Recent Stanford Publications in PubMed
- Wishbone identifies bifurcating developmental trajectories from single-cell data.Setty M, Tadmor MD, Reich-Zeliger S, Angel O, Salame TM, Kathail P, Choi K, Bendall S, Friedman N, Pe'er DNat Biotechnol
- Advancing Benchmarks for Genome Sequencing.Zook JM, Salit MCell Syst
- Phylogenetic Profiling for Probing the Modular Architecture of the Human Genome.Dey G, Meyer TCell Syst
- Fundamental Limits of Search.Kannan S, Tse DCell Syst
- Perfect and Near-Perfect Adaptation in Cell Signaling.Ferrell JECell Syst
- Cytokine-Stimulated Phosphoflow of Whole Blood Using CyTOF Mass Cytometry.Fernandez R, Maecker HBio Protoc
- The big challenges in modeling human and environmental well-being.Tuljapurkar SF1000Res
- Report of the GRAPPA-OMERACT Psoriatic Arthritis Working Group from the GRAPPA 2015 Annual Meeting.Orbai AM, Mease PJ, de Wit M, Kalyoncu U, Campbell W, Tillett W, Eder L, Elmamoun M, FitzGerald O, Gladman DD, Goel N, Gossec L, Lindsay CA, Steinkoenig I, Helliwell PS, McHugh NJ, Strand V, Ogdie AJ Rheumatol
- Two cases of histiocytic sarcoma with BCL2 translocations and occult or subsequent follicular lymphoma.Fernandez-Pol S, Bangs CD, Cherry A, Arber DA, Gratzinger DHum Pathol
- Fibroblast Growth Factor 2 Modulates Hypothalamic Pituitary Axis Activity and Anxiety Behavior Through Glucocorticoid Receptors.Salmaso N, Stevens HE, McNeill J, ElSayed M, Ren Q, Maragnoli ME, Schwartz ML, Tomasi S, Sapolsky RM, Duman R, Vaccarino FMBiol Psychiatry
- Is the canonical RAF-MEK-ERK signaling pathway a therapeutic target in SCLC?Cristea S, Sage JJ Thorac Oncol
- National prevalence, causes, and risk factors for bariatric surgery readmissions.Garg T, Rosas U, Rivas H, Azagury D, Morton JMAm J Surg
- Children with lower respiratory tract infections and serum 25-hydroxyvitamin D3 levels: A case-control study.Velarde López AA, Gerber JS, Leonard MB, Xie D, Schinnar R, Strom BLPediatr Pulmonol
- Age-Dependent Pancreatic Gene Regulation Reveals Mechanisms Governing Human β Cell Function.Arda HE, Li L, Tsai J, Torre EA, Rosli Y, Peiris H, Spitale RC, Dai C, Gu X, Qu K, Wang P, Wang J, Grompe M, Scharfmann R, Snyder MS, Bottino R, Powers AC, Chang HY, Kim SKCell Metab
- Trends in Testosterone Prescription and Public Health Concerns.Gabrielsen JS, Najari BB, Alukal JP, Eisenberg MLUrol Clin North Am
- Optogenetic modulation in stroke recovery.Pendharkar AV, Levy SL, Ho AL, Sussman ES, Cheng MY, Steinberg GKNeurosurg Focus
- Radiation-induced brain injury: low-hanging fruit for neuroregeneration.Burns TC, Awad AJ, Li MD, Grant GANeurosurg Focus
- Neurorestoration after stroke.Azad TD, Veeravagu A, Steinberg GKNeurosurg Focus
- Prioritizing schizophrenia endophenotypes for future genetic studies: An example using data from the COGS-1 family study.Millard SP, Shofer J, Braff D, Calkins M, Cadenhead K, Freedman R, Green MF, Greenwood TA, Gur R, Gur R, Lazzeroni LC, Light GA, Olincy A, Nuechterlein K, Seidman L, Siever L, Silverman J, Stone WS, Sprock J, Sugar CA, Swerdlow NR, Tsuang M, Turetsky B, Radant A, Tsuang DWSchizophr Res
- CDX2 as a Prognostic Biomarker in Stage II and Stage III Colon Cancer.Dalerba P, Sahoo D, Paik S, Guo X, Yothers G, Song N, Wilcox-Fogel N, Forgó E, Rajendran PS, Miranda SP, Hisamori S, Hutchison J, Kalisky T, Qian D, Wolmark N, Fisher GA, van de Rijn M, Clarke MFN Engl J Med
- Maternal use of oral contraceptives and risk of birth defects in Denmark: prospective, nationwide cohort study.Charlton BM, Mølgaard-Nielsen D, Svanström H, Wohlfahrt J, Pasternak B, Melbye MBMJ
- The Questions We Cannot Answer.Waliany SAcad Med
- Lymphoid Hyperplasia of the Appendix: A Potential Pitfall in the Sonographic Diagnosis of Appendicitis.Xu Y, Jeffrey RB, DiMaio MA, Olcott EWAJR Am J Roentgenol
- Enrollment Yield and Reasons for Screen Failure in a Large Prehospital Stroke Trial.Kim DH, Saver JL, Starkman S, Liebeskind DS, Ali LK, Restrepo L, Kim-Tenser M, Valdes-Sueiras M, Eckstein M, Pratt F, Stratton S, Hamilton S, Conwit R, Sanossian N, Field Administration of Stroke Therapy–Magnesium (FAST-MAG) Trial Nurse-Coordinators and InvestigatorsStroke
- Coffee and caffeine consumption and the risk of hypertension in postmenopausal women.Rhee JJ, Qin F, Hedlin HK, Chang TI, Bird CE, Zaslavsky O, Manson JE, Stefanick ML, Winkelmayer WCAm J Clin Nutr
- The Children's Hepatic tumors International Collaboration (CHIC): Novel global rare tumor database yields new prognostic factors in hepatoblastoma and becomes a research model.Czauderna P, Haeberle B, Hiyama E, Rangaswami A, Krailo M, Maibach R, Rinaldi E, Feng Y, Aronson D, Malogolowkin M, Yoshimura K, Leuschner I, Lopez-Terrada D, Hishiki T, Perilongo G, von Schweinitz D, Schmid I, Watanabe K, Derosa M, Meyers REur J Cancer
- Survival in familial and non-familial breast cancer by age and stage at diagnosis.Kharazmi E, Försti A, Sundquist K, Hemminki KEur J Cancer
- Exploring the Relationship Between Stereotype Perception and Residents' Well-Being.Salles A, Mueller CM, Cohen GLJ Am Coll Surg
- Where Do We Stand With Aspirin for the Prevention of Colorectal Cancer? The USPSTF Recommendations.Chan AT, Ladabaum UGastroenterology
- An active site rearrangement within the Tetrahymena group I ribozyme releases nonproductive interactions and allows formation of catalytic interactions.Sengupta RN, Van Schie SN, Giambaşu G, Dai Q, Yesselman JD, York D, Piccirilli JA, Herschlag DRNA
- Systematic Motorcycle Management and Health Care Delivery: A Field Trial.Mehta KM, Rerolle F, Rammohan SV, Albohm DC, Muwowo G, Moseson H, Sept L, Lee HL, Bendavid EAm J Public Health
- Sociodemographic Predictors of Vaccination Exemptions on the Basis of Personal Belief in California.Yang YT, Delamater PL, Leslie TF, Mello MMAm J Public Health
- Risk of Recurrent Arterial Ischemic Stroke in Childhood: A Prospective International Study.Fullerton HJ, Wintermark M, Hills NK, Dowling MM, Tan M, Rafay MF, Elkind MS, Barkovich AJ, deVeber GA, VIPS InvestigatorsStroke
- Surgeons' Leadership Styles and Team Behavior in the Operating Room.Hu YY, Parker SH, Lipsitz SR, Arriaga AF, Peyre SE, Corso KA, Roth EM, Yule SJ, Greenberg CCJ Am Coll Surg
- Blood Volume Monitoring to Assist Fluid Management in Hemodialysis Patients.Hussein WF, Arramreddy R, Sun SJ, Doss-McQuitty S, Schiller BAm J Kidney Dis
- Apolipoprotein E Mediates Evasion From Hepatitis C Virus Neutralizing Antibodies.Fauvelle C, Felmlee DJ, Crouchet E, Lee J, Heydmann L, Lefèvre M, Magri A, Hiet MS, Fofana I, Habersetzer F, Foung SK, Milne R, Patel AH, Vercauteren K, Meuleman P, Zeisel MB, Bartenschlager R, Schuster C, Baumert TFGastroenterology
- Oncologic Outcomes After Transoral Robotic Surgery: A Multi-institutional Study.de Almeida JR, Li R, Magnuson JS, Smith RV, Moore E, Lawson G, Remacle M, Ganly I, Kraus DH, Teng MS, Miles BA, White H, Duvvuri U, Ferris RL, Mehta V, Kiyosaki K, Damrose EJ, Wang SJ, Kupferman ME, Koh YW, Genden EM, Holsinger FCJAMA Otolaryngol Head Neck Surg
- Pathobiology of Helicobacter pylori-Induced Gastric Cancer.Amieva M, Peek RMGastroenterology
- Ambrisentan and Tadalafil Up-front Combination Therapy in Scleroderma-associated Pulmonary Arterial Hypertension.Hassoun PM, Zamanian RT, Damico R, Lechtzin N, Khair R, Kolb TM, Tedford RJ, Hulme OL, Housten T, Pisanello C, Sato T, Pullins EH, Corona-Villalobos CP, Zimmerman SL, Gashouta MA, Minai OA, Torres F, Girgis RE, Chin K, Mathai SCAm J Respir Crit Care Med
- Total Exposure Study Analysis consortium: a cross-sectional study of tobacco exposures.Bergen AW, Krasnow R, Javitz HS, Swan GE, Li MD, Baurley JW, Chen X, Murrelle L, Zedler BBMC Public Health
- Evaluation of the International Prognostic Score (IPS-7) and a Simpler Prognostic Score (IPS-3) for advanced Hodgkin lymphoma in the modern era.Diefenbach CS, Li H, Hong F, Gordon LI, Fisher RI, Bartlett NL, Crump M, Gascoyne RD, Wagner H, Stiff PJ, Cheson BD, Stewart DA, Kahl BS, Friedberg JW, Blum KA, Habermann TM, Tuscano JM, Hoppe RT, Horning SJ, Advani RHBr J Haematol
- Smartphone apps for snoring.Camacho M, Robertson M, Abdullatif J, Certal V, Kram YA, Ruoff CM, Brietzke SE, Capasso RJ Laryngol Otol
- Association of worker characteristics and early reimbursement for physical therapy, chiropractic and opioid prescriptions with workers' compensation claim duration, for cases of acute low back pain: an observational cohort study.Busse JW, Ebrahim S, Heels-Ansdell D, Wang L, Couban R, Walter SDBMJ Open
- Shockingly Early: Chromatin-Mediated Loss of the Heat Shock Response.Booth LN, Brunet AMol Cell
- Fabrication of healthy and disease-mimicking retinal phantoms with tapered foveal pits for optical coherence tomography.Lee GC, Smith GT, Agrawal M, Leng T, Ellerbee AKJ Biomed Opt
- Chemodetection and Destruction of Host Urea Allows Helicobacter pylori to Locate the Epithelium.Huang JY, Sweeney EG, Sigal M, Zhang HC, Remington SJ, Cantrell MA, Kuo CJ, Guillemin K, Amieva MRCell Host Microbe
- A Plea to Reassess the Role of United States Medical Licensing Examination Step 1 Scores in Residency Selection.Prober CG, Kolars JC, First LR, Melnick DEAcad Med
- Human V4 and ventral occipital retinotopic maps.Winawer J, Witthoft NVis Neurosci
- Salvage Conservation Laryngeal Surgery After Radiation Therapy Failure.Chen MM, Holsinger FC, Laccourreye OOtolaryngol Clin North Am
- Practical dose point-based methods to characterize dose distribution in a stationary elliptical body phantom for a cone-beam C-arm CT system.Choi JH, Constantin D, Ganguly A, Girard E, Morin RL, Dixon RL, Fahrig RMed Phys
- Imaging surveillance and survival for surgically resected non-small-cell lung cancer.Backhus LM, Farjah F, Liang CK, He H, Varghese TK, Au DH, Flum DR, Zeliadt SBJ Surg Res
- Treatment Approaches to Locally Advanced Pancreatic Adenocarcinoma.Pollom EL, Koong AC, Ko AHHematol Oncol Clin North Am
- Supporting Medical Students' Pursuit of Longitudinal Patient Experiences: Piloting an Innovative Visit Notification Tool at the Massachusetts General Hospital.Elmore SN, Kopecky KE, Jennings K, de Moya M, Beresin G, Wright DEAcad Med
- Synthetic biology: Ribosomal ties that bind.Puglisi JDNature
- Localized Ambient Solidity Separation Algorithm Based Computer User Segmentation.Sun X, Zhang T, Chai Y, Liu YComput Intell Neurosci
- Management of Intercarpal Ligament Injuries Associated with Distal Radius Fractures.Desai MJ, Kamal RN, Richard MJHand Clin
- Tamibarotene in patients with acute promyelocytic leukaemia relapsing after treatment with all-trans retinoic acid and arsenic trioxide.Sanford D, Lo-Coco F, Sanz MA, Di Bona E, Coutre S, Altman JK, Wetzler M, Allen SL, Ravandi F, Kantarjian H, Cortes JEBr J Haematol
- In an Age of Open Access to Research Policies: Physician and Public Health NGO Staff Research Use and Policy Awareness.Moorhead LL, Holzmeyer C, Maggio LA, Steinberg RM, Willinsky JPLoS One
- Musical Preferences are Linked to Cognitive Styles.Greenberg DM, Baron-Cohen S, Stillwell DJ, Kosinski M, Rentfrow PJPLoS One
- Challenges to Learning Evidence-Based Medicine and Educational Approaches to Meet These Challenges: A Qualitative Study of Selected EBM Curricula in U.S. and Canadian Medical Schools.Maggio LA, ten Cate O, Chen HC, Irby DM, O'Brien BCAcad Med
- Very long haplotype tracts characterized at high resolution from HLA homozygous cell lines.Norman PJ, Norberg SJ, Nemat-Gorgani N, Royce T, Hollenbach JA, Shults Won M, Guethlein LA, Gunderson KL, Ronaghi M, Parham PImmunogenetics
- Habitat Heterogeneity Affects Plant and Arthropod Species Diversity and Turnover in Traditional Cornfields.Martínez E, Rös M, Bonilla MA, Dirzo RPLoS One
- Monitoring Cerebrovascular Reactivity through the Use of Arterial Spin Labeling in Patients with Moyamoya Disease.Yun TJ, Paeng JC, Sohn CH, Kim JE, Kang HS, Yoon BW, Choi SH, Kim JH, Lee HY, Han MH, Zaharchuk GRadiology
- Genetic Variants Associated with Port-Wine Stains.Frigerio A, Wright K, Wooderchak-Donahue W, Tan OT, Margraf R, Stevenson DA, Grimmer JF, Bayrak-Toydemir PPLoS One
- Elevated pretransplant pulmonary vascular resistance index does not predict mortality after isolated orthotopic heart transplantation in children: A retrospective analysis of the UNOS database.Chiu P, Schaffer JM, Sheikh AY, Ha R, Reinhartz O, Mainwaring R, Reitz BAPediatr Transplant
- Evaluation of ERG and SPINK1 by Immunohistochemical Staining and Clinicopathological Outcomes in a Multi-Institutional Radical Prostatectomy Cohort of 1067 Patients.Brooks JD, Wei W, Hawley S, Auman H, Newcomb L, Boyer H, Fazli L, Simko J, Hurtado-Coll A, Troyer DA, Carroll PR, Gleave M, Lance R, Lin DW, Nelson PS, Thompson IM, True LD, Feng Z, McKenney JKPLoS One
- Selective Pressures Explain Differences in Flower Color among Gentiana lutea Populations.Sobral M, Veiga T, Domínguez P, Guitián JA, Guitián P, Guitián JMPLoS One
- The Relationship Between Industry and Pain Societies, Part 1: Demystification and Legitimization of Continuing Medical Education.Darnall BD, Schatman MEPain Med
- Synthetic RNAi triggers and their use in chronic hepatitis B therapies with curative intent.Gish RG, Yuen MF, Chan HL, Given BD, Lai CL, Locarnini SA, Lau JY, Wooddell CI, Schluep T, Lewis DLAntiviral Res
- Chronic hepatitis B: Virology, natural history, current management and a glimpse at future opportunities.Gish RG, Given BD, Lai CL, Locarnini SA, Lau JY, Lewis DL, Schluep TAntiviral Res
- In vitro immunomodulation for enhancing T cell-based diagnosis of Mycobacterium tuberculosis infection.Slater M, Tran MC, Platt L, Luu LT, Phan HT, Pham PT, Do TB, Nguyen HT, Gaur RL, Parsonnet J, Cattamanchi A, Luo R, Nahid P, Banaei NDiagn Microbiol Infect Dis
- Tripeptidyl Peptidase II Mediates Levels of Nuclear Phosphorylated ERK1 and ERK2.Wiemhoefer A, Stargardt A, van der Linden WA, Renner MC, van Kesteren RE, Stap J, Raspe MA, Tomkinson B, Kessels HW, Ovaa H, Overkleeft HS, Florea B, Reits EAMol Cell Proteomics
- Long-term Stability of Urinary Biomarkers of Acute Kidney Injury in Children.Schuh MP, Nehus E, Ma Q, Haffner C, Bennett M, Krawczeski CD, Devarajan PAm J Kidney Dis
- Nonlinear Effects of Noxious Thermal Stimulation and Working Memory Demands on Subjective Pain Perception.Sturgeon JA, Tieu MM, Jastrzab LE, McCue R, Gandhi V, Mackey SCPain Med
- Associations Between Ankle-Brachial Index and Cognitive Function: Results From the Lifestyle Interventions and Independence for Elders Trial.Espeland MA, Newman AB, Sink K, Gill TM, King AC, Miller ME, Guralnik J, Katula J, Church T, Manini T, Reid KF, McDermott MM, LIFE Study GroupJ Am Med Dir Assoc
- Risk Factors for Prolonged Postpartum Length of Stay Following Cesarean Delivery.Blumenfeld YJ, El-Sayed YY, Lyell DJ, Nelson LM, Butwick AJAm J Perinatol
- Pediatric Patient and Hospital Characteristics Associated With Treatment of Peritonsillar Abscess and Peritonsillar Cellulitis.Nguyen T, Haberland CA, Hernandez-Boussard TClin Pediatr (Phila)
- Computational modeling of chemo-bio-mechanical coupling: a systems-biology approach toward wound healing.Buganza Tepole A, Kuhl EComput Methods Biomech Biomed Engin
- How have fisheries affected parasite communities?Wood CL, Lafferty KDParasitology
Wishbone identifies bifurcating developmental trajectories from single-cell data.
Nat Biotechnol. 2016 May 2;
Authors: Setty M, Tadmor MD, Reich-Zeliger S, Angel O, Salame TM, Kathail P, Choi K, Bendall S, Friedman N, Pe'er D
Recent single-cell analysis technologies offer an unprecedented opportunity to elucidate developmental pathways. Here we present Wishbone, an algorithm for positioning single cells along bifurcating developmental trajectories with high resolution. Wishbone uses multi-dimensional single-cell data, such as mass cytometry or RNA-Seq data, as input and orders cells according to their developmental progression, and it pinpoints bifurcation points by labeling each cell as pre-bifurcation or as one of two post-bifurcation cell fates. Using 30-channel mass cytometry data, we show that Wishbone accurately recovers the known stages of T-cell development in the mouse thymus, including the bifurcation point. We also apply the algorithm to mouse myeloid differentiation and demonstrate its generalization to additional lineages. A comparison of Wishbone to diffusion maps, SCUBA and Monocle shows that it outperforms these methods both in the accuracy of ordering cells and in the correct identification of branch points.
PMID: 27136076 [PubMed - as supplied by publisher]
Advancing Benchmarks for Genome Sequencing.
Cell Syst. 2015 Sep 23;1(3):176-177
Authors: Zook JM, Salit M
Several recent benchmarking efforts provide reference datasets and samples to improve genome sequencing and calling of germline and somatic mutations.
PMID: 27135909 [PubMed - as supplied by publisher]
Phylogenetic Profiling for Probing the Modular Architecture of the Human Genome.
Cell Syst. 2015 Aug 26;1(2):106-115
Authors: Dey G, Meyer T
Information about functional connections between genes can be derived from patterns of coupled loss of their homologs across multiple species. This comparative approach, termed phylogenetic profiling, has been successfully used to infer genetic interactions in bacteria and eukaryotes. Rapid progress in sequencing eukaryotic species has enabled the recent phylogenetic profiling of the human genome, resulting in systematic functional predictions for uncharacterized human genes. Importantly, groups of co-evolving genes reveal widespread modularity in the underlying genetic network, facilitating experimental analyses in human cells as well as comparative studies of conserved functional modules across species. This strategy is particularly successful in identifying novel metabolic proteins and components of multi-protein complexes. The targeted sequencing of additional key eukaryotes and the incorporation of improved methods to generate and compare phylogenetic profiles will further boost the predictive power and utility of this evolutionary approach to the functional analysis of gene interaction networks.
PMID: 27135799 [PubMed - as supplied by publisher]
Fundamental Limits of Search.
Cell Syst. 2015 Aug 26;1(2):102-103
Authors: Kannan S, Tse D
Ideas from information theory and topology, along with recognition of a recurring structure found in many biological datasets, accelerate search across diverse biological domains.
PMID: 27135798 [PubMed - as supplied by publisher]
Perfect and Near-Perfect Adaptation in Cell Signaling.
Cell Syst. 2016 Feb 24;2(2):62-67
Authors: Ferrell JE
Adaptation is an important basic feature of cellular regulation. Previous theoretical work has identified three types of circuits-negative feedback loops, incoherent feedforward systems, and state-dependent inactivation systems-that can achieve perfect or near-perfect adaptation. Recent work has added another strategy, termed antithetic integral feedback, to the list of motifs capable of robust perfect adaptation. Here, we discuss the properties, limitations, and biological relevance of each of these circuits.
PMID: 27135159 [PubMed - as supplied by publisher]
Cytokine-Stimulated Phosphoflow of Whole Blood Using CyTOF Mass Cytometry.
Bio Protoc. 2015 Jun 5;5(11)
Authors: Fernandez R, Maecker H
The ability to assess the function of a range of cytokine, antigen receptor, and Toll-like receptor (TLR) signaling pathways in a range of immune cells could provide a kind of fingerprint of the state of the human immune system. The mass cytometry or CyTOF, platform allows for the parallel application of about 40 labeled antibodies to a single sample, creating the possibility to read out many cell types and signaling pathways in a single small blood sample. We developed such a mass cytometry panel, consisting of 22 antibodies to cell surface lineage markers and 8 antibodies to phospho-specific epitopes of signaling proteins. These antibodies were chosen to discriminate all major white blood cell lineages, to a level of detail that includes subsets such as naïve, central memory, effector memory, and late effector CD4+ and CD8+T cells, naïve, transitional, and switched memory B cells, plasmablasts, myeloid and plasmacytoid dendritic cells, CD16+ and CD16+CD56+ NK cells, CD16+ and classical monocytes etc. 32 such cell subsets are defined in our standard gating scheme. The eight phospho-specific antibodies were chosen to represent major signaling nodes responsive to cytokine, TLR, and antigen receptor signaling. This antibody panel is used with 8 standard stimulation conditions (unstimulated, IFNa, IL-6, IL-7, IL-10, IL-21, LPS, PMA+ ionomycin), although other stimuli can be added. Comparison of healthy controls to subjects with immune deficiencies of unknown etiology may help elucidate the mechanisms of such deficiencies. Phosphorylation of tyrosine, serine, and threonine residues is critical for the control of protein activity involved in various cellular events. An assortment of kinases and phosphatases regulate intracellular protein phosphorylation in many different cell signaling pathways, such as T and B cell signaling, those regulating apoptosis, growth and cell cycle control, plus those involved with cytokine, chemokine, and stress responses. Phosphoflow assays combine phospho-specific antibodies with the power of flow cytometry to enhance phospho protein study. In our assay, peripheral blood mononuclear cells are stimulated by cytokines, fixed, surface-stained with a cocktail of antibodies labeled with MAXPAR (Brand Name) metal-chelating polymers and permeabilized with methanol. They are then stained with intracellular phospho-specific antibodies. We use a CyTOF™ mass cytometer to acquire the ICP-MS data. The current mass window selected is approximately AW 103-203, which includes the lanthanides used for most antibody labeling, as well as iridium and rhodium for DNA intercalators. Subsequent analysis of the dual count signal data using FlowJo software allows for cell types to be analyzed based on the dual count signal in each mass channel. The percentage of each cell type is determined and reported as a percent of the parent cell type. Median values are reported to quantitate the level of phosphorylation of each protein in response to stimulation. Comparing the level of phosphorylation between samples can offer insight to the status of the immune system. Whole blood stimulation is the closest to the in vivo condition and it allows for assessment of granulocyte population as well as lymphocytes and monocytes.
PMID: 27135045 [PubMed - as supplied by publisher]
The big challenges in modeling human and environmental well-being.
Authors: Tuljapurkar S
This article is a selective review of quantitative research, historical and prospective, that is needed to inform sustainable development policy. I start with a simple framework to highlight how demography and productivity shape human well-being. I use that to discuss three sets of issues and corresponding challenges to modeling: first, population prehistory and early human development and their implications for the future; second, the multiple distinct dimensions of human and environmental well-being and the meaning of sustainability; and, third, inequality as a phenomenon triggered by development and models to examine changing inequality and its consequences. I conclude with a few words about other important factors: political, institutional, and cultural.
PMID: 27134734 [PubMed]
Report of the GRAPPA-OMERACT Psoriatic Arthritis Working Group from the GRAPPA 2015 Annual Meeting.
J Rheumatol. 2016 May;43(5):965-9
Authors: Orbai AM, Mease PJ, de Wit M, Kalyoncu U, Campbell W, Tillett W, Eder L, Elmamoun M, FitzGerald O, Gladman DD, Goel N, Gossec L, Lindsay CA, Steinkoenig I, Helliwell PS, McHugh NJ, Strand V, Ogdie A
The GRAPPA-OMERACT psoriatic arthritis (PsA) working group is in the process of updating the PsA core domain set to improve and standardize the measurement of PsA outcomes. Work streams comprise literature reviews of domains and outcome measurement instruments, an international qualitative research project with PsA patients to generate domains important to patients, outcome measurement instrument assessment, conduct of domain consensus panels with patients and physicians, and evidence-based selection of instruments. Patient research partners are involved in each of the projects. The working group will present findings and seek endorsement for the new PsA core domain set, outcome measurement set, and research agenda at the OMERACT meeting in May 2016.
PMID: 27134271 [PubMed - in process]
Two cases of histiocytic sarcoma with BCL2 translocations and occult or subsequent follicular lymphoma.
Hum Pathol. 2016 Apr 28;
Authors: Fernandez-Pol S, Bangs CD, Cherry A, Arber DA, Gratzinger D
Histiocytic sarcoma is rare and difficult to distinguish from histologic mimics such as myeloid sarcoma due to its relatively nonspecific immunoprofile. A subset of histiocytic sarcomas are clonally related to synchronous or metachronous follicular lymphomas. Interestingly, the histiocytic tumor component has been shown to harbor BCL2 gene translocations that are identical to those found in the lymphoma. We present one case of histiocytic sarcoma and initially occult follicular lymphoma in which detection of a BCL2 gene translocation helped support the diagnosis. We also provide follow up regarding a previously published case of histiocytic sarcoma with IGH/BCL2 fusion gene in which the patient subsequently developed follicular lymphoma and, later, diffuse large B-cell lymphoma. Our findings suggest that BCL2 gene translocations are a recurrent feature of a distinct subset of histiocytic sarcomas that are associated with follicular lymphoma; the follicular lymphoma component may be clinically occult at the time of diagnosis. Testing for an IGH/BCL2 translocation should be considered in the diagnostic workup of difficult to characterize neoplasms with histiocytic/monocytic morphology and immunoprofile.
PMID: 27134111 [PubMed - as supplied by publisher]
Fibroblast Growth Factor 2 Modulates Hypothalamic Pituitary Axis Activity and Anxiety Behavior Through Glucocorticoid Receptors.
Biol Psychiatry. 2016 Mar 2;
Authors: Salmaso N, Stevens HE, McNeill J, ElSayed M, Ren Q, Maragnoli ME, Schwartz ML, Tomasi S, Sapolsky RM, Duman R, Vaccarino FM
BACKGROUND: Despite strong evidence linking fibroblast growth factor 2 (FGF2) with anxiety and depression in both rodents and humans, the molecular mechanisms linking FGF2 with anxiety are not understood.
METHODS: We compare 1) mice that lack a functional Fgf2 gene (Fgf2 knockout [KO]), 2) wild-type mice, and 3) Fgf2 KO with adult rescue by FGF2 administration on measures of anxiety, depression, and motor behavior, and further investigate the mechanisms of this behavior by cellular, molecular, and neuroendocrine studies.
RESULTS: We demonstrate that Fgf2 KO mice have increased anxiety, decreased hippocampal glucocorticoid receptor (GR) expression, and increased hypothalamic-pituitary-adrenal axis activity. FGF2 administration in adulthood was sufficient to rescue the entire phenotype. Blockade of GR in adult mice treated with FGF2 precluded the therapeutic effects of FGF2 on anxiety behavior, suggesting that GR is necessary for FGF2 to regulate anxiety behavior. The level of Egr-1/NGFI-A was decreased in Fgf2 KO mice and was reestablished with FGF2 treatment. By chromatin immunoprecipitation studies, we found decreased binding of EGR-1 to the GR promoter region in Fgf2 KO mice. Finally, we examined anxiety behavior in FGF receptor (FGFR) KO mice; however, FGFR1, FGFR2, and FGFR3 KO mice did not mimic the phenotype of Fgf2 KO mice, suggesting a role for other receptor subtypes (i.e., FGFR5).
CONCLUSIONS: These data suggest that FGF2 levels are critically related to anxiety behavior and hypothalamic-pituitary-adrenal axis activity, likely through modulation of hippocampal glucocorticoid receptor expression, an effect that is likely receptor mediated, albeit not by FGFR1, FGFR2, and FGFR3.
PMID: 27133954 [PubMed - as supplied by publisher]
Is the canonical RAF-MEK-ERK signaling pathway a therapeutic target in SCLC?
J Thorac Oncol. 2016 Apr 28;
Authors: Cristea S, Sage J
The activity of the RAF-MEK-ERK signaling pathway is critical for the proliferation of normal and cancerous cells. Oncogenic mutations driving the development of lung adenocarcinoma often activate this signaling pathway. In contrast, pathway activity levels and their biological roles are not well established in small cell lung cancer (SCLC), a fast-growing neuroendocrine lung cancer subtype. Here we discuss the function of the RAF-MEK-ERK kinase pathway and the mechanisms leading to its activation in SCLC cells. In particular, we argue that activation of this pathway may be beneficial to the survival, proliferation and spread of SCLC cells in response to multiple stimuli. We also consider evidence that high levels of RAF-MEK-ERK pathway activity may be detrimental to SCLC tumors, including in part by interfering with their neuroendocrine fate. Based on these observations, we examine when small molecules targeting kinases in the RAF-MEK-ERK pathway may be useful therapeutically in SCLC patients, including in combination with other therapeutic agents.
PMID: 27133774 [PubMed - as supplied by publisher]
National prevalence, causes, and risk factors for bariatric surgery readmissions.
Am J Surg. 2016 Mar 19;
Authors: Garg T, Rosas U, Rivas H, Azagury D, Morton JM
BACKGROUND: Readmissions are often used as a quality metric particularly in bariatric surgery.
METHODS: Laparoscopic Roux en Y gastric bypass, laparoscopic adjustable gastric banding, and laparoscopic sleeve gastrectomy were identified using Current Procedure Terminology codes in the 2012 National Surgical Quality Improvement Program public use file.
RESULTS: A total of 18,296 patients were included, 10,080 (55.1%) were laparoscopic Roux en Y gastric bypass, 1,829 (10.0%) were laparoscopic adjustable gastric banding, and 6,387 (34.9%) were laparoscopic sleeve gastrectomy. Among all patients, 955 (5.22%) were readmitted. Patients with readmissions had a higher proportion of body mass index greater than 50 (30.2% vs 24.6%, P < .001), higher index operative time (132 minutes vs 115, P < .001) and greater proportion with length of stay greater than 4 days (9.57% vs 3.36%, P < .001). Readmitted patients were more likely to have diabetes (31.1% vs 27.7%, P = .02), chronic obstructive pulmonary disease (2.63% vs 1.72%, P = .04), and hypertension (54.5% vs 50.8%, P = .03). Overall, 40.6% of readmitted patients had a complication. Common readmissions were gastrointestinal-related (45.0%), dietary (33.5%), and bleeding (6.57%). Readmission was independently associated with African-American race (odds ratio [OR] = 1.53, P = .02), complication (OR = 11.3, 95%, P < .001), and resident involvement (OR = .53, P = .04).
CONCLUSIONS: A 30-day readmission after bariatric surgery is prevalent and closely associated with complications.
PMID: 27133197 [PubMed - as supplied by publisher]
Children with lower respiratory tract infections and serum 25-hydroxyvitamin D3 levels: A case-control study.
Pediatr Pulmonol. 2016 May 1;
Authors: Velarde López AA, Gerber JS, Leonard MB, Xie D, Schinnar R, Strom BL
BACKGROUND: Pneumonia is the leading cause of death in children under age of 5 years worldwide. The role of vitamin D in respiratory infections including pneumonia is unclear; therefore, we aimed to determine if children with lower respiratory tract infections had low serum 25-hydroxyvitamin D3 .
METHODS: We performed a case-control study of children ages 3-60 months from the Guatemala City metropolitan area, hospitalized with community-acquired pneumonia between September and December 2012. Controls were selected from the well-baby/care immunization clinics serving the population from which cases emerged. We analyzed serum 25-hydroxyvitamin D3 levels and conducted parental interviews to assess subject age, sex, race, feeding type, vitamin D supplementation, frequency of sun exposure, and maternal education. Height and weight were ascertained from medical records. Complete information was available for 70 (83%) of 84 eligible cases and 68 (60%) of 113 eligible controls.
RESULTS: The median (IQR) serum 25-hydroxyvitamin D3 concentration for cases was 23.2 ng/ml (14.4-29.9) compared to 27.5 ng/ml (21.4-32.3) in controls (P = 0.006). Multiple regression analysis using an a priori cut-point for vitamin D of <20 ng/ml showed that children with lower respiratory tract infections were more likely to have low 25-hydroxyvitamin D3 levels than controls (adjusted odds ratio 2.4, 95% confidence interval 1.1-5.2, P = 0.02).
CONCLUSIONS: Children with lower respiratory tract infections in Guatemala had low 25-hydroxyvitamin D3 levels. Pediatr Pulmonol. © 2016 Wiley Periodicals, Inc.
PMID: 27133156 [PubMed - as supplied by publisher]
Age-Dependent Pancreatic Gene Regulation Reveals Mechanisms Governing Human β Cell Function.
Cell Metab. 2016 Apr 27;
Authors: Arda HE, Li L, Tsai J, Torre EA, Rosli Y, Peiris H, Spitale RC, Dai C, Gu X, Qu K, Wang P, Wang J, Grompe M, Scharfmann R, Snyder MS, Bottino R, Powers AC, Chang HY, Kim SK
Intensive efforts are focused on identifying regulators of human pancreatic islet cell growth and maturation to accelerate development of therapies for diabetes. After birth, islet cell growth and function are dynamically regulated; however, establishing these age-dependent changes in humans has been challenging. Here, we describe a multimodal strategy for isolating pancreatic endocrine and exocrine cells from children and adults to identify age-dependent gene expression and chromatin changes on a genomic scale. These profiles revealed distinct proliferative and functional states of islet α cells or β cells and histone modifications underlying age-dependent gene expression changes. Expression of SIX2 and SIX3, transcription factors without prior known functions in the pancreas and linked to fasting hyperglycemia risk, increased with age specifically in human islet β cells. SIX2 and SIX3 were sufficient to enhance insulin content or secretion in immature β cells. Our work provides a unique resource to study human-specific regulators of islet cell maturation and function.
PMID: 27133132 [PubMed - as supplied by publisher]
Trends in Testosterone Prescription and Public Health Concerns.
Urol Clin North Am. 2016 May;43(2):261-71
Authors: Gabrielsen JS, Najari BB, Alukal JP, Eisenberg ML
Testosterone supplementation therapy (TST) has become increasingly popular since the turn of the century. Most prescriptions in the U.S. are written by primary care providers, endocrinologists, or urologists. The FDA has requests pharmaceutical companies provide more long term data on efficacy and safety of testosterone products. Results from these studies will help define the appropriate population for TST going forward. It is hoped that these data combined with physician and public education will minimize inappropriate prescribing and allow those likely to benefit from TST to receive it.
PMID: 27132584 [PubMed - in process]
Optogenetic modulation in stroke recovery.
Neurosurg Focus. 2016 May;40(5):E6
Authors: Pendharkar AV, Levy SL, Ho AL, Sussman ES, Cheng MY, Steinberg GK
Stroke is one of the leading contributors to morbidity, mortality, and health care costs in the United States. Although several preclinical strategies have shown promise in the laboratory, few have succeeded in the clinical setting. Optogenetics represents a promising molecular tool, which enables highly specific circuit-level neuromodulation. Here, the conceptual background and preclinical body of evidence for optogenetics are reviewed, and translational considerations in stroke recovery are discussed.
PMID: 27132527 [PubMed - in process]
Radiation-induced brain injury: low-hanging fruit for neuroregeneration.
Neurosurg Focus. 2016 May;40(5):E3
Authors: Burns TC, Awad AJ, Li MD, Grant GA
Brain radiation is a fundamental tool in neurooncology to improve local tumor control, but it leads to profound and progressive impairments in cognitive function. Increased attention to quality of life in neurooncology has accelerated efforts to understand and ameliorate radiation-induced cognitive sequelae. Such progress has coincided with a new understanding of the role of CNS progenitor cell populations in normal cognition and in their potential utility for the treatment of neurological diseases. The irradiated brain exhibits a host of biochemical and cellular derangements, including loss of endogenous neurogenesis, demyelination, and ablation of endogenous oligodendrocyte progenitor cells. These changes, in combination with a state of chronic neuroinflammation, underlie impairments in memory, attention, executive function, and acquisition of motor and language skills. Animal models of radiation-induced brain injury have demonstrated a robust capacity of both neural stem cells and oligodendrocyte progenitor cells to restore cognitive function after brain irradiation, likely through a combination of cell replacement and trophic effects. Oligodendrocyte progenitor cells exhibit a remarkable capacity to migrate, integrate, and functionally remyelinate damaged white matter tracts in a variety of preclinical models. The authors here critically address the opportunities and challenges in translating regenerative cell therapies from rodents to humans. Although valiant attempts to translate neuroprotective therapies in recent decades have almost uniformly failed, the authors make the case that harnessing human radiation-induced brain injury as a scientific tool represents a unique opportunity to both successfully translate a neuroregenerative therapy and to acquire tools to facilitate future restorative therapies for human traumatic and degenerative diseases of the central nervous system.
PMID: 27132524 [PubMed - in process]
Neurorestoration after stroke.
Neurosurg Focus. 2016 May;40(5):E2
Authors: Azad TD, Veeravagu A, Steinberg GK
Recent advancements in stem cell biology and neuromodulation have ushered in a battery of new neurorestorative therapies for ischemic stroke. While the understanding of stroke pathophysiology has matured, the ability to restore patients' quality of life remains inadequate. New therapeutic approaches, including cell transplantation and neurostimulation, focus on reestablishing the circuits disrupted by ischemia through multidimensional mechanisms to improve neuroplasticity and remodeling. The authors provide a broad overview of stroke pathophysiology and existing therapies to highlight the scientific and clinical implications of neurorestorative therapies for stroke.
PMID: 27132523 [PubMed - in process]
Prioritizing schizophrenia endophenotypes for future genetic studies: An example using data from the COGS-1 family study.
Schizophr Res. 2016 Apr 28;
Authors: Millard SP, Shofer J, Braff D, Calkins M, Cadenhead K, Freedman R, Green MF, Greenwood TA, Gur R, Gur R, Lazzeroni LC, Light GA, Olincy A, Nuechterlein K, Seidman L, Siever L, Silverman J, Stone WS, Sprock J, Sugar CA, Swerdlow NR, Tsuang M, Turetsky B, Radant A, Tsuang DW
Past studies describe numerous endophenotypes associated with schizophrenia (SZ), but many endophenotypes may overlap in information they provide, and few studies have investigated the utility of a multivariate index to improve discrimination between SZ and healthy community comparison subjects (CCS). We investigated 16 endophenotypes from the first phase of the Consortium on the Genetics of Schizophrenia, a large, multi-site family study, to determine whether a subset could distinguish SZ probands and CCS just as well as using all 16. Participants included 345 SZ probands and 517 CCS with a valid measure for at least one endophenotype. We used both logistic regression and random forest models to choose a subset of endophenotypes, adjusting for age, gender, smoking status, site, parent education, and the reading subtest of the Wide Range Achievement Test. As a sensitivity analysis, we re-fit models using multiple imputations to determine the effect of missing values. We identified four important endophenotypes: antisaccade, Continuous Performance Test-Identical Pairs 3-digit version, California Verbal Learning Test, and emotion identification. The logistic regression model that used just these four endophenotypes produced essentially the same results as the model that used all 16 (84% vs. 85% accuracy). While a subset of endophenotypes cannot replace clinical diagnosis nor encompass the complexity of the disease, it can aid in the design of future endophenotypic and genetic studies by reducing study cost and subject burden, simplifying sample enrichment, and improving the statistical power of locating those genetic regions associated with schizophrenia that may be the easiest to identify initially.
PMID: 27132484 [PubMed - as supplied by publisher]
CDX2 as a Prognostic Biomarker in Stage II and Stage III Colon Cancer.
N Engl J Med. 2016 Jan 21;374(3):211-22
Authors: Dalerba P, Sahoo D, Paik S, Guo X, Yothers G, Song N, Wilcox-Fogel N, Forgó E, Rajendran PS, Miranda SP, Hisamori S, Hutchison J, Kalisky T, Qian D, Wolmark N, Fisher GA, van de Rijn M, Clarke MF
Background The identification of high-risk stage II colon cancers is key to the selection of patients who require adjuvant treatment after surgery. Microarray-based multigene-expression signatures derived from stem cells and progenitor cells hold promise, but they are difficult to use in clinical practice. Methods We used a new bioinformatics approach to search for biomarkers of colon epithelial differentiation across gene-expression arrays and then ranked candidate genes according to the availability of clinical-grade diagnostic assays. With the use of subgroup analysis involving independent and retrospective cohorts of patients with stage II or stage III colon cancer, the top candidate gene was tested for its association with disease-free survival and a benefit from adjuvant chemotherapy. Results The transcription factor CDX2 ranked first in our screening test. A group of 87 of 2115 tumor samples (4.1%) lacked CDX2 expression. In the discovery data set, which included 466 patients, the rate of 5-year disease-free survival was lower among the 32 patients (6.9%) with CDX2-negative colon cancers than among the 434 (93.1%) with CDX2-positive colon cancers (hazard ratio for disease recurrence, 3.44; 95% confidence interval [CI], 1.60 to 7.38; P=0.002). In the validation data set, which included 314 patients, the rate of 5-year disease-free survival was lower among the 38 patients (12.1%) with CDX2 protein-negative colon cancers than among the 276 (87.9%) with CDX2 protein-positive colon cancers (hazard ratio, 2.42; 95% CI, 1.36 to 4.29; P=0.003). In both these groups, these findings were independent of the patient's age, sex, and tumor stage and grade. Among patients with stage II cancer, the difference in 5-year disease-free survival was significant both in the discovery data set (49% among 15 patients with CDX2-negative tumors vs. 87% among 191 patients with CDX2-positive tumors, P=0.003) and in the validation data set (51% among 15 patients with CDX2-negative tumors vs. 80% among 106 patients with CDX2-positive tumors, P=0.004). In a pooled database of all patient cohorts, the rate of 5-year disease-free survival was higher among 23 patients with stage II CDX2-negative tumors who were treated with adjuvant chemotherapy than among 25 who were not treated with adjuvant chemotherapy (91% vs. 56%, P=0.006). Conclusions Lack of CDX2 expression identified a subgroup of patients with high-risk stage II colon cancer who appeared to benefit from adjuvant chemotherapy. (Funded by the National Comprehensive Cancer Network, the National Institutes of Health, and others.).
PMID: 26789870 [PubMed - indexed for MEDLINE]
Maternal use of oral contraceptives and risk of birth defects in Denmark: prospective, nationwide cohort study.
Authors: Charlton BM, Mølgaard-Nielsen D, Svanström H, Wohlfahrt J, Pasternak B, Melbye M
STUDY QUESTION: Is oral contraceptive use around the time of pregnancy onset associated with an increased risk of major birth defects?
METHODS: In a prospective observational cohort study, data on oral contraceptive use and major birth defects were collected among 880,694 live births from Danish registries between 1997 and 2011. We conservatively assumed that oral contraceptive exposure lasted up to the most recently filled prescription. The main outcome measure was the number of major birth defects throughout one year follow-up (defined according to the European Surveillance of Congenital Anomalies classification). Logistic regression estimated prevalence odds ratios of any major birth defect as well as categories of birth defect subgroups.
STUDY ANSWER AND LIMITATIONS: Prevalence of major birth defects (per 1000 births) was consistent across each oral contraceptive exposure group (25.1, never users; 25.0, use >3 months before pregnancy onset (reference group); 24.9, use 0-3 months before pregnancy onset (that is, recent use); 24.8, use after pregnancy onset). No increase in prevalence of major birth defects was seen with oral contraceptive exposure among women with recent use before pregnancy (prevalence odds ratio 0.98 (95% confidence interval 0.93 to 1.03)) or use after pregnancy onset (0.95 (0.84 to 1.08)), compared with the reference group. There was also no increase in prevalence of any birth defect subgroup (for example, limb defects). It is unknown whether women took oral contraceptives up to the date of their most recently filled prescription. Also, the rarity of birth defects made disaggregation of the results difficult. Residual confounding was possible, and the analysis lacked information on folate, one of the proposed mechanisms.
WHAT THIS STUDY ADDS: Oral contraceptive exposure just before or during pregnancy does not appear to be associated with an increased risk of major birth defects.
FUNDING, COMPETING INTERESTS, DATA SHARING: BMC was funded by the Harvard T H Chan School of Public Health's Maternal Health Task Force and Department of Epidemiology Rose Traveling Fellowship; training grant T32HD060454 in reproductive, perinatal, and paediatric epidemiology and award F32HD084000 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development; and grant T32CA09001 from the National Cancer Institute. The authors have no competing interests or additional data to share.
PMID: 26738512 [PubMed - indexed for MEDLINE]
The Questions We Cannot Answer.
Acad Med. 2016 Jan;91(1):25
Authors: Waliany S
PMID: 26714137 [PubMed - indexed for MEDLINE]
Lymphoid Hyperplasia of the Appendix: A Potential Pitfall in the Sonographic Diagnosis of Appendicitis.
AJR Am J Roentgenol. 2016 Jan;206(1):189-94
Authors: Xu Y, Jeffrey RB, DiMaio MA, Olcott EW
OBJECTIVE: The objective of this study was to test the hypothesis that thickening of the lamina propria, a finding produced by lymphoid hyperplasia, is significantly associated with false-positive sonographic diagnoses of appendicitis in 6- to 8-mm noncompressible appendixes.
MATERIALS AND METHODS: Sonograms of 119 consecutive patients with suspected appendicitis and 6- to 8-mm noncompressible appendixes were retrospectively blindly evaluated for thickening of the lamina propria (short axis thickness ≥ 1 mm). The reference standard for appendicitis was pathologic analysis of resected specimens. Results were compared with the two-tailed Fisher exact test.
RESULTS: Thirty-one patients (26.1%) had a thickened lamina propria and 88 (73.9%) did not. Of the 27 pediatric patients with a thickened lamina propria, five (18.5%) had true-positive and 22 (81.5%) had false-positive sonograms for appendicitis; among the 55 pediatric patients without a thickened lamina propria, 27 (49.1%) had true-positive and 28 (50.9%) had false-positive sonograms for appendicitis (p = 0.009). Similar differences in adult patients were not statistically significant. All five pediatric patients with appendicitis and thickened lamina propria also showed two or more findings of periappendiceal fluid, hyperechoic periappendiceal fat, or mural hyperemia on color Doppler examination, compared with two of 22 similar pediatric patients without appendicitis (p < 0.001).
CONCLUSION: Lymphoid hyperplasia may result in a noncompressible appendix 6-8 mm in diameter and may be misdiagnosed as appendicitis in pediatric patients. True-positive diagnoses of appendicitis can be accurately identified by the presence of at least two additional findings from the group of periappendiceal fluid, hyperechoic periappendiceal fat, and mural hyperemia. Identifying the characteristic sonographic appearance of lymphoid hyperplasia may help prevent false-positive misdiagnoses of appendicitis.
PMID: 26700351 [PubMed - indexed for MEDLINE]
Enrollment Yield and Reasons for Screen Failure in a Large Prehospital Stroke Trial.
Stroke. 2016 Jan;47(1):232-5
Authors: Kim DH, Saver JL, Starkman S, Liebeskind DS, Ali LK, Restrepo L, Kim-Tenser M, Valdes-Sueiras M, Eckstein M, Pratt F, Stratton S, Hamilton S, Conwit R, Sanossian N, Field Administration of Stroke Therapy–Magnesium (FAST-MAG) Trial Nurse-Coordinators and Investigators
BACKGROUND AND PURPOSE: The enrollment yield and reasons for screen failure in prehospital stroke trials have not been well delineated.
METHODS: The Field Administration of Stroke Therapy-Magnesium (FAST-MAG) trial identified patients for enrollment using a 2 stage screening process-paramedics in person followed by physician-investigators by cell phone. Outcomes of consecutive screening calls from paramedics to enrolling physician-investigators were prospectively recorded.
RESULTS: From 2005 to 2012, 4458 phone calls were made by paramedics to physician-investigators, an average of 1 call per vehicle every 135.7 days. A total of 1700 (38.1%) calls resulted in enrollments. The rate of enrollment of stroke mimics was 3.9%. Among the 2758 patients not enrolled, 3140 reasons for screen failure were documented. The most common reasons for nonenrollment were >2 hours from last known well (17.2%), having a prestroke condition causing disability (16.1%), and absence of a consent provider (9.5%). Novel barriers for phone informed consent specific to the prehospital setting were infrequent, but included: cell phone connection difficulties (3.2%), patient being hard of hearing (1.4%), insufficient time to complete consent (1.3%), or severely dysarthric (1.3%).
CONCLUSIONS: In this large, multicenter prehospital trial, nearly 40% of every calls from the field to physician-investigators resulted in trial enrollments. The most common reasons for nonenrollment were out of window last known well time, prestroke confounding medical condition, and absence of a consent provider.
CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00059332.
PMID: 26658446 [PubMed - indexed for MEDLINE]
Coffee and caffeine consumption and the risk of hypertension in postmenopausal women.
Am J Clin Nutr. 2016 Jan;103(1):210-7
Authors: Rhee JJ, Qin F, Hedlin HK, Chang TI, Bird CE, Zaslavsky O, Manson JE, Stefanick ML, Winkelmayer WC
BACKGROUND: The associations of coffee and caffeine intakes with the risk of incident hypertension remain controversial.
OBJECTIVE: We sought to assess longitudinal relations of caffeinated coffee, decaffeinated coffee, and total caffeine intakes with mean blood pressure and incident hypertension in postmenopausal women in the Women's Health Initiative Observational Study.
DESIGN: In a large prospective study, type and amount of coffee and total caffeine intakes were assessed by using self-reported questionnaires. Hypertension status was ascertained by using measured blood pressure and self-reported drug-treated hypertension. The mean intakes of caffeinated coffee, decaffeinated coffee, and caffeine were 2-3 cups/d, 1 cup/d, and 196 mg/d, respectively. Using multivariable linear regression, we examined the associations of baseline intakes of caffeinated coffee, decaffeinated coffee, and caffeine with measured systolic and diastolic blood pressures at annual visit 3 in 29,985 postmenopausal women who were not hypertensive at baseline. We used Cox proportional hazards models to estimate HRs and their 95% CIs for time to incident hypertension.
RESULTS: During 112,935 person-years of follow-up, 5566 cases of incident hypertension were reported. Neither caffeinated coffee nor caffeine intake was associated with mean systolic or diastolic blood pressure, but decaffeinated coffee intake was associated with a small but clinically irrelevant decrease in mean diastolic blood pressure. Decaffeinated coffee intake was not associated with mean systolic blood pressure. Intakes of caffeinated coffee, decaffeinated coffee, and caffeine were not associated with the risk of incident hypertension (P-trend > 0.05 for all).
CONCLUSION: In summary, these findings suggest that caffeinated coffee, decaffeinated coffee, and caffeine are not risk factors for hypertension in postmenopausal women.
PMID: 26657046 [PubMed - indexed for MEDLINE]
The Children's Hepatic tumors International Collaboration (CHIC): Novel global rare tumor database yields new prognostic factors in hepatoblastoma and becomes a research model.
Eur J Cancer. 2016 Jan;52:92-101
Authors: Czauderna P, Haeberle B, Hiyama E, Rangaswami A, Krailo M, Maibach R, Rinaldi E, Feng Y, Aronson D, Malogolowkin M, Yoshimura K, Leuschner I, Lopez-Terrada D, Hishiki T, Perilongo G, von Schweinitz D, Schmid I, Watanabe K, Derosa M, Meyers R
INTRODUCTION: Contemporary state-of-the-art management of cancer is increasingly defined by individualized treatment strategies. For very rare tumors, like hepatoblastoma, the development of biologic markers, and the identification of reliable prognostic risk factors for tailoring treatment, remains very challenging. The Children's Hepatic tumors International Collaboration (CHIC) is a novel international response to this challenge.
METHODS: Four multicenter trial groups in the world, who have performed prospective controlled studies of hepatoblastoma over the past two decades (COG; SIOPEL; GPOH; and JPLT), joined forces to form the CHIC consortium. With the support of the data management group CINECA, CHIC developed a centralized online platform where data from eight completed hepatoblastoma trials were merged to form a database of 1605 hepatoblastoma cases treated between 1988 and 2008. The resulting dataset is described and the relationships between selected patient and tumor characteristics, and risk for adverse disease outcome (event-free survival; EFS) are examined.
RESULTS: Significantly increased risk for EFS-event was noted for advanced PRETEXT group, macrovascular venous or portal involvement, contiguous extrahepatic disease, primary tumor multifocality and tumor rupture at enrollment. Higher age (≥ 8 years), low AFP (<100 ng/ml) and metastatic disease were associated with the worst outcome.
CONCLUSION: We have identified novel prognostic factors for hepatoblastoma, as well as confirmed established factors, that will be used to develop a future common global risk stratification system. The mechanics of developing the globally accessible web-based portal, building and refining the database, and performing this first statistical analysis has laid the foundation for future collaborative efforts. This is an important step for refining of the risk based grouping and approach to future treatment stratification, thus we think our collaboration offers a template for others to follow in the study of rare tumors and diseases.
PMID: 26655560 [PubMed - indexed for MEDLINE]
Survival in familial and non-familial breast cancer by age and stage at diagnosis.
Eur J Cancer. 2016 Jan;52:10-8
Authors: Kharazmi E, Försti A, Sundquist K, Hemminki K
We aimed to compare the survival in familial and sporadic breast cancer (BC) patients who were diagnosed at an identical age and TNM stage. The Nationwide Swedish Family-Cancer Database including all Swedes born after 1931 and their biological parents, totalling >14.7 million individuals, was used. Hazard ratios (HRs) were calculated for women with BC in a first-degree relative (FDR) versus BC patients without positive family history. There was no difference in survival of familial BC patients who were diagnosed at higher TNM status or older age (>40) compared to sporadic BC cases diagnosed at the same late TNM stage. Young BC patients (age <40) in early stages had the worst survival when their FDR was diagnosed with single (HR: 2.0-3.7) or multiple (HR: 2.4-7.1) BC at any age. We concluded that there is no difference in survival of familial and non-familial BC patients who are diagnosed at higher TNM status or older ages (>40). Young familial BC patients (age <40), diagnosed at early stage, have the poorer survival compared to sporadic cases. Our results urge the need for identifying the underling genetic component for such a difference in survival of familial BC.
PMID: 26630529 [PubMed - indexed for MEDLINE]
Exploring the Relationship Between Stereotype Perception and Residents' Well-Being.
J Am Coll Surg. 2016 Jan;222(1):52-8
Authors: Salles A, Mueller CM, Cohen GL
BACKGROUND: Medicine has historically been a male-dominated field, and there remains a stereotype that men are better physicians than women. For female residents, and in particular female surgical residents, chronically contending with this stereotype can exact a toll on their psychological health. The objective of this study was to determine the relationship between women surgeons' psychological health and their perception of other people's endorsement of the stereotype (stereotype perception).
STUDY DESIGN: This is a correlational study based on survey data collected from 14 residency programs at one medical center from September 2010 to March 2011. The participants were 384 residents (representing an 80% response rate). The main survey measures were the Dupuy Psychological General Well-Being Scale and the Maslach Burnout Inventory.
RESULTS: Among female surgical residents, we found that those with higher degrees of stereotype perception had poorer psychological health than those with lower degrees of stereotype perception (β = -0.44, p = 0.002). For men, there was no relationship between stereotype perception and psychological health (β = 0.015; p = 0.92). Among nonsurgeons, there was no relationship between stereotype perception and psychological health for either women or men (β = -0.016; p = 0.78; β = -0.0050; p = 0.97, respectively).
CONCLUSIONS: The data suggest that women in surgical training, but not men, can face a stressor--stereotype perception--that is negatively associated with their psychological health. This same relationship does not seem to exist for women in nonsurgical training programs. Efforts should be made to further understand this relationship and investigate possible interventions to level the playing field for male and female surgical trainees.
PMID: 26616033 [PubMed - indexed for MEDLINE]
Where Do We Stand With Aspirin for the Prevention of Colorectal Cancer? The USPSTF Recommendations.
Gastroenterology. 2016 Jan;150(1):14-8
Authors: Chan AT, Ladabaum U
PMID: 26602220 [PubMed - indexed for MEDLINE]
An active site rearrangement within the Tetrahymena group I ribozyme releases nonproductive interactions and allows formation of catalytic interactions.
RNA. 2016 Jan;22(1):32-48
Authors: Sengupta RN, Van Schie SN, Giambaşu G, Dai Q, Yesselman JD, York D, Piccirilli JA, Herschlag D
Biological catalysis hinges on the precise structural integrity of an active site that binds and transforms its substrates and meeting this requirement presents a unique challenge for RNA enzymes. Functional RNAs, including ribozymes, fold into their active conformations within rugged energy landscapes that often contain misfolded conformers. Here we uncover and characterize one such "off-pathway" species within an active site after overall folding of the ribozyme is complete. The Tetrahymena group I ribozyme (E) catalyzes cleavage of an oligonucleotide substrate (S) by an exogenous guanosine (G) cofactor. We tested whether specific catalytic interactions with G are present in the preceding E•S•G and E•G ground-state complexes. We monitored interactions with G via the effects of 2'- and 3'-deoxy (-H) and -amino (-NH(2)) substitutions on G binding. These and prior results reveal that G is bound in an inactive configuration within E•G, with the nucleophilic 3'-OH making a nonproductive interaction with an active site metal ion termed MA and with the adjacent 2'-OH making no interaction. Upon S binding, a rearrangement occurs that allows both -OH groups to contact a different active site metal ion, termed M(C), to make what are likely to be their catalytic interactions. The reactive phosphoryl group on S promotes this change, presumably by repositioning the metal ions with respect to G. This conformational transition demonstrates local rearrangements within an otherwise folded RNA, underscoring RNA's difficulty in specifying a unique conformation and highlighting Nature's potential to use local transitions of RNA in complex function.
PMID: 26567314 [PubMed - indexed for MEDLINE]
Systematic Motorcycle Management and Health Care Delivery: A Field Trial.
Am J Public Health. 2016 Jan;106(1):87-94
Authors: Mehta KM, Rerolle F, Rammohan SV, Albohm DC, Muwowo G, Moseson H, Sept L, Lee HL, Bendavid E
OBJECTIVES: We investigated whether managed transportation improves outreach-based health service delivery to rural village populations.
METHODS: We examined systematic transportation management in a small-cluster interrupted time series field trial. In 8 districts in Southern Zambia, we followed health workers at 116 health facilities from September 2011 to March 2014. The primary outcome was the average number of outreach trips per health worker per week. Secondary outcomes were health worker productivity, motorcycle performance, and geographical coverage.
RESULTS: Systematic fleet management resulted in an increase of 0.9 (SD = 1.0) trips to rural villages per health worker per week (P < .001), village-level health worker productivity by 20.5 (SD = 5.9) patient visits, 10.2 (SD = 1.5) measles immunizations, and 5.2 (SD = 5.4) child growth assessments per health worker per week. Motorcycle uptime increased by 3.5 days per week (P < .001), use by 1.5 days per week (P < .001), and mean distance by 9.3 kilometers per trip (P < .001). Geographical coverage of health outreach increased in experimental (P < .001) but not control districts.
CONCLUSIONS: Systematic motorcycle management improves basic health care delivery to rural villages in resource-poor environments through increased health worker productivity and greater geographical coverage.
PMID: 26562131 [PubMed - indexed for MEDLINE]
Sociodemographic Predictors of Vaccination Exemptions on the Basis of Personal Belief in California.
Am J Public Health. 2016 Jan;106(1):172-7
Authors: Yang YT, Delamater PL, Leslie TF, Mello MM
OBJECTIVES: We examined the variability in the percentage of students with personal belief exemptions (PBEs) from mandatory vaccinations in California schools and communities according to income, education, race, and school characteristics.
METHODS: We used spatial lag models to analyze 2007-2013 PBE data from the California Department of Public Health. The analyses included school- and regional-level models, and separately examined the percentage of students with exemptions in 2013 and the change in percentages over time.
RESULTS: The percentage of students with PBEs doubled from 2007 to 2013, from 1.54% to 3.06%. Across all models, higher median household income and higher percentage of White race in the population, but not educational attainment, significantly predicted higher percentages of students with PBEs in 2013. Higher income, White population, and private school type significantly predicted greater increases in exemptions from 2007 to 2013, whereas higher educational attainment was associated with smaller increases.
CONCLUSIONS: Personal belief exemptions are more common in areas with a higher percentage of White race and higher income.
PMID: 26562114 [PubMed - indexed for MEDLINE]
Risk of Recurrent Arterial Ischemic Stroke in Childhood: A Prospective International Study.
Stroke. 2016 Jan;47(1):53-9
Authors: Fullerton HJ, Wintermark M, Hills NK, Dowling MM, Tan M, Rafay MF, Elkind MS, Barkovich AJ, deVeber GA, VIPS Investigators
BACKGROUND AND PURPOSE: Published cohorts of children with arterial ischemic stroke (AIS) in the 1990s to early 2000s reported 5-year cumulative recurrence rates approaching 20%. Since then, utilization of antithrombotic agents for secondary stroke prevention in children has increased. We sought to determine rates and predictors of recurrent stroke in the current era.
METHODS: The Vascular Effects of Infection in Pediatric Stroke (VIPS) study enrolled 355 children with AIS at 37 international centers from 2009 to 2014 and followed them prospectively for recurrent stroke. Index and recurrent strokes underwent central review and confirmation, as well as central classification of causes of stroke, including arteriopathies. Other predictors were measured via parental interview or chart review.
RESULTS: Of the 355 children, 354 survived their acute index stroke, and 308 (87%) were treated with an antithrombotic medication. During a median follow-up of 2.0 years (interquartile range, 1.0-3.0), 40 children had a recurrent AIS, and none had a hemorrhagic stroke. The cumulative stroke recurrence rate was 6.8% (95% confidence interval, 4.6%-10%) at 1 month and 12% (8.5%-15%) at 1 year. The sole predictor of recurrence was the presence of an arteriopathy, which increased the risk of recurrence 5-fold when compared with an idiopathic AIS (hazard ratio, 5.0; 95% confidence interval, 1.8-14). The 1-year recurrence rate was 32% (95% confidence interval, 18%-51%) for moyamoya, 25% (12%-48%) for transient cerebral arteriopathy, and 19% (8.5%-40%) for arterial dissection.
CONCLUSIONS: Children with AIS, particularly those with arteriopathy, remain at high risk for recurrent AIS despite increased utilization of antithrombotic agents. Therapies directed at the arteriopathies themselves are needed.
PMID: 26556824 [PubMed - indexed for MEDLINE]
Surgeons' Leadership Styles and Team Behavior in the Operating Room.
J Am Coll Surg. 2016 Jan;222(1):41-51
Authors: Hu YY, Parker SH, Lipsitz SR, Arriaga AF, Peyre SE, Corso KA, Roth EM, Yule SJ, Greenberg CC
BACKGROUND: The importance of leadership is recognized in surgery, but the specific impact of leadership style on team behavior is not well understood. In other industries, leadership is a well-characterized construct. One dominant theory proposes that transactional (task-focused) leaders achieve minimum standards and transformational (team-oriented) leaders inspire performance beyond expectations.
STUDY DESIGN: We videorecorded 5 surgeons performing complex operations. Each surgeon was scored on the Multifactor Leadership Questionnaire, a validated method for scoring transformational and transactional leadership style, by an organizational psychologist and a surgeon researcher. Independent coders assessed surgeons' leadership behaviors according to the Surgical Leadership Inventory and team behaviors (information sharing, cooperative, and voice behaviors). All coders were blinded. Leadership style (Multifactor Leadership Questionnaire) was correlated with surgeon behavior (Surgical Leadership Inventory) and team behavior using Poisson regression, controlling for time and the total number of behaviors, respectively.
RESULTS: All surgeons scored similarly on transactional leadership (range 2.38 to 2.69), but varied more widely on transformational leadership (range 1.98 to 3.60). Each 1-point increase in transformational score corresponded to 3 times more information-sharing behaviors (p < 0.0001) and 5.4 times more voice behaviors (p = 0.0005) among the team. With each 1-point increase in transformational score, leaders displayed 10 times more supportive behaviors (p < 0.0001) and displayed poor behaviors 12.5 times less frequently (p < 0.0001). Excerpts of representative dialogue are included for illustration.
CONCLUSIONS: We provide a framework for evaluating surgeons' leadership and its impact on team performance in the operating room. As in other fields, our data suggest that transformational leadership is associated with improved team behavior. Surgeon leadership development, therefore, has the potential to improve the efficiency and safety of operative care.
PMID: 26481409 [PubMed - indexed for MEDLINE]
Blood Volume Monitoring to Assist Fluid Management in Hemodialysis Patients.
Am J Kidney Dis. 2016 Jan;67(1):166-8
Authors: Hussein WF, Arramreddy R, Sun SJ, Doss-McQuitty S, Schiller B
PMID: 26439585 [PubMed - indexed for MEDLINE]
Apolipoprotein E Mediates Evasion From Hepatitis C Virus Neutralizing Antibodies.
Gastroenterology. 2016 Jan;150(1):206-217.e4
Authors: Fauvelle C, Felmlee DJ, Crouchet E, Lee J, Heydmann L, Lefèvre M, Magri A, Hiet MS, Fofana I, Habersetzer F, Foung SK, Milne R, Patel AH, Vercauteren K, Meuleman P, Zeisel MB, Bartenschlager R, Schuster C, Baumert TF
BACKGROUND & AIMS: Efforts to develop an effective vaccine against hepatitis C virus (HCV) have been hindered by the propensity of the virus to evade host immune responses. HCV particles in serum and in cell culture associate with lipoproteins, which contribute to viral entry. Lipoprotein association has also been proposed to mediate viral evasion of the humoral immune response, though the mechanisms are poorly defined.
METHODS: We used small interfering RNAs to reduce levels of apolipoprotein E (apoE) in cell culture-derived HCV-producing Huh7.5-derived hepatoma cells and confirmed its depletion by immunoblot analyses of purified viral particles. Before infection of naïve hepatoma cells, we exposed cell culture-derived HCV strains of different genotypes, subtypes, and variants to serum and polyclonal and monoclonal antibodies isolated from patients with chronic HCV infection. We analyzed the interaction of apoE with viral envelope glycoprotein E2 and HCV virions by immunoprecipitation.
RESULTS: Through loss-of-function studies on patient-derived HCV variants of several genotypes and subtypes, we found that the HCV particle apoE allows the virus to avoid neutralization by patient-derived antibodies. Functional studies with human monoclonal antiviral antibodies showed that conformational epitopes of envelope glycoprotein E2 domains B and C were exposed after depletion of apoE. The level and conformation of virion-associated apoE affected the ability of the virus to escape neutralization by antibodies.
CONCLUSIONS: In cell-infection studies, we found that HCV-associated apoE helps the virus avoid neutralization by antibodies against HCV isolated from chronically infected patients. This method of immune evasion poses a challenge for the development of HCV vaccines.
PMID: 26404951 [PubMed - indexed for MEDLINE]
Oncologic Outcomes After Transoral Robotic Surgery: A Multi-institutional Study.
JAMA Otolaryngol Head Neck Surg. 2015 Dec;141(12):1043-51
Authors: de Almeida JR, Li R, Magnuson JS, Smith RV, Moore E, Lawson G, Remacle M, Ganly I, Kraus DH, Teng MS, Miles BA, White H, Duvvuri U, Ferris RL, Mehta V, Kiyosaki K, Damrose EJ, Wang SJ, Kupferman ME, Koh YW, Genden EM, Holsinger FC
IMPORTANCE: Large patient cohorts are necessary to validate the efficacy of transoral robotic surgery (TORS) in the management of head and neck cancer.
OBJECTIVES: To review oncologic outcomes of TORS from a large multi-institutional collaboration and to identify predictors of disease recurrence and disease-specific mortality.
DESIGN, SETTING, AND PARTICIPANTS: A retrospective review of records from 410 patients undergoing TORS for laryngeal and pharyngeal cancers from January 1, 2007, through December 31, 2012, was performed. Pertinent data were obtained from 11 participating medical institutions.
INTERVENTIONS: Select patients received radiation therapy and/or chemotherapy before or after TORS.
MAIN OUTCOMES AND MEASURES: Locoregional control, disease-specific survival, and overall survival were calculated. We used Kaplan-Meier survival analysis with log-rank testing to evaluate individual variable association with these outcomes, followed by multivariate analysis with Cox proportional hazards regression modeling to identify independent predictors.
RESULTS: Of the 410 patients treated with TORS in this study, 364 (88.8%) had oropharyngeal cancer. Of these 364 patients, information about post-operative adjuvant therapy was known about 338: 106 (31.3) received radiation therapy alone, and 72 (21.3%) received radiation therapy with concurrent chemotherapy. Neck dissection was performed in 323 patients (78.8%). Mean follow-up time was 20 months. Local, regional, and distant recurrence occurred in 18 (4.4%), 15 (3.7%), and 10 (2.4%) of 410 patients, respectively. Seventeen (4.1%) died of disease, and 13 (3.2%) died of other causes. The 2-year locoregional control rate was 91.8% (95% CI, 87.6%-94.7%), disease-specific survival 94.5% (95% CI, 90.6%-96.8%), and overall survival 91% (95% CI, 86.5%-94.0%). Multivariate analysis identified improved survival among women (P = .05) and for patients with tumors arising in tonsil (P = .01). Smoking was associated with worse overall all-cause mortality (P = .01). Although advanced age and tobacco use were associated with locoregional recurrence and disease-specific survival, they, as well as tumor stage and other adverse histopathologic features, did not remain significant on multivariate analysis.
CONCLUSIONS AND RELEVANCE: This large, multi-institutional study supports the role of TORS within the multidisciplinary treatment paradigm for the treatment of head and neck cancer, especially for patients with oropharyngeal cancer. Favorable oncologic outcomes have been found across institutions. Ongoing comparative clinical trials funded by the National Cancer Institute will further evaluate the role of robotic surgery for patients with head and neck cancers.
PMID: 26402479 [PubMed - indexed for MEDLINE]
Pathobiology of Helicobacter pylori-Induced Gastric Cancer.
Gastroenterology. 2016 Jan;150(1):64-78
Authors: Amieva M, Peek RM
Colonization of the human stomach by Helicobacter pylori and its role in causing gastric cancer is one of the richest examples of a complex relationship among human cells, microbes, and their environment. It is also a puzzle of enormous medical importance given the incidence and lethality of gastric cancer worldwide. We review recent findings that have changed how we view these relationships and affected the direction of gastric cancer research. For example, recent data have indicated that subtle mismatches between host and microbe genetic traits greatly affect the risk of gastric cancer. The ability of H pylori and its oncoprotein CagA to reprogram epithelial cells and activate properties of stemness show the sophisticated relationship between H pylori and progenitor cells in the gastric mucosa. The observation that cell-associated H pylori can colonize the gastric glands and directly affect precursor and stem cells supports these observations. The ability to mimic these interactions in human gastric organoid cultures as well as animal models will allow investigators to more fully unravel the extent of H pylori control on the renewing gastric epithelium. Finally, our realization that external environmental factors, such as dietary components and essential micronutrients, as well as the gastrointestinal microbiota, can change the balance between H pylori's activity as a commensal or a pathogen has provided direction to studies aimed at defining the full carcinogenic potential of this organism.
PMID: 26385073 [PubMed - indexed for MEDLINE]
Ambrisentan and Tadalafil Up-front Combination Therapy in Scleroderma-associated Pulmonary Arterial Hypertension.
Am J Respir Crit Care Med. 2015 Nov 1;192(9):1102-10
Authors: Hassoun PM, Zamanian RT, Damico R, Lechtzin N, Khair R, Kolb TM, Tedford RJ, Hulme OL, Housten T, Pisanello C, Sato T, Pullins EH, Corona-Villalobos CP, Zimmerman SL, Gashouta MA, Minai OA, Torres F, Girgis RE, Chin K, Mathai SC
BACKGROUND: Scleroderma-associated pulmonary arterial hypertension (SSc-PAH) is a rare disease characterized by a very dismal response to therapy and poor survival. We assessed the effects of up-front combination PAH therapy in patients with SSc-PAH.
METHODS: In this prospective, multicenter, open-label trial, 24 treatment-naive patients with SSc-PAH received ambrisentan 10 mg and tadalafil 40 mg daily for 36 weeks. Functional, hemodynamic, and imaging (cardiac magnetic resonance imaging and echocardiography) assessments at baseline and 36 weeks included changes in right ventricular (RV) mass and pulmonary vascular resistance as co-primary endpoints and stroke volume/pulmonary pulse pressure ratio, tricuspid annular plane systolic excursion, 6-minute walk distance, and N-terminal pro-brain natriuretic peptide as secondary endpoints.
RESULTS: At 36 weeks, we found that treatment had resulted in significant reductions in median (interquartile range [IQR]) RV mass (28.0 g [IQR, 20.6-32.9] vs. 32.5 g [IQR, 23.2-41.4]; P < 0.05) and median pulmonary vascular resistance (3.1 Wood units [IQR, 2.0-5.7] vs. 6.9 Wood units [IQR, 4.0-12.9]; P < 0.0001) and in improvements in median stroke volume/pulmonary pulse pressure ratio (2.6 ml/mm Hg [IQR, 1.8-3.5] vs. 1.4 ml/mm Hg [IQR 8.9-2.4]; P < 0.0001) and mean ( ± SD) tricuspid annular plane systolic excursion (2.2 ± 0.12 cm vs. 1.65 ± 0.11 cm; P < 0.0001), 6-minute walk distance (395 ± 99 m vs. 343 ± 131 m; P = 0.001), and serum N-terminal pro-brain natriuretic peptide (647 ± 1,127 pg/ml vs. 1,578 ± 2,647 pg/ml; P < 0.05).
CONCLUSIONS: Up-front combination therapy with ambrisentan and tadalafil significantly improved hemodynamics, RV structure and function, and functional status in treatment-naive patients with SSc-PAH and may represent a very effective therapy for this patient population. In addition, we identified novel hemodynamic and imaging biomarkers that could have potential value in future clinical trials. Clinical trial registered with www.clinicaltrials.gov (NCT01042158).
PMID: 26360334 [PubMed - indexed for MEDLINE]
Total Exposure Study Analysis consortium: a cross-sectional study of tobacco exposures.
BMC Public Health. 2015;15:866
Authors: Bergen AW, Krasnow R, Javitz HS, Swan GE, Li MD, Baurley JW, Chen X, Murrelle L, Zedler B
BACKGROUND: The Total Exposure Study was a stratified, multi-center, cross-sectional study designed to estimate levels of biomarkers of tobacco-specific and non-specific exposure and of potential harm in U.S. adult current cigarette smokers (≥one manufactured cigarette per day over the last year) and tobacco product non-users (no smoking or use of any nicotine containing products over the last 5 years). The study was designed and sponsored by a tobacco company and implemented by contract research organizations in 2002-2003. Multiple analyses of smoking behavior, demographics, and biomarkers were performed. Study data and banked biospecimens were transferred from the sponsor to the Virginia Tobacco and Health Research Repository in 2010, and then to SRI International in 2012, for independent analysis and dissemination.
METHODS: We analyzed biomarker distributions overall, and by biospecimen availability, for comparison with existing studies, and to evaluate generalizability to the entire sample. We calculated genome-wide statistical power for a priori hypotheses. We performed clinical chemistries, nucleic acid extractions and genotyping, and report correlation and quality control metrics.
RESULTS: Vital signs, clinical chemistries, and laboratory measures of tobacco specific and non-specific toxicants are available from 3585 current cigarette smokers, and 1077 non-users. Peripheral blood mononuclear cells, red blood cells, plasma and 24-h urine biospecimens are available from 3073 participants (2355 smokers and 719 non-users). In multivariate analysis, participants with banked biospecimens were significantly more likely to self-identify as White, to be older, to have increased total nicotine equivalents per cigarette, decreased serum cotinine, and increased forced vital capacity, compared to participants without. Effect sizes were small (Cohen's d-values ≤ 0.11). Power for a priori hypotheses was 57 % in non-Hispanic Black (N = 340), and 96 % in non-Hispanic White (N = 1840), smokers. All DNA samples had genotype completion rates ≥97.5 %; 68 % of RNA samples yielded RIN scores ≥6.0.
CONCLUSIONS: Total Exposure Study clinical and laboratory assessments and biospecimens comprise a unique resource for cigarette smoke health effects research. The Total Exposure Study Analysis Consortium seeks to perform molecular studies in multiple domains and will share data and analytic results in public repositories and the peer-reviewed literature. Data and banked biospecimens are available for independent or collaborative research.
PMID: 26346437 [PubMed - indexed for MEDLINE]
Evaluation of the International Prognostic Score (IPS-7) and a Simpler Prognostic Score (IPS-3) for advanced Hodgkin lymphoma in the modern era.
Br J Haematol. 2015 Nov;171(4):530-8
Authors: Diefenbach CS, Li H, Hong F, Gordon LI, Fisher RI, Bartlett NL, Crump M, Gascoyne RD, Wagner H, Stiff PJ, Cheson BD, Stewart DA, Kahl BS, Friedberg JW, Blum KA, Habermann TM, Tuscano JM, Hoppe RT, Horning SJ, Advani RH
The International Prognostic Score (IPS-7) is the most commonly used risk stratification tool for advanced Hodgkin lymphoma (HL), however recent studies suggest the IPS-7 is less discriminating due to improved outcomes with contemporary therapy. We evaluated the seven variables for IPS-7 recorded at study entry for 854 patients enrolled on Eastern Cooperative Oncology Group 2496 trial. Univariate and multivariate Cox models were used to assess their prognostic ability for freedom from progression (FFP) and overall survival (OS). The IPS-7 remained prognostic however its prognostic range has narrowed. On multivariate analysis, two factors (age, stage) remained significant for FFP and three factors (age, stage, haemoglobin level) for OS. An alternative prognostic index, the IPS-3, was constructed using age, stage and haemoglobin level, which provided four distinct risk groups [FFP (P = 0·0001) and OS (P < 0·0001)]. IPS-3 outperformed the IPS-7 on risk prediction for both FFP and OS by model fit and discrimination criteria. Using reclassification calibration, 18% of IPS-7 low risk patients were re-classified as intermediate risk and 13% of IPS-7 intermediate risk patients as low risk. For patients with advanced HL, the IPS-3 may provide a simpler and more accurate framework for risk assessment in the modern era. Validation of these findings in other large data sets is planned.
PMID: 26343802 [PubMed - indexed for MEDLINE]
Smartphone apps for snoring.
J Laryngol Otol. 2015 Oct;129(10):974-9
Authors: Camacho M, Robertson M, Abdullatif J, Certal V, Kram YA, Ruoff CM, Brietzke SE, Capasso R
OBJECTIVE: To identify and systematically evaluate user-friendly smartphone snoring apps.
METHODS: The Apple iTunes app store was searched for snoring apps that allow recording and playback. Snoring apps were downloaded, evaluated and rated independently by four authors. Two patients underwent polysomnography, and the data were compared with simultaneous snoring app recordings, and one patient used the snoring app at home.
RESULTS: Of 126 snoring apps, 13 met the inclusion and exclusion criteria. The most critical app feature was the ability to graphically display the snoring events. The Quit Snoring app received the highest overall rating. When this app's recordings were compared with in-laboratory polysomnography data, app snoring sensitivities ranged from 64 to 96 per cent, and snoring positive predictive values ranged from 93 to 96 per cent. A chronic snorer used the app nightly for one month and tracked medical interventions. Snoring decreased from 200 to 10 snores per hour, and bed partner snoring complaint scores decreased from 9 to 2 (on a 0-10 scale).
CONCLUSION: Select smartphone apps are user-friendly for recording and playing back snoring sounds. Preliminary comparison of more than 1500 individual snores demonstrates the potential clinical utility of such apps; however, further validation testing is recommended.
PMID: 26333720 [PubMed - indexed for MEDLINE]
Association of worker characteristics and early reimbursement for physical therapy, chiropractic and opioid prescriptions with workers' compensation claim duration, for cases of acute low back pain: an observational cohort study.
BMJ Open. 2015;5(8):e007836
Authors: Busse JW, Ebrahim S, Heels-Ansdell D, Wang L, Couban R, Walter SD
OBJECTIVE: To assess the association between early reimbursement for physiotherapy, chiropractic and opioid prescriptions for acute low back pain (LBP) with disability claim duration.
DESIGN: Observational cohort study.
SETTING AND PARTICIPANTS: From a random sample of 6665 claims for acute, uncomplicated LBP approved by the Ontario Workplace Safety and Insurance Board (WSIB) in 2005, we analysed 1442 who remained on full benefits at 4 weeks after claim approval.
PRIMARY OUTCOME MEASURE: Our primary outcome was WSIB claim duration.
RESULTS: We had complete data for all but 3 variables, which had <15% missing data, and we included missing data as a category for these factors. Our time-to-event analysis was adjusted for demographic, workplace and treatment factors, but not injury severity, although we attempted to include a sample with very similar, less-severe injuries. Regarding significant factors and treatment variables in our adjusted analysis, older age (eg, HR for age ≥ 55 vs <25=0.52; 99% CI 0.36 to 0.74) and WSIB reimbursement for opioid prescription in the first 4 weeks of a claim (HR=0.68; 99% CI 0.53 to 0.88) were associated with longer claim duration. Higher predisability income was associated with longer claim duration, but only among persistent claims (eg, HR for active claims at 1 year with a predisability income >$920 vs ≤$480/week=0.34; 99% CI 0.17 to 0.68). Missing data for union membership (HR=1.27; 99% CI 1.01 to 1.59), and working for an employer with a return-to-work programme were associated with fewer days on claim (HR=1.78; 99% CI 1.45 to 2.18). Neither reimbursement for physiotherapy (HR=1.01; 99% CI 0.86 to 1.19) nor chiropractic care (HR for active claims at 60 days=1.15; 99% CI 0.94 to 1.41) within the first 4 weeks was associated with claim duration. Our meta-analysis of 3 studies (n=51,069 workers) confirmed a strong association between early opioid use and prolonged claim duration (HR=0.57, 95% CI 0.48 to 0.69; low certainty evidence).
CONCLUSIONS: Our analysis found that early WSIB reimbursement for physiotherapy or chiropractic care, in claimants fully off work for more than 4 weeks, was not associated with claim duration, and that early reimbursement for opioids predicted prolonged claim duration. Well-designed randomised controlled trials are needed to verify our findings and establish causality between these variables and claim duration.
PMID: 26310398 [PubMed - indexed for MEDLINE]
Shockingly Early: Chromatin-Mediated Loss of the Heat Shock Response.
Mol Cell. 2015 Aug 20;59(4):515-6
Authors: Booth LN, Brunet A
In this issue of Molecular Cell, Labbadia and Morimoto (2015) show that there is a precipitous decline in stress resistance at the onset of reproduction in C. elegans and that this transition is regulated by changes in repressive chromatin marks.
PMID: 26295957 [PubMed - indexed for MEDLINE]
Fabrication of healthy and disease-mimicking retinal phantoms with tapered foveal pits for optical coherence tomography.
J Biomed Opt. 2015 Aug;20(8):85004
Authors: Lee GC, Smith GT, Agrawal M, Leng T, Ellerbee AK
Optical coherence tomography (OCT) has become a standard tool in ophthalmology clinics for diagnosing many retinal diseases. Nonetheless, the technical and clinical communities still lack a standardized phantom that could aid in evaluating and normalizing the many protocols and systems used for diagnosis. Existing retinal phantoms are able to mimic the thickness and scattering properties of the retinal layers but are unable to model the morphology of the foveal pit, particularly the tapering of the retinal layers. This work demonstrates a new fabrication procedure that is capable of reliably and consistently replicating the shape and tapered appearance of the retinal layers near the foveal pit using a combination of spin-coating and replica molding. We characterize the effects of using different mold sizes which enable us to achieve a range of pit dimensions. We also present a modified procedure to replicate two diseased states of the retinal tissue, such as retinal detachment and dry aged-related macular degeneration. The ability to create an anatomically correct foveal pit for healthy and disease-mimicking phantoms will allow for a new standard better suited for intra- and inter-system evaluation and for improved comparison of retinal segmentation algorithms
PMID: 26287985 [PubMed - indexed for MEDLINE]
Chemodetection and Destruction of Host Urea Allows Helicobacter pylori to Locate the Epithelium.
Cell Host Microbe. 2015 Aug 12;18(2):147-56
Authors: Huang JY, Sweeney EG, Sigal M, Zhang HC, Remington SJ, Cantrell MA, Kuo CJ, Guillemin K, Amieva MR
The gastric pathogen Helicobacter pylori interacts intimately with the gastric mucosa to avoid the microbicidal acid in the stomach lumen. The cues H. pylori senses to locate and colonize the gastric epithelium have not been well defined. We show that metabolites emanating from human gastric organoids rapidly attract H. pylori. This response is largely controlled by the bacterial chemoreceptor TlpB, and the main attractant emanating from epithelia is urea. Our previous structural analyses show that TlpB binds urea with high affinity. Here we demonstrate that this tight binding controls highly sensitive responses, allowing detection of urea concentrations as low as 50 nM. Attraction to urea requires that H. pylori urease simultaneously destroys the signal. We propose that H. pylori has evolved a sensitive urea chemodetection and destruction system that allows the bacterium to dynamically and locally modify the host environment to locate the epithelium.
PMID: 26269952 [PubMed - indexed for MEDLINE]
A Plea to Reassess the Role of United States Medical Licensing Examination Step 1 Scores in Residency Selection.
Acad Med. 2016 Jan;91(1):12-5
Authors: Prober CG, Kolars JC, First LR, Melnick DE
The three-step United States Medical Licensing Examination (USMLE) was developed by the National Board of Medical Examiners and the Federation of State Medical Boards to provide medical licensing authorities a uniform evaluation system on which to base licensure. The test results appear to be a good measure of content knowledge and a reasonable predictor of performance on subsequent in-training and certification exams. Nonetheless, it is disconcerting that the test preoccupies so much of students' attention with attendant substantial costs (in time and money) and mental and emotional anguish. There is an increasingly pervasive practice of using the USMLE score, especially the Step 1 component, to screen applicants for residency. This is despite the fact that the test was not designed to be a primary determinant of the likelihood of success in residency. Further, relying on Step 1 scores to filter large numbers of applications has unintended consequences for students and undergraduate medical education curricula. There are many other factors likely to be equally or more predictable of performance during residency. The authors strongly recommend a move away from using test scores alone in the applicant screening process and toward a more holistic evaluation of the skills, attributes, and behaviors sought in future health care providers. They urge more rigorous study of the characteristics of students that predict success in residency, better assessment tools for competencies beyond those assessed by Step 1 that are relevant to success, and nationally comparable measures from those assessments that are easy to interpret and apply.
PMID: 26244259 [PubMed - indexed for MEDLINE]
Human V4 and ventral occipital retinotopic maps.
Vis Neurosci. 2015 Jan;32:E020
Authors: Winawer J, Witthoft N
The ventral surface of the human occipital lobe contains multiple retinotopic maps. The most posterior of these maps is considered a potential homolog of macaque V4, and referred to as human V4 ("hV4"). The location of the hV4 map, its retinotopic organization, its role in visual encoding, and the cortical areas it borders have been the subject of considerable investigation and debate over the last 25 years. We review the history of this map and adjacent maps in ventral occipital cortex, and consider the different hypotheses for how these ventral occipital maps are organized. Advances in neuroimaging, computational modeling, and characterization of the nearby anatomical landmarks and functional brain areas have improved our understanding of where human V4 is and what kind of visual representations it contains.
PMID: 26241699 [PubMed - indexed for MEDLINE]
Salvage Conservation Laryngeal Surgery After Radiation Therapy Failure.
Otolaryngol Clin North Am. 2015 Aug;48(4):667-75
Authors: Chen MM, Holsinger FC, Laccourreye O
Conservation laryngeal surgery (CLS) includes time-honored approaches such as the vertical partial laryngectomy and the open horizontal supraglottic laryngectomy, as well as the supracricoid partial laryngectomy and transoral laser microsurgery. Carefully selected patients can undergo transoral endoscopic or open CLS for early to intermediate stage recurrent tumors of the glottic and supraglottic larynx. Patient factors, such as comorbid pulmonary disease, are essential in selecting patients for CLS, especially after previous radiation therapy. This article reviews the preoperative indications and postoperative management of salvage CLS after radiation therapy for laryngeal cancer.
PMID: 26233791 [PubMed - indexed for MEDLINE]
Practical dose point-based methods to characterize dose distribution in a stationary elliptical body phantom for a cone-beam C-arm CT system.
Med Phys. 2015 Aug;42(8):4920-32
Authors: Choi JH, Constantin D, Ganguly A, Girard E, Morin RL, Dixon RL, Fahrig R
PURPOSE: To propose new dose point measurement-based metrics to characterize the dose distributions and the mean dose from a single partial rotation of an automatic exposure control-enabled, C-arm-based, wide cone angle computed tomography system over a stationary, large, body-shaped phantom.
METHODS: A small 0.6 cm(3) ion chamber (IC) was used to measure the radiation dose in an elliptical body-shaped phantom made of tissue-equivalent material. The IC was placed at 23 well-distributed holes in the central and peripheral regions of the phantom and dose was recorded for six acquisition protocols with different combinations of minimum kVp (109 and 125 kVp) and z-collimator aperture (full: 22.2 cm; medium: 14.0 cm; small: 8.4 cm). Monte Carlo (MC) simulations were carried out to generate complete 2D dose distributions in the central plane (z = 0). The MC model was validated at the 23 dose points against IC experimental data. The planar dose distributions were then estimated using subsets of the point dose measurements using two proposed methods: (1) the proximity-based weighting method (method 1) and (2) the dose point surface fitting method (method 2). Twenty-eight different dose point distributions with six different point number cases (4, 5, 6, 7, 14, and 23 dose points) were evaluated to determine the optimal number of dose points and their placement in the phantom. The performances of the methods were determined by comparing their results with those of the validated MC simulations. The performances of the methods in the presence of measurement uncertainties were evaluated.
RESULTS: The 5-, 6-, and 7-point cases had differences below 2%, ranging from 1.0% to 1.7% for both methods, which is a performance comparable to that of the methods with a relatively large number of points, i.e., the 14- and 23-point cases. However, with the 4-point case, the performances of the two methods decreased sharply. Among the 4-, 5-, 6-, and 7-point cases, the 7-point case (1.0% [±0.6%] difference) and the 6-point case (0.7% [±0.6%] difference) performed best for method 1 and method 2, respectively. Moreover, method 2 demonstrated high-fidelity surface reconstruction with as few as 5 points, showing pixelwise absolute differences of 3.80 mGy (±0.32 mGy). Although the performance was shown to be sensitive to the phantom displacement from the isocenter, the performance changed by less than 2% for shifts up to 2 cm in the x- and y-axes in the central phantom plane.
CONCLUSIONS: With as few as five points, method 1 and method 2 were able to compute the mean dose with reasonable accuracy, demonstrating differences of 1.7% (±1.2%) and 1.3% (±1.0%), respectively. A larger number of points do not necessarily guarantee better performance of the methods; optimal choice of point placement is necessary. The performance of the methods is sensitive to the alignment of the center of the body phantom relative to the isocenter. In body applications where dose distributions are important, method 2 is a better choice than method 1, as it reconstructs the dose surface with high fidelity, using as few as five points.
PMID: 26233218 [PubMed - indexed for MEDLINE]
Imaging surveillance and survival for surgically resected non-small-cell lung cancer.
J Surg Res. 2016 Jan;200(1):171-6
Authors: Backhus LM, Farjah F, Liang CK, He H, Varghese TK, Au DH, Flum DR, Zeliadt SB
INTRODUCTION: The importance of imaging surveillance after treatment for lung cancer is not well characterized. We examined the association between initial guideline recommended imaging surveillance and survival among early-stage resected non-small-cell lung cancer (NSCLC) patients.
METHODS: A retrospective study was conducted using Surveillance, Epidemiology, and End Results-Medicare data (1995-2010). Surgically resected patients, with stage I and II NSCLC, were categorized by imaging received during the initial surveillance period (4-8 mo) after surgery. Primary outcome was overall survival. Secondary treatment interventions were examined as intermediary outcomes.
RESULTS: Most (88%) patients had at least one outpatient clinic visit, and 24% received an initial computerized tomography (CT) during the first surveillance period. Five-year survival by initial surveillance imaging was 61% for CT, 58% for chest radiography, and 60% for no imaging. After adjustment, initial CT was not associated with improved overall survival (hazard ratio [HR], 1.04; 95% confidence interval [CI] 0.96-1.14). On subgroup analysis, restricted to patients with demonstrated initial postoperative follow-up, CT was associated with a lower overall risk of death for stage I patients (HR, 0.85; 95% CI, 0.74-0.98), but not for stage II (HR, 1.01; 95% CI, 0.71-1.42). There was no significant difference in rates of secondary interventions predicted by type of initial imaging surveillance.
CONCLUSIONS: Initial surveillance CT is not associated with improved overall or lung cancer-specific survival among early-stage NSCLC patients undergoing surgical resection. Stage I patients with early follow-up may represent a subpopulation that benefits from initial surveillance although this may be influenced by healthy patient selection bias.
PMID: 26231974 [PubMed - indexed for MEDLINE]
Treatment Approaches to Locally Advanced Pancreatic Adenocarcinoma.
Hematol Oncol Clin North Am. 2015 Aug;29(4):741-59
Authors: Pollom EL, Koong AC, Ko AH
This article focuses on the management of locally advanced pancreatic cancer, which should be treated as a distinct entity separate from metastatic disease and borderline resectable disease. Although the role, timing, and sequencing of radiation relative to systemic therapy in this disease are controversial, an emerging treatment paradigm involves induction chemotherapy, followed by consolidative chemoradiation in patients who do not progress. In addition, new chemotherapy regimens as well as novel radiosensitizers have shown promise and need to be tested further in the locally advanced setting. Advances in radiotherapy have enabled stereotactic body radiotherapy and should continue to be prospectively evaluated.
PMID: 26226908 [PubMed - indexed for MEDLINE]
Supporting Medical Students' Pursuit of Longitudinal Patient Experiences: Piloting an Innovative Visit Notification Tool at the Massachusetts General Hospital.
Acad Med. 2016 Jan;91(1):70-4
Authors: Elmore SN, Kopecky KE, Jennings K, de Moya M, Beresin G, Wright DE
PROBLEM: Both medical educators and students have an increasing interest in longitudinal patient experiences (LPE) that allow students to work with patients at multiple points in time, often across multiple clinical settings. Despite this interest in LPE, following patients over time and across health systems remains a challenge.
APPROACH: In August 2012-May 2013, with faculty support, two third-year medical students implemented a pilot program at the Massachusetts General Hospital (MGH) in the third-year block clerkship curriculum. One of the authors modified an existing novel, electronic visit notification tool (VNT) that integrates with the electronic medical record (EMR) to help students follow patients longitudinally. Students added patients to their cohort after obtaining the patient's verbal consent. Each week, the VNT sent students e-mails notifying them of all scheduled appointments for their cohort patients at all Partners HealthCare-affiliated sites.
OUTCOMES: Each pilot student added approximately 20 patients to her cohort and followed 3-5 patients consistently. The pilot students felt the VNT made it significantly easier to follow patients over time, their appreciation of chronic illness care developed, and they gained a greater understanding of the integrated nature of patient care.
NEXT STEPS: On the basis of student interest, the tool was made available to all MGH third-year students in March-May 2013 and offered to all MGH third-year students at the beginning of the next clinical year. Notification tools such as the VNT may enhance a hospital's existing EMR and facilitate longitudinal educational goals across all clinical clerkship models.
PMID: 26222324 [PubMed - indexed for MEDLINE]
Synthetic biology: Ribosomal ties that bind.
Nature. 2015 Aug 6;524(7563):45-6
Authors: Puglisi JD
PMID: 26222027 [PubMed - indexed for MEDLINE]
Localized Ambient Solidity Separation Algorithm Based Computer User Segmentation.
Comput Intell Neurosci. 2015;2015:829201
Authors: Sun X, Zhang T, Chai Y, Liu Y
Most of popular clustering methods typically have some strong assumptions of the dataset. For example, the k-means implicitly assumes that all clusters come from spherical Gaussian distributions which have different means but the same covariance. However, when dealing with datasets that have diverse distribution shapes or high dimensionality, these assumptions might not be valid anymore. In order to overcome this weakness, we proposed a new clustering algorithm named localized ambient solidity separation (LASS) algorithm, using a new isolation criterion called centroid distance. Compared with other density based isolation criteria, our proposed centroid distance isolation criterion addresses the problem caused by high dimensionality and varying density. The experiment on a designed two-dimensional benchmark dataset shows that our proposed LASS algorithm not only inherits the advantage of the original dissimilarity increments clustering method to separate naturally isolated clusters but also can identify the clusters which are adjacent, overlapping, and under background noise. Finally, we compared our LASS algorithm with the dissimilarity increments clustering method on a massive computer user dataset with over two million records that contains demographic and behaviors information. The results show that LASS algorithm works extremely well on this computer user dataset and can gain more knowledge from it.
PMID: 26221133 [PubMed - indexed for MEDLINE]
Management of Intercarpal Ligament Injuries Associated with Distal Radius Fractures.
Hand Clin. 2015 Aug;31(3):409-16
Authors: Desai MJ, Kamal RN, Richard MJ
The prevalence of ligamentous injury associated with fractures of the distal radius is reported to be as high as 69% with injury to the scapholunate interosseous ligament and lunotriquetral interosseous ligament occurring in 16% to 40% and 8.5% to 15%, respectively. There is a lack of consensus on which patients should undergo advanced imaging, arthroscopy, and treatment and whether this changes their natural history. Overall, patients with high-grade intercarpal ligament injuries are shown to have longer-term disability and sequelae compared with those with lower-grade injuries. This article reviews the diagnosis and treatment options for these injuries.
PMID: 26205702 [PubMed - indexed for MEDLINE]
Tamibarotene in patients with acute promyelocytic leukaemia relapsing after treatment with all-trans retinoic acid and arsenic trioxide.
Br J Haematol. 2015 Nov;171(4):471-7
Authors: Sanford D, Lo-Coco F, Sanz MA, Di Bona E, Coutre S, Altman JK, Wetzler M, Allen SL, Ravandi F, Kantarjian H, Cortes JE
Treatment of acute promyelocytic leukaemia (APL) with arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) is highly effective first-line therapy, although approximately 5-10% of patients relapse. Tamibarotene is a synthetic retinoid with activity in APL patients who relapse after chemotherapy and ATRA, but has not been studied in relapse after treatment with ATO and ATRA. We report on a phase II study of tamibarotene in adult patients with relapsed or refractory APL after treatment with ATRA and ATO (n = 14). Participants were treated with tamibarotene (6 mg/m(2) /d) during induction and for up to six cycles of consolidation. The overall response rate was 64% (n = 9), the rate of complete cytogenetic response was 43% (n = 6) and the rate of complete molecular response was 21% (n = 3). Relapse was frequent with 7 of 9 responders relapsing after a median of 4·6 months (range 1·6-26·8 months). The median event-free survival (EFS) was 3·5 months [95% confidence interval (CI) 0-8·6 months] and the median overall survival (OS) was 9·5 months (95% CI 5·9-13·1 months). These results demonstrate that tamibarotene has activity in relapsed APL after treatment with ATO and ATRA and further studies using tamibarotene as initial therapy and in combination with ATO are warranted.
PMID: 26205361 [PubMed - indexed for MEDLINE]
In an Age of Open Access to Research Policies: Physician and Public Health NGO Staff Research Use and Policy Awareness.
PLoS One. 2015;10(7):e0129708
Authors: Moorhead LL, Holzmeyer C, Maggio LA, Steinberg RM, Willinsky J
INTRODUCTION: Through funding agency and publisher policies, an increasing proportion of the health sciences literature is being made open access. Such an increase in access raises questions about the awareness and potential utilization of this literature by those working in health fields.
METHODS: A sample of physicians (N=336) and public health non-governmental organization (NGO) staff (N=92) were provided with relatively complete access to the research literature indexed in PubMed, as well as access to the point-of-care service UpToDate, for up to one year, with their usage monitored through the tracking of web-log data. The physicians also participated in a one-month trial of relatively complete or limited access.
RESULTS: The study found that participants' research interests were not satisfied by article abstracts alone nor, in the case of the physicians, by a clinical summary service such as UpToDate. On average, a third of the physicians viewed research a little more frequently than once a week, while two-thirds of the public health NGO staff viewed more than three articles a week. Those articles were published since the 2008 adoption of the NIH Public Access Policy, as well as prior to 2008 and during the maximum 12-month embargo period. A portion of the articles in each period was already open access, but complete access encouraged a viewing of more research articles.
CONCLUSION: Those working in health fields will utilize more research in the course of their work as a result of (a) increasing open access to research, (b) improving awareness of and preparation for this access, and (c) adjusting public and open access policies to maximize the extent of potential access, through reduction in embargo periods and access to pre-policy literature.
PMID: 26200794 [PubMed - indexed for MEDLINE]
Musical Preferences are Linked to Cognitive Styles.
PLoS One. 2015;10(7):e0131151
Authors: Greenberg DM, Baron-Cohen S, Stillwell DJ, Kosinski M, Rentfrow PJ
Why do we like the music we do? Research has shown that musical preferences and personality are linked, yet little is known about other influences on preferences such as cognitive styles. To address this gap, we investigated how individual differences in musical preferences are explained by the empathizing-systemizing (E-S) theory. Study 1 examined the links between empathy and musical preferences across four samples. By reporting their preferential reactions to musical stimuli, samples 1 and 2 (Ns = 2,178 and 891) indicated their preferences for music from 26 different genres, and samples 3 and 4 (Ns = 747 and 320) indicated their preferences for music from only a single genre (rock or jazz). Results across samples showed that empathy levels are linked to preferences even within genres and account for significant proportions of variance in preferences over and above personality traits for various music-preference dimensions. Study 2 (N = 353) replicated and extended these findings by investigating how musical preferences are differentiated by E-S cognitive styles (i.e., 'brain types'). Those who are type E (bias towards empathizing) preferred music on the Mellow dimension (R&B/soul, adult contemporary, soft rock genres) compared to type S (bias towards systemizing) who preferred music on the Intense dimension (punk, heavy metal, and hard rock). Analyses of fine-grained psychological and sonic attributes in the music revealed that type E individuals preferred music that featured low arousal (gentle, warm, and sensual attributes), negative valence (depressing and sad), and emotional depth (poetic, relaxing, and thoughtful), while type S preferred music that featured high arousal (strong, tense, and thrilling), and aspects of positive valence (animated) and cerebral depth (complexity). The application of these findings for clinicians, interventions, and those on the autism spectrum (largely type S or extreme type S) are discussed.
PMID: 26200656 [PubMed - indexed for MEDLINE]
Challenges to Learning Evidence-Based Medicine and Educational Approaches to Meet These Challenges: A Qualitative Study of Selected EBM Curricula in U.S. and Canadian Medical Schools.
Acad Med. 2016 Jan;91(1):101-6
Authors: Maggio LA, ten Cate O, Chen HC, Irby DM, O'Brien BC
PURPOSE: Evidence-based medicine (EBM) is a fixture in many medical school curricula. Yet, little is known about the challenges medical students face in learning EBM or the educational approaches that medical schools use to overcome these challenges.
METHOD: A qualitative multi-institutional case study was conducted between December 2013 and July 2014. On the basis of the Association of American Medical Colleges 2012 Medical School Graduation Questionnaire data, the authors selected 22 U.S. and Canadian Liaison Committee on Medical Education-accredited medical schools with graduates reporting confidence in their EBM skills. Participants were interviewed and asked to submit EBM curricular materials. Interviews were audio-recorded, transcribed, and analyzed using an inductive approach.
RESULTS: Thirty-one EBM instructors (17 clinicians, 11 librarians, 2 educationalists, and 1 epidemiologist) were interviewed from 17 medical schools (13 in the United States, 4 in Canada). Four common EBM learning challenges were identified: suboptimal role models, students' lack of willingness to admit uncertainty, a lack of clinical context, and students' difficulty mastering EBM skills. Five educational approaches to these challenges that were common across the participating institutions were identified: integrating EBM with other courses and content, incorporating clinical content into EBM training, EBM faculty development, EBM whole-task exercises, and longitudinal integration of EBM.
CONCLUSIONS: The identification of these four learner-centered EBM challenges expands on the literature on challenges in teaching and practicing EBM, and the identification of these five educational approaches provides medical educators with potential strategies to inform the design of EBM curricula.
PMID: 26200580 [PubMed - indexed for MEDLINE]
Very long haplotype tracts characterized at high resolution from HLA homozygous cell lines.
Immunogenetics. 2015 Sep;67(9):479-85
Authors: Norman PJ, Norberg SJ, Nemat-Gorgani N, Royce T, Hollenbach JA, Shults Won M, Guethlein LA, Gunderson KL, Ronaghi M, Parham P
The HLA region of chromosome 6 contains the most polymorphic genes in humans. Spanning ~5 Mbp the densely packed region encompasses approximately 175 expressed genes including the highly polymorphic HLA class I and II loci. Most of the other genes and functional elements are also polymorphic, and many of them are directly implicated in immune function or immune-related disease. For these reasons, this complex genomic region is subject to intense scrutiny by researchers with the common goal of aiding further understanding and diagnoses of multiple immune-related diseases and syndromes. To aid assay development and characterization of the classical loci, a panel of cell lines partially or fully homozygous for HLA class I and II was assembled over time by the International Histocompatibility Working Group (IHWG). Containing a minimum of 88 unique HLA haplotypes, we show that this panel represents a significant proportion of European HLA allelic and haplotype diversity (60-95 %). Using a high-density whole genome array that includes 13,331 HLA region SNPs, we analyzed 99 IHWG cells to map the coordinates of the homozygous tracts at a fine scale. The mean homozygous tract length within chromosome 6 from these individuals is 21 Mbp. Within HLA, the mean haplotype length is 4.3 Mbp, and 65 % of the cell lines were shown to be homozygous throughout the entire region. In addition, four cell lines are homozygous throughout the complex KIR region of chromosome 19 (~250 kbp). The data we describe will provide a valuable resource for characterizing haplotypes, designing and refining imputation algorithms and developing assay controls.
PMID: 26198775 [PubMed - indexed for MEDLINE]
Habitat Heterogeneity Affects Plant and Arthropod Species Diversity and Turnover in Traditional Cornfields.
PLoS One. 2015;10(7):e0128950
Authors: Martínez E, Rös M, Bonilla MA, Dirzo R
The expansion of the agricultural frontier by the clearing of remnant forests has led to human-dominated landscape mosaics. Previous studies have evaluated the effect of these landscape mosaics on arthropod diversity at local spatial scales in temperate and tropical regions, but little is known about fragmentation effects in crop systems, such as the complex tropical traditional crop systems that maintain a high diversity of weeds and arthropods in low-Andean regions. To understand the factors that influence patterns of diversity in human-dominated landscapes, we investigate the effect of land use types on plant and arthropod diversity in traditionally managed cornfields, via surveys of plants and arthropods in twelve traditional cornfields in the Colombian Andes. We estimated alpha and beta diversity to analyze changes in diversity related to land uses within a radius of 100 m to 1 km around each cornfield. We observed that forests influenced alpha diversity of plants, but not of arthropods. Agricultural lands had a positive relationship with plants and herbivores, but a negative relationship with predators. Pastures positively influenced the diversity of plants and arthropods. In addition, forest cover seemed to influence changes in plant species composition and species turnover of herbivore communities among cornfields. The dominant plant species varied among fields, resulting in high differentiation of plant communities. Predator communities also exhibited high turnover among cornfields, but differences in composition arose mainly among rare species. The crop system evaluated in this study represents a widespread situation in the tropics, therefore, our results can be of broad significance. Our findings suggest that traditional agriculture may not homogenize biological communities, but instead could maintain the regional pool of species through high beta diversity.
PMID: 26197473 [PubMed - indexed for MEDLINE]
Monitoring Cerebrovascular Reactivity through the Use of Arterial Spin Labeling in Patients with Moyamoya Disease.
Radiology. 2016 Jan;278(1):205-13
Authors: Yun TJ, Paeng JC, Sohn CH, Kim JE, Kang HS, Yoon BW, Choi SH, Kim JH, Lee HY, Han MH, Zaharchuk G
PURPOSE: To assess arterial spin labeling in the identification of impaired cerebrovascular reactivity in patients with moyamoya disease.
MATERIALS AND METHODS: The institutional review board approved this prospective study, and written informed consent was obtained from all patients. A prospective study was conducted in 78 subjects with moyamoya disease (of whom 31 underwent unilateral direct arterial anastomosis). The concordance between the cerebrovascular reactivity index values from arterial spin labeling and single photon emission computed tomography (SPECT) was assessed by using Bland-Altman analysis, and the area under the receiver operating characteristic curve was used to evaluate the diagnostic accuracy of arterial spin labeling to depict impaired cerebrovascular reactivity (in which the cerebrovascular reactivity index value is less than 0% on SPECT images).
RESULTS: The cerebrovascular reactivity index from arterial spin labeling had a lower value than that from SPECT (mean difference, -4.2%). The area under the receiver operating characteristic curve for arterial spin labeling in the detection of impaired cerebrovascular reactivity was at least 0.85. On the anastomotic side, a significant increase was found between the cerebrovascular reactivity index values on arterial spin labeling images obtained preoperatively and those obtained 6 months after surgery, as well as on SPECT images (mean ± standard deviation values of cerebrovascular reactivity index increased by 5.9% ± 10.9 and 3.0% ± 6.3 for arterial spin labeling and SPECT, respectively).
CONCLUSION: Arterial spin labeling has excellent performance in the identification of impaired cerebrovascular reactivity in patients with moyamoya disease, and it has the potential to serve as a noninvasive imaging tool to monitor cerebrovascular reactivity in patients with moyamoya disease.
PMID: 26197057 [PubMed - indexed for MEDLINE]
Genetic Variants Associated with Port-Wine Stains.
PLoS One. 2015;10(7):e0133158
Authors: Frigerio A, Wright K, Wooderchak-Donahue W, Tan OT, Margraf R, Stevenson DA, Grimmer JF, Bayrak-Toydemir P
BACKGROUND: Port-wine stains (PWS) are capillary malformations, typically located in the dermis of the head and neck, affecting 0.3% of the population. Current theories suggest that port-wine stains are caused by somatic mutations that disrupt vascular development.
OBJECTIVES: Understanding PWS genetic determinants could provide insight into new treatments.
METHODS: Our study used a custom next generation sequencing (NGS) panel and digital polymerase chain reaction to investigate genetic variants in 12 individuals with isolated port-wine stains. Importantly, affected and healthy skin tissue from the same individual were compared. A subtractive correction method was developed to eliminate background noise from NGS data. This allowed the detection of a very low level of mosaicism.
RESULTS: A novel somatic variant GNAQ, c.547C>G, p.Arg183Gly was found in one case with 4% allele frequency. The previously reported GNAQ c.548G>A, p.Arg183Gln was confirmed in 9 of 12 cases with an allele frequency ranging from 1.73 to 7.42%. Digital polymerase chain reaction confirmed novel variants detected by next generation sequencing. Two novel somatic variants were also found in RASA1, although neither was predicted to be deleterious.
CONCLUSIONS: This is the second largest study on isolated, non-syndromic PWS. Our data suggest that GNAQ is the main genetic determinant in this condition. Moreover, isolated port-wine stains are distinct from capillary malformations seen in RASA1 disorders, which will be helpful in clinical evaluation.
PMID: 26192947 [PubMed - indexed for MEDLINE]
Elevated pretransplant pulmonary vascular resistance index does not predict mortality after isolated orthotopic heart transplantation in children: A retrospective analysis of the UNOS database.
Pediatr Transplant. 2015 Sep;19(6):623-33
Authors: Chiu P, Schaffer JM, Sheikh AY, Ha R, Reinhartz O, Mainwaring R, Reitz BA
OHT is the definitive therapy in end-stage heart failure. Elevated PVRI is considered a relative contraindication to isolated OHT; this assumption is re-evaluated using data from the UNOS database. A retrospective review of de-identified data from the UNOS dataset was performed. There were 1943 pediatric OHT recipients between 10/87 and 12/11 with sufficient data for analysis. Cox regression was performed to examine the effect of baseline characteristics on post-transplant survival. Patients were propensity matched, and Kaplan-Meier survival analysis was performed comparing cohorts of patients using thresholds of 6 and 9 WU × m(2) . PVRI was not a significant predictor of post-transplant outcomes in either univariate or multivariate Cox regression. Kaplan-Meier analysis revealed no difference in survival between both unmatched and propensity-matched OHT recipients. In conclusion, elevated PVRI was not associated with post-transplant mortality in pediatric OHT recipients. A prospective study assessing the current use of PVRI ≥6 as a threshold to contraindicate isolated OHT should be undertaken. Removing this potentially unnecessary restriction on transplant candidacy may make this life-saving therapy available to a greater number of patients.
PMID: 26179628 [PubMed - indexed for MEDLINE]
Evaluation of ERG and SPINK1 by Immunohistochemical Staining and Clinicopathological Outcomes in a Multi-Institutional Radical Prostatectomy Cohort of 1067 Patients.
PLoS One. 2015;10(7):e0132343
Authors: Brooks JD, Wei W, Hawley S, Auman H, Newcomb L, Boyer H, Fazli L, Simko J, Hurtado-Coll A, Troyer DA, Carroll PR, Gleave M, Lance R, Lin DW, Nelson PS, Thompson IM, True LD, Feng Z, McKenney JK
Distinguishing between patients with early stage, screen detected prostate cancer who must be treated from those that can be safely watched has become a major issue in prostate cancer care. Identification of molecular subtypes of prostate cancer has opened the opportunity for testing whether biomarkers that characterize these subtypes can be used as biomarkers of prognosis. Two established molecular subtypes are identified by high expression of the ERG oncoprotein, due to structural DNA alterations that encode for fusion transcripts in approximately ½ of prostate cancers, and over-expression of SPINK1, which is purportedly found only in ERG-negative tumors. We used a multi-institutional prostate cancer tissue microarray constructed from radical prostatectomy samples with associated detailed clinical data and with rigorous selection of recurrent and non-recurrent cases to test the prognostic value of immunohistochemistry staining results for the ERG and SPINK1 proteins. In univariate analysis, ERG positive cases (419/1067; 39%) were associated with lower patient age, pre-operative serum PSA levels, lower Gleason scores (≤ 3+4=7) and improved recurrence free survival (RFS). On multivariate analysis, ERG status was not correlated with RFS, disease specific survival (DSS) or overall survival (OS). High-level SPINK1 protein expression (33/1067 cases; 3%) was associated with improved RFS on univariate and multivariate Cox regression analysis. Over-expression of either protein was not associated with clinical outcome. While expression of ERG and SPINK1 proteins was inversely correlated, it was not mutually exclusive since 3 (0.28%) cases showed high expression of both. While ERG and SPINK1 appear to identify discrete molecular subtypes of prostate cancer, only high expression of SPINK1 was associated with improved clinical outcome. However, by themselves, neither ERG nor SPINK1 appear to be useful biomarkers for prognostication of early stage prostate cancer.
PMID: 26172920 [PubMed - indexed for MEDLINE]
Selective Pressures Explain Differences in Flower Color among Gentiana lutea Populations.
PLoS One. 2015;10(7):e0132522
Authors: Sobral M, Veiga T, Domínguez P, Guitián JA, Guitián P, Guitián JM
Flower color variation among plant populations might reflect adaptation to local conditions such as the interacting animal community. In the northwest Iberian Peninsula, flower color of Gentiana lutea varies longitudinally among populations, ranging from orange to yellow. We explored whether flower color is locally adapted and the role of pollinators and seed predators as agents of selection by analyzing the influence of flower color on (i) pollinator visitation rate and (ii) escape from seed predation and (iii) by testing whether differences in pollinator communities correlate with flower color variation across populations. Finally, (iv) we investigated whether variation in selective pressures explains flower color variation among 12 G. lutea populations. Flower color influenced pollinator visits and differences in flower color among populations were related to variation in pollinator communities. Selective pressures on flower color vary among populations and explain part of flower color differences among populations of G. lutea. We conclude that flower color in G. lutea is locally adapted and that pollinators play a role in this adaptation.
PMID: 26172378 [PubMed - indexed for MEDLINE]
The Relationship Between Industry and Pain Societies, Part 1: Demystification and Legitimization of Continuing Medical Education.
Pain Med. 2015 Jul;16(7):1251
Authors: Darnall BD, Schatman ME
PMID: 26138746 [PubMed - indexed for MEDLINE]
Synthetic RNAi triggers and their use in chronic hepatitis B therapies with curative intent.
Antiviral Res. 2015 Sep;121:97-108
Authors: Gish RG, Yuen MF, Chan HL, Given BD, Lai CL, Locarnini SA, Lau JY, Wooddell CI, Schluep T, Lewis DL
Current therapies for chronic hepatitis B virus infection (CHB) - nucleos(t)ide analogue reverse transcriptase inhibitors and interferons - result in low rates of functional cure defined as sustained off-therapy seroclearance of hepatitis B surface antigen (HBsAg). One likely reason is the inability of these therapies to consistently and substantially reduce the levels of viral antigen production. Accumulated evidence suggests that high serum levels of HBsAg result in exhaustion of the host immune system, rendering it unable to mount the effective antiviral response required for HBsAg clearance. New mechanistic approaches are required to produce high rates of HBsAg seroclearance in order to greatly reduce off-treatment disease progression. Already shown to be a clinically viable means of reducing gene expression in a number of other diseases, therapies based on RNA interference (RNAi) can directly target hepatitis B virus transcripts with high specificity, profoundly reducing the production of viral proteins. The fact that the viral RNA transcripts contain overlapping sequences means that a single RNAi trigger can result in the degradation of all viral transcripts, including all messenger RNAs and pregenomic RNA. Advances in the design of RNAi triggers have increased resistance to degradation and reduced nonspecific innate immune stimulation. Additionally, new methods to effectively deliver the trigger to liver hepatocytes, and specifically to the cytoplasmic compartment, have resulted in increased efficacy and tolerability. An RNAi-based drug currently in clinical trials is ARC-520, a dynamic polyconjugate in which the RNAi trigger is conjugated to cholesterol, which is coinjected with a hepatocyte-targeted, membrane-active peptide. Phase 2a clinical trial results indicate that ARC-520 was well tolerated and resulted in significant, dose-dependent reduction in HBsAg for up to 57days in CHB patients. RNAi-based therapies may play an important role in future therapeutic regimes aimed at improving HBsAg seroclearance and eliminating the need for lifelong therapy. This paper forms part of a symposium in Antiviral Research on "An unfinished story: from the discovery of the Australia antigen to the development of new curative therapies for hepatitis B."
PMID: 26129970 [PubMed - indexed for MEDLINE]
Chronic hepatitis B: Virology, natural history, current management and a glimpse at future opportunities.
Antiviral Res. 2015 Sep;121:47-58
Authors: Gish RG, Given BD, Lai CL, Locarnini SA, Lau JY, Lewis DL, Schluep T
The host immune system plays an important role in chronic hepatitis B (CHB), both in viral clearance and hepatocellular damage. Advances in our understanding of the natural history of the disease have led to redefining the major phases of infection, with the "high replicative, low inflammatory" phase now replacing what was formerly termed the "immune tolerant" phase, and the "nonreplicative phase" replacing what was formerly termed the "inactive carrier" phase. As opposed to the earlier view that HBV establishes chronic infection by exploiting the immaturity of the neonate's immune system, new findings on trained immunity show that the host is already somewhat "matured" following birth, and is actually very capable of responding immunologically, potentially altering future hepatitis B treatment strategies. While existing therapies are effective in reducing viral load and necroinflammation, often restoring the patient to near-normal health, they do not lead to a cure except in very rare cases and, in many patients, viremia rebounds after cessation of treatment. Researchers are now challenged to devise therapies that will eliminate infection, with a particular focus on eliminating the persistence of viral cccDNA in the nuclei of hepatocytes. In the context of chronic hepatitis B, new definitions of 'cure' are emerging, such as 'functional' and 'virological' cure, defined by stable off-therapy suppression of viremia and antigenemia, and the normalization of serum ALT and other liver-related laboratory tests. Continued advances in the understanding of the complex biology of chronic hepatitis B have resulted in the development of new, experimental therapies targeting viral and host factors and pathways previously not accessible to therapy, approaches which may lead to virological cures in the near term and functional cures upon long term follow-up. This article forms part of a symposium in Antiviral Research on "An unfinished story: from the discovery of the Australia antigen to the development of new curative therapies for hepatitis B."
PMID: 26092643 [PubMed - indexed for MEDLINE]
In vitro immunomodulation for enhancing T cell-based diagnosis of Mycobacterium tuberculosis infection.
Diagn Microbiol Infect Dis. 2015 Sep;83(1):41-5
Authors: Slater M, Tran MC, Platt L, Luu LT, Phan HT, Pham PT, Do TB, Nguyen HT, Gaur RL, Parsonnet J, Cattamanchi A, Luo R, Nahid P, Banaei N
Interferon-gamma release assays have limited sensitivity for detecting latent tuberculosis infection. In this study, we determine if the addition of immunomodulators to the QuantiFERON-TB Gold In-Tube (QFT-GIT) increased test sensitivity without compromising specificity. We prospectively compared QFT-GIT results with and without incubation with 2 immunomodulators (lipopolysaccharide [LPS] and polyinosine-polycytidylic acid [PolyIC]) in 2 cohorts-113 culture-confirmed tuberculosis (TB) subjects in Hanoi, Vietnam, and 226 documented QFT-GIT-negative, low TB risk health care workers undergoing annual TB screening at a US academic institution. Sensitivity of the tests in TB subjects was 84.1% with the standard QFT-GIT and 85.8% and 74.3% after incubation with LPS and PolyIC, respectively. Specificity in low TB risk health care workers was 100% with the standard QFT-GIT by design and 86.7% with LPS and 63.3% with PolyIC. In conclusion, use of the 2 immunomodulators did not improve sensitivity of the QFT-GIT in TB patients and reduced specificity in low-risk health care workers.
PMID: 26081239 [PubMed - indexed for MEDLINE]
Tripeptidyl Peptidase II Mediates Levels of Nuclear Phosphorylated ERK1 and ERK2.
Mol Cell Proteomics. 2015 Aug;14(8):2177-93
Authors: Wiemhoefer A, Stargardt A, van der Linden WA, Renner MC, van Kesteren RE, Stap J, Raspe MA, Tomkinson B, Kessels HW, Ovaa H, Overkleeft HS, Florea B, Reits EA
Tripeptidyl peptidase II (TPP2) is a serine peptidase involved in various biological processes, including antigen processing, cell growth, DNA repair, and neuropeptide mediated signaling. The underlying mechanisms of how a peptidase can influence this multitude of processes still remain unknown. We identified rapid proteomic changes in neuroblastoma cells following selective TPP2 inhibition using the known reversible inhibitor butabindide, as well as a new, more potent, and irreversible peptide phosphonate inhibitor. Our data show that TPP2 inhibition indirectly but rapidly decreases the levels of active, di-phosphorylated extracellular signal-regulated kinase 1 (ERK1) and ERK2 in the nucleus, thereby down-regulating signal transduction downstream of growth factors and mitogenic stimuli. We conclude that TPP2 mediates many important cellular functions by controlling ERK1 and ERK2 phosphorylation. For instance, we show that TPP2 inhibition of neurons in the hippocampus leads to an excessive strengthening of synapses, indicating that TPP2 activity is crucial for normal brain function.
PMID: 26041847 [PubMed - indexed for MEDLINE]
Long-term Stability of Urinary Biomarkers of Acute Kidney Injury in Children.
Am J Kidney Dis. 2016 Jan;67(1):56-61
Authors: Schuh MP, Nehus E, Ma Q, Haffner C, Bennett M, Krawczeski CD, Devarajan P
BACKGROUND: Recent meta-analyses support the utility of urinary biomarkers for the diagnosis and prognosis of acute kidney injury. It is critical to establish optimal sample handling conditions for short-term processing and long-term urinary storage prior to widespread clinical deployment and meaningful use in prospective clinical trials.
STUDY DESIGN: Prospective study.
SETTING & PARTICIPANTS: 80 children (median age, 1.1 [IQR, 0.5-4.2] years) undergoing cardiac surgery with cardiopulmonary bypass at our center. 50% of patients had acute kidney injury (defined as ≥50% increase in serum creatinine from baseline).
PREDICTORS: We tested the effect on biomarker concentrations of short-term urine storage in ambient, refrigerator, and freezer conditions. We also tested the effects of multiple freeze-thaw cycles, as well as prolonged storage for 5 years.
OUTCOMES: Urine concentrations of neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule 1 (KIM-1), and interleukin 18 (IL-18).
MEASUREMENTS: All biomarkers were measured using commercially available kits.
RESULTS: All 3 biomarkers were stable in urine stored at 4°C for 24 hours, but showed significant degradation (5.6%-10.1% from baseline) when stored at 25°C. All 3 biomarkers showed only a small although significant decrease in concentration (0.77%-2.9% from baseline) after 3 freeze-thaw cycles. Similarly, all 3 biomarkers displayed only a small but significant decrease in concentration (0.84%-3.2%) after storage for 5 years.
LIMITATIONS: Only the 3 most widely studied biomarkers were tested. Protease inhibitors were not evaluated.
CONCLUSIONS: Short-term storage of urine samples for measurement of NGAL, KIM-1, and IL-18 may be performed at 4°C for up to 24 hours, but not at room temperature. These urinary biomarkers are stable at -80°C for up to 5 years of storage. Our results are reassuring for the deployment of these assays as biomarkers in clinical practice, as well as in prospective clinical studies requiring long-term urine storage.
PMID: 26032628 [PubMed - indexed for MEDLINE]
Nonlinear Effects of Noxious Thermal Stimulation and Working Memory Demands on Subjective Pain Perception.
Pain Med. 2015 Jul;16(7):1301-10
Authors: Sturgeon JA, Tieu MM, Jastrzab LE, McCue R, Gandhi V, Mackey SC
OBJECTIVE: A bidirectional relationship between working memory (WM) and acute pain has long been assumed, but equivocal evidence exists regarding this relationship. This study characterized the relationship between WM and acute pain processing in healthy individuals using an adapted Sternberg WM task.
DESIGN: Participants completed a Sternberg task while receiving noxious thermal stimulation. Participants received a pseudorandom presentation of four different temperatures (baseline temperatures and individually determined low-, medium-, and high-temperature stimuli) and four levels of Sternberg task difficulty (0-, 3-, 6-, and 9-letter strings).
SUBJECTS: Twenty-eight healthy participants were recruited from Stanford University and the surrounding community to complete this study.
RESULTS: A nonlinear interaction between intensity of thermal stimulation and difficulty of the Sternberg task was noted. Increased cognitive load from the Sternberg task resulted in increased perception of pain in low-intensity thermal stimulation but suppressed pain perception in high-intensity thermal stimulation. Thermal stimulation had no significant effect on participants' response time or accuracy on the Sternberg task regardless of intensity level.
CONCLUSIONS: Pain perception appears to decrease as a function of WM load only for sufficiently noxious stimuli. However, increasing noxious stimuli did not affect cognitive performance. These complex relationships may reflect a shared cognitive space that can become "overloaded" with input of multiple stimuli of sufficient intensity.
PMID: 25929747 [PubMed - indexed for MEDLINE]
Associations Between Ankle-Brachial Index and Cognitive Function: Results From the Lifestyle Interventions and Independence for Elders Trial.
J Am Med Dir Assoc. 2015 Aug 1;16(8):682-9
Authors: Espeland MA, Newman AB, Sink K, Gill TM, King AC, Miller ME, Guralnik J, Katula J, Church T, Manini T, Reid KF, McDermott MM, LIFE Study Group
OBJECTIVE: The objective of this study was to evaluate cross-sectional and longitudinal associations between ankle-brachial index (ABI) and indicators of cognitive function.
DESIGN: Randomized clinical trial (Lifestyle Interventions and Independence for Elders Trial).
SETTING: Eight US academic centers.
PARTICIPANTS: A total of 1601 adults ages 70-89 years, sedentary, without dementia, and with functional limitations.
MEASUREMENTS: Baseline ABI and interviewer- and computer-administered cognitive function assessments were obtained. These assessments were used to compare a physical activity intervention with a health education control. Cognitive function was reassessed 24 months later (interviewer-administered) and 18 or 30 months later (computer-administered) and central adjudication was used to classify individuals as having mild cognitive impairment, probable dementia, or neither.
RESULTS: Lower ABI had a modest independent association with poorer cognitive functioning at baseline (partial r = 0.09; P < .001). Although lower baseline ABI was not associated with overall changes in cognitive function test scores, it was associated with higher odds for 2-year progression to a composite of either mild cognitive impairment or probable dementia (odds ratio 2.60 per unit lower ABI; 95% confidence interval 1.06-6.37). Across 2 years, changes in ABI were not associated with changes in cognitive function.
CONCLUSION: In an older cohort sedentary individuals with dementia and with functional limitations, lower baseline ABI was independently correlated with cognitive function and associated with greater 2-year risk for progression to mild cognitive impairment or probable dementia.
PMID: 25869993 [PubMed - indexed for MEDLINE]
Risk Factors for Prolonged Postpartum Length of Stay Following Cesarean Delivery.
Am J Perinatol. 2015 Jul;32(9):825-32
Authors: Blumenfeld YJ, El-Sayed YY, Lyell DJ, Nelson LM, Butwick AJ
OBJECTIVE: This study aims to identify risk factors for prolonged postpartum length of stays (LOS) after cesarean delivery (CD).
STUDY DESIGN: Patients undergoing CD were sourced from a multicenter registry of 19 academic centers between 1999 and 2002 (n = 57,067). Prolonged postpartum LOS was defined as a hospitalization duration ≥ 90th centile. Maternal, antepartum, perioperative, and neonatal variables were compared between women with and without prolonged postpartum LOS.
RESULTS: The 90th centile for postpartum LOS was 4 days, with 14,954 women experiencing prolonged postpartum LOS. Women with perioperative complications had the highest independent risk for a prolonged postpartum LOS: ileus (adjusted odds ratio [aOR] = 12.28; 95% confidence interval CI = 8.98-16.8); endometritis (aOR = 10.45; 95% CI = 9.51-11.5), and wound complications (aOR = 5.49; 95% CI = 4.54-6.63). Several antepartum, perioperative, and neonatal variables were associated with a prolonged postpartum LOS.
CONCLUSION: Perioperative complications had the highest risk for prolonged LOS after CD. Strategies to reduce perioperative complications are needed to decrease the health care burden of prolonged post-CD LOS.
PMID: 25594218 [PubMed - indexed for MEDLINE]
Pediatric Patient and Hospital Characteristics Associated With Treatment of Peritonsillar Abscess and Peritonsillar Cellulitis.
Clin Pediatr (Phila). 2015 Nov;54(13):1240-6
Authors: Nguyen T, Haberland CA, Hernandez-Boussard T
OBJECTIVE: To identify patient and hospital characteristics associated with the choice of treatment for pediatric patients who present in the acute setting with peritonsillar abscess/cellulitis (PTA/PTC).
STUDY DESIGN: A retrospective cohort study was performed using Healthcare Cost and Utilization Project emergency department, ambulatory, and inpatient state databases for the years 2010 and 2011. Children aged 0 to 17 years were identified using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis code for PTA/PTC. The main outcome of interest was treatment received, which included medical therapy alone, incision and drainage (IND) or tonsillectomy. Multiple logistic regression analyses were conducted to model non-clinical factors associated with treatment received after adjusting for age, hospital state, race, primary expected payer, existing chronic condition(s), and type of hospital.
RESULTS: We identified 2994 patients who presented with PTA/PTC. The most common treatment choice was medical therapy alone (30.8%), followed by IND (30.5%) and tonsillectomy (9.4%). There were significant associations between treatment choice and race, primary payer status, and type of hospital (P < .05). We found that Hispanic patients, those with Medicaid as their primary expected payer, and those treated at a designated children's hospital were 3 nonclinical factors independently associated with an increase in likelihood of receiving tonsillectomy as treatment.
CONCLUSION: There are important nonclinical factors associated with treatment of children who present in the acute setting with PTA/PTC. Additional research is recommended to understand these observed differences in care and how they may affect health outcomes.
PMID: 25589309 [PubMed - indexed for MEDLINE]
Computational modeling of chemo-bio-mechanical coupling: a systems-biology approach toward wound healing.
Comput Methods Biomech Biomed Engin. 2016;19(1):13-30
Authors: Buganza Tepole A, Kuhl E
Wound healing is a synchronized cascade of chemical, biological, and mechanical phenomena, which act in concert to restore the damaged tissue. An imbalance between these events can induce painful scarring. Despite intense efforts to decipher the mechanisms of wound healing, the role of mechanics remains poorly understood. Here, we establish a computational systems biology model to identify the chemical, biological, and mechanical mechanisms of scar formation. First, we introduce the generic problem of coupled chemo-bio-mechanics. Then, we introduce the model problem of wound healing in terms of a particular chemical signal, inflammation, a particular biological cell type, fibroblasts, and a particular mechanical model, isotropic hyperelasticity. We explore the cross-talk between chemical, biological, and mechanical signals and show that all three fields have a significant impact on scar formation. Our model is the first step toward rigorous multiscale, multifield modeling in wound healing. Our formulation has the potential to improve effective wound management and optimize treatment on an individualized patient-specific basis.
PMID: 25421487 [PubMed - indexed for MEDLINE]
How have fisheries affected parasite communities?
Parasitology. 2015 Jan;142(1):134-44
Authors: Wood CL, Lafferty KD
To understand how fisheries affect parasites, we conducted a meta-analysis of studies that contrasted parasite assemblages in fished and unfished areas. Parasite diversity was lower in hosts from fished areas. Larger hosts had a greater abundance of parasites, suggesting that fishing might reduce the abundance of parasites by selectively removing the largest, most heavily parasitized individuals. After controlling for size, the effect of fishing on parasite abundance varied according to whether the host was fished and the parasite's life cycle. Parasites of unfished hosts were more likely to increase in abundance in response to fishing than were parasites of fished hosts, possibly due to compensatory increases in the abundance of unfished hosts. While complex life cycle parasites tended to decline in abundance in response to fishing, directly transmitted parasites tended to increase. Among complex life cycle parasites, those with fished hosts tended to decline in abundance in response to fishing, while those with unfished hosts tended to increase. However, among directly transmitted parasites, responses did not differ between parasites with and without fished hosts. This work suggests that parasite assemblages are likely to change substantially in composition in increasingly fished ecosystems, and that parasite life history and fishing status of the host are important in predicting the response of individual parasite species or groups to fishing.
PMID: 24598058 [PubMed - indexed for MEDLINE]
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