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Lazar, Joseph. "A note on tension reduction in the national railroad adjustment board system." Behavioral Science 7, no. 4 (January 17, 2007): 474–76. http://dx.doi.org/10.1002/bs.3830070407.
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Cullen, Donald E., and Charles Rehmus. "The National Mediation Board at 50: Its Impact on Railroad and Airline Labor Disputes." Industrial and Labor Relations Review 41, no. 1 (October 1987): 152. http://dx.doi.org/10.2307/2523878.
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Raj, Phani K., and Edward W. Pritchard. "Hazardous Materials Transportation on U.S. Railroads: Application of Risk Analysis Methods to Decision Making in Development of Regulations." Transportation Research Record: Journal of the Transportation Research Board 1707, no. 1 (January 2000): 22–26. http://dx.doi.org/10.3141/1707-03.
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The Office of Safety of the Federal Railroad Administration (FRA) is responsible for ensuring public and personnel safety in U.S. railroad operations. This office ensures the safe rail transportation of hazardous materials by conducting inspections of railroad operations and equipment, including tank cars, and developing safety-related regulations. In the past few years, the Office of Safety has been using risk analysis as a tool in making rational regulatory decisions on hazardous materials transportation in tank cars. A risk analysis protocol developed by FRA is described to evaluate the risks to the U.S. population arising from the transportation of different types of chemicals in tank cars on the U.S. railroad system. Following several recommendations of the National Transportation Safety Board requiring the shipment of several hazardous chemicals in highly protected, pressure-rated tank cars rather than in the minimum packaging authorized by the Code of Federal Regulations, a risk-based evaluation was made on the effect of implementing these recommendations on the overall risk reduction. The risk results were presented in the parameters of Military Standard 882-B. Policy decisions were made based on the results.
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Cullen, Donald E. "Book Review: Labor and Employment Law: The National Mediation Board at 50: Its Impact on Railroad and Airline Labor Disputes." ILR Review 41, no. 1 (October 1987): 152–53. http://dx.doi.org/10.1177/001979398704100119.
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Waters, Clay. "Monitoring the Movies: The Fight Over Film Censorship in Early Twentieth-Century Urban America by Meridith Broussard." Journal of Intellectual Freedom & Privacy 3, no. 2-3 (January 15, 2019): 15. http://dx.doi.org/10.5860/jifp.v3i2-3.6777.
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The chapters are arranged chronologically, retracing the national fight over film content, as various taboo subjects like abortion, white slavery, and racial intermarriage were addressed (or exploited) within the emerging medium. Similar ground was covered by Lee Grieveson in Policing Cinema: Movies and Censorship in Early-Twentieth-Century America (2004), the subject of a lengthy note in Monitoring the Movies. But Fronc’s work is bolstered by voluminous correspondence from the National Board of Review of Motion Pictures, and the 40 pages of notes (in addition to an appendix, bibliography, and index) signal a comprehensive appraisal of this facet of the Progressive era. Along the way, there are a few light anecdotes, including one involving a melodramatic film about a railroad strike that featured a scene of a burning trestle, a special effect that meant the film’s costs ran into “many hundreds of dollars” (40).
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Grisinger, Joanna. "Law in Action: The Attorney General's Committee on Administrative Procedure." Journal of Policy History 20, no. 3 (July 2008): 379–418. http://dx.doi.org/10.1353/jph.0.0020.
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The story of American political development in the twentieth century is in no small part the story of administration. Administrative agencies, bureaus, and departments tasked with handling the work of the federal government had been a feature of governance since the early republic. With the creation of the Interstate Commerce Commission in 1887, however, administrative agencies and independent regulatory commissions began to proliferate across the federal landscape. By the end of the massive expansion of federal power that characterized the New Deal, Americans very much experienced government through their interactions with bureaucrats and with administrative boards. Individuals and businesses claimed benefits from the Railroad Retirement Board and Veterans Administration, defended themselves against claims of unfair competition before the Federal Trade Commission, requested permits from the Federal Alcohol Administration and the Federal Communications Commission, and sought to resolve labor disputes before the National Labor Relations Board.
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Klose, Marianne, Kirstine Stochholm, Jurgita Janukonyté, Louise Lehman Christensen, Arieh S. Cohen, Aase Wagner, Peter Laurberg, Jens Sandahl Christiansen, Marianne Andersen, and Ulla Feldt-Rasmussen. "Patient reported outcome in posttraumatic pituitary deficiency: results from The Danish National Study on posttraumatic hypopituitarism." European Journal of Endocrinology 172, no. 6 (June 2015): 753–62. http://dx.doi.org/10.1530/eje-14-1069.
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ObjectivePosttraumatic pituitary hormone deficiency is often suggested. The impact of these predominantly mild and often irreproducible deficiencies on outcome is less clear. The aim of the present study was to describe patient reported outcome in a nationala prioriunselected cohort of patients with traumatic brain injury (TBI) in relation to deficiencies identified upon pituitary assessment.Design and methodsWe conducted a nationwide population-based cohort study. Participants were Danish patients with a head trauma diagnosis recorded in the Danish Board of Health diagnostic code registry; 439 patients (and 124 healthy controls) underwent assessment of anterior pituitary function 2.5 years (median) after TBI. Questionnaires on health-related quality of life (QoL) (SF36, EuroQoL-5D, QoL assessment of GH deficiency in adults) and fatigue (MFI-20) were completed in parallel to pituitary assessment.ResultsPatients with TBI had significant detriments in QoL. Impairment (mainly physical scales) related to pituitary deficiency, although only partially confirmed after adjustment for demographic differences. Hypogonadotropic hypogonadism related to several QoL scores. Increasing impairments were observed with declining total testosterone concentrations (men), but not free testosterone concentrations or any other hormone concentrations. Total testosterone was not independently related to impaired QoL and fatigue, after adjustment for demographics, and treatment with antidiabetics, opioids, antidepressants, and anticonvulsants.ConclusionsOnly a very limited relationship between pituitary hormone deficiencies and QoL/fatigue was demonstrated. Due to the dominating influence of concurrent comorbidities, pituitary deficiencies were not independently related to QoL/fatigue. Causality is still to be shown, and whether substitution therapy could be of additional relevance in selected patients needs to be proven.
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McGillen, Gloria G., Leticia D. Martinez, Colleen L. Eddy, J. Robina Onwong’a, Alexis Rhames, and Chan Jeong Park. "Student Affiliates of Seventeen (SAS) 2020 Report: Transitioning to Leadership in a Historic Year." Counseling Psychologist 48, no. 8 (October 12, 2020): 1131–48. http://dx.doi.org/10.1177/0011000020964189.
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The University of Missouri–Columbia was selected to host the Student Affiliates of Seventeen (SAS) Executive Board from 2019–2022 and began their term in August 2019, following a successful three-year tenure by Ball State University. The new executive board has anchored its term in four pillars—Growth and Sustainability, Justice and Equity, Excellence and Innovation, and Wellness and Positive Development—which have guided the organization over the past year. This report reviews the purpose of SAS and discusses membership development, programming, advocacy, and the organizational development activities of the organization, including progress on goals to increase and engage membership and foster a more equitable and socially just organization that embraces liberation as a value. Counseling psychology students’ and the organization’s response and adjustment to the COVID-19 pandemic and national reckoning with police brutality and anti-Black racism are also discussed.
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Narin van Court, Wade A., Michael S. Hildebrand, and Gregory G. Noll. "WHAT RECENT HHFT DERAILMENT FIRES TELL US." International Oil Spill Conference Proceedings 2017, no. 1 (May 1, 2017): 2078–95. http://dx.doi.org/10.7901/2169-3358-2017.1.2078.
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ABSTRACT ID: 2017-145. In July 2016, TRC Environmental Corporation (TRC) and Hildebrand and Noll Associates, Inc. (HNA) were requested to develop planning guidance on train derailments involving large volumes/high concentrations of denatured ethanol for the Massachusetts Emergency Management Agency (MEMA). As part of this project, as well as similar projects conducted by HNA for other clients, TRC and HNA assessed current firefighting strategies for the release of ethanol and/or crude oil from High Hazard Flammable Trains (HHFT) and developed the planning assumptions necessary to prepare for these types of incidents. For these projects, studies and in-depth analyses of 27 HHFT derailments resulting in tank cars breaches that occurred in the United States and Canada involving denatured ethanol1 (ethanol) and/or crude oil2 from 2006 through 2015 were performed. The analyses were primarily based on the information from the National Transportation Safety Board (NTSB), Federal Railroad Administration (FRA), and/or Transport Canada (TC) databases, with supplemental information from news reports in some cases. The objective of these analyses was to identify key planning assumptions that would be used in developing appropriate firefighting strategies by focusing on the number and types of cars derailed, approximate train speeds at the time of the derailment, number of cars breached, amount of product released, and whether or not the released product caught fire. Additionally, the studies included obtaining and reviewing information on the properties and characteristics of ethanol, crude oils, and other Class 3 flammable materials, as well as information for railroad tank cars. Insights and understandings gained from these studies were used to further develop the firefighting strategies for HHFT derailment fires.
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Moe, Terry M. "Control and Feedback in Economic Regulation: The Case of the NLRB." American Political Science Review 79, no. 4 (December 1985): 1094–116. http://dx.doi.org/10.2307/1956250.
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This article presents an empirical analysis of the National Labor Relations Board, focusing on the balance the agency strikes between the interests of business and labor. It is oriented by a theoretical framework that, relative to popular models, takes a broader view of the causal structure of regulatory performance—one that simultaneously allows for presidents, congressional committees, the courts, agency staff, constituents, and economic conditions. The empirical results are instructive. All of these factors prove to have significant impacts on NLRB decisions. In addition, the core regulatory actors —Board members, staff, and constituents—are shown to engage in mutually adaptive adjustment: each is responsive to the decisions of each of the others, and their reciprocal relationships impart equilibrating properties to the system as a whole. Thus, the evidence points to a varied set of important determinants and to the dynamic nature of their interconnection. To the extent that these findings are at all characteristic of other regulatory agencies, simple popular models of regulation are likely to give anemic explanations, if not highly distorted accounts, of why agencies behave as they do.
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Laugen, R. Todd. "Struggles for the Public Interest: Organized Labor and State Mediation in Postwar America." Journal of the Gilded Age and Progressive Era 4, no. 1 (January 2005): 69–82. http://dx.doi.org/10.1017/s1537781400003662.
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In his 1906 Annual Message to Congress, President Theodore Roosevelt urged support for a bill to mandate the government investigation of labor disputes before allowing workers to strike. In an “age of great corporate and labor combinations,” the president insisted “the public has itself an interest which can not wisely be disregarded; an interest not merely of general convenience, for the question of a just and proper public policy must also be considered.” Congress at the time was unmoved. Yet Roosevelt's proposal signaled a growing movement to compel the investigation and arbitration of major labor conflicts. This movement peaked in the years soon after World War I. Advocates for government mediation insisted that an impartial commission of experts could peacefully negotiate workplace disputes and spare the consuming public the contests of will and force associated with major strikes. The Progressive Era arbitration of railroad and mining conflicts established important precedents and have received significant attention from scholars. National mediation boards, however, rarely assumed the power to order participation. Such efforts were more prominent at die state level. In 1915 Colorado legislators largely implemented Roosevelt's proposal, creating the first government board with powers to ban strikes and lockouts pending an investigation in industries affected with a public interest. Soon after the war, Kansas expanded upon the Colorado precedent with a compulsory arbitration board to regulate a host of indus-tries deemed essential to the public. Programs for state mediation of labor conflicts in the postwar period were particularly bound up with questions of compulsion in the public interest.
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Hirji, Shah, Fields, Orhurhu, Bhulani, White, Mody, and Swanson. "The Impact of Hospital Size on National Trends and Outcomes Following Open Esophagectomy." Medicina 55, no. 10 (October 3, 2019): 669. http://dx.doi.org/10.3390/medicina55100669.
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Background and Objectives: Previous studies have demonstrated superior patient outcomes for thoracic oncology patients treated at high-volume surgery centers compared to low-volume centers. However, the specific role of overall hospital size in open esophagectomy morbidity and mortality remains unclear. Materials and Methods: Patients aged >18 years who underwent open esophagectomy for primary malignant neoplasia of the esophagus between 2002 and 2014 were identified using the National Inpatient Sample. Minimally invasive procedures were excluded. Discharges were stratified by hospital size (large, medium, and small) and analyzed using trend and multivariable regression analyses. Results: Over a 13-year period, a total of 69,840 open esophagectomy procedures were performed nationally. While the proportion of total esophagectomies performed did not vary by hospital size, in-hospital mortality trends decreased for all hospitals (large (7.2% to 3.7%), medium (12.8% vs. 4.9%), and small (12.8% vs. 4.9%)), although this was only significant for large hospitals (P < 0.01). After controlling for patient demographics, comorbidities, admission, and hospital-level factors, hospital length of stay (LOS), total inflation-adjusted costs, in-hospital mortality, and complications (cardiac, respiratory, vascular, and bleeding) did not vary by hospital size (all P > 0.05). Conclusions: After risk adjustment, patient morbidity and in-hospital mortality appear to be comparable across all institutions, including small hospitals. While there appears to be an increased push for referring patients to large hospitals, our findings suggest that there may be other factors (such as surgeon type, hospital volume, or board status) that are more likely to impact the results; these need to be further explored in the current era of episode-based care.
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Pertiwi, Imanda Firmantyas Putri, Rosana Eri Puspita, and Saifudin Saifudin. "Responsibility and Accountability of University Social and Environmental Performances: A Sustainability Balanced Scorecard Model." Shirkah: Journal of Economics and Business 6, no. 1 (March 9, 2021): 1. http://dx.doi.org/10.22515/shirkah.v6i1.343.
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Since research on the use of sustainability balanced scorecard to assess university social and environmental performances still remains unexplored, this study aims to fill the gap by examining the acceptance of the idea of the State Islamic Religious Colleges (PTKIN) performances in terms of responsibility for social and environmental aspects based on the sustainability balanced scorecard model. Drawing on a qualitative research, eight respondents from the Board of National Accreditation for Higher Education (BAN-PT) and PTKIN policymakers were interviewed. The results indicated that PTKIN must pay more attention to social and environmental perspectives. It was further revealed that although BAN-PT regulation has explicitly included these two perspectives, there were several indicators that still need to be added according to the sustainability balanced scorecard model. Moreover, the results depicted several challenges such as budgeting, regulations, and paradigms that required some adjustment from the policymakers. These results contribute as fruitful insights for university policymakers in developing strategies to enhance university performances, particularly in social and environmental aspects.
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Popov, V. "To devalue or not to devalue?" Acta Oeconomica 61, no. 3 (September 1, 2011): 255–79. http://dx.doi.org/10.1556/aoecon.61.2011.3.1.
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If there is a negative terms of trade or financial shock leading to the deterioration in the balance of payments, there are two basic options for a country that has limited foreign exchange reserves. First, a country can maintain a fixed exchange rate (or even a currency board) and wait until the reduction of foreign exchange reserves leads to the reduction of money supply: this will drive domestic prices down and stimulate exports, raise interest rates and stimulate the inflow of capital, and finally will correct the balance of payments. Second, the country can allow the devaluation of national currency — flexible exchange rate will automatically bring the balance of payments back into the equilibrium. Because national prices are less flexible than exchange rates, the first type of adjustment is associated with the greater reduction of output.The empirical evidence on East European countries and other transition economies for the 1998–99 period (outflow of capital after the 1997 Asian and 1998 Russian currency crises and slowdown of output growth rates) suggests that the second type of policy response (devaluation) was associated with smaller loss of output than the first type (monetary contraction). The 2008–09 developments provide additional evidence for this hypothesis.
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Raja, Jawad, Jiann Lin Loo, Rajvinder Sambhi, and Somashekara Shivashankar. "Manualising the induction of higher trainees in psychiatry for North Wales: The CiSGC Guide (“Croeso i Seiciatreg Gogledd Cymru”)." BJPsych Open 7, S1 (June 2021): S214—S215. http://dx.doi.org/10.1192/bjo.2021.572.
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AimsThere is a significant period of adjustment for new higher trainees in psychiatry given the presence of inter-trust differences in the National Health Services (NHS). It may take some time for a trainee to become familiar with the new administrative system and workflow of the new environment, which may be even longer for an international medical graduate (IMG). Although there is an existing induction system, having a written structured manual will assist the trainees to get through this process more easily. Hence, this Quality Improvement Project (QIP) outlined the creation of an induction manual that serves as a starter pack to facilitate the settling-in process of new North Wales higher trainees in psychiatry, i.e. the “Croeso i Seiciatreg Gogledd Cymru” (CiSGC) guide (means Welcome to North Wales Psychiatry in Welsh).MethodThe induction manual was initially drafted by the authors based on the available printed policies and information online. Further input and from different stakeholders were obtained to triangulate and enrich the manual. Specific links and further references were included in the manual for the reference of prospective manual users. Authors’ contact details were included for any further clarification, suggestions or input.ResultThe manual consisted of four sections: A) General Process before, during and after Reporting Duty, B) Trainees’ Duty, 3) Speciality-specific Guidance, and 4) Health Board-related Information. The General Process section covered the visa-related information, post-acceptance paperwork process, access to email and hospital informative system, medical practice-related issues (including section 12(2) approval and medical indemnity). The Trainees’ Duty section briefed on time-tabling and clinical duty. The Specialty-specific Guide provided important information related to training. Lastly, the section of Health Board-related Information highlighted the administrative structure of the NHS Health Board, important contact numbers, link to information. Specialty specific sections were created for general adult psychiatry and old age psychiatry as there is no other higher training of psychiatry in North Wales at the moment. Further sections in the pipeline include substance misuse and liaison psychiatry.ConclusionThis induction manual is neither prescriptive nor exhaustive. It serves as a generic reference to facilitate new trainees in their adjustment process. Further review and revision will be conducted before every induction process to ensure the information is up-to-date and incorporating new input from the trainees.
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Chiou, Howard, Jeffrey K. Jopling, Jennifer Yang Scott, Meghan Ramsey, Kelly Vranas, Todd H. Wagner, and Arnold Milstein. "Detecting organisational innovations leading to improved ICU outcomes: a protocol for a double-blinded national positive deviance study of critical care delivery." BMJ Open 7, no. 6 (June 2017): e015930. http://dx.doi.org/10.1136/bmjopen-2017-015930.
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IntroductionThere is substantial variability in intensive care unit (ICU) utilisation and quality of care. However, the factors that drive this variation are poorly understood. This study uses a novel adaptation of positive deviance approach—a methodology used in public health that assumes solutions to challenges already exist within the system to detect innovations that are likely to improve intensive care.Methods and analysisWe used the Philips eICU Research Institute database, containing 3.3 million patient records from over 50 health systems across the USA. Acute Physiology and Chronic Health Evaluation IVa scores were used to identify the study cohort, which included ICU patients whose outcomes were felt to be most sensitive to organisational innovations. The primary outcomes included mortality and length of stay. Outcome measurements were directly standardised, and bootstrapped CIs were calculated with adjustment for false discovery rate. Using purposive sampling, we then generated a blinded list of five positive outliers and five negative comparators.Using rapid qualitative inquiry (RQI), blinded interdisciplinary site visit teams will conduct interviews and observations using a team ethnography approach. After data collection is completed, the data will be unblinded and analysed using a cross-case method to identify themes, patterns and innovations using a constant comparative grounded theory approach. This process detects the innovations in intensive care and supports an evaluation of how positive deviance and RQI methods can be adapted to healthcare.Ethics and disseminationThe study protocol was approved by the Stanford University Institutional Review Board (reference: 39509). We plan on publishing study findings and methodological guidance in peer-reviewed academic journals, white papers and presentations at conferences.
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Wong, Shirly Siew-Ling, Toh-Hao Tan, Shazali Abu Mansor, and Venus Khim-Sen Liew. "Rethinking and Moving Beyond GDP: A New Measure of Sarawak Economy Panorama." International Business Research 11, no. 12 (November 29, 2018): 127. http://dx.doi.org/10.5539/ibr.v11n12p127.
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Despite the relatively strong adjustment in the global economy outlook, the Malaysian economy remains uncertain as the ringgit movement lies ambiguously ahead while volatile capital flows, inflationary pressure, and the vulnerable external sector and global trade remain intense. The Sarawak economy, which relies heavily on primary commodities and export earnings from oil-based industries, will soon face a noxious mixture of economic risks following the decrease in commodity prices. Thus, it is essential to develop a well-timed signaling mechanism to estimate the unpredictable economic forces that develop from the complex and multidimensional issues of domestic and global economies. The ideology of indicator construction from the Conference Board will be applied in this study to build a composite leading indicator, called the Sarawak Business Cycle Indicator (SBCI), to trace the cyclical movement of the aggregate economic activity in Sarawak. In this respect, the SBCI, which has demonstrated statistical significance with an average leading power of 3.5 months, is expected to be important in reflecting a notable economic outlook for the State. More importantly, the SBCI will serve as a valuable reference to act as a short-term forecasting tool to provide insight at both the national and state levels.
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Joanne Bellamy, H., and G. J. T. Swanson. "The effect of parity age and month of calving on milk fat and protein yield fat and protein percent for the five major dairy breeds." Proceedings of the British Society of Animal Production (1972) 1989 (March 1989): 138. http://dx.doi.org/10.1017/s0308229600011284.
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Records oolleoted from National Milk Reoords (NMR) are used by the Milk Marketing Board (MMB) to produoe genetio evaluations for bulls (Improved Contemporary Comparisons), cows (Cow Genetic Indices) and a management index for cows (Cow Production Index). It is Important to eliminate systematic environmental effects such as age at calving, month of calving and parity. The need for such adjustments and the factors involved have been documented by Schmidt and Van Vleck (1974). The purpose of this study was to calculate new adjustment factors for each dairy breed for inclusion In bull and cow evaluations.Sire identified milk reoords of at least 200 days from cows completing laotations in 1885/8S were seleoted from the NMR data base for Ayrshires (A), Jerseys U) and Guernseys (G). Shorthorn (S) records from 1984 were also selected in order to provide sufficient data for analysis. A 10% sample of records were selected for Friesian/Holsteins (F/H) from 1987. The first five lactations were Included. The analyses were performed upon 16,878 S, 37,668 A, 38,925 J, 26,008 G and 80,445 F/H reoords respectively The data were analysed using a least square analysis of varianoe (Harvey 1977).
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Harashima, Saki, Maiko Fujimori, Tatsuo Akechi, Tomohiro Matsuda, Kumiko Saika, Takaaki Hasegawa, Keisuke Inoue, et al. "Suicide, other externally caused injuries and cardiovascular death following a cancer diagnosis: study protocol for a nationwide population-based study in Japan (J-SUPPORT 1902)." BMJ Open 9, no. 7 (July 2019): e030681. http://dx.doi.org/10.1136/bmjopen-2019-030681.
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IntroductionA growing body of literature has demonstrated that cancer patients have a higher risk of suicide and cardiovascular mortality compared with the general population, especially immediately after a cancer diagnosis. Using data from the National Cancer Registry in Japan launched in January 2016, we will conduct the first nationwide population-based study in Japan to compare incidence of death by suicide, other externally caused injuries (ECIs) and cardiovascular disease following a cancer diagnosis with that of the general population in Japan. We will also aim to identify the patient subgroups and time periods associated with particularly high risk.Methods and analysisOur study subjects will consist of cancer cases diagnosed between 1 January 2016 and 31 December 2016 in Japan and they will be observed until 31 December 2018. We will calculate standardised mortality ratios (SMRs) and excess absolute risks (EARs) for suicide, other ECIs and cardiovascular death compared with the general population in Japan, after adjustment for sex, age and prefecture. SMRs and EARs will be calculated separately in relation to a number of factors: sex; age at diagnosis; time since cancer diagnosis; prefecture of residence at diagnosis; primary tumour site; behaviour code of tumour; extension of tumour; whether definitive surgery of the primary site was performed; and presence/absence of multiple primary tumours.Ethics and disseminationThe study protocol was approved by the institutional review board and ethics committee of the National Cancer Center Japan and Nagoya City University Graduate School of Medical Sciences. The findings will be disseminated through peer-reviewed publications and conference presentations.Trial registration numberUMIN000035118; Pre-results.
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Pereira, Alfredo Marvão, and Rui Manuel Pereira. "On the Effects of Infrastructure Investments on the Regional Economic Mix in Portugal." Journal of Economics and Public Finance 5, no. 3 (September 1, 2019): p375. http://dx.doi.org/10.22158/jepf.v5n3p375.
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In this paper, we deal with the issue of the effects of infrastructure investments on the regional mix of economic activity in Portugal. To address this issue we use a new data set for infrastructure investments in Portugal at the level of the NUTS II. We use a region-specific VAR approach, which considers, for each region, not only the effects of infrastructure investments in the region itself but also the regional spillover effects for each region from infrastructure investments elsewhere. Our results can be summarized as follows. First, we find that the largest aggregate effects are for investments in municipal roads, airports, ports, and education. Second, regional spillovers are very important across the board, and are particularly relevant for municipal roads and highways. Third, we find that for road transportation infrastructures, investments in national roads shift the regional concentration of economic activity towards North, Lisbon, and Alentejo, while investments in municipal roads have the same effects for Centre and investments in highways once again in North, Lisbon and Alentejo. For other transportation infrastructures the shifts in regional economic composition occur in North and Alentejo for railroad investments, Lisbon, Alentejo, and Algarve for airport investment, and Centre and Algarve for port infrastructure investments. Finally, investments in both education and health shift the regional output mix towards North and Centre, and in the case of health Alentejo as well. Accordingly, the aggregate effects of infrastructure investments hides a wide variety of effects across regions and across different infrastructure assets. Being mindful of these differences is fundamental in designing policies that help with aggregate economic performance without increasing regional disparities.
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Gupta, Sweta, Sadiya Khan, Sanjiv Shah, Ekaterina Klyachko, Abigail S. Baldridge, Mesut Eren, Aaron T. Place, et al. "Heterozygosity for Loss-of-Function Mutation in SERPINE1 (PAI-1 Gene) Linked with Longer Absolute Telomere Length." Blood 128, no. 22 (December 2, 2016): 4953. http://dx.doi.org/10.1182/blood.v128.22.4953.4953.
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Abstract Introduction: Plasminogen activator inhibitor-1 (PAI-1) is an important component of the senescence-associated secretome that contributes directly to cellular senescence. Telomeres, the nucleotide repeat structures located at the ends of chromosomes, shorten progressively with each round of cellular replication and telomere attrition is associated with cellular senescence. In murine models, genetic or pharmacologic inhibition of PAI-1 results in preservation of telomere length. Identification of a unique Amish kindred that harbors a loss-of-function mutation in SERPINE1 (c.699_700dupTA), which encodes PAI-1, provides a novel opportunity to assess the effects of lifelong PAI-1 deficiency on leukocyte telomere length (LTL) in humans. Methods: We conducted an observational study in the Old Order Amish, a founder population who originally settled in Berne, Indiana characterized by a homogeneous diet and lifestyle, and included participants aged 18 years and older. All study participants were genotyped for the c.699_700dupTA frameshift mutation in SERPINE1. For the primary analysis, we excluded participants who were homozygous for the null SERPINE1 mutation (n=7) due to their young age (18-34 years old) and small sample size. Relative LTL was quantified from peripheral blood using Southern blot of the terminal restriction fragments. We tested the association of SERPINE1 mutation status with LTL, after adjustment for age, sex, and relatedness in SOLAR. Results: A total of 170 participants were enrolled with mean age 46±19 years. Forty-three participants were identified as carriers of the null SERPINE1 mutation with an overall minor (null) allele frequency of 16% in the study population. SERPINE1 carriers had a significantly greater LTL compared with noncarriers, after adjustment for age, sex, and family structure (p=0.039; FIGURE). Every 1-year increase in age of study participant was associated with a 30 base pair decrease in LTL (p<0.0001). Conclusions: Heterozygosity for the null SERPINE1 gene, encoding a senescence-associated protein, PAI-1, is associated with longer LTL in a rare loss-of-function cohort. In addition, LTL is strongly and inversely correlated with chronologic age and supports the hypothesis that PAI-1 may contribute to cellular and organismal aging as reflected by LTL. Figure Mean telomere restriction fragments (kilobase pairs) as a function of age and genotype Figure. Mean telomere restriction fragments (kilobase pairs) as a function of age and genotype Disclosures Shapiro: CSL Behring: Other: Clinical research protocols; Kedrion Biopharma: Consultancy; Daiichi Sankyo: Other: Clinical research protocols; OPKO: Other: Clinical research protocols; National Hemophilia Foundation: Membership on an entity's Board of Directors or advisory committees; PTC Therapeutics: Other: Clinical research protocols; Novo Nordisk Hemophilia Foundation: Membership on an entity's Board of Directors or advisory committees; Baxter/Baxalta/Shire: Membership on an entity's Board of Directors or advisory committees, Other: Clinical research protocols; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Other: Clinical research protocols; Biogen: Membership on an entity's Board of Directors or advisory committees, Other: Clinical research protocols; Genentech: Membership on an entity's Board of Directors or advisory committees; American Thrombosis and Hemostasis Network: Other: Medical Director; ProMetic Life Sciences: Consultancy; Bayer healthcare Pharmaceuticals: Other: International network on pediatric hemophilia; Novartis: Other: Clinical research protocols; Selexys: Other: Clinical research protocols; Octopharma: Other: Clinical research protocols.
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Kamble, Shital, Shelby D. Reed, Chelsea Grussemeyer, and Marilyn J. Telen. "In-Hospital Outcomes Among Sickle Cell Patients with Acute Chest Syndrome: Results From a National Database." Blood 114, no. 22 (November 20, 2009): 1367. http://dx.doi.org/10.1182/blood.v114.22.1367.1367.
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Abstract Abstract 1367 Poster Board I-389 Objective: Acute chest syndrome is the leading cause of death and the second most common cause of hospitalization in patients with sickle cell disease (SCD), yet there are no recent estimates of its associated impact on medical resource use and costs. In this study, we compared inpatient mortality, length of stay (LOS) and total costs among hospital discharges for SCD patients with acute chest syndrome (ACS), SCD patients with crisis, and SCD with neither ACS nor crisis (controls). Methods: Using the 2006 Nationwide Inpatient Sample (NIS) data of the Healthcare Cost and Utilization Project, we developed three groups of discharges with SCD (Clinical Classification Code 61): (1) ACS with or without crisis on the basis of ICD-9-CM codes 517.3 (ACS) or 486 (pneumonia), (2) sickle cell crisis without ACS, using ICD-9-CM codes 282.42, 282.62, 282.64 or 282.69; and (3) SCD patients without a diagnosis of ACS or sickle cell crisis. We excluded cases representing elective admissions, patients discharged to short-term hospitals, born in the hospital, and women giving birth. We used generalized linear regression models to compare LOS (negative binomial distribution, log link) and inpatient costs (gamma distribution, log link) between study groups while controlling for gender, age, payer, 29 comorbidities, and hospital characteristics, including rural vs. urban location, teaching status, bed size, ownership type, and hospital region. We did not perform adjusted comparisons for mortality due to small numbers. Results: We identified 2,971 discharges with ACS, 13,593 with sickle cell crisis, and 4,040 with neither condition coded. Median age was 25 for ACS, 27 for sickle cell crisis, and 29 for sickle cell ‘controls’. Females represented 50.8% of discharges with ACS, 56.1% of discharges with sickle cell crisis, and 55.8% of sickle cell controls. Inpatient mortality was low across all three groups (Table). After adjustment for patient and hospital characteristics, discharges with ACS incurred hospital stays that were 24% longer (95%CI: 1.20-1.28, P<.0001) than those with crisis and 68% longer (95%CI: 1.62-1.74, P>.0001) than SCD controls. Similarly, inpatient costs among ACS discharges were 45% higher (95%CI: 1.40-1.49) than discharges with sickle cell crisis and 62% higher (95%CI: 1.56-1.68,P<.0001) than for SCD controls. Discharges for patients with sickle cell crisis were 35% longer (95%CI: 1.31-1.39, P<.0001) and 12% more costly (95%CI: 1.09-1.15, P<.0001) than for sickle cell controls. Conclusion: SCD patients admitted to the hospital with ACS incur significantly higher costs and longer stays than SCD patients with crisis or neither of these conditions. Disclosures: No relevant conflicts of interest to declare.
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Rose, Fred G., David A. Rutan, Thomas Charlock, G. Louis Smith, and Seiji Kato. "An Algorithm for the Constraining of Radiative Transfer Calculations to CERES-Observed Broadband Top-of-Atmosphere Irradiance." Journal of Atmospheric and Oceanic Technology 30, no. 6 (June 1, 2013): 1091–106. http://dx.doi.org/10.1175/jtech-d-12-00058.1.
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Abstract NASA’s Clouds and the Earth’s Radiant Energy System (CERES) project is responsible for operation and data processing of observations from scanning radiometers on board the Tropical Rainfall Measuring Mission (TRMM), Terra, Aqua, and Suomi National Polar-Orbiting Partnership (NPP) satellites. The clouds and radiative swath (CRS) CERES data product contains irradiances computed using a radiative transfer model for nearly all CERES footprints in addition to top-of-atmosphere (TOA) irradiances derived from observed radiances by CERES instruments. This paper describes a method to constrain computed irradiances by CERES-derived TOA irradiances using Lagrangian multipliers. Radiative transfer model inputs include profiles of atmospheric temperature, humidity, aerosols and ozone, surface temperature and albedo, and up to two sets of cloud properties for a CERES footprint. Those inputs are adjusted depending on predefined uncertainties to match computed TOA and CERES-derived TOA irradiance. Because CERES instantaneous irradiances for an individual footprint also include uncertainties, primarily due to the conversion of radiance to irradiance using anisotropic directional models, the degree of the constraint depends on CERES-derived TOA irradiance as well. As a result of adjustment, TOA computed-minus-observed standard deviations are reduced from 8 to 4 W m−2 for longwave irradiance and from 15 to 6 W m−2 for shortwave irradiance. While agreement of computed TOA with CERES-derived irradiances improves, comparisons with surface observations show that model constrainment to the TOA does not reduce computation bias error at the surface. After constrainment, shortwave down at the surface has an increased bias (standard deviation) of 1% (0.5%) and longwave increases by 0.2% (0.1%). Clear-sky changes are negligible.
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Björk Brämberg, Elisabeth, Lars Sandman, Therese Hellman, and Lydia Kwak. "Facilitators, barriers and ethical values related to the coordination of return-to-work among employees on sick leave due to common mental disorders: a protocol for a qualitative study (the CORE-project)." BMJ Open 9, no. 9 (September 2019): e032463. http://dx.doi.org/10.1136/bmjopen-2019-032463.
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IntroductionDiagnoses related to common mental disorders such as anxiety, depression, adjustment disorders and stress-related disorders are one of the leading causes of long-term sick leave for both women and men in Organisation for Economic Co-operation and Development countries. To increase the rate of return-to-work workplace involvement in a coordinated return-to-work process has been included in recent best practice guidelines. This form of cooperation is a complex process, involving political structures and a wide range of stakeholders. The study’s first aim is to describe facilitators and barriers to the coordination of return-to-work from the perspectives of: (A) employees on sick leave due to common mental disorders, (B) employers, (C) rehabilitation coordinators, (D) physicians and (E) other stakeholders. The second aim is to identify ethical issues that arise in the coordination of return-to-work and analyse how these can be resolved.Methods and analysisThe study has a qualitative design using interviews with employees on sick leave due to common mental disorders, employers, rehabilitation coordinators, physicians and other stakeholders. The study is conducted in the Swedish primary healthcare. Employees, employers and rehabilitation coordinators are recruited via primary healthcare centres. Rehabilitation coordinators receive information about the study and those who consent to participation are asked to recruit employees and employers. Interview guides have been developed from the consolidated framework for implementation research and ethical values and norms found in Swedish healthcare, social services and workplace legislation. Data will be analysed with qualitative content analysis reflecting manifest and latent content, and ethical issues will be analysed by means of reflective equilibrium methodology.Ethics and disseminationThe study was approved by the Regional Ethical Review Board in Stockholm, Sweden (Reg.no 2018/677-31/2 and 2018/2119–32). The findings will be disseminated through publication in scientific journals, social media, seminars and national and international conferences.
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McMinn, Megan A., Pekka Martikainen, Emma Gorman, Harri Rissanen, Tommi Härkänen, Hanna Tolonen, Alastair H. Leyland, and Linsay Gray. "Validation of non-participation bias methodology based on record-linked Finnish register-based health survey data: a protocol paper." BMJ Open 9, no. 4 (April 2019): e026187. http://dx.doi.org/10.1136/bmjopen-2018-026187.
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IntroductionDecreasing participation levels in health surveys pose a threat to the validity of estimates intended to be representative of their target population. If participants and non-participants differ systematically, the results may be biased. The application of traditional non-response adjustment methods, such as weighting, can fail to correct for such biases, as estimates are typically based on the sociodemographic information available. Therefore, a dedicated methodology to infer on non-participants offers advancement by employing survey data linked to administrative health records, with reference to data on the general population. We aim to validate such a methodology in a register-based setting, where individual-level data on participants and non-participants are available, taking alcohol consumption estimation as the exemplar focus.Methods and analysisWe made use of the selected sample of the Health 2000 survey conducted in Finland and a separate register-based sample of the contemporaneous population, with follow-up until 2012. Finland has nationally representative administrative and health registers available for individual-level record linkage to the Health 2000 survey participants and invited non-participants, and the population sample. By comparing the population sample and the participants, synthetic observations representing the non-participants may be generated, as per the developed methodology. We can compare the distribution of the synthetic non-participants with the true distribution from the register data. Multiple imputation was then used to estimate alcohol consumption based on both the actual and synthetic data for non-participants, and the estimates can be compared to evaluate the methodology’s performance.Ethics and disseminationEthical approval and access to the Health 2000 survey data and data from administrative and health registers have been given by the Health 2000 Scientific Advisory Board, Statistics Finland and the National Institute for Health and Welfare. The outputs will include two publications in public health and statistical methodology journals and conference presentations.
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Nevarez, Nicole M., Brian C. Brajcich, Jason Liu, Ryan Ellis, Clifford Y. Ko, Henry A. Pitt, Michael I. D'Angelica, and Adam C. Yopp. "Cefoxitin versus piperacillin–tazobactam as surgical antibiotic prophylaxis in patients undergoing pancreatoduodenectomy: protocol for a randomised controlled trial." BMJ Open 11, no. 3 (March 2021): e048398. http://dx.doi.org/10.1136/bmjopen-2020-048398.
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IntroductionAlthough antibiotic prophylaxis is established in reducing postoperative surgical site infections (SSIs), the optimal antibiotic for prophylaxis in pancreatoduodenectomy (PD) remains unclear. The study objective is to evaluate if administration of piperacillin–tazobactam as antibiotic prophylaxis results in decreased 30-day SSI rate compared with cefoxitin in patients undergoing elective PD.Methods and analysisThis study will be a multi-institution, double-arm, non-blinded randomised controlled superiority trial. Adults ≥18 years consented to undergo PD for all indications who present to institutions participating in the National Surgical Quality Improvement Program Hepato-Pancreato-Biliary (NSQIP HPB) Collaborative will be included. Data collection will use the NSQIP HPB Collaborative Surgical Clinical Reviewers. Patients will be randomised to either 1–2 g intravenous cefoxitin or 3.375–4.5 g intravenous piperacillin–tazobactam within 60 min of surgical incision. The primary outcome will be 30-day postoperative SSI rate following PD. Secondary outcomes will include 30-day postoperative mortality; specific postoperative complication rate; and unplanned reoperation, length of stay, and hospital readmission. A subset of patients will have bacterial isolates and sensitivities of intraoperative bile cultures and SSIs. Postoperative SSIs and secondary outcomes will be analysed using logistic regression models with the primary predictor as the randomised treatment group. Additional adjustment will be made for preoperative biliary stent presence. Additionally, bacterial cultures and isolates will be summarised by presence of bacterial species and antibiotic sensitivities.Ethics and disseminationThis study is approved by the Institutional Review Board at Memorial Sloan Kettering Cancer Center. This trial will evaluate the effect of piperacillin–tazobactam compared with cefoxitin as antibiotic prophylaxis on the hazard of postoperative SSIs. The results will be disseminated regardless of the effect of the intervention on study outcomes. The manuscript describing the effect of the intervention will be submitted to a peer-reviewed journal when data collection and analyses are complete.Trial registration numberNCT03269994.
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Henrici, Ryan C., Casey Sautter, Robert Opoka, Ruth Namazzi, Gregory S. Park, Dibyadyuti John, Andrea L. Conroy, Russell E. Ware, and Chandy C. John. "Profound Alteration of Host Response in Severe Malarial Anemia By Sickle Cell Disease: Reduction of Parasite Sequestration and Inflammation, Upregulation of Angiopoietin-2." Blood 134, Supplement_1 (November 13, 2019): 2283. http://dx.doi.org/10.1182/blood-2019-129566.
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Introduction. Plasmodium falciparum malaria is a major cause of morbidity in African children with sickle cell anemia (SCA). Factors associated with severe disease and mortality in malaria, including tumor necrosis factor (TNF)-alpha and components of the angiopoietin (Angpt)-Tie-2 system, have also been implicated in the pathogenesis and clinical severity of SCA. However, there is no data on how these factors are altered in children with SCA during severe malaria. Methods. A total of 232 children who presented with severe malarial anemia (hemoglobin < 5 g/dL with Plasmodium parasitemia on peripheral blood smear) were enrolled in a prospective study of severe malaria at Mulago National Referral Hospital in Kampala, Uganda. No child had known SCA at the time of severe malarial anemia diagnosis. Samples from enrolled children were subsequently tested by genotyping for the presence of hemoglobin S (HbS) using a TaqMan assay at rs334. Clinical and laboratory parameters, plasma markers of inflammation and endothelial activation, and the estimated total, sequestered, and circulating parasite biomass were compared in children with HbSS compared to HbAA. Results. The study cohort included 208 children with HbAA (90.4%), 22 children with HbSS (9.6%), and 2 with HbAS. Children with HbSS were older than children with HbAA (Table 1), so all comparisons were adjusted for age. Children with HbSS versus HbAA did not differ significantly in duration of symptoms, clinical signs, disease severity, or degree of peripheral P. falciparum parasitemia. However, children with HbSS had significantly lower concentrations of PfHRP2, a marker of total parasite biomass, and lower levels of estimated sequestered parasite biomass (Table 1). Children with HbSS had pronounced leukocytosis, a feature of chronic inflammation in SCA, but had significantly lower concentrations of the inflammatory biomarkers C-reactive protein and alpha-1-acid glycoprotein and the pro-inflammatory cytokine TNF-alpha than children with HbAA (Table 1). In contrast, concentrations of angiopoietin-2 (Angpt-2), a marker of endothelial dysregulation that has been associated with mortality in severe malaria, were 3-fold greater in children with HbSS than HbAA (Table 1), and were associated with an increased risk of post-discharge recurrent malaria in the cohort, after adjustment for age, sex, and hemoglobin S genotype (odds ratio per log-10 increase in Angpt-2 [95% confidence interval], 2.11 [1.01, 4.38]). Conclusion. In this population, undiagnosed SCA is common in children with severe malarial anemia. During episodes of severe malarial anemia, children with SCA suppress parasite sequestration and inflammation but upregulate Angpt-2, which may increase risk of recurrence of malaria. Disclosures Conroy: ALC: Patents & Royalties: angiopoietin-1, angiopoietin-2. Ware:Addmedica: Other: Research Drug Donation; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Nova Laboratories: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Membership on an entity's Board of Directors or advisory committees; Novartis: Other: DSMB; Bristol Myers Squibb: Other: Research Drug Donation.
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Alexe, M., P. Bergamaschi, A. Segers, R. Detmers, A. Butz, O. Hasekamp, S. Guerlet, et al. "Inverse modelling of CH<sub>4</sub> emissions for 2010–2011 using different satellite retrieval products from GOSAT and SCIAMACHY." Atmospheric Chemistry and Physics 15, no. 1 (January 9, 2015): 113–33. http://dx.doi.org/10.5194/acp-15-113-2015.
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Abstract. At the beginning of 2009 new space-borne observations of dry-air column-averaged mole fractions of atmospheric methane (XCH4) became available from the Thermal And Near infrared Sensor for carbon Observations–Fourier Transform Spectrometer (TANSO-FTS) instrument on board the Greenhouse Gases Observing SATellite (GOSAT). Until April 2012 concurrent {methane (CH4) retrievals} were provided by the SCanning Imaging Absorption spectroMeter for Atmospheric CartograpHY (SCIAMACHY) instrument on board the ENVironmental SATellite (ENVISAT). The GOSAT and SCIAMACHY XCH4 retrievals can be compared during the period of overlap. We estimate monthly average CH4 emissions between January 2010 and December 2011, using the TM5-4DVAR inverse modelling system. In addition to satellite data, high-accuracy measurements from the Cooperative Air Sampling Network of the National Oceanic and Atmospheric Administration Earth System Research Laboratory (NOAA ESRL) are used, providing strong constraints on the remote surface atmosphere. We discuss five inversion scenarios that make use of different GOSAT and SCIAMACHY XCH4 retrieval products, including two sets of GOSAT proxy retrievals processed independently by the Netherlands Institute for Space Research (SRON)/Karlsruhe Institute of Technology (KIT), and the University of Leicester (UL), and the RemoTeC "Full-Physics" (FP) XCH4 retrievals available from SRON/KIT. The GOSAT-based inversions show significant reductions in the root mean square (rms) difference between retrieved and modelled XCH4, and require much smaller bias corrections compared to the inversion using SCIAMACHY retrievals, reflecting the higher precision and relative accuracy of the GOSAT XCH4. Despite the large differences between the GOSAT and SCIAMACHY retrievals, 2-year average emission maps show overall good agreement among all satellite-based inversions, with consistent flux adjustment patterns, particularly across equatorial Africa and North America. Over North America, the satellite inversions result in a significant redistribution of CH4 emissions from North-East to South-Central United States. This result is consistent with recent independent studies suggesting a systematic underestimation of CH4 emissions from North American fossil fuel sources in bottom-up inventories, likely related to natural gas production facilities. Furthermore, all four satellite inversions yield lower CH4 fluxes across the Congo basin compared to the NOAA-only scenario, but higher emissions across tropical East Africa. The GOSAT and SCIAMACHY inversions show similar performance when validated against independent shipboard and aircraft observations, and XCH4 retrievals available from the Total Carbon Column Observing Network (TCCON).
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Gordeuk, Victor R., Barbara Kroner, Norma Pugh, Jane S. Hankins, Abdullah Kutlar, Allison A. King, Nirmish Shah, Julie Kanter, Jeffrey Glassberg, and Marsha Treadwell. "Hydroxyurea Use and Outcomes of Pregnancy in Sickle Cell Disease." Blood 136, Supplement 1 (November 5, 2020): 33. http://dx.doi.org/10.1182/blood-2020-143315.
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Background. Hydroxyurea reduces pain crises, acute chest syndrome and blood transfusions in sickle cell disease (SCD), but potential detrimental effects on fertility and birth outcomes are an impediment to its use. Patient data on the effects of hydroxyurea when taken during conception and pregnancy are scarce. The Sickle Cell Disease Implementation Consortium (SCDIC) is a cooperative research program of eight clinical centers, a data coordinating center, and the National Heart, Lung, and Blood Institute (NHLBI). One of the SCDIC programs is an SCD patient registry including at least 300 participants from each center. Methods. The SCDIC Registry retrospectively questioned participants regarding pregnancy history, hydroxyurea use and pregnancy outcomes. Of 2436 subjects 15-45 years of age, 2375 answered at least one pregnancy-related question, including hydroxyurea use during conception, the month and year the pregnancy ended, the outcome (live birth, stillbirth, miscarriage, abortion, currently pregnant), hydroxyurea use during pregnancy and what trimester (females only), and for live births - prematurity, birth weight < 5.5 lbs, and medical complications in the baby. The primary outcome was miscarriage or stillbirth, with separate analyses for males and females. Univariate logistic regression was used to identify significant covariates and predictors, and multivariate logistic regression was used to select the best fitting models. All models included severe sickle cell genotype, pregnancy order (1-3, 4-6, >6) and history of miscarriage or stillbirth at each pregnancy WResults. Among 1,357 women, 1797 pregnancies were reported for a crude rate of 1.32 pregnancies per woman; among 1018 men, 620 pregnancy conceptions were reported for a rate of 0.61 per man. Overall, in 221 (12.3%) of reported pregnancies in women and in 122 (19.7%) of reported pregnancies conceived by men, conception occurred while on hydroxyurea (P<0.001). We further analyzed 2062 pregnancies that did not end in elective abortion as reported by 920 individuals. Pregnancy order, severe sickling genotype of the parent and prior history of still birth or miscarriage were significantly associated with stillbirth or miscarriage in univariate analyses. After adjustment for these covariates, hydroxyurea use at conception was associated with a 2.1-fold increase in the odds of miscarriage or stillbirth in pregnancies conceived by males (P = 0.046) and hydroxyurea use at conception and during the first trimester was associated with a 3.3-fold increase in the odds of miscarriage or stillbirth in pregnancies conceived by women (P<0.001). Hydroxyurea use at conception and during the first trimester was also independently associated with birth weight <5.5 lbs (OR 2.4, P=0.01), but not prematurity or medical problems in the newborn. Discussion. There are important limitations to our study. The pregnancy history is self-reported and therefore complicated by recall bias. The completion of the reproductive history form varied by age. The dates of pregnancies ending in miscarriage were more often missing than other outcomes, so we could not use age at pregnancy in statistical analyses. Males may not have known or remembered all of the pregnancies they conceived that did not end in live birth, and we did not collect information about the female partners of males with SCD. Furthermore, the availability and use of hydroxyurea has increased over time. Nevertheless, our results suggest that the use of hydroxyurea at conception in males and at conception and the first trimester in females may be associated with adverse pregnancy outcomes. Our findings support advising patients who plan a pregnancy to temporarily discontinue hydroxyurea before attempting to conceive and during the first trimester in females, and to provide alternative approaches to prevent SCD complications during this time. Disclosures Gordeuk: Novartis: Consultancy; Ironwood: Research Funding; Imara: Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; CSL Behring: Consultancy, Research Funding. Hankins:Novartis: Research Funding; National Heart, Lung, and Blood Institute: Honoraria, Research Funding; American Society of Pediatric Hematology/Oncology: Honoraria; LINKS Incorporate Foundation: Research Funding; MJH Life Sciences: Consultancy, Patents & Royalties; Global Blood Therapeutics: Consultancy, Research Funding; UptoDate: Consultancy. Kutlar:Novartis Pharmaceuticals: Consultancy, Research Funding; Global Blood Therapeutics: Research Funding, Speakers Bureau; Micelle Biopharma: Consultancy; NIH/NHLBI (SCDIC): Research Funding; Novo Nordisk: Research Funding; Forma Therapeutics: Research Funding; REACH: Other: DSMB Member; NOHARM: Other: DSMB Member; Bluebird Bio: Other: DSMB Member. King:Amphivena Therapeutics: Research Funding; Bioline: Consultancy; Celgene: Consultancy; Cell Works: Consultancy; Incyte: Consultancy; Magenta Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novimmune: Research Funding; RiverVest: Consultancy; Tioma Therapuetics: Consultancy; WUGEN: Current equity holder in private company. Shah:Alexion: Speakers Bureau; Bluebird Bio: Consultancy; Novartis: Consultancy, Research Funding, Speakers Bureau; Global Blood Therapeutics: Consultancy, Research Funding, Speakers Bureau; CSL Behring: Consultancy. Kanter:BEAM: Membership on an entity's Board of Directors or advisory committees; SCDAA Medical and Research Advisory Board: Membership on an entity's Board of Directors or advisory committees; AGIOS: Membership on an entity's Board of Directors or advisory committees; bluebird bio, inc: Consultancy, Honoraria; Novartis: Consultancy; Sanofi: Consultancy; Medscape: Honoraria; Guidepoint Global: Honoraria; GLG: Honoraria; Jeffries: Honoraria; Cowen: Honoraria; Wells Fargo: Honoraria; NHLBI Sickle Cell Advisory Board: Membership on an entity's Board of Directors or advisory committees. Treadwell:UpToDate: Honoraria; Global Blood Therapeutics: Consultancy.
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Valdrez, Kátia, Elisabete Alves, Teresa Coelho, and Susana Silva. "Prevalência do Uso de Diagnóstico Genético Pré-Implantação na Unidade Clínica de Paramiloidose do Centro Hospitalar do Porto." Acta Médica Portuguesa 27, no. 6 (December 30, 2014): 710. http://dx.doi.org/10.20344/amp.4972.
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<strong>Introduction:</strong> The Familial Amyloid Polyneuropathy, with the world’s largest focus in Portugal, is recognized by the National Board of Assisted Reproductive Technologies as a serious disease eligible for Preimplantation Genetic Diagnosis. This study aims to determine the prevalence of the use of Preimplantation Genetic Diagnosis in FAP carriers followed in Unidade Clínica de Paramiloidose, Centro Hospitalar do Porto, and to identify the associated factors.<br /><strong>Material and Methods:</strong> Between January and May 2013, a representative sample of Portuguese Familial Amyloid Polyneuropathy carriers, aged between 18 and 55 years, was systematically recruited. The analysis is based on 111 carriers with previous familial diagnosis, who reported having ever tried to get pregnant after 2001. Data on sociodemographic characteristics and use of Preimplantation Genetic Diagnosis were collected through a self-administered questionnaire. Proportions were compared using the chi-square test. Crude and adjusted odds ratios (OR) and the respective confidence intervals of 95% (95% CI) were estimated using multivariate<br />logistic regression.<br /><strong>Results:</strong> The prevalence of use of Preimplantation Genetic Diagnosis was 20.7% (95% CI: 13.6-29.5). After adjustment, a household income above 1000 €/month (OR = 11.87; 95% CI 2.87-49.15) was directly associated with the use of Preimplantation Genetic Diagnosis, while carriers with an individual diagnosis (OR = 0.15; 95% CI 0.04-0.57) and children born after 2001 (OR = 0.07; 95% CI 0.02-0.32) revealed a prevalence of use significantly lower than those with a individual diagnosis and children born before 2001.<br /><strong>Discussion:</strong> The low prevalence of use of Preimplantation Genetic Diagnosis, as well as the less frequent use of the technique by those with a lower household income, shows the importance of improving access to Preimplantation Genetic Diagnosis in the case of Familial Amyloid Polyneuropathy.<br /><strong>Conclusion:</strong> This work contributes to increase the sensitivity of health professionals around the use and accessibility to Preimplantation Genetic Diagnosis among Familial Amyloid Polyneuropathy carriers.<br /><strong>Keywords:</strong> Preimplantation Diagnosis; Amyloid Neuropathies, Familial; Genetic Testing; Assisted Reproductive Technologies.
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Lorch, Daniel, Daniel Spevack, and Jane Little. "Chronic Kidney Disease and Mild Elevations in Pulmonary Arterial Systolic Pressure Are Associated with Increased Mortality in Adult Patients with Sickle Cell Disease." Blood 114, no. 22 (November 20, 2009): 1539. http://dx.doi.org/10.1182/blood.v114.22.1539.1539.
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Abstract Abstract 1539 Poster Board I-562 Background Pulmonary arterial hypertension (PAH) has recently been shown to be an important predictor of prognosis in sickle cell disease (SCD). We studied this association in a large population of adults with SCD. Methods and Results 215 patients with sickle cell syndromes in whom echoes had been performed, 113 as outpatients and 102 as inpatients, were identified from our database. Clinical characteristics were analyzed, and survival data were extracted from a national mortality registry. At the time of examination, subjects were 39 ± 14 years old, with hematocrits (Hcts) of 23.6 ± 4.4. 78 out of 213 patients who had undergone echoes had PAH (PASP ≥ 40 mmHg) on echocardiogram. Those patients were older (41 ± 15 vs 37 ± 13 years, p=0.03), had higher creatinine values (1.3 vs 0.9 mg/dL, p=0.01) higher serum alkaline phosphatase levels (172.2 ± 23.2 vs 104.5 ± 5.5 U/L, p=.0058), and were more often taking anti-hypertensive medications (38 vs 17%, p<0.001). During a median follow-up of 7.8 years [interquartile range (IR); 3.9, 10.0] there were 30 deaths. In a multivariate Cox proportional hazards model, PAH (hazard ratio (HR) 11.3; 95% CI 2.7, 47.9), chronic kidney disease (CKD) (HR 17.0; 95% CI 3.7, 79.1, defined as an estimated glomerular filtration rate, eGFR, of <60 cc/min/1.73 m2) and hyperbilirubinemia (HR 13.1; 95% CI 2.0, 83.9) independently predicted mortality after adjustment for inpatient/outpatient status, age, sex, blood counts, measurement of chamber size and ventricular function on echocardiogram, oxygen saturation, history of transfusion and background medical therapy. The association of PAH and mortality was not modified by inpatient/outpatient status (p=0.6). Conclusion In a community-based academic center, we found that mild elevation in PASP on echocardiogram, whenever obtained (see figure), depressions in eGFR (see figure), and hyperbilirubinemia were highly predictive for mortality in sickle cell disease. It is unclear whether these relationships are causal or an epiphenomenon of severe underlying disease. Hemolysis (lower Hcts, higher Lactate dehydrogenase levels), implicated in other studies, was not prominent in the PAH cohort. Disclosures No relevant conflicts of interest to declare.
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Barnes, Richard FW, Thomas J. Cramer, Afrah S. Sait, Rebecca Kruse-Jarres, Doris V. Quon, and Annette von Drygalski. "The Hypertension of Hemophilia Is Associated with Vascular Joint Remodeling and Cannot be Explained By the Usual Cardiovascular Risk Factors." Blood 126, no. 23 (December 3, 2015): 762. http://dx.doi.org/10.1182/blood.v126.23.762.762.
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Patients with hemophilia (PWH) have a higher prevalence of hypertension and intracranial hemorrhage than the general male population. However, the etiology of the hypertension, and to what extent blood pressure and associations with cardiovascular risk factors vary from the general population, is incompletely understood. We therefore investigated the prevalence of hypertension as well as the associations of blood pressure measurements with usual cardiovascular risk factors, in a cross-sectional analysis of a cohort of 486 PWH. The PWH (median age 38 years) came from 3 geographically different areas in the United States. They were compared against males from the contemporary National Health and Nutrition Examination Survey (NHANES), matched for age and race in a 1:5 ratio. Subsequently, at the University of California San Diego, a pilot cohort of PWH (n=28; median age 37 years) was examined prospectively for hypertension and associations with hemophilia-specific risk factors pertaining to joint health. PWH had a significantly higher prevalence of hypertension compared to subjects from NHANES. The prevalence of hypertension was 53.4% in PWH compared to 28.8 % in NHANES (p<0.01). In untreated (not taking anti-hypertensive medications) and treated subjects median systolic blood pressure (SBP) and diastolic blood pressure (DBP) were significantly higher in PWH than in NHANES. Differences in prevalence of hypertension and blood pressure measurements were most pronounced in the youngest age group (18-29 years). In untreated PWH median SBP and DBP were 125 and 78 mmHg (118 and 72 mmHg in NHANES), and in treated PWH 134 and 84 (127 and 76 mmHg in NAHES), respectively; all p-values <0.0001. However, despite higher blood pressures the usual cardiovascular risk profile was better in PWH compared to NHANES, in that body mass index (BMI), total cholesterol, smoking and diabetes were lower and renal function was better. While the usual cardiovascular risk factors were associated with blood pressure in both PWH and NHANES, they did not account for the differences between the two groups. Whether each risk factor was considered by itself, or in combination with the others in multivariate models, the blood pressure differences remained. Therefore, to elucidate to what extent hemophilia-specific factors might play a role in the pathophysiology of hypertension, we assessed hypertension and blood pressures in association with joint health parameters in a pilot cohort of young adult PWH. These patients underwent prospective baseline examination of 6 joints (both elbows, knees and ankles, n=168) for joint pain (Visual Analogue Scale 0-10), radiographic Pettersson score (maximum score 78), clinical Hemophilia Joint Health Score (HJHS, maximum score 120), severity of hemophilia (severe vs mild/moderate), clotting factor usage, and joint vascular perfusion quantified with Power Doppler (PD, maximum score 54) and high resolution musculoskeletal ultrasound. We found that 54% were hypertensive, similar to the larger cohort. In univariate analysis, PD score was the risk factor most strongly associated with hypertension (p = 0.07). After adjustment for confounders, the odds for hypertension increased by 1.29 (95% CI: 1.04, 1.60; p = 0.02) for each unit increase in PD score. Moreover, there was a strong association of PD scores with SBP when adjusted for confounders. In conclusion, our findings demonstrate that PWH not only have a significantly higher prevalence of hypertension, but also significantly higher blood pressures compared to the general population, even when treated with anti-hypertensive medications. The difference in blood pressures could not be explained by the usual cardiovascular risk factors but appeared to be strongly associated with the degree of vascular changes in the joint. Based on previous findings that vascular remodeling is a prominent feature of hemophilic arthropathy and may be mediated systemically, we postulate that vascular remodeling is associated with the etiology of hypertension in hemophilia. These findings warrant further basic and clinical investigation. Disclosures Kruse-Jarres: Octapharma: Consultancy, Honoraria; CSL Behring: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Novo Nordisk: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Bayer: Consultancy, Honoraria; Baxter: Consultancy, Honoraria. Quon:Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Grifols: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Biogen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Baxter: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. von Drygalski:Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Baxalta: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biogen: Honoraria, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Hematherix Inc: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.
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Cheah, Chan Yoon, Martin Hutchings, Kirsty Rady, Kerry J. Savage, Musa F. Alzahrani, Laurie H. Sehn, Sally Barrington, et al. "The Absolute Number of Extranodal Sites Detected By PET-CT Is a Powerful Predictor of Secondary Central Nervous System Involvement in Patients with Diffuse Large B-Cell Lymphoma Treated with R-CHOP." Blood 126, no. 23 (December 3, 2015): 3905. http://dx.doi.org/10.1182/blood.v126.23.3905.3905.
Full textAbstract:
Abstract Background Central nervous system (CNS) relapse in patients with diffuse large B-cell lymphoma (DLBCL) is an infrequent but devastating complication. The German Risk model which includes the 5 IPI risk factors plus involvement of the kidneys has been validated in 2 large independent cohorts (Schmitz, ICML 2013; Savage, ASH 2014; El-Galaly, ICML 2015). In this model, the presence of >1 extranodal site of involvement contributes only 1 point. However, the precise impact of the extent of extranodal disease in PET-CT staged patients is unknown. Patients and Methods We identified patients with newly diagnosed DLBCL presenting to hospitals in Denmark, Canada, the United Kingdom and Australia through systematic searches of national/local lymphoma registries. Inclusion criteria were: staging included PET-CT, primary treatment with R-CHOP or similar regimen ± CNS prophylaxis. Patients treated with high-dose regimens (such as R-HyperCVAD) and those with CNS involvement at diagnosis were excluded. Medical records and PET-CT reports were reviewed for clinical information and outcome. Multiple lesions in one organ or set of paired organs/ tissue were counted as a single extranodal site, and the spleen and Waldeyer's ring were not included as extranodal sites. Time to CNS relapse was determined using the method of Kaplan and Meier, with univariate analysis of absolute number of extranodal sites associated with CNS relapse performed using competing risk regression with death before CNS relapse as competing risk. Multivariate analyses (adjusted for elevated LDH, age>60 y and performance status>1) were performed using Cox proportional hazards to identify the specific increase in risk attributable to the absolute number of extranodal sites of involvement. Involvement of the kidney/adrenals and advanced disease stage were not included in the adjustment because of their intrinsic relationship to number of extranodal sites. Results 1,536 patients meeting the above criteria were included, with the following characteristics: median age 65 y (range 17-92), 63% stage III/IV, 39% B symptoms, 50% elevated LDH, 15% performance status >1 and 39%, 36%, 15%, 6% and 3% had 0, 1, 2, 3 and 4+ extranodal sites of involvement, respectively. 79% received no specific CNS-directed prophylaxis; 8% received intrathecal chemotherapy alone, 5% received systemic high-dose anti-metabolites and 8% received both intrathecal and systemic. After a median follow-up of 41 (interquartile range 28-61) months, 62 (4%) patients developed CNS relapse at a median of 9 (range 4-78) months from initial diagnosis. The 3-y incidence of CNS relapse, unadjusted and adjusted hazard ratios for CNS relapse according to number of extranodal sites of involvement are presented in Table 1. The competing risk regression analysis for CNS relapse using absolute number of extranodal sites of involvement is displayed in Figure 1; >2 vs 2 or fewer extranodal sites was associated with markedly increased risk of CNS progression (P <0.0001). Conclusions In patients with newly diagnosed DLBCL staged with PET-CT and treated with R-CHOP, the presence of 3 or more extranodal sites of involvement is associated with markedly increased CNS relapse risk, even when adjusting for other variables. This finding may reflect the greater sensitivity of PET-CT for detection of extranodal disease compared with CT alone. This population would be suitable for prospective studies evaluating the efficacy of prophylaxis strategies and predictive biomarker studies. Table 1. Risk of CNS relapse according to number of extranodal sites at initial diagnosis. *adjusted for LDH, age>60 y and performance status >1 Number of extranodal sites n (%) 3-year incidence % (95%CI) Unadjusted hazard ratio HR (95% CI) Adjusted hazard ratio* HR (95% CI) 0 602 (39) 1.7 (0.9-3.5) 1.0 (ref) 1.0 (ref) 1 559 (36) 4.0 (2.5-6.4) 3.0 (1.3-6.7) 3.1 (1.3-7.2) 2 230 (15) 4.8 (2.4-9.4) 3.4 (1.3-8.5) 2.8 (1.0-7.5) 3 92 (6) 12.8 (6.6-24.0) 8.1 (3.1-20.9) 6.3 (2.2-17.6) 4+ 53 (3) 32.1 (20.1-48.8) 22.0 (9.0-53.6) 17.2 (6.5-45.8) Figure 1. Competing risk regression analysis depicting cumulative incidence of CNS relapse according to absolute number of extranodal sites of involvement. Figure 1. Competing risk regression analysis depicting cumulative incidence of CNS relapse according to absolute number of extranodal sites of involvement. Disclosures Hutchings: Takeda: Research Funding. Connors:Roche: Research Funding; Seattle Genetics: Research Funding. Seymour:Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Phebra: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Infinity: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech, Inc.: Membership on an entity's Board of Directors or advisory committees. Villa:Roche: Research Funding.
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Peyvandi, Flora, Pier Mannuccio Mannucci, Isabella Garagiola, Mohsen Elalfy, Amal El-Beshlawy, Madatha V. Ramanan, Peyman Eshghi, et al. "Source of Factor VIII Replacement (PLASMATIC OR RECOMBINANT) and Incidence of Inhibitory Alloantibodies in Previously Untreated Patients with Severe Hemophilia a: The Multicenter Randomized Sippet Study." Blood 126, no. 23 (December 3, 2015): 5. http://dx.doi.org/10.1182/blood.v126.23.5.5.
Full textAbstract:
Abstract Background We conducted an investigator-driven, multicenter, open label, randomized study to establish whether the source of factor VIII (FVIII) replacement (plasma-derived, pd; or recombinant, r) affects the rate of inhibitory alloantibodies in previously untreated patients (PUPs) with severe hemophilia A. Methods Between 2010 and 2014, 303 PUPs who provided consent through their tutors were screened at 42 participating sites in 14 countries from Africa, the Americas, Asia and Europe. The original aim was to screen 300 patients, randomize 270 (10% screening failure) and follow them for 50 exposure days (ED) or 3 years. Once the intended numbers were included, follow-up was terminated due to logistic and budgetary reasons. Screening criteria were age <6 yrs, plasma FVIII activity <1%, no previous treatment with FVIII concentrates, minimal exposure (less than 5 times) to blood components. Eligible patients were 1:1 block-randomized to a FVIII source class and exclusively treated with a single pd- or rFVIII product, that within each class was allocated on the basis of site licensing and availability. Patients were monitored for inhibitor onset at pre-established and frequent time intervals. Primary outcome was any FVIII inhibitor at titres ≥0.4 BU/ml as assayed centrally. High-titred inhibitors (peak levels >5 BU/ml) were a secondary outcome. Patients were censored at the end of the follow-up (50 EDs, 3 years or study end), at inhibitor development or drop-out. Kaplan-Meier and Cox regression survival analyses took into account as putative confounders FVIII gene mutations, ethnicity, hemophilia and inhibitor family history, previous blood component exposure, therapeutic regimen, age at first treatment and country site. Results Of 303 screened patients, 39 were screening failures, and 13 were excluded because 3 patients had received >5 treatments with blood components and 10 were not infused after randomization. The remaining 251 patients were analysed and 35 had truncated follow-up (25 dropout, 10 study termination). Patients were aged 0-81 months at randomization (median 14 months) and received between 1 and 50 infusions of FVIII concentrates (median 22). Of those who did not develop an inhibitor, over 70% had >20 ED. 76 patients developed an inhibitor, of which 50 were high-titred. The cumulative inhibitor incidence was 35.4% (95% confidence interval (CI95) 28.9-41.9%). 90% of inhibitors developed within 20 EDs, both for all and high-titre inhibitors. After randomization 125 patients received pdFVIII and 126 rFVIII. The putative confounders were equally divided between the two product class arms. There were 29 inhibitors (20 high-titred) in the group treated with the class of pdFVIII and 47 (30 high-titred) in those treated with rFVIII. The cumulative inhibitor incidence was 26.7% (CI95 18.3-35.1%) for pdFVIII and 44.5% (CI95 34.7-54.3%) for rFVIII (Figure). For high-titre inhibitors the cumulative incidence was 18.5% (CI95 12.1-26.9%) for pdFVIII and 28.4% (CI95 19.6-37.2%) for rFVIII. By univariate Cox regression analysis rFVIII was associated with an 87% higher incidence of inhibitors than pdFVIII (hazard ratio (HR) 1.87, CI95 1.18-2.97). For high-titre inhibitors the rate was 70% increased (HR 1.70, CI95 0.96-2.99). The associations did not materially change after adjustment for putative confounders: in adjusted models the rate remained 70-90% elevated for rFVIII vs pdFVIII. When analysis was restricted to sites that had not randomized patients to a second generation full length rFVIII or pdFVIII (n=131 patients, 25 inhibitors), the risk of other rFVIII concentrates vs pdFVIII was still twofold increased (HR 1.99, CI95 1.00-3.99). Conclusions The rFVIII product class was associated with a 1.87-fold higher incidence of inhibitors than the pdFVIII class. This difference remained even when second generation full length rFVIII concentrate was excluded from the analyses. The results of this randomized study have implications in the choice of product for management of PUPs, as inhibitor development remains a major challenge in the management of haemophilia A. (Funded by the Angelo Bianchi Bonomi Foundation, Italian Ministry of Health, Grifols, Kedrion and LFB - Registed at EudraCT 2009-001186-88). Figure 1. Figure 1. Disclosures Peyvandi: Octapharma: Other: Investigator; LFB, Kedrion, Novonordisk, Bayer, Roche, CSL Behring.: Consultancy, Honoraria, Research Funding. Mannucci:Novonordisk, Grifols, Kedrion, Bayer, Biotest, Baxalta: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Karimi:Octapharma: Other: Investigator. Young:Baxter, Grifols: Consultancy, Honoraria. Santagostino:Roche: Speakers Bureau; Bayer: Speakers Bureau; Baxter/Baxalta: Speakers Bureau; Octapharma: Speakers Bureau; Biotest: Speakers Bureau; Novo Nordisk: Speakers Bureau; Kedrion: Speakers Bureau; Biogen/Sobi: Speakers Bureau; CSL Behring: Speakers Bureau; Pfizer: Research Funding, Speakers Bureau. Mancuso:Baxter, Pfizer, CSL Behring, Baxter, Sobi/Biotest: Consultancy; Novo Nordisk, Bayer: Speakers Bureau. Mahlangu:Biogen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Research Funding; NovoNordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biotest: Honoraria, Membership on an entity's Board of Directors or advisory committees. Bonanad:Baxalta: Research Funding. Ewing:Baxter, Novo Nordisk, Grifols, Bayer, Kedrion: Honoraria. Owaidah:King abdulaziz city for science, Novo Nordisk, Bayer: Honoraria, Research Funding. Kobrinsky:Octapharma: Speakers Bureau; CSL Behring: Speakers Bureau; Sanofi: Speakers Bureau; Kedrion Biopharma: Membership on an entity's Board of Directors or advisory committees. Kavakli:Baxter: Other: advisory board member and received educational and investigational support; Bayer: Other: advisory board member and received educational and investigational support; Novo Nordisk: Other: advisory board member and received educational and investigational support; Pfizer: Other: advisory board member and received educational and investigational support; Bio Products Laboratory: Other: received educational and investigational support; CSL Behring: Other: received educational and investigational support; Octapharma: Other: received educational and investigational support. Manco-Johnson:Baxter, bayer, biogen, CSL Behring, NovoNordish: Honoraria. Neme:Novo Nordisk and Pfizer: Other: fees for speaking. Wicklund:NovoNordisk, Bayer, Baxter (now Baxalta), Biogen-Idec, CSL-Behring, National Hemophilia Foundation: Honoraria, Membership on an entity's Board of Directors or advisory committees. Zulfikar:Eczacýbaþý-Baxter, Pfizer, Novo Nordisk: Consultancy, Honoraria, Research Funding.
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Cutler, Corey, Stephanie J. Lee, Sally Arai, Marcello Rotta, Behyar Zoghi, Aravind Ramakrishnan, David Eiznhamer, et al. "Belumosudil for Chronic Graft-Versus-Host Disease (cGVHD) after 2 or More Prior Lines of Therapy: The Rockstar Study (KD025-213)." Blood 136, Supplement 1 (November 5, 2020): 45–46. http://dx.doi.org/10.1182/blood-2020-139445.
Full textAbstract:
Introduction: Belumosudil (KD025) is a novel oral selective rho-associated coiled-coil kinase 2 (ROCK2) inhibitor specifically designed for the treatment of cGVHD, an immune-mediated inflammatory and fibrotic disorder. In a previous dose-finding study (KD025-208, N=54), two-thirds of patients, including those with fibrotic and inflammatory manifestations, achieved a partial or complete response with belumosudil. Herein, we report on the top-line results (6 months after the last patient in) from the pivotal phase 2 trial (ROCKstar [KD025-213], N=132). Methods: This phase 2, open-label, randomized, multicenter study evaluated belumosudil 200 mg QD (n=66) and BID (n=66) in patients with cGVHD who received 2 to 5 prior lines of therapy (LOT). Treatment continued until clinically significant progression of cGVHD. The primary end point was overall response rate (ORR), defined per the 2014 National Institutes of Health Consensus Criteria. Additional end points included duration of response (DOR), Lee Symptom Scale (LSS) score, failure-free survival (FFS), corticosteroid (CS) dose reductions and overall survival. The study was powered such that the lower bound of the 95% confidence interval (CI) excludes 30%, with appropriate multiplicity adjustment. Results: At enrollment, the median age was 56 years, the median time from cGVHD diagnosis to enrollment was 29 months, 67% of patients had severe cGVHD, 52% had ≥4 organs involved, 72% had received ≥3 prior LOT (including ibrutinib [n=46] or ruxolitinib [n=38]) and 73% were refractory to their last LOT. The baseline characteristics of both arms were well balanced. With a median follow-up of 8 months, the ORR (95% CI) with belumosudil 200 mg QD and BID was 73% (60%-83%) and 74% (62%-84%), respectively (Table 1). In patients who previously received ruxolitinib (29%), the ORR with belumosudil 200 mg QD and BID was 65% (41%-85%) and 72% (47%-90%), respectively. In patients who previously received ibrutinib (35%), the ORR with belumosudil 200 mg QD and BID was 73% (50%-89%) and 71% (49%-87%), respectively. High ORRs were seen in all patient subgroups, regardless of length of time from diagnosis to treatment, including those with severe cGVHD, involvement of ≥4 organs and a refractory response to prior LOT (Figure 1). The response rate was similar across all affected organs. The median time to response was 4 weeks. Of responders, 49% have maintained response for ≥20 weeks. The median DOR has not yet been reached. Clinically meaningful improvement (≥7-point reduction) in LSS score on consecutive assessments was observed in 39% and 33% of patients in the QD and BID groups, respectively. Both responders (43%) and nonresponders (17%) experienced a clinically meaningful improvement in LSS score. FFS was 77% (69%-84%) at 6 months. CS and calcineurin inhibitor discontinuations were seen in 18% and 13% of patients, respectively. Belumosudil was well tolerated, with >95% relative dose intensity in 83% of patients. Drug discontinuation occurred in 10% of patients due to possible drug-related adverse events (AEs), 3% due to progression of underlying disease and 12% due to progression of cGVHD. AEs were consistent with those expected in patients with cGVHD receiving CS and other immunosuppressants (Table 2). Common AEs included fatigue (32%), diarrhea (29%), nausea (26%), cough (24%), dyspnea (24%), upper respiratory tract infection (23%), peripheral edema (21%) and headache (20%). At least 1 serious AE occurred in 34% of patients. Twenty-three percent of patients had at least 1 liver-related investigation; the most common was increased gamma-glutamyltransferase (11%), and only 1 patient showed an increase in bilirubin. Eight patients died during the study; 5 due to AEs (1 possibly related to belumosudil) and 3 during long-term follow-up (>28 days after last dose). There were no reports of cytomegalovirus reactivation or infection. Conclusion: Treatment with belumosudil at both doses resulted in high ORRs across key subgroups, meeting the primary end point of this pivotal randomized trial in cGVHD. Responses were durable and clinically meaningful, irrespective of patient and cGVHD characteristics, and were seen in patients who previously received ruxolitinib and ibrutinib. Belumosudil was well tolerated, with limited and manageable AEs. Further studies will evaluate its use earlier in disease management. The 12-month data analysis will be presented at ASH 2020. Disclosures Cutler: Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kadmon: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Medsenic: Consultancy, Membership on an entity's Board of Directors or advisory committees; Generon: Consultancy, Membership on an entity's Board of Directors or advisory committees; Mesoblast: Consultancy, Membership on an entity's Board of Directors or advisory committees. Lee:Pfizer: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Amgen: Research Funding; Kadmon: Research Funding; AstraZeneca: Research Funding; Novartis: Research Funding; Takeda: Research Funding; Syndax: Research Funding. Rotta:Merck: Speakers Bureau; Jazz Pharma: Speakers Bureau. Ramakrishnan:Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Cigna: Honoraria. Eiznhamer:Kadmon Corporation, LLC: Current Employment, Current equity holder in publicly-traded company. Schueller:Kadmon Corporation, LLC: Current Employment, Current equity holder in publicly-traded company. Yang:Kadmon Corporation, LLC: Current Employment, Current equity holder in publicly-traded company. Green:Kadmon Corporation, LLC: Current Employment, Current equity holder in publicly-traded company. Aggarwal:Kadmon Corporation, LLC: Consultancy; Angiocrine Bioscience, Inc: Current Employment, Other: stock options. Blazar:BlueRock Therapeutics: Research Funding; BlueRock Therapeuetic: Consultancy; Fate Therapeutics Inc.: Research Funding; Magenta Therapeutics: Consultancy; Childrens' Cancer Research Fund: Research Funding; KidsFirst Fund: Research Funding; Tmunity: Other: Co-founder. Jagasia:Ocugen: Other; Mallinckrodt: Research Funding; Janssen: Research Funding.
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Venkatakrishnan, Karthik, Ramesh K. Ramanathan, John Sarantopoulos, Daniel L. Mulkerin, Stephen I. Shibata, Anne Hamilton, Afshin Dowlati, et al. "Pharmacokinetics and Safety of Bortezomib In Patients with Advanced Malignancies and Varying Degrees of Liver Dysfunction: Results of the Phase 1 National Cancer Institute Organ Dysfunction Working Group Study NCI 6432." Blood 116, no. 21 (November 19, 2010): 3975. http://dx.doi.org/10.1182/blood.v116.21.3975.3975.
Full textAbstract:
Abstract Abstract 3975 Background: Bortezomib (btz, VELCADE®) is approved in the US for the treatment of patients (pts) with multiple myeloma, and for the treatment of pts with mantle cell lymphoma who have received at least one prior therapy. Btz is oxidatively metabolized by hepatic cytochrome P450 enzymes to pharmacologically inactive deboronated metabolites. Thus, btz pharmacokinetics (PK) may be altered in pts with hepatic impairment (HI). This phase 1 study was undertaken to evaluate the PK and safety of btz in pts with varying grades of HI and to inform dosing recommendations in these subpopulations. Here we present the available interim results. Methods: Pts with advanced malignancies were assigned to four groups based on hepatic function (bilirubin and aspartate aminotransferase [AST] levels relative to the upper limit of normal [ULN]) using the classification developed for organ dysfunction studies by the National Cancer Institute's Cancer Therapy Evaluation Program. Normal function was defined as bilirubin and AST ≤ULN. Pts with mild HI had bilirubin ≤ULN and AST >ULN, or bilirubin >1.0–1.5 × ULN (with any AST). Moderate and severe HI were defined as bilirubin >1.5–3 × ULN and >3 × ULN, respectively, with any AST. Pts received btz on days 1, 4, 8, and 11 of 21-day cycles. Pts with normal hepatic function received btz at the standard dose of 1.3 mg/m2. Pts with severe, moderate, and mild HI received escalating doses of btz from starting doses of 0.5, 0.7, and 1.0 mg/m2, respectively, via a standard 3+3 design to 1.3 mg/m2. Serial blood samples were collected for 24 hours post-dose on days 1 and 8 of cycle 1 for measurement of btz plasma concentrations. Individual values of dose-normalized (DN) area under the concentration–time curve from time zero to the point of last quantifiable concentration (AUC) and maximum concentration (Cmax) were calculated by noncompartmental analysis. PK parameters were summarized by hepatic function and subject to an analysis of variance to estimate the ratio of geometric means and 90% confidence intervals (CIs) for each HI group relative to the control group. Results: A total of 53 pts were treated, 14 with normal hepatic function, and 16, 9, and 14 with mild, moderate, and severe HI, respectively. Median age was 62 years (range 30–85), 53% were female, 94% were white, and 11/58/30% had ECOG performance status 0/1/2. Dose escalation proceeded to 1.3 mg/m2 in pts with mild HI; data collection is ongoing at 1.0 mg/m2 in pts with moderate and severe HI. The most common adverse events (AEs) were fatigue (53%), nausea (42%), and dyspnea (32%). For most AEs, no association was apparent between increased incidence and poorer hepatic function; the incidence of elevated AST was 7, 25, 33, and 36% in the normal group and mild, moderate, and severe HI groups, respectively. PK data were available for 51 pts. Geometric mean DN AUC was 30.2, 23.0, 50.3, and 47.7 (ng.hr/mL)/(mg/m2) on day 1 and 52.2, 51.9, 83.4, and 80.3 (ng.hr/mL)/(mg/m2) on day 8 in pts with normal hepatic function and mild, moderate, and severe HI, respectively. Respective values for geometric mean DN Cmax were 56.7, 38.2, 66.0, and 84.2 (ng/mL)/(mg/m2) on day 1, and 88.9, 79.6, 59.2, and 96.1 (ng/mL)/(mg/m2) on day 8. Geometric least square mean ratios for DN AUC and DN Cmax between groups are shown in the table. Compared to pts with normal hepatic function, mild HI did not alter DN AUC and DN Cmax. However, mean DN AUC was increased by approximately 60% in pts with moderate or severe HI. Conclusions: Pts with mild HI do not require a starting dose adjustment and should be treated per the recommended dose of btz. Pts with moderate or severe HI should be started at a reduced dose of 0.7 mg/m2 during the first cycle, and a subsequent dose escalation to 1.0 mg/m2 or further dose reduction to 0.5 mg/m2 may be considered based on pt tolerance. These data have resulted in an update to the US Prescribing Information for VELCADE®. Comparison vs normal Geometric least square mean ratio (90% CI) Day 1 Day 8 DN AUC Mild HI 0.833 (0.603–1.151) 0.954 (0.664–1.371) Moderate HI 1.662 (1.136–2.430) 1.538 (0.969–2.440) Severe HI 1.578 (1.139–2.186) 1.477 (1.046–2.085) Average of moderate/severe HI 1.619 (1.199–2.186) 1.507 (1.075–2.113) DN Cmax Mild HI 0.697 (0.446–1.090) 0.879 (0.528–1.463) Moderate HI 1.162 (0.688–1.962) 0.612 (0.318–1.178) Severe HI 1.483 (0.947–2.323) 1.023 (0.633–1.653) Average of moderate/severe HI 1.313 (0.868–1.986) 0.791 (0.493–1.271) Disclosures: Venkatakrishnan: Millennium Pharmaceuticals: Employment. Off Label Use: Discussion of Velcade in patients with advanced non-hematologic malignancies is included. Takimoto:Johnson & Johnson: Employment, Equity Ownership. Neuwirth:Millennium Pharmaceuticals, Inc.: Employment. Parasuraman:Millennium Pharmaceuticals: Employment, Equity Ownership. LoRusso:Millennium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding.
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Wilson, Nicola. "SP2 Management of ethylene glycol poisoning in an adolescent: a clinical pearl." Archives of Disease in Childhood 105, no. 9 (August 19, 2020): e1.2-e2. http://dx.doi.org/10.1136/archdischild-2020-nppg.2.
Full textAbstract:
Situation16 year old girl admitted with suspected ingestion of ethylene glycol. She was treated with fomepizole and continuous renal replacement therapy (CRRT).How the Pharmacy Team ContributedEthanol was prescribed until fomepizole arrived. The volume of ethanol to be administered was calculated wrongly by the consultant due to confusion about the available strength. The Paediatric Intensive Care Unit (PICU) pharmacist intervened and the correct dosage information was given.PICU pharmacist used Toxbase to determine the correct treatment of ethylene glycol poisoning and advised on dosing regime, including adjustment due to CRRT. The pharmacist facilitated prescribing on the electronic system (added drug to system, set up administration instructions and assisted with prescribing – pharmacist was not an Independent Prescriber). This allowed medical staff to concentrate on resuscitation, monitoring cardiac function, inserting intravenous lines and obtaining access for CRRT.The PICU pharmacist and pharmacy technician co-ordinated initial supply of fomepizole. Fomepizole is usually ordered directly from the manufacturer during office hours. The patient presented in the early evening so further supply had to be obtained from a hospital hundreds of miles away after referring to the Rarely Used Medicines list. Pharmacist contacted appropriate on-call pharmacist and arranged for transfer of medicines via courier. Pharmacy technician arranged for further supply form the manufacturer the following day.Pharmacy technician arranged supply of additional dialysis fluids for CRRT due to the higher than usual administration rate.Without contribution from the pharmacy team the patient is likely to have been given the wrong dose of ethanol and fomepizole, and there would have been delay in initiation of treatment followed by an interruption, as it was wrongly assumed that it was kept as stock in the adjoining ‘adult hospital’ and subsequent supply from a local hospital would not have been sought by ward staff until original supply ran out.OutcomeEthylene glycol poisoning was confirmed on laboratory testing. Levels of ethylene glycol fell steadily over 36 hours, allowing CRRT and fomepizole to stop. Patient was discharged from PICU after 48 hours with no apparent long-lasting effects, but was referred to various specialities including renal, gastroenterology and psychology.Patient and family denied knowledge of intentional or accidental ingestion. Police investigation was inconclusive.Lessons to be LearnedLarger supplies of fomepizole are now kept in stock within Health Board. Supplies were missing from emergency cupboards when stock was needed, despite being on stock lists, necessitating courier fees to transfer stock from elsewhere. Procedures reviewed to ensure that stock is available in emergency cupboards at all times.This patient demonstrated that current (target) stock levels of fomepizole were inadequate for providing treatment during CRRT as the required doses are substantially higher (administered every four hours rather than every twelve hours) and would have lasted less than 12 hours for this average sized teenager. National Rarely Used Medicines list was updated to reflect actual stock levels and other hospitals increased their stockholding due to the realisation that existing stock was inadequate and that further supplies were hard to obtain out of working hours.
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Czyżewski, Dariusz. "Comparison of luminance distribution on the lighting surface of power LEDs." Photonics Letters of Poland 11, no. 4 (December 31, 2019): 118. http://dx.doi.org/10.4302/plp.v11i4.966.
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This work presents luminance distributions across the surface of mid- and high-power diodes. The changes in luminance on diode surfaces following changes in the observation angle were verified. On the basis of the conducted tests, non-uniform luminance distribution on LED surface for diverse observation angles (including the axial direction) was observed. Moreover, it was concluded that luminance changes is not in line with the Lambert’s law. As the result of the research it was also concluded that alterations of the power-supply conditions do not exert any significant impact on the gradient of luminance changes on the surfaces of examined LEDs. Full Text: PDF ReferencesJ. Fan, J. Cao, Ch. Yu, Ch. Qian, X. Fan, G. Zhang, A design and qualification of LED flip Chip-on-Board module with tunable color temperatures, Microelectronics reliability, ISSN 0026-2714, Nº. 84, 2018, pp. 140-148, CrossRef K. Bonislawski, I. Fryc, The study on optical properties of LEDs used for vehicle control lighting, Przeglad Elektrotechniczny, 2012, ISSN 0033-2097, Vol. 88, Issue 3A, pp. 119-120 DirectLink T. Kawabata, Y. Ohno, Optical measurements of OLED panels for lighting applications, Journal of Modern Optics 60(14), 2013, pp. 1176-1186 CrossRef P. Pracki, U. Blaszczak, The issues of interior lighting on the example of an educational building adjustment to nZEB standard, IEEE Lighting Conference of the Visegrad Countries (Lumen V4), IEEE (17 November 2016) CrossRef P. Tabaka, Analysis of electrical parameters of prime set bulb equivalents suitable for dimming, Przeglad Elektrotechniczny, 2015, R. 91, No. 5, pp. 100-106, ISSN 0033-2097 CrossRef D. Czyżewski, The street lighting luminaires with LEDs. Przeglad Elektrotechniczny, 86, 2009, pp. 276-279 DirectLink C. C. Miller; Y. Zong; Y. Ohno, LED photometric calibrations at the National Institute of Standards and Technology and future measurement needs of LEDs, Proc. SPIE Vol. 5530, Fourth International Conference on Solid State Lighting; (2004) CrossRef D. Mozyrska Dorota; M. Wyrwas; I. Fryc, The determination of the LEDs colorimetric parameters, in the range of their operating temperature, Przeglad Elektrotechniczny, Vol. 88, Issue: 4A, 2012, pp. 232-234 CrossRef K. Baran, A. Różowicz, H. Wachta, S. Różowicz, D. Mazur, Thermal Analysis of the Factors Influencing Junction Temperature of LED Panel Sources, Energies, 12, 3941, 2019 CrossRef D. Czyżewski, Research on Luminance Distributions of Chip-On-Board Light-Emitting Diodes, Crystals 9(12), 645, 2019. CrossRef L. Zheng, Z. Guo, W. Yan, Y. Lin, Y. Lu, H.C. Kuo, Z. Chen, L. Zhu, T. Wu, Y. Gao, Research on a Camera-Based Microscopic Imaging System to Inspect the Surface Luminance of the Micro-LED Array. IEEE Access 6, 2018, 51329-51336. CrossRef S. Słomiński, Selected Problems in Modern Methods of Luminance Measurement of Multisource LED Luminaires. Light Eng. 24, 2016, pp. 45-50. DirectLink I. Fryc, P. Jakubowski, K. Kołacz, Analysis of optical radiation parameters of compact discharge HID lamps and LED COB modules used for illuminating shop windows, Przeglad Elektrotechniczny, 2017, R. 93, nr 11, pp. 186-189. CrossRef I. Fryc, Measurement techniques of optical LEDs properties performed with compliance conformity with CIE 127:2007 standard, Przeglad Elektrotechniczny, 2009,ISSN 0033-2097,Vol. 85,Issue:11,pp.317-319. DirectLink I. Fryc, T. Dimitrova-Grekow, An Automated System for Evaluation of the Quality of Light Sources, 2016 IEEE Lighting Conference of the Visegrad Countries (Lumen V4), IEEE (17 November 2016), CrossRef CIE 235:2019, Optical measurement of led modules and light engines, ISBN 978-3-902842-25-1, DOI: 10.25039/TR.235.2019. CrossRef D. Czyżewski, Investigation of COB LED luminance distribution, In Proceedings of the 2016 IEEE Lighting Conference of the Visegrad Countries (Lumen V4), IEEE (17 November 2016) CrossRef I. Rotscholl, K. Trampert; U. Krüger; F. Schmidt, Spectral near field data of LED systems for optical simulations, Proceedings SPIE Volume 11144,Phot. and Educ. in Measur. Sc. 2019, CrossRef
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Borjas-Howard, James Francis, Casper Rokx, Colette Smit, Ferdinand Wit, Elise Pieterman, Karina Meijer, Bart Rijnders, Wouter Bierman, and Vladimir Tichelaar. "Incidence and Risk Factors for Venous Thrombosis in Human Immunodeficiency Virus (HIV) Infection, Data from the Dutch Athena Cohort Study." Blood 128, no. 22 (December 2, 2016): 271. http://dx.doi.org/10.1182/blood.v128.22.271.271.
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Abstract Introduction HIV-infected patients have an increased risk of venous thrombosis (VT), but the most recently published data are from before 2007 (Rasmussen et al. HIV Med2011). However, since 2008, recommended CD4+ T-cell thresholds for starting combination anti-retroviral therapy (cART) have steadily increased from 200 to the current (2015) recommendation to start cART irrespective of CD4+ count. As the increased risk of VT is predominantly the result of the HIV-associated pro-inflammatory state, we hypothesize that initiation of cART at higher CD4+ T-cell counts might have attenuated the risk of VT over the last decade. However, in contrast and more controversial is the possible prothrombotic effect of certain antiretroviral agents, namely abacavir (ABC) and HIV protease inhibitors (PI). To elucidate this, we assessed the relationship of CD4+ T-cell counts and cART regimens with the risk of VT, using data from the Dutch ATHENA cohort. Methods ATHENA is the Dutch National HIV cohort study, prospectively collecting data of all HIV-infected patients in the Netherlands. As VT is not routinely registered, we developed a strategy of targeted VT case finding through the registered use of anticoagulants (recorded since January 2003). Any anticoagulant use registered in ATHENA led to a review of a patients medical records looking for a VT diagnosis (either confirmed by radiological examination or by clinicians correspondence/ resumes). We confirmed the sensitivity (100% sensitivity) of our search strategy in a pilot study in one participating center and used it to collect VT cases in twelve HIV treatment centers (>70% of all HIV-infected patients in care in the Netherlands). Main outcome was occurrence of a first VT: deep vein thrombosis of the lower/upper extremity (no more distal than popliteal/subclavian vein), pulmonary embolism, splanchnic and/or cerebral VT. Data were analyzed using Cox regression. Covariates of interest were HIV-specific events (coded as CDC-C events), CD4+ & CD8+ T-cell counts, HIV-RNA viral load, use of antiretroviral medication (by class), history of intra-venous drug use and classic VT risk factors (pregnancy, malignancy and hospitalization). Covariates remaining significant after correction for classic VT risk factors (table 1, adjusted), were forced into two fully adjusted models; one excluding (Model 1) and one including hospitalization as a covariate (Model 2). This enabled separation of effects for variables that are not confounded by hospitalization (i.e. in most cases, hospitalization is a consequence- not the cause- of infection/inflammation) and variables potentially confounded by hospitalization (i.e. starting cART during a hospitalization). Results 14,386 eligible patients were included. Median age at inclusion was 40 years, 79% was male. There were 229 VTs during 97,556 years of follow up (2.3 VT per 1000 person years [py]). All classic risk factors introduced were independently associated with VT. HIV specific markers except CD4+/CD8+ T-cell ratio were independently associated with VT, with CD4+ T-cell count category showing a consistent decrease in hazard for VT for each category. The absolute VT risk in patients with CD4+ count >500 was close to that of the general population (1.3 [95%CI 1.0-1.6] versus 1.2 VTs per 1000 py [Silverstein et al, Arch Int Med, 1998]). We did not observe an association between VT and PIs or ABC, but we did for the use of integrase inhibitors (INIs). The effect lost statistical significance after adjustment for hospitalization. Conclusions Overall, HIV-infected patients have a twofold increased risk of VT compared with the general population. This risk declined progressively with increasing CD4+ T-cell counts, from 7.1 to 1.3 VTs per 1000 py for CD4+ T-cell counts >500, thereby approaching the incidence of the general population. Markers for more advanced HIV-disease (higher viral load, AIDS-defining illness) were also associated with an elevated risk of VT. INIs (at that time only raltegravir) were the only antiretroviral agents associated with increased VT risk, with a borderline significance in a fully adjusted model. This association might be due to confounding by indication, as at the time, INIs were mostly used in patients with prior therapy failure or comorbidities. Overall, our findings suggest that the elevated risk in the HIV-infected population is explained by uncontrolled HIV infection and provoking factors. Disclosures Rokx: Virology Education: Honoraria; Janssen-Cilag: Honoraria; Boehringer-Ingelheim: Honoraria; Gilead: Honoraria, Other: travel grants; ViiV Healthcare: Honoraria, Other: travel grant; Merck & Co: Research Funding; MSD: Other: travel grant. Wit:Abbvie: Other: travel grant; Janssen-Cilag: Other: travel grant; ViiV Healthcare: Other: travel grant; MSD: Other: travel grant; Bristol-Myers Squibb: Other: travel grant; Gilead Sciences: Honoraria, Other: travel grant; Boeringer Ingelheim: Other: travel grant. Meijer:Baxter: Research Funding; Bayer: Honoraria, Research Funding; Pfizer: Research Funding; Sanquin: Honoraria, Research Funding; Boehringer Ingelheim: Honoraria; Bristol-Myers Squibb: Honoraria. Rijnders:AbbVie: Membership on an entity's Board of Directors or advisory committees, Other: Travel grants; EUR trust fund: Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants; ViiV Healthcare: Other: Travel grants; Gilead Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants, Research Funding; Great Lakes Pharmaceuticals, inc.: Honoraria; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees, Other: Travel grants; MSD: Membership on an entity's Board of Directors or advisory committees, Other: Travel grants, Research Funding. Bierman:Janssen-Cilag: Other: unrestricted symposium support grant, Research Funding. Tichelaar:Bayer: Other: travel grant; Baxter: Other: travel grant.
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Son, Hoang Thanh, and Truong Van Anh. "Determination of drainage corridor in the downstream Vu Gia - Han river, Da Nang city." VIETNAM JOURNAL OF EARTH SCIENCES 41, no. 1 (January 8, 2019): 46–58. http://dx.doi.org/10.15625/0866-7187/41/1/13546.
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Flood is one of the most well-known phenomena in the Central Vietnam where Da Nang city is located. As the most area in the central coastal part, this city frequently suffers to flood without any prevented structure like sea dike or river levee. The only thing that can help to the response for flood is emergency plans. Therefore, flooding still causes great damages to the economic development and social stability in this region. For ensuring the sustainable development of Da Nang city under the impacts of climate change and sea level rising, it requests a change in direction of the solution, from the flood control to the adaptation and living with floods through spatial planning to make a good condition for optimal drainage corridors. This paper suggests a design flood drainage corridors for Da Nang city that was developed by combining of mathematical model, GIS, hydro-meteorological documents of Vu Gia - Thu Bon basin from 2009 to present. These proposal solutions include (i) widening of the riverbed and providing a river corridor protection along both river banks; (ii) creating of drainage channels for the land between the rivers and (iii) creating of space for floodwater in an appropriate time. The result was so good and it helps to reduce the flood in Da Nang from 5% to 10%. Therefore this would be a scientific basis for identifying the flood drainage corridors of other river basins in the central coastal region without typical dike cover.ReferencesBruun et al., 2013 On the Frontiers of Climate and Environmental Change: Vulnerabilities and Adaptation in Central Vietnam, Springer Verlag, Berlin, Germany.CCFSC (Central Committee for Flood and Storm Control), 2005. “National Report on Disasters in Vietnam.”, the World Conference on Disaster Reduction, January 18–22, Kobe-Hyogo, Japan.Da Nang Statistical Office, 2016. Statistical Yearbook, Statistical publishing house, Hanoi.Da Nang University of Science and Technology, 2014. Project of Da Nang Hydrology and Urban Development Simulation Model supported by Rockefeller, Stored report of the Climate Change Coordination Office, Da Nang.Da Nang City Steering Board for Storm and Flood Prevention and Search and Rescue, Resume of the Flood Prevention and Search and Rescue works from 2000 to 2016, Stored report of the Office of People’s Committee of Da Nang city.Dang Thi Kim Nhung, 2016. Review of flood prevention planning in the central provinces from Quang Binh to Binh Thuan. Proceedings of the 55th anniversary of InstituteofWater Resources Planning, Hanoi.Decision No. 2357/QD-TTG dated 04 December 2013 approving the adjustment of general planning of Da Nang city by 2030 with a vision toward 2050.Decree No. 43/2015/ND-CP dated on 6 May 2015. Hanoi establishment and management of water source protection corridors.DHI Dan Mach, 2011. MIKE 11(RR+HD) - A Modelling system for rivers and channels, User guide.DHI Dan Mach, 2011. MIKE 21- Flow Model FM, User guide.Dinh Phung Bao, 2013. The study using GIS for flood prevention mapping system in Vu Gia-Thu Bon river basin, Stored report of the Mid-Central regional hydrometeorological center, Da Nang.FEMA, 1995. Managing Floodplain Development in Approximate Zone A Areas - A Guide for Obtaining and Developing Base Flood (100-year) Flood Elevations - FEMA 265.Floodway: https://www.fema.gov/floodplain-management/floodway#0.Hoang Ngoc Tuan, 2016. Comprehensive assessment of resistance of surface water resource to the climate change of the city, Stored report of Climate Change Coordination Office, Da Nang.Hoang Thai Binh, 2017. Determination of flood drainage corridor in the downstream area of Vu Gia - Thu Bon river (in Da Nang city) when the hydropower system in the upper in operation in the context of climate change. Final report of project’s code VAST-NĐP.12/15-16, Hanoi.JICA, 2009. Report Project for Building Disaster Resilient Societies in Central Regions of Vietnam.LUCCI, 2015. Study on the land use and climate change interactions in Central Vietnam, http://www.lucci-vietnam.info/vn/.Ministry of natural resources and environment, 2016. Climate change, sea level rise scenarios for Vietnam.NRWA Waterways Section And BG&E Pty LTD, 2006. Floodway Design Guide, Government of Western Australia.Nguyen Kim Loi, 2016. The support system for Flood warning (case study in Vu Gia - Thu Bon river basin, Quang Nam province), Agricultural Publishing House, Hanoi.SRV (Socialist Republic of Vietnam), 2007. National Strategy for Natural Disaster Prevention, Response and Mitigation to 2020. November 16. Hanoi, VietnamTran Tuan, Bui Dung, 2012. The.Natural Disasters in Vietnam A SYNTHESIS FROM A SOCIOECONOMIC PERSPECTIVE, 179-198.Vu Thi Thu Lan, 2011. Field survey and hydraulic modeling of Thu Bon river basin, Quang Nam province, Stored report of Steering Board for Storm and Flood Prevention of Quang Nam.Vu Thi Thu Lan, 2013. Flood prevention mapping of Vu Gia-Thu Bon river and Thach Han-Ben Hai river in scale 1/10.000. Stored report of Office for Water Resources Projects, Ministry of Agriculture & Rural Development, Hanoi.Vu Thi Thu Lan, 2013. The study of natural disasters variation (floods and droughts) in Quang Nam in the context of climate change, J. Sci. of the Earth, Hanoi, 35(1), 66-74.World Bank, 2012. Fiscal Impact of Natural Disasters in Vietnam, http://www.worldbank.org/fpd/drfip.
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Angelucci, Emanuele, Junmin Li, Peter L. Greenberg, Wu Depei, Ming Hou, Efreen Montaño Figueroa, Guadalupe Rodriguez, et al. "Safety and Efficacy, Including Event-Free Survival, of Deferasirox Versus Placebo in Iron-Overloaded Patients with Low- and Int-1-Risk Myelodysplastic Syndromes (MDS): Outcomes from the Randomized, Double-Blind Telesto Study." Blood 132, Supplement 1 (November 29, 2018): 234. http://dx.doi.org/10.1182/blood-2018-99-111134.
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Abstract Background: MDS comprise a group of disorders characterized by bone marrow (BM) failure, cytogenetic and molecular alterations, and progression to acute myeloid leukemia (AML). Most lower-risk MDS patients (pts) eventually need chronic red blood cell (RBC) transfusions because of impaired hematopoiesis, resulting in iron overload (IO) that damages organ function and contributes to shortened survival. Though iron chelation therapy (ICT) has been consistently shown to improve outcomes in lower-risk MDS pts, most studies had limitations (eg retrospective analyses, registry studies, pts not stratified by performance status). As such, a prospective, controlled study of ICT and survival in Low/Intermediate (Int-1)-risk MDS pts was needed. Aims: TELESTO (NCT00940602) was a Phase II randomized, double-blind study that evaluated event-free survival (EFS) and safety of deferasirox (DFX) vs placebo (PBO) in Low/Int-1-risk MDS pts. Methods : Eligible pts were aged ≥18 yrs, had IPSS Low/Int-1-risk MDS (confirmed by BM examination within 6 months of study entry), serum ferritin (SF) >1000 ng/mL, transfusion history of 15-75 pRBC units, without cardiac, liver and renal abnormalities. Pts were randomized 2:1 to DFX (dispersible tablets; 10-40 mg/kg/day based on dosing guidelines) or PBO. Primary objective was to evaluate DFX and PBO for EFS, measured by a composite primary endpoint of time to first non-fatal event (related to cardiac and liver function and transformation to AML) or death, whichever occurred first; events were confirmed by an independent adjudication committee. With a planned sample size of 210 pts, no hypotheses were planned to be tested; statistical tests are exploratory, P values associated with treatment effect are nominal. Results: 225 pts were randomized to DFX (n=149) or PBO (n=76); 72.4% had Int-1 MDS, 60.9% were male, mean age was 61.0 yrs; baseline characteristics were balanced, but more pts in the DFX arm were aged ≥75 yrs (25.5% vs 17.1%). DFX and PBO pts received a mean of 20.28 and 20.27 international units of pRBC transfusions 6 months prior to randomization. Median time on treatment was longer with DFX vs PBO (587.5 vs 370.5 days); 43.9% and 25.0% of DFX and PBO pts received treatment for ≥2 yrs. Median EFS was prolonged by 349 days with DFX (1440 days; 95%CI 1167-1559) vs PBO (1091 days; 95%CI 820-1348): 36.4% risk reduction in EFS with DFX (P=0.015 [Figure 1]). Estimated EFS at 3 yrs was 61.5% (95%CI 52.2-69.6) with DFX and 47.3% (95%CI 31.8-61.3) with PBO. Events that occurred first with DFX (n=62; 41.6%) and PBO (n=37; 48.7%) included: worsening cardiac function (1.3 vs 2.6%); hospitalization for congestive heart failure (0.7 vs 3.9%); liver function impairment (0.7 vs 1.3%); progression to AML (6.7 vs 7.9%); death (32.2 vs 32.9%). Robustness of the positive treatment effect with DFX was confirmed by various sensitivity analyses, including censoring pts with premature treatment discontinuation and subsequent ICT. Median overall survival (OS) was 1907 days (95%CI: 1440-not estimable) with DFX and 1509 days (95%CI 1095-1804) with PBO; HR 0.832 (95%CI 0.54-1.28, P=0.200). ICT after study treatment discontinuation may have diluted any potential OS difference. SF declined over time with DFX and increased in the PBO arm (Figure 2). Most frequently reported AEs (≥20% in either arm) were diarrhea, pyrexia, upper respiratory tract infection, cough and increased blood creatinine. After adjustment for exposure, rates were: diarrhea (24.7 vs 23.9%), pyrexia (21.8 vs 18.7%), upper respiratory tract infection (16.7 vs 22.7%), cough (12.6 vs 11.3%) and increased blood creatinine (15.9 vs 0.9%) in the DFX and PBO arms, respectively. Most frequently reported severe AEs (≥5% in either arm) were anemia, pyrexia, thrombocytopenia and lung infection. When adjusted for the different exposure time, the rate of all severe AEs per 100 pt-yrs was overall comparable. Summary/conclusions: TELESTO is the first prospective, randomized study in Low/Int-1-risk MDS pts with IO to show ICT with DFX provides clinical benefit across multiple tissues, leading to longer EFS (including cardiac and liver events and transformation to AML) vs PBO. The safety profile was as expected, consistent with previous studies of DFX in adult MDS pts with IO. Considering the current treatment landscape, it is unlikely that a similar, randomized trial can be performed. These results support the use of DFX in Low/Int-1-risk MDS pts with IO. Disclosures Angelucci: Celgene: Honoraria, Other: Chair DMC; Vertex Pharmaceuticals Incorporated (MA) and CRISPR CAS9 Therapeutics AG (CH): Other: Chair DMC; Jazz Pharmaceuticals Italy: Other: Local ( national) advisory board; Roche Italy: Other: Local (national) advisory board; Novartis: Honoraria, Other: Chair Steering Comiittee TELESTO Protocol. Rodriguez:Novartis: Speakers Bureau. Dong:Novartis: Employment. Ghosh:Novartis: Employment. Bornstein:Novartis: Employment.
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Dimopoulos, Meletios A., Maria Roussou, Nikolaos Kanellias, Maria Gavriatopoulou, Magdalini Migkou, Ioannis Panagiotidis, Evangelos Eleutherakis-Papaiakovou, et al. "Pomalidomide with Low Dose Dexamethasone Is Effective Irrespective of Primary or Secondary Resistance to Lenalidomide but the IMiD-Free Interval Is Important." Blood 128, no. 22 (December 2, 2016): 3310. http://dx.doi.org/10.1182/blood.v128.22.3310.3310.
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Abstract Pomalidomide with low dose dexamethasone (Pd) is a standard treatment for patients who have failed both lenalidomide (Len) & bortezomib (Bor). Phase III studies showed that Pd is active irrespective of the number of prior therapies and whether Len or Bor were the last therapies prior to Pd. However, it remains unclear what is the activity of Pd when administered immediately after refractoriness to Len or when is administered following secondary resistance. Furthermore, the importance of the time elapsed from the administration of Len to Pd has not been explored. We analyzed the outcomes of 116 consecutive patients with MM after failure of both Len & Bor that were treated in the Department of Clinical Therapeutics, National and Kapodistrian University of Athens, and who all received pomalidomide 4 mg with weekly dexamethasone. Median age was 62 years (range 38-86 years); median number of prior treatments was 4 (range 1-9), 58% had received ASCT, 73% were refractory to the last Bor-based regimen and 90% were refractory to the last Len-based regimen. All patients had MM refractory to the last regimen, but 40% had ≥PR to their most recent regimen prior to development of refractoriness. The last regimen prior to Pd included Bor in 62 (53%), Len in 35 (30%) and conventional chemo in 19 (17%). On intent to treat, 34 (29%) patients achieved ≥PR (CR: 3%, VGPR: 7%, PR: 19%). In those which received Len just prior to Pd, ≥PR rate was 26% vs 33% for Bor and 21% for other regimens (p=0.55). Among patients with <PR to any prior Len therapy (primary resistance to Len, N=45) ≥PR was 24% vs 31% for those who had ≥PR to any prior Len during the course of their disease (secondary resistance to Len, N=71) (p=0.42). Among patients who received Len just prior to Pd and who achieved ≥PR before development of resistance, 29% achieved ≥PR vs 18% for those with <PR (p=0.49). Thus, Pd was effective irrespective of primary or secondary refractoriness to Len. Median follow up was 29 months and 95 (83%) patients have progressed or died. Median PFS was 5.2 months (95% CI 3.8-6.5). Patients who received Len as their last treatment before Pd had PFS similar to that of patients who received either Bor or other regimens (p=0.8). Patients who had ≥PR when treated with Len immediately before Pd (secondary resistant to Len), had PFS similar to that of those with <PR (p=0.61). PFS of patients with primary vs secondary resistance to Len was 4.9 vs 6.5 months (p=0.18). After Pd, 59 (51%) patients received further therapy. PFS2 for all patients is 9.6 months (95% CI 7.6 -10.4). PFS2 was similar for patients who received Len vs Bor or other therapies immediately prior to Pd (9 vs 9.9 vs 7.4 months, p=0.55). For those who had Len just prior to Pd those who achieved ≥PR before development of Len resistance PFS2 was 9.7 vs 7.2 months for those who had <PR (p=0.36) and was similar for patients with primary vs secondary resistance to Len (8.7 vs 9.7 months, p=0.4). Median OS was 13 months (95% CI 9.7-16). OS of patients who received Len immediately before Pd was 11.3 vs 13 months for Bor (p=0.486). Among patients who received Len as their last regimen and who achieved ≥PR before development of resistance, there was a trend for longer OS (16.6 vs 9.9 months for those with <PR, p=0.3) and OS was 12.7 vs 15.7 months for patients with primary vs secondary resistance to Len (p=0.4). We then evaluated the role of time elapsed from the last exposure to Len until start of Pd. Median time from the last Len dose to Pd was 8 months; however, further analysis revealed that ≥PR was 68% for patients (N=29) who had ≥18 months since the last dose of Len. PFS of patients with an interval ≥18 months was 10.5 vs 4 months for those with <18 months (p=0.002) and OS was 20 vs 15 months for those with an interval 12-18 months vs 10 months for those with <12 months interval (p=0.01). These effects remained significant even after adjustment for the number of prior therapies and primary or secondary Len resistance. In conclusion, Pd is active in MM patients refractory to Len, independently of primary or secondary resistance to Len or if Len was used just prior to Pd. However, patients with ≥18 months of Len-free interval may have longer PFS and OS irrespectively of prior lines of therapy. These data indicate the potential role of "clonal tides" and the emergence of IMiD-sensitive clones after "IMiD-free" periods, but further investigation is needed to identify optimal treatment strategy. Disclosures Dimopoulos: Genesis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Delimpasi:Genesis: Honoraria; Amgen: Honoraria; Janssen: Honoraria. Terpos:Genesis: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Amgen: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Travel expenses, Research Funding; BMS: Consultancy, Honoraria; Novartis: Honoraria; Celgene: Honoraria. Kastritis:Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Genesis: Consultancy, Honoraria.
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Pine, Meghann S., Li Wang, Richard Ho, Jennifer Domm, and Haydar Frangoul. "Comparison of Pre-Cryopreserved and Post Thaw and Wash Total Nucleated Cell Count On Major Outcomes Following Unrelated Cord Blood Transplant in Children." Blood 114, no. 22 (November 20, 2009): 3336. http://dx.doi.org/10.1182/blood.v114.22.3336.3336.
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Abstract Abstract 3336 Poster Board III-224 Engraftment and overall survival after umbilical cord blood transplant is highly dependent on the total nucleated cell count (TNC). Current standard post thaw processing includes a wash step to remove dimethyl sulfoxide (DMSO), lysed red cells and stroma. The contribution of the wash step to cell loss and ultimately the dose of cells available for transplant is not well described. To investigate the amount of cell loss after washing and its impact on major outcomes compared to pre-cryopreserved TNC, we analyzed data from 310 patients prospectively enrolled on a National Heart Lung Blood Institute (NHLBI) sponsored cord blood transplant study between 1999 and 2003. Dataset was obtained after signed agreement with the NHLBI and local IRB approval. There were 310 patients ≤18 years of age with malignant (N=217) or non-malignant (N=93) disease enrolled on this trial. Only single cord units were used. All cord blood units were thawed and washed using an identical process developed by Rubinstein et al. All patients received myeloablative preparative regimen with either total body irradiation or busulfan based regimens with cyclosporine and prednisone GVHD prophylaxis. All patients received anti-thymocyte globulin as part of their conditioning regimen. For the overall survival, Cox proportional hazard models were generated for pre-wash cell dose and post-wash cell dose separately and then combined in one model. All models included identical covariates. Total cell dose was modeled as a continuous variable with appropriate transformation using restricted cubic lines to account for non-linear relationships. For transplant related mortality (TRM) and neutrophil engraftment, competing risk analyses were used. These analyses were done with adjustment for age, gender, disease (malignant versus nonmalignant), performance status (<90 versus ≥90), HLA (3-4/6 versus 5-6/6 match), and CMV status. The median age was 4.59 years (range 0.04 – 17.90) with 188 (61%) male, 249 patients (80%) had a performance status of ≥90. 166 patients (54%) received a cord blood unit matched at 3/6 or 4/6 HLA antigens and 144 patients (46%) received a cord blood unit matched at 5/6 or 6/6 HLA antigens. The median pre-cryopreserved TNC per kg was 6.93 × 107/kg (range 1.5-80.9 × 107/kg). The median TNC recovery after thawing and washing (PTW) was 5.43 × 107/kg (range 1-31.6 × 107/kg). The average cell recovery was 89% after thawing and washing. Neutrophil engraftment was significantly associated with higher pre-cryopreserved (p=0,003) and PTW TNC infused (p=0.005); younger age (p=0.03), better HLA match (p=0.03). The risk of transplant related mortality was significantly higher among older patients (p=0.02), female patients (p=0.02) and those receiving 3-4/6 HLA matched cord units (p=0.02). Neither the pre-cryopreserved or PTW TNC were significant contributing factors. The risk of grade II-IV acute GVHD was significantly higher among older patients (p=0.04) and those receiving higher pre-cryopreserved TNC (p=0.02) but not higher PTW TNC (p=0.07). Overall survival was significantly better among younger patients (p=0.02), male recipients (p<0.001), patients with non-malignant diseases (p<0.001), patients with performance status >90 (p=0.04) and those receiving 5-6/6 HLA matched cord units (p=0.04). Pre-cryopreserved and PTW TNC did not influence overall survival. In conclusion, pre-cryopreserved and post thaw and wash TNC were equally predictive for major outcomes of unrelated cord blood transplant in children. Disclosures No relevant conflicts of interest to declare.
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Kistangari, Gaurav, Keith R. McCrae, Swapna Thota, Nicholas Schiltz, and Siran M. Koroukian. "The Effect Of Insurance Status and Comorbidities On Outcomes After Splenectomy Among Patients With ITP." Blood 122, no. 21 (November 15, 2013): 3560. http://dx.doi.org/10.1182/blood.v122.21.3560.3560.
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Abstract Background Importance of individual’s insurance status in access and quality of health care has been well documented in published literature. Lack of or inadequate insurance may be associated with negative health consequences. Currently there are no studies that have examined the relation between the insurance status and splenectomy outcomes among patients with Immune thrombocytopenia (ITP) Splenectomy has been the standard second-line treatment for adults with ITP for several decades. Recently published guidelines by American Society of Hematology for the management of ITP gave splenectomy a strong recommendation based on its sustained remission rates and long-term experience. Despite its effectiveness in achieving durable response, there has been a tendency among physicians to avoid or delay splenectomy due to the fear of removing a healthy organ, a long-term risk of sepsis and mortality associated with surgery. Previously reported mortality rates for splenectomy in ITP were around 0.2 - 1%. However, the effect of insurance status and the prevalence of common comorbidities that can influence postoperative outcomes have not been explored in this population. The following study, representative of a national cohort of ITP patients who underwent splenectomy, assesses the effect of insurance type and comorbidities on postoperative mortality and length of stay in hospital following splenectomy. We hypothesized that uninsured or federally funded health insurance and underlying comorbidities might have an unfavorable effect on the outcomes. Methods Within the Health Care Utilization Project Nationwide Inpatient Sample (NIS), we identified 9419 (n=9419) patients who underwent splenectomy for ITP between 2004-2009. The presence of comorbidities was assessed based on Elixhauser’s comorbid conditions and patients were categorized based on presence of ≥ 3, ≥2 or ≤1 comorbid conditions. Multiple logistic regression analyses was performed to evaluate the effect of insurance type on inpatient mortality rate after adjusting for age, sex, race, and number of comorbidities. Furthermore, the effect of comorbidities on inpatient mortality was analyzed after adjusting for other variables such as age, type of insurance and race. Hospital length of stay (LOS) was dichotomized as prolonged if LOS > 9 days (third quartile) or short if LOS< 9 days. The study protocol was approved by Case Western Reserve University Institutional Review Board. Results During the six-year period between 2004-2009, a weighted estimate of 9419 patients were identified who underwent splenectomy for ITP. Inpatient postoperative mortality was 3.1% and overall median LOS was 9 days. Most patients were privately insured (47.6%), followed by Medicare (35.1%), Medicaid (8.6%) and uninsured (8.5%). 2% of Medicare, 0.2% of Medicaid, 0.7% of uninsured and 0.16% of privately insured patients died. On multivariable analysis there was no significant difference in mortality among Medicare, Medicaid and uninsured patients when compared to privately insured patients. Medicaid patients had prolonged length of stay as compared to privately insured patients (aOR 2.55, CI 1.71-3.79, P< 0.0001). Patients with higher comorbidities had higher mortality rates and length of stay after adjusting for age, race and insurance type. Patients with ≥ 3 comorbid conditions were three times more likely to die (aOR 3.03, CI 1.4-6.2, p<0.01) and six times more likely to have prolonged hospital stay (aOR 6.4, CI 4.8-8.6, p<0.001) as compared to patients with ≤1 comorbid condition. Conclusion Patients who are privately insured have similar mortality rates as compared to Medicare and Medicaid and uninsured population. Preoperative comorbidities are associated with increased risk of mortality, and risk adjustment is necessary while evaluating patients with ITP undergoing splenectomy. Disclosures: No relevant conflicts of interest to declare.
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Pinsky, Brett, Hui Huang, April Teitelbaum, Dixie-Lee Esseltine, and Henry J. Henk. "Multiple Myeloma: Patient out-of-Pocket Costs and Health Care Utilization." Blood 114, no. 22 (November 20, 2009): 1366. http://dx.doi.org/10.1182/blood.v114.22.1366.1366.
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Abstract Abstract 1366 Poster Board I-388 Background: Multiple myeloma (MM) is a complex disease that places a significant burden on patients and their caregivers. Novel agents have different administration methods (oral versus intravenous [IV]) and differ in terms of patient convenience (such as number of visits) and costs. This study compared the burden of patient visits and out-of-pocket costs for MM patients treated with bortezomib (BOR; Velcade®; IV administration), lenalidomide (LEN; Revlimid®; oral), thalidomide (THAL; Thalomid®; oral), or other unspecified chemotherapies or radiation therapy. Methods: This retrospective cohort study used claims data from a large national US commercial health plan representing approximately 14 million members. Patients aged 318 yrs, diagnosed with MM between January 1 2005 and September 30 2007, and treated with BOR, LEN, THAL, or other unspecified chemotherapies or radiation therapy during this period were included in the study. Patient costs and resource utilization data were analyzed at the treatment level. Treatment episodes (defined as each course of therapy) were identified from records for each patient; some patients had multiple episodes. Health care utilization (according to number of ambulatory patient visits) and inflation-adjusted patient out-of-pocket costs, including co-pays and deductibles, were examined for 1 yr from the beginning of each treatment episode. An ambulatory visit was defined as any visit with a unique day and a unique provider ID in an outpatient or office setting. Descriptive analyses were supplemented with multivariate regression analyses to control for patient characteristics, comorbidities, and line of treatment (more prior lines of therapy are indicative of more advanced disease). Results: A total of 2,642 treatment episodes were identified for the 1,900 MM patients included in the study. The majority of episodes were classified as “other chemotherapy or radiation therapy” (n=1,759, 66.6%). The second most common treatment episode was THAL (n=549, 20.8%), followed by BOR (n=244, 9.2%) and LEN (n=90, 3.4%). There were no differences among treatment groups in terms of inpatient or emergency room visits in the year following treatment initiation. As expected, patients treated with BOR appeared to have more ambulatory visits compared with patients treated with LEN, which is administered orally; however, this difference was not significant after adjustment for patient characteristics, line of treatment, and comorbidities by multivariate analysis (Table). The total adjusted patient out-of-pocket costs for the year after treatment initiation were significantly less for patients treated with BOR ($3,504) than for those treated with THAL ($4,443, p<0.05) or LEN ($4,766, p<0.05) (Table). These differences were greatest for Medicare patients, with the adjusted patient costs of THAL ($8,824) and LEN ($12,568) respectively, nearly 2 and 3 times greater than the adjusted costs of BOR ($4,395). Conclusions: In this study, the perceived advantage of orally administered drugs (THAL, LEN) in terms of fewer patient visits was not significant. In addition, direct out-of-pocket costs were significantly higher for patients treated with the oral drugs THAL and LEN compared with the IV drug BOR, especially for Medicare patients, likely due to the Coverage Gap, commonly known as the “donut hole”, in Medicare Part D. Disclosures: Huang: Milllennium: Employment, Equity Ownership. Teitelbaum: Spectrum Pharmaceuticals: Consultancy; EGEN: Consultancy, Honoraria; CV Therapeutics: Consultancy. Esseltine: Milllennium: Employment, Equity Ownership.
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Clarkson, Paul, David Challis, Jane Hughes, Brenda Roe, Linda Davies, Ian Russell, Martin Orrell, et al. "Components, impacts and costs of dementia home support: a research programme including the DESCANT RCT." Programme Grants for Applied Research 9, no. 6 (June 2021): 1–132. http://dx.doi.org/10.3310/pgfar09060.
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Background Over half of people with dementia live at home. We know little about what home support could be clinically effective or cost-effective in enabling them to live well. Objectives We aimed to (1) review evidence for components of home support, identify their presence in the literature and in services in England, and develop an appropriate economic model; (2) develop and test a practical memory support package in early-stage dementia, test the clinical effectiveness and cost-effectiveness of routine home support in later-stage dementia and design a toolkit based on this evidence; and (3) elicit the preferences of staff, carers and people with dementia for home support inputs and packages, and evaluate the cost-effectiveness of these approaches in early- and later-stage dementia. Design We undertook (1) an evidence synthesis, national surveys on the NHS and social care and an economic review; (2) a multicentre pragmatic randomised trial [Dementia Early Stage Cognitive Aids New Trial (DESCANT)] to estimate the clinical effectiveness and cost-effectiveness of providing memory aids and guidance to people with early-stage dementia (the DESCANT intervention), alongside process evaluation and qualitative analysis, an observational study of existing care packages in later-stage dementia along with qualitative analysis, and toolkit development to summarise this evidence; and (3) consultation with experts, staff and carers to explore the balance between informal and paid home support using case vignettes, discrete choice experiments to explore the preferences of people with dementia and carers between home support packages in early- and later-stage dementia, and cost–utility analysis building on trial and observational study. Setting The national surveys described Community Mental Health Teams, memory clinics and social care services across England. Recruitment to the trial was through memory services in nine NHS trusts in England and one health board in Wales. Recruitment to the observational study was through social services in 17 local authorities in England. Recruitment for the vignette and preference studies was through memory services, community centres and carers’ organisations. Participants People aged > 50 years with dementia within 1 year of first attendance at a memory clinic were eligible for the trial. People aged > 60 years with later-stage dementia within 3 months of a review of care needs were eligible for the observational study. We recruited staff, carers and people with dementia for the vignette and preference studies. All participants had to give written informed consent. Main outcome measures The trial and observational study used the Bristol Activities of Daily Living Scale as the primary outcome and also measured quality of life, capability, cognition, general psychological health and carers’ sense of competence. Methods Owing to the heterogeneity of interventions, methods and outcome measures, our evidence and economic reviews both used narrative synthesis. The main source of economic studies was the NHS Economic Evaluation Database. We analysed the trial and observational study by linear mixed models. We analysed the trial by ‘treatment allocated’ and used propensity scores to minimise confounding in the observational study. Results Our reviews and surveys identified several home support approaches of potential benefit. In early-stage dementia, the DESCANT trial had 468 randomised participants (234 intervention participants and 234 control participants), with 347 participants analysed. We found no significant effect at the primary end point of 6 months of the DESCANT intervention on any of several participant outcome measures. The primary outcome was the Bristol Activities of Daily Living Scale, for which scores range from 0 to 60, with higher scores showing greater dependence. After adjustment for differences at baseline, the mean difference was 0.38, slightly but not significantly favouring the comparator group receiving treatment as usual. The 95% confidence interval ran from –0.89 to 1.65 (p = 0.56). There was no evidence that more intensive care packages in later-stage dementia were more effective than basic care. However, formal home care appeared to help keep people at home. Staff recommended informal care that cost 88% of formal care, but for informal carers this ratio was only 62%. People with dementia preferred social and recreational activities, and carers preferred respite care and regular home care. The DESCANT intervention is probably not cost-effective in early-stage dementia, and intensive care packages are probably not cost-effective in later-stage dementia. From the perspective of the third sector, intermediate intensity packages were cheaper but less effective. Certain elements may be driving these results, notably reduced use of carers’ groups. Limitations Our chosen outcome measures may not reflect subtle outcomes valued by people with dementia. Conclusions Several approaches preferred by people with dementia and their carers have potential. However, memory aids aiming to affect daily living activities in early-stage dementia or intensive packages compared with basic care in later-stage dementia were not clinically effective or cost-effective. Future work Further work needs to identify what people with dementia and their carers prefer and develop more sensitive outcome measures. Study registration Current Controlled Trials ISRCTN12591717. The evidence synthesis is registered as PROSPERO CRD42014008890. Funding This project was funded by the National Institute for Health Research (NIHR) Programme Grants for Applied Research programme and will be published in full in Programme Grants for Applied Research; Vol. 9, No. 6. See the NIHR Journals Library website for further project information.
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McManigle, William C., Rachel A. DiCioccio, Sarah Anand, Zhiguo Li, Jonathan C. Poe, Krista R. Nichols, Amy N. Suthers, et al. "Evaluation of the Oral SYK Inhibitor Fostamatinib in Patients after Allogeneic Transplantation for Chronic Graft-Versus-Host Disease." Blood 134, Supplement_1 (November 13, 2019): 4521. http://dx.doi.org/10.1182/blood-2019-130742.
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Our group previously showed that B cells signal aberrantly through the B cell receptor (BCR) in allogeneic hematopoietic stem cell transplant (HCT) patients with active chronic graft-versus-host disease (cGVHD). Preclinical mouse studies have demonstrated the importance of the proximal BCR molecule, spleen tyrosine kinase (SYK), in cGVHD development. Hypothesizing that the oral small molecule SYK inhibitor, fostamatinib, would safely target aberrant BCR-activated B cells in HCT patients, we are conducting a single-center, investigator-initiated phase 1 trial (NCT02611063). Our primary objective is to evaluate the safety and tolerability of fostamatinib in patients early after HCT and in those with refractory active cGVHD. Secondary objectives include assessment of cGVHD manifestations, B cell activation, and immune recovery. Methods: All patients receive HCT treatment per program standards at Duke University. Prophylaxis (P-cGVHD) subjects enroll 80-150 days after HCT and have no evidence of cGVHD. P-cGVHD subjects receive drug for up to 1 year post-transplant (215-285 fostamatinib days). Steroid-refractory cGVHD (SR-cGVHD) subjects enroll with active cGVHD that persists despite systemic high-dose steroids. SR-cGVHD subjects receive drug for up to 365 days total. For all enrollees, modified continual reassessment criteria are used to determine starting dose (100mg daily, 150mg daily, or 100mg twice BID) and any needed dose modifications. We monitor for drug-limiting toxicities (DLTs), adverse events (AEs), and cGVHD manifestations using NIH cGVHD consensus criteria at up to 12 follow-up visits. Results: 15 of a planned 18 total patients have enrolled. In the P-cGVHD group (n=5), of the 4 patients who completed treatment (mean 239 fostamatinib days), 1 patient developed cGVHD while enrolled and 2 patients subsequently developed cGVHD, 4 and 6 weeks after study completion. The fifth P-cGVHD subject discontinued therapy on study day 155 (provider decision to initiate donor lymphocyte infusion for low CD3+ chimerism). In the SR-cGVHD group (n=10), 2 patients completed treatment (mean 365 fostamatinib days); 3 patients withdrew (mean 132 fostamatinib days), for non-cardiac chest pain, progression of cGVHD, and moved away; and 5 patients are actively enrolled (mean 207 fostamatinib days). Both SR-cGVHD patients who completed the study clinically improved while on fostamatinib and requested continuation of drug. A total of 2, 9, and 4 patients have been initiated on 100mg daily, 150mg daily, and 100mg BID, respectively. At the 100mg daily dose, no DLTs were noted. At the 150mg daily dose, 1 patient developed liver function test (LFT) elevation. At the 100mg BID dose, 2 patients developed LFT elevation and 1 patient developed non-cardiac chest pain. One patient required dose adjustment: 100mg BID to 150mg daily, for LFT elevation. Two serious AEs possibly related to fostamatinib occurred: 1 patient developed non-cardiac chest pain and 1 patient developed a deep venous thrombosis. No probably- or definitely-related serious AEs occurred. To assess whether fostamatinib effectively targets aberrantly activated B cells, we examined subjects' whole blood using flow cytometry. When comparing CD19+ B cells on study day 1 versus study day 60 in the SR-cGVHD group (n=7), we found the relative proportion of CD19+CD38+IgDlow plasmablast-like cells was decreased (p=0.03, Fig 1A-B), suggesting fostamatinib 'hit target.' Importantly, in the P-cGVHD group, total lymphocyte and B cell counts did not decrease during day 1 to day 225 (Fig 1C-D), suggesting fostamatinib did not affect immune recovery when given early after HCT. Further investigations with functional assays are underway. Conclusions: This study demonstrates for the first time that fostamatinib is safe and tolerated in HCT recipients both early after transplant and in those with active cGVHD. Importantly, fostamatinib does not appear to hinder lymphocyte or B cell recovery when initiated between days 80-150 after HCT. Additionally, fostamatinib may effectively target aberrantly activated B cells in patients with active SR-cGVHD. Fostamatinib, now FDA-approved for treatment of immune thrombocytopenia, merits a phase 2, randomized controlled trial to assess efficacy as a prophylactic agent against cGVHD. This work was supported by a National Institutes of Health grant, NIH (NHLBI) R01 HL 129061. Fostamatinib was supplied by Rigel. Disclosures Horwitz: Abbvie Inc: Membership on an entity's Board of Directors or advisory committees. Gasparetto:BMS: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; Celgene: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; Janssen: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed . Sung:Novartis: Research Funding; Merck: Research Funding; Seres: Research Funding. Rizzieri:Celgene, Gilead, Seattle Genetics, Stemline: Other: Speaker; AbbVie, Agios, AROG, Bayer, Celgene, Gilead, Jazz, Novartis, Pfizer, Sanofi, Seattle Genetics, Stemline, Teva: Other: Advisory Board; AROG, Bayer, Celgene, Celltron, Mustang, Pfizer, Seattle Genetics, Stemline: Consultancy; Stemline: Research Funding.
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Everitt, Hazel, Sabine Landau, Paul Little, Felicity L. Bishop, Gillian O’Reilly, Alice Sibelli, Rachel Holland, et al. "Therapist telephone-delivered CBT and web-based CBT compared with treatment as usual in refractory irritable bowel syndrome: the ACTIB three-arm RCT." Health Technology Assessment 23, no. 17 (April 2019): 1–154. http://dx.doi.org/10.3310/hta23170.
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Background Irritable bowel syndrome (IBS) affects 10–22% of people in the UK. Abdominal pain, bloating and altered bowel habits affect quality of life and can lead to time off work. Current treatment relies on a positive diagnosis, reassurance, lifestyle advice and drug therapies, but many people suffer ongoing symptoms. Cognitive–behavioural therapy (CBT) is recommended in guidelines for patients with ongoing symptoms but its availability is limited. Objectives To determine the clinical effectiveness and cost-effectiveness of therapist telephone-delivered CBT (TCBT) and web-based CBT (WCBT) with minimal therapist support compared with treatment as usual (TAU) in refractory IBS. Design This was a three-arm randomised controlled trial. Setting This trial took place in UK primary and secondary care. Participants Adults with refractory IBS (clinically significant symptoms for 12 months despite first-line therapies) were recruited from 74 general practices and three gastroenterology centres from May 2014 to March 2016. Interventions TCBT – patient CBT self-management manual, six 60-minute telephone sessions over 9 weeks and two 60-minute booster sessions at 4 and 8 months (8 hours’ therapist time). WCBT – interactive, tailored web-based CBT, three 30-minute telephone sessions over 9 weeks and two 30-minute boosters at 4 and 8 months (2.5 hours’ therapist time). Main outcome measures Primary outcomes – IBS symptom severity score (IBS SSS) and Work and Social Adjustment Scale (WSAS) at 12 months. Cost-effectiveness [quality-adjusted life-years (QALYs) and health-care costs]. Results In total, 558 out of 1452 patients (38.4%) screened for eligibility were recruited – 186 were randomised to TCBT, 185 were randomised to WCBT and 187 were randomised to TAU. The mean baseline Irritable Bowel Syndrome Symptom Severity Score (IBS SSS) was 265.0. An intention-to-treat analysis with multiple imputation was carried out at 12 months; IBS SSS were 61.6 points lower in the TCBT arm [95% confidence interval (CI) 89.5 to 33.8; p < 0.001] and 35.2 points lower in the WCBT arm (95% CI 57.8 to 12.6; p = 0.002) than in the TAU arm (IBS SSS of 205.6). The mean WSAS score at 12 months was 10.8 in the TAU arm, 3.5 points lower in the TCBT arm (95% CI 5.1 to 1.9; p < 0.001) and 3.0 points lower in the WCBT arm (95% CI 4.6 to 1.3; p = 0.001). For the secondary outcomes, the Subject’s Global Assessment showed an improvement in symptoms at 12 months (responders) in 84.8% of the TCBT arm compared with 41.7% of the TAU arm [odds ratio (OR) 6.1, 95% CI 2.5 to 15.0; p < 0.001] and 75.0% of the WCBT arm (OR 3.6, 95% CI 2.0 to 6.3; p < 0.001). Patient enablement was 78.3% (responders) for TCBT, 23.5% for TAU (OR 9.3, 95% CI 4.5 to 19.3; p < 0.001) and 54.8% for WCBT (OR 3.5, 95% CI 2.0 to 5.9; p < 0.001). Adverse events were similar between the trial arms. The incremental cost-effectiveness ratio (ICER) (QALY) for TCBT versus TAU was £22,284 and for WCBT versus TAU was £7724. Cost-effectiveness reduced after imputation for missing values. Qualitative findings highlighted that, in the CBT arms, there was increased capacity to cope with symptoms, negative emotions and challenges of daily life. Therapist input was important in supporting WCBT. Conclusions In this large, rigorously conducted RCT, both CBT arms showed significant improvements in IBS outcomes compared with TAU. WCBT had lower costs per QALY than TCBT. Sustained improvements in IBS symptoms are possible at an acceptable cost. Suggested future research work is longer-term follow-up and research to translate these findings into usual clinical practice. Future work Longer-term follow-up and research to translate these findings into usual clinical practice is needed. Trial registration Current Controlled Trials ISRCTN44427879. Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment (HTA) programme and will be published in full in Health Technology Assessment; Vol. 23, No. 17. See the NIHR Journals Library website for further project information. The University of Southampton sponsored this study. Funding was received from the NIHR HTA Board and the NIHR Clinical Research Network and support was received from the NIHR Clinical Research Network.
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Li, Ang, Nicole M. Kuderer, Jeremy L. Warner, Aakash Desai, Dimpy P. Shah, Julie Fu, Monica Li, et al. "Incidence of and Risk Factors for Venous Thromboembolism Among Hospitalized Patients with Cancer and COVID-19: Report from the COVID-19 and Cancer Consortium (CCC19) Registry." Blood 136, Supplement 1 (November 5, 2020): 56–58. http://dx.doi.org/10.1182/blood-2020-138834.
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Introduction: Hospitalized patients with COVID-19 may have increased risk of venous thromboembolism (VTE) and pulmonary embolism (PE). Cancer and anti-cancer therapies are well-known additional risk factors for VTE. Nonetheless, the VTE risk in patients with both cancer and COVID-19 infection remains unknown as recent studies have not found an association due to sample size limitations. We report the incidence of and risk factors for VTE and PE among hospitalized patients with cancer and COVID-19. Methods: The COVID-19 and Cancer Consortium (CCC19) developed an international retrospective cohort study (NCT04354701) to investigate the clinical course and complications of COVID-19 among adult patients with an active or previous history of cancer. For the current study, cumulative incidences of clinically detected VTE and PE were analyzed among hospitalized patients with laboratory confirmed SARS-CoV-2. Pre-specified subgroup analysis was performed to examine the interaction between intensive care unit (ICU) admission and recent anti-cancer therapy on VTE outcomes. Bivariable logistic regression analyses were conducted to assess the association between baseline variables and VTE; unadjusted odds ratios (OR) and 95% confidence interval (CI) were reported. These variables included age, sex, obesity (BMI>30), race/ethnicity, performance status, comorbidities, blood type, history of VTE, recent surgery, recent anti-cancer therapy, cancer subtype VTE risk grouping (adapted from Khorana Score), pre-admission anticoagulant or antiplatelet use, and ICU admission status. Results: From March 17, 2020 to July 31, 2020, 3914 patients were enrolled in the CCC19 registry. For the present analysis, patients were excluded if they had inadequate follow-up <4 weeks (n=950), were not admitted to the hospital (n=1008), or had unknown VTE outcomes (n=327). Among the 1629 hospitalized patients, the median follow-up was 35 days. Patients were comprised from 3 countries (92% US, 6% Canada, 2% Spain), with a median age of 70, 45% female, and a median comorbidity score of 3. Racial/ethnic breakdown included 44% White, 26% Black, 14% Hispanic, and 13% Other. A past history of VTE was reported in 9% of patients; pre-admission anticoagulant use and antiplatelet use were reported in 25% and 35% of patients, respectively. The most common cancer types included prostate (18%), breast (15%), and lymphoma (14%). Based on the VTE risk grouping adapted from the original Khorana Score, 34% were low-risk, 29% were high-risk, and 6% were very high-risk. The receipt of anti-cancer therapy within 3 months of diagnosis was observed in 39% of patients (17% cytotoxic chemotherapy, 11% targeted therapy, 7% endocrine therapy, and 5% immunotherapy). The overall incidence of inhospital VTE and PE was 9.3% and 5.2%, respectively. The corresponding estimates were 13.4% and 7.9% among the ICU subgroup. On bivariable analysis, significant predictors of VTE included ICU admission, recent anti-cancer therapy, active cancer status, cancer subtype VTE risk grouping, and pre-admission antiplatelet use (Table 1). Pre-admission anticoagulant use had significant associations with PE but not VTE. Multivariable adjustment is ongoing to identify independent risk factor for VTE and clarify the impact of pre-admission anticoagulant/antiplatelet use controlled for other potential confounders. Both ICU admission status and anti-cancer therapy increased the risk of VTE independently. Non-ICU patients not on anti-cancer therapy had the lowest incidence of VTE (4.5%), whose estimate was similar to that reported in the non-cancer hospitalized population with COVID-19 infection. Patients with either ICU admission or recent anti-cancer therapy had the intermediate risk (11.0%), whereas ICU patients with recent anti-cancer therapy had the highest risk (16.7%). We did not observe confounding or effect modification by the ICU subgroup on the association between anti-cancer therapy and VTE. Conclusion: In this cohort study of hospitalized patients with cancer and COVID-19, recent anti-cancer therapy, active disease, high-risk VTE cancer subtypes, and ICU admission have increased risk of VTE and PE, while pre-admission anticoagulant/antiplatelet therapy may reduce the risk. This information will aid in developing a risk prediction tool for VTE in hospitalized patients with cancer and COVID-19. Disclosures Kuderer: G1 Therapeutics: Consultancy; Total Health: Consultancy; Invitae: Consultancy; Beyond Springs: Consultancy; Bristol-Myers Squibb: Consultancy; celldex: Consultancy; Bayer: Consultancy; Spectrum Pharmaceuticals: Consultancy; Janssen: Consultancy. Warner:HemOnc.orgLLC: Other: Shareholder/Stockholder/Stock options; IBM Watson Health: Consultancy; Westat: Consultancy; National Cancer Institute: Research Funding. Shah:American Cancer Society and the Hope Foundation for Cancer Research: Research Funding; National Cancer Institute: Research Funding. Zon:Amagma Therapeutics.: Consultancy, Other: stockholder. Shah:Aspen Pharma: Research Funding. Gulati:Puma Biotechnology: Consultancy; AstraZeneca: Research Funding; Isoray: Research Funding. Khaki:Merck: Other: share/stockholder; Pfizer: Other: share/stockholder. Thompson:AIM Specialty Health, BMS, GlaxoSmithKline, Takeda, Via Oncology: Membership on an entity's Board of Directors or advisory committees; Synapse Precision Medical Council: Other: Travel expenses; Doximity: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Grivas:Oncogenex: Research Funding; Immunomedics: Research Funding; Debiopharm: Research Funding; Bavarian Nordic,: Research Funding; QED Therapeutics: Honoraria; Seattle Genetics: Honoraria; Roche: Honoraria; Pfizer: Honoraria, Research Funding; Mirati Therapeutics: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Janssen: Honoraria; Heron Therapeutics: Honoraria; GlaxoSmithKline: Honoraria; Genzyme: Honoraria; Genentech: Honoraria, Research Funding; Foundation Medicine: Honoraria; Exelixis: Honoraria; EMD Serono: Honoraria; Driver: Honoraria; Clovis Oncology: Honoraria, Research Funding; Bristol-Myers Squibb,: Consultancy, Honoraria, Research Funding, Speakers Bureau; Biocept: Honoraria; Bayer: Honoraria, Research Funding; Astra Zeneca: Honoraria, Research Funding. de Lima Lopes:Bavarian Nordic: Research Funding; NOVARTIS: Research Funding; Tesaro: Research Funding; GSK: Research Funding; G1 Therapeutics: Research Funding; adaptimmune: Research Funding; BMS: Research Funding; Lilly: Research Funding; Merck Sharp & Dohme: Research Funding; Astra Zeneca: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Boehringer Ingelheim: Honoraria; Janssen: Research Funding; rgenix: Research Funding; Blueprint Medicines: Research Funding; Genentech: Research Funding; Roche: Research Funding; EMD Serono: Research Funding. Shyr:Roche: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Johnson & Johnson: Consultancy; GlaxoSmithKline: Consultancy; AstraZeneca: Consultancy, Speakers Bureau; Boehringer Ingelheim: Speakers Bureau; Eisai: Speakers Bureau. Pennell:Merck: Consultancy; Cota: Consultancy; Inivata: Consultancy; G1 Therapeutics: Consultancy; Astrazeneca: Consultancy; BMS: Consultancy; Eli Lilly: Consultancy; Amgen: Consultancy; Genentech: Consultancy. Friese:Eli Lilly: Consultancy; Patient-Centered Outcomes Research Institute: Membership on an entity's Board of Directors or advisory committees; Agency for Healthcare Research and Quality: Research Funding; National Cancer Institute: Research Funding; Merck Foundation: Research Funding; National Comprehensive Cancer Network: Research Funding; Pfizer: Research Funding; Eli Lilly: Consultancy. Patel:reast Cancer Research Foundation: Research Funding; Sanofi: Research Funding; Odonate Therapeutics: Research Funding; Radius: Honoraria; Genentech: Research Funding. Halmos:Foundation Medicine: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Guardant Health: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Boehringer-Ingelheim: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Eli-Lilly: Research Funding; Advaxis: Research Funding; Mirati: Research Funding; Takeda: Research Funding; GSK: Research Funding; AbbVie: Research Funding; Genentech: Consultancy; TPT: Consultancy. Choueiri:Pfizer: Consultancy, Honoraria, Research Funding; Pionyr: Consultancy, Other; Merck: Consultancy, Honoraria, Research Funding; Roche Products Limited: Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; F. Hoffmann-La Roche: Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Lilly: Consultancy, Research Funding; Peloton: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Tempest: Consultancy, Other; Lilly Ventures: Consultancy; International Patent Application No. PCT/US2018/12209, entitled "PBRM1 Biomarkers Predictive of Anti-Immune Checkpoint Response," filed January 3, 2018, claiming priority to U.S. Provisional Patent Application No. 62/445,094, filed January 11, 2017: Patents & Royalties; Prometheus Labs: Consultancy, Honoraria, Research Funding; Corvus: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; Alexion: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Bristol Myers-Squibb/ER Squibb and sons LLC: Consultancy, Honoraria, Research Funding; Cerulean: Consultancy, Honoraria, Research Funding; Eisai: Consultancy, Honoraria, Research Funding; oundation Medicine Inc.: Consultancy, Honoraria, Research Funding; International Patent Application No. PCT/US2018/058430, entitled "Biomarkers of Clinical Response and Benefit to Immune Checkpoint Inhibitor Therapy," filed October 31, 2018, claiming priority to U.S. Provisional Patent Application No. 62/581,175, filed N: Patents & Royalties; Calithera: Research Funding; Analysis Group: Research Funding; Sanofi/Aventis: Consultancy, Honoraria, Research Funding; Takeda: Research Funding; EMD Serono: Consultancy, Honoraria; Up-to-Date: Consultancy, Honoraria; NCCN: Consultancy, Honoraria; Lilly Oncology: Consultancy, Honoraria; Heron Therapeutics: Consultancy, Honoraria; Lancet Oncology: Honoraria; NEJM: Honoraria; American Society of Medical Oncology: Honoraria; Harborside Press: Honoraria; Navinata Healthcare: Honoraria; Platform Q: Honoraria; L-path, Kidney Cancer Journal, Clinical Care Options: Honoraria; Research to Practice: Honoraria; PeerView and PER: Honoraria; OnClive: Honoraria; Genentech: Consultancy, Honoraria, Research Funding; Ipsen: Consultancy, Honoraria, Research Funding; Tracon: Research Funding; Exelixis: Consultancy, Honoraria, Research Funding; Analysis Group: Consultancy, Honoraria; Michael J. Hennessy (MJH) Associates, Inc: Honoraria. Peters:Debiopharm: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria; Blueprint Medicines: Consultancy, Honoraria; Bioinvent: Consultancy, Honoraria; Biocartis: Consultancy, Honoraria; Eli Lilly: Consultancy, Honoraria; F. Hoffmann-La Roche: Consultancy, Honoraria, Research Funding; Foundation Medicine: Consultancy, Honoraria; Illumina: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Merck Sharp and Dohme: Consultancy, Honoraria, Research Funding; Merck Serono: Consultancy, Honoraria, Research Funding; Merrimack: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Pharma Mar: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Regeneron: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Vaccibody: Consultancy, Honoraria; Biodesix: Research Funding; Daiichi Sankyo: Consultancy, Honoraria; Clovis: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding. Painter:Roche: Other: stock or other ownership; OPKO Health Inc: Other: stock or other ownership; Inovio: Other: stock or other ownership; Epizyme: Other: stock or other ownership; Pfizer: Other: stock or other ownership. Rini:Astra-Zeneca: Research Funding; PTC Therapeutics: Other: Sotckholder/stock options; Surface Oncology: Consultancy; Synthorx: Consultancy; 3D Medicine: Consultancy; Arravive: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; AVEO: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Merck: Consultancy, Research Funding. Lyman:Amgen: Research Funding; Mylan: Consultancy; Beyond Spring: Consultancy; Samsung: Consultancy; Sandoz: Consultancy; Invitae: Consultancy; Spectrum: Consultancy; G1 Therapeutics: Consultancy. Connors:Bristol-Myers Squibb: Consultancy, Honoraria; Portola: Honoraria; CSL Behring: Research Funding; Takeda: Honoraria; Abbott: Consultancy, Honoraria. Rosovsky:Bristol-Myers Squibb: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Dova: Consultancy; Portola: Consultancy.
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Niederwieser, Dietger, Helen Baldomero, Yoshiko Atsuta, Mahmoud Aljurf, Adriana Seber, Hildegard T. Greinix, Mickey Koh, et al. "One and Half Million Hematopoietic Stem Cell Transplants (HSCT). Dissemination, Trends and Potential to Improve Activity By Telemedicine from the Worldwide Network for Blood and Marrow Transplantation (WBMT)." Blood 134, Supplement_1 (November 13, 2019): 2035. http://dx.doi.org/10.1182/blood-2019-125232.
Full textAbstract:
HSCT is the only curative option for many malignant and non-malignant diseases. The WBMT was founded as an umbrella organization of societies involved in cellular therapies with the mission of promoting excellence in HSCT. As a non-governmental organization in official relation with the World Health Organization (WHO), the WBMT assisted in the founding of regional societies (Latin America Blood and Marrow Transplantation Group and African Blood and Marrow Transplantation Group), performs global activity surveys, conducts workshops and provides expert support for programs in evolving countries. In this retrospective evaluation we analyzed worldwide activity trends in HSCT up to the year 2016 and evaluated possibilities of improving availability of HSCT by the use of telemedicine. Methods: HSCT activity was collected annually from member societies, national registries and individual centers including donor type (allogeneic/autologous), stem cell source (bone marrow/peripheral blood stem cells/cord blood) and indications for transplant. Transplant rates (TR) were calculated as HSCT/10 million inhabitants without adjustment for patients transplanted in a country other than that of primary residence. Country team density (TD) was defined as teams/10 million inhabitants. Workshops were organized in a number of locations where there was little or no HSCT activity or where improvement in one or more aspect of local or regional HSCT activity was requested, including Vietnam, Brazil, China, South Africa and Morocco. Other countries were paired with established centers using WBMT affiliated partners. In two countries, a pilot program was established involving a 6 month physician training in a JACIE/FACT accredited center followed by daily telemedicine-guided supervision of clinical activities. Results: From 1957-2016 a total of 1,298,897 HSCT (57.1% autologous) procedures were collected. By the end of 2016, HSCT activity was reported from 87 of the 195 WHO member states. A total of 89,070 HSCT from 1662 centers was reported in 2016. Assuming a frequency of 84,000/year, 1.5 million HSCT will be reached in 2019, only 7 years after the 1 million report in 2012 (Figure 1). The global activity/year increased continuously from 10,000/year in 1991 to 82,718 first HSCT/year in 2016 with a global increase of >7% (7.0% in autologous and 7.8% in allogeneic HSCT). As in previous years, slightly more autologous (53.5%) than allogeneic and more related (53,6%) than unrelated HSCT were reported. The further increase in related HSCT was caused mainly by an increase of non-identical family donors (39.5% of related HSCT). Increase in activities according to regions is given in Figure 2. TR and TD varied according to region and are highest in Nord America with 511.2 TR, followed by Europe with 390.9 TR, Latin America with 63.9 TR, APBMT with 46.2 TR and Africa/EMRO with 32.8 TR. In contrast, TD was highest in Europe (7.5 TD) followed by Nord America (6.0 TD), APBMT (1.9 TD), Latin America (1.9 TD) and Africa/EMRO (0.4 TD). Commonest indications were lymphoproliferative diseases for autologous and leukemia for allogeneic HSCT and continue to rise (Figure 3 autologous and Figure 4 allogeneic HSCT). Graft source were predominantly peripheral blood in autologous (99.7%) and 65% in unrelated HSCT, while umbilical cord blood as a stem cell source (13.8% of all unrelated) declined. More than 150 HSCT were performed in one country and one center without activities using daily telemedicine-guided supervision. In conclusion, the global distribution and activities are increasing continuously by more than 7,0% per year with numbers currently running at app. 90,000/year. Of note is the increase of haploidentical HSCT activity, while the use of umbilical cord blood HSCT continues to decrease. TR data show significant gaps between regions. Supervisory telemedicine is a powerful tool to overcome lack of experience and establish JACIE/FACT compatible new programs with collateral benefits for conventional hematology, blood banking, microbiology and virology. Abbreviations: EUR, Europe; AMR/PHA, America; SEAR/WPR, South-East Asia/Western Pacific; AFR/EMRO, African/Eastern Mediterranean. Disclosures Niederwieser: Daichii: Speakers Bureau; Cellectis: Consultancy. Atsuta:Kyowa Kirin Co., Ltd: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Mochida Pharmaceutical Co. Ltd: Honoraria; Janssen Paharmaceutical K.K.: Honoraria. Worel:Sanofi Genzyme, Malinckrodt Therakos: Research Funding; Jazz, Sanofi, Celgene, Novartis, Malinckrodt Therakos: Honoraria; Sanofi Genzyme, Malinckrodt Therakos: Speakers Bureau. Galeano:Szabo SA: Other: (Equity interest). Novitzky:Astellas, Roche: Consultancy. Szer:Prevail Therapeutics: Honoraria, Other: Travel, Research Funding; Novartis: Honoraria, Other: Travel, Research Funding; MSD: Honoraria, Other: Travel, Research Funding; Celgene: Honoraria, Other: Travel, Research Funding; Amgen: Honoraria, Other: Travel, Research Funding; Alexion: Honoraria, Other: Travel, Research Funding; Sanofi: Honoraria, Other: Travel, Research Funding; Takeda: Honoraria, Other: Travel, Research Funding; Pfizer: Honoraria, Other: Travel, Research Funding. Kröger:Celgene: Honoraria, Research Funding; DKMS: Research Funding; JAZZ: Honoraria; Medac: Honoraria; Neovii: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Riemser: Research Funding; Sanofi-Aventis: Research Funding. Weisdorf:Incyte: Research Funding; Pharmacyclics: Consultancy; Fate Therapeutics: Consultancy. Pasquini:Amgen: Consultancy; BMS: Research Funding; Medigene: Consultancy; Pfizer: Other: Advisory Board; Novartis: Research Funding; Kit Pharma: Research Funding.