tbuckley/cabot-search huggingface dataset:
The bacterial aetiology of pleural empyema. A descriptive and comparative metagenomic study
Authors: R. Dyrhovden, R.M. Nygaard, R. Patel, E. Ulvestad, Ø. Kommedal
Journal: Clinical Microbiology and Infection (2018)

<h2>Abstract</h2><h3>Objectives</h3> The view of pleural empyema as a complication of bacterial pneumonia is changing because many patients lack evidence of underlying pneumonia. To further our understanding of pathophysiological mechanisms, we conducted in-depth microbiological characterization of empyemas in clinically well-characterized patients and investigated observed microbial parallels between pleural empyemas and brain abscesses. <h3>Methods</h3> Culture-positive and/or 16S rRNA gene PCR-positive pleural fluids were analysed using massive parallel sequencing of the 16S rRNA and <i>rpoB</i> genes. Clinical details were evaluated by medical record review. Comparative analysis with brain abscesses was performed using metagenomic data from a national Norwegian study. <h3>Results</h3> Sixty-four individuals with empyema were included. Thirty-seven had a well-defined microbial aetiology, while 27, all of whom had community-acquired infections, did not. In the latter subset, <i>Fusobacterium nucleatum</i> and/or <i>Streptococcus intermedius</i> was detected in 26 patients, of which 18 had additional facultative and/or anaerobic species in various combinations. For this group, there was 65.5% species overlap with brain abscesses; predisposing factors included dental infection, minor chest trauma, chronic obstructive pulmonary disease, drug abuse, alcoholism and diabetes mellitus. Altogether, massive parallel sequencing yielded 385 bacterial detections, whereas culture detected 38 (10%) and 16S rRNA gene PCR/Sanger-based sequencing detected 87 (23%). <h3>Conclusions</h3> A subgroup of pleural empyema appears to be caused by a set of bacteria not normally considered to be involved in pneumonia. Such empyemas appear to have a similar microbial profile to oral/sinus-derived brain abscesses, supporting spread from the oral cavity, potentially haematogenously. We suggest reserving the term 'primary empyema' for these infections.
Bone stress injuries in male distance runners: higher modified Female Athlete Triad Cumulative Risk Assessment scores predict increased rates of injury
Authors: Emily Kraus, Adam S Tenforde, Aurelia Nattiv, Kristin L Sainani, Andrea Kussman, Megan Deakins-Roche, Sonal Singh, Brian Young Kim, Michelle T Barrack, Michael Fredericson
Journal: British Journal of Sports Medicine (2018)

Bone stress injuries (BSI) are common in runners of both sexes. The purpose of this study was to determine if a modified Female Athlete Triad Cumulative Risk Assessment tool would predict BSI in male distance runners.156 male runners at two collegiate programmes were studied using mixed retrospective and prospective design for a total of 7 years. Point values were assigned using risk assessment categories including low energy availability, low body mass index (BMI), low bone mineral density (BMD) and prior BSI. The outcome was subsequent development of BSI. Statistical models used a mixed effects Poisson regression model with p<0.05 as threshold for significance. Two regression analyses were performed: (1) baseline risk factors as the independent variable; and (2) annual change in risk factors (longitudinal data) as the independent variable.42/156 runners (27%) sustained 61 BSIs over an average 1.9 years of follow-up. In the baseline risk factor model, each 1 point increase in prior BSI score was associated with a 57% increased risk for prospective BSI (p=0.0042) and each 1 point increase in cumulative risk score was associated with a 37% increase in prospective BSI risk (p=0.0079). In the longitudinal model, each 1 point increase in cumulative risk score was associated with a 27% increase in prospective BSI risk (p=0.05). BMI (rate ratio (RR)=1.91, p=0.11) and BMD (RR=1.58, p=0.19) risk scores were not associated with BSI.A modified cumulative risk assessment tool may help identify male runners at elevated risk for BSI. Identifying risk factors may guide treatment and prevention strategies.
Abstract 18059: Clinical Profile and Prognostic Significance of Post-Discharge Hemodilution Among Patients Hospitalized for Heart Failure: Insights From the EVEREST Trial
Authors: Stephen J Greene, Gregg C Fonarow, Baljash S Cheema, Andrew P Ambrosy, Muthiah Vaduganathan, Haris P Subacius, Javed Butler, Mihai Gheorghiade
Journal: Circulation (2017)

Introduction: Hemoconcentration during hospitalization for acute heart failure (HF) correlates with superior decongestion and improved post-discharge outcomes. However, the relationship between early post-discharge hemodilution, markers of congestion, and clinical outcomes is unknown.Methods: The EV
Tyrosine Kinase Inhibitors with or without Donor Lymphocyte Infusion Continue to Provide Long-Term Survival after Relapse of Chronic Myeloid Leukemia Following Hematopoietic Cell Transplantation
Authors: Sarah Ann Schmidt, Jennifer Holter Chakrabarty, Ying Liu, Zhen-Huan Hu, Kirsten M. Williams, Edwin P. Alyea, Uday Popat, Ronald Sobecks, Bart L Scott, Wael Saber
Journal: Blood (2018)
The Mechanisms By Which Mutant-NPM1 Uncouples Differentiation from Proliferation Are Reversed By Several Drugs, Enabling Rational Multi-Component Non-Cytotoxic Differentiation Therapy
Authors: Xiaorong Gu, Quteba Ebrahem, Reda Z. Mahfouz, Metis Hasipek, Francis Enane, Tomas Radivoyevitch, Nicolas Rapin, Bartlomiej P. Przychodzen, Ramesh Balusu, Claudiu V Cotta, David Wald, Zhenbo Hu, Yosef Landesman, Maria Paola Martelli, Brunangelo Falini, Hetty E. Carraway, Jaroslaw P. Maciejewski, Babal K Jha, Yogenthiran Saunthararajah
Journal: Blood (2017)
Precise Modeling of IKZF1 Alterations in Human B-Cell Acute Lymphoblastic Leukemia Cell Lines Reveals Distinct Chemosensitivity, Homing, and Engraftment Properties
Authors: Jason H. Rogers, Rohit Gupta, Jaime M. Reyes, Lorenzo Brunetti, Michael C. Gundry, Tidie Song, Cade Johnson, Carlo D. D. Cristobal, Margaret A. Goodell, Rachel E. Rau
Journal: Blood (2018)
Efficacy and Safety of CD19 Chimeric Antigen Receptor (CAR) T Cell Therapy for B-Cell Acute Lymphocytic Leukemia (B-cell ALL) in a Large Cohort Including Patients with Extramedullary Disease(EMD), High Leukemia Burden, BCR-ABL (+) Mutation,TP53 Mutation, and Post-Transplant Relapse
Authors: Xian Zhang, Xin-an Lu, Junfang Yang, Fanyong LV, Min Xiong, Jianping Zhang, Xiaosu Zhou, Ting He, Peihua Lu
Journal: Blood (2018)
GDF15 Provides an Endocrine Signal of Nutritional Stress in Mice and Humans
Authors: Satish Patel, Anna Alvarez-Guaita, Audrey Melvin, Debra Rimmington, Alessia Dattilo, Emily L. Miedzybrodzka, Irene Cimino, Anne-Catherine Maurin, Geoffrey P. Roberts, Claire L. Meek, Samuel Virtue, Lauren M. Sparks, Stephanie A. Parsons, Leanne M. Redman, George A. Bray, Alice P. Liou, Rachel M. Woods, Sion A. Parry, Per B. Jeppesen, Anders J. Kolnes, Heather P. Harding, David Ron, Antonio Vidal-Puig, Frank Reimann, Fiona M. Gribble, Carl J. Hulston, I. Sadaf Farooqi, Pierre Fafournoux, Steven R. Smith, Jorgen Jensen, Danna Breen, Zhidan Wu, Bei B. Zhang, Anthony P. Coll, David B. Savage, Stephen O’Rahilly
Journal: Cell Metabolism (2019)

GDF15 is an established biomarker of cellular stress. The fact that it signals via a specific hindbrain receptor, GFRAL, and that mice lacking GDF15 manifest diet-induced obesity suggest that GDF15 may play a physiological role in energy balance. We performed experiments in humans, mice, and cells to determine if and how nutritional perturbations modify GDF15 expression. Circulating GDF15 levels manifest very modest changes in response to moderate caloric surpluses or deficits in mice or humans, differentiating it from classical intestinally derived satiety hormones and leptin. However, GDF15 levels do increase following sustained high-fat feeding or dietary amino acid imbalance in mice. We demonstrate that GDF15 expression is regulated by the integrated stress response and is induced in selected tissues in mice in these settings. Finally, we show that pharmacological GDF15 administration to mice can trigger conditioned taste aversion, suggesting that GDF15 may induce an aversive response to nutritional stress.
Abstract 16993: Sex Differences in Renal Transporter Profile Indicate Lower Proximal Reabsorption in Females
Authors: Luciana C Veiras, An Tran, Donna L Ralph, Adriana Castello Costa Girardi, Alicia A McDonough
Journal: Circulation (2015)

Females have lower blood pressure than males before menopause, blunted hypertensive response to AngII, and a leftward shift in pressure natriuresis. Estrogen decreases renal ACE and AT1R and increases NO and AT2R. At the renal transporter level, distal tubule Na+-Cl- cotransporter (NCC) is upregulated by estrogen and more abundant in females, while the loop of Henle (LH) Na+-K+-2Cl- cotransporter (NKCC2) is less abundant. This study aimed to compare female to male apical Na+ transporters’ abundance, distribution, phosphorylation and cleavage and to determine the functional consequences of the differences. Sprague Dawley rats were fasted overnight then fed a 0%KCl meal before termination. The figure displays relative abundance of total and modified (P -phosphorylated, CL-cleaved, FL-full length) transporters expressed along the nephron in females versus males (defined as 1.0), determined by quantitative immunoblotting. Lower abundance of NaPi2, villin, myosin VI, together with higher NHE3-P (inactivation marker) suggest less proximal tubule (PT) reabsorption in females. Confocal immunohistochemistry confirmed that NHE3 localized to the base of the PT microvilli in females (not males) and endogenous CLi+, a marker of volume leaving the PT, was twice as high in females than males. While LH NKCC2 and its regulatory kinase SPAK were not significantly different, distal NCC, and activated NCC-P were more abundant in females, although thiazide sensitive natriuresis was not greater. ENaC α and γ subunits were more activated (-CL) in females. A saline challenge (7% of b.w. saline, i.p.) demonstrated that females excreted a saline load more rapidly than males. Taken together, these results suggest that lower proximal transporters and reabsorption provoke a volume load dependent elevation in NCC and ENaC. This profile in females likely facilitates pressure natriuresis and maintains lower blood pressures.
Tofacitinib Treatment and Molecular Analysis of Cutaneous Sarcoidosis
Authors: William Damsky, Durga Thakral, Nkiruka Emeagwali, Anjela Galan, Brett King
Journal: New England Journal of Medicine (2018)

There is evidence that Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling plays a role in the pathogenesis of sarcoidosis. We treated a patient with cutaneous sarcoidosis with the JAK inhibitor tofacitinib; the patient had not previously had a response to medications and had not received systemic glucocorticoids. This treatment resulted in clinical and histologic remission of her skin disease. Sequencing of RNA and immunohistochemical examination of skin-lesion samples obtained from the patient before and during therapy and immunohistochemical testing of lesion samples obtained from other patients with cutaneous sarcoidosis support a role for JAK-STAT signaling in cutaneous sarcoidosis. (Funded by the Ranjini and Ajay Poddar Resource Fund for Dermatologic Diseases Research and others.).
Illuminating the genome-wide activity of genome editors for safe and effective therapeutics
Authors: Yong Cheng, Shengdar Q. Tsai
Journal: Genome biology (2018)

Genome editing holds remarkable promise to transform human medicine as new therapies that can directly address the genetic causes of disease. However, concerns remain about possible undesired biological consequences of genome editors, particularly the introduction of unintended 'off-target' mutations. Here, we discuss both important considerations for therapeutic genome editing and our understanding of the functional impact of undesired off-target mutations. An important challenge for the future will be the development of new approaches for predicting and defining the probable function of unintended genome-editing mutations, which will inspire confidence in the next generation of promising genome-editing therapies.
Efficacy of Supervised Pelvic Floor Muscle Training and Biofeedback vs Attention-Control Treatment in Adults With Fecal Incontinence
Authors: Anja Ussing, Inge Dahn, Ulla Due, Michael Sørensen, Janne Petersen, Thomas Bandholm
Journal: Clinical Gastroenterology and Hepatology (2018)

Pelvic floor muscle training (PFMT) in combination with conservative treatment is recommended as first-line treatment for patients with fecal incontinence, although its efficacy is unclear. We investigated whether supervised PFMT in combination with conservative treatment is superior to attention-control massage treatment and conservative treatment in adults with fecal incontinence.We performed a randomized, controlled, superiority trial of patients with fecal incontinence at a tertiary care center at a public hospital in Denmark. Ninety-eight adults with fecal incontinence were randomly assigned to groups that received supervised PFMT and biofeedback plus conservative treatment or attention-control treatment plus conservative treatment. The primary outcome was rating of symptom changes, after 16 weeks, based on scores from the Patient Global Impression of Improvement scale. Secondary outcomes were changes in the Vaizey incontinence score (Vaizey Score), Fecal Incontinence Severity Index, and Fecal Incontinence Quality of Life Scale.In the intention-to-treat analysis, participants in the PFMT group were significantly more likely to report improvement in incontinence symptoms based on Patient Global Impression of Improvement scale scores (unadjusted odds ratio, 5.16; 95% CI, 2.18-12.19; P = .0002). The PFMT group had a larger reduction in the mean Vaizey Score (reduction, -1.83 points; 95% CI, -3.57 to -0.08; P = .04). There were no significant differences in condition-specific quality of life. In the per-protocol analyses, the superiority of PFMT was increased. No adverse events were reported.This randomized controlled trial of adults with fecal incontinence provides support for a superior effect of supervised PFMT in combination with conservative treatment compared with attention-control massage treatment and conservative treatment. We found that participants who received supervised PFMT had 5-fold higher odds of reporting improvements in fecal incontinence symptoms and had a larger mean reduction of incontinence severity based on the Vaizey Score compared with attention control massage treatment. Clinicaltrials.gov no: NCT01705535.
Case 39-2018: An 18-Year-Old Man with Diplopia and Proptosis of the Left Eye
Authors: Daniel R. Lefebvre, Katherine L. Reinshagen, Michael K. Yoon, John H. Stone, Anna M. Stagner
Journal: New England Journal of Medicine (2018)

An 18-year-old man presented with diplopia and proptosis of the left eye. Magnetic resonance imaging showed enlargement and increased enhancement of the left medial and inferior rectus muscles, with a central area of hypoenhancement of the medial rectus muscle. A diagnostic procedure was performed.
Abstract 13684: Subclinical Atherosclerosis in Diabetic Patients with Low to Intermediate Risk: Coronary Computed Tomographic Angiographic Findings from Matched Asymptomatic Individuals with and without Diabetes
Authors: Young-rak Cho, Young-Dae Kim, Soo-Hoon Lee, Gyung-Min Park, Sung Ho Her, Dong-Bin Kim
Journal: Circulation (2014)

Objectives: The purpose of this study was to investigate the effect of subclinical atherosclerosis in asymptomatic individuals with low to intermediate risk according to the presence or absence of ...
Identification of a Loss-of-Function Mutation in the Context of Glutaminase Deficiency and Neonatal Epileptic Encephalopathy
Authors: Lynne Rumping, Benjamin Büttner, Oliver Maier, Holger Rehmann, Maarten Lequin, Jan-Ulrich Schlump, Bernhard Schmitt, Birgit Schiebergen-Bronkhorst, Hubertus C. M. T. Prinsen, Michele Losa, Ralph Fingerhut, Johannes R. Lemke, Fried J. T. Zwartkruis, Roderick H. J. Houwen, Judith J. M. Jans, Nanda M. Verhoeven-Duif, Peter M. van Hasselt, Rami Jamra
Journal: JAMA Neurology (2018)

The identification and understanding of the monogenic causes of neurodevelopmental disorders are of high importance for personalized treatment and genetic counseling.To identify and characterize novel genes for a specific neurodevelopmental disorder characterized by refractory seizures, respiratory failure, brain abnormalities, and death in the neonatal period; describe the outcome of glutaminase deficiency in humans; and understand the underlying pathological mechanisms.We performed exome sequencing of cases of neurodevelopmental disorders without a clear genetic diagnosis, followed by genetic and bioinformatic evaluation of candidate variants and genes. Establishing pathogenicity of the variants was achieved by measuring metabolites in dried blood spots by a hydrophilic interaction liquid chromatography method coupled with tandem mass spectrometry. The participants are 2 families with a total of 4 children who each had lethal, therapy-refractory early neonatal seizures with status epilepticus and suppression bursts, respiratory insufficiency, simplified gyral structures, diffuse volume loss of the brain, and cerebral edema. Data analysis occurred from October 2017 to June 2018.Early neonatal epileptic encephalopathy with glutaminase deficiency and lethal outcome.A total of 4 infants from 2 unrelated families, each of whom died less than 40 days after birth, were included. We identified a homozygous frameshift variant p.(Asp232Glufs*2) in GLS in the first family, as well as compound heterozygous variants p.(Gln81*) and p.(Arg272Lys) in GLS in the second family. The GLS gene encodes glutaminase (Enzyme Commission 3.5.1.2), which plays a major role in the conversion of glutamine into glutamate, the main excitatory neurotransmitter of the central nervous system. All 3 variants probably lead to a loss of function and thus glutaminase deficiency. Indeed, glutamine was increased in affected children (available z scores, 3.2 and 11.7). We theorize that the potential reduction of glutamate and the excess of glutamine were a probable cause of the described physiological and structural abnormalities of the central nervous system.We identified a novel autosomal recessive neurometabolic disorder of loss of function of glutaminase that leads to lethal early neonatal encephalopathy. This inborn error of metabolism underlines the importance of GLS for appropriate glutamine homeostasis and respiratory regulation, signal transduction, and survival.
Randall-type monoclonal immunoglobulin deposition disease: novel insights from a nationwide cohort study
Authors: Florent Joly, Camille Cohen, Vincent Javaugue, Sébastien Bender, Mohamed Belmouaz, Bertrand Arnulf, Bertrand Knebelmann, Mathilde Nouvier, Vincent Audard, François Provot, Viviane Gnemmi, Dominique Nochy, Jean Michel Goujon, Arnaud Jaccard, Guy Touchard, Jean Paul Fermand, Christophe Sirac, Frank Bridoux
Journal: Blood (2018)
Erratum to: Discovery and refinement of genetic loci associated with cardiometabolic risk using dense imputation maps : (Nature Genetics, (2016), 48, 11, (1303-1312), 10.1038/ng.3668)
Authors: V. Iotchkova, J. Huang, J.A. Morris, D. Jain, C. Barbieri, K. Walter, J. Min, L. Chen, W. Astle, M. Cocca, P. Deelen, H. Elding, A.-E. Farmaki, C.S. Franklin, M. Frånberg, T.R. Gaunt, A. Hofman, T. Jiang, M.E. Kleber, G. Lachance, J. Luan, G. Malerba, A. Matchan, D. Mead, Y. Memari, I. Ntalla, K. Panoutsopoulou, R. Pazoki, J.R.B. Perry, F. Rivadeneira Ramirez, M. Sabater-Lleal, B. Sennblad, S. Shin, L. Southam, M. Traglia, F. vanDijk, E.M. vanLeeuwen, G. Zaza, W. Zhang, N. Amin, A. Butterworth, J.C. Chambers, G.V. Dedoussis, A. Dehghan, O.H. Franco, L. Franke, M. Frontini, G. Gambaro, P. Gasparini, A. Hamsten, A.J. Isaacs, J.S. Kooner, C. Kooperberg, C. Langenberg, W. März, R.A. Scott, Swertz, D. Toniolo, A.G. Uitterlinden, C.M. vanDuijn, H. Watkins, E. Zeggini, M.T. Maurano, N.J. Timpson, A.P. Reiner, P.L. Auer, N. Soranzo
Journal: Nature Genetics (2018)
Cross resistance of melanoma cells to apoptosis induced by TRAIL and chemotherapy
Authors: Peter Hersey, Xu Dong Zhang, Jing Jing Wu, Susan K. Gillespie
Journal: Cancer Research (2005)

5366  We have previously hypothesized that resistance of melanoma to chemotherapy may be due to immune selection of melanoma cells that are resistant to apoptosis induced by the immune system. In particular, to TNF-related apoptosis inducing ligand (TRAIL), which is expressed on CD4 T cells, monocytes, NK cells and dendritic cells. To test this hypothesis we have taken TRAIL resistant cells and tested their cross-resistance to Cisplatin, Vincristine and Histone deacetylase inhibitors. This showed extensive cross-resistance between the chemotherapeutic drugs and both TRAIL and FasL-induced apoptosis. The role of the survival ERK1/2, Akt and PKC pathways in cross-resistance was examined by use of inhibitors of these pathways (U0126, LY294002, GF109203X) in short term (16hr) apoptosis assays. There was no significant reversal of resistance in the presence of these signal pathway inhibitors. The TRAIL selected cells had low Fas TRAIL-R1 and R2, FADD and caspase-8 proteins but normal levels of Bcl-2 anti-apoptotic and IAP proteins. Major differences between parental and TRAIL selected cells were low or absent p53 and low levels of pro-apoptotic Bid, Bim, PUMA and Bad. Levels of the activated form of PKC-δ (the pro-apoptotic isoform of PKC) were also barely detectable. These phenotypes appeared stable in that they were unchanged after 2 weeks in the absence of TRAIL. These results suggest that TRAIL induces apoptotic resistant cells by selection of cells with low receptor and DISC levels and cells with low or null p53 status that are unable to upregulate pro-apoptotic BH3 only sensor proteins. The basis for selection of p53 null cells by TRAIL is not clear. These findings support the hypothesis that TRAIL expression in vivo may be an important factor resulting in selection of melanoma cells that are resistant to apoptosis both to TRAIL and some forms of chemotherapy. We believe these studies will assist in identifying drugs that do not show cross-resistance to the agents in this study.
Deep Molecular Response in Imatinib First-Line 418 Newly Diagnosed CP CML Patients.
Authors: Franck Emmanuel Nicolini, Vincent Alcazer, Pascale Cony-Makhoul, Stephanie Dulucq, Sandrine Hayette, Isabelle Tigaud, Liliana Villa, Mohamad Sobh, Stephane Morisset, Francois-Xavier Mahon, Gabriel Etienne
Journal: Blood (2018)