A phase I pharmacokinetic study of hypoxic abdominal stop-flow perfusion with gemcitabine in patients with advanced pancreatic cancer and refractory malignant ascites

Purpose: As no curative treatment for advanced pancreatic and biliary cancer with malignant ascites exists, new modalities possibly improving the response to available chemotherapies must be explored. This phase I study assesses the feasibility, tolerability and pharmacokinetics of a regional treatment of gemcitabine administered in escalating doses by the stop-flow approach to patients with advanced abdominal malignancies (adenocarcinoma of the pancreas, n=8, and cholangiocarcinoma of the liver, n=1). Experimental design: Gemcitabine at 500, 750 and 1,125mg/m2 was administered to three patients at each dose level by loco-regional chemotherapy, using hypoxic abdominal stop-flow perfusion. This was achieved by an aorto-caval occlusion by balloon catheters connected to an extracorporeal circuit. Gemcitabine and its main metabolite 2′,2′-difluorodeoxyuridine (dFdU) concentrations were measured by high performance liquid chromatography with UV detection in the extracorporeal circuit during the 20min of stop-flow perfusion, and in peripheral plasma for 420min. Blood gases were monitored during the stop-flow perfusion and hypoxia was considered stringent if two of the following endpoints were met: pH≤7.2, pO2 nadir ratio ≤0.70 or pCO2 peak ratio ≥1.35. The tolerability of this procedure was also assessed. Results: Stringent hypoxia was achieved in four patients. Very high levels of gemcitabine were rapidly reached in the extracorporeal circuit during the 20min of stop-flow perfusion, with C max levels in the abdominal circuit of 246 (±37%), 2,039 (±77%) and 4,780 (±7.3%)μg/ml for the three dose levels 500, 750 and 1,125mg/m2, respectively. These C max were between 13 (±51%) and 290 (±12%) times higher than those measured in the peripheral plasma. Similarly, the abdominal exposure to gemcitabine, calculated as AUCt0-20, was between 5.5 (±43%) and 200 (±66%)-fold higher than the systemic exposure. Loco-regional exposure to gemcitabine was statistically higher in presence of stringent hypoxia (P<0.01 for C max and AUCt0-20, both normalised to the gemcitabine dose). Toxicities were acceptable considering the complexity of the procedure and were mostly hepatic; it was not possible to differentiate the respective contributions of systemic and regional exposures. A significant correlation (P<0.05) was found between systemic C max of gemcitabine and the nadir of both leucocytes and neutrophils. Conclusions: Regional exposure to gemcitabine—the current standard drug for advanced adenocarcinoma of the pancreas—can be markedly enhanced using an optimised hypoxic stop-flow perfusion technique, with acceptable toxicities up to a dose of 1,125mg/m2. However, the activity of gemcitabine under hypoxic conditions is not as firmly established as that of other drugs such as mitomycin C, melphalan or tirapazamine. Further studies of this investigational modality, but with bioreductive drugs, are therefore warranted first to evaluate the tolerance in a phase I study and later on to assess whether it does improve the response to chemotherap

Hypertension burden in Luxembourg: Individual risk factors and geographic variations, 2013 to 2015 European Health Examination Survey

Hypertension is a modifiable risk factor for cardiovascular disease, but it remains the main cause of death in Luxembourg. We aimed to estimate the current prevalence of hypertension, associated risk factors, and its geographic variation in Luxembourg.Cross-sectional, population-based data on 1497 randomly selected Luxembourg residents aged 25 to 64 years were collected as part of the European Health Examination Survey from 2013 to 2015. Hypertension was defined as systolic/diastolic blood pressure ≥140/90 mm Hg, self-report of a physician diagnosis or on antihypertensive medication. Standard and Bayesian regressions were used to examine associations between hypertension and covariates, and also geographic distribution of hypertension across the country.Nearly 31% of Luxembourg residents were hypertensive, and over 70% of those were either unaware of their condition or not adequately controlled. The likelihood of hypertension was lower in men more physically active (odds ratio [95% credible region] 0.6 [0.4, 0.9]) and consuming alcohol daily (0.3 [0.1, 0.8]), and higher in men with a poor health perception (1.6 [1.0, 2.7]) and in women experiencing depressive symptoms (1.8 [1.3, 2.7]). There were geographic variations in hypertension prevalence across cantons and municipalities. The highest odds ratio was observed in the most industrialized region (South-West) (1.2 [0.9, 1.6]) with a positive effect at 90% credible region.In Luxembourg, the vast majority of people with hypertension are either unaware of their condition or not adequately controlled, which constitutes a major, neglected public health challenge. There are geographic variations in hypertension prevalence in Luxembourg, hence the role of individual and regional risk factors along with public health initiatives to reduce disease burden should be considered

Prescription of concomitant medications in patients treated with Nifurtimox Eflornithine Combination Therapy (NECT) for T.b. gambiense second stage sleeping sickness in the Democratic Republic of the Congo

Nifurtimox eflornithine combination therapy (NECT) to treat human African trypanosomiasis (HAT), commonly called sleeping sickness, was added to the World Health Organisation's (WHO) Essential Medicines List in 2009 and to the Paediatric List in 2012. NECT was further tested and documented in a phase IIIb clinical trial in the Democratic Republic of Congo (DRC) assessing the safety, effectiveness, and feasibility of implementation under field conditions (NECT-FIELD study). This trial brought a unique possibility to examine concomitant drug management.; This is a secondary analysis of the NECT-FIELD study where 629 second stage gambiense HAT patients were treated with NECT, including children and pregnant and breastfeeding women in six general reference hospitals located in two provinces. Concomitant drugs were prescribed by the local investigators as needed. Patients underwent daily evaluations, including vital signs, physical examination, and adverse event monitoring. Concomitant medication was documented from admission to discharge. Patients' clinical profiles on admission and safety profile during specific HAT treatment were similar to previously published reports. Prescribed concomitant medications administered during the hospitalization period, before, during, and immediately after NECT treatment, were mainly analgesics/antipyretics, anthelmintics, antimalarials, antiemetics, and sedatives. Use of antibiotics was reasonable and antibiotics were often prescribed to treat cellulitis and respiratory tract infections. Prevention and treatment of neurological conditions such as convulsions, loss of consciousness, and coma was used in approximately 5% of patients.; The prescription of concomitant treatments was coherent with the clinical and safety profile of the patients. However, some prescription habits would need to be adapted in the future to the evolving available pharmacopoeia. A list of minimal essential medication that should be available at no cost to patients in treatment wards is proposed to help the different actors to plan, manage, and adequately fund drug supplies for advanced HAT infected patients.; The initial study was registered at ClinicalTrials.gov, number NCT00906880

Trade-offs between biodiversity and agriculture are moving targets in dynamic landscapes

1. Understanding how biodiversity responds to intensifying agriculture is critical to mitigating the trade-offs between them. These trade-offs are particularly strong in tropical and subtropical deforestation frontiers, yet it remains unclear how changing landscape context in such frontiers alters agriculture?biodiversity trade?offs.2. We focus on the Argentinean Chaco, a global deforestation hotspot, to explore how landscape context shapes trade-off curves between agricultural intensity and avian biodiversity. We use a space-for-time approach and integrate a large field dataset of bird communities (197 species, 234 survey plots), three agricultural intensity metrics (meat yield, energy yield and profit) and a range of environmental covariates in a hierarchical Bayesian occupancy framework.3. Woodland extent in the landscape consistently determines how individual bird species, and the bird community as a whole, respond to agricultural intensity.Many species switch in their fundamental response, from decreasing occupancy with increased agricultural intensity when woodland extent in the landscape is low (loser species), to increasing occupancy with increased agricultural intensity when woodland extent is high (winner species).4. This suggests that landscape context strongly mediates who wins and loses along agricultural intensity gradients. Likewise, where landscapes change, such as in deforestation frontiers, the very nature of the agriculture?biodiversity trade?offs can change as landscapes transformation progresses.5. Synthesis and applications. Schemes to mitigate agriculture?biodiversity trade?offs,such as land sparing or sharing, must consider landscape context. Strategies that are identified based on a snapshot of data risk failure in dynamic landscapes, particularly where agricultural expansion continues to reduce natural habitats. Rather than a single, fixed strategy, adaptive management of agriculture?biodiversity trade?offs is needed in such situations. Here we provide a toolset for considering changing landscape contexts when exploring such trade-offs. This can help to better align agriculture and biodiversity in tropical and subtropical deforestation frontiers.Fil: Macchi, Leandro. Universidad Nacional de Tucumán. Instituto de Ecología Regional. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Instituto de Ecología Regional; ArgentinaFil: Decarre, Julieta. Instituto Nacional de Tecnología Agropecuaria. Centro de Investigación de Recursos Naturales. Instituto de Recursos Biológicos; ArgentinaFil: Goijman, Andrea Paula. Instituto Nacional de Tecnología Agropecuaria. Centro de Investigación de Recursos Naturales. Instituto de Recursos Biológicos; ArgentinaFil: Mastrangelo, Matias Enrique. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Mar del Plata. Facultad de Ciencias Agrarias. Laboratorio de Agroecología; ArgentinaFil: Blendinger, Pedro Gerardo. Universidad Nacional de Tucumán. Instituto de Ecología Regional. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Instituto de Ecología Regional; ArgentinaFil: Gavier Pizarro, Gregorio. Instituto Nacional de Tecnología Agropecuaria. Centro de Investigación de Recursos Naturales. Instituto de Recursos Biológicos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Murray, Francisco. Instituto Nacional de Tecnología Agropecuaria. Centro Regional La Pampa-San Luis. Estación Experimental Agropecuaria San Luis. Agencia de Extensión Rural San Luis; ArgentinaFil: Piquer Rodríguez, María. Universidad Nacional de Tucumán. Instituto de Ecología Regional. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Instituto de Ecología Regional; ArgentinaFil: Semper Pascual, Asunción. Humboldt-universitat Zu Berlin. Geography Department.; AlemaniaFil: Kuemmerle, Tobias. Humboldt-universitat Zu Berlin. Geography Department.; Alemani

In-hospital safety in field conditions of Nifurtimox Eflornithine Combination Therapy (NECT) for T. B. Gambiense Sleeping Sickness

Trypanosoma brucei (T.b.) gambiense Human African trypanosomiasis (HAT; sleeping sickness) is a fatal disease. Until 2009, available treatments for 2(nd) stage HAT were complicated to use, expensive (eflornithine monotherapy), or toxic, and insufficiently effective in certain areas (melarsoprol). Recently, nifurtimox-eflornithine combination therapy (NECT) demonstrated good safety and efficacy in a randomised controlled trial (RCT) and was added to the World Health Organisation (WHO) essential medicines list (EML). Documentation of its safety profile in field conditions will support its wider use

Increasing synergistic effects of habitat destruction and hunting on mammals over three decades in the Gran Chaco

Habitat destruction and overexploitation are the main threats to biodiversity and where they co-occur, their combined impact is often larger than their individual one. Yet, detailed knowledge of the spatial footprints of these threats is lacking, including where they overlap and how they change over time. These knowledge gaps are real barriers for effective conservation planning. Here, we develop a novel approach to reconstruct the individual and combined footprints of both threats over time. We combine satellite-based land-cover change maps, habitat suitability models and hunting pressure models to demonstrate our approach for the community of larger mammals (48 species > 1 kg) across the 1.1 million km2 Gran Chaco region, a global deforestation hotspot covering parts of Argentina, Bolivia and Paraguay. This provides three key insights. First, we find that the footprints of habitat destruction and hunting pressure expanded considerably between 1985 and 2015, across ~40% of the entire Chaco – twice the area affected by deforestation. Second, both threats increasingly acted together within the ranges of larger mammals in the Chaco (17% increase on average, ± 20% SD, cumulative increase of co-occurring threats across 465 000 km2), suggesting large synergistic effects. Conversely, core areas of high-quality habitats declined on average by 38%. Third, we identified remaining priority areas for conservation in the northern and central Chaco, many of which are outside the protected area network. We also identify hotspots of high threat impacts in central Paraguay and northern Argentina, providing a spatial template for threat-specific conservation action. Overall, our findings suggest increasing synergistic effects between habitat destruction and hunting pressure in the Chaco, a situation likely common in many tropical deforestation frontiers. Our work highlights how threats can be traced in space and time to understand their individual and combined impact, even in situations where data are sparse.Fil: Romero-Muñoz, Alfredo. Humboldt-Universität zu Berlin; AlemaniaFil: Benítez-López, Ana. Consejo Superior de Investigaciones Científicas. Estación Biológica de Doñana; EspañaFil: Zurell, Damaris. Humboldt-Universität zu Berlin; AlemaniaFil: Baumann, Matthias. Humboldt-Universität zu Berlin; AlemaniaFil: Camino, Micaela. Proyecto Quimilero; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Nordeste. Centro de Ecología Aplicada del Litoral. Universidad Nacional del Nordeste. Centro de Ecología Aplicada del Litoral; ArgentinaFil: Decarre, Julieta. Instituto Nacional de Tecnología Agropecuaria. Centro de Investigación de Recursos Naturales. Instituto de Recursos Biológicos; ArgentinaFil: Castillo, Hugo del. Guyra Paraguay; ParaguayFil: Giordano, Anthony J.. University of California; Estados UnidosFil: Gómez-Valencia, Bibiana. Instituto de Investigación de Recursos Biológicos Alexander Von Humboldt, Bogota; Colombia. Universidad de Buenos Aires; ArgentinaFil: Levers, Christian. Humboldt-Universität zu Berlin; AlemaniaFil: Noss, Andrew J.. University of Florida; Estados UnidosFil: Quiroga, Verónica Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Diversidad y Ecología Animal. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas Físicas y Naturales. Instituto de Diversidad y Ecología Animal; ArgentinaFil: Thompson, Jeffrey J.. Guyra Paraguay; ParaguayFil: Torres, Ricardo Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Diversidad y Ecología Animal. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas Físicas y Naturales. Instituto de Diversidad y Ecología Animal; ArgentinaFil: Velilla, Marianela. Guyra Paraguay; ParaguayFil: Weiler, Andrea. Universidad Nacional de Asunción; ParaguayFil: Kuemmerle, Tobias. Humboldt-Universität zu Berlin; Alemani

Development of a pharmacovigilance system in a resource-limited country : the experience of the Democratic Republic of Congo

Implementation of pharmacovigilance (PV) systems in resource-limited countries is a real endeavor. Despite country- and continent-specific challenges, the Democratic Republic of the Congo (DRC) has been able to develop one of the most active PV systems in the sub-Saharan Africa. The World Health Organization (WHO) regional Office identified the DRC experience to set up a PV system for antimalarial drugs safety monitoring as a 'best practice' that needed to be documented in order to help DRC improve its PV system and to be scaled up in other African countries. In response to the WHO request, a best practices and bottlenecks analysis was conducted in 2015. This analysis was updated in 2018 in the light of the minimum requirements of the WHO to set up a PV system taking into account other guidance for PV systems. The following themes were retained for analysis: (1) creation of the national PV center; (2) implementation of PV in the health system; (3) data collection and analysis; (4) collaboration with public health programs; (5) collaboration with the National Regulatory Authority. Lessons learnt from the DRC experience show that it is possible to implement PV systems in order to promote patients' safety in resource limited sub-Saharan African countries with no guaranteed funding. The ability of national PV centers to collaborate with Public health stakeholders, including public health authorities at all levels as well as public health programs, and to use existing health information systems are considered the main key to success and may substantially reduce the cost of PV activities

Rewilding complex ecosystems

BACKGROUND: Rapid global change is creating fundamental challenges for the persistence of natural ecosystems and their biodiversity. Conservation efforts aimed at the protection of landscapes have had mixed success, and there is an increasing awareness that the long-term protection of biodiversity requires inclusion of flexible restoration along with protection. Rewilding is one such approach that has been both promoted and criticized in recent years. Proponents emphasize the potential of rewilding to tap opportunities for restoration while creating benefits for both ecosystems and societies. Critics discuss the lack of a consistent definition of rewilding and insufficient knowledge about its potential outcomes. Other criticisms arise from the mistaken notion that rewilding actions are planned without considering societal acceptability and benefits. Here, we present a framework for rewilding actions that can serve as a guideline for researchers and managers. The framework is applicable to a variety of rewilding approaches, ranging from passive to trophic rewilding, and aims to promote beneficial interactions between society and nature. ADVANCES: The concept of rewilding has evolved from its initial emphasis on protecting large, connected areas for large carnivore conservation to a process-oriented, dynamic approach. On the basis of concepts from resilience and complexity theory of social-ecological systems, we identify trophic complexity, stochastic disturbances, and dispersal as three critical components of natural ecosystem dynamics. We propose that the restoration of these processes, and their interactions, can lead to increased self-sustainability of ecosystems and should be at the core of rewilding actions. Building on these concepts, we develop a framework to design and evaluate rewilding plans. Alongside ecological restoration goals, our framework emphasizes people’s perceptions and experiences of wildness and the regulating and material contributions from restoring nature. These societal aspects are important outcomes and may be critical factors for the success of rewilding initiatives (see the figure). We further identify current societal constraints on rewilding and suggest actions to mitigate them. OUTLOOK: The concept of rewilding challenges us to rethink the way we manage nature and to broaden our vision about how nature will respond to changes that society brings, both intentionally and unintentionally. The effects of rewilding actions will be specific to each ecosystem, and thus a deep understanding of the processes that shape ecosystems is critical to anticipate these effects and to take appropriate management actions. In addition, the decision of whether a rewilding approach is desirable should consider stakeholders’ needs and expectations. To this end, structured restoration planning—based on participatory processes involving researchers, managers, and stakeholders—that includes monitoring and adaptive management can be used. With the recent designation of 2021–2030 as the “decade of ecosystem restoration” by the United Nations General Assembly, policy- and decision-makers could push rewilding topics to the forefront of discussions about how to reach post-2020 biodiversity goals

Concurrent Oral 1 - Therapy of rheumatic disease: OP4. Effectiveness of Rituximab in Rheumatoid Arthritis: Results from the British Society for Rheumatology Biologics Register (BSRBR)

Background: Rituximab (RTX) in combination with methotrexate (MTX) has been licensed since 2006 for the management of severe active rheumatoid arthritis (RA) in patients who have failed at least one anti-tumour necrosis factor (anti-TNF) therapy. Published clinical trials have demonstrated the efficacy of RTX in improving both clinical symptoms and patients' physical function. This study aimed to assess the effectiveness of RTX in RA patients treated in routine clinical practice by examining clinical and patient reported outcomes six months after receiving a first course of RTX. Methods: The analysis involved 550 RA patients registered with the BSRBR, who were starting RTX and were followed up for at least 6 months. Change in Disease Activity Score (DAS28) and European League Against Rheumatism (EULAR) response were used to assess the clinical response while change in Health Assessment Questionnaire (HAQ) score was used to assess the physical function of the patients 6 months after starting RTX. The change in DAS28 and HAQ was compared between seronegative and seropositive patients and anti-TNF naïve patients versus anti-TNF failures. The response was also compared between patients receiving RTX in combination with MTX, other non-biologic disease modifying anti-rheumatic drugs (nbDMARDs) or no nbDMARDs. Results: The mean (s.d.) age of the cohort was 59 (12) years and 78% of the patients were females. The patients had a mean (s.d.) of 15 (10) years of disease duration. 16% were biologic naïve while 84% were anti-TNF failures. 32% of the patients were seronegative and 68% were seropositive. The mean (95% CI) DAS28 at baseline was 6.2 (6.1, 6.3) which decreased to 4.8 (4.7, 4.9) at 6 months of follow up. 16% were EULAR good responders, 43% were moderate responders and 41% were non responders. The mean (95% CI) change in HAQ was −0.1 (−0.2, −0.1) (Table 1). The mean change in DAS28 was similar in seropositive and seronegative patients (p = 0.18) while the anti-TNF naïve patients showed a greater reduction in DAS28 scores than anti-TNF failures (p = 0.05). Patients receiving RTX in combination with MTX showed similar changes in DAS28 and HAQ compared to patients receiving RTX alone or with other nbDMARDs. Conclusions: RTX has proven to be effective in the routine clinical practice. Anti-TNF naïve patients seem to benefit more from RTX treatment than anti-TNF failures. Disclosure statement: The authors have declared no conflicts of interes

Expatriates managers' cultural intelligence as promoter of knowledge transfer in multinational companies

This study analyzes the role of the Cultural Intelligence (CQ) of expatriate managers in the processes of Conventional (CKT) and Reverse Knowledge Transfer (RKT) in Multinational Companies (MNCs). The Partial Least Squares-Structural Equation Modeling (PLS-SEM) technique was adopted to analyze the data from a survey of 103 senior expatriate managers working in Croatia. The study reveals how CQ, in all of its four dimensions (metacognitive, cognitive, behavioral, and motivational), acts as a knowledge de-codification and codification filter, assisting managers in the Knowledge Transfer process. The study also reveals how previous international experience does not moderate the positive effect of CQ on both CKT and RKT, offering important theoretical and practical insights to support MNCs in the KT process