Funding Opportunity RFA-DA-18-014 from the NIH Guide for Grants and Contracts. The purpose of this funding opportunity is to identify genetic and epigenetic factors that affect the recovery of the CD4+ T cells in response to anti-retroviral therapy in HIV infected people who inject drugs infected

Notice NOT-HG-17-012 from the NIH Guide for Grants and Contracts

Notice NOT-AI-17-033 from the NIH Guide for Grants and Contracts

Funding Opportunity PA-17-452 from the NIH Guide for Grants and Contracts. This funding opportunity announcement (FOA) issued by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) encourages research project grants (R01) investigating the incidence, course, and outcomes of pregnancy among women with disabilities. Areas of interest also include studies to inform preconceptional and antenatal counseling and strategies for addressing barriers to prenatal care, and management of pregnancy, the puerperium, and the transition to parenthood in order to optimize outcomes for women with physical, intellectual and developmental, and/or sensory disabilities and their families. Applicants are encouraged to include women with disabilities and members of the community in the design and conduct of their research.

Funding Opportunity PA-17-451 from the NIH Guide for Grants and Contracts. This funding opportunity announcement (FOA) issued by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) encourages small research project grants (R03) investigating the incidence, course, and outcomes of pregnancy among women with disabilities. Areas of interest also include studies to inform preconceptional and antenatal counseling and strategies for addressing barriers to prenatal care, and management of pregnancy, the puerperium, and the transition to parenthood in order to optimize outcomes for women with physical, intellectual and developmental, and/or sensory disabilities and their families. Applicants are encouraged to include women with disabilities and members of the community in the design and conduct of their research.

Related Articles

A Fast Association Test for Identifying Pathogenic Variants Involved in Rare Diseases.

Am J Hum Genet. 2017 Jul 06;101(1):104-114

Authors: Greene D, NIHR BioResource, Richardson S, Turro E

Abstract
We present a rapid and powerful inference procedure for identifying loci associated with rare hereditary disorders using Bayesian model comparison. Under a baseline model, disease risk is fixed across all individuals in a study. Under an association model, disease risk depends on a latent bipartition of rare variants into pathogenic and non-pathogenic variants, the number of pathogenic alleles that each individual carries, and the mode of inheritance. A parameter indicating presence of an association and the parameters representing the pathogenicity of each variant and the mode of inheritance can be inferred in a Bayesian framework. Variant-specific prior information derived from allele frequency databases, consequence prediction algorithms, or genomic datasets can be integrated into the inference. Association models can be fitted to different subsets of variants in a locus and compared using a model selection procedure. This procedure can improve inference if only a particular class of variants confers disease risk and can suggest particular disease etiologies related to that class. We show that our method, called BeviMed, is more powerful and informative than existing rare variant association methods in the context of dominant and recessive disorders. The high computational efficiency of our algorithm makes it feasible to test for associations in the large non-coding fraction of the genome. We have applied BeviMed to whole-genome sequencing data from 6,586 individuals with diverse rare diseases. We show that it can identify multiple loci involved in rare diseases, while correctly inferring the modes of inheritance, the likely pathogenic variants, and the variant classes responsible.

PMID: 28669401 [PubMed - indexed for MEDLINE]

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Electronic Health Record Based Algorithm to Identify Patients with Autism Spectrum Disorder.

PLoS One. 2016;11(7):e0159621

Authors: Lingren T, Chen P, Bochenek J, Doshi-Velez F, Manning-Courtney P, Bickel J, Wildenger Welchons L, Reinhold J, Bing N, Ni Y, Barbaresi W, Mentch F, Basford M, Denny J, Vazquez L, Perry C, Namjou B, Qiu H, Connolly J, Abrams D, Holm IA, Cobb BA, Lingren N, Solti I, Hakonarson H, Kohane IS, Harley J, Savova G

Abstract
OBJECTIVE: Cohort selection is challenging for large-scale electronic health record (EHR) analyses, as International Classification of Diseases 9th edition (ICD-9) diagnostic codes are notoriously unreliable disease predictors. Our objective was to develop, evaluate, and validate an automated algorithm for determining an Autism Spectrum Disorder (ASD) patient cohort from EHR. We demonstrate its utility via the largest investigation to date of the co-occurrence patterns of medical comorbidities in ASD.
METHODS: We extracted ICD-9 codes and concepts derived from the clinical notes. A gold standard patient set was labeled by clinicians at Boston Children's Hospital (BCH) (N = 150) and Cincinnati Children's Hospital and Medical Center (CCHMC) (N = 152). Two algorithms were created: (1) rule-based implementing the ASD criteria from Diagnostic and Statistical Manual of Mental Diseases 4th edition, (2) predictive classifier. The positive predictive values (PPV) achieved by these algorithms were compared to an ICD-9 code baseline. We clustered the patients based on grouped ICD-9 codes and evaluated subgroups.
RESULTS: The rule-based algorithm produced the best PPV: (a) BCH: 0.885 vs. 0.273 (baseline); (b) CCHMC: 0.840 vs. 0.645 (baseline); (c) combined: 0.864 vs. 0.460 (baseline). A validation at Children's Hospital of Philadelphia yielded 0.848 (PPV). Clustering analyses of comorbidities on the three-site large cohort (N = 20,658 ASD patients) identified psychiatric, developmental, and seizure disorder clusters.
CONCLUSIONS: In a large cross-institutional cohort, co-occurrence patterns of comorbidities in ASDs provide further hypothetical evidence for distinct courses in ASD. The proposed automated algorithms for cohort selection open avenues for other large-scale EHR studies and individualized treatment of ASD.

PMID: 27472449 [PubMed - indexed for MEDLINE]

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Protocol-Driven Decision Support within e-Referral Systems to Streamline Patient Consultation, Triaging and Referrals from Primary Care to Specialist Clinics.

J Med Syst. 2017 Sep;41(9):139

Authors: Maghsoud-Lou E, Christie S, Abidi SR, Abidi SSR

Abstract
Patient referral is a protocol where the referring primary care physician refers the patient to a specialist for further treatment. The paper-based current referral process at times lead to communication and operational issues, resulting in either an unfulfilled referral request or an unnecessary referral request. Despite the availability of standardized referral protocols they are not readily applied because they are tedious and time-consuming, thus resulting in suboptimal referral requests. We present a semantic-web based Referral Knowledge Modeling and Execution Framework to computerize referral protocols, clinical guidelines and assessment tools in order to develop a computerized e-Referral system that offers protocol-based decision support to streamline and standardize the referral process. We have developed a Spinal Problem E-Referral (SPER) system that computerizes the Spinal Condition Consultation Protocol (SCCP) mandated by the Halifax Infirmary Division of Neurosurgery (Halifax, Canada) for referrals for spine related conditions (such as back pain). The SPER system executes the ontologically modeled SCCP to determine (i) patient's triaging option as per severity assessments stipulated by SCCP; and (b) clinical recommendations as per the clinical guidelines incorporated within SCCP. In operation, the SPER system identifies the critical cases and triages them for specialist referral, whereas for non-critical cases SPER system provides clinical guideline based recommendations to help the primary care physician effectively manage the patient. The SPER system has undergone a pilot usability study and was deemed to be easy to use by physicians with potential to improve the referral process within the Division of Neurosurgery at QEII Health Science Center, Halifax, Canada.

PMID: 28766103 [PubMed - in process]

rs2841277 (PLD4) is associated with susceptibility and rs4672495 is associated with disease activity in rheumatoid arthritis.

Oncotarget. 2017 Jul 18;:

Authors: Chen WC, Wang WC, Lu HF, Okada Y, Chang WP, Chou YH, Chang HH, Huang JD, Chen DY, Chang WC

Abstract
Rheumatoid arthritis (RA) is one of the most common autoimmune diseases, can lead to long-term joint damage, chronic pain, and loss of motor function in the hands, and may share some common genetic factors with other autoimmune disorders, such as ankylosing spondylitis (AS). Many single-nucleotide polymorphisms (SNPs) were reported by genome-wide association studies (GWASs) of RA, but some of them have not been examined in the Taiwanese population. In this study, for 15 SNPs reported in previous RA and AS GWASs, we investigated their association with RA in a Taiwanese population. Based on 334 RA patients recruited from the Taichung Veterans General Hospital and 16,036 healthy subjects from the Taiwan Biobank (TWB) project, we observed that subjects having minor allele C at rs2841277 (phospholipase D family, member 4 (PLD4)) have lower susceptibility of RA, compare to those having genotype TT (Odds ratio (OR) = 0.6, p = 3.0 x 10-6). Among the RA patients, we observed that subjects having GG at rs4672495 have a lower proportion of severe RA, compare to other subjects (OR = 0.09, p = 5.6 x 10-3). Results of a bioinformatics approach showed that rs2841277 is able to influence expression of LINC00638 and AHNAK2 and rs4672495 is able to influence the expression of B3GNT2. In summary, this study replicated an association of rs2841277 with RA susceptibility and showed an AS-associated SNP, rs4672495, is associated with RA activity in the Taiwanese population.

PMID: 28767437 [PubMed - as supplied by publisher]

Clarifying Busulfan Metabolism and Drug Interactions to Support New Therapeutic Drug Monitoring Strategies: A Comprehensive Review.

Expert Opin Drug Metab Toxicol. 2017 Aug 02;:

Authors: Myers AL, Kawedia JD, Champlin RE, Kramer MA, Nieto Y, Ghose R, Andersson BS

Abstract
INTRODUCTION: Busulfan (Bu) is an alkylating agent with a limited therapeutic margin and exhibits inter-patient variability in pharmacokinetics (PK). Despite decades of use, mechanisms of Bu PK-based drug-drug interactions (DDIs), as well as the negative downstream effects of these DDIs, have not been fully characterized. Areas covered: This article provides an overview of Bu PK, with a primary focus on how known and potentially unknown drug metabolism pathways influence Bu-associated DDIs. In addition, pharmacogenomics of Bu chemotherapy and Bu-related DDIs observed in the stem cell transplant clinic (SCT) are summarized. Finally the increasing importance of Bu therapeutic drug monitoring is highlighted. Expert Opinion: Mechanistic studies of Bu metabolism have shown that in addition to GST isoenzymes, other oxidative enzymes (CYP, FMO) and ABC/MDR drug transporters likely contribute to the overall clearance of Bu. Despite many insights, results from clinical studies, especially in polypharmacy settings and between pediatric and adult patients, remain conflicting. Further basic science and clinical investigative efforts are required to fully understand the key factors determining Bu PK characteristics and its effects on complications after SCT. Improved TDM strategies are promising components to further investigate, for instance DDI mechanisms and patient outcomes, in the highly complex SCT treatment setting.

PMID: 28766962 [PubMed - as supplied by publisher]

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Reply to WB Grant.

Am J Clin Nutr. 2017 Aug;106(2):700-701

Authors: Byberg L, Olsson E, Karlström B, Cederholm T, Melhus H, Sjögren P, Kilander L

PMID: 28765386 [PubMed - in process]

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Reply to Y Mao and H Yu.

Am J Clin Nutr. 2017 Aug;106(2):698-699

Authors: Byberg L, Olsson E, Karlström B, Cederholm T, Melhus H, Sjögren P, Kilander L

PMID: 28765384 [PubMed - in process]

Related Articles

C-reactive protein and cardiovascular risk in bipolar disorder patients: A systematic review.

Prog Neuropsychopharmacol Biol Psychiatry. 2017 Jul 29;:

Authors: Marshe VS, Pira S, Mantere O, Bosche B, Looper KJ, Herrmann N, Müller DJ, Rej S

Abstract
OBJECTIVES: New research is revealing a strong association between inflammatory markers with bipolar disorder (BD), potentially due to the high prevalence of cardiovascular disease and cardiovascular risk factors in BD. We aimed to synthesize the literature examining the association between the clinically most relevant inflammatory marker, C-reactive protein (CRP) and cardiovascular disease and cardiovascular risk factors in patients with BD.
METHODS: MEDLINE, Embase and PsychInfo were systematically searched for all relevant English language articles published prior to April 2017. Articles were included if they examined the association between CRP and cardiovascular risk factors/disease in BD.
RESULTS: Fifteen relevant articles were retrieved. Studies were mostly cross-sectional and heterogeneous in the cardiovascular risk factors investigated. Overall, elevated CRP was associated with increased risk of metabolic syndrome, elevated body mass index, higher waist circumference, and obesity. CRP was inconsistently associated with elevated fasting glucose, insulin levels, serum triglycerides, total cholesterol levels, and low high density lipoprotein (HDL) levels. Atypical antipsychotic use may mediate some of these effects. No study examined CRP's association with actual cardiovascular disease (e.g. coronary artery disease) in BD.
CONCLUSIONS: In BD, CRP is associated with increases in several cardiovascular risk factors, suggesting that systemic inflammation could be a shared driving force for both outcomes of BD and cardiovascular risk. Further longitudinal research is needed in this area to verify causality, including an examination of actual cardiovascular disease. Non-pharmacological and pharmacological treatments with anti-inflammatory effects should also be investigated, particularly in patients with increased CRP, for their potential to reduce cardiovascular risk in BD.

PMID: 28764912 [PubMed - as supplied by publisher]

Related Articles

Physicians' pharmacogenomics information needs and seeking behavior: a study with case vignettes.

BMC Med Inform Decis Mak. 2017 Aug 01;17(1):113

Authors: Heale BSE, Khalifa A, Stone BL, Nelson S, Del Fiol G

Abstract
BACKGROUND: Genetic testing, especially in pharmacogenomics, can have a major impact on patient care. However, most physicians do not feel that they have sufficient knowledge to apply pharmacogenomics to patient care. Online information resources can help address this gap. We investigated physicians' pharmacogenomics information needs and information-seeking behavior, in order to guide the design of pharmacogenomics information resources that effectively meet clinical information needs.
METHODS: We performed a formative, mixed-method assessment of physicians' information-seeking process in three pharmacogenomics case vignettes. Interactions of 6 physicians' with online pharmacogenomics resources were recorded, transcribed, and analyzed for prominent themes. Quantitative data included information-seeking duration, page navigations, and number of searches entered.
RESULTS: We found that participants searched an average of 8 min per case vignette, spent less than 30 s reviewing specific content, and rarely refined search terms. Participants' information needs included a need for clinically meaningful descriptions of test interpretations, a molecular basis for the clinical effect of drug variation, information on the logistics of carrying out a genetic test (including questions related to cost, availability, test turn-around time, insurance coverage, and accessibility of expert support).Also, participants sought alternative therapies that would not require genetic testing.
CONCLUSION: This study of pharmacogenomics information-seeking behavior indicates that content to support their information needs is dispersed and hard to find. Our results reveal a set of themes that information resources can use to help physicians find and apply pharmacogenomics information to the care of their patients.

PMID: 28764766 [PubMed - in process]

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Up-Regulation of CYP2C19 Expression by BuChang NaoXinTong via PXR Activation in HepG2 Cells.

PLoS One. 2016;11(7):e0160285

Authors: Sun H, Lou XY, Wu XY, Wang H, Qu Q, Tan SL, Ruan JS, Qu J, Chen H

Abstract
BACKGROUND: Cytochrome P450 2C19 (CYP2C19) is an important drug-metabolizing enzyme (DME), which is responsible for the biotransformation of several kinds of drugs such as proton pump inhibitors, platelet aggregation inhibitors and antidepressants. Previous studies showed that Buchang NaoXinTong capsules (NXT) increased the CYP2C19 metabolic activity in vitro and enhanced the antiplatelet effect of clopidogrel in vivo. However, the underlying molecular mechanism remained unclear. In the present study, we examined whether Pregnane X receptor (PXR) plays a role in NXT-mediated regulation of CYP2C19 expression.
METHODS: We applied luciferase assays, real-time quantitative PCR (qPCR), Western blotting and cell-based analysis of metabolic activity experiments to investigate the NXT regulatory effects on the CYP2C19 promoter activity, the mRNA/ protein expression and the metabolic activity.
RESULTS: Our results demonstrated that NXT significantly increased the CYP2C19 promoter activity when co-transfected with PXR in HepG2 cells. Mutations in PXR responsive element abolished the NXT inductive effects on the CYP2C19 promoter transcription. Additionally, NXT incubation (150 and 250μg/mL) also markedly up-regulated endogenous CYP2C19 mRNA and protein levels in PXR-transfected HepG2 cells. Correspondingly, NXT leaded to a significant enhancement of the CYP2C19 catalytic activity in PXR-transfected HepG2 cells.
CONCLUSION: In summary, this is the first study to suggest that NXT could induce CYP2C19 expression via PXR activation.

PMID: 27467078 [PubMed - indexed for MEDLINE]

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Targeting surface voids to counter membrane disorders in lipointoxication-related diseases.

J Cell Sci. 2016 Jun 15;129(12):2368-81

Authors: Ferru-Clément R, Spanova M, Dhayal S, Morgan NG, Hélye R, Becq F, Hirose H, Antonny B, Vamparys L, Fuchs PF, Ferreira T

Abstract
Saturated fatty acids (SFA), which are abundant in the so-called western diet, have been shown to efficiently incorporate within membrane phospholipids and therefore impact on organelle integrity and function in many cell types. In the present study, we have developed a yeast-based two-step assay and a virtual screening strategy to identify new drugs able to counter SFA-mediated lipointoxication. The compounds identified here were effective in relieving lipointoxication in mammalian β-cells, one of the main targets of SFA toxicity in humans. In vitro reconstitutions and molecular dynamics simulations on bilayers revealed that these molecules, albeit according to different mechanisms, can generate voids at the membrane surface. The resulting surface defects correlate with the recruitment of loose lipid packing or void-sensing proteins required for vesicular budding, a central cellular process that is precluded under SFA accumulation. Taken together, the results presented here point at modulation of surface voids as a central parameter to consider in order to counter the impacts of SFA on cell function.

PMID: 27142833 [PubMed - indexed for MEDLINE]

Mutation in the COX4I1 gene is associated with short stature, poor weight gain and increased chromosomal breaks, simulating Fanconi anemia.

Eur J Hum Genet. 2017 Aug 02;:

Authors: Abu-Libdeh B, Douiev L, Amro S, Shahrour M, Ta-Shma A, Miller C, Elpeleg O, Saada A

Abstract
We describe a novel autosomal recessive form of mitochondrial disease in a child with short stature, poor weight gain, and mild dysmorphic features with highly suspected Fanconi anemia due to a mutation in COX4I1 gene. Whole Exome Sequencing was performed then followed by Sanger confirmation, identified a K101N mutation in COX4I1, segregating with the disease. This nuclear gene encodes the common isoform of cytochrome c oxidase (COX) subunit 4 (COX 4-1), an integral regulatory part of COX (respiratory chain complex IV) the terminal electron acceptor of the mitochondrial respiratory chain. The patient's fibroblasts disclosed decreased COX activity, impaired ATP production, elevated ROS production, decreased expression of COX4I1 mRNA and undetectable (COX4) protein. COX activity and ATP production were restored by lentiviral transfection with the wild-type gene. Our results demonstrate the first human mutation in the COX4I1 gene linked to diseases and confirm its role in the pathogenesis. Thus COX4I1 mutations should be considered in any patient with features suggestive of this diagnosis.European Journal of Human Genetics advance online publication, 2 August 2017; doi:10.1038/ejhg.2017.112.

PMID: 28766551 [PubMed - as supplied by publisher]

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Deep sequencing reveals variations in somatic cell mosaic mutations between monozygotic twins with discordant psychiatric disease.

Hum Genome Var. 2017;4:17032

Authors: Morimoto Y, Ono S, Imamura A, Okazaki Y, Kinoshita A, Mishima H, Nakane H, Ozawa H, Yoshiura KI, Kurotaki N

Abstract
Monozygotic (MZ) twins have been thought to be genetically identical. However, recent studies have shown discordant variants between them. We performed whole-exome sequencing (WES) in five MZ twin pairs with discordant neurodevelopmental disorders and one healthy control MZ twin to detect discordant variants. We identified three discordant variants confirmed by deep sequencing after analysis by personalized next-generation sequencing (NGS). Three mutations in FBXO38 (chr5:147774428;T>G), SMOC2 (chr6:169051385;A>G) and TDRP (chr8:442616;A>G), were detected with low allele frequency of mutant alleles on deep sequencing, suggesting that these loci are mosaic due to somatic mutations in a developmental stage. Our results suggest that deep sequencing analysis would be an adequate method to detect discordant mutations in candidate genes responsible for heritable diseases.

PMID: 28765789 [PubMed]

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Whole-Exomes Sequencing Delineates Gene Variants Profile in a Young Saudi Male with Familial Hypercholesterolemia: Case Report.

J Clin Diagn Res. 2017 Jun;11(6):GD01-GD06

Authors: Nuglozeh E

Abstract
Familial hypercholesterolemia is an autosomal dominant genetic disease characterized by earlier elevated Low-Density Lipoprotein (LDL) cholesterol levels and increased risk for premature Myocardial Infarction (MI). Albeit the diagnosis of some medical Familial Hypercholesterolemia (FH) cases are due to mutations in PCSK9, APOB, or LDLR, detection of mutation rate and profiles relies heavily on different gene pools and ethnicity. We ran exome sequencing on blood genomic DNA (gDNA) from a 26-year-old Saudi patient on Ion Proton Platform (Ion Torrent, Guilford, Connecticut, USA) as part of a pilot study preluding the establishment of the Saudi Human Genome project. The sequencing results were analysed using Ion suit Bioinformatics system. The patient was matched with a lady of lean body mass and Welsh descent, who suffered from hypercholesterolemia. The first analysis of known FH genes identified five mutations in APOB, 25 mutations of known genes linked to FH, six mutations in LPR2, one mutation in LDLR, and three mutations in PCSK9. Finally, using disease filter algorithms, we filtered out more than 2000 intronic synonymous variants with likely no biological functions. No major new locus was found in FH. However, via variant reduction and TVC protocols we detected 15 new variants, among which 14 genes are linked to hypercholesterolemia, type-I, and type-II diabetes. We also detected three mutations in PCSK9 and confirmed one by Sanger. Taken together, this report suggests that the genetic determinant of FH in this Saudi patient is likely to be heterogeneous, complicating the diagnostic and novel gene discovery process.

PMID: 28764195 [PubMed]

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REST Final-Exon-Truncating Mutations Cause Hereditary Gingival Fibromatosis.

Am J Hum Genet. 2017 Jul 06;101(1):149-156

Authors: Bayram Y, White JJ, Elcioglu N, Cho MT, Zadeh N, Gedikbasi A, Palanduz S, Ozturk S, Cefle K, Kasapcopur O, Coban Akdemir Z, Pehlivan D, Begtrup A, Carvalho CMB, Paine IS, Mentes A, Bektas-Kayhan K, Karaca E, Jhangiani SN, Muzny DM, Baylor-Hopkins Center for Mendelian Genomics, Gibbs RA, Lupski JR

Abstract
Hereditary gingival fibromatosis (HGF) is the most common genetic form of gingival fibromatosis that develops as a slowly progressive, benign, localized or generalized enlargement of keratinized gingiva. HGF is a genetically heterogeneous disorder and can be transmitted either as an autosomal-dominant or autosomal-recessive trait or appear sporadically. To date, four loci (2p22.1, 2p23.3-p22.3, 5q13-q22, and 11p15) have been mapped to autosomes and one gene (SOS1) has been associated with the HGF trait observed to segregate in a dominant inheritance pattern. Here we report 11 individuals with HGF from three unrelated families. Whole-exome sequencing (WES) revealed three different truncating mutations including two frameshifts and one nonsense variant in RE1-silencing transcription factor (REST) in the probands from all families and further genetic and genomic analyses confirmed the WES-identified findings. REST is a transcriptional repressor that is expressed throughout the body; it has different roles in different cellular contexts, such as oncogenic and tumor-suppressor functions and hematopoietic and cardiac differentiation. Here we show the consequences of germline final-exon-truncating mutations in REST for organismal development and the association with the HGF phenotype.

PMID: 28686854 [PubMed - indexed for MEDLINE]