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- Genome Editing in Mouse Spermatogonial Stem/Progenitor Cells Using Engineered Nucleases.Fanslow DA, Wirt SE, Barker JC, Connelly JP, Porteus MH, Dann CTPLoS One
- Addressing the Knowledge Gap in Clinical Recommendations for Management and Complete Excision of Clinically Atypical Nevi/Dysplastic Nevi: Pigmented Lesion Subcommittee Consensus Statement.Kim CC, Swetter SM, Curiel-Lewandrowski C, Grichnik JM, Grossman D, Halpern AC, Kirkwood JM, Leachman SA, Marghoob AA, Ming ME, Nelson KC, Veledar E, Venna SS, Chen SCJAMA Dermatol
- RNA regulons in Hox 5' UTRs confer ribosome specificity to gene regulation.Xue S, Tian S, Fujii K, Kladwang W, Das R, Barna MNature
- Functional transformations of odor inputs in the mouse olfactory bulb.Adam Y, Livneh Y, Miyamichi K, Groysman M, Luo L, Mizrahi AFront Neural Circuits
- Salt-Stress Regulation of Root System Growth and Architecture in Arabidopsis Seedlings.Duan L, Sebastian J, Dinneny JRMethods Mol Biol
- Strategies to Increase Genome Editing Frequencies and to Facilitate the Identification of Edited Cells.Porteus MMethods Mol Biol
- Using Phage Integrases in a Site-Specific Dual Integrase Cassette Exchange Strategy.Geisinger JM, Calos MPMethods Mol Biol
- GWAS identifies four novel eosinophilic esophagitis loci.Sleiman PM, Wang ML, Cianferoni A, Aceves S, Gonsalves N, Nadeau K, Bredenoord AJ, Furuta GT, Spergel JM, Hakonarson HNat Commun
- False positive 18F-fluorodeoxyglucose positron emission tomography/computed tomography liver lesion mimicking metastasis in 2 patients with gastroesophageal cancer.Paudel N, Kunz PL, Poultsides GA, Koong AC, Chang DTPract Radiat Oncol
- Visible-light-enhanced gating effect at the LaAlO3/SrTiO3 interface.Lei Y, Li Y, Chen YZ, Xie YW, Chen YS, Wang SH, Wang J, Shen BG, Pryds N, Hwang HY, Sun JRNat Commun
- Perspective: Catch melanoma early.Swetter SM, Geller ACNature
- NEUROIMAGING AND THE FUTURE OF PERSONALIZED TREATMENT IN PSYCHIATRY.Etkin ADepress Anxiety
- Updated Field Synopsis and Systematic Meta-Analyses of Genetic Association Studies in Cutaneous Melanoma: The MelGene Database.Antonopoulou K, Stefanaki I, Lill CM, Chatzinasiou F, Kypreou K, Karagianni F, Athanasiadis E, Spyrou GM, Ioannidis JP, Bertram L, Evangelou E, Stratigos AJJ Invest Dermatol
- O-022 Integrin α4β7: Discovery of Gut-Restrictive Oral Peptide Antagonists that are Active in Murine Models of Inflammatory Bowel Disease.Larry M, Ashok B, Lu B, Genet Z, Vinh T, Natalie S, Herodion C, Brian F, Caiding X, Jennifer D, Thamil A, Aida H, Dinesh P, David LInflamm Bowel Dis
- Osteoclast Derivation from Mouse Bone Marrow.Tevlin R, McArdle A, Chan CK, Pluvinage J, Walmsley GG, Wearda T, Marecic O, Hu MS, Paik KJ, Senarath-Yapa K, Atashroo DA, Zielins ER, Wan DC, Weissman IL, Longaker MTJ Vis Exp
- Educating Health Care Professionals on Human Trafficking.Grace AM, Lippert S, Collins K, Pineda N, Tolani A, Walker R, Jeong M, Trounce MB, Graham-Lamberts C, Bersamin M, Martinez J, Dotzler J, Vanek J, Storfer-Isser A, Chamberlain LJ, Horwitz SMPediatr Emerg Care
- Adrenergic Receptor Genotype Influences Heart Failure Severity and β-Blocker Response in Children with Dilated Cardiomyopathy.Reddy S, Fung A, Manlhiot C, Tierney ES, Chung WK, Blume E, Kaufman BD, Goldmuntz E, Colan S, Mital SPediatr Res
- Effect of the alkali insertion ion on the electrochemical properties of nickel hexacyanoferrate electrodes.Lee HW, Pasta M, Wang RY, Ruffo R, Cui YFaraday Discuss
- Epigenetic and in vivo comparison of diverse MSC sources reveals an endochondral signature for human hematopoietic niche formation.Reinisch A, Etchart N, Thomas D, Hofmann NA, Fruehwirth M, Sinha S, Chan CK, Senarath-Yapa K, Seo E, Wearda T, Hartwig UF, Beham-Schmid C, Trajanoski S, Lin Q, Wagner W, Dullin C, Alves F, Andreeff M, Weissman IL, Longaker MT, Schallmoser K, Majeti R, Strunk DBlood
- Collaborative regression.Gross SM, Tibshirani RBiostatistics
- Bone Marrow Characteristics Associated with Changes in Infarct Size after STEMI: A Biorepository Evaluation from the CCTRN TIME Trial.Schutt RC, Trachtenberg B, Cooke JP, Traverse JH, Henry TD, Pepine CJ, Willerson JT, Perin EC, Ellis SG, Zhao D, Bhatnagar A, Johnstone BH, Lai D, Resende M, Ebert RF, Wu JC, Sayre SL, Orozco A, Zierold C, Simari RD, Moyé L, Cogle CR, Taylor DCirc Res
Genome Editing in Mouse Spermatogonial Stem/Progenitor Cells Using Engineered Nucleases.
PLoS One. 2014;9(11):e112652
Authors: Fanslow DA, Wirt SE, Barker JC, Connelly JP, Porteus MH, Dann CT
Editing the genome to create specific sequence modifications is a powerful way to study gene function and promises future applicability to gene therapy. Creation of precise modifications requires homologous recombination, a very rare event in most cell types that can be stimulated by introducing a double strand break near the target sequence. One method to create a double strand break in a particular sequence is with a custom designed nuclease. We used engineered nucleases to stimulate homologous recombination to correct a mutant gene in mouse "GS" (germline stem) cells, testicular derived cell cultures containing spermatogonial stem cells and progenitor cells. We demonstrated that gene-corrected cells maintained several properties of spermatogonial stem/progenitor cells including the ability to colonize following testicular transplantation. This proof of concept for genome editing in GS cells impacts both cell therapy and basic research given the potential for GS cells to be propagated in vitro, contribute to the germline in vivo following testicular transplantation or become reprogrammed to pluripotency in vitro.
PMID: 25409432 [PubMed - as supplied by publisher]
Addressing the Knowledge Gap in Clinical Recommendations for Management and Complete Excision of Clinically Atypical Nevi/Dysplastic Nevi: Pigmented Lesion Subcommittee Consensus Statement.
JAMA Dermatol. 2014 Nov 19;
Authors: Kim CC, Swetter SM, Curiel-Lewandrowski C, Grichnik JM, Grossman D, Halpern AC, Kirkwood JM, Leachman SA, Marghoob AA, Ming ME, Nelson KC, Veledar E, Venna SS, Chen SC
Importance: The management of clinically atypical nevi/dysplastic nevi (CAN/DN) is controversial, with few data to guide the process. Management recommendations for DN with positive histologic margins were developed by the Delphi method to achieve consensus among members of the Pigmented Lesion Subcommittee (PLS) of the Melanoma Prevention Working Group (MPWG) after reviewing the current evidence.
Objectives: To outline key issues related to the management of CAN/DN: (1) biopsies of CAN and how positive margins arise, (2) whether incompletely excised DN evolve into melanoma, (3) current data on the outcomes of DN with positive histologic margins, (4) consensus recommendations, and (5) a proposal for future studies, including a large-scale study to help guide the management of DN with positive margins.
Evidence Review: The literature, including recent studies examining management and outcomes of DN with positive margins between 2009 to 2014, was reviewed.
Findings: A consensus statement by the PLS of the MPWG following review of the literature, group discussions, and a structured Delphi method consensus.
Conclusions and Relevance: This consensus statement reviews the complexities of management of CAN/DN. A review of the literature and 2 rounds of a structured Delphi consensus resulted in the following recommendations: (1) mildly and moderately DN with clear margins do not need to be reexcised, (2) mildly DN biopsied with positive histologic margins without clinical residual pigmentation may be safely observed rather than reexcised, and (3) observation may be a reasonable option for management of moderately DN with positive histologic margins without clinically apparent residual pigmentation; however, more data are needed to make definitive recommendations in this clinical scenario.
PMID: 25409291 [PubMed - as supplied by publisher]
RNA regulons in Hox 5' UTRs confer ribosome specificity to gene regulation.
Nature. 2014 Nov 19;
Authors: Xue S, Tian S, Fujii K, Kladwang W, Das R, Barna M
Emerging evidence suggests that the ribosome has a regulatory function in directing how the genome is translated in time and space. However, how this regulation is encoded in the messenger RNA sequence remains largely unknown. Here we uncover unique RNA regulons embedded in homeobox (Hox) 5' untranslated regions (UTRs) that confer ribosome-mediated control of gene expression. These structured RNA elements, resembling viral internal ribosome entry sites (IRESs), are found in subsets of Hox mRNAs. They facilitate ribosome recruitment and require the ribosomal protein RPL38 for their activity. Despite numerous layers of Hox gene regulation, these IRES elements are essential for converting Hox transcripts into proteins to pattern the mammalian body plan. This specialized mode of IRES-dependent translation is enabled by an additional regulatory element that we term the translation inhibitory element (TIE), which blocks cap-dependent translation of transcripts. Together, these data uncover a new paradigm for ribosome-mediated control of gene expression and organismal development.
PMID: 25409156 [PubMed - as supplied by publisher]
Functional transformations of odor inputs in the mouse olfactory bulb.
Front Neural Circuits. 2014;8:129
Authors: Adam Y, Livneh Y, Miyamichi K, Groysman M, Luo L, Mizrahi A
Sensory inputs from the nasal epithelium to the olfactory bulb (OB) are organized as a discrete map in the glomerular layer (GL). This map is then modulated by distinct types of local neurons and transmitted to higher brain areas via mitral and tufted cells. Little is known about the functional organization of the circuits downstream of glomeruli. We used in vivo two-photon calcium imaging for large scale functional mapping of distinct neuronal populations in the mouse OB, at single cell resolution. Specifically, we imaged odor responses of mitral cells (MCs), tufted cells (TCs) and glomerular interneurons (GL-INs). Mitral cells population activity was heterogeneous and only mildly correlated with the olfactory receptor neuron (ORN) inputs, supporting the view that discrete input maps undergo significant transformations at the output level of the OB. In contrast, population activity profiles of TCs were dense, and highly correlated with the odor inputs in both space and time. Glomerular interneurons were also highly correlated with the ORN inputs, but showed higher activation thresholds suggesting that these neurons are driven by strongly activated glomeruli. Temporally, upon persistent odor exposure, TCs quickly adapted. In contrast, both MCs and GL-INs showed diverse temporal response patterns, suggesting that GL-INs could contribute to the transformations MCs undergo at slow time scales. Our data suggest that sensory odor maps are transformed by TCs and MCs in different ways forming two distinct and parallel information streams.
PMID: 25408637 [PubMed - as supplied by publisher]
Salt-Stress Regulation of Root System Growth and Architecture in Arabidopsis Seedlings.
Methods Mol Biol. 2015;1242:105-122
Authors: Duan L, Sebastian J, Dinneny JR
In order to acclimate to the soil environment, plants need to constantly optimize their root system architecture for efficient resource uptake. Roots are highly sensitive to changes in their surrounding environment and root system responses to a stress such as salinity and drought can be very dynamic and complex in nature. These responses can be manifested differentially at the cellular, tissue, or organ level and between the types of roots in a root system. Therefore, various approaches must be taken to quantify and characterize these responses. In this chapter, we review methods to study basic root growth traits, such as root length, cell cycle activity and meristem size, cell shape and size that form the basis for the emergent properties of the root system. Methods for the detailed analysis of lateral root initiation and postemergence growth are described. Finally, several live-imaging systems, which allow for dynamic imaging of the root, will be explored. Together these tools provide insight into the regulatory steps that sculpt the root system upon environmental change and can be used as the basis for the evaluation of genetic variation affecting these pathways.
PMID: 25408448 [PubMed - as supplied by publisher]
Strategies to Increase Genome Editing Frequencies and to Facilitate the Identification of Edited Cells.
Methods Mol Biol. 2015;1239:281-289
Authors: Porteus M
The power of genome editing is increasingly recognized as it has become more accessible to a wide range of scientists and a wider range of uses has been reported. Nonetheless, an important practical aspect of the strategy is develop methods to increase the frequency of genome editing or methods that enrich for genome-edited cells such that they can be more easily identified. This chapter discusses several different approaches including the use of cold-shock, exonucleases, surrogate markers, specialized donor vectors, and oligonucleotides to enhance the frequency of genome editing or to facilitate the identification of genome-edited cells.
PMID: 25408413 [PubMed - as supplied by publisher]
Using Phage Integrases in a Site-Specific Dual Integrase Cassette Exchange Strategy.
Methods Mol Biol. 2015;1239:29-38
Authors: Geisinger JM, Calos MP
ΦC31 integrase, a site-specific large serine recombinase, is a useful tool for genome engineering in a variety of eukaryotic species and cell types. ΦC31 integrase performs efficient recombination between its attB site and either its own placed attP site or a partially mismatched genomic pseudo attP site. Bxb1 integrase, another large serine recombinase, has a similar level of recombinational activity, but recognizes only its own attB and attP sites. Previously, we have used these integrases sequentially to integrate plasmid DNA into the genome. This approach relied on placing a landing pad attP for Bxb1 integrase in the genome by using phiC31 integrase-mediated recombination at a genomic pseudo attP site. In this chapter, we present a protocol for using these integrases simultaneously to facilitate cassette exchange at a predefined location. This approach permits greater control and accuracy over integration. We also present a general method for using polymerase chain reaction assays to verify that the desired cassette exchange occurred successfully.
PMID: 25408400 [PubMed - as supplied by publisher]
GWAS identifies four novel eosinophilic esophagitis loci.
Nat Commun. 2014;5:5593
Authors: Sleiman PM, Wang ML, Cianferoni A, Aceves S, Gonsalves N, Nadeau K, Bredenoord AJ, Furuta GT, Spergel JM, Hakonarson H
Eosinophilic esophagitis (EoE) is an allergic disorder characterized by infiltration of the oesophagus with eosinophils. We had previously reported association of the TSLP/WDR36 locus with EoE. Here we report genome-wide significant associations at four additional loci; c11orf30 and STAT6, which have been previously associated with both atopic and autoimmune diseases, and two EoE-specific loci, ANKRD27 that regulates the trafficking of melanogenic enzymes to epidermal melanocytes and CAPN14, that encodes a calpain whose expression is highly enriched in the oesophagus. The identification of five EoE loci, not only expands our aetiological understanding of the disease but may also represent new therapeutic targets to treat the most debilitating aspect of EoE, oesophageal inflammation and remodelling.
PMID: 25407941 [PubMed - as supplied by publisher]
False positive 18F-fluorodeoxyglucose positron emission tomography/computed tomography liver lesion mimicking metastasis in 2 patients with gastroesophageal cancer.
Pract Radiat Oncol. 2014;4(6):368-371
Authors: Paudel N, Kunz PL, Poultsides GA, Koong AC, Chang DT
PMID: 25407856 [PubMed - as supplied by publisher]
Visible-light-enhanced gating effect at the LaAlO3/SrTiO3 interface.
Nat Commun. 2014;5:5554
Authors: Lei Y, Li Y, Chen YZ, Xie YW, Chen YS, Wang SH, Wang J, Shen BG, Pryds N, Hwang HY, Sun JR
Electrostatic gating field and light illumination are two widely used stimuli for semiconductor devices. Via capacitive effect, a gate field modifies the carrier density of the devices, while illumination generates extra carriers by exciting trapped electrons. Here we report an unusual illumination-enhanced gating effect in a two-dimensional electron gas at the LaAlO3/SrTiO3 interface, which has been the focus of emergent phenomena exploration. We find that light illumination decreases, rather than increases, the carrier density of the gas when the interface is negatively gated through the SrTiO3 layer, and the density drop can be 20 times as large as that caused by the conventional capacitive effect. This effect is further found to stem from an illumination-accelerated interface polarization, an originally extremely slow process. This unusual effect provides a promising controlling of the correlated oxide electronics in which a much larger gating capacity is demanding due to their intrinsic larger carrier density.
PMID: 25407837 [PubMed - as supplied by publisher]
Perspective: Catch melanoma early.
Nature. 2014 Nov 19;515(7527):S117
Authors: Swetter SM, Geller AC
PMID: 25407708 [PubMed - as supplied by publisher]
NEUROIMAGING AND THE FUTURE OF PERSONALIZED TREATMENT IN PSYCHIATRY.
Depress Anxiety. 2014 Nov;31(11):899-901
Authors: Etkin A
PMID: 25407576 [PubMed - as supplied by publisher]
Updated Field Synopsis and Systematic Meta-Analyses of Genetic Association Studies in Cutaneous Melanoma: The MelGene Database.
J Invest Dermatol. 2014 Nov 19;
Authors: Antonopoulou K, Stefanaki I, Lill CM, Chatzinasiou F, Kypreou K, Karagianni F, Athanasiadis E, Spyrou GM, Ioannidis JP, Bertram L, Evangelou E, Stratigos AJ
We updated a field synopsis of cutaneous melanoma (CM) genetics by systematically retrieving and combining data from genetic association studies published as of August 31, 2013. Data were available from 197 studies, which included 83,343 CM cases and 187,809 controls and reported on 1,126 polymorphisms in 289 different genes. Random-effects meta-analyses of 81 eligible polymorphisms evaluated in >4 datasets confirmed 20 SNPs across ten loci (TYR, AFG3L1P, CDK10, MYH7B, SLC45A2, MTAP, ATM, CLPTM1L, FTO and CASP8) that have previously been published with genome-wide significant evidence for association (P<5 × 10(-8)) with CM risk, with certain variants possibly functioning as proxies of already tagged genes. Four other loci (MITF, CCND1, MX2, PLA2G6) were also significantly associated with 5 × 10(-8)<P<1 × 10(-3). In supplementary meta-analyses derived from GWAS, one additional locus located 11 kb upstream of ARNT (chromosome 1q21) showed genome-wide statistical significance with CM. Our approach serves as a useful model in analyzing and integrating the reported germline alterations involved in CM.Journal of Investigative Dermatology accepted article preview online, 19 November 2014. doi:10.1038/jid.2014.491.
PMID: 25407435 [PubMed - as supplied by publisher]
O-022 Integrin α4β7: Discovery of Gut-Restrictive Oral Peptide Antagonists that are Active in Murine Models of Inflammatory Bowel Disease.
Inflamm Bowel Dis. 2014 Dec;20 Suppl 1:S14
Authors: Larry M, Ashok B, Lu B, Genet Z, Vinh T, Natalie S, Herodion C, Brian F, Caiding X, Jennifer D, Thamil A, Aida H, Dinesh P, David L
BACKGROUND:: The α4β7 integrin is a clinically validated target for inflammatory bowel disease (IBD). The anti-α4β7 antibody vedolizumab is approved by the FDA for treating moderate-to-severe ulcerative colitis and Crohn's disease. Vedolizumab binds to α4β7 on circulating memory/effector T cells in the blood and blocks their homing to intestinal tissues expressing the ligand MAdCAM-1. The aim of this study is to develop orally stable α4β7 antagonist peptides that act locally in the intestinal tissue. These peptides have minimal systemic exposure, yet are effective in blocking T cell homing and are efficacious in murine models of IBD.
METHODS:: Potent, selective and orally stable peptide antagonists of α4β7 integrin were identified through Protagonist's peptide and peptidomimetic technology platform. To evaluate oral stability, the peptides were incubated in a variety of ex vivo intestinal/colonic washes or simulated gastric/intestinal fluids, and half-lives determined by mass spectrometry. Pharmacokinetic (PK), pharmacodynamic (PD) and chronic colitis studies were conducted in mice.
RESULTS:: The peptides are potent against α4β7, but not α4β1 and αLβ2 as measured in biochemical and cell adhesion assays. In α4β7 specific cell adhesion assays, the peptides block adhesion of the human RPMI 8866 cell line (B cell lymphoblastoid) or mouse TK-1 (T cell lymphoblast) to immobilized MAdCAM-1 (IC50 < 20 nM). In the α4β1 or αLβ2 specific cell adhesion assay using human Jurkat cells, they are inactive up to the highest tested concentration, 100 μM. To facilitate oral delivery, we chemically engineered the peptides to be resistant to chemical and proteolytic degradation in a variety of gastric and intestinal fluids, while maintaining their potency and selectivity. PK studies in normal or dextran sodium sulfate (DSS) treated mice and rats showed that oral dosing results in exposure in the small intestine, colon and mesenteric lymph nodes (MLN), but no significant measurable levels in the blood and urine. A PD assay was used to assess the effect of oral dosing on trafficking of endogenous memory T cells in the mouse. Mice treated with DSS were orally dosed daily with peptides for 9 or 13 days, and harvested tissues were analyzed by FACS. FACS analysis of tissues from animals dosed with peptides showed that there is a reduction of CD4 CD44 CD45RB β7 T cells in the MLN and Peyer's Patches, but not in the spleen or blood. There was also marked reduction of clinical disease symptoms. We also evaluated these peptides in a T cell adoptive transfer chronic colitis model. Daily oral dosing with peptides reduced the severity of disease as measured by colon weight length ratio and histology.
CONCLUSIONS:: Potent, selective and orally stable peptide antagonists of α4β7 integrin were shown in oral PK studies to have significant exposure in intestinal tissues, but not blood and urine. Despite low blood exposure, these peptides block T cell homing to gut associated lymphoid tissue and attenuate disease in murine models of IBD. These results support the therapeutic potential of locally blocking T cell homing while minimizing immunogenicity and the risk of opportunistic infections associated with systemically delivered immunosuppressants and biologics.
PMID: 25407177 [PubMed - as supplied by publisher]
Osteoclast Derivation from Mouse Bone Marrow.
J Vis Exp. 2014;(93)
Authors: Tevlin R, McArdle A, Chan CK, Pluvinage J, Walmsley GG, Wearda T, Marecic O, Hu MS, Paik KJ, Senarath-Yapa K, Atashroo DA, Zielins ER, Wan DC, Weissman IL, Longaker MT
Osteoclasts are highly specialized cells that are derived from the monocyte/macrophage lineage of the bone marrow. Their unique ability to resorb both the organic and inorganic matrices of bone means that they play a key role in regulating skeletal remodeling. Together, osteoblasts and osteoclasts are responsible for the dynamic coupling process that involves both bone resorption and bone formation acting together to maintain the normal skeleton during health and disease. As the principal bone-resorbing cell in the body, changes in osteoclast differentiation or function can result in profound effects in the body. Diseases associated with altered osteoclast function can range in severity from lethal neonatal disease due to failure to form a marrow space for hematopoiesis, to more commonly observed pathologies such as osteoporosis, in which excessive osteoclastic bone resorption predisposes to fracture formation. An ability to isolate osteoclasts in high numbers in vitro has allowed for significant advances in the understanding of the bone remodeling cycle and has paved the way for the discovery of novel therapeutic strategies that combat these diseases. Here, we describe a protocol to isolate and cultivate osteoclasts from mouse bone marrow that will yield large numbers of osteoclasts.
PMID: 25407120 [PubMed - as supplied by publisher]
Educating Health Care Professionals on Human Trafficking.
Pediatr Emerg Care. 2014 Nov 18;
Authors: Grace AM, Lippert S, Collins K, Pineda N, Tolani A, Walker R, Jeong M, Trounce MB, Graham-Lamberts C, Bersamin M, Martinez J, Dotzler J, Vanek J, Storfer-Isser A, Chamberlain LJ, Horwitz SM
BACKGROUND: The US Department of State estimates that there are between 4 and 27 million individuals worldwide in some form of modern slavery. Recent studies have demonstrated that 28% to 50% of trafficking victims in the United States encountered health care professionals while in captivity, but were not identified and rescued. This study aimed to determine whether an educational presentation increased emergency department (ED) providers' recognition of human trafficking (HT) victims and knowledge of resources to manage cases of HT.
METHODS: The 20 largest San Francisco Bay Area EDs were randomized into intervention (10 EDs) or delayed intervention comparison groups (10 EDs) to receive a standardized educational presentation containing the following: background about HT, relevance of HT to health care, clinical signs in potential victims, and referral options for potential victims. Participants in the delayed intervention group completed a pretest in the period the immediate intervention group received the educational presentation, and all participants were assessed immediately before (pretest) and after (posttest) the intervention. The intervention effect was tested by comparing the pre-post change in the intervention group to the change in 2 pretests in the delayed intervention group adjusted for the effect of clustering within EDs. The 4 primary outcomes were importance of knowledge of HT to the participant's profession (5-point Likert scale), self-rated knowledge of HT (5-point Likert scale), knowledge of who to call for potential HT victims (yes/no), and suspecting that a patient was a victim of HT (yes/no).
FINDINGS: There were 258 study participants from 14 EDs; 141 from 8 EDs in the intervention group and 117 from 7 EDs in the delayed intervention comparison group, of which 20 served as the delayed intervention comparison group. Participants in the intervention group reported greater increases in their level of knowledge about HT versus those in the delayed intervention comparison group (1.42 vs -0.15; adjusted difference = 1.57 [95% confidence interval, 1.02-2.12]; P < 0.001). Pretest ratings of the importance of knowledge about HT to the participant's profession were high in both groups and there was no intervention effect (0.31 vs 0.55; -0.24 [-0.90-0.42], P = 0.49). Knowing who to call for potential HT victims increased from 7.2% to 59% in the intervention group and was unchanged (15%) in the delayed intervention comparison group (61.4% [28.5%-94.4%]; P < 0.01). The proportion of participants who suspected their patient was a victim of HT increased from 17% to 38% in the intervention group and remained unchanged (10%) in the delayed intervention comparison group (20.9 [8.6%-33.1%]; P < 0.01).
INTERPRETATION: A brief educational intervention increased ED provider knowledge and self-reported recognition of HT victims.
PMID: 25407038 [PubMed - as supplied by publisher]
Adrenergic Receptor Genotype Influences Heart Failure Severity and β-Blocker Response in Children with Dilated Cardiomyopathy.
Pediatr Res. 2014 Nov 19;
Authors: Reddy S, Fung A, Manlhiot C, Tierney ES, Chung WK, Blume E, Kaufman BD, Goldmuntz E, Colan S, Mital S
BackgroundAdrenergic receptor (ADR) genotypes are associated with heart failure (HF) and β-blocker response in adults. We assessed the influence of ADR genotypes in children with dilated cardiomyopathy (DCM).Methods91 children with advanced DCM and 44 with stable DCM were genotyped for 3 ADR genotypes associated with HF risk in adults: α2cdel322-325, β1Arg389, and β2Arg16. Data were analyzed by genotype and β-blocker use. Mean age at enrollment was 8.5 years.ResultsOne-year event-free survival was 51% in advanced and 80% in stable DCM. High-risk genotypes were associated with higher left ventricular (LV) filling pressures, higher systemic and pulmonary vascular resistance, greater decline in LV ejection fraction (p<0.05), and a higher frequency of mechanical circulatory support while awaiting transplant (p=0.05). While β-blockers did not reduce heart failure severity in the overall cohort, in the subset with multiple high-risk genotypes, those receiving β-blockers showed better preservation of cardiac function and hemodynamics compared to those not receiving β-blockers (interaction p<0.05).ConclusionOur study identifies genetic risk markers that may help in the identification of patients at risk for developing decompensated HF and who may benefit from early institution of β-blocker therapy before progression to decompensated HF.Pediatric Research (2014); doi:10.1038/pr.2014.183.
PMID: 25406899 [PubMed - as supplied by publisher]
Effect of the alkali insertion ion on the electrochemical properties of nickel hexacyanoferrate electrodes.
Faraday Discuss. 2014 Nov 14;
Authors: Lee HW, Pasta M, Wang RY, Ruffo R, Cui Y
Nickel hexacyanoferrate (NiHCFe) is an attractive cathode material in both aqueous and organic electrolytes due to a low-cost synthesis using earth-abundant precursors and also due to its open framework, Prussian blue-like crystal structure that enables ultra-long cycle life, high energy efficiency, and high power capability. Herein, we explored the effect of different alkali ions on the insertion electrochemistry of NiHCFe in aqueous and propylene carbonate-based electrolytes. The large channel diameter of the structure offers fast solid-state diffusion of Li(+), Na(+), and K(+) ions in aqueous electrolytes. However, all alkali ions in organic electrolytes and Rb(+) and Cs(+) in aqueous electrolytes show a quasi-reversible electrochemical behavior that results in poor galvanostatic cycling performance. Kinetic regimes in aqueous electrolyte were also determined, highlighting the effect of the size of the alkali ion on the electrochemical properties.
PMID: 25406368 [PubMed - as supplied by publisher]
Epigenetic and in vivo comparison of diverse MSC sources reveals an endochondral signature for human hematopoietic niche formation.
Blood. 2014 Nov 18;
Authors: Reinisch A, Etchart N, Thomas D, Hofmann NA, Fruehwirth M, Sinha S, Chan CK, Senarath-Yapa K, Seo E, Wearda T, Hartwig UF, Beham-Schmid C, Trajanoski S, Lin Q, Wagner W, Dullin C, Alves F, Andreeff M, Weissman IL, Longaker MT, Schallmoser K, Majeti R, Strunk D
In the last decade there has been a rapid expansion in clinical trials using mesenchymal stromal cells (MSCs) from a variety of tissues. However, despite similarities in morphology, immunophenotype and differentiation behavior in vitro, MSCs sourced from distinct tissues do not necessarily have equivalent biological properties. We performed a genome-wide methylation, transcription and in vivo evaluation of MSCs from human bone marrow (BM), white adipose tissue, umbilical cord and skin cultured in humanized media. Surprisingly, only BM-derived MSCs spontaneously formed a bone marrow cavity through a vascularized cartilage intermediate in vivo that was progressively replaced by hematopoietic tissue and bone. Only BM-derived MSCs exhibited a chondrogenic transcriptional program with hypomethylation and increased expression of RUNX3, RUNX2, BGLAP, MMP13 and ITGA10 consistent with a latent and primed skeletal developmental potential. The humanized MSC-derived microenvironment permitted homing and maintenance of long-term murine SLAM(+) hematopoietic stem cells (HSCs) as well as human CD34(+)/CD38(-)/CD90(+)/CD45RA(+) HSCs after cord blood transplantation. These studies underscore the profound differences in developmental potential between MSC sources independent of donor age with implications for their clinical use. We also demonstrate a tractable human niche model for studying homing and engraftment of human hematopoietic cells in normal and neoplastic states.
PMID: 25406351 [PubMed - as supplied by publisher]
Biostatistics. 2014 Nov 17;
Authors: Gross SM, Tibshirani R
We consider the scenario where one observes an outcome variable and sets of features from multiple assays, all measured on the same set of samples. One approach that has been proposed for dealing with these type of data is "sparse multiple canonical correlation analysis" (sparse mCCA). All of the current sparse mCCA techniques are biconvex and thus have no guarantees about reaching a global optimum. We propose a method for performing sparse supervised canonical correlation analysis (sparse sCCA), a specific case of sparse mCCA when one of the datasets is a vector. Our proposal for sparse sCCA is convex and thus does not face the same difficulties as the other methods. We derive efficient algorithms for this problem that can be implemented with off the shelf solvers, and illustrate their use on simulated and real data.
PMID: 25406332 [PubMed - as supplied by publisher]
Bone Marrow Characteristics Associated with Changes in Infarct Size after STEMI: A Biorepository Evaluation from the CCTRN TIME Trial.
Circ Res. 2014 Nov 18;
Authors: Schutt RC, Trachtenberg B, Cooke JP, Traverse JH, Henry TD, Pepine CJ, Willerson JT, Perin EC, Ellis SG, Zhao D, Bhatnagar A, Johnstone BH, Lai D, Resende M, Ebert RF, Wu JC, Sayre SL, Orozco A, Zierold C, Simari RD, Moyé L, Cogle CR, Taylor D
Rationale: Despite significant interest in bone marrow mononuclear cell (BMC) therapy for ischemic heart disease, current techniques have resulted in only modest benefits. However, select patients have shown improvements after autologous BMC therapy, but the contributing factors are unclear. Objective: The purpose of this study was to identify BMC characteristics associated with a reduction in infarct size following STEMI. Methods and Results: This prospective study comprised patients consecutively enrolled in the CCTRN TIME trial who agreed to have their BMCs stored and analyzed at the CCTRN Biorepository. Change in infarct size between baseline (3 days after percutaneous coronary intervention) and 6-month follow-up was measured by cardiac magnetic resonance imaging (cMRI). Infarct-size measurements and BMC phenotype and function data were obtained for 101 patients (mean age, 56.5 years; mean screening ejection fraction, 37%; mean baseline cMRI ejection fraction, 45%). At 6 months, 75 patients (74.3%) showed a reduction in infarct size (mean change, -21.0%±17.6%). Multiple regression analysis indicated that infarct size reduction was greater in patients who had a larger percentage of CD31+ BMCs (P=0.046) and in those with faster BMC growth rates in CFU-Hill and ECFC functional assays (P=0.033 and P=0.032, respectively). Conclusions: This study identified BMC characteristics associated with a better clinical outcome in patients with STEMI and highlighted the importance of endothelial precursor activity in regenerating infarcted myocardium. Furthermore, it suggests that for these STEMI patients, myocardial repair was more dependent on baseline BMC characteristics than on whether the patient underwent intracoronary BMC transplantation.
PMID: 25406300 [PubMed - as supplied by publisher]
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