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\"Nobility and Kingship in Medieval England is a major new account of the relationship between Edward I and his earls, and of the role of the English nobility in thirteenth-century governance. Re-evaluating crown-noble relations of the period, Spencer challenges traditional interpretations of Edward's reign, showing that his reputed masterfulness has been overplayed and that his kingship was far subtler, and therefore more effective, than this stereotype would suggest. Drawing from key earldoms such as Lincoln, Lancaster, Cornwall and Warenne, the book reveals how nobles created local followings and exercised power at a local level as well as surveying the political, governmental, social and military lives of the earls, prompting us to rethink our perception of their position in thirteenth-century politics. Adopting a powerful revisionist perspective, Spencer presents a major new statement about thirteenth-century England; one which will transform our understanding of politics and kingship in the period\"-- Provided by publisher.

Ciltacabtagene autoleucel (cilta-cel), a B-cell maturation antigen (BCMA)-directed CAR T-cell therapy, is effective in heavily pretreated patients with relapsed or refractory multiple myeloma. We investigated cilta-cel in earlier treatment lines in patients with lenalidomide-refractory disease. In this phase 3, randomized, open-label trial, we assigned patients with lenalidomide-refractory multiple myeloma to receive cilta-cel or the physician's choice of effective standard care. All the patients had received one to three previous lines of treatment. The primary outcome was progression-free survival. A total of 419 patients underwent randomization (208 to receive cilta-cel and 211 to receive standard care). At a median follow-up of 15.9 months (range, 0.1 to 27.3), the median progression-free survival was not reached in the cilta-cel group and was 11.8 months in the standard-care group (hazard ratio, 0.26; 95% confidence interval [CI], 0.18 to 0.38; P<0.001). Progression-free survival at 12 months was 75.9% (95% CI, 69.4 to 81.1) in the cilta-cel group and 48.6% (95% CI, 41.5 to 55.3) in the standard-care group. More patients in the cilta-cel group than in the standard-care group had an overall response (84.6% vs. 67.3%), a complete response or better (73.1% vs. 21.8%), and an absence of minimal residual disease (60.6% vs. 15.6%). Death from any cause was reported in 39 patients and 46 patients, respectively (hazard ratio, 0.78; 95% CI, 0.5 to 1.2). Most patients reported grade 3 or 4 adverse events during treatment. Among the 176 patients who received cilta-cel in the as-treated population, 134 (76.1%) had cytokine release syndrome (grade 3 or 4, 1.1%; no grade 5), 8 (4.5%) had immune effector cell-associated neurotoxicity syndrome (all grade 1 or 2), 1 had movement and neurocognitive symptoms (grade 1), 16 (9.1%) had cranial nerve palsy (grade 2, 8.0%; grade 3, 1.1%), and 5 (2.8%) had CAR-T-related peripheral neuropathy (grade 1 or 2, 2.3%; grade 3, 0.6%). A single cilta-cel infusion resulted in a lower risk of disease progression or death than standard care in lenalidomide-refractory patients with multiple myeloma who had received one to three previous therapies. (Funded by Janssen and Legend Biotech; CARTITUDE-4 ClinicalTrials.gov number, NCT04181827.).

At a New Orleans halfway house for girls, Nell Sweetzer attempts to recover from her trauma, but the demon that possessed her returns with an even more horrific plan.

The addition of subcutaneous daratumumab to bortezomib, lenalidomide, and dexamethasone therapy and to lenalidomide maintenance therapy had a significant benefit on progression-free survival among patients with multiple myeloma.

Treatment of multiple myeloma has substantially changed over the past decade with the introduction of several classes of new effective drugs that have greatly improved the rates and depth of response. Response criteria in multiple myeloma were developed to use serum and urine assessment of monoclonal proteins and bone marrow assessment (which is relatively insensitive). Given the high rates of complete response seen in patients with multiple myeloma with new treatment approaches, new response categories need to be defined that can identify responses that are deeper than those conventionally defined as complete response. Recent attempts have focused on the identification of residual tumour cells in the bone marrow using flow cytometry or gene sequencing. Furthermore, sensitive imaging techniques can be used to detect the presence of residual disease outside of the bone marrow. Combining these new methods, the International Myeloma Working Group has defined new response categories of minimal residual disease negativity, with or without imaging-based absence of extramedullary disease, to allow uniform reporting within and outside clinical trials. In this Review, we clarify several aspects of disease response assessment, along with endpoints for clinical trials, and highlight future directions for disease response assessments.

The addition of elotuzumab (a monoclonal antibody against SLAMF7) to lenalidomide plus dexamethasone produced a significant increase in progression-free survival as compared with lenalidomide plus dexamethasone alone. Multiple myeloma, a malignant disease of monoclonal plasma cells, has a median overall survival of approximately 5 years. 1 Despite improvements in treatment outcomes with proteasome inhibitors and immunomodulatory drugs, most patients continue to have a relapse, and new treatment approaches are needed. Combination therapy may be key to overcoming drug resistance and improving long-term treatment outcomes. Lenalidomide, an immunomodulatory drug, in combination with dexamethasone is a standard regimen in patients with relapsed or refractory disease. 2 , 3 Three-drug combinations are emerging for patients with previously treated multiple myeloma 3 but may be limited by toxic effects. Agents with new mechanisms of action . . .

Bortezomib with dexamethasone is a standard treatment option for relapsed or refractory multiple myeloma. Carfilzomib with dexamethasone has shown promising activity in patients in this disease setting. The aim of this study was to compare the combination of carfilzomib and dexamethasone with bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma. In this randomised, phase 3, open-label, multicentre study, patients with relapsed or refractory multiple myeloma who had one to three previous treatments were randomly assigned (1:1) using a blocked randomisation scheme (block size of four) to receive carfilzomib with dexamethasone (carfilzomib group) or bortezomib with dexamethasone (bortezomib group). Randomisation was stratified by previous proteasome inhibitor therapy, previous lines of treatment, International Staging System stage, and planned route of bortezomib administration if randomly assigned to bortezomib with dexamethasone. Patients received treatment until progression with carfilzomib (20 mg/m2 on days 1 and 2 of cycle 1; 56 mg/m2 thereafter; 30 min intravenous infusion) and dexamethasone (20 mg oral or intravenous infusion) or bortezomib (1·3 mg/m2; intravenous bolus or subcutaneous injection) and dexamethasone (20 mg oral or intravenous infusion). The primary endpoint was progression-free survival in the intention-to-treat population. All participants who received at least one dose of study drug were included in the safety analyses. The study is ongoing but not enrolling participants; results for the interim analysis of the primary endpoint are presented. The trial is registered at ClinicalTrials.gov, number NCT01568866. Between June 20, 2012, and June 30, 2014, 929 patients were randomly assigned (464 to the carfilzomib group; 465 to the bortezomib group). Median follow-up was 11·9 months (IQR 9·3–16·1) in the carfilzomib group and 11·1 months (8·2–14·3) in the bortezomib group. Median progression-free survival was 18·7 months (95% CI 15·6–not estimable) in the carfilzomib group versus 9·4 months (8·4–10·4) in the bortezomib group at a preplanned interim analysis (hazard ratio [HR] 0·53 [95% CI 0·44–0·65]; p<0·0001). On-study death due to adverse events occurred in 18 (4%) of 464 patients in the carfilzomib group and in 16 (3%) of 465 patients in the bortezomib group. Serious adverse events were reported in 224 (48%) of 463 patients in the carfilzomib group and in 162 (36%) of 456 patients in the bortezomib group. The most frequent grade 3 or higher adverse events were anaemia (67 [14%] of 463 patients in the carfilzomib group vs 45 [10%] of 456 patients in the bortezomib group), hypertension (41 [9%] vs 12 [3%]), thrombocytopenia (39 [8%] vs 43 [9%]), and pneumonia (32 [7%] vs 36 [8%]). For patients with relapsed or refractory multiple myeloma, carfilzomib with dexamethasone could be considered in cases in which bortezomib with dexamethasone is a potential treatment option. Onyx Pharmaceuticals, Inc., an Amgen subsidiary.

PurposeThis article focuses on critical areas that must be adjusted and adopted in the post-Covid era. It explores strategies that are needed for the post-Covid period in cruise tourism in the Caribbean with special reference to endemic gaps in the sustainable development of cruising in Jamaica which resulted in the pre-pandemic status quo. The article aims to recommend ways of creating a road map for greater sustainability for cruise tourism in the Caribbean, the most tourism-dependent region of the world.Design/methodology/approachThe main approach is via the frame of sustainable development pillars. The methodology involved interviews with tourism and cruise industry executives and content analysis of company documents of the Jamaica Tourist Board. Additional primary data were collected from a large cruise line serving the Caribbean market. This exercise was primarily to derive insights on their customer satisfaction data. Primary data were also collected on Covid testing by Baywest Medical in Montego Bay Jamaica.FindingsIt is clear from the data that the cruise industry in Jamaica has not maximized its potential. This is largely due to the posture of large private cruise lines, which have negotiated solely in favour of their bottom line. It was also found that Jamaica has suffered from its own slow approach to the diversification of its ports and surrounding communities. Additionally, another major finding revealed that the matter of visitors has been inadequately addressed; despite cruise line data indicating a need for safer, more seamless spaces. The major strength identified is the creation of “resilient corridors” in Jamaica, which have worked well in support of the return of stopover arrivals since 2021. In fact, reported Covid cases related to the corridor have a positivity rate of less than 1% while the national figure is 9.9% for the month of July 2021, according to the Ministry of Health and Wellness.Research limitations/implicationsThis article highlights gaps in the current construct of Caribbean cruising and plots a path to bridging those gaps. The major limitation is that it focuses on the case of Jamaica. Future research should consider other islands in the region and seek to gather data directly from guests when the industry reopens, as opposed to the current approach of guest comments through cruise line documents.Practical implicationsThe practical implications are that policy-makers will be able to apply the recommendations for creating a partnership of equals, greater port and product diversification, visitor safety improvement and optimizing the resilient corridors. This will have a significant economic impact arising from greater flows of guests and extended time spent on shore.Social implicationsThe absence of cruising has had a major impact on the socioeconomics of communities in closeness, proximity to cruising, as evidenced in craft markets and ground transportation. These groupings are considered to be particularly vulnerable.Originality/valueThis paper is the first to excavate the specific hurdles, which must be tackled in the post-Covid era in Jamaica. It is of particular value to local policy-makers, local businesses and cruise lines serving the Caribbean region.

High-dose melphalan plus autologous stem-cell transplantation (ASCT) is the standard approach in transplant-eligible patients with newly diagnosed myeloma. Our aims were to compare consolidation with high-dose melphalan plus ASCT versus chemotherapy (cyclophosphamide and dexamethasone) plus lenalidomide, and maintenance with lenalidomide plus prednisone versus lenalidomide alone. We did an open-label, randomised, multicentre, phase 3 study at 59 centres in Australia, Czech Republic, and Italy. We enrolled transplant-eligible patients with newly diagnosed myeloma aged 65 years or younger. Patients received a common induction with four 28-day cycles of lenalidomide (25 mg, days 1–21) and dexamethasone (40 mg, days 1, 8, 15, and 22) and subsequent chemotherapy with cyclophosphamide (3 g/m2) followed by granulocyte colony-stimulating factor for stem-cell mobilisation and collection. Using a 2 × 2 partial factorial design, we randomised patients to consolidation with either chemotherapy plus lenalidomide (six cycles of cyclophosphamide [300 mg/m2, days 1, 8, and 15], dexamethasone [40 mg, days 1, 8, 15, and 22], and lenalidomide [25 mg, days 1–21]) or two courses of high-dose melphalan (200 mg/m2) and ASCT. We also randomised patients to maintenance with lenalidomide (10 mg, days 1–21) plus prednisone (50 mg, every other day) or lenalidomide alone. A simple randomisation sequence was used to assign patients at enrolment into one of the four groups (1:1:1:1 ratio), but the treatment allocation was disclosed only when the patient reached the end of the induction and confirmed their eligibility for consolidation. Both the patient and the treating clinician did not know the consolidation and maintenance arm until that time. The primary endpoint was progression-free survival assessed by intention-to-treat. The trial is ongoing and some patients are still receiving maintenance. This study is registered at ClinicalTrials.gov, number NCT01091831. 389 patients were enrolled between July 6, 2009, and May 6, 2011, with 256 eligible for consolidation (127 high-dose melphalan and ASCT and 129 chemotherapy plus lenalidomide) and 223 eligible for maintenance (117 lenalidomide plus prednisone and 106 lenalidomide alone). Median follow-up was 52·0 months (IQR 30·4–57·6). Progression-free survival during consolidation was significantly shorter with chemotherapy plus lenalidomide compared with high-dose melphalan and ASCT (median 28·6 months [95% CI 20·6–36·7] vs 43·3 months [33·2–52·2]; hazard ratio [HR] for the first 24 months 2·51, 95% CI 1·60–3·94; p<0·0001). Progression-free survival did not differ between maintenance treatments (median 37·5 months [95% CI 27·8–not evaluable] with lenalidomide plus prednisone vs 28·5 months [22·5–46·5] with lenalidomide alone; HR 0·84, 95% CI 0·59–1·20; p=0·34). Fewer grade 3 or 4 adverse events were recorded with chemotherapy plus lenalidomide than with high-dose melphalan and ASCT; the most frequent were haematological (34 [26%] of 129 patients vs 107 [84%] of 127 patients), gastrointestinal (six [5%] vs 25 [20%]), and infection (seven [5%] vs 24 [19%]). Haematological serious adverse events were reported in two (2%) patients assigned chemotherapy plus lenalidomide and no patients allocated high-dose melphalan and ASCT. Non-haematological serious adverse events were reported in 13 (10%) patients assigned chemotherapy plus lenalidomide and nine (7%) allocated high-dose melphalan and ASCT. During maintenance, adverse events did not differ between groups. The most frequent grade 3 or 4 adverse events were neutropenia (nine [8%] of 117 patients assigned lenalidomide plus prednisone vs 14 [13%] of 106 allocated lenalidomide alone), infection (eight [8%] vs five [5%]), and systemic toxicities (seven [6%] vs two [2%]). Non-haematological serious adverse events were reported in 13 (11%) patients assigned lenalidomide plus prednisone versus ten (9%) allocated lenalidomide alone. Four patients died because of adverse events, three from infections (two during induction and one during consolidation) and one because of cardiac toxic effects. Consolidation with high-dose melphalan and ASCT remains the preferred option in transplant-eligible patients with multiple myeloma, despite a better toxicity profile with chemotherapy plus lenalidomide. Celgene.

Purpose This paper aims to provide a comparative analysis of sustainable tourism development across the Anglophone Caribbean region from the post-independence period of 1962 to the 2020s. The perspective explores the implications of insularity, tourism investment and the pace of technology adoption on the potential realisation of the sustainable development goals (SDGs) in the islands of Jamaica, Barbados, Trinidad and Tobago and the Eastern Caribbean States. Design/methodology/approach The viewpoint uses secondary data from grey literature such as government policy documents, academic literature, newspapers and consultancy reports to explore the central themes and provide a conceptual framework for the paper. Findings The findings reveal that Caribbean Small Island Developing States (SIDS) are nearer to the light-green single-sector approach to sustainable tourism development. The overarching findings reveal that the region’s heavy focus on economic priorities results in less attention to competitiveness challenges such as environmental management, social equity and technological innovations. Research limitations/implications The research presents a comprehensive overview of the tourism development trajectory of other tourism-dependent island-states. The research offers lessons and cross-learning opportunities that may be useful to decision-makers within SIDS. The main limitation is that the findings may only be transferable and generalised to the extent that other jurisdictions bear similar macroeconomic governance structures and cultural characteristics to Caribbean SIDS. Practical implications This paper provides a meaningful discussion and contributes to the body of knowledge on the history of Caribbean tourism development, the challenges and future potential of sustainability and lends itself to opportunities for future research in the Caribbean and other SIDS. Social implications The study outlines the social implications for inclusive, responsible and sustainable tourism that can potentially take Caribbean SIDS from slow growth to efficiency in developing the tourism product, including the technological environment. This can reduce inequalities, contribute to socio-economic development and improve the region’s human capital. Originality/value This paper provides a comprehensive comparative analysis of Caribbean tourism development specific to Jamaica, Trinidad and Tobago, Barbados and the Eastern Caribbean States. No previous work has been done to compare tourism development within this grouping. Hence, this paper is essential in informing decision-makers and providing the foundation for continuing research in this area. 目的 这篇观点性论文对英语加勒比地区从1962年独立后到本世纪20年代的可持续旅游发展进行了比较分析。该研究前瞻性探讨了牙买加、巴巴多斯、特立尼达和多巴哥以及东加勒比国家的保守性、旅游投资和技术采用速度对潜在实现可持续发展目标的启示。 设计/方法/方法 该研究利用灰色文献中的二手数据, 如政府政策文件、学术文献、报纸和咨询报告, 进行中心主题探索, 并为论文提供概念性框架。 研究结果 研究结果显示, 加勒比小岛屿发展中国家(SIDS)更接近于以轻绿的单一部门方式实现可持续旅游发展。总体研究结果显示, 该地区过于关注经济优先事项, 导致对环境管理、社会公平和技术创新等竞争力挑战的关注较少。 研究局限/启示 本研究全面展现了一些依赖旅游发展的岛屿国家的旅游发展路径概览。这项研究为小岛屿发展中国家的决策者提供了可能有用的经验和交叉学习机会。本文研究局限在于, 只有在与加勒比小岛屿发展中国家类似的宏观经济管理结构和文化特征的行政区, 研究结果才可能转移和推广。 实践意义 这篇论文提供了有意义的讨论, 有助于认知加勒比旅游发展史、可持续发展的挑战和未来潜力, 并为加勒比和其他小岛屿发展中国家的未来研究提供了机会。 社会影响 该研究概述了包容性、负责任和可持续的旅游发展的社会启示, 这些启示可能使加勒比小岛屿发展中国家从缓慢发展转变为开发旅游产品(包括技术环境)的效率。这有助于减少不平等现象, 促进社会经济发展, 并改善该地区的人力资本。 独创性/价值 本文提供了加勒比旅游发展的综合比较分析, 具体到牙买加、特立尼达和多巴哥、巴巴多斯和东加勒比国家。此前没有研究对这些国家的旅游业发展进行比较。因此, 这篇论文为决策者提供必要信息和为这一领域的继续研究建立了基础。 Propósito Este trabajo ofrece un análisis comparativo del desarrollo del turismo sostenible en toda la región del Caribe anglófono desde el período posterior a la independencia de 1962 hasta la década de 2020. Se explora las implicaciones de la insularidad, la inversión turística y el ritmo de adopción de la tecnología en la posible realización de los Objetivos de Desarrollo Sostenible (ODS) en las islas de Jamaica, Barbados, Trinidad y Tobago y los Estados del Caribe Oriental. Diseño/metodología/enfoque El análisis se basa en datos secundarios bibliográficos a partir de documentos de política gubernamental, literatura académica, periódicos e informes de consultoría para explorar los temas centrales y proporcionar un marco conceptual en este documento. Conclusiones Las conclusiones revelan que los pequeños estados insulares en desarrollo (Caribbean Small Island Developing States, SIDS) están más próximos del enfoque del turismo como único sector económico o sostenibilidad débil para el desarrollo del turismo sostenible. Las conclusiones generales revelan que la fuerte concentración de la región en las prioridades económicas hace que se preste menos atención a los retos de la competitividad, como la gestión medioambiental, la equidad social y las innovaciones tecnológicas. Limitaciones/implicaciones de la investigación La investigación presenta una visión global de la trayectoria de desarrollo turístico de otros Estados insulares dependientes del turismo. La investigación ofrece lecciones y oportunidades de aprendizaje que pueden ser útiles para los responsables de la toma de decisiones en los SIDS. La principal limitación es que las conclusiones sólo pueden ser transferibles y generalizadas en la medida en que otras jurisdicciones tengan estructuras de gobernanza macroeconómica y características culturales similares a las de los SIDS del Caribe. Implicaciones practices Este documento ofrece un análisis significativo y contribuye al conjunto de conocimientos sobre la historia del desarrollo del turismo en el Caribe, los retos y el potencial futuro de la sostenibilidad, y se presta a oportunidades para futuras investigaciones en el Caribe y otros SIDS. Implicaciones sociales El estudio esboza las implicaciones sociales del turismo inclusivo, responsable y sostenible que puede llevar a los SIDS del Caribe de un crecimiento lento a la eficiencia en el desarrollo del producto turístico, incluyendo el entorno tecnológico. Esto puede reducir las desigualdades, contribuir al desarrollo socioeconómico y mejorar el capital humano de la región. Originalidad/valor Este trabajo proporciona un análisis comparativo exhaustivo del desarrollo del turismo en el Caribe, específico para Jamaica, Trinidad y Tobago, Barbados y los Estados del Caribe Oriental. No se ha realizado ningún trabajo anterior para comparar el desarrollo del turismo dentro de esta agrupación. Por ello, este trabajo es esencial para informar a los responsables de la toma de decisiones y sentar las bases para continuar la investigación en este ámbito.