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The software engineering community has produced numerous tools, techniques, and methodologies for practitioners to analyze and optimize memory usage during software execution. However, little is known about the actual needs of programmers when analyzing memory behavior and how they use tools to address those needs. We conducted an exploratory study (i) to understand what a programmer needs to know when analyzing memory behavior and (ii) how a programmer finds that information with current tools. From our observations, we provide a catalog of 34 questions programmers ask themselves when analyzing memory behavior. We also report a detailed analysis of how some tools are used to answer these questions and the difficulties participants face during the process. Finally, we present four recommendations to guide researchers and developers in designing, evaluating, and improving memory behavior analysis tools.

Background: Brain metastases (BM) and lactate dehydrogenase (LDH) levels above the upper limit of normal (ULN) are associated with poor prognosis in patients with melanoma. Although treatment with the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib have demonstrated long-term clinical benefit in patients with melanoma, data on their efficacy in patients with BM are limited.Methods: DESCRIBE Italy is an observational, retrospective, real-world study evaluating dabrafenib plus trametinib in 499 patients with BRAFV600-mutant stage III unresectable or stage IV melanoma from various sites across Italy. Here, we analyzed the clinical outcomes for the subgroup of patients receiving first-line treatment and presenting with BM at diagnosis and assessed the impact of predictive factors such as LDH levels and the presence of other metastases on median progression-free survival (mPFS).Results: Overall, 325 evaluable patients were on first-line therapy and are the focus of this analysis; of these, 76 patients (23.4%) had BM at baseline. mPFS was lower for patients with BM at baseline compared with overall patients (8.7 months vs 9.3 months, respectively). Patients with BM at diagnosis and LDH >ULN had a considerably shorter mPFS compared with patients with LDH ⩽ULN (5.3 months vs 9.9 months, respectively). mPFS was noticeably longer for patients with cerebral metastases only compared with patients with cerebral and other metastases (15.0 months vs 8.7 months, respectively).Conclusions: Dabrafenib plus trametinib showed effectiveness in a real-world population of patients with advanced BRAFV600-mutated melanoma and BM at baseline, supporting its use in this population with poor outcomes.

ABSTRACTThis contribution explores the acquisition, circulation and negotiation of knowledge related to mobility and border crossing among migrants at the French-Italian border of Ventimiglia. Despite governmental deterrence policies and border controls, the pursuit of “secondary movements” seems not to decrease, and is increasingly putting Europe to the test. In this context, the underground knowledge network that exists can be used to circumvent legal and geographical borders and to gain access to forms of citizenship. The “right” information is thus fundamental in determining the level of risk embedded in the various pathways and practices of de-bordering, as well as in constructing specific behaviors and migration carriers. To examine contentious information issues, we have participated in activities supporting the Progetto20k collective, including: Eufemia Info&legal point, an independent solidarity center in Ventimiglia; and the Italian-French Border Guide, a project designed to produce and spread mobility knowledge.

How cannabis legalization affects users’ behaviors? In this paper, we describe changes in the way users access cannabis in Uruguay before and after the implementation of cannabis regulation. We explore the differences between users that access through the legal, black, and gray markets. To do so, we rely on two face-to-face surveys of high-frequency users using the Respondent Driven Sample technique. The first survey was conducted at the beginning of the regulation implementation in 2014, and the second one in 2017. Results indicate that cannabis users gradually moved to the legal market, and most switched to the gray market. Furthermore, users kept acquiring cannabis from the black market even when using legal mechanisms. Considering these results, we argue that the strict regulations imposed in Uruguay may have operated as barriers for consumers to abandon the black market completely. These findings show that the specifics of each legalization policy matter.

Early control of elevated blood pressure is the most promising treatment for acute intracerebral haemorrhage. We aimed to establish whether implementing a goal-directed care bundle incorporating protocols for early intensive blood pressure lowering and management algorithms for hyperglycaemia, pyrexia, and abnormal anticoagulation, implemented in a hospital setting, could improve outcomes for patients with acute spontaneous intracerebral haemorrhage.

Les résultats de l’essai pivot multicentrique randomisé de phase 3 CheckMate 067 chez des patients atteints de mélanome avancé ont montré des améliorations de la survie sans progression et de la survie globale (OS) avec nivolumab (NIVO) plus ipilimumab (IPI) ou NIVO en monothérapie par rapport à IPI en monothérapie. Nous présentons maintenant les résultats finaux de l’étude CheckMate 067, avec un suivi minimum de 10ans, représentant la durée de suivi la plus longue jamais rapportée pour une étude de phase 3 impliquant un traitement à base d’anti-PD-1 (NIVO), toutes tumeurs confondues.

The malt industry has specific requirements for malting barley (Hordeum vulgareL.) grain protein concentration (from 9.5 to 13%) and size (>85%), which could be affected by nitrogen (N) fertilization. We aimed to (a) define and explain the economic optimum nitrogen rate (EONR) for grain yield in feed (EONRf) and malting barley (EONRm), and (b) analyze if grain quality requirements are reached at the EONRm. We evaluated six N rates (0, 40, 80, 120, 160, and 200 kg N ha−1) in field experiments (14 site‐years). At each site‐year, the EONR was calculated using two fertilizer cost to grain price ratios, 6:1 for feed and 4:1 for malting barley. On average, maximum yield and protein response to N were 1,681 kg ha−1and 2%, respectively. There was no consistent effect of N fertilization on grain size. The EONRf was explained by N availability and maximum yield response to N (y= 130 – 0.37N availability + 0.03N response, r2= .89), and EONRm was explained solely by N availability (y= 320 – 0.93N availability, r2= .75). The overall EONRm was 134 kg N ha−1. At sites with low soil N availability and high yield response to N, an average N rate of 69 kg ha−1greater than the EONRm was necessary to reach 9.5% protein. Otherwise, the EONRf could be used (106 kg N ha−1) and grains be sold as feed barley. These results are useful to adjust N fertilizer recommendations to satisfy the malting industry demand while reducing the economic and environmental impacts of fertilization. The mean economic optimum N rate (EONR) for feed barley was 106 ± 48 kg N ha−1.The mean EONR for malting barley was 134 ± 55 kg N ha−1.N availability and maximum N response explained the differences in EONR.Sites with low N availability and high grain yield response to N did not reach 9.5% protein at the EONR.Grain size was within malting industry requirements, even at high N rates.

Pembrolizumab prolongs progression-free and overall survival among patients with advanced melanoma and recurrence-free survival in resected stage III disease. KEYNOTE-716 assessed pembrolizumab as adjuvant therapy in patients with completely resected, high-risk, stage II melanoma. We report results from the planned first and second interim analyses for recurrence-free survival.

IMPORTANCE: Whether the severity and mortality of COVID-19 in patients with cancer have improved in terms of disease management and capacity is yet to be defined. OBJECTIVE: To test whether severity and mortality from COVID-19 among patients with cancer have improved during the course of the pandemic. DESIGN, SETTING, AND PARTICIPANTS: OnCovid is a European registry that collects data on consecutive patients with solid or hematologic cancer and COVID-19. This multicenter case series study included real-world data from 35 institutions across 6 countries (UK, Italy, Spain, France, Belgium, and Germany). This update included patients diagnosed between February 27, 2020, and February, 14, 2021. Inclusion criteria were confirmed diagnosis of SARS-CoV-2 infection and a history of solid or hematologic cancer. EXPOSURES: SARS-CoV-2 infection. MAIN OUTCOMES AND MEASURES: Deaths were differentiated at 14 days and 3 months as the 2 landmark end points. Patient characteristics and outcomes were compared by stratifying patients across 5 phases (February to March 2020, April to June 2020, July to September 2020, October to December 2020, and January to February 2021) and across 2 major outbreaks (February to June 2020 and July 2020 to February 2021). RESULTS: At data cutoff, 2795 consecutive patients were included, with 2634 patients eligible for analysis (median [IQR] age, 68 [18-77] years ; 52.8% men). Eligible patients demonstrated significant time-dependent improvement in 14-day case-fatality rate (CFR) with estimates of 29.8% (95% CI, 0.26-0.33) for February to March 2020; 20.3% (95% CI, 0.17-0.23) for April to June 2020; 12.5% (95% CI, 0.06-22.90) for July to September 2020; 17.2% (95% CI, 0.15-0.21) for October to December 2020; and 14.5% (95% CI, 0.09-0.21) for January to February 2021 (all P < .001) across the predefined phases. Compared with the second major outbreak, patients diagnosed in the first outbreak were more likely to be 65 years or older (974 of 1626 [60.3%] vs 564 of 1008 [56.1%]; P = .03), have at least 2 comorbidities (793 of 1626 [48.8%] vs 427 of 1008 [42.4%]; P = .001), and have advanced tumors (708 of 1626 [46.4%] vs 536 of 1008 [56.1%]; P < .001). Complications of COVID-19 were more likely to be seen (738 of 1626 [45.4%] vs 342 of 1008 [33.9%]; P < .001) and require hospitalization (969 of 1626 [59.8%] vs 418 of 1008 [42.1%]; P < .001) and anti–COVID-19 therapy (1004 of 1626 [61.7%] vs 501 of 1008 [49.7%]; P < .001) during the first major outbreak. The 14-day CFRs for the first and second major outbreaks were 25.6% (95% CI, 0.23-0.28) vs 16.2% (95% CI, 0.13-0.19; P < .001), respectively. After adjusting for country, sex, age, comorbidities, tumor stage and status, anti–COVID-19 and anticancer therapy, and COVID-19 complications, patients diagnosed in the first outbreak had an increased risk of death at 14 days (hazard ratio [HR], 1.85; 95% CI, 1.47-2.32) and 3 months (HR, 1.28; 95% CI, 1.08-1.51) compared with those diagnosed in the second outbreak. CONCLUSIONS AND RELEVANCE: The findings of this registry-based study suggest that mortality in patients with cancer diagnosed with COVID-19 has improved in Europe; this improvement may be associated with earlier diagnosis, improved management, and dynamic changes in community transmission over time.

Clinical and epidemiological studies employ long-term temperature storage but the effect of temperature on the stability of oxidative stress (OS) markers is unknown. We investigated the effects of storage at −20 °C and −80 °C over 4–9 months on F2-isoprostanes (F2-IsoP) and 8-hydroxy-2′-deoxyguanosine (8-OHdG) levels in urine of children, a population group among whom the measurement of these markers is still limited.

Most genetic susceptibility to cutaneous melanoma remains to be discovered. Meta-analysis genome-wide association study (GWAS) of 36,760 cases of melanoma (67% newly genotyped) and 375,188 controls identified 54 significant (P< 5 × 10−8) loci with 68 independent single nucleotide polymorphisms. Analysis of risk estimates across geographical regions and host factors suggests the acral melanoma subtype is uniquely unrelated to pigmentation. Combining this meta-analysis with GWAS of nevus count and hair color, and transcriptome association approaches, uncovered 31 potential secondary loci for a total of 85 cutaneous melanoma susceptibility loci. These findings provide insights into cutaneous melanoma genetic architecture, reinforcing the importance of nevogenesis, pigmentation and telomere maintenance, together with identifying potential new pathways for cutaneous melanoma pathogenesis.

Supplemental Digital Content is available in the text.Given the approval of dabrafenib in patients with BRAF-mutant metastatic melanoma, a better understanding of treatment patterns and clinical outcomes with dabrafenib in a clinical setting is warranted. We performed a retrospective chart review of patients who received dabrafenib in a compassionate use setting through the Named Patient Program (DESCRIBE I study) during December 2010–August 2013 in Europe, New Zealand and Australia. Of the 331 Named Patient Program patients included, the majority (95.8%) had stage IV disease at dabrafenib initiation and 39.9% had brain metastases (BMs). Dabrafenib was used first line in 67.7% of patients, and median treatment duration was 6.4 months. Dabrafenib was well tolerated. Common grade 2/3 adverse events were hyperkeratosis (7.6%), pyrexia/fever (6.6%), fatigue (5.1%), hand-foot syndrome (5.4%) and nausea (3.6%). Overall response rate was 45.9%, median progression-free survival was 5.2 months (95% confidence interval, 4.2–6.1 months), and median overall survival was 12.4 months (95% confidence interval, 10.2–15.0 months). In patients with known brain metastases (n= 132) versus patients without (n= 199), overall response rate was 42.4% versus 48.2%, progression-free survival was 3.9 months (95% confidence interval, 3.8–5.5 months) versus 5.9 months (95% confidence interval, 4.8–7.8 months) and overall survival was 9.5 months (95% confidence interval, 6.7–12.4 months) versus 15 months (95% confidence interval, 11.1–20.5 months), respectively. Safety and effectiveness of dabrafenib in patients with unresectable advanced BRAFV600–mutant melanoma treated in an Named Patient Program was similar to the clinical trial experience, demonstrating effectiveness of dabrafenib in a nontrial setting.

Blocking programmed death 1 (PD-1) may enhance the durability of anti-tumor responses that are induced by the combined inhibition of BRAF and MEK1. Here we performed a randomized phase 2 trial (NCT02130466), in which patients with treatment-naive BRAFV600E/K-mutant, advanced melanoma received the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib together with the PD-1-blocking antibody pembrolizumab (triplet; n?=?60) or placebo (doublet; n?=?60). The primary end point of progression-free survival was numerically improved in the triplet group—16.0?months—compared with 10.3?months in the doublet group (hazard ratio, 0.66; P?=?0.043); however, the trial did not reach the planned benefit for a statistically significant improvement. Median duration of response was 18.7?months (95% confidence interval, 10.1–22.1) and 12.5?months (95%?confidence interval, 6.0–14.1); 59.8 and 27.8% of responses were estimated to have lasted for more than 18 months for triplet and doublet treatment, respectively. Grade 3–5 treatment-related adverse events occurred in 58.3 and 26.7% of patients treated with triplet and doublet therapies, respectively, which were most commonly fever, increased transaminase levels and rash. One patient who received triplet therapy died of pneumonitis. In summary, triplet therapy with dabrafenib, trametinib and pembrolizumab conferred numerically longer progression-free survival and duration of response with a higher rate of grade 3/4 adverse events compared with the doublet therapy of dabrafenib, trametinib and placebo.

The detection of methane on Mars has been interpreted as indicating that geochemical or biotic activities could persist on Mars today1. A number of different measurements of methane show evidence of transient, locally elevated methane concentrations and seasonal variations in background methane concentrations2–5. These measurements, however, are difficult to reconcile with our current understanding of the chemistry and physics of the Martian atmosphere6,7, which—given methane’s lifetime of several centuries—predicts an even, well mixed distribution of methane1,6,8. Here we report highly sensitive measurements of the atmosphere of Mars in an attempt to detect methane, using the ACS and NOMAD instruments onboard the ESA-Roscosmos ExoMars Trace Gas Orbiter from April to August 2018. We did not detect any methane over a range of latitudes in both hemispheres, obtaining an upper limit for methane of about 0.05 parts per billion by volume, which is 10 to 100 times lower than previously reported positive detections2,4. We suggest that reconciliation between the present findings and the background methane concentrations found in the Gale crater4would require an unknown process that can rapidly remove or sequester methane from the lower atmosphere before it spreads globally.

ABSTRACTSince the second part of the twentieth century, Chile has become the largest copper producer in the world, being the pyrometallurgical processing of sulfides concentrates a central part of it.Since the introduction of the Peirce-Smith and later the Hoboken converters in Chilean smelters, some modifications were made to these reactors, including feeding of copper concentrate and intensive oxygen enrichment utilisation to increase their productivity. These modifications, and the use of bone dry concentrates, later became part of the new Teniente technology to smelt concentrates. All these innovations also influenced other processes, such as slag and gas treatment.This paper shows how pyrometallurgical processing of copper concentrates has been developed in Chile and how the Teniente reactor was conceived and implemented. Also, a comparison between nonferrous and ferrous technologies in terms of instrumentation and control, and some new processes being developed at laboratory and scale are shown.

Since the second part of the twentieth century, Chile has become the largest copper producer in the world, being the pyrometallurgical processing of sulfides concentrates a central part of it.Since the introduction of the Peirce-Smith and later the Hoboken converters in Chilean smelters, some modifications were made to these reactors, including feeding of copper concentrate and intensive oxygen enrichment utilisation to increase their productivity. These modifications, and the use of bone dry concentrates, later became part of the new Teniente technology to smelt concentrates. All these innovations also influenced other processes, such as slag and gas treatment.This paper shows how pyrometallurgical processing of copper concentrates has been developed in Chile and how the Teniente reactor was conceived and implemented. Also, a comparison between nonferrous and ferrous technologies in terms of instrumentation and control, and some new processes being developed at laboratory and scale are shown.

Patients with cancer are presumed to have a higher risk to contract SARS-CoV-2 infection, because of their immunosuppressed status. The impact and course of COVID-19 infection in cancer patients receiving immunotherapy remains unknown.

Geoffroy’s cat (Leopardus geoffroyi) is a small Neotropical felid whose social behavior remains poorly understood. We used simultaneous radiotelemetry (4 males and 3 females) and camera trapping to examine the spatial structure and dynamics of a population of this species in the Brazilian pampas (part of the Uruguayan Savannah ecoregion), including assessment of interindividual genetic relatedness. Home ranges (HRs) and core areas of males were larger than those of females. Males were significantly heavier than females, and linear regression analyses indicated that body mass of males significantly influenced HR size, whereas the relationship was not significant for females. When we performed a joint analysis comparing our data to those reported previously for other study sites, we observed the same patterns. We detected extensive HR and core area overlap among most of our monitored individuals, with no clear sex-based pattern. Moreover, our molecular data indicated that most of the sampled individuals were unrelated, and that the levels of HR and core area overlap were not significantly influenced by genetic relatedness. These results suggest that some interindividual tolerance and relaxation in territoriality may occur in Geoffroy’s cat. We detected only minor changes in HR and core area size and overlap between seasons, indicating that the spatial structure we observed was temporally stable. On a broader perspective, our cross-site comparisons illustrate the usefulness of performing multiple ecological studies employing comparable methods at different locations to better understand the ecology of wild felid populations.A espécie Leopardus geoffroyié um felídeo neotropical de pequeno porte, cujo comportamento social é ainda pouco conhecido. O presente estudo examinou a estrutura e a dinâmica espacial de uma população dessa espécie, incluindo a primeira avaliação da relação de parentesco entre seus indivíduos. Além disso, os tamanhos de áreas de vida e a massa corporal da população estudada foram comparados estatisticamente com os resultados de estudos prévios, gerando dados globais para a espécie. O trabalho de campo foi conduzido entre novembro de 2013 e setembro de 2015, em propriedades rurais localizadas na Serra do Caverá, sul do Brasil (na ecorregião da Savana Uruguai). Foram registradas 516 imagens de L. geoffroyie foram capturados 12 indivíduos desta espécie, sete (4M e 3F) dos quais puderam ser monitorados com rádio-telemetria. Observou-se que os machos possuem áreas de vida, de uso e massa corporal maiores do que as fêmeas. Os resultados das análises de regressão linear indicaram que a massa corporal dos machos influenciou positiva e significativamente o tamanho das áreas de vida dos mesmos, relação esta que não ocorreu entre as fêmeas. Esse resultado ocorreu tanto na população estudada como nos dados globais. Também foi observada uma extensa sobreposição de áreas de vida e de uso, indicando algum grau de socialidade (tolerância) nesta população. Os resultados da análise de parentesco indicaram que a maioria dos indivíduos capturados desta população não eram parentes. Além disso, a relação genética parece não influenciar a sobreposição de área de vida, o que sugere que esta população, na escala estudada, possui uma estrutura sócio-espacial distinta da proposição tradicional na qual os machos tenderiam a dispersar por maiores distâncias e as fêmeas seriam filopátricas. Em uma perspectiva mais ampla, as comparações aqui apresentadas ilustram a utilidade de se realizar estudos ecológicos empregando métodos comparáveis ​​em diferentes locais, a fim de entender melhor a ecologia das populações de felídeos silvestres.

The Neotropical region currently harbors 8 recognized species of small cats, including the margay (Leopardus wiedii) and jaguarundi (Puma yagouaroundi). These similar-sized species have broad geographic distributions and commonly occur in sympatry. We constructed species occurrence databases and used the maximum entropy (Maxent) modeling approach to develop models of habitat suitability for each of these species. We identified the environmental predictors with the highest importance for species occurrence and evaluated how they influence habitat suitability for both wild cats. Variables related to temperature and precipitation were good predictors of species occurrence, with both cats responding similarly to them. However, margay showed higher variation in habitat suitability depending on local climatic predictors. The estimated models indicated high niche similarity (> 76%) between these cats, but despite this we identified different areas with the most favorable conditions for each species’ occurrence. Approximately 50% and 72% of the entire suitable area were estimated as being moderately to highly suitable for margay and jaguarundi, respectively, with the margay model comprising a higher proportion of forest environments in comparison to that of the jaguarundi. These findings will be relevant in the context of conservation planning when indicating the priority areas for their long-term preservation.A região Neotropical possui atualmente oito espécies de pequenos felídeos, incluindo o gato-maracajá (Leopardus wiedii) e o jaguarundi (Puma yagouaroundi). Estas duas espécies apresentam ampla distribuição geográfica nos neotrópicos, ocorrendo geralmente em simpatria e compartilhando vários aspectos biogeográficos. Neste trabalho, construímos um banco com dados de ocorrência destas espécies e usamos o método de máxima entropia (Maxent) para obter modelos de adequabilidade de habitat para cada uma delas. Os preditores ambientais com maior percentual de contribuição aos modelos gerados foram identificados, sendo ainda avaliado como cada um deles influencia na adequabilidade de habitat estimada para as espécies. Variáveis associadas com temperatura e precipitação foram identificadas como importantes para a ocorrência das espécies, com os dois felídeos respondendo similarmente a elas. No entanto, para o gato-maracajá foi identificada uma maior variação na adequabilidade de habitat estimada, de acordo com os valores locais das variáveis climáticas. Os modelos resultaram em uma grande similaridade nos nichos ecológicos (> 76%), mas apesar disto diferentes áreas foram identificadas como apresentando as condições mais favoráveis à ocorrência de cada espécie. Considerando a área total estimada como adequada para cada um dos felídeos, apenas 50% e 72% destas foram classificadas como moderada a altamente adequadas para a ocorrência do gato-maracajá e do jaguarundi, respectivamente, com o modelo gerado para o gato-maracajá compreendendo uma maior proporção de ambientes florestais em comparação ao modelo gerado para o jaguarundi. Estes resultados provêm informações relevantes para a compreensão da ecologia destas espécies, bem como para o delineamento de estratégias de conservação com foco nestes felídeos, como a indicação de áreas prioritárias à sua preservação em longo prazo.

IMPORTANCE: Chromosome 6p amplification is associated with more benign behavior for uveal melanomas (UMs) with an otherwise high risk of metastasis conferred by chromosome 3 monosomy. Chromosome 6p contains several members of the B7 family of immune regulator genes, including butyrophilin-like 2 (BTNL2; OMIM, 606000), which is associated with prostate cancer risk and autoimmune diseases. OBJECTIVE: To investigate the expression and variant allele frequencies of BTNL2, a candidate gene for chromosome 6 amplification, in patients with UM. DESIGN, SETTING, AND PARTICIPANTS: In this case-control study, we analyzed the expression of BTNL2 in UM cell lines and human macrophages in patients with UM. Variants of BTNL2 were analyzed using probes for polymerase chain reaction and high-resolution melting. The association of missense variants rs28362679 and rs41441651 with tumor risk was analyzed in 209 patients with UM and 116 matched control patients as well as 12 UM and 64 other tumor cell lines. Genes that were differentially expressed in M1- and M2-polarized macrophages were identified by microarray analysis of 111 patients with UM, and the association of the expression of these genes with disease-free survival was analyzed by Cox regression analysis. Data were collected from September 2013 to November 2015. MAIN OUTCOMES AND MEASURES: Butyrophilin-like 2 single-nucleotide variants were associated with UM risk; M1 and M2 macrophage-specific gene expression was associated with disease-free survival. RESULTS: We genotyped a total of 325 patients. Of the 209 patients with UM, 124 (59.3%) were male, 114 (54.5%) were Italian, and 95 (45.5%) were German; the mean (range) age was 65 (27-94) years. Of the 116 Italian control patients, 67 (57.8%) were female, and the mean (range) age was 39 (21-88) years. Butyrophilin-like 2 is expressed in patients with UM and macrophages. The frequency of the rs28362679 variant was higher in patients with UM (16 of 209 [7.7%]; 95% CI, 4.7-12.2) than frequencies from European Variation Archive and Exome Aggregation Consortium data (2134 of 118 564 [1.8%]; 95% CI, 1.7-1.9) and Exome Sequencing Project data (100 of 4540 [2.2%]; 95% CI, 1.8-2.7) but were not higher compared with Italian control patients (10 of 116 [8.6%]; 95% CI, 4.6-15.4). The rs41441651 variant was present in 5 patients with UM (2.4%; 95% CI, 0.9-5.7), 2 Italian control patients (1.7%; 95% CI, 0.1-6.5), 2846 patients from European Variation Archive and Exome Aggregation Consortium data (2.4%; 95% CI, 2.3-2.5), and 23 patients from Exome Sequencing Project data (0.5%; 95% CI, 0.3-0.8). Human UM cells express M1 and M2 macrophage-specific genes, whose expression is associated with disease-free survival. CONCLUSIONS AND RELEVANCE: Butyrophilin-like 2, expressed at various levels by UM cells and macrophages, might interfere with the immune control of the tumor. Butyrophilin-like 2 variants showed highly variable frequencies among ethnically related cohorts. There was no enrichment of BTNL2 variants in patients with UM compared with control patients.

What are the determinants of public support for marijuana legalization? In the last 3 years, Uruguay and the states of Colorado and Washington have legalized the production, sale, and consumption of recreational marijuana. Although Uruguay and the United States have followed different paths toward legalization, these cases provide an excellent opportunity to explore the relationship between drug policy implementation and public opinion in different political contexts. Using logistic regressions on data from the 2014 AmericasBarometer cross-national surveys conducted in Uruguay, the United States, and El Salvador, this article examines citizen views toward marijuana regulation and the individual determinants of support for legalization in a comparative fashion. Results underline the role of political socialization variables in those countries in which legalization is being debated. Across countries, some of the most important factors for predicting positive attitudes toward marijuana regulation are related to political tolerance, ideology, and the views toward the government.

Un bénéfice clinique durable a été obtenu avec l’association nivolumab (NIVO)+ipilimumab (IPI), dont une survie globale (SG) de 49 % et une survie spécifique liée au mélanome (SSM) de 56 %, sans atteindre la SSM médiane après un suivi minimum de 6,5 ans. Nous rapportons ici des résultats montrant que l’efficacité se maintient à 7,5 ans.

IMPORTANCE: Conventional melanoma serum biomarkers (S100 and lactate dehydrogenase [LDH]) perform poorly in patients with uveal melanoma, and the search for new biomarkers is needed. A high expression of the oncoprotein c-Met in primary uveal melanoma is associated with metastatic progression, and c-Met is released as a soluble ectodomain through ADAM10- and ADAM17-mediated cleavage, suggesting a possible role as biomarker. OBJECTIVE: To determine the potential role of soluble c-Met (sc-Met) as a biomarker of uveal melanoma progression in comparison with S100 and LDH. DESIGN, SETTING, AND PARTICIPANTS: Soluble c-Met was studied in the conditioned medium of 9 uveal melanoma cell lines and in the blood serum samples of 24 mice with uveal melanoma xenografts, 57 patients with uveal melanoma (17 patients whose tumors metastasized and 40 patients whose tumors did not metastasize), and 37 healthy donors. We collected blood samples for as long as 5 years after treatment of the primary tumor. The concentration of sc-Met was measured using enzyme-linked immunosorbent assays, and the receiver operating characteristic curve was used to evaluate sensitivity and specificity in the identification of metastatic uveal melanoma. The study began on May 2, 2011, and the last samples were collected in January 2015. MAIN OUTCOMES AND MEASURES: Levels of sc-Met in uveal melanoma cell cultures and in the blood serum samples of xenotransplanted mice, of healthy donors, and of patients with uveal melanoma during follow-up. RESULTS: The conditioned medium of uveal melanoma cell lines and the blood serum samples of mice with uveal melanoma xenografts contained significant levels of sc-Met. Patients with metastatic disease had significantly higher serum levels of sc-Met (median level, 590 ng/mL [range, 246-12 856 ng/mL]) than did patients without metastatic disease (median level, 296 ng/mL [range, 201-469 ng/mL]) (P &lt; .001) and healthy donors (median level, 285 ng/mL [range, 65-463 ng/mL]) (P &lt; .001). Analysis of receiver operating characteristic curves for sc-Met levels in patients with nonmetastatic uveal melanoma vs patients with metastatic uveal melanoma yielded an area under the curve of 0.82 (95% CI, 0.68-0.95) (P &lt; .001), which was superior to the areas under the curve achieved with S100 or LDH markers. Patients with progressive metastatic disease showed further increases in sc-Met level, whereas stable patients did not. CONCLUSIONS AND RELEVANCE: The present pilot study suggests that sc-Met should be further exploited as a biomarker for monitoring of uveal melanoma.