307 resultados para Warrantti, Warrants


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An exploratory phase II biomarker-embedded trial (LPT109747; NCT00526669) designed to determine the association of lapatinib-induced fluoropyrimidine gene changes with efficacy of lapatinib plus capecitabine as first-line treatment for advanced gastric cancer or gastroesophageal junction adenocarcinoma independent of tumor HER2 status. Tumor biopsies obtained before and after 7-day lapatinib (1,250 mg) to analyze changes in gene expression, followed by a 14-day course of capecitabine (1,000 mg/m(2) twice daily, 14/21 days) plus lapatinib 1,250 mg daily. Blood samples were acquired for pharmacokinetic analysis. Primary clinical objectives were response rate (RR) and 5-month progression-free survival (PFS). Secondary objectives were overall survival (OS), PFS, time to response, duration of response, toxicity, and identification of associations between lapatinib pharmacokinetics and biomarker endpoints. Primary biomarker objectives were modulation of 5-FU-pathway genes by lapatinib, effects of germline SNPs on treatment outcome, and trough steady-state plasma lapatinib concentrations. Sixty-eight patients were enrolled; (75% gastric cancer, 25% gastroesophageal junction). Twelve patients (17.9%) had confirmed partial response, 31 (46.3%) had stable disease, and 16 (23.9%) had progressive disease. Median PFS and OS were 3.3 and 6.3 months, respectively. Frequent adverse events included diarrhea (45%), decreased appetite (39%), nausea (36%), and fatigue (36%). Lapatinib induced no changes in gene expression from baseline and no significant associations were found for SNPs analyzed. Elevated baseline HER3 mRNA expression was associated with a higher RR (33% vs. 0%; P = 0.008). Lapatinib plus capecitabine was well tolerated, demonstrating modest antitumor activity in patients with advanced gastric cancer. The association of elevated HER3 and RR warrants further investigation as an important player for HER-targeted regimens in combination with capecitabine

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BACKGROUND AND AIMS: Although it has become clear that aneurysmal and occlusive arterial disease represent two distinct etiologic entities, it is still unknown whether the two vascular pathologies are prognostically different. We aim to assess the long-term vital prognosis of patients with abdominal aortic aneurysmal disease (AAA) or peripheral artery disease (PAD), focusing on possible differences in survival, prognostic risk profiles and causes of death. METHODS: Patients undergoing elective surgery for isolated AAA or PAD between 2003 and 2011 were retrospectively included. Differences in postoperative survival were determined using Kaplan-Meier and Cox regression analysis. Prognostic risk profiles were also established with Cox regression analysis. RESULTS: 429 and 338 patients were included in the AAA and PAD groups, respectively. AAA patients were older (71.7 vs. 63.3 years, p < 0.001), yet overall survival following surgery did not differ (HR: 1.16, 95% CI: 0.87-1.54). Neither was type of vascular disease associated with postoperative cardiovascular nor cancer-related death. However, in comparison with age- and gender-matched general populations, cardiovascular mortality was higher in PAD than AAA patients (48.3% vs. 17.3%). Survival of AAA and PAD patients was negatively affected by age, history of cancer and renal insufficiency. Additional determinants in the PAD group were diabetes and ischemic heart disease. CONCLUSIONS: Long-term survival after surgery for PAD and AAA is similar. However, overall life expectancy is significantly worse among PAD patients. The contribution of cardiovascular disease towards mortality in PAD patients warrants more aggressive secondary prevention to reduce cardiovascular mortality and improve longevity.

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Management of riverine and coastal ecosystems warrants enhanced understanding of how different stakeholders perceive and depend upon different kinds of ecosystem services. Employing a mixed methods approach, this study compares and contrasts the use and perceptions of upstream residents, downstream residents, tourism officials, and conservation organizations regarding the value of 30 ecosystem services provided by the Wami River and its estuary in Tanzania, and investigates their perceptions of the main threats to this system. Our findings reveal that all of the stakeholder groups place a high value on the provision of domestic water, habitat for wild plants and animals, tourism, and erosion control, and a relatively low value on the prevention of saltwater intrusion, refuge from predators, spiritual fulfillment, nonrecreational hunting, and the provision of traditional medications and inorganic materials for construction. Differences emerge, however, between the groups in the value assigned to the conservation of riverine and estuarine fauna and the provision of raw materials for building and handicrafts. Declining fish populations and an increasing human population are identified by the residents and conservation employees, respectively, as their prime concerns regarding the future conditions of the Wami River and its estuary. These groups also acknowledge increasing salinity levels and the loss of mangroves as other key concerns. The identification of these mutual interests and shared concerns can help build common ground among stakeholders while the recognition of potential tensions can assist managers in balancing and reconciling the multiple needs and values of these different groups.

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We evaluate whether society can adequately be conceptualized as a component of social-ecological systems, given social theory and the current outputs of systems-based research. A mounting critique from the social sciences posits that resilience theory has undertheorized social entities with the concept of social-ecological systems. We trace the way that use of the term has evolved, relating to social science theory. Scientometic and network analysis provide a wide range of empirical data about the origin, growth, and use of this term in academic literature. A content analysis of papers in Ecology and Society demonstrates a marked emphasis in research on institutions, economic incentives, land use, population, social networks, and social learning. These findings are supported by a review of systems science in 18 coastal assessments. This reveals that a systems-based conceptualization tends to limit the kinds of social science research favoring quantitative couplings of social and ecological components and downplaying interpretive traditions of social research. However, the concept of social-ecological systems remains relevant because of the central insights concerning the dynamic coupling between humans and the environment, and its salient critique about the need for multidisciplinary approaches to solve real world problems, drawing on heuristic devices. The findings of this study should lead to more circumspection about whether a systems approach warrants such claims to comprehensiveness. Further methodological advances are required for interdisciplinarity. Yet there is evidence that systems approaches remain highly productive and useful for considering certain social components such as land use and hybrid ecological networks. We clarify advantages and restrictions of utilizing such a concept, and propose a reformulation that supports engagement with wider traditions of research in the social sciences.

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A rapidly changing business environment has necessitated most small and medium sized enterprises with international ambitions to reconsider their sources of competitive advantage. To survive in the face of a changing business environment, firms should utilize their dynamic organizational capabilities as well as their internationalization capabilities. Firms develop a competitive advantage if they can exploit their unique organizational competences in a new or foreign market and also if they can acquire new capabilities as a result of engaging in foreign markets. The acquired capabilities from foreign locations enhance the existing capability portfolio of a firm with a desire to internationalize. The study combined the research streams of SME organizational dynamic capability and internationalization capability to build a complete picture on the existing knowledge. An intensive case study was used for empirically testing the theoretical framework of the study and compared with the literature on various organizational capability factors and internationalization capabilities. Sormay Oy was selected because it is a successful medium sized company operating in Finland in the manufacturing industry which has a high international profile. In addition, it has sufficient rate of growth in sales that warrants it to engage internationally in matters such as, acquisitions, joint ventures and partnerships. The key findings of the study suggests that, medium sized manufacturing firms have a set of core competences arising from their organizational capabilities which were identified to be employee know how and relationship with stakeholders which aid the firm in its quest for attaining competitive advantage, ensuring production flexibility and gaining benefits present in a network. In addition, internationalization capabilities were identified under both the RAT test and CAT test whereby the primary findings suggests that, firms that outperform their competitors produce products that meet specific customer and country requirements, foresee the pitfalls of imitation brought about by the foreign local companies and members of a particular network through joint ventures, acquisitions or partnerships as well as those firms that are capable to acquire new capabilities in the foreign markets and successfully use these acquired capabilities to enhance or renew their capability portfolio for their competitive advantage. Additional significant findings under internationalization capabilities were discovered whereby, Sormay Oy was able to develop a new market space for its products despite the difficult institutional environment present in Russia.

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Defining needs is difficult due to the inherent complexity of the concept of 'need', so it is not surprising that numerous definitions have been proposed. 'Health' consists of a wide range of characteristics so 'health needs' ought to include personal and social care, health care, accommodation, finance, education, employment and leisure, transport and access.Target-driven standards in areas of health care with a high political profile appear to be replacing the concept of universal provision and clinical need; this major change in clinical care warrants a re-evaluation of health care outcomes. Identifying who might benefit from this new approach to health care is equally important if scarce resources are to be fully and appropriately utilised. If the goal of care is 'optimal health', the key marker of success ought to be to ascertain individual patients' health care needs (HCN) and tailor services accordingly. Wide variation in the description of 'needs' directly affects policies and services intended to meet a population's health care needs. Consequently, the definition of 'needs' has important implications for healthcare provision- the more constrained the definition, the less healthcare will be made available and vice versa. This paper describes some common definitions of needs and discusses their respective benefits and disadvantages in terms of health care provision and their potential impact on health policy

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Este artigo tem como objetivo situar interlocuções disciplinares na busca de caminhos para a delimitação de uma área específica da pesquisa em Educação no Brasil, a qual se denomina de Pedagogia da Infância ou da Educação Infantil (Rocha, 1999). Inicialmente e de forma sintética,são recuperados elementos conceituais presentes em publicações e pesquisas para, em seguida, apresentar uma revisão do percurso e das construções teóricas já realizadas, as quais afirmam a necessidade de consolidação de um diálogo disciplinar para o estudo da educação infantil, sobretudo a partir dos estudos sociais da infância. Posteriormente, o artigo apresenta alguns exercícios de possibilidades dessas interlocuções, em particular, tomando o estudo de Buss-Simão (2012) acerca das relações sociais no âmbito do contexto educativo para a pequena infância. Por fim, concluímos com a indicação de perspectivas e demandas de aprofundamentos relativas aos processos de socialização e à constituição da experiência das crianças na educação infantil.

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Antonio Salieri’s La calamita de’ cuori (1774) warrants musicological attention for what it can tell us about Salieri’s compositional craft and what it reveals about the development of form in Viennese Italian-language comic opera of the mid- and late-eighteenth century. In Part I of this dissertation, I explore the performance history of La calamita, present the first plot synopsis and English translation of the libretto, and describe the variants between Carlo Goldoni’s 1752 libretto and the revised version created for Salieri’s opera. I have collated Salieri’s holograph score, Österreichische Nationalbibliothek, Vienna, Mus. Hs. 16.508, with four copies having different relationships to it, and I propose a stemma that represents the relationships between these five sources. The analyses in Part II contribute to our understanding of formal practices in eighteenth-century drammi giocosi. My study of Salieri’s La calamita reveals his reliance on a clearly defined binary structure, referred to in this dissertation as “operatic binary form,” in almost half of the arias, ensembles, and instrumental movements of this opera. Salieri’s consistent use of operatic binary form led me to explore its use in drammi giocosi by other prominent composers of this time, including Baldassare Galuppi’s La calamita de’ cuori (1752), Wolfgang Amadeus Mozart’s Il dissoluto punito, ossia Il Don Giovanni (1787), and selected arias by Pasquale Anfossi, Florian Leopold Gassmann, Giuseppe Gazzaniga, Franz Joseph Haydn, Giovanni Paisiello, and Niccolò Piccinni dating from 1760 to 1774. This study showed that Salieri and his peers adhered to a recognizable tonal plan and set of design elements in their operatic binary forms, and that their arias fall into three distinct categories defined by the tonality at the beginning of the second half of the binary structure. The analysis presented here adds to our present understanding of operatic form in mid- and late-century drammi giocosi and shows that in La calamita de’ cuori, Salieri was following the normative formal procedures of his time.

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This dissertation project aims to establish Scandinavian trombone solo and chamber works as a major contribution to the trombone repertoire. From the late 19th century to modern day, Scandinavian composers have produced a steady output of trombone works of substantial musical quality. Deep-rooted in the traditions of strong military wind bands, Scandinavia has also produced an unusual number of trombone virtuosos, ranging from those holding positions in leading orchestras, and internationally renowned pedagogues, to trombonists enjoying careers as soloists. In this study I propose that it is the symbiotic relationship between strong performers and traditionally nationalist composers that created the fertile environment for the large number of popular trombone solo and chamber repertoire not seen in any other region besides the Paris Conservatory and its infamous test pieces. I also interpret the selected repertoire through the prism of nationalism and influence of folk music, and convey that the allure of the mystic Nordic folk influences enhances the appeal of the Scandinavian trombone repertoire to world-wide audiences and performers. The dissertation project was realized over three solo recitals, each showcasing the music of Sweden, Norway, and Denmark respectively. For each program, I looked to choose a standard work from the trombone solo repertoire, a work written for or by a native virtuoso, and a lesser-known work that warrants the attention of other performers for its musical qualities. The recital of Swedish music presented Mandrake in the Corner by Christian Lindberg, Subadobe by Frederik Högberg, A Christian Song by Jan Sandström, and Concertino for trombone and strings by Lars-Erik Larsson. The recital of Norwegian music presented Concerto for Trombone op. 76 by Egil Hovland, Ordner Seg by Øystein Baadsvik, Elegi by Magne Amdahl, and Concerto in F major by Ole Olsen. The recital of Danish music presented Rapsodia Borealis by Søren Hyldgaard, Madrigal by Bo Gunge, Romance for trombone and piano by Axel Jørgensen, Concerto for trombone by Launy Grøndahl, and Three Swedish Tunes by Mogens Andresen. Through the performance of works from these three countries, the dissertation establishes Scandinavia as a rich source of solo trombone repertoire perpetuated by nationalist composers and virtuosos, as well as providing a brief survey of Scandinavian trombone works of various instrumentation and difficulty levels to be enjoyed by student, professional, and amateur performers and their audience.

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Glioblastoma (GBM) is a highly aggressive and fatal brain cancer that is associated with a number of diagnostic, therapeutic, and treatment monitoring challenges. At the time of writing, inhibition of a protein called poly (ADP-ribose) polymerase-1 (PARP-1) in combination with chemotherapy was being investigated as a novel approach for the treatment of these tumours. However, human studies have encountered toxicity problems due to sub-optimal PARP-1 inhibitor and chemotherapeutic dosing regiments. Nuclear imaging of PARP-1 could help to address these issues and provide additional insight into potential PARP-1 inhibitor resistance mechanisms. Furthermore, nuclear imaging of the translocator protein (TSPO) could be used to improve GBM diagnosis, pre-surgical planning, and treatment monitoring as TSPO is overexpressed by GBM lesions in good contrast to surrounding brain tissue. To date, relatively few nuclear imaging radiotracers have been discovered for PARP-1. On the other hand, numerous tracers exist for TSPO many of which have been investigated in humans. However, these TSPO radiotracers suffer from either poor pharmacokinetic properties or high sensitivity to human TSPO polymorphism that can affect their binding to TSPO. Bearing in mind the above and the high attrition rates associated with advancement of radiotracers to the clinic, there is a need for novel radiotracers that can be used to image PARP-1 and TSPO. This thesis reports the pre-clinical discovery programme that led to the identification of two potent PARP-1 inhibitors, 4 and 17, that were successfully radiolabelled to generate the potential SPECT and PET imaging agents [123I]-4 and [18F]-17 respectively. Evaluation of these radiotracers in mice bearing subcutaneous human GBM xenografts using ex vivo biodistribution techniques revealed that the agents were retained in tumour tissue due to specific PARP-1 binding. This thesis also describes the pre-clinical in vivo evaluation of [18F]-AB5186, which is a novel radiotracer discovered previously within the research group with potential for PET imaging of TSPO. Using ex vivo autoradiography and PET imaging the agent was revealed to accumulate in intracranial human GBM tumour xenografts in good contrast to surrounding brain tissue, which was due to specific binding to TSPO. The in vivo data for all three radiolabelled compounds warrants further pre-clinical investigations with potential for clinical advancement in mind.

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La circulation extracorporelle (CEC) est une technique utilisée en chirurgie cardiaque effectuée des milliers de fois chaque jour à travers le monde. L’instabilité hémodynamique associée au sevrage de la CEC difficile constitue la principale cause de mortalité en chirurgie cardiaque et l’hypertension pulmonaire (HP) a été identifiée comme un des facteurs de risque les plus importants. Récemment, une hypothèse a été émise suggérant que l'administration prophylactique (avant la CEC) de la milrinone par inhalation puisse avoir un effet préventif et faciliter le sevrage de la CEC chez les patients atteints d’HP. Toutefois, cette indication et voie d'administration pour la milrinone n'ont pas encore été approuvées par les organismes réglementaires. Jusqu'à présent, la recherche clinique sur la milrinone inhalée s’est principalement concentrée sur l’efficacité hémodynamique et l'innocuité chez les patients cardiaques, bien qu’aucun biomarqueur n’ait encore été établi. La dose la plus appropriée pour l’administration par nébulisation n'a pas été déterminée, de même que la caractérisation des profils pharmacocinétiques (PK) et pharmacodynamiques (PD) suite à l'inhalation. L'objectif de notre recherche consistait à caractériser la relation exposition-réponse de la milrinone inhalée administrée chez les patients subissant une chirurgie cardiaque sous CEC. Une méthode analytique par chromatographie liquide à haute performance couplée à un détecteur ultraviolet (HPLC-UV) a été optimisée et validée pour le dosage de la milrinone plasmatique suite à l’inhalation et s’est avérée sensible et précise. La limite de quantification (LLOQ) était de 1.25 ng/ml avec des valeurs de précision intra- et inter-dosage moyennes (CV%) <8%. Des patients souffrant d’HP pour lesquels une chirurgie cardiaque sous CEC était prévue ont d’abord été recrutés pour une étude pilote (n=12) et, par la suite, pour une étude à plus grande échelle (n=28) où la milrinone (5 mg) était administrée par inhalation pré-CEC. Dans l'étude pilote, nous avons comparé l'exposition systémique de la milrinone peu après son administration avec un nébuliseur pneumatique ou un nébuliseur à tamis vibrant. L’efficacité des nébuliseurs en termes de dose émise et dose inhalée a également été déterminée in vitro. Dans l'étude à plus grande échelle conduite en utilisant exclusivement le nébuliseur à tamis vibrant, la dose inhalée in vivo a été estimée et le profil pharmacocinétique de la milrinone inhalée a été pleinement caractérisé aux niveaux plasmatique et urinaire. Le ratio de la pression artérielle moyenne sur la pression artérielle pulmonaire moyenne (PAm/PAPm) a été choisi comme biomarqueur PD. La relation exposition-réponse de la milrinone a été caractérisée pendant la période d'inhalation en étudiant la relation entre l'aire sous la courbe de l’effet (ASCE) et l’aire sous la courbe des concentrations plasmatiques (ASC) de chacun des patients. Enfin, le ratio PAm/PAPm a été exploré comme un prédicteur potentiel de sortie de CEC difficile dans un modèle de régression logistique. Les expériences in vitro ont démontré que les doses émises étaient similaires pour les nébuliseurs pneumatique (64%) et à tamis vibrant (68%). Cependant, la dose inhalée était 2-3 fois supérieure (46% vs 17%) avec le nébuliseur à tamis vibrant, et ce, en accord avec les concentrations plasmatiques. Chez les patients, en raison des variations au niveau des facteurs liés au circuit et au ventilateur causant une plus grande dose expirée, la dose inhalée a été estimée inférieure (30%) et cela a été confirmé après récupération de la dose de milrinone dans l'urine 24 h (26%). Les concentrations plasmatiques maximales (Cmax: 41-189 ng/ml) et l'ampleur de la réponse maximale ΔRmax-R0 (0-65%) ont été observées à la fin de l'inhalation (10-30 min). Les données obtenues suite aux analyses PK sont en accord avec les données publiées pour la milrinone intraveineuse. Après la période d'inhalation, les ASCE individuelles étaient directement reliées aux ASC (P=0.045). Enfin, notre biomarqueur PD ainsi que la durée de CEC ont été identifiés comme des prédicteurs significatifs de la sortie de CEC difficile. La comparaison des ASC et ASCE correspondantes a fourni des données préliminaires supportant une preuve de concept pour l'utilisation du ratio PAm/PAPm comme biomarqueur PD prometteur et justifie de futures études PK/PD. Nous avons pu démontrer que la variation du ratio PAm/PAPm en réponse à la milrinone inhalée contribue à la prévention de la sortie de CEC difficile.

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Background: Benefits of mobile phone deployment for children <5 in low-resource settings remain unproven. The target population of the current demonstration study in Bushenyi District, Uganda, presented with acute fever, pneumonia, or diarrhoea and were treated by community health workers (CHWs) providing integrated community case management (iCCM). Methods: An observational study was conducted in five parishes (47 villages) served by CHWs well versed in iCCM with supplemental training in mobile phone use. Impact was assessed by quantitative measures and qualitative evaluation through household surveys, focus group discussions, and key informant interviews. Results: CHWs in targeted sites improved child healthcare through mobile phone use coupled with iCCM. Of acutely ill children, 92.6% were correctly managed. Significant improvements in clinical outcomes compared to those obtained by CHWs with enhanced iCCM training alone were unproven in this limited demonstration. Nonetheless, qualitative evaluation showed gains in treatment planning, supply management, and logistical efficiency. Provider confidence and communications were enhanced as was ease and accuracy of record keeping. Conclusion: Mobile phones appear synergistic with iCCM to bolster basic supportive care for acutely ill children provided by CHWs. The full impact of expanded mobile phone deployment warrants further evaluation prior to scaling up in low-resource settings.

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No doubt shall be placed when qualifying torture as one of the cruellest crime offences against human beings. It is widely known that the first torture practices go back to the Middle Ages, where torture mechanisms and devices were used as a legitimate means of punishment, extraction of confessions or executions. Brutal techniques such as ‘Judas Cradle’, ‘The Rack’ or the ‘Rat Torture’ were indeed, the ones commonly used. Moreover, some centuries onwards, torture warrants were permitted and authorised by Privy Councils in legislations such as the English one. However, examples like that were the only ones which public accountability was given to, whereas off-the-book practices remained in silence in other countries for long lasting years. Nowadays, in the 21st century, there are innumerable enforced laws and provisions that prohibit the act of torture, to be precise, physical and psychological torture. Nonetheless, not only are these legislations necessary for fighting torture, but also ad hoc courts and specialised committees continuously report the existence of this crime offence.

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Background and Aim: Maternal morbidity and mortality statistics remain unacceptably high in Malawi. Prominent among the risk factors in the country is anaemia in pregnancy, which generally results from nutritional inadequacy (particularly iron deficiency) and malaria, among other factors. This warrants concerted efforts to increase iron intake among reproductive-age women. This study, among women in Malawi, examined factors determining intake of supplemental iron for at least 90 days during pregnancy. Methods: A weighted sample of 10,750 women (46.7%), from the 23,020 respondents of the 2010 Malawi Demographic and Health Survey (MDHS), were utilized for the study. Univariate, bivariate, and regression techniques were employed. While univariate analysis revealed the percent distributions of all variables, bivariate analysis was used to examine the relationships between individual independent variables and adherence to iron supplementation. Chi-square tests of independence were conducted for categorical variables, with the significance level set at P < 0.05. Two binary logistic regression models were used to evaluate the net effect of independent variables on iron supplementation adherence. Results: Thirty-seven percent of the women adhered to the iron supplementation recommendations during pregnancy. Multivariate analysis indicated that younger age, urban residence, higher education, higher wealth status, and attending antenatal care during the first trimester were significantly associated with increased odds of taking iron supplementation for 90 days or more during pregnancy (P < 0.01). Conclusions: The results indicate low adherence to the World Health Organization’s iron supplementation recommendations among pregnant women in Malawi, and this contributes to negative health outcomes for both mothers and children. Focusing on education interventions that target populations with low rates of iron supplement intake, including campaigns to increase the number of women who attend antenatal care clinics in the first trimester, are recommended to increase adherence to iron supplementation recommendations.