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Journal articles on the topic 'Escalator clause'
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Cattabrini, Francesco. "Franco Modigliani and the Italian Left-Wing: the Debate over Labor Cost (1975-1978)." HISTORY OF ECONOMIC THOUGHT AND POLICY, no. 1 (January 2012): 75–95. http://dx.doi.org/10.3280/spe2012-001006.
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In 1975 in Italy, as a result of an agreement between the Trade Unions and the Italian Manufacturers' Association, the escalator clause mechanism was changed, establishing a 100% indexation of wages to the rate of inflation. This crucial event led to the so-called "Modigliani controversy". This paper aims to examine the debate that arose in Italy following Franco Modigliani's proposals over labor cost. Our main focus will be on the public debate that raised among economists, the majority of whom were part of the wide intellectual area gravitating around the left wing. Modigliani's contributions sharpened the conflicts within the left and this resulted in a debate that ended with the acceptance of "Modigliani's recipe": a reduction in real wages was deemed necessary to bring Italy out of the economic crisis.
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Park,Se-Won. "Price Escalation Clause of Letter of Credit." International Commerce and Information Review 16, no. 2 (2014): 89–109. http://dx.doi.org/10.15798/kaici.16.2.201403.89.
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Berger, K. P. "Law and Practice of Escalation Clauses." Arbitration International 22, no. 1 (2006): 1–18. http://dx.doi.org/10.1093/arbitration/22.1.1.
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Vroman, Wayne. "Cost-of-Living Escalators and Price-Wage Linkages in the U.S. Economy, 1968–1980." ILR Review 38, no. 2 (1985): 225–35. http://dx.doi.org/10.1177/001979398503800205.
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This paper examines the importance of cost-of-living escalator clauses as a link between price changes and money wage changes. It surveys the possible kinds of price-wage linkages and estimates the importance of COLAs in overall wage changes in the economy. The author concludes that despite growth in the coverage and yields of escalator clauses since the mid-1960s, they still accounted in 1980 for less than 10 percent of total money wage changes in the U.S. economy and are therefore not a major cause of inflation.
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Loulakis, Michael C., and Lauren P. McLaughlin. "Subcontractor Recovers Material Escalation Costs despite No-Damages-for-Delay Clause." Civil Engineering Magazine Archive 82, no. 2 (2012): 88. http://dx.doi.org/10.1061/ciegag.0000707.
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Steinbach, Armin. "The ‘Haircut’ of Public Creditors under EU Law." European Constitutional Law Review 12, no. 2 (2016): 223–39. http://dx.doi.org/10.1017/s1574019616000171.
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Haircut of public creditors as next step in the escalation of the euro debt crisis? – Exploring the boundaries set by the EU Treaty on debt restructuring – Limitations imposed by no-bailout clause and prohibition of monetary state financing – Standards set inPringleandGauweiler– Haircut on nominal debt infringes no-bailout clause – Active involvement by European Central Bank violates ban on monetary state financing – Other forms of ‘soft haircuts’ may be compatible with EU law
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Maran, Ramachandran, Senthil Rajendran, and Satyanarayana Kalidindi. "Material cost and escalation clauses in Indian construction contracts." Proceedings of the Institution of Civil Engineers - Construction Materials 164, no. 2 (2011): 95–108. http://dx.doi.org/10.1680/coma.900036.
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Hartebrodt, Christoph, and Falko Stenzel. "Alternative Preisbildungsmodelle – eine realitätsnahe Option?" Schweizerische Zeitschrift fur Forstwesen 164, no. 7 (2013): 181–89. http://dx.doi.org/10.3188/szf.2013.0181.
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Alternative pricing models – a realistic option? The use of alternative pricing models as a means to automatize or at least facilitate the pricing of timber and thereby also reduce the volatility of timber prices has been under consideration for the past several years. The possibilities and limitations of such alternative pricing models are examined in this article using a retrospective comparative analysis. Overall, the results of six pricing models (these are: annual contract, quarterly contract, attenuation of the rate of change, mixed pricing, regression analysis derived price escalation clause, and self-fulfilling contract) are compared with the development of real timber prices between 2000 and 2010 of the state forest enterprise of Baden-Württemberg (Germany) and analyzed using a set of performance measures. It turns out that there is a conflict of objectives between determining the exact figure of the market price by alternative pricing models and reducing the volatility of timber prices. Thus, quarterly contracts show the market price well, though display no relevant volatility reduction effect; conversely, contracts with a defined attenuation rate lead to a substantial reduction of volatility but also to maximizing deviations from the market price. It is also questionable in how far price escalation clauses, that is, models which were calibrated from regression analysis on the basis of historical data, are able to predict the future development of market prices. At the moment, alternative pricing models can therefore hardly replace the real market-negotiated timber price. They can though support pricing negotiations between buyers and sellers, but primarily in time periods not characterized by a pronounced dynamic.
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Gómez Jene, Miguel. "El convenio arbitral: statu quo = The arbitration agreement: statu quo." CUADERNOS DE DERECHO TRANSNACIONAL 9, no. 2 (2017): 7. http://dx.doi.org/10.20318/cdt.2017.3862.
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Resumen: Este estudio analiza la jurisprudencia actual (internacional, comparada y española) en interpretación de las normas internacionales y de fuente interna que regulan la eficacia del convenio arbitral. La irrupción en el tráfico de nuevos tipos de convenios arbitrales (cláusulas híbridas y cláusulas escalación), así como la falta de una regulación ad hoc para determinados supuestos (extensión de los efectos del convenio a terceros no firmantes) exigen un estudio comparado de las soluciones dadas a estas cuestiones en las jurisdicciones con mayor tradición arbitral. Por último, se analizan las posibles consecuencias que la reciente jurisprudencia del TS sobre el principio Kompetenz-kompetenz (“tesis débil”) puede tener sobre el efecto positivo del convenio arbitral; así como la posible extensión al ámbito del convenio arbitral de la jurisprudencia del TS sobre responsabilidad por incumplimiento de una cláusula de sumisión a tribunales españoles.Palabras clave: Convenio arbitral. Voluntad inequívoca: Ley aplicable al convenio arbitral. Extensión de los efectos del convenio arbitral. Cláusulas híbridas. Cláusulas escalación. Efectos positivo y negativo del convenio arbitral. Tesis débil de la Kompetenz-kompetenz. Responsabilidad.Abstract: This paper analyzes the current case law (international, comparative and Spanish) in interpretation of international and internal norms that regulate the effectiveness of the arbitration agreement. The emergence of new types of arbitration agreements (hybrid clause and escalation clause), as well as the lack of an ad hoc regulation for certain assumptions (extension of the effects of the agreement to non-signatory third parties) require a comparative study of the Solutions given to these issues in jurisdictions with a greater tradition of arbitration. Finally, the possible consequences that the recent Supreme Court case law on the Kompetenz-kompetenz principle (“soft Thesis”) can have on the positive effect of the arbitration agreement are analyzed, as well as the possible extension to the scope of the arbitration agreement of the Supreme Court case law on liability for breach of a clause of submission to Spanish courts.Keywords: Arbitration agreement. Unequivocal will. Applicable law to the arbitration agreement. Extension of Effects of the arbitration agreement. Hybrid clause. Escalation clause. Positive and negative effects of the arbitration agreement. Soft thesis of Kompetenz-kompetenz. Liability.
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Chaphalkar, N. B., and Sayali S. Sandbhor. "Application of neural networks in resolution of disputes for escalation clause using neuro-solutions." KSCE Journal of Civil Engineering 19, no. 1 (2014): 10–16. http://dx.doi.org/10.1007/s12205-014-1161-3.
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Thompson, Jeffrey R., and William I. Ausich. "Testing for escalation in Lower Mississippian camerate crinoids." Paleobiology 41, no. 1 (2015): 89–107. http://dx.doi.org/10.1017/pab.2014.6.
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AbstractCrinoids were relatively unaffected by the end-Devonian Hangenberg mass extinction event. Major clades of Devonian durophagous fishes suffered significant extinctions, however, and the dominant surviving clades were biting or nipping predators. In part as a response to the Hangenberg event, early Mississippian crinoids underwent an adaptive radiation, while fish clades with a shell-crushing durophagous strategy diversified. Durophagous predators are inferred to have been more effective predators on camerate crinoids; and it is hypothesized, following the predictions of escalation, that through the early Mississippian, camerate crinoids evolved more effective anti-predatory strategies in response. We test this hypothesis of escalation by examining the changes in spinosity and plate convexity among camerate crinoids throughout this interval. A new method was formulated to test for an increase in convexity of the tegmen plates. Traits inAgaricocrinus,Aorocrinus, andDorycrinus(Family Coelocrinidae) were tested for congruence to the escalation hypothesis, and results were mixed. Convexity of tegmen plates inAgaricocrinus, spine length/calyx diameter inAorocrinus, calyx size inAorocrinus, central spine length inDorycrinus, and spine width inDorycrinusdid not have size increase trends supporting escalation. Rather than an increase in convexity, the variance of convexity inAgaricocrinustegmen plates narrowed, which could reflect an optimum. Alternatively, morphological change consistent with the escalation hypothesis occurred in calyx size ofAgaricocrinusand in lateral spine length and calyx size inDorycrinus. Furthermore, central and lateral spine length, parameters of the spine width, and size trends support escalation whenAorocrinusandDorycrinusare treated as a lineage. Thus, inferred escalation acted on traits differently within a single lineage and was relevant for both speciation and the diversification of a new genus.
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Mekonen, Hamelmal, Alemu Mosisa Legesse, and Frikot Mulatu Ameya. "Investigation of Price Escalation and Its Mitigation Mechanisms on Selected Building Construction Projects of Jimma University." Jordan Journal of Civil Engineering 17, no. 2 (2023): 194–202. http://dx.doi.org/10.14525/jjce.v17i2.03.
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Fee escalation in construction refers to a boom in the price of an item inside the preliminary agreement or the bottom cost of an undertaking. racking production mission fees must be an ongoing procedure that must always be carried out on all projects, because the reasons for which the price will increase vary from project to project and due to the construction segment. The motive of this observation was to assess fee escalation, escalation factors and mitigation mechanisms in deciding on construction initiatives. From February 1 to 30, 2020, a questionnaire was administered to twelve workers and interviews with seven key informants were conducted for an in-depth look at four selected Jimma University construction projects, which were project A to project D. Relative importance index values were generated and ranked for the elements affecting fee escalation to see their relative significance. It was found that there has been a moderate degree of charge increase within the initiatives studied, from 12% to 21%. The mitigation modalities observed with the aid of the projects, particularly inserting escalation clauses in contractual agreements, making changes requiring funding and increasing time limits, seem to be inadequate, as they do not provide a foundation for choices and remedy of disputes instead of mitigating the escalation of tasks starting from 3.21% to 12%. KEYWORDS: Escalation, Mitigation, Price, Construction projects.
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Kaufman, Roger T., and Geoffrey Woglom. "The Degree of Indexation in Major U.S. Union Contracts." ILR Review 39, no. 3 (1986): 439–48. http://dx.doi.org/10.1177/001979398603900310.
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The authors propose that the most appropriate measure of the degree of indexation in a union contract is the marginal elasticity of the average expected wage during the life of the contract with respect to unanticipated changes in the price level. They present estimates of this elasticity for 68 U.S. contracts negotiated between 1971 and 1983 with cost-of-living escalators. The average degree of indexation in the sample, .48, is considerably smaller than previous estimates of similar marginal elasticities because the estimation method more accurately incorporates caps, minimum COLAs, and the exact specification of the COLA clauses.
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Oliveira, Mara Edilara Batista de. "AS ESCALAS GEOGRÁFICAS DE PODER COMO FORMAS DE SUBORDINAÇÃO E INSUBORDINAÇÃO NA LUTA PELA EDUCAÇÃO DO CAMPO NO BRASIL/The geographical scales of power as ways of subordination and insubordination in the fight for rural education in Brazil." REVISTA NERA, no. 46 (January 17, 2019): 79–105. http://dx.doi.org/10.47946/rnera.v0i46.5578.
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Este artigo tem como preocupação central as formas de apropriação do Estado das demandas da classe trabalhadora rural no âmbito da Educação do Campo no Brasil, e a consequente transformação dessas demandas em mais uma forma de subordinação do trabalhador rural ao capital. Acreditamos que essas formas de apropriação passam por uma estrutura organizativa do capital, por meio das ações do Estado, que se dá de forma escalar. Diante dessa problemática, o artigo caminha no sentido de contribuir com a construção de uma análise dessa estrutura escalar de poder armada “desde cima”, desvendando assim estratégias de controle e dominação dos “desde baixo”, os quais podem assim, diante do conhecimento dessas estratégias, construir suas próprias estruturas escalares “desde baixo” como forma de contra-poder e de insubordinação ao capital. No nosso estudo essa análise escalar é construída sob um olhar para a implantação do ProJovem Campo – Saberes da Terra na Paraíba, programa do Estado apresentado como parte das políticas em Educação do Campo no Brasil, enquanto uma estrutura escalar de poder “desde cima”; e para a estrutura organizativa do MST como uma estrutura escalar “desde baixo” que resiste e se recria na luta pela educação do campo.
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Bessa, Pedro, and Túlio Ottoni. "Primeiro passo em direção à modificação da gravidade: Teorias Escalar-Tensoriais e f(R)." Cadernos de Astronomia 3, no. 2 (2022): 128–43. http://dx.doi.org/10.47456/cad.astro.v3n2.37208.
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A relatividade geral, apesar de seus sucessos, é hoje entendida como uma teoria aberta a possibilidades de modificação. Neste artigo buscamos introduzir de maneira didática a base de uma classe de teorias que busca preencher algumas lacunas deixadas pela relatividade geral, as teorias f(R) e escalar-tensoriais. Construímos as teorias a partir de um princípio de ação e obtemos suas equações de campo. Mostramos a equivalência entre as duas teorias e comentamos sobre mecanismos de blindagem. Por fim, mostramos alguns resultados observacionais sobre modificações da relatividade geral dentro do contexto dessas teorias.
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Wilson, William W., and Bruce Dahl. "Grain Contracting Strategies to Induce Delivery and Performance in Volatile Markets." Journal of Agricultural and Applied Economics 41, no. 2 (2009): 363–76. http://dx.doi.org/10.1017/s1074070800002844.
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One of the impacts of higher prices along with greater volatility in futures and basis is that there is pressure for an escalation in cash contracting for grain. This volatility has resulted in an unprecedented level of contracting with growers in recent years. There is a wide array of cash contracts with varying terms. There is also a growing realization of growers not delivering on contracts, in part due to escalation in postcontract prices. These are evolving as major strategic issues for buyers and the marketing system, particularly as buyers seek to use such contracting strategies as an element of risk mitigation. There are three purposes of this article. First is to provide a broad survey of contract terms used in grain contracting with growers. Second, we illustrate some issues in contracting of some of the grains (durum, malting barley) in the upper Midwest. Third, we show some of the common contract clauses being adapted in these contracts. Finally, we summarize these issues with respect to industry implications.
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Vörös, Attila. "Escalation reflected in ornamentation and diversity history of brachiopod clades during the Mesozoic marine revolution." Palaeogeography, Palaeoclimatology, Palaeoecology 291, no. 3-4 (2010): 474–80. http://dx.doi.org/10.1016/j.palaeo.2010.03.018.
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C Pedro, Gabriel. "Práticas curriculares de geografia em escolas públicas do Rio de Janeiro: a perspectiva das professoras: um estudo dos diários de classe." Anekumene, no. 3 (February 2, 2012): 141–52. http://dx.doi.org/10.17227/anekumene.2012.num3.7523.
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Este trabalho busca investigar o cotidiano escolar através da perspectiva de professoras de séries iniciais no ensino de Geografia, entendendo este cotidiano como uma realidade complexa e dinâmica. Esta investigação se deu pela análise dos diários de classe destas professoras, procurando os principais problemas com os quais elas se deparam ao ensinar Geografia para as séries iniciais, os chamados dilemas (Zabalza, 1994). Escolheu-se trabalhar com os dilemas porque, segundo Straforini (2008), existem muitas dificuldades no ato de ensinar Geografia para as séries iniciais do Ensino Fundamental no atual contexto de mundo altamente complexo e multi-escalar. Os diários nos propiciam um olhar privilegiado tanto sobre as práticas pessoais destes professores quanto sobre os seus pensamentos, crenças e convicções que por sua vez fomentaram, construíram/re-construíram e justificaram as suas práticas.
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Zambrano, German E., and Bruto M. Pimentel. "CANONICAL STRUCTURE OF GAUGE INVARIANCE PROCA'S ELECTRODYNAMICS THEORY." MOMENTO, no. 56 (January 1, 2018): 26–44. http://dx.doi.org/10.15446/mo.n56.69823.
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La electrodinámica de Proca describe una teoría de fotones masivos que no es invariante de gauge. En este trabajo se mostrará que la libertad de gauge es restaurada si un campo escalar es apropiadamente incorporado en la teoría. El método de Dirac es utilizado para realizar un detallado análisis de la estructura de vínculos de la misma. Apropiadas condiciones de gauge fueron derivadas con el fin de eliminar los vínculos de primera clase y obtener los corchetes de Dirac entre las variables dinámicas independientes. De manera alternativa, la formulación simplectica generalizada es utilizada para estudiar la teoría electromagnética de Proca invariante de gauge. Después de fijar el gauge, los corchetes generalizados son calculados y la equivalencia con los corchetes de Dirac es mostrada.
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Bibi, Bushra, Ke Jian, and Abid Hussain. "Melting Glaciers and the Indus Water Treaty: A Looming Crisis." Global Strategic & Securities Studies Review VIII, no. I (2023): 22–30. http://dx.doi.org/10.31703/gsssr.2023(viii-i).03.
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The Indus Waters Treaty was created in 1960 to allocate water between India and Pakistan. Climate change was not considered then, but hydrology and conflict resolution have progressed. Climate change has altered water availability, including volume, timing, frequency, and quality. Population growth, urbanization,and climatic events have impacted Pakistan’s water supply. This tension could escalate into conflict without addressing the treaty’s knowledge and practice gaps. Advancements in transboundary watercourse management, environmental monitoring, and data acquisition are necessary. Water remains a source of tension, and prompt action is needed to ensure sustainable water resource management. One possible solution to this issue is to integrate modern knowledge on climate change into the IWT and harmonize it with the current set of international water laws and regulations. Hence, it is imperative to formulate a framework enabling both countries to reach a consensus and introduce climate change-related clauses and provisions into the IWT.
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Bibi, Bushra, Ke Jian, and Abid Hussain. "Melting Glaciers and the Indus Water Treaty: A Looming Crisis." Global Legal Studies Review VIII, no. II (2023): 1–8. http://dx.doi.org/10.31703/glsr.2023(viii-ii).01.
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The Indus Waters Treaty was created in 1960 to allocate water between India and Pakistan. Climate change was not considered then, but hydrology and conflict resolution have progressed. Climate change has altered water availability, including volume, timing, frequency, and quality. Population growth, urbanization, and climatic events have impacted Pakistan’s water supply. This tension could escalate into conflict without addressing the treaty’s knowledge and practice gaps. Advancements in transboundary watercourse management, environmental monitoring, and data acquisition are necessary. Water remains a source of tension, and prompt action is needed to ensure sustainable water resource management. One possible solution to this issue is to integrate modern knowledge on climate change into the IWT and harmonize it with the current set of international water laws and regulations. Hence, it is imperative to formulate a framework enabling both countries to reach a consensus and introduce climate change-related clauses and provisions into the IWT.
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Jacobsen, Jeppe T. "Cyber offense in NATO: challenges and opportunities." International Affairs 97, no. 3 (2021): 703–20. http://dx.doi.org/10.1093/ia/iiab010.
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Abstract As a response to the Russian invasion of Crimea, NATO returned to the core military concepts of deterrence and collective defence. This NATO adaption has recently come to include attempts to integrate offensive cyber effects into NATO force structure and response doctrine. The article argues—counter to what is publicly declared—that such an integration does little to strengthen NATO's deterrence posture and is unlikely to deter non-military, hybrid cyber activity below the threshold of collective defence. The article identifies several practical challenges to the current integration effort, which include the temporal dimension of developing exploits, battle damage assessment and deconfliction. With these challenges in mind, the article suggests that deploying minor and less resourceful cyber effects that cause persistent ‘cyber annoyances’ holds an unappreciated potential as they can drain opponent resources, disturb vital IT-systems and complicate decision-making. The article ends by arguing that NATO should not adapt its collective defence clause to cyberspace. A more active NATO in cyberspace risks undermining the cyber-intelligence norm that so far has prevented escalation and thereby increasing the likelihood that Russia misinterprets intelligence and active cyber defence activities as military preparation, armament or an attack in the making.
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Ferrero, Mario. "Domanda di inflazione come «bene pubblico» e regimi di indicizzazione dei redditi*." Journal of Public Finance and Public Choice 3, no. 3 (1985): 159–71. http://dx.doi.org/10.1332/251569298x15668907117174.
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Abstract The traditional approach to inflation as a tax does not take any account of the state of indexation of the economy, as if universal «implicit» indexation of individual incomes to inflation by adjustment of inflationary expectations prevailed. This article shows that if - as is the case in much of the real world today - explicit indexation through wage escalator clauses and the like is sufficiently widespread but does not cover all individuals in the economy, then it may become feasible and attractive for a coalition of voters to pass inflationary budgets. Since budget choices and the determination of the associated inflation tax are outcomes of a collective (political) decision process while indexation is privately negotiated in the market, indexed voters may try to make non-indexed voters pay the bill of budget benefits to themselves through the inflation tax. Inflation thus becomes a peculiar, negative public good with a private exit: the inflation tax can now be individually avoided through indexation, and a demand for inflation in the literal meaning can manifest itself through the electoral process. Various properties of this perverse budget-inflation game are discussed, showing that the only natural way out of it appears to be universal indexation, which would eliminate the incentive to free-riding behavior by the indexed voters, though at some transitional cost to society.
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Marques Neto, Roberto. "ZOOGEOMORFOLOGIA: INFLUÊNCIAS DA FAUNA NA EVOLUÇÃO E DINÂMICA DOS SISTEMAS GEOMORFOLÓGICOS." Caminhos de Geografia 20, no. 72 (2019): 275–93. http://dx.doi.org/10.14393/rcg207245796.
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O enfoque zoogeomorfológico se estabelece a partir do papel dos animais como agentes geomórficos, e, embora perfaça uma importante interface entre a Geomorfologia e a Biogeografia, são raros os estudos pautados na referida abordagem no escopo da cultura geomorfológica brasileira. A falta de estudos em zoogeomorfologia e a premissa de que animais, vertebrados e invertebrados, influenciam na dinâmica e evolução de sistemas geomorfológicos, se inscrevendo explicitamente nos fluxos de matéria e energia, foram os elementos motivadores deste trabalho, cujo objetivo é discutir de forma sistemática os animais como agentes geomórficos, propondo uma classificação de tais ações a partir de sua manifestação escalar, expressão espacial e efeitos na estrutura superficial da paisagem mediante uma abordagem sistêmica. A discussão aqui apresentada foca enfaticamente os vertebrados, atentando de forma mais detalhada para a mastofauna, classe considerada como a de maior influência nos processos de superfície, para a qual foi constatada importância significativa e que varia em modalidade (pisoteio, escavação, chafurdação, etc.) e intensidade conforme diferentes táxons e distintos contextos bioclimáticos.
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Quintanar Pérez, María Eugenia, Eric Ávila Vales, and Herminio Blancarte Suárez. "La diferencial de una función de varias variables:una propuesta de enseñanza-aprendizaje." El cálculo y su enseñanza 2 (December 31, 2011): 23–38. http://dx.doi.org/10.61174/recacym.v2i1.143.
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De acuerdo a la experiencia personal, en los cursos impartidos del cálculo diferencial de varias variables, encontramos que la definición de la diferencial de una función en varias variables tiene dificultades intrínsecas para entenderse y asimilarse por parte de la mayoría de los estudiantes del curso de cálculo. Analizaremos varios aspectos de este problema de enseñanza-aprendizaje y consideraremos una propuesta de enseñanza, relacionada con la caracterización de la diferencial de una función escalar a través del llamado error lineal de aproximación y la extensión continua del cociente de dicho error lineal y el incremente del punto, a toda una vecindad del cero. Asimismo, el recurso del uso de la calculadora en clase, para calcular valores del algunos ejemplos de funciones diferenciables escalares y su comparación con los valores aproximados proporcionados por sus respectivas diferenciales; consideramos que puede ser un recurso didáctico interesante, para abordar este problema de enseñanza-aprendizaje.
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Moya Delgado, Octaviano. "La élite política en Sinaloa: conformación y permanencia, 1950-2010." Intersticios Sociales, no. 5 (March 1, 2013): 37. http://dx.doi.org/10.55555/is.5.61.
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Una de las preocupaciones más evidentes de la sociedad es saber quiénes gobiernan y la forma en que lo hacen. Aun cuando importantes teóricos de la democracia representativa han concluido que los supuestos de una clase superior que dirige y otra dirigida han quedado rebasados para explicar la realidad de algunos regímenes, lo cierto es que son los miembros de los partidos y ciertos grupos de la sociedad quienes logran escalar y permanecer en los espacios de poder. El objetivo general es conocer bajo qué circunstancias o condiciones se conforma la élite política en Sinaloa. Se toma Sinaloa que pese a no ser una entidad tan importante sus políticos han mantenido fuerte presencia en la política nacional, desde los gobiernos posrevolucionarios hasta los del Partido Acción Nacional (pan) en la alternancia política. La hipótesis planteada sostiene que la conformación de la élite política sinaloense es consecuencia de elementos del control y presencia territorial que ejercen pequeños grupos regionales y cuyo proceso de reclutamiento y socialización obedece más a cuestiones familiares o de parentesco que de tipo profesional.
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Paudel, Top Narayan, Subash Kumar Bhattarai, and Uttam Neupane. "Analysis of Payment Delay in Road Construction Projects: The Case Road Division Surkhet, Nepal." International Journal on Engineering Technology and Infrastructure Development 1, no. 1 (2024): 36–51. http://dx.doi.org/10.3126/injet-indev.v1i1.67935.
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Payment has been an issue of major concern in the construction industry and most contractors reported that they have gone through late payment situations in government-funded projects. The issue of delayed payment in the construction industry is a global phenomenon. The objective of this research is to analyze the payment delays in the Department of Road, Road Division Surkhet construction projects. Altogether there are 61 projects under construction. Each representative from the contractor and all engineers from the Employer are selected as respondents. The Cronbach's alpha test was run, and the overall alpha value was found to be 0.978. The employer’s topmost rank is ‘unavailability of the budget under cause attributable to the employer, contractors' failure to understand the contract agreement under causes attributable to the contractor, and differing site conditions under causes beyond the party’s control. In contrast, the contractor ranks the topmost cause as unavailability of the budget, contractors' failure to follow certain procedures in a claim, and price escalation of the major construction materials respectively. The view of the employer emphasized that the delay in payment brings significant effects on the delay in project progress and creates cash flow problems for contractors with the value. Whereas contractors emphasized that the delay in payment creates cash flow problems for contractors. The employer has suggested that the contractor submit the latest progress work invoicing with adequate documents while asking for the payment to reduce the delay time in payment. In contrast, the contractor has suggested that both parties should understand the terms or clauses of payment in the project. The combined view of employer and contractor emphasized that Both parties should understand and should compel the terms or clauses of payment in the project to reduce the delay in the payment. The Hypothesis test also showed that there is a significant difference between the view of employer and contractor on the causes, effects, and possible solutions to reduce delay in the payment.
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Monda, V. M. "Association of GLP-1 RA once weekly and basal insulin: a valid therapeutic option from the complications of SARS-CoV-2 infection too?" Journal of AMD 24, no. 4 (2022): 295. http://dx.doi.org/10.36171/jamd21.24.4.5.
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Gli agonisti recettoriali del glucagon like peptide-1 (GLP1-RAs) sono un gruppo di farmaci antidiabetici con una rilevante azione sul controllo glicemico, basata sull’aumento della secrezione di insulina glucosio-dipendente con concomitante riduzione della secrezione di glucagone e ritardato svuotamento gastrico. I GLP1-RA hanno inoltre attività pleiotropiche come proprietà antinfiammatorie, antitrombotiche e antiobesogeniche, con evidenti benefici su eventi cardiovascolari maggiori, mortalità cardiovascolare e danno renale. Tutto ciò rende questa classe di farmaci un elemento chiave nella gestione dei pazienti con diabete tipo 2 e potenzialmente utile nei soggetti con COVID-19 (2019nCoV – Coronavirus disease 2019, COVID-19). Per le proprietà antinfiammatorie è stato ipotizzato che le terapie a base di incretino-mimetici esercitino effetti benefici sugli esiti di COVID-19. Qui riportiamo un caso di una donna di 82 anni con diabete tipo 2 scarsamente controllato, che utilizzava un regime insulinico basal-bolus più metformina. Il miglioramento del controllo glicemico ottenuto passando dal trattamento con insulina basale al GLP-1RA aggiunto al regime insulinico basale, con la sospensione dell’insulina prandiale (trattamento di de-escalation) in questo caso è risultato associato agli effetti benefici sugli esiti di COVID-19. PAROLE CHIAVE GLP1-RAs; DMT2; SARS-CoV-2; COVID-19.
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Gurung, Hem Prasad, and Brijendra KC. "Issues and Challenges of Class C Contractors in Pokhara." Technical Journal 3, no. 1 (2023): 14–21. http://dx.doi.org/10.3126/tj.v3i1.61934.
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This study entitled “Issues and Challenges of Class C Contractors in Pokhara” was carried out for all Class C Contractors registered in Contractors’ Association of Nepal (CAN) Kaski. This study aims to investigate the issues and challenges faced by Class C contractors in Pokhara. Expert interview were conducted after thoroughly reviewing the literature and reports of the Nepalese construction industry to identify the major problems of Nepalese contractors. The data were collection through questionnaire surveys and interviews. The main objective was to identify the burning issues and challenges of Class C contractors of Pokhara.The findings revealed that most of the construction firms in Pokhara are engaged in different sectors of constructions and few firms are specialized in particular construction work i.e. Road construction and maintenance. These firms meet equipment capacity as per CBA 2055 & CBR 2056 and are financially and technically viable for bidding process as per Qualification Criteria of PPA 2063 & PPR 2064. The results indicated that the major issues and challenges of contractors in Pokhara are competitive pre-qualification process during bidding, low bidding and corruption, hiring qualified human resources, work experience, delay in payment, political intervention, job insecurity, price escalation and inflation, insecurity due to hooliganism in construction site, revenue and taxation, government rules and regulations, contract documents, etc. Based on the findings of the study, it is concluded that the government and concerned authorities should implement flexible and appropriate policies and laws with standard guidelines for prequalification criteria and formulate amendments in standard bidding documents containing clauses under new procurement act. Amendments like bidding capacity of classified contractors, price escalation and inflation, JV prequalification criteria, duty privilege for construction equipment, high rate of registration, renewable fee and vehicle tax, VAT system, present income tax assessment procedure, etc. should be revised under new procurement act. The study can also be useful for benchmarking the status of Class C Contractors in Pokhara.
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Fischer, Jérémie. "Les Juifs vus par un prêtre français en exil: l’antijudaïsme dans les Mémoires de l’abbé Pochard (1796-1830)." Poznańskie Studia Teologiczne, no. 30 (August 24, 2018): 141–58. http://dx.doi.org/10.14746/pst.2016.30.06.
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The article is an attempt to show the leading elements of the attitude towards Jews, the attitude of Father Claude-Antoine Pochard (1766-1833), tutor in the family of a Gniezno governor Joseph Skórzewski. Numerous trips across Polish territories and neighboring countries enabled him to come into direct contact with Jewish issues in Central and Eastern Europe, and his up till now unpublished memoirs shed light on some interesting aspects of the history of European Jews.The article consists of three parts. The first part presents direct or indirect contacts of Father Pochard with Jews during his trip to Bavaria, Saxony, Prussia, Wielkopolska, the land annexed by Russia and Lithuania. The second part shows Fr. Pochard’s reactions to the presence of Jews – dislike and avoiding closer contacts. There is also an attempt to show the difference in the positions of both the Catholic side, represented by Fr. Pochard, and the Jewish side, the climate of hostility and mutual prejudices. The third and last part shows cases where Fr. Pochard revises his views in contact with professionalism and honesty encountered in traveling Jewish innkeepers and merchants, and also other specific moments when there was escalation of tension in his relations with the Jews. The whole article is an interesting panorama of Christian-Jewish relations in the first half of the nineteenth century, when there were economic contacts but no cultural exchange.
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Varesi, Gastón. "De la crisis del régimen neo-desarrollista y la hegemonía kirchnerista al triunfo de Cambiemos." Temas y Debates, no. 35 (September 4, 2018): 13–38. http://dx.doi.org/10.35305/tyd.v0i35.399.
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En 2015, Cambiemos derrotó al kirchnerismo, accediendo al gobierno nacional y estableciendo un punto de inflexión. El artículo se pregunta ¿cuáles fueron las tensiones que hicieron posible aquel resultado, tanto a nivel del régimen neo-desarrollista como de la construcción hegemónica en que se sustentaba? Para responder a este interrogante nos proponemos indagar acerca del cambio de relaciones de fuerzas, desde un enfoque multi-dimensional y multi-escalar, identificando los factores de crisis en los planos de la acumulación y de la hegemonía, visualizando distintos límites y contradicciones que coadyuvaron al desgaste del proyecto que dirigió la Argentina entre 2003 y 2015. Partimos de un análisis de tres núcleos claves del proceso de acumulación: las políticas, las variables económicas y las fracciones de clase; daremos cuenta de la conformación de distintos desequilibrios como la persistente inflación, la crisis energética, la reticencia inversora, la fuga de capitales, entre otros, que fueron erosionando las cuentas públicas y externas, en un contexto de alta extranjerización y concentración que favoreció la capacidad de veto del gran capital sobre las iniciativas del kirchnerismo. Asimismo, abordaremos distintos aspectos de la estrategia hegemónica de esta fuerza, su potencia, límites y desgaste, con el fin de gestar una lectura integradora del período estudiado.
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Franz, Tobias. "Urban Governance and Economic Development in Medellín." Latin American Perspectives 44, no. 2 (2016): 52–70. http://dx.doi.org/10.1177/0094582x16668313.
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Many of the academic analyses calling Medellín’s development an “urban miracle” fall short with regard to discussion of the political economic implications of institutional shifts. An emerging transnational capitalist class promoted ‘good governance’ reforms and the embedding of neoliberalism in the urban context. Medellín’s neoliberal development agenda is not only a market-led strategy but also a particular form of hierarchic rule and distribution of power. Increased economic activities in the tertiary sector, the promotion of flexible labor markets, and the incorporation of the city into the global economy at the lower end of the value chain have not served as sustainable growth escalators for Medellín’s economy. The city continues to have high rates of un- and underemployment and is still the country’s most unequal city. These developments can by no means be described as miraculous. Muchos de los análisis académicos que describen el desarrollo de Medellín como un “milagro urbano” se quedan cortos en cuanto a la discusión de las implicaciones político-económicas de los cambios institucionales. Una nueva clase capitalista transnacional promovió las reformas de buena gobernanza y la incorporación del neoliberalismo en el contexto urbano. El plan de desarrollo neoliberal de Medellín no es sólo una estrategia orientada al mercado sino que también es una forma jerárquica de gobierno y distribución del poder. El aumento de las actividades económicas en el sector sectario, la promoción de un mercado laboral flexible y la incorporación de la ciudad en la economía global en el nivel más bajo de la cadena de valor no han servido como palancas para el crecimiento económico sustentable de Medellín. La ciudad sigue teniendo las tasas de desempleo y subempleo más altas de Colombia y todavía es la ciudad más desigual del país. Estos desarrollos no pueden ser descritos en modo alguno como milagrosos.
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Yun, Mylinh, Jay Varkey, Renee Spinke, et al. "STOP-BSI: Reducing Methicillin-Resistant Staphylococcus aureus Bloodstream Infections in Oncology Patients." Infection Control & Hospital Epidemiology 41, S1 (2020): s391. http://dx.doi.org/10.1017/ice.2020.1029.
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Background: Hospital-acquired methicillin-resistant Staphylococcus aureus bloodstream infections (MRSA BSIs) are associated with serious morbidity and mortality in immunocompromised patients. Of all MRSA BSIs at our academic medical center, 63% occurred in the oncology units. A multidisciplinary team was formed to address the improvement opportunity: the clinical nurse specialist, hospital epidemiologist, unit leaders, nurse champions and representatives from infection prevention, pharmacy and information technology. The goal was to decrease the incidence of hospital-onset MRSA BSI in the oncology wards by 10 infections in 2016 by implementing daily chlorohexidine (CHG) bathing and weekly nasal povidone-iodine antisepsis in July 2016. Methods: The strategically targeting oncology with povidone-iodine nasal antisepsis and bathing with CHG Staph reduction initiative (STOP-BSI) was a quality improvement project consisting of daily CHG baths for all oncology patients and nasal povidone-iodine on admission and weekly thereafter. Nurses and patient care technicians were trained on how to administer CHG treatments. Education was also provided to patients on how to use CHG bath wipes to self-administer the nasal antisepsis. Education resources were created to help answer concerns of the staff, patient, or family, and an escalation process was developed for treatment refusal. CHG bath audits were performed to measure compliance and to identify barriers to the process. Results: By the end of 2016, the number of infections decreased by 5 on the oncology units. The number of infections continued to decrease each year. The bone marrow transplant (BMT) unit decreased from 8 infections in 2015 to 3 in 2018. The hematology oncology unit infections decreased from 5 infections in 2015 to 0 in 2018. The medical oncology unit infections decreased from 2 infections in 2015 to 0 in 2018. The CLABSI rates per 1,000 line days trended downward after some time. Conclusions: Implementing daily CHG baths and weekly povidone-iodine nasal antisepsis reduced the number of MRSA BSI infections in the oncology population. The CLABSI rates decreased after barriers to the process were removed.Funding: NoneDisclosures: None
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Mey, Mattheus Theodorus. "The Value Relevance Of Straight-Lining Lease Expenses." International Business & Economics Research Journal (IBER) 15, no. 6 (2016): 301–14. http://dx.doi.org/10.19030/iber.v15i6.9830.
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The International Accounting Standards Board envisions the global acceptance of International Financial Reporting Standards (IFRS). Despite attempting convergence with IFRS, some national accounting standard setters, such as in India allow for certain carve-outs in their own accounting standards so as to meet country-specific requirements for fair presentation. Indian Accounting Standards allow for operating leases with fixed inflationary linked escalations to be accounted for on an as-incurred basis in contrast to the existing requirement in IFRS to straight-line such leases. This study explores whether operating lease expenses with fixed inflationary linked escalations and accounted for on a straight-line basis provide incremental value relevance beyond the as-incurred basis.This study exploits an occurrence in South Africa, where listed companies that previously accounted for operating leases with fixed inflationary-linked escalation clauses on an as-incurred basis, were required to straight-line those leases. Using the Ohlson (1995) valuation model this empirical study investigates the incremental value relevance of the straight-line basis over the as-incurred basis.Results show a significant change in the association between property-related operating lease expenses and market value indicators after the effect of straight-lining is introduced. This suggests that the straight-line basis provide investors with more value relevant information than when accounting for the expense as-incurred.Findings from this study prompt national accounting setters that allow for operating leases with fixed inflationary linked escalations to be accounted for on an as-incurred basis to consider first whether the straight-line basis do not provide more relevant information. Limiting the choice of accounting treatment may enhance comparability of financial statements.
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Flórez-Martinez, Alexander, Cristhian Manuel Durán-Acevedo, and Jeniffer Katerine Carrillo-Gómez. "Análisis de volátiles en el proceso de fermentado de cacao, mediante una nariz electrónica para el control de calidad del producto en Norte de Santander-Cúcuta." Respuestas 25, no. 2 (2020): 133–46. http://dx.doi.org/10.22463/0122820x.2955.
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El presente estudio consiste de una nariz electrónica compuesta de 10 sensores de gases de tipo MQ para la clasificación de muestras de CLON ICS-95 de cacao. El desarrollo de las pruebas fue de tipo cualitativo, obteniendo una huella digital que caracterizó cada clase, las cuales fueron: Fermentado deseado: 144 horas, sobre-fermentado y mala fermentación cacao infectado con monilia. Todos los sensores usados en las diferentes pruebas fueron de material de óxidos metálicos con capacidad de medir diversos tipos de gases, butanos, propanos, alcoholes, monóxido de carbono en diferentes concentraciones, donde al hacer contacto con los volátiles asociados producen una alteración en el voltaje de salida. Las señales se adquirieron mediante un sistema de adquisición de datos basado en tarjeta Arduino y uso del software Labview, permitiendo el almacenamiento de los datos. El algoritmo para la extracción de parámetros, pre-procesamiento y procesamiento de datos se realizó mediante el uso de software Python. Los resultados se analizaron implementando análisis de componente principales PCA y ejecución de dos métodos de pre-procesamiento de datos, como el centrado y escalado de datos, logrando un porcentaje de varianza en los componentes principales de 97.8% y con el método Manhattan se obtuvo un 93.8% del porcentaje de varianza en la componente principal PC1. Con estos resultados se logró observar que el sistema de olfato electrónico fue capaz de clasificar los datos de acuerdo a las clases definidas, fermentado deseado: 144 horas, sobre-fermentado y mala fermentación cacao infectado con monilia
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Vallejos Meriño, Carlos, Nicolás Gómez Álvarez, and Kevin Isaias Campos Campos. "Impacto de la clase de Educación Física en escolares diagnosticados con Trastornos del Espectro Autista al interior de una Escuela Especial en Chile (Impact of the physical education class on schoolchildren diagnosed with Autism Spectrum Disorders in a Special School in Chile)." Retos 52 (January 15, 2024): 499–508. http://dx.doi.org/10.47197/retos.v52.102286.
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En niños diagnosticados con Trastornos del Espectro Autista (TEA) la práctica de actividad física en el contexto escolar (clase de educación física) es una estrategia viable para mejorar la aptitud física y habilidades motoras, combatir el sobrepeso y obesidad y disminuir comportamientos inapropiados. El objetivo de esta investigación fue evaluar el impacto de una intervención multimodal de 12 semanas en la clase de Educación Física sobre el rendimiento motor y estado nutricional de estudiantes de una Escuela Especial de Copiapó. La investigación corresponde a un enfoque cuantitativo, con diseño cuasiexperimental sin grupo control. Participaron 12 estudiantes diagnosticados con TEA (9 hombres y 3 mujeres), cuya edad fue de 12.91±1.12 años. Los escolares participaron de un programa multimodal con frecuencia de dos sesiones por semana. Se utilizó el Test de caminata 6 minutos, salto horizontal sin impulso, test MABC-2, fuerza de prensión manual, peso, estatura e Índice de Masa Corporal (IMC). De acuerdo con los resultados no es posible modificar el estado nutricional de los estudiantes, se logran mejoras significativas en el puntaje escalar general de la Batería MABC-2; test de salto horizontal sin carrera y test de caminata de 6 minutos. En conclusión, una intervención multimodal de 12 semanas en la clase de educación física en un establecimiento de educación especial no logró disminuir los niveles de malnutrición por exceso, en cambio, se lograron efectos relevantes en la aptitud física, siendo un tipo de intervención con altas posibilidades de ser replicada en contextos similares. Palabras claves: Educación física; Desarrollo motor; Estado nutricional; Educación especial; Autismo Abstract. In children diagnosed with Autism Spectrum Disorders (ASD), the practice of physical activity in the school context (physical education class) is a viable strategy to improve physical fitness and motor skills, combat overweight and obesity and reduce inappropriate behaviors. The objective of this research was to evaluate the impact of a 12-week multimodal intervention in the Physical Education class on the motor performance and nutritional status of students from a Special School in Copiapó. The research corresponds to a quantitative approach, with a quasi-experimental design without a control group. Twelve students diagnosed with ASD (9 males and 3 females), whose age was 12.91±1.12 years, participated. The students participated in a multimodal program with a frequency of two sessions per week. The 6-minute walk test, horizontal jump without impulse, MABC-2 test, manual grip strength, weight, height and Body Mass Index (BMI) were used. According to the results it is not possible to modify the nutritional status of the students, significant improvements are achieved in the general scalar score of the MABC-2 Battery; horizontal jump test without running and 6-minute walk test. In conclusion, a 12-week multimodal intervention in the physical education class in a special education establishment did not manage to decrease the levels of excess malnutrition, on the other hand, relevant effects on physical fitness were achieved, being a type of intervention with high possibilities of being replicated in similar contexts. Keywords: Physical education; Motor development; Nutritional condition; Special education; Autism
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Kant, Immanuel, and Carlos Másmela Arroyave. "Acerca de un tono exaltado que recientemente se alza en la filosofía." Estudios de Filosofía, no. 4 (August 1, 1991): 99–114. http://dx.doi.org/10.17533/udea.ef.339700.
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El nombre de filosofía, después de haber perdido su primer significado, el de una sabiduría científica de la vida, ha llegado muy pronto a ser demandado como título de ornamentación del entendimiento en pensadores más allá de lo común, para los que la filosofía representa ahora una clase de develamiento de un misterio. Para los ascetas del desierto de Macario la filosofía era su monaquismo. El alquimista se denominaba philosophus per ignem. Las logias de los tiempos antiguos y modernos son adeptas a un misterio transmitido por tradición, del que celosamente nada han querido revelar (philosophus per initiationem.) Finalmente, los más recientes poseedores de tal misterio son aquellos que lo tienen en ellos mismos, aunque desgraciadamente no pueden enunciarlo y comunicarlo universalmente a través del lenguaje (philosophus per inspirationem. Pero si hubiera un conocimiento de lo suprasensible (que desde el punto de vista teórico solamente es un verdadero misterio), el cual es posible develar perfectamente en el entendimiento humano desde un punto de vista práctico, dicho conocimiento, al proceder de este entendimiento como una facultad del conocimiento por conceptos, permanecería sin embargo muy inferior con respecto a aquel que podría percibirse de manera inmediatapor el entendimiento como una facultad de la intuición, porque por medio del primer conocimiento, el entendimiento discursivo tiene que consagrar mucho trabajo, primero al análisis y luego a la composición de sus conceptos según principios, y escalar con dificultad muchos peldaños para hacer progresos en el conocimiento, mientras que una intuición intelectual comprendería y presentaría el objeto inmediatamente y de golpe.
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Renaudeau, Céline, Pierre Gimbergues, Eugénie Guillot, et al. "Abstract OT1-09-01: Axillary surgery de-escalation after neoadjuvant chemotherapy in breast cancer patients with initially involved node: the GANEA 3 trial." Cancer Research 83, no. 5_Supplement (2023): OT1–09–01—OT1–09–01. http://dx.doi.org/10.1158/1538-7445.sabcs22-ot1-09-01.
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Abstract Background: In breast cancer patients, neoadjuvant chemotherapy (NAC) allows to obtain pathological complete response (pCR). In case of initially involved node before NAC, pCR after NAC could make it possible to avoid axillary surgery. The aim of our study was to address parameters to build a tool able to accurately select patients at a high probability of axillary pCR after NAC. Method: GANEA 3 was a French prospective multi institutional cohorts of breast cancer patients with a proven axillary involved node treated with NAC (NCT03630913). Initially involved node was clipped before treatment. Each patient received, before and after NAC, a bilateral mammography, a Magnetic Resonance Imaging (MRI), an axillary sonography. After NAC breast, conservative or radical, and axillary surgery, were performed. Breast surgery allowed to measure breast tumor residual and to perform a Sataloff classification. Targeted axillary detection (TAD) was defined as the combination of the resection of the clipped node and SLN dissection. Axillary clipped node, sentinel lymph node (SLN) and axillary lymph node dissection (ALND) were always performed. ALND allowed to assess the false negative rate (FNR) of axillary clipped node and SLN dissection. A total of 500 included patients is planned to close this still ongoing trial. Results : From January 2019 to March 2022, 405 patients were included from 18 institutions. We present here the results of the 260 first patients, who experienced a complete treatment with NAC courses and post NAC breast and axillary surgery. Among these patients, SBR grade was III in 52%, OR and PR were positive in 59% and 46% respectively, HER2 was overexpressed in 40%, 26% were triple negative and pCR was present in 28%. FNR of the SLN detection was 21.1%, 9% for the clipped node alone and 6% for the TAD. Histopronostic grading, progesteron receptors, HER2 expression, MRI results and Sataloff grading of breast residual tumor were indepently linked with global pCR (breast and axilla) in multivariate analysis. The Area Under the Curve (AUC) model was 0.91 with 82% correctly patients classified. The false negative rate of no pCR classified patients was 14%. Conclusion : Intermediate results of Ganea 3 trial showed that operable breast cancer patients with an initially involved axillary node treated with NAC, showed that TAD allows to reduce the FNR of axillary surgery. Patients with histopronostic grade 3, negative progesteron receptors, HER2 overexpression, a normal MRI after NAC and a breast Sataloff A, have a low risk of axillary tumour residual burden and could be safely spare from any axillary surgery. Large prospective trials are needed to confirm the safety of this surgical de-escalation. Citation Format: Céline Renaudeau, Pierre Gimbergues, Eugénie Guillot, Marie-Pierre Chauvet, Marian Gutowski, Eva Jouve, Philippe Rauch, Monique Cohen, Christelle Faure, Marie-Martine Padeano, Vivien Ceccato, Catherine Uzan, Anne-Sophie Bats, Hélène Charitansky, Pierre-François Dupré, Augustin Reynard, Séverine Alran, Cécile Bendavid-Athias, Loïc Campion, Isabelle Doutriaux, Jean-Marc Classe. Axillary surgery de-escalation after neoadjuvant chemotherapy in breast cancer patients with initially involved node: the GANEA 3 trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT1-09-01.
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Bellon, Anne, Omar Saavedra, Ingrid M. Desar, et al. "Abstract CT064: Impact of food and high gastric pH on the bioavailability of the WEE1 inhibitor Debio 0123 assessed in a phase 1 dose escalation study." Cancer Research 84, no. 7_Supplement (2024): CT064. http://dx.doi.org/10.1158/1538-7445.am2024-ct064.
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Abstract Debio 0123 (D0123), an oral, brain-penetrant, highly selective WEE1 inhibitor, is currently in clinical development, both in combination and as monotherapy, for the treatment of patients with solid tumors. Food and gastric acid-reducing agents e.g. proton pump inhibitors (PPIs) may modify the solubility, bioavailability, safety and efficacy of oral cancer drugs. Polymedication in cancer patients is common and food restrictions can impact patient compliance and wellbeing. In order to adequately inform drug dosing in clinical trials, effects of food and high gastric pH on D0123 bioavailability were studied over three cycles in patients treated in the dose escalation of a Phase 1 study of D0123 in combination with Carboplatin (CTID NCT03968653).D0123 was given on Days 1-3 and 8-10 of each 21-day cycle in combination with carboplatin on Day 1. Current standard administration of D0123 is in fasted conditions and PPIs are prohibited. Dose-limiting toxicities were evaluated in cycle 1. The effect of food and high-gastric pH were assessed in cycles 2 and 3, respectively. In cycle 2 on Day 10, patients were receiving a high-fat meal and in cycle 3, the PPI lanzoprazole 30 mg BID was administered from Day 7 to 11. PK parameters (area under the curve (AUC), maximum concentration (Cmax)) were determined post-Day 10 dose and compared between cycle 1 (fasted) and cycle 2 (fed) or 3 (high gastric pH). Preliminary data from 3 cohorts, 3 dose levels (n=10) resulted in about 5 pairwise comparisons for food and for high gastric pH effects. Absence of D0123 accumulation between cycles was confirmed, allowing for inter-cycle comparison. Oral bioavailability of D0123 appears pH-dependent, suggesting that co-medication with PPIs should be avoided. In contrast, food intake has a limited impact on drug absorption, at all doses tested. Furthermore, D0123 administration with food may increase treatment convenience and tolerability, leading to its implementation in other D0123 trials. TABLE 1. NAND Mean change [ min ; max ] Effect of food (cycle 2 versus cycle 1) Effect of high gastric pH (cycle 3 versus cycle 1) AUC24 -3% [ -17% ; +8% ] -31% [ -39%; -23% ] Cmax -10% [ -26% ; 0% ] -33% [ -41% ; -20% ] Citation Format: Anne Bellon, Omar Saavedra, Ingrid M. Desar, Mathilde Jalving, Jourik A. Gietema, Carla van Herpen, Stefan van Ravensteijn, Esteban Rodrigo Imedio, Sylvia van Haren, Melanie Wirth, Sandrine Micallef, Vito Dozio, Rikke Frederiksen Franzen, Marie-Claude Roubaudi-Fraschini, Valerie Nicolas-Metral, Hans Gelderblom. Impact of food and high gastric pH on the bioavailability of the WEE1 inhibitor Debio 0123 assessed in a phase 1 dose escalation study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT064.
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Dos Santos, Acácio Bento, Nelson Vieira da Silva Meirelles, and Paulo Rogério Barbosa Silva. "PROPOSTA METODOLOGICA PARA O ENSINO COOPERATIVISTA NA EDUCAÇÃO PROFISSIONAL E TECNOLÓGICA." REVISTA FOCO 17, no. 3 (2024): e4553. http://dx.doi.org/10.54751/revistafoco.v17n3-015.
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A sociedade brasileira é caracterizada pelo grau de desigualdade entre as classes, sendo refletido tanto no âmbito educacional, quanto no profissional. Tamanha dualidade é encontrada em todos os resultados econômicos e sociais do Brasil e no seu ciclo de subdesenvolvimento. O modelo capitalista impede os pequenos produtores/empreendedores desenvolverem seus negócios, que por sinal tem alto grau de falência. Boa parte deste problema é a competição desleal existente no contexto do mercado brasileiro, onde os grandes conseguem escalar produção e reduzir custos encarando as barreiras de mercado, como competição abrupta e altos impostos de forma mais tranquila que os pequenos, que muitas vezes se quer conseguem pagar suas contas básicas. Dentro deste contexto, busca-se algumas alternativas de atuação no mercado que proporcione ao pequeno produtor/empreendedor maior sustentabilidade de negócio para melhoria de sua realidade. Para solução deste problema se tem a aplicação de métodos de economia solidária, a exemplo da dinâmica cooperativista como alternativa ao modelo atual de competição. Nesse contexto o objetivo principal será aplicar uma metodologia de ensino do modelo cooperativista como alternativa ao padrão capitalista atual para atuação dos alunos do curso técnico em agropecuária no mercado de trabalho, outros objetivos são abordar a temática da consciência de classe, investigar a capacidade de compreensão dos discentes sobre seu contexto social e elaborar uma sequência didática para aplicação dos conteúdos sobre o sistema cooperativista. Serão realizados, além de levantamento bibliográfico, entrevistas semi-estruturadas para diagnóstico do grau de entendimento dos discentes sobre o tema do cooperativismo e identificação do público participante da pesquisa, esta pesquisa será de cunho qualitativo através da metodologia de pesquisa ação, com a utilização de metodologias ativas para aplicação da metodologia proposta e seguirá a linha de pesquisa de práticas educativas aos discentes do curso técnico em agropecuária do Instituto Federal de Alagoas, campus Satuba.
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Bunge, Eveline M., Bernard Hoet, Liddy Chen, et al. "The changing epidemiology of human monkeypox—A potential threat? A systematic review." PLOS Neglected Tropical Diseases 16, no. 2 (2022): e0010141. http://dx.doi.org/10.1371/journal.pntd.0010141.
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Monkeypox, a zoonotic disease caused by an orthopoxvirus, results in a smallpox-like disease in humans. Since monkeypox in humans was initially diagnosed in 1970 in the Democratic Republic of the Congo (DRC), it has spread to other regions of Africa (primarily West and Central), and cases outside Africa have emerged in recent years. We conducted a systematic review of peer-reviewed and grey literature on how monkeypox epidemiology has evolved, with particular emphasis on the number of confirmed, probable, and/or possible cases, age at presentation, mortality, and geographical spread. The review is registered with PROSPERO (CRD42020208269). We identified 48 peer-reviewed articles and 18 grey literature sources for data extraction. The number of human monkeypox cases has been on the rise since the 1970s, with the most dramatic increases occurring in the DRC. The median age at presentation has increased from 4 (1970s) to 21 years (2010–2019). There was an overall case fatality rate of 8.7%, with a significant difference between clades—Central African 10.6% (95% CI: 8.4%– 13.3%) vs. West African 3.6% (95% CI: 1.7%– 6.8%). Since 2003, import- and travel-related spread outside of Africa has occasionally resulted in outbreaks. Interactions/activities with infected animals or individuals are risk behaviors associated with acquiring monkeypox. Our review shows an escalation of monkeypox cases, especially in the highly endemic DRC, a spread to other countries, and a growing median age from young children to young adults. These findings may be related to the cessation of smallpox vaccination, which provided some cross-protection against monkeypox, leading to increased human-to-human transmission. The appearance of outbreaks beyond Africa highlights the global relevance of the disease. Increased surveillance and detection of monkeypox cases are essential tools for understanding the continuously changing epidemiology of this resurging disease.
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Belada, David, Jacob Haaber Christensen, Kristina Drott, et al. "Subcutaneous Epcoritamab in Combination with R-CHOP in Patients with Previously Untreated High-Risk Diffuse Large B-Cell Lymphoma: Preliminary Results from a Phase 1/2 Trial." Blood 138, Supplement 1 (2021): 1413. http://dx.doi.org/10.1182/blood-2021-146569.
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Abstract Background: In patients (pts) with newly diagnosed diffuse large B-cell lymphoma (DLBCL) that is considered high risk (revised International Prognostic Index [R-IPI]: 3-5), standard treatment with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is associated with a 4-year overall survival rate of 55% (Sehn et al, Blood 2007). Epcoritamab (DuoBody ®-CD3×CD20) is a subcutaneously administered bispecific antibody that simultaneously binds to CD3 on T cells and CD20 on malignant B cells to induce T-cell-mediated killing. Single-agent epcoritamab demonstrated a manageable safety profile and substantial antitumor activity in pts with heavily pretreated B-cell non-Hodgkin lymphoma (NHL) in the first-in-human phase 1/2 trial (EPCORE NHL-1; NCT03625037). Among pts with relapsed/refractory DLBCL treated at the identified recommended phase 2 dose (RP2D) of 48 mg (n=8), the overall response rate was 88% and the complete response rate was 38% (Hutchings, Lancet, in press). These encouraging data supported initiation of the EPCORE NHL-2 phase 1/2 trial (NCT04663347), which is evaluating epcoritamab in combination with various standard of care therapies in pts with B-cell NHL. We present data from arm 1 of this trial, in which epcoritamab in combination with R-CHOP is evaluated in pts with previously untreated high-risk DLBCL. Methods: Adults with previously untreated DLBCL and an R-IPI score ≥3 received flat-dose epcoritamab in combination with standard R-CHOP for 6 cycles followed by epcoritamab monotherapy. The study includes a dose-escalation cohort (epcoritamab doses: dose level 1 = 24 mg; dose level 2 = 48 mg). Step-up dosing of epcoritamab (ie, priming and intermediate doses before first full dose) and corticosteroid prophylaxis were used as previously described (Hutchings, Lancet, in press) to mitigate cytokine release syndrome (CRS). Tumor response was evaluated by positron emission tomography-computed tomography obtained once every 6 weeks for the first 24 weeks. Results: As of July 15, 2021, 9 pts have been treated with the combination of epcoritamab + R-CHOP (4 with epcoritamab 24 mg; 5 with 48 mg). Median age was 66 years (range, 56-78). All pts had stage III-IV disease. At data cutoff, all pts remained on treatment with a median follow-up of 12.2 weeks (range, 2.2-28.2). The most common treatment-emergent adverse events were CRS (56%; all grade 1/2), anemia (56%; grade 1-3), neutropenia (44%; all grade 3/4), fatigue (33%; all grade 1/2), and peripheral neuropathy (33%; all grade 1/2). Notably, no grade ≥3 CRS events or cases of febrile neutropenia were reported. No dose-limiting toxicities have been observed. Four pts have had ≥1 response assessment, with 3 achieving complete metabolic response (CMR; all in the epcoritamab 24 mg dose-escalation cohort) and 1 pt achieving partial metabolic response (epcoritamab 48 mg cohort) by week 6; 2 of the 3 pts with CMR had response assessments at 6 months, and both remained in CMR at that time. Both dose cohorts have been cleared by the Dose Escalation Committee and Safety Committee, and the expansion part has been opened to enroll additional pts. Conclusions: These preliminary data from a small number of pts suggest that epcoritamab in combination with R-CHOP has a manageable safety profile with no new safety signals. Adverse events were similar to those previously reported for epcoritamab and R-CHOP individually. All evaluable pts achieved early responses, and all pts remain on treatment. Updated and additional data from pts treated in the expansion phase will be presented. These findings warrant further evaluation of epcoritamab for the treatment of high-risk, newly diagnosed DLBCL. Disclosures Belada: Genmab: Research Funding. Drott: Roche: Honoraria; Kyowa Kirin: Honoraria; Respiratorius AB: Membership on an entity's Board of Directors or advisory committees. Narkhede: TG Therapeautics: Research Funding; Genmab: Other: Medical writing support, Research Funding; Genentech/Roche: Research Funding; Gilead: Research Funding. Elliot: Genmab: Current Employment, Patents & Royalties: P158-US-PSP3 . Liu: Genmab: Current Employment. Cota Stirner: AbbVie: Current Employment. Abbas: Genmab: Current Employment. Falchi: Abbvie: Consultancy, Research Funding; Genmab: Consultancy, Research Funding; Roche: Research Funding; Genetech: Research Funding. Clausen: Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expences ASH 2019; Gilead: Consultancy, Other: Travel expences 15th ICML ; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees.
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Wotman, Michael, Brandon Gold, Megan D'Andrea, et al. "Association of HPV genotype and phylogenic clade with oropharyngeal cancer outcomes." Journal of Clinical Oncology 41, no. 16_suppl (2023): 6058. http://dx.doi.org/10.1200/jco.2023.41.16_suppl.6058.
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6058 Background: Human papillomavirus (HPV) is a causative agent of oropharyngeal squamous cell carcinoma (HPVOPC). There are multiple different HPV genotypes based on variations in the nucleotide sequence of the L1 capsid, with HPV16 being most common in HPVOPC (85%). HPV genotypes can be further classified into phylogenic clades, including alpha-9 (A9) and alpha-7 (A7). HPVOPC is associated with a more favorable prognosis than HPV-negative disease, but the impact of specific HPV genotype and phylogenic clade on patient outcomes is not well understood and has profound implications for de-escalation studies in HPVOPC. Methods: A retrospective cohort study was conducted at a large multicenter health system. Patients diagnosed with non-metastatic HPVOPC or unknown primary from 2012-2021 and treated with curative intent were included. Low-risk HPV types (6, 11, etc) and local recurrences were excluded. HPV molecular typing was prospectively performed according to institutional protocol. Cox regressions were used to measure the effect of HPV genotype (16 versus non-16) on overall survival (OS) and event-free survival (EFS). Gender, smoking status, alcohol use, ECOG performance status, T stage, N stage, and subsite (oropharynx versus known primary) were covariates. A secondary survival analysis according to high-risk HPV clade (A9 versus A7) was also performed. Results: The total cohort included 520 patients, the majority of whom were HPV16 (86.9%, n = 452), A9 clade (97.1%, n = 505), oropharynx primary (94.8%, n = 493), male (86.9%, n = 452), white (72.5%, n = 377), non-Hispanic (74.2%, n = 386), non-active smokers (88.3%, n = 459), ECOG 0 (75.6%, n = 393), and N2 stage (65.2%, n = 339). The most common non-16 HPV genotypes were 18 (n = 7), 33 (n = 21), and 35 (n = 29). HPV genotype was not associated with OS (HR = 1.64, 95% CI 0.85-3.16, p= 0.14) or EFS (HR = 1.15, 95% CI 0.64-2.07, p= 0.65). A7 clade was associated with a worse OS compared to A9 in the univariate analysis (HR = 3.43, 95% CI 1.07-10.97, p= 0.04), but not in the multivariate analysis (HR = 1.67, 95% CI 0.45-6.17, p = 0.44). Finally, HPV clade was not associated with EFS (HR = 1.38, 95% CI 0.34-5.60, p= 0.66). Conclusions: While HPV genotype was not associated with survival differences in patients with HPVOPC, HPV A7 clade only predicted worse OS in univariate analysis. Although the total cohort size was large, this analysis was limited by small numbers of subjects with non-16 HPV genotypes and non-A9 clade, which is reflective of the predominance of HPV16 in HPVOPC. Thus, a pooled multicenter collaboration is needed to further address this question. Moreover, future studies should investigate whether outcomes may be related to intratypic HPV16 variants that affect oncoprotein function and/or immunogenicity. Detection of a subgroup of HPVOPC with possible inferior outcomes has important implications for studying treatment de-escalation in HPVOPC.
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Echols, Jane, Ashley Gamble, Lisa Berry, Lynn Dowling, and Michael Wheeler. "572 Integrating Shared Governance Principles with Real-time Technology to Improve Infection Rates in a Large Burn Center with Patients of Varying Acuity Levels." Journal of Burn Care & Research 42, Supplement_1 (2021): S136—S137. http://dx.doi.org/10.1093/jbcr/irab032.222.
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Abstract Introduction Increased job satisfaction, and nursing retention are outcomes that have been related to nursing empowerment.1 Probably one of the most beneficial results of nursing empowerment is improved patient outcomes.1 Empowering nurses is not always an easy task, but the nursing best practice of shared governance through unit-based councils gives nurses the ability to mobilize resources within their own groups to get things done. Couple this mobilization of resources with real-time technology that provides a true clinical picture of outcomes, and this creates a template for success. Methods This is a nursing Quality Improvement project. Shared governance in the form of unit-based councils created within all of our patient care units has proven to be part of the equation for improved infection rates in all units. Our number of CAUTI AND CLABIS from 2018–2019 were reduced, we significantly reduced the number of device days (hospital-wide) for both foleys and central lines, which was also a goal. Through extensive nursing education, utilizing nurse driven protocol for foley removal, increased use of bladder scanning (each unit now has their own bladder scanner) and teaching about de-escalation of central lines/PICC lines as soon as possible, we have been able to reduce our device days overall. Alongside this nursing best practice, a new nursing data portal that allows for real time data collection to identify breaks in protocol with regards to central line and foley maintenance leading to CAUTIs and CLABSIs was also implemented, which allowed nursing to have direct impact on achieving success. Results Percent Change 2018 – 2019 CAUTI BU = 83% decrease, 3E burn = 100% decrease, 4W burn = 100% decrease Overall decrease = 90% CLABSI BU = 85%, 3E burn = 67% increase, 4W burn = no change Overall decrease = 78% Conclusions Implementation of nursing best practice efforts such as shared governance and unit-based councils, coupled with cutting edge technological resources directly contribute to improved infection rate outcomes. Another result of these efforts is the overall positivity fostered among nursing staff, boosting their sense of empowerment and creating better retention rates in all our units.
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Kater, Arnon P., Jacob Haaber Christensen, Hans Herluf Bentzen, et al. "Subcutaneous Epcoritamab in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia: Preliminary Results from the Epcore CLL-1 Trial." Blood 138, Supplement 1 (2021): 2627. http://dx.doi.org/10.1182/blood-2021-146563.
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Abstract Background: Small molecules such as Bruton tyrosine kinase (BTK) and B-cell lymphoma 2 (BCL2) inhibitors have transformed the management of chronic lymphocytic leukemia (CLL). However, such treatments are not curative, and patients (pts) with relapsed or refractory (R/R) CLL following multiple targeted treatments present an emergent challenge with very limited therapeutic options. In addition, success rates of autologous T-cell-based therapies in CLL have been disappointing. In vitro data in CLL cells suggest potentially high efficacy of bispecific T-cell engagers (Martens et al, J Immunother Cancer 2020), but clinical data are extremely limited. Epcoritamab (GEN3013; DuoBody ®-CD3×CD20) is a bispecific antibody that can induce potent activation and cytotoxic activity of CD4+ and CD8+ T cells to specifically eliminate CD20-expressing cells (van der Horst et al, Blood Cancer J 2021). In the first-in-human trial in R/R B-cell non-Hodgkin lymphoma (B-NHL; EPCORE NHL-1; NCT03625037), epcoritamab showed manageable safety and meaningful antitumor activity across a range of aggressive and indolent B-NHLs. The most common treatment-emergent adverse events (AEs) were pyrexia (69%), cytokine release syndrome (CRS; 59%), and injection-site reaction (47%); CRS events were all grade 1-2 and most occurred in cycle 1 (Clausen et al, J Clin Oncol 2021). However, as CLL is characterized by presence of (high numbers of) circulating tumor cells, acquired T-cell dysfunction, and variable expression of CD20, data obtained in B-NHL are difficult to extrapolate to CLL. Herein we present the first results from the dose-escalation part of a phase 1b/2 trial evaluating epcoritamab in pts with R/R CLL. Methods: In this open-label, multicenter, phase 1b/2 trial, toxicity and efficacy of epcoritamab are investigated in adults with R/R CLL (EPCORE CLL-1; NCT04623541). Eligible pts previously received ≥2 lines of systemic antineoplastic therapy, including treatment with (or intolerance to) a BTK inhibitor. Epcoritamab is subcutaneously administered via 1-mL injections in 4-week cycles as follows: once weekly in cycles 1-3, every 2 weeks in cycles 4-9, and monthly in cycles ≥10 until progression or unacceptable toxicity. Step-up dosing during cycle 1 (ie, priming dose followed by an intermediate dose, then full doses) is used in combination with steroid prophylaxis to reduce the risk of CRS. In the dose-escalation part, pts with R/R CLL received epcoritamab at 2 full-dose levels (24 and 48 mg) according to a modified 3+3 design. Primary end points of the dose-escalation part included dose-limiting toxicities (DLTs) during the first 28-day treatment cycle and the incidence and severity of AEs, CRS, immune effector cell-associated neurotoxicity syndrome (ICANS), and tumor lysis syndrome (TLS). Results: The first pt was enrolled on November 30, 2020. As of July 12, 2021, 7 pts with R/R CLL received epcoritamab subcutaneously administered at 2 full-dose levels: 24 mg (n=3) and 48 mg (n=4). Six pts completed the DLT evaluation period, and 5 pts had a full response assessment. Pts had received a median of 4 lines of prior therapy (range, 2-5). Six of 7 pts had poor-risk features of del(17p), TP53 mutations, or both. Three of 7 pts had bulky disease. No DLTs occurred at 24 or 48 mg. The most common treatment-emergent AEs (>30%) were CRS (100%), fatigue (71%), injection-site reaction (43%), and nausea (43%). All pts experienced CRS in the first cycle, but no CRS events were higher than grade 2. No cases of ICANS were observed. TLS was not observed. Antileukemic activity has been observed at both dose levels, with partial responses in 3 of 5 pts. Updated clinical and pharmacokinetic data, including data for additional pts treated with epcoritamab, will be presented. Conclusions: These data suggest that epcoritamab is well tolerated in pts with R/R CLL at dose levels up to 48 mg and has clinical activity in pts with high-risk features. The expansion part of this study in pts with R/R CLL and Richter syndrome will open later this year. Disclosures Kater: Janssen, AstraZeneca: Other: Ad Board, steering committee, Research Funding; BMS, Roche/Genentech: Other: Ad Board, , Research Funding; Genmab, LAVA: Other: Ad Board, Steering Committee; Abbvie: Honoraria, Other: Ad Board, Research Funding. Niemann: CSL Behring, Genmab, Takeda, Octapharma: Consultancy; Abbvie, AstraZeneca, Janssen: Consultancy, Research Funding; Novo Nordisk Foundation: Research Funding. Hutchings: Roche: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Novartis: Research Funding; Incyte: Research Funding; Janssen: Honoraria, Research Funding; Genmab: Consultancy, Honoraria, Research Funding; Celgene: Research Funding; Genentech: Honoraria, Research Funding. Chen: Genmab: Current Employment. Rios: Genmab: Current Employment. Palenski: AbbVie: Current Employment. Li: Genmab: Current Employment. Mato: AbbVie: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; MSKCC: Current Employment; Genmab: Research Funding; Johnson and Johnson: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; LOXO: Consultancy, Research Funding; Nurix: Research Funding; DTRM BioPharma: Consultancy, Research Funding; TG Therapeutics: Consultancy, Other: DSMB, Research Funding; BeiGene: Consultancy, Research Funding; Acerta/AstraZeneca: Consultancy, Research Funding; AstraZeneca: Consultancy; Sunesis: Consultancy, Research Funding.
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Waizenegger, Irene C., Hengyu Lu, Claus Thamer, et al. "Abstract 2667: Trial in progress: Phase 1 study of BI 1823911, an irreversible KRASG12C inhibitor targeting KRAS in its GDP-loaded state, as monotherapy and in combination with the pan-KRAS SOS1 inhibitor BI 1701963 in solid tumors expressing KRASG12C mutation." Cancer Research 82, no. 12_Supplement (2022): 2667. http://dx.doi.org/10.1158/1538-7445.am2022-2667.
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Abstract Inhibition of KRASG12C mediated signaling and the therapeutic impact in non-small cell lung cancer (NSCLC) whose tumors carry this mutation was demonstrated clinically by sotorasib and adagrasib leading to approval of sotorasib in KRASG12C mutant NSCLC. These encouraging data are currently changing the treatment paradigm for patients with KRASG12C-mutated tumors. However only a fraction of patients is initially responding to these compounds and patients who achieved an objective response ultimately progressed on-treatment. It became clear from these studies that KRASG12C inhibitors require a combination partner to either achieve a deeper response initially or to prevent development of resistance. Multiple rational combination approaches are currently investigated with the goal to prolong duration of response or to overcome KRASG12C inhibitor resistance. The KRASG12C inhibitor BI 1823911 is more potent compared to sotorasib or adagrasib and showed comparable in vivo efficacy at a dose of 60 mg/kg vs. 100 mg/kg of either sotorasib or adagrasib in preclinical studies. The pan-KRAS SOS1 inhibitor BI 1701963 is the first direct KRAS signaling modifier, which entered phase I clinical trials both as a monotherapy as well as in combination with KRASG12C inhibitors, MEK inhibitors and irinotecan. Pan-KRAS SOS1 inhibitors exhibit activity against a broad spectrum of KRAS alleles, including the major G12D/V/C and G13D oncoproteins, while sparing the interaction of KRAS with SOS2. In the presented combination concept BI 1701963 shifts the balance of KRASG12C to its GDP-loaded form, which is the state to which BI 1823911 covalently binds to. Here, we present pre-clinical data showing enhanced pathway modulation and synergistic anti-tumor effects following vertical pathway inhibition of BI 1823911 in combination with BI 1701963. Our preclinical results supported the start of a phase I trial (NCT04973163), investigating the safety, tolerability, recommended dose and preliminary efficacy of BI 1823911 alone and in combination with the pan-KRAS SOS1 inhibitor BI 1701963. The trial includes cohorts of patients with KRASG12C mutant solid tumors, such as NSCLC, CRC, cholangiocarcinoma, and pancreatic adenocarcinoma, both KRAS therapy naïve or KRAS therapy relapsed. The first patients in the trial were treated in the monotherapy arm, dose escalation started at a dose of 50 mg. The combination therapy part is expected to start in Q1 2022. Primary endpoints include dose-limiting toxicities, treatment-emergent or -related adverse events. Secondary endpoints include pharmacokinetic properties of combination regimens and preliminary efficacy. Citation Format: Irene C. Waizenegger, Hengyu Lu, Claus Thamer, Fabio Savarese, Daniel Gerlach, Dorothea Rudolph, Christopher P. Vellano, Marcelo Marotti, John Heymach, Scott Kopetz, Timothy P. Heffernan, Joseph R. Marszalek, Mark P. Petronczki, Marco H. Hofmann, Norbert Kraut. Trial in progress: Phase 1 study of BI 1823911, an irreversible KRASG12C inhibitor targeting KRAS in its GDP-loaded state, as monotherapy and in combination with the pan-KRAS SOS1 inhibitor BI 1701963 in solid tumors expressing KRASG12C mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2667.
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Gil-Gil, Miguel, Miguel Martín, Eva Carrasco, et al. "Abstract PO2-19-05: Randomized Phase II trial evaluating three anti-diarrhoeal prophylaxis strategies in patients with HER2+/HR+ early breast cancer treated with extended adjuvant neratinib (DIANER GEICAM/2018-06)." Cancer Research 84, no. 9_Supplement (2024): PO2–19–05—PO2–19–05. http://dx.doi.org/10.1158/1538-7445.sabcs23-po2-19-05.
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Abstract Background: Neratinib (NER), and irreversible pan-HER tyrosine kinase inhibitor, is approved for the extended adjuvant treatment of HER2+/HR+ early breast cancer (EBC) patients within 1 year of trastuzumab (T)-based therapy completion. The ExteNET trial showed that the extended adjuvant NER compared with placebo modifies the risk of recurrence by an absolute rate of 2.5% at 5 years in HR+/HER2+ patients (Martin et al., 2017). However, without prespecified prophylaxis, diarrhoea was the most common reason for NER discontinuation in the first three cycles in said study. The CONTROL trial evaluated effectiveness of different anti-diarrhoeal strategies showing a reduction of severe diarrhoea and early discontinuation when indirectly compared to ExteNET (Chan et al., 2022). DIANER (NCT05252988) evaluates the 3 best reported anti-diarrhoeal strategies from CONTROL in patients receiving NER as per European approved label. Trial design and patients: DIANER is an international, multicenter, controlled, randomized, phase II study. Patients with HER2+/HR+ EBC (stage IB-IIIC) who completed prior neo/adjuvant T-based therapy within 2 weeks and 1 year will be included and randomized 1:1:1 to 3 treatment arms. Arm A: NER (240 mg/day[d] x 1 year) + loperamide (12 mg/d x 14 d → 8 mg/d till end of cycle 2 → as needed [PRN]), Arm B: NER dose escalation (120 mg/d x 7 d → 160 mg/d till d 14 → 240 mg/d x 13 cycles) + loperamide PRN, and Arm C: NER (like Arm A) + loperamide (12 mg/d x 14 d → 8 mg/d till end of cycle 1 → PRN) + colesevelam (3,750 mg/d x 28 d). Patients are stratified by menopausal status and prior anti-HER2 therapy (T versus T + pertuzumab). Specific aims: Primary objective is incidence of NER discontinuations due to diarrhoea in the first 3 cycles. Secondary objectives are: incidence of NER discontinuations; AEs and hospitalizations; duration, severity, and treatments for diarrhoea; NER exposure; and health-related quality of life (HRQoL) using FACT B and EQ5D-5L. Exploratory objectives include HRQoL using STIDAT; minimal residual disease and molecular alterations. Statistical methods: A maximum of 315 pts (105 per arm) will be needed using a Simon’s optimal two-stage design with the hypotheses of a desirable early discontinuation rate of 5% (H1) versus an undesirable early discontinuation rate of 13% (H0). In the first stage, arms with ≥ 4 pts discontinuing due to diarrhoea in the first 3 cycles, will be closed for enrolment. The 2-sided 90% confidence intervals using the method described by Koyama et al. (Koyama and Chen 2008) will be provided for the primary endpoint at the end of the 2nd stage of the Simon 2-stage design. Present accrual and target accrual: DIANER will take place in 81 sites in 5 European countries. As of Jul 10/2023 the study is open in 52 sites in Spain with 80 randomized patients. Contact information for people with a specific interest in the trial: Evelia Cortazar (Geicam PM): ecortazar@geicam.org Citation Format: Miguel Gil-Gil, Miguel Martín, Eva Carrasco, Elena Galve, Noelia Martínez-Jáñez, Santiago González-Santiago, Barbara Adamo, María Valero, Clara Martínez, Angel Guerrero, Silvia Antolin Novoa, Manuel Ruíz - Borrego, Isabel Blancas, Raquel Andrés, José L Alonso-Romero, ANDREA Vethencourt, J. Ignacio Chacón, Natalia Chavarría, Enrique Espinosa, Blanca Hernando, Encarnación Adrover, Federico Rojo, Maribel Casas, Leanne McCulloch, Jean-Claude Vedovato. Randomized Phase II trial evaluating three anti-diarrhoeal prophylaxis strategies in patients with HER2+/HR+ early breast cancer treated with extended adjuvant neratinib (DIANER GEICAM/2018-06) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-19-05.
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Bischoff, Werner, Cheryl Kieta, Tiffany LaFontaine, and Corrianne Billings. "2457. Improved Identification of Primary Infection Sites in Suspect Central Line Bloodstream Infections (CLABSI) through Preliminary Blood Culture Notifications." Open Forum Infectious Diseases 10, Supplement_2 (2023). http://dx.doi.org/10.1093/ofid/ofad500.2075.
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Abstract Background Central Line Bloodstream Infections (CLABSI) pose a significant risk for patients with high burden of morbidity and mortality. Accurate and timely identification of these events is paramount for the development of effective interventions. Methods A quasi-experimental (before/after) study included all inpatients with central venous catheters (CVC) admitted to five acute care hospitals in North Carolina. Starting in 03/2022 all preliminary blood culture results were evaluated within 24 hours by surveillance infection preventionists (SIP) and results indicative of potential CVC infection were escalated to medical teams. Escalation included identification of potential primary site infections, and discussion of the need for further testing and documentation. Mid-P exact tests were used to compare CLABSI burden before and after the intervention. Results From 03/22 through 03/23 preliminary blood culture results in a total of 498 cases were reviewed by SIP. Of those, 201 (40%) were escalated to the IP team with 94 determined to be CLABSI, and 107 (53%) referred to further assessment by IP and medical teams. A primary infection site other than CVC was established based on escalation conversations in 23 events leading to a reduction in potential CLABSI cases by 11.4%. Standardized Infection Ratios for all and publicly reportable locations were reduced by 13% and 27% (table 1). Of the 23 events interventions led to the establishment of a primary site of infection or documentation for exclusion criteria: pneumonia (9, 39%), burn (6, 26%), endocarditis (2, 9%), patient line injection (2, 9%), central line documentation clarification (1, 4%), intraabdominal infection (1, 4%), necrotizing enterocolitis (1, 4%), and skin infection (1, 4%). Interventions included imaging studies, culture collection of purulent sites, and documentation clarification including: abnormal/changes in wound characteristics, patient line injection, central line documentation. Conclusion Moving the process of CLABSI identification from finalized blood cultures to preliminary blood culture results improved the accuracy of CLABSI detection. Early inclusion of medical teams in the discussion of potential CLABSI increased awareness of the source of infection. Disclosures All Authors: No reported disclosures
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Florez-Martinez, Alexander, Jesus Omar Vargas-Flórez, Harold Esneider Pérez -Waltero, and Lucas Fernando Quintana-Fuentes. "Análisis de componentes principales utilizando python para identificar clúster asociados a muestras de cacao seco sano e infectado con monilia en Norte de Santander." Aibi revista de investigación, administración e ingeniería, June 4, 2020, 16–22. http://dx.doi.org/10.15649/2346030x.712.
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El resultado del proyecto de investigación está asociado a data proveniente de la implementación de un sistema electrónico multisensorial o común mente denominado olfato electrónico. Mediante el uso de un sistema de adquisición de datos y software LabView se almacena la data de la concentración de volátiles asociados a muestras de cacao sano e infectado con monilia, aplicado en la fase o etapa de secado. Una vez adquirido los datos se procede a implementar el software Python para el preprocesamiento y procesamiento de data, permitiendo al usuario por medio de un gráfico identificar el clúster asociados a cada clase, cacao sano o con monilia. Como método para aprendizaje de automático no supervisado, se implementa análisis de componentes principales PCA para el respectivo procesamiento. Los resultados obtenidos varían de acuerdo al método de preprocesado de datos, para el desarrollo se implementó un escalador robusto y preprocesado euclidiano, el cual presenta mejores resultados de agrupamiento de muestras por clase.
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Beckman, Martina, Emily Firmenich, Conrad R. Cole, David B. Haslam, Joel E. Mortensen, and Joshua D. Courter. "Characterization of initial CLABSI culture results to support antimicrobial de‐escalation in pediatric GI inpatients." Journal of Pediatric Gastroenterology and Nutrition, April 29, 2024. http://dx.doi.org/10.1002/jpn3.12228.
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AbstractObjectivesCentral Line‐associated Bloodstream Infections (CLABSIs) pose a serious mortality and morbidity risk. An institutional protocol was developed for the evaluation and empirical antibiotic treatment of possible CLABSIs. The potential impact of de‐escalating antimicrobial therapy based on initial Gram stain and molecular identification was assessed.MethodsAll positive blood cultures from patients admitted to the gastroenterology service at a large pediatric medical center were collected from 1/1/14 to 12/31/20. Cultures that were negative, repeated, or causative organisms that were unable to be identified with susceptibility data were excluded. Timepoints and organism(s) from each culture were recorded. Polymicrobial cultures were classified as containing only gram‐positive organisms (polymicrobial GP), only gram‐negative organisms (polymicrobial GN), or mixed spectrum.ResultsDuring the 6‐year period, 361 positive blood cultures were included in the study. Single isolates were identified in 79.5% (287/361) of cultures. Polymicrobial cultures from confirmed central line source accounted for 15.0% (54/361), with 6.4% (23/361) Polymicrobial GP, 4.4% (16/361) Polymicrobial GN, and 4.2% (15/361) being mixed‐spectrum cultures. Both organism types were detected on initial gram‐stain in 40% (6/15) of the mixed‐spectrum cultures, another 26.7% (4/15) had the opposite‐spectrum organism identified within an average of <3 h and the remaining 33.3% (5/15) had the opposite‐spectrum organism identified by culture growth.ConclusionsPolymicrobial mixed‐spectrum cultures accounted for <5% of positive blood cultures and most isolates were identified within 3 h of first positivity. This may allow for further investigation of early de‐escalation of therapy for this population and limit antimicrobial exposure.