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Abstract We utilize ocean 10‐m wind speed (U10m) from the microwave Multi‐sensor Advanced Climatology data set to examine the coupling between convective cloud and precipitation processes, synoptic state, and U10m and to evaluate the representation of U10m in global climate models (GCMs). We find that midlatitude U10m is underestimated by GCMs relative to observations. We examine two potential mechanisms to explain this model behavior: cold pool formation in cold air outbreaks (CAOs) associated with downdrafts that enhance U10m and sea surface temperature (SST) gradients affecting U10m through thermally forced surface winds at regional scales. When the effects of the CAO index (M) and SST gradients on U10m are accounted for, a relationship between GCM horizontal resolution and U10m appears. The strongest correlation between resolution and U10m is over the western boundary currents characterized by frequent CAOs atop strong SST gradients which drives the strongest surface fluxes on Earth.

The Southern Ocean is critically important for global climate yet poorly represented by climate models. Here the authors trace sea surface temperature biases in this region to cloud-related errors in atmospheric-model simulated surface heat fluxes and provide a pathway to improve the models.

'In the original HTML version of this Article, ref.12 was incorrectly cited in the first sentence of the first paragraph of the Introduction. The correct citation is ref. 2. This has now been corrected in the HTML version of the Article; the PDF version was correct at the time of publication.’

Indications for immune checkpoint inhibitor therapy are increasing. As the population ages, many patients receiving such drugs will be older adults. Such patients are under-represented in clinical trials, and therefore the safety of immune checkpoint inhibitors in this population has not been adequately assessed. A retrospective multicenter analysis of toxicities was performed in patients with advanced or metastatic solid cancers receiving anti-programmed cell death protein 1 (anti-PD-1) and/or anti-CTLA4 antibodies across three age cohorts (

BackgroundIdentifying stage II patients with colorectal cancer (CRC) at higher risk of progression is a clinical priority in order to optimize the advantages of adjuvant chemotherapy while avoiding unnecessary toxicity. Recently, the intensity and the quality of the host immune response in the tumor microenvironment have been reported to have an important role in tumorigenesis and an inverse association with tumor progression. This association is well established in microsatellite instable CRC. In this work, we aim to assess the usefulness of measures of T-cell infiltration as prognostic biomarkers in 640 stage II, CRC tumors, 582 of them confirmed microsatellite stable.Methods and findingsWe measured both the quantity and clonality index of T cells by means of T-cell receptor (TCR) immunosequencing in a discovery dataset (95 patients with colon cancer diagnosed at stage II and microsatellite stable, median age 67, 30% women) and replicated the results in 3 additional series of stage II patients from 2 countries. Series 1 and 2 were recruited in Barcelona, Spain and included 112 fresh frozen (FF, median age 69, 44% women) and 163 formalin-fixed paraffin-embedded (FFPE, median age 67, 39% women) samples, respectively. Series 3 included 270 FFPE samples from patients recruited in Haifa, Northern Israel, as part of a large case-control study of CRC (median age 73, 46% women). Median follow-up time was 81.1 months. Cox regression models were fitted to evaluate the prognostic value of T-cell abundance and Simpson clonality of TCR variants adjusting by sex, age, tumor location, and stage (IIA and IIB). In the discovery dataset, higher TCR abundance was associated with better prognosis (hazard ratio [HR] for ≥Q1 = 0.25, 95% CI 0.10-0.63, P = 0.003). A functional analysis of gene expression on these tumors revealed enrichment in pathways related to immune response. Higher values of clonality index (lower diversity) were not associated with worse disease-free survival, though the HR for ≥Q3 was 2.32 (95% CI 0.90-5.97, P = 0.08). These results were replicated in an independent FF dataset (TCR abundance: HR = 0.30, 95% CI 0.12-0.72, P = 0.007; clonality: HR = 3.32, 95% CI 1.38-7.94, P = 0.007). Also, the association with prognosis was tested in 2 independent FFPE datasets. The same association was observed with TCR abundance (HR = 0.41, 95% CI 0.18-0.93, P = 0.03 and HR = 0.56, 95% CI 0.31-1, P = 0.042, respectively, for each FFPE dataset). However, the clonality index was associated with prognosis only in the FFPE dataset from Israel (HR = 2.45, 95% CI 1.39-4.32, P = 0.002). Finally, a combined analysis combining all microsatellite stable (MSS) samples demonstrated a clear prognosis value both for TCR abundance (HR = 0.39, 95% CI 0.26-0.57, P = 1.3e-06) and the clonality index (HR = 2.13, 95% CI 1.44-3.15, P = 0.0002). These associations were also observed when variables were considered continuous in the models (HR per log2 of TCR abundance = 0.85, 95% CI 0.78-0.93, P = 0.0002; HR per log2 or clonality index = 1.16, 95% CI 1.03-1.31, P = 0.016).LimitationsThis is a retrospective study, and samples had been preserved with different methods. Validation series lack complete information about microsatellite instability (MSI) status and pathology assessment. The Molecular Epidemiology of Colorectal Cancer (MECC) study had information about overall survival instead of progression-free survival.ConclusionResults from this study demonstrate that tumor lymphocytes, assessed by TCR repertoire quantification based on a sequencing method, are an independent prognostic factor in microsatellite stable stage II CRC.

Background: There is insufficient evidence to support clinical decision-making for cancer patients diagnosed with COVID-19 due to the lack of large studies.Methods: We used data from a single large UK Cancer Center to assess the demographic/clinical characteristics of 156 cancer patients with a confirmed COVID-19 diagnosis between 29 February and 12 May 2020. Logistic/Cox proportional hazards models were used to identify which demographic and/or clinical characteristics were associated with COVID-19 severity/death.Results: 128 (82%) presented with mild/moderate COVID-19 and 28 (18%) with a severe case of the disease. An initial cancer diagnosis >24 months before COVID-19 [OR: 1.74 (95% CI: 0.71–4.26)], presenting with fever [6.21 (1.76–21.99)], dyspnea [2.60 (1.00–6.76)], gastro-intestinal symptoms [7.38 (2.71–20.16)], or higher levels of C-reactive protein [9.43 (0.73–121.12)] were linked with greater COVID-19 severity. During a median follow-up of 37 days, 34 patients had died of COVID-19 (22%). Being of Asian ethnicity [3.73 (1.28–10.91)], receiving palliative treatment [5.74 (1.15–28.79)], having an initial cancer diagnosis >24 months before [2.14 (1.04–4.44)], dyspnea [4.94 (1.99–12.25)], and increased CRP levels [10.35 (1.05–52.21)] were positively associated with COVID-19 death. An inverse association was observed with increased levels of albumin [0.04 (0.01–0.04)].Conclusions: A longer-established diagnosis of cancer was associated with increased severity of infection as well as COVID-19 death, possibly reflecting the effects a more advanced malignant disease has on this infection. Asian ethnicity and palliative treatment were also associated with COVID-19 death in cancer patients.

Abstract: Recent regulation mandates that ships conduct mid-ocean ballast water exchange (BWE) prior to discharging foreign ballast in U.S. territorial waters. We investigated the utility of dissolved concentration measurements for 6 elements (Ba, P, Mn, U, V and Mo) in the ballast tanks of ships operating in the North Pacific and Atlantic oceans as tracers of mid-ocean BWE. Relatively conservative elements Mo, U and V provided little additional information beyond that obtained from salinity, whereas nonconservative Ba, P and Mn offered greater resolution. The utility of Ba, P and Mn was further examined in the context of three criteria: (1) stability, or whether tracers maintain stable concentrations in ballast tanks over time; (2) fidelity, or the degree to which tracer concentrations in ballast tanks faithfully reflect concentrations at their ocean source; and (3) predictability, or the degree to which ballast tanks have a predictable and restricted range of tracer concentrations following BWE. We found that in water held in ballast tanks over time, average stability increased for Mn21%>3%) and fidelity increased in the same direction. While Ba and P usually increased discrimination at high salinities, Mn was typically the most sensitive indicator of BWE and the presence of residual port water in partially exchanged tanks. Ba, P and Mn in tanks exchanged in the Atlantic exhibited different concentration ranges compared to tanks exchanged in the Pacific, suggesting that if trace elements are to be used to verify BWE, criteria for discriminating between exchanged and unexchanged ballast tanks may need to be basin-specific. [Copyright &y& Elsevier]

Background: Weight loss (WL) reduces bone mass and increases fracture risk. Mechanisms regulating calcium metabolism during WL are unclear. Objective: The objective was to assess the effect of 6 wk of WL at 2 different amounts of calcium intake [normal (NlCa): 1 g/d; high (HiCa): 1.8 g/d] on true fractional calcium absorption (TFCA), bone turnover, and bone-regulating hormones in overweight postmenopausal women. Design: Seventy-three women (body mass index, 26.9±1.9 kg/m2) were recruited either to consume a moderately energy-restricted diet (WL group) or to maintain their body weight [weight-maintenance (WM) group] and were randomly assigned to either the HiCa or the NlCa group in a double-blind manner. Subjects underwent weekly diet counseling, and measurements were taken at baseline and after 6 wk. Results: Fifty-seven women completed the study and had a baseline TFCA of 24.9±7.4%. Energy restriction significantly decreased the total calcium absorbed (P < 0.05) in the WL group (n = 32) compared with the WM group (n=25; analysis of covariance). Regression analysis showed that a greater rate of weight loss suppressed TFCA and the total calcium absorbed (P<0.05) in the HiCa group. The women in the NlCa WL group absorbed inadequate amounts of calcium (195±49 mg/d), whereas the women in the HiCaWL group absorbed adequate amounts (348±118 mg/d). Parathyroid hormone explained 22% of the variance in calcium absorbed in the NlCa group only. Conclusions: We suggest that WL is associated with elevated calcium requirements that, if not met, could activate the calcium parathyroid hormone axis to absorb more calcium. Normal intakes of calcium during energy restriction result in inadequate total calcium absorption and could ultimately compromise calcium balance and bone mass. [ABSTRACT FROM AUTHOR]

Patients with metastatic melanoma were treated with tremelimumab and interferon-α (IFN) in a previously reported clinical trial [NCT00610857]. Responses were assessed by RECIST criteria as complete (CR) or partial (PR), stable disease (SD) or progressive disease (PD). In this study, T-cell receptor (TCR) beta-chain repertoire was immunosequenced in peripheral blood mononuclear cells (PBMC) specimens (N = 33) and tumor samples (N = 18) utilizing the immunoSEQ® Assay to determine repertoire clonality and T cell fractions at pre-treatment (tumor and PBMC), one month (PBMC) and 3 months (PBMC) time points and evaluate its association with clinical outcomes. In the pretreatment tumor microenvironment (TME), T cell clonality was significantly (p = .035) different and greater in patients who achieved disease control (CR, PR, SD) versus those with non-disease control (PD) as best response to treatment. Further, there was significantly (p = .001) increased TCR fraction in tissue of responders (CR, PR) versus non-responders (PD, SD). In examining T cell clonality in the circulation (PBMC), no significant associations were found in the pretreatment samples. However, early on-treatment (4 weeks) there was a significant decrease in T cell clonality that was associated with improved overall survival (p = .01) and progression-free survival (p = .04). In addition, analysis of temporal changes in tumor-infiltrating lymphocytes (TIL) and peripheral TCR repertoire revealed that responders had significantly higher clonal expansion of TIL in the circulation at 4 weeks than non-responders (p = .036). Our study provided interesting mechanistic data related to CTLA-4 Blockade and IFN and potential biomarkers of immunotherapeutic benefit.

There is growing evidence that CD8+ cytotoxic T lymphocyte (CTL) responses can contribute to long-term remission of many malignancies. The etiological agent of adult T-cell leukemia/lymphoma (ATL), human T lymphotropic virus type-1 (HTLV-1), contains highly immunogenic CTL epitopes, but ATL patients typically have low frequencies of cytokine-producing HTLV-1-specific CD8+ cells in the circulation. It remains unclear whether patients with ATL possess CTLs that can kill the malignant HTLV-1 infected clone. Here we used flow cytometric staining of TCRVβ and cell adhesion molecule-1 (CADM1) to identify monoclonal populations of HTLV-1-infected T cells in the peripheral blood of patients with ATL. Thus, we quantified the rate of CD8+-mediated killing of the putative malignant clone in ex vivo blood samples. We observed that CD8+ cells from ATL patients were unable to lyse autologous ATL clones when tested directly ex vivo. However, short in vitro culture restored the ability of CD8+ cells to kill ex vivo ATL clones in some donors. The capacity of CD8+ cells to lyse HTLV-1 infected cells which expressed the viral sense strand gene products was significantly enhanced after in vitro culture, and donors with an ATL clone that expressed the HTLV-1 Tax gene were most likely to make a detectable lytic CD8+ response to the ATL cells. We conclude that some patients with ATL possess functional tumour-specific CTLs which could be exploited to contribute to control of the disease.

This article is the first in a three-part series on translation quality. The articles build on one another by addressing definitions of translation, quality, and finally translation quality. Concerning the meaning of translation, many definitions have been proposed in the translation-studies literature. This article, however, is not a literature review. Instead, it describes a "landscape" within which various definitions of translation can be "planted.” This landscape is delimited by two axes—namely, scope and specifications—and provides a framework for discussing such questions as (a) the relationship between translation and localization and (b) the role of translation specifications. Within that landscape, this article presents two opposing views about the definition of translation. The authors disagree about which of these views is most useful, but they agree that stakeholders must clearly define translation before they can meaningfully address translation quality.

One way to answer the question “What is translation quality?” is to start with a framework put forward by Garvin (1984). That framework describes five approaches to determining quality: Transcendent, Product-Based, User-Based, Production-Based ("manufacturing" being Garvin’s term) and Value-Based. Garvin does not claim that any one of these approaches is sufficient unto itself. Rather, a well-rounded view of quality requires all five. The present article briefly describes these five approaches to quality and references the work of several of the most visible and respected people in the discipline of quality management. Following that presentation, the article discusses arguments for and against applying quality-management approaches to the translation industry. The authors of this article disagree about the relevance of quality management to the translation industry, but they do agree that stakeholders should take a position on the issue.

Many problems in the translation industry revolve around customer dissatisfaction with someone’s translation quality and disputes between translators when one is revising the work of the other. To determine whether someone has attained translation quality, one must be able to measure it. To measure translation quality, one must be able to define it. And to define translation quality, one must be able to define both translation and quality. Our two prior articles have addressed these terms respectively. Those articles do not resolve disagreements about these terms; indeed, we authors have unresolved disagreements among ourselves. However, the articles outline how different definitions can radically affect people’s expectations about translation and quality. This third article builds on the first two and presents two contrasting definitions of translation quality, a narrow one and a broad one. The narrow definition matches with the narrow definition of translation in the first article and an emphasis on the transcendent view of quality in the second article, while the broad definition matches with the broad definition of translation the first article and an integration of the five approaches in quality management from the second article. The authors strongly disagree about which definition of translation quality is better for the translation industry. Rather than pretending to be the end of this discussion, it hopes to encourage a continuation of the debate that has taken place among the authors.