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Context: Palliative care is an essential health service, with over 56.8 million people needing it yearly, particularly in low- and middle-income countries. The World Health Assembly has recognized palliative care as an ethical responsibility and called for comprehensive primary health care. The World Health Organization has published a technical report titled "Assessing the Development of Palliative Care Worldwide," as a crucial first step in addressing palliative care. The report includes 14 indicators to help decision-makers identify service provision gaps and inform health priorities, piloted by WHO's ATLANTES in Benin, Morocco, and Uruguay as part of a global assessment., Objectives: To describe, for the three countries, the primary outcomes and lessons learned to enable replication in further countries., Methods: A step-by-step description of the assessment project, a summary of the main results obtained through evaluations, and a description of how the selected countries effectively implemented the WHO indicators through a six-step process, including a phase of action plan design. We advocated a 'Do-it-yourself' approach., Results: The summary data from three country reports reveals national development at a national level. A SWOT analysis involving consultants and program managers was conducted. A stakeholder guide was developed, providing trigger questions and practical recommendations for assessing development using specific indicators. Full information can be found in the specific published reports., Conclusion: The WHO approach has proven effective in identifying health system deficiencies and disseminating information about palliative care evaluation processes. The report provides a 'Do-it-yourself' approach, encouraging self-management without expert guidance., (Copyright © 2024 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

The current study aimed to investigate the association between predicted vitamin D status and depression in a prospective Spanish cohort of university graduates. The SUN Project is a dynamic cohort study designed to investigate multiple aspects of health and lifestyle. Participants were asked to complete a comprehensive questionnaire consisting of 556 items, that included a validated food-frequency questionnaire. Participants initially free of depression were classified as incident cases if they reported a medical diagnosis of depression during follow-up. Serum vitamin D levels were predicted by a previously validated equation. Vitamin D deficiency was defined as vitamin D levels below 20 ng/mL. Cox models were used to estimate adjusted hazard ratios (HR) and 95% confidence intervals (95% CI). We included 15,175 Spanish university graduates [mean (SD) age: 36.9 year (11.5)] followed-up for a median of 12.7 years. Among 192,976 person-years of follow-up, we identified 753 incident cases of depression. Participants with vitamin D deficiency had a 27% higher risk of depression as compared to those with vitamin D sufficiency (HR: 1.27, 95% CI: 1.09-1.48; p = 0.002) after adjusting for potential confounders. Furthermore, a significant effect modification by female sex was observed with higher depression risks associated with vitamin D deficiency in women than in men (p for interaction = 0.034). In educated middle-aged Spanish adults, we observed a direct association between vitamin D deficiency and the risk of depression, that was stronger among women., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Palliative care is essential to global health services as it improves the quality of life of patients, their families and caregivers. The ATLANTES Global Observatory of Palliative Care (University of Navarra) was created a decade ago to promote a positive attitude towards patients with advanced illness in society and medicine. To do so, and over the past 15 years, ATLANTES has mapped palliative care data worldwide using public health, macro and comparative perspectives in different atlases. These have enabled data to be contextualised and good examples to be identified concisely and graphically. Atlases have been widely employed as advocacy tools within international institutions and ministries of health. While the aim and the perspective have remained unalterable over time, the methods and design have evolved throughout the publications from sober cartography and static infographics to big interactive data visualisation web tools. By embracing technology, ATLANTES has developed an open-access web mapping tool reuniting information from regional atlases, favouring global access to data. In 2022, matching the increasingly recognised need for robust monitoring of palliative care worldwide, ATLANTES became a WHO Collaborating Centre for the Global Monitoring of Palliative Care Development. This attempt to bridge the gap and ensure equitable care information in countries with limited palliative care access has resulted today in more accessible, self-explanatory, and visually appealing palliative care data., (© 2024. The Author(s).)

Engagement of the receptor programmed cell death molecule 1 (PD-1) by its ligands PD-L1 and PD-L2 inhibits T cell-mediated immune responses. Blocking such signaling provides the clinical effects of PD-1-targeted immunotherapy. Here, we investigated the mechanisms underlying PD-1-mediated inhibition. Because dynamic actin remodeling is crucial for T cell functions, we characterized the effects of PD-1 engagement on actin remodeling at the immunological synapse, the interface between a T cell and an antigen-presenting cell (APC) or target cell. We used microscopy to analyze the formation of immunological synapses between PD-1 + Jurkat cells or primary human CD8 + cytotoxic T cells and APCs that presented T cell-activating antibodies and were either positive or negative for PD-L1. PD-1 binding to PD-L1 inhibited T cell spreading induced by antibody-mediated activation, which was characterized by the absence of the F-actin-dense distal lamellipodial network at the immunological synapse and the Arp2/3 complex, which mediates branched actin formation. PD-1-induced inhibition of actin remodeling also prevented the characteristic deformation of T cells that contact APCs and the release of cytotoxic granules. We showed that the effects of PD-1 on actin remodeling did not require its tyrosine-based signaling motifs, which are thought to mediate the co-inhibitory effects of PD-1. Our study highlights a previously unappreciated mechanism of PD-1-mediated suppression of T cell activity, which depends on the regulation of actin cytoskeleton dynamics in a signaling motif-independent manner.

Obesity is associated with a higher risk of several types of cancer, grouped as obesity-related cancers (ORC). Vitamin D deficiency is more prevalent in obese subjects, and it has been suggested to play a role in the association between obesity and cancer risk. The aim of the study was to analyze the association between vitamin D intake and the subsequent risk of ORC in a prospective Spanish cohort of university graduates. The SUN Project, initiated in 1999, is a prospective dynamic multipurpose cohort. Participants answered a 556-item lifestyle baseline questionnaire that included a validated food-frequency questionnaire. We performed Cox regression models to estimate the hazard ratios (HRs) of ORC according to quartiles of energy-adjusted vitamin D intake (diet and supplements). We included 18,017 participants (mean age = 38 years, SD = 12 years), with a median follow-up of 12 years. Among 206,783 person-years of follow-up, we identified 225 cases of ORC. We found no significant associations between vitamin D intake and ORC risk after adjusting for potential confounders: HR Q2vsQ1 = 1.19 (95% CI 0.81-1.75), HR Q3vsQ1 = 1.20 (95% CI 0.81-1.78), and HR Q4vsQ1 = 1.02 (95% CI 0.69-1.51). Dietary and supplemented vitamin D do not seem to be associated with ORC prevention in the middle-aged Spanish population.

Background: The travel distance from home to a treatment centre, which may impact the stage at diagnosis, has not been investigated for retinoblastoma, the most common childhood eye cancer. We aimed to investigate the travel burden and its impact on clinical presentation in a large sample of patients with retinoblastoma from Africa and Europe., Methods: A cross-sectional analysis including 518 treatment-naïve patients with retinoblastoma residing in 40 European countries and 1024 treatment-naïve patients with retinoblastoma residing in 43 African countries., Results: Capture rate was 42.2% of expected patients from Africa and 108.8% from Europe. African patients were older (95% CI -12.4 to -5.4, p<0.001), had fewer cases of familial retinoblastoma (95% CI 2.0 to 5.3, p<0.001) and presented with more advanced disease (95% CI 6.0 to 9.8, p<0.001); 43.4% and 15.4% of Africans had extraocular retinoblastoma and distant metastasis at the time of diagnosis, respectively, compared to 2.9% and 1.0% of the Europeans. To reach a retinoblastoma centre, European patients travelled 421.8 km compared to Africans who travelled 185.7 km (p<0.001). On regression analysis, lower-national income level, African residence and older age (p<0.001), but not travel distance (p=0.19), were risk factors for advanced disease., Conclusions: Fewer than half the expected number of patients with retinoblastoma presented to African referral centres in 2017, suggesting poor awareness or other barriers to access. Despite the relatively shorter distance travelled by African patients, they presented with later-stage disease. Health education about retinoblastoma is needed for carers and health workers in Africa in order to increase capture rate and promote early referral., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Context: Approximately 170,000 children in need of palliative care die every year in Europe without access to it. This field remains an evolving specialty with unexplored development., Objectives: To conduct the first regional assessment of pediatric palliative care (PPC) development and provision using data from the European Association for Palliative Care atlas of palliative care 2019., Methods: Two surveys were conducted. The first one included a single question regarding PPC service provision and was addressed by European Association for Palliative Care atlas informants. The second one included 10 specific indicators derived from an open-ended interview and rating process; a specific network of informants was enabled and used as respondents. Data were analyzed and presented in the map of the figure., Results: Data on PPC service provision were gathered from 51 of 54 (94%) European countries. Additional data were collected in 34 of 54 (62%) countries. A total of 680 PPC services were identified including 133 hospices, 385 home care services, and 162 hospital services. Nineteen countries had specific standards and norms for the provision of PPC. Twenty-two countries had a national association, and 14 countries offered education for either pediatric doctors or nurses. In seven countries, specific neonatal palliative care referral services were identified., Conclusion: PPC provision is flourishing across the region; however, development is less accentuated in low-to-middle-income countries. Efforts need to be devoted to the conceptualization and definition of the models of care used to respond to the unmet need of PPC in Europe. The question whether specialized services are required or not should be further explored. Strategies to regulate and cover patients in need should be adapted to each national health system., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Service provision is a key domain to assess national-level palliative care development. Three editions of the European Association for Palliative Care (EAPC) Atlas of Palliative Care monitored the changes in service provision across Europe since 2005., Aim: To study European trends of specialized service provision at home care teams, hospital support teams, and inpatient palliative care services between 2005 and 2019., Design: Secondary analysis was conducted drawing from databases on the number of specialized services in 2005, 2012, and 2019. Ratios of services per 100,000 inhabitants and increase rates on number of services for three periods were calculated. Analysis of variance (ANOVA) analyses were conducted to determine significant changes and chi-square to identify countries accounting for the variance. Income-level and sub-regional ANOVA analysis were undertaken., Setting: 51 countries., Results: Forty-two countries (82%) increased the number of specialized services between 2005 and 2019 with changes for home care teams (104% increase-rate), inpatient services (82%), and hospital support teams (48%). High-income countries showed significant increase in all types of services ( p  < 0.001), while low-to-middle-income countries showed significant increase only for inpatient services. Central-Eastern European countries showed significant improvement in home care teams and inpatient services, while Western countries showed significant improvement in hospital support and home care teams. Home care was the most prominent service in Western Europe., Conclusion: Specialized service provision increased throughout Europe, yet ratios per 100,000 inhabitants fell below the EAPC recommendations. Western Europe ratios' achieved half of the suggested services, while Central-Eastern countries achieved only a fourth. High-income countries and Western European countries account for the major increase. Central-Eastern Europe and low-to-middle-income countries reported little increase on specialized service provision.

Importance: Early diagnosis of retinoblastoma, the most common intraocular cancer, can save both a child's life and vision. However, anecdotal evidence suggests that many children across the world are diagnosed late. To our knowledge, the clinical presentation of retinoblastoma has never been assessed on a global scale., Objectives: To report the retinoblastoma stage at diagnosis in patients across the world during a single year, to investigate associations between clinical variables and national income level, and to investigate risk factors for advanced disease at diagnosis., Design, Setting, and Participants: A total of 278 retinoblastoma treatment centers were recruited from June 2017 through December 2018 to participate in a cross-sectional analysis of treatment-naive patients with retinoblastoma who were diagnosed in 2017., Main Outcomes and Measures: Age at presentation, proportion of familial history of retinoblastoma, and tumor stage and metastasis., Results: The cohort included 4351 new patients from 153 countries; the median age at diagnosis was 30.5 (interquartile range, 18.3-45.9) months, and 1976 patients (45.4%) were female. Most patients (n = 3685 [84.7%]) were from low- and middle-income countries (LMICs). Globally, the most common indication for referral was leukocoria (n = 2638 [62.8%]), followed by strabismus (n = 429 [10.2%]) and proptosis (n = 309 [7.4%]). Patients from high-income countries (HICs) were diagnosed at a median age of 14.1 months, with 656 of 666 (98.5%) patients having intraocular retinoblastoma and 2 (0.3%) having metastasis. Patients from low-income countries were diagnosed at a median age of 30.5 months, with 256 of 521 (49.1%) having extraocular retinoblastoma and 94 of 498 (18.9%) having metastasis. Lower national income level was associated with older presentation age, higher proportion of locally advanced disease and distant metastasis, and smaller proportion of familial history of retinoblastoma. Advanced disease at diagnosis was more common in LMICs even after adjusting for age (odds ratio for low-income countries vs upper-middle-income countries and HICs, 17.92 [95% CI, 12.94-24.80], and for lower-middle-income countries vs upper-middle-income countries and HICs, 5.74 [95% CI, 4.30-7.68])., Conclusions and Relevance: This study is estimated to have included more than half of all new retinoblastoma cases worldwide in 2017. Children from LMICs, where the main global retinoblastoma burden lies, presented at an older age with more advanced disease and demonstrated a smaller proportion of familial history of retinoblastoma, likely because many do not reach a childbearing age. Given that retinoblastoma is curable, these data are concerning and mandate intervention at national and international levels. Further studies are needed to investigate factors, other than age at presentation, that may be associated with advanced disease in LMICs.

Context: International consensus on indicators is necessary to standardize the global assessment of palliative care (PC) development., Objectives: To identify the best indicators to assess current national-level PC development., Methods: Experts in PC development were invited to rate 45 indicators organized by domains of the World Health Organization Public Health Strategy in a two-round RAND/UCLA-modified Delphi process. In the first round, experts rated indicators by relevance, measurability, and feasibility (1-9). Ratings were used to calculate a global score (1-9). Indicators scoring >7 proceeded to the second round for fine-tuning of global scores. Median, confidence interval, Content Validity Index, and Disagreement Index were calculated. Indicators scoring a lower limit 95% confidence interval of ≥7 and a Content Validity Index of ≥0.30 were selected., Results: 24 experts representing five continents and several organizations completed the study. 25 indicators showed a high content validity and level of agreement. Policy indicators (n = 8) included the existence of designated staff in the National Ministry of Health and the inclusion of PC services in the basic health package and in the primary care level list of services. Education indicators (n = 4) focused on processes of official specialization for physicians, inclusion of teaching at the undergraduate level, and PC professorship. Use of medicines indicators (n = 4) consisted of opioid consumption, availability, and prescription requirements. Services indicators (n = 6) included number and type of services for adults and children. Additional indicators for professional activity (n = 3) were identified., Conclusion: The first list including 25 of the best indicators to evaluate PC development at a national level has been identified., (Copyright © 2019 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

A methodology based on CFD-RANS simulations (WA CFD-RANS, Weighted Averaged Computational Fluid Dynamic-Reynolds-Averaged Navier-Stokes simulations) which includes appropriate modifications, has been applied to compute the annual, seasonal, and hourly average concentration of NO 2 and NO X throughout the city of Pamplona (Spain) at pedestrian level during 2016. The results have been evaluated using measurements provided both by the city's network of air quality monitoring stations and by a network of mobile microsensors carried around by cyclists during their daily commutes, obtaining a maximum relative error lower than 30% when computing NO 2 annual average concentrations. The model has taken into account the actual city layout in three dimensions, as well as the traffic emissions. The resulting air pollution maps provided information critical for studying the traffic-related health effects of NO 2 and their associated external costs in the city of Pamplona and the spatial representativeness of the current network of air quality monitoring stations (it has not been carried out for an entire city to date). The developed methodology can be applied to similar cities, providing useful information for the decision-makers., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Living in a geographically higher altitude affects oxygen availability. The possible connection between environmental factors and the development of metabolic syndrome (MetS) feature is not fully understood, being the available epidemiological evidence still very limited. The aim of the present study was to evaluate the longitudinal association between altitude and incidence of MetS and each of its components in a prospective Spanish cohort, The Seguimiento Universidad de Navarra (SUN) project. Our study included 6860 highly educated subjects (university graduates) free from any MetS criteria at baseline. The altitude of residence was imputed with the postal code of each individual subject residence according to the data of the Spanish National Cartographic Institute and participants were categorized into tertiles. MetS was defined according to the harmonized definition. Cox proportional hazards models were used to assess the association between the altitude of residence and the risk of MetS during follow-up. After a median follow-up period of 10 years, 462 incident cases of MetS were identified. When adjusting for potential confounders, subjects in the highest category of altitude (>456 m) exhibited a significantly lower risk of developing MetS compared to those in the lowest tertile (<122 m) of altitude of residence [Model 2: Hazard ratio = 0.75 (95% Confidence interval: 0.58-0.97); p for trend = 0.029]. Living at geographically higher altitude was associated with a lower risk of developing MetS in the SUN project. Our findings suggest that geographical elevation may be an important factor linked to metabolic diseases.