levels. Furthermore, severe hypertriglyceridemia is associated with an increased risk of acute pancreatitis, irrespective of its effect on risk of cardiovascular disease. We review the causes and classification of elevated triglyceride levels, the clinical manifestations of primary hypertriglyceridemia and the management of patients with elevated triglyceride levels.

Heterozygous familial hypercholesterolemia: an underrecognized cause of early cardiovascular disease.

Heterozygous familial hypercholesterolemia (HeFH) is a monogenic disorder that affects about 1 in 500 people, with a higher prevalence in certain subpopulations such as people of Quebecois, Christian Lebanese and Dutch South Afrikaner extraction. HeFH is characterized by cholesterol deposits affecting the corneas, eyelids and extensor tendons; elevated plasma concentrations of low-density lipoprotein (LDL) cholesterol; and accelerated vascular disease, especially coronary artery disease (CAD). Although HeFH is genetically heterogeneous, it is most often caused by heterozygous mutations in the LDLR gene encoding the LDL receptor. We describe a man who was diagnosed with HeFH after he had a myocardial infarction at 33 years of age. By DNA sequence analysis, he was found to have a heterozygous splicing mutation in his LDLR gene. This discovery expanded the growing mutational spectrum in patients with HeFH in Ontario. Given that HeFH is a treatable cause of early vascular disease, it is important that this condition be recognized, diagnosed and treated in affected patients; but as yet, there is no consensus on the best approach. Diagnostic criteria based on family history and clinical presentation have been proposed for patients with suspected HeFH. Biochemical or molecular screening might be considered to detect new cases of HeFH in populations with a relatively high HeFH prevalence and a relatively small number of possible causative mutations. So far, however, the most cost-effective and efficient systematic strategy to detect previously undiagnosed cases of HeFH is still cascade testing: clinical and biochemical screening of close relatives of the proband patient diagnosed with HeFH. Pharmacologic treatment of HeFH is cost-effective.