Meta-analysis of the diagnostic and clinical utility of genome and exome sequencing and chromosomal microarray in children with suspected genetic diseases.

NPJ Genom Med. 2018;3:16

Authors: Clark MM, Stark Z, Farnaes L, Tan TY, White SM, Dimmock D, Kingsmore SF

Abstract
Genetic diseases are leading causes of childhood mortality. Whole-genome sequencing (WGS) and whole-exome sequencing (WES) are relatively new methods for diagnosing genetic diseases, whereas chromosomal microarray (CMA) is well established. Here we compared the diagnostic utility (rate of causative, pathogenic, or likely pathogenic genotypes in known disease genes) and clinical utility (proportion in whom medical or surgical management was changed by diagnosis) of WGS, WES, and CMA in children with suspected genetic diseases by systematic review of the literature (January 2011-August 2017) and meta-analysis, following MOOSE/PRISMA guidelines. In 37 studies, comprising 20,068 children, diagnostic utility of WGS (0.41, 95% CI 0.34-0.48, I2 = 44%) and WES (0.36, 95% CI 0.33-0.40, I2 = 83%) were qualitatively greater than CMA (0.10, 95% CI 0.08-0.12, I2 = 81%). Among studies published in 2017, the diagnostic utility of WGS was significantly greater than CMA (P < 0.0001, I2 = 13% and I2 = 40%, respectively). Among studies featuring within-cohort comparisons, the diagnostic utility of WES was significantly greater than CMA (P < 0.001, I2 = 36%). The diagnostic utility of WGS and WES were not significantly different. In studies featuring within-cohort comparisons of WGS/WES, the likelihood of diagnosis was significantly greater for trios than singletons (odds ratio 2.04, 95% CI 1.62-2.56, I2 = 12%; P < 0.0001). Diagnostic utility of WGS/WES with hospital-based interpretation (0.42, 95% CI 0.38-0.45, I2 = 48%) was qualitatively higher than that of reference laboratories (0.29, 95% CI 0.27-0.31, I2 = 49%); this difference was significant among studies published in 2017 (P < .0001, I2 = 22% and I2 = 26%, respectively). The clinical utility of WGS (0.27, 95% CI 0.17-0.40, I2 = 54%) and WES (0.17, 95% CI 0.12-0.24, I2 = 76%) were higher than CMA (0.06, 95% CI 0.05-0.07, I2 = 42%); this difference was significant for WGS vs CMA (P < 0.0001). In conclusion, in children with suspected genetic diseases, the diagnostic and clinical utility of WGS/WES were greater than CMA. Subgroups with higher WGS/WES diagnostic utility were trios and those receiving hospital-based interpretation. WGS/WES should be considered a first-line genomic test for children with suspected genetic diseases.

PMID: 30002876 [PubMed]

Novel variants in COL4A4 and COL4A5 are rare causes of FSGS in two unrelated families.

Hum Genome Var. 2018;5:15

Authors: Hines SL, Agarwal A, Ghandour M, Nabeel A, Mohammad AN, Atwal PS

Abstract
We report two female patients with focal segmental glomerulosclerosis and chronic kidney disease. The first patient was found to have a heterozygous, de novo, pathogenic variant in COL4A5 (c.141+1G>A, IVS2+1G>A), which is associated with Alport syndrome. The second patient was found to have a heterozygous, likely pathogenic variant in COL4A4 (c.2842G>T). Both these variants in COL4A5 and COL4A4 are novel, and they were detected using whole exome sequencing and gene panel testing, respectively. Additionally, we discuss the complexities of diagnosis in such cases and the benefits of using the abovementioned diagnostic approaches.

PMID: 30002862 [PubMed]

Network-based approach to prediction and population-based validation of in silico drug repurposing.

Nat Commun. 2018 Jul 12;9(1):2691

Authors: Cheng F, Desai RJ, Handy DE, Wang R, Schneeweiss S, Barabási AL, Loscalzo J

Abstract
Here we identify hundreds of new drug-disease associations for over 900 FDA-approved drugs by quantifying the network proximity of disease genes and drug targets in the human (protein-protein) interactome. We select four network-predicted associations to test their causal relationship using large healthcare databases with over 220 million patients and state-of-the-art pharmacoepidemiologic analyses. Using propensity score matching, two of four network-based predictions are validated in patient-level data: carbamazepine is associated with an increased risk of coronary artery disease (CAD) [hazard ratio (HR) 1.56, 95% confidence interval (CI) 1.12-2.18], and hydroxychloroquine is associated with a decreased risk of CAD (HR 0.76, 95% CI 0.59-0.97). In vitro experiments show that hydroxychloroquine attenuates pro-inflammatory cytokine-mediated activation in human aortic endothelial cells, supporting mechanistically its potential beneficial effect in CAD. In summary, we demonstrate that a unique integration of protein-protein interaction network proximity and large-scale patient-level longitudinal data complemented by mechanistic in vitro studies can facilitate drug repurposing.

PMID: 30002366 [PubMed - in process]

Regulating Rare Disease: Safely Facilitating Access to Orphan Drugs.

Fordham Law Rev. 2018 Mar;86(4):1889-921

Authors: Bannister JB

Abstract
While approximately one in ten Americans suffers from a rare disease, only 5 percent of rare diseases have a U.S. Food and Drug Administration (FDA) approved treatment. Congressional and regulatory efforts to stimulate the development of rare-disease treatments, while laudable, have not resolved the fundamental issues surrounding rare-disease treatment development. Indeed, small patient populations, incomplete scientific understanding of rare diseases, and high development costs continually limit the availability of rare-disease treatments. To illustrate the struggle of developing and approving safe rare-disease treatments, this Note begins by discussing the approval of Eteplirsen, the first drug approved for treating a rare disease called Duchenne muscular dystrophy. After exploring the current drug regulation system and how this impacts the availability of rare-disease treatments, this Note examines the 21st Century Cures Act's patient experience data provisions and the currently pending Trickett Wendler Right to Try Act. Ultimately, the unmet therapeutic needs of rare-disease patients can be met while protecting patient safety. This Note reasons that, if carefully implemented, the 21st Century Cures Act and the Trickett Wendler Right to Try Act could work in tandem to safely facilitate patient access to rare-disease treatments.

PMID: 29993206 [PubMed - indexed for MEDLINE]

Retrovesical malignant fibrous histiocytoma: a rare tumor.

BMJ Case Rep. 2017 Dec 02;2017:

Authors: Pathak S, Soni TP, Gupta AK, Sharma LM

Abstract
Malignant fibrous histiocytoma (MFH) originating from the retrovesical space is a very rare tumour. A 61-year-old man presented to our hospital with complaints of retention of urine and burning sensation during micturition since 6 months. CT scan abdomen showed a large retrovesical mass between the urinary bladder and rectum, measuring 11×9×12 cm, displacing the urinary bladder. Serum PSA (Prostate Specific Antigen) value was within normal range. Biopsy from retrovesical mass and immunohistochemistry was suggestive of MFH. Wide excision of the retrovesical mass was done. Histopathology confirmed the diagnosis of MFH. He received adjuvant radiotherapy. He is on regular follow-up since the last 2 years after radiotherapy with no signs and symptoms of disease recurrence.

PMID: 29197849 [PubMed - indexed for MEDLINE]

Prior opioid exposure influences parents' sharing of their children's CYP2D6 research results.

Pharmacogenomics. 2017 Aug;18(13):1199-1213

Authors: Myers MF, Zhang X, McLaughlin B, Kissell D, Perry CL, Veerkamp M, Zhang K, Holm IA, Prows CA

Abstract
AIM: To determine parents' use of their children's CYP2D6 research result. We hypothesized that perceived utility, likelihood of sharing and actual sharing of results would differ between parents with children previously exposed (cases) or unexposed (controls) to opioids.
METHODS: We returned results by phone (baseline). We surveyed parents about perceived utility and likelihood of sharing their child's research result at baseline, and actual sharing at 3 and 12 months.
RESULTS: Cases were more likely than controls to agree that they (p = 0.022) and the doctors (p = 0.041) could use the results to care for their child, to report higher likelihood of sharing (p = 0.042) and to actually share results with the child's doctor (p = 0.026).
CONCLUSION: Prior opioid exposure influenced perceived clinical utility and sharing behaviors.

PMID: 28745549 [PubMed - indexed for MEDLINE]

Anaplastic Large T-Cell Lymphoma Associated with Breast Implants - Rare Disease.

Isr Med Assoc J. 2017 Jun;19(6):390-392

Authors: Ben-Nun O, Bitterman N, Tadmor T, Bejar J, Shalata A, Yarin H, Calderon N

PMID: 28647941 [PubMed - indexed for MEDLINE]

Any-k: Anytime Top-k Tree Pattern Retrieval in Labeled Graphs.

Proc Int World Wide Web Conf. 2018 Apr;2018:489-498

Authors: Yang X, Nicholson PK, Ajwani D, Riedewald M, Gatterbauer W, Sala A

Abstract
Many problems in areas as diverse as recommendation systems, social network analysis, semantic search, and distributed root cause analysis can be modeled as pattern search on labeled graphs (also called "heterogeneous information networks" or HINs). Given a large graph and a query pattern with node and edge label constraints, a fundamental challenge is to find the top-k matches according to a ranking function over edge and node weights. For users, it is difficult to select value k. We therefore propose the novel notion of an any-k ranking algorithm: for a given time budget, return as many of the top-ranked results as possible. Then, given additional time, produce the next lower-ranked results quickly as well. It can be stopped anytime, but may have to continue until all results are returned. This paper focuses on acyclic patterns over arbitrary labeled graphs. We are interested in practical algorithms that effectively exploit (1) properties of heterogeneous networks, in particular selective constraints on labels, and (2) that the users often explore only a fraction of the top-ranked results. Our solution, KARPET, carefully integrates aggressive pruning that leverages the acyclic nature of the query, and incremental guided search. It enables us to prove strong non-trivial time and space guarantees, which is generally considered very hard for this type of graph search problem. Through experimental studies we show that KARPET achieves running times in the order of milliseconds for tree patterns on large networks with millions of nodes and edges.

PMID: 30003197 [PubMed]

Multiplexed detection of DOCK8, PGM3 and STAT3 proteins for the diagnosis of Hyper-Immunoglobulin E syndrome using gold nanoparticles-based immunosensor array platform.

Biosens Bioelectron. 2018 Jun 28;117:613-619

Authors: Eissa S, Abdulkarim H, Dasouki M, Al Mousa H, Arnout R, Al Saud B, Rahman AA, Zourob M

Abstract
Multiplexed biosensors hold great promise for early diagnosis of diseases where the detection of multiple biomarkers is required. Hyper Immunoglobulin E syndromes (HIES) are rare primary immunodeficiency disorders associated with mutations either in the signal transducer and activator of transcription 3 (STAT3), dedicator of cytokinesis 8 DOCK8) or phosphoglucomutase 3 (PGM3) genes. Yet, the diagnosis of HIES is challenged by the complexity of the existing laboratory assays. Here, we report for the first time the development of a multiplexed electrochemical immunosensor for the simultaneous detection of DOCK8, STAT3 and PGM3 proteins. The immunosensor was constructed on carbon array electrodes that were first modified by electrodeposition of gold nanoparticles (AuNPs). The array electrodes were then used to immobilize specific antibodies for the three proteins after the functionalization of the electrodes with cysteamine/glutaraldehyde linkers. The simultaneous detection of the DOCK8, PGM3 and STAT3 proteins was successfully realized by the immunosensor with respective limits of detections of 3.1, 2.2 and 3.5 pg/ml. The immunosensor has shown good sensitivity as well as selectivity against other proteins such as cystic fibrosis transmembrane conductance regulator (CFTR) and Duchenne Muscular Dystrophy (DMD). Moreover, the immunosensor was successfully applied in human serum samples showing capability to distinguish the HIES from the control samples.

PMID: 30005381 [PubMed - as supplied by publisher]

SLC6A14, an amino acid transporter, modifies the primary CF defect in fluid secretion.

Elife. 2018 Jul 13;7:

Authors: Ahmadi S, Xia S, Wu YS, Di Paola M, Kissoon R, Luk C, Lin F, Du K, Rommens J, Bear C

Abstract
The severity of intestinal disease associated with Cystic Fibrosis (CF) is variable in the patient population and this variability is partially conferred by the influence of modifier genes. Genome-wide association studies have identified SLC6A14, an electrogenic amino acid transporter, as a genetic modifier of CF-associated meconium ileus. The purpose of the current work was to determine the biological role of Slc6a14, by disrupting its expression in CF mice bearing the major mutation, F508del. We found that disruption of Slc6a14 worsened the intestinal fluid secretion defect characteristic of these mice. In vitro studies of mouse intestinal organoids revealed that exacerbation of the primary defect was associated with reduced arginine uptake across the apical membrane, with aberrant nitric oxide and cyclic GMP mediated regulation of the major CF-causing mutant protein. Together, these studies highlight the role of this apical transporter in modifying cellular nitric oxide levels, residual function of the major CF mutant and potentially, its promise as a therapeutic target.

PMID: 30004386 [PubMed - as supplied by publisher]

PEGylated enhanced cell penetrating peptide nanoparticles for lung gene therapy.

J Control Release. 2018 Jul 03;285:35-45

Authors: Osman G, Rodriguez J, Chan SY, Chisholm J, Duncan G, Kim N, Tatler AL, Shakesheff KM, Hanes J, Suk JS, Dixon JE

Abstract
The lung remains an attractive target for the gene therapy of monogenetic diseases such as cystic fibrosis (CF). Despite over 27 clinical trials, there are still very few gene therapy vectors that have shown any improvement in lung function; highlighting the need to develop formulations with improved gene transfer potency and the desirable physiochemical characteristics for efficacious therapy. Herein, we introduce a novel cell penetrating peptide (CPP)-based non-viral vector that utilises glycosaminoglycan (GAG)-binding enhanced transduction (GET) for highly efficient gene transfer. GET peptides couple directly with DNA through electrostatic interactions to form nanoparticles (NPs). In order to adapt the GET peptide for efficient in vivo delivery, we engineered PEGylated versions of the peptide and employed a strategy to form DNA NPs with different densities of PEG coatings. We were able to identify candidate formulations (PEGylation rates ≥40%) that shielded the positively charged surface of particles, maintained colloidal stability in bronchoalveolar lavage fluid (BALF) and retained gene transfer activity in human bronchial epithelial cell lines and precision cut lung slices (PCLS) in vitro. Using multiple particle tracking (MPT) technology, we demonstrated that PEG-GET complexes were able to navigate the mucus mesh and diffuse rapidly through patient CF sputum samples ex vivo. When tested in mouse lung models in vivo, PEGylated particles demonstrated superior biodistribution, improved safety profiles and efficient gene transfer of a reporter luciferase plasmid compared to non-PEGylated complexes. Furthermore, gene expression was significantly enhanced in comparison to polyethylenimine (PEI), a non-viral gene carrier that has been widely tested in pre-clinical settings. This work describes an innovative approach that combines novel GET peptides for enhanced transfection with a tuneable PEG coating for efficacious lung gene therapy.

PMID: 30004000 [PubMed - as supplied by publisher]

Testosterone enhances expression and functional activity of epithelial sodium channel (ENaC), Cystic Fibrosis transmembrane regulator (CFTR) and sodium hydrogen exchanger (NHE) in vas deferens of sex-steroid deficient male rats.

Steroids. 2018 Jul 09;:

Authors: Ramli NSK, Giribabu N, Salleh N

Abstract
Effects of testosterone on expression and functional activity of ENaC, CFTR and NHE in vas deferens were investigated.
METHODS: Orchidectomized, adult male rats were given 125 and 250μg/kg/day testosterone subcutaneously, with or without flutamide and finasteride for seven consecutive days. At the end of the treatment, rats were anesthetized and vas deferens were perfused. Changes in vas deferens fluid secretion rate, pH, HCO3-, Cl- and Na+ concentrations were recorded in the presence of amiloride and Cftr inh-172. Rats were then sacrificed and vas deferens were harvested and subjected for molecular biological analysis Results:Testosterone treatment caused the fluid secretion rate, pH and HCO3- concentrations to decrease but Cl- and Na+ concentrations to increase, where upon amiloride administration, the pH and HCO3- concentration increased but Cl- and Na+ concentrations further increased. In testosterone-treated rats, administration of Cftr inh-172 caused all fluid parameters to decrease. In testosterone-treated rats co-administered with flutamide or finasteride, pH and HCO3- concentration increased but fluid secretion rate, Cl- and Na+ concentrations decreased and these parameters were not affected by amiloride or Cftr inh-172 administration. Under testosterone influence, CFTR and γ-ENaC were highly expressed at the apical membrane while NHE-1 and 4 were highly expressed at the basolateral membrane of vas deferens epithelium. Meanwhile, NHE-2 and 3 were highly expressed at the apical membrane.
CONCLUSIONS: Differential expression of ENaC, CFTR and NHE in vas deferens under testosterone influence indicated the important role of these transporters in creating optimal fluid microenvironment that is essential for preserving male fertility.

PMID: 30003911 [PubMed - as supplied by publisher]

Analysis of oxygen uptake efficiency parameters in young people with cystic fibrosis.

Eur J Appl Physiol. 2018 Jul 12;:

Authors: Tomlinson OW, Barker AR, Chubbock LV, Stevens D, Saynor ZL, Oades PJ, Williams CA

Abstract
PURPOSE: This study characterised oxygen uptake efficiency (OUE) in children with mild-to-moderate cystic fibrosis (CF). Specifically, it investigated (1) the utility of OUE parameters as potential submaximal surrogates of peak oxygen uptake ([Formula: see text]), and (2) the relationship between OUE and disease severity.
METHODS: Cardiopulmonary exercise test (CPET) data were collated from 72 children [36 CF, 36 age- and sex-matched controls (CON)], with OUE assessed as its highest 90-s average (plateau; OUEP), the gas exchange threshold (OUEGET) and respiratory compensation point (OUERCP). Pearson's correlation coefficients, independent t tests and factorial ANOVAs assessed differences between groups and the use of OUE measures as surrogates for [Formula: see text].
RESULTS: A significant (p < 0.05) reduction in allometrically scaled [Formula: see text] and all OUE parameters was found in CF. Significant (p < 0.05) correlations between measurements of OUE and allometrically scaled [Formula: see text], were observed in CF (r = 0.49-0.52) and CON (r = 0.46-0.52). Furthermore, measures of OUE were significantly (p < 0.05) correlated with pulmonary function (FEV1%predicted) in CF (r = 0.38-0.46), but not CON (r = -0.20-0.14). OUEP was able to differentiate between different aerobic fitness tertiles in CON but not CF.
CONCLUSIONS: OUE parameters were reduced in CF, but were not a suitable surrogate for [Formula: see text]. Clinical teams should, where possible, continue to utilise maximal CPET parameters to measure aerobic fitness in children and adolescents with CF. Future research should assess the prognostic utility of OUEP as it does appear sensitive to disease status and severity.

PMID: 30003381 [PubMed - as supplied by publisher]

Exome Chip Analysis Identifies Low-Frequency and Rare Variants in MRPL38 for White Matter Hyperintensities on Brain Magnetic Resonance Imaging.

Stroke. 2018 Jul 12;:

Authors: Jian X, Satizabal CL, Smith AV, Wittfeld K, Bis JC, Smith JA, Hsu FC, Nho K, Hofer E, Hagenaars SP, Nyquist PA, Mishra A, Adams HHH, Li S, Teumer A, Zhao W, Freedman BI, Saba Y, Yanek LR, Chauhan G, van Buchem MA, Cushman M, Royle NA, Bryan RN, Niessen WJ, Windham BG, DeStefano AL, Habes M, Heckbert SR, Palmer ND, Lewis CE, Eiriksdottir G, Maillard P, Mathias RA, Homuth G, Valdés-Hernández MDC, Divers J, Beiser AS, Langner S, Rice KM, Bastin ME, Yang Q, Maldjian JA, Starr JM, Sidney S, Risacher SL, Uitterlinden AG, Gudnason VG, Nauck M, Rotter JI, Schreiner PJ, Boerwinkle E, van Duijn CM, Mazoyer B, von Sarnowski B, Gottesman RF, Levy D, Sigurdsson S, Vernooij MW, Turner ST, Schmidt R, Wardlaw JM, Psaty BM, Mosley TH, DeCarli CS, Saykin AJ, Bowden DW, Becker DM, Deary IJ, Schmidt H, Kardia SLR, Ikram MA, Debette S, Grabe HJ, Longstreth WT, Seshadri S, Launer LJ, Fornage M, neuroCHARGE Working Group

Abstract
BACKGROUND AND PURPOSE: White matter hyperintensities (WMH) on brain magnetic resonance imaging are typical signs of cerebral small vessel disease and may indicate various preclinical, age-related neurological disorders, such as stroke. Though WMH are highly heritable, known common variants explain a small proportion of the WMH variance. The contribution of low-frequency/rare coding variants to WMH burden has not been explored.
METHODS: In the discovery sample we recruited 20 719 stroke/dementia-free adults from 13 population-based cohort studies within the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, among which 17 790 were of European ancestry and 2929 of African ancestry. We genotyped these participants at ≈250 000 mostly exonic variants with Illumina HumanExome BeadChip arrays. We performed ethnicity-specific linear regression on rank-normalized WMH in each study separately, which were then combined in meta-analyses to test for association with single variants and genes aggregating the effects of putatively functional low-frequency/rare variants. We then sought replication of the top findings in 1192 adults (European ancestry) with whole exome/genome sequencing data from 2 independent studies.
RESULTS: At 17q25, we confirmed the association of multiple common variants in TRIM65, FBF1, and ACOX1 (P<6×10-7). We also identified a novel association with 2 low-frequency nonsynonymous variants in MRPL38 (lead, rs34136221; PEA=4.5×10-8) partially independent of known common signal (PEA(conditional)=1.4×10-3). We further identified a locus at 2q33 containing common variants in NBEAL1, CARF, and WDR12 (lead, rs2351524; Pall=1.9×10-10). Although our novel findings were not replicated because of limited power and possible differences in study design, meta-analysis of the discovery and replication samples yielded stronger association for the 2 low-frequency MRPL38 variants (Prs34136221=2.8×10-8).
CONCLUSIONS: Both common and low-frequency/rare functional variants influence WMH. Larger replication and experimental follow-up are essential to confirm our findings and uncover the biological causal mechanisms of age-related WMH.

PMID: 30002152 [PubMed - as supplied by publisher]

Identification of mutations in the PI3K-AKT-mTOR signalling pathway in patients with macrocephaly and developmental delay and/or autism.

Mol Autism. 2017;8:66

Authors: Yeung KS, Tso WWY, Ip JJK, Mak CCY, Leung GKC, Tsang MHY, Ying D, Pei SLC, Lee SL, Yang W, Chung BH

Abstract
Background: Macrocephaly, which is defined as a head circumference greater than or equal to + 2 standard deviations, is a feature commonly observed in children with developmental delay and/or autism spectrum disorder. Although PTEN is a well-known gene identified in patients with this syndromic presentation, other genes in the PI3K-AKT-mTOR signalling pathway have also recently been suggested to have important roles. The aim of this study is to characterise the mutation spectrum of this group of patients.
Methods: We performed whole-exome sequencing of 21 patients with macrocephaly and developmental delay/autism spectrum disorder. Sources of genomic DNA included blood, buccal mucosa and saliva. Germline mutations were validated by Sanger sequencing, whereas somatic mutations were validated by droplet digital PCR.
Results: We identified ten pathogenic/likely pathogenic mutations in PTEN (n = 4), PIK3CA (n = 3), MTOR (n = 1) and PPP2R5D (n = 2) in ten patients. An additional PTEN mutation, which was classified as variant of unknown significance, was identified in a patient with a pathogenic PTEN mutation, making him harbour bi-allelic germline PTEN mutations. Two patients harboured somatic PIK3CA mutations, and the level of somatic mosaicism in blood DNA was low. Patients who tested positive for mutations in the PI3K-AKT-mTOR pathway had a lower developmental quotient than the rest of the cohort (DQ = 62.8 vs. 76.1, p = 0.021). Their dysmorphic features were non-specific, except for macrocephaly. Among the ten patients with identified mutations, brain magnetic resonance imaging was performed in nine, all of whom showed megalencephaly.
Conclusion: We identified mutations in the PI3K-AKT-mTOR signalling pathway in nearly half of our patients with macrocephaly and developmental delay/autism spectrum disorder. These patients have subtle dysmorphic features and mild developmental issues. Clinically, patients with germline mutations are difficult to distinguish from patients with somatic mutations, and therefore, sequencing of buccal or saliva DNA is important to identify somatic mosaicism. Given the high diagnostic yield and the management implications, we suggest implementing comprehensive genetic testing in the PI3K-AKT-mTOR pathway in the clinical evaluation of patients with macrocephaly and developmental delay and/or autism spectrum disorder.

PMID: 29296277 [PubMed - indexed for MEDLINE]

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