Image Navigation and Registration (INR) Performance Assessment Tool Set (IPATS) for the GOES-R Advanced Baseline Imager and Geostationary Lightning Mapper

NASA Technical Reports Server (NTRS)

DeLuccia, Frank J.; Houchin, Scott; Porter, Brian C.; Graybill, Justin; Haas, Evan; Johnson, Patrick D.; Isaacson, Peter J.; Reth, Alan D.

2016-01-01

The GOES-R Flight Project has developed an Image Navigation and Registration (INR) Performance Assessment Tool Set (IPATS) for measuring Advanced Baseline Imager (ABI) and Geostationary Lightning Mapper (GLM) INR performance metrics in the post-launch period for performance evaluation and long term monitoring. For ABI, these metrics are the 3-sigma errors in navigation (NAV), channel-to-channel registration (CCR), frame-to-frame registration (FFR), swath-to-swath registration (SSR), and within frame registration (WIFR) for the Level 1B image products. For GLM, the single metric of interest is the 3-sigma error in the navigation of background images (GLM NAV) used by the system to navigate lightning strikes. 3-sigma errors are estimates of the 99.73rd percentile of the errors accumulated over a 24 hour data collection period. IPATS utilizes a modular algorithmic design to allow user selection of data processing sequences optimized for generation of each INR metric. This novel modular approach minimizes duplication of common processing elements, thereby maximizing code efficiency and speed. Fast processing is essential given the large number of sub-image registrations required to generate INR metrics for the many images produced over a 24 hour evaluation period. Another aspect of the IPATS design that vastly reduces execution time is the off-line propagation of Landsat based truth images to the fixed grid coordinates system for each of the three GOES-R satellite locations, operational East and West and initial checkout locations. This paper describes the algorithmic design and implementation of IPATS and provides preliminary test results.

Cost effectiveness of targeted HIV prevention interventions for female sex workers in India.

PubMed

Prinja, Shankar; Bahuguna, Pankaj; Rudra, Shalini; Gupta, Indrani; Kaur, Manmeet; Mehendale, S M; Chatterjee, Susmita; Panda, Samiran; Kumar, Rajesh

2011-06-01

To ascertain the cost effectiveness of targeted interventions for female sex workers (FSW) under the National AIDS Control Programme in India. A compartmental mathematical Markov state model was used over a 20-year time horizon (1995-2015) to estimate the cost effectiveness of FSW targeted interventions, with a health system perspective. The incremental costs and effects of FSW targeted interventions were compared against a baseline scenario of mass media for the general population alone. The incremental cost-effectiveness ratio was computed at a 3% discount rate using HIV infections averted and disability-adjusted life-years (DALY) as benefit measures. It was assumed that the transmission of the HIV virus moves from a high-risk group (FSW) to the client population and finally to the general population (partners of clients). Targeted interventions for FSW result in a reduction of 47% (1.6 million) prevalent and 36% (2.7 million) cumulative HIV cases, respectively, in 2015. Adult HIV prevalence in India, with and without (mass media only) FSW interventions, would be 0.25% and 0.48% in 2015. Indian government and development partners spend an average US $104 (INR4680) per HIV infection averted and US $10.7 (INR483) per DALY averted. Discounting at 3%, FSW targeted interventions cost US $105.5 (INR4748) and US $10.9 (INR490) per HIV case and DALY averted, respectively. At the current gross domestic product in India, targeted intervention is a cost-effective strategy for HIV prevention in India.

Validation of the Individualized Numeric Rating Scale (INRS): a pain assessment tool for nonverbal children with intellectual disability.

PubMed

Solodiuk, Jean C; Scott-Sutherland, Jennifer; Meyers, Margie; Myette, Beth; Shusterman, Christine; Karian, Victoria E; Harris, Sion Kim; Curley, Martha A Q

2010-08-01

Clinical observations suggest that nonverbal children with severe intellectual disability exhibit pain in a wide variety yet uniquely individual ways. Here, we investigate the feasibility and describe the initial psychometrics properties of the Individualized Numeric Rating Scale (INRS), a personalized pain assessment tool for nonverbal children with intellectual disability based on the parent's knowledge of the child. Parents of 50 nonverbal children with severe intellectual disability scheduled for surgery were able to complete the task of describing then rank ordering their child's usual and pain indicators. The parent, bedside nurse and research assistant (RA) triad then simultaneously yet independently scored the patient's post-operative pain using the INRS for a maximum of two sets of pre/post paired observations. A total of 170 triad assessments were completed before (n=85) and after (n=85) an intervention to manage the child's pain. INRS inter-rater agreement between the parents and research nurse was high (ICC 0.82-0.87) across all ratings. Parent and bedside nurse agreement (ICC 0.65-0.74) and bedside nurse and research nurse agreement (ICC 0.74-0.80) also suggest good reliability. A moderate to strong correlation (0.63-0.73) between INRS ratings and NCCPC-PV total scores provides evidence of convergent validity. These results provide preliminary data that the INRS is a valid and reliable tool for assessing pain in nonverbal children with severe intellectual disability in an acute care setting. Copyright (c) 2010 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

The economic costs of routine INR monitoring in infants and children--examining point-of-care devices used within the home setting compared to traditional anticoagulation clinic monitoring.

PubMed

Gaw, James R; Crowley, Steven; Monagle, Paul; Jones, Sophie; Newall, Fiona

2013-07-01

The use of point-of-care (POC) devices within the home for routine INR monitoring has demonstrated reliability, safety and effectiveness in the management of infants and children requiring long-term warfarin therapy. However, a comprehensive cost-analysis of using this method of management, compared to attending anticoagulation clinics has not been reported. The aim of this study was to compare the estimated societal costs of attending anticoagulation clinics for routine INR monitoring to using a POC test in the home. This study used a comparative before-and-after design that included 60 infants and children managed via the Haematology department at a tertiary paediatric centre. Each participant was exposed to both modes of management at various times for a period of ≥3 months. A questionnaire, consisting of 25 questions was sent to families to complete and return. Data collected included: the frequency of monitoring, mode of travel to and from clinics, total time consumed, and primary carer's income level. The home monitoring cohort saved a total of 1 hour 19 minutes per INR test compared to attending anticoagulation clinics and had a cost saving to society of $66.83 (AUD) per INR test compared to traditional care; incorporating health sector costs, travel expenses and lost time. The traditional model of care requires a considerable investment of time per test from both child and carer. Home INR monitoring in infants and children provides greater societal economic benefits compared to traditional models. Copyright © 2013 Elsevier Ltd. All rights reserved.

Guidelines for certification of International Normalized Ratio (INR) for vitamin K antagonists monitoring according to the EN ISO 22870 standards.

PubMed

Brionne-François, Marie; Bauters, Anne; Mouton, Christine; Voisin, Sophie; Flaujac, Claire; Le Querrec, Agnès; Lasne, Dominique

2018-06-01

Point of care testing (POCT) must comply with regulatory requirements according to standard EN ISO 22870, which identify biologists as responsible for POCT. INR for vitamin K antagonists (VKAs) monitoring is a test frequently performed in haemostasis laboratories. Bedside INR is useful in emergency room, in particular in case of VKAs overdosage but also for specific populations of patients like paediatrics or geriatrics. INR POCT devices are widely used at home by the patients for self-testing, but their use in the hospital by the clinical staff for bedside measurement is growing, with devices which now comply with standard for POCT accreditation for hospital use. The majority of point of care devices for INR monitoring has shown a good precision and accuracy with results similar to those obtained in laboratory. With the aim to help the multidisciplinary groups for POCT supervision, the medical departments and the biologists to be in accordance with the standard, we present the guidelines of the GFHT (Groupe français d'étude sur l'hémostase et la thrombose, subcommittee "CEC et biologie délocalisée") for the certification of POCT INR. These guidelines are based on the SFBC guidelines for the certification of POCT and on the analysis of the literature to ascertain the justification of clinical need and assess the analytical performance of main analysers used in France, as well as on a survey conducted with biologists.

Bleeding complications and mortality in warfarin-treated VTE patients, dependence of INR variability and iTTR.

PubMed

Sandén, Per; Renlund, Henrik; Svensson, Peter J; Själander, Anders

2017-01-05

High quality of warfarin treatment is important to prevent recurrence of venous thromboembolism (VTE) without bleeding complications. The aim of this study was to examine the effect of individual time in therapeutic range (iTTR) and International Normalised Ratio (INR) variability on bleeding risk and mortality in a large cohort of well-managed patients with warfarin due to VTE. A cohort of 16612 patients corresponding to 19502 treatment periods with warfarin due to VTE between January 1, 2006 and December 31, 2011 was retrieved from the Swedish national quality register AuriculA and matched with the Swedish National Patient Register for bleeding complications and background characteristics and the Cause of death register for occurrence and date of death. The rate of bleeding was 1.79 (confidence interval (CI) 95 % 1.66-1.93) per 100 treatment years among all patients. Those with poor warfarin treatment quality had a higher rate of clinically relevant bleeding, both when measured as iTTR below 70 %, 2.91 (CI 95 % 2.61-3.21) or as INR variability over the mean value 0.85, 2.61 (CI 95 % 2.36-2.86). Among those with both high INR variability and low iTTR the risk of clinically relevant bleeding was clearly increased hazard ratio (HR) 3.47 (CI 95 % 2.89-4.17). A similar result was found for all-cause mortality with a HR of 3.67 (CI 95 % 3.02-4.47). Both a low iTTR and a high INR variability increase the risk of bleeding complications or mortality. When combining the two treatment quality indicators patients at particular high risk of bleeding or death can be identified.

POCT PT INR - Is it adequate for patient care? A comparison of the Roche Coaguchek XS vs. Stago Star vs. Siemens BCS in patients routinely seen in an anticoagulation clinic.

PubMed

Baker, Wendy S; Albright, Kathleen J; Berman, Megan; Spratt, Heidi; Mann, Peggy A; Unabia, Jaime; Petersen, John R

2017-09-01

In this study we examined the difference in patient INR values as measured by the POCT CoaguChek XS device and central laboratory Stago Evolution and Siemens BCS XP analyzers. This study composed of 100 warfarin therapy patients and 20 coagulation normal subjects, showed that the difference between the POCT and clinical laboratory values increased with increasing INR and was exacerbated by the use of different thromboplastin reagents by the POCT and central lab. The CoaguChek XS and on-site Stago analyzers which used human recombinant (ISI=1.01) and rabbit brain thromboplastin (ISI=1.25), respectively, showed reasonable agreement for INR<3.0 (k=0.62) but significant difference for INR≥3.0 (k=0.10). In contrast, the CoaguChek XS and Siemens BCS XP, which both employed human recombinant thromboplastin (BCS ISI=1.02), showed greater agreement for the complete range INR values (INR<3.0 k=0.84; INR≥3.0 k=0.70). ECAA Poller calibrant data showed the automated instruments were performing as expected, indicating that ISI calibrations were correct but insufficient to standardize the INR values for the different thromboplastin methods across the full range of measured INRs. Central lab verification of POCT INR>5.0 with the Stago Evolution prevented adverse treatment events for the warfarin therapy patients in the six months preceding and following this investigation. Copyright © 2017 Elsevier B.V. All rights reserved.

Failure mode and effects analysis to reduce risk of anticoagulation levels above the target range during concurrent antimicrobial therapy.

PubMed

Daniels, Lisa M; Barreto, Jason N; Kuth, John C; Anderson, Jeremy R; Zhang, Beilei; Majka, Andrew J; Morgenthaler, Timothy I; Tosh, Pritish K

2015-07-15

A failure mode and effects analysis (FMEA) was conducted to analyze the clinical and operational processes leading to above-target International Normalized Ratios (INRs) in warfarin-treated patients receiving concurrent antimicrobial therapy. The INRs of patients on long-term warfarin therapy who received a course of trimethoprim-sulfamethoxazole, metronidazole, fluconazole, miconazole, or voriconazole (highly potentiating antimicrobials, or HPAs) between September 1 and December 31, 2011, were compared with patients on long-term warfarin therapy who did not receive any antimicrobial during the same period. A multidisciplinary team of physicians, pharmacists, and a systems analyst was then formed to complete a step-by-step outline of the processes involved in warfarin management and concomitant HPA therapy, followed by an FMEA. Patients taking trimethoprim-sulfamethoxazole, metronidazole, or fluconazole demonstrated a significantly increased risk of having an INR of >4.5. The FMEA identified 134 failure modes. The most common failure modes were as follows: (1) electronic medical records did not identify all patients receiving warfarin, (2) HPA prescribers were unaware of recommended warfarin therapy when HPAs were prescribed, (3) HPA prescribers were unaware that a patient was taking warfarin and that the drug interaction is significant, and (4) warfarin managers were unaware that an HPA had been prescribed for a patient. An FMEA determined that the risk of adverse events caused by concomitantly administering warfarin and HPAs can be decreased by preemptively identifying patients receiving warfarin, having a care process in place, alerting providers about the patient's risk status, and notifying providers at the anticoagulation clinic. Copyright © 2015 by the American Society of Health-System Pharmacists, Inc. All rights reserved.

Exposure to Non-Therapeutic INR in a High Risk Cardiovascular Patient: Potential Hazard Reduction with Genotype-guided Warfarin (Coumadin®) Dosing

PubMed Central

Rodríguez-Vélez, Rosángela; Ortiz-Rivera, Oscar J.; Bower, Bruce; Gorowski, Krystyna; Windemuth, Andreas; Villagra, David; Kocherla, Mohan; Seip, Richard L; D'Agostino, Darrin; Vergara, Cunegundo; Ruaño, Gualberto; Duconge, Jorge

2013-01-01

A case to illustrate the utility of genetic screening in warfarin (Coumadin®) management is reported. A 45 year-old woman of Puerto Rican ancestry was admitted to the emergency room twice within one month with chest pain. She was diagnosed with congestive heart failure, which was stabilized both times. At her second release, warfarin therapy was initiated at 5 mg/day to prevent thrombus formation and was lowered to 3.75 mg/day at day 7 by her primary physician. International Normalized Ratio (INR) test results in the follow-up period at days 1, 7, and 10 of warfarin therapy were 4.5, 6.5, and 7.3, respectively—far in excess of the therapeutic range, despite the lower dosage in effect from day 7 onward. the patient achieved target INR over the next 43 days after downward adjustment of the dose to a dose of 1.5 mg/day by trial and error. DNA-typing specific for the CYP2C9*2, *3, *4, *5, *6 alleles and seven variants in the VKORC1 gene, including the VKORC1-1639 G>A polymorphism, revealed the presence of combinatorial CYP2C9*2/*3 and VKORC1-1639 G/A genotypes in this patient. Entering the patient's demographic and genotype status data into independent algorithms available in the public domain to predict effective warfarin dose yielded predicted doses which ranged from 1.5 to 1.8 mg/day. Notably, the prediction of 1.5 mg/day, which was generated by the online resource www.warfarindosing.org, coincided with the patient's actual effective warfarin dose. We conclude that the rapid rise in INR observed upon the initiation of warfarin therapy and the final effective warfarin dose of 1.5 mg/day, are attributable in some part to the presence of two minor alleles in CYP2C9, which together significantly reduce warfarin metabolism. Warfarin genotyping can therefore inform the clinician of the predicted effective warfarin dose. the results highlight the potential for warfarin genetic testing to improve patient care. PMID:21261182

Measuring Image Navigation and Registration Performance at the 3-Sigma Level Using Platinum Quality Landmarks

NASA Technical Reports Server (NTRS)

Carr, James L.; Madani, Houria

2007-01-01

Geostationary Operational Environmental Satellite (GOES) Image Navigation and Registration (INR) performance is specified at the 3- level, meaning that 99.7% of a collection of individual measurements must comply with specification thresholds. Landmarks are measured by the Replacement Product Monitor (RPM), part of the operational GOES ground system, to assess INR performance and to close the INR loop. The RPM automatically discriminates between valid and invalid measurements enabling it to run without human supervision. In general, this screening is reliable, but a small population of invalid measurements will be falsely identified as valid. Even a small population of invalid measurements can create problems when assessing performance at the 3-sigma level. This paper describes an additional layer of quality control whereby landmarks of the highest quality ("platinum") are identified by their self-consistency. The platinum screening criteria are not simple statistical outlier tests against sigma values in populations of INR errors. In-orbit INR performance metrics for GOES-12 and GOES-13 are presented using the platinum landmark methodology.

A Pilot Study to Evaluate Effectiveness of INR Self-Testing in Elderly Patients.

PubMed

Pogge, Elizabeth

2015-12-01

To determine if international normalized ratio (INR) patient self-testing (PST) resulted in an increased time in therapeutic range (TTR) in an elderly population when compared with clinic testing over a six-month period. A pilot study and retrospective chart review from August 2010 to August 2014. Ambulatory, anticoagulation clinic with two locations in Sun City West and Peoria, Arizona. Of 91 patients, the data of 20 patients who were 65 years of age or older and had at least six months of pre- and post-PST INR data were extracted and analyzed. The primary outcome evaluated improvement of TTR during post-PST in elderly patients compared with clinic management over a six-month period. Secondary outcomes assessed patients' satisfaction with PST and identified barriers to PST. The post-PST mean TTR significantly increased to 73% from 63.6% for the first six months of PST (P = 0.04). Participants were satisfied with PST, with an average score ranging from 4.6 to 5 on a Likert scale of 1 to 5 on 10 satisfaction survey questions. Cost was identified as the most common barrier to PST, with 43% of patients not participating in PST because of financial burden. With appropriate screening and training, PST is associated with improved TTRs and higher patient satisfaction in elderly patients when compared with clinic testing. Barriers identified to PST include cost, the complex process, and noncompliance.

Non-vitamin K antagonist oral anticoagulants compared with warfarin at different levels of INR control in atrial fibrillation: A meta-analysis of randomized trials.

PubMed

Carmo, João; Ferreira, Jorge; Costa, Francisco; Carmo, Pedro; Cavaco, Diogo; Carvalho, Salomé; Morgado, Francisco; Adragão, Pedro; Mendes, Miguel

2017-10-01

The efficacy and safety of warfarin for stroke prevention in atrial fibrillation (AF) depend on the time in the therapeutic range (TTR) with an international normalised ratio (INR) of 2.0-3.0. This meta-analysis focused the relative efficacy and safety of non-VKA oral anticoagulants (NOAC) compared with warfarin at different thresholds of centre's TTR (cTTR). We searched PubMed, Embase, CENTRAL and websites of regulatory agencies, limiting searches to randomized phase 3 trials. Primary outcomes were stroke or systemic embolism (SSE) and major or non-major clinically relevant (NMCR) bleeding. We used a random-effects model to pool effect on outcomes according to different thresholds of cTTR. Four TTR sub-studies with a total of 71,222 patients were included. The benefit of NOAC in reducing SSE compared with warfarin was significantly higher in patients at cTTR<60% (HR 0.79, 95% CI 0.68-0.90) and at 60% to <70% (0.82, 0.71-0.95) but not at ≥70% (1.00, 0.82-1.23) with a significant interaction for cTTR<70% or ≥70% (p=0.042). The risk of major or NMCR bleeding was significantly lower with NOAC as compared with warfarin in patients at all sub-groups (0.67, 0.54-0.83 for patients at cTTR<60% and 0.75, 0.63-0.89 at 60% to <70%) except for cTTR≥70% (HR 0.84, 0.64-1.11), but the interaction for cTTR<70% or ≥70% was not statistically significant (p=0.271). The superiority in efficacy of NOAC compared with warfarin for stroke prevention is lost above a cTTR threshold of approximately 70%, but the relative safety appears to be less modified by the centre-based quality of INR control. Copyright © 2017 Elsevier B.V. All rights reserved.

Practicability of patient self-testing of oral anticoagulant therapy by the international normalized ratio (INR) using a portable whole blood monitor. A pilot investigation.

PubMed

Hasenkam, J M; Knudsen, L; Kimose, H H; Grønnesby, H; Attermann, J; Andersen, N T; Pilegaard, H K

1997-01-01

The prophylactic efficacy of long-term oral anticoagulant treatment (OAT) has been demonstrated in a number of clinical conditions with increased tendency to thromboembolism, and the number of individuals subjected to OAT in the industrialised world has increased substantially in recent years. Since this therapy requires considerable resources from both the health care system and the patients, the feasibility of patients' self-monitoring and self-management of OAT has been investigated (1,2,3). The anticipated advantages of this approach include improved convenience and compliance for the patient, who may increase his apprehension for managing the treatment. In addition, self-testing allows for more frequent control compared to the conventional out-patient approach. Importantly, a prerequisite for conceiving a safe and operational concept for patient self-management (PSM) is the availability of a portable INR monitoring system with an accuracy, precision, reproducibility, and long-term reliability comparable to standard coagulometric equipment. The purpose of the present study was to evaluate the feasibility of a commercially available INR-monitor. CoaguChek, for patient self-testing, through a step-wise investigation of the performance characteristics of the equipment in the laboratory, in command of the patient, and during self-testing and self-adjustment of treatment at home. Laboratory INR values were used as reference.

Thermal Neutron Tomography for Cultural Heritage at INR

NASA Astrophysics Data System (ADS)

Dinca, Marin; Mandescu, Dragos

The neutron and gamma imaging facility placed at the tangential channel of the TRIGA-ACPR from INR was used for tomography investigations on a test object with good results and shortly followed its involvement for tomography investigations on prehistoric statues of clay from the Arges County Museum. This activity was performed in connection with a research contract with IAEA with title ;The neutron and gamma imaging method combined with neutron-based analytical methods for cultural heritage research;, in the frame of a current CRP, that helps curators to reveal the internal structure and composition of the objects. The detector system has been developed based on two interchangeable scintillators, one for thermal neutrons and the other one for gamma radiations, a mirror of float glass coated with aluminum and two interchangeable CCD cameras. Experiments of tomography imaging for two prehistoric statues of clay with CCD STARLIGHT XPRESS SXV-H9 camera with XD-4 type image intensifier are presented in this paper. The tomography reconstructions with Octopus software have shown the potential of good results even for 100 projections/1800. This was a good opportunity for the dissemination of the investigation methods based on neutrons for cultural heritage and beyond this area.

Venom Concentrations and Clotting Factor Levels in a Prospective Cohort of Russell's Viper Bites with Coagulopathy.

PubMed

Isbister, Geoffrey K; Maduwage, Kalana; Scorgie, Fiona E; Shahmy, Seyed; Mohamed, Fahim; Abeysinghe, Chandana; Karunathilake, Harendra; O'Leary, Margaret A; Gnanathasan, Christeine A; Lincz, Lisa F

2015-01-01

Russell's viper envenoming is a major problem in South Asia and causes venom induced consumption coagulopathy. This study aimed to investigate the kinetics and dynamics of venom and clotting function in Russell's viper envenoming. In a prospective cohort of 146 patients with Russell's viper envenoming, we measured venom concentrations, international normalised ratio [INR], prothrombin time (PT), activated partial thromboplastin time (aPTT), coagulation factors I, II, V, VII, VIII, IX and X, and von Willebrand factor antigen. The median age was 39 y (16-82 y) and 111 were male. The median peak INR was 6.8 (interquartile range [IQR]: 3.7 to >13), associated with low fibrinogen [median,<0.01 g/L; IQR: <0.01-0.9 g/L), low factor V levels [median,<5%; IQR: <5-4%], low factor VIII levels [median,40%; IQR: 12-79%] and low factor X levels [median, 48%; IQR: 29-67%]. There were smaller reductions in factors II, IX and VII over time. All factors recovered over 48 h post-antivenom. The median INR remained >3 at 6 h post-antivenom but had reduced to <2, by 24 h. The aPTT had also returned to close to normal (<50 sec) at 24 h. Factor VII, VIII and IX levels were unusually high pre-antivenom, median peak concentrations of 393%, 307% and 468% respectively. Pre-antivenom venom concentrations and the INR (r = 0.20, p = 0.02) and aPTT (r = 0.19, p = 0.03) were correlated (non-parametric Spearman analysis). Russell's viper coagulopathy results in prolonged aPTT, INR, low fibrinogen, factors V, VIII and X which recover over 48 h. Severity of clotting abnormalities was associated with venom concentrations.

A randomized trial comparing INR monitoring devices in patients with anticoagulation self-management: evaluation of a novel error-grid approach.

PubMed

Hemkens, Lars G; Hilden, Kristian M; Hartschen, Stephan; Kaiser, Thomas; Didjurgeit, Ulrike; Hansen, Roland; Bender, Ralf; Sawicki, Peter T

2008-08-01

In addition to the metrological quality of international normalized ratio (INR) monitoring devices used in patients' self-management of long-term anticoagulation, the effectiveness of self-monitoring with such devices has to be evaluated under real-life conditions with a focus on clinical implications. An approach to evaluate the clinical significance of inaccuracies is the error-grid analysis as already established in self-monitoring of blood glucose. Two anticoagulation monitors were compared in a real-life setting and a novel error-grid instrument for oral anticoagulation has been evaluated. In a randomized crossover study 16 patients performed self-management of anticoagulation using the INRatio and the CoaguChek S system. Main outcome measures were clinically relevant INR differences according to established criteria and to the error-grid approach. A lower rate of clinically relevant disagreements according to Anderson's criteria was found with CoaguChek S than with INRatio without statistical significance (10.77% vs. 12.90%; P = 0.787). Using the error-grid we found principally consistent results: More measurement pairs with discrepancies of no or low clinical relevance were found with CoaguChek S, whereas with INRatio we found more differences with a moderate clinical relevance. A high rate of patients' satisfaction with both of the point of care devices was found with only marginal differences. A principal appropriateness of the investigated point-of-care devices to adequately monitor the INR is shown. The error-grid is useful for comparing monitoring methods with a focus on clinical relevance under real-life conditions beyond assessing the pure metrological quality, but we emphasize that additional trials using this instrument with larger patient populations are needed to detect differences in clinically relevant disagreements.

Plasma Metabolomics Biosignature According to HIV Stage of Infection, Pace of Disease Progression, Viremia Level and Immunological Response to Treatment.

PubMed

Scarpellini, Bruno; Zanoni, Michelle; Sucupira, Maria Cecilia Araripe; Truong, Hong-Ha M; Janini, Luiz Mario Ramos; Segurado, Ismael Dale Cotrin; Diaz, Ricardo Sobhie

2016-01-01

We evaluated plasma samples HIV-infected individuals with different phenotypic profile among five HIV-infected elite controllers and five rapid progressors after recent HIV infection and one year later and from 10 individuals subjected to antiretroviral therapy, five of whom were immunological non-responders (INR), before and after one year of antiretroviral treatment compared to 175 samples from HIV-negative patients. A targeted quantitative tandem mass spectrometry metabolomics approach was used in order to determine plasma metabolomics biosignature that may relate to HIV infection, pace of HIV disease progression, and immunological response to treatment. Twenty-five unique metabolites were identified, including five metabolites that could distinguish rapid progressors and INRs at baseline. Severe deregulation in acylcarnitine and sphingomyelin metabolism compatible with mitochondrial deficiencies was observed. β-oxidation and sphingosine-1-phosphate-phosphatase-1 activity were down-regulated, whereas acyl-alkyl-containing phosphatidylcholines and alkylglyceronephosphate synthase levels were elevated in INRs. Evidence that elite controllers harbor an inborn error of metabolism (late-onset multiple acyl-coenzyme A dehydrogenase deficiency [MADD]) was detected. Blood-based markers from metabolomics show a very high accuracy of discriminating HIV infection between varieties of controls and have the ability to predict rapid disease progression or poor antiretroviral immunological response. These metabolites can be used as biomarkers of HIV natural evolution or treatment response and provide insight into the mechanisms of the disease.

UNUSUAL WARFARIN DOSE TO ACHIEVE THERAPEUTIC INR IN A 4-MONTH OLD CHILD: NON-GENETICS RISK FACTORS ARE STILL A CHALLENGE.

PubMed

Okumura, Lucas Miyake; Negretto, Giovanna Webster; Carvalho, Clarissa Gutiérrez

2017-01-01

To report a case of a 4-month old girl that required 0.7 mg/kg/day (5 mg) of warfarin and discuss relevant risk factors for requiring higher doses. In November 2015, a 5 kg female infant (36-week preterm) was admitted to the hospital due to status epilepticus and fever. Diazepam, phenytoin and ceftriaxone were prescribed. Cerebrospinal fluid contained 7 leukocytes, 150 mg/dL proteins, 1 mg/dL glucose and gram positive cocci were observed. Cranial tomography suggested hypodense signs in the cerebellum, right temporal lobe and left basal nuclei, which was consistent with pneumococcal meningitis-induced infectious vasculitis. She required low molecular weight heparin and warfarin for post-encephalitis thrombosis. About 10 days were required to achieve therapeutic INR, and warfarin was adjusted five times since the initial prescription. The risk factors for higher warfarin doses were age and enteral tube feeding. Phenobarbital and prednisone might also have contributed with one of the highest warfarin dose ever reported. Despite current importance given to genetics testing, clinicians should attempt to identify common contributing factors for prolonged non-therapeutic INR, to minimize the risk of coagulation, and to reduce costs of hospital stay and laboratory exams.

Plasma Metabolomics Biosignature According to HIV Stage of Infection, Pace of Disease Progression, Viremia Level and Immunological Response to Treatment

PubMed Central

Scarpelini, Bruno; Zanoni, Michelle; Sucupira, Maria Cecilia Araripe; Truong, Hong-Ha M.; Janini, Luiz Mario Ramos; Segurado, Ismael Dale Cotrin; Diaz, Ricardo Sobhie

2016-01-01

Background We evaluated plasma samples HIV-infected individuals with different phenotypic profile among five HIV-infected elite controllers and five rapid progressors after recent HIV infection and one year later and from 10 individuals subjected to antiretroviral therapy, five of whom were immunological non-responders (INR), before and after one year of antiretroviral treatment compared to 175 samples from HIV-negative patients. A targeted quantitative tandem mass spectrometry metabolomics approach was used in order to determine plasma metabolomics biosignature that may relate to HIV infection, pace of HIV disease progression, and immunological response to treatment. Results Twenty-five unique metabolites were identified, including five metabolites that could distinguish rapid progressors and INRs at baseline. Severe deregulation in acylcarnitine and sphingomyelin metabolism compatible with mitochondrial deficiencies was observed. β-oxidation and sphingosine‐1‐phosphate-phosphatase-1 activity were down-regulated, whereas acyl-alkyl-containing phosphatidylcholines and alkylglyceronephosphate synthase levels were elevated in INRs. Evidence that elite controllers harbor an inborn error of metabolism (late-onset multiple acyl-coenzyme A dehydrogenase deficiency [MADD]) was detected. Conclusions Blood-based markers from metabolomics show a very high accuracy of discriminating HIV infection between varieties of controls and have the ability to predict rapid disease progression or poor antiretroviral immunological response. These metabolites can be used as biomarkers of HIV natural evolution or treatment response and provide insight into the mechanisms of the disease. PMID:27941971

Confidence level estimation in multi-target classification problems

NASA Astrophysics Data System (ADS)

Chang, Shi; Isaacs, Jason; Fu, Bo; Shin, Jaejeong; Zhu, Pingping; Ferrari, Silvia

2018-04-01

This paper presents an approach for estimating the confidence level in automatic multi-target classification performed by an imaging sensor on an unmanned vehicle. An automatic target recognition algorithm comprised of a deep convolutional neural network in series with a support vector machine classifier detects and classifies targets based on the image matrix. The joint posterior probability mass function of target class, features, and classification estimates is learned from labeled data, and recursively updated as additional images become available. Based on the learned joint probability mass function, the approach presented in this paper predicts the expected confidence level of future target classifications, prior to obtaining new images. The proposed approach is tested with a set of simulated sonar image data. The numerical results show that the estimated confidence level provides a close approximation to the actual confidence level value determined a posteriori, i.e. after the new image is obtained by the on-board sensor. Therefore, the expected confidence level function presented in this paper can be used to adaptively plan the path of the unmanned vehicle so as to optimize the expected confidence levels and ensure that all targets are classified with satisfactory confidence after the path is executed.

Factors influencing warfarin response in hospitalized patients

PubMed Central

Abdel-Aziz, Mahmoud I.; Ali, Mostafa A. Sayed; Hassan, Ayman K.M.; Elfaham, Tahani H.

2015-01-01

The objective of this study was to investigate the influence of simultaneous factors that potentially keep patients far from achieving target INR range at discharge in hospitalized patients. Prospective cross-sectional observational study conducted at the Cardiology Department and Intensive Care Unit (ICU) of the Assiut University Hospitals. One-hundred and twenty patients were enrolled in the study from July 2013 to January 2014. Outcome measures were discharge INRs, bleeding and thromboembolic episodes. Bivariate analysis and multinomial logistic regression were conducted to determine independent risk factors that can keep patients outside target INR range. Patients who were newly initiated warfarin on hospital admission were given low initiation dose (2.8 mg ± 0.9). They were more likely to have INR values below 1.5 during hospital stay, 13 (27.7%) patients compared with 9 (12.3%) previously treated patients, respectively (p = .034). We found that the best predictors of achieving below target INR range relative to within target INR range were; shorter hospital stay periods (OR, 0.82 for every day increase [95% CI, 0.72–0.94]), being a male patient (OR, 2.86 [95% CI, 1.05–7.69]), concurrent infection (OR, 0.21 [95% CI, 0.07–0.59]) and new initiation of warfarin therapy on hospital admission (OR, 3.73 [95% CI, 1.28–10.9]). Gender, new initiation of warfarin therapy on hospital admission, shorter hospital stay periods and concurrent infection can have a significant effect on discharge INRs. Initiation of warfarin without giving loading doses increases the risk of having INRs below 1.5 during hospital stay and increases the likelihood of a patient to be discharged with INR below target range. Following warfarin dosing nomograms and careful monitoring of the effect of various factors on warfarin response should be greatly considered. PMID:26702259

Quality of life in children participating in a non-selective INR self-monitoring VKA-education programme.

PubMed

Amedro, Pascal; Bajolle, Fanny; Bertet, Helena; Cheurfi, Radhia; Lasne, Dominique; Nogue, Erika; Auquier, Pascal; Picot, Marie-Christine; Bonnet, Damien

2018-03-01

The quality of life (QoL) of children receiving vitamin K antagonist (VKA) treatment has been scarcely studied. To assess QoL of children, and its evolution, throughout our non-selective international normalized ratio (INR) self-monitoring education programme. Children and parents completed QoL questionnaires (Qualin, PedsQL) during education sessions. Scores were compared with those from controls. A total of 111 children (mean±standard deviation age 8.7±5.4 years) were included over a 3-year period. Indications for VKA treatment were congenital heart diseases (valve replacement [42.3%], total cavopulmonary connection [29.7%]), myocardiopathy (11.7%), coronary aneurysm (7.2%), venous/intracardiac thrombosis (4.5%), pulmonary artery hypertension (1.8%), arrhythmia (0.9%) and extra-cardiac disease (1.8%). Eighty children, 105 mothers and 74 fathers completed the QoL questionnaires. QoL was good among children aged 1-4 years and moderately impaired in those aged between 5 and 18 years. There was no significant relationship between self-reported QoL and patient's sex, type of VKA, number of group sessions attended, disease duration or time of diagnosis (prenatal or postnatal). QoL scores were significantly lower among children with congenital heart diseases compared with other diseases. There were few differences in QoL between children under transient VKA treatment and those treated for life. Parental proxy QoL scoring correlated well with but was significantly lower than child self-assessments. QoL reported by mothers increased throughout the education programme, independently of any improvement of the health condition. This QoL study provides original data from a large cohort of children and their parents participating in a formalized INR self-monitoring education programme for VKA treatment. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Assessment of the efficacy of a novel tailored vitamin K dosing regimen in lowering the International Normalised Ratio in over-anticoagulated patients: a randomised clinical trial.

PubMed

Kampouraki, Emmanouela; Avery, Peter J; Wynne, Hilary; Biss, Tina; Hanley, John; Talks, Kate; Kamali, Farhad

2017-09-01

Current guidelines advocate using fixed-doses of oral vitamin K to reverse excessive anticoagulation in warfarinised patients who are either asymptomatic or have minor bleeds. Over-anticoagulated patients present with a wide range of International Normalised Ratio (INR) values and response to fixed doses of vitamin K varies. Consequently a significant proportion of patients remain outside their target INR after vitamin K administration, making them prone to either haemorrhage or thromboembolism. We compared the performance of a novel tailored vitamin K dosing regimen to that of a fixed-dose regimen with the primary measure being the proportion of over-anticoagulated patients returning to their target INR within 24 h. One hundred and eighty-one patients with an index INR > 6·0 (asymptomatic or with minor bleeding) were randomly allocated to receive oral administration of either a tailored dose (based upon index INR and body surface area) or a fixed-dose (1 or 2 mg) of vitamin K. A greater proportion of patients treated with the tailored dose returned to within target INR range compared to the fixed-dose regimen (68·9% vs. 52·8%; P = 0·026), whilst a smaller proportion of patients remained above target INR range (12·2% vs. 34·0%; P < 0·001). Individualised vitamin K dosing is more accurate than fixed-dose regimen in lowering INR to within target range in excessively anticoagulated patients. © 2017 John Wiley & Sons Ltd.

Examining the target levels of state renewable portfolio standards

NASA Astrophysics Data System (ADS)

Helwig, Laurence Douglas

At present 37 U.S. states have passed Renewable Portfolio Standards (RPS) or have a legislative driven goal that supports investment in renewable energy (RE) technologies. Previous research has identified economic, governmental, ideological and infrastructural characteristics as key predictors of policy adoption and renewable energy deployment efforts (Carley, 2009; Davis & Davis, 2009; Bohn & Lant, 2009; Lyon & Yin, 2010). To date, only a few studies have investigated the target levels of renewable portfolio standards. Carley & Miller (2012) found that policies of differing stringencies were motivated by systematically different factors that included governmental ideology. The purpose of this dissertation is to replicate and expand upon earlier models that predicted RPS adoption and RE deployment efforts by adding regulatory, infrastructural and spatial characteristics to predict RPS target levels. Hypotheses were tested using three alternative measurements of RPS target level strength to determine to what extent a combination of explanatory variables explain variation in policy target levels. Multivariate linear regression and global spatial autocorrelation results indicated that multiple state internal determinants influenced RPS target level including average electricity price, state government ideology and to a lesser extent actual RE potential capacity. In addition, some diffusion effects were found to exist that indicated that states are setting their RPS target levels lower than their neighboring states and a local geo-spatial clustering effect was observed in the target levels for a grouping of northeastern states.

Calculation of Cumulative Distributions and Detection Probabilities in Communications and Optics.

DTIC Science & Technology

1986-03-31

result, Figure 3.1 shows the additional SNR required (often called the CFAR loss) for the MLD, CMLD , and OSD in a multiple target environment to...Notice that although the CFAR loss increases with INR for the MLD, the CMLD and OSD have a bounded loss as the INR + w. These results have been more...false-alarm rate ( CFAR ) when the background noise level is unknown. In Section 2 we described the application of saddlepoint integration techniques to

A kick in the shins: the financial impact of uncontrolled warfarin use in pre-tibial haematomas.

PubMed

Thomson, W L; Pujol-Nicolas, A; Tahir, A; Siddiqui, H

2014-01-01

Warfarin is increasingly prescribed in the elderly population for a number of medical conditions. Pre-tibial haematomas are a common cause of morbidity in this group. The aim of the study was to identify the proficiency of INR monitoring at a primary care level in correlation with their recommended INR range and to study the treatment outcome in this group. A retrospective single-centre study of patients diagnosed with pre-tibial haematomas was conducted over a two-year period. Length of hospital stay, time delay until operative intervention, blood transfusion and warfarin reversal requirements, social care input and cost to the NHS were considered. A total of 62 patients were admitted with pre-tibial haematomas of which 20 were on Warfarin. Females were predominantly more affected (5.6:1). The mechanism of injury was as a result of minor trauma. The mean INR level was 3.8 with a standard deviation of 3.1. Mean length of hospital stay was 11 days with a standard deviation of 13.6. Nine patients required skin grafting. Average cost for the acute episode was £3500 per patient. INR levels were significantly outwith the target range causing substantial patient morbidity and imposing a significant financial burden on the NHS. Tighter regulation at a primary care level should help reduce this risk. Copyright © 2012 Elsevier Ltd. All rights reserved.

Orbit targeting specialist function: Level C formulation requirements

NASA Technical Reports Server (NTRS)

Dupont, A.; Mcadoo, S.; Jones, H.; Jones, A. K.; Pearson, D.

1978-01-01

A definition of the level C requirements for onboard maneuver targeting software is provided. Included are revisions of the level C software requirements delineated in JSC IN 78-FM-27, Proximity Operations Software; Level C Requirements, dated May 1978. The software supports the terminal phase midcourse (TPM) maneuver, braking and close-in operations as well as supporting computation of the rendezvous corrective combination maneuver (NCC), and the terminal phase initiation (TPI). Specific formulation is contained here for the orbit targeting specialist function including the processing logic, linkage, and data base definitions for all modules. The crew interface with the software is through the keyboard and the ORBIT-TGT display.

Suboptimal Anticoagulant Management in Japanese Patients with Nonvalvular Atrial Fibrillation Receiving Warfarin for Stroke Prevention.

PubMed

Hirano, Teruyuki; Kaneko, Hirokazu; Mishina, Sari; Wang, Feng; Morita, Satoshi

2017-10-01

Atrial fibrillation (AF) is the most common cardiac arrhythmia, with increasing prevalence in Japan. Although prothrombin time-international normalized ratio (PT-INR) targets for monitoring warfarin therapy in patients with nonvalvular AF (NVAF) are well defined, real-world patient characteristics and PT-INR levels remain unknown among Japanese patients with NVAF who initiate and continue warfarin (warfarin maintainers) versus those who switch from warfarin to direct oral anticoagulants (DOACs; warfarin switchers). Patients with NVAF receiving oral anticoagulants between February 2013 and June 2015 were identified using a nationwide electronic medical record (EMR) database from 69 hospitals in Japan. Demographics and characteristics of patients, PT-INR, time in therapeutic range (TTR), and frequency in range (FIR) of PT-INR between warfarin maintainers and warfarin switchers were assessed. A total of 1705 patients met inclusion criteria and were examined (1501 warfarin maintainers versus 204 warfarin switchers). CHADS 2 , CHA 2 DS 2 -VASc, and HAS-BLED scores were comparable between groups. However, these scores were significantly higher among warfarin switchers at the time of switching than at the time of warfarin initiation. Furthermore, TTR and FIR of PT-INR were lower in warfarin switchers than in maintainers. Nevertheless, TTR and FIR were below 50% (PT-INR, 1.6-2.6) in both patient groups. In this EMR-based clinical study, patients who switched to DOACs had both poor or inadequate PT-INR control and higher risk factors of stroke. Many patients receiving warfarin did not achieve sufficient PT-INR therapeutic range. DOACs could be recommended in Japanese patients with NVAF with inadequate PT-INR control and increased risk of stroke. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

International normalized ratio self-management lowers the risk of thromboembolic events after prosthetic heart valve replacement.

PubMed

Eitz, Thomas; Schenk, Soren; Fritzsche, Dirk; Bairaktaris, Andreas; Wagner, Otto; Koertke, Heinrich; Koerfer, Reiner

2008-03-01

Although prosthetic valves are durable and easy to implant, the need for lifetime warfarin-based anticoagulation restricts their exclusive usage. We investigated if anticoagulation self-management improves outcome in a single-center series. Between 1994 and 1998, 765 patients with prosthetic valve replacements were prospectively enrolled and randomized to receive conventional anticoagulation management by their primary physician (group 1, n = 295) or to pursue anticoagulation self-management (group 2, n = 470). A study head office was implemented to coordinate and monitor anticoagulation protocols, international normalized ratios (INR), and adverse events. Patients were instructed on how to obtain and test their own blood samples and to adjust warfarin dosages according to the measured INR (target range, 2.5 to 4). Mean INR values were slightly yet significantly smaller in group 1 than in group 2 (2.8 +/- 0.7 vs 3.0 +/- .6, p < 0.001). Moreover, INR values of patients with conventional INR management were frequently measured outside the INR target range, whereas those with anticoagulation self-management mostly remained within the range (35% vs 21%, p < 0.001). In addition, the scatter of INR values was smaller if self-managed. Freedom from thromboembolism at 3, 12, and 24 months, respectively, was 99%, 95%, and 91% in group 1 compared with 99%, 98%, and 96% in group 2 (p = 0.008). Bleeding events were similar in both groups. Time-related multivariate analysis identified INR self-management and higher INR as independent predictors for better outcome. Anticoagulation self-management can improve INR profiles up to 2 years after prosthetic valve replacement and reduce adverse events. Current indications of prosthetic rather than biologic valve implantations may be extended if the benefit of INR self-management is shown by future studies with longer follow-up.

Bleeding events and associated factors in a cohort of adult patients taking warfarin in Sarawak, Malaysia.

PubMed

Edwards, Frances; Arkell, Paul; Fong; Roberts, Lesley M; Gendy, David; Wong, Christina Siew-Hie; Ngu, Joanna Chee Yien; Tiong, Lee Len; Bibi, Faridha Mohd Salleh; Lai, Lana Yin Hui; Ong, Tiong Kiam; Abouyannis, Michael

2014-01-01

Evidence is emerging that rates of adverse events in patients taking warfarin may vary with ethnicity. This study investigated the rates of bleeds and thromboembolic events, the international normalised ratio (INR) status and the relationship between INR and bleeding events in Malaysia. Patients attending INR clinic at the Heart Centre, Sarawak General Hospital were enrolled on an ad hoc basis from May 2010 and followed up for 1 year. At each routine visit, INR was recorded and screening for bleeding or thromboembolism occurred. Variables relating to INR control were used as predictors of bleeds in logistic regression models. 125 patients contributed to 140 person-years of follow-up. The rates of major bleed, thromboembolic event and minor bleed per 100 person-years of follow-up were 1.4, 0.75 and 34.3. The median time at target range calculated using the Rosendaal method was 61.6% (IQR 44.6–74.1%). Of the out-of-range readings, 30.0% were below range and 15.4% were above. INR variability, (standard deviation of individuals’ mean INR), was the best predictor of bleeding events, with an odds ratio of 3.21 (95% CI 1.10–9.38). Low rates of both major bleeds and thromboembolic events were recorded, in addition to a substantial number of INR readings under the recommended target range. This may suggest that the recommended INR ranges may not represent the optimal warfarin intensity for this population and that a lower intensity of therapy, as observed in this cohort, could be beneficial in preventing adverse events.

Population Impact of Drug Interactions with Warfarin: A Real-World Data Approach.

PubMed

Martín-Pérez, Mar; Gaist, David; de Abajo, Francisco J; Rodríguez, Luis A García

2018-03-01

 To investigate the population impact of previously reported interactions between warfarin and other drugs on international normalized ratio (INR) levels.  Using The Health Improvement Network (THIN), a United Kingdom primary care database, a cohort of warfarin users between 2005 and 2013 ( N  = 121,962) was followed until the first qualifying prescription for the potential interacting drugs was evaluated. Sixteen sub-cohorts, one for each study drug, and a control sub-cohort of warfarin were ascertained. Short-term changes in INR levels were assessed by comparing INR values measured before and after initiation of the interacting drug with paired Student's t -test. We also evaluated the proportion of patients with INR values outside the therapeutic range (INR: 2-3).  Miconazole use was associated with the highest mean increase in INR (+3.35), followed by amiodarone (+1.28), fluconazole (+0.79), metronidazole (+0.75) and nystatin (+0.65). After subtracting the natural INR variation observed in the control sub-cohort, supra-therapeutic levels (INR > 3) were found in 53.2% (miconazole), 45.5% (amiodarone), 23.3% (metronidazole), 23.2% (fluconazole) and 17.6% (nystatin) of patients initiating treatment with these drugs. Carbamazepine use was associated with a mean INR decrease of -0.63 and infra-therapeutic levels (INR < 2) were observed in 46.2% of patients initiating carbamazepine. For all other drugs, the change was small to moderate, in absolute INR units (+0.23 to +0.55) and in the proportion of patients with INR levels out of therapeutic range (<16%).  Clinically potentially important interactions were observed in several study drugs. The majority of them, although confirmed, had little impact after adjusting for standard INR variability in the general population of warfarin users. Schattauer GmbH Stuttgart.

Telemedicine-guided, very low-dose international normalized ratio self-control in patients with mechanical heart valve implants.

PubMed

Koertke, Heinrich; Zittermann, Armin; Wagner, Otto; Secer, Songuel; Sciangula, Alfonso; Saggau, Werner; Sack, Falk-Udo; Ennker, Jürgen; Cremer, Jochen; Musumeci, Francesco; Gummert, Jan F

2015-06-01

To study in patients performing international normalized ratio (INR) self-control the efficacy and safety of an INR target range of 1.6-2.1 for aortic valve replacement (AVR) and 2.0-2.5 for mitral valve replacement (MVR) or double valve replacement (DVR). In total, 1304 patients undergoing AVR, 189 undergoing MVR and 78 undergoing DVR were randomly assigned to low-dose INR self-control (LOW group) (INR target range, AVR: 1.8-2.8; MVR/DVR: 2.5-3.5) or very low-dose INR self-control once a week (VLO group) and twice a week (VLT group) (INR target range, AVR: 1.6-2.1; MVR/DVR: 2.0-2.5), with electronically guided transfer of INR values. We compared grade III complications (major bleeding and thrombotic events; primary end-points) and overall mortality (secondary end-point) across the three treatment groups. Two-year freedom from bleedings in the LOW, VLO, and VLT groups was 96.3, 98.6, and 99.1%, respectively (P = 0.008). The corresponding values for thrombotic events were 99.0, 99.8, and 98.9%, respectively (P = 0.258). The risk-adjusted composite of grade III complications was in the per-protocol population (reference: LOW-dose group) as follows: hazard ratio = 0.307 (95% CI: 0.102-0.926; P = 0.036) for the VLO group and = 0.241 (95% CI: 0.070-0.836; P = 0.025) for the VLT group. The corresponding values of 2-year mortality were = 1.685 (95% CI: 0.473-5.996; P = 0.421) for the VLO group and = 4.70 (95% CI: 1.62-13.60; P = 0.004) for the VLT group. Telemedicine-guided very low-dose INR self-control is comparable with low-dose INR in thrombotic risk, and is superior in bleeding risk. Weekly testing is sufficient. Given the small number of MVR and DVR patients, results are only valid for AVR patients. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.

Clinical manifestations and outcomes of antithrombotic treatment of the Tan Tock Seng Hospital Singapore antiphospholipid syndrome cohort.

PubMed

Tan, B E; Thong, B Y H; Shivananda, S; Han, W W; Chng, H H

2009-07-01

To examine the clinical manifestations, intensity of oral anticoagulation and outcomes in the prevention of recurrent thromboses in patients with antiphospholipid syndrome (APS) in a tertiary rheumatology centre in Singapore. Retrospective case review of consecutive patients with APS attending a rheumatology clinic from 1st January 2004 to 31st December 2005. There were 59 (44%) patients with definite APS and 75 (56%) with probable APS. Systemic lupus erythematosus (SLE) was the most common cause of secondary APS. Hypertension and hyperlipidaemia were the most common cardiovascular comorbidities. The most common manifestations were haematological (thrombocytopaenia and haemolytic anaemia), neurological (seizure, headache) and pulmonary hypertension. Among those with definite APS, there were similar proportions with arterial and venous thromboses. Recurrent thromboses occurred in 14 (23.7%) patient with definite APS receiving warfarin, comprising 14 (73.7%) episodes of arterial and 5 (26.3%) episodes of venous thromboses. Recurrent arterial thromboses occurred at international normalized ratio (INR) of <2 in 5 (35.7%), INR 2-3 in 6 (42.9%), INR > 3 in 3 (21.4%) episodes, respectively. Recurrent venous thromboses occurred at INR < 2 in 4 (80.0%) and INR > 3 in 1 (20.0%) episode, respectively. Twenty-eight episodes of bleeding occurred in 21 (35.6%) patients, the majority (78.6%) being minor bleeding. Two-thirds of all major bleeds occurred at INR >/= 3. Venous and arterial thromboses were equally common in our patients with definite APS, although recurrent thromboses were more common in the arterial circulation. Target INR > 3 was associated with lower rates of recurrent arterial thromboses but higher rates of major and recurrent bleeding. Target INR >/= 2 appeared to be sufficient to prevent recurrent venous thromboses.

76 FR 12942 - Proposed Information Collection; Comment Request; Defining Target Levels for Ecosystem Components...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-03-09

... Collection; Comment Request; Defining Target Levels for Ecosystem Components: A Socio-Ecological Approach... numerous species, and a mean level of species placement within a predator/prey chain or food web can serve...-based Management, when target levels for indicators exist. Because targets are an expression of the...

Inadvertent exaggerated anticoagulation following use of bismuth subsalicylate in an enterally fed patient receiving warfarin therapy.

PubMed

Bingham, Angela L; Brown, Rex O; Dickerson, Roland N

2013-12-01

We report a case of an inadvertent increase in the international normalized ratio (INR) after the addition of bismuth subsalicylate for the treatment of diarrhea in an enterally fed patient receiving warfarin therapy. A 56-year-old Caucasian female presented to the trauma intensive care unit (ICU) with multiple lower extremity fractures. Warfarin was initiated for deep vein thrombosis prophylaxis due to the patient's inability to ambulate. The target INR was 2-3. Continuous intragastric enteral feeding was withheld 1 hour before and 1 hour after intragastric administration of warfarin. Bismuth subsalicylate 30 mL every 4 hours was prescribed for diarrhea. Within 3 days after starting bismuth subsalicylate therapy, the patient's INR increased from 2.56 to 3.54 and minor bleeding was noted from the patient's tracheostomy site. No significant change in warfarin dosage, variability in vitamin K intake, or medications that potentially alter warfarin metabolism were present during the unexpected rise in INR. When the bismuth subsalicylate was discontinued, the patient's INR stabilized into the target range on the same warfarin dose given at the time of the supratherapeutic INR. Salicylate displaces warfarin from plasma protein binding sites and may result in a significant increase in INR secondary to redistribution of warfarin to the free active form. Evaluation of this case report using the Drug Interaction Probability Scale and Naranjo Adverse Drug Reaction Probability Scale yielded scores consistent with a probable adverse drug interaction. Bismuth subsalicylate exaggerates warfarin's anticoagulant response and its concurrent use during warfarin therapy should be avoided.

Investigations of internal noise levels for different target sizes, contrasts, and noise structures

NASA Astrophysics Data System (ADS)

Han, Minah; Choi, Shinkook; Baek, Jongduk

2014-03-01

To describe internal noise levels for different target sizes, contrasts, and noise structures, Gaussian targets with four different sizes (i.e., standard deviation of 2,4,6 and 8) and three different noise structures(i.e., white, low-pass, and highpass) were generated. The generated noise images were scaled to have standard deviation of 0.15. For each noise type, target contrasts were adjusted to have the same detectability based on NPW, and the detectability of CHO was calculated accordingly. For human observer study, 3 trained observers performed 2AFC detection tasks, and correction rate, Pc, was calculated for each task. By adding proper internal noise level to numerical observer (i.e., NPW and CHO), detectability of human observer was matched with that of numerical observers. Even though target contrasts were adjusted to have the same detectability of NPW observer, detectability of human observer decreases as the target size increases. The internal noise level varies for different target sizes, contrasts, and noise structures, demonstrating different internal noise levels should be considered in numerical observer to predict the detection performance of human observer.

Joint sparsity based heterogeneous data-level fusion for target detection and estimation

NASA Astrophysics Data System (ADS)

Niu, Ruixin; Zulch, Peter; Distasio, Marcello; Blasch, Erik; Shen, Dan; Chen, Genshe

2017-05-01

Typical surveillance systems employ decision- or feature-level fusion approaches to integrate heterogeneous sensor data, which are sub-optimal and incur information loss. In this paper, we investigate data-level heterogeneous sensor fusion. Since the sensors monitor the common targets of interest, whose states can be determined by only a few parameters, it is reasonable to assume that the measurement domain has a low intrinsic dimensionality. For heterogeneous sensor data, we develop a joint-sparse data-level fusion (JSDLF) approach based on the emerging joint sparse signal recovery techniques by discretizing the target state space. This approach is applied to fuse signals from multiple distributed radio frequency (RF) signal sensors and a video camera for joint target detection and state estimation. The JSDLF approach is data-driven and requires minimum prior information, since there is no need to know the time-varying RF signal amplitudes, or the image intensity of the targets. It can handle non-linearity in the sensor data due to state space discretization and the use of frequency/pixel selection matrices. Furthermore, for a multi-target case with J targets, the JSDLF approach only requires discretization in a single-target state space, instead of discretization in a J-target state space, as in the case of the generalized likelihood ratio test (GLRT) or the maximum likelihood estimator (MLE). Numerical examples are provided to demonstrate that the proposed JSDLF approach achieves excellent performance with near real-time accurate target position and velocity estimates.

Contributions of procoagulants and anticoagulants to the international normalized ratio and thrombin generation assay in patients treated with warfarin: potential role of protein Z as a powerful determinant of coagulation assays.

PubMed

Choi, Qute; Kim, Ji-Eun; Hyun, Jungwon; Han, Kyou-Sup; Kim, Hyun Kyung

2013-07-01

The effects of warfarin are measured with the international normalized ratio (INR). However, the thrombin generation assay (TGA) may offer more information about global coagulation. We analyzed the monitoring performance of the TGA and INR and investigated the impact of procoagulants (fibrinogen, factor (F)II, FVII, FIX, and FX) and anticoagulants (proteins C, S, and Z) on them. The TGA was performed on a calibrated automated thrombogram, producing lag time, endogenous thrombin potential (ETP), and peak thrombin in 239 patients treated with warfarin. Pro- and anticoagulant levels were also measured. The INR was significantly and inversely correlated with ETP. The therapeutic range of ETP comparable to an INR range of 2.0-3.0 was 290.1-494.6. ETP showed comparable performance to the INR as a warfarin-monitoring parameter with respect to clinical complication rate. The median levels of FII, FVII, FIX, and FX and proteins C and Z tended to decrease gradually with increasing anticoagulation intensity according to the INR or ETP. Of note, protein Z levels decreased dramatically with increasing anticoagulation status. INRs were significantly determined by FII, FVII, and protein Z. ETP was significantly dependent on FVII, and proteins C and Z concentration. Protein Z significantly reduced the total amount of thrombin generation and prolonged PT value in vitro. The INR and ETP exhibit similar efficacy for warfarin monitoring according to the clinical complication rate. Protein Z is considered to be a significant determinant of INR and ETP in patients on warfarin therapy. Copyright © 2013 Elsevier Ltd. All rights reserved.

The effects of a low international normalized ratio on thromboembolic and bleeding complications in patients with mechanical mitral valve replacement

PubMed Central

2014-01-01

Background Mechanical heart valve replacement has an inherent risk of thromboembolic events (TEs). Current guidelines recommend an international normalized ratio (INR) of at least 2.5 after mechanical mitral valve replacement (MVR). This study aimed to evaluate the effects of a low INR (2.0–2.5) on thromboembolic and bleeding complications in patients with mechanical MVR on warfarin therapy. Methods One hundred and thirty-five patients who underwent mechanical MVR were enrolled in this study. The end points of this study were defined as TEs (valve thrombosis, transient ischemic attack, stroke) and bleeding (all minor and major bleeding) complications. Patients were followed up for a mean of 39.6 months and the mean INR of the patients was calculated. After data collection, patients were divided into 3 groups according to their mean INR, as follows: group 1 (n = 34), INR <2.0; group 2 (n = 49), INR 2.0–2.5; and group 3 (n = 52), INR >2.5. Results A total of 22 events (10 [7.4%] thromboembolic and 12 [8.8%] bleeding events) occurred in the follow-up period. The mean INR was an independent risk factor for the development of TEs. Mean INR and neurological dysfunction were independent risk factors for the development of bleeding events. A statistically significant positive correlation was found between the log mean INR and all bleeding events, and a negative correlation was found between the log mean INR and all TEs. The total number of events was significantly lower in group 2 than in groups 1 and 3 (P = 0.036). Conclusions This study showed that a target INRs of 2.0–2.5 are acceptable for preventing TEs and safe in terms of bleeding complications in patients with mechanical MVR. PMID:24885719

Contribution of rivaroxaban to the international normalized ratio when switching to warfarin for anticoagulation as determined by simulation studies

PubMed Central

Siegmund, Hans-Ulrich; Burghaus, Rolf; Kubitza, Dagmar; Coboeken, Katrin

2015-01-01

Aim This study evaluated the influence of rivaroxaban 20 mg once daily on international normalized ratio (INR) during the co-administration period when switching from rivaroxaban to warfarin. Methods We developed a calibrated coagulation model that was qualified with phase I clinical data. Prothrombin time and INR values were simulated by use of phospholipid concentrations that matched Neoplastin Plus® and Innovin® reagents. To simulate the combined effects of rivaroxaban and warfarin on INR during switching, warfarin initiation was simulated by adjusting the magnitude of the warfarin effect to reach the desired target INRs over the course of 21 days. The warfarin effect values (obtained every 6 h) and the desired rivaroxaban plasma concentrations were used. Nomograms were generated from rivaroxaban induced increases in INR. Results The simulation had good prediction quality. Rivaroxaban induced increases in the total INR from the warfarin attributed INR were seen, which increased with rivaroxaban plasma concentration. When the warfarin only INR was 2.0–3.0, the INR contribution of rivaroxaban with Neoplastin Plus® was 0.5–1.2, decreasing to 0.3–0.6 with Innovin® at median trough rivaroxaban plasma concentrations (38 μg l−1). Conclusions The data indicate that measuring warfarin induced changes in INR are best performed at trough rivaroxaban concentrations (24 h after rivaroxaban dosing) during the co-administration period when switching from rivaroxaban to warfarin. Furthermore, Innovin® is preferable to Neoplastin Plus® because of its substantially lower sensitivity to rivaroxaban, thereby reducing the influence of rivaroxaban on the measured INR. PMID:25510952

Patterns of international normalized ratio values among new warfarin patients with nonvalvular atrial fibrillation.

PubMed

Nelson, Winnie W; Milentijevic, Dejan; Wang, Li; Baser, Onur; Damaraju, C V; Schein, Jeffrey R

2016-12-01

Limited information exists regarding the relationship between international normalized ratio (INR) control/stability and the discontinuation of warfarin therapy among patients with nonvalvular atrial fibrillation (NVAF). This study evaluated the association between INR stabilization and warfarin discontinuation and assessed INR patterns before and after INR stabilization among patients (≥18 years) with NVAF who newly initiated warfarin (Veterans Health Administration datasets; October 1, 2007 through September 30, 2012). Achievement of INR stabilization (≥3 consecutive in-range therapeutic INR measurements ≥7 days apart) was examined from warfarin initiation through the end of warfarin exposure. Proportion of time in therapeutic range during warfarin exposure was calculated (Rosendaal method) and categorized as at least 60% or less than 60%. Among 34 346 patients, 49.4% achieved INR stabilization (mean time to stabilization, 98 days). Approximately 40% of INR values were out-of-range, even after achieving stabilization. During 30 days following an INR 4.0 or higher, patients had more INR testing than the overall mean (2.51 vs. 1.67 tests). Warfarin discontinuation was 4.2 times more likely among patients without INR stabilization versus those with INR stabilization (P < 0.00001). Patients with poor INR control (time in therapeutic range <60%) were 1.76 times more likely to discontinue warfarin within 1 year (P < 0.0001). INR stabilization is a better predictor of warfarin discontinuation than poor INR control. Improved approaches are necessary to maintain appropriate anticoagulation levels among patients with NVAF.

Should there be a target level of docosahexaenoic acid in breast milk?

PubMed

Jackson, Kristina Harris; Harris, William S

2016-03-01

This article examines the evidence for and against establishing a target level of docosahexaenoic acid (DHA) in breast milk. Two target levels for milk DHA have been recently proposed. One (∼0.3% of milk fatty acids) was based on milk DHA levels achieved in women consuming the amount of DHA recommended by the American Academy of Pediatrics for pregnant and lactating women (at least 200 mg DHA/day). Another (∼1.0%) was based on biomarker studies of populations with differing lifelong intakes of fish. Populations or research cohorts with milk DHA levels of 1.0% are associated with intakes that allow both the mother and infant to maintain relatively high DHA levels throughout lactation. Lower milk DHA levels may signal suboptimal maternal stores and possibly suboptimal infant intakes. Based on the current data, a reasonable milk DHA target appears to be approximately 0.3%, which is about the worldwide average. Although this may not be the 'optimal' level (which remains to be defined), it is clearly an improvement over the currently low milk DHA levels (∼0.2%) seen in many Western populations.

International normalized ratio stability in warfarin-experienced patients with nonvalvular atrial fibrillation.

PubMed

Nelson, Winnie W; Desai, Sunita; Damaraju, Chandrasekharrao V; Lu, Lang; Fields, Larry E; Wildgoose, Peter; Schein, Jeffery R

2015-06-01

Maintaining stable levels of anticoagulation using warfarin therapy is challenging. Few studies have examined the stability of the international normalized ratio (INR) in patients with nonvalvular atrial fibrillation (NVAF) who have had ≥6 months' exposure to warfarin anticoagulation for stroke prevention. Our objective was to describe INR control in NVAF patients who had been receiving warfarin for at least 6 months. Using retrospective patient data from the CoagClinic™ database, we analyzed data from NVAF patients treated with warfarin to assess the quality of INR control and possible predictors of poor INR control. Time within, above, and below the recommended INR range (2.0-3.0) was calculated for patients who had received warfarin for ≥6 months and had three or more INR values. The analysis also assessed INR patterns and resource utilization of patients with an INR >4.0. Logistic regression models were used to determine factors associated with poor INR control. Patients (n = 9433) had an average of 1.6 measurements per 30 days. Mean follow-up time was 544 days. Approximately 39% of INR values were out of range, with 23% of INR values being <2.0 and 16% being >3.0. Mean percent time with INR in therapeutic range was 67%; INR <2.0 was 19% and INR >3.0 was 14%. Patients with more than one reading of INR >4.0 (~39%) required an average of one more visit and took 3 weeks to return to an in-range INR. Male sex and age >75 years were predictive of better INR control, whereas a history of heart failure or diabetes were predictive of out-of-range INR values. However, patient characteristics did not predict the likelihood of INR >4.0. Out-of-range INR values remain frequent in patients with NVAF treated with warfarin. Exposure to high INR values was common, resulting in increased resource utilization.

Interaction between gemfibrozil and warfarin: case report and review of the literature.

PubMed

Dixon, Dave L; Williams, Virginia G

2009-06-01

Possible procoagulant effects can occur when lipid-lowering fibric acid derivatives, such as gemfibrozil and fenofibrate, are taken concomitantly with warfarin. Although there are several detailed reports of fenofibrate potentiating the anticoagulant effects of warfarin, few case reports have been published regarding an interaction between gemfibrozil and warfarin. We describe a 62-year-old man who was taking warfarin for paroxysmal atrial fibrillation and came to the anticoagulation clinic for a routine follow-up. For 9 months, the patient's international normalized ratio (INR) had been stable (target range 2.0-3.0) with warfarin 45 mg/week. At this clinic visit, however, his INR was supratherapeutic at 5.8; the only identified change in his drug therapy was the addition of gemfibrozil 600 mg twice/day, started 3 weeks earlier. The patient denied any changes in his dietary intake of vitamin K, alcohol use, or addition of nonprescription or herbal agents. Recent laboratory tests revealed no signs of thyroid abnormalities and only an insignificant elevation in his alanine aminotransferase level. His warfarin dose was decreased to 35-37.5 mg/week (a 22% reduction), and a therapeutic INR was maintained until gemfibrozil was later discontinued because of myalgia. After consecutive subtherapeutic INRs, his warfarin dose was increased to 45 mg/week and a therapeutic INR was maintained. Use of the Drug Interaction Probability Scale indicated that the likelihood of the gemfibrozil-warfarin interaction was probable. The exact mechanism of the proposed interactions between fibric acid derivatives and warfarin remains unknown but may be multifactorial through inhibition of cytochrome P450 isoenzymes, displacement from protein binding sites, or changes in coagulation factor synthesis. Regardless of the fibric acid derivative chosen, an empiric dosage reduction of 20% and close INR monitoring are warranted in patients receiving warfarin.

Anticoagulants and the propagation phase of thrombin generation.

PubMed

Orfeo, Thomas; Gissel, Matthew; Butenas, Saulius; Undas, Anetta; Brummel-Ziedins, Kathleen E; Mann, Kenneth G

2011-01-01

The view that clot time-based assays do not provide a sufficient assessment of an individual's hemostatic competence, especially in the context of anticoagulant therapy, has provoked a search for new metrics, with significant focus directed at techniques that define the propagation phase of thrombin generation. Here we use our deterministic mathematical model of tissue-factor initiated thrombin generation in combination with reconstructions using purified protein components to characterize how the interplay between anticoagulant mechanisms and variable composition of the coagulation proteome result in differential regulation of the propagation phase of thrombin generation. Thrombin parameters were extracted from computationally derived thrombin generation profiles generated using coagulation proteome factor data from warfarin-treated individuals (N = 54) and matching groups of control individuals (N = 37). A computational clot time prolongation value (cINR) was devised that correlated with their actual International Normalized Ratio (INR) values, with differences between individual INR and cINR values shown to derive from the insensitivity of the INR to tissue factor pathway inhibitor (TFPI). The analysis suggests that normal range variation in TFPI levels could be an important contributor to the failure of the INR to adequately reflect the anticoagulated state in some individuals. Warfarin-induced changes in thrombin propagation phase parameters were then compared to those induced by unfractionated heparin, fondaparinux, rivaroxaban, and a reversible thrombin inhibitor. Anticoagulants were assessed at concentrations yielding equivalent cINR values, with each anticoagulant evaluated using 32 unique coagulation proteome compositions. The analyses showed that no anticoagulant recapitulated all features of warfarin propagation phase dynamics; differences in propagation phase effects suggest that anticoagulants that selectively target fXa or thrombin may

Decision-level fusion of SAR and IR sensor information for automatic target detection

NASA Astrophysics Data System (ADS)

Cho, Young-Rae; Yim, Sung-Hyuk; Cho, Hyun-Woong; Won, Jin-Ju; Song, Woo-Jin; Kim, So-Hyeon

2017-05-01

We propose a decision-level architecture that combines synthetic aperture radar (SAR) and an infrared (IR) sensor for automatic target detection. We present a new size-based feature, called target-silhouette to reduce the number of false alarms produced by the conventional target-detection algorithm. Boolean Map Visual Theory is used to combine a pair of SAR and IR images to generate the target-enhanced map. Then basic belief assignment is used to transform this map into a belief map. The detection results of sensors are combined to build the target-silhouette map. We integrate the fusion mass and the target-silhouette map on the decision level to exclude false alarms. The proposed algorithm is evaluated using a SAR and IR synthetic database generated by SE-WORKBENCH simulator, and compared with conventional algorithms. The proposed fusion scheme achieves higher detection rate and lower false alarm rate than the conventional algorithms.

Protocol adherence and the ability to achieve target haemoglobin levels in haemodialysis patients.

PubMed

Chan, Kevin; Moran, John; Hlatky, Mark; Lafayette, Richard

2009-06-01

Anemia management remains complicated in patients with endstage renal disease on hemodialysis. We wished to evaluate the effect of protocol adherence to EPO and intravenous iron dosing on achieving the desired range of hemoglobin levels. A cohort of hemodialysis patients was studied to evaluate the rate of adherence to EPO and iron dosing protocols over a 5 month period. A database was completed to evaluate all known comorbidities, demographic factors, and facility issues that might affect hemoglobin levels. A logistic regression model was employed to evaluate the effect of adherence to the anemia protocols on the probability of achieving a hemoglobin level below, within or above the targeted range of 11-12.5 g/dl. Among 2114 patients, we found that adherence to both the EPO and iron dosing protocol resulted in the greatest probability of achieving the target hemoglobin range (56 +/- 5% in anemia protocol adherent patients versus 42 +/- 7% in non adherent patients). This was predominantly due to a lowered risk of having above target hemoglobin levels rather than below. The use of the anemia protocols was associated with lower rates of hospitalization (9 +/- 0.7 visits/100 months in adherent group vs 15 +/- 2 in non adherent group) and lower utilization of both EPO and intravenous iron. Furthermore, patients in the adherent groups had less variability of their hemoglobin levels month by month, at least as judged by standard deviation. Adherence to anemia protocols, as practiced in the dialysis units included in this cohort, may improve hemodialysis patients' ability to achieve target hemoglobin levels, and by avoiding above target hemoglobin values, lower drug utilization and reduce variability of hemoglobin levels.

Global climate targets and future consumption level: an evaluation of the required GHG intensity

NASA Astrophysics Data System (ADS)

Girod, Bastien; van Vuuren, Detlef Peter; Hertwich, Edgar G.

2013-03-01

Discussion and analysis on international climate policy often focuses on the rather abstract level of total national and regional greenhouse gas (GHG) emissions. At some point, however, emission reductions need to be translated to consumption level. In this article, we evaluate the implications of the strictest IPCC representative concentration pathway for key consumption categories (food, travel, shelter, goods, services). We use IPAT style identities to account for possible growth in global consumption levels and indicate the required change in GHG emission intensity for each category (i.e. GHG emission per calorie, person kilometer, square meter, kilogram, US dollar). The proposed concept provides guidance for product developers, consumers and policymakers. To reach the 2 °C climate target (2.1 tCO2-eq. per capita in 2050), the GHG emission intensity of consumption has to be reduced by a factor of 5 in 2050. The climate targets on consumption level allow discussion of the feasibility of this climate target at product and consumption level. In most consumption categories products in line with this climate target are available. For animal food and air travel, reaching the GHG intensity targets with product modifications alone will be challenging and therefore structural changes in consumption patterns might be needed. The concept opens up possibilities for further research on potential solutions on the consumption and product level to global climate mitigation.

Comparison of the CoaguChek XS handheld coagulation analyzer and conventional laboratory methods measuring international normalised ratio (INR) values during the time to therapeutic range after mechanical valve surgery.

PubMed

Bardakci, Hasmet; Altıntaş, Garip; Çiçek, Omer Faruk; Kervan, Umit; Yilmaz, Sevinc; Kaplan, Sadi; Birincioglu, Cemal Levent

2013-05-01

To compare the international normalised ratio (INR) value of patients evaluated using the CoaguChek XS versus conventional laboratory methods, in the period after open-heart surgery for mechanical valve replacement until a therapeutic range is achieved using vitamin K antagonists (VKA) together with low molecular weight heparin (LMWH). One hundred and five patients undergoing open-heart surgery for mechanical valve replacement were enrolled. Blood samples were collected from patients before surgery, and on the second and fifth postoperative days, simultaneously for both the point of care device and conventional laboratory techniques. Patients were administered VKA together with LMWH at therapeutic doses (enoxaparin 100 IU/kg twice daily) subcutaneously, until an effective range was achieved on approximately the fifth day after surgery. The mean INR values using the CoaguChek XS preoperatively and on the second and fifth days postoperatively were 1.20 (SD ± 0.09), 1.82 (SD ± 0.45), and 2.55 (SD ± 0.55), respectively. Corresponding results obtained using conventional laboratory techniques were 1.18 (SD ± 0.1), 1.81 (SD ± 0.43), and 2.51 (SD ± 0.58). The correlation coefficient was r = 0.77 preoperatively, r = 0.981 on postoperative day 2, and r = 0.983 on postoperative day 5. Results using the CoaguChek XS Handheld Coagulation Analyzer correlated strongly with conventional laboratory methods, in the bridging period between open-heart surgery for mechanical valve replacement and the achievement of a therapeutic range on warfarin and LMWH. © 2013 Wiley Periodicals, Inc.

International Normalized Ratio Is Significantly Elevated With Rivaroxaban and Apixaban Drug Therapies: A Retrospective Study.

PubMed

Ofek, Fanny; Bar Chaim, Samuel; Kronenfeld, Nirit; Ziv-Baran, Tomer; Berkovitch, Matitiahu

2017-05-01

Direct factor Xa inhibitors such as rivaroxaban or apixaban may prolong prothrombin time (PT) and elevate international normalized ratio (INR). However, these tests are not reliable for assessing the anticoagulation effects of these agents. PT assay sensitivity is relatively weak at therapeutic drug concentrations and is subjected to significant variations depending on the reagent used. Conversion of PT to INR may even increase the variability. We conducted a retrospective cross-sectional study aiming to assess the prevalence and extent of INR elevation in hospitalized patients receiving rivaroxaban or apixaban as part of their home medications and to find out whether other existing factors could elevate INR apart from the drug entity itself. The data collected from 218 hospitalized patients׳ charts included PT and INR taken on admission, patients׳ characteristics, laboratory results, other medications regularly used, and coexisting clinical conditions. No statistically significant association between INR elevation and the parameters examined was found in our study. INR was significantly elevated in both drug groups (P < 0.001), with 84.2% of rivaroxaban patients and 78.3% of apixaban patients presenting with INR levels above the higher limit of the normal range. Furthermore, INR was significantly higher in the rivaroxaban group than in the apixaban group (P < 0.001). Both of the reviewed drugs significantly elevated INR. Moreover, rivaroxaban elevates INR significantly more than apixaban, and there are apparently no other factors affecting INR but the drugs themselves. Larger prospective studies are needed to confirm and clarify the clinical significance of these results. Copyright © 2017 Elsevier HS Journals, Inc. All rights reserved.

The Variation of Work Productivity and Muscle Activities at Different Levels of Production Target

NASA Astrophysics Data System (ADS)

Nur, Nurhayati Mohd; Dawal, Siti Zawiah Md; Dahari, Mahidzal; Zuhairah Mahmud Zuhudi, Nurul

2017-10-01

This paper aims to investigate the variation of work productivity and muscle activities among workers performing industrial repetitive tasks at four different levels of production target. The work productivity and muscle activities data were recorded from twenty workers at four levels of production target corresponding to “participative (PS1)”, “normal (PS2)”, “high (PS3)” and “very high (PS4)”. The results showed that worker productivity was found to increase at higher production target and there was a significant change (p < 0.005) in work productivity across the four different production targets. The muscle activities were found to increase at higher production target and correspond to more discomfort and a higher rate of muscle fatigue. The results indicated that working with a higher production target results in higher worker productivity, but could lead to higher risk of WMSDs.

Characteristics of functional enrichment and gene expression level of human putative transcriptional target genes.

PubMed

Osato, Naoki

2018-01-19

Transcriptional target genes show functional enrichment of genes. However, how many and how significantly transcriptional target genes include functional enrichments are still unclear. To address these issues, I predicted human transcriptional target genes using open chromatin regions, ChIP-seq data and DNA binding sequences of transcription factors in databases, and examined functional enrichment and gene expression level of putative transcriptional target genes. Gene Ontology annotations showed four times larger numbers of functional enrichments in putative transcriptional target genes than gene expression information alone, independent of transcriptional target genes. To compare the number of functional enrichments of putative transcriptional target genes between cells or search conditions, I normalized the number of functional enrichment by calculating its ratios in the total number of transcriptional target genes. With this analysis, native putative transcriptional target genes showed the largest normalized number of functional enrichments, compared with target genes including 5-60% of randomly selected genes. The normalized number of functional enrichments was changed according to the criteria of enhancer-promoter interactions such as distance from transcriptional start sites and orientation of CTCF-binding sites. Forward-reverse orientation of CTCF-binding sites showed significantly higher normalized number of functional enrichments than the other orientations. Journal papers showed that the top five frequent functional enrichments were related to the cellular functions in the three cell types. The median expression level of transcriptional target genes changed according to the criteria of enhancer-promoter assignments (i.e. interactions) and was correlated with the changes of the normalized number of functional enrichments of transcriptional target genes. Human putative transcriptional target genes showed significant functional enrichments. Functional

Comparison of Warfarin use in terms of efficacy and safety in two different polyclinics

PubMed Central

Kılıç, Salih; Kemal, Hatice Soner; Yüce, Elif İlkay; Şimşek, Evrim; Yağmur, Burcu; Akgül, Nuray Memişoğlu; Çınar, Cahide Soydaş; Zoghi, Mehdi; Gürgün, Cemil

2017-01-01

Objective: This study compared the efficacy and safety of warfarin in specialized international normalized ratio (INR) outpatient clinic (INR-C) and in general cardiology outpatient clinic (General-C). Methods: Herein, 381 consecutive patients with a regular follow-up at INR-C (n=233) or General-C (n=148) for at least 1 year were retrospectively included. While INR-C patients were followed by a single experienced trained nurse, General-C patients were followed by a different cardiologist who worked in a rotational principle every month. During controls, demographic characteristics, INR levels, bleeding events, ischemic stroke, and transient ischemic attacks in the last 1 year were recorded. Primary endpoint was defined as the evaluation of the combined major bleeding and ischemic event, and secondary endpoint was defined as the evaluation of them separately. Results: The mean age of the patients was 62±12.86 and 43.8% were male. Mean time in therapeutic range (TTR) level was statistically higher in INR-C than that in General-C (68.8%±15.88 and 51.6%±23.04, respectively; p<0.001). Primary outcomes were significantly higher in General-C than that in INR-C [13.5% (20) and 6.4% (15); respectively, p=0.020]. Overall, major bleeding was observed in 25 patients (6.5%) and (2.6%) ischemic event was observed in 10 patients. In General-C patients, both major bleeding (8.8% vs. 5.2%; p=0.163) and the ischemic event (4.7% vs. 1.3%; p=0.051) were more, and no statistically significant differences were detected between the two clinics. Conclusion: The findings of our study demonstrate that patients followed in INR-C had higher TTR levels and lower bleeding and ischemic events rates that those followed in General-C. PMID:29145216

Improving Warfarin Management Within the Medical Home: A Health-System Approach.

PubMed

Rose, Anne E; Robinson, Erin N; Premo, Joan A; Hauschild, Lori J; Trapskin, Philip J; McBride, Ann M

2017-03-01

Anticoagulation clinics have been considered the optimal strategy for warfarin management with demonstrated improved patient outcomes through increased time in therapeutic international normalized ratio (INR) range, decreased critical INR values, and decreased anticoagulation-related adverse events. However, not all health systems are able to support a specialized anticoagulation clinic or may see patient volume exceed available anticoagulation clinic resources. The purpose of this study was to utilize an anticoagulation clinic model to standardize warfarin management in a primary care clinic setting. A warfarin management program was developed that included standardized patient assessment, protocolized warfarin-dosing algorithm, and electronic documentation and reporting tools. Primary care clinics were targeted for training and implementation of this program. The warfarin management program was applied to over 2000 patients and implemented at 39 clinic sites. A total of 160 nurses and 15 pharmacists were trained on the program. Documentation of warfarin dose and date of the next INR increased from 70% to 90% (P <.0001), documentation occurring within 24 hours of the INR result increased from 75% to 87% (P <.0001), and monitoring the INR at least every 4 weeks increased from 71% to 83% (P <.0001) per patient encounter. Time in therapeutic INR range improved from 65% to 75%. Incorporating a standardized approach to warfarin management in the primary care setting significantly improves warfarin-related documentation and time in therapeutic INR range. Copyright © 2016 Elsevier Inc. All rights reserved.

International normalized ratio self-testing and self-management: improving patient outcomes.

PubMed

Pozzi, Matteo; Mitchell, Julia; Henaine, Anna Maria; Hanna, Najib; Safi, Ola; Henaine, Roland

2016-01-01

Long term oral anti-coagulation with vitamin K antagonists is a risk factor of hemorrhagic or thromebomlic complications. Periodic laboratory testing of international normalized ratio (INR) and a subsequent dose adjustment are therefore mandatory. The use of home testing devices to measure INR has been suggested as a potential way to improve the comfort and compliance of the patients and their families, the frequency of monitoring and, finally, the management and safety of long-term oral anticoagulation. In pediatric patients, increased doses to obtain and maintain the therapeutic target INR, more frequent adjustments and INR testing, multiple medication, inconstant nutritional intake, difficult venepunctures, and the need to go to the laboratory for testing (interruption of school and parents' work attendance) highlight those difficulties. After reviewing the most relevant published studies of self-testing and self-management of INR for adult patients and children on oral anticoagulation, it seems that these are valuable and effective strategies of INR control. Despite an unclear relationship between INR control and clinical effects, these self-strategies provide a better control of the anticoagulant effect, improve patients and their family quality of life, and are an appealing solution in term of cost-effectiveness. Structured education and knowledge evaluation by trained health care professionals is required for children, to be able to adjust their dose treatment safely and accurately. However, further data are necessary in order to best define those patients who might better benefit from this multidisciplinary approach.

Evaluation of protein C and protein S levels in patients with diabetes mellitus receiving therapy with statins and ACE inhibitors or angiotensin II receptor blockers.

PubMed

Aktaş, Şerife; Uçak, Sema; Kurt, Fatma; Taşdemir, Mehmet; Kutlu, Orkide; Eker, Pınar

2018-01-01

To evaluate protein C, protein S level in patients with diabetes mellitus receiving statin and ACE inhibitor/ARB therapy. 95 patients were included in the study and divided into four groups depending on the use of statin and ACE inhibitor/ARB therapy. Group 1 comprised of patients receiving statin therapy (n = 15), Group 2 comprised of patients receiving ACE inhibitor/ARB therapy (n = 31), Group 3 comprised of patients receiving statin and ACE inhibitor/ARB therapy (n = 23), and Group 4 comprised of patients who did not receive either statin or ACE inhibitor/ARB therapy (n = 26). These four groups were compared with respect to protein C, protein S, fibrinogen, D-dimer, INR, and aPTT levels. There were statistically significant differences with respect to protein C levels. Group 1 and group 2 had higher protein C levels compared with group 4. (p < .01). Similarly, Group 3 had higher protein C levels compared with group 4. (p < .01). There was no significant difference between the groups with respect to protein S, INR, aPTT, and D-dimer levels. Diabetic patients receiving statin or ACE inhibitor/ARB therapy had higher protein C levels. Use of statin and ACE inhibitor/ARB therapy in diabetic patients decrease hypercoagulability and therefore could reduce the occurrence of cardiovascular events. Copyright © 2017 Elsevier B.V. All rights reserved.

OPS MCC level B/C formulation requirements: Area targets and space volumes processor

NASA Technical Reports Server (NTRS)

Bishop, M. J., Jr.

1979-01-01

The level B/C mathematical specifications for the area targets and space volumes processor (ATSVP) are described. The processor is designed to compute the acquisition-of-signal (AOS) and loss-of-signal (LOS) times for area targets and space volumes. The characteristics of the area targets and space volumes are given. The mathematical equations necessary to determine whether the spacecraft lies within the area target or space volume are given. These equations provide a detailed model of the target geometry. A semianalytical technique for predicting the AOS and LOS time periods is disucssed. This technique was designed to bound the actual visibility period using a simplified target geometry model and unperturbed orbital motion. Functional overview of the ATSVP is presented and it's detailed logic flow is described.

Can oral vitamin K before elective surgery substitute for preoperative heparin bridging in patients on vitamin K antagonists?

PubMed

Steib, A; Barre, J; Mertes, M; Morel, M H; Nathan, N; Ozier, Y; Treger, M; Samama, C M

2010-03-01

After a vitamin K antagonist (VKA) overdose, 1-2 mg of oral vitamin K can lower the International Normalized Ratio (INR) to the therapeutic range. To establish whether oral vitamin K can substitute for heparin bridging and decrease the INR to < or = 1.5 before elective surgery. Patients on long-term VKAs were randomized either to heparin bridging after the last VKA dose on day -5 before surgery (group H) or to VKA treatment until day -2, followed by 1 mg of oral vitamin K on the day before surgery (group K). Blood clotting variables were assessed on days -5/-2, 1 and 0, and postoperatively. If the target INR was not achieved 2 h before incision, surgery was deferred or performed after injection of prothrombin complex concentrate (PCC). In 30 of 94 included patients, baseline INR was outside the chosen range (18, INR < 2; 12, INR > 3.5), leaving 34 eligible patients in group H and 30 in group K. The groups were balanced in terms of body mass index, VKA treatment duration and indication, scheduled surgery, preoperative and postoperative hemoglobin, and blood loss. The INR was significantly higher in group K on days -1 and 0 than in group H. An INR < or = 1.5 was not achieved in 20 group K patients (66%). Surgery was postponed or performed after PCC injection in 12 of these 20 patients. Oral vitamin K (1 mg) cannot substitute for heparin bridging before surgery. In addition, one-third of patients on VKAs were exposed to a risk of bleeding (overdose) or thrombosis (underdose), thus highlighting the need for new oral anticoagulants.

Classification of video sequences into chosen generalized use classes of target size and lighting level.

PubMed

Leszczuk, Mikołaj; Dudek, Łukasz; Witkowski, Marcin

The VQiPS (Video Quality in Public Safety) Working Group, supported by the U.S. Department of Homeland Security, has been developing a user guide for public safety video applications. According to VQiPS, five parameters have particular importance influencing the ability to achieve a recognition task. They are: usage time-frame, discrimination level, target size, lighting level, and level of motion. These parameters form what are referred to as Generalized Use Classes (GUCs). The aim of our research was to develop algorithms that would automatically assist classification of input sequences into one of the GUCs. Target size and lighting level parameters were approached. The experiment described reveals the experts' ambiguity and hesitation during the manual target size determination process. However, the automatic methods developed for target size classification make it possible to determine GUC parameters with 70 % compliance to the end-users' opinion. Lighting levels of the entire sequence can be classified with an efficiency reaching 93 %. To make the algorithms available for use, a test application has been developed. It is able to process video files and display classification results, the user interface being very simple and requiring only minimal user interaction.

Racial/Ethnic Differences in Knowledge of Personal and Target Levels of Cardiovascular Health Indicators.

PubMed

Ma, Mindy; Ma, Alyson

2015-10-01

This study aimed to examine ethnic differences in knowledge of personal and target levels of cardiovascular health indicators between non-Hispanic whites and African Americans. A secondary objective was to evaluate the associations between knowledge of cardiovascular health indicators and health promotion behaviors. Participants (66.7% female) consisted of 265 whites and 428 African Americans, ages 18 and older recruited from primary care clinics and churches. Respondents completed a brief survey on blood pressure (BP), total cholesterol, blood glucose, body mass index (BMI), diet, and physical activity. Whites were more likely than African Americans to report knowing their personal and target levels of cardiovascular health indicators. Knowledge of personal BP and/or BMI was positively associated with actual physical activity, and awareness of personal blood glucose was positively associated with healthy dietary practices for participants in both groups. Among whites, awareness of personal BP and knowledge of target levels for BP, total cholesterol, and BMI were also associated with healthy diet. Results suggest there are racial/ethnic disparities in knowledge of personal and ideal levels of cardiovascular health indicators, and that this knowledge is related to health promotion behaviors. Targeted educational efforts are warranted to enhance knowledge of personal risk indicators among African Americans.

Personalized Prediction of Glaucoma Progression Under Different Target Intraocular Pressure Levels Using Filtered Forecasting Methods.

PubMed

Kazemian, Pooyan; Lavieri, Mariel S; Van Oyen, Mark P; Andrews, Chris; Stein, Joshua D

2018-04-01

To generate personalized forecasts of how patients with open-angle glaucoma (OAG) experience disease progression at different intraocular pressure (IOP) levels to aid clinicians with setting personalized target IOPs. Secondary analyses using longitudinal data from 2 randomized controlled trials. Participants with moderate or advanced OAG from the Collaborative Initial Glaucoma Treatment Study (CIGTS) or the Advanced Glaucoma Intervention Study (AGIS). By using perimetric and tonometric data from trial participants, we developed and validated Kalman Filter (KF) models for fast-, slow-, and nonprogressing patients with OAG. The KF can generate personalized and dynamically updated forecasts of OAG progression under different target IOP levels. For each participant, we determined how mean deviation (MD) would change if the patient maintains his/her IOP at 1 of 7 levels (6, 9, 12, 15, 18, 21, or 24 mmHg) over the next 5 years. We also model and predict changes to MD over the same time horizon if IOP is increased or decreased by 3, 6, and 9 mmHg from the level attained in the trials. Personalized estimates of the change in MD under different target IOP levels. A total of 571 participants (mean age, 64.2 years; standard deviation, 10.9) were followed for a mean of 6.5 years (standard deviation, 2.8). Our models predicted that, on average, fast progressors would lose 2.1, 6.7, and 11.2 decibels (dB) MD under target IOPs of 6, 15, and 24 mmHg, respectively, over 5 years. In contrast, on average, slow progressors would lose 0.8, 2.1, and 4.1 dB MD under the same target IOPs and time frame. When using our tool to quantify the OAG progression dynamics for all 571 patients, we found no statistically significant differences over 5 years between progression for black versus white, male versus female, and CIGTS versus AGIS participants under different target IOPs (P > 0.05 for all). To our knowledge, this is the first clinical decision-making tool that generates personalized

The pharmacology and management of the vitamin K antagonists: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy.

PubMed

Ansell, Jack; Hirsh, Jack; Poller, Leon; Bussey, Henry; Jacobson, Alan; Hylek, Elaine

2004-09-01

allow the INR to return to normal, and beginning therapy with full-dose unfractionated heparin or full-dose low-molecular-weight heparin as the INR falls (Grade 2C). In patients undergoing dental procedures, we suggest the use of tranexamic acid mouthwash (Grade 2B) or epsilon amino caproic acid mouthwash without interrupting anticoagulant therapy (Grade 2B) if there is a concern for local bleeding. For most patients who have a lupus inhibitor, we suggest a therapeutic target INR of 2.5 (range, 2.0 to 3.0) [Grade 2B]. In patients with recurrent thromboembolic events with a therapeutic INR or other additional risk factors, we suggest a target INR of 3.0 (range, 2.5 to 3.5) [Grade 2C]. As models of anticoagulation monitoring and management, we recommend that clinicians incorporate patient education, systematic INR testing, tracking, and follow-up, and good communication with patients concerning results and dosing decisions (Grade 1C+).

Cost of curative pediatric services in a public sector setting.

PubMed

Krishnan, Anand; Arora, Narendra K; Pandav, Chandrakant S; Kapoor, Suresh K

2005-08-01

To estimate the cost of ambulatory (out-patient) and in-patient pediatric health services for the year 1999 provided by All India Institute of Medical Sciences (AIIMS) at all the three levels-primary, secondary and tertiary level. The costing module developed by Children's Vaccines Initiative (CVI) was used. This rapid assessment tool focuses on collection of data at macro level by using key informants like doctors, nursing staff, accountant, store keeper, engineer etc. Cost per beneficiary was estimated separately for in-patients and out-patients and was calculated by dividing the total cost of the services by the number of beneficiaries for the year 1999. For the out-patient, the beneficiaries were the total out-patient attendees and for the in-patient, it was the total pediatric admissions multiplied by mean duration of stay in days. The cost per out-patient visit was INR.20.2 (US0.44 dollars@1US dollars=INR.46) at primary level, higher than INR14.5 (US0.31 dollars) at the secondary level, while at tertiary level it was INR 33.8 (US 0.73 dollars). At the primary and secondary level, non-physician cost was more than the physician cost, and for tertiary level, physician cost was much higher than the other costs. There were no in-patient services at primary level. The cost of in-patient services at secondary level was estimated as INR 419.30 (US 9.1 dollars) per patient per day with a bed occupancy rate of 60%. Two-fifths of the cost was due to nursing and other supportive staff and one fifth due to the doctor costs and overhead costs. The unit cost of INR 928 (US 20.2 dollars) per patient per day incurred at AIIMS with a bed occupancy rate of 100% was almost twice that of secondary level. In contrast to the secondary level, almost half the total costs at tertiary level was due to the doctors costs. Effective use of resources at lower level of care especially ambulatory care at primary level and inpatient care at secondary level can result in much higher savings

Switching from rivaroxaban to warfarin: an open label pharmacodynamic study in healthy subjects

PubMed Central

Moore, Kenneth Todd; Byra, William; Vaidyanathan, Seema; Natarajan, Jaya; Ariyawansa, Jay; Salih, Hiba; Turner, Kenneth C

2015-01-01

Aims The primary objective was to explore the pharmacodynamic changes during transition from rivaroxaban to warfarin in healthy subjects. Safety, tolerability and pharmacokinetics were assessed as secondary objectives. Methods An open label, non-randomized, sequential two period study. In treatment period 1 (TP1), subjects received rivaroxaban 20 mg once daily (5 days), followed by co-administration with a warfarin loading dose regimen of 5 or 10 mg (for the 10 mg regimen, the dose could be uptitrated to attain target international normalized ratio [INR] ≥2.0) once daily (2–4 days). When trough INR values ≥2.0 were attained, rivaroxaban was discontinued and warfarin treatment continued as monotherapy (INR 2.0–3.0). During treatment period 2, subjects received the same warfarin regimen as in TP1, but without rivaroxaban. Results During co-administration, maximum INR and prothrombin time (PT) values were higher than with rivaroxaban or warfarin monotherapy. The mean maximum effect (Emax) for INR after co-administration was 2.79–4.15 (mean PT Emax 41.0–62.7 s), compared with 1.41–1.74 (mean PT Emax 20.1–25.2 s) for warfarin alone. However, rivaroxaban had the smallest effect on INR at trough rivaroxaban concentrations. Neither rivaroxaban nor warfarin significantly affected maximum plasma concentrations of the other drug. Conclusions The combined pharmacodynamic effects during co-administration of rivaroxaban and warfarin were greater than additive, but the pharmacokinetics of both drugs were unaffected. Co-administration was well tolerated. When transitioning from rivaroxaban to warfarin, INR monitoring during co-administration should be performed at the trough rivaroxaban concentration to minimize the effect of rivaroxaban on INR. PMID:25475601

Activation Levels, Handling, and Storage of Activated Components in the Target Hall at FRIB

NASA Astrophysics Data System (ADS)

Georgobiani, D.; Bennett, R.; Bollen, G.; Kostin, M.; Ronningen, R.

2018-06-01

The Facility for Rare Isotope Beams (FRIB) is a major new scientific user facility under construction in the United States for nuclear science research with beams of rare isotopes. 400 kW beam operations with heavy ions ranging from oxygen to uranium will create a high radiation environment for many components, particularly for the beam line components located in the target hall, where approximately 100 kW of beam power are dissipated in the target and another 300 kW are dissipated in the beam dump. Detailed studies of the component activation, their remote handling, storage, and transport, have been performed to ensure safe operation levels in this environment. Levels of activation are calculated for the beam line components within the FRIB target hall.

Effects of Tramadol Coadministration on Prothrombin Time-International Normalized Ratio in Patients Receiving Warfarin.

PubMed

Hosono, Tomomi; Kondo, Aiko; Kambayashi, Yasuyuki; Homma, Masato

2017-01-01

Several case studies have reported a possible drug interaction between warfarin and tramadol where tramadol coadministration enhanced the antithrombotic effects of warfarin. To assess this drug interaction, changes in prothrombin time-international normalized ratio (PT-INR) before and after tramadol coadministration were investigated in patients receiving warfarin. For this study, we examined 54 patients (male/female: 22/32, 68.4±12.7 years) who were being treated with warfarin for deep vein thrombosis, atrial fibrillation, arteriosclerosis obliterans, congestive heart failure, and other vascular diseases. Significant increases in PT-INR were observed 9.5 (1-118) d after coadministration of tramadol (1.81±0.56 vs. 2.47±1.10, p<0.01). Twenty-eight patients (PT-INR increased group) with PT-INR elevation of greater than 0.5 or dose reduction of warfarin after coadministration of tramadol were compared with other groups of patients to find drug interaction risk factors. Logistic regression analysis revealed that lower levels of albumin (3.5 g/dL or less) [odds ratio (OR) 22.1; 95%CI 2.9-169.9]; lower eGFR (50 mL/min or less) (OR 7.7; 95%CI 1.4-42.0); and PT-INR before tramadol coadministration (OR 38.2; 95%CI 3.7-397.6) were characteristic of the PT-INR increased group. These results suggest that tramadol coadministration enhanced the antithrombotic effects of warfarin in patients with higher PT-INR, lower albumin levels and decreased renal function as the risk factors for this drug interaction.

In Potential Stroke Patients on Warfarin, the International Normalized Ratio Predicts Ischemia.

PubMed

Cao, Cathy; Martinelli, Ashley; Spoelhof, Brian; Llinas, Rafael H; Marsh, Elisabeth B

2017-01-01

Stroke can occur in patients on warfarin despite anticoagulation. Patients with a low international normalized ratio (INR) should theoretically be at greater risk for ischemia than those who are therapeutic. Therefore, INR may be able to indicate whether new neurological deficits are more likely strokes or stroke mimics in patients on warfarin. This study evaluates the association and predictive value of INR in determining the likelihood of ischemia. Patients were identified using the acute stroke registry at a Primary Stroke Center from January 2013 through December 2014. All adult patients undergoing evaluation for acute stroke with prior documented use of warfarin and an INR level at presentation were included. Data were collected regarding patient demographics, medical comorbidities, stroke severity, reason for anticoagulation, and laboratory studies including INR. Student t tests and χ2 analysis were used to evaluate factors associated with increased likelihood of ischemia (stroke or transient ischemic attack) versus mimic. Significant results were entered into a multivariable regression analysis. Sensitivity and specificity analyses were conducted to determine the predictive value of INR for ischemic risk. 116 patients were included; 46 were diagnosed with ischemia, 70 were diagnosed as mimics. 75% of patients were on warfarin for atrial fibrillation versus 25% for venous thrombosis. A statistically significant difference in mean INR for patients with ischemia (n = 46) versus mimics (n = 70) was observed (1.7 vs. 2.8; p < 0.001). In multivariable analysis, both sub-therapeutic INR (p < 0.001) and atrial fibrillation (p = 0.014) were predictors of ischemia. In patients with an INR ≥2, the predictive value of having a non-ischemic etiology was 79%. No patient with an INR of ≥3.6 was found to have ischemia. Sub-therapeutic INR and atrial fibrillation are strongly associated with ischemia in patients on warfarin presenting with acute neurologic symptoms

DOE Office of Scientific and Technical Information (OSTI.GOV)

Koval, G.N.; Kuzmina, A.I.; Kolomiets, N.F.

In this paper results of the long term of control of tritium concentration in the water fractions in the region close to the tritium laboratories of INR NAS of Ukraine are presented. The regular observations for the tritium concentration in the water fractions (thawed water of the snow cover, birch juice and sewer water) in the influence region of tritium laboratories shows small amount of tritium concentration in all kinds of investigated water fractions in comparison with the tritium concentration in the reper points. The proper connection of the levels of tritium concentration of the water samples with the quantitymore » of the technology production is observed. In common, the tritium pollution on the territory of INR shows the tendency for a considerable decrease of the environmental pollution levels from year to year. It can be explained by the perfection of the production technology of tritium structures and targets as well as the rising of the qualification of the personnel. 3 refs., 4 figs.« less

Adaptive bi-level programming for optimal gene knockouts for targeted overproduction under phenotypic constraints

PubMed Central

2013-01-01

Background Optimization procedures to identify gene knockouts for targeted biochemical overproduction have been widely in use in modern metabolic engineering. Flux balance analysis (FBA) framework has provided conceptual simplifications for genome-scale dynamic analysis at steady states. Based on FBA, many current optimization methods for targeted bio-productions have been developed under the maximum cell growth assumption. The optimization problem to derive gene knockout strategies recently has been formulated as a bi-level programming problem in OptKnock for maximum targeted bio-productions with maximum growth rates. However, it has been shown that knockout mutants in fact reach the steady states with the minimization of metabolic adjustment (MOMA) from the corresponding wild-type strains instead of having maximal growth rates after genetic or metabolic intervention. In this work, we propose a new bi-level computational framework--MOMAKnock--which can derive robust knockout strategies under the MOMA flux distribution approximation. Methods In this new bi-level optimization framework, we aim to maximize the production of targeted chemicals by identifying candidate knockout genes or reactions under phenotypic constraints approximated by the MOMA assumption. Hence, the targeted chemical production is the primary objective of MOMAKnock while the MOMA assumption is formulated as the inner problem of constraining the knockout metabolic flux to be as close as possible to the steady-state phenotypes of wide-type strains. As this new inner problem becomes a quadratic programming problem, a novel adaptive piecewise linearization algorithm is developed in this paper to obtain the exact optimal solution to this new bi-level integer quadratic programming problem for MOMAKnock. Results Our new MOMAKnock model and the adaptive piecewise linearization solution algorithm are tested with a small E. coli core metabolic network and a large-scale iAF1260 E. coli metabolic network

Adaptive bi-level programming for optimal gene knockouts for targeted overproduction under phenotypic constraints.

PubMed

Ren, Shaogang; Zeng, Bo; Qian, Xiaoning

2013-01-01

Optimization procedures to identify gene knockouts for targeted biochemical overproduction have been widely in use in modern metabolic engineering. Flux balance analysis (FBA) framework has provided conceptual simplifications for genome-scale dynamic analysis at steady states. Based on FBA, many current optimization methods for targeted bio-productions have been developed under the maximum cell growth assumption. The optimization problem to derive gene knockout strategies recently has been formulated as a bi-level programming problem in OptKnock for maximum targeted bio-productions with maximum growth rates. However, it has been shown that knockout mutants in fact reach the steady states with the minimization of metabolic adjustment (MOMA) from the corresponding wild-type strains instead of having maximal growth rates after genetic or metabolic intervention. In this work, we propose a new bi-level computational framework--MOMAKnock--which can derive robust knockout strategies under the MOMA flux distribution approximation. In this new bi-level optimization framework, we aim to maximize the production of targeted chemicals by identifying candidate knockout genes or reactions under phenotypic constraints approximated by the MOMA assumption. Hence, the targeted chemical production is the primary objective of MOMAKnock while the MOMA assumption is formulated as the inner problem of constraining the knockout metabolic flux to be as close as possible to the steady-state phenotypes of wide-type strains. As this new inner problem becomes a quadratic programming problem, a novel adaptive piecewise linearization algorithm is developed in this paper to obtain the exact optimal solution to this new bi-level integer quadratic programming problem for MOMAKnock. Our new MOMAKnock model and the adaptive piecewise linearization solution algorithm are tested with a small E. coli core metabolic network and a large-scale iAF1260 E. coli metabolic network. The derived knockout

Advanced age, anticoagulation intensity, and risk for intracranial hemorrhage among patients taking warfarin for atrial fibrillation.

PubMed

Fang, Margaret C; Chang, Yuchiao; Hylek, Elaine M; Rosand, Jonathan; Greenberg, Steven M; Go, Alan S; Singer, Daniel E

2004-11-16

targeting INRs less than 2.0. Similarly, INRs of 3.5 or greater should be avoided.

Using the Instructional Level as a Criterion to Target Reading Interventions

ERIC Educational Resources Information Center

Parker, David C.; Burns, Matthew K.

2014-01-01

The instructional hierarchy offers a useful framework for targeting academic interventions. Within this framework, the accuracy with which a student reads might function as an indicator that the student should receive an intervention that focuses either on accuracy or on fluency. The current study examined whether the instructional level for…

Cost analysis of a managed care decentralized outpatient pharmacy anticoagulation service.

PubMed

Anderson, Robert J

2004-01-01

To determine the per-patient-per-month (PPPM) cost of a decentralized outpatient pharmacy anticoagulation service (OPAS) in patients with chronic atrial fibrillation (AF) who were maintained on warfarin sodium therapy in a managed care setting, to compare the annual costs versus the risk for stroke, and to assess the quality of the anticoagulant management. Data were collected retrospectively from clinical, research, and administrative claims databases. Patient demographic data were stratified to include age and risk factors for stroke. Inclusion criteria for the study were adult patients (>18 years) who were maintained on chronic warfarin therapy with a diagnosis of AF (diagnosis code 427.31) and continuously enrolled during calendar year 2000. The cost analysis included the personnel cost of clinical pharmacy specialists, direct and indirect cost of laboratory tests for international normalized ratios (INR), and anticoagulant (warfarin plus bridge therapy with a low molecular weight heparin) drug cost and dispensing fee. The percentage of INR values within or near target was used to evaluate the effectiveness of the service. A total of 97 patients on chronic warfarin therapy for AF were identified for cost analysis. The demographics for these patients included the following: 71% were male, with 32% of the patients over the age of 75 years, and 60% had 1 or more identifiable risk factors for stroke. Utilizing established criteria, 80.4% of the sample was considered to be at high risk for ischemic stroke. A majority of the patients (94.8%) had nonvalvular disease, with an INR goal in the range of 2 to 3 in 91.8% of the cases. The PPPM cost for the OPAS monitoring service was $51.25, distributed as $13.78 (27%) in personnel costs for monitoring pharmacists, $18.38 (36%) for lab tests, and $19.09 (37%) for anticoagulant drug costs. These costs did not significantly differ among patient groups with various risks for ischemic stroke. For nonvalvular AF patients, the

[Change in Perioperative Hemostatic Function in Patients Undergoing Hepatic Resection for Primary and Metastatic Liver Cancer].

PubMed

Komasawa, Nobuyasu; Ueki, Ryusuke; Atagi, Kazuaki; Nishi, Shinichi

2015-08-01

Patients undergoing primary hepatic resection often develop hemostatic dysfunction associated with cirrhosis. We retrospectively surveyed pre- and postoperative prothrombin time (PT) and the PT expressed as international normalized ratio (PT-INR) in 39 patients undergoing primary liver resection. We also compared PT changes between primary and metastatic cancer cases (8 cases). Postoperative PT-INR was 1.40 ± 0.38, which was significantly prolonged compared to preoperative PT-INR of 1.08 ± 0.07. Preoperative PT was over 70% in all 39 patients undergoing primary liver resection, whereas postoperative PT was less than 60% in 13 of 39 patients. No significant difference was found in preoperative PT-INR between primary and metastatic cancer cases, but postoperative PT-INR was significantly prolonged in primary cancer cases. Patients undergoing primary liver resection are susceptible to hemostatic dysfunction, even with preoperative PT levels within normal limits.

Meigo governs dendrite targeting specificity by modulating Ephrin level and N-glycosylation

PubMed Central

Sekine, Sayaka U; Haraguchi, Shuka; Chao, Kinhong; Kato, Tomoko; Luo, Liqun; Miura, Masayuki; Chihara, Takahiro

2016-01-01

Neural circuit assembly requires precise dendrite and axon targeting. We identified an evolutionarily conserved endoplasmic reticulum (ER) protein, Meigo, from a mosaic genetic screen in Drosophila melanogaster. Meigo was cell-autonomously required in olfactory receptor neurons and projection neurons to target their axons and dendrites to the lateral antennal lobe and to refine projection neuron dendrites into individual glomeruli. Loss of Meigo induced an unfolded protein response and reduced the amount of neuronal cell surface proteins, including Ephrin. Ephrin overexpression specifically suppressed the projection neuron dendrite refinement defect present in meigo mutant flies, and ephrin knockdown caused a similar projection neuron dendrite refinement defect. Meigo positively regulated the level of Ephrin N-glycosylation, which was required for its optimal function in vivo. Thus, Meigo, an ER-resident protein, governs neuronal targeting specificity by regulating ER folding capacity and protein N-glycosylation. Furthermore, Ephrin appears to be an important substrate that mediates Meigo’s function in refinement of glomerular targeting. PMID:23624514

Changes in the level of perforin and its transcript during effector and target cell interactions.

PubMed

Kim, K K; Blakely, A; Zhou, Z; Davis, J; Clark, W; Kwon, B S

1993-05-01

Perforin is a cytoplasmic granule protein expressed in cytotoxic lymphocytes, and is capable of lysing target cells. This protein is induced as cytotoxic T cells are activated, and the mRNA expression is modulated by various stimulators. These observations suggest possible changes in the level of perforin transcripts and protein when killer lymphocytes meet specific target cells leading to target cell death. To address this question, we examined three murine T-cell clones and primary human NK cells in perforin expression. When the cytotoxic lymphocytes were exposed to sensitive targets, perforin mRNA disappeared within 5 to 30 min and appeared within an hour thereafter. Among the murine T cell clones, L3 and OE4 showed two phases of mRNA decrease while human NK cells and the third murine T cell clone, AB.1, showed only one phase of mRNA loss during a 240 min period. The data indicate that when cytotoxic lymphocytes receive signals from a sensitive target, the cells rapidly degrade previously accumulated perforin mRNA and synthesize new transcripts. Interestingly, heat shock protein 70 mRNA was induced as the perforin mRNA levels recovered, while P55 Il-2 receptor mRNA was downregulated within 5 min after exposure to targets. The perforin protein level also rapidly decreased immediately after the interaction with the target, followed by a recovery, and then another decrease as seen in primary human NK cells, OE4 and L3 cells. However, in the AB.1 clone, no change in perforin content was detectable, despite the loss of perforin mRNA.(ABSTRACT TRUNCATED AT 250 WORDS)

Experimental techniques for in-ring reaction experiments

NASA Astrophysics Data System (ADS)

Mutterer, M.; Egelhof, P.; Eremin, V.; Ilieva, S.; Kalantar-Nayestanaki, N.; Kiselev, O.; Kollmus, H.; Kröll, T.; Kuilman, M.; Chung, L. X.; Najafi, M. A.; Popp, U.; Rigollet, C.; Roy, S.; von Schmid, M.; Streicher, B.; Träger, M.; Yue, K.; Zamora, J. C.; the EXL Collaboration

2015-11-01

As a first step of the EXL project scheduled for the New Experimental Storage Ring at FAIR a precursor experiment (E105) was performed at the ESR at GSI. For this experiment, an innovative differential pumping concept, originally proposed for the EXL recoil detector ESPA, was successfully applied. The implementation and essential features of this novel technical concept will be discussed, as well as details on the detectors and the infrastructure around the internal gas-jet target. With 56Ni(p, p)56Ni elastic scattering at 400 MeV u-1, a nuclear reaction experiment with stored radioactive beams was realized for the first time. Finally, perspectives for a next-generation EXL-type setup are briefly discussed.

Symmorphic Intersecting Nodal Rings in Semiconducting Layers

NASA Astrophysics Data System (ADS)

Gong, Cheng; Xie, Yuee; Chen, Yuanping; Kim, Heung-Sik; Vanderbilt, David

2018-03-01

The unique properties of topological semimetals have strongly driven efforts to seek for new topological phases and related materials. Here, we identify a critical condition for the existence of intersecting nodal rings (INRs) in symmorphic crystals, and further classify all possible kinds of INRs which can be obtained in the layered semiconductors with Amm2 and Cmmm space group symmetries. Several honeycomb structures are suggested to be topological INR semimetals, including layered and "hidden" layered structures. Transitions between the three types of INRs, named as α , β , and γ type, can be driven by external strains in these structures. The resulting surface states and Landau-level structures, more complicated than those resulting from a simple nodal loop, are also discussed.

Impact of genetic factors (VKORC1, CYP2C9, CYP4F2 and EPHX1) on the anticoagulation response to fluindione

PubMed Central

Lacut, Karine; Ayme-Dietrich, Estelle; Gourhant, Lenaick; Poulhazan, Elise; Andro, Marion; Becquemont, Laurent; Mottier, Dominique; Le Gal, Gregoire; Verstuyft, Celine

2012-01-01

AIM Genetic variants of the enzyme that metabolizes warfarin, cytochrome P-450 2C9 (CYP2C9) and of a key pharmacologic target of vitamin K antagonists, vitamin K epoxide reductase (VKORC1), contribute to differences in patients' responses to coumarin derivatives. The role of these variants in fluindione response is unknown. Our aim was to assess whether genetic factors contribute to the variability in the response to fluindione. METHODS Four hundred sixty-five patients with a venous thromboembolic event treated by fluindione for at least 3 months with a target international normalized ratio (INR) of 2.0 to 3.0 were studied. VKORC1, CYP2C9, CYP4F2 and EPHX1 genotypes were assessed. INR checks, fluindione doses and bleeding events were collected. RESULTS VKORC1 genotype had a significant impact on early anticoagulation (INR value ≥2 after the first two intakes) (P < 0.0001), on the time required to reach a first INR within the therapeutic range (P < 0.0001) and on the time to obtain a first INR value > 4 (P = 0.0002). The average daily dose of fluindione during the first period of stability was significantly associated with the VKORC1 genotype: 19.8 mg (±5.5) for VKORC1 CC, 14.7 mg (±6.2) for VKORC1 CT and 8.2 mg (±2.5) for VKORC1 TT (P < 0.0001). CYP2C9, CYP4F2 and EPHX1 genotypes did not significantly influence the response to fluindione. CONCLUSIONS VKORC1 genotype strongly affected anticoagulation induced by fluindione whereas CYP2C9, CYP4F2 and EPHX1 genotypes seemed less determining. PMID:21883387

Targeted health department expenditures benefit birth outcomes at the county level.

PubMed

Bekemeier, Betty; Yang, Youngran; Dunbar, Matthew D; Pantazis, Athena; Grembowski, David E

2014-06-01

Public health leaders lack evidence for making decisions about the optimal allocation of resources across local health department (LHD) services, even as limited funding has forced cuts to public health services while local needs grow. A lack of data has also limited examination of the outcomes of targeted LHD investments in specific service areas. This study used unique, detailed LHD expenditure data gathered from state health departments to examine the influence of maternal and child health (MCH) service investments by LHDs on health outcomes. A multivariate panel time-series design was used in 2013 to estimate ecologic relationships between 2000-2010 LHD expenditures on MCH and county-level rates of low birth weight and infant mortality. The unit of analysis was 102 LHD jurisdictions in Washington and Florida. Results indicate that LHD expenditures on MCH services have a beneficial relationship with county-level low birth weight rates, particularly in counties with high concentrations of poverty. This relationship is stronger for more targeted expenditure categories, with expenditures in each of the three specific examined MCH service areas demonstrating the strongest effects. Findings indicate that specific LHD investments in MCH have an important effect on related health outcomes for populations in poverty and likely help reduce the costly burden of poor birth outcomes for families and communities. These findings underscore the importance of monitoring the impact of these evolving investments and ensuring that targeted, beneficial investments are not lost but expanded upon across care delivery systems. Copyright © 2014 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.

Economic Analysis of Delivering Primary Health Care Services through Community Health Workers in 3 North Indian States

PubMed Central

Prinja, Shankar; Jeet, Gursimer; Verma, Ramesh; Kumar, Dinesh; Bahuguna, Pankaj; Kaur, Manmeet; Kumar, Rajesh

2014-01-01

Background We assessed overall annual and unit cost of delivering package of services and specific services at sub-centre level by CHWs and cost effectiveness of Government of India’s policy of introducing a second auxiliary nurse midwife (ANM) at the sub-centre compared to scenario of single ANM sub-centre. Methods We undertook an economic costing of health services delivered by CHWs, from a health system perspective. Bottom-up costing method was used to collect data on resources spent in 50 randomly selected sub-centres selected from 4 districts. Mean unit cost along with its 95% confidence intervals were estimated using bootstrap method. Multiple linear regression model was used to standardize cost and assess its determinants. Results Annually it costs INR 1.03 million (USD 19,381), or INR 187 (USD 3.5) per capita per year, to provide a package of preventive, curative and promotive services through community health workers. Unit costs for antenatal care, postnatal care, DOTS treatment and immunization were INR 525 (USD 10) per full ANC care, INR 767 (USD 14) per PNC case registered, INR 974 (USD 18) per DOTS treatment completed and INR 97 (USD 1.8) per child immunized in routine immunization respectively. A 10% increase in human resource costs results in 6% rise in per capita cost. Similarly, 10% increment in the ANC case registered per provider through-put results in a decline in unit cost ranging from 2% in the event of current capacity utilization to 3% reduction in case of full capacity utilization. Incremental cost of introducing 2nd ANM at sub-centre level per unit percent increase ANC coverage was INR 23,058 (USD 432). Conclusion Our estimates would be useful in undertaking full economic evaluations or equity analysis of CHW programs. Government of India’s policy of hiring 2nd ANM at sub-centre level is very cost effective from Indian health system perspective. PMID:24626285

Quality of anticoagulation management with warfarin among outpatients in a tertiary hospital in Addis Ababa, Ethiopia: a retrospective cross-sectional study.

PubMed

Fenta, Teferi Gedif; Assefa, Tamrat; Alemayehu, Bekele

2017-06-06

Warfarin is the most widely used anticoagulant in the world. The difficulty of managing warfarin contributes to great potential for patient harm, both from excessive anticoagulation and insufficient anticoagulation. This study assessed the International Normalized Ratio (INR) control outcome measures and warfarin dose adjustment practices at cardiology and hematology outpatient clinics at a teaching hospital in Addis Ababa, Ethiopia. The study was based on a cross - sectional study design involving 360 retrospective patients' chart review among outpatients who received warfarin for its various indications. The mean frequency of INR monitoring per patient was 62.9 days (17.2-143.7 days). Patients spent 52.2%, 29.0% and 18.8% of the time in sub-therapeutic, therapeutic and supra-therapeutic ranges, respectively. The daily warfarin dose was increased 50.9% and 36.9% and decreased in 52.8% and 60.9% of the time for occurrences of sub-therapeutic and supra-therapeutic INRs to achieve target ranges of 2.0-3.0 and 2.5-3.5, respectively. The quality of anticoagulation management with warfarin among outpatients in Tikur Anbessa Specialized Hospital was sub-optimal. This was reflected by low Time in Therapeutic Range (TTR), longer than recommended INR monitoring frequency, and minimal actions taken to adjust warfarin dose after occurrences of non-therapeutic INRs.

Combating Terrorism: A Conceptual Framework for Targeting at the Operational Level

DTIC Science & Technology

2004-06-17

for Joint Intelligence Preparation of the Battlespace. The key process is the JIPB which is tried and tested , offering a very logical and clear...Intelligence Preparation of the Battlespace (JIPB) process, as published in Joint Publication 2-01.3, Joint Tactics, Techniques, and Procedures for Joint...Intelligence Preparation of the Battlespace, 24 May 2000, for its application to targeting terrorism at the operational level. The

An evaluation of patient self-testing competency of prothrombin time for managing anticoagulation: pre-randomization results of VA Cooperative Study #481--The Home INR Study (THINRS).

PubMed

Dolor, Rowena J; Ruybalid, R Lynne; Uyeda, Lauren; Edson, Robert G; Phibbs, Ciaran; Vertrees, Julia E; Shih, Mei-Chiung; Jacobson, Alan K; Matchar, David B

2010-10-01

Prior studies suggest patient self-testing (PST) of prothrombin time (PT) can improve the quality of anticoagulation (AC) and reduce complications (e.g., bleeding and thromboembolic events). "The Home INR Study" (THINRS) compared AC management with frequent PST using a home monitoring device to high-quality AC management (HQACM) with clinic-based monitoring on major health outcomes. A key clinical and policy question is whether and which patients can successfully use such devices. We report the results of Part 1 of THINRS in which patients and caregivers were evaluated for their ability to perform PST. Study-eligible patients (n = 3643) were trained to use the home monitoring device and evaluated after 2-4 weeks for PST competency. Information about demographics, medical history, warfarin use, medications, plus measures of numeracy, literacy, cognition, dexterity, and satisfaction with AC were collected. Approximately 80% (2931 of 3643) of patients trained on PST demonstrated competency; of these, 8% (238) required caregiver assistance. Testers who were not competent to perform PST had higher numbers of practice attempts, higher cuvette wastage, and were less able to perform a fingerstick or obtain blood for the cuvette in a timely fashion. Factors associated with failure to pass PST training included increased age, previous stroke history, poor cognition, and poor manual dexterity. A majority of patients were able to perform PST. Successful home monitoring of PT with a PST device required adequate levels of cognition and manual dexterity. Training a caregiver modestly increased the proportion of patients who can perform PST.

Role of thromboelastography and rapid thromboelastography to assess the pharmacodynamic effects of vitamin K antagonists.

PubMed

Franchi, Francesco; Hammad, Jafri Syed; Rollini, Fabiana; Tello-Montoliu, Antonio; Patel, Ronakkumar; Darlington, Andrew; Kraemer, Dale F; Cho, Jung Rae; DeGroat, Christopher; Bhatti, Mona; Taha, Mohamad; Angiolillo, Dominick J

2015-07-01

Thromboelastography (TEG) measures the effects of antithrombotic agents by assessing global functional clotting status by evaluating the viscoelastic properties of in vitro clot formation. Recently, rapid TEG (r-TEG), which uses tissue factor in addition to standard kaolin to accelerate activation of the clotting cascade, has been proposed to obtain more immediate results. The correlation between results of TEG or r-TEG with international normalized ratio (INR) in patients on vitamin K antagonist (VKA) therapy has not been explored and represents the aim of this study. Patients on chronic therapy with VKAs (n = 100) were included in an observational prospective pharmacodynamic study. The correlation between TEG parameters, in particular markers of thrombus generation [Reaction time (R), maximum rate of thrombus generation (MRTG), and time to maximum rate of thrombus generation (TMRTG)], and INR values as well as the concordance between these parameters and therapeutic INR ranges were evaluated. In addition, in a subgroup of subjects (n = 17), the correlation of r-TEG parameters with TEG parameters and INR values was also assessed. No correlation was found between INR and TEG parameters of thrombus generation, in particular between INR and R (r = 0.189, p = 0.06), MRTG (r = -0.027, p = 0.79), and TMRTG (r = 0.188, p = 0.06). Further, no concordance was found between these parameters and recommended INR ranges. Significant Spearman correlations were found between INR and activated clotting time (rS = 0.546, p < 0.001), r-R (rS = 0.572, p = 0.017), and r-TMRTG (rS = 0.510, p = 0.037), but not r-MRTG (rS = 0.131, p = 0.617). Results were obtained in 24 ± 6 versus 12 ± 4 min with TEG and r-TEG, respectively (p < 0.001). In patients on chronic VKA therapy, TEG is not a useful tool to evaluate VKA anticoagulant effect, compared with standard INR measurements. However, r-TEG parameters of thrombus generation correlate with INR levels, suggesting a possible role of this

Predicting IGF-1R therapy response in bone sarcomas: immuno-SPECT imaging with radiolabeled R1507

PubMed Central

Fleuren, Emmy D.G.; Versleijen-Jonkers, Yvonne M.H.; van de Luijtgaarden, Addy C.M.; Molkenboer-Kuenen, Janneke D.M.; Heskamp, Sandra; Roeffen, Melissa H.S.; van Laarhoven, Hanneke W.M.; Houghton, Peter J.; Oyen, Wim J.G.; Boerman, Otto C.; van der Graaf, Winette T.A.

2011-01-01

Purpose To investigate whether 111In-R1507 immuno-SPECT, a novel non-invasive, in vivo screening method to visualize membranous Insulin-like Growth Factor 1 Receptor (IGF-1R) expression and accessibility, can be used to predict IGF-1R treatment (R1507) responsein bone sarcomas. Experimental design BALB/c nude mice were subcutaneously implanted with IGF-1R-expressing human bone sarcoma xenografts (OS-1, EW-5 and EW-8) which demonstrated high, modest or no response, respectively, to R1507, a monoclonal antibody targeting the extracellular domain of IGF-1R. An IGF-1R-negative tumor (OS-33), unresponsive to IGF-1R inhibitors, was examined as well. Mice were injected with indium-111 labeled R1507 (111In-R1507). Biodistribution and immuno-SPECT/CT imaging studies were performed 1, 3 and 7 days p.i. in mice with OS-1 and EW-5 xenografts and 3 days p.i. in mice with EW-8 and OS-33 xenografts. Results Biodistribution studies showed specific accumulation of 111In-R1507 in OS-1 and EW-5 xenografts (27.5±6.5%ID/g and 14.0±2.8%ID/g, 3 days p.i., respectively). Most importantly, 111In-R1507 uptake in IGF-1R-positive, but unresponsive, EW-8 xenografts (6.5±1.5%ID/g, 3 days p.i.) was similar to that of the IGF-1R-negative OS-33 tumor (5.5±0.6%ID/g, 3 days p.i.). Uptake in normal tissues was low and non-specific. Corresponding immuno-SPECT images clearly discriminated between high, modest and non-responding tumors by demonstrating a homogeneous (OS-1), heterogeneous (EW-5) or non-specific (EW-8 and OS-33)tumor uptake of 111In-R1507. Conclusions 111In-R1507 immuno-SPECT is an excellent method to visualize membranous IGF-1R expression and target accessibility in vivo in human bone sarcoma xenografts and may serve as an independent marker to predict IGF-1R therapy (R1507) responsein bone sarcoma patients. PMID:22038993

Targeted quantification of low ng/mL level proteins in human serum without immunoaffinity depletion

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shi, Tujin; Sun, Xuefei; Gao, Yuqian

2013-07-05

We recently reported an antibody-free targeted protein quantification strategy, termed high-pressure, high-resolution separations with intelligent selection and multiplexing (PRISM) for achieving significantly enhanced sensitivity using selected reaction monitoring (SRM) mass spectrometry. Integrating PRISM with front-end IgY14 immunoaffinity depletion, sensitive detection of targeted proteins at 50-100 pg/mL levels in human blood plasma/serum was demonstrated. However, immunoaffinity depletion is often associated with undesired losses of target proteins of interest. Herein we report further evaluation of PRISM-SRM quantification of low-abundance serum proteins without immunoaffinity depletion and the multiplexing potential of this technique. Limits of quantification (LOQs) at low ng/mL levels with a medianmore » CV of ~12% were achieved for proteins spiked into human female serum using as little as 2 µL serum. PRISM-SRM provided up to ~1000-fold improvement in the LOQ when compared to conventional SRM measurements. Multiplexing capability of PRISM-SRM was also evaluated by two sets of serum samples with 6 and 21 target peptides spiked at the low attomole/µL levels. The results from SRM measurements for pooled or post-concatenated samples were comparable to those obtained from individual peptide fractions in terms of signal-to-noise ratios and SRM peak area ratios of light to heavy peptides. PRISM-SRM was applied to measure several ng/mL-level endogenous plasma proteins, including prostate-specific antigen, in clinical patient sera where correlation coefficients > 0.99 were observed between the results from PRISM-SRM and ELISA assays. Our results demonstrate that PRISM-SRM can be successfully used for quantification of low-abundance endogenous proteins in highly complex samples. Moderate throughput (50 samples/week) can be achieved by applying the post-concatenation or fraction multiplexing strategies. We anticipate broad applications for targeted PRISM

Clinical experience with three-factor prothrombin complex concentrate to reverse warfarin anticoagulation in intracranial hemorrhage.

PubMed

Switzer, Jeffrey A; Rocker, Jody; Mohorn, Phillip; Waller, Jennifer L; Hughes, Douglas; Bruno, Askiel; Nichols, Fenwick T; Hess, David C; Natarajan, Kavita; Fagan, Susan C

2012-09-01

The effectiveness of prothrombin complex concentrate (PCC) products available in the United States that contain low levels of factor VII (3-factor PCC) has not been tested. The purpose of this study was to review our experience with 3-factor PCC (Profilnine) in the setting of warfarin-associated intracranial hemorrhage (wICH). In November 2007, we implemented a protocol for reversal of anticoagulation in wICH using Profilnine. Additional treatment with fresh-frozen plasma was at the discretion of the treating physician. Medical records of all patients receiving PCC for wICH between November 1, 2007, and December 7, 2011 were reviewed. Correction of the international normalized rate (INR) was defined as an INR <1.4. Seventy wICH patients were treated with Profilnine, including 46 (66%) with intraparenchymal hemorrhage, 22 (31%) with subdural hemorrhage, and 2 (3%) with subarachnoid hemorrhage. Mean INR was reduced from 3.36 to 1.96, and in 44 (62.9%) patients the INR corrected to <1.4. Baseline INR ≥3.0 decreased the likelihood of INR correction. Concomitant administration of fresh-frozen plasma (mean, 2.6 U) did not increase the likelihood of INR correction. Seven (10%) patients had serious adverse events during their hospital course, including 2 sudden deaths from suspected pulmonary embolism. Reversal of coagulopathy in wICH with Profilnine was incomplete and associated with serious adverse events. In the absence of available 4-factor PCC, options for urgent reversal of anticoagulation in wICH remain limited.

Targeted quantification of low ng/mL level proteins in human serum without immunoaffinity depletion

PubMed Central

Shi, Tujin; Sun, Xuefei; Gao, Yuqian; Fillmore, Thomas L.; Schepmoes, Athena A.; Zhao, Rui; He, Jintang; Moore, Ronald J.; Kagan, Jacob; Rodland, Karin D.; Liu, Tao; Liu, Alvin Y.; Smith, Richard D.; Tang, Keqi; Camp, David G.; Qian, Wei-Jun

2013-01-01

We recently reported an antibody-free targeted protein quantification strategy, termed high-pressure, high-resolution separations with intelligent selection and multiplexing (PRISM) for achieving significantly enhanced sensitivity using selected reaction monitoring (SRM) mass spectrometry. Integrating PRISM with front-end IgY14 immunoaffinity depletion, sensitive detection of targeted proteins at 50–100 pg/mL levels in human blood plasma/serum was demonstrated. However, immunoaffinity depletion is often associated with undesired losses of target proteins of interest. Herein we report further evaluation of PRISM-SRM quantification of low-abundance serum proteins without immunoaffinity depletion. Limits of quantification (LOQ) at low ng/mL levels with a median coefficient of variation (CV) of ~12% were achieved for proteins spiked into human female serum. PRISM-SRM provided >100-fold improvement in the LOQ when compared to conventional LC-SRM measurements. PRISM-SRM was then applied to measure several low-abundance endogenous serum proteins, including prostate-specific antigen (PSA), in clinical prostate cancer patient sera. PRISM-SRM enabled confident detection of all target endogenous serum proteins except the low pg/mL-level cardiac troponin T. A correlation coefficient >0.99 was observed for PSA between the results from PRISM-SRM and immunoassays. Our results demonstrate that PRISM-SRM can successful quantify low ng/mL proteins in human plasma or serum without depletion. We anticipate broad applications for PRISM-SRM quantification of low-abundance proteins in candidate biomarker verification and systems biology studies. PMID:23763644

Seasonal variation in the international normalized ratio of neonates and its relationship with ambient temperature.

PubMed

Iijima, Shigeo; Sekii, Katsuyuki; Baba, Toru; Ueno, Daizo; Ohishi, Akira

2016-07-19

The morbidity and mortality rates due to cardiovascular events such as myocardial infarction are known to exhibit seasonal variations. Moreover, changes in the ambient temperature are reportedly associated with an increase in these events, which may potentially involve blood coagulation markers. Bleeding due to vitamin K deficiency in neonates, which is associated with high mortality and a high frequency of neurological sequelae, is more commonly observed during the summer season and in warm regions in Japan. To determine the presence of seasonal variation and the influence of ambient temperature on blood coagulation markers in healthy term neonates, we assessed the international normalized ratio (INR) values measured using CoaguChek XS. We studied 488 consecutive healthy term neonates who were born at a perinatal center between July 2012 and June 2013. The INR values were measured using CoaguChek XS in 4-day-old neonates who received nursing care in the newborn nursery throughout the duration of hospitalization. The seasonal variations in the INR values and environmental effects on the INR were assessed. The mean monthly INR values peaked in July (1.13 ± 0.08), whereas the lowest values were observed in January (1.05 ± 0.08). Higher levels of INR were observed during the summer season (June to August) than during the winter season (December to February). Simple linear regression analysis indicated the presence of weakly positive but significant correlations between INR and outdoor temperature (r = 0.25, p < 0.001), outdoor relative humidity (r = 0.19, p < 0.001), and room relative humidity (r = 0.24, p < 0.001), and the presence of a significant negative correlation between INR and room temperature (r = -0.13, p = 0.02). Furthermore, multiple linear regression analysis showed that only outdoor temperature significantly influenced the INR. A seasonal variation in the INR values was observed among neonates, possibly due to

Meta-analysis of major bleeding events on aspirin versus vitamin K antagonists in randomized trials.

PubMed

Ambrosi, P; Daumas, A; Villani, P; Giorgi, R

2017-03-01

The relative bleeding risk of aspirin versus vitamin K antagonists (VKA) is unclear. Most of previous meta-analyses included trials with target INR for VKA therapy far beyond usually recommended range (2-3). The aim of this study was to compare the bleeding risk of aspirin and VKA, as indicated by the aggregate body of clinical evidence including data from the recently published WARCEF trial. In this meta-analysis we included randomized controlled trials that compared aspirin to VKA (1.4<INR<3.5) for the prevention of arterial thrombosis with a minimum of three month follow-up and of 50 patients per treatment arm. The outcome measures were major bleedings and intracranial bleedings. Ten eligible trials including 9047 patients were included, 451 of whom experienced major bleedings and 62 had intracranial bleeding. The 10 studies were homogeneous in spite of different clinical settings, including atrial fibrillation, heart failure and cerebral ischemia from arterial origin. Mean achieved INR on VKA varied from to 2.1 to 2.6. Compared with VKA, aspirin had an overall lower major bleeding risk (relative risk=0.58; 95% CI: 0.46-0.75; p<0.001). There was a non-significant trend for a lower intracranial bleeding risk on aspirin versus VKA (relative risk=0.65; 95% CI: 0.40-1.06; p=0.09). Major bleeding risk is substantially lower on aspirin than on VKA targeting current usual INR range. Physicians should take into account this data when choosing between different antithrombotic regimens. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

Antisense oligonucleotides targeting translation inhibitory elements in 5' UTRs can selectively increase protein levels.

PubMed

Liang, Xue-Hai; Sun, Hong; Shen, Wen; Wang, Shiyu; Yao, Joyee; Migawa, Michael T; Bui, Huynh-Hoa; Damle, Sagar S; Riney, Stan; Graham, Mark J; Crooke, Rosanne M; Crooke, Stanley T

2017-09-19

A variety of diseases are caused by deficiencies in amounts or activity of key proteins. An approach that increases the amount of a specific protein might be of therapeutic benefit. We reasoned that translation could be specifically enhanced using trans-acting agents that counter the function of negative regulatory elements present in the 5' UTRs of some mRNAs. We recently showed that translation can be enhanced by antisense oligonucleotides (ASOs) that target upstream open reading frames. Here we report the amount of a protein can also be selectively increased using ASOs designed to hybridize to other translation inhibitory elements in 5' UTRs. Levels of human RNASEH1, LDLR, and ACP1 and of mouse ACP1 and ARF1 were increased up to 2.7-fold in different cell types and species upon treatment with chemically modified ASOs targeting 5' UTR inhibitory regions in the mRNAs encoding these proteins. The activities of ASOs in enhancing translation were sequence and position dependent and required helicase activity. The ASOs appear to improve the recruitment of translation initiation factors to the target mRNA. Importantly, ASOs targeting ACP1 mRNA significantly increased the level of ACP1 protein in mice, suggesting that this approach has therapeutic and research potentials. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

Validating An Analytic Completeness Model for Kepler Target Stars Based on Flux-level Transit Injection Experiments

NASA Astrophysics Data System (ADS)

Catanzarite, Joseph; Burke, Christopher J.; Li, Jie; Seader, Shawn; Haas, Michael R.; Batalha, Natalie; Henze, Christopher; Christiansen, Jessie; Kepler Project, NASA Advanced Supercomputing Division

2016-06-01

The Kepler Mission is developing an Analytic Completeness Model (ACM) to estimate detection completeness contours as a function of exoplanet radius and period for each target star. Accurate completeness contours are necessary for robust estimation of exoplanet occurrence rates.The main components of the ACM for a target star are: detection efficiency as a function of SNR, the window function (WF) and the one-sigma depth function (OSDF). (Ref. Burke et al. 2015). The WF captures the falloff in transit detection probability at long periods that is determined by the observation window (the duration over which the target star has been observed). The OSDF is the transit depth (in parts per million) that yields SNR of unity for the full transit train. It is a function of period, and accounts for the time-varying properties of the noise and for missing or deweighted data.We are performing flux-level transit injection (FLTI) experiments on selected Kepler target stars with the goal of refining and validating the ACM. “Flux-level” injection machinery inserts exoplanet transit signatures directly into the flux time series, as opposed to “pixel-level” injection, which inserts transit signatures into the individual pixels using the pixel response function. See Jie Li's poster: ID #2493668, "Flux-level transit injection experiments with the NASA Pleiades Supercomputer" for details, including performance statistics.Since FLTI is affordable for only a small subset of the Kepler targets, the ACM is designed to apply to most Kepler target stars. We validate this model using “deep” FLTI experiments, with ~500,000 injection realizations on each of a small number of targets and “shallow” FLTI experiments with ~2000 injection realizations on each of many targets. From the results of these experiments, we identify anomalous targets, model their behavior and refine the ACM accordingly.In this presentation, we discuss progress in validating and refining the ACM, and we

Evaluation of the clinical and economic impact of a brand name-to-generic warfarin sodium conversion program.

PubMed

Witt, Daniel M; Tillman, Donald J; Evans, Christy M; Plotkin, Tatyana V; Sadler, Melanie A

2003-03-01

Substitution of generic warfarin initially was discouraged because of concerns regarding therapeutic failure or toxicity. Although subsequent research with AB-rated (i.e., bioequivalent) warfarin did not confirm initial concerns, the issue is not settled for all clinicians. We sought to provide additional information regarding the clinical and economic impact of warfarin conversion by analyzing a real-life sample of patients receiving long-term anticoagulation therapy who were switched from brand name to generic warfarin. Patients who had been taking warfarin for at least 180 days and had received uninterrupted oral anticoagulation 90 days before and 90 days after switching to generic warfarin were included. The switch date was based on the first time generic warfarin was dispensed from our pharmacies. The primary end point was the calculated amount of time each patient's international normalized ratio (INR) values were within the patient-specific target INR range in the 90 days before and after the switch. Data regarding adverse events and medical resource utilization were also collected. Pharmacoeconomic analyses were performed. The analysis included 2299 patients. The overall difference in calculated time INR values were below (22.6% before vs 26.1% after switch, p<0.0001) and within (65.9% before vs 63.3% after switch, p=0.0002) the therapeutic INR range was statistically but not clinically significant. Only 28.0% of patients experienced a change in therapeutic INR control of 10% or less, 33.1% experienced INR control that improved by greater than 10%, and 38.9% experienced INR control that worsened by more than 10%. The difference in total treatment costs associated with brand name and generic warfarin was 3128 dollars/100 patient-years in favor of the generic product. Sensitivity analyses revealed that cost savings associated with warfarin conversion in this health care system were highly dependent on the difference between warfarin costs and cost of treating

Calculation of Cumulative Distributions and Detection Probabilities in Communications and Optics.

DTIC Science & Technology

1984-10-01

the CMLD . As an example of a particular result, Figure 8.1 shows the additional SNR required (often called the CFAR loss) for the MLD, CMLD , and OSD in...the background noise level is known. Notice that although the CFAR loss increases with INR for the MLD, the CMLD and OSD have a bounded loss as the INR...Radar Detectors (J. A. Ritcey) Mean-level detectors (MLD) are commonly used in radar to maintain a constant -*! false-alarm rate ( CFAR ) when the

Evaluation of the marker of hypercoagulability prothrombin fragment F 1+2 in patients with mechanical or biological heart valve prostheses.

PubMed

Ferreira, Claudia Natália; Vieira, Lauro Mello; Dusse, Luci Maria Sant'Ana; Amaral, Carlos Faria Santos; de Magalhães Esteves, William Antônio; Fenelon, Lúcia Maria Amorim; das Graças Carvalho, Maria

2002-11-01

To investigate whether patients with heart valve prostheses and similar International Normalized Ratios (INR) have the same level of protection against thromboembolic events, that is, whether the anticoagulation intensity is related to the intensity of hypercoagulability suppression. INR and plasma levels of prothrombin fragment 1+2 (F1+2) were assessed in blood samples of 27 patients (7 with mechanical heart valves and 20 with biological heart valves) and 27 blood samples from healthy donors that were not taking any medication. Increased levels of F1+2 were observed in blood samples of 5 patients with heart valve prostheses taking warfarin. These findings reinforce the idea that even though patients may have INRs, within the therapeutic spectrum, they are not free from new thromboembolic events. Determination of the hypercoagulability marker F1+2 might result in greater efficacy and safety for the use of oral anticoagulants, resulting in improved quality of life for patients.

Drosophila Insulin receptor regulates the persistence of injury-induced nociceptive sensitization

PubMed Central

Patel, Atit A.

2018-01-01

ABSTRACT Diabetes-associated nociceptive hypersensitivity affects diabetic patients with hard-to-treat chronic pain. Because multiple tissues are affected by systemic alterations in insulin signaling, the functional locus of insulin signaling in diabetes-associated hypersensitivity remains obscure. Here, we used Drosophila nociception/nociceptive sensitization assays to investigate the role of Insulin receptor (Insulin-like receptor, InR) in nociceptive hypersensitivity. InR mutant larvae exhibited mostly normal baseline thermal nociception (absence of injury) and normal acute thermal hypersensitivity following UV-induced injury. However, their acute thermal hypersensitivity persists and fails to return to baseline, unlike in controls. Remarkably, injury-induced persistent hypersensitivity is also observed in larvae that exhibit either type 1 or type 2 diabetes. Cell type-specific genetic analysis indicates that InR function is required in multidendritic sensory neurons including nociceptive class IV neurons. In these same nociceptive sensory neurons, only modest changes in dendritic morphology were observed in the InRRNAi-expressing and diabetic larvae. At the cellular level, InR-deficient nociceptive sensory neurons show elevated calcium responses after injury. Sensory neuron-specific expression of InR rescues the persistent thermal hypersensitivity of InR mutants and constitutive activation of InR in sensory neurons ameliorates the hypersensitivity observed with a type 2-like diabetic state. Our results suggest that a sensory neuron-specific function of InR regulates the persistence of injury-associated hypersensitivity. It is likely that this new system will be an informative genetically tractable model of diabetes-associated hypersensitivity. PMID:29752280

International normalized ratio stabilization in newly initiated warfarin patients with nonvalvular atrial fibrillation.

PubMed

Nelson, Winnie W; Desai, Sunita; Damaraju, C V; Lu, Lang; Fields, Larry E; Wildgoose, Peter; Schein, Jeff R

2014-12-01

Warfarin is effective for stroke prevention in patients with atrial fibrillation (AF), but international normalized ratio (INR) levels fluctuate and frequent monitoring is necessary. This study used data from a large anticoagulation management service database to analyze the relationship between INR stabilization and warfarin utilization for >1 year in patients with nonvalvular AF (NVAF). Anticoagulation records from a large US electronic database collected from 2006 to 2010 were analyzed. Patients with NVAF and ≥ 3 INR values in the dataset were identified (n = 15,276). INR stabilization was defined as the first three consecutive INR values between 2.0 and 3.0 after warfarin initiation. One quarter of patients (n = 3809) failed to reach INR stabilization. After initial stabilization, 30% of subsequent INR values were out of range. The mean (± standard deviation [SD]) follow-up time from stabilization to the end of study for these patients was 494.2 ± 418.1 days. Age ≥ 75 years (odds ratio [OR] = 1.17, 95% confidence interval [CI] = 1.08-1.27), hypertension (OR = 1.19, 95% CI = 1.10-1.29), or prior stroke (OR = 1.29, 95% CI = 1.04-1.61) were positively associated with achieving stabilization; heart failure was negatively associated with stabilization (OR = 0.78, 95% CI = 0.70-0.87). Male gender (p < 0.0001) and hypertension were associated with earlier stabilization (p = 0.0013); heart failure was associated with later stabilization (p = 0.0098). Patients who achieved INR stabilization within 1 year were 10 times more likely to remain on warfarin than patients who did not achieve it. Observational data may contain incomplete records. Data on adherence, concurrent medications, vitamin K intake, genotype, reasons for discontinuation of monitoring, and patient outcomes were not available in the dataset. The study findings were generalizable only to patients with AF who were managed by anticoagulation clinics. Given the importance of stroke prevention among

High-Intensity Targeted Screening for Elevated Blood Lead Levels Among Children in 2 Inner-City Chicago Communities

PubMed Central

Dignam, Timothy A.; Evens, Anne; Eduardo, Eduard; Ramirez, Shokufeh M.; Caldwell, Kathleen L.; Kilpatrick, Nikki; Noonan, Gary P.; Flanders, W. Dana; Meyer, Pamela A.; McGeehin, Michael A.

2004-01-01

Objectives. We assessed the prevalence of elevated blood lead levels (≥ 10 micrograms of lead per deciliter of blood), risk factors, and previous blood lead testing among children in 2 high-risk Chicago, Ill, communities. Methods. Through high-intensity targeted screening, blood lead levels were tested and risks were assessed among a representative sample of children aged 1 to 5 years who were at risk for lead exposure. Results. Of the 539 children who were tested, 27% had elevated blood lead levels, and 61% had never been tested previously. Elevated blood lead levels were associated with chipped exterior house paint. Conclusions. Most of the children who lived in these communities—where the prevalence for elevated blood lead levels among children was 12 times higher than the national prevalence—were not tested for lead poisoning. Our findings highlight the need for targeted community outreach that includes testing blood lead levels in accordance with the American Academy of Pediatrics’ recommendations. PMID:15514235

Specific Increase of Protein Levels by Enhancing Translation Using Antisense Oligonucleotides Targeting Upstream Open Frames.

PubMed

Liang, Xue-Hai; Shen, Wen; Crooke, Stanley T

2017-01-01

A number of diseases are caused by low levels of key proteins; therefore, increasing the amount of specific proteins in human bodies is of therapeutic interest. Protein expression is downregulated by some structural or sequence elements present in the 5' UTR of mRNAs, such as upstream open reading frames (uORF). Translation initiation from uORF(s) reduces translation from the downstream primary ORF encoding the main protein product in the same mRNA, leading to a less efficient protein expression. Therefore, it is possible to use antisense oligonucleotides (ASOs) to specifically inhibit translation of the uORF by base-pairing with the uAUG region of the mRNA, redirecting translation machinery to initiate from the primary AUG site. Here we review the recent findings that translation of specific mRNAs can be enhanced using ASOs targeting uORF regions. Appropriately designed and optimized ASOs are highly specific, and they act in a sequence- and position-dependent manner, with very minor off-target effects. Protein levels can be increased using this approach in different types of human and mouse cells, and, importantly, also in mice. Since uORFs are present in around half of human mRNAs, the uORF-targeting ASOs may thus have valuable potential as research tools and as therapeutics to increase the levels of proteins for a variety of genes.

Two-tiered control of epithelial growth and autophagy by the insulin receptor and the ret-like receptor, stitcher.

PubMed

O'Farrell, Fergal; Wang, Shenqiu; Katheder, Nadja; Rusten, Tor Erik; Samakovlis, Christos

2013-07-01

Body size in Drosophila larvae, like in other animals, is controlled by nutrition. Nutrient restriction leads to catabolic responses in the majority of tissues, but the Drosophila mitotic imaginal discs continue growing. The nature of these differential control mechanisms that spare distinct tissues from starvation are poorly understood. Here, we reveal that the Ret-like receptor tyrosine kinase (RTK), Stitcher (Stit), is required for cell growth and proliferation through the PI3K-I/TORC1 pathway in the Drosophila wing disc. Both Stit and insulin receptor (InR) signaling activate PI3K-I and drive cellular proliferation and tissue growth. However, whereas optimal growth requires signaling from both InR and Stit, catabolic changes manifested by autophagy only occur when both signaling pathways are compromised. The combined activities of Stit and InR in ectodermal epithelial tissues provide an RTK-mediated, two-tiered reaction threshold to varying nutritional conditions that promote epithelial organ growth even at low levels of InR signaling.

Two-Tiered Control of Epithelial Growth and Autophagy by the Insulin Receptor and the Ret-Like Receptor, Stitcher

PubMed Central

O'Farrell, Fergal; Wang, Shenqiu; Katheder, Nadja

2013-01-01

Body size in Drosophila larvae, like in other animals, is controlled by nutrition. Nutrient restriction leads to catabolic responses in the majority of tissues, but the Drosophila mitotic imaginal discs continue growing. The nature of these differential control mechanisms that spare distinct tissues from starvation are poorly understood. Here, we reveal that the Ret-like receptor tyrosine kinase (RTK), Stitcher (Stit), is required for cell growth and proliferation through the PI3K-I/TORC1 pathway in the Drosophila wing disc. Both Stit and insulin receptor (InR) signaling activate PI3K-I and drive cellular proliferation and tissue growth. However, whereas optimal growth requires signaling from both InR and Stit, catabolic changes manifested by autophagy only occur when both signaling pathways are compromised. The combined activities of Stit and InR in ectodermal epithelial tissues provide an RTK-mediated, two-tiered reaction threshold to varying nutritional conditions that promote epithelial organ growth even at low levels of InR signaling. PMID:23935447

Extended International Normalized Ratio testing intervals for warfarin-treated patients.

PubMed

Barnes, G D; Kong, X; Cole, D; Haymart, B; Kline-Rogers, E; Almany, S; Dahu, M; Ekola, M; Kaatz, S; Kozlowski, J; Froehlich, J B

2018-05-15

Essentials Warfarin typically requires International Normalized Ratio (INR) testing at least every 4 weeks. We implemented extended INR testing for stable warfarin patients in six anticoagulation clinics. Use of extended INR testing increased from 41.8% to 69.3% over the 3 year study. Use of extended INR testing appeared safe and effective. Background A previous single-center randomized trial suggested that patients with stable International Normalized Ratio (INR) values could safely receive INR testing as infrequently as every 12 weeks. Objective To test the success of implementation of an extended INR testing interval for stable warfarin patients in a practice-based, multicenter collaborative of anticoagulation clinics. Methods At six anticoagulation clinics, patients were identified as being eligible for extended INR testing on the basis of prior INR value stability and minimal warfarin dose changes between 2014 and 2016. We assessed the frequency with which anticoagulation clinic providers recommended an extended INR testing interval (> 5 weeks) to eligible patients. We also explored safety outcomes for eligible patients, including next INR values, bleeding events, and emergency department visits. Results At least one eligible period for extended INR testing was identified in 890 of 3362 (26.5%) warfarin-treated patients. Overall, the use of extended INR testing in eligible patients increased from 41.8% in the first quarter of 2014 to 69.3% in the fourth quarter of 2016. The number of subsequent out-of-range next INR values were similar between eligible patients who did and did not have an extended INR testing interval (27.3% versus 28.4%, respectively). The numbers of major bleeding events were not different between the two groups, but rates of clinically relevant non-major bleeding (0.02 per 100 patient-years versus 0.09 per 100 patient-years) and emergency department visits (0.07 per 100 patient-years versus 0.19 per 100 patient-years) were lower for

Elevated microRNA-34a in obesity reduces NAD+ levels and SIRT1 activity by directly targeting NAMPT.

PubMed

Choi, Sung-E; Fu, Ting; Seok, Sunmi; Kim, Dong-Hyun; Yu, Eunkyung; Lee, Kwan-Woo; Kang, Yup; Li, Xiaoling; Kemper, Byron; Kemper, Jongsook Kim

2013-12-01

SIRT1 is an NAD(+)-dependent deacetylase that is implicated in prevention of many age-related diseases including metabolic disorders. As SIRT1 deacetylase activity is dependent on NAD(+) levels and the development of compounds that directly activate SIRT1 has been controversial, indirectly activating SIRT1 through enhancing NAD(+) bioavailability has received increasing attention. NAD(+) levels are reduced in obesity and the aged, but the underlying mechanisms remain unclear. We recently showed that hepatic microRNA-34a (miR-34a), which is elevated in obesity, directly targets and decreases SIRT1 expression. Here, we further show that miR-34a reduces NAD(+) levels and SIRT1 activity by targeting NAMPT, the rate-limiting enzyme for NAD(+) biosynthesis. A functional binding site for miR-34a is present in the 3' UTR of NAMPT mRNA. Hepatic overexpression of miR-34a reduced NAMPT/NAD(+) levels, increased acetylation of the SIRT1 target transcriptional regulators, PGC-1α, SREBP-1c, FXR, and NF-κB, and resulted in obesity-mimetic outcomes. The decreased NAMPT/NAD(+) levels were independent of miR-34a effects on SIRT1 levels as they were also observed in SIRT1 liver-specific knockout mice. Further, the miR-34a-mediated decreases were reversed by treatment with the NAD(+) intermediate, nicotinamide mononucleotide. Conversely, antagonism of miR-34a in diet-induced obese mice restored NAMPT/NAD(+) levels and alleviated steatosis, inflammation, and glucose intolerance. Anti-miR-34a-mediated increases in NAD(+) levels were attenuated when NAMPT was downregulated. Our findings reveal a novel function of miR-34a in reducing both SIRT1 expression and activity in obesity. The miR-34a/NAMPT axis presents a potential target for treating obesity- and aging-related diseases involving SIRT1 dysfunction like steatosis and type 2 diabetes. © 2013 the Anatomical Society and John Wiley & Sons Ltd.

Study on relationship between expression level and molecular conformations of gene drugs targeting to hepatoma cells in vitro

PubMed Central

Yang, Dong-Ye; Lu, Fang-Gen; Tang, Xi-Xiang; Zhao, Shui-Ping; Ouyang, Chun-Hui; Wu, Xiao-Ping; Liu, Xiao-Wei; Wu, Xiao-Ying

2003-01-01

AIM: To increase exogenous gene expression level by modulating molecular conformations of targeting gene drugs. METHODS: The full length cDNAs of both P40 and P35 subunits of human interleukin 12 were amplified through polymerase chain reaction (PCR) and cloned into eukaryotic expressing vectors pcDNA3.1 (±) to construct plasmids of P (+)/IL-12, P (+)/P40 and P (-)/P35. These plasmids were combined with ASOR-PLL to form two targeting gene drugs [ASOR-PLL-P (+)/IL-12 and ASOR-PLL-P (+)/P40 + ASOR-PLL-P (-)/P35] in optimal ratios. The conformations of these two drugs at various concentrations adjuvant were examined under electron microscope (EM) and the drugs were transfected into HepG2 (ASGr+) cells. Semi-quantitative reverse transcription polymerase chain reaction (RT-PCR) was performed with total RNA extracted from the transfected cells to determine the hIL12 mRNA transcript level. The hIL12 protein in the cultured supernatant was measured with enzyme-linked immunosorbent assay (ELISA) 48 hours after transfection. RESULTS: Targeting gene drugs, whose structures were granular and circle-like and diameters ranged from 25 nm to 150 nm, had the highest hIL-12 expression level. The hIL-12 expression level in the group co-transfected with ASOR-PLL-P (+)/P40 and ASOR-PLL-P (-)/P35 was higher than that of ASOR-PLL-P (+)/IL-12 transfected group. CONCLUSION: The molecular conformations of targeting gene drugs play an important role in exogenous gene expression level, the best structures are granular and circle-like and their diameters range from 25 nm to 150 nm. The sizes and linking styles of exogenous genes also have some effects on their expression level. PMID:12970883

Infrared small target enhancement: grey level mapping based on improved sigmoid transformation and saliency histogram

NASA Astrophysics Data System (ADS)

Wan, Minjie; Gu, Guohua; Qian, Weixian; Ren, Kan; Chen, Qian

2018-06-01

Infrared (IR) small target enhancement plays a significant role in modern infrared search and track (IRST) systems and is the basic technique of target detection and tracking. In this paper, a coarse-to-fine grey level mapping method using improved sigmoid transformation and saliency histogram is designed to enhance IR small targets under different backgrounds. For the stage of rough enhancement, the intensity histogram is modified via an improved sigmoid function so as to narrow the regular intensity range of background as much as possible. For the part of further enhancement, a linear transformation is accomplished based on a saliency histogram constructed by averaging the cumulative saliency values provided by a saliency map. Compared with other typical methods, the presented method can achieve both better visual performances and quantitative evaluations.

Cooperative fuzzy games approach to setting target levels of ECs in quality function deployment.

PubMed

Yang, Zhihui; Chen, Yizeng; Yin, Yunqiang

2014-01-01

Quality function deployment (QFD) can provide a means of translating customer requirements (CRs) into engineering characteristics (ECs) for each stage of product development and production. The main objective of QFD-based product planning is to determine the target levels of ECs for a new product or service. QFD is a breakthrough tool which can effectively reduce the gap between CRs and a new product/service. Even though there are conflicts among some ECs, the objective of developing new product is to maximize the overall customer satisfaction. Therefore, there may be room for cooperation among ECs. A cooperative game framework combined with fuzzy set theory is developed to determine the target levels of the ECs in QFD. The key to develop the model is the formulation of the bargaining function. In the proposed methodology, the players are viewed as the membership functions of ECs to formulate the bargaining function. The solution for the proposed model is Pareto-optimal. An illustrated example is cited to demonstrate the application and performance of the proposed approach.

Cooperative Fuzzy Games Approach to Setting Target Levels of ECs in Quality Function Deployment

PubMed Central

Yang, Zhihui; Chen, Yizeng; Yin, Yunqiang

2014-01-01

Quality function deployment (QFD) can provide a means of translating customer requirements (CRs) into engineering characteristics (ECs) for each stage of product development and production. The main objective of QFD-based product planning is to determine the target levels of ECs for a new product or service. QFD is a breakthrough tool which can effectively reduce the gap between CRs and a new product/service. Even though there are conflicts among some ECs, the objective of developing new product is to maximize the overall customer satisfaction. Therefore, there may be room for cooperation among ECs. A cooperative game framework combined with fuzzy set theory is developed to determine the target levels of the ECs in QFD. The key to develop the model is the formulation of the bargaining function. In the proposed methodology, the players are viewed as the membership functions of ECs to formulate the bargaining function. The solution for the proposed model is Pareto-optimal. An illustrated example is cited to demonstrate the application and performance of the proposed approach. PMID:25097884

Comparing thrombin generation in patients with hemophilia A and patients on vitamin K antagonists.

PubMed

de Koning, M L Y; Fischer, K; de Laat, B; Huisman, A; Ninivaggi, M; Schutgens, R E G

2017-05-01

Essentials It is unknown if hemophilia patients with atrial fibrillation need anticoagulation. Endogenous thrombin potentials (ETP) in hemophilia patients and patients on coumarins were compared. Severe hemophilia patients had comparable ETP to therapeutic international normalized ratio (INR). In non-severe hemophilia, 33% had higher ETP than therapeutic INR and may need anticoagulation. Click to hear Dr Negrier's perspective on global assays for assessing coagulation SUMMARY: Background It is unknown whether patients with hemophilia A with atrial fibrillation require treatment with vitamin K antagonists (VKAs) to the same extent as the normal population. Objective To compare hemostatic potential in hemophilia patients and patients on VKAs using thrombin generation (TG). Methods In this cross-sectional study, TG, initiated with 1pM tissue factor, was measured in 133 patients with severe (FVIII < 1%, n = 15) and non-severe (FVIII 1-50%, n = 118) hemophilia A, 97 patients on a VKA with an international normalized ratio (INR) ≥ 1.5 and healthy controls. Endogenous thrombin potential (ETP) (nm*min) was compared according to FVIII level (< 1%, 1-19% and 20-50%) with healthy controls and patients with sub-therapeutic INR (1.5-1.9) and therapeutic INR (≥ 2.0). Medians and interquartile ranges (IQRs) were calculated. Results Compared with healthy controls (898 [IQR 803-1004]), both hemophilia patients and patients on VKAs had lower median ETPs at 304 (196-449) and 176 (100-250), respectively. ETP was quite similar in severe hemophilia patients (185 [116-307]) and patients with a therapeutic INR (156 [90-225]). Compared with patients with therapeutic INR, ETP in patients with FVIII 1-19% and patients with FVIII 20-50% was higher at 296 (203-430) and 397 (219-632), respectively. All patients with therapeutic INR had an ETP < 400. Considering this threshold, 93% of severe hemophilia patients, 70% of patients with FVIII 1-19% and 52% of patients with FVIII 20-50% had an

Supervised Patient Self-Testing of Warfarin Therapy Using an Online System

PubMed Central

2013-01-01

Background Point-of-care international normalized ratio (INR) monitoring devices simplify warfarin management by allowing selected patients to monitor their own therapy in their homes. Patient self-testing (PST) has been shown to improve the clinical outcomes of warfarin therapy compared to usual care. Objective To compare management of warfarin therapy using PST combined with online supervision by physicians via a custom system with usual warfarin management, which involved laboratory testing and physician dosing. Methods Interested patients were recruited via community pharmacies to participate in a warfarin PST training program. Participants were required to have a long-term indication for warfarin, have been taking warfarin for at least 6 months, and have Internet access in their home. The training involved two sessions covering theoretical aspects of warfarin therapy, use of the CoaguChek XS, and the study website. Following training, patients monitored their INR once weekly for up to 3 months. Patients and physicians utilized a secure website to communicate INR values, dosage recommendations, and clinical incidents. Physicians provided a 6-12 month history of INR results for comparison with study results. The percentage of time spent within the therapeutic INR range (TTR) was the primary outcome, with participants acting as their own historical controls. The percentage of INR tests in range and participant satisfaction were secondary outcomes. Results Sixteen patients completed training requirements. The mean age of participants was 69.8 (SD 10.1) years. TTR improved significantly from 66.4% to 78.4% during PST (P=.01), and the number of tests within the target range also improved significantly (from 66.0% at prior to the study to 75.9% during PST; P=.04). Patients and physicians expressed a high degree of satisfaction with the monitoring strategy and online system. Conclusions PST supported by an online system for supervision was associated with improved INR

Vitamin K antagonist control in patients with atrial fibrillation in Asia compared with other regions of the world: Real-world data from the GARFIELD-AF registry.

PubMed

Oh, Seil; Goto, Shinya; Accetta, Gabriele; Angchaisuksiri, Pantep; Camm, A John; Cools, Frank; Haas, Sylvia; Kayani, Gloria; Koretsune, Yukihiro; Lim, Toon Wei; Misselwitz, Frank; van Eickels, Martin; Kakkar, Ajay K

2016-11-15

To compare the distribution of international normalized ratios (INRs) in patients receiving vitamin K antagonist (VKA) for newly diagnosed atrial fibrillation in Eastern and Southeastern Asia and in other regions of the world (ORW) represented in the ongoing, global observational study GARFIELD-AF. 3621 and 13,541 patients were recruited prospectively in 2010-2013 from Asia and ORW, respectively. At baseline, excluding patients with unknown antithrombotic treatment, 1356 (37.8%) in Asia and 7081 (53.3%) in ORW received VKA (±antiplatelets). INR readings during 1-year follow-up were analyzed for VKA-treated patients with ≥3 measurements (878 [64.7%] patients in Asia, 4452 [62.9%] in ORW). VKA-treated patients in Asia were younger than those in ORW (mean 67.1 vs 71.3years), with a lower CHA 2 DS 2 -VASc score (3.0 vs 3.5), but a similar HAS-BLED score (1.3 vs 1.4). Mean INR was lower in Asia than in ORW (2.0 vs 2.4). The proportion of time in the therapeutic range, defined using the multinational target of 2.0-3.0, was substantially lower in Asia (31.1% vs 54.1%). In Asia and ORW, 59.3% and 28.2% of INRs were <2, and 9.6% and 17.7% were >3, respectively. The same trend was found in different age groups (<65, 65-74, ≥75years). GARFIELD-AF data demonstrate a difference in the distribution of INRs in patients from Asia versus other regions under current real-world practice. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Insulin and 20-hydroxyecdysone action in Bombyx mori: Glycogen content and expression pattern of insulin and ecdysone receptors in fat body.

PubMed

Keshan, Bela; Thounaojam, Bembem; Kh, Sanathoibi D

2017-01-15

Insulin and ecdysone signaling play a critical role on the growth and development of insects including Bombyx mori. Our previous study showed that Bombyx larvae reached critical weight for metamorphosis between day 3.5 and 4 of the fifth larval instar. The present study showed that the effect of insulin on the accumulation of glycogen in fat body of Bombyx larvae depends on the critical growth period. When larvae are in active growth period (before reaching critical weight), insulin caused increased accumulation of glycogen, while its treatment in larvae at terminal growth period (after critical period) resulted in an increased mobilization of glycogen. During terminal growth period, insulin and 20-hydroxyecdysone (20E) showed an antagonistic effect on the accumulation of fat body glycogen in fed, food deprived and decapitated larvae as well as in isolated abdomens. Insulin treatment decreased the glycogen content, whereas, 20E increased it. Food deprivation and decapitation caused an increase in the transcript levels of insulin receptor (InR) and this increase in InR expression might be attributed to a decrease in synthesis/secretion of insulin-like peptides, as insulin treatment in these larvae showed a down-regulation in InR expression. However, insulin showed an up-regulation in InR in isolated abdomens and it suggests that in food deprived and decapitated larvae, the exogenous insulin may interact with some head and/or thoracic factors in modulating the expression of InR. Moreover, in fed larvae, insulin-mediated increase in InR expression indicates that its regulation by insulin-like peptides also depends on the nutritional status of the larvae. The treatment of 20E in fed larvae showed an antagonistic effect on the transcript levels since a down-regulation in InR expression was observed. 20E treatment also led to a decreased expression of InR in food deprived and decapitated larvae as well as in isolated abdomens. Insulin and 20E also modulated the

Squalene epoxidase as a target for manipulation of squalene levels in the yeast Saccharomyces cerevisiae.

PubMed

Garaiová, Martina; Zambojová, Veronika; Simová, Zuzana; Griač, Peter; Hapala, Ivan

2014-03-01

Squalene is a valuable natural substance with several biotechnological applications. In the yeast Saccharomyces cerevisiae, it is produced in the isoprenoid pathway as the first precursor dedicated to ergosterol biosynthesis. The aim of this study was to explore the potential of squalene epoxidase encoded by the ERG1 gene as the target for manipulating squalene levels in yeast. Highest squalene levels (over 1000 μg squalene per 10(9)  cells) were induced by specific point mutations in ERG1 gene that reduced activity of squalene epoxidase and caused hypersensitivity to terbinafine. This accumulation of squalene in erg1 mutants did not significantly disturb their growth. Treatment with squalene epoxidase inhibitor terbinafine revealed a limit in squalene accumulation at 700 μg squalene per 10(9)  cells which was associated with pronounced growth defects. Inhibition of squalene epoxidase activity by anaerobiosis or heme deficiency resulted in relatively low squalene levels. These levels were significantly increased by ergosterol depletion in anaerobic cells which indicated feedback inhibition of squalene production by ergosterol. Accumulation of squalene in erg1 mutants and terbinafine-treated cells were associated with increased cellular content and aggregation of lipid droplets. Our results prove that targeted genetic manipulation of the ERG1 gene is a promising tool for increasing squalene production in yeast. © 2013 Federation of European Microbiological Societies. Published by John Wiley & Sons Ltd.

Acquired absolute vitamin K deficiency in a patient undergoing warfarin therapy.

PubMed

Takada, Hiroaki; Toru, Hifumi; Bunya, Naofumi; Kiriu, Nobuaki; Kato, Hiroshi; Koido, Yuichi; Yasuhiro, Kuroda

2014-06-01

We report a case of absolute vitamin K deficiency (VKD) diagnosed by measuring serum VK levels in an elderly woman undergoing warfarin therapy. A 78-year-old woman was admitted to our hospital because of dyspnea and sore throat diagnosed as pharyngitis 1 week before admission. On admission, the sore throat had exacerbated and dyspnea developed. She had history of atrial fibrillation, for which warfarin 1.5 mg/d was started approximately 10 years prior and her international normalized ratio (INR) had been maintained at an acceptable therapeutic level. Blood results revealed unmeasurable INR and abnormally prolonged activated partial thromboplastin time (APTT). She was diagnosed with adenoiditis and warfarin-related coagulopathy and administered intravenous VK (20 mg) and fresh frozen plasma (FFP; 4 U), which improved INR and APTT. Since the coagulopathy responded to intravenous VK administration, the patient was clinically diagnosed with warfarin-related relative VKD. Approximately 1 month later, she returned with complaints of sore throat. Blood results indicated abnormal INR (7.22) and APTT (N80.0 s). She was diagnosed with recurrent adenoiditis and VK deficient coagulopathy. The patient’s serum VK levels were low (VK1 level, 0.13 ng/mL; VK2 levels, 0.85 ng/mL). Initial treatment of VK (20 mg) and FFP followed by intravenous VK (20 mg/d) for 6 days, her symptoms dissipated. Warfarin was suspected to have caused absolute VKD. Severe coagulopathy in patients undergoing warfarin therapy is primarily caused by, relative VKD. However, the possibility of warfarin-related absolute VKD should be suspected when INRis not sufficiently improved by intravenous VK administration.

Kepler Planet Detection Metrics: Per-Target Flux-Level Transit Injection Tests of TPS for Data Release 25

NASA Technical Reports Server (NTRS)

Burke, Christopher J.; Catanzarite, Joseph

2017-01-01

Quantifying the ability of a transiting planet survey to recover transit signals has commonly been accomplished through Monte-Carlo injection of transit signals into the observed data and subsequent running of the signal search algorithm (Gilliland et al., 2000; Weldrake et al., 2005; Burke et al., 2006). In order to characterize the performance of the Kepler pipeline (Twicken et al., 2016; Jenkins et al., 2017) on a sample of over 200,000 stars, two complementary injection and recovery tests are utilized:1. Injection of a single transit signal per target into the image or pixel-level data, hereafter referred to as pixel-level transit injection (PLTI), with subsequent processing through the Photometric Analysis (PA), Presearch Data Conditioning (PDC), Transiting Planet Search (TPS), and Data Validation (DV) modules of the Kepler pipeline. The PLTI quantification of the Kepler pipeline's completeness has been described previously by Christiansen et al. (2015, 2016); the completeness of the final SOC 9.3 Kepler pipeline acting on the Data Release 25 (DR25) light curves is described by Christiansen (2017).2. Injection of multiple transit signals per target into the normalized flux time series data with a subsequent transit search using a stream-lined version of the Transiting Planet Search (TPS) module. This test, hereafter referred to as flux-level transit injection (FLTI), is the subject of this document. By running a heavily modified version of TPS, FLTI is able to perform many injections on selected targets and determine in some detail which injected signals are recoverable. Significant numerical efficiency gains are enabled by precomputing the data conditioning steps at the onset of TPS and limiting the search parameter space (i.e., orbital period, transit duration, and ephemeris zero-point) to a small region around each injected transit signal.The PLTI test has the advantage that it follows transit signals through all processing steps of the Kepler pipeline, and

Interdisciplinary concepts for design and implementation of mixed reality interactive neurorehabilitation systems for stroke.

PubMed

Baran, Michael; Lehrer, Nicole; Duff, Margaret; Venkataraman, Vinay; Turaga, Pavan; Ingalls, Todd; Rymer, W Zev; Wolf, Steven L; Rikakis, Thanassis

2015-03-01

Interactive neurorehabilitation (INR) systems provide therapy that can evaluate and deliver feedback on a patient's movement computationally. There are currently many approaches to INR design and implementation, without a clear indication of which methods to utilize best. This article presents key interactive computing, motor learning, and media arts concepts utilized by an interdisciplinary group to develop adaptive, mixed reality INR systems for upper extremity therapy of patients with stroke. Two INR systems are used as examples to show how the concepts can be applied within: (1) a small-scale INR clinical study that achieved integrated improvement of movement quality and functionality through continuously supervised therapy and (2) a pilot study that achieved improvement of clinical scores with minimal supervision. The notion is proposed that some of the successful approaches developed and tested within these systems can form the basis of a scalable design methodology for other INR systems. A coherent approach to INR design is needed to facilitate the use of the systems by physical therapists, increase the number of successful INR studies, and generate rich clinical data that can inform the development of best practices for use of INR in physical therapy. © 2015 American Physical Therapy Association.

Interdisciplinary Concepts for Design and Implementation of Mixed Reality Interactive Neurorehabilitation Systems for Stroke

PubMed Central

Lehrer, Nicole; Duff, Margaret; Venkataraman, Vinay; Turaga, Pavan; Ingalls, Todd; Rymer, W. Zev; Wolf, Steven L.; Rikakis, Thanassis

2015-01-01

Interactive neurorehabilitation (INR) systems provide therapy that can evaluate and deliver feedback on a patient's movement computationally. There are currently many approaches to INR design and implementation, without a clear indication of which methods to utilize best. This article presents key interactive computing, motor learning, and media arts concepts utilized by an interdisciplinary group to develop adaptive, mixed reality INR systems for upper extremity therapy of patients with stroke. Two INR systems are used as examples to show how the concepts can be applied within: (1) a small-scale INR clinical study that achieved integrated improvement of movement quality and functionality through continuously supervised therapy and (2) a pilot study that achieved improvement of clinical scores with minimal supervision. The notion is proposed that some of the successful approaches developed and tested within these systems can form the basis of a scalable design methodology for other INR systems. A coherent approach to INR design is needed to facilitate the use of the systems by physical therapists, increase the number of successful INR studies, and generate rich clinical data that can inform the development of best practices for use of INR in physical therapy. PMID:25425694

Factors associated with failure to correct the international normalised ratio following fresh frozen plasma administration among patients treated for warfarin-related major bleeding. An analysis of electronic health records.

PubMed

Menzin, J; White, L A; Friedman, M; Nichols, C; Menzin, J; Hoesche, J; Bergman, G E; Jones, C

2012-04-01

This study assessed the frequency and factors associated with failure to correct international normalised ratio (INR) in patients administered fresh frozen plasma (FFP) for warfarin-related major bleeding. This retrospective database analysis used electronic health records from an integrated health system. Patients who received FFP between 01/01/2004 and 01/31/2010, and who met the following criteria were selected: major haemorrhage diagnosis the day before to the day after initial FFP administration; INR ≥2 on the day before or the day of FFP and another INR result available; warfarin prescription within 90 days. INR correction (defined as INR ≤1.3) was evaluated at the last available test up to one day following FFP. A total of 414 patients met selection criteria (mean age 75 years, 53% male, mean Charlson score 2.5). Patients presented with gastrointestinal bleeding (58%), intracranial haemorrhage (38%) and other bleed types (4%). The INR of 67% of patients remained uncorrected at the last available test up to one day following receipt of FFP. In logistic regression analysis, the INR of patients who were older, those with a Charlson score of 4 or greater, and those with non-ICH bleeds (odds ratio vs. intracranial bleeding 0.48; 95% confidence interval 0.31-0.76) were more likely to remain uncorrected within one day following FFP administration. In an alternative definition of correction, (INR ≤1.5), 39% of patients' INRs remained uncorrected. For a substantial proportion of patients, the INRs remain inadequately or uncorrected following FFP administration, with estimates varying depending on the INR threshold used.

Acute physical exercise is safe in patients with primary antiphospholipid syndrome with exclusive venous thrombosis and under oral anticoagulation with warfarin.

PubMed

Garcia, Carolina Borges; Seguro, Luciana Parente Costa; Perandini, Luiz Augusto; de Sá Pinto, Ana Lúcia; Lima, Fernanda Rodrigues; Negrão, Carlos Eduardo; Bonfa, Eloisa; Borba, Eduardo Ferreira

2014-12-01

The purpose of present study was to evaluate the effects of maximal acute physical exercise on prothrombin time/international normalized ratio (PT/INR) in patients with primary antiphospholipid syndrome (PAPS) under oral anticoagulation with warfarin and the safety of acute exercise in regard to thrombosis and bleeding risk. Eighteen physically inactive women with PAPS (Sydney criteria) with exclusive venous events and without thrombocytopenia were included. All patients were under stable warfarin therapy (PT/INR target: 2.0-3.0). Eighteen age-matched healthy sedentary women without thrombosis/bleeding disorders were selected as controls. All subjects performed a maximal exercise test, and capillary blood samples were obtained pre-, post- and at 1-h post-exercise (recovery time) for PT/INR analysis using a portable CoaguCheck. PAPS patients and controls had similar mean age (31.50 ± 8.06 vs. 29.61 ± 7.05 years, p = 0.46) and body mass index (24.16 ± 3.67 vs. 24.66 ± 2.71 kg/m(2), p = 0.65). PAPS had a mild but significant increase in PT/INR value at 1-h post-exercise (recovery) compared with pre- (2.33 ± 0.34 vs. 2.26 ± 0.29, p = 0.001) and post-exercise (2.33 ± 0.34 vs. 2.26 ± 0.32, p = 0.001) that was observed in 61.11 % of these patients. None of the subjects had thrombotic or bleeding complications related to the acute exercise. Acute exercise in patients with PAPS with exclusive venous thrombosis was safe with a minor increase in PT/INR. This is an important step to introduce regular exercise training as a therapeutic tool in the management of these patients.

Monitoring anticoagulant therapy with vitamin K antagonists in patients with antiphospholipid syndrome.

PubMed

Isert, Mecki; Miesbach, Wolfgang; Schüttfort, Gundolf; Weil, Yvonne; Tirneci, Vanessa; Kasper, Alexander; Weber, Adele; Lindhoff-Last, Edelgard; Herrmann, Eva; Linnemann, Birgit

2015-08-01

Because of the possible interference of antiphospholipid antibodies (APL) with the phospholipid component of thromboplastin reagents, concerns have been raised about the validity of international normalized ratio (INR) testing to monitor anticoagulant therapy with vitamin K antagonists in patients with antiphospholipid syndrome (APS). To investigate the reliability of the INR, we determined the INR using various prothrombin time (PT) assays and compared the results with those of a chromogenic factor X (CFX) assay. The study cohort consisted of 40 APS patients and 100 APL-negative patients who were on anticoagulant therapy for reasons other than APS. The agreement (i.e. the percentage of patients with a difference ≤0.5 INR units) between the PT-derived INR and CFX-derived INR equivalents was only moderate in both patient groups. The best agreement with CFX-derived INR equivalents was observed for the Thromborel S reagent in APS patients (69.1 %) and for Neoplastin Plus in APL-negative patients (72.0 %). Regarding the results for the point-of-care system CoaguChek XS, an agreement between the INR and the CFX-derived INR equivalent was less frequently observed in the APS patients (55.6 vs. 67.8 %; p = 0.050). When considering all 3058 pairs of INR tests within the international sensitivity index (ISI)-calibrated range of 1.5 to 4.5 s, we did not observe a higher variability of INR values in either the APS patient group or the subgroup of APS patients positive for lupus coagulants compared with the APL-negative controls. In conclusion, monitoring vitamin K antagonists (VKA) therapy with laboratory INR measurements seems to be suitable for the majority of APS patients.

Identifying Drug-Drug Interactions by Data Mining: A Pilot Study of Warfarin-Associated Drug Interactions.

PubMed

Hansen, Peter Wæde; Clemmensen, Line; Sehested, Thomas S G; Fosbøl, Emil Loldrup; Torp-Pedersen, Christian; Køber, Lars; Gislason, Gunnar H; Andersson, Charlotte

2016-11-01

Knowledge about drug-drug interactions commonly arises from preclinical trials, from adverse drug reports, or based on knowledge of mechanisms of action. Our aim was to investigate whether drug-drug interactions were discoverable without prior hypotheses using data mining. We focused on warfarin-drug interactions as the prototype. We analyzed altered prothrombin time (measured as international normalized ratio [INR]) after initiation of a novel prescription in previously INR-stable warfarin-treated patients with nonvalvular atrial fibrillation. Data sets were retrieved from clinical work. Random forest (a machine-learning method) was set up to predict altered INR levels after novel prescriptions. The most important drug groups from the analysis were further investigated using logistic regression in a new data set. Two hundred and twenty drug groups were analyzed in 61 190 novel prescriptions. We rediscovered 2 drug groups having known interactions (β-lactamase-resistant penicillins [dicloxacillin] and carboxamide derivatives) and 3 antithrombotic/anticoagulant agents (platelet aggregation inhibitors excluding heparin, direct thrombin inhibitors [dabigatran etexilate], and heparins) causing decreasing INR. Six drug groups with known interactions were rediscovered causing increasing INR (antiarrhythmics class III [amiodarone], other opioids [tramadol], glucocorticoids, triazole derivatives, and combinations of penicillins, including β-lactamase inhibitors) and two had a known interaction in a closely related drug group (oripavine derivatives [buprenorphine] and natural opium alkaloids). Antipropulsives had an unknown signal of increasing INR. We were able to identify known warfarin-drug interactions without a prior hypothesis using clinical registries. Additionally, we discovered a few potentially novel interactions. This opens up for the use of data mining to discover unknown drug-drug interactions in cardiovascular medicine. © 2016 American Heart Association

Does Janani Shishu Suraksha Karyakram ensure cost-free institutional delivery? A cross-sectional study in rural Bankura of West Bengal, India.

PubMed

Mondal, Janmenjoy; Mukhopadhyay, Dipta Kanti; Mukhopadhyay, Sujishnu; Sinhababu, Apurba

2015-01-01

Janani Shishu Suraksha Karyakram (JSSK) was launched in India to ensure cost-free institutional delivery. 1) To assess the awareness of recently delivered women regarding JSSK 2) To estimate the cost of institutional delivery and its differentials. A community-based, cross-sectional study was conducted in a rural community in Bankura, West Bengal, India in 2013, among 210 women who delivered babies in the last 12 months. Information regarding sociodemographic and health service-related variables as well as item-wise costs incurred for institutional delivery were collected. Costs were expressed in Indian National Rupee (INR). A nonparametric, bivariate analysis was performed to examine the difference in median cost. All components of JSSK were known to 12.9% women; the highest (77.1%) for admission and lowest (29.0%) for blood transfusion. The median (±IQR) costs of delivery in the Block level Primary Health Center (PHC), medical college, and private facilities were INR 205.0 (±825.0), 900.0 (±1013.0), and 6600.0 (±16195.0), respectively. Median cost of normal delivery in a private facility (INR 2750.0) was 3.6 times of that in a government facility (INR 765.0). Median direct cost of caesarian section (CS) in a government facility (INR 1100.0) was nearly one-fifteenth of that in a private facility (INR 16,350.0). Cash incentives under Janani Suraksha Yojana for poor and socially marginalized women could not cover the cost of CS delivery in a government facility. Gaps existed in the awareness of beneficiaries regarding entitlement under JSSK. Drugs and transport were two major causes of out-of-pocket (OOP) expenditure in public health facilities.

A Case Report of a Patient Carrying CYP2C9*3/4 Genotype with Extremely Low Warfarin Dose Requirement

PubMed Central

Lee, Soo-Youn; Nam, Myung-Hyun; Kim, June Soo

2007-01-01

We report a case of intolerance to warfarin dosing due to impaired drug metabolism in a patient with CYP2C9*3/*4. A 73-yr-old woman with atrial fibrilation was taking warfarin. She attained a high prothrombin time international normalized ratio (INR) at the standard doses during the induction of anticoagulation and extremely low dose of warfarin (6.5 mg/week) was finally chosen to reach the target INR. Genotyping for CYP2C9 revealed that this patient had a genotype CYP2C9*3/*4. This is the first Korean compound heterozygote for CYP2C9*3 and *4. This case suggests the clinical usefulness of pharmacogenetic testing for individualized dosage adjustments of warfarin. PMID:17596671

A case report of a patient carrying CYP2C9*3/4 genotype with extremely low warfarin dose requirement.

PubMed

Lee, Soo Youn; Nam, Myung Hyun; Kim, June Soo; Kim, Jong Won

2007-06-01

We report a case of intolerance to warfarin dosing due to impaired drug metabolism in a patient with CYP2C9*3/*4. A 73-yr-old woman with atrial fibrilation was taking warfarin. She attained a high prothrombin time international normalized ratio (INR) at the standard doses during the induction of anticoagulation and extremely low dose of warfarin (6.5 mg/week) was finally chosen to reach the target INR. Genotyping for CYP2C9 revealed that this patient had a genotype CYP2C9*3/*4. This is the first Korean compound heterozygote for CYP2C9*3 and *4. This case suggests the clinical usefulness of pharmacogenetic testing for individualized dosage adjustments of warfarin.

The quest for population-level cancer recurrence data; current deficiencies and targets for improvement.

PubMed

In, Haejin; Simon, Cassie A; Phillips, Jerri Linn; Posner, Mitchell C; Ko, Clifford Y; Winchester, David P

2015-05-01

Cancer recurrence is a critical outcome in cancer care. However, population-level recurrence information is currently unavailable. Tumor registries provide an opportunity to generate this information, but require major reform. Our objectives were to (1) determine causes for variability in collection of recurrence, and (2) identify targets for intervention. On-site interviews and observations of tumor registry follow-up procedures were conducted at Commission on Cancer (CoC) accredited hospitals. Information regarding registry resources (caseload, staffing, chart availability), follow-up methods and perceived causes for difficulty in obtaining recurrence information was obtained. Seven NCI/academic, 5 comprehensive community and 2 community centers agreed to participate. Hospitals were inconsistent in their investigation of cancer recurrence, resulting in underreporting of rates of recurrence. Hospital characteristics, registry staffing, staff qualifications and medical chart access influenced follow-up practices. Coding standards and definitions for recurrence were suboptimal, resulting in hospital variability of recurrence reporting. Finally, inability to identify cases lost to follow-up in collected data prevents accurate analysis of recurrence rates. Tumor registries collect varying degrees of recurrence information and provide the underpinnings to capture population-level cancer recurrence data. Targets for intervention are listed, and provide a roadmap to obtain this critical information in cancer care. © 2015 Wiley Periodicals, Inc.

miRNA-29a targets COL3A1 to regulate the level of type III collagen in pig.

PubMed

Chuan-Hao, Li; Wei, Chen; Jia-Qing, Hu; Yan-Dong, Wang; Shou-Dong, Wang; Yong-Qing, Zeng; Hui, Wang

2016-10-30

COL3A1 encodes the protein, collagen type III alpha 1, which is an important component of collagen. Collagen can have a considerable effect on the processing quality of meat, and is nutritious. Bioinformatic analysis using Targetscan showed that COL3A1 could be a target gene of miRNA-29a. Moreover, we found that Laiwu pigs have higher levels of type III collagen and lower levels of miRNA-29a than Landrace pigs. Therefore, we hypothesized that miRNA-29a suppresses the expression of COL3A1 by targeting its 3'-UTR. miRNA-29a appears to play an inhibitory role in the regulation of COL3A1 in PK15 cells because of the following: (1) overexpression of miRNA-29a resulted in a significant down-regulation of COL3A1 protein levels (2) overexpression of miRNA-29a significantly decreased the level of COL3A1 mRNA. (3) The activity of a COL3A1 luciferase reporter was significant reduced by miRNA-29a. Furthermore, the levels of miRNA-29a and collagen type III in four tissues in Laiwu and Landrace pigs were consistent with the above observations. In this study, we identified COL3A1 as a direct target for miRNA-29a, which will inform further studies of meat quality. Copyright © 2016 Elsevier B.V. All rights reserved.

The Target of the Question: A Taxonomy of Textual Features for Cambridge University "O" Levels English

ERIC Educational Resources Information Center

Benjamin, Shanti Isabelle

2015-01-01

This study investigates the typical textual features that are most frequently targeted in short-answer reading comprehension questions of the Cambridge University "O" Level English Paper 2. Test writers' awareness of how textual features impact on understanding of meanings in text decisions will determine to great extent their decisions…

Identifying the bleeding trauma patient: predictive factors for massive transfusion in an Australasian trauma population.

PubMed

Hsu, Jeremy Ming; Hitos, Kerry; Fletcher, John P

2013-09-01

Military and civilian data would suggest that hemostatic resuscitation results in improved outcomes for exsanguinating patients. However, identification of those patients who are at risk of significant hemorrhage is not clearly defined. We attempted to identify factors that would predict the need for massive transfusion (MT) in an Australasian trauma population, by comparing those trauma patients who did receive massive transfusion with those who did not. Between 1985 and 2010, 1,686 trauma patients receiving at least 1 U of packed red blood cells were identified from our prospectively maintained trauma registry. Demographic, physiologic, laboratory, injury, and outcome variables were reviewed. Univariate analysis determined significant factors between those who received MT and those who did not. A predictive multivariate logistic regression model with backward conditional stepwise elimination was used for MT risk. Statistical analysis was performed using SPSS PASW. MT patients had a higher pulse rate, lower Glasgow Coma Scale (GCS) score, lower systolic blood pressure, lower hemoglobin level, higher Injury Severity Score (ISS), higher international normalized ratio (INR), and longer stay. Initial logistic regression identified base deficit (BD), INR, and hemoperitoneum at laparotomy as independent predictive variables. After assigning cutoff points of BD being greater than 5 and an INR of 1.5 or greater, a further model was created. A BD greater than 5 and either INR of 1.5 or greater or hemoperitoneum was associated with 51 times increase in MT risk (odds ratio, 51.6; 95% confidence interval, 24.9-95.8). The area under the receiver operating characteristic curve for the model was 0.859. From this study, a combination of BD, INR, and hemoperitoneum has demonstrated good predictability for MT. This tool may assist in the determination of those patients who might benefit from hemostatic resuscitation. Prognostic study, level III.

Ezetimibe enhances and stabilizes anticoagulant effect of warfarin.

PubMed

Hashikata, Takehiro; Yamaoka-Tojo, Minako; Kakizaki, Ryota; Nemoto, Teruyoshi; Fujiyoshi, Kazuhiro; Namba, Sayaka; Kitasato, Lisa; Hashimoto, Takuya; Ishii, Shunsuke; Kameda, Ryo; Shimohama, Takao; Tojo, Taiki; Ako, Junya

2017-01-01

Ezetimibe reduces plasma levels of low-density lipoprotein cholesterol by inhibiting Niemann-Pick C1-like protein 1 (NPC1L1). A recent study demonstrated that NPC1L1 plays an important role in absorption of fat-soluble vitamins including vitamin K. We evaluated whether the add-on treatment of ezetimibe affects anticoagulation in patients taking warfarin. Between October 2007 and March 2015, the administration of ezetimibe was started to a total of 101 outpatients who were already on oral anticoagulation with warfarin. We retrospectively analyzed blood lipid levels, prothrombin time international normalized ratio (PT-INR) and time in therapeutic INR range (TTR). Seventy-one patients (70 %) showed increase in PT-INR after ezetimibe treatment (1.96 ± 0.45 to 2.20 ± 0.61, p < 0.001). It was necessary to reduce the warfarin dose in 9 of 101 patients for clinical indication. There was a significant positive correlation between change in PT-INR and statin usage at baseline (p = 0.03). The mean value of changes in PT-INR of patients with taking statin was significantly larger than that of patients without taking statin (0.34 ± 0.54 vs. 0.06 ± 0.36, p = 0.03). There was an increase in the TTR (52 ± 26 to 61 ± 23 %, p < 0.0001) and a decrease in the frequency to change the dose of warfarin after the ezetimibe treatment [45 times of 735 examination days (6 %) to 20 times of 695 examination days (3 %), p = 0.02]. Our data suggest possible drug interaction between warfarin and ezetimibe. Ezetimibe may increase and stabilize the anticoagulant effect of warfarin, especially in patients taking statins.

Results of a Regional Effort to Improve Warfarin Management.

PubMed

Rose, Adam J; Park, Angela; Gillespie, Christopher; Van Deusen Lukas, Carol; Ozonoff, Al; Petrakis, Beth Ann; Reisman, Joel I; Borzecki, Ann M; Benedict, Ashley J; Lukesh, William N; Schmoke, Timothy J; Jones, Ellen A; Morreale, Anthony P; Ourth, Heather L; Schlosser, James E; Mayo-Smith, Michael F; Allen, Arthur L; Witt, Daniel M; Helfrich, Christian D; McCullough, Megan B

2017-05-01

Improved anticoagulation control with warfarin reduces adverse events and represents a target for quality improvement. No previous study has described an effort to improve anticoagulation control across a health system. To describe the results of an effort to improve anticoagulation control in the New England region of the Veterans Health Administration (VA). Our intervention encompassed 8 VA sites managing warfarin for more than 5000 patients in New England (Veterans Integrated Service Network 1 [VISN 1]). We provided sites with a system to measure processes of care, along with targeted audit and feedback. We focused on processes of care associated with site-level anticoagulation control, including prompt follow-up after out-of-range international normalized ratio (INR) values, minimizing loss to follow-up, and use of guideline-concordant INR target ranges. We used a difference-in-differences (DID) model to examine changes in anticoagulation control, measured as percentage time in therapeutic range (TTR), as well as process measures and compared VISN 1 sites with 116 VA sites located outside VISN 1. VISN 1 sites improved on TTR, our main indicator of quality, from 66.4% to 69.2%, whereas sites outside VISN 1 improved from 65.9% to 66.4% (DID 2.3%, P < 0.001). Improvement in TTR correlated strongly with the extent of improvement on process-of-care measures, which varied widely across VISN 1 sites. A regional quality improvement initiative, using performance measurement with audit and feedback, improved TTR by 2.3% more than control sites, which is a clinically important difference. Improving relevant processes of care can improve outcomes for patients receiving warfarin.

Comparison of international normalized ratio audit parameters in patients enrolled in GARFIELD-AF and treated with vitamin K antagonists.

PubMed

Fitzmaurice, David A; Accetta, Gabriele; Haas, Sylvia; Kayani, Gloria; Lucas Luciardi, Hector; Misselwitz, Frank; Pieper, Karen; Ten Cate, Hugo; Turpie, Alexander G G; Kakkar, Ajay K

2016-08-01

Vitamin K antagonist (VKA) therapy for stroke prevention in atrial fibrillation (AF) requires monitoring of the international normalized ratio (INR). We evaluated the agreement between two INR audit parameters, frequency in range (FIR) and proportion of time in the therapeutic range (TTR), using data from a global population of patients with newly diagnosed non-valvular AF, the Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF). Among 17 168 patients with 1-year follow-up data available at the time of the analysis, 8445 received VKA therapy (±antiplatelet therapy) at enrolment, and of these patients, 5066 with ≥3 INR readings and for whom both FIR and TTR could be calculated were included in the analysis. In total, 70 905 INRs were analysed. At the patient level, TTR showed higher values than FIR (mean, 56·0% vs 49·8%; median, 59·7% vs 50·0%). Although patient-level FIR and TTR values were highly correlated (Pearson correlation coefficient [95% confidence interval; CI], 0·860 [0·852-0·867]), estimates from individuals showed widespread disagreement and variability (Lin's concordance coefficient [95% CI], 0·829 [0·821-0·837]). The difference between FIR and TTR explained 17·4% of the total variability of measurements. These results suggest that FIR and TTR are not equivalent and cannot be used interchangeably. © 2016 John Wiley & Sons Ltd.

Impact of a pharmacist-driven warfarin management protocol on achieving therapeutic International Normalized Ratios.

PubMed

Downing, Amanda; Mortimer, Molly; Hiers, Jill

2016-03-01

Warfarin is a high alert medication and a challenge to dose and monitor. Pharmacist-driven warfarin management has been shown to decrease the time international normalized ratio (INR) is out of range, which may reduce undesired outcomes. The purpose of this study is to assess the effect of the implementation of a pharmacist-driven warfarin management protocol on the achievement of therapeutic INRs. A warfarin management protocol was developed using evidence based literature and similar protocols from other institutions. Pharmacists utilized the protocol to provide patient specific warfarin dosing upon provider referral. To evaluate the protocol's impact, a retrospective chart review pre- and post-implementation was completed for admitted patients receiving warfarin. Three hundred twenty-seven charts were reviewed for pre- and post-implementation data. INRs within therapeutic range increased from 27.8% before protocol implementation to 38.5% after implementation. There was also a reduction in subtherapeutic INRs (55.3% pre to 39% post) and supratherapeutic INRs 5 or above (3.7% pre to 2.6% post). Supratherapeutic INRs between 3 and 5 did increase from 13.2% before protocol implementation to 19.9% in the pharmacist managed group. In addition to reducing the time to achievement of therapeutic INRs by 0.5 days, implementation of the protocol resulted in an increased the number of patients with at least one therapeutic INR during admission (35% pre to 40% post). The implementation of a pharmacist-driven warfarin dosing protocol increased therapeutic INRs, and decreased the time to therapeutic range, as well as the proportion of subtherapeutic INRs and supratherapeutic INRs 5 or greater. Additional benefits of the protocol include documentation of Joint Commission National Patient Safety Goal compliance, promotion of interdisciplinary collaboration and increased continuity of care. Copyright © 2016 by the American Society of Health-System Pharmacists, Inc. All rights

Safety and Efficacy of Warfarin Therapy in Kawasaki Disease.

PubMed

Baker, Annette L; Vanderpluym, Christina; Gauvreau, Kimberly A; Fulton, David R; de Ferranti, Sarah D; Friedman, Kevin G; Murray, Jenna M; Brown, Loren D; Almond, Christopher S; Evans-Langhorst, Margaret; Newburger, Jane W

2017-10-01

To describe the safety and efficacy of warfarin for patients with Kawasaki disease and giant coronary artery aneurysms (CAAs, ≥8 mm). Giant aneurysms are managed with combined anticoagulation and antiplatelet therapies, heightening risk of bleeding complications. We reviewed the time in therapeutic range; percentage of international normalization ratios (INRs) in range (%); bleeding events, clotting events; INRs ≥6; INRs ≥5 and <6; and INRs <1.5. In 9 patients (5 male), median age 14.4 years (range 7.1-22.8 years), INR testing was prescribed weekly to monthly and was done by home monitor (n = 5) or laboratory (n = 3) or combined (1). Median length of warfarin therapy was 7.2 years (2.3-13.3 years). Goal INR was 2.0-3.0 (n = 6) or 2.5-3.5 (n = 3), based on CAA size and history of CAA thrombosis. All patients were treated with aspirin; 1 was on dual antiplatelet therapy and warfarin. The median time in therapeutic range was 59% (37%-85%), and median percentage of INRs in range was 68% (52%-87%). INR >6 occurred in 3 patients (4 events); INRs ≥5 <6 in 7 patients (12 events); and INR <1.5 in 5 patients (28 events). The incidence of major bleeding events and clinically relevant nonmajor bleeding events were each 4.3 per 100 patient-years (95% CI 0.9-12.6). New asymptomatic coronary thrombosis was detected by imaging in 2 patients. Bleeding and clotting complications are common in patients with Kawasaki disease on warfarin and aspirin, with INRs in range only two-thirds of the time. Future studies should evaluate the use of direct oral anticoagulants in children as an alternative to warfarin. Copyright © 2017 Elsevier Inc. All rights reserved.

F-18-FDG-PET Confined Radiotherapy of Locally Advanced NSCLC With Concomitant Chemotherapy: Results of the PET-PLAN Pilot Trial

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fleckenstein, Jochen; Hellwig, Dirk; Kremp, Stephanie

2011-11-15

Purpose: The integration of fluoro-deoxy-D-glucose positron emission tomography (FDG-PET) in the process of radiotherapy (RT) planning of locally advanced non-small-cell lung cancer (NSCLC) may improve diagnostic accuracy and minimize interobserver variability compared with target volume definition solely based on computed tomography. Furthermore, irradiating only FDG-PET-positive findings and omitting elective nodal regions may allow dose escalation by treating smaller volumes. The aim of this prospective pilot trial was to evaluate the therapeutic safety of FDG-PET-based RT treatment planning with an autocontour-derived delineation of the primary tumor. Methods and Materials: Eligible patients had Stages II-III inoperable NSCLC, and simultaneous, platinum-based radiochemotherapy wasmore » indicated. FDG-PET and computed tomography acquisitions in RT treatment planning position were coregistered. The clinical target volume (CTV) included the FDG-PET-defined primary tumor, which was autodelineated with a source-to-background algorithm, plus FDG-PET-positive lymph node stations. Limited by dose restrictions for normal tissues, prescribed total doses were in the range of 66.6 to 73.8 Gy. The primary endpoint was the rate of out-of-field isolated nodal recurrences (INR). Results: As per intent to treat, 32 patients received radiochemotherapy. In 15 of these patients, dose escalation above 66.6 Gy was achieved. No Grade 4 toxicities occurred. After a median follow-up time of 27.2 months, the estimated median survival time was 19.3 months. During the observation period, one INR was observed in 23 evaluable patients. Conclusions: FDG-PET-confined target volume definition in radiochemotherapy of NSCLC, based on a contrast-oriented source-to-background algorithm, was associated with a low risk of INR. It might provide improved tumor control because of dose escalation.« less

Warfarin and bosentan interaction in a patient with pulmonary hypertension secondary to bilateral pulmonary emboli.

PubMed

Spangler, Mikayla L; Saxena, Shailendra

2010-01-01

Bosentan is an endothelin-receptor antagonist that reportedly induces both cytochrome P450 (CYP) 3A4 and CYP2C9 enzymes, which are also involved in warfarin metabolism. We present a case report describing a probable drug interaction between warfarin and bosentan in a patient with pulmonary hypertension. A 52-year-old black female (weight, 77 kg) diagnosed with pulmonary hypertension secondary to bilateral pulmonary emboli had a stable international normalized ratio (INR; target range, 2-3) with a weekly warfarin dose of 52.5 mg for 2 months before the initiation of bosentan therapy. Other concurrent medications included telmisartan/ hydrochlorothiazide 40/12.5 mg once daily and a daily multivitamin (which contained no vitamin K). Three weeks after starting bosentan 62.5 mg BID, a therapeutic INR concentration was reached with a weekly warfarin dose 14% higher (an increase of 7.5 mg/wk) than her weekly warfarin dose before initiation of bosentan. After a brief discontinuation (7 days) and retitration of bosentan and warfarin, the final weekly warfarin dose (75 mg/wk) was 43% greater (an increase of 22.5 mg/wk) than the previously stable dose, which enabled the patient to reach her therapeutic INR goal range of 2 to 3. Bosentan has CYP3A4- and CYP2C9-inducing properties and is therefore likely to cause decreased concentrations of warfarin. We describe here a probable drug interaction between bosentan and warfarin that resulted in a 43% increase in warfarin dose to maintain the patient's therapeutic INR.

COPPER-64 Production Studies with Natural Zinc Targets at Deuteron Energy up to 19 Mev and Proton Energy from 141 Down to 31 Mev

NASA Astrophysics Data System (ADS)

Bonardi, Mauro L.; Birattari, Claudio; Groppi, Flavia; Song Mainard, Hae; Zhuikov, Boris L.; Kokhanyuk, Vladimir M.; Lapshina, Elena V.; Mebel, Michail V.; Menapace, Enzo

2004-07-01

High specific activity no-carrier-added 64Cu is a β-/β+ emitting radionuclide of increasing interest for PET imaging, as well as systemic and targeted radioimmunotherapy of tumors. Its peculiarity of intense Auger emitter is still under investigation. The cross-sections for production of 64Cu from Zn target of natural isotopic composition were measured in the deuteron energy range from threshold up to 19 MeV and proton energy range from 141 down to 31 MeV. The stacked-foil technique was used at both K=38 cyclotron of JRC-Ispra of CEC, Italy and 160 MeV intersection point of INR proton-LINAC in Troitsk, Russia. Several Ga, Zn, Cu, Ni, Co, V, Fe and Mn radionuclides were detected in Zn targets at the EOB. Optimized irradiation conditions are reported as a function of deuteron energy and energy loss into the Zn target, as well as target irradiation time and cooling time after radiochemistry. The activity of n.c.a. 64Cu was measured through its only γ emission of 1346 keV (i.e. 0.473 % intensity) both by instrumental and radiochemical methods, due to the non-specificity of annihilation radiation at 511 keV. To this last purpose, it was necessary to carry out a selective radiochemical separation of GaIII radionuclides by liquid/liquid extraction from the bulk of irradiated Zn targets and other spallation products, which remained in the 7 M HCl aqueous phase. Anion exchange chromatography tests had been carried out to separate the 64Cu from all others radionuclides in n.c.a. form. Theoretical calculations of cross-sections were performed with codes EMPIRE II and PENELOPE for deuteron reactions and CEF model and HMS-ALICE hybrid model for proton reactions. The theoretical results are presented and compared with the experimental values.

Systems level mapping of metabolic complexity in Mycobacterium tuberculosis to identify high-value drug targets.

PubMed

Vashisht, Rohit; Bhat, Ashwini G; Kushwaha, Shreeram; Bhardwaj, Anshu; Brahmachari, Samir K

2014-10-11

The effectiveness of current therapeutic regimens for Mycobacterium tuberculosis (Mtb) is diminished by the need for prolonged therapy and the rise of drug resistant/tolerant strains. This global health threat, despite decades of basic research and a wealth of legacy knowledge, is due to a lack of systems level understanding that can innovate the process of fast acting and high efficacy drug discovery. The enhanced functional annotations of the Mtb genome, which were previously obtained through a crowd sourcing approach was used to reconstruct the metabolic network of Mtb in a bottom up manner. We represent this information by developing a novel Systems Biology Spindle Map of Metabolism (SBSM) and comprehend its static and dynamic structure using various computational approaches based on simulation and design. The reconstructed metabolism of Mtb encompasses 961 metabolites, involved in 1152 reactions catalyzed by 890 protein coding genes, organized into 50 pathways. By accounting for static and dynamic analysis of SBSM in Mtb we identified various critical proteins required for the growth and survival of bacteria. Further, we assessed the potential of these proteins as putative drug targets that are fast acting and less toxic. Further, we formulate a novel concept of metabolic persister genes (MPGs) and compared our predictions with published in vitro and in vivo experimental evidence. Through such analyses, we report for the first time that de novo biosynthesis of NAD may give rise to bacterial persistence in Mtb under conditions of metabolic stress induced by conventional anti-tuberculosis therapy. We propose such MPG's as potential combination of drug targets for existing antibiotics that can improve their efficacy and efficiency for drug tolerant bacteria. The systems level framework formulated by us to identify potential non-toxic drug targets and strategies to circumvent the issue of bacterial persistence can substantially aid in the process of TB drug

Health literacy and knowledge in a cohort of Australian patients taking warfarin.

PubMed

Yiu, Angela W; Bajorek, Beata V

2018-01-01

To 1) characterise older patients taking warfarin, 2) assess these patients' level of warfarin knowledge, and 3) describe their strengths and limitations in health literacy, and 4) explore relationships between participants' characteristics, warfarin knowledge and health literacy. A warfarin knowledge questionnaire and Health Literacy Questionnaire (HLQ) were administered to older patients (aged >65 years, N=34) taking warfarin in an Australian general practice setting. Key gaps in participant knowledge pertained to the consequences of an international normalized ratio (INR) being below the target INR range and safety issues such as when to seek medical attention. A limitation for participants with a lower level of health literacy was the ability to appraise health information. Patients who needed assistance in completing the HLQs had significantly lower warfarin knowledge scores (p=0.03). Overseas-born participants and those taking 5 or more long-term medications had lower HLQ scores for specific scales (p<0.05). In this study warfarin knowledge gaps and a limitation of health literacy amongst a small sample of older patients were identified. The findings suggest that education and resources may need to be tailored to the needs of older patients taking warfarin and their carers to address these knowledge gaps and limitations in health literacy. Patients who may need greater support include those that need assistance in completing the HLQ, are overseas-born, or are taking 5 or more long-term medications.

The Importance of Reagent Lot Registration in External Quality Assurance/Proficiency Testing Schemes.

PubMed

Stavelin, Anne; Riksheim, Berit Oddny; Christensen, Nina Gade; Sandberg, Sverre

2016-05-01

Providers of external quality assurance (EQA)/proficiency testing schemes have traditionally focused on evaluation of measurement procedures and participant performance and little attention has been given to reagent lot variation. The aim of the present study was to show the importance of reagent lot registration and evaluation in EQA schemes. Results from the Noklus (Norwegian Quality Improvement of Primary Care Laboratories) urine albumin/creatinine ratio (ACR) and prothrombin time international normalized ratio (INR) point-of-care EQA schemes from 2009-2015 were used as examples in this study. The between-participant CV for Afinion ACR increased from 6%-7% to 11% in 3 consecutive surveys. This increase was caused by differences between albumin reagent lots that were also observed when fresh urine samples were used. For the INR scheme, the CoaguChek INR results increased with the production date of the reagent lots, with reagent lot medians increasing from 2.0 to 2.5 INR and from 2.7 to 3.3 INR (from the oldest to the newest reagent lot) for 2 control levels, respectively. These differences in lot medians were not observed when native patient samples were used. Presenting results from different reagent lots in EQA feedback reports can give helpful information to the participants that may explain their deviant EQA results. Information regarding whether the reagent lot differences found in the schemes can affect patient samples is important and should be communicated to the participants as well as to the manufacturers. EQA providers should consider registering and evaluating results from reagent lots. © 2016 American Association for Clinical Chemistry.

Monitoring of treatment with vitamin K antagonists: recombinant thromboplastins are more sensitive to factor VII than tissue-extract thromboplastins.

PubMed

Biedermann, J S; van den Besselaar, A M H P; de Maat, M P M; Leebeek, F W G; Kruip, M J H A

2017-03-01

Essentials Differences in sensitivity to factor VII (FVII) have been suggested between thromboplastins. FVII-induced International Normalized Ratio (INR) changes differ between commercial reagents. Recombinant human thromboplastins are more sensitive to FVII than tissue-extract thromboplastins. Thromboplastin choice may affect FVII-mediated INR stability. Background Differences regarding sensitivity to factor VII have been suggested for recombinant human and tissue-extract thromboplastins used for International Normalized Ratio (INR) measurement, but the evidence is scarce. Differences in FVII sensitivity are clinically relevant, as they can affect INR stability during treatment with vitamin K antagonists (VKAs). Objectives To determine whether commercial thromboplastins react differently to changes in FVII. Methods We studied the effect of addition of FVII on the INR in plasma by using three tissue-extract (Neoplastin C1+, Hepato Quick, and Thromborel S) and three recombinant human (Recombiplastin 2G, Innovin, and CoaguChek XS) thromboplastins. Three different concentrations of purified human FVII (0.006, 0.012 and 0.062 μg mL -1 plasma), or buffer, were added to five certified pooled plasmas of patients using VKAs (INR of 1.5-3.5). Changes in FVII activity were measured with two bioassays (Neoplastin and Recombiplastin), and relative INR changes were compared between reagents. Results After addition of 0.062 μg mL -1 FVII, FVII activity in the pooled plasmas increased by approximately 20% (Neoplastin) or 32% (Recombiplastin) relative to the activity in pooled normal plasma. All thromboplastins showed dose-dependent INR decreases. The relative INR change in the pooled plasmas significantly differed between the six thromboplastins. No differences were observed among recombinant or tissue-extract thromboplastins. Pooled results indicated that the FVII-induced INR change was greater for recombinant than for tissue-extract thromboplastins. Conclusions Differences

Preclinical PET imaging of EGFR levels: pairing a targeting with a non-targeting Sel-tagged Affibody-based tracer to estimate the specific uptake.

PubMed

Cheng, Qing; Wållberg, Helena; Grafström, Jonas; Lu, Li; Thorell, Jan-Olov; Hägg Olofsson, Maria; Linder, Stig; Johansson, Katarina; Tegnebratt, Tetyana; Arnér, Elias S J; Stone-Elander, Sharon; Ahlzén, Hanna-Stina Martinsson; Ståhl, Stefan

2016-12-01

Though overexpression of epidermal growth factor receptor (EGFR) in several forms of cancer is considered to be an important prognostic biomarker related to poor prognosis, clear correlations between biomarker assays and patient management have been difficult to establish. Here, we utilize a targeting directly followed by a non-targeting tracer-based positron emission tomography (PET) method to examine some of the aspects of determining specific EGFR binding in tumors. The EGFR-binding Affibody molecule ZEGFR:2377 and its size-matched non-binding control ZTaq:3638 were recombinantly fused with a C-terminal selenocysteine-containing Sel-tag (ZEGFR:2377-ST and ZTaq:3638-ST). The proteins were site-specifically labeled with DyLight488 for flow cytometry and ex vivo tissue analyses or with (11)C for in vivo PET studies. Kinetic scans with the (11)C-labeled proteins were performed in healthy mice and in mice bearing xenografts from human FaDu (squamous cell carcinoma) and A431 (epidermoid carcinoma) cell lines. Changes in tracer uptake in A431 xenografts over time were also monitored, followed by ex vivo proximity ligation assays (PLA) of EGFR expressions. Flow cytometry and ex vivo tissue analyses confirmed EGFR targeting by ZEGFR:2377-ST-DyLight488. [Methyl-(11)C]-labeled ZEGFR:2377-ST-CH3 and ZTaq:3638-ST-CH3 showed similar distributions in vivo, except for notably higher concentrations of the former in particularly the liver and the blood. [Methyl-(11)C]-ZEGFR:2377-ST-CH3 successfully visualized FaDu and A431 xenografts with moderate and high EGFR expression levels, respectively. However, in FaDu tumors, the non-specific uptake was large and sometimes equally large, illustrating the importance of proper controls. In the A431 group observed longitudinally, non-specific uptake remained at same level over the observation period. Specific uptake increased with tumor size, but changes varied widely over time in individual tumors. Total (membranous and cytoplasmic) EGFR

Monitoring of international normalized ratios: comparison of community nurses with family physicians.

PubMed

Levine, Max A; Shao, Wei; Klein, Douglas

2012-08-01

To determine whether community-based, nurse-led monitoring of the international normalized ratio (INR) in patients requiring long-term warfarin therapy was comparable to traditional physician monitoring. A retrospective cohort analysis of patients taking long-term warfarin therapy. The study used data gathered from 3 family medicine clinics in a primary care network in Edmonton, Alta. Medical records of patients currently taking warfarin were examined. Implementation of nurse-led monitoring in a primary care network in place of standard family physician INR monitoring. The degree of INR control before and after the implementation of nurse-run INR monitoring was assessed. The average proportion of time spent outside of therapeutic INR ranges, as well as the average number of days between successive INR readings, was calculated and compared. The degree of control placed patients into either a good-control group (out of range ≤ 25% of the time) or a moderate-control group (out of range > 25% of the time) and these groups were compared. Before nurse monitoring, INR values were out of range 20.4% of the time; after nurse monitoring they were out of range 19.2% of the time (P = .115); the time between sequential INR readings also did not differ before and after implementation of nurse monitoring (23.9 vs 21.6 days, P = .789). Nurse-led monitoring of INR is as effective as traditional physician monitoring. Advantages of nurse-led monitoring might include freeing family physicians to see more patients or to spend less time at work. It might also represent potential cost savings.

Prospective evaluation of a bivalirudin to warfarin transition nomogram.

PubMed

Hohlfelder, Benjamin; Sylvester, Katelyn W; Rimsans, Jessica; DeiCicchi, David; Connors, Jean M

2017-05-01

Bivalirudin may cause a falsely prolonged international normalized ratio (INR) that complicates the discontinuation of bivalirudin when used as a bridge to warfarin. To prospectively validate our novel bivalirudin to warfarin transition nomogram, adult patients who received bivalirudin as a bridge to warfarin between July 2015 and June 2016 were prospectively evaluated, utilizing our predictive nomogram. The major outcome of our analysis was the correlation between the predicted change in INR upon bivalirudin discontinuation based on the nomogram, and the actual change in INR upon bivalirudin discontinuation. The major outcome was analyzed using the Pearson's correlation test. A Pearson's correlation coefficient >0.6 was considered to be a strong correlation. Bivalirudin was used as a bridge to warfarin in 29 patients. The majority of patients (86%) included in the analysis had a ventricular assist device. The median initial bivalirudin rate was 0.07 mg/kg/h and the mean increase in INR when starting bivalirudin was 0.6. The mean final weight-based bivalirudin rate was 0.08 mg/kg/h and the mean change in INR after stopping bivalirudin was 0.7. The Pearson correlation coefficient between the predicted change in INR upon bivalirudin discontinuation and the actual change in INR upon bivalirudin discontinuation was 0.86 (p < 0.001). After bivalirudin discontinuation, 68% of patients had a therapeutic INR. The results of this prospective analysis successfully validated our novel bivalirudin to warfarin transition nomogram. There was a very strong correlation between the predicted change and actual change in INR upon bivalirudin discontinuation.

Paramedic Initiation of Neuroprotective Agent Infusions: Successful Achievement of Target Blood Levels and Attained Level Effect on Clinical Outcomes in the FAST-MAG Pivotal Trial (Field Administration of Stroke Therapy - Magnesium).

PubMed

Shkirkova, Kristina; Starkman, Sidney; Sanossian, Nerses; Eckstein, Marc; Stratton, Samuel; Pratt, Frank; Conwit, Robin; Hamilton, Scott; Sharma, Latisha; Liebeskind, David; Restrepo, Lucas; Valdes-Sueiras, Miguel; Saver, Jeffrey L

2017-07-01

Paramedic use of fixed-size lumen, gravity-controlled tubing to initiate intravenous infusions in the field may allow rapid start of neuroprotective therapy for acute stroke. In a large, multicenter trial, we evaluated its efficacy in attaining target serum levels of candidate neuroprotective agent magnesium sulfate and the relation of achieved magnesium levels to outcome. The FAST-MAG phase 3 trial (Field Administration of Stroke Therapy - Magnesium) randomized 1700 patients within 2 hours of onset to paramedic-initiated, a 15-minute loading intravenous infusion of magnesium or placebo followed by a 24-hour maintenance dose. The drug delivery strategy included fixed-size lumen, gravity-controlled tubing for field drug administration, and a shrink-wrapped ambulance kit containing both the randomized field loading and hospital maintenance doses for seamless continuation. Among patient randomized to active treatment, magnesium levels in the first 72 hours were assessed 987 times in 572 patients. Mean patient age was 70 years (SD±14 years), and 45% were women. During the 24-hour period of active infusion, mean achieved serum level was 3.91 (±0.8), consistent with trial target. Mg levels were increased by older age, female sex, lower weight, height, body mass index, and estimated glomerular filtration rate, and higher blood urea nitrogen, hemoglobin, and higher hematocrit. Adjusted odds for clinical outcomes did not differ by achieved Mg level, including disability at 90 days, symptomatic hemorrhage, or death. Paramedic infusion initiation using gravity-controlled tubing permits rapid achievement of target serum levels of potential neuroprotective agents. The absence of association of clinical outcomes with achieved magnesium levels provides further evidence that magnesium is not biologically neuroprotective in acute stroke. © 2017 American Heart Association, Inc.

Laser-induced breakdown spectroscopic detection of trace level heavy metal in solutions on a laser-pretreated metallic target.

PubMed

Niu, Sheng; Zheng, Lijuan; Khan, Abdul Qayyum; Feng, Guang; Zeng, Heping

2018-03-01

A fast and sensitive analysis for trace level heavy metals in aqueous solution was realized by using an improved laser induced breakdown spectroscopy (LIBS) methodology. Solutions containing heavy metal elements, Ni, Cr, and Cd, were concentrated in a laser-pretreated area (25 × 20mm 2 ) of a polished aluminum target surface, wherein pretreated grooves enabled homogeneous distribution of the metallic solutions in the well-defined area, and laser ablation of the aluminum target produced unique plasma excitation of various metallic ions. For 1-mL solutions deposited, we obtained an analytical precision of about 7% relative standard deviation (RSD), and limits of detection (LODs) of 22, 19, and 184μg/L for Ni, Cr, and Cd, respectively. Moreover, the laser-pretreated metallic microstructure allowed more solution deposited with the help of a hot plate, which supported improvement of LODs to sub-μg/L level for Cr and Ni and μg/L level for Cd with about 20-mL solution engaged in the enrichment processes. The applicability of the proposed methodology was validated on certified reference materials and real river water. Copyright © 2017 Elsevier B.V. All rights reserved.

Natural antisense transcript-targeted regulation of inducible nitric oxide synthase mRNA levels.

PubMed

Yoshigai, Emi; Hara, Takafumi; Araki, Yoshiro; Tanaka, Yoshito; Oishi, Masaharu; Tokuhara, Katsuji; Kaibori, Masaki; Okumura, Tadayoshi; Kwon, A-Hon; Nishizawa, Mikio

2013-04-01

Natural antisense transcripts (asRNAs) are frequently transcribed from mammalian genes. Recently, we found that non-coding asRNAs are transcribed from the 3' untranslated region (3'UTR) of the rat and mouse genes encoding inducible nitric oxide synthase (iNOS), which catalyzes the production of the inflammatory mediator nitric oxide. The iNOS asRNA stabilizes iNOS mRNA by interacting with the mRNA 3'UTR. Furthermore, single-stranded 'sense' oligonucleotides corresponding to the iNOS mRNA sequence were found to reduce iNOS mRNA levels by interfering with mRNA-asRNA interactions in rat hepatocytes. This method was named natural antisense transcript-targeted regulation (NATRE) technology. In this study, we detected human iNOS asRNA expressed in hepatocarcinoma and colon carcinoma tissues. The human iNOS asRNA harbored a sequence complementary to an evolutionarily conserved region of the iNOS mRNA 3'UTR. When introduced into hepatocytes, iNOS sense oligonucleotides that were modified by substitution with partial phosphorothioate bonds and locked nucleic acids or 2'-O-methyl nucleic acids greatly reduced levels of iNOS mRNA and iNOS protein. Moreover, sense oligonucleotides and short interfering RNAs decreased iNOS mRNA to comparable levels. These results suggest that NATRE technology using iNOS sense oligonucleotides could potentially be used to treat human inflammatory diseases and cancers by reducing iNOS mRNA levels. Copyright © 2013 Elsevier Inc. All rights reserved.

International normalized ratio testing with a point-of-care coagulometer in 1-month-old infants: A comparison with Normotest.

PubMed

Iijima, Shigeo; Baba, Toru; Ueno, Daizo; Ohishi, Akira

2016-09-01

Early infants are at risk of vitamin K (VK) deficiency-associated bleeding unless they receive VK prophylaxis. A coagulation screening test might be necessary to detect prophylactic failure, but it is rarely conducted owing to the difficulty of blood sampling. CoaguChek XS is a portable, point-of-care (POC) coagulation analyzer that determines international normalized ratios (INRs) using only small volumes of blood. Although POC tests assessing INR have become widespread for adults, studies have not been performed in early infancy. This study aimed to determine the reference interval (RI) for INR for 1-month-old infants using the CoaguChek XS and to compare INRs with Normotest (NT) values to evaluate its efficacy as a VK deficiency screening test. This study included 578 consecutive 1-month-old, healthy, term infants who underwent a 1-month health checkup. CoaguChek XS INRs and NT values were analyzed for each subject. The enrolled neonates were orally administered VK 6-12h and 4days after birth. An INR RI for 1-month-old infants was established using the CoaguChek XS (range of 0.9-1.1). On the other hand, the NT RI was 69%-130%. We observed a significant inverse correlation between INRs and NT values. Our study is the first to establish an INR RI using the CoaguChek XS for 1-month-old, healthy, term infants. CoaguChek XS INR was more convenient to test than NT. However, we could not demonstrate its efficacy as a VK deficiency screening test because no infant had an aberrant NT value or a bleeding disorder. Copyright © 2016 Elsevier Ltd. All rights reserved.

Evaluation of warfarin management with international normalized ratio self-testing and online remote monitoring and management plus low-dose vitamin k with genomic considerations: a pilot study.

PubMed

Bussey, Henry I; Bussey, Marie; Bussey-Smith, Kristin L; Frei, Christopher R

2013-11-01

As better international normalized ratio (INR) control and self-testing reduce events in warfarin-treated patients, and vitamin K supplementation may improve INR control, our primary objective was to evaluate the effect of a system combining frequent INR self-testing with online remote monitoring and management (STORM₂) and low-dose vitamin K supplementation on INR control; our secondary objectives were to assess the impact of STORM₂ on clinician time and to evaluate the influence of pharmacogenomics on INR stability and warfarin dose after vitamin K supplementation. Prospective pre- and postintervention study. Freestanding clinical research center. Fifty-five patients treated with long-term warfarin therapy who were referred from four anticoagulation clinics and seven medical practices. All patients performed weekly INR self-testing and received vitamin K 100 µg/day and online anticoagulation management for 1 year. INR control and time required for anticoagulation management were assessed, and an analysis of warfarin dosing and INR stability by genetic polymorphism subgroup (vitamin K epoxide reductase complex 1 [VKORC1] and cytochrome P450 2C9 isoenzyme) was performed; vitamin K product content was also analyzed. The percentage of time that the INR is within the time in therapeutic range (TTR) improved from 56% before the intervention to 81% after the intervention (p<0.0001), and time spent at extreme INR values of lower than 1.5 or higher than 5 was reduced from 3.1% to 0.4% (p=0.01). Clinician time was less than 10 minutes per four patient visits per month. Genetic polymorphisms did not correlate with INR stability or the increase in warfarin dose after vitamin K supplementation. The content of the vitamin K product, however, was only 34-76% of the labeled amount. Patients with the GG VKORC1 genotype required a higher warfarin dose than predicted by the genomic-based dosing chart in the warfarin package insert. The 25% point improvement in TTR with STORM�

Factors determining patients’ intentions to use point-of-care testing medical devices for self-monitoring: the case of international normalized ratio self-testing

PubMed Central

Shah, Syed Ghulam Sarwar; Barnett, Julie; Kuljis, Jasna; Hone, Kate; Kaczmarski, Richard

2013-01-01

Purpose To identify factors that determine patients’ intentions to use point-of-care medical devices, ie, portable coagulometer devices for self-testing of the international normalized ratio (INR) required for ongoing monitoring of blood-coagulation intensity among patients on long-term oral anticoagulation therapy with vitamin K antagonists, eg, warfarin. Methods A cross-sectional study that applied the technology-acceptance model through a self-completed questionnaire, which was administered to a convenience sample of 125 outpatients attending outpatient anticoagulation services at a district general hospital in London, UK. Data were analyzed using descriptive statistics, factor analyses, and structural equation modeling. Results The participants were mainly male (64%) and aged ≥ 71 years (60%). All these patients were attending the hospital outpatient anticoagulation clinic for INR testing; only two patients were currently using INR self-testing, 84% of patients had no knowledge about INR self-testing using a portable coagulometer device, and 96% of patients were never offered the option of the INR self-testing. A significant structural equation model explaining 79% of the variance in patients’ intentions to use INR self-testing was observed. The significant predictors that directly affected patients’ intention to use INR self-testing were the perception of technology (β = 0.92, P < 0.001), trust in doctor (β = −0.24, P = 0.028), and affordability (β = 0.15, P = 0.016). In addition, the perception of technology was significantly affected by trust in doctor (β = 0.43, P = 0.002), age (β = −0.32, P < 0.001), and affordability (β = 0.23, P = 0.013); thereby, the intention to use INR self-testing was indirectly affected by trust in doctor (β = 0.40), age (β = −0.29), and affordability (β = 0.21) via the perception of technology. Conclusion Patients’ intentions to use portable coagulometers for INR self-testing are affected by patients�

PT and INR Test

MedlinePlus

... Cancer Therapy Glucose Tests Gonorrhea Testing Gram Stain Growth Hormone Haptoglobin hCG Pregnancy hCG Tumor Marker HDL Cholesterol ... Semen Analysis Serotonin Serum Free Light Chains Sex Hormone Binding Globulin ... Transferrin Receptor Stool Culture Stool Elastase Strep ...

Improving the management of warfarin in aged-care facilities utilising innovative technology: a proof-of-concept study.

PubMed

Bereznicki, Luke R E; Jackson, Shane L; Kromdijk, Wiete; Gee, Peter; Fitzmaurice, Kimbra; Bereznicki, Bonnie J; Peterson, Gregory M

2014-02-01

In aged-care facilities (ACFs) monitoring of warfarin can be logistically challenging and International Normalised Ratio (INR control) is often suboptimal. We aimed to determine whether an integrated information and communications technology system and the use of point-of-care (POC) monitors by nursing staff could improve the INR control of aged-care facility residents who take warfarin. Nursing staff identified residents who were prescribed warfarin in participating ACFs. A computer program (MedePOC) was developed to store and transmit INR results from the ACFs to general practitioners (GPs) for dosage adjustment. Nursing staff received training in the use of the CoaguChek XS point-of-care INR monitor and the MedePOC software. Following a run-in phase, eligible patients were monitored weekly for up to 12 weeks. The primary outcome was the change in the time in therapeutic range (TTR) in the intervention phase compared to the TTR in the 12 months preceding the study. All GPs, nursing staff and patients were surveyed for their experiences and opinions of the project. Twenty-four patients and 19 GPs completed the trial across six ACFs. The mean TTR for all patients improved non-significantly from 58.9 to 60.6% (P=0.79) and the proportion of INR tests in range improved non-significantly from 57.1 to 64.1% (P=0.21). The mean TTR improved in 14 patients (58%) and in these patients the mean absolute improvement in TTR was 23.1%. A post hoc analysis of the INR data using modified therapeutic INR ranges to reflect the dosage adjustment practices of GPs suggested that the intervention did lead to improved INR control. The MedePOC program and POC monitoring was well received by nursing staff. Weekly POC INR monitoring conducted in ACFs and electronic communication of the results and warfarin doses resulted in non-significant improvements in INR control in a small cohort of elderly residents. Further research involving modification to the communication strategy and a longer

Development and Validation of a Novel Vancomycin Dosing Nomogram for Achieving High-Target Trough Levels at 2 Canadian Teaching Hospitals

PubMed Central

Thalakada, Rosanne; Legal, Michael; Lau, Tim T Y; Luey, Tiffany; Batterink, Josh; Ensom, Mary H H

2012-01-01

Background: Recent guidelines recommend a vancomycin trough (predose) level between 15 and 20 mg/L in the treatment of invasive gram-positive infections, but most initial dosing nomograms are designed to achieve lower targets (5–15 mg/L). Clinicians need guidance about appropriate initial dosing to achieve the higher target. Objective: To develop and validate a high-target vancomycin dosing nomogram to achieve trough levels of 15–20 mg/L. Methods: A retrospective study was conducted at 2 teaching hospitals, St Paul’s Hospital and Vancouver General Hospital in Vancouver, British Columbia. Patients who were treated with vancomycin between January 2008 and June 2010 and who had achieved a trough level of 14.5–20.5 mg/L were identified. Demographic and clinical data were collected. Multiple linear regression was used to develop a vancomycin dosing nomogram for each hospital site. An integrated nomogram was constructed by merging the data from the 2 hospitals. A unique set of patients at each institution was used for validating their respective nomograms and a pooled group of patients for validating the integrated nomogram. Predictive success was evaluated, and a nomogram was deemed significantly different from another nomogram if p < 0.05 via “χ2 testing. Results: Data from 78 patients at one hospital and 91 patients at the other were used in developing the respective institutional nomograms. For each hospital’s data set, both age and initial serum creatinine were significantly associated with the predicted dosing interval (p < 0.001). Validation in a total of 105 test patients showed that the integrated nomogram had a predictive success rate of 56%. Conclusions: A novel vancomycin dosing nomogram was developed and validated at 2 Canadian teaching hospitals. This integrated nomogram is a tool that clinicians can use in selecting appropriate initial vancomycin regimens on the basis of age and serum creatinine, to achieve high-target levels of 15–20 mg

Nuclear Security: Target Analysis-rev

DOE Office of Scientific and Technical Information (OSTI.GOV)

Singh, Surinder Paul; Gibbs, Philip W.; Bultz, Garl A.

2014-03-01

The objectives of this presentation are to understand target identification, including roll-up and protracted theft; evaluate target identification in the SNRI; recognize the target characteristics and consequence levels; and understand graded safeguards.

Out-of-range international normalized ratio values and healthcare cost among new warfarin patients with non-valvular atrial fibrillation.

PubMed

Nelson, Winnie W; Wang, Li; Baser, Onur; Damaraju, C V; Schein, Jeffrey R

2015-05-01

Patients with out-of-range international normalized ratio (INR) values <2.0 and >3.0 have been associated with increased risk of thromboembolic and bleeding events. INR monitoring is costly, because of associated physician and nurse time, laboratory resource use, and dose adjustments. This study assessed the healthcare cost burden associated with out-of-range INR among warfarin initiator patients diagnosed with non-valvular atrial fibrillation (NVAF) in the US Veterans Health Administration (VHA) population. Adult NVAF patients (≥18 years) initiating warfarin were selected from the VHA dataset for the study period October 1, 2007-September 30, 2012. Only valid INR measurements (0.5 ≤ INR ≤ 20) were examined for the follow-up period, from the index date (warfarin initiation date) until the end of warfarin exposure or death. All-cause healthcare costs within 30 days were measured starting from the second month (31 days post-index date) to the end of the study period. Costs for inpatient stays, emergency room, outpatient facility, physician office visits, and other services were computed separately. Multiple regression was performed using the generalized linear model for overall cost analysis. In total, 29,463 patients were included in the study sample. Mean costs for out-of-range INR ranged from $3419 to $5126. Inpatient, outpatient, outpatient pharmacy, and total costs were significantly higher after patients experienced out-of-range results (INR < 2, INR > 3), compared with in-range INR (2 ≤ INR ≤ 3). When exposed to out-of-range INR, patients also incurred higher mean total costs within 2-6 months ($3840-$5820) than after the first 6 months ($2789-$3503) of warfarin therapy. In the VHA population, INR measures outside of the 2-3 range were associated with significantly higher healthcare costs. Increased costs were especially apparent when INR values were below 2, although INR measures above 3 were also associated with higher costs

A liquid chromatography-tandem mass spectrometry-based targeted proteomics assay for monitoring P-glycoprotein levels in human breast tissue.

PubMed

Yang, Ting; Chen, Fei; Xu, Feifei; Wang, Fengliang; Xu, Qingqing; Chen, Yun

2014-09-25

P-glycoprotein (P-gp) can efflux drugs from cancer cells, and its overexpression is commonly associated with multi-drug resistance (MDR). Thus, the accurate quantification of P-gp would help predict the response to chemotherapy and for prognosis of breast cancer patients. An advanced liquid chromatography-tandem mass spectrometry (LC/MS/MS)-based targeted proteomics assay was developed and validated for monitoring P-gp levels in breast tissue. Tryptic peptide 368IIDNKPSIDSYSK380 was selected as a surrogate analyte for quantification, and immuno-depleted tissue extract was used as a surrogate matrix. Matched pairs of breast tissue samples from 60 patients who were suspected to have drug resistance were subject to analysis. The levels of P-gp were quantified. Using data from normal tissue, we suggested a P-gp reference interval. The experimental values of tumor tissue samples were compared with those obtained from Western blotting and immunohistochemistry (IHC). The result indicated that the targeted proteomics approach was comparable to IHC but provided a lower limit of quantification (LOQ) and could afford more reliable results at low concentrations than the other two methods. LC/MS/MS-based targeted proteomics may allow the quantification of P-gp in breast tissue in a more accurate manner. Copyright © 2014 Elsevier B.V. All rights reserved.

The forward masking effects of low-level laser glare on target location performance in a visual search task

NASA Astrophysics Data System (ADS)

Reddix, M. D.; Dandrea, J. A.; Collyer, P. D.

1992-01-01

The present study examined the effects of low-intensity laser glue, far below a level that would cause ocular damage or flashblindness, on the visually guided performance of aviators. With a forward-masking paradigm, this study showed that the time at which laser glare is experienced, relative to initial acquisition of visual information, differentially affects the speed and accuracy of target-location performance. Brief exposure (300 ms) to laser glare, terminating with a visual scene's onset, produced significant decrements in target-location performance relative to a no-glare control whereas a 150 and 300-ms delay of display onset (DDO) had very little effect. The intensity of the light entering the eye and producing these effects was far below the Maximum Permissible Exposure (MPE) limit for safe viewing of coherent light produced by an argon laser. In addition, these effects were modulated by the distance of the target from the center of the visual display. This study demonstrated that the presence of laser glare is not sufficient, in and of itself, to diminish target-location performance. The time at which laser glare is experienced is an important factor in determining the probability and extent of visually mediated performance decrements.

Multiple Level Crowding: Crowding at the Object Parts Level and at the Object Configural level.

PubMed

Kimchi, Ruth; Pirkner, Yossef

2015-01-01

In crowding, identification of a peripheral target in the presence of nearby flankers is worse than when the target appears alone. Prevailing theories hold that crowding occurs because of integration or "pooling" of low-level features at a single, relatively early stage of visual processing. Recent studies suggest that crowding can occur also between high-level object representations. The most relevant findings come from studies with faces and may be specific to faces. We examined whether crowding can occur at the object configural level in addition to part-level crowding, using nonface objects. Target (a disconnected square or diamond made of four elements) identification was measured at varying eccentricities. The flankers were similar either to the target parts or to the target configuration. The results showed crowding in both cases: Flankers interfered with target identification such that identification accuracy decreased with an increase in eccentricity, and no interference was observed at the fovea. Crowding by object parts, however, was weaker and had smaller spatial extent than crowding by object configurations; we related this finding to the relationship between crowding and perceptual organization. These results provide strong evidence that crowding occurs not only between object parts but also between configural representations of objects. © The Author(s) 2015.

[Quality control of oral anticoagulant therapy in Primary Care in Madrid City, Spain: CHRONOS-TAO study].

PubMed

Alonso Roca, Rafael; Figueroa Guerrero, Carmen Arlene; Mainar de Paz, Victoria; Arribas García, M Paz; Sánchez Perruca, Luis; Rodríguez Barrientos, Ricardo; Casado López, Mariano; Pedraza Flechas, Ana M

2015-09-07

To determine quality control of patients with oral anticoagulant treatment recruited in Primary Care (PC) using the Rosendaal method to estimate time in therapeutic range (TTR) and comparing it with fraction of international normalized ratio (INR) in range and cross-sectional analysis (last INR registred). A retrospective observational study based on electronic medical record in routine clinical practice. PC centers (262) in Madrid. We included all patients with acenocumarol treatment, with an INR therapeutic range established between 2 and 3. We excluded patients with valvular pathology and disrupted clinical follow up in PC (<3 INR determinations in the studied period, a period of>90 days or ≥ 3 periods of>60 days between 2 determinations). The final population was 49,312 patients. The variables considered were all INR values and their respective dates. TTR was calculated by the 3 methods above mentioned. We considered "therapeutic range" INR between 2-3 and "adjusted range" INR between 1.8-3.2. Optimal control for each patient was considered TTR>60%. By using Rosendaal method, TTR was 66.8% (81.7% adjusted), with a percentage of total INR in range was 58.8% (66.5% adjusted), and, with the cross-sectional analysis, it was 70.5% (76.8% adjusted). Mean TTR was 65% (standard deviation 20.3), and the percentage of patients with TTR>60% was 63.3% (88.1% adjusted). The quality control of patients with oral anticoagulants in PC in Madrid is acceptable, similar or higher to other studies and pivotal trials of new anticoagulants. Compared to the Rosendaal method, total fraction of INR underestimates quality control, and cross-sectional analysis slightly overestimates it. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

Rapid bedside coagulometry prior to urgent neurosurgical procedures in anticoagulated patients.

PubMed

Beynon, Christopher; Jakobs, Martin; Rizos, Timolaos; Unterberg, Andreas W; Sakowitz, Oliver W

2014-01-01

With the increased use of oral anticoagulation with vitamin K antagonists, emergency physicians encounter a growing number of patients requiring a rapid reversal of anticoagulant effects in order to perform urgent surgical procedures. Initiation of these procedures can be delayed because the coagulation status has to be assessed through examination of blood samples in central laboratories (CL). This delay may lead to negative effects, especially in potentially life-threatening conditions such as intracranial haemorrhage. Point-of-care (POC) devices for assessment of international normalized ratio (POC INR) have improved the management of anticoagulation therapy in the outpatient setting. The use of these devices may also have beneficial effects in the treatment of anticoagulated patients requiring urgent neurosurgical procedures. The primary aim of this study was to analyse the potential of POC-guided assessment of INR to reduce time to potentially life-saving neurosurgery in this setting. Feasibility and accuracy as well as the gain of time through the use of this device were analysed. The POC coagulometer CoaguChek XS(®) was used in 17 patients with a history of anticoagulant use and a condition requiring urgent anticoagulant reversal prior to neurosurgical procedures (burr-hole trepanation: n = 8, craniotomy: n = 7, laminectomy: n = 2). No technical difficulties occurred and rapid assessment of INR was achieved in all cases within 2 min. POC INR values correlated well with CL INR assessment with a mean INR deviation of 0.036 ± 0.12. The mean gain of time through the use of the POC INR device compared with CL assessment of INR was 47 ± 6 min (range: 37-61 min). Our initial experiences with a POC INR device in anticoagulated patients undergoing urgent neurosurgical procedures demonstrate that its use may contribute to an improved management of these patients.

Probable interaction between warfarin and rifaximin in a patient treated for small intestine bacterial overgrowth.

PubMed

Hoffman, Justin Thomas; Hartig, Christine; Sonbol, Eyman; Lang, Megan

2011-05-01

To report a case in which the anticoagulant effects of warfarin were attenuated during concomitant administration of rifaximin, possibly through induction of CYP3A4 following increased absorption of rifaximin in a patient with small intestine bacterial overgrowth (SIBO). A 49-year-old African American female had received effective anticoagulant therapy for 5 months with a target international normalized ratio (INR) of 2.0-3.5 on a warfarin regimen of 7.5 mg daily. Five days following initiation of rifaximin 400 mg 3 times daily to treat SIBO, her INR had fallen to 1.2 and remained suppressed throughout the duration of her rifaximin regimen despite incremental warfarin dosage increases (highest dose, 15 mg/day for 2 days, followed by 11.25 mg/day). Twelve days after completion of the rifaximin treatment course, the INR was supratherapeutic at 4.2, requiring titration to her baseline warfarin dosage to achieve an INR within the target range. Similar results were obtained following rechallenge with rifaximin. Rifaximin has been shown in vitro to induce the CYP3A4 enzyme for which the R-isomer of warfarin is a known substrate. The lack of in vivo CYP3A4 induction with rifaximin in other patient populations has repeatedly been attributed to its minimal oral bioavailability, while a recent study found that patients with SIBO had a clinically significant increase in intestinal permeability. In this patient population it is plausible that rifaximin bioavailability increases enough to induce CYP3A4, leading to clinically significant reductions in the bioavailability of CYP3A4 substrates, including R-warfarin. An objective causality assessment of this case revealed that a warfarin-rifaximin interaction was probable. No other drug dosages were altered during the timeframe in question, and the patient had an impeccable medication adherence history; we therefore ruled out these potential etiologies. To our knowledge, an interaction between warfarin and rifaximin has not been

Effect of home testing of international normalized ratio on clinical events.

PubMed

Matchar, David B; Jacobson, Alan; Dolor, Rowena; Edson, Robert; Uyeda, Lauren; Phibbs, Ciaran S; Vertrees, Julia E; Shih, Mei-Chiung; Holodniy, Mark; Lavori, Philip

2010-10-21

Warfarin anticoagulation reduces thromboembolic complications in patients with atrial fibrillation or mechanical heart valves, but effective management is complex, and the international normalized ratio (INR) is often outside the target range. As compared with venous plasma testing, point-of-care INR measuring devices allow greater testing frequency and patient involvement and may improve clinical outcomes. We randomly assigned 2922 patients who were taking warfarin because of mechanical heart valves or atrial fibrillation and who were competent in the use of point-of-care INR devices to either weekly self-testing at home or monthly high-quality testing in a clinic. The primary end point was the time to a first major event (stroke, major bleeding episode, or death). The patients were followed for 2.0 to 4.75 years, for a total of 8730 patient-years of follow-up. The time to the first primary event was not significantly longer in the self-testing group than in the clinic-testing group (hazard ratio, 0.88; 95% confidence interval, 0.75 to 1.04; P=0.14). The two groups had similar rates of clinical outcomes except that the self-testing group reported more minor bleeding episodes. Over the entire follow-up period, the self-testing group had a small but significant improvement in the percentage of time during which the INR was within the target range (absolute difference between groups, 3.8 percentage points; P<0.001). At 2 years of follow-up, the self-testing group also had a small but significant improvement in patient satisfaction with anticoagulation therapy (P=0.002) and quality of life (P<0.001). As compared with monthly high-quality clinic testing, weekly self-testing did not delay the time to a first stroke, major bleeding episode, or death to the extent suggested by prior studies. These results do not support the superiority of self-testing over clinic testing in reducing the risk of stroke, major bleeding episode, and death among patients taking warfarin

In-patient international normalized ratio self-testing instruction after mechanical heart valve implantation.

PubMed

Thompson, Jess L; Sundt, Thoralf M; Sarano, Maurice E; Santrach, Paula J; Schaff, Hartzell V

2008-06-01

Patient self-testing of the international normalized ratio (INR) has been shown to improve management of anticoagulation with warfarin and reduce risks of thromboembolism and bleeding. Self-testing instruction usually begins several weeks after hospital discharge. We evaluated the feasibility of in-hospital INR self-testing instruction in patients recovering from valve replacement. We instituted an education program on a self-testing device before hospital discharge in 50 adult patients (median age, 54 years; 66% men) undergoing cardiac valve replacement with mechanical prostheses. Patients were monitored for 1 month to assess their ability to self-test and the accuracy of the INR measurements. Self-testing instruction began on postoperative day 4 (range, 1 to 8 days). Each patient had an average of 3.5 teaching sessions; each session lasted approximately 20 minutes. One month after discharge, all patients (98%) but 1 were able to self-test. No patient required interval instruction. One bleeding episode occurred in a patient whose INR exceeded the therapeutic range. Once warfarin doses were stabilized, 5 patients had subtherapeutic INR values on self-testing. The mean INR test result obtained from the coagulometer correlated well with values obtained by laboratory determination (r = 0.79). This evaluation of an in-hospital education program demonstrates that patients are able to learn INR self-testing and that most will continue to use the method without the need for interval instruction. Improved anticoagulation management by early introduction of INR self-testing should reduce thromboembolic and hemorrhagic complications after valve replacement.

The relation between international normalized ratio and mortality in acute pulmonary embolism: A retrospective study.

PubMed

Kırış, Tuncay; Yazıcı, Selcuk; Durmuş, Gündüz; Çanga, Yiğit; Karaca, Mustafa; Nazlı, Cem; Dogan, Abdullah

2018-01-01

Acute pulmonary embolism (PE) is a serious clinical disease characterized by a high mortality rate. The aim of this study was to assess the prognostic value of international normalized ratio (INR) in acute PE patients not on anticoagulant therapy. The study included 244 hospitalized acute PE patients who were not receiving previous anticoagulant therapy. Based on their 30-day mortality, patients were categorized as survivors or non-survivors. INR was measured during the patients' admission, on the same day as the diagnosis of PE but before anticoagulation started. Thirty-day mortality occurred in 39 patients (16%). INR was higher in non-survivors than in survivors (1.3±0.4 vs 1.1±0.3, P=.003). In multivariate analysis, INR (HR: 3.303, 95% CI: 1.210-9.016, P=.020) was independently associated with 30-day mortality from PE. Inclusion of INR in a model with simplified pulmonary embolism severity index (sPESI) score improved the area under the receiver operating characteristics (ROC) curve from 0.736 (95% CI: 0.659-0.814) to 0.775 (95% CI: 0.701-0.849) (P=.028). Also, the addition of INR to sPESI score enhanced the net reclassification improvement (NRI=8.8%, P<.001) and integrated discrimination improvement (IDI=0.043, P=.027). Elevated INR may have prognostic value for 30-day mortality in acute PE patients not on anticoagulation. Combining INR with sPESI score improved the predictive value for all-cause mortality. However, further large-scale studies are needed to confirm it's prognostic role. © 2017 Wiley Periodicals, Inc.

The Orinoco megadelta as a conservation target in the face of the ongoing and future sea level rise.

PubMed

Vegas-Vilarrúbia, T; Hernández, E; Rull, Valentí; Rull Vegas, Elisa

2015-05-15

Currently, risk assessments related to rising sea levels and the adoption of defensive or adaptive measures to counter these sea level increases are underway for densely populated deltas where economic losses might be important, especially in the developed world. However, many underpopulated deltas harbouring high biological and cultural diversity are also at risk but will most likely continue to be ignored as conservation targets. In this study, we explore the potential effects of erosion, inundation and salinisation on one of the world's comparatively underpopulated megadeltas, the Orinoco Delta. With a 1 m sea level rise expected to occur by 2100, several models predict a moderate erosion of the delta's shorelines, migration or loss of mangroves, general inundation of the delta with an accompanying submersion of wetlands, and an increase in the distance to which sea water intrudes into streams, resulting in harm to the freshwater biota and resources. The Warao people are the indigenous inhabitants of the Orinoco Delta and currently are subject to various socioeconomic stressors. Changes due to sea level rise will occur extremely rapidly and cause abrupt shifts in the Warao's traditional environments and resources, resulting in migrations and abandonment of their ancestral territories. However, evidence indicates that deltaic aggradation/accretion processes at the Orinoco delta due to allochthonous sediment input and vegetation growth could be elevating the surface of the land, keeping pace with the local sea level rise. Other underpopulated and large deltas of the world also may risk immeasurable biodiversity and cultural losses and should not be forgotten as important conservation targets. Copyright © 2015. Published by Elsevier B.V.

Homocysteine Test

MedlinePlus

... Time and International Normalized Ratio (PT/INR) PSEN1 Quantitative Immunoglobulins Red Blood Cell (RBC) Antibody Identification Red ... and heart disease remains an active area of research. At present, however, the use of homocysteine levels ...

«Interventional Neuroradiology: a Neuroscience sub-specialty?»

PubMed Central

Rodesch, Georges; Picard, Luc; Berenstein, Alex; Biondi, Alessandra; Bracard, Serge; Choi, In Sup; Feng, Ling; Hyogo, Toshio; LeFeuvre, David; Leonardi, Marco; Mayer, Thomas; Miyashi, Shigeru; Muto, Mario; Piske, Ronie; Pongpech, Sirintara; Reul, Jurgen; Söderman, Michael; Suh, Dae Chul; Tampieri, Donatella; Taylor, Allan; Terbrugge, Karel; Valavanis, Anton; van den Berg, René

2013-01-01

Summary Interventional Neuroradiology (INR) is not bound by the classical limits of a speciality, and is not restricted by standard formats of teaching and education. Open and naturally linked towards neurosciences, INR has become a unique source of novel ideas for research, development and progress allowing new and improved approaches to challenging pathologies resulting in better anatomo-clinical results. Opening INR to Neurosciences is the best way to keep it alive and growing. Anchored in Neuroradiology, at the crossroad of neurosciences, INR will further participate to progress and innovation as it has often been in the past. PMID:24355160

«Interventional Neuroradiology: a Neuroscience sub-specialty?»

PubMed Central

Rodesch, Georges; Picard, Luc; Berenstein, Alex; Biondi, Alessandra; Bracard, Serge; Choi, In Sup; Feng, Ling; Hyogo, Toshio; LeFeuvre, David; Leonardi, Marco; Mayer, Thomas; Miyashi, Shigeru; Muto, Mario; Piske, Ronie; Pongpech, Sirintara; Reul, Jurgen; Soderman, Michael; Chuh, Dae Sul; Tampieri, Donatella; Taylor, Allan; Terbrugge, Karel; Valavanis, Anton; van den Berg, René

2013-01-01

Summary Interventional Neuroradiology (INR) is not bound by the classical limits of a speciality, and is not restricted by standard formats of teaching and education. Open and naturally linked towards neurosciences, INR has become a unique source of novel ideas for research, development and progress allowing new and improved approaches to challenging pathologies resulting in better anatomo-clinical results. Opening INR to Neurosciences is the best way to keep it alive and growing. Anchored in Neuroradiology, at the crossroad of neurosciences, INR will further participate to progress and innovation as it has often been in the past. PMID:24070073

System-level multi-target drug discovery from natural products with applications to cardiovascular diseases.

PubMed

Zheng, Chunli; Wang, Jinan; Liu, Jianling; Pei, Mengjie; Huang, Chao; Wang, Yonghua

2014-08-01

The term systems pharmacology describes a field of study that uses computational and experimental approaches to broaden the view of drug actions rooted in molecular interactions and advance the process of drug discovery. The aim of this work is to stick out the role that the systems pharmacology plays across the multi-target drug discovery from natural products for cardiovascular diseases (CVDs). Firstly, based on network pharmacology methods, we reconstructed the drug-target and target-target networks to determine the putative protein target set of multi-target drugs for CVDs treatment. Secondly, we reintegrated a compound dataset of natural products and then obtained a multi-target compounds subset by virtual-screening process. Thirdly, a drug-likeness evaluation was applied to find the ADME-favorable compounds in this subset. Finally, we conducted in vitro experiments to evaluate the reliability of the selected chemicals and targets. We found that four of the five randomly selected natural molecules can effectively act on the target set for CVDs, indicating the reasonability of our systems-based method. This strategy may serve as a new model for multi-target drug discovery of complex diseases.

Systems-level modeling of mycobacterial metabolism for the identification of new (multi-)drug targets.

PubMed

Rienksma, Rienk A; Suarez-Diez, Maria; Spina, Lucie; Schaap, Peter J; Martins dos Santos, Vitor A P

2014-12-01

Systems-level metabolic network reconstructions and the derived constraint-based (CB) mathematical models are efficient tools to explore bacterial metabolism. Approximately one-fourth of the Mycobacterium tuberculosis (Mtb) genome contains genes that encode proteins directly involved in its metabolism. These represent potential drug targets that can be systematically probed with CB models through the prediction of genes essential (or the combination thereof) for the pathogen to grow. However, gene essentiality depends on the growth conditions and, so far, no in vitro model precisely mimics the host at the different stages of mycobacterial infection, limiting model predictions. These limitations can be circumvented by combining expression data from in vivo samples with a validated CB model, creating an accurate description of pathogen metabolism in the host. To this end, we present here a thoroughly curated and extended genome-scale CB metabolic model of Mtb quantitatively validated using 13C measurements. We describe some of the efforts made in integrating CB models and high-throughput data to generate condition specific models, and we will discuss challenges ahead. This knowledge and the framework herein presented will enable to identify potential new drug targets, and will foster the development of optimal therapeutic strategies. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

A gargantuan acetaminophen level in an acidemic patient treated solely with intravenous N-acetylcysteine.

PubMed

Zell-Kanter, Michele; Coleman, Patrick; Whiteley, Patrick M; Leikin, Jerrold B

2013-01-01

The objective of this report is to describe an acidemic patient with one of the largest recorded acetaminophen ingestions in a patient with acidemia who was treated with supportive care and intravenous (IV) N-acetylcysteine. A 59-year-old female with a history of depression was found comatose. In the Emergency Department, she was obtunded with agonal respirations and immediately intubated. Activated charcoal was given through a nasogastric tube. An initial acetaminophen serum level was 1141 mg/L. The patient was started on IV N-acetylcysteine. The acetaminophen level peaked 2 hours later at 1193 mg/L. She was continued on the IV N-acetylcysteine protocol. The next day her aspartate aminotransferase was 3150 U/L, alanine aminotransferase was 2780 U/L, and creatinine phosphokinase was 16,197 U/L. There was no elevation in bilirubin or international normalized ratio (INR). Transaminase levels decreased on day 3 and normalized by day 4 when she was transferred to a psychiatric unit. Few cases have been reported of strikingly elevated acetaminophen levels in poisoned patients who did not receive hemodialysis. These patients did have increased lactate levels, and some had normal liver function tests. All of these patients received N-acetylcysteine and survived the poisoning without sequelae. This patient in this report was unique in that she had the highest reported serum acetaminophen level with acidosis and was treated successfully with only IV N-acetylcysteine and supportive care.

Pharmacodynamics and pharmacokinetics during the transition from warfarin to rivaroxaban: a randomized study in healthy subjects

PubMed Central

Kubitza, Dagmar; Becka, Michael; Mück, Wolfgang; Krätzschmar, Jöern

2014-01-01

Aims This study investigated relevant pharmacodynamic and pharmacokinetic parameters during the transition from warfarin to rivaroxaban in healthy male subjects. Methods Ninety-six healthy men were randomized into the following three groups: warfarin [international normalized ratio (INR) 2.0–3.0] transitioned to rivaroxaban 20 mg once daily (od; group A); warfarin (INR 2.0–3.0) followed by placebo od (group B); and rivaroxaban alone 20 mg od (group C) for 4 days. Anti-factor Xa activity, inhibition of factor Xa activity, prothrombin time (PT), activated partial thromboplastin time, HepTest, prothrombinase-induced clotting time, factor VIIa activity, factor IIa activity, endogenous thrombin potential and pharmacokinetics were measured. Results An additive effect was observed on the PT and PT/INR during the initial transition period. The mean maximal prolongation of PT was 4.39-fold [coefficient of variation (CV) 18.03%; range 3.39–6.50] of the baseline value in group A, compared with 1.88-fold (CV 10.35%; range 1.53–2.21) in group B and 1.57-fold (CV 9.98%; range 1.37–2.09) in group C. Rivaroxaban had minimal influence on the PT/INR at trough levels. Inhibition of factor Xa activity, activated partial thromboplastin time and endogenous thrombin potential were also enhanced, but to a lesser extent. In contrast, the effects of rivaroxaban on anti-factor Xa activity, HepTest and prothrombinase-induced clotting time were not affected by pretreatment with warfarin. Conclusions Changes in pharmacodynamics during the transition from warfarin to rivaroxaban vary depending on the test used. A supra-additive effect on PT/INR is expected during the initial period of transition, but pretreatment with warfarin does not influence the effect of rivaroxaban on anti-factor Xa activity. PMID:24528331

Changes in serial laboratory test results in snakebite patients: when can we safely exclude envenoming?

PubMed

Ireland, Graham; Brown, Simon G A; Buckley, Nicholas A; Stormer, Jeff; Currie, Bart J; White, Julian; Spain, David; Isbister, Geoffrey K

2010-09-06

To determine which laboratory tests are first associated with severe envenoming after a snakebite, when (ie, how long after the bite) the test results become abnormal, and whether this can determine a safe observation period after suspected snakebite. Prospective cohort study of 478 patients with suspected or confirmed snakebite recruited to the Australian Snakebite Project from January 2002 to April 2009, who had at least three sets of laboratory test results and at least 12 hours of observation in hospital after the bite. Severe envenoming was defined as venom-induced consumption coagulopathy (VICC), myotoxicity, neurotoxicity or thrombotic microangiopathy. International normalised ratio (INR), activated partial thromboplastin time (aPTT), creatine kinase (CK) level, and neurological examination. There were 240 patients with severe envenoming, 75 with minor envenoming and 163 non-envenomed patients. Of 206 patients with VICC, 178 had an INR > 1.2 (abnormal) on admission, and the remaining 28 had an INR > 1.2 within 12 hours of the bite. Of 33 patients with myotoxicity, a combination of CK > 250 U/L and an abnormal aPTT identified all but two cases by 12 hours; one of these two was identified within 12 hours by leukocytosis. Nine cases of isolated neurotoxicity had a median time of onset after the bite of 4 hours (range, 35 min - 12 h). The combination of serial INR, aPTT and CK tests and repeated neurological examination identified 213 of 222 severe envenoming cases (96%) by 6 hours and 238 of 240 (99%) by 12 hours. Laboratory parameters (INR, aPTT and CK) and neurological reassessments identified nearly all severe envenoming cases within 12 hours of the bite, even in this conservative analysis that assumed normal test results if the test was not done.

Hierarchical effects on target detection and conflict monitoring

PubMed Central

Cao, Bihua; Gao, Feng; Ren, Maofang; Li, Fuhong

2016-01-01

Previous neuroimaging studies have demonstrated a hierarchical functional structure of the frontal cortices of the human brain, but the temporal course and the electrophysiological signature of the hierarchical representation remains unaddressed. In the present study, twenty-one volunteers were asked to perform a nested cue-target task, while their scalp potentials were recorded. The results showed that: (1) in comparison with the lower-level hierarchical targets, the higher-level targets elicited a larger N2 component (220–350 ms) at the frontal sites, and a smaller P3 component (350–500 ms) across the frontal and parietal sites; (2) conflict-related negativity (non-target minus target) was greater for the lower-level hierarchy than the higher-level, reflecting a more intensive process of conflict monitoring at the final step of target detection. These results imply that decision making, context updating, and conflict monitoring differ among different hierarchical levels of abstraction. PMID:27561989

Laboratory assessment of warfarin reversal with global coagulation tests versus international normalized ratio in patients with intracranial bleeding.

PubMed

Voils, Stacy A; Martin, Erika J; Mohammed, Bassem M; Bayrlee, Ahmad; Brophy, Donald F

2015-06-01

We assess the in-vivo relationship between international normalized ratio (INR) and global coagulation tests in patients with life-threatening bleeding who received prothrombin complex concentrate (PCC) for warfarin reversal. This was a prospective pilot study in adult patients with intracranial bleeding related to anticoagulation with warfarin. Thromboelastography (TEG), thrombin generation parameters and INR were assessed at baseline, 30  min, 2 and 24  h after PCC. Changes in laboratory parameters and relationship between INR and global coagulation tests were assessed over time. Eight patients mean [standard deviation (SD)] age 72 (16) were included and received mean (SD) dose of PCC 24 (5) units/kg. Four patients died during the study, all with INR values more than 1.5 thirty minutes after PCC. Mean (SD) INR was 3.0 (1.3) and decreased significantly to 1.8 (0.48) thirty minutes after PCC (P < 0.01). Baseline endogenous thrombin potential and thrombin peak were 890  nmol/min and 123  nmol and increased significantly to 1943  nmol/min (P < 0.01) and 301  nmol (P < 0.01) 30  min after PCC administration. Reaction (R)-time decreased significantly (P = 0.02), and maximum amplitude and overall coagulation index (CI) significantly increased during treatment (P < 0.01, respectively). Thrombin generation and TEG values corrected after PCC administration; however, INR did not fully correct. Patients that died tended to be older with prolonged INR values across the study period. INR and TEG values correlated well with thrombin generation before administration of PCC, but this relationship was lost afterward.

Targeted Entry via Somatostatin Receptors Using a Novel Modified Retrovirus Glycoprotein That Delivers Genes at Levels Comparable to Those of Wild-Type Viral Glycoproteins

PubMed Central

Li, Fang; Ryu, Byoung Y.; Krueger, Robin L.; Heldt, Scott A.

2012-01-01

Here we report a novel viral glycoprotein created by replacing a natural receptor-binding sequence of the ecotropic Moloney murine leukemia virus envelope glycoprotein with the peptide ligand somatostatin. This new chimeric glycoprotein, which has been named the Sst receptor binding site (Sst-RBS), gives targeted transduction based on three criteria: (i) a gain of the use of a new entry receptor not used by any known virus; (ii) targeted entry at levels comparable to gene delivery by wild-type ecotropic Moloney murine leukemia virus and vesicular stomatitis virus (VSV) G glycoproteins; and (iii) a loss of the use of the natural ecotropic virus receptor. Retroviral vectors coated with Sst-RBS gained the ability to bind and transduce human 293 cells expressing somatostatin receptors. Their infection was specific to target somatostatin receptors, since a synthetic somatostatin peptide inhibited infection in a dose-dependent manner and the ability to transduce mouse cells bearing the natural ecotropic receptor was effectively lost. Importantly, vectors coated with the Sst-RBS glycoprotein gave targeted entry of up to 1 × 106 transducing U/ml, a level comparable to that seen with infection of vectors coated with the parental wild-type ecotropic Moloney murine leukemia virus glycoprotein through the ecotropic receptor and approaching that of infection of VSV G-coated vectors through the VSV receptor. To our knowledge, this is the first example of a glycoprotein that gives targeted entry of retroviral vectors at levels comparable to the natural capacity of viral envelope glycoproteins. PMID:22013043

Long-Term Update of NRG Oncology RTOG 0319: A Phase 1 and 2 Trial to Evaluate 3-Dimensional Conformal Radiation Therapy Confined to the Region of the Lumpectomy Cavity for Stage I and II Breast Carcinoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rabinovitch, Rachel, E-mail: rachel.rabinovitch@ucdenver.edu; Moughan, Jennifer; Vicini, Frank

Purpose: NRG Oncology RTOG 0319 was the first cooperative group trial in the United States to evaluate 3-dimensional conformal radiation therapy (3D-CRT) accelerated partial breast irradiation (APBI). This report updates secondary endpoints of toxicity and efficacy. Methods and Materials: Patients with stage I or II invasive breast cancer (tumor size ≤3 cm, ≤3 positive lymph nodes, negative margins) were eligible for 3D-CRT APBI: 38.5 Gy in 10 twice-daily fractions. Patient characteristics and treatment details have previously been reported. Adverse events were graded with CTCAE v3.0 (National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0). This analysis updates the rates of ipsilateral breastmore » recurrence (IBR), contralateral breast recurrence, ipsilateral node recurrence (INR), metastatic sites (distant metastases [DM]), mastectomy, disease-free survival, mastectomy-free survival, and overall survival. Results: Of 58 enrolled patients, 52 were eligible, with a median age of 61 years; 94% had stage I cancer and 83% had estrogen receptor positive disease. The median follow-up period was 8 years (minimum-maximum, 1.7-9.0 years). The 7-year estimate of isolated IBR (no DM) was 5.9%. The 7-year estimates of all IBRs, INR, mastectomy rate, and DM were 7.7%, 5.8%, 7.7%, and 7.7%, respectively. All 4 IBRs were invasive, of which 3 had a component within the planning target volume. The patterns of failure were as follows: 3 IBRs, 1 INR, 2 DM, 1 INR plus DM, and 1 IBR plus INR plus DM. The 7-year estimates of mastectomy-free survival, disease-free survival, and overall survival were 71.2%, 71.2%, and 78.8%, respectively. Thirteen patients died: 3 of breast cancer and 10 of other causes. Grade 3 (G3) treatment-related adverse events were reported by 4 patients (7.7%). No G3 pain or pulmonary or cardiac toxicities were reported. Conclusions: This phase 1 and 2 trial of 3D-CRT APBI continues to show durable tumor control and

Adjusted-dose warfarin versus low-intensity, fixed-dose warfarin plus aspirin for high-risk patients with atrial fibrillation: Stroke Prevention in Atrial Fibrillation III randomised clinical trial.

PubMed

1996-09-07

Adjusted-dose warfarin is highly efficacious for prevention of ischaemic stroke in patients with atrial fibrillation (AF). However, this treatment carries a risk of bleeding and the need for frequent medical monitoring. We sought an alternative that would be safer and easier to administer to patients with AF who are at high-risk of thromboembolism. 1044 patients with AF and with at least one thromboembolic risk factor (congestive heart failure or left ventricular fractional shortening < or = 25%, previous thromboembolism, systolic blood pressure of more than 160 mm Hg at study enrollment, or being a woman aged over 75 years) were randomly assigned either a combination of low-intensity, fixed-dose warfarin (international normalised ratio [INR] 1.2-1.5 for initial dose adjustment) and aspirin (325 mg/day) or adjusted-dose warfarin (INR 2.0-3.0). Drugs were given open-labelled. The mean INR during follow-up of patients taking combination therapy (n = 521) was 1.3, compared with 2.4 for those taking adjusted-dose warfarin (n = 523). During follow-up, 54% of INRs in patients taking combination therapy were 1.2-1.5 and 34% were less than 1.2. The trial was stopped after a mean, follow-up of 1.1 years when the rate of ischaemic stroke and systemic embolism (primary events) in patients given combination therapy (7.9% per year) was significantly higher than in those given adjusted-dose warfarin (1.9% per year) at an interim analysis (p < 0.0001), an absolute reduction of 6.0% per year (95% Cl 3.4, 8.6) by adjusted-dose warfarin. The annual rates of disabling stroke (5.6% vs 1.7%, p = 0.0007) and of primary event or vascular death (11.8% vs 6.4%, p = 0.002), were also higher with combination therapy. The rates of major bleeding were similar in both treatment groups. Low-intensity, fixed-dose warfarin plus aspirin in this regimen is insufficient for stroke prevention in patients with non-valvular AF at high-risk for thromboembolism; adjusted-dose warfarin (target INR 2

Long-Term Update of NRG Oncology RTOG 0319: A Phase 1 and 2 Trial to Evaluate 3-Dimensional Conformal Radiation Therapy Confined to the Region of the Lumpectomy Cavity for Stage I and II Breast Carcinoma.

PubMed

Rabinovitch, Rachel; Moughan, Jennifer; Vicini, Frank; Pass, Helen; Wong, John; Chafe, Susan; Petersen, Ivy; Arthur, Douglas W; White, Julia

2016-12-01

NRG Oncology RTOG 0319 was the first cooperative group trial in the United States to evaluate 3-dimensional conformal radiation therapy (3D-CRT) accelerated partial breast irradiation (APBI). This report updates secondary endpoints of toxicity and efficacy. Patients with stage I or II invasive breast cancer (tumor size ≤3 cm, ≤3 positive lymph nodes, negative margins) were eligible for 3D-CRT APBI: 38.5 Gy in 10 twice-daily fractions. Patient characteristics and treatment details have previously been reported. Adverse events were graded with CTCAE v3.0 (National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0). This analysis updates the rates of ipsilateral breast recurrence (IBR), contralateral breast recurrence, ipsilateral node recurrence (INR), metastatic sites (distant metastases [DM]), mastectomy, disease-free survival, mastectomy-free survival, and overall survival. Of 58 enrolled patients, 52 were eligible, with a median age of 61 years; 94% had stage I cancer and 83% had estrogen receptor positive disease. The median follow-up period was 8 years (minimum-maximum, 1.7-9.0 years). The 7-year estimate of isolated IBR (no DM) was 5.9%. The 7-year estimates of all IBRs, INR, mastectomy rate, and DM were 7.7%, 5.8%, 7.7%, and 7.7%, respectively. All 4 IBRs were invasive, of which 3 had a component within the planning target volume. The patterns of failure were as follows: 3 IBRs, 1 INR, 2 DM, 1 INR plus DM, and 1 IBR plus INR plus DM. The 7-year estimates of mastectomy-free survival, disease-free survival, and overall survival were 71.2%, 71.2%, and 78.8%, respectively. Thirteen patients died: 3 of breast cancer and 10 of other causes. Grade 3 (G3) treatment-related adverse events were reported by 4 patients (7.7%). No G3 pain or pulmonary or cardiac toxicities were reported. This phase 1 and 2 trial of 3D-CRT APBI continues to show durable tumor control and minimal G3 toxicity, comparable to other APBI techniques. Mature

Delineating CD4 dependency of HIV-1: Adaptation to infect low level CD4 expressing target cells widens cellular tropism but severely impacts on envelope functionality

PubMed Central

Beauparlant, David; Rusert, Peter; Magnus, Carsten; Weber, Jacqueline; Uhr, Therese; Clapham, Paul R.; Metzner, Karin J.

2017-01-01

A hallmark of HIV-1 infection is the continuously declining number of the virus’ predominant target cells, activated CD4+ T cells. With diminishing CD4+ T cell levels, the capacity to utilize alternate cell types and receptors, including cells that express low CD4 receptor levels such as macrophages, thus becomes crucial. To explore evolutionary paths that allow HIV-1 to acquire a wider host cell range by infecting cells with lower CD4 levels, we dissected the evolution of the envelope-CD4 interaction under in vitro culture conditions that mimicked the decline of CD4high target cells, using a prototypic subtype B, R5-tropic strain. Adaptation to CD4low targets proved to severely alter envelope functions including trimer opening as indicated by a higher affinity to CD4 and loss in shielding against neutralizing antibodies. We observed a strikingly decreased infectivity on CD4high target cells, but sustained infectivity on CD4low targets, including macrophages. Intriguingly, the adaptation to CD4low targets altered the kinetic of the entry process, leading to rapid CD4 engagement and an extended transition time between CD4 and CCR5 binding during entry. This phenotype was also observed for certain central nervous system (CNS) derived macrophage-tropic viruses, highlighting that the functional perturbation we defined upon in vitro adaptation to CD4low targets occurs in vivo. Collectively, our findings suggest that CD4low adapted envelopes may exhibit severe deficiencies in entry fitness and shielding early in their evolution. Considering this, adaptation to CD4low targets may preferentially occur in a sheltered and immune-privileged environment such as the CNS to allow fitness restoring compensatory mutations to occur. PMID:28264054

Direct measurement of kilo-tesla level magnetic field generated with laser-driven capacitor-coil target by proton deflectometry

NASA Astrophysics Data System (ADS)

Law, K. F. F.; Bailly-Grandvaux, M.; Morace, A.; Sakata, S.; Matsuo, K.; Kojima, S.; Lee, S.; Vaisseau, X.; Arikawa, Y.; Yogo, A.; Kondo, K.; Zhang, Z.; Bellei, C.; Santos, J. J.; Fujioka, S.; Azechi, H.

2016-02-01

A kilo-tesla level, quasi-static magnetic field (B-field), which is generated with an intense laser-driven capacitor-coil target, was measured by proton deflectometry with a proper plasma shielding. Proton deflectometry is a direct and reliable method to diagnose strong, mm3-scale laser-produced B-field; however, this was not successful in the previous experiment. A target-normal-sheath-accelerated proton beam is deflected by Lorentz force in the laser-produced magnetic field with the resulting deflection pattern recorded on a radiochromic film stack. A 610 ± 30 T of B-field amplitude was inferred by comparing the experimental proton pattern with Monte-Carlo calculations. The amplitude and temporal evolutions of the laser-generated B-field were also measured by a differential magnetic probe, independently confirming the proton deflectometry measurement results.

Impact of clinical pharmacist intervention in anticoagulation clinic in Sudan.

PubMed

Ahmed, Nahid Osman; Osman, Bashier; Abdelhai, Yassein Mohamed; El-Hadiyah, Tariq Muhammed Hashim

2017-08-01

Background Many trials have compared anticoagulation management provided by a pharmacist led anticoagulation clinic versus usual physician care showing the role for clinical pharmacist in the management of anticoagulant therapy, and demonstrating excellent outcomes. In Sudan, there is no published research evaluating the role of pharmacist in providing pharmaceutical care for patients taking warfarin. Objective The objective of the study is to assess the role of clinical pharmacist intervention in warfarin patients compared to usual medical care. Setting This study was conducted in Ahmed Gasim cardiac surgery and renal transplant center warfarin clinic. Methods One hundred thirty-five patients were randomly selected from adult patients on warfarin therapy The history of INR records, and adverse effects for the past year, were recorded. Then patients' warfarin dose adjustments according to INR, was done by the clinical pharmacist for one year. Patients received continuous verbal education and written information about warfarin. Main outcome measure The primary outcome for this study was the INR control, while the secondary outcomes were the bleeding events and hospitalization due to warfarin. Results After the clinical pharmacist intervention there was significant (P < 0.01) improvement in INR control and a significant (P < 0.05) reduction in incidence of bleeding after clinical pharmacist intervention. Hospitalization due to warfarin related complications (bleeding, high INR, low INR) was also significantly (P < 0.001) reduced. Conclusion Clinical pharmacists intervention in warfarin therapy improve INR control, reduce bleeding and hospitalization due to warfarin complications.

Effect of ramadan fasting on acenocoumarol-induced antocoagulant effect.

PubMed

Mzoughi, Khadija; Zairi, Ihsen; Fennira, Sana; Kamoun, Sofien; Jnifene, Zouhayer; Ben Moussa, Fethia; Kraiem, Sondos

2017-10-01

Eating patterns, food intake and type of alimentation vary greatly during the month of ramadan. Furthermore, fasting, which practiced during the month of ramadan, can have an impact on drug's metabolism. These two factors, fasting and eating habits changes during the month of ramadan, may impact acenocoumarol anticoagulant effect, translated by variations of INR values. The aim of our study was to see ramadan fasting effects on INR variations in patients treated by acenocoumarol. A prospective monocentric study was conducted during the ramadan month on fasting outpatients that were treated by acenocoumarol. Baseline INR values (e.i. most recent available value before the month of ramadan) were compared to INR values obtained during the month of ramadan. All patients were monitored for signs of secondary haemorrhagic complications linked to treatment by anti-vitamin K (AVK). Thirty patients were included in the study with a sex ratio 1. Patients mean age was 65 years. Around two thirds of the patients were treated by AVK for atrial fibrillation. The majority of patients (94%) have been treated by AVK for more than a year. Mean INR was significantly higher during the month of ramadan than baseline (3.51 vs 2.52; p< 0.0001). There were also more overdoses during the month of ramadan than baseline (9 vs. 0; p=0.014). The increased INR values highlights the need of a close monitoring of INR values during the month of ramadan, particularly in patients with a high haemorrhagic risk.

A Novel mRNA Level Subtraction Method for Quick Identification of Target-Orientated Uniquely Expressed Genes Between Peanut Immature Pod and Leaf

PubMed Central

2010-01-01

Subtraction technique has been broadly applied for target gene discovery. However, most current protocols apply relative differential subtraction and result in great amount clone mixtures of unique and differentially expressed genes. This makes it more difficult to identify unique or target-orientated expressed genes. In this study, we developed a novel method for subtraction at mRNA level by integrating magnetic particle technology into driver preparation and tester–driver hybridization to facilitate uniquely expressed gene discovery between peanut immature pod and leaf through a single round subtraction. The resulting target clones were further validated through polymerase chain reaction screening using peanut immature pod and leaf cDNA libraries as templates. This study has resulted in identifying several genes expressed uniquely in immature peanut pod. These target genes can be used for future peanut functional genome and genetic engineering research. PMID:21406066

GOES I/M image navigation and registration

NASA Technical Reports Server (NTRS)

Fiorello, J. L., Jr.; Oh, I. H.; Kelly, K. A.; Ranne, L.

1989-01-01

Image Navigation and Registration (INR) is the system that will be used on future Geostationary Operational Environmental Satellite (GOES) missions to locate and register radiometric imagery data. It consists of a semiclosed loop system with a ground-based segment that generates coefficients to perform image motion compensation (IMC). The IMC coefficients are uplinked to the satellite-based segment, where they are used to adjust the displacement of the imagery data due to movement of the imaging instrument line-of-sight. The flight dynamics aspects of the INR system is discussed in terms of the attitude and orbit determination, attitude pointing, and attitude and orbit control needed to perform INR. The modeling used in the determination of orbit and attitude is discussed, along with the method of on-orbit control used in the INR system, and various factors that affect stability. Also discussed are potential error sources inherent in the INR system and the operational methods of compensating for these errors.

Asymmetries in visual search for conjunctive targets.

PubMed

Cohen, A

1993-08-01

Asymmetry is demonstrated between conjunctive targets in visual search with no detectable asymmetries between the individual features that compose these targets. Experiment 1 demonstrated this phenomenon for targets composed of color and shape. Experiment 2 and 4 demonstrate this asymmetry for targets composed of size and orientation and for targets composed of contrast level and orientation, respectively. Experiment 3 demonstrates that search rate of individual features cannot predict search rate for conjunctive targets. These results demonstrate the need for 2 levels of representations: one of features and one of conjunction of features. A model related to the modified feature integration theory is proposed to account for these results. The proposed model and other models of visual search are discussed.

Effectiveness and safety of a 10mg warfarin initiation nomogram in Asian population.

PubMed

Chandriah, Haarathi; Kumolosasi, Endang; Islahudin, Farida; Makmor-Bakry, Mohd

2015-05-01

Anticoagulant responses to warfarin vary among patients, based on genetic factors, diet, concomitant medications, and disease state. We evaluated the effectiveness and safety of a 10mg warfarin initiation nomogram in an Asian population. Retrospective cross-sectional audit studies were conducted from March 2009 to March 2010. The use of a 10mg-loading dose to initiate warfarin treatment resulted in 33(84.6%) patients attaining a therapeutic INR within four days (mean time, 2.6 days). There was no significant correlation between age, gender, race, and serum albumin for the time to reach a therapeutic INR. A significant correlation was noted for patient's baseline INR and time to reach a therapeutic INR (P<0.05). No significant differences were observed in time to reach a therapeutic INR in patients treated with specific class of concomitant drugs or patients with specific disease states. The overall incidence of over-anticoagulation was 35.9%; however, no bleeding episodes were encountered. In conclusion, the use of a 10mg warfarin nomogram was effective in rapidly achieving a therapeutic INR. However, the nomogram's safety is debatable owing to the high over-anticoagulation rate warfarin-administered patients. Caution is recommended in the initiation of warfarin treatment using the 10mg nomogram.

The drug target genes show higher evolutionary conservation than non-target genes.

PubMed

Lv, Wenhua; Xu, Yongdeng; Guo, Yiying; Yu, Ziqi; Feng, Guanglong; Liu, Panpan; Luan, Meiwei; Zhu, Hongjie; Liu, Guiyou; Zhang, Mingming; Lv, Hongchao; Duan, Lian; Shang, Zhenwei; Li, Jin; Jiang, Yongshuai; Zhang, Ruijie

2016-01-26

Although evidence indicates that drug target genes share some common evolutionary features, there have been few studies analyzing evolutionary features of drug targets from an overall level. Therefore, we conducted an analysis which aimed to investigate the evolutionary characteristics of drug target genes. We compared the evolutionary conservation between human drug target genes and non-target genes by combining both the evolutionary features and network topological properties in human protein-protein interaction network. The evolution rate, conservation score and the percentage of orthologous genes of 21 species were included in our study. Meanwhile, four topological features including the average shortest path length, betweenness centrality, clustering coefficient and degree were considered for comparison analysis. Then we got four results as following: compared with non-drug target genes, 1) drug target genes had lower evolutionary rates; 2) drug target genes had higher conservation scores; 3) drug target genes had higher percentages of orthologous genes and 4) drug target genes had a tighter network structure including higher degrees, betweenness centrality, clustering coefficients and lower average shortest path lengths. These results demonstrate that drug target genes are more evolutionarily conserved than non-drug target genes. We hope that our study will provide valuable information for other researchers who are interested in evolutionary conservation of drug targets.

Contingent attentional capture occurs by activated target congruence.

PubMed

Ariga, Atsunori; Yokosawa, Kazuhiko

2008-05-01

Contingent attentional capture occurs when a stimulus property captures an observer's attention, usually related to the observer's top-down attentional set for target-defining properties. In this study, we examined whether contingent attentional capture occurs for a distractor that does not share the target-defining property at a physical level, but does share that property at an abstract level of representation. In a rapid serial visual presentation stream, we defined the target by color (e.g., a green-colored Japanese kanji character). Before the target onset, we presented a distractor that referred to the target-defining color (e.g., a white-colored character meaning "green"). We observed contingent attentional capture by the distractor, which was reflected by a deficit in identifying the subsequent target. This result suggests that because of the attentional set, stimuli were scanned on the basis of the target-defining property at an abstract semantic level of representation.

Target-present guessing as a function of target prevalence and accumulated information in visual search.

PubMed

Peltier, Chad; Becker, Mark W

2017-05-01

Target prevalence influences visual search behavior. At low target prevalence, miss rates are high and false alarms are low, while the opposite is true at high prevalence. Several models of search aim to describe search behavior, one of which has been specifically intended to model search at varying prevalence levels. The multiple decision model (Wolfe & Van Wert, Current Biology, 20(2), 121--124, 2010) posits that all searches that end before the observer detects a target result in a target-absent response. However, researchers have found very high false alarms in high-prevalence searches, suggesting that prevalence rates may be used as a source of information to make "educated guesses" after search termination. Here, we further examine the ability for prevalence level and knowledge gained during visual search to influence guessing rates. We manipulate target prevalence and the amount of information that an observer accumulates about a search display prior to making a response to test if these sources of evidence are used to inform target present guess rates. We find that observers use both information about target prevalence rates and information about the proportion of the array inspected prior to making a response allowing them to make an informed and statistically driven guess about the target's presence.

The Censored Mean-Level Detector for Multiple Target Environments.

DTIC Science & Technology

1984-03-01

rate ( CFAR ) detectors known as censored mean-level detectors ( CMLD ). The CMLD , a special case of which is the mean-level detector (or zell-averaged...detectors known as censored mean- level detectors ( CMLD ). The CMLD , a special case of which is the mean-level detector (or cell-averaged CFAR detector), is...CENSORED MEAN-LEVEL DETECTOR The censored mean-level detector ( CMLD ) is a generalization of the traditional mean-level detector (MLD) or cell-averaged CFAR

Preliminary GOES-R ABI navigation and registration assessment results

NASA Astrophysics Data System (ADS)

Tan, B.; Dellomo, J.; Wolfe, R. E.; Reth, A. D.

2017-12-01

The US Geostationary Operational Environmental Satellite - R Series (GOES-R) was launched on November 19, 2016, and was designated GOESR-16 upon reaching geostationary orbit ten days later. The Advanced Baseline Imager (ABI) is the primary instrument on the GOES-R series for imaging Earth's surface and atmosphere to aid in weather prediction and climate monitoring. We developed algorithms and software for independent verification of the ABI Image Navigation and Registration (INR). Since late January 2017, four INR metrics have been continuously generated to monitor the ABI INR performance: navigation (NAV) error, channel-to-channel registration (CCR) error, frame-to-frame registration (FFR) error, and within-frame registration (WIFR) error. In this paper, we will describe the fundamental algorithm used for the image registration and briefly discuss the processing flow of INR Performance Assessment Tool Set (IPATS) developed for ABI INR. The assessment of the accuracy shows that IPATS measurements error is about 1/20 of the size of a pixel. Then the GOES-16 NAV assessments results, the primary metric, from January to August 2017, will be presented. The INR has improved over time as post-launch tests were performed and corrections were applied. The mean NAV error of the visible and near infrared (VNIR) channels dropped from 20 μrad in January to around 5 μrad (+/-4 μrad, 1 σ) in June, while the mean NAV error of long wave infrared (LWIR) channels dropped from around 70 μrad in January to around 5 μrad (+/-15 μrad, 1 σ) in June. A full global ABI image is composed with 22 east-west direction swaths. The swath-wise NAV error analysis shows that there was some variation in the mean swath-wise NAV errors. The variations are about as much as 20% of the scene NAV mean errors. As expected, the swaths over the tropical area have far fewer valid assessments (matchups) than those in mid-latitude region due to cloud coverage. It was also found that there was a rotation

Optical Imaging of Targeted β-Galactosidase in Brain Tumors to Detect EGFR Levels

PubMed Central

Broome, Ann-Marie; Ramamurthy, Gopal; Lavik, Kari; Liggett, Alexander; Kinstlinger, Ian; Basilion, James

2015-01-01

A current limitation in molecular imaging is that it often requires genetic manipulation of cancer cells for noninvasive imaging. Other methods to detect tumor cells in vivo using exogenously delivered and functionally active reporters, such as β-gal, are required. We report the development of a platform system for linking β-gal to any number of different ligands or antibodies for in vivo targeting to tissue or cells, without the requirement for genetic engineering of the target cells prior to imaging. Our studies demonstrate significant uptake in vitro and in vivo of an EGFR-targeted β-gal complex. We were then able to image orthotopic brain tumor accumulation and localization of the targeted enzyme when a fluorophore was added to the complex, as well as validate the internalization of the intravenously administered β-gal reporter complex ex vivo. After fluorescence imaging localized the β-gal complexes to the brain tumor, we topically applied a bioluminescent β-gal substrate to serial sections of the brain to evaluate the delivery and integrity of the enzyme. Finally, robust bioluminescence of the EGFR-targeted β-gal complex was captured within the tumor during noninvasive in vivo imaging. PMID:25775241

Optical imaging of targeted β-galactosidase in brain tumors to detect EGFR levels.

PubMed

Broome, Ann-Marie; Ramamurthy, Gopal; Lavik, Kari; Liggett, Alexander; Kinstlinger, Ian; Basilion, James

2015-04-15

A current limitation in molecular imaging is that it often requires genetic manipulation of cancer cells for noninvasive imaging. Other methods to detect tumor cells in vivo using exogenously delivered and functionally active reporters, such as β-gal, are required. We report the development of a platform system for linking β-gal to any number of different ligands or antibodies for in vivo targeting to tissue or cells, without the requirement for genetic engineering of the target cells prior to imaging. Our studies demonstrate significant uptake in vitro and in vivo of an EGFR-targeted β-gal complex. We were then able to image orthotopic brain tumor accumulation and localization of the targeted enzyme when a fluorophore was added to the complex, as well as validate the internalization of the intravenously administered β-gal reporter complex ex vivo. After fluorescence imaging localized the β-gal complexes to the brain tumor, we topically applied a bioluminescent β-gal substrate to serial sections of the brain to evaluate the delivery and integrity of the enzyme. Finally, robust bioluminescence of the EGFR-targeted β-gal complex was captured within the tumor during noninvasive in vivo imaging.

Effects of Marine Fish Oils on the Anticoagulation Status of Patients Receiving Chronic Warfarin Therapy.

PubMed

Bender; Kraynak; Chiquette; Linn; Clark; Bussey

1998-07-01

The purpose of this placebo-controlled, randomized, double-blinded, parallel study was to determine the existence and magnitude of effect of various doses of fish oil supplements on International Normalized Ratio (INR) determinations in patients receiving chronic warfarin therapy. Patients from anticoagulation clinics from both the Brady Green Community Health Center and Audie L. Murphy Veterans Administration in San Antonio, Texas were enrolled in the study. The enrolled subjects included 5 males and 11 females, all of whom were receiving chronic warfarin therapy for indications requiring oral anticoagulation. All enrolled patients underwent a 4-week placebo monitoring period in which INRs were determined on a weekly basis. If the INRs were found to be stable, patients were randomized to receive a 4-week treatment period of either placebo capsules (n = 6), 3 grams of fish oil daily (n = 5), or 6 grams of fish oil daily (n = 5). Patients were followed on a twice-weekly basis for INR determinations and adverse reactions. Five patients were discontinued from the study due to noncompliance (2) and unstable INRs (3). There was no statistically significant difference in INRs between the placebo lead-in and treatment period within each group (P = 0.82). There was also no difference in INRs found between groups (P= 0.41). One bruising episode was reported, yet no major bleeding episodes were observed during the study. Fish oil supplementation in doses of 3-6 grams per day does not seem to create a statistically significant effect on the anticoagulation status of patients receiving chronic warfarin therapy.

Efficacy and safety of dabigatran compared with warfarin at different levels of international normalised ratio control for stroke prevention in atrial fibrillation: an analysis of the RE-LY trial.

PubMed

Wallentin, Lars; Yusuf, Salim; Ezekowitz, Michael D; Alings, Marco; Flather, Marcus; Franzosi, Maria Grazia; Pais, Prem; Dans, Antonio; Eikelboom, John; Oldgren, Jonas; Pogue, Janice; Reilly, Paul A; Yang, Sean; Connolly, Stuart J

2010-09-18

Effectiveness and safety of warfarin is associated with the time in therapeutic range (TTR) with an international normalised ratio (INR) of 2·0-3·0. In the Randomised Evaluation of Long-term Anticoagulation Therapy (RE-LY) trial, dabigatran versus warfarin reduced both stroke and haemorrhage. We aimed to investigate the primary and secondary outcomes of the RE-LY trial in relation to each centre's mean TTR (cTTR) in the warfarin population. In the RE-LY trial, 18 113 patients at 951 sites were randomly assigned to 110 mg or 150 mg dabigatran twice daily versus warfarin dose adjusted to INR 2·0-3·0. Median follow-up was 2·0 years. For 18 024 patients at 906 sites, the cTTR was estimated by averaging TTR for individual warfarin-treated patients calculated by the Rosendaal method. We compared the outcomes of RE-LY across the three treatment groups within four groups defined by the quartiles of cTTR. RE-LY is registered with ClinicalTrials.gov, number NCT00262600. The quartiles of cTTR for patients in the warfarin group were: less than 57·1%, 57·1-65·5%, 65·5-72·6%, and greater than 72·6%. There were no significant interactions between cTTR and prevention of stroke and systemic embolism with either 110 mg dabigatran (interaction p=0·89) or 150 mg dabigatran (interaction p=0·20) versus warfarin. Neither were any significant interactions recorded with cTTR with regards to intracranial bleeding with 110 mg dabigatran (interaction p=0·71) or 150 mg dabigatran (interaction p=0·89) versus warfarin. There was a significant interaction between cTTR and major bleeding when comparing 150 mg dabigatran with warfarin (interaction p=0·03), with less bleeding events at lower cTTR but similar events at higher cTTR, whereas rates of major bleeding were lower with 110 mg dabigatran than with warfarin irrespective of cTTR. There were significant interactions between cTTR and effects of both 110 mg and 150 mg dabigatran versus warfarin on the composite of all

Optimal Design of Gradient Materials and Bi-Level Optimization of Topology Using Targets (BOTT)

NASA Astrophysics Data System (ADS)

Garland, Anthony

of gradient material designs. A macroscopic gradient can be achieved by varying the microstructure or the mesostructures of an object. The mesostructure interpretation allows for more design freedom since the mesostructures can be tuned to have non-isotropic material properties. A new algorithm called Bi-level Optimization of Topology using Targets (BOTT) seeks to find the best distribution of mesostructure designs throughout a single object in order to minimize an objective value. On the macro level, the BOTT algorithm optimizes the macro topology and gradient material properties within the object. The BOTT algorithm optimizes the material gradient by finding the best constitutive matrix at each location with the object. In order to enhance the likelihood that a mesostructure can be generated with the same equivalent constitutive matrix, the variability of the constitutive matrix is constrained to be an orthotropic material. The stiffness in the X and Y directions (of the base coordinate system) can change in addition to rotating the orthotropic material to align with the loading at each region. Second, the BOTT algorithm designs mesostructures with macroscopic properties equal to the target properties found in step one while at the same time the algorithm seeks to minimize material usage in each mesostructure. The mesostructure algorithm maximizes the strain energy of the mesostructures unit cell when a pseudo strain is applied to the cell. A set of experiments reveals the fundamental relationship between target cell density and the strain (or pseudo strain) applied to a unit cell and the output effective properties of the mesostructure. At low density, a few mesostructure unit cell design are possible, while at higher density the mesostructure unit cell designs have many possibilities. Therefore, at low densities the effective properties of the mesostructure are a step function of the applied pseudo strain. At high densities, the effective properties of the

Early Therapy Intensity Level (TIL) Predicts Mortality in Spontaneous Intracerebral Hemorrhage.

PubMed

Ziai, Wendy C; Siddiqui, Aazim A; Ullman, Natalie; Herrick, Daniel B; Yenokyan, Gayane; McBee, Nichol; Lane, Karen; Hanley, Daniel F

2015-10-01

Outcome from spontaneous intracerebral hemorrhage (sICH) may depend on patient-care variability. We developed as ICH-specific therapy intensity level (TIL) metric using evidence-based elements in a high severity sICH cohort. This is a cohort study of 170 patients with sICH and any intraventricular hemorrhage treated in 2 academic neuroICUs. Pre-defined quality indicators were identified based on current guidelines, scientific evidence, and likelihood of care documentation in first 72 h of hospital admission. We assessed performance on each indicator and association with discharge mortality. Significant indicators were aggregated to develop a TIL score. The predictive validity of the best fit TIL score was tested with threefold cross-validation of multivariate logistic regression models of in-hospital survival and good outcome (modified Rankin score 0-3). Median ICH score was 3; discharge mortality was 51.2%. Five/19 tested variables were significantly associated with lower discharge mortality: no DNR/withdrawal of treatment within 24 h of admission, target glucose within 4 h of high glucose, no recurrent hyperpyrexia, clinical reversal of herniation/intracranial pressure >20 mmHg within 60 min of detection, and reversal of INR (<1.4) within 2 h of first elevation. One point was given for each or if not applicable. Median TIL score was significantly higher in survivors versus non-survivors (5[1] vs. 3[1]; P < 0.001). A 4-point aggregated TIL score was most predictive of discharge survival (area under receiving operating characteristic curve 0.85, 95% CI 0.80-0.90) and good outcome (AUC 0.84) and was an independent predictor of both (survival: OR 7.10; 95% CI 3.57-14.11; P < 0.001; good outcome: OR 3.10; 95% CI 1.06-8.79; P < 0.001). A simplified TIL score using evidenced-based patient-care parameters within first 3 days of admission after sICH was significantly associated with early mortality and good outcome. The next step is prospective validation of the

Image Navigation and Registration Performance Assessment Evaluation Tools for GOES-R ABI and GLM

NASA Technical Reports Server (NTRS)

Houchin, Scott; Porter, Brian; Graybill, Justin; Slingerland, Philip

2017-01-01

The GOES-R Flight Project has developed an Image Navigation and Registration (INR) Performance Assessment Tool Set (IPATS) for measuring Advanced Baseline Imager (ABI) and Geostationary Lightning Mapper (GLM) INR performance metrics in the post-launch period for performance evaluation and long term monitoring. IPATS utilizes a modular algorithmic design to allow user selection of data processing sequences optimized for generation of each INR metric. This novel modular approach minimizes duplication of common processing elements, thereby maximizing code efficiency and speed. Fast processing is essential given the large number of sub-image registrations required to generate INR metrics for the many images produced over a 24 hour evaluation period. This paper describes the software design and implementation of IPATS and provides preliminary test results.

The Effect of Target Language and Code-Switching on the Grammatical Performance and Perceptions of Elementary-Level College French Students

ERIC Educational Resources Information Center

Viakinnou-Brinson, Lucie; Herron, Carol; Cole, Steven P.; Haight, Carrie

2012-01-01

Grammar instruction is at the center of the target language (TL) and code-switching debate. Discussion revolves around whether grammar should be taught in the TL or using the TL and the native language (L1). This study investigated the effects of French-only grammar instruction and French/English grammar instruction on elementary-level students'…

Rat health status affects bioavailability, target tissue levels, and bioactivity of grape seed flavanols.

PubMed

Margalef, Maria; Pons, Zara; Iglesias-Carres, Lisard; Quiñones, Mar; Bravo, Francisca Isabel; Arola-Arnal, Anna; Muguerza, Begoña

2017-02-01

Studying the flavanol metabolism is essential to identify bioactive compounds, as beneficial effects of flavanols have been attributed to their metabolic products. However, host-related factors, including pathological conditions, may affect flavanol metabolism and, thus, their bioactivity. This study aims to elucidate whether hypertension affects grape seed flavanol metabolism, influencing their bioactivity in relation to hypertension. Grape seed flavanols' effect on blood pressure (BP) was studied in spontaneously hypertensive rats (SHR) and healthy Wistar rats 6 h after grape seed extract administration (375 mg/kg). Animals were then sacrificed, and plasma bioavailability and aorta distribution of flavanol metabolites were studied by HPLC-MS/MS in both the groups. Grape seed flavanols were only able to decrease BP in SHR. Plasma total flavanol metabolites showed similar levels, being the difference noticed in specific metabolites' concentrations. Specifically, microbial metabolites showed quantitative and qualitative differences between both health states. Moreover, aorta total concentrations were found decreased in SHR. Interestingly, flavanol microbial metabolites were specifically increased SHR aortas, showing qualitative differences in small phenolic forms. This study demonstrates important differences in bioactivity and target tissue metabolite levels between healthy and diseased rats, indicating potential metabolites responsible of the anti-hypertensive effect. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Direct costs of osteoporosis and hip fracture: an analysis for the Mexican Social Insurance Health Care System.

PubMed

Carlos, Fernando; Clark, Patricia; Maciel, Humberto; Tamayo, Juan A

2009-01-01

To compare costs of diagnosis and annual treatment of osteoporosis and hip fracture between the Instituto Nacional de Rehabilitación (INR) and the protocol used by the Seguro Popular de Salud (SPSS). Direct costs gathered in a prospective study with real cases at the INR are presented, and then this data is re-analyzed with the methodology and protocol for the SPSS to estimate the costs of those cases if treated with the SPSS protocol. Important differences were found in the cost of hip fracture: the SPSS estimates ($37,363.73 MXN) almost double the INR cost ($20,286.86 MXN ). This discrepancy was caused by the different types of surgeries the INR and SPSS protocols call for (the SPSS assumes that all hip fractures will necessitate a hip replacement) and the cost of subsequent hospitalization. A prospective study at the SPSS is needed to validate these results. Important differences were found between treatment of the same osteoporosis related problems at the INR and SPSS. We recommend revising the SPSS protocol to include less costly surgical treatments.

Use of a plastic insulin dosage guide to correct blood glucose levels out of the target range and for carbohydrate counting in subjects with type 1 diabetes.

PubMed

Kaufman, F R; Halvorson, M; Carpenter, S

1999-08-01

To improve glycemic control, a hand-held plastic Insulin Dosage Guide was developed to correct blood glucose levels outside of the target range. Protocol 1: Some 40 children (mean age 10.6+/-4.6 years) were randomly assigned for 3 months to use a written-on-paper algorithm or the Insulin Dosage Guide to correct abnormal blood glucose levels. Mean HbA1c and blood glucose levels and time to teach insulin dosage correction were compared. Protocol 2: The Insulin Dosage Guide was used by 83 subjects (mean age 11.4+/-4.3 years) for 1 year, and mean HbA1c levels, blood glucose levels, and number of consecutive high blood glucose values taken before and after the year were compared. Protocol 3: Some 20 patients (mean age 10.1+/-3.7 years) using rapid-acting insulin and 64 patients (mean age 15.9+/-3.6 years) using an insulin pump and rapid-acting insulin used the Insulin Dosage Guide and had mean blood glucose levels, HbA1c, and percentage of blood glucose levels outside of the target range determined. Protocol 1: There was a significant reduction in mean HbA1c (P = 0.04) and blood glucose levels (P = 0.05) and in the time needed to teach how to correct blood glucose values using the Insulin Dosage Guide compared with the paper algorithm. Protocol 2: There was a decrease in mean HbA1c levels (P = 0.0001) and a decrease in the mean number of consecutive blood glucose levels (P = 0.001) over the 1-year time period. Protocol 3: With rapid-acting insulin, there was a significant increase in the percentage of blood glucose levels within the target range (1 month, P = 0.04; at 3 months, P = 0.03). With the insulin pump, there was a high rate (90%) of blood glucose levels in the target range during pump initiation when the Insulin Dosage Guide was used. This inexpensive hand-held plastic card, which is portable and easy to use, may help patients improve glycemia and successfully manage diabetes.

Switching between global and local levels: the level repetition effect and its hemispheric asymmetry

PubMed Central

Kéïta, Luc; Bedoin, Nathalie; Burack, Jacob A.; Lepore, Franco

2014-01-01

The global level of hierarchical stimuli (Navon’s stimuli) is typically processed quicker and better than the local level; further differential hemispheric dominance is described for local (left hemisphere, LH) and global (right hemisphere, RH) processing. However, neuroimaging and behavioral data indicate that stimulus category (letter or object) could modulate the hemispheric asymmetry for the local level processing. Besides, when the targets are unpredictably displayed at the global or local level, the participant has to switch between levels, and the magnitude of the switch cost increases with the number of repeated-level trials preceding the switch. The hemispheric asymmetries associated with level switching is an unresolved issue. LH areas may be involved in carrying over the target level information in case of level repetition. These areas may also largely participate in the processing of level-changed trials. Here we hypothesized that RH areas underly the inhibitory mechanism performed on the irrelevant level, as one of the components of the level switching process. In an experiment using a within-subject design, hierarchical stimuli were briefly presented either to the right or to the left visual field. 32 adults were instructed to identify the target at the global or local level. We assessed a possible RH dominance for the non-target level inhibition by varying the attentional demands through the manipulation of level repetitions (two or gour repeated-level trials before the switch). The behavioral data confirmed a LH specialization only for the local level processing of letter-based stimuli, and detrimental effect of increased level repetitions before a switch. Further, data provides evidence for a RH advantage in inhibiting the non-target level. Taken together, the data supports the notion of the existence of multiple mechanisms underlying level-switch effects. PMID:24723903

A case report of targeted therapy with apatinib in a patient with advanced gastric cancer and high serum level of alpha-fetoprotein

PubMed Central

Zhu, Xue-Ru; Zhu, Mei-Ling; Wang, Qing; Xue, Wen-Ji; Wang, Yi-Wei; Wang, Rui-Fen; Chen, Si-Yu; Zheng, Lei-Zhen

2016-01-01

Abstract Background: Alpha-fetoprotein (AFP) is an important marker for hepatocellular carcinoma, and the detection of serum AFP is currently the principle method for the diagnosis of hepatocellular carcinoma. The prevalence of gastric cancer (GC) with high level of serum AFP is extremely rare, but has unique clinical features. Case summary: We herein present a rare case with GC and high level of serum AFP. A 64-year-old Chinese female underwent gastrectomy was diagnosed as gastric adenocarcinoma and the pathological stage was T1bN0M0, IA. With the progression of disease, the tumor widely metastasized and the serum AFP level increased progressively with the highest level of 3396 ng/mL. She successively entered into 3 lines palliative systematic chemotherapy and fourth-line targeted therapy of apatinib, a small molecule tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor-2. Although previous studies suggested that the prognosis of this special type of GC was poor, this patient lived for 22 months after tumor transfer. Apatinib kept her progression-free survival for 5 months, and the overall survival was 4.5 years. Conclusion: So, we speculate that maybe we can focus apatinib on serum AFP elevated GC patients. PMID:27631210

Image navigation and registration performance assessment tool set for the GOES-R Advanced Baseline Imager and Geostationary Lightning Mapper

NASA Astrophysics Data System (ADS)

De Luccia, Frank J.; Houchin, Scott; Porter, Brian C.; Graybill, Justin; Haas, Evan; Johnson, Patrick D.; Isaacson, Peter J.; Reth, Alan D.

2016-05-01

The GOES-R Flight Project has developed an Image Navigation and Registration (INR) Performance Assessment Tool Set (IPATS) for measuring Advanced Baseline Imager (ABI) and Geostationary Lightning Mapper (GLM) INR performance metrics in the post-launch period for performance evaluation and long term monitoring. For ABI, these metrics are the 3-sigma errors in navigation (NAV), channel-to-channel registration (CCR), frame-to-frame registration (FFR), swath-to-swath registration (SSR), and within frame registration (WIFR) for the Level 1B image products. For GLM, the single metric of interest is the 3-sigma error in the navigation of background images (GLM NAV) used by the system to navigate lightning strikes. 3-sigma errors are estimates of the 99. 73rd percentile of the errors accumulated over a 24 hour data collection period. IPATS utilizes a modular algorithmic design to allow user selection of data processing sequences optimized for generation of each INR metric. This novel modular approach minimizes duplication of common processing elements, thereby maximizing code efficiency and speed. Fast processing is essential given the large number of sub-image registrations required to generate INR metrics for the many images produced over a 24 hour evaluation period. Another aspect of the IPATS design that vastly reduces execution time is the off-line propagation of Landsat based truth images to the fixed grid coordinates system for each of the three GOES-R satellite locations, operational East and West and initial checkout locations. This paper describes the algorithmic design and implementation of IPATS and provides preliminary test results.

Image Navigation and Registration Performance Assessment Tool Set for the GOES-R Advanced Baseline Imager and Geostationary Lightning Mapper

NASA Technical Reports Server (NTRS)

De Luccia, Frank J.; Houchin, Scott; Porter, Brian C.; Graybill, Justin; Haas, Evan; Johnson, Patrick D.; Isaacson, Peter J.; Reth, Alan D.

2016-01-01

The GOES-R Flight Project has developed an Image Navigation and Registration (INR) Performance Assessment Tool Set (IPATS) for measuring Advanced Baseline Imager (ABI) and Geostationary Lightning Mapper (GLM) INR performance metrics in the post-launch period for performance evaluation and long term monitoring. For ABI, these metrics are the 3-sigma errors in navigation (NAV), channel-to-channel registration (CCR), frame-to-frame registration (FFR), swath-to-swath registration (SSR), and within frame registration (WIFR) for the Level 1B image products. For GLM, the single metric of interest is the 3-sigma error in the navigation of background images (GLM NAV) used by the system to navigate lightning strikes. 3-sigma errors are estimates of the 99.73rd percentile of the errors accumulated over a 24-hour data collection period. IPATS utilizes a modular algorithmic design to allow user selection of data processing sequences optimized for generation of each INR metric. This novel modular approach minimizes duplication of common processing elements, thereby maximizing code efficiency and speed. Fast processing is essential given the large number of sub-image registrations required to generate INR metrics for the many images produced over a 24-hour evaluation period. Another aspect of the IPATS design that vastly reduces execution time is the off-line propagation of Landsat based truth images to the fixed grid coordinates system for each of the three GOES-R satellite locations, operational East and West and initial checkout locations. This paper describes the algorithmic design and implementation of IPATS and provides preliminary test results.

Depletion of polycistronic transcripts using short interfering RNAs: cDNA synthesis method affects levels of non-targeted genes determined by quantitative PCR.

PubMed

Hanning, Jennifer E; Groves, Ian J; Pett, Mark R; Coleman, Nicholas

2013-05-21

Short interfering RNAs (siRNAs) are often used to deplete viral polycistronic transcripts, such as those encoded by human papillomavirus (HPV). There are conflicting data in the literature concerning how siRNAs targeting one HPV gene can affect levels of other genes in the polycistronic transcripts. We hypothesised that the conflict might be partly explained by the method of cDNA synthesis used prior to transcript quantification. We treated HPV16-positive cervical keratinocytes with siRNAs targeting the HPV16 E7 gene and used quantitative PCR to compare transcript levels of E7 with those of E6 and E2, viral genes located upstream and downstream of the target site respectively. We compared our findings from cDNA generated using oligo-dT primers alone with those from cDNA generated using a combination of random hexamer and oligo-dT primers. Our data show that when polycistronic transcripts are targeted by siRNAs, there is a period when untranslatable cleaved mRNA upstream of the siRNA binding site remains detectable by PCR, if cDNA is generated using random hexamer primers. Such false indications of mRNA abundance are avoided using oligo-dT primers. The period corresponds to the time taken for siRNA activity and degradation of the cleaved transcripts. Genes downstream of the siRNA binding site are detectable during this interval, regardless of how the cDNA is generated. These data emphasise the importance of the cDNA synthesis method used when measuring transcript abundance following siRNA depletion of polycistronic transcripts. They provide a partial explanation for erroneous reports suggesting that siRNAs targeting HPV E7 can have gene-specific effects.

Depletion of polycistronic transcripts using short interfering RNAs: cDNA synthesis method affects levels of non-targeted genes determined by quantitative PCR

PubMed Central

2013-01-01

Background Short interfering RNAs (siRNAs) are often used to deplete viral polycistronic transcripts, such as those encoded by human papillomavirus (HPV). There are conflicting data in the literature concerning how siRNAs targeting one HPV gene can affect levels of other genes in the polycistronic transcripts. We hypothesised that the conflict might be partly explained by the method of cDNA synthesis used prior to transcript quantification. Findings We treated HPV16-positive cervical keratinocytes with siRNAs targeting the HPV16 E7 gene and used quantitative PCR to compare transcript levels of E7 with those of E6 and E2, viral genes located upstream and downstream of the target site respectively. We compared our findings from cDNA generated using oligo-dT primers alone with those from cDNA generated using a combination of random hexamer and oligo-dT primers. Our data show that when polycistronic transcripts are targeted by siRNAs, there is a period when untranslatable cleaved mRNA upstream of the siRNA binding site remains detectable by PCR, if cDNA is generated using random hexamer primers. Such false indications of mRNA abundance are avoided using oligo-dT primers. The period corresponds to the time taken for siRNA activity and degradation of the cleaved transcripts. Genes downstream of the siRNA binding site are detectable during this interval, regardless of how the cDNA is generated. Conclusions These data emphasise the importance of the cDNA synthesis method used when measuring transcript abundance following siRNA depletion of polycistronic transcripts. They provide a partial explanation for erroneous reports suggesting that siRNAs targeting HPV E7 can have gene-specific effects. PMID:23693071

Dietary Vitamin K intake and anticoagulation control during the initiation phase of warfarin therapy: A prospective cohort study

USDA-ARS?s Scientific Manuscript database

The effect of varying levels of dietary vitamin K intake on therapeutic International Normalized Ratio (INR) values among patients starting warfarin therapy has not been well studied. We performed a prospective cohort study among 282 patients to explore the independent associations between usual in...

Hypofibrinogenemia induced by tigecycline: a potentially life-threatening coagulation disorder.

PubMed

Sabanis, Nikolaos; Paschou, Eleni; Gavriilaki, Eleni; Kalaitzoglou, Asterios; Vasileiou, Sotirios

2015-01-01

A 74-year-old female patient with end-stage renal disease, undergoing periodic hemodialysis, was hospitalized due to infection by multidrug-resistant Acinetobacter baumannii after hip replacement surgery. She was treated with tigecycline, a glycylcycline agent. Subsequently she developed coagulation disorders as substantiated by increased international normalized ratio (INR), prolonged partial thromboplastin time (aPTT), and severe hypofibrinogenemia, followed by transaminasemia, cholestasis, and anemia. Ultrasonography and computed tomography revealed no underlying pathological entities. Tigecycline was discontinued and the patient underwent daily hemodialysis and received multiple fresh frozen plasma transfusions. Additionally, she was treated with colistin. Her clinical and laboratory status improved. We suggest that patients treated with tigecycline should be monitored for changes in INR, aPTT, and fibrinogen levels to avoid severe, life-threatening coagulation disturbances.

Is Endoscopic Therapy Safe for Upper Gastrointestinal Bleeding in Anticoagulated Patients With Supratherapeutic International Normalized Ratios?

PubMed

Shim, Choong Nam; Chung, Hyun Soo; Park, Jun Chul; Shin, Sung Kwan; Lee, Sang Kil; Lee, Yong Chan; Kim, Ha Yan; Kim, Dong Wook; Lee, Hyuk

2016-01-01

The management of upper gastrointestinal bleeding (UGIB) in anticoagulated patients with supratherapeutic international normalized ratios (INRs) presents a challenge. The purpose of the study was to evaluate the safety of endoscopic therapy for UGIB in anticoagulated patients with supratherapeutic INR in terms of rebleeding and therapeutic outcomes. One hundred ninety-two anticoagulated patients who underwent endoscopic treatment for UGIB were enrolled in the study. Patients were divided into 2 groups based on the occurrence of rebleeding within 30 days of the initial therapeutic endoscopy: no-rebleeding group (n = 168) and rebleeding group (n = 24). The overall rebleeding rate was 12.5%. Bleeding from gastric cancer and bleeding at the duodenum were significantly related to rebleeding in a univariate analysis. Multivariate analysis determined that presenting symptoms other than melena (hematemesis, hematochezia, or others) (odds ratio, 3.93; 95% confidence interval, 1.44-10.76) and bleeding from gastric cancer (odds ratio, 6.10; 95% confidence interval, 1.27-29.25) were significant factors predictive of rebleeding. Supratherapeutic INR at the time of endoscopic therapy was not significantly associated with rebleeding in either univariate or multivariate analysis. Significant differences in bleeding-related mortality, additional intervention to control bleeding, length of hospital stay, and transfusion requirements were revealed between the rebleeding and no-rebleeding groups. There were no significant differences in therapeutic outcomes between patients with INR within the therapeutic range and those with supratherapeutic INR. Supratherapeutic INR at the time of endoscopic therapy did not change rebleeding and therapeutic outcomes. Thus, we should consider endoscopic therapy for UGIB in anticoagulated patients, irrespective of INR at the time of endoscopic therapy.

The international normalized ratio does not reflect bleeding risk in esophageal variceal hemorrhage.

PubMed

Hshieh, Tammy T; Kaung, Aung; Hussain, Syed; Curry, Michael P; Sundaram, Vinay

2015-01-01

The international normalized ratio (INR) has not been validated as a predictor of bleeding risk in cirrhotics. The aim of this study was to determine whether elevation in the INR correlated with risk of esophageal variceal hemorrhage and whether correction of the INR prior to endoscopic therapy affects failure to control bleeding. Patient records were retrospectively reviewed from January 1, 2000 to December 31, 2010. Cases were cirrhotics admitted to the hospital due to bleeding esophageal varices. Controls were cirrhotics with a history of non-bleeding esophageal varices admitted with ascites or encephalopathy. All variceal bleeders were treated with octreotide, antibiotics, and band ligation. Failure to control bleeding was defined according to the Baveno V criteria. We analyzed 74 cases and 74 controls. The mean INR at presentation was lower in those with bleeding varices compared to non-bleeders (1.61 vs 1.74, P = 0.03). Those with bleeding varices had higher serum sodium (136.1 vs 133.8, P = 0.02), lower hemoglobin (9.59 vs 11.0, P < 0.001), and lower total bilirubin (2.47 vs 5.50, P < 0.001). Multivariable logistic regression showed total bilirubin to inversely correlate with bleeding (OR = 0.74). Bleeders received a mean of 1.14 units of fresh frozen plasma (FFP) prior to endoscopy (range 0-11 units). Of the 14 patients (20%) with failure to control bleeding, median INR (1.8 vs 1.5, P = 0.02) and median units of FFP transfused (2 vs 0, P = 0.01) were higher than those with hemostasis after the initial endoscopy. The INR reflects liver dysfunction, not bleeding risk. Correction of INR with FFP has little effect on hemostasis.

Utility of a point-of-care device for rapid determination of prothrombin time in trauma patients: a preliminary study.

PubMed

David, Jean-Stéphane; Levrat, Albrice; Inaba, Kenji; Macabeo, Caroline; Rugeri, Lucia; Fontaine, Oriane; Cheron, Aurélie; Piriou, Vincent

2012-03-01

Rapid and accurate determination of prothrombin time in trauma patients may help to faster control of bleeding induced coagulopathy. The goal of this prospective observational study was to investigate the accuracy of bedside measurements of prothrombin time by the mean of a point-of-care device (INRatio) in trauma patients. Fifty blood samples were drawn at admission and during the acute care phase for standard coagulation assays (prothrombin time, International Normalized Ratio [INR], and fibrinogen) and INRatio testing (INR(A)) from 48 trauma patients. Standard coagulation assays were available after a mean of 66 minutes. Median Injury Severity Score was 18, and 16 patients (33%) had a coagulopathy. Significant correlation was found between INR and INR(A) (r: 0.93, 95% confidence interval: 0.87-0.96). The mean difference (bias) for INR was 0.00, and standard deviation (precision) of the difference was 0.78. However, in cases where there was decreased hemoglobin (<10 gr · L(-1)) and fibrinogen (<1.5 gr · L(-1)), bias and precision were increased. To predict the need for fresh frozen plasma transfusion (INR > 1.5), INR(A) cutoff value of 1.3 resulted in a sensitivity of 92% and a specificity of 79%. The area under the receiver operating characteristic curve was 0.946 (95% confidence interval: 0,845-0,982). INRatio may be a useful device in the management of trauma patients with ongoing or suspected coagulopathy that may help to save at least 60 minutes in the process of obtaining a prothrombin time result. It may allow earlier detection of coagulopathy and, together with vital sign and hemoglobin, may help to guide fresh frozen plasma transfusion.

Efficacy and safety of a pharmacist-managed inpatient anticoagulation service for warfarin initiation and titration.

PubMed

Wong, Y M; Quek, Y-N; Tay, J C; Chadachan, V; Lee, H K

2011-10-01

Anticoagulation consultations provided by a pharmacist-staffed inpatient service, similar to the experience reported in outpatient anticoagulation clinics, can potentially improve anticoagulation control and outcomes. At Tan Tock Seng Hospital, a 1200-bed acute care teaching hospital in Singapore, pharmacist-managed anticoagulation clinics have been in place since 1997. Pharmacist-managed services were extended to inpatient consultations in anticoagulation management from April 2006. Our objective was to assess the effect of implementing a pharmacist-managed inpatient anticoagulation service. This was a single-centre cohort study. Baseline data from 1 January 2006 to 31 March 2006 were collected and compared with post-implementation data from 1 April 2006 to 31 March 2007. Patients newly started on warfarin for deep vein thrombosis, pulmonary embolism or atrial fibrillation in general medicine and surgery departments were included. The three endpoints were as follows: (i) percentage of international normalized ratios (INRs) achieving therapeutic range within 5 days, (ii) INRs more than 4 during titration and (iii) subtherapeutic INRs on discharge. A total of 26 patients in the control period were compared with 144 patients who had received dosing consultations by a pharmacist during the initiation of warfarin. The provision of pharmacist consult resulted in 88% compared to 38% (P < 0·001) of INR values achieving therapeutic range within 5 days. There was a reduction in INR values of more than 4 during titration from 27% to 2% (P < 0·001), and subtherapeutic INR values on discharge without low molecular weight heparin from 15% to 0% (P < 0·001). The mean time to therapeutic INR was reduced from 6·5 to 3·9 days (P < 0·001) and mean length of stay after initiation of warfarin from 11 to 7·7 days (P = 0·004). Inpatient anticoagulation care and outcomes were significantly improved by a pharmacist-managed anticoagulation service. The time to therapeutic INR was

Target: Lifestyle.

ERIC Educational Resources Information Center

Poehlman, Eric T.

1985-01-01

"Target: Lifestyle" is a physical education curriculum adopted by Detroit Country Day School which incorporates instruction in nutrition, physical fitness, first aid, and lifetime sports. This curriculum aims to influence student attitudes and lifestyles in health and physical fitness. Four levels of instruction are described. (DF)

Out of pocket expenditure to deliver at public health facilities in India: a cross sectional analysis.

PubMed

Issac, Anns; Chatterjee, Susmita; Srivastava, Aradhana; Bhattacharyya, Sanghita

2016-08-24

To expand access to safe deliveries, some developing countries have initiated demand-side financing schemes promoting institutional delivery. In the context of conditional cash incentive scheme and free maternity care in public health facilities in India, studies have highlighted high out of pocket expenditure (OOPE) of Indian families for delivery and maternity care. In this context the study assesses the components of OOPE that women incurred while accessing maternity care in public health facilities in Uttar Pradesh, India. It also assesses the determinants of OOPE and the level of maternal satisfaction while accessing care from these facilities. It is a cross-sectional analysis of 558 recently delivered women who have delivered at four public health facilities in Uttar Pradesh, India. All OOPE related information was collected through interviews using structured pre-tested questionnaires. Frequencies, Mann-Whitney test and categorical regression were used for data reduction. The analysis showed that the median OOPE was INR 700 (US$ 11.48) which varied between INR 680 (US$ 11.15) for normal delivery and INR 970 (US$ 15.9) for complicated cases. Tips for getting services (consisting of gifts and tips for services) with a median value of INR 320 (US$ 5.25) contributed to the major share in OOPE. Women from households with income more than INR 4000 (US$ 65.57) per month, general castes, primi-gravida, complicated delivery and those not accompanied by community health workers incurred higher OOPE. The significant predictors for high OOPE were caste (General Vs. OBC, SC/ST), type of delivery (Complicated Vs. Normal), and presence of ASHA (No Vs. Yes). OOPE while accessing care for delivery was one among the least satisfactory items and 76 % women expressed their dissatisfaction. Even though services at the public health facilities in India are supposed to be provided free of cost, it is actually not free, and the women in this study paid almost half of their mandated

Hepatobiliary magnetic resonance imaging in patients with liver disease: correlation of liver enhancement with biochemical liver function tests.

PubMed

Kukuk, Guido M; Schaefer, Stephanie G; Fimmers, Rolf; Hadizadeh, Dariusch R; Ezziddin, Samer; Spengler, Ulrich; Schild, Hans H; Willinek, Winfried A

2014-10-01

To evaluate hepatobiliary magnetic resonance imaging (MRI) using Gd-EOB-DTPA in relation to various liver function tests in patients with liver disorders. Fifty-one patients with liver disease underwent Gd-EOB-DTPA-enhanced liver MRI. Based on region-of-interest (ROI) analysis, liver signal intensity was calculated using the spleen as reference tissue. Liver-spleen contrast ratio (LSCR) and relative liver enhancement (RLE) were calculated. Serum levels of total bilirubin, gamma glutamyl transpeptidase (GGT), aspartate aminotransferase (AST), alanine aminotransferase (ALT), glutamate dehydrogenase (GLDH), lactate dehydrogenase (LDH), serum albumin level (AL), prothrombin time (PT), creatinine (CR) as well as international normalised ratio (INR) and model for end-stage liver disease (MELD) score were tested for correlation with LSCR and RLE. Pre-contrast LSCR values correlated with total bilirubin (r = -0.39; p = 0.005), GGT (r = -0.37; p = 0.009), AST (r = -0.38; p = 0.013), ALT (r = -0.29; p = 0.046), PT (r = 0.52; p < 0.001), GLDH (r = -0.55; p = 0.044), INR (r = -0.42; p = 0.003), and MELD Score (r = -0.53; p < 0.001). After administration of Gd-EOB-DTPA bilirubin (r = -0.45; p = 0.001), GGT (r = -0.40; p = 0.004), PT (r = 0.54; p < 0.001), AST (r = -0.46; p = 0.002), ALT (r = -0.31; p = 0.030), INR (r = -0.45; p = 0.001) and MELD Score (r = -0.56; p < 0.001) significantly correlated with LSCR. RLE correlated with bilirubin (r = -0.40; p = 0.004), AST (r = -0.38; p = 0.013), PT (r = 0.42; p = 0.003), GGT (r = -0.33; p = 0.020), INR (r = -0.36; p = 0.011) and MELD Score (r = -0.43; p = 0.003). Liver-spleen contrast ratio and relative liver enhancement using Gd-EOB-DTPA correlate with a number of routinely used biochemical liver function tests, suggesting that hepatobiliary MRI may serve as a

Levels in N 12 via the N 14 ( p ,   t ) reaction using the JENSA gas-jet target

DOE PAGES

Chipps, K. A.; Pain, S. D.; Greife, U.; ...

2015-09-25

As one of a series of physics cases to demonstrate the unique benefit of the new Jet Experiments in Nuclear Structure and Astrophysics gas-jet target for enabling next-generation transfer reaction studies, the ¹⁴N (p, t)¹²N reaction was studied for the first time, using a pure jet of nitrogen, in an attempt to resolve conflicting information on the structure of ¹²N. A new level at 4.561-MeV excitation energy in ¹²N was found.

Monitoring of anticoagulant therapy in heart disease: considerations for the current assays.

PubMed

Boroumand, Mohammadali; Goodarzynejad, Hamidreza

2010-01-01

, and congenital factor deficiencies. In contrast to marked progress in the standardization of PT reagents for INR reporting, no standardization system has been globally adopted for standardization of PTT reagents. Recently College of American Pathologists recommend that individual laboratories establish their own therapeutic range by using aPTT values calibrated against accepted therapeutic unfractionated heparin (UFH) levels calibrated against accepted therapeutic UFH levels performing anti-Xa test (which is the most accurate assay for monitoring UFH therapy).Herein, we review recent data on the monitoring of conventional anticoagulant agents. Marked interlaboratory variability still exists for PT, INR, and PTT tests. Further research should be focused on improving the standardization and calibration of these assays.

Serum Leptin Is a Biomarker of Malnutrition in Decompensated Cirrhosis

PubMed Central

Rachakonda, Vikrant; Borhani, Amir A.; Dunn, Michael A.; Andrzejewski, Margaret; Martin, Kelly; Behari, Jaideep

2016-01-01

Background and Aims Malnutrition is a leading cause of morbidity and mortality in cirrhosis. There is no consensus as to the optimal approach for identifying malnutrition in end-stage liver disease. The aim of this study was to measure biochemical, serologic, hormonal, radiographic, and anthropometric features in a cohort of hospitalized cirrhotic patients to characterize biomarkers for identification of malnutrition. Design In this prospective observational cohort study, 52 hospitalized cirrhotic patients were classified as malnourished (42.3%) or nourished (57.7%) based on mid-arm muscle circumference < 23 cm and dominant handgrip strength < 30 kg. Anthropometric measurements were obtained. Appetite was assessed using the Simplified Nutrition Appetite Questionnaire (SNAQ) score. Fasting levels of serum adipokines, cytokines, and hormones were determined using Luminex assays. Logistic regression analysis was used to determine features independently associated with malnutrition. Results Subjects with and without malnutrition differed in several key features of metabolic phenotype including wet and dry BMI, skeletal muscle index, visceral fat index and HOMA-IR. Serum leptin levels were lower and INR was higher in malnourished subjects. Serum leptin was significantly correlated with HOMA-IR, wet and dry BMI, mid-arm muscle circumference, skeletal muscle index, and visceral fat index. Logistic regression analysis revealed that INR and log-transformed leptin were independently associated with malnutrition. Conclusions Low serum leptin and elevated INR are associated with malnutrition in hospitalized patients with end-stage liver disease. PMID:27583675

Four-trophic level food webs reveal the cascading impacts of an invasive plant targeted for biocontrol.

PubMed

López-Núñez, Francisco A; Heleno, Ruben H; Ribeiro, Sérgio; Marchante, Hélia; Marchante, Elizabete

2017-03-01

Biological invasions are a major threat to biodiversity and as such understanding their impacts is a research priority. Ecological networks provide a valuable tool to explore such impacts at the community level, and can be particularly insightful for planning and monitoring biocontrol programmes, including the potential for their seldom evaluated indirect non-target effects. Acacia longifolia is among the worst invasive species in Portugal, and has been recently targeted for biocontrol by a highly specific gall-wasp. Here we use an ambitious replicated network approach to: (1) identify the mechanisms by which direct and indirect impacts of A. longifolia can cascade from plants to higher trophic levels, including gallers, their parasitoids and inquilines; (2) reveal the structure of the interaction networks between plants, gallers, parasitoids and inquilines before the biocontrol; and (3) explore the potential for indirect interactions among gallers, including those established with the biocontrol agent, via apparent competition. Over a 15-month period, we collected 31,737 galls from native plants and identified all emerging insects, quantifying the interactions between 219 plant-, 49 galler-, 65 parasitoid- and 87 inquiline-species-one of the largest ecological networks to date. No galls were found on any of the 16 alien plant species. Invasion by A. longifolia caused an alarming simplification of plant communities, with cascading effects to higher trophic levels, namely: a decline of overall gall biomass, and on the richness, abundance and biomass of galler insects, their parasitoids, and inquilines. Correspondingly, we detected a significant decline in the richness of interactions between plants and galls. The invasion tended to increase overall interaction evenness by promoting the local extinction of the native plants that sustained more gall species. However, highly idiosyncratic responses hindered the detection of further consistent changes in network

Influence of kidney function on risk of supratherapeutic international normalized ratio-related hemorrhage in warfarin users: a prospective cohort study

USDA-ARS?s Scientific Manuscript database

Background: Anticoagulation management is difficult in chronic kidney disease, with frequent supratherapeutic international normalized ratios (INRs >/= 4) increasing hemorrhagic risk. We evaluated whether the interaction of INR and lower estimated glomerular filtration rate (eGFR) increases hemorrha...

Phospholipase D and the Maintenance of Phosphatidic Acid Levels for Regulation of Mammalian Target of Rapamycin (mTOR)*

PubMed Central

Foster, David A.; Salloum, Darin; Menon, Deepak; Frias, Maria A.

2014-01-01

Phosphatidic acid (PA) is a critical metabolite at the heart of membrane phospholipid biosynthesis. However, PA also serves as a critical lipid second messenger that regulates several proteins implicated in the control of cell cycle progression and cell growth. Three major metabolic pathways generate PA: phospholipase D (PLD), diacylglycerol kinase (DGK), and lysophosphatidic acid acyltransferase (LPAAT). The LPAAT pathway is integral to de novo membrane phospholipid biosynthesis, whereas the PLD and DGK pathways are activated in response to growth factors and stress. The PLD pathway is also responsive to nutrients. A key target for the lipid second messenger function of PA is mTOR, the mammalian/mechanistic target of rapamycin, which integrates both nutrient and growth factor signals to control cell growth and proliferation. Although PLD has been widely implicated in the generation of PA needed for mTOR activation, it is becoming clear that PA generated via the LPAAT and DGK pathways is also involved in the regulation of mTOR. In this minireview, we highlight the coordinated maintenance of intracellular PA levels that regulate mTOR signals stimulated by growth factors and nutrients, including amino acids, lipids, glucose, and Gln. Emerging evidence indicates compensatory increases in one source of PA when another source is compromised, highlighting the importance of being able to adapt to stressful conditions that interfere with PA production. The regulation of PA levels has important implications for cancer cells that depend on PA and mTOR activity for survival. PMID:24990952

Pooled Patient-Level Meta-analysis of Children and Adults Completing a Computer-Based Anxiety Intervention Targeting Attentional Bias

PubMed Central

Price, Rebecca B.; Wallace, Meredith; Kuckertz, Jennie M.; Amir, Nader; Graur, Simona; Cummings, Logan; Popa, Paul; Carlbring, Per; Bar-Haim, Yair

2016-01-01

Computer-based approaches, such as Attention Bias Modification (ABM), could help improve access to care for anxiety. Study-level meta-analyses of ABM have produced conflicting findings and leave critical questions unresolved regarding ABM’s mechanisms of action and clinical potential. We pooled patient-level datasets from randomized controlled trials of children and adults with high-anxiety. Attentional bias (AB) towards threat, the target mechanism of ABM, was tested as an outcome and a mechanistic mediator and moderator of anxiety reduction. Diagnostic remission and Liebowitz Social Anxiety Scale (LSAS) were clinical outcomes available in enough studies to enable pooling. Per-patient data were obtained on at least one outcome from 13/16 eligible studies [86% of eligible participants; n=778]. Significant main effects of ABM on diagnostic remission (ABM—22.6%, control—10.8%; OR=2.57; p=.006) and AB (β*(95%CI)=−.63(−.83, −.42); p<.00005) were observed. There was no main effect of ABM on LSAS. However, moderator analyses suggested ABM was effective for patients who were younger (≤37y), trained in the lab, and/or assessed by clinicians. Under the same conditions where ABM was effective, mechanistic links between AB and anxiety reduction were supported. Under these specific circumstances, ABM reduces anxiety and acts through its target mechanism, supporting ABM’s theoretical basis while simultaneously suggesting clinical indications and refinements to improve its currently limited clinical potential. PMID:27693664

The clinical evaluation of International Normalized Ratio variability and control in conventional oral anticoagulant administration by use of the variance growth rate.

PubMed

Ibrahim, S; Jespersen, J; Poller, L

2013-08-01

The time in target International Normalized Ratio (INR) range (TIR) is used to assess the control and intensity of oral anticoagulation, but it does not measure variation in the INR. The value of assessing INR variability by use of the variance growth rate (VGR) as a predictor of events was investigated in patients treated with warfarin. Three different methods of VGR determination (A, B1, and B2) together with the TIR were studied. Method A measures both INR variability and control, but methods B1 and B2 measure variability only. The VGR and TIR were determined over three time periods: overall follow-up to an event, and 6 months and 3 months before an event. Six hundred and sixty-one control patients were matched to 158 cases (bleeding, thromboembolism, or death). With all VGR methods, the risk of an event was greater in unstable patients at 6 months before an event than in stable patients. Method A demonstrated the greatest risk 3 months before an event in the unstable VGR group as compared with the stable group (odds ratio 3.3, 95% confidence interval 1.9-5.7, P < 0.005). The risk of an event was 1.9 times greater in patients with a low TIR (< 39%) than in those with a high TIR (> 80%) in the 3-month period (P = 0.02). Risk of bleeding was significantly greater in the 3-month period in patients with unstable VGR, with the greatest risk found with method B2 (P < 0.01). Patients with unstable anticoagulation have a significantly increased risk of 'clinical events' at 3 and 6 months before an event. The VGR can be incorporated into computer-dosage programs, and may offer additional safety when oral anticoagulation is monitored. © 2013 International Society on Thrombosis and Haemostasis.

Interaction Between Dietary Vitamin K Intake and Anticoagulation by Vitamin K Antagonists: Is It Really True?: A Systematic Review.

PubMed

Violi, Francesco; Lip, Gregory Yh; Pignatelli, Pasquale; Pastori, Daniele

2016-03-01

Educational advice is often given to patients starting treatment with vitamin K Antagonists (VKAs). A great emphasis is made on nutritional information. Common belief is that dietary vitamin K intake could counteract the anticoagulant effect by VKAs and for many years, patients have been discouraged to consume vitamin-K-rich foods, such as green leafy vegetables.The objective of this study is to summarize the current evidence supporting the putative interaction between dietary vitamin K intake and changes in INR with the VKAs.Data sources are MEDLINE via PubMed and Cochrane database.All clinical studies investigating the relationship between dietary vitamin K and measures of anticoagulation were included. We excluded all studies of supplementation of vitamin K alone.We performed a systematic review of the literature up to October 2015, searching for a combination of "food," "diet," "vitamin K," "phylloquinone," "warfarin," "INR," "coagulation," and "anticoagulant."Two dietary interventional trials and 9 observational studies were included. We found conflicting evidence on the effect of dietary intake of vitamin K on coagulation response. Some studies found a negative correlation between vitamin K intake and INR changes, while others suggested that a minimum amount of vitamin K is required to maintain an adequate anticoagulation. Median dietary intake of vitamin K1 ranged from 76 to 217 μg/day among studies, and an effect on coagulation may be detected only for high amount of vitamin intake (>150 μg/day).Most studies included patients with various indications for VKAs therapy, such as atrial fibrillation, prosthetic heart valves, and venous thromboembolism. Thus, INR target was dishomogeneous and no subanalyses for specific populations or different anticoagulants were conducted. Measures used to evaluate anticoagulation stability were variable.The available evidence does not support current advice to modify dietary habits when starting therapy with VKAs

Direct and indirect cost of myasthenia gravis: A prospective study from a tertiary care teaching hospital in India.

PubMed

Sonkar, Kamlesh Kumar; Bhoi, Sanjeev Kumar; Dubey, Deepanshu; Kalita, Jayantee; Misra, Usha Kant

2017-04-01

Myasthenia gravis (MG) requires lifelong treatment. The cost of management MG is very high in developed countries but there is no information on the cost of management of MG in the developing countries. This study reports the direct and indirect cost and predictors of cost of MG in a tertiary care teaching hospital in India. In a prospective hospital based study, from a tertiary hospital in India 66 consecutive patient during 2014-2015 were included. The age of the patients ranged between 6 and 75years. The severity of MG was assessed by myasthenia gravis foundation association (MGFA) class (MGFA) I-V. The patient data was collected s and their direct cost was calculated from the computerized Hospital information system. The indirect cost was calculated from patient's memory, checking the bills of transportation and wages loss by the patient or the care giver. Total annual cost of MG ranged between INR (4560-532227) with median INR 61390.5 (US$911.64). The median cost of outpatient department (OPD) consultation of 16 patients was INR 20439.9 (US$303.53), of 50 admitted patients was INR 44311.8 (US$658.03) and 21 intensive care unit (ICU) patients was INR 59574.3 (US$ 884.6) and the direct cost of thymectomy was INR 45000 (US$ 668.25). Direct cost was related to indirect cost (r=0.55; p=0.0001). Predictors of patient outcome were severity of MG, ICU admission, and thymectomy. The total median cost for management of myasthenia gravis was INR 61390.5 (4560-532227, US$911.64) per year, and the cost was mainly determined by the severity of MG. Copyright © 2016 Elsevier Ltd. All rights reserved.

A multicenter study of plasma use in the United States.

PubMed

Triulzi, Darrell; Gottschall, Jerome; Murphy, Edward; Wu, Yanyun; Ness, Paul; Kor, Daryl; Roubinian, Nareg; Fleischmann, Debra; Chowdhury, Dhuly; Brambilla, Donald

2015-06-01

Detailed information regarding plasma use in the United States is needed to identify opportunities for practice improvement and design of clinical trials of plasma therapy. Ten US hospitals collected detailed medical information from the electronic health records for 1 year (2010-2011) for all adult patients transfused with plasma. A total of 72,167 units of plasma were transfused in 19,596 doses to 9269 patients. The median dose of plasma was 2 units (interquartile range, 2-4; range 1-72); 15% of doses were 1 unit, and 45% were 2 units. When adjusted by patient body weight (kg), the median dose was 7.3 mL/kg (interquartile range, 5.5-12.0). The median pretransfusion international normalized ratio (INR) was 1.9 (25%-75% interquartile range, 1.6-2.6). A total of 22.5% of plasma transfusions were given to patients with an INR of less than 1.6 and 48.5% for an INR of 2.0 or more. The median posttransfusion INR was 1.6 (interquartile range, 1.4-2.0). Only 42% of plasma transfusions resulted in a posttransfusion INR of less than 1.6. Correction of INR increased as the plasma dose increased from 1 to 4 units (p < 0.001). There was no difference in the INR response to different types of plasma. The most common issue locations were general ward (38%) and intensive care unit (ICU; 42%). This large database describing plasma utilization in the United States provides evidence for both inadequate dosing and unnecessary transfusion. Measures to improve plasma transfusion practice and clinical trials should be directed at patients on medical and surgical wards and in the ICU where plasma is most commonly used. © 2014 AABB.

The International Normalized Ratio does not Reflect Bleeding Risk in Esophageal Variceal Hemorrhage

PubMed Central

Hshieh, Tammy T.; Kaung, Aung; Hussain, Syed; Curry, Michael P.; Sundaram, Vinay

2015-01-01

Background/Aims: The international normalized ratio (INR) has not been validated as a predictor of bleeding risk in cirrhotics. The aim of this study was to determine whether elevation in the INR correlated with risk of esophageal variceal hemorrhage and whether correction of the INR prior to endoscopic therapy affects failure to control bleeding. Patients and Methods: Patient records were retrospectively reviewed from January 1, 2000 to December 31, 2010. Cases were cirrhotics admitted to the hospital due to bleeding esophageal varices. Controls were cirrhotics with a history of non-bleeding esophageal varices admitted with ascites or encephalopathy. All variceal bleeders were treated with octreotide, antibiotics, and band ligation. Failure to control bleeding was defined according to the Baveno V criteria. Results: We analyzed 74 cases and 74 controls. The mean INR at presentation was lower in those with bleeding varices compared to non-bleeders (1.61 vs 1.74, P = 0.03). Those with bleeding varices had higher serum sodium (136.1 vs 133.8, P = 0.02), lower hemoglobin (9.59 vs 11.0, P < 0.001), and lower total bilirubin (2.47 vs 5.50, P < 0.001). Multivariable logistic regression showed total bilirubin to inversely correlate with bleeding (OR = 0.74). Bleeders received a mean of 1.14 units of fresh frozen plasma (FFP) prior to endoscopy (range 0-11 units). Of the 14 patients (20%) with failure to control bleeding, median INR (1.8 vs 1.5, P = 0.02) and median units of FFP transfused (2 vs 0, P = 0.01) were higher than those with hemostasis after the initial endoscopy. Conclusions: The INR reflects liver dysfunction, not bleeding risk. Correction of INR with FFP has little effect on hemostasis. PMID:26228370

Alternative calculations of individual patient time in therapeutic range while taking warfarin: results from the ROCKET AF trial.

PubMed

Singer, Daniel E; Hellkamp, Anne S; Yuan, Zhong; Lokhnygina, Yuliya; Patel, Manesh R; Piccini, Jonathan P; Hankey, Graeme J; Breithardt, Günter; Halperin, Jonathan L; Becker, Richard C; Hacke, Werner; Nessel, Christopher C; Mahaffey, Kenneth W; Fox, Keith A A; Califf, Robert M

2015-03-03

In the ROCKET AF (Rivaroxaban-Once-daily, oral, direct Factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation) trial, marked regional differences in control of warfarin anticoagulation, measured as the average individual patient time in the therapeutic range (iTTR) of the international normalized ratio (INR), were associated with longer inter-INR test intervals. The standard Rosendaal approach can produce biased low estimates of TTR after an appropriate dose change if the follow-up INR test interval is prolonged. We explored the effect of alternative calculations of TTR that more immediately account for dose changes on regional differences in mean iTTR in the ROCKET AF trial. We used an INR imputation method that accounts for dose change. We compared group mean iTTR values between our dose change-based method with the standard Rosendaal method and determined that the differences between approaches depended on the balance of dose changes that produced in-range INRs ("corrections") versus INRs that were out of range in the opposite direction ("overshoots"). In ROCKET AF, the overall mean iTTR of 55.2% (Rosendaal) increased up to 3.1% by using the dose change-based approach, depending on assumptions. However, large inter-regional differences in anticoagulation control persisted. TTR, the standard measure of control of warfarin anticoagulation, depends on imputing daily INR values for the vast majority of follow-up days. Our TTR calculation method may better reflect the impact of warfarin dose changes than the Rosendaal approach. In the ROCKET AF trial, this dose change-based approach led to a modest increase in overall mean iTTR but did not materially affect the large inter-regional differences previously reported. URL: ClinicalTrials.gov. Unique identifier: NCT00403767. © 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Alternative Calculations of Individual Patient Time in Therapeutic Range While Taking Warfarin: Results From the ROCKET AF Trial

PubMed Central

Singer, Daniel E.; Hellkamp, Anne S.; Yuan, Zhong; Lokhnygina, Yuliya; Patel, Manesh R.; Piccini, Jonathan P.; Hankey, Graeme J.; Breithardt, Günter; Halperin, Jonathan L.; Becker, Richard C.; Hacke, Werner; Nessel, Christopher C.; Mahaffey, Kenneth W.; Fox, Keith A. A.; Califf, Robert M.

2015-01-01

Background In the ROCKET AF (Rivaroxaban–Once‐daily, oral, direct Factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation) trial, marked regional differences in control of warfarin anticoagulation, measured as the average individual patient time in the therapeutic range (iTTR) of the international normalized ratio (INR), were associated with longer inter‐INR test intervals. The standard Rosendaal approach can produce biased low estimates of TTR after an appropriate dose change if the follow‐up INR test interval is prolonged. We explored the effect of alternative calculations of TTR that more immediately account for dose changes on regional differences in mean iTTR in the ROCKET AF trial. Methods and Results We used an INR imputation method that accounts for dose change. We compared group mean iTTR values between our dose change–based method with the standard Rosendaal method and determined that the differences between approaches depended on the balance of dose changes that produced in‐range INRs (“corrections”) versus INRs that were out of range in the opposite direction (“overshoots”). In ROCKET AF, the overall mean iTTR of 55.2% (Rosendaal) increased up to 3.1% by using the dose change–based approach, depending on assumptions. However, large inter‐regional differences in anticoagulation control persisted. Conclusions TTR, the standard measure of control of warfarin anticoagulation, depends on imputing daily INR values for the vast majority of follow‐up days. Our TTR calculation method may better reflect the impact of warfarin dose changes than the Rosendaal approach. In the ROCKET AF trial, this dose change–based approach led to a modest increase in overall mean iTTR but did not materially affect the large inter‐regional differences previously reported. Clinical Trial Registration URL: ClinicalTrials.gov. Unique identifier: NCT00403767. PMID:25736441

Managing the therapeutic dilemma: patients with spontaneous intracerebral hemorrhage and urgent need for anticoagulation.

PubMed

Bertram, M; Bonsanto, M; Hacke, W; Schwab, S

2000-03-01

Physicians face a therapeutic dilemma in patients with acute hemorrhagic stroke requiring long-term, high-intensity anticoagulants because this treatment increases the risk of intracranial hemorrhage (ICH) 8- to 11-fold. We retrospectively studied 15 patients with ICH which occurred under anticoagulation with phenprocoumon, with an international norrmalized ratio (INR) of 2.5-6.5 on admission. Hemispheric, thalamic, cerebellar, intraventricular, or subarachnoid hemorrhage without aneurysm occurred. Absolute indications for anticoagulation were double, mitral, or aortic valve replacement, combined mitral valve failure with atrial fibrillation and atrial enlargement, internal carotid artery-jugular vein graft, frequently recurring deep vein thrombosis with risk of pulmonary embolism, and severe nontreatable ischemic heart disease. As soon as the diagnosis of ICH was established, INR normalization was attempted in all patients by administration of prothrombin complex, fresh frozen plasma, or vitamin K. After giving phenprocoumon antagonists (and neurosurgical therapy in four patients) heparin administration was started. Nine patients received full-dose intravenous and six low-dose subcutaneous heparin. The following observations were made: (a) All patients with effective, full-dose heparin treatment with a 1.5- to 2-fold elevation in partial thromboplastin time after normalization of the INR were discharged without complication. (b) Three of four of the patients with only incomplete correction of the INR (> 1.35) experienced relevant rebleeding within 3 days (all patients with an INR higher than 1.5), two of whom were on full-dose heparin. (c) Three of seven of the patients with normalized INR and without significant PTT elevation developed severe cerebral embolism. Although our data are based on a retrospective analysis, they support treatment with intravenous heparin (partial thromboplastin time 1.5-2 times baseline value) after normalization of the INR in patients

A multicenter study of plasma use in the United States

PubMed Central

Triulzi, Darrell; Gottschall, Jerome; Murphy, Edward; Wu, Yanyun; Ness, Paul; Kor, Daryl; Roubinian, Nareg; Fleischmann, Debra; Chowdhury, Dhuly; Brambilla, Donald

2016-01-01

Background Detailed information regarding plasma use in the United States is needed to identify opportunities for practice improvement and design of clinical trials of plasma therapy. Study Design and Methods Ten US hospitals collected detailed medical information from the electronic health records for 1 year (2010-2011) for all adult patients transfused with plasma. Results A total of 72,167 units of plasma were transfused in 19,596 doses to 9269 patients. The median dose of plasma was 2 units (interquartile range, 2-4; range 1-72); 15% of doses were 1 unit, and 45% were 2 units. When adjusted by patient body weight (kg), the median dose was 7.3 mL/kg (interquartile range, 5.5-12.0). The median pretransfusion international normalized ratio (INR) was 1.9 (25%-75% interquartile range, 1.6-2.6). A total of 22.5% of plasma transfusions were given to patients with an INR of less than 1.6 and 48.5% for an INR of 2.0 or more. The median posttransfusion INR was 1.6 (interquartile range, 1.4-2.0). Only 42% of plasma transfusions resulted in a posttransfusion INR of less than 1.6. Correction of INR increased as the plasma dose increased from 1 to 4 units (p < 0.001). There was no difference in the INR response to different types of plasma. The most common issue locations were general ward (38%) and intensive care unit (ICU; 42%). Conclusion This large database describing plasma utilization in the United States provides evidence for both inadequate dosing and unnecessary transfusion. Measures to improve plasma transfusion practice and clinical trials should be directed at patients on medical and surgical wards and in the ICU where plasma is most commonly used. PMID:25522888

Activated Prothrombin Complex Concentrate versus Plasma for Reversal of Warfarin-Associated Hemorrhage.

PubMed

Rowe, Anthony Shaun; Mahbubani, Pinky S; Bucklin, Mason H; Clark, Christopher T; Hamilton, Leslie A

2016-11-01

To evaluate the efficacy and safety of an activated four-factor prothrombin complex concentrate (aPCC) versus plasma for the reversal of warfarin-associated hemorrhage. Single-center, retrospective cohort analysis of adult patients with warfarin-associated hemorrhage treated with either aPCC or plasma. Patients received either aPCC or plasma as treatment for warfarin-associated hemorrhage between January 1, 2011, and July 1, 2013. Patients with missing data points were excluded from the final analysis. Of the 276 patients included in the final analysis, 128 received aPCC and 148 received plasma. None. Those patients who received aPCC achieved a lower posttreatment INR (1.1 [0.1] vs 1.6 [0.5]; p<0.05). In addition, patients who received aPCC had a 4.3 times higher odds of achieving an INR of less than 1.4 (97 [75.8%] vs 65 [43.9%]; p<0.05; odds ratio [OR] = 4.3 [95% confidence interval (CI) 2.6-7.3]). When controlling for vitamin K administration, history of diabetes mellitus, receipt of the recommended reversal agent dose, and pretreatment INR, aPCC administration remained an independent predictor for achieving an international normalized ratio (INR) of less than 1.4 in the first 24 hours after treatment (OR = 3.75 [95% CI 2.11-6.65]; p<0.001). In addition, there was no statistical difference between the groups with regard to occurrences of infusion reaction, pulmonary embolism, deep vein thrombosis, stroke, or myocardial infarction. Compared with patients who received plasma, patients who received aPCC achieved a lower posttreatment INR, had a larger INR change, and were more likely to achieve an INR less than the prespecified goal. Those patients who received aPCC did not have a higher incidence of thromboembolic events. © 2016 Pharmacotherapy Publications, Inc.

Characteristics, management and attainment of lipid target levels in diabetic and cardiac patients enrolled in Disease Management Program versus those in routine care: LUTZ registry

PubMed Central

2009-01-01

Background Since 2002 the sick funds in Germany have widely implemented disease management programs (DMPs) for patients with type 2 diabetes mellitus (DM) and coronary heart disease (CHD). Little is known about the characteristics, treatment and target attainment lipid levels of these patients enrolled in DMPs compared to patients in routine care (non-DMP). Methods In an open, non-interventional registry (LUTZ) in Germany, 6551 physicians documented 15,211 patients with DM (10,110 in DMP, 5101 in routine care) and 14,222 (6259 in DMP, 7963 in routine care) over a follow-up period of 4 months. They received the NCEP ATP III guidelines as a reminder on lipid level targets. Results While demographic characteristics of DMP patients were similar to routine care patients, the former had higher rates of almost all cardiovascular comorbidities. Patients in DMPs received pharmacological treatment (in almost all drug classes) more often than non-DMP patients (e.g. antiplatelets: in DM 27.0% vs 23.8%; in CHD 63.0% vs. 53.6%). The same applied for educational measures (on life style changes and diet etc.). The rate of target level attainment for low density lipoprotein cholesterol (LDL-C) < 100 mg/dl was somewhat higher in DMP patients at inclusion compared to non-DMP patients (DM: 23.9% vs. 21.3%; CHD: 30.6% vs. 23.8%) and increased after 4 months (DM: 38.3% vs. 36.9%; CHD: 49.8% vs. 43.3%). Individual LDL-C target level attainment rates as assessed by the treating physicians were higher (at 4 months in DM: 59.6% vs. 56.5%; CHD: 49.8% vs 43.3%). Mean blood pressure (BP) and HbA1c values were slightly lowered during follow-up, without substantial differences between DMP and non-DMP patients. Conclusion Patients with DM, and (to a greater extent) with CHD in DMPs compared to non-DMP patients in routine care have a higher burden of comorbidities, but also receive more intensive pharmacological treatment and educational measures. The present data support that the substantial

The interval between prothrombin time tests and the quality of oral anticoagulants treatment in patients with chronic atrial fibrillation.

PubMed

Shalev, Varda; Rogowski, Ori; Shimron, Orit; Sheinberg, Bracha; Shapira, Itzhak; Seligsohn, Uri; Berliner, Shlomo; Misgav, Mudi

2007-01-01

The incidence of stroke in patients with atrial fibrillation (AF) can be significantly reduced with warfarin therapy especially if optimally controlled. To evaluate the effect of the interval between consecutive prothrombin time measurements on the time in therapeutic range (INR 2-3) in a cohort of patients with AF on chronic warfarin treatment in the community. All INR measurements available from a relatively large cohort of patients with chronic AF were reviewed and the mean interval between consecutive INR tests of each patient was correlated with the time in therapeutic range (TTR). Altogether 251,916 INR measurements performed in 4408 patients over a period of seven years were reviewed. Sixty percent of patients had their INR measured on average every 2 to 3 weeks and most others were followed at intervals of 4 weeks or longer. A small proportion (3.6%) had their INR measured on average every week. A significant decline in the time in therapeutic range was observed as the intervals between tests increased. At one to three weeks interval the TTR was 48%, at 4 weeks interval 45% and at 5 weeks 41% (P<0.0005). A five percent increment in TTR was observed if more tests were performed at multiplications of exactly 7 days (43% vs 48% P<0.0001). A better control with an increase in the TTR was observed in patients with atrial fibrillation if prothrombin time tests are performed at regular intervals of no longer than 3 weeks.

Cost comparison and economic implications of commonly used originator and generic chemotherapy drugs in India.

PubMed

Lopes, G de L

2013-09-01

Cancer treatments have improved outcomes but access to medications is an issue around the world and especially so in low- and middle-income countries, such as India. Generic substitution may lead to significant cost savings. The author aimed to compare the cost and estimate potential cost savings per cycle, per patient, and for the country as a whole with generic substitution of frequently used chemotherapy drugs in the treatment of common cancers in India. Generic paclitaxel (Taxol), docetaxel (Taxotere), gemcitabine, oxaliplatin and irinotecan cost from 8.9% to 36% of their equivalent branded originator drug, resulting in cost savings of ~ Indian Rupees (INR) 11,000 to >INR 90,000 (USD 200-1600, Euro 160-1300) per cycle; and ~INR 50,000 to >INR 240,000 (USD 900-4300, Euro 700-3400) per patient. Overall, potential yearly savings for health systems in India were nearly INR 47 billion (~USD 843 million, Euro 670 million). In conclusion, generic substitution for frequently used chemotherapy drugs in the treatment of common cancers has an enormous potential to generate significant cost savings and increase access to cancer treatments in India and other low- and middle-income countries.

[Folic acid fortified foods available in Spain: types of products, level of fortification and target population groups].

PubMed

Samaniego Vaesken, M L; Alonso-Aperte, E; Varela-Moreiras, G

2009-01-01

Folic acid is a potentially relevant factor in the prevention of a number of pathologies (congenital abnormalities, cardiovascular disease, colorectal cancer and neurocognitive decline). This has led to the introduction of different strategies in order to increase folate intake: nutritional education, pharmacological supplementation and mandatory or voluntary fortification of staple foods with folic acid. In Spain there is a growing number of folic acid fortified products on a voluntary basis, but there is also a lack of reliable data to assess their impact on the population's dietary folate intakes. To gather a better knowledge of folic acid food fortification practices in Spain. A Food Composition Database was developed using data from a market study. Also, previously published data of unfortified staple foods from Food Composition Tables was reviewed. The Database included 260 folic acid fortified food items and it was periodically updated. Food groups included were primarily "Cereals and derivatives" (52%) followed by "Dairy products". Most of these foodstuffs lacked a target population for their consumption (37%) or were aimed at "Weight control" (28%) and "Children" (23%), but only 2% targeted women at a reproductive age. Number of unfortified foods included was 690. Fortification levels declared by manufacturers ranged between 15 and 430% of the Recommended Dietary Allowances (RDA) for folic acid per 100 g/ml, and simultaneous addition of B6 and B12 vitamins was observed in 75% of the products. Currently, Spain market offers a significant number of folic acid fortified products on a voluntary basis and at a level > or = 15% of the RDA per 100 g/ml or serving declared by manufacturers.

When blood is thinner than water.

PubMed

Gude, Dilip; Abbas, Aslam; Mohiuddin, Hina

2013-01-01

Antagonists of vitamin K dependant clotting factors are commonly used as treatment/prophylaxis for anticoagulation. Due to their narrow therapeutic window, a wide range of complications including death may occur. International normalized ratio (INR) is monitored to measure adequacy/excess of anticoagulation. There is a plethora of risk factors that may contribute to the uncontrollably high INR values. We describe our experience of a case of deep venous thrombosis wherein the patient had an overshoot of INR during anticoagulation therapy. We review the literature and discuss management in such scenarios.

Multiple target laser ablation system

DOEpatents

Mashburn, D.N.

1996-01-09

A laser ablation apparatus and method are provided in which multiple targets consisting of material to be ablated are mounted on a movable support. The material transfer rate is determined for each target material, and these rates are stored in a controller. A position detector determines which target material is in a position to be ablated, and then the controller controls the beam trigger timing and energy level to achieve a desired proportion of each constituent material in the resulting film. 3 figs.

Multiple target laser ablation system

DOEpatents

Mashburn, Douglas N.

1996-01-01

A laser ablation apparatus and method are provided in which multiple targets consisting of material to be ablated are mounted on a movable support. The material transfer rate is determined for each target material, and these rates are stored in a controller. A position detector determines which target material is in a position to be ablated, and then the controller controls the beam trigger timing and energy level to achieve a desired proportion of each constituent material in the resulting film.

CRISPR/Cas9-mediated gene knockout is insensitive to target copy number but is dependent on guide RNA potency and Cas9/sgRNA threshold expression level

PubMed Central

Yuen, Garmen; Khan, Fehad J.; Gao, Shaojian; Stommel, Jayne M.; Batchelor, Eric; Wu, Xiaolin

2017-01-01

Abstract CRISPR/Cas9 is a powerful gene editing tool for gene knockout studies and functional genomic screens. Successful implementation of CRISPR often requires Cas9 to elicit efficient target knockout in a population of cells. In this study, we investigated the role of several key factors, including variation in target copy number, inherent potency of sgRNA guides, and expression level of Cas9 and sgRNA, in determining CRISPR knockout efficiency. Using isogenic, clonal cell lines with variable copy numbers of an EGFP transgene, we discovered that CRISPR knockout is relatively insensitive to target copy number, but is highly dependent on the potency of the sgRNA guide sequence. Kinetic analysis revealed that most target mutation occurs between 5 and 10 days following Cas9/sgRNA transduction, while sgRNAs with different potencies differ by their knockout time course and by their terminal-phase knockout efficiency. We showed that prolonged, low level expression of Cas9 and sgRNA often fails to elicit target mutation, particularly if the potency of the sgRNA is also low. Our findings provide new insights into the behavior of CRISPR/Cas9 in mammalian cells that could be used for future improvement of this platform. PMID:29036671

CRISPR/Cas9-mediated gene knockout is insensitive to target copy number but is dependent on guide RNA potency and Cas9/sgRNA threshold expression level.

PubMed

Yuen, Garmen; Khan, Fehad J; Gao, Shaojian; Stommel, Jayne M; Batchelor, Eric; Wu, Xiaolin; Luo, Ji

2017-11-16

CRISPR/Cas9 is a powerful gene editing tool for gene knockout studies and functional genomic screens. Successful implementation of CRISPR often requires Cas9 to elicit efficient target knockout in a population of cells. In this study, we investigated the role of several key factors, including variation in target copy number, inherent potency of sgRNA guides, and expression level of Cas9 and sgRNA, in determining CRISPR knockout efficiency. Using isogenic, clonal cell lines with variable copy numbers of an EGFP transgene, we discovered that CRISPR knockout is relatively insensitive to target copy number, but is highly dependent on the potency of the sgRNA guide sequence. Kinetic analysis revealed that most target mutation occurs between 5 and 10 days following Cas9/sgRNA transduction, while sgRNAs with different potencies differ by their knockout time course and by their terminal-phase knockout efficiency. We showed that prolonged, low level expression of Cas9 and sgRNA often fails to elicit target mutation, particularly if the potency of the sgRNA is also low. Our findings provide new insights into the behavior of CRISPR/Cas9 in mammalian cells that could be used for future improvement of this platform. Published by Oxford University Press on behalf of Nucleic Acids Research 2017.

Assessment of anticoagulation treatments in non-valvular atrial fibrillation patients diagnosed in a basic health area.

PubMed

Aguilera Alcaraz, Beatriz M; Abellán Huerta, José; Carbayo Herencia, Julio Antonio; Ariza Copado, Consuelo; Hernández Menárguez, Fernando; Abellán Alemán, José

Atrial fibrillation (AF) is the most common cardiac arrhythmia. To assess the need for anticoagulation is essential for its management. Our objective was to investigate whether the indication of anticoagulation was adequate in patients diagnosed with non-valvular AF, given the CHA2-DS2-VASc scale, measuring the International Normalizad Ratio range (INR) in patients treated with anti-vitamin K drugs. This is an observational and cross sectional study. 232 patients with atrial fibrillation were included. We analyzed demographic, the CHA2-DS2-VASc and HAS-BLED variables, the treatment and INR values for 6 consequentive months. The confrontation of variables was performed using chi-square and Mantel-Haenzel test. The prevalence of AF was 1.05%. The 88.4% had CHA2-DS2-VASc ≥ 2. The 71.1% were taking anticoagulants, of which 58.2% were under antivitamin k. The 46.7% of patients taking antivitamin K, presented inadequate range of INR. There was a greater prescription of antivitamin k in patients with persistent or permanent AF compared to the paroxysmal form (62.8 vs. 37.2% p<.001). The use of drugs that increase bleeding was associated with a worse control of INR after adjustment for the main variables of clinical relevance (odds ratio 2.17 [1.02-4.59], p=.043). The level of anticoagulation with antivitamin K was inadequate in our sample, despite a proper follow up and adherence to treatment. Patients with paroxysmal AF received less antivitamin K than those with persistent/permanent AF. Copyright © 2017 Sociedad Española de Arteriosclerosis. Publicado por Elsevier España, S.L.U. All rights reserved.

Eye tracking a self-moved target with complex hand-target dynamics

PubMed Central

Landelle, Caroline; Montagnini, Anna; Madelain, Laurent

2016-01-01

Previous work has shown that the ability to track with the eye a moving target is substantially improved when the target is self-moved by the subject's hand compared with when being externally moved. Here, we explored a situation in which the mapping between hand movement and target motion was perturbed by simulating an elastic relationship between the hand and target. Our objective was to determine whether the predictive mechanisms driving eye-hand coordination could be updated to accommodate this complex hand-target dynamics. To fully appreciate the behavioral effects of this perturbation, we compared eye tracking performance when self-moving a target with a rigid mapping (simple) and a spring mapping as well as when the subject tracked target trajectories that he/she had previously generated when using the rigid or spring mapping. Concerning the rigid mapping, our results confirmed that smooth pursuit was more accurate when the target was self-moved than externally moved. In contrast, with the spring mapping, eye tracking had initially similar low spatial accuracy (though shorter temporal lag) in the self versus externally moved conditions. However, within ∼5 min of practice, smooth pursuit improved in the self-moved spring condition, up to a level similar to the self-moved rigid condition. Subsequently, when the mapping unexpectedly switched from spring to rigid, the eye initially followed the expected target trajectory and not the real one, thereby suggesting that subjects used an internal representation of the new hand-target dynamics. Overall, these results emphasize the stunning adaptability of smooth pursuit when self-maneuvering objects with complex dynamics. PMID:27466129

Quality of anticoagulation control and hemorrhage risk among African American and European American warfarin users.

PubMed

Limdi, Nita A; Brown, Todd M; Shendre, Aditi; Liu, Nianjun; Hill, Charles E; Beasley, Timothy M

2017-10-01

We evaluated whether percent time in target range (PTTR), risk of over-anticoagulation [international normalized ratio (INR)>4], and risk of hemorrhage differ by race. As PTTR is a strong predictor of hemorrhage risk, we also determined the influence of PTTR on the risk of hemorrhage by race. Among 1326 warfarin users, PTTR was calculated as the percentage of interpolated INR values within the target range of 2.0-3.0. PTTR was also categorized as poor (PTTR<60%), good (60≤PTTR<70%), or excellent (PTTR≥70%) anticoagulation control. Over-anticoagulation was defined as INR more than 4 and major hemorrhages included serious, life-threatening, and fatal bleeding episodes. Logistic regression and survival analyses were carried out to evaluate the association of race with PTTR (≥60 vs. <60) and major hemorrhages, respectively. Compared with African Americans, European Americans had higher PTTR (57.6 vs. 49.1%; P<0.0001) and were more likely to attain 60≤PTTR<70% (22.9 vs. 13.1%; P<0.001) or PTTR of at least 70% (26.9 vs. 18.2%; P=0.001). Older (>65 years) patients without venous thromboembolism indication and chronic kidney disease were more likely to attain PTTR of at least 60%. After accounting for clinical and genetic factors, and PTTR, African Americans had a higher risk of hemorrhage [hazard ratio (HR)=1.58; 95% confidence interval (CI): 1.04-2.41; P=0.034]. Patients with 60≤PTTR<70% (HR=0.62; 95% CI: 0.38-1.02; P=0.058) and PTTR of at least 70% (HR=0.27; 95% CI: 0.15-0.49; P<0.001) had a lower risk of hemorrhage compared with those with PTTR less than 60%. Despite the provision of warfarin management through anticoagulation clinics, African Americans achieve a lower overall PTTR and have a significantly higher risk of hemorrhage. Personalized medicine interventions tailored to African American warfarin users need to be developed.

Quality of warfarin control in atrial fibrillation patients in South East Queensland, Australia.

PubMed

Bernaitis, N; Badrick, T; Davey, A K; Anoopkumar-Dukie, S

2016-08-01

Warfarin is widely prescribed to decrease the risk of stroke in atrial fibrillation (AF) patients. Due to patient variability in response, regular monitoring is required, and time in therapeutic range (TTR) used to indicate quality of warfarin control with a TTR>60% is recommended. Recently, an Australian Government review of anticoagulants identified the need to establish current warfarin control and determine the potential place of the newer oral anticoagulants. To determine warfarin control by a pathology practice in Queensland, Australia and identify factors influencing TTR. Retrospective data were collected from Sullivan Nicolaides Pathology, a major pathology practice offering a warfarin care programme in Australia. Patients enrolled in their programme as of September 2014 were included in the study. TTR was calculated using INR test results, and test dates using the Rosendaal method with mean patient TTR were used for analysis and comparison. Exclusions were target therapeutic range outside 2.0-3.0, less than two INR tests and programme treatment time of less than 30 days. The eligible 3692 AF patients had 73.6% of INR tests within the therapeutic range. The mean TTR was 81%, with 97% of patients above a TTR of 60%. TTR was not significantly influenced by age, gender or socioeconomic factors. The observed mean TTR of over 80% is superior to the minimum recommended threshold of 60%. The TTR achieved by the Queensland pathology practice demonstrates that dedicated warfarin programmes can produce high-quality warfarin care, ensuring the full benefit of warfarin for Australian patients. © 2016 Royal Australasian College of Physicians.

Population-level impact of an accelerated HIV response plan to reach the UNAIDS 90-90-90 target in Côte d’Ivoire: Insights from mathematical modeling

PubMed Central

Diabaté, Souleymane; Alary, Michel; Diouf, Daouda; Abo, Kouamé; Boily, Marie-Claude

2017-01-01

Background National responses will need to be markedly accelerated to achieve the ambitious target of the Joint United Nations Programme on HIV/AIDS (UNAIDS). This target aims for 90% of HIV-positive individuals to be aware of their status, for 90% of those aware to receive antiretroviral therapy (ART), and for 90% of those on treatment to have a suppressed viral load by 2020, with each individual target reaching 95% by 2030. We aimed to estimate the impact of various treatment-as-prevention scenarios in Côte d’Ivoire, one of the countries with the highest HIV incidence in West Africa, with unmet HIV prevention and treatment needs, and where key populations are important to the broader HIV epidemic. Methods and findings An age-stratified dynamic model was developed and calibrated to epidemiological and programmatic data using a Bayesian framework. The model represents sexual and vertical HIV transmission in the general population, female sex workers (FSW), and men who have sex with men (MSM). We estimated the impact of scaling up interventions to reach the UNAIDS targets, as well as the impact of 8 other scenarios, on HIV transmission in adults and children, compared to our baseline scenario that maintains 2015 rates of testing, ART initiation, ART discontinuation, treatment failure, and levels of condom use. In 2015, we estimated that 52% (95% credible intervals: 46%–58%) of HIV-positive individuals were aware of their status, 72% (57%–82%) of those aware were on ART, and 77% (74%–79%) of those on ART were virologically suppressed. Reaching the UNAIDS targets on time would avert 50% (42%–60%) of new HIV infections over 2015–2030 compared to 30% (25%–36%) if the 90-90-90 target is reached in 2025. Attaining the UNAIDS targets in FSW, their clients, and MSM (but not in the rest of the population) would avert a similar fraction of new infections (30%; 21%–39%). A 25-percentage-point drop in condom use from the 2015 levels among FSW and MSM would

Population-level impact of an accelerated HIV response plan to reach the UNAIDS 90-90-90 target in Côte d'Ivoire: Insights from mathematical modeling.

PubMed

Maheu-Giroux, Mathieu; Vesga, Juan F; Diabaté, Souleymane; Alary, Michel; Baral, Stefan; Diouf, Daouda; Abo, Kouamé; Boily, Marie-Claude

2017-06-01

National responses will need to be markedly accelerated to achieve the ambitious target of the Joint United Nations Programme on HIV/AIDS (UNAIDS). This target aims for 90% of HIV-positive individuals to be aware of their status, for 90% of those aware to receive antiretroviral therapy (ART), and for 90% of those on treatment to have a suppressed viral load by 2020, with each individual target reaching 95% by 2030. We aimed to estimate the impact of various treatment-as-prevention scenarios in Côte d'Ivoire, one of the countries with the highest HIV incidence in West Africa, with unmet HIV prevention and treatment needs, and where key populations are important to the broader HIV epidemic. An age-stratified dynamic model was developed and calibrated to epidemiological and programmatic data using a Bayesian framework. The model represents sexual and vertical HIV transmission in the general population, female sex workers (FSW), and men who have sex with men (MSM). We estimated the impact of scaling up interventions to reach the UNAIDS targets, as well as the impact of 8 other scenarios, on HIV transmission in adults and children, compared to our baseline scenario that maintains 2015 rates of testing, ART initiation, ART discontinuation, treatment failure, and levels of condom use. In 2015, we estimated that 52% (95% credible intervals: 46%-58%) of HIV-positive individuals were aware of their status, 72% (57%-82%) of those aware were on ART, and 77% (74%-79%) of those on ART were virologically suppressed. Reaching the UNAIDS targets on time would avert 50% (42%-60%) of new HIV infections over 2015-2030 compared to 30% (25%-36%) if the 90-90-90 target is reached in 2025. Attaining the UNAIDS targets in FSW, their clients, and MSM (but not in the rest of the population) would avert a similar fraction of new infections (30%; 21%-39%). A 25-percentage-point drop in condom use from the 2015 levels among FSW and MSM would reduce the impact of reaching the UNAIDS targets

Preliminary clinical evaluation of a noninvasive device for the measurement of coagulability in the elderly.

PubMed

Lerman, Yaffa; Werber, Moshe M; Fine, Ilya; Kemelman, Polina

2011-01-01

The feasibility of the noninvasive assessment of blood 'coagulability' (the tendency to coagulate) has been tested by using a novel device, the Thrombo-Monitor. It monitors, by using the principles of near infra-red (NIR) dynamic light scattering, the tendency of blood to create clots. The Thrombo-Monitor observes the very initial changes of blood viscosity, which occurs due to the temporarily induced stasis of capillary blood of the finger. One hundred and fifteen patients aged >65 years (matched by age and sex) participated in the study. Patients were initially divided into four groups based on the patient's medical therapy. The study groups were: warfarin, enoxaparin, aspirin and/or clopidogrel, and a control group. The medications were given according to the patient's comorbidities (eg, atrial fibrillation [AF], status post pulmonary embolism [S/p PE], status post cerebrovascular accident [S/p CVA]). The Thrombo-Monitor Index (TMI) is a noninvasive index, derived on the basis of laboratory test results of international normalized ratio (INR) and prothrombin time (PT) values. For the group of patients who were treated only with warfarin, TMI was adjusted by using the jackknife statistical approach to create maximum correlation and linearity with INR and PT values that ranged from 1.1 to 5.0. For all warfarin patients (N = 35) the TMI was found to have a good correlation with INR and PT values (R(2) = 0.64, P < 0.00001); mean TMI = 1.86 (SD = 0.91); mean INR and PT = 2.3 (SD = 0.91). The calibration curve thus generated was used to calculate the TMI for all other groups: aspirin group, mean TMI = 1.3 (SD = 0.14, N = 23), corresponding approximately to INR and PT values of 1.036; enoxaparin group (N = 24), mean TMI = 1.34 (SD = 0.304), corresponding to mean INR and PT values of 1.07 (SD = 0.3); control group, INR and PT ≥ 1 (N = 32), mean TMI = 1.24 (SD = 0.32). R(2) of all control and warfarin patients (N = 67) was 0.55 (P < 0.00001). In summary, the newly

Phospholipase D and the maintenance of phosphatidic acid levels for regulation of mammalian target of rapamycin (mTOR).

PubMed

Foster, David A; Salloum, Darin; Menon, Deepak; Frias, Maria A

2014-08-15

Phosphatidic acid (PA) is a critical metabolite at the heart of membrane phospholipid biosynthesis. However, PA also serves as a critical lipid second messenger that regulates several proteins implicated in the control of cell cycle progression and cell growth. Three major metabolic pathways generate PA: phospholipase D (PLD), diacylglycerol kinase (DGK), and lysophosphatidic acid acyltransferase (LPAAT). The LPAAT pathway is integral to de novo membrane phospholipid biosynthesis, whereas the PLD and DGK pathways are activated in response to growth factors and stress. The PLD pathway is also responsive to nutrients. A key target for the lipid second messenger function of PA is mTOR, the mammalian/mechanistic target of rapamycin, which integrates both nutrient and growth factor signals to control cell growth and proliferation. Although PLD has been widely implicated in the generation of PA needed for mTOR activation, it is becoming clear that PA generated via the LPAAT and DGK pathways is also involved in the regulation of mTOR. In this minireview, we highlight the coordinated maintenance of intracellular PA levels that regulate mTOR signals stimulated by growth factors and nutrients, including amino acids, lipids, glucose, and Gln. Emerging evidence indicates compensatory increases in one source of PA when another source is compromised, highlighting the importance of being able to adapt to stressful conditions that interfere with PA production. The regulation of PA levels has important implications for cancer cells that depend on PA and mTOR activity for survival. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

Microtubule-Targeting Therapy for Prostate Cancer

DTIC Science & Technology

2007-02-01

that were done to achieve the above specific goals. 1. Biological effects of ribozyme -carrying adenoviruses that target stathmin mRNA in human...prostate cancer cells: A ribozyme is a small RNA molecule that acts stoichiometrically to cleave multiple target RNA molecules [1]. This unique ability...of a ribozyme to degrade multiple target RNA molecules is a more efficient approach for down regulating genes that are expressed at very high levels

Model for End-stage Liver Disease excluding INR (MELD-XI) score in critically ill patients: Easily available and of prognostic relevance.

PubMed

Wernly, Bernhard; Lichtenauer, Michael; Franz, Marcus; Kabisch, Bjoern; Muessig, Johanna; Masyuk, Maryna; Hoppe, Uta C; Kelm, Malte; Jung, Christian

2017-01-01

MELD-XI, an adapted version of Model for End-stage Liver Disease (MELD) score excluding INR, was reported to predict outcomes e.g. in patients with acute heart failure. We aimed to evaluate MELD-XI in critically ill patients admitted to an intensive care unit (ICU) for prognostic relevance. A total of 4381 medical patients (66±14 years, 2862 male) admitted to a German ICU between 2004 and 2009 were included and retrospectively investigated. Admission diagnoses were e.g. myocardial infarction (n = 2034), sepsis (n = 694) and heart failure (n = 688). We divided our patients in two cohorts basing on their MELD-XI score and evaluated the MELD-XI score for its prognostic relevance regarding short-term and long-term survival. Optimal cut-offs were calculated by means of the Youden-Index. Patients with a MELD-XI score >12 had pronounced laboratory signs of organ failure and more comorbidities. MELD-XI >12 was associated with an increase in short-term (27% vs 6%; HR 4.82, 95%CI 3.93-5.93; p<0.001) and long-term (HR 3.69, 95%CI 3.20-4.25; p<0.001) mortality. In a univariate Cox regression analysis for all patients MELD-XI was associated with increased long-term mortality (changes per score point: HR 1.06, 95%CI 1.05-1.07; p<0.001) and remained to be associated with increased mortality after correction in a multivariate regression analysis for renal failure, liver failure, lactate concentration, blood glucose concentration, oxygenation and white blood count (HR 1.04, 95%CI 1.03-1.06; p<0.001). Optimal cut-off for the overall cohort was 11 and varied remarkably depending on the admission diagnosis: myocardial infarction (9), pulmonary embolism (9), cardiopulmonary resuscitation (17) and pneumonia (17). We performed ROC-analysis and compared the AUC: SAPS2 (0.78, 95%CI 0.76-0.80; p<0.0001) and APACHE (0.76, 95%CI 0.74-0.78; p<0.003) score were superior to MELD-XI (0.71, 95%CI 0.68-0.73) for prediction of mortality. The easily calculable MELD-XI score is a robust and reliable

Personalising e-learning modules: targeting Rasmussen levels using XML.

PubMed

Renard, J M; Leroy, S; Camus, H; Picavet, M; Beuscart, R

2003-01-01

The development of Internet technologies has made it possible to increase the number and the diversity of on-line resources for teachers and students. Initiatives like the French-speaking Virtual Medical University Project (UMVF) try to organise the access to these resources. But both teachers and students are working on a partly redundant subset of knowledge. From the analysis of some French courses we propose a model for knowledge organisation derived from Rasmussen's stepladder. In the context of decision-making Rasmussen has identified skill-based, rule-based and knowledge-based levels for the mental process. In the medical context of problem-solving, we apply these three levels to the definition of three students levels: beginners, intermediate-level learners, experts. Based on our model, we build a representation of the hierarchical structure of data using XML language. We use XSLT Transformation Language in order to filter relevant data according to student level and to propose an appropriate display on students' terminal. The model and the XML implementation we define help to design tools for building personalised e-learning modules.

Targeting malignant mitochondria with therapeutic peptides

PubMed Central

Constance, Jonathan E; Lim, Carol S

2013-01-01

The current status of peptides that target the mitochondria in the context of cancer is the focus of this review. Chemotherapy and radiotherapy used to kill tumor cells are principally mediated by the process of apoptosis that is governed by the mitochondria. The failure of anticancer therapy often resides at the level of the mitochondria. Therefore, the mitochondrion is a key pharmacological target in cancer due to many of the differences that arise between malignant and healthy cells at the level of this ubiquitous organelle. Additionally, targeting the characteristics of malignant mitochondria often rely on disruption of protein–protein interactions that are not generally amenable to small molecules. We discuss anticancer peptides that intersect with pathological changes in the mitochondrion. PMID:22946430

Cost of treatment for head and neck cancer in India

PubMed Central

Chauhan, Akashdeep Singh; Ghoshal, Sushmita; Verma, Roshan; Oinam, Arun S.

2018-01-01

There are no published data on the cost of cancer treatment for guiding reimbursement decisions in India. The present study was designed to estimate the cost of treating head and neck cancer (HNC) with the aim of determining package rates. The present study was undertaken in the Departments of Radiotherapy and Otolaryngology of a large tertiary care hospital in North India. Economic health system costs incurred were assessed using a bottom-up methodology. Data on all resources–capital or recurrent, incurred on the delivery of HNC treatment were collected from April 2014 to March 2015. Following the cost-of-illness approach, patients were interviewed to elicit out-of-pocket (OOP) expenditure. A total of INR 40,993,017 (USD 0.67 million) was spent on radiotherapy care for treating HNC during 1 year. Salaries constituted the major component (42.6%) of this cost, followed by equipment/furniture (29%), space rent (20.7%), overheads and consumables (7.7%). In addition, INR 47,191 (USD 773) per HNC patient was spent on the surgery. Furthermore, patients spent an average amount ranging from INR 12,575 (USD 206) to INR 65,257 (USD 1069) on the different treatment therapies. In terms of package rates, cobalt radiotherapy alone was the cheapest (INR 38,714, USD 634), while intensity modulated radiotherapy (IMRT) was most expensive (INR 192,914, USD 3161). The estimates from the present study could be used for developing package rates under various publicly financed health insurance schemes as well as for the planning for creation of new cancer centres. PMID:29324861

Increased serum miR-300 level serves as a potential biomarker of lipopolysaccharide-induced lung injury by targeting IκBα.

PubMed

Cao, Wei; Dai, Hong; Yang, Shengqing; Liu, Zhijun; Yi Chen, Qian

2017-01-10

MicroRNAs (miRs) are reported to play key roles in various disease models. In this study, the functional role of miR-300 in the regulation of lung injury was explored to assess the feasibility of serum miR-300 as a potential biomarker for lung injury. Firstly, the expression of miR-300 was studied in the serum of 50 lung injury patients and 50 healthy controls. And the expression of miR-300 was also explored in the serum and lung tissues of mouse models. To further explore the possible mechanism in which miR-300 may contribute to lung injury, the target genes of miR-300 were predicted by TargetScan and validated using dual luciferase reporter assay. Moreover, the expression of inflammation factors was studied after transfection of miR-300 mimics and inhibitors into A549 cells. Here, we first identified that the level of miR-300 was significantly upregulated in the blood samples of acute lung injury patients compared with healthy control. Meanwhile, miR-300 was also found to be enhanced in the blood samples and lung tissues of LPS-induced mouse models. Further study showed that miR-300 significantly suppressed the expression of IκBα and luciferase reporter assay showed that IκBα was a target gene of miR-300. More importantly, the levels of inflammatory factors, such as TNFα, COX-2, iNOS, IL-6 and IL8, were significantly upregulated accompanied by overexpression of miR-300 in A549 cells. In summary, enhanced miR-300 expression in the peripheral blood contributed to the lung injury mainly by inhibiting the expression of IκBα.

Educational Level, Anticoagulation Quality, and Clinical Outcomes in Elderly Patients with Acute Venous Thromboembolism: A Prospective Cohort Study.

PubMed

Hofmann, Eveline; Faller, Nicolas; Limacher, Andreas; Méan, Marie; Tritschler, Tobias; Rodondi, Nicolas; Aujesky, Drahomir

2016-01-01

Whether the level of education is associated with anticoagulation quality and clinical outcomes in patients with acute venous thromboembolism (VTE) is uncertain. We thus aimed to investigate the association between educational level and anticoagulation quality and clinical outcomes in elderly patients with acute VTE. We studied 817 patients aged ≥65 years with acute VTE from a Swiss prospective multicenter cohort study (09/2009-12/2013). We defined three educational levels: 1) less than high school, 2) high school, and 3) post-secondary degree. The primary outcome was the anticoagulation quality, expressed as the percentage of time spent in the therapeutic INR range (TTR). Secondary outcomes were the time to a first recurrent VTE and major bleeding. We adjusted for potential confounders and periods of anticoagulation. Overall, 56% of patients had less than high school, 25% a high school degree, and 18% a post-secondary degree. The mean percentage of TTR was similar across educational levels (less than high school, 61%; high school, 64%; and post-secondary, 63%; P = 0.36). Within three years of follow-up, patients with less than high school, high school, and a post-secondary degree had a cumulative incidence of recurrent VTE of 14.2%, 12.9%, and 16.4%, and a cumulative incidence of major bleeding of 13.3%, 15.1%, and 15.4%, respectively. After adjustment, educational level was neither associated with anticoagulation quality nor with recurrent VTE or major bleeding. In elderly patients with VTE, we did not find an association between educational level and anticoagulation quality or clinical outcomes.

Target prioritization and strategy selection for active case-finding of pulmonary tuberculosis: a tool to support country-level project planning.

PubMed

Nishikiori, Nobuyuki; Van Weezenbeek, Catharina

2013-02-02

Despite the progress made in the past decade, tuberculosis (TB) control still faces significant challenges. In many countries with declining TB incidence, the disease tends to concentrate in vulnerable populations that often have limited access to health care. In light of the limitations of the current case-finding approach and the global urgency to improve case detection, active case-finding (ACF) has been suggested as an important complementary strategy to accelerate tuberculosis control especially among high-risk populations. The present exercise aims to develop a model that can be used for county-level project planning. A simple deterministic model was developed to calculate the number of estimated TB cases diagnosed and the associated costs of diagnosis. The model was designed to compare cost-effectiveness parameters, such as the cost per case detected, for different diagnostic algorithms when they are applied to different risk populations. The model was transformed into a web-based tool that can support national TB programmes and civil society partners in designing ACF activities. According to the model output, tuberculosis active case-finding can be a costly endeavor, depending on the target population and the diagnostic strategy. The analysis suggests the following: (1) Active case-finding activities are cost-effective only if the tuberculosis prevalence among the target population is high. (2) Extensive diagnostic methods (e.g. X-ray screening for the entire group, use of sputum culture or molecular diagnostics) can be applied only to very high-risk groups such as TB contacts, prisoners or people living with human immunodeficiency virus (HIV) infection. (3) Basic diagnostic approaches such as TB symptom screening are always applicable although the diagnostic yield is very limited. The cost-effectiveness parameter was sensitive to local diagnostic costs and the tuberculosis prevalence of target populations. The prioritization of appropriate target

Early and late effects of coumarin therapy started before percutaneous coronary intervention: Clinical, angiographic and cost-effective outcome of the Balloon Angioplasty and Anticoagulation Study (BAAS).

PubMed

Ten Berg, J M; Kelder, J C; Suttorp, M J; Mast, E G; Bal, E T; Ernst, J M P G; Plokker, H W M

2002-05-01

Coronary angioplasty frequently creates a thrombogenic surface with subsequent mural thrombosis that may lead to acute complications and possibly stimulates the development of restenosis. Whether coumarins can prevent these complications is unclear. In the Balloon Angioplasty and Anticoagulation Study (BAAS), the effect of coumarins started before the procedure on early and late outcome was studied. Patients were randomised to aspirin only or to aspirin plus coumarins. Half of the patients were randomised to undergo six-month angiographic follow-up. Study medication was started one week before coronary angioplasty and the target international normalised ratio (INR) was 2.1-4.8 during angioplasty and six-month follow-up. 'Optimal' anticoagulation was defined as an INR in the target range for at least 70% of the follow-up time. In addition, cost-effectiveness of coumarin treatment was measured. At one year death, myocardial infarction, target-lesion revascularisation and stroke were observed in 14.3% of the 530 patients randomised to aspirin plus coumarin versus in 20.3% of the 528 patients randomised to aspirin alone (relative risk 0.71; 95% CI 0.54-0.93). The incidence of major bleedings and false aneurysms during hospitalisation was 3.2% and 1.0%, respectively, (relative risk 3.39; 95% CI 1.26-9.11). Optimal anticoagulation was an independent predictor of late thrombotic events (relative risk, 0.33; 95% CI, 0.19-0.57). Quantitative coronary analysis was performed of 301 lesions in the ASA group and of 297 lesions in the coumarin group. At six months, the minimal luminal diameter was similar in the ASA and coumarin group. However, optimal anticoagulation was an independent predictor of angiographic outcome at six months. Optimal anticoagulation led to a 0.21 mm (95% CI: 0.05-0.37) larger MLD as compared with suboptimal anticoagulation whereas aspirin use led to a 0.12 mm (95% CI -0.28-0.04) smaller MLD. When including all costs, the savings associated with coumarin

Elevated International Normalized Ratio in a Patient Taking Warfarin and Mauby: A Case Report.

PubMed

Sorbera, Maria; Joseph, Tina; DiGregorio, Robert V

2017-10-01

We describe a 70-year-old Haitian man who had been taking warfarin for 5 years for atrial fibrillation and pulmonary hypertension. This patient had his international normalized ratio (INR) checked in the pharmacist-run anticoagulation clinic and was followed monthly. Prior to the interaction, his INR was therapeutic for 5 months while taking warfarin 10.5 mg/d. The patient presented with an INR > 8.0. Patient held 4 days of warfarin and restarted on warfarin 8.5 mg/d. Two weeks later, his INR was 2.5. After continuing dose, patient presented 2 weeks later and INR was 4.8. Upon further questioning, the patient stated he recently began ingesting mauby. Mauby is a bitter dark liquid extracted from the bark of the mauby tree that is commonly used in the Caribbean population as a folk remedy with many health benefits. This case report illustrates that mauby may have a probable drug-herb interaction (Naranjo Algorithm Score of 6) when given with warfarin. There is a lack of published literature and unclear information on the Internet describing the interaction of mauby and warfarin. Health professionals should be cautious regarding interactions between warfarin and mauby until the interaction is fully elucidated.

Dental postoperative bleeding complications in patients with suspected and documented liver disease.

PubMed

Hong, C H; Scobey, M W; Napenas, J J; Brennan, M T; Lockhart, P B

2012-10-01

The aims of this study were to determine the frequency of bleeding complications following dental procedures in patients with known or suspected chronic liver disease and whether international normalized ratio (INR) determination could aid in predicting bleeding complications in these patients. We identified 90 patients (mean age: 51 ± 9 years) in this retrospective chart review. Sixty-nine patients had a known history of chronic liver disease and 21 had suspected chronic liver disease. Descriptive statistics were determined. Independent sample t-test and one-way variance test were utilized for continuous variables and chi-square test for dichotomous variables. The mean INR value for all patients was 1.2 ± 0.3. The INR value was significantly associated with the diagnosis of liver cirrhosis, the diagnoses of Hepatitis B and C together, the presence of ascites alone, and the number of clinical signs and symptoms (i.e. ascites, jaundice and encephalopathy) present. Nine patients with INR values between 1.5 and 2 underwent invasive dental procedures without postoperative bleeding complications. There were no episodes of postoperative bleeding in patients. The findings suggest that clinicians should not rely solely on an INR value to predict post-procedure bleeding in patients with liver disease. © 2012 John Wiley & Sons A/S.

Criteria for training and accreditation in Interventional Neuroradiology-Neurointervention, approved by the Spanish Group of Interventional Neuroradiology (GENI), the Spanish Society of Neuroradiology (SENR), the Spanish Group of Cerebrovascular Diseases (GEECV), the Spanish Society of Neurology (SEN), and the vascular disease specialists in the Spanish Society of Neurosurgery (SENEC). Requirements for accreditation in Interventional Neuroradiology-Neurointervention for institutions and specialists.

PubMed

Fortea, F; Masjuan, J; Arikán-Abello, F; Rovira, A; González, A; Arenillas, J; Fernández Alen, J; Gállego, J

2017-03-01

The development of endovascular techniques has put Interventional Neuroradiology (INR) as the first-option treatment in the majority of vascular diseases of the central nervous system. Scientific societies in developed countries have created standard procedures for training and accreditation for a safe practice in these procedures. In Spain, we are waiting for the development of the legislation on the accreditation for specialists which will establish the official formative model to achieve an accreditation in INR. Until this moment comes, it is necessary to establish standards that define desirable minimums for the formative period in INR. Radiology specialists as well as neurologists and neurosurgeons will have access to INR accreditation. Specific requirements for the hospitals that wish to offer this technique and training should also be defined. The Spanish Group of Interventional Neuroradiology (GENI), the Spanish Society of Neuroradiology (SENR), the Spanish Group of Cerebrovascular Diseases (GEECV), the Spanish Society of Neurology (SEN) and the Spanish Society of Neurosurgery (SENEC) have approved the content of this document and will create a committee in order to put into practice the accreditation of formative centres and INR specialists. Copyright © 2016 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.

The Risk of Overanticoagulation with Antibiotic Use in Outpatients on Stable Warfarin Regimens

PubMed Central

Glasheen, Jeffrey J; Fugit, Randolph V; Prochazka, Allan V

2005-01-01

BACKGROUND Medication interactions account for a significant proportion of overanticoagulation in warfarin users. However, little is known about the incidence or degree of interaction with commonly used oral antibiotics. OBJECTIVE To investigate the incidence and degree of overanticoagulation associated with commonly used oral antibiotics. DESIGN Retrospective cohort study of patients using warfarin who initiated an antibiotic (azithromycin, levofloxacin, or trimethoprim/sulfamethoxazole (TMP/SMX)) or terazosin for clinical indications between January 1998 and December 2002. The incidence of international normalized ratio (INR) elevation and the degree of change and bleeding events after institution of either medication type was recorded. SUBJECTS Patients at a university-affiliated Veteran's Affairs Medical Center. RESULTS The mean change in INR was −0.15 for terazosin, 0.51 for azithromycin, 0.85 for levofloxacin, and 1.76 for TMP/SMX. These mean INR changes in the antibiotic groups were all statistically different from the terazosin group. The incidence of supratherapeutic INR was 5% for terazosin, 31% for azithromycin, 33% for levofloxacin, and 69% for TMP/SMX. The incidence of absolute INR >4.0 was 0% for terazosin, 16% for azithromycin, 19% for levofloxacin, and 44% for TMP/SMX. CONCLUSIONS Among acutely ill outpatients, oral antibiotics (azithromycin, levofloxacin, and TMP/SMX) increase the incidence and degree of overanticoagulation. PMID:16050864

Cryogenic target system for hydrogen layering

DOE PAGES

Parham, T.; Kozioziemski, B.; Atkinson, D.; ...

2015-11-24

Here, a cryogenic target positioning system was designed and installed on the National Ignition Facility (NIF) target chamber. This instrument incorporates the ability to fill, form, and characterize the NIF targets with hydrogen isotopes needed for ignition experiments inside the NIF target bay then transport and position them in the target chamber. This effort brought to fruition years of research in growing and metrologizing high-quality hydrogen fuel layers and landed it in an especially demanding operations environment in the NIF facility. D-T (deuterium-tritium) layers for NIF ignition experiments have extremely tight specifications and must be grown in a very highlymore » constrained environment: a NIF ignition target inside a cryogenic target positioner inside the NIF target bay. Exquisite control of temperature, pressure, contaminant level, and thermal uniformity are necessary throughout seed formation and layer growth to create an essentially-groove-free single crystal layer.« less

Staufen2 regulates neuronal target RNAs.

PubMed

Heraud-Farlow, Jacki E; Sharangdhar, Tejaswini; Li, Xiao; Pfeifer, Philipp; Tauber, Stefanie; Orozco, Denise; Hörmann, Alexandra; Thomas, Sabine; Bakosova, Anetta; Farlow, Ashley R; Edbauer, Dieter; Lipshitz, Howard D; Morris, Quaid D; Bilban, Martin; Doyle, Michael; Kiebler, Michael A

2013-12-26

RNA-binding proteins play crucial roles in directing RNA translation to neuronal synapses. Staufen2 (Stau2) has been implicated in both dendritic RNA localization and synaptic plasticity in mammalian neurons. Here, we report the identification of functionally relevant Stau2 target mRNAs in neurons. The majority of Stau2-copurifying mRNAs expressed in the hippocampus are present in neuronal processes, further implicating Stau2 in dendritic mRNA regulation. Stau2 targets are enriched for secondary structures similar to those identified in the 3' UTRs of Drosophila Staufen targets. Next, we show that Stau2 regulates steady-state levels of many neuronal RNAs and that its targets are predominantly downregulated in Stau2-deficient neurons. Detailed analysis confirms that Stau2 stabilizes the expression of one synaptic signaling component, the regulator of G protein signaling 4 (Rgs4) mRNA, via its 3' UTR. This study defines the global impact of Stau2 on mRNAs in neurons, revealing a role in stabilization of the levels of synaptic targets. Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.

[Hereditary heterozygous factor VII deficiency in patients undergoing surgery : Clinical relevance].

PubMed

Woehrle, D; Martinez, M; Bolliger, D

2016-10-01

A hereditary deficiency in coagulation factor VII (FVII) may affect the international normalized ratio (INR) value. However, FVII deficiency is occasionally associated with a tendency to bleed spontaneously. We hypothesized that perioperative substitution with coagulation factor concentrates might not be indicated in most patients. In this retrospective data analysis, we included all patients with hereditary heterozygous FVII deficiency who underwent surgical procedures at the University Hospital Basel between December 2010 and November 2015. In addition, by searching the literature, we identified publications reporting patients with FVII deficiency undergoing surgical procedures without perioperative substitution. We identified 22 patients undergoing 46 surgical procedures, resulting in a prevalence of 1:1500-2000. Coagulation factor concentrates were administered during the perioperative period in 15 procedures (33 %), whereas in the other 31 procedures (66 %), FVII deficiency was not substituted. No postoperative bleeding or thromboembolic events were reported. In addition, we found no differences in pre- and postoperative hemoglobin and coagulation parameters, with the exception of an improved postoperative INR value in the substituted group. In the literature review, we identified five publications, including 125 patients with FVII deficiency, undergoing 213 surgical procedures with no perioperative substitution. Preoperative substitution using coagulation factor concentrates does not seem to be mandatory in patients with an FVII level ≥15 %. For decision-making on preoperative substitution, patient history of an increased tendency to bleed may be more important than the FVII level or increased INR value.

Ex vivo evaluation of 4 different viscoelastic assays for detecting moderate to severe coagulopathy during liver transplantation.

PubMed

Abuelkasem, Ezeldeen; Mazzeffi, Michael A; Lu, Shu Yang; Planinsic, Raymond M; Sakai, Tetsuro; Tanaka, Kenichi A

2016-04-01

Prolonged prothrombin time (PT) and its ratio are routinely used for the assessment of candidates for liver transplantation (LT), but intraoperative coagulation management of transfusion is hindered by its long turnaround time. Abnormal reaction time (R time) on thromboelastography (TEG) or clotting time (CT) of rotational thromboelastometry (ROTEM) are presumably an alternative, but there is a paucity of clinical data on abnormal R time/CT values compared to PT during LT. After receiving institutional review board approval and informed consent, we obtained blood samples from 36 LT patients for international normalized ratio (INR), factor (F) X level, and viscoelastic tests (EXTEM/INTEM and kaolin/rapid TEG) at baseline and 30 minutes after graft reperfusion. Receiver operating characteristic (ROC) curves were calculated for INR > 1.5 and viscoelastic R time/CT thresholds to assess the ability to diagnose FX deficiency at the moderate (<50%) or severe (<35%) level. The FX deficiency data were calculated using cutoff values of INR (>1.5) and abnormal R time/CT for TEG and ROTEM. Tissue factor (TF)-activated INR and EXTEM-CT performed well in diagnosing FX below 50%, but rapid TEG with combined TF and kaolin activators failed. Improved performance of INTEM-CT in diagnosing FX below 35% underlies multifactorial deficiency involving both intrinsic and common pathways. In conclusion, the differences among different viscoelastic tests and clinical situations should be carefully considered when they are used to guide transfusion during LT. © 2015 American Association for the Study of Liver Diseases.

A biochemical approach to identifying microRNA targets

PubMed Central

Karginov, Fedor V.; Conaco, Cecilia; Xuan, Zhenyu; Schmidt, Bryan H.; Parker, Joel S.; Mandel, Gail; Hannon, Gregory J.

2007-01-01

Identifying the downstream targets of microRNAs (miRNAs) is essential to understanding cellular regulatory networks. We devised a direct biochemical method for miRNA target discovery that combined RNA-induced silencing complex (RISC) purification with microarray analysis of bound mRNAs. Because targets of miR-124a have been analyzed, we chose it as our model. We honed our approach both by examining the determinants of stable binding between RISC and synthetic target RNAs in vitro and by determining the dependency of both repression and RISC coimmunoprecipitation on miR-124a seed sites in two of its well characterized targets in vivo. Examining the complete spectrum of miR-124 targets in 293 cells yielded both a set that were down-regulated at the mRNA level, as previously observed, and a set whose mRNA levels were unaffected by miR-124a. Reporter assays validated both classes, extending the spectrum of mRNA targets that can be experimentally linked to the miRNA pathway. PMID:18042700

Burglar Target Selection

PubMed Central

Townsley, Michael; Bernasco, Wim; Ruiter, Stijn; Johnson, Shane D.; White, Gentry; Baum, Scott

2015-01-01

Objectives: This study builds on research undertaken by Bernasco and Nieuwbeerta and explores the generalizability of a theoretically derived offender target selection model in three cross-national study regions. Methods: Taking a discrete spatial choice approach, we estimate the impact of both environment- and offender-level factors on residential burglary placement in the Netherlands, the United Kingdom, and Australia. Combining cleared burglary data from all study regions in a single statistical model, we make statistical comparisons between environments. Results: In all three study regions, the likelihood an offender selects an area for burglary is positively influenced by proximity to their home, the proportion of easily accessible targets, and the total number of targets available. Furthermore, in two of the three study regions, juvenile offenders under the legal driving age are significantly more influenced by target proximity than adult offenders. Post hoc tests indicate the magnitudes of these impacts vary significantly between study regions. Conclusions: While burglary target selection strategies are consistent with opportunity-based explanations of offending, the impact of environmental context is significant. As such, the approach undertaken in combining observations from multiple study regions may aid criminology scholars in assessing the generalizability of observed findings across multiple environments. PMID:25866418

Optimum viewing distance for target acquisition

NASA Astrophysics Data System (ADS)

Holst, Gerald C.

2015-05-01

Human visual system (HVS) "resolution" (a.k.a. visual acuity) varies with illumination level, target characteristics, and target contrast. For signage, computer displays, cell phones, and TVs a viewing distance and display size are selected. Then the number of display pixels is chosen such that each pixel subtends 1 min-1. Resolution of low contrast targets is quite different. It is best described by Barten's contrast sensitivity function. Target acquisition models predict maximum range when the display pixel subtends 3.3 min-1. The optimum viewing distance is nearly independent of magnification. Noise increases the optimum viewing distance.

Maximizing in vivo target clearance by design of pH-dependent target binding antibodies with altered affinity to FcRn.

PubMed

Yang, Danlin; Giragossian, Craig; Castellano, Steven; Lasaro, Marcio; Xiao, Haiguang; Saraf, Himanshu; Hess Kenny, Cynthia; Rybina, Irina; Huang, Zhong-Fu; Ahlberg, Jennifer; Bigwarfe, Tammy; Myzithras, Maria; Waltz, Erica; Roberts, Simon; Kroe-Barrett, Rachel; Singh, Sanjaya

2017-10-01

Antibodies with pH-dependent binding to both target antigens and neonatal Fc receptor (FcRn) provide an alternative tool to conventional neutralizing antibodies, particularly for therapies where reduction in antigen level is challenging due to high target burden. However, the requirements for optimal binding kinetic framework and extent of pH dependence for these antibodies to maximize target clearance from circulation are not well understood. We have identified a series of naturally-occurring high affinity antibodies with pH-dependent target binding properties. By in vivo studies in cynomolgus monkeys, we show that pH-dependent binding to the target alone is not sufficient for effective target removal from circulation, but requires Fc mutations that increase antibody binding to FcRn. Affinity-enhanced pH-dependent FcRn binding that is double-digit nM at pH 7.4 and single-digit nM at pH 6 achieved maximal target reduction when combined with similar target binding affinities in reverse pH directions. Sustained target clearance below the baseline level was achieved 3 weeks after single-dose administration at 1.5 mg/kg. Using the experimentally derived mechanistic model, we demonstrate the essential kinetic interplay between target turnover and antibody pH-dependent binding during the FcRn recycling, and identify the key components for achieving maximal target clearance. These results bridge the demand for improved patient dosing convenience with the "know-how" of therapeutic modality by design.

The effect of amiodarone on warfarin anticoagulation: a register-based nationwide cohort study involving the Swedish population.

PubMed

Holm, J; Lindh, J D; Andersson, M L; Mannheimer, B

2017-03-01

Essentials Data on the effect of introducing amiodarone in patients already using warfarin regime are scarce. Information on 754 patients was extracted from three nationwide registers in Sweden. With amiodaron, 37% of patients had an international normalized ratio (INR) over 3.0 To avoid bleeding, the initiation of amiodarone should be accompanied by closer INR monitoring. Background Data indicate that the interaction between warfarin and amiodarone results in an increased warfarin effect. There are several large, well-performed studies using genetic and clinical factors such as co-medication to predict an adequate starting dose of warfarin. However, longitudinal data on the effect of introducing amiodarone in patients on an ongoing warfarin regime are more scarce. Objectives An investigation of how initiation of amiodarone affects the anticoagulant effect and dosing of warfarin, using data from three nationwide registries. Patients/Methods In a retrospective cohort study including 754 patients, warfarin doses were compared between two 4-week periods, before and 18-21 weeks after initiating co-treatment with amiodarone. In addition, warfarin doses and international normalized ratio (INR) values were calculated week-by-week after the initiation of amiodarone. Results The initiation of amiodarone increased the mean INR from 2.6 to 3.1. The proportion of patients with a supratherapeutic INR over 3.0 and 4.0 increased from 12% to 37% and 0.9% to 5.5%, respectively. The subsequent mean decrease in warfarin dose was 24.6% (95% confidence interval [CI], 23.5, 25.6). The frequency of INR monitoring within 1 and 2 weeks after initiation of amiodarone was 67% and 90%. Conclusions Although warfarin doses in most patients were within the therapeutic range, more than one in three patients initiating co-treatment with amiodarone were exposed to a supratherapeutic anticoagulative effect within 3 weeks. In order to further avoid severe unnecessary bleeding, the initiation of

Economic evaluation of seizures associated with solitary cysticercus granuloma.

PubMed

Murthy, J M K; Rajshekar, G

2007-01-01

Patients with solitary cysticercus granuloma (SCG) develop acute symptomatic seizures because of the inflammatory response of the brain and the seizures are self-limiting. Thus seizure disorder associated with SCG provides a good model to study the total cost of illness (COI). COI of new-onset seizures associated with SCG was studied in 59 consecutive patients registered at the epilepsy clinic. Direct treatment-related costs and indirect costs, man-days lost and wages lost were evaluated. The relative cost was calculated as the percentage of per capita gross national product (GNP) at current prices for the year 1997-1998. The total COI, for treating seizure disorder associated with SCG per the period of CT resolution of the lesion per patient was INR 7273.7 (US$ 174.66, I$ 943.16) and he/she would be spending 50.9% of per capita GNP The direct cost per patient was INR 5916 (US$ 137.14, 41.4% of per capita GNP). If the patient had received only AEDs for the period of resolution of CT lesion, the cost would be INR 5702.48 (US$132.2, 40% of per capita GNP). The extra expenditure on albendazole and steroid was INR 213.72 (US$ 4.95), 3.6% of the total direct cost and 20.7% of the medication cost. Indirect cost (average wage loss) per patient was INR 1312.7 (US$ 30.42) and it accounted for 9% of per capita GNP. The one-time expenditure at present costs (adjusted for inflation) to the nation to treat all the prevalence cases is to the tune of INR 1.184 billion (US$ 2.605) and 0.0037% of GNP. This study suggests that seizure disorder associated with SCG, a potentially preventable disorder, is a good model to study the total COI. The one-time expenditure at present costs to the nation to treat all the prevalence cases of seizure disorder associated with SCG is to the tune of INR 1.184 billion (US$ 2.605 million) and 0.0037% of GNP.

Assessing the relative potency of (S)- and (R)-warfarin with a new PK-PD model, in relation to VKORC1 genotypes.

PubMed

Ferrari, Myriam; Pengo, Vittorio; Barolo, Massimiliano; Bezzo, Fabrizio; Padrini, Roberto

2017-06-01

The purpose of this study is to develop a new pharmacokinetic-pharmacodynamic (PK-PD) model to characterise the contribution of (S)- and (R)-warfarin to the anticoagulant effect on patients in treatment with rac-warfarin. Fifty-seven patients starting warfarin (W) therapy were studied, from the first dose and during chronic treatment at INR stabilization. Plasma concentrations of (S)- and (R)-W and INRs were measured 12, 36 and 60 h after the first dose and at steady state 12-14 h after dosing. Patients were also genotyped for the G>A VKORC1 polymorphism. The PK-PD model assumed a linear relationship between W enantiomer concentration and INR and included a scaling factor k to account for a different potency of (R)-W. Two parallel compartment chains with different transit times (MTT 1 and MTT 2 ) were used to model the delay in the W effect. PD parameters were estimated with the maximum likelihood approach. The model satisfactorily described the mean time-course of INR, both after the initial dose and during long-term treatment. (R)-W contributed to the rac-W anticoagulant effect with a potency of about 27% that of (S)-W. This effect was independent of VKORC1 genotype. As expected, the slope of the PK/PD linear correlation increased stepwise from GG to GA and from GA to AA VKORC1 genotype (0.71, 0.90 and 1.49, respectively). Our PK-PD linear model can quantify the partial pharmacodynamic activity of (R)-W in patients contemporaneously exposed to therapeutic (S)-W plasma levels. This concept may be useful in improving the performance of future algorithms aiming at identifying the most appropriate W maintenance dose.

Abnormalities of laboratory coagulation tests versus clinically evident coagulopathic bleeding: results from the prehospital resuscitation on helicopters study (PROHS).

PubMed

Chang, Ronald; Fox, Erin E; Greene, Thomas J; Swartz, Michael D; DeSantis, Stacia M; Stein, Deborah M; Bulger, Eileen M; Melton, Sherry M; Goodman, Michael D; Schreiber, Martin A; Zielinski, Martin D; O'Keeffe, Terence; Inaba, Kenji; Tomasek, Jeffrey S; Podbielski, Jeanette M; Appana, Savitri; Yi, Misung; Johansson, Pär I; Henriksen, Hanne H; Stensballe, Jakob; Steinmetz, Jacob; Wade, Charles E; Holcomb, John B

2018-04-01

Laboratory-based evidence of coagulopathy (LC) is observed in 25-35% of trauma patients, but clinically-evident coagulopathy (CC) is not well described. Prospective observational study of adult trauma patients transported by helicopter from the scene to nine Level 1 trauma centers in 2015. Patients meeting predefined highest-risk criteria were divided into CC+ (predefined as surgeon-confirmed bleeding from uninjured sites or injured sites not controllable by sutures) or CC-. We used a mixed-effects, Poisson regression with robust error variance to test the hypothesis that abnormalities on rapid thrombelastography (r-TEG) and international normalized ratio (INR) were independently associated with CC+. Of 1,019 highest-risk patients, CC+ (n=41, 4%) were more severely injured (median ISS 32 vs 17), had evidence of LC on r-TEG and INR, received more transfused blood products at 4 hours (37 vs 0 units), and had greater 30-day mortality (59% vs 12%) than CC- (n=978, 96%). The overall incidence of LC was 39%. 30-day mortality was 22% vs 9% in those with and without LC. In two separate models, r-TEG K-time >2.5 min (RR 1.3, 95% CI 1.1-1.7), r-TEG mA <55 mm (RR 2.5, 95% CI 2.0-3.2), platelet count <150 x 10 9 /L (RR 1.2, 95% CI 1.1-1.3), and INR >1.5 (RR 5.4, 95% CI 1.8-16.3) were independently associated with CC+. A combined regression model was not generated because too few patients underwent both r-TEG and INR. CC was rare compared to LC. CC was associated with poor outcomes and impairment of both clotting factor and platelet-mediated coagulation components. Copyright © 2017 Elsevier Inc. All rights reserved.

Results of the performance verification of the CoaguChek XS system.

PubMed

Plesch, W; Wolf, T; Breitenbeck, N; Dikkeschei, L D; Cervero, A; Perez, P L; van den Besselaar, A M H P

2008-01-01

This is the first paper reporting a performance verification study of a point-of-care (POC) monitor for prothrombin time (PT) testing according to the requirements given in chapter 8 of the International Organization for Standardization (ISO) 17593:2007 standard "Clinical laboratory testing and in vitro medical devices - Requirements for in vitro monitoring systems for self-testing of oral anticoagulant therapy". The monitor under investigation was the new CoaguChek XS system which is designed for use in patient self testing. Its detection principle is based on the amperometric measurement of the thrombin activity generated by starting the coagulation cascade using a recombinant human thromboplastin. The system performance verification study was performed at four study centers using venous and capillary blood samples on two test strip lots. Laboratory testing was performed from corresponding frozen plasma samples with six commercial thromboplastins. Samples from 73 normal donors and 297 patients on oral anticoagulation therapy were collected. Results were assessed using a refined data set of 260 subjects according to the ISO 17593:2007 standard. Each of the two test strip lots met the acceptance criteria of ISO 17593:2007 versus all thromboplastins (bias -0.19 to 0.18 INR; >97% of data within accuracy limits). The coefficient of variation for imprecision of the PT determinations in INR ranged from 2.0% to 3.2% in venous, and from 2.9% to 4.0% in capillary blood testing. Capillary versus venous INR data showed agreement of results with regression lines equal to the line of identity. The new system demonstrated a high level of trueness and accuracy, and low imprecision in INR testing. It can be concluded that the CoaguChek XS system complies with the requirements in chapter 8 of the ISO standard 17593:2007.

Defining when to initiate massive transfusion: a validation study of individual massive transfusion triggers in PROMMTT patients.

PubMed

Callcut, Rachael A; Cotton, Bryan A; Muskat, Peter; Fox, Erin E; Wade, Charles E; Holcomb, John B; Schreiber, Martin A; Rahbar, Mohammad H; Cohen, Mitchell J; Knudson, M Margaret; Brasel, Karen J; Bulger, Eileen M; Del Junco, Deborah J; Myers, John G; Alarcon, Louis H; Robinson, Bryce R H

2013-01-01

Early predictors of massive transfusion (MT) would prevent undertriage of patients likely to require MT. This study validates triggers using the Prospective Observational Multicenter Major Trauma Transfusion (PROMMTT) study. All enrolled patients in PROMMTT were analyzed. The initial emergency department value for each trigger (international normalized ratio [INR], systolic blood pressure, hemoglobin, base deficit, positive result for Focused Assessment for the Sonography of Trauma examination, heart rate, temperature, and penetrating injury mechanism) was compared for patients receiving MT (≥ 10 U of packed red blood cells in 24 hours) versus no MT. Adjusted odds ratios (ORs) for MT are reported using multiple logistic regression. If all triggers were known, a Massive Transfusion Score (MTS) was created, with 1 point assigned for each met trigger. A total of 1,245 patients were prospectively enrolled with 297 receiving an MT. Data were available for all triggers in 66% of the patients including 67% of the MTs (199 of 297). INR was known in 87% (1,081 of 1,245). All triggers except penetrating injury mechanism and heart rate were valid individual predictors of MT, with INR as the most predictive (adjusted OR, 2.5; 95% confidence interval, 1.7-3.7). For those with all triggers known, a positive INR trigger was seen in 49% receiving MT. Patients with an MTS of less than 2 were unlikely to receive MT (negative predictive value, 89%). If any two triggers were present (MTS ≥ 2), sensitivity for predicting MT was 85%. MT was present in 33% with an MTS of 2 greater compared with 11% of those with MTS of less than 2 (OR, 3.9; 95% confidence interval, 2.6-5.8; p < 0.0005). Parameters that can be obtained early in the initial emergency department evaluation are valid predictors for determining the likelihood of MT. Diagnostic, level II.

Warfarin monitoring in nursing homes assessed by case histories. Do recommendations and electronic alerts affect judgements?

PubMed

Teruel, Reyes Serrano; Thue, Geir; Fylkesnes, Svein Ivar; Sandberg, Sverre; Kristoffersen, Ann Helen

2017-09-01

Older adults treated with warfarin are prone to complications, and high-quality monitoring is essential. The aim of this case history based study was to assess the quality of warfarin monitoring in a routine situation, and in a situation with an antibiotic-warfarin interaction, before and after receiving an electronic alert. In April 2014, a national web-based survey with two case histories was distributed among Norwegian nursing home physicians and general practitioners working part-time in nursing homes. Case A represented a patient on stable warfarin treatment, but with a substantial INR increase within the therapeutic interval. Case B represented a more challenging patient with trimethoprim sulfamethoxazole (TMS) treatment due to pyelonephritis. In both cases, the physicians were asked to state the next warfarin dose and the INR recall interval. In case B, the physicians could change their suggestions after receiving an electronic alert on the TMS-warfarin interaction. Three hundred and ninety eight physicians in 292 nursing homes responded. Suggested INR recall intervals and warfarin doses varied substantially in both cases. In case A, 61% gave acceptable answers according to published recommendations, while only 9% did so for case B. Regarding the TMS-warfarin interaction in case history B, the electronic alert increased the percentage of respondents correctly suggesting a dose reduction from 29% to 53%. Having an INR instrument in the nursing home was associated with shortened INR recall times. Practical advice on handling of warfarin treatment and drug interactions is needed. Electronic alerts as presented in electronic medical records seem insufficient to change practice. Availability of INR instruments may be important regarding recall time.

Relation of psychological distress to the international normalized ratio in patients with venous thromboembolism with and without oral anticoagulant therapy.

PubMed

Von Känel, R; Vökt, F; Biasiutti, F Demarmels; Stauber, S; Wuillemin, W A; Lukas, P S

2012-08-01

Psychological distress might affect the international normalized ratio (INR), but effects might vary depending on oral anticoagulant (OAC) therapy. To investigate the association of psychological distress with INR and clotting factors of the extrinsic pathway in patients with and without OAC therapy. We studied 190 patients with a previous venous thromboembolism (VTE); 148 had discontinued OAC therapy and 42 had ongoing OAC therapy. To assess psychological distress, all patients completed validated questionnaires to measure symptoms of depression, anxiety, worrying, anger and hostility. INR, fibrinogen, factor (F)II:C, FV:C, FVII:C and FX:C were measured as part of outpatient thrombophilia work-up. In VTE patients without OAC therapy, the odds of a reduced INR (< 1.00) were significantly increased from 1.5 to 1.8 times for an increase of 1 standard deviation (SD) in symptoms of depression, anxiety, worrying and anger, respectively, after adjusting for gender, age, body mass index, socioeconomic status, hematocrit and C-reactive protein. Worrying, anger and hostility also showed significant direct associations with FVII:C. In patients with OAC therapy, INR was unrelated to a negative affect; however, lower FVII:C related to anxiety and worrying as well as lower FX:C related to anger and hostility were observed in patients with OAC therapy compared with those without OAC therapy. Psychological distress was associated with a reduced INR in VTE patients without OAC therapy. The direction of the association between psychological distress and activity in some clotting factors of the extrinsic coagulation pathway might differ depending on whether VTE patients are under OAC therapy or not. © 2012 International Society on Thrombosis and Haemostasis.

Laboratory assessment of novel oral anticoagulants: method suitability and variability between coagulation laboratories.

PubMed

Helin, Tuukka A; Pakkanen, Anja; Lassila, Riitta; Joutsi-Korhonen, Lotta

2013-05-01

Laboratory tests to assess novel oral anticoagulants (NOACs) are under evaluation. Routine monitoring is unnecessary, but under special circumstances bioactivity assessment becomes crucial. We analyzed the effects of NOACs on coagulation tests and the availability of specific assays at different laboratories. Plasma samples spiked with dabigatran (Dabi; 120 and 300 μg/L) or rivaroxaban (Riva; 60, 146, and 305 μg/L) were sent to 115 and 38 European laboratories, respectively. International normalized ratio (INR) and activated partial thromboplastin time (APTT) were analyzed for all samples; thrombin time (TT) was analyzed specifically for Dabi and calibrated anti-activated factor X (anti-Xa) activity for Riva. We compared the results with patient samples. Results of Dabi samples were reported by 73 laboratories (13 INR and 9 APTT reagents) and Riva samples by 22 laboratories (5 INR and 4 APTT reagents). Both NOACs increased INR values; the increase was modest, albeit larger, for Dabi, with higher CV, especially with Quick (vs Owren) methods. Both NOACs dose-dependently prolonged the APTT. Again, the prolongation and CVs were larger for Dabi. The INR and APTT results varied reagent-dependently (P < 0.005), with less prolongation in patient samples. TT results (Dabi) and calibrated anti-Xa results (Riva) were reported by only 11 and 8 laboratories, respectively. The screening tests INR and APTT are suboptimal in assessing NOACs, having high reagent dependence and low sensitivity and specificity. They may provide information, if laboratories recognize their limitations. The variation will likely increase and the sensitivity differ in clinical samples. Specific assays measure NOACs accurately; however, few laboratories applied them. © 2013 American Association for Clinical Chemistry.

Time to achieving therapeutic international normalized ratio increases hospital length of stay after heart valve replacement surgery.

PubMed

Arendt, Christopher J; Hong, Joon Hwa; Daly, Richard C; Scott, Christopher; Mehta, Ramila A; Bailey, Kent; Pathak, Jyotishman; Pereira, Naveen L

2017-05-01

Achieving a therapeutic international normalized ratio (INR) before hospital discharge is an important inpatient goal for patients undergoing mechanical cardiac valve replacement (MCVR). The use of clinical algorithms has reduced the time to achieve therapeutic INR (TTI) with warfarin therapy. Whether TTI prolongs length of stay (LOS) is unknown. Patients who underwent MCVR over a consecutive 42-month period were included. Clinical data were obtained from the Society of Thoracic Surgeons Adult Cardiac Surgery database and electronic medical records. Therapeutic INR was defined as per standard guidelines. Warfarin dose was prescribed using an inpatient pharmacy-managed algorithm and computer-based dosing tool. International normalized ratio trajectory, procedural needs, and drug interactions were included in warfarin dose determination. There were 708 patients who underwent MCVR, of which 159 were excluded for reasons that would preclude or interrupt warfarin use. Among the remainder of 549 patients, the average LOS was 6.4days and mean TTI was 3.5days. Landmark analysis showed that subjects in hospital on day 4 (n=542) who achieved therapeutic INR were more likely to be discharged by day 6 compared with those who did not achieve therapeutic INR (75% vs 59%, P<.001). Multivariable proportional hazards regression with TTI as a time-dependent effect showed a strong association with discharge (P=.0096, hazard ratio1.3) after adjustment for other significant clinical covariates. Time to achieve therapeutic INR is an independent predictor of LOS in patients requiring anticoagulation with warfarin after MCVR surgery. Alternative dosing and anticoagulation strategies will need to be adopted to reduce LOS in these patients. Copyright © 2017 Elsevier Inc. All rights reserved.

Cost-effectiveness study comparing cefoperazone-sulbactam to a three-drug combination for treating intraabdominal infections in an Indian health-care setting.

PubMed

Kochhar, Puja; Suvarna, Viraj; Duttagupta, Sandeep; Sarkar, Shirsendu

2008-03-01

This article presents the methodology and results of the pharmacoeconomic analysis of the Magnex Against Standard COmbination Therapy study comparing cefoperazone-sulbactam (Magnex) versus ceftazidime+ amikacin+metronidazole, in the treatment of intra-abdominal infections. This prospective, open label, phase IV study was conducted at 17 study sites in India and randomized subjects to receive either cefoperazone-sulbactam or the combination. Pharmacoeconomic analysis was included as a secondary objective and conducted in the clinical efficacy-evaluable (CEE) and the successfully treated patients. All comparisons between treatment groups were conducted using analysis of variance (ANOVA) or Wilcoxon Two-Sample tests. All costs were reported as Indian Rupee (INR) and actual unit costs collected in 2006 were used for the analyses [1 USD approximately 40 INR; 1 Euro approximately 56 INR]. In the CEE and the successfully treated subset of patients, the average cost of treatment was numerically lower in the cefoperazone-sulbactam arm (not statistically significant). The analyses found that the cost-effectiveness ratio (CER) for cefoperazone-sulbactam was INR 17,640.53 and that for the comparator group was INR 22,075.16. Additionally, the incremental CER results showed that the cost of treatment was INR 21,505.59 lower per additional successfully treated patient in the cefoperazone-sulbactam group. The present study was the first of its kind to be conducted in the "price sensitive" Indian health-care setting. Though study was not powered for the difference in average cost of treatments, there was a trend favoring cefoperazone sulbactam. The findings from this study should encourage further conduct of similar analyses and increase the knowledge regarding pharmacoeconomics in India.

Safety and Outcomes of Transradial Access in Patients with International Normalized Ratio 1.5 or above.

PubMed

Titano, Joseph J; Biederman, Derek M; Zech, John; Korff, Ricki; Ranade, Mona; Patel, Rahul; Kim, Edward; Nowakowski, Francis; Lookstein, Robert; Fischman, Aaron M

2018-03-01

To examine the safety and outcomes for patients undergoing transradial noncoronary interventions with international normalized ratio (INR) ≥1.5. A retrospective review of 2,271 transradial access (TRA) cases performed from July 2012 to July 2016 was conducted. Criteria for inclusion were moderate bleeding risk cases with preprocedure INR ≥1.5. Within the study period, there were 176 moderate bleeding risk procedures (transarterial chemoembolization: 70/176 [39.8%]; Barbeau B: 121/176 [68.8%]; 5-F sheath: 157/176 [89.2%]) performed on 122 patients (age 61.6 ± 12.1 years, 68.9% male, body mass index 28.0 kg/m 2 ) with INR ≥1.5. Technical success was achieved in 98.9% of cases. Grade 1/2 hematomas developed in 10 cases (5.7%). Age ≥65 years (P = .042) and female sex (P = .046) were predictive of access site bleeding complications. Fresh frozen plasma (FFP) transfusion was administered in 11.4% of cases (n = 20). Baseline INR and creatinine were significantly different between transfused and nontransfused cases (P values .006 and .028, respectively). Minor access site bleeding occurred in 3/20 cases (15%) receiving prior FFP transfusion and 7/156 nontransfused cases (4.5%), with no significant difference between these 2 groups (P = .072). TRA in patients with elevated INR appears to be safe in our experience. Age ≥65 years and female sex were associated with increased incidence of access site bleeding. Although INR correction was not standardized in this cohort, preprocedure FFP transfusion did not decrease bleeding complications. Copyright © 2017 SIR. Published by Elsevier Inc. All rights reserved.

[Perioperative changes of coagulation functions in the local advanced liver cancer patients receiving liver transplantation].

PubMed

Wang, Hao-Yuan; Zhao, Qing-Yu; Yuan, Yun-Fei

2008-07-01

Liver transplantation is widely accepted as an effective therapy of hepatoma. Perioperative dynamic observation of coagulation function is important for graft-receivers. This study was to explore perioperative changes of coagulation functions in the local advanced liver cancer patients who received liver transplantation. Clinical data of 31 local advanced liver cancer patients, underwent liver transplantation from Sep. 2003 to Jan. 2007, were analyzed. Platelet (PLT) counting, prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), fibrinogen (Fib) and international normalized ratio (INR) before operation, at anhepatic phase and the first week after operation were analyzed to evaluate congulation function. The coagulation functions of most patients were normal before operation. The six parameters varied significantly at anhepatic phase and on most days of the first week after operation when compared with the preoperative levels (P<0.05). The elevation of PT, APTT, TT and INR and the decrease of Fib and PLT were more apparent at anhepatic phase when compared with the preoperative levels [PT: (19.51+/-3.78) s vs. (14.16+/-1.46) sû APTT: (77.01+/-30.51) s vs. (40.19+/-4.11) sû TT: (27.50+/-15.10) s vs. (19.46+/-3.05) sû INR: 1.61+/-0.37 vs. 1.11+/-0.16û Fib: (1.73+/-0.70) g/L vs. (3.38+/-1.00) g/Lû PLT: (108+/-60)x10(9)/L vs. (184+/-108)x10(9)/L, all P<0.01]. In the first week after operation, the elevated PT, APTT, TT and INR levels decreased gradually, APTT was even lower than the preoperative level [(32.05+/-6.50) s vs. (40.19+/-4.11) s, P<0.01]. These changes appeared usually on 1-2 days after operation. Decreased PLT and Fib regained slowly at the first week after operation when compared with the preoperative levels [Fib: (2.13+/-0.53) g/L vs. (3.38+/-1.00) g/L, P<0.01û PLT: (145+/-90)x10(9)/L vs. 184+/-108]x10(9)/L, P<0.05], but the values were normal. According to stratification analysis, the hypocoagulability was more

TargetNet: a web service for predicting potential drug-target interaction profiling via multi-target SAR models.

PubMed

Yao, Zhi-Jiang; Dong, Jie; Che, Yu-Jing; Zhu, Min-Feng; Wen, Ming; Wang, Ning-Ning; Wang, Shan; Lu, Ai-Ping; Cao, Dong-Sheng

2016-05-01

Drug-target interactions (DTIs) are central to current drug discovery processes and public health fields. Analyzing the DTI profiling of the drugs helps to infer drug indications, adverse drug reactions, drug-drug interactions, and drug mode of actions. Therefore, it is of high importance to reliably and fast predict DTI profiling of the drugs on a genome-scale level. Here, we develop the TargetNet server, which can make real-time DTI predictions based only on molecular structures, following the spirit of multi-target SAR methodology. Naïve Bayes models together with various molecular fingerprints were employed to construct prediction models. Ensemble learning from these fingerprints was also provided to improve the prediction ability. When the user submits a molecule, the server will predict the activity of the user's molecule across 623 human proteins by the established high quality SAR model, thus generating a DTI profiling that can be used as a feature vector of chemicals for wide applications. The 623 SAR models related to 623 human proteins were strictly evaluated and validated by several model validation strategies, resulting in the AUC scores of 75-100 %. We applied the generated DTI profiling to successfully predict potential targets, toxicity classification, drug-drug interactions, and drug mode of action, which sufficiently demonstrated the wide application value of the potential DTI profiling. The TargetNet webserver is designed based on the Django framework in Python, and is freely accessible at http://targetnet.scbdd.com .

TargetNet: a web service for predicting potential drug-target interaction profiling via multi-target SAR models

NASA Astrophysics Data System (ADS)

Yao, Zhi-Jiang; Dong, Jie; Che, Yu-Jing; Zhu, Min-Feng; Wen, Ming; Wang, Ning-Ning; Wang, Shan; Lu, Ai-Ping; Cao, Dong-Sheng

2016-05-01

Drug-target interactions (DTIs) are central to current drug discovery processes and public health fields. Analyzing the DTI profiling of the drugs helps to infer drug indications, adverse drug reactions, drug-drug interactions, and drug mode of actions. Therefore, it is of high importance to reliably and fast predict DTI profiling of the drugs on a genome-scale level. Here, we develop the TargetNet server, which can make real-time DTI predictions based only on molecular structures, following the spirit of multi-target SAR methodology. Naïve Bayes models together with various molecular fingerprints were employed to construct prediction models. Ensemble learning from these fingerprints was also provided to improve the prediction ability. When the user submits a molecule, the server will predict the activity of the user's molecule across 623 human proteins by the established high quality SAR model, thus generating a DTI profiling that can be used as a feature vector of chemicals for wide applications. The 623 SAR models related to 623 human proteins were strictly evaluated and validated by several model validation strategies, resulting in the AUC scores of 75-100 %. We applied the generated DTI profiling to successfully predict potential targets, toxicity classification, drug-drug interactions, and drug mode of action, which sufficiently demonstrated the wide application value of the potential DTI profiling. The TargetNet webserver is designed based on the Django framework in Python, and is freely accessible at http://targetnet.scbdd.com.

Perpetrators and targets of bullying at work: role stress and individual differences.

PubMed

Matthiesen, Stig Berge; Einarsen, Ståle

2007-01-01

A workplace survey study (N = 2215, response rate 47%) revealed that about 16% of the sample may be categorized as either perpetrators (5.4%), provocative victims (2.1%), or as targets of bullying (8.3%). Targets of bullying, provocative victims, and bullies were compared with those 84% who do not report any involvement with respect to bullying at work, self-esteem, aggressive tendencies, prior experiences of bullying, or experiences of role stress. Perpetrators were found to have a higher level of aggression than did the comparison group and the targets. Provocative victims manifested a low level of self-esteem and social competency combined with a high level of aggressiveness. Targets of bullying revealed low levels of self-esteem and social competency. Targets, provocative victims, and perpetrators reported elevated levels of role stress in the form of unclear or conflicting demands and expectations around work tasks and daily work.

Choosing a therapy electron accelerator target.

PubMed

Hutcheon, R M; Schriber, S O; Funk, L W; Sherman, N K

1979-01-01

Angular distributions of photon depth dose produced by 25-MeV electrons incident on several fully stopping single-element targets (C, Al, Cu, Mo, Ta, Pb) and two composite layered targets (Ni-Al, W-Al) were studied. Depth-dose curves measured using TLD-700 (thermoluminescent dosimeter) chips embedded in lucite phantoms. Several useful therapy electron accelerator design curves were determined, including relative flattener thickness as a function of target atomic number, "effective" bremsstrahlung endpoint energy or beam "hardness" as a function of target atomic number and photon emission angle, and estimates of shielding thickness as a function of angle required to reduce the radiation outside the treatment cone to required levels.

Model for End-stage Liver Disease excluding INR (MELD-XI) score in critically ill patients: Easily available and of prognostic relevance

PubMed Central

Wernly, Bernhard; Lichtenauer, Michael; Franz, Marcus; Kabisch, Bjoern; Muessig, Johanna; Masyuk, Maryna; Hoppe, Uta C.; Kelm, Malte; Jung, Christian

2017-01-01

Purpose MELD-XI, an adapted version of Model for End-stage Liver Disease (MELD) score excluding INR, was reported to predict outcomes e.g. in patients with acute heart failure. We aimed to evaluate MELD-XI in critically ill patients admitted to an intensive care unit (ICU) for prognostic relevance. Methods A total of 4381 medical patients (66±14 years, 2862 male) admitted to a German ICU between 2004 and 2009 were included and retrospectively investigated. Admission diagnoses were e.g. myocardial infarction (n = 2034), sepsis (n = 694) and heart failure (n = 688). We divided our patients in two cohorts basing on their MELD-XI score and evaluated the MELD-XI score for its prognostic relevance regarding short-term and long-term survival. Optimal cut-offs were calculated by means of the Youden-Index. Results Patients with a MELD-XI score >12 had pronounced laboratory signs of organ failure and more comorbidities. MELD-XI >12 was associated with an increase in short-term (27% vs 6%; HR 4.82, 95%CI 3.93–5.93; p<0.001) and long-term (HR 3.69, 95%CI 3.20–4.25; p<0.001) mortality. In a univariate Cox regression analysis for all patients MELD-XI was associated with increased long-term mortality (changes per score point: HR 1.06, 95%CI 1.05–1.07; p<0.001) and remained to be associated with increased mortality after correction in a multivariate regression analysis for renal failure, liver failure, lactate concentration, blood glucose concentration, oxygenation and white blood count (HR 1.04, 95%CI 1.03–1.06; p<0.001). Optimal cut-off for the overall cohort was 11 and varied remarkably depending on the admission diagnosis: myocardial infarction (9), pulmonary embolism (9), cardiopulmonary resuscitation (17) and pneumonia (17). We performed ROC-analysis and compared the AUC: SAPS2 (0.78, 95%CI 0.76–0.80; p<0.0001) and APACHE (0.76, 95%CI 0.74–0.78; p<0.003) score were superior to MELD-XI (0.71, 95%CI 0.68–0.73) for prediction of mortality. Conclusions The easily

Prospective pilot trial of PerMIT versus standard anticoagulation service management of patients initiating oral anticoagulation.

PubMed

Borgman, Mark P; Pendleton, Robert C; McMillin, Gwendolyn A; Reynolds, Kristen K; Vazquez, Sara; Freeman, Andrew; Wilson, Andrew; Valdes, Roland; Linder, Mark W

2012-09-01

We performed a randomised pilot trial of PerMIT, a novel decision support tool for genotype-based warfarin initiation and maintenance dosing, to assess its efficacy for improving warfarin management. We prospectively studied 26 subjects to compare PerMIT-guided management with routine anticoagulation service management. CYP2C9 and VKORC1 genotype results for 13 subjects randomly assigned to the PerMIT arm were recorded within 24 hours of enrolment. To aid in INR interpretation, PerMIT calculates estimated loading and maintenance doses based on a patient's genetic and clinical characteristics and displays calculated S-warfarin plasma concentrations based on planned or administered dosages. In comparison to control subjects, patients in the PerMIT study arm demonstrated a 3.6-day decrease in the time to reach a stabilised INR within the target therapeutic range (4.7 vs. 8.3 days, p = 0.015); a 12.8% increase in time spent within the therapeutic interval over the first 25 days of therapy (64.3% vs. 55.3%, p = 0.180); and a 32.9% decrease in the frequency of warfarin dose adjustments per INR measurement (38.3% vs. 57.1%, p = 0.007). Serial measurements of plasma S-warfarin concentrations were also obtained to prospectively evaluate the accuracy of the pharmacokinetic model during induction therapy. The PerMIT S-warfarin plasma concentration model estimated 62.8% of concentrations within 0.15 mg/l. These pilot data suggest that the PerMIT method and its incorporation of genotype/phenotype information may help practitioners increase the safety, efficacy, and efficiency of warfarin therapeutic management.

Implementation and evaluation of a pharmacist-led electronic visit program for diabetes and anticoagulation care in a patient-centered medical home.

PubMed

Hawes, Emily M; Lambert, Erika; Reid, Alfred; Tong, Gretchen; Gwynne, Mark

2018-04-13

Results of a study evaluating quality-of-care, financial, and patient satisfaction outcomes of pharmacist-conducted telehealth visits for diabetes management and warfarin monitoring are reported. A retrospective pre-post study was conducted to determine the impact of an electronic visit (e-visit) program targeting 2 groups of outpatients: adults with uncontrolled diabetes and warfarin-treated adults performing patient self-testing (PST) for monitoring of International Normalized Ratio (INR) values. A total of 36 patients participated in the e-visit program during the 2-year study period. Among warfarin-treated patients, the percentage of INR values in the desired range increased relative to preenrollment values (from 62.5% to 72.7%, p = 0.07), and the frequency of extreme INR values (values of <1.5 or >5.0) decreased (from 4.8% to 0.01%, p = 0.01); the margin per patient was $300 during the first year and $191 annually thereafter. In the diabetes group, a decrease from baseline in glycosylated hemoglobin values of 3.4 percentage points was observed at 5.7 months after enrollment ( p < 0.001), with significant improvements in frequencies of statin use, aspirin use, and blood pressure control; the margin was $100 per patient. The overall median patient satisfaction survey score was 39 of 40. An online e-visit model for warfarin monitoring was an efficient, safe, and cost-effective method for implementing PST. Pharmacist-led management of diabetes through e-visits, often in combination with in-person visits, generated revenue while significantly improving clinical outcomes. Copyright © 2018 by the American Society of Health-System Pharmacists, Inc. All rights reserved.

SETI target selection.

PubMed

Latham, D W; Soderblom, D R

1995-01-01

The NASA High Resolution Microwave Survey consists of two complementary elements: a Sky Survey of the entire sky to a moderate level of sensitivity; and a Targeted Search of nearby stars, one at a time, to a much deeper level of sensitivity. In this paper we propose strategies for target selection. We have two goals: to improve the chances of successful detection of signals from technical civilizations that inhabit planets around solar-type stars, and to minimize the chances of missing signals from unexpected sites. For the main Targeted Search survey of approximately 1000 nearby solar-type stars, we argue that the selection criteria should be heavily biased by what we know about the origin and evolution of life here on Earth. We propose that observations of stars with stellar companions orbiting near the habitable zone should be de-emphasized, because such companions would prevent the formation of habitable planets. We also propose that observations of stars younger than about three billion years should be de-emphasized in favor of older stars, because our own technical civilization took longer than three billion years to evolve here on Earth. To provide the information needed for the preparation of specific target lists, we have undertaken an inventory of a large sample of solar-type stars out to a distance of 60 pc, with the goal of characterizing the relevant astrophysical properties of these stars, especially their ages and companionship. To complement the main survey, we propose that a modest sample of the nearest stars should be observed without any selection biases whatsoever. Finally, we argue that efforts to identify stars with planetary systems should be expanded. If found, such systems should receive intensive scrutiny.

Triple therapy in cadaveric renal transplantation: role of induction cyclosporine and targeted levels to avoid rejection.

PubMed

Khauli, R B; Wilson, J M; Baker, S P; Valliere, S A; Lovewell, T D; Stoff, J S

1995-06-01

nonnephrotoxic groups (85.6% versus 79.6%). Long-term function was not influenced by the occurrence of acute nephrotoxicity events. These findings confirm the efficacy of triple therapy with induction cyclosporine in cadaveric transplantation, yielding improved short-term and intermediate graft survival without any adverse effects on long-term graft function. Specific cyclosporine level monitoring is invaluable, particularly initially, with high target levels of 200 ng./ml. or greater. The use of calcium blockers may have allowed higher cyclosporine dosing in the first 3 months, mitigating against cyclosporine associated chronic nephrotoxicity.

Qualitative Immune Modulation by Interleukin-2 (IL-2) Adjuvant Therapy in Immunological Non Responder HIV-Infected Patients

PubMed Central

Sabbatini, Francesca; Bandera, Alessandra; Ferrario, Giulio; Trabattoni, Daria; Marchetti, Giulia; Franzetti, Fabio; Clerici, Mario; Gori, Andrea

2010-01-01

Background Treatment of HIV-infected patients with interleukin-2 (IL-2) produces significant increases in CD4 T cell counts; however an associated qualitative improvement in cells function has yet to be conclusively demonstrated. By measuring mycobacterial killing activity, we evaluated IL-2-mediated functional immune enhancement ex vivo in immunological non-responders (INRs). Methods and Findings PBMC from 12 immunological non-responders (INRs) (CD4+<200/µl, HIV-RNA<50 cp/ml) on combination antiretroviral treatment (cART) were collected at baseline, and after 3 IL-2 cycles. Eight INRs receiving only cART were studied as controls. After 21 days of PBMC incubation with a virulent M. avium suspension, counts of residual colony forming units (CFUs) and concentrations of TNF-α, IL-10 and IFN-γ were determined. In IL-2 treated patients, a significant reduction in mean residual CFUs of PBMC cultures was observed (p<0.01). Moreover, following IL-2 treatment, significant increases in PBMC's IFNγ production (p = 0.02) and substantial reductions in IL-10 levels were observed. Conclusions IL-2 therapy restores the ability of the lympho-monocyte system in eliciting an effective response against mycobacterial infections. Our data indicate the possibility of a clinical role held by IL-2 in enhancing the immune function of subjects unable to achieve immune competence through cART alone. PMID:21124762

Secure FAST: Security Enhancement in the NATO Time Sensitive Targeting Tool

DTIC Science & Technology

2010-11-01

designed to aid in the tracking and prosecuting of Time Sensitive Targets. The FAST tool provides user level authentication and authorisation in terms...level authentication and authorisation in terms of security. It uses operating system level security but does not provide application level security for...and collaboration tool, designed to aid in the tracking and prosecuting of Time Sensitive Targets. The FAST tool provides user level authentication and

Vision-Based Target Finding and Inspection of a Ground Target Using a Multirotor UAV System.

PubMed

Hinas, Ajmal; Roberts, Jonathan M; Gonzalez, Felipe

2017-12-17

In this paper, a system that uses an algorithm for target detection and navigation and a multirotor Unmanned Aerial Vehicle (UAV) for finding a ground target and inspecting it closely is presented. The system can also be used for accurate and safe delivery of payloads or spot spraying applications in site-specific crop management. A downward-looking camera attached to a multirotor is used to find the target on the ground. The UAV descends to the target and hovers above the target for a few seconds to inspect the target. A high-level decision algorithm based on an OODA (observe, orient, decide, and act) loop was developed as a solution to address the problem. Navigation of the UAV was achieved by continuously sending local position messages to the autopilot via Mavros. The proposed system performed hovering above the target in three different stages: locate, descend, and hover. The system was tested in multiple trials, in simulations and outdoor tests, from heights of 10 m to 40 m. Results show that the system is highly reliable and robust to sensor errors, drift, and external disturbance.

Diversity, expression and mRNA targeting abilities of Argonaute-targeting miRNAs among selected vascular plants.

PubMed

Jagtap, Soham; Shivaprasad, Padubidri V

2014-12-02

Micro (mi)RNAs are important regulators of plant development. Across plant lineages, Dicer-like 1 (DCL1) proteins process long ds-like structures to produce micro (mi) RNA duplexes in a stepwise manner. These miRNAs are incorporated into Argonaute (AGO) proteins and influence expression of RNAs that have sequence complementarity with miRNAs. Expression levels of AGOs are greatly regulated by plants in order to minimize unwarranted perturbations using miRNAs to target mRNAs coding for AGOs. AGOs may also have high promoter specificity-sometimes expression of AGO can be limited to just a few cells in a plant. Viral pathogens utilize various means to counter antiviral roles of AGOs including hijacking the host encoded miRNAs to target AGOs. Two host encoded miRNAs namely miR168 and miR403 that target AGOs have been described in the model plant Arabidopsis and such a mechanism is thought to be well conserved across plants because AGO sequences are well conserved. We show that the interaction between AGO mRNAs and miRNAs is species-specific due to the diversity in sequences of two miRNAs that target AGOs, sequence diversity among corresponding target regions in AGO mRNAs and variable expression levels of these miRNAs among vascular plants. We used miRNA sequences from 68 plant species representing 31 plant families for this analysis. Sequences of miR168 and miR403 are not conserved among plant lineages, but surprisingly they differ drastically in their sequence diversity and expression levels even among closely related plants. Variation in miR168 expression among plants correlates well with secondary structures/length of loop sequences of their precursors. Our data indicates a complex AGO targeting interaction among plant lineages due to miRNA sequence diversity and sequences of miRNA targeting regions among AGO mRNAs, thus leading to the assumption that the perturbations by viruses that use host miRNAs to target antiviral AGOs can only be species-specific. We also show

[Analysis on long-term compliance of anticoagulation treatment and demands of disease management in patients with atrial fibrillation].

PubMed

Zuo, Hui-juan; Su, Jiang-lian; Lin, Yun; Zeng, Zhe-chun; Wang, Jin-wen

2010-08-24

To analyze the long-term compliance of oral anticoagulant therapy and the demands of disease management in patient with atrial fibrillation (AF). Inpatients with AF taking warfarin were collected from Department of Internal Medicine from January 1 to December 31, 2008. Inpatients from departments of surgery, ophthalmology, otorhinolaryngology, dermatology and pediatrics and those on a previous warfarin therapy were excluded. The data of patient profiles, medical history and anticoagulant treatment were collected from electronic medical record. And the status of anticoagulant treatment one year later and demands of disease management were inquired by telephone. A total of 268 AF patients received a telephone survey. Among them, 145 patients (54.1%) continued taking warfarin. Gender, age, type of AF, duration of AF and history of ischemic stroke was not significantly associated with the compliance of anticoagulant treatment. The odds ratio was 1.74 (95%CI: 0.67-4.47), 0.87 (95%CI: 0.30-2.53), 1.59 (95%CI: 0.35-1.09), 1.09 (95%CI: 0.61-1.93) and 0.44 (95%CI: 0.12-1.60) respectively. Among patients on warfarin, INR was monitored monthly in 88 patients (60.7%) and 70 patients (48.3%) had an INR value of 2.0-3.0. Among 123 withdrawal patients, 88 patients (71.5%) terminated treatment within 6 month. The common reasons included patient ignorance about long-term anticoagulant treatment (35.0%) and switching to aspirin because of a poor effect (24.4%). About 80% of patients wished to obtain instructions about INR monitoring and adjustment of drug dosage. Among them, 196/268 patients (73.1%) wished for a regular follow-up. And 176/196 patients (89.8%) opted for a telephone follow-up and 150/176 patients (85.2%) wanted to receive monthly instructions. The compliance of anticoagulation treatment and the target-meeting proportion of INR value are relative low. And the common reasons of withdrawal are patient ignorance about long-term anticoagulant treatment and switching to

A new approach to hierarchical data analysis: Targeted maximum likelihood estimation for the causal effect of a cluster-level exposure.

PubMed

Balzer, Laura B; Zheng, Wenjing; van der Laan, Mark J; Petersen, Maya L

2018-01-01

We often seek to estimate the impact of an exposure naturally occurring or randomly assigned at the cluster-level. For example, the literature on neighborhood determinants of health continues to grow. Likewise, community randomized trials are applied to learn about real-world implementation, sustainability, and population effects of interventions with proven individual-level efficacy. In these settings, individual-level outcomes are correlated due to shared cluster-level factors, including the exposure, as well as social or biological interactions between individuals. To flexibly and efficiently estimate the effect of a cluster-level exposure, we present two targeted maximum likelihood estimators (TMLEs). The first TMLE is developed under a non-parametric causal model, which allows for arbitrary interactions between individuals within a cluster. These interactions include direct transmission of the outcome (i.e. contagion) and influence of one individual's covariates on another's outcome (i.e. covariate interference). The second TMLE is developed under a causal sub-model assuming the cluster-level and individual-specific covariates are sufficient to control for confounding. Simulations compare the alternative estimators and illustrate the potential gains from pairing individual-level risk factors and outcomes during estimation, while avoiding unwarranted assumptions. Our results suggest that estimation under the sub-model can result in bias and misleading inference in an observational setting. Incorporating working assumptions during estimation is more robust than assuming they hold in the underlying causal model. We illustrate our approach with an application to HIV prevention and treatment.

Aligning corporate greenhouse-gas emissions targets with climate goals

NASA Astrophysics Data System (ADS)

Krabbe, Oskar; Linthorst, Giel; Blok, Kornelis; Crijns-Graus, Wina; van Vuuren, Detlef P.; Höhne, Niklas; Faria, Pedro; Aden, Nate; Pineda, Alberto Carrillo

2015-12-01

Corporate climate action is increasingly considered important in driving the transition towards a low-carbon economy. For this, it is critical to ensure translation of global goals to greenhouse-gas (GHG) emissions reduction targets at company level. At the moment, however, there is a lack of clear methods to derive consistent corporate target setting that keeps cumulative corporate GHG emissions within a specific carbon budget (for example, 550-1,300 GtCO2 between 2011 and 2050 for the 2 °C target). Here we propose a method for corporate emissions target setting that derives carbon intensity pathways for companies based on sectoral pathways from existing mitigation scenarios: the Sectoral Decarbonization Approach (SDA). These company targets take activity growth and initial performance into account. Next to target setting on company level, the SDA can be used by companies, policymakers, investors or other stakeholders as a benchmark for tracking corporate climate performance and actions, providing a mechanism for corporate accountability.

Targeting Sphingosine Kinase-1 To Inhibit Melanoma

PubMed Central

Madhunapantula, SubbaRao V.; Hengst, Jeremy; Gowda, Raghavendra; Fox, Todd E.; Yun, Jong K; Robertson, Gavin P.

2012-01-01

SUMMARY Resistance to therapies develops rapidly for melanoma leading to more aggressive disease. Therefore, agents are needed that specifically inhibit proteins or pathways controlling the development of this disease, which can be combined, dependent on genes deregulated in a particular patient’s tumors. This study shows that elevated sphingosine-1-phosphate (S-1-P) levels resulting from increased activity of sphingosine kinase-1 (SPHK1) occur in advanced melanomas. Targeting SPHK1 using siRNA decreased anchorage dependent and independent growth as well as sensitized melanoma cells to apoptosis inducing agents. Pharmacological SPHK1 inhibitors SKI-I but not SKI-II decreased S-1-P content, elevated ceramide levels, caused a G2-M block and induced apoptotic cell death in melanomas. Targeting SPHK1 using siRNA or the pharmacological agent called SKI-I, decreased the levels of pAKT. Furthermore, SKI-I inhibited the expression of CYCLIN D1 protein and increased the activity of caspase-3/7, which in turn led to the degradation of PARP. In animals, SKI-I but not SKI-II retarded melanoma growth by 25-40%. Thus, targeting SPHK1 using siRNAs or SKI-I has therapeutic potential for melanoma treatment either alone or in combination with other targeted agents. PMID:22236408

Cost of Delivering Health Care Services in Public Sector Primary and Community Health Centres in North India.

PubMed

Prinja, Shankar; Gupta, Aditi; Verma, Ramesh; Bahuguna, Pankaj; Kumar, Dinesh; Kaur, Manmeet; Kumar, Rajesh

2016-01-01

With the commitment of the national government to provide universal healthcare at cheap and affordable prices in India, public healthcare services are being strengthened in India. However, there is dearth of cost data for provision of health services through public system like primary & community health centres. In this study, we aim to bridge this gap in evidence by assessing the total annual and per capita cost of delivering the package of health services at PHC and CHC level. Secondly, we determined the per capita cost of delivering specific health services like cost per antenatal care visit, per institutional delivery, per outpatient consultation, per bed-day hospitalization etc. We undertook economic costing of fourteen public health facilities (seven PHCs and CHCs each) in three North-Indian states viz., Haryana, Himachal Pradesh and Punjab. Bottom-up costing method was adopted for collection of data on all resources spent on delivery of health services in selected health facilities. Analysis was undertaken using a health system perspective. The joint costs like human resource, capital, and equipment were apportioned as per the time value spent on a particular service. Capital costs were discounted and annualized over the estimated life of the item. Mean annual costs and unit costs were estimated along with their 95% confidence intervals using bootstrap methodology. The overall annual cost of delivering services through public sector primary and community health facilities in three states of north India were INR 8.8 million (95% CI: 7,365,630-10,294,065) and INR 26.9 million (95% CI: 22,225,159.3-32,290,099.6), respectively. Human resources accounted for more than 50% of the overall costs at both the level of PHCs and CHCs. Per capita per year costs for provision of complete package of preventive, curative and promotive services at PHC and CHC were INR 170.8 (95% CI: 131.6-208.3) and INR162.1 (95% CI: 112-219.1), respectively. The study estimates can be used

Atmospheric electromagnetic pulse propagation effects from thick targets in a terawatt laser target chamber.

PubMed

Remo, John L; Adams, Richard G; Jones, Michael C

2007-08-20

Generation and effects of atmospherically propagated electromagnetic pulses (EMPs) initiated by photoelectrons ejected by the high density and temperature target surface plasmas from multiterawatt laser pulses are analyzed. These laser radiation pulse interactions can significantly increase noise levels, thereby obscuring data (sometimes totally) and may even damage sensitive probe and detection instrumentation. Noise effects from high energy density (approximately multiterawatt) laser pulses (approximately 300-400 ps pulse widths) interacting with thick approximately 1 mm) metallic and dielectric solid targets and dielectric-metallic powder mixtures are interpreted as transient resonance radiation associated with surface charge fluctuations on the target chamber that functions as a radiating antenna. Effective solutions that minimize atmospheric EMP effects on internal and proximate electronic and electro-optical equipment external to the system based on systematic measurements using Moebius loop antennas, interpretations of signal periodicities, and dissipation indicators determining transient noise origin characteristics from target emissions are described. Analytic models for the effect of target chamber resonances and associated noise current and temperature in a probe diode laser are described.

Atmospheric electromagnetic pulse propagation effects from thick targets in a terawatt laser target chamber

NASA Astrophysics Data System (ADS)

Remo, John L.; Adams, Richard G.; Jones, Michael C.

2007-08-01

Generation and effects of atmospherically propagated electromagnetic pulses (EMPs) initiated by photoelectrons ejected by the high density and temperature target surface plasmas from multiterawatt laser pulses are analyzed. These laser radiation pulse interactions can significantly increase noise levels, thereby obscuring data (sometimes totally) and may even damage sensitive probe and detection instrumentation. Noise effects from high energy density (approximately multiterawatt) laser pulses (˜300-400 ps pulse widths) interacting with thick (˜1 mm) metallic and dielectric solid targets and dielectric-metallic powder mixtures are interpreted as transient resonance radiation associated with surface charge fluctuations on the target chamber that functions as a radiating antenna. Effective solutions that minimize atmospheric EMP effects on internal and proximate electronic and electro-optical equipment external to the system based on systematic measurements using Moebius loop antennas, interpretations of signal periodicities, and dissipation indicators determining transient noise origin characteristics from target emissions are described. Analytic models for the effect of target chamber resonances and associated noise current and temperature in a probe diode laser are described.

Atmospheric electromagnetic pulse propagation effects from thick targets in a terawatt laser target chamber

DOE PAGES

Remo, John L.; Adams, Richard G.; Jones, Michael C.

2007-08-16

Generation and effects of atmospherically propagated electromagnetic pulses (EMPs) initiated by photoelectrons ejected by the high density and temperature target surface plasmas from multiterawatt laser pulses are analyzed. These laser radiation pulse interactions can significantly increase noise levels, thereby obscuring data (sometimes totally) and may even damage sensitive probe and detection instrumentation. Noise effects from high energy density (approximately multiterawatt) laser pulses (~300–400 ps pulse widths) interacting with thick (~1 mm) metallic and dielectric solid targets and dielectric–metallic powder mixtures are interpreted as transient resonance radiation associated with surface charge fluctuations on the target chamber that functions as a radiatingmore » antenna. Effective solutions that minimize atmospheric EMP effects on internal and proximate electronic and electro-optical equipment external to the system based on systematic measurements using Moebius loop antennas, interpretations of signal periodicities, and dissipation indicators determining transient noise origin characteristics from target emissions are described. Analytic models for the effect of target chamber resonances and associated noise current and temperature in a probe diode laser are described.« less

Cost-effectiveness analysis of telephone-based support for the management of pressure ulcers in people with spinal cord injury in India and Bangladesh.

PubMed

Arora, M; Harvey, L A; Glinsky, J V; Chhabra, H S; Hossain, M S; Arumugam, N; Bedi, P K; Cameron, I D; Hayes, A J

2017-08-15

To determine from a societal perspective the cost-effectiveness and cost-utility of telephone-based support for management of pressure ulcers. Cost-effectiveness and cost-utility analysis of a randomised clinical trial. Tertiary centre in India and Bangladesh. An economic evaluation was conducted alongside a randomised clinical trial comparing 12 weeks of telephone-based support (intervention group) with usual care (control group). The analyses evaluated costs and health outcomes in terms of cm 2 reduction of pressure ulcers size and quality-adjusted life years (QALYs) gained. All costs were in Indian Rupees (INR) and then converted to US dollars (USD). The mean (95% confidence interval) between-group difference for the reduction in size of pressure ulcers was 0.53 (-3.12 to 4.32) cm 2 , favouring the intervention group. The corresponding QALYs were 0.027 (0.004-0.051), favouring the intervention group. The mean total cost per participant in the intervention group was INR 43 781 (USD 2460) compared to INR 42 561 (USD 2391) for the control group. The per participant cost of delivering the intervention was INR 2110 (USD 119). The incremental cost-effectiveness ratio was INR 2306 (USD 130) per additional cm 2 reduction in the size of the pressure ulcer and INR 44 915 (USD 2523) per QALY gained. In terms of QALYs, telephone-based support to help people manage pressure ulcers at home provides good value for money and has an 87% probability of being cost-effective, based on 3 times gross domestic product. Sensitivity analyses were performed using the overall cost data with and without productivity costs, and did not alter this conclusion.Spinal Cord advance online publication, 15 August 2017; doi:10.1038/sc.2017.87.

Can Sequential Coagulation Monitoring Predict Major Haemorrhage in Extremely Low Birth Weight Infants?

PubMed

Thanhaeuser, Margarita; Binder, Christoph; Derhaschnig, Ulla; Jilma, Bernd; Kornsteiner-Krenn, Margit; Huber-Dangl, Mercedes; Repa, Andreas; Kreissl, Alexandra; Berger, Angelika; Haiden, Nadja

2018-06-04

 Bleeds such as intra-ventricular (IVH) and pulmonary haemorrhage (PH) are life-threatening events in extremely low birth weight (ELBW) infants. Serial coagulation monitoring by measuring the international normalized ratio (INR) with small volume samples might facilitate early diagnosis and possibly prevent major bleeds.  This was a prospective longitudinal study performed in ELBW infants, who received serial INR monitoring by point of care testing during their first 30 days of life. The primary objective was to explore whether INR monitoring could predict major bleeding events (IVH, PH). Secondary objectives were mortality and feasibility in this patient population.  A total of 127 ELBW infants were stratified into a bleeding and a non-bleeding group. Bleeding events occurred in 31% (39/127) of the infants, whereupon 24% developed IVH and 9% PH. Infants in the bleeding group were 4 days younger at birth ( p  = 0.05) and had a substantially higher mortality rate of 26% versus 5% in controls ( p  = 0.005). Median INR during the first 3 days before a bleeding event was 1.55 (95% confidence interval [CI]: 1.39-1.74) compared with the control group with 1.45 (95% CI: 1.44-1.58; p  = 0.81). Platelet counts were significantly lower in the bleeding group on the 3rd day and during the 2nd to 4th week of life.  Serial coagulation monitoring by an INR point of care testing is feasible in ELBW infants but could not predict bleeding events. Further studies with daily monitoring of INR and platelet counts during the first days of life might be able to more precisely detect a risk of major haemorrhage in ELBW infants. Schattauer GmbH Stuttgart.

REVIEWS OF TOPICAL PROBLEMS: Neutrinos from stellar core collapses: present status of experiments

NASA Astrophysics Data System (ADS)

Ryazhskaya, Ol'ga G.

2006-10-01

The responses of the existing underground detectors to neutrino bursts from collapsing stars evolving in accordance with various models are considered. The interpretation of the results of detecting neutrino radiation from the SN1987A supernova explosion is discussed. A combination of large scintillation counters interlayered with iron slabs (as a target for the electron neutrino interaction) is suggested as a detector for core collapse neutrinos. Bounds for the galactic rate of core collapses based on 28 years of observations by neutrino telescopes of RAS INR, LSD, and LVD detectors are presented.

The coagulopathy of acute liver failure and implications for intracranial pressure monitoring.

PubMed

Munoz, Santiago J; Rajender Reddy, K; Lee, William

2008-01-01

The development of coagulopathy in acute liver failure (ALF) is universal. The severity of the coagulopathy is often assessed by determination of the prothrombin time and International Normalized Ratio (INR). In more than 1,000 ALF cases, the severity of the coagulopathy was moderate in 81% (INR 1.5-5.0), severe in 14% (INR 5.0-10.0), and very severe in 5% (INR > 10.0). Certain etiologies were associated with more severe coagulopathy, whereas ALF caused by fatty liver of pregnancy had the least severe coagulopathy. Management consisted of transfusions of FFP in 92%. Overall, FFP administered during the first week of admission amounted to 13.7 +/- 15 units. Patients who received an ICP monitor had significantly more FFP transfused than those managed without ICP monitor (22.7 +/- 2.4 vs. 12.3 +/- 0.8 units FFP; P < 0.001). Only a minority of patients developed gastrointestinal bleeding or had an intracranial pressure monitor installed. Further research is necessary to explore the reasons clinicians transfuse ALF patients with large amounts of FFP in the absence of active bleeding or invasive procedures.

[Comparison of quality and hemorragic risk of oral anticoagulant therapy using acenocoumarol versus warfarin].

PubMed

Oliva Berini, Elvira; Galán Alvarez, Pilar; Pacheco Onrubia, Ana María

2008-06-21

Long half life oral anticoagulants have shown a higher anticoagulation stability and a lower hemorragic risk than those of a short half life. We have compared therapeutic stability and hemorragic risk of acenocoumarol versus warfarin in 2 groups of patients on preventive anticoagulation because of atrial fibrilation (international normalised ratio [INR]: 2-3). Data on 120 patients treated with acenocoumarol and 120 on warfarin treatment who had started and continued treatment in our hospital for a minimum of a year was collected. The percentage of visits within the intended range of INR (2 to 3) was 65.5% with warfarin and 63.4% with acenocoumarol. Thirty percent of patients on warfarin had 75% or more of their controls within range, while for those treated with acenocoumarol this percentage was 22.5%. In the acenocoumarol group, 0.3 visits/patient/year presented an INR > or = 6 versus 0.07 in the warfarin group (p = 0.003). Patients treated with acenocoumarol show a higher risk of presenting with an INR > or = 6, but no statistically significant differences are observed in therapeutic stability.

Risk-targeted maps for Romania

NASA Astrophysics Data System (ADS)

Vacareanu, Radu; Pavel, Florin; Craciun, Ionut; Coliba, Veronica; Arion, Cristian; Aldea, Alexandru; Neagu, Cristian

2018-03-01

Romania has one of the highest seismic hazard levels in Europe. The seismic hazard is due to a combination of local crustal seismic sources, situated mainly in the western part of the country and the Vrancea intermediate-depth seismic source, which can be found at the bend of the Carpathian Mountains. Recent seismic hazard studies have shown that there are consistent differences between the slopes of the seismic hazard curves for sites situated in the fore-arc and back-arc of the Carpathian Mountains. Consequently, in this study we extend this finding to the evaluation of the probability of collapse of buildings and finally to the development of uniform risk-targeted maps. The main advantage of uniform risk approach is that the target probability of collapse will be uniform throughout the country. Finally, the results obtained are discussed in the light of a recent study with the same focus performed at European level using the hazard data from SHARE project. The analyses performed in this study have pointed out to a dominant influence of the quantile of peak ground acceleration used for anchoring the fragility function. This parameter basically alters the shape of the risk-targeted maps shifting the areas which have higher collapse probabilities from eastern Romania to western Romania, as its exceedance probability increases. Consequently, a uniform procedure for deriving risk-targeted maps appears as more than necessary.

Effects of target typicality on categorical search.

PubMed

Maxfield, Justin T; Stalder, Westri D; Zelinsky, Gregory J

2014-10-01

The role of target typicality in a categorical visual search task was investigated by cueing observers with a target name, followed by a five-item target present/absent search array in which the target images were rated in a pretest to be high, medium, or low in typicality with respect to the basic-level target cue. Contrary to previous work, we found that search guidance was better for high-typicality targets compared to low-typicality targets, as measured by both the proportion of immediate target fixations and the time to fixate the target. Consistent with previous work, we also found an effect of typicality on target verification times, the time between target fixation and the search judgment; as target typicality decreased, verification times increased. To model these typicality effects, we trained Support Vector Machine (SVM) classifiers on the target categories, and tested these on the corresponding specific targets used in the search task. This analysis revealed significant differences in classifier confidence between the high-, medium-, and low-typicality groups, paralleling the behavioral results. Collectively, these findings suggest that target typicality broadly affects both search guidance and verification, and that differences in typicality can be predicted by distance from an SVM classification boundary. © 2014 ARVO.

Word Criticality Analysis. MOS: 57H. Skill Levels 1 & 2.

DTIC Science & Technology

1981-09-01

systul 642 SYSUOIJMP 641 * VSLTI 2’.1l 0 32 3136 FR Ps 140 UATAK3 SYS 711 0 -A4 n 01-9ni17 *yul PASJ1 0 a 111 131 F PS f%44 SYS97DII.7O?5A45.Rtvnnmf.𔃾FF...1- 21, 2 1-191, 1o slip S G 3- 131 , I c, 3- 12. 1 - SSt.IticlINr. 3- 68,7 3- 7,1 t Sw ITL - 3- 9,2 0o 41 I I 1-111 1 , W 3- )0:3 TILF 3A 11,1 1- 7, 1...4 1 r *,*9 4HASP-11.z,,-+I...Z ..END JCI 1 ..... 1.12.54 +,M 7 FEA 07 .... ROOM 540 .... TMERC1I7 .... L I5’.’T~jF .............. " r

Limitations of contrast enhancement for infrared target identification

NASA Astrophysics Data System (ADS)

Du Bosq, Todd W.; Fanning, Jonathan D.

2009-05-01

Contrast enhancement and dynamic range compression are currently being used to improve the performance of infrared imagers by increasing the contrast between the target and the scene content. Automatic contrast enhancement techniques do not always achieve this improvement. In some cases, the contrast can increase to a level of target saturation. This paper assesses the range-performance effects of contrast enhancement for target identification as a function of image saturation. Human perception experiments were performed to determine field performance using contrast enhancement on the U.S. Army RDECOM CERDEC NVESD standard military eight target set using an un-cooled LWIR camera. The experiments compare the identification performance of observers viewing contrast enhancement processed images at various levels of saturation. Contrast enhancement is modeled in the U.S. Army thermal target acquisition model (NVThermIP) by changing the scene contrast temperature. The model predicts improved performance based on any improved target contrast, regardless of specific feature saturation or enhancement. The measured results follow the predicted performance based on the target task difficulty metric used in NVThermIP for the non-saturated cases. The saturated images reduce the information contained in the target and performance suffers. The model treats the contrast of the target as uniform over spatial frequency. As the contrast is enhanced, the model assumes that the contrast is enhanced uniformly over the spatial frequencies. After saturation, the spatial cues that differentiate one tank from another are located in a limited band of spatial frequencies. A frequency dependent treatment of target contrast is needed to predict performance of over-processed images.

Epidemiology, demographics, and outcomes of craniomaxillofacial gunshot wounds in a level I trauma center.

PubMed

Tholpady, Sunil S; DeMoss, Patrick; Murage, Kariuki P; Havlik, Robert J; Flores, Roberto L

2014-07-01

Gunshot injuries to the craniomaxillofacial region are a challenge to the trauma and reconstructive surgeon. Although management of these injuries has been standardized and early rather than late intervention is advocated, the patient characteristics before, during, and after have been poorly elucidated. A prospectively maintained Level I trauma center database was queried as to gunshot wounds of the craniomaxillofacial skeleton. Over a five-year period (2007-2011), 168 patients were identified with these injuries. Charts were reviewed as to demographics, presentations, and outcomes and these were tested for significant relationships with hospital length of stay, numbers and types of procedures, morbidity, and mortality. Gunshot wounds to the craniofacial skeleton resulted in 71 deaths in this patient population. Those that died were significantly older, presented with a lower GCS, had a shorter LOS, and a higher INR than those that lived. Subgroup analysis of mechanism demonstrated mortality was more likely to occur as a result of self-inflicted injury in whites and due to assault in the African-American population. Data gathered from this study disputes some commonly held beliefs regarding the epidemiology of gunshot injuries and should allow for better characterization of which outcomes are consistent with which presentations. Published by Elsevier Ltd.

Coexistence of Bilirubin ≥10 mg/dL and Prothrombin Time-International Normalized Ratio ≥1.6 on Day 7: A Strong Predictor of Early Graft Loss After Living Donor Liver Transplantation.

PubMed

Okamura, Yusuke; Yagi, Shintaro; Sato, Toshiya; Hata, Koichiro; Ogawa, Eri; Yoshizawa, Atsushi; Kamo, Naoko; Yamashiki, Noriyo; Okajima, Hideaki; Kaido, Toshimi; Uemoto, Shinji

2018-03-01

Early allograft dysfunction (EAD) defined by serum total bilirubin (TB) of 10 mg/dL or greater or prothrombin time-international normalized ratio (PT-INR) of 1.6 or greater on postoperative day 7 (POD 7) or aminotransferase greater than 2000 IU/L within the first week, is associated with early graft loss after deceased-donor liver transplantation. We aimed to determine the prognostic impact of the EAD definition in living-donor liver transplantation (LDLT). We analyzed the validity of the EAD definition and its impact on early graft survival in 260 adult recipients who underwent primary LDLT. Eighty-four (32.3%) patients met the EAD criteria; 59 (22.7%) and 46 (17.7%) patients had TB of 10 mg/dL or greater and PT-INR of 1.6 or greater on POD 7, respectively, and 22 (8.5%) patients satisfied both criteria. Graft survival differed significantly when stratified according to TB of 10 mg/dL or greater and PT-INR of 1.6 or greater (P < 0.0001). PT-INR of 1.6 or greater resulted in higher graft mortality (risk ratio [RR], 3.87; P < 0.0001 at 90 days; RR, 2.97; P < 0.0001 at 180 days), as did TB of 10 mg/dL or greater (RR, 1.89; P = 0.027 at 90 days; RR, 1.91; P = 0.006 at 180 days). Coexistence of TB of 10 mg/dL or greater and PT-INR of 1.6 or greater was strongly associated with early graft loss (59.1%, RR, 6.97 at 90 days; 68.2%; RR, 5.75 at 180 days). In Cox regression analysis, PT-INR of 1.6 or greater and TB of 10 mg/dL or greater on POD 7 were significant risk factors for early graft loss (hazard ratio, 4.10; 95% confidence interval, 2.35-7.18; P < 0.0001, and hazard ratio, 2.43; 95% confidence interval, 1.39-4.24; P = 0.0018, respectively). TB of 10 mg/dL or greater and/or PT-INR of 1.6 or greater on POD 7 predicted early graft loss after LDLT, and their coexistence worsened patient outcomes.

Liver as a target for oligonucleotide therapeutics.

PubMed

Sehgal, Alfica; Vaishnaw, Akshay; Fitzgerald, Kevin

2013-12-01

Oligonucleotide-based therapeutics are an emerging class of drugs that hold the promise for silencing "un-druggable" targets,thus creating unique opportunities for innovative medicines. As opposed to gene therapy, oligonucleotides are considered to be more akin to small molecule therapeutics because they are small,completely synthetic in origin, do not integrate into the host genome,and have a defined duration of therapeutic activity after which effects recover to baseline. They offer a high degree of specificity at the genetic level, thereby reducing off-target effects.At the same time, they provide a strategy for targeting any gene in the genome, including transcripts that produce mutated proteins.Oligonucleotide-based therapeutics include short interfering RNA (siRNA), that degrade target mRNA through RISC mediated RNAi; anti-miRs, that target miRNAs; miRNA mimics, that regulate target mRNA; antisense oligonucleotides, that may be working through RNAseH mediated mRNA decay; mRNA upregulation,by targeting long non-coding RNAs; and oligonucleotides induced alternative splicing [1]. All these approaches require some minimal degree of homology at the nucleic acid sequence level for them to be functional. The different mechanisms of action and their relevant activity are outlined in Fig. 1. Besides homology,RNA secondary structure has also been exploited in the case of ribozymes and aptamers, which act by binding to nucleic acids or proteins, respectively. While there have been many reports of gene knockdown and gene modulation in cell lines and mice with all these methods, very few have advanced to clinical stages.The main obstacle to date has been the safe and effective intracellular delivery of these compounds in higher species, including humans. Indeed, their action requires direct interaction with DNA/RNA within the target cell so even when one solves the issues of tissue and cellular access, intracellular/intranuclear location represents yet another barrier to

Whole-Genome Thermodynamic Analysis Reduces siRNA Off-Target Effects

PubMed Central

Chen, Xi; Liu, Peng; Chou, Hui-Hsien

2013-01-01

Small interfering RNAs (siRNAs) are important tools for knocking down targeted genes, and have been widely applied to biological and biomedical research. To design siRNAs, two important aspects must be considered: the potency in knocking down target genes and the off-target effect on any nontarget genes. Although many studies have produced useful tools to design potent siRNAs, off-target prevention has mostly been delegated to sequence-level alignment tools such as BLAST. We hypothesize that whole-genome thermodynamic analysis can identify potential off-targets with higher precision and help us avoid siRNAs that may have strong off-target effects. To validate this hypothesis, two siRNA sets were designed to target three human genes IDH1, ITPR2 and TRIM28. They were selected from the output of two popular siRNA design tools, siDirect and siDesign. Both siRNA design tools have incorporated sequence-level screening to avoid off-targets, thus their output is believed to be optimal. However, one of the sets we tested has off-target genes predicted by Picky, a whole-genome thermodynamic analysis tool. Picky can identify off-target genes that may hybridize to a siRNA within a user-specified melting temperature range. Our experiments validated that some off-target genes predicted by Picky can indeed be inhibited by siRNAs. Similar experiments were performed using commercially available siRNAs and a few off-target genes were also found to be inhibited as predicted by Picky. In summary, we demonstrate that whole-genome thermodynamic analysis can identify off-target genes that are missed in sequence-level screening. Because Picky prediction is deterministic according to thermodynamics, if a siRNA candidate has no Picky predicted off-targets, it is unlikely to cause off-target effects. Therefore, we recommend including Picky as an additional screening step in siRNA design. PMID:23484018

Assessment of cardiovascular risk and target organ damage among adult patients with primary hypertension in Thika Level 5 Hospital, Kenya: a criteria-based clinical audit.

PubMed

Mwita, Clifford Chacha; Akello, Walter; Sisenda, Gloria; Ogoti, Evans; Tivey, David; Munn, Zachary; Mbogo, David

2013-06-01

Appropriate management of hypertension reduces the risk of death from stroke and cardiac disease and includes routine assessment for target organ damage and estimation of cardiovascular risk. However, implementation of evidence-based hypertension management guidelines is unsatisfactory. We explore the use of audit and feedback as a quality improvement (QI) strategy for reducing the knowledge practice gap in hypertension care in a resource poor setting. The aim of this study is to determine the level of compliance to evidence-based guidelines on assessment of cardiovascular risk and target organ damage among patients with hypertension in Thika Level 5 Hospital in central Kenya and to implement best practice with regard to evidence utilisation among clinicians in the hospital. A retrospective clinical audit done in three phases spread over 5 months. Phase one involved identifying five audit criteria on assessment of cardiovascular risk and target organ damage in patients with hypertension and conducting a baseline audit in which compliance to audit criteria, blood pressure control and drug prescription practices were assessed. Phase two involved identifying barriers to compliance to audit criteria and strategies to overcoming these barriers. The third phase was a follow-up audit. There was no use of a cardiovascular risk assessment tool in both audits (0% vs. 0%; P = 1.00). Testing urine for haematuria and proteinuria reduced from 13% to 8% (P = 0.230) while taking a blood sample for measuring blood glucose, electrolytes and creatinine levels improved from 11% to 17% (P = 0.401). Performance of fundoscopy and electrocardiography remained unchanged at 2% and 8%, respectively (P = 0.886 and P = 0.898). High patient load was identified as the biggest barrier to implementation of best practice. Blood pressure control improved from 33% to 70% (P ≤ 0.001), whereas the proportion of patients on two or more recommended antihypertensive drugs rose

Warfarin Patients With Anemia Show Trend of Out-of-Range International Normalized Ratio Frequency With Point-of-Care Testing in an Anticoagulation Clinic.

PubMed

DeRemer, Christina E; McMichael, Bliss; Young, Henry N

2018-01-01

Many factors influence international normalized ratio (INR); however, few studies have examined the impact of anemia in warfarin patients. The primary objective of this study was to explore the relationship between in-clinic anemia and the control of INR within an anticoagulation clinic. A retrospective chart review was performed on a random sample of patients seen in an academic medical center pharmacy-managed anticoagulation clinic. Hemochron® Signature Elite machine was utilized to monitor point-of-care (POC) INR. In-clinic anemia was defined as hematocrit <32%. Statistical analyses were conducted using STATA MP a webbased platform ( https://www.stata.com/statamp/ ). Of the 300 patients analyzed, 45 (15%) patients had in-clinic anemia. Patients with in-clinic anemia were more likely to be younger ( P < .05), female ( P < .05), and have a diagnosis of sickle cell disease or anemia ( P < .05). In the unadjusted logistic regression model, patients with in-clinic anemia were less likely to have an in-range INR ( OR: 0.52; 95% CI: 0.27-0.98). The adjusted regression model did not show significance. Study results suggest that in-clinic anemia may be more prevalent among younger, female patients prescribed warfarin, and patients diagnosed with in-clinic anemia may be a risk factor for out-of-range INR. Pharmacists practicing in anticoagulation clinics can incorporate this information into patient care practice in efforts to maintain optimal management.

Warfarin-drug interactions: An emphasis on influence of polypharmacy and high doses of amoxicillin/clavulanate.

PubMed

Abdel-Aziz, Mahmoud I; Ali, Mostafa A Sayed; Hassan, Ayman K M; Elfaham, Tahani H

2016-01-01

The objective of this study was to investigate the effect of polypharmacy and high doses of amoxicillin/clavulanate on warfarin response in hospitalized patients. This was a prospective cross-sectional observational study on 120 patients from July 2013 to January 2014. Potentially interacting drugs were classified according to their tendency of increasing international normalized ratio (INR) or bleeding risk. The 87.5% of patients prescribed high-dose amoxicillin/clavulanate (10-12 g daily) compared with 28.9% of patients prescribed a normal dose (up to 3.6 g daily) had INR values ≥ 4 during the hospital stay (P ≤ .001). Increased number of potentially interacting drugs that are known to increase INR was a significant predictor of having INR values ≥ 4 (OR, 2.5; 95%CI, 1.3-4.7), and increased number of potentially interacting drugs that are known to increase bleeding risk was a significant predictor of experiencing bleeding episodes (OR, 3.1; 95%CI, 1.3-7.3). High doses of amoxicillin/clavulanate were associated with a higher risk of over-anticoagulation when combined with warfarin than were normal doses. Increased risk of having INR ≥ 4 and bleeding events was associated with increased numbers of potentially interacting drugs prescribed, indicating that polypharmacy is a problem of concern. Frequent monitoring of warfarin therapy along with patients' medications is necessary to avoid complications. © 2015, The American College of Clinical Pharmacology.

Properties of Protein Drug Target Classes

PubMed Central

Bull, Simon C.; Doig, Andrew J.

2015-01-01

Accurate identification of drug targets is a crucial part of any drug development program. We mined the human proteome to discover properties of proteins that may be important in determining their suitability for pharmaceutical modulation. Data was gathered concerning each protein’s sequence, post-translational modifications, secondary structure, germline variants, expression profile and drug target status. The data was then analysed to determine features for which the target and non-target proteins had significantly different values. This analysis was repeated for subsets of the proteome consisting of all G-protein coupled receptors, ion channels, kinases and proteases, as well as proteins that are implicated in cancer. Machine learning was used to quantify the proteins in each dataset in terms of their potential to serve as a drug target. This was accomplished by first inducing a random forest that could distinguish between its targets and non-targets, and then using the random forest to quantify the drug target likeness of the non-targets. The properties that can best differentiate targets from non-targets were primarily those that are directly related to a protein’s sequence (e.g. secondary structure). Germline variants, expression levels and interactions between proteins had minimal discriminative power. Overall, the best indicators of drug target likeness were found to be the proteins’ hydrophobicities, in vivo half-lives, propensity for being membrane bound and the fraction of non-polar amino acids in their sequences. In terms of predicting potential targets, datasets of proteases, ion channels and cancer proteins were able to induce random forests that were highly capable of distinguishing between targets and non-targets. The non-target proteins predicted to be targets by these random forests comprise the set of the most suitable potential future drug targets, and should therefore be prioritised when building a drug development programme. PMID

Effect of Patient Set-up and Respiration motion on Defining Biological Targets for Image-Guided Targeted Radiotherapy

NASA Astrophysics Data System (ADS)

McCall, Keisha C.

Identification and monitoring of sub-tumor targets will be a critical step for optimal design and evaluation of cancer therapies in general and biologically targeted radiotherapy (dose-painting) in particular. Quantitative PET imaging may be an important tool for these applications. Currently radiotherapy planning accounts for tumor motion by applying geometric margins. These margins create a motion envelope to encompass the most probable positions of the tumor, while also maintaining the appropriate tumor control and normal tissue complication probabilities. This motion envelope is effective for uniform dose prescriptions where the therapeutic dose is conformed to the external margins of the tumor. However, much research is needed to establish the equivalent margins for non-uniform fields, where multiple biological targets are present and each target is prescribed its own dose level. Additionally, the size of the biological targets and close proximity make it impractical to apply planning margins on the sub-tumor level. Also, the extent of high dose regions must be limited to avoid excessive dose to the surrounding tissue. As such, this research project is an investigation of the uncertainty within quantitative PET images of moving and displaced dose-painting targets, and an investigation of the residual errors that remain after motion management. This included characterization of the changes in PET voxel-values as objects are moved relative to the discrete sampling interval of PET imaging systems (SPECIFIC AIM 1). Additionally, the repeatability of PET distributions and the delineating dose-painting targets were measured (SPECIFIC AIM 2). The effect of imaging uncertainty on the dose distributions designed using these images (SPECIFIC AIM 3) has also been investigated. This project also included analysis of methods to minimize motion during PET imaging and reduce the dosimetric impact of motion/position-induced imaging uncertainty (SPECIFIC AIM 4).

Ultrasonic liquid level detector

DOEpatents

Kotz, Dennis M.; Hinz, William R.

2010-09-28

An ultrasonic liquid level detector for use within a shielded container, the detector being tubular in shape with a chamber at its lower end into which liquid from in the container may enter and exit, the chamber having an ultrasonic transmitter and receiver in its top wall and a reflector plate or target as its bottom wall whereby when liquid fills the chamber a complete medium is then present through which an ultrasonic wave may be transmitted and reflected from the target thus signaling that the liquid is at chamber level.

Information theoretic partitioning and confidence based weight assignment for multi-classifier decision level fusion in hyperspectral target recognition applications

NASA Astrophysics Data System (ADS)

Prasad, S.; Bruce, L. M.

2007-04-01

There is a growing interest in using multiple sources for automatic target recognition (ATR) applications. One approach is to take multiple, independent observations of a phenomenon and perform a feature level or a decision level fusion for ATR. This paper proposes a method to utilize these types of multi-source fusion techniques to exploit hyperspectral data when only a small number of training pixels are available. Conventional hyperspectral image based ATR techniques project the high dimensional reflectance signature onto a lower dimensional subspace using techniques such as Principal Components Analysis (PCA), Fisher's linear discriminant analysis (LDA), subspace LDA and stepwise LDA. While some of these techniques attempt to solve the curse of dimensionality, or small sample size problem, these are not necessarily optimal projections. In this paper, we present a divide and conquer approach to address the small sample size problem. The hyperspectral space is partitioned into contiguous subspaces such that the discriminative information within each subspace is maximized, and the statistical dependence between subspaces is minimized. We then treat each subspace as a separate source in a multi-source multi-classifier setup and test various decision fusion schemes to determine their efficacy. Unlike previous approaches which use correlation between variables for band grouping, we study the efficacy of higher order statistical information (using average mutual information) for a bottom up band grouping. We also propose a confidence measure based decision fusion technique, where the weights associated with various classifiers are based on their confidence in recognizing the training data. To this end, training accuracies of all classifiers are used for weight assignment in the fusion process of test pixels. The proposed methods are tested using hyperspectral data with known ground truth, such that the efficacy can be quantitatively measured in terms of target

Strategies for targeting primate neural circuits with viral vectors

PubMed Central

El-Shamayleh, Yasmine; Ni, Amy M.

2016-01-01

Understanding how the brain works requires understanding how different types of neurons contribute to circuit function and organism behavior. Progress on this front has been accelerated by optogenetics and chemogenetics, which provide an unprecedented level of control over distinct neuronal types in small animals. In primates, however, targeting specific types of neurons with these tools remains challenging. In this review, we discuss existing and emerging strategies for directing genetic manipulations to targeted neurons in the adult primate central nervous system. We review the literature on viral vectors for gene delivery to neurons, focusing on adeno-associated viral vectors and lentiviral vectors, their tropism for different cell types, and prospects for new variants with improved efficacy and selectivity. We discuss two projection targeting approaches for probing neural circuits: anterograde projection targeting and retrograde transport of viral vectors. We conclude with an analysis of cell type-specific promoters and other nucleotide sequences that can be used in viral vectors to target neuronal types at the transcriptional level. PMID:27052579

Evolution of regulatory targets for drinking water quality.

PubMed

Sinclair, Martha; O'Toole, Joanne; Gibney, Katherine; Leder, Karin

2015-06-01

The last century has been marked by major advances in the understanding of microbial disease risks from water supplies and significant changes in expectations of drinking water safety. The focus of drinking water quality regulation has moved progressively from simple prevention of detectable waterborne outbreaks towards adoption of health-based targets that aim to reduce infection and disease to a level well below detection limits at the community level. This review outlines the changes in understanding of community disease and waterborne risks that prompted development of these targets, and also describes their underlying assumptions and current context. Issues regarding the appropriateness of selected target values, and how continuing changes in knowledge and practice may influence their evolution, are also discussed.

UniDrug-target: a computational tool to identify unique drug targets in pathogenic bacteria.

PubMed

Chanumolu, Sree Krishna; Rout, Chittaranjan; Chauhan, Rajinder S

2012-01-01

Targeting conserved proteins of bacteria through antibacterial medications has resulted in both the development of resistant strains and changes to human health by destroying beneficial microbes which eventually become breeding grounds for the evolution of resistances. Despite the availability of more than 800 genomes sequences, 430 pathways, 4743 enzymes, 9257 metabolic reactions and protein (three-dimensional) 3D structures in bacteria, no pathogen-specific computational drug target identification tool has been developed. A web server, UniDrug-Target, which combines bacterial biological information and computational methods to stringently identify pathogen-specific proteins as drug targets, has been designed. Besides predicting pathogen-specific proteins essentiality, chokepoint property, etc., three new algorithms were developed and implemented by using protein sequences, domains, structures, and metabolic reactions for construction of partial metabolic networks (PMNs), determination of conservation in critical residues, and variation analysis of residues forming similar cavities in proteins sequences. First, PMNs are constructed to determine the extent of disturbances in metabolite production by targeting a protein as drug target. Conservation of pathogen-specific protein's critical residues involved in cavity formation and biological function determined at domain-level with low-matching sequences. Last, variation analysis of residues forming similar cavities in proteins sequences from pathogenic versus non-pathogenic bacteria and humans is performed. The server is capable of predicting drug targets for any sequenced pathogenic bacteria having fasta sequences and annotated information. The utility of UniDrug-Target server was demonstrated for Mycobacterium tuberculosis (H37Rv). The UniDrug-Target identified 265 mycobacteria pathogen-specific proteins, including 17 essential proteins which can be potential drug targets. UniDrug-Target is expected to accelerate

DeepMirTar: a deep-learning approach for predicting human miRNA targets.

PubMed

Wen, Ming; Cong, Peisheng; Zhang, Zhimin; Lu, Hongmei; Li, Tonghua

2018-06-01

MicroRNAs (miRNAs) are small noncoding RNAs that function in RNA silencing and post-transcriptional regulation of gene expression by targeting messenger RNAs (mRNAs). Because the underlying mechanisms associated with miRNA binding to mRNA are not fully understood, a major challenge of miRNA studies involves the identification of miRNA-target sites on mRNA. In silico prediction of miRNA-target sites can expedite costly and time-consuming experimental work by providing the most promising miRNA-target-site candidates. In this study, we reported the design and implementation of DeepMirTar, a deep-learning-based approach for accurately predicting human miRNA targets at the site level. The predicted miRNA-target sites are those having canonical or non-canonical seed, and features, including high-level expert-designed, low-level expert-designed, and raw-data-level, were used to represent the miRNA-target site. Comparison with other state-of-the-art machine-learning methods and existing miRNA-target-prediction tools indicated that DeepMirTar improved overall predictive performance. DeepMirTar is freely available at https://github.com/Bjoux2/DeepMirTar_SdA. lith@tongji.edu.cn, hongmeilu@csu.edu.cn. Supplementary data are available at Bioinformatics online.

Erratum.

PubMed

2015-04-01

In issue 21.1 three of the DOIs were printed incorrectly, please see below for the correct information. Andrea Giorgianni, et al. Flow-diverter stenting of post-traumatic bilateral anterior cerebral artery pseudoaneurysm: A case report. Doi: 10.15274/INR-2014-10059 Correct: Doi: 10.1177/1591019915575441 Lee-Anne Slater, et al. Effect of flow diversion with silk on aneurysm size: A single center experience. Doi: 10.15274/INR-2014-10062 Correct DOI: 10.1177/1591019915576433 Robert J McDonald, et al. Periprocedural safety of Pipeline therapy for unruptured cerebral aneurysms: Analysis of 279 Patients in a multihospital database. Doi: 10.15274/INR-2014-10074 Correct DOI: 10.1177/1591019915576289. © The Author(s) 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

Targeted support and telecare in staffed housing for people with intellectual disabilities: impact on staffing levels and objective lifestyle indicators.

PubMed

Perry, Jonathan; Firth, Caroline; Puppa, Michael; Wilson, Rick; Felce, David

2012-01-01

Increased provision of out-of-family residential support is required because of demographic changes within the intellectual disabilities population. Residential support now has to be provided in a climate requiring both financial constraint and high quality service outcomes. The aim was to evaluate the quality of life consequences of living with less intensive staff support, resulting from the introduction of more targeted staff allocation coupled with telecare. The study comprised 91 participants who lived in 33 settings. The targeted support/telecare intervention was implemented at staggered intervals in 25 of these settings (63 participants). Data on a range of participant and setting descriptors, quality of care, and a range of objective lifestyle indicators were collected at four points in time over 2 years. Impact of the intervention was evaluated using within-group comparisons over time. Comparison between pre- and post-intervention showed that staffing levels were significantly reduced by 23%, whereas they were constant in the absence of intervention. One health indicator improved in the absence of intervention and another improved following intervention. There were no significant changes in any other lifestyle indicators (safety, money, social and community activity, independence or choice). A combination of targeted support and telecare had no adverse short-term affect on participants' quality of life, but reduced staff input so it seems that they have a role to play in the strategic development of out-of-family placements for adults with intellectual disabilities. Further research is needed to explore in more detail how efficiency is achieved in practice. © 2011 Blackwell Publishing Ltd.

Coagulation tests show significant differences in patients with breast cancer.

PubMed

Tas, Faruk; Kilic, Leyla; Duranyildiz, Derya

2014-06-01

Activated coagulation and fibrinolytic system in cancer patients is associated with tumor stroma formation and metastasis in different cancer types. The aim of this study is to explore the correlation of blood coagulation assays for various clinicopathologic factors in breast cancer patients. A total of 123 female breast cancer patients were enrolled into the study. All the patients were treatment naïve. Pretreatment blood coagulation tests including PT, APTT, PTA, INR, D-dimer, fibrinogen levels, and platelet counts were evaluated. Median age of diagnosis was 51 years old (range 26-82). Twenty-two percent of the group consisted of metastatic breast cancer patients. The plasma level of all coagulation tests revealed statistically significant difference between patient and control group except for PT (p<0.001 for all variables except for PT; p=0.08). Elderly age (>50 years) was associated with higher D-dimer levels (p=0.003). Metastatic patients exhibited significantly higher D-dimer values when compared with early breast cancer patients (p=0.049). Advanced tumor stage (T3 and T4) was associated with higher INR (p=0.05) and lower PTA (p=0.025). In conclusion, coagulation tests show significant differences in patients with breast cancer.

High blood sugar levels significantly impact the prognosis of colorectal cancer patients through down-regulation of microRNA-16 by targeting Myb and VEGFR2

PubMed Central

Huang, Ching-Wen; Lu, Chien-Yu; Miao, Zhi-Feng; Chang, Se-Fen; Juo, Suh-Hang Hank; Wang, Jaw-Yuan

2016-01-01

The high prevalence of type 2 diabetes mellitus in colorectal cancer patients is a crucial public health issue worldwide. The deregulation of microRNAs has been shown to be associated with the progression of CRC; however, the effects of high blood sugar levels on miR deregulation and, in turn, CRC remain unexplored. In this study, 520 CRC patients were classified into two groups according to their blood sugar levels (≧110 or <110 mg/dL). Clinicopathologic features, clinical outcomes, and serum miR-16 levels of the two groups were then analyzed, while cell cycles, cell proliferation, migration, and cellular miR-16 expression were investigated via D-(+)-glucose administration. Additionally, the target genes of miR-16 were identified. Through multivariate analysis, both the disease-free survival and overall survival of the CRC patients were found to be associated with the UICC stage, perineural invasion, and blood glucose levels (P < 0.05). Serum miR-16 levels were significantly lower in the high blood glucose patients than in the normal blood glucose patients (P = 0.0329). With D-(+)-glucose administration, the proliferation and migration of CRC cells in vitro increased remarkably (P < 0.05), while their accumulation in the G1 phase decreased significantly. Cellular miR-16 expression was suppressed by D-(+)-glucose administration. The expression levels of two target genes, Myb and VEGFR2, were affected significantly by miR-16, while glucose administration inhibited miR-16 expression and enhanced tumor cell proliferation and migration. Hyperglycemia can impact the clinical outcomes of CRC patients, likely by inhibiting miR-16 expression and the expression of its downstream genes Myb and VEGFR2. PMID:26934556

Robust Targeting for the Smartphone Video Guidance Sensor

NASA Technical Reports Server (NTRS)

Carter, Christopher

2017-01-01

The Smartphone Video Guidance Sensor (SVGS) is a miniature, self-contained autonomous rendezvous and docking sensor developed using a commercial off the shelf Android-based smartphone. It aims to provide a miniaturized solution for rendezvous and docking, enabling small satellites to conduct proximity operations and formation flying while minimizing interference with a primary payload. Previously, the sensor was limited by a slow (2 Hz) refresh rate and its use of retro-reflectors, both of which contributed to a limited operating environment. To advance the technology readiness level, a modified approach was developed, combining a multi-colored LED target with a focused target-detection algorithm. Alone, the use of an LED system was determined to be much more reliable, though slower, than the retro-reflector system. The focused target-detection system was developed in response to this problem to mitigate the speed reduction of using color. However, it also improved the reliability. In combination these two methods have been demonstrated to dramatically increase sensor speed and allow the sensor to select the target even with significant noise interfering with the sensor, providing millimeter level accuracy at a range of two meters with a 1U target.

Robust Targeting for the Smartphone Video Guidance Sensor

NASA Technical Reports Server (NTRS)

Carter, C.

2017-01-01

The Smartphone Video Guidance Sensor (SVGS) is a miniature, self-contained autonomous rendezvous and docking sensor developed using a commercial off the shelf Android-based smartphone. It aims to provide a miniaturized solution for rendezvous and docking, enabling small satellites to conduct proximity operations and formation flying while minimizing interference with a primary payload. Previously, the sensor was limited by a slow (2 Hz) refresh rate and its use of retro-reflectors, both of which contributed to a limited operating environment. To advance the technology readiness level, a modified approach was developed, combining a multi-colored LED target with a focused target-detection algorithm. Alone, the use of an LED system was determined to be much more reliable, though slower, than the retro-reflector system. The focused target-detection system was developed in response to this problem to mitigate the speed reduction of using color. However it also improved the reliability. In combination these two methods have been demonstrated to dramatically increase sensor speed and allow the sensor to select the target even with significant noise interfering with the sensor, providing millimeter level precision at a range of two meters with a 1U target.

Reducing health inequalities with interventions targeting behavioral factors among individuals with low levels of education - A rapid review.

PubMed

Vilhelmsson, Andreas; Östergren, Per-Olof

2018-01-01

Individuals with low levels of education systematically have worse health than those with medium or high levels of education. Yet there are few examples of attempts to summarize the evidence supporting the efficacy of interventions targeting health-related behavior among individuals with low education levels, and a large part of the literature is descriptive rather than analytical. A rapid review was carried out to examine the impact of such interventions. Special attention was given to the relative impact of the interventions among individuals with low education levels and their potential to reduce health inequality. Of 1,365 articles initially identified, only 31 were deemed relevant for the review, and of those, nine met the inclusion and quality criteria. The comparability of included studies was limited due to differences in study design, sample characteristics, and definitions of exposure and outcome variables. Therefore, instead of performing a formal meta-analysis, an overall assessment of the available evidence was made and summarized into some general conclusions. We found no support for the notion that the methods used to reduce smoking decrease inequalities in health between educational groups. Evidence was also limited for decreasing inequality through interventions regarding dietary intake, physical activity and mental health. Only one study was found using an intervention designed to decrease socioeconomic inequalities by increasing the use of breast cancer screening. Thus, we concluded that there is a lack of support regarding this type of intervention as well. Therefore, the main conclusion is that solid evidence is lacking for interventions aimed at individual determinants of health and that more research is needed to fill this gap in knowledge.

Learning across Levels

ERIC Educational Resources Information Center

Stahl, Gerry

2013-01-01

The theme of this year's Computer-Supported Collaborative Learning (CSCL) 2013 conference--"To see the world 'and' a grain of sand: Learning across levels of space, time and scale"--targets a provocative challenge for CSCL, namely that the interactions of collaborative learning be understood, supported and analysed at multiple levels. As the…

Microbiological effectiveness and cost of disinfecting water by boiling in semi-urban India.

PubMed

Clasen, Thomas; McLaughlin, Catherine; Nayaar, Neeru; Boisson, Sophie; Gupta, Romesh; Desai, Dolly; Shah, Nimish

2008-09-01

Despite shortcomings, boiling is the most common means of treating water at home and the benchmark against which emerging point-of-use water treatment approaches are measured. In a 5-month study, we assessed the microbiological effectiveness and cost of the practice among 218 self-reported boilers relying on unprotected water supplies. Boiling was associated with a 99% reduction in geometric mean fecal coliforms (FCs; P < 0.001). Despite high levels of fecal contamination in source water, 59.6% of stored drinking water samples from self-reported boilers met the World Health Organization standard for safe drinking water (0 FC/100 mL), and 5.7% were between 1 and 10 FC/100 mL. Nevertheless, 40.4% of stored drinking water samples were positive for FCs, with 25.1% exceeding 100 FC/100 mL. The estimated monthly fuel cost for boiling was INR 43.8 (US$0.88) for households using liquid petroleum gas and INR 34.7 (US$0.69) for households using wood.

Intercepting moving targets: does memory from practice in a specific condition of target displacement affect movement timing?

PubMed

de Azevedo Neto, Raymundo Machado; Teixeira, Luis Augusto

2011-05-01

This investigation aimed at assessing the extent to which memory from practice in a specific condition of target displacement modulates temporal errors and movement timing of interceptive movements. We compared two groups practicing with certainty of future target velocity either in unchanged target velocity or in target velocity decrease. Following practice, both experimental groups were probed in the situations of unchanged target velocity and target velocity decrease either under the context of certainty or uncertainty about target velocity. Results from practice showed similar improvement of temporal accuracy between groups, revealing that target velocity decrease did not disturb temporal movement organization when fully predictable. Analysis of temporal errors in the probing trials indicated that both groups had higher timing accuracy in velocity decrease in comparison with unchanged velocity. Effect of practice was detected by increased temporal accuracy of the velocity decrease group in situations of decreased velocity; a trend consistent with the expected effect of practice was observed for temporal errors in the unchanged velocity group and in movement initiation at a descriptive level. An additional point of theoretical interest was the fast adaptation in both groups to a target velocity pattern different from that practiced. These points are discussed under the perspective of integration of vision and motor control by means of an internal forward model of external motion.

Price-Performance Ratio Analysis Of Enteral Vitamin K Formulations.

PubMed

Rose, Patrick; Cwikla, Gregory; Miller, Christopher; Probst, Luke; Seabury, Robert

2018-03-01

Vitamin K compounded oral solution costs significantly less on a per-milligram basis compared with tablet formulations. Current literature has shown that international normalized ratio (INR) lowering in the reversal of vitamin K antagonists (VKAs) occurs to a similar degree when using vitamin K oral solution compared with tablet formulations. To compare drug spending on vitamin K oral solution versus tablet using a price-performance ratio (PPR). A retrospective chart review was conducted at a tertiary care academic medical center to compare INR reversal of VKA-induced coagulopathy on a price basis for vitamin K oral solution versus tablet. The price of the oral solution accounted for supplies and labor. A PPR was calculated based upon the following formula: vitamin K formulation cost divided by the hourly percent change in INR following vitamin K administration. The PPR for vitamin K tablets was 27.0 compared with 5.8 for the oral solution ( P = 0.006). Utilization of vitamin K solution resulted in a significantly reduced cost per INR-lowering effect relative to commercially available tablets. Utilization of a compounded vitamin K solution represents an enticing means of cost-savings in the hospital setting.

MCC level C formulation requirements. Shuttle TAEM targeting

NASA Technical Reports Server (NTRS)

Carman, G. L.; Montez, M. N.

1980-01-01

The level C requirements for the shuttle orbiter terminal area energy management (TAEM) guidance and flight control functions to be incorporated into the Mission Control Center entry profile planning processor are described. This processor is used for preentry evaluation of the entry through landing maneuvers, and includes a simplified three degree-of-freedom model of the body rotational dynamics that is necessary to account for the effects of attitude response on the trajectory dynamics. This simulation terminates at TAEM-autoland interface.

Targeted alpha therapy using short-lived alpha-particles and the promise of nanobodies as targeting vehicle

PubMed Central

Dekempeneer, Yana; Keyaerts, Marleen; Krasniqi, Ahmet; Puttemans, Janik; Muyldermans, Serge; Lahoutte, Tony; D’huyvetter, Matthias; Devoogdt, Nick

2016-01-01

ABSTRACT Introduction: The combination of a targeted biomolecule that specifically defines the target and a radionuclide that delivers a cytotoxic payload offers a specific way to destroy cancer cells. Targeted radionuclide therapy (TRNT) aims to deliver cytotoxic radiation to cancer cells and causes minimal toxicity to surrounding healthy tissues. Recent advances using α-particle radiation emphasizes their potential to generate radiation in a highly localized and toxic manner because of their high level of ionization and short range in tissue. Areas covered: We review the importance of targeted alpha therapy (TAT) and focus on nanobodies as potential beneficial vehicles. In recent years, nanobodies have been evaluated intensively as unique antigen-specific vehicles for molecular imaging and TRNT. Expert opinion: We expect that the efficient targeting capacity and fast clearance of nanobodies offer a high potential for TAT. More particularly, we argue that the nanobodies’ pharmacokinetic properties match perfectly with the interesting decay properties of the short-lived α-particle emitting radionuclides Astatine-211 and Bismuth-213 and offer an interesting treatment option particularly for micrometastatic cancer and residual disease. PMID:27145158

Sustained high plasma plasminogen activator inhibitor-1 levels are associated with severity and mortality in septic patients.

PubMed

Lorente, Leonardo; Martín, María M; Borreguero-León, Juan M; Solé-Violán, Jordi; Ferreres, José; Labarta, Lorenzo; Díaz, César; Jiménez, Alejandro; Páramo, José A

2014-07-01

Higher plasma plasminogen activator inhibitor-1 (PAI-1) levels have been reported in septic patients. However, some questions remain unanswered, such as whether there is an association between plasma PAI-1 levels and sepsis severity and mortality, and inflammation state during the first week. Multicenter, observational and prospective study carried out in six Spanish Intensive Care Units of 260 patients with severe sepsis. Circulating levels of PAI-1 and tumour necrosis factor (TNF)-α were measured at day 1, 4 and 8. End-point was 30-day mortality. Nonsurviving septic patients (n=89) presented higher PAI-1 levels than surviving (n=171) at day 1 (58.4 (33.3-83.8) vs 36.5 (21.1-62.5) ng/mL; p<0.001), 4 (34.0 (14.7-53.3) vs 16.2 (10.2-27.4) ng/mL; p<0.001) and 8 (30.6 (16.2-47.8) vs 18.9 (10.4-29.5) ng/mL; p=0.004). We found a positive correlation of PAI-1 levels with SOFA, lactic acid, aPTT, INR and TNF-α, and negative with platelet count at day 1, 4 and 8. Logistic regression analyses showed that PAI-1 levels at day 1 (p<0.001), 4 (p<0.001) and 8 (p=0.001) were associated with 30-day mortality. On ROC curve analysis to predict 30- day survival, the area under the curve of PAI-1 levels at day 1, 4 and 8 were 0.65 (95% CI=0.58-0.72; p<0.001), 0.69 (95% CI=0.60-0.78; p<0.001) and 0.65 (95% CI=0.54-0.75; p=0.005) respectively. The most interesting findings of our study, to our knowledge the largest series reporting PAI-1 levels during follow-up in septic patients, were that plasma PAI-1 levels during the first week were associated with inflammation, severity and mortality. Copyright © 2014 Elsevier Ltd. All rights reserved.

[Target volume margins for lung cancer: internal target volume/clinical target volume].

PubMed

Jouin, A; Pourel, N

2013-10-01

The aim of this study was to carry out a review of margins that should be used for the delineation of target volumes in lung cancer, with a focus on margins from gross tumour volume (GTV) to clinical target volume (CTV) and internal target volume (ITV) delineation. Our review was based on a PubMed literature search with, as a cornerstone, the 2010 European Organisation for Research and Treatment of Cancer (EORTC) recommandations by De Ruysscher et al. The keywords used for the search were: radiotherapy, lung cancer, clinical target volume, internal target volume. The relevant information was categorized under the following headings: gross tumour volume definition (GTV), CTV-GTV margin (first tumoural CTV then nodal CTV definition), in field versus elective nodal irradiation, metabolic imaging role through the input of the PET scanner for tumour target volume and limitations of PET-CT imaging for nodal target volume definition, postoperative radiotherapy target volume definition, delineation of target volumes after induction chemotherapy; then the internal target volume is specified as well as tumoural mobility for lung cancer and respiratory gating techniques. Finally, a chapter is dedicated to planning target volume definition and another to small cell lung cancer. For each heading, the most relevant and recent clinical trials and publications are mentioned. Copyright © 2013. Published by Elsevier SAS.

Plasma clot formation and clot lysis to compare effects of different anticoagulation treatments on hemostasis in patients with atrial fibrillation.

PubMed

Königsbrügge, Oliver; Weigel, Günter; Quehenberger, Peter; Pabinger, Ingrid; Ay, Cihan

2018-02-07

The effect of direct oral anticoagulants (DOACs) on turbidimetric measurements of plasma clot formation and susceptibility to fibrinolysis may facilitate a comparison between different classes of anticoagulants in plasma samples. We obtained 424 citrate plasma samples from 226 atrial fibrillation patients on anticoagulation and 24 samples without anticoagulation serving as controls. As comparators, we measured the international normalized ratio (INR) for phenprocoumon samples (N = 166), anti-Xa for low molecular weight heparin (LMWH) samples (N = 42), and DOAC levels with mass spectrometry (dabigatran N = 40, rivaroxaban N = 110, apixaban N = 42). Plasma clot formation and lysis were recorded continuously on a photometer after addition of an activation mix (tissue factor 2 pmol/l and tissue plasminogen activator 333 ng/ml). We used linear regression and ANCOVA for correlation analysis. Clot formation lag phase was prolonged in the presence of anticoagulants in a concentration-dependent manner for DOACs (dabigatran Spearman r = 0.74; rivaroxaban r = 0.78; apixaban r = 0.72, all p < 0.0001), INR dependent for phenprocoumon (r = 0.59, p < 0.0001), anti-Xa level dependent in LMWH samples (r = 0.90, p < 0.0001). Maximum rate of clot formation and peak clot turbidity were reduced in the presence of anticoagulants, but correlated only moderately with the comparator measures of anticoagulation. The clot lysis time was inversely correlated with DOAC concentrations in the presence of recombinant thrombomodulin. A direct ex vivo comparison between the effects of different classes of anticoagulants is possible with turbidimetric measurement of plasma clot formation and lysis. Anticoagulation inhibited clot formation in a plasma concentration manner for DOACs, INR dependent for phenprocoumon, and anti-Xa dependent for LMWH. Susceptibility to fibrinolysis increased with increasing DOAC concentrations.

International Normalized Ratio values in group versus individual appointments in a pharmacist-managed anticoagulation clinic.

PubMed

Griffin, Brooke L; Burkiewicz, Jill S; Peppers, Laura R; Warholak, Terri L

2009-07-01

The clinical effectiveness of a group-visit model versus individual point-of-care visits is compared by International Normalized Ratio (INR) monitoring in a pharmacist-managed anticoagulation clinic. This study was a prospective, randomized, repeated-measures, two-group, intention-to-treat comparison and survey at a pharmacist-managed anticoagulation clinic in a managed-care ambulatory care setting. Patients were eligible for this study if they were taking warfarin therapy for at least 30 days, had a goal INR range, and provided consent. At a routine point-of-care visit, eligible patients were randomly invited to participate in group visits. The number of visits and INR values were documented prospectively for both groups during the 16-week study period. Of the 45 patients who consented and enrolled in group visits, 28 patients participated for the 16-week study period. The control group included 108 patients seen by a pharmacist for individual anticoagulation appointments. No significant difference in the percentage of INR values within the therapeutic range was detected between patients in the group-visit model versus patients receiving individual visits (59% versus 56.6%, respectively; p = 0.536). Seventy-three percent of INR values for patients who attended group visits were within +/- 0.2 of the desired INR range compared with 71.9% of those in the control group ( p = 0.994). In addition, 79% of group-visit patients were within the therapeutic range at their last clinic visit compared with 67% of patients who attended individual appointments (p = 0.225). Group visits were preferred by 51% (n = 38) of patients who completed the satisfaction survey. Of the 92 patients who declined group-visit participation, 36% indicated that the time of day that group visits were offered was inconvenient. There were no thromboembolic or hemorrhagic events documented in either group during the study period. Group visits in a pharmacist-managed anticoagulation clinic may provide

Exploiting social influence to magnify population-level behaviour change in maternal and child health: study protocol for a randomised controlled trial of network targeting algorithms in rural Honduras

PubMed Central

Shakya, Holly B; Stafford, Derek; Hughes, D Alex; Keegan, Thomas; Negron, Rennie; Broome, Jai; McKnight, Mark; Nicoll, Liza; Nelson, Jennifer; Iriarte, Emma; Ordonez, Maria; Airoldi, Edo; Fowler, James H; Christakis, Nicholas A

2017-01-01

Introduction Despite global progress on many measures of child health, rates of neonatal mortality remain high in the developing world. Evidence suggests that substantial improvements can be achieved with simple, low-cost interventions within family and community settings, particularly those designed to change knowledge and behaviour at the community level. Using social network analysis to identify structurally influential community members and then targeting them for intervention shows promise for the implementation of sustainable community-wide behaviour change. Methods and analysis We will use a detailed understanding of social network structure and function to identify novel ways of targeting influential individuals to foster cascades of behavioural change at a population level. Our work will involve experimental and observational analyses. We will map face-to-face social networks of 30 000 people in 176 villages in Western Honduras, and then conduct a randomised controlled trial of a friendship-based network-targeting algorithm with a set of well-established care interventions. We will also test whether the proportion of the population targeted affects the degree to which the intervention spreads throughout the network. We will test scalable methods of network targeting that would not, in the future, require the actual mapping of social networks but would still offer the prospect of rapidly identifying influential targets for public health interventions. Ethics and dissemination The Yale IRB and the Honduran Ministry of Health approved all data collection procedures (Protocol number 1506016012) and all participants will provide informed consent before enrolment. We will publish our findings in peer-reviewed journals as well as engage non-governmental organisations and other actors through venues for exchanging practical methods for behavioural health interventions, such as global health conferences. We will also develop a ‘toolkit’ for practitioners to

Exploiting social influence to magnify population-level behaviour change in maternal and child health: study protocol for a randomised controlled trial of network targeting algorithms in rural Honduras.

PubMed

Shakya, Holly B; Stafford, Derek; Hughes, D Alex; Keegan, Thomas; Negron, Rennie; Broome, Jai; McKnight, Mark; Nicoll, Liza; Nelson, Jennifer; Iriarte, Emma; Ordonez, Maria; Airoldi, Edo; Fowler, James H; Christakis, Nicholas A

2017-03-13

Despite global progress on many measures of child health, rates of neonatal mortality remain high in the developing world. Evidence suggests that substantial improvements can be achieved with simple, low-cost interventions within family and community settings, particularly those designed to change knowledge and behaviour at the community level. Using social network analysis to identify structurally influential community members and then targeting them for intervention shows promise for the implementation of sustainable community-wide behaviour change. We will use a detailed understanding of social network structure and function to identify novel ways of targeting influential individuals to foster cascades of behavioural change at a population level. Our work will involve experimental and observational analyses. We will map face-to-face social networks of 30 000 people in 176 villages in Western Honduras, and then conduct a randomised controlled trial of a friendship-based network-targeting algorithm with a set of well-established care interventions. We will also test whether the proportion of the population targeted affects the degree to which the intervention spreads throughout the network. We will test scalable methods of network targeting that would not, in the future, require the actual mapping of social networks but would still offer the prospect of rapidly identifying influential targets for public health interventions. The Yale IRB and the Honduran Ministry of Health approved all data collection procedures (Protocol number 1506016012) and all participants will provide informed consent before enrolment. We will publish our findings in peer-reviewed journals as well as engage non-governmental organisations and other actors through venues for exchanging practical methods for behavioural health interventions, such as global health conferences. We will also develop a 'toolkit' for practitioners to use in network-based intervention efforts, including public

Constraints in distortion-invariant target recognition system simulation

NASA Astrophysics Data System (ADS)

Iftekharuddin, Khan M.; Razzaque, Md A.

2000-11-01

Automatic target recognition (ATR) is a mature but active research area. In an earlier paper, we proposed a novel ATR approach for recognition of targets varying in fine details, rotation, and translation using a Learning Vector Quantization (LVQ) Neural Network (NN). The proposed approach performed segmentation of multiple objects and the identification of the objects using LVQNN. In this current paper, we extend the previous approach for recognition of targets varying in rotation, translation, scale, and combination of all three distortions. We obtain the analytical results of the system level design to show that the approach performs well with some constraints. The first constraint determines the size of the input images and input filters. The second constraint shows the limits on amount of rotation, translation, and scale of input objects. We present the simulation verification of the constraints using DARPA's Moving and Stationary Target Recognition (MSTAR) images with different depression and pose angles. The simulation results using MSTAR images verify the analytical constraints of the system level design.

Characterizing Health Information for Different Target Audiences.

PubMed

Sun, Yueping; Hou, Zhen; Hou, Li; Li, Jiao

2015-01-01

Different groups of audiences in health care: health professionals and health consumers, each have different information needs. Health monographs targeting different audiences are created by leveraging readers' background knowledge. The NCI's Physician Data Query (PDQ®) Cancer Information Summaries provide parallel cancer information and education resources with different target audiences. In this paper, we used targeted audience-specific cancer information PDQs to measure characteristic differences on the element level between audiences. In addition, we compared vocabulary coverage. Results show a significant difference between the professional and patient version of cancer monographs in both content organization and vocabulary. This study provides a new view to assess targeted audience-specific health information, and helps editors to improve the quality and readability of health information.

Texture metric that predicts target detection performance

NASA Astrophysics Data System (ADS)

Culpepper, Joanne B.

2015-12-01

Two texture metrics based on gray level co-occurrence error (GLCE) are used to predict probability of detection and mean search time. The two texture metrics are local clutter metrics and are based on the statistics of GLCE probability distributions. The degree of correlation between various clutter metrics and the target detection performance of the nine military vehicles in complex natural scenes found in the Search_2 dataset are presented. Comparison is also made between four other common clutter metrics found in the literature: root sum of squares, Doyle, statistical variance, and target structure similarity. The experimental results show that the GLCE energy metric is a better predictor of target detection performance when searching for targets in natural scenes than the other clutter metrics studied.

Investigation of apoptotic events at molecular level induced by SERS guided targeted theranostic nanoprobe

NASA Astrophysics Data System (ADS)

Narayanan, Nisha; Nair, Lakshmi V.; Karunakaran, Varsha; Joseph, Manu M.; Nair, Jyothi B.; N, Ramya A.; Jayasree, Ramapurath S.; Maiti, Kaustabh Kumar

2016-06-01

Herein, we have examined distinctive structural and functional variations of cellular components during apoptotic cell death induced by a targeted theranostic nanoprobe, MMP-SQ@GNR@LAH-DOX, which acted as a SERS ``on/off'' probe in the presence of a MMP protease and executed synergistic photothermal chemotherapy, as reflected by the SERS fingerprinting, corresponding to the phosphodiester backbone of DNA.Herein, we have examined distinctive structural and functional variations of cellular components during apoptotic cell death induced by a targeted theranostic nanoprobe, MMP-SQ@GNR@LAH-DOX, which acted as a SERS ``on/off'' probe in the presence of a MMP protease and executed synergistic photothermal chemotherapy, as reflected by the SERS fingerprinting, corresponding to the phosphodiester backbone of DNA. Electronic supplementary information (ESI) available. See DOI: 10.1039/c6nr03385g

TargetLink, a new method for identifying the endogenous target set of a specific microRNA in intact living cells.

PubMed

Xu, Yan; Chen, Yan; Li, Daliang; Liu, Qing; Xuan, Zhenyu; Li, Wen-Hong

2017-02-01

MicroRNAs are small non-coding RNAs acting as posttranscriptional repressors of gene expression. Identifying mRNA targets of a given miRNA remains an outstanding challenge in the field. We have developed a new experimental approach, TargetLink, that applied locked nucleic acid (LNA) as the affinity probe to enrich target genes of a specific microRNA in intact cells. TargetLink also consists a rigorous and systematic data analysis pipeline to identify target genes by comparing LNA-enriched sequences between experimental and control samples. Using miR-21 as a test microRNA, we identified 12 target genes of miR-21 in a human colorectal cancer cell by this approach. The majority of the identified targets interacted with miR-21 via imperfect seed pairing. Target validation confirmed that miR-21 repressed the expression of the identified targets. The cellular abundance of the identified miR-21 target transcripts varied over a wide range, with some targets expressed at a rather low level, confirming that both abundant and rare transcripts are susceptible to regulation by microRNAs, and that TargetLink is an efficient approach for identifying the target set of a specific microRNA in intact cells. C20orf111, one of the novel targets identified by TargetLink, was found to reside in the nuclear speckle and to be reliably repressed by miR-21 through the interaction at its coding sequence.

Manual lateralization in macaques: handedness, target laterality and task complexity.

PubMed

Regaiolli, Barbara; Spiezio, Caterina; Vallortigara, Giorgio

2016-01-01

Non-human primates represent models to understand the evolution of handedness in humans. Despite several researches have been investigating non-human primates handedness, few studies examined the relationship between target position, hand preference and task complexity. This study aimed at investigating macaque handedness in relation to target laterality and tastiness, as well as task complexity. Seven pig-tailed macaques (Macaca nemestrina) were involved in three different "two alternative choice" tests: one low-level task and two high-level tasks (HLTs). During the first and the third tests macaques could select a preferred food and a non-preferred food, whereas by modifying the design of the second test, macaques were presented with no-difference alternative per trial. Furthermore, a simple-reaching test was administered to assess hand preference in a social context. Macaques showed hand preference at individual level both in simple and complex tasks, but not in the simple-reaching test. Moreover, target position seemed to affect hand preference in retrieving an object in the low-level task, but not in the HLT. Additionally, individual hand preference seemed to be affected from the tastiness of the item to be retrieved. The results suggest that both target laterality and individual motivation might influence hand preference of macaques, especially in simple tasks.

Induction of Autophagy and Apoptosis via PI3K/AKT/TOR Pathways by Azadirachtin A in Spodoptera litura Cells.

PubMed

Shao, Xuehua; Lai, Duo; Zhang, Ling; Xu, Hanhong

2016-10-18

Azadirachtin is one of the most effective botanical insecticides and has been widely used in pest control. Toxicological reports show that azadirachtin can induce apoptosis in various insect cell lines. However, studies of azadirachtin-induced autophagy in cultured insect cells are lacking. This study reports that azadirachtin A significantly inhibits cell proliferation by inducing autophagic and apoptotic cell death in Spodoptera litura cultured cell line (SL-1 cell). Characteristic autophagolysosome and Atg8-PE (phosphatidylethanolamine) accumulation were observed by electron microscopy and western blotting, indicating that azadirachtin triggered autophagy in SL-1 cell. Furthermore, azadirachtin inhibited survival signaling by blocking the activation of PI3K, AKT and the down-stream target of rapamycin. Similar to the positive control of starvation, azadirachtin induced the activation of insulin receptor (InR) via a cellular feedback mechanism. In addition, the autophagy-related 5 (Atg5), a molecular switch of autophagy and apoptosis, was truncated (tAtg5) to trigger cytochrome c release into the cytoplasm under azadirachtin stress, which indicated that azadirachtin induced apoptosis through autophagy. Our findings suggest that azadirachtin primarily induced autophagy in SL-1 cell by dysregulating InR- and PI3K/AKT/TOR pathways, then stimulated apoptosis by activating tAtg5.

Induction of Autophagy and Apoptosis via PI3K/AKT/TOR Pathways by Azadirachtin A in Spodoptera litura Cells

PubMed Central

Shao, Xuehua; Lai, Duo; Zhang, Ling; Xu, Hanhong

2016-01-01

Azadirachtin is one of the most effective botanical insecticides and has been widely used in pest control. Toxicological reports show that azadirachtin can induce apoptosis in various insect cell lines. However, studies of azadirachtin-induced autophagy in cultured insect cells are lacking. This study reports that azadirachtin A significantly inhibits cell proliferation by inducing autophagic and apoptotic cell death in Spodoptera litura cultured cell line (SL-1 cell). Characteristic autophagolysosome and Atg8-PE (phosphatidylethanolamine) accumulation were observed by electron microscopy and western blotting, indicating that azadirachtin triggered autophagy in SL-1 cell. Furthermore, azadirachtin inhibited survival signaling by blocking the activation of PI3K, AKT and the down-stream target of rapamycin. Similar to the positive control of starvation, azadirachtin induced the activation of insulin receptor (InR) via a cellular feedback mechanism. In addition, the autophagy-related 5 (Atg5), a molecular switch of autophagy and apoptosis, was truncated (tAtg5) to trigger cytochrome c release into the cytoplasm under azadirachtin stress, which indicated that azadirachtin induced apoptosis through autophagy. Our findings suggest that azadirachtin primarily induced autophagy in SL-1 cell by dysregulating InR- and PI3K/AKT/TOR pathways, then stimulated apoptosis by activating tAtg5. PMID:27752103

Time-reversal optical tomography: detecting and locating extended targets in a turbid medium

NASA Astrophysics Data System (ADS)

Wu, Binlin; Cai, W.; Xu, M.; Gayen, S. K.

2012-03-01

Time Reversal Optical Tomography (TROT) is developed to locate extended target(s) in a highly scattering turbid medium, and estimate their optical strength and size. The approach uses Diffusion Approximation of Radiative Transfer Equation for light propagation along with Time Reversal (TR) Multiple Signal Classification (MUSIC) scheme for signal and noise subspaces for assessment of target location. A MUSIC pseudo spectrum is calculated using the eigenvectors of the TR matrix T, whose poles provide target locations. Based on the pseudo spectrum contours, retrieval of target size is modeled as an optimization problem, using a "local contour" method. The eigenvalues of T are related to optical strengths of targets. The efficacy of TROT to obtain location, size, and optical strength of one absorptive target, one scattering target, and two absorptive targets, all for different noise levels was tested using simulated data. Target locations were always accurately determined. Error in optical strength estimates was small even at 20% noise level. Target size and shape were more sensitive to noise. Results from simulated data demonstrate high potential for application of TROT in practical biomedical imaging applications.

Cost of Delivering Health Care Services in Public Sector Primary and Community Health Centres in North India

PubMed Central

Gupta, Aditi; Verma, Ramesh; Bahuguna, Pankaj; Kumar, Dinesh; Kaur, Manmeet; Kumar, Rajesh

2016-01-01

Background With the commitment of the national government to provide universal healthcare at cheap and affordable prices in India, public healthcare services are being strengthened in India. However, there is dearth of cost data for provision of health services through public system like primary & community health centres. In this study, we aim to bridge this gap in evidence by assessing the total annual and per capita cost of delivering the package of health services at PHC and CHC level. Secondly, we determined the per capita cost of delivering specific health services like cost per antenatal care visit, per institutional delivery, per outpatient consultation, per bed-day hospitalization etc. Methods We undertook economic costing of fourteen public health facilities (seven PHCs and CHCs each) in three North-Indian states viz., Haryana, Himachal Pradesh and Punjab. Bottom-up costing method was adopted for collection of data on all resources spent on delivery of health services in selected health facilities. Analysis was undertaken using a health system perspective. The joint costs like human resource, capital, and equipment were apportioned as per the time value spent on a particular service. Capital costs were discounted and annualized over the estimated life of the item. Mean annual costs and unit costs were estimated along with their 95% confidence intervals using bootstrap methodology. Results The overall annual cost of delivering services through public sector primary and community health facilities in three states of north India were INR 8.8 million (95% CI: 7,365,630–10,294,065) and INR 26.9 million (95% CI: 22,225,159.3–32,290,099.6), respectively. Human resources accounted for more than 50% of the overall costs at both the level of PHCs and CHCs. Per capita per year costs for provision of complete package of preventive, curative and promotive services at PHC and CHC were INR 170.8 (95% CI: 131.6–208.3) and INR162.1 (95% CI: 112–219

The Role of Sex Work Pay in Moderating the Effect of Mobile Phone Solicitation on Condom Practices: An Analysis of Female Sex Workers in India

PubMed Central

Navani-Vazirani, S; Heylen, E; Deardorff, J; Srikrishnan, AK; Vasudevan, CK; Solomon, D; Ekstrand, ML

2017-01-01

Mobile phones remain a largely untapped resource in the ongoing challenge to address Female Sex Worker (FSW) health, including HIV prevention services, in India. An important step towards designing effective mobile phone-based initiatives for FSWs is clarifying the contextual influences of mobile phone solicitation on sexual risk behavior. In this paper, we extend previously identified associations between mobile phone solicitation and condom practices by examining whether this association is moderated by sex work pay and offer key considerations for future research and implementation. Specifically, we conducted an analysis among 589 Indian FSWs, where FSWs who did not use mobile phones to solicit clients had the lowest mean sex work pay (INR 394/ USD 6.54) compared to FSWs who used both mobile and traditional strategies (INR 563/ USD 9.34). Our analysis indicate low paid FSWs who used mobile phones concurrently with traditional strategies had 2.46 times higher odds of inconsistent condom use compared to low paid FSWs who did not use mobile phones for client solicitation. No such effect was identified among high paid FSWs. These findings also identified group level differences among FSWs reporting different mobile phone solicitation strategies, including violence, client condom use and HIV status. Our results indicate that low pay does moderate the association between mobile phone solicitation and condom practices, but only among a sub-set of low paid FSWs. These findings also demonstrate the utility of classification by different mobile phone solicitation strategies for accurate assessment of sexual risk among mobile phone soliciting FSWs. In turn, this paves the way for novel approaches to utilize mobile phones for FSW HIV prevention. We discuss one such example, a mobile phone-based rapid screening tool for acute HIV infection targeting Indian FSWs. PMID:29202126

The Role of Sex Work Pay in Moderating the Effect of Mobile Phone Solicitation on Condom Practices: An Analysis of Female Sex Workers in India.

PubMed

Navani-Vazirani, S; Heylen, E; Deardorff, J; Srikrishnan, A K; Vasudevan, C K; Solomon, D; Ekstrand, M L

2017-01-01

Mobile phones remain a largely untapped resource in the ongoing challenge to address Female Sex Worker (FSW) health, including HIV prevention services, in India. An important step towards designing effective mobile phone-based initiatives for FSWs is clarifying the contextual influences of mobile phone solicitation on sexual risk behavior. In this paper, we extend previously identified associations between mobile phone solicitation and condom practices by examining whether this association is moderated by sex work pay and offer key considerations for future research and implementation. Specifically, we conducted an analysis among 589 Indian FSWs, where FSWs who did not use mobile phones to solicit clients had the lowest mean sex work pay (INR 394/ USD 6.54) compared to FSWs who used both mobile and traditional strategies (INR 563/ USD 9.34). Our analysis indicate low paid FSWs who used mobile phones concurrently with traditional strategies had 2.46 times higher odds of inconsistent condom use compared to low paid FSWs who did not use mobile phones for client solicitation. No such effect was identified among high paid FSWs. These findings also identified group level differences among FSWs reporting different mobile phone solicitation strategies, including violence, client condom use and HIV status. Our results indicate that low pay does moderate the association between mobile phone solicitation and condom practices, but only among a sub-set of low paid FSWs. These findings also demonstrate the utility of classification by different mobile phone solicitation strategies for accurate assessment of sexual risk among mobile phone soliciting FSWs. In turn, this paves the way for novel approaches to utilize mobile phones for FSW HIV prevention. We discuss one such example, a mobile phone-based rapid screening tool for acute HIV infection targeting Indian FSWs.

Testing Saliency Parameters for Automatic Target Recognition

NASA Technical Reports Server (NTRS)

Pandya, Sagar

2012-01-01

A bottom-up visual attention model (the saliency model) is tested to enhance the performance of Automated Target Recognition (ATR). JPL has developed an ATR system that identifies regions of interest (ROI) using a trained OT-MACH filter, and then classifies potential targets as true- or false-positives using machine-learning techniques. In this project, saliency is used as a pre-processing step to reduce the space for performing OT-MACH filtering. Saliency parameters, such as output level and orientation weight, are tuned to detect known target features. Preliminary results are promising and future work entails a rigrous and parameter-based search to gain maximum insight about this method.

Synthetic aperture radar operator tactical target acquisition research

NASA Technical Reports Server (NTRS)

Hershberger, M. L.; Craig, D. W.

1978-01-01

A radar target acquisition research study was conducted to access the effects of two levels of 13 radar sensor, display, and mission parameters on operator tactical target acquisition. A saturated fractional-factorial screening design was employed to examine these parameters. Data analysis computed ETA squared values for main and second-order effects for the variables tested. Ranking of the research parameters in terms of importance to system design revealed four variables (radar coverage, radar resolution/multiple looks, display resolution, and display size) accounted for 50 percent of the target acquisition probability variance.

Selective pressures for accurate altruism targeting: evidence from digital evolution for difficult-to-test aspects of inclusive fitness theory.

PubMed

Clune, Jeff; Goldsby, Heather J; Ofria, Charles; Pennock, Robert T

2011-03-07

Inclusive fitness theory predicts that natural selection will favour altruist genes that are more accurate in targeting altruism only to copies of themselves. In this paper, we provide evidence from digital evolution in support of this prediction by competing multiple altruist-targeting mechanisms that vary in their accuracy in determining whether a potential target for altruism carries a copy of the altruist gene. We compete altruism-targeting mechanisms based on (i) kinship (kin targeting), (ii) genetic similarity at a level greater than that expected of kin (similarity targeting), and (iii) perfect knowledge of the presence of an altruist gene (green beard targeting). Natural selection always favoured the most accurate targeting mechanism available. Our investigations also revealed that evolution did not increase the altruism level when all green beard altruists used the same phenotypic marker. The green beard altruism levels stably increased only when mutations that changed the altruism level also changed the marker (e.g. beard colour), such that beard colour reliably indicated the altruism level. For kin- and similarity-targeting mechanisms, we found that evolution was able to stably adjust altruism levels. Our results confirm that natural selection favours altruist genes that are increasingly accurate in targeting altruism to only their copies. Our work also emphasizes that the concept of targeting accuracy must include both the presence of an altruist gene and the level of altruism it produces.

Effect of Insulin Resistance on Monounsaturated Fatty Acid Levels: A Multi-cohort Non-targeted Metabolomics and Mendelian Randomization Study

PubMed Central

Ganna, Andrea; Brandmaier, Stefan; Broeckling, Corey D.; Prenni, Jessica E.; Wang-Sattler, Rui; Peters, Annette; Strauch, Konstantin; Meitinger, Thomas; Giedraitis, Vilmantas; Ärnlöv, Johan; Berne, Christian; Gieger, Christian; Ripatti, Samuli; Lind, Lars; Sundström, Johan; Ingelsson, Erik

2016-01-01

Insulin resistance (IR) and impaired insulin secretion contribute to type 2 diabetes and cardiovascular disease. Both are associated with changes in the circulating metabolome, but causal directions have been difficult to disentangle. We combined untargeted plasma metabolomics by liquid chromatography/mass spectrometry in three non-diabetic cohorts with Mendelian Randomization (MR) analysis to obtain new insights into early metabolic alterations in IR and impaired insulin secretion. In up to 910 elderly men we found associations of 52 metabolites with hyperinsulinemic-euglycemic clamp-measured IR and/or β-cell responsiveness (disposition index) during an oral glucose tolerance test. These implicated bile acid, glycerophospholipid and caffeine metabolism for IR and fatty acid biosynthesis for impaired insulin secretion. In MR analysis in two separate cohorts (n = 2,613) followed by replication in three independent studies profiled on different metabolomics platforms (n = 7,824 / 8,961 / 8,330), we discovered and replicated causal effects of IR on lower levels of palmitoleic acid and oleic acid. A trend for a causal effect of IR on higher levels of tyrosine reached significance only in meta-analysis. In one of the largest studies combining “gold standard” measures for insulin responsiveness with non-targeted metabolomics, we found distinct metabolic profiles related to IR or impaired insulin secretion. We speculate that the causal effects on monounsaturated fatty acid levels could explain parts of the raised cardiovascular disease risk in IR that is independent of diabetes development. PMID:27768686

Topical Antimycotics for Oral Candidiasis in Warfarin Users.

PubMed

Hellfritzsch, Maja; Pottegård, Anton; Pedersen, Andreas James Thestrup; Burghle, Alaa; Mouaanaki, Fatima; Hallas, Jesper; Grove, Erik Lerkevang; Damkier, Per

2017-04-01

Treatment for oral candidiasis in warfarin users may be complicated by drug-drug interactions (DDIs) between warfarin and topically applied antimycotics. However, current knowledge of these putative DDIs is merely based on case series. We therefore performed a cohort cross-over study with the objective to evaluate the potential DDIs between warfarin and miconazole oral gel or nystatin oral solution. The cohort consisted of individuals using warfarin in the period of 1998-2012 (n ≈ 7400). We collected data on cohort members' measurements of the international normalized ratio (INR) from a clinical database, and obtained information on their use of topically applied miconazole and nystatin from a regional prescription register. Potential DDIs were assessed by comparing INR values before and after initiation of an antimycotic drug. Among 17 warfarin users exposed to miconazole oral gel, the mean INR increased from 2.5 (95% CI: 2.1-2.8) to 3.8 (95% CI: 2.8-4.8) after exposure, corresponding to a mean INR increase of 1.4 (95% CI: 0.3-2.4). Among 30 warfarin users exposed to nystatin oral solution, the mean INR was 2.7 (95% CI: 2.3-3.1) before and 2.5 (95% CI: 2.2-2.9) after exposure. In conclusion, we found evidence supporting a clinically relevant drug-drug interaction between warfarin and miconazole oral gel. In contrast, we did not find any indication of an interaction between warfarin and nystatin oral solution. Nystatin rather than miconazole should be preferred when treating warfarin users for oral candidiasis. © 2016 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

Effectiveness of a real-time clinical decision support system for computerized physician order entry of plasma orders.

PubMed

Yazer, Mark H; Triulzi, Darrell J; Reddy, Vivek; Waters, Jonathan H

2013-12-01

We investigated the effect of implementing adaptive plasma ordering criteria in the computerized physician order entry (CPOE) system, with alerts that were automatically generated if the recipient's antecedent international normalized ratio (INR) did not meet the institutional criteria. In a regional health care system consisting of 11 hospitals using a common CPOE, data on the number of plasma orders and alerts that were generated were collected over a 4-month period before prescribers were required to select an indication for plasma. When adaptive ordering was implemented prescribers had to choose from prepopulated indications for plasma: INR of 1.6 or greater with bleeding, INR of 1.6 or greater before an invasive procedure, therapeutic exchange, massive transfusion, and other. Regardless of the antecedent INR the alert did not trigger if massive transfusion or plasmapheresis was selected. Information on prescribers and recipients was collected during this 5-month period. In the 4-month period before the adaptive alerts were implemented, 42.9% of the plasma orders generated an alert; in the 5-month period thereafter the alert rate was significantly lower at 27.9% (p < 0.0001). The percentage of heeded alerts increased during the adaptive alert period (24.3% vs. 17.1%, respectively, p = 0.004). A significant percentage (45%) of other plasma orders were for periprocedure or bleeding patients whose antecedent INR was less than 1.6. There were significant differences in prescriber specialties among those who ordered plasma using the other indication compared to all plasma orders. Electronic interventions improve compliance with plasma guidelines but as implemented are not sufficient to completely curtail non-evidence-based ordering. © 2013 American Association of Blood Banks.

Prediction of posthepatectomy liver failure using transient elastography in patients with hepatitis B related hepatocellular carcinoma.

PubMed

Lei, Jie-Wen; Ji, Xiao-Yu; Hong, Jun-Feng; Li, Wan-Bin; Chen, Yan; Pan, Yan; Guo, Jia

2017-12-29

It is essential to accurately predict Postoperative liver failure (PHLF) which is a life-threatening complication. Liver hardness measurement (LSM) is widely used in non-invasive assessment of liver fibrosis. The aims of this study were to explore the application of preoperative liver stiffness measurements (LSM) by transient elastography in predicting postoperative liver failure (PHLF) in patients with hepatitis B related hepatocellular carcinoma. The study included 247 consecutive patients with hepatitis B related hepatocellular carcinoma who underwent hepatectomy between May 2015 and September 2015. Detailed preoperative examinations including LSM were performed before hepatectomy. The endpoint was the development of PHLF. All of the patients had chronic hepatitis B defined as the presence of hepatitis B surface antigen (HBsAg) for more than 6 months and 76 (30.8%) had cirrhosis. PHLF occurred in 37 (14.98%) patients. Preoperative LSM (odds ratio, OR, 1.21; 95% confidence interval, 95% CI: 1.13-1.29; P < 0.001) and international normalized ratio (INR) (OR, 1.07; 95% CI: 1.01-1.12; P < 0.05) were revealed to be independent risk factors for PHLF, and a new model was defined as LSM-INR index (LSM-INR index = 0.191*LSM + 6.317*INR-11.154). The optimal cutoff values of LSM and LSM-INR index for predicting PHLF were 14 kPa (AUC 0.86, 95% CI: 0.811-0.901, P < 0.001) and -1.92 (AUC 0.87, 95% CI: 0.822-0.909, P < 0.001), respectively. LSM can be helpful for surgeons to make therapeutic decisions in patients with hepatitis B related hepatocellular carcinoma.

No Dose Adjustment is Recommended for Digoxin, Warfarin, Atorvastatin or a Combination Oral Contraceptive When Coadministered with Dulaglutide.

PubMed

de la Peña, Amparo; Cui, Xuewei; Geiser, Jeanne; Loghin, Corina

2017-11-01

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) for the treatment of type 2 diabetes mellitus are known to delay gastric emptying (GE). The potential effect of the GLP-1 RA dulaglutide on the pharmacokinetics (PK) of four orally administered drugs and on the pharmacodynamic (PD) effect of warfarin was investigated. In four separate clinical pharmacology studies, digoxin, warfarin, atorvastatin and Ortho-Cyclen ® were orally administered to healthy subjects with and without a subcutaneous dose of dulaglutide 1.5 mg. The effect of dulaglutide coadministration was assessed based on the PK parameters of key analytes. For warfarin PD, the effect of dulaglutide on the international normalized ratio (INR) was evaluated. Areas under the concentration-time curves (AUCs) with and without dulaglutide were similar for all analytes except atorvastatin, where it was reduced by 21%. Maximum concentrations (C max ) were generally lower following coadministration with dulaglutide, with statistically significant reductions (90% confidence intervals of geometric least squares means ratios outside 0.80-1.25) for all analytes except R-warfarin. For all analytes, there was a general trend for the time to C max (t max ) to increase following coadministration with dulaglutide. For warfarin, dulaglutide coadministration had no statistically significant effect on the maximum INR (INR max ); however, a 2% increase in area under the INR curve (AUC INR ) was observed. Dulaglutide did not affect the absorption of the tested medications to a clinically relevant degree. Based on the PK and PD evaluations, no dose adjustments for digoxin, warfarin, atorvastatin and Ortho-Cyclen ® are recommended when coadministered with dulaglutide. NCT01458210, NCT01436201, NCT01432938, and NCT01250834.

Evaluation of the Q analyzer, a new cap-piercing fully automated coagulometer with clotting, chromogenic, and immunoturbidometric capability.

PubMed

Kitchen, Steve; Woolley, Anita

2013-01-01

The Q analyzer is a recently launched fully automated photo-optical analyzer equipped with primary tube cap-piercing and capable of clotting, chromogenic, and immunoturbidometric tests. The purpose of the present study was to evaluate the performance characteristics of the Q analyzer with reagents from the instrument manufacturer. We assessed precision and throughput when performing coagulation screening tests, prothrombin time (PT)/international normalized ratio (INR), activated partial thromboplastin time (APTT), and fibrinogen assay by Clauss assay. We compared results with established reagent instrument combinations in widespread use. Precision of PT/INR and APTT was acceptable as indicated by total precision of around 3%. The time to first result was 3  min for an INR and 5  min for PT/APTT. The system produced 115 completed samples per hour when processing only INRs and 60 samples (120 results) per hour for PT/APTT combined. The sensitivity of the DG-APTT Synth/Q method to mild deficiency of factor VIII (FVIII), IX, and XI was excellent (as indicated by APTTs being prolonged above the upper limit of the reference range). The Q analyzer was associated with high precision, acceptable throughput, and good reliability. When used in combination with DG-PT reagent and manufacturer's instrument-specific international sensitivity index, the INRs obtained were accurate. The Q analyzer with DG-APTT Synth reagent demonstrated good sensitivity to isolated mild deficiency of FVIII, IX, and XI and had the advantage of relative insensitivity to mild FXII deficiency. Taken together, our data indicate that the Q hemostasis analyzer was suitable for routine use in combination with the reagents evaluated.

Capillary whole blood testing by a new portable monitor. Comparison with standard determination of the international normalized ratio.

PubMed

de Miguel, Dunia; Burgaleta, Carmen; Reyes, Eduardo; Pascual, Teresa

2003-07-01

We evaluated a new portable monitor (AvoSure PT PRO, Menarini Diagnostics, Firenze, Italy) developed to test the prothrombin time in capillary blood and plasma by comparing it with the standard laboratory determination. We studied 62 patients receiving acenocoumarol therapy. The international normalized ratio (INR) in capillary blood was analyzed by 2 methods: AvoSure PT PRO and Thrombotrack Nycomed Analyzer (Axis-Shield, Dundee, Scotland). Parallel studies were performed in plasma samples by a reference method using the Behring Coagulation Timer (Behring Diagnostics, Marburg, Germany). Plasma samples also were tested with the AvoSure PT PRO. Correlation was good for INR values for capillary blood and plasma samples by AvoSure PT PRO and our reference method (R2 = 0.8596) and for capillary blood samples tested by the AvoSure PT PRO and Thrombotrack Nycomed Analyzer (R2 = 0.8875). The correlation for INR in capillary blood and plasma samples by AvoSure PT PRO was 0.6939 (P < .0004). Capillary blood determinations are rapid and effective for monitoring oral anticoagulation therapy and have a high correlation to plasma determinations. AvoSure PT PRO is accurate for controlling INR in plasma and capillary blood samples, may be used in outpatient clinics, and has advantages over previous portable monitors.

PAX3-FOXO1: Zooming in on an "undruggable" target.

PubMed

Wachtel, Marco; Schäfer, Beat W

2018-06-01

Driver oncogenes are prime targets for therapy in tumors many of which, including leukemias and sarcomas, express recurrent fusion transcription factors. One specific example for such a cancer type is alveolar rhabdomyosarcoma, which is associated in the majority of cases with the fusion protein PAX3-FOXO1. Since fusion transcription factors are challenging targets for development of small molecule inhibitors, indirect inhibitory strategies for this type of oncogenes represent a more promising approach. One can envision strategies at different molecular levels including upstream modifiers and activators, epigenetic and transcriptional co-regulators, and downstream effector targets. In this review, we will discuss the current knowledge regarding potential therapeutic targets that might contribute to indirect interference with PAX3-FOXO1 activity in alveolar rhabdomyosarcoma at the different molecular levels and extrapolate these findings to fusion transcription factors in general. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Audible sonar images generated with proprioception for target analysis.

PubMed

Kuc, Roman B

2017-05-01

Some blind humans have demonstrated the ability to detect and classify objects with echolocation using palatal clicks. An audible-sonar robot mimics human click emissions, binaural hearing, and head movements to extract interaural time and level differences from target echoes. Targets of various complexity are examined by transverse displacements of the sonar and by target pose rotations that model movements performed by the blind. Controlled sonar movements executed by the robot provide data that model proprioception information available to blind humans for examining targets from various aspects. The audible sonar uses this sonar location and orientation information to form two-dimensional target images that are similar to medical diagnostic ultrasound tomograms. Simple targets, such as single round and square posts, produce distinguishable and recognizable images. More complex targets configured with several simple objects generate diffraction effects and multiple reflections that produce image artifacts. The presentation illustrates the capabilities and limitations of target classification from audible sonar images.

Incorporating signal-dependent noise for hyperspectral target detection

NASA Astrophysics Data System (ADS)

Morman, Christopher J.; Meola, Joseph

2015-05-01

The majority of hyperspectral target detection algorithms are developed from statistical data models employing stationary background statistics or white Gaussian noise models. Stationary background models are inaccurate as a result of two separate physical processes. First, varying background classes often exist in the imagery that possess different clutter statistics. Many algorithms can account for this variability through the use of subspaces or clustering techniques. The second physical process, which is often ignored, is a signal-dependent sensor noise term. For photon counting sensors that are often used in hyperspectral imaging systems, sensor noise increases as the measured signal level increases as a result of Poisson random processes. This work investigates the impact of this sensor noise on target detection performance. A linear noise model is developed describing sensor noise variance as a linear function of signal level. The linear noise model is then incorporated for detection of targets using data collected at Wright Patterson Air Force Base.

Magnetic stem cell targeting to the inner ear

NASA Astrophysics Data System (ADS)

Le, T. N.; Straatman, L.; Yanai, A.; Rahmanian, R.; Garnis, C.; Häfeli, U. O.; Poblete, T.; Westerberg, B. D.; Gregory-Evans, K.

2017-12-01

Severe sensorineural deafness is often accompanied by a loss of auditory neurons in addition to injury of the cochlear epithelium and hair cell loss. Cochlear implant function however depends on a healthy complement of neurons and their preservation is vital in achieving optimal results. We have developed a technique to target mesenchymal stem cells (MSCs) to a deafened rat cochlea. We then assessed the neuroprotective effect of systematically delivered MSCs on the survival and function of spiral ganglion neurons (SGNs). MSCs were labeled with superparamagnetic nanoparticles, injected via the systemic circulation, and targeted using a magnetized cochlea implant and external magnet. Neurotrophic factor concentrations, survival of SGNs, and auditory function were assessed at 1 week and 4 weeks after treatments and compared against multiple control groups. Significant numbers of magnetically targeted MSCs (>30 MSCs/section) were present in the cochlea with accompanied elevation of brain-derived neurotrophic factor and glial cell-derived neurotrophic factor levels (p < 0.001). In addition we saw improved survival of SGNs (approximately 80% survival at 4 weeks). Hearing threshold levels in magnetically targeted rats were found to be significantly better than those of control rats (p < 0.05). These results indicate that magnetic targeting of MSCs to the cochlea can be accomplished with a magnetized cochlear permalloy implant and an external magnet. The targeted stem cells release neurotrophic factors which results in improved SGN survival and hearing recovery. Combining magnetic cell-based therapy and cochlear implantation may improve cochlear implant function in treating deafness.

Drug target inference through pathway analysis of genomics data

PubMed Central

Ma, Haisu; Zhao, Hongyu

2013-01-01

Statistical modeling coupled with bioinformatics is commonly used for drug discovery. Although there exist many approaches for single target based drug design and target inference, recent years have seen a paradigm shift to system-level pharmacological research. Pathway analysis of genomics data represents one promising direction for computational inference of drug targets. This article aims at providing a comprehensive review on the evolving issues is this field, covering methodological developments, their pros and cons, as well as future research directions. PMID:23369829

DNA targeting specificity of RNA-guided Cas9 nucleases.

PubMed

Hsu, Patrick D; Scott, David A; Weinstein, Joshua A; Ran, F Ann; Konermann, Silvana; Agarwala, Vineeta; Li, Yinqing; Fine, Eli J; Wu, Xuebing; Shalem, Ophir; Cradick, Thomas J; Marraffini, Luciano A; Bao, Gang; Zhang, Feng

2013-09-01

The Streptococcus pyogenes Cas9 (SpCas9) nuclease can be efficiently targeted to genomic loci by means of single-guide RNAs (sgRNAs) to enable genome editing. Here, we characterize SpCas9 targeting specificity in human cells to inform the selection of target sites and avoid off-target effects. Our study evaluates >700 guide RNA variants and SpCas9-induced indel mutation levels at >100 predicted genomic off-target loci in 293T and 293FT cells. We find that SpCas9 tolerates mismatches between guide RNA and target DNA at different positions in a sequence-dependent manner, sensitive to the number, position and distribution of mismatches. We also show that SpCas9-mediated cleavage is unaffected by DNA methylation and that the dosage of SpCas9 and sgRNA can be titrated to minimize off-target modification. To facilitate mammalian genome engineering applications, we provide a web-based software tool to guide the selection and validation of target sequences as well as off-target analyses.

Lactobacillus rhamnosus ATCC 7469 exopolysaccharides synergizes with low level ionizing radiation to modulate signaling molecular targets in colorectal carcinogenesis in rats.

PubMed

Zahran, Walid E; Elsonbaty, Sawsan M; Moawed, Fatma S M

2017-08-01

Combination therapy that targets cellular signaling pathway represents an alternative therapy for the treatment of colon cancer (CRC). The present study was therefore aimed to investigate the probable interaction of Lactobacillus rhamnosus ATCC 7469 exopolysaccharides (EPS) with low level ionizing γ radiation (γ-R) exposure against dimethylhydrazine (DMH)- induced colorectal carcinogenesis in rats. Colon cancer was induced with 20mg DMH/kg BW. Rats received daily by gastric gavage 100mg EPS/Kg BW concomitant with 1Gy γ-R over two months. Colonic oxidative and inflammatory stresses were assessed. The change in the expression of p-p38 MAPK, p-STAT3, β-catenin, NF-kB, COX-2 and iNOS was evaluated by western blotting and q-PCR. It was found that DMH treatment significantly induced colon oxidative injury accompanied by inflammatory disturbance along with increased protein expression of the targeted signaling factors p-p38 MAPK, p-STAT3 and β-catenin. The mRNA gene expression of NF-kB, COX-2 and iNOS was significantly higher in DMH-treated animals. It's worthy to note that colon tissues with DMH treatment showed significant dysplasia and anaplasia of the glandular mucosal lining epithelium with loses of goblet cells formation, pleomorphism in the cells and hyperchromachia in nuclei. Interestingly, EPS treatment with γ-R exposure showed statistically significant amelioration of the oxidative and inflammatory biomarkers with modulated signaling molecular factors accompanied by improved histological structure against DMH-induced CRC. In conclusion, our findings showed that Lactobacillus rhamnosus ATCC 7469 EPS with low level γ-R in synergistic interaction are efficacious control against CRC progression throughout the modulation of key signaling growth factors associated with inflammation via antioxidant mediated anti-inflammatory and anti-proliferative activities. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Can Patients Who Develop Cerebral Death in Fulminant Liver Failure Despite Liver Transplantation Be Previously Forseen?

PubMed

Sarici, K B; Karakas, S; Otan, E; Ince, V; Koc, C; Koc, S; Bayraktar, H; Aydin, C; Kayaalp, C; Gungor, S; Kablan, Y; Yilmaz, S

2017-04-01

The outcome of medical treatment is worse in fulminant liver failure (FLF) developing on acute or chronic ground. Recently, liver transplantations with the use of living and cadaveric donors have been performed in these diseases and good results obtained. In this study, we aimed to present the factors affecting the recovery of cerebral functions after liver transplantation in hepatic encephalopathy (HE) developing in FLF, to identify irreversible patient groups and to prevent unnecessary liver transplantation. In Inonu University's Liver Transplant Institute, 69 patients who made an emergency notice to the National Coordination Center for liver transplantation owing to FLF from January 2012 to December 2015 were included in the study. Patients were divided into 2 groups. Group 1 consisted of 52 patients who underwent liver transplantation and recovered normal brain function, and group 2 had 17 patients who underwent liver transplantation and did not recover normal brain function and had cerebral death. All patients were evaluated before surgery for clinical encephalopathy stage, light reflex, and convulsions. Groups were compared and assessed according to age (>40, 10-40 and <10 years), body mass index, etiologic factor, preoperative laboratory values, transplantation type, mortality, and encephalopathy level. Multivariate analysis was done for specific parameters. Prothrombin time (PT), international normalized ratio (INR), and total bilirubin values were significantly different between the groups. There was no significant difference between the groups regarding ammonia and lactate levels. There was a statistically significant difference between the groups regarding sodium and potassium levels from serum electrolytes. However, the averages of both groups were within normal limits. pH and total bilirubin levels were meaningful for multivariate analysis. HE reversibility, mortality, and morbidity are important in patients with HE who undergo liver

Hearing Sensation Levels of Emitted Biosonar Clicks in an Echolocating Atlantic Bottlenose Dolphin

PubMed Central

Li, Songhai; Nachtigall, Paul E.; Breese, Marlee; Supin, Alexander Ya.

2012-01-01

Emitted biosonar clicks and auditory evoked potential (AEP) responses triggered by the clicks were synchronously recorded during echolocation in an Atlantic bottlenose dolphin (Tursiops truncatus) trained to wear suction-cup EEG electrodes and to detect targets by echolocation. Three targets with target strengths of −34, −28, and −22 dB were used at distances of 2 to 6.5 m for each target. The AEP responses were sorted according to the corresponding emitted click source levels in 5-dB bins and averaged within each bin to extract biosonar click-related AEPs from noise. The AEP amplitudes were measured peak-to-peak and plotted as a function of click source levels for each target type, distance, and target-present or target-absent condition. Hearing sensation levels of the biosonar clicks were evaluated by comparing the functions of the biosonar click-related AEP amplitude-versus-click source level to a function of external (in free field) click-related AEP amplitude-versus-click sound pressure level. The results indicated that the dolphin's hearing sensation levels to her own biosonar clicks were equal to that of external clicks with sound pressure levels 16 to 36 dB lower than the biosonar click source levels, varying with target type, distance, and condition. These data may be assumed to indicate that the bottlenose dolphin possesses effective protection mechanisms to isolate the self-produced intense biosonar beam from the animal's ears during echolocation. PMID:22238654

Hearing sensation levels of emitted biosonar clicks in an echolocating Atlantic bottlenose dolphin.

PubMed

Li, Songhai; Nachtigall, Paul E; Breese, Marlee; Supin, Alexander Ya

2012-01-01

Emitted biosonar clicks and auditory evoked potential (AEP) responses triggered by the clicks were synchronously recorded during echolocation in an Atlantic bottlenose dolphin (Tursiops truncatus) trained to wear suction-cup EEG electrodes and to detect targets by echolocation. Three targets with target strengths of -34, -28, and -22 dB were used at distances of 2 to 6.5 m for each target. The AEP responses were sorted according to the corresponding emitted click source levels in 5-dB bins and averaged within each bin to extract biosonar click-related AEPs from noise. The AEP amplitudes were measured peak-to-peak and plotted as a function of click source levels for each target type, distance, and target-present or target-absent condition. Hearing sensation levels of the biosonar clicks were evaluated by comparing the functions of the biosonar click-related AEP amplitude-versus-click source level to a function of external (in free field) click-related AEP amplitude-versus-click sound pressure level. The results indicated that the dolphin's hearing sensation levels to her own biosonar clicks were equal to that of external clicks with sound pressure levels 16 to 36 dB lower than the biosonar click source levels, varying with target type, distance, and condition. These data may be assumed to indicate that the bottlenose dolphin possesses effective protection mechanisms to isolate the self-produced intense biosonar beam from the animal's ears during echolocation.

A combination of process of care and clinical target among type 2 diabetes mellitus patients in general medical clinics and specialist diabetes clinics at hospital levels.

PubMed

Sieng, Sokha; Hurst, Cameron

2017-08-07

This study compares a combination of processes of care and clinical targets among patients with type 2 diabetes mellitus (T2DM) between specialist diabetes clinics (SDCs) and general medical clinics (GMCs), and how differences between these two types of clinics differ with hospital type (community, provincial and regional). Type 2 diabetes mellitus patient medical records were collected from 595 hospitals (499 community, 70 provincial, 26 regional) in Thailand between April 1 to June 30, 2012 resulting in a cross-sectional sample of 26,860 patients. Generalized linear mixed modeling was conducted to examine associations between clinic type and quality of care. The outcome variables of interest were split into clinical targets and process of care. A subsequent subgroup analysis was conducted to examine if the nature of clinical target and process of care differences between GMCs and SDCs varied with hospital type (regional, provincial, community). Regardless of the types of hospitals (regional, provincial, or community) patients attending SDCs were considerably more likely to have eye and foot exam. In terms of larger hospitals (regional and provincial) patients attending SDCs were more likely to achieve HbA1c exam, All FACE exam, BP target, and the Num7Q. Interestingly, SDCs performed better than GMCs at only provincial hospitals for LDL-C target and the All7Q. Finally, patients with T2DM who attended community hospital-GMCs had a better chance of achieving the blood pressure target than patients who attended community hospital-SDCs. Specialized diabetes clinics outperform general medical clinics for both regional and provincial hospitals for all quality of care indicators and the number of quality of care indicators achieved was never lower. However, this better performance of SDC was not observed in community hospital. Indeed, GMCs outperformed SDCs for some quality of care indicators in the community level setting.

New Equilibrium Models of Drug-Receptor Interactions Derived from Target-Mediated Drug Disposition.

PubMed

Peletier, Lambertus A; Gabrielsson, Johan

2018-05-14

In vivo analyses of pharmacological data are traditionally based on a closed system approach not incorporating turnover of target and ligand-target kinetics, but mainly focussing on ligand-target binding properties. This study incorporates information about target and ligand-target kinetics parallel to binding. In a previous paper, steady-state relationships between target- and ligand-target complex versus ligand exposure were derived and a new expression of in vivo potency was derived for a circulating target. This communication is extending the equilibrium relationships and in vivo potency expression for (i) two separate targets competing for one ligand, (ii) two different ligands competing for a single target and (iii) a single ligand-target interaction located in tissue. The derived expressions of the in vivo potencies will be useful both in drug-related discovery projects and mechanistic studies. The equilibrium states of two targets and one ligand may have implications in safety assessment, whilst the equilibrium states of two competing ligands for one target may cast light on when pharmacodynamic drug-drug interactions are important. The proposed equilibrium expressions for a peripherally located target may also be useful for small molecule interactions with extravascularly located targets. Including target turnover, ligand-target complex kinetics and binding properties in expressions of potency and efficacy will improve our understanding of within and between-individual (and across species) variability. The new expressions of potencies highlight the fact that the level of drug-induced target suppression is very much governed by target turnover properties rather than by the target expression level as such.

Mitochondrial targeting of recombinant RNAs modulates the level of a heteroplasmic mutation in human mitochondrial DNA associated with Kearns Sayre Syndrome

PubMed Central

Comte, Caroline; Tonin, Yann; Heckel-Mager, Anne-Marie; Boucheham, Abdeldjalil; Smirnov, Alexandre; Auré, Karine; Lombès, Anne; Martin, Robert P.; Entelis, Nina; Tarassov, Ivan

2013-01-01

Mitochondrial mutations, an important cause of incurable human neuromuscular diseases, are mostly heteroplasmic: mutated mitochondrial DNA is present in cells simultaneously with wild-type genomes, the pathogenic threshold being generally >70% of mutant mtDNA. We studied whether heteroplasmy level could be decreased by specifically designed oligoribonucleotides, targeted into mitochondria by the pathway delivering RNA molecules in vivo. Using mitochondrially imported RNAs as vectors, we demonstrated that oligoribonucleotides complementary to mutant mtDNA region can specifically reduce the proportion of mtDNA bearing a large deletion associated with the Kearns Sayre Syndrome in cultured transmitochondrial cybrid cells. These findings may be relevant to developing of a new tool for therapy of mtDNA associated diseases. PMID:23087375

Gene silencing in Tribolium castaneum as a tool for the targeted identification of candidate RNAi targets in crop pests.

PubMed

Knorr, Eileen; Fishilevich, Elane; Tenbusch, Linda; Frey, Meghan L F; Rangasamy, Murugesan; Billion, Andre; Worden, Sarah E; Gandra, Premchand; Arora, Kanika; Lo, Wendy; Schulenberg, Greg; Valverde-Garcia, Pablo; Vilcinskas, Andreas; Narva, Kenneth E

2018-02-01

RNAi shows potential as an agricultural technology for insect control, yet, a relatively low number of robust lethal RNAi targets have been demonstrated to control insects of agricultural interest. In the current study, a selection of lethal RNAi target genes from the iBeetle (Tribolium castaneum) screen were used to demonstrate efficacy of orthologous targets in the economically important coleopteran pests Diabrotica virgifera virgifera and Meligethes aeneus. Transcript orthologs of 50 selected genes were analyzed in D. v. virgifera diet-based RNAi bioassays; 21 of these RNAi targets showed mortality and 36 showed growth inhibition. Low dose injection- and diet-based dsRNA assays in T. castaneum and D. v. virgifera, respectively, enabled the identification of the four highly potent RNAi target genes: Rop, dre4, ncm, and RpII140. Maize was genetically engineered to express dsRNA directed against these prioritized candidate target genes. T 0 plants expressing Rop, dre4, or RpII140 RNA hairpins showed protection from D. v. virgifera larval feeding damage. dsRNA targeting Rop, dre4, ncm, and RpII140 in M. aeneus also caused high levels of mortality both by injection and feeding. In summary, high throughput systems for model organisms can be successfully used to identify potent RNA targets for difficult-to-work with agricultural insect pests.

Retrospective evaluation of a method to predict fresh-frozen plasma dosage in anticoagulated patients.

PubMed

Frazee, Lawrence A; Bourguet, Claire C; Gutierrez, Wilson; Elder-Arrington, Jacinta; Elackattu, Alphi E P; Haller, Nairmeen Awad

2008-01-01

In the United States, fresh-frozen plasma (FFP) is commonly used for urgent reversal of warfarin; however, dosage recommendations are difficult to find. If validated, a proposed method that uses a nonlinear relationship between international normalized ratio (INR) and clotting factor activity (CFa) would be useful. This study retrospectively evaluated a proposed equation with adult medical inpatients who received FFP for warfarin reversal. For each patient the equation was used to predict the dose of FFP required to achieve the observed change in INR, which was then compared to the actual dose. The equation was considered successful if the predicted dose was within +/-20% of the actual dose. Subgroup analyses included subjects who received concomitant vitamin K; subjects with supratherapeutic INRs (>3); and subjects with significantly elevated INRs (>5). Of the 209 patients screened, 91 met criteria for inclusion in the study. Use of the equation to calculate the predicted dose of FFP was successful in 11 patients (12.1%) with use of actual body weight for prediction and in 23 patients (25.3%) with use of ideal body weight (P = 0.02). The equation performed similarly in all subgroups analyzed. The mean predicted FFP dose was significantly greater than the actual dose in all patients when actual body weight was used (925.2 mL vs. 620.6 mL; P < 0.001). Least-squares regression modeling of repeat INR (converted to CFa) produced a model that accounted for 57% of the variance in repeat INR. The value predicted from the model was closer to the actual CFa than was the value predicted from the published equation in every comparison, but it was statistically different only when actual body weight was used. This study revealed that a published equation for calculation of FFP dose to reverse oral anticoagulation resulted in doses that were significantly higher than the actual dose. Use of ideal body weight improved accuracy but was still not successful for the majority of

Barriers and facilitators to reducing frequent laboratory testing for patients who are stable on warfarin: a mixed methods study of de-implementation in five anticoagulation clinics.

PubMed

Barnes, Geoffrey D; Misirliyan, Sevan; Kaatz, Scott; Jackson, Elizabeth A; Haymart, Brian; Kline-Rogers, Eva; Kozlowski, Jay; Krol, Gregory; Froehlich, James B; Sales, Anne

2017-07-14

Patients on chronic warfarin therapy require regular laboratory monitoring to safely manage warfarin. Recent studies have challenged the need for routine monthly blood draws in the most stable warfarin-treated patients, suggesting the safety of less frequent laboratory testing (up to every 12 weeks). De-implementation efforts aim to reduce the use of low-value clinical practices. To explore barriers and facilitators of a de-implementation effort to reduce the use of frequent laboratory tests for patients with stable warfarin management in nurse/pharmacist-run anticoagulation clinics, we performed a mixed-methods study conducted within a state-wide collaborative quality improvement collaborative. Using a mixed-methods approach, we conducted post-implementation semi-structured interviews with a total of eight anticoagulation nurse or pharmacist staff members at five participating clinic sites to assess barriers and facilitators to de-implementing frequent international normalized ratio (INR) laboratory testing among patients with stable warfarin control. Interview guides were based on the Tailored Implementation for Chronic Disease (TICD) framework. Informed by interview themes, a survey was developed and administered to all anticoagulation clinical staff (n = 62) about their self-reported utilization of less frequent INR testing and specific barriers to de-implementing the standard (more frequent) INR testing practice. From the interviews, four themes emerged congruent with TICD domains: (1) staff overestimating their actual use of less frequent INR testing (individual health professional factors), (2) barriers to appropriate patient engagement (incentives and resources), (3) broad support for an electronic medical record flag to identify potentially eligible patients (incentives and resources), and (4) the importance of personalized nurse/pharmacist feedback (individual health professional factors). In the survey (65% response rate), staff report offering less

Impact of optimal anticoagulation therapy on chronic venous ulcer healing in thrombophilic patients with post-thrombotic syndrome.

PubMed

Hinojosa, C A; Olivares-Cruz, S; Laparra-Escareno, H; Sanchez-Castro, S; Tamayo-Garcia, B; Anaya-Ayala, J E

2016-12-02

Post-thrombotic syndrome (PTS) is the long-term sequelae of deep venous thrombosis (DVT). PTS clinical manifestations include chronic leg pain, oedema, lipodermatosclerosis and ulcers. The objective of this study is to determine in patients with documented history of thrombophilias and DVT whether the number of previous thrombotic events and optimal anticoagulation therapy are associated with the time to venous ulcer healing following the start of compression therapy. Retrospective analysis performed in thrombophilic patients under the age of 50 years old with chronic venous ulcers secondary to DVT at the wound clinic in the National Institute of Medical Sciences and Nutrition 'Salvador Zubirán ' in Mexico City. Variables such as the number or episodes of thrombotic events, type of hypercoagulable disorder, optimal anticoagulation therapy with Warfarin monitored by therapeutic International Normalised Ratio (INR) (2-3) and compliance to compression therapy were examined. Patients that underwent superficial or perforator vein interruption or endovascular recanalisation of deep veins were excluded from the study. From a database of 29 patients with chronic venous ulcers followed in our clinic from January 1992 to September 2012, only 13 patients (61% female) met the inclusion criteria. Mean age±standard deviation (SD) was 32±12 years old. Of these, seven (54%) patients with suboptimal INR presented with an average of two previous thrombotic events and the remaining six (46%) patients with optimal INR only one event (p=0.28), the mean time to the clinical manifestation of a venous ulcer after the first episode of DVT was 39 months (range: 12-72) for patients with suboptimal INR and 82 months (range: 12-216) for those with optimal anticoagulation therapy (p=0.11). During the mean follow-up period of 52 months, all patients in optimal anticoagulation healed their ulcer; their mean time for wound healing was 44 months (range: 4-102). In the suboptimal INR group, only

Less is more: Patient-level meta-analysis reveals paradoxical dose-response effects of a computer-based social anxiety intervention targeting attentional bias.

PubMed

Price, Rebecca B; Kuckertz, Jennie M; Amir, Nader; Bar-Haim, Yair; Carlbring, Per; Wallace, Meredith L

2017-12-01

The past decade of research has seen considerable interest in computer-based approaches designed to directly target cognitive mechanisms of anxiety, such as attention bias modification (ABM). By pooling patient-level datasets from randomized controlled trials of ABM that utilized a dot-probe training procedure, we assessed the impact of training "dose" on relevant outcomes among a pooled sample of 693 socially anxious adults. A paradoxical effect of the number of training trials administered was observed for both posttraining social anxiety symptoms and behavioral attentional bias (AB) toward threat (the target mechanism of ABM). Studies administering a large (>1,280) number of training trials showed no benefit of ABM over control conditions, while those administering fewer training trials showed significant benefit for ABM in reducing social anxiety (P = .02). These moderating effects of dose were not better explained by other examined variables and previously identified moderators, including patient age, training setting (laboratory vs. home), or type of anxiety assessment (clinician vs. self-report). Findings inform the optimal dosing for future dot-probe style ABM applications in both research and clinical settings, and suggest several novel avenues for further research. © 2017 Wiley Periodicals, Inc.

A General Strategy for Targeting Drugs to Bone.

PubMed

Jahnke, Wolfgang; Bold, Guido; Marzinzik, Andreas L; Ofner, Silvio; Pellé, Xavier; Cotesta, Simona; Bourgier, Emmanuelle; Lehmann, Sylvie; Henry, Chrystelle; Hemmig, René; Stauffer, Frédéric; Hartwieg, J Constanze D; Green, Jonathan R; Rondeau, Jean-Michel

2015-11-23

Targeting drugs to their desired site of action can increase their safety and efficacy. Bisphosphonates are prototypical examples of drugs targeted to bone. However, bisphosphonate bone affinity is often considered too strong and cannot be significantly modulated without losing activity on the enzymatic target, farnesyl pyrophosphate synthase (FPPS). Furthermore, bisphosphonate bone affinity comes at the expense of very low and variable oral bioavailability. FPPS inhibitors were developed with a monophosphonate as a bone-affinity tag that confers moderate affinity to bone, which can furthermore be tuned to the desired level, and the relationship between structure and bone affinity was evaluated by using an NMR-based bone-binding assay. The concept of targeting drugs to bone with moderate affinity, while retaining oral bioavailability, has broad application to a variety of other bone-targeted drugs. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Factors associated with tumor size of hepatocellular carcinoma

NASA Astrophysics Data System (ADS)

Siregar, G. A.; Buulolo, B. A.

2018-03-01

Determining the association of age and laboratory parameters with tumor size of hepatocellular carcinoma (HCC). The study was at Adam Malik Hospital Medan from June- December 2016. 100 HCC patients were enrolled; those with excluding liver metastatic. Baseline characteristics of gender, age, obtaining etiology of HCC. Liver function tests, viral marker, and INR were done. Based on tumor size from abdomen CT, patients were three groups: tumor size below 3 cm, 3-5 cm, and above 5 cm size. Patients were also divided based on Child-Pugh class. Correlation of age and laboratory results with tumor size of HCC patients were analyzed. Age have negative correlation with tumor size in HCC patients (r=-0.297, p=0.032) while AFP have positive correlation with tumor size (r0.446, p=<0.001). Total bilirubin, AST, and ALT have negative correlation but non-significant (r=-0.045, -0.078, - 0.126 respectively). Albumin and INR have positive correlation but non-significant (r=0.021, 0.112 respectively). Our study suggests that older age correlates with smaller tumor size, while AFP level has a significant correlation with tumor size in HCC patients. AFP level may be a useful marker for determining the prognosis of HCC patients.

Harnessing the PI3K/Akt/mTOR pathway in T-cell acute lymphoblastic leukemia: Eliminating activity by targeting at different levels

PubMed Central

Ricci, Francesca; Tabellini, Giovanna; Chiarini, Francesca; Tazzari, Pier Luigi; Melchionda, Fraia; Buontempo, Francesca; Pagliaro, Pasqualepaolo; Pession, Andrea; McCubrey, James A.; Martelli, Alberto M.

2012-01-01

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignant hematological disorder arising in the thymus from T-cell progenitors. T-ALL mainly affects children and young adults, and remains fatal in 20% of adolescents and 50% of adults, despite progress in polychemotherapy protocols. Therefore, innovative targeted therapies are desperately needed for patients with a dismal prognosis. Aberrant activation of PI3K/Akt/mTOR signaling is a common event in T-ALL patients and portends a poor prognosis. Preclinical studies have highlighted that modulators of PI3K/Akt/mTOR signaling could have a therapeutic relevance in T-ALL. However, the best strategy for inhibiting this highly complex signal transduction pathway is still unclear, as the pharmaceutical companies have disclosed an impressive array of small molecules targeting this signaling network at different levels. Here, we demonstrate that a dual PI3K/PDK1 inhibitor, NVP-BAG956, displayed the most powerful cytotoxic effects against T-ALL cell lines and primary patients samples, when compared with a pan class I PI3K inhibitor (GDC-0941), an allosteric Akt inhibitor (MK-2206), an mTORC1 allosteric inhibitor (RAD-001), or an ATP-competitive mTORC1/mTORC2 inhibitor (KU-63794). Moreover, we also document that combinations of some of the aforementioned drugs strongly synergized against T-ALL cells at concentrations well below their respective IC50. This observation indicates that vertical inhibition at different levels of the PI3K/Akt/mTOR network could be considered as a future innovative strategy for treating T-ALL patients. PMID:22885370

Harnessing the PI3K/Akt/mTOR pathway in T-cell acute lymphoblastic leukemia: eliminating activity by targeting at different levels.

PubMed

Bressanin, Daniela; Evangelisti, Camilla; Ricci, Francesca; Tabellini, Giovanna; Chiarini, Francesca; Tazzari, Pier Luigi; Melchionda, Fraia; Buontempo, Francesca; Pagliaro, Pasqualepaolo; Pession, Andrea; McCubrey, James A; Martelli, Alberto M

2012-08-01

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignant hematological disorder arising in the thymus from T-cell progenitors. T-ALL mainly affects children and young adults, and remains fatal in 20% of adolescents and 50% of adults, despite progress in polychemotherapy protocols. Therefore, innovative targeted therapies are desperately needed for patients with a dismal prognosis. Aberrant activation of PI3K/Akt/mTOR signaling is a common event in T-ALL patients and portends a poor prognosis. Preclinical studies have highlighted that modulators of PI3K/Akt/mTOR signaling could have a therapeutic relevance in T-ALL. However, the best strategy for inhibiting this highly complex signal transduction pathway is still unclear, as the pharmaceutical companies have disclosed an impressive array of small molecules targeting this signaling network at different levels. Here, we demonstrate that a dual PI3K/PDK1 inhibitor, NVP-BAG956, displayed the most powerful cytotoxic affects against T-ALL cell lines and primary patients samples, when compared with a pan class I PI3K inhibitor (GDC-0941), an allosteric Akt inhibitor (MK-2206), an mTORC1 allosteric inhibitor (RAD-001), or an ATP-competitive mTORC1/mTORC2 inhibitor (KU63794). Moreover, we also document that combinations of some of the aforementioned drugs strongly synergized against T-ALL cells at concentrations well below their respective IC50. This observation indicates that vertical inhibition at different levels of the PI3K/Akt/mTOR network could be considered as a future innovative strategy for treating T-ALL patients.

Stereotypical rapid source level regulation in the harbour porpoise biosonar

NASA Astrophysics Data System (ADS)

Linnenschmidt, Meike; Kloepper, Laura N.; Wahlberg, Magnus; Nachtigall, Paul E.

2012-09-01

Some odontocetes and bats vary both click intensity and receiver sensitivity during echolocation, depending on target range. It is not known how this so-called automatic gain control is regulated by the animal. The source level of consecutive echolocation clicks from a harbour porpoise was measured with a hydrophone array while the animal detected an aluminium cylinder at 2, 4 or 8 m distance in a go/no-go paradigm. On-axis clicks had source levels of 145-174 dB re 1 μPa peak-to-peak. During target-present trials the click trains reached comparable source levels independent of the range to the target after three clicks. After an additional click, the source level was reduced for the 2 and 4 m trials until it equalled the one-way transmission loss. During target-absent trials, the source level remained high throughout the entire click train. Given typical values of harbour porpoise inter-click intervals, the source level reduction commenced within a few 100 ms from the first click in the click train. This may indicate a sub-cortically regulated source level regulation in the harbour porpoise.

Stereotypical rapid source level regulation in the harbour porpoise biosonar.

PubMed

Linnenschmidt, Meike; Kloepper, Laura N; Wahlberg, Magnus; Nachtigall, Paul E

2012-09-01

Some odontocetes and bats vary both click intensity and receiver sensitivity during echolocation, depending on target range. It is not known how this so-called automatic gain control is regulated by the animal. The source level of consecutive echolocation clicks from a harbour porpoise was measured with a hydrophone array while the animal detected an aluminium cylinder at 2, 4 or 8 m distance in a go/no-go paradigm. On-axis clicks had source levels of 145-174 dB re 1 μPa peak-to-peak. During target-present trials the click trains reached comparable source levels independent of the range to the target after three clicks. After an additional click, the source level was reduced for the 2 and 4 m trials until it equalled the one-way transmission loss. During target-absent trials, the source level remained high throughout the entire click train. Given typical values of harbour porpoise inter-click intervals, the source level reduction commenced within a few 100 ms from the first click in the click train. This may indicate a sub-cortically regulated source level regulation in the harbour porpoise.

Comparative Response of Platelet fV and Plasma fV to Activated Protein C and Relevance to a Model of Acute Traumatic Coagulopathy

DTIC Science & Technology

2014-06-12

inducing concen tration. To test this hypothesis, we investigated the concentration of aPC required to induce significant delays in clot time, decrease...instructions and mixed with 50 ml plasma ( pre incubated at 37 uC). The Mean Normal PT is listed as 13.5 s for this device, and INR is calculated by...and pair wise comparison Bonferroni posttests . Results Nanomolar aPC Is Required to Prolong PT/INR PT measurements in fVdp are delayed compared to

MitoQ--a mitochondria-targeted antioxidant.

PubMed

Tauskela, Joseph S

2007-06-01

MitoQ is an orally active antioxidant that has the ability to target mitochondrial dysfunction. The agent is currently under development by Antipodean Pharmaceuticals Inc in phase II clinical trials for Parkinson's disease and liver damage associated with HCV infection. MitoQ has demonstrated encouraging preclinical results in numerous studies in isolated mitochondria, cells and tissues undergoing oxidative stress and apoptotic death. MitoQ aims to not only mimic the role of the endogenous mitochondrial antioxidant coenzyme Q10 (CoQ10), but also to augment substantially the antioxidant capacity of CoQ to supraphysiological levels in a mitochondrial membrane potential-dependent manner. MitoQ represents the first foray into the clinic in an attempt to deliver an antioxidant to an intracellular region that is responsible for the formation of increased levels of potentially deleterious reactive oxygen species. Results from the clinical trials with MitoQ will have important repercussions on the relevance of a mitochondrial-targeted approach.

PSMA-Targeted Theranostic Nanocarrier for Prostate Cancer

PubMed Central

Flores, Orielyz; Santra, Santimukul; Kaittanis, Charalambos; Bassiouni, Rania; Khaled, Amr S; Khaled, Annette R.; Grimm, Jan; Perez, J Manuel

2017-01-01

Herein, we report the use of a theranostic nanocarrier (Folate-HBPE(CT20p)) to deliver a therapeutic peptide to prostate cancer tumors that express PSMA (folate hydrolase 1). The therapeutic peptide (CT20p) targets and inhibits the chaperonin-containing TCP-1 (CCT) protein-folding complex, is selectively cytotoxic to cancer cells, and is non-toxic to normal tissue. With the delivery of CT20p to prostate cancer cells via PSMA, a dual level of cancer specificity is achieved: (1) selective targeting to PSMA-expressing prostate tumors, and (2) specific cytotoxicity to cancer cells with minimal toxicity to normal cells. The PSMA-targeting theranostic nanocarrier can image PSMA-expressing cells and tumors when a near infrared dye is used as cargo. Meanwhile, it can be used to treat PSMA-expressing tumors when a therapeutic, such as the CT20p peptide, is encapsulated within the nanocarrier. Even when these PSMA-targeting nanocarriers are taken up by macrophages, minimal cell death is observed in these cells, in contrast with doxorubicin-based therapeutics that result in significant macrophage death. Incubation of PSMA-expressing prostate cancer cells with the Folate-HBPE(CT20p) nanocarriers induces considerable changes in cell morphology, reduction in the levels of integrin β1, and lower cell adhesion, eventually resulting in cell death. These results are relevant as integrin β1 plays a key role in prostate cancer invasion and metastatic potential. In addition, the use of the developed PSMA-targeting nanocarrier facilitates the selective in vivo delivery of CT20p to PSMA-positive tumor, inducing significant reduction in tumor size. PMID:28744329

Effect of vitamin K2 on the anticoagulant activity of warfarin during the perioperative period of catheter ablation: Population analysis of retrospective clinical data.

PubMed

Zhou, Zhi; Yano, Ikuko; Odaka, Sumiko; Morita, Yosuke; Shizuta, Satoshi; Hayano, Mamoru; Kimura, Takeshi; Akaike, Akinori; Inui, Ken-Ichi; Matsubara, Kazuo

2016-01-01

Catheter ablation is a non-medication therapy for atrial fibrillation, and during the procedure, warfarin is withdrawn in the preoperative period to prevent the risk of bleeding. In case of emergency, vitamin K2 can be intravenously administered to antagonize the anticoagulant activity of warfarin. The aims of this study were to conduct population pharmacokinetic/pharmacodynamic modeling for retrospective clinical data and to investigate the effect of vitamin K2 on the anticoagulant activity of warfarin in the perioperative period of catheter ablation. A total of 579 international normalized ratio (INR) values of prothrombin time from 100 patients were analyzed using the nonlinear mixed-effects modeling program NONMEM. A 1-compartment model was adapted to the pharmacokinetics of warfarin and vitamin K2, and the indirect response model was used to investigate the relationship between plasma concentration and the pharmacodynamic response of warfarin and vitamin K2. Since no plasma concentration data for warfarin and vitamin K2 were available, 3 literally available pharmacokinetic parameters were used to simultaneously estimate 1 pharmacokinetic parameter and 5 pharmacodynamic parameters. The population parameters obtained not only successfully explained the observed INR values, but also indicated an increase in sensitivity to warfarin in patients with reduced renal function. Simulations using these parameters indicated that vitamin K2 administration of more than 20 mg caused a slight dose-dependent decrease in INR on the day of catheter ablation and a delayed INR elevation after warfarin re-initiation. A pharmacokinetic/pharmacodynamic model was successfully built to explain the retrospective INR data during catheter ablation. Simulation studies suggest that vitamin K2 should be administered with care and that more than 20 mg is unnecessary in the preoperative period of catheter ablation.

Normalization of coagulopathy is associated with improved outcome after isolated traumatic brain injury.

PubMed

Epstein, Daniel S; Mitra, Biswadev; Cameron, Peter A; Fitzgerald, Mark; Rosenfeld, Jeffrey V

2016-07-01

Acute traumatic coagulopathy (ATC) has been reported in the setting of isolated traumatic brain injury (iTBI) and is associated with poor outcomes. We aimed to evaluate the effectiveness of procoagulant agents administered to patients with ATC and iTBI during resuscitation, hypothesizing that timely normalization of coagulopathy may be associated with a decrease in mortality. A retrospective review of the Alfred Hospital trauma registry, Australia, was conducted and patients with iTBI (head Abbreviated Injury Score [AIS] ⩾3 and all other body AIS <3) and coagulopathy (international normalized ratio ⩾1.3) were selected for analysis. Data on procoagulant agents used (fresh frozen plasma, platelets, cryoprecipitate, prothrombin complex concentrates, tranexamic acid, vitamin K) were extracted. Among patients who had achieved normalization of INR or survived beyond 24hours and were not taking oral anticoagulants, the association of normalization of INR and death at hospital discharge was analyzed using multivariable logistic regression analysis. There were 157 patients with ATC of whom 68 (43.3%) received procoagulant products within 24hours of presentation. The median time to delivery of first products was 182.5 (interquartile range [IQR] 115-375) minutes, and following administration of coagulants, time to normalization of INR was 605 (IQR 274-1146) minutes. Normalization of INR was independently associated with significantly lower mortality (adjusted odds ratio 0.10; 95% confidence interval 0.03-0.38). Normalization of INR was associated with improved mortality in patients with ATC in the setting of iTBI. As there was a substantial time lag between delivery of products and eventual normalization of coagulation, specific management of coagulopathy should be implemented as early as possible. Copyright © 2016 Elsevier Ltd. All rights reserved.

Warfarin Poisoning with Delayed Rebound Toxicity.

PubMed

Berling, Ingrid; Mostafa, Ahmed; Grice, Jeffrey E; Roberts, Michael S; Isbister, Geoffrey K

2017-02-01

Intentional poisoning with warfarin is not the same as over-anticoagulation, for which guidelines exist. The coagulopathy resulting from a warfarin overdose is reversed with vitamin K 1 , the dose and timing of which is often guided by experience with the management of over-anticoagulation with warfarin therapy, rather than acute overdose. We report a case of a 50-year-old man who ingested an unknown amount of his warfarin, venlafaxine, and paracetamol. He presented with an international normalized ratio (INR) of 2.5, which steadily increased over 24 h to 7, despite receiving an initial 1 mg of vitamin K 1 . He was then treated with 5 mg vitamin K 1 , and once the INR returned to 4.5, 40 h post ingestion, he was discharged home. He was also treated with a full course of acetylcysteine for the paracetamol overdose. The following day his INR rebounded to 8.5 and he suffered a spontaneous epistaxis requiring readmission; he was treated with low titrated doses of vitamin K 1 . The warfarin concentration was 74.6 μg/mL 26 h post ingestion and decreased to 3.7 μg/mL over 72 h. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Our case highlights the risk of a rebound elevated INR even 3 days after acute warfarin overdose despite treatment with vitamin K 1 . Understanding the pharmacokinetics of vitamin K 1 in comparison with warfarin, repeat INR testing, and continued treatment with oral vitamin K 1 may help avoid complications of rebound coagulopathy in warfarin overdose. Crown Copyright © 2016. Published by Elsevier Inc. All rights reserved.

Anticoagulation Control in Patients With Nonvalvular Atrial Fibrillation Attended at Primary Care Centers in Spain: The PAULA Study.

PubMed

Barrios, Vivencio; Escobar, Carlos; Prieto, Luis; Osorio, Genoveva; Polo, José; Lobos, José María; Vargas, Diego; García, Nicolás

2015-09-01

To determine the current status of anticoagulation control in patients with nonvalvular atrial fibrillation treated with vitamin K antagonists in the primary care setting in Spain. The PAULA study was a multicenter cross-sectional/retrospective observational study conducted throughout Spain. The study included patients with nonvalvular atrial fibrillation who had been receiving vitamin K antagonist therapy during the past year and were attended at primary care centers. International normalized ratio (INR) values over the past 12 months were recorded. The degree of anticoagulation control was defined as the time the patient had remained within the therapeutic range and was determined by both the direct method (poor control < 60%) and by the Rosendaal method (poor control < 65%). The study assessed 1524 patients (mean age, 77.4 ± 8.7 years; 48.6% women; 64.2% in permanent atrial fibrillation; CHADS2 mean, 2.3 ± 1.2; CHA2DS2-VASc, 3.9 ± 1.5, and HAS-BLED, 1.6 ± 0.9). The mean number of INR readings recorded per patient was 14.4 ± 3.8. A total of 56.9% of patients had adequate INR control according to the direct method and 60.6% according to the Rosendaal method. The multivariate analysis identified the following predictors for poor INR control: female sex, dietary habits potentially affecting anticoagulation with vitamin K antagonists, multidrug therapy, and a history of labile INR. Approximately 40% of patients (43.1% by the direct method and 39.4% by the Rosendaal method) with nonvalvular atrial fibrillation who were receiving anticoagulation therapy with vitamin K antagonists in primary care in Spain had poor anticoagulation control during the previous 12 months. Copyright © 2015 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.

Prophylactic Plasma Transfusion Before Interventional Radiology Procedures Is Not Associated With Reduced Bleeding Complications.

PubMed

Warner, Matthew A; Woodrum, David A; Hanson, Andrew C; Schroeder, Darrell R; Wilson, Gregory A; Kor, Daryl J

2016-08-01

To determine the association between prophylactic plasma transfusion and periprocedural red blood cell (RBC) transfusion rates in patients with elevated international normalized ratio (INR) values undergoing interventional radiology procedures. In this retrospective cohort study, adult patients undergoing interventional radiology procedures with a preprocedural INR available within 30 days of the procedure during a study period of January 1, 2009, to December 31, 2013, were eligible for inclusion. Baseline characteristics, coagulation parameters, transfusion requirements, and procedural details were extracted. Univariate and multivariable propensity-matched analyses were used to assess the relationships between prophylactic plasma transfusion and the outcomes of interest, with a primary outcome assessed a priori of RBC transfusion occurring during the procedure or within the first 24 hours postprocedurally. A total of 18,204 study participants met inclusion criteria for this study, and 1803 (9.9%) had an INR of 1.5 or greater before their procedure. Of these 1803 patients, 196 patients (10.9%) received prophylactic plasma transfusion with a median time of 1.9 hours (interquartile range [IQR], 1.1-3.2 hours) between plasma transfusion initiation and procedure initiation. In multivariable propensity-matched analysis, plasma administration was associated with increased periprocedural RBC transfusions (odds ratio, 2.20; 95% CI, 1.38-3.50; P<.001) and postprocedural intensive care unit admission rates (odds ratio, 2.11; 95% CI, 1.41-3.14; P<.001) as compared with those who were not transfused preprocedurally. Similar relationships were seen at higher INR thresholds for plasma transfusion. In patients undergoing interventional radiology procedures, preprocedural plasma transfusions given in the setting of elevated INR values were associated with increased periprocedural RBC transfusions. Additional research is needed to clarify this potential association between

Design and rationale for the WARFA trial: a randomized controlled cross-over trial testing the therapeutic equivalence of branded and generic warfarin in atrial fibrillation patients in Brazil.

PubMed

Freitas, Carolina Gomes; Walsh, Michael; Atallah, Álvaro Nagib

2017-06-07

Warfarin is a commonly used anticoagulant. Whether a given dose of the different formulations of Brazilian warfarin will result in the same effect on the international normalized ratio (INR) is uncertain. The aim of the WARFA trial is to determine whether the branded and two generic warfarins available in Brazil differ in their effect on the INR. WARFA is a cross-over RCT comparing three warfarins. The formulations tested are the branded Marevan® (Uniao Quimica/Farmoquimica) and two generic warfarin (manufactured respectively by Uniao Quimica Farmaceutica Nacional and Laboratorio Teuto Brasileiro). All of them were manufactured in Brazil, are available in all settings of the Brazilian healthcare system and were purchased from retail drugstores. Eligible participants had atrial fibrillation or flutter, had been using warfarin for at least 2 months with a therapeutic range of 2.0-3.0 and had low variability in INR results during the 1st period of the trial. Our primary outcome, for which we have an equality hypothesis, is the difference between warfarins in the mean absolute difference between two INR results, obtained after three and 4 weeks with each drug. Our secondary outcomes, that will be tested for inequality (except for the mean INR, which will be tested for equality), include the difference in the warfarin dose, and time in therapeutic range. Clinical events and adherence were also recorded and will be reported. To our knowledge, WARFA will be the first comparison of the more readily applicable INR results between branded and generic warfarins in Brazil. WARFA is important because warfarins are commonly switched between in the course of a chronic treatment in Brazil. Final results of WARFA are expected in May 2017. ClinicalTrials.gov NCT02017197 . Registered 11 December 2013.

Prophylactic Plasma Transfusion Prior to Interventional Radiology Procedures Is Not Associated with Reduced Bleeding Complications

PubMed Central

Warner, Matthew A.; Woodrum, David A.; Hanson, Andrew C.; Schroeder, Darrell R.; Wilson, Gregory A.; Kor, Daryl J.

2016-01-01

Objective To determine the association between prophylactic plasma transfusion and periprocedural RBC transfusion rates in patients with elevated INR values undergoing interventional radiology procedures. Patients and Methods In this retrospective cohort study, adult patients undergoing interventional radiology procedures with a preprocedural INR available within 30 days of the procedure during a study period of Jan 1st, 2009 to Dec 31st, 2013 were eligible for inclusion. Baseline characteristics, coagulation parameters, transfusion requirements, and procedural details were extracted. Univariate and multivariable propensity-matched analyses were used to assess the relationships between prophylactic plasma transfusion and the outcomes of interest, with a primary outcome assessed a priori of RBC transfusion occurring during the procedure or within the first 24 hours post-procedurally. Results A total of 18,204 study participants met inclusion criteria for this study, and 1,803 (9.9%) had an INR ≥ 1.5 prior to their procedure. Among these, 196 patients (10.9%) received prophylactic plasma transfusion with a median (interquartile range) time between plasma initiation and procedural start of 1.9 (1.1 – 3.2) hours. In multivariable propensity-matched analysis, plasma administration was associated with increased periprocedural RBC transfusions [OR (95% CI) = 2.20 (1.38 – 3.50); P<.001] and postprocedural ICU admission rates [OR (95% CI) = 2.11 (1.41 – 3.14); P<.001] compared to those who were not transfused preprocedurally. Similar relationships were seen at higher INR thresholds for plasma transfusion. Conclusion In patients undergoing interventional radiology procedures, preprocedural plasma transfusions given in the setting of elevated INR values were associated with increased periprocedural RBC transfusions. Additional research is needed to clarify this potential association between preprocedural plasma and periprocedural RBC transfusion. PMID:27492911

A Production System Model of Capturing Reactive Moving Targets. M.S. Thesis

NASA Technical Reports Server (NTRS)

Jagacinski, R. J.; Plamondon, B. D.; Miller, R. A.

1984-01-01

Subjects manipulated a control stick to position a cursor over a moving target that reacted with a computer-generated escape strategy. The cursor movements were described at two levels of abstraction. At the upper level, a production system described transitions among four modes of activity; rapid acquisition, close following, a predictive mode, and herding. Within each mode, differential equations described trajectory-generating mechanisms. A simulation of this two-level model captures the targets in a manner resembling the episodic time histories of human subjects.

Key Ingredients-Target Groups, Methods and Messages, and Evaluation-of Local-Level, Public Interventions to Counter Stigma and Discrimination: A Lived Experience Informed Selective Narrative Literature Review.

PubMed

Ashton, Laura J; Gordon, Sarah E; Reeves, Racheal A

2018-04-01

A proliferation of recent literature provides substantial direction as to the key ingredients-target groups, messages and methods, and evaluation-of local-level, public interventions to counter stigma and discrimination. This paper provides a selective narrative review of that literature from the perspective or standpoint of anti-stigma experts with lived experience of mental distress, the key findings of which have been synthesised and presented in diagrammatic overviews (infographics). These are intended to guide providers in planning, delivering and evaluating lived experience-directed local-level, public interventions to counter stigma and discrimination in accord with current best practice.

Design of ligand-targeted nanoparticles for enhanced cancer targeting

NASA Astrophysics Data System (ADS)

Stefanick, Jared F.

Ligand-targeted nanoparticles are increasingly used as drug delivery vehicles for cancer therapy, yet have not consistently produced successful clinical outcomes. Although these inconsistencies may arise from differences in disease models and target receptors, nanoparticle design parameters can significantly influence therapeutic efficacy. By employing a multifaceted synthetic strategy to prepare peptide-targeted nanoparticles with high purity, reproducibility, and precisely controlled stoichiometry of functionalities, this work evaluates the roles of polyethylene glycol (PEG) coating, ethylene glycol (EG) peptide-linker length, peptide hydrophilicity, peptide density, and nanoparticle size on tumor targeting in a systematic manner. These parameters were analyzed in multiple disease models by targeting human epidermal growth factor receptor 2 (HER2) in breast cancer and very late antigen-4 (VLA-4) in multiple myeloma to demonstrate the widespread applicability of this approach. By increasing the hydrophilicity of the targeting peptide sequence and simultaneously optimizing the EG peptide-linker length, the in vitro cellular uptake of targeted liposomes was significantly enhanced. Specifically, including a short oligolysine chain adjacent to the targeting peptide sequence effectively increased cellular uptake ~80-fold using an EG6 peptide-linker compared to ~10-fold using an EG45 linker. In vivo, targeted liposomes prepared in a traditional manner lacking the oligolysine chain demonstrated similar biodistribution and tumor uptake to non-targeted liposomes. However, by including the oligolysine chain, targeted liposomes using an EG45 linker significantly improved tumor uptake ~8-fold over non-targeted liposomes, while the use of an EG6 linker decreased tumor accumulation and uptake, owing to differences in cellular uptake kinetics, clearance mechanisms, and binding site barrier effects. To further improve tumor targeting and enhance the selectivity of targeted