tbuckley/cabot-search huggingface dataset:
Surgical stabilisation of the spine compared with a programme of intensive rehabilitation for the management of patients with chronic low back pain: cost utility analysis based on a randomised controlled trial
Authors: Oliver Rivero-Arias, Helen Campbell, Alastair Gray, Jeremy Fairbank, Helen Frost, James Wilson-MacDonald
Journal: BMJ (2005)

<h3>Abstract</h3> <h3>Introduction</h3> Caly, Druce (1) reported that ivermectin inhibited SARS-CoV-2 <i>in vitr</i>o for up to 48 h using ivermectin at 5μM. The concentration resulting in 50% inhibition (IC<sub>50,</sub> 2 µM) was &gt;35x higher than the maximum plasma concentration (Cmax) after oral administration of the approved dose of ivermectin when given fasted. <h3>Method</h3> Simulations were conducted using an available population pharmacokinetic model to predict total (bound and unbound) and unbound plasma concentration-time profiles after a single and repeat fasted administration of the approved dose of ivermectin (200 μg/kg), 60 mg, and 120 mg. Plasma total Cmax was determined and then multiplied by the lung:plasma ratio reported in cattle to predict the lung Cmax after administration of each single dose. <h3>Results</h3> Plasma ivermectin concentrations of total (bound and unbound) and unbound concentrations do not reach the IC<sub>50</sub>, even for a dose level 10x higher than the approved dose. Even with higher exposure in lungs than plasma, ivermectin is unlikely to reach the IC<sub>50</sub> in lungs after single oral administration of the approved dose (predicted lung: 0.0857 µM) or at doses 10x higher that the approved dose administered orally (predicted lung: 0.817 µM). <h3>Conclusions</h3> The likelihood of a successful clinical trial using the approved dose of ivermectin is low. Combination therapy should be evaluated <i>in vitro</i>. Re-purposing drugs for use in COVID-19 treatment is an ideal strategy but is only feasible when product safety has been established and experiments of re-purposed drugs are conducted at clinically relevant concentrations.
Social and racial disparities in the use of non-standard breast cancer adjuvant chemotherapy regimens
Authors: J. J. Griggs, E. Culakova, M. E. Sorbero, J. Crawford, D. C. Dale, D. A. Wolff, M. S. Poniewierski, G. H. Lyman
Journal: Journal of Clinical Oncology (2006)

6036 Background: Economically disadvantaged and black women have worse stage-specific breast cancer outcomes than other women, even after controlling for tumor histologic features. Disparities quality of chemotherapy may contribute to differences in outcome. The purpose of this study was to investigate the use of non-standard breast cancer adjuvant chemotherapy regimens in black women and those of lower socioeconomic status (SES). Methods: Detailed information on patient, disease, and treatment factors was collected prospectively on 1,006 patients receiving adjuvant chemotherapy for early-stage breast cancer in 115 oncology practices throughout the US. All patients signed informed consent. Regimens included in the guidelines of the National Comprehensive Cancer Network were considered standard regimens; all others were considered non-standard. Receipt of non-standard regimens was examined according to clinical and non-clinical factors. Differences between groups were assessed using a chi-square test. Multivariate logistic regression was used to identify factors associated with use of non-standard regimens. Results: Non-standard regimens were used in the treatment of 136 (14%) of the participants. Black patients were twice as likely to receive a non-standard regimen as whites (23% vs. 12%, p = .0014). Patients with less than a high school education were twice as likely to receive a non-standard regimen compared with those with a college education (21% vs. 8%, p = 0.0011). Other factors associated with non-standard chemotherapy regimens were past chemotherapy exposure (p &lt; .0001), higher stage disease (p &lt; .0001) and geographic location (p = 0.0059). Age, comorbidity, body mass index, type of insurance, and employment status were not associated with receipt of non-standard chemotherapy. In multivariate analysis, all variables that were significant in the bivariate analysis remained independently associated with receipt of non-standard chemotherapy. Conclusions: The more frequent use of non-guideline concordant adjuvant chemotherapy regimens in black women and women with lower SES may contribute to their less favorable outcomes. These findings offer an opportunity to improve patient care and perhaps cancer outcomes. [Table: see text]
Redistribution of substrates to adipose tissue promotes obesity in mice with selective insulin resistance in muscle
Authors: Jason K. Kim, M. Dodson Michael, Stephen F. Previs, Odile D. Peroni, Franck Mauvais-Jarvis, Susanne Neschen, Barbara B. Kahn, C. Ronald Kahn, Gerald I. Shulman
Journal: Journal of Clinical Investigation (2000)

Obesity and insulin resistance in skeletal muscle are two major factors in the pathogenesis of type 2 diabetes. Mice with muscle-specific inactivation of the insulin receptor gene (MIRKO) are normoglycemic but have increased fat mass. To identify the potential mechanism for this important association, we examined insulin action in specific tissues of MIRKO and control mice under hyperinsulinemic-euglycemic conditions. We found that insulin-stimulated muscle glucose transport and glycogen synthesis were decreased by about 80% in MIRKO mice, whereas insulin-stimulated fat glucose transport was increased threefold in MIRKO mice. These data demonstrate that selective insulin resistance in muscle promotes redistribution of substrates to adipose tissue thereby contributing to increased adiposity and development of the prediabetic syndrome.
Biomarkers in pulmonary hypertension
Authors: G. Warwick, P. S. Thomas, D. H. Yates
Journal: European Respiratory Journal (2008)

There have been significant recent advances in the understanding of the pathophysiology of pulmonary hypertension, and a growing number of therapeutic agents have become available to the treating physician. Traditional methods of diagnosing and monitoring this condition have comprised echocardiography and right heart catheterisation, in addition to functional measures, such as estimation of functional class and the 6-min walk test. An increasing number of biomarkers have been described that are elevated in pulmonary hypertension and which may assist the clinician in diagnosis and in the assessment of disease severity and response to treatment. The present article details the more important biomarkers, their potential applications and the evidence supporting their use.
Clinician’s Guide to Chronic Obstructive Pulmonary Disease
Authors: N.C. Thomson
Journal: European Respiratory Journal (2006)

Edited by T. Howes and D. Bellamy    Published by Hodder Arnold, 2005    Pages: 224. Price \#8364;.36.50. ISBN: 0340816953

Chronic obstructive pulmonary disease (COPD) has always been an important issue for specialist clinicians and patients with the disease. More recently, it has become of increased interest to nonspecialist clinicians, as well as the research community, pharmaceutical industry and …
Prevention of Human Diaphragm Atrophy with Short Periods of Electrical Stimulation
Authors: NAJIB T. AYAS, F. DENNIS McCOOL, ROBERT GORE, STEVEN L. LIEBERMAN, ROBERT BROWN
Journal: American Journal of Respiratory and Critical Care Medicine (1999)

We determined whether prolonged complete inactivation of the human diaphragm results in atrophy and whether this could be prevented by brief periods of electrical phrenic nerve stimulation. We studied a subject with high spinal cord injury who required removal of his left phrenic nerve pacemaker (PNP) and the reinstitution of positive-pressure ventilation for 8 mo. During this time, the right phrenic nerve was stimulated 30 min per day. Thickness of each diaphragm (tdi) was determined by ultrasonography. Maximal tidal volume (Vt) was measured during stimulation of each diaphragm separately. After left PNP reimplantation, Vt and tdi were measured just before the resumption of electrical stimulation and serially for 33 wk. On the previously nonfunctioning side, there were substantial changes in Vt (from 220 to 600 ml) and tdi (from 0.18 to 0.34 cm). On the side that had been stimulated, neither Vt nor tdi changed appreciably (Vt from 770 to 900 ml; tdi from 0.25 to 0.28 cm). We conclude that prolonged inactivation of the diaphragm causes atrophy which may be prevented by brief periods of daily phrenic nerve stimulation.
Hawkeye: an interactive visual analytics tool for genome assemblies
Authors: Michael C Schatz, Adam M Phillippy, Ben Shneiderman, Steven L Salzberg
Journal: Genome biology (2007)

Genome sequencing remains an inexact science, and genome sequences can contain significant errors if they are not carefully examined. Hawkeye is our new visual analytics tool for genome assemblies, designed to aid in identifying and correcting assembly errors. Users can analyze all levels of an assembly along with summary statistics and assembly metrics, and are guided by a ranking component towards likely mis-assemblies. Hawkeye is freely available and released as part of the open source AMOS project http://amos.sourceforge.net/hawkeye .
P87 Klebsiella Pneumoniae Survival On Plastic Valved Holding Chamber Bodies
Authors: M. Sanders, R. Bruin
Journal: Thorax (2014)

<h3>Introduction and objectives</h3> <i>Klebsiella pneumoniae</i> (KPN) is an opportunistic pathogen for patients with chronic pulmonary disease. In-use single time-point sampling of valved holding chamber spacer (VHC) bodies has shown evidence (Cohen and Cohen, JAMA 2003, 290:195–196) of bacterial contamination particularly with <i>Pseudomonas</i> species and <i>Klebsiella</i>. We are not aware of multi time-point bacterial survival research and, accordingly, have assessed <i>in vitro</i> two plastic VHC body materials which are in common use in the UK. <h3>Methods</h3> Test pieces, in n = 5 sub-group samples (Samples), of polystyrene (sterile Control) and of VHC bodies of AeroChamber Plus, Trudell Medical International (ACP) and A2A Spacer, Clement Clarke International Ltd. (A2A) were equilibrated for 24 h at 20°C/65% relative humidity (RH). Samples were inoculated with 100 muL distilled-water aliquots of KPN 3.6 × 10<sup>6</sup> cells.mL<sup>-1</sup> and incubated at 20°C in 65% RH chambers. KPN surface survival was measured at 0, 24, 48 and 72 h time-points using a method based on ISO Standard 22196:2007 (Askew, Efficacy Assessment of Treated Articles: A Guidance, February 2014 http://dx.doi.org/10.6027/NA2014–904) and total viable count enumerated. 72 h data (Log<sub>10</sub> Colony Forming Units (CFU).cm<sup>-2</sup>) were analysed using one-way analysis of variance. <h3>Results</h3> Geometric mean CFU.cm<sup>-2</sup> data are given in the table. Control and ACP KPN populations declined to the 48 h time-point, thereafter increasing (Control) and remaining constant (ACP). A2A KPN population showed a constant decline, with no re-growth. At 72 h, Log<sub>10</sub> CFU KPN data for A2A were significantly smaller (p &lt; 0.05) compared to ACP (-0.47 difference, 95% CI -0.81 to -0.13) and to Control (0.74 difference, 95% CI 0.41 to 1.08). <h3>Conclusions</h3> We interpret the 72 h increase in Control KPN as the outcome of the initial decline creating dead cell matter that acted as a nutrient source. The stability (ACP) and significant decline (A2A) in KPN is therefore an interesting finding. We subscribe the latter to the presence of an antimicrobial additive in the body polymer material. The clinical implications of these findings are relevant to VHC hygiene and patient health, and require further investigation.
Systemic Retinoic Acid Treatment Induces Sodium/Iodide Symporter Expression and Radioiodide Uptake in Mouse Breast Cancer Models
Authors: Takahiko Kogai, Yoko Kanamoto, Lisa H. Che, Katsumi Taki, Farhad Moatamed, James J. Schultz, Gregory A. Brent
Journal: Cancer Research (2004)

Abstract Lactating breast tissue and some breast cancers express the sodium/iodide symporter (NIS) and concentrate iodide. We recently demonstrated that all-trans retinoic acid (tRA) induces both NIS gene expression and iodide accumulation in vitro in well-differentiated human breast cancer cells (MCF-7). In the present study, we investigated the in vivo efficacy and specificity of tRA-stimulated iodide accumulation in mouse breast cancer models. Immunodeficient mice with MCF-7 xenograft tumors were treated with systemic tRA for 5 days. Iodide accumulation in the xenograft tumors was markedly increased, ∼15-fold greater than levels without treatment, and the effects were tRA dose dependent. Iodide accumulation in other organs was not significantly influenced by tRA treatment. Significant induction of NIS mRNA and protein in the xenograft tumors was observed after tRA treatment. Iodide accumulation and NIS mRNA expression were also selectively induced in breast cancer tissues in transgenic mice expressing the oncogene, polyoma virus middle T antigen. These data demonstrate selective induction of functional NIS in breast cancer by tRA. Treatment with short-term systemic retinoic acid, followed by radioiodide administration, is a potential tool in the diagnosis and treatment of some differentiated breast cancer.
The extraordinary tale of Dartford, the hospital town
Authors: Nick Black
Journal: Journal of the Royal Society of Medicine (2009)

Between 1877 and 1903 something extraordinary in the history of health services happened in a small north Kent town. The number of hospital beds in Dartford increased a staggering 60-fold to reach almost 10,000, this in a local population of just over 20,000. The earlier history of the town offers no clues as to why this happened. Tracing the developments of the 11 hospitals over the 26-year period reveals the role of three powerful bodies establishing facilities to meet the needs of Londoners: the City of London Corporation, the Metropolitan Asylums Board and London County Council. It is also apparent that there was no careful strategic plan but a series of opportunistic and pragmatic decisions, facilitated by the lack of any effective local opposition as occurred within London. The staggering increase in hospital beds in Dartford in the late 19th century is just an exceptional example of the way health services so often develop.
Intermittent High-Dose Intravenous Interferon Alfa-2b for Adjuvant Treatment of Stage III Melanoma: Final Analysis of a Randomized Phase III Dermatologic Cooperative Oncology Group Trial
Authors: Peter Mohr, Axel Hauschild, Uwe Trefzer, Alexander Enk, Wolfgang Tilgen, Carmen Loquai, Helen Gogas, Thomas Haalck, Josef Koller, Reinhard Dummer, Ralf Gutzmer, Norbert Brockmeyer, Erhard Hölzle, Cord Sunderkötter, Cornelia Mauch, Annette Stein, Lars A. Schneider, Maurizio Podda, Daniela Göppner, Dirk Schadendorf, Michael Weichenthal
Journal: Journal of Clinical Oncology (2015)

To evaluate the efficacy, safety, tolerability, and quality of life (QoL) in patients receiving intravenous, intermittent high-dose interferon alfa-2b (IFN-α-2b [iHDI]) compared with standard high-dose IFN-α-2b (HDI).Patients with stage III resected lymph node or in-transit metastasis from cutaneous malignant melanoma were randomly assigned to receive either a standard HDI regimen or three courses of IFN-α-2b 20 MIU/m(2) administered intravenously 5 days a week for 4 weeks then repeated every 4 months. Distant metastasis-free survival was the primary end point for efficacy analysis. In addition, relapse-free survival, overall survival, safety as determined by Common Terminology Criteria for Adverse Events criteria, and QoL were secondary end points.Of 649 patients enrolled, 22 patients were excluded from the intent-to-treat analysis. The remaining 627 patients were well balanced between the arms according to sex, age, and stage. After a median follow-up of 55 months, a multivariable Cox model revealed no significant differences for distant metastasis-free survival (hazard ratio [HR], 1.21; P = .12) or overall survival (HR, 1.01; P = .85). In contrast, the difference for relapse-free survival was significant (HR, 1.27; P = .03), favoring standard HDI. Early termination of treatment because of adverse events or QoL occurred significantly more often with HDI than with iHDI (26.0% v 14.8%; P < .001).Although the safety and QoL profiles for the intermittent regimen were favorable, no significant difference was observed for survival while the HR for relapse with iHDI was increased. Therefore, an iHDI regimen, as tested here, cannot be recommended as adjuvant treatment for high-risk melanoma.
Immunohistochemical Double-Hit Score Is a Strong Predictor of Outcome in Patients With Diffuse Large B-Cell Lymphoma Treated With Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone
Authors: Tina Marie Green, Ken H. Young, Carlo Visco, Zijun Y. Xu-Monette, Attilio Orazi, Ronald S. Go, Ole Nielsen, Ole V. Gadeberg, Torben Mourits-Andersen, Mikael Frederiksen, Lars Møller Pedersen, Michael Boe Møller
Journal: Journal of Clinical Oncology (2012)

Approximately 5% of diffuse large B-cell lymphomas (DLBCLs) are double-hit lymphomas (DHLs) with translocations of both MYC and BCL2. DHLs are characterized by poor outcome. We tested whether DLBCLs with high expression of MYC protein and BCL2 protein share the clinical features and poor prognosis of DHLs.Paraffin-embedded lymphoma samples from 193 patients with de novo DLBCL who were uniformly treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) were studied using immunohistochemistry for MYC, BCL2, CD10, BCL6, and MUM1/interferon regulatory factor 4, and fluorescent in situ hybridization (FISH) for MYC and BCL2.FISH analysis identified DHL in 6% of patients, who showed the expected poor overall survival (OS; P = .002). On the basis of immunohistochemical MYC and BCL2 expression, a double-hit score (DHS) was assigned to all patients with DLBCL. The DHS-2 group, defined by high expression of both MYC and BCL2 protein, comprised 29% of the patients. DHS 2 was significantly associated with lower complete response rate (P = .004), shorter OS (P < .001), and shorter progression-free survival (PFS; P < .001). The highly significant correlation with OS and PFS was maintained in multivariate models that controlled for the International Prognostic Index and the cell-of-origin subtype (OS, P < .001; PFS, P < .001). DHS was validated in an independent cohort of 116 patients who were treated with R-CHOP.The immunohistochemical DHS defined a large subset of DLBCLs with double-hit biology and was strongly associated with poor outcome in patients treated with R-CHOP.
Mechanism-Based Concepts of Size and Maturity in Pharmacokinetics
Authors: B.J. Anderson, N.H.G. Holford
Journal: The Annual Review of Pharmacology and Toxicology (2007)

Growth and development can be investigated using readily observable demographic factors such as weight and age. Size is the primary covariate and can be referenced to a 70-kg person with allometry using a coefficient of 0.75 for clearance and 1 for volume. The use of these coefficients is supported by fractal geometric concepts and observations from diverse areas in biology. Fat free mass (FFM) might be expected to do better than total body weight when there are wide variations in fat affecting body composition. Clearance pathways develop in the fetus before birth. The use of postnatal age as a descriptor of maturation is unsatisfactory because birth may occur prematurely; therefore postmenstrual age is a superior predictor of elimination function. A sigmoid E max model (Hill equation) describes gradual maturation of clearance in early life leading to a mature adult clearance achieved at a later age.
Training of junior doctors into pleural procedures - The impact of a new pleural service
Authors: Nicola-Xan Hutchinson, Candy Lee, Jacqueline Gardner, Isobel Mitchell, Laurence Gray, Alina Ionescu
Journal: European Respiratory Journal (2012)

The British Thoracic Society and Royal College of Radiologists have set up guidelines for pleural services (PS). Specialist registrars (SpR) in Wales rotate every 12-18 months.  Aims: To evaluate 1.PS across Welsh Hospitals; 2. the impact of a PS on the training into pleural procedures.  Methods: 1. A questionnaire was sent to all 16 hospitals where SpRs train in Wales; 2. Pleural procedures, supervision, use of pleural ultrasound (US), timing of the procedure from admission to hospital were compared for a year prior to and following the setting up of a PS in a large hospital (630,000 - 21% population of Wales).  Results: 61.5% had one respiratory Consultant trained at level 1 pleural US, 46.2% had US in clinic. 76.9% had practical training. A PS reduced the waiting time from admission to pleural aspiration (PA) and intercostal chest drain (ICD) insertion; mean (range) 2.9 (0-12) and 4.5 (0-15) days before the PS to within 24 and 48 hours respectively. Prior to the PS respiratory trainees (all grades) performed a mean of 5 pleural procedures (4 ICDs) per month, none Consultant supervised. After the PS started SpRs performed a mean of 4.6 PA - in-patients, 3.9 - out-patients and 4.5 ICDs per month. 50% of PA and 30.2% of ICDs were Consultant supervised, all done under US guidance after PS was set up, none before). pH was done on 20% of samples and 26.6% had no cytology on initial sample; after PS cytology was performed on 100% of samples sent and pH on 90%.  In conclusion, the provision of PS and training varies across hospitals in Wales. The opening of a PS reduced waiting times and improved the analysis of the samples. The referrals to PS, number of procedures, use of US and supervision increased.
<i>O</i> -Linked GlcNAc Modification of Cardiac Myofilament Proteins
Authors: Genaro A. Ramirez-Correa, Wenhai Jin, Zihao Wang, Xin Zhong, Wei Dong Gao, Wagner B. Dias, Cecilia Vecoli, Gerald W. Hart, Anne M. Murphy
Journal: Circulation Research (2008)

In addition to O-phosphorylation, O-linked modifications of serine and threonine by beta-N-acetyl-D-glucosamine (GlcNAc) may regulate muscle contractile function. This study assessed the potential role of O-GlcNAcylation in cardiac muscle contractile activation. To identify specific sites of O-GlcNAcylation in cardiac myofilament proteins, a recently developed methodology based on GalNAz-biotin labeling followed by dithiothreitol replacement and light chromatography/tandem mass spectrometry site mapping was adopted. Thirty-two O-GlcNAcylated peptides from cardiac myofilaments were identified on cardiac myosin heavy chain, actin, myosin light chains, and troponin I. To assess the potential physiological role of the GlcNAc, force-[Ca(2+)] relationships were studied in skinned rat trabeculae. Exposure to GlcNAc significantly decreased calcium sensitivity (pCa50), whereas maximal force (F(max)) and Hill coefficient (n) were not modified. Using a pan-specific O-GlcNAc antibody, it was determined that acute exposure of myofilaments to GlcNAc induced a significant increase in actin O-GlcNAcylation. This study provides the first identification of O-GlcNAcylation sites in cardiac myofilament proteins and demonstrates their potential role in regulating myocardial contractile function.