tbuckley/cabot-search huggingface dataset:
Lack of Concordance Between Empirical Scores and Physician Assessments of Stroke and Bleeding Risk in Atrial Fibrillation
Authors: Benjamin A. Steinberg, Sunghee Kim, Laine Thomas, Gregg C. Fonarow, Elaine Hylek, Jack Ansell, Alan S. Go, Paul Chang, Peter Kowey, Bernard J. Gersh, Kenneth W. Mahaffey, Daniel E. Singer, Jonathan P. Piccini, Eric D. Peterson
Journal: Circulation (2014)

Background— Physicians treating patients with atrial fibrillation (AF) must weigh the benefits of anticoagulation in preventing stroke versus the risk of bleeding. Although empirical models have been developed to predict such risks, the degree to which these coincide with clinicians’ estimates is unclear. Methods and Results— We examined 10 094 AF patients enrolled in the Outcomes Registry for Better Informed Treatment of AF (ORBIT-AF) registry between June 2010 and August 2011. Empirical stroke and bleeding risks were assessed by using the congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, and previous stroke or transient ischemic attack (CHADS 2 ) and Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) scores, respectively. Separately, physicians were asked to categorize their patients’ stroke and bleeding risks: low risk (&lt;3%); intermediate risk (3%–6%); and high risk (&gt;6%). Overall, 72% (n=7251) in ORBIT-AF had high-risk CHADS 2 scores (≥2). However, only 16% were assessed as high stroke risk by physicians. Although 17% (n=1749) had high ATRIA bleeding risk (score ≥5), only 7% (n=719) were considered so by physicians. The associations between empirical and physician-estimated stroke and bleeding risks were low (weighted Kappa 0.1 and 0.11, respectively). Physicians weighed hypertension, heart failure, and diabetes mellitus less significantly than empirical models in estimating stroke risk; physicians weighted anemia and dialysis less significantly than empirical models when estimating bleeding risks. Anticoagulation use was highest among patients with high stroke risk, assessed by either empirical model or physician estimates. In contrast, physician and empirical estimates of bleeding had limited impact on treatment choice. Conclusions— There is little agreement between provider-assessed risk and empirical scores in AF. These differences may explain, in part, the current divergence of anticoagulation treatment decisions from guideline recommendations. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01165710.
The Evolutionary History of Drosophila buzzatii. XXXV. Inversion Polymorphism and Nucleotide Variability in Different Regions of the Second Chromosome
Authors: H. Laayouni
Journal: Molecular Biology and Evolution (2003)

Inversions are portions of a chromosome where the gene order is reversed relative to a standard reference orientation. Because of reduced levels of recombination in heterokaryotypes, inversions have a potentially important effect on patterns of nucleotide variability in those genomic regions close to, or included in, the inverted fragments. Here we report sequence variation at three anonymous regions (STSs) located at different positions in relation to second-chromosome inversion breakpoints in 29 isochromosomal lines derived from an Argentinean population of Drosophila buzzatii. In agreement with previous findings in Drosophila, gene flux (crossing over and/or gene conversion) between arrangements seems to appreciably increase as we approach the middle sections of inversion 2j, and patterns of nucleotide variability within, as well as genetic differentiation between chromosome arrangements, are comparable to those observed at the molecular marker outside the inverted fragments. On the other hand, nucleotide diversity near the proximal breakpoint of inversion 2j is reduced when contrasted with that found at the other regions, particularly in the case of derived inverted chromosomes. Using the data from the breakpoint, we estimate that the inversion polymorphism is approximately 1.63 N generations old, where N is the effective population size. An excess of low-frequency segregating polymorphisms is detected; mostly in the ancestral 2st arrangement and probably indicating a population expansion that predates the coalescent time of inversion 2j. Heterogeneity in mutation rates between the markers linked to the inversions may be sufficient to explain the different levels of nucleotide diversity observed. When considered in the context of other studies on patterns of variation relative to physical distance to inversion breakpoints, our data appear to be consistent with the conclusion that inversions are unlikely to be “long-lived” balanced polymorphisms.
Renal Angiotensin-Converting Enzyme Is Essential for the Hypertension Induced by Nitric Oxide Synthesis Inhibition
Authors: Jorge F. Giani, Tea Janjulia, Nikhil Kamat, Dale M. Seth, Wendell-Lamar B. Blackwell, Kandarp H. Shah, Xiao Z. Shen, Sebastien Fuchs, Eric Delpire, Jorge E. Toblli, Kenneth E. Bernstein, Alicia A. McDonough, Romer A. Gonzalez-Villalobos
Journal: Journal of the American Society of Nephrology (2014)

The kidney is an important source of angiotensin-converting enzyme (ACE) in many species, including humans. However, the specific effects of local ACE on renal function and, by extension, BP control are not completely understood. We previously showed that mice lacking renal ACE, are resistant to the hypertension induced by angiotensin II infusion. Here, we examined the responses of these mice to the low-systemic angiotensin II hypertensive model of nitric oxide synthesis inhibition with L-NAME. In contrast to wild-type mice, mice without renal ACE did not develop hypertension, had lower renal angiotensin II levels, and enhanced natriuresis in response to L-NAME. During L-NAME treatment, the absence of renal ACE was associated with blunted GFR responses; greater reductions in abundance of proximal tubule Na+/H+ exchanger 3, Na+/Pi co-transporter 2, phosphorylated Na+/K+/Cl− cotransporter, and phosphorylated Na+/Cl− cotransporter; and greater reductions in abundance and processing of the γ isoform of the epithelial Na+ channel. In summary, the presence of ACE in renal tissue facilitates angiotensin II accumulation, GFR reductions, and changes in the expression levels and post-translational modification of sodium transporters that are obligatory for sodium retention and hypertension in response to nitric oxide synthesis inhibition.
Effect of ethylene vinyl acetate (EVA) closed cell foam on transmitted forces in mouthguard material
Authors: B Westerman, P M Stringfellow, J A Eccleston, D J Harbrow
Journal: British Journal of Sports Medicine (2002)

Objectives: To compare transmitted forces through ethylene vinyl acetate (EVA) mouthguard material and the same EVA material with gas inclusions in the form of a closed cell foam. Method: EVA mouthguard materials with and without foam gas inclusions and 4 mm thick were impacted with a constant force from an impact pendulum. Various porosity levels in the foam materials were produced by 1%, 5%, and 10% by weight foaming agent. The forces transmitted through the EVA after energy absorption by the test materials were measured with a force sensor and compared. Results: Only minor non-significant differences in transmitted forces through the EVA with and without foam were shown. Conclusions: The inclusion of gas in the form of a closed cell foam in 4 mm thick EVA mouthguard materials did not improve the impact performance of the EVA mouthguard material.
Prenatal diagnosis of homozygous alpha thalassaemia by direct DNA analysis of uncultured amniotic fluid cells.
Authors: V Chan, A Ghosh, T K Chan, V Wong, D Todd
Journal: BMJ (1984)

Prenatal diagnosis of homozygous alpha thalassaemia was performed in eight successive patients at risk using DNA from uncultured amniotic fluid cells. The presence of alpha gene was determined by restriction endonuclease mapping and hybridisation with cloned alpha and beta globin probes. This method is reliable and may be performed at 16 weeks of gestation.
AT-51 * PHASE I STUDY OF PANOBINOSTAT AND FRACTIONATED STEREOTACTIC RE-IRRADIATION THERAPY (FSRT) FOR RECURRENT HIGH GRADE GLIOMAS
Authors: W. Shi, Y. R. Lawrence, M. Werner-wasik, J. Evans, D. Andrews, J. Glass, L. Kim, V. B. Ad, Y. Moshel, K. Judy, C. Farrell, N. Simon, A. Dicker
Journal: Neuro-Oncology (2014)

PURPOSE: To perform a phase I study to evaluate the safety, and tolerability of panobinostat, an HDAC inhibitor, when combined with fractionated stereotactic re-irradiation therapy (FSRT) for recurrent gliomas. METHODS: Patients with recurrent gliomas (WHO grade II-IV) were eligible for this trial. FSRT was prescribed to 30-35 Gy delivered in 10 daily fractions. Panobinostat was administrated orally once daily every Monday, Wednesday, and Friday concurrently with radiation treatment. The panobinostat dose was escalated from 10 to 30 mg using a 3 + 3 trial design. RESULTS: A total of 16 patients were enrolled on the trial. Four patients were excluded. There were no treatment related grade 3 or higher toxicities in the 10 mg or 20 mg cohort. In the 30 mg panobinostat cohort, one patient developed grade 3 leukopenia and grade 4 neutropenia which was possibly related to the treatment. The minimum follow up of the living patients is 8.5 m. The 4-m progression survival (PFS) of all the evaluable patients is 87%, and 6-m PFS of 56%. The medial overall survival is 9.5 m. There is a suggestion of dose response to the panobinostat. The 4-m PFS is 100%, 100%, and 67% for 30 mg, 20 mg, and 10 mg cohort respectively. The 6-m PFS is 83%, 33%, and 67% for 30 mg, 20 mg, and 10 mg cohort respectively. The overall survival for the 30 mg cohort is not reached with a median follow up of 11.5 m. CONCLUSIONS: Panobinostat administrated with FSRT is well tolerated at a 30 mg dose. There is a suggestion of a dose response with panobinostat. The median overall survival is not reached with a median follow up of 11.5 m for the 30 mg cohort. A phase II trial is warranted to confirm the efficacy of combining panobinostat with FSRT for recurrent gliomas.
Whose Right to Know? The Subjectivity of Mothers in Mandatory Paternity Testing
Authors: Erin Heidt-Forsythe, Michelle L. McGowan
Journal: The American Journal of Bioethics (2013)

Click to increase image sizeClick to decrease image size Acknowledgments Financial support for the research and authorship of this manuscript was provided by the National Human Genome Research Institute (P50 HG003390). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Human Genome Research Institute or National Institutes of Health.
Postpartum Thyroiditis and Autoimmune Thyroiditis in Women of Childbearing Age: Recent Insights and Consequences for Antenatal and Postnatal Care
Authors: Alex F. Muller, Hemmo A. Drexhage, Arie Berghout
Journal: Endocrine Reviews (2001)

Abstract Postpartum thyroiditis is a syndrome of transient or permanent thyroid dysfunction occurring in the first year after delivery and based on an autoimmune inflammation of the thyroid. The prevalence ranges from 5–7%. We discuss the role of antibodies (especially thyroid peroxidase antibodies), complement, activated T cells, and apoptosis in the outbreak of postpartum thyroiditis. Postpartum thyroiditis is conceptualized as an acute phase of autoimmune thyroid destruction in the context of an existing and ongoing process of thyroid autosensitization. From pregnancy an enhanced state of immune tolerance ensues. A rebound reaction to this pregnancy-associated immune suppression after delivery explains the aggravation of autoimmune syndromes in the puerperal period, e.g., the occurrence of clinically overt postpartum thyroiditis. Low thyroid reserve due to autoimmune thyroiditis is increasingly recognized as a serious health problem. 1) Thyroid autoimmunity increases the probability of spontaneous fetal loss. 2) Thyroid failure due to autoimmune thyroiditis—often mild and subclinical—can lead to permanent and significant impairment in neuropsychological performance of the offspring. 3) Evidence is emerging that as women age subclinical hypothyroidism—as a sequel of postpartum thyroiditis—predisposes them to cardiovascular disease. Hence, postpartum thyroiditis is no longer considered a mild and transient disorder. Screening is considered.
Sino-Atrial Reciprocation in the Isolated Rabbit Heart
Authors: JAOK HAN, ANNA Mae MALOZZI, GORDON K. MOE
Journal: Circulation Research (1968)

Reciprocal beats between sinus node and atrium were studied in isolated rabbit heart tissue by microelectrode techniques. Early premature atrial responses which entered the sinus node frequently emerged to re-excite the atrium as "echoes." When the premature atrial beats discharged some but not all nodal areas, the atrial echoes, in turn, appeared to re-enter the sinus node. Repetitive reciprocation involving the sino-atrial circuit was occasionally observed. Anatomic and temporal patterns of excitation at multiple recording sites suggest that "entrance" block and slow conduction of premature impulses within the sinus node may explain the observed reciprocation. The results support the hypothesis that self-sustained reciprocation in a sino-atrial circuit might be responsible for some cases of paroxysmal atrial tachycardia.
Post–Glucose Load Plasma α-Dicarbonyl Concentrations Are Increased in Individuals With Impaired Glucose Metabolism and Type 2 Diabetes: The CODAM Study
Authors: Dionne E. Maessen, Nordin M. Hanssen, Jean L. Scheijen, Carla J. van der Kallen, Marleen M. van Greevenbroek, Coen D. Stehouwer, Casper G. Schalkwijk
Journal: Diabetes Care (2015)

There is increasing evidence that postprandial glucose excursions play an important role in the development of vascular complications. The underlying mechanism is unknown, but glucose-derived formation of reactive α-dicarbonyl compounds may explain why acute hyperglycemia leads to increased risk for diabetes complications. In the current study, we investigated whether α-dicarbonyls are increased after a glucose load in individuals without or with impaired glucose metabolism (IGM) and type 2 diabetes.Cross-sectional, linear analyses were performed in the Cohort on Diabetes and Atherosclerosis Maastricht (CODAM [n = 574, 61% men, 60 years old]) study. Individuals with normal glucose metabolism (n = 279), IGM (n = 120), and type 2 diabetes (n = 92) who had complete data on an oral glucose tolerance test (OGTT) and were not on insulin treatment were included in the study population. Plasma α-dicarbonyl (methylglyoxal [MGO], glyoxal [GO], and 3-deoxyglucosone [3-DG]) levels were measured in the fasting state and in samples of the OGTT by ultra-performance liquid chromatography-tandem mass spectrometry.The presence of both IGM and type 2 diabetes was significantly associated with higher α-dicarbonyl incremental areas under the curve (iAUCs), as calculated from the OGTT (for IGM, MGO β = 0.190 [95% CI 0.106-0.274], GO β = 0.287 [95% CI 0.172-0.401], and 3-DG β = 0.285 [95% CI 0.221-0.349]; for type 2 diabetes, MGO β = 0.293 [95% CI 0.180-0.405], GO β = 0.536 [95% CI 0.382-0.689], and 3-DG β = 0.542 [95% CI 0.456-0.628]). Adjustment for glucose iAUC attenuated these associations. iAUCs of the α-dicarbonyls correlated highly with glucose iAUC but not with fasting glucose levels or HbA1c.The increased levels of α-dicarbonyls during an OGTT in individuals with IGM and type 2 diabetes underline the potential importance of α-dicarbonyl stress as a candidate to explain the increased risk of diabetes complications in individuals with postprandial hyperglycemia.
Long-Term Clinical and Molecular Follow-up of Large Animals Receiving Retrovirally Transduced Stem and Progenitor Cells: No Progression to Clonal Hematopoiesis or Leukemia
Authors: Hans-Peter Kiem, Stephanie Sellers, Bobbie Thomasson, Julia C Morris, John F Tisdale, Peter A Horn, Peiman Hematti, Rima Adler, Ken Kuramoto, Boris Calmels, Aylin Bonifacino, Jiong Hu, Christof von Kalle, Manfred Schmidt, Brian Sorrentino, Arthur Nienhuis, C.Anthony Blau, Robert G Andrews, Robert E Donahue, Cynthia E Dunbar
Journal: Molecular Therapy (2004)

There has been significant progress toward clinically relevant levels of retroviral gene transfer into hematopoietic stem cells (HSC), and the therapeutic potential of HSC-based gene transfer has been convincingly demonstrated in children with severe combined immunodeficiency syndrome (SCID). However, the subsequent development of leukemia in two children with X-linked SCID who were apparently cured after transplantation of retrovirally corrected CD34+ cells has raised concerns regarding the safety of gene therapy approaches utilizing integrating vectors. Nonhuman primates and dogs represent the best available models for gene transfer safety and efficacy and are particularly valuable for evaluation of long-term effects. We have followed 42 rhesus macaques, 23 baboons, and 17 dogs with significant levels of gene transfer for a median of 3.5 years (range 1-7) after infusion of CD34+ cells transduced with retroviral vectors expressing marker or drug-resistance genes. None developed abnormal hematopoiesis or leukemia. Integration site analysis confirmed stable, polyclonal retrovirally marked hematopoiesis, without progression toward mono- or oligoclonality over time. These results suggest that retroviral integrations using replication-incompetent vectors, at copy numbers achieved using standard protocols, are unlikely to result in leukemogenesis and that patient- or transgene-specific factors most likely contributed to the occurrence of leukemia in the X-SCID gene therapy trial.
Patient-Centered, Direct-Access Online Care for Management of Atopic Dermatitis
Authors: April W. Armstrong, Mary Ann Johnson, Steven Lin, Emanual Maverakis, Nasim Fazel, Fu-Tong Liu
Journal: JAMA Dermatology (2014)

<h3>Importance</h3> New models of health care delivery for dermatological care have the potential to increase access and improve patient-centered outcomes. <h3>Objective</h3> To compare effectiveness of a direct-access, online model for follow-up dermatologic care in pediatric and adult patients with atopic dermatitis with that of in-person office visits. <h3>Design, Setting, and Participants</h3> This was a 1-year, randomized controlled equivalency clinical trial in medically underserved areas, outpatient clinics, and the general community. Participants included children and adults with atopic dermatitis with access to the Internet, computers, and digital cameras. <h3>Interventions</h3> After an initial in-person visit, patients were randomized 1:1 to direct-access online or usual in-person care for follow-up management of atopic dermatitis. In the direct-access online group, patients captured and transmitted clinical images and history asynchronously to dermatologists online; dermatologists evaluated the clinical information, provided recommendations and education, and prescribed medications online asynchronously. In the in-person group, patients visited dermatologists in their offices for follow-up care. <h3>Main Outcomes and Measures</h3> Atopic dermatitis disease severity as assessed by patient-oriented eczema measure (POEM) and investigator global assessment (IGA). <h3>Results</h3> A total of 156 children and adults were randomized. Between baseline and 12 months, the mean (SD) within-group difference in POEM score in patients in the direct-access online group was −5.1 (5.48) (95% CI, −6.32 to −3.88); in the in-person group, the within-group difference was −4.86 (4.87) (95% CI, −6.27 to −3.46). The difference in the change in POEM scores between the 2 groups was 0.24 (6.59) (90% CI, −1.70 to 1.23), which was contained within the predetermined 2.5 equivalence margin. The percentage of patients achieving clearance or near-clearance of their disease (IGA score of 0 or 1) was 38.4% (95% CI, 27.7% to 49.3%) in the direct-access online group and 43.6% (95% CI, 32.6%-54.6%) in the in-person group. The difference in the percent of patients achieving clearance or near-clearance between the 2 groups was 5.1% (90% CI, 1.7%-8.6%), which was contained within the predetermined 10% equivalence margin. <h3>Conclusions and Relevance</h3> The direct-access online model results in<i>equivalent</i>improvements in atopic dermatitis clinical outcomes as in-person care. Direct-access online care may represent an innovative model of delivering dermatological services to patients with chronic skin diseases. <h3>Trial Registration</h3> clinicaltrials.gov Identifier:NCT00985894
Short-term and long-term epoprostenol (prostacyclin) therapy in pulmonary hypertension secondary to connective tissue diseases: results of a pilot study
Authors: M Humbert, O Sanchez, M Fartoukh, JL Jagot, C Le Gall, O Sitbon, F Parent, G Simonneau
Journal: European Respiratory Journal (1999)

Continuous intravenous epoprostenol improves exercise capacity, haemodynamics, and survival in severe primary pulmonary hypertension. Pulmonary hypertension can also be life-threatening in patients with connective tissue diseases. In a prospective open monocentre uncontrolled study, the effects of epoprostenol were evaluated in patients with severe pulmonary hypertension secondary to connective tissue diseases who were unresponsive to oral vasodilators (including calcium channel blockers) and continued to be in the New York Heart Association (NYHA) functional class III or IV despite conventional medical therapy. Seventeen patients received epoprostenol administered by a portable infusion pump associated with conventional therapy (oral anticoagulants, diuretics, supplemental oxygen). During the first six weeks of therapy, two (12%) patients died, of pulmonary oedema (n = 1) and severe sepsis (n = 1). In the fifteen remaining subjects, clinical and haemodynamic parameters improved significantly at six weeks. These patients were subsequently monitored for 80+/-48 (range 14-154) weeks after initiation of epoprostenol. Five (33%) patients died, of right heart failure (n = 2), severe sepsis (n = 2) or syncope (n = 1) and two patients were successfully transplanted 24 and 52 weeks after initiation of epoprostenol. Seven of the remaining eight patients had a persistent clinical improvement. Short-term epoprostenol therapy is effective in some patients with connective tissue diseases as demonstrated by better clinical status and haemodynamics at six weeks. However, this study reports several cases of early and late major complications including severe sepsis and pulmonary oedema. Additional information is needed to evaluate the benefit: risk ratio of long-term epoprostenol therapy in pulmonary hypertension secondary to connective tissue diseases.