Extensive "halo naevi" phenomenon and regression of melanin during nivolumab treatment in metastatic melanoma: A predictor of a better outcome?

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Performance of non-invasive respiratory function indices in predicting clinical outcomes in patients hospitalized for COVID-19 pneumonia in medical and sub-intensive wards: a retrospective cohort study

Coronavirus disease 2019 (COVID-19) is a newly recognized infectious disease which can lead to acute respiratory distress syndrome requiring ventilatory support and intensive care unit admission. The aim of our study is to evaluate the performance of two non-invasive respiratory function indices (the ROX index and the SatO2/FiO2 ratio), as compared to the traditional PaO2/FiO2 ratio, in predicting a clinically relevant composite outcome (death or intubation) in hospitalized patients for COVID-19 pneumonia. Four hospital centers in Northern Italy conducted an observational retrospective cohort study during the first wave of COVID-19 pandemic. Four hundred and fifty-six patients with COVID-19 pneumonia admitted to medical or sub-intensive wards were enrolled. Clinical, laboratory, and respiratory parameters, for the calculation of different indices, were measured at hospital admission. In medical wards (Verona and Padua) the PaO2/FiO2 ratio, ROX index and SatO2/FiO2 ratio were able to predict intubation or death with good accuracy (AUROC for the PaO2/FiO2 ratio, ROX index and SatO2/FiO2 ratio of 75%, 75% and 74%, respectively). Regarding sub-intensive wards (Milan and Mantua), none of the three respiratory function indices was significantly associated with the composite outcome. In patients admitted to medical wards for COVID-19 pneumonia, the ROX index and the SatO2/FiO2 ratio demonstrated not only good performance in predicting intubation or death, but their accuracy was comparable to that of the PaO2/FiO2 ratio. In this setting, where repeated arterial blood gas tests are not always feasible, they could be considered a reliable alternative to the invasive PaO2/FiO2 ratio

Sun-induced chlorophyll fluorescence and photochemical reflectance index improve remote-sensing gross primary production estimates under varying nutrient availability in a typical Mediterranean savanna ecosystem

Este estudio investiga las diferentes actuaciones de ópticas sobre los índices para estimar la producción primaria bruta (GPP) del estrato herbáceo de una sabana mediterránea con diferente disponibilidad de nitrógeno (N) y de fósforo (P). La fluorescencia de la clorofila inducida por el sol sobre el rendimiento calculado en 760 nm (FY760), escala de índice de reflectancia fotoquímica (sPRI), MERIS terrestre (índice de clorofila MTCI) y el índice de vegetación de diferencia normalizada (NDVI) fueron calculadas desde cerca de la superficie y las mediciones de espectroscopia de campo recolectados se hicieron utilizando espectrómetros de alta resolución espectral, que abarcan las regiones del infrarrojo cercano visible. La GPP fue medida utilizando cámaras de dosel en las mismas localidades muestreadas por los espectrómetros. Hemos probado si la eficiencia del uso de los modelos de luz (LUE) impulsados por cantidades de teledetección (RSMs) pueden hacer un mejor seguimiento de los cambios en la GPP causada por fuentes de nutrientes en comparación con aquellos impulsados exclusivamente por datos meteorológicos (MM). En particular, comparamos los espectáculos de diferentes formulaciones de RSM -basándose en la utilización de FY760 o sPRI como proxy para LUE y NDVI MTCI o como una fracción de la radiación fotosintéticamente activa absorbida (APAR f)- con las clásicas de MM. Los resultados mostraron mayor GPP en la N -parcelas experimentales fertilizadas durante el período de crecimiento. Estas diferencias en la GPP desaparecieron en el período de secado, cuando los efectos de la senescencia enmascarada contiene diferencias de potencial debido a la planta N. Por consiguiente, MTCI estaba estrechamente relacionada con la media de la planta N, contenida a través de tratamientos (r2 D 0:86, p < 0:01), porque estaba mal relacionados con GPP (r2 D 0:45, p < 0:05). Por el contrario sPRI y FY760 se correlacionaban bien con GPP durante todo el período de medición. Los resultados revelaron que la relación entre el GPP y FY760 no es única en los tratamientos, pero no se ve afectada por la disponibilidad de N. Los resultados de un análisis de validación cruzada mostró que el MM (AICcv D 127, MEcv D 0:879) superó a RSM (AICcv D 140, MEcv D 0:8737,) cuando la humedad del suelo fue utilizada para restringir la dinámica estacional de LUE. Sin embargo, el análisis residual demostró que las predicciones de GPP con MM son inexactas cuando no revela explícitamente unas variables climáticas en cambios relacionados con el parámetro de nutrientes LUE. Estos resultados sugieren que RSM es un medio valioso para diagnosticar los efectos inducidos por los nutrientes en la actividad fotosintética.This study investigates the performances of different optical indices to estimate gross primary production (GPP) of herbaceous stratum in a Mediterranean savanna with different nitrogen (N) and phosphorous (P) availability. Sun-induced chlorophyll fluorescence yield computed at 760 nm (Fy760), scaled photochemical reflectance index (sPRI), MERIS terrestrial-chlorophyll index (MTCI) and normalized difference vegetation index (NDVI) were computed from near-surface field spectroscopy measurements collected using high spectral resolution spectrometers covering the visible near-infrared regions. GPP was measured using canopy chambers on the same locations sampled by the spectrometers. We tested whether light-use efficiency (LUE) models driven by remote-sensing quantities (RSMs) can better track changes in GPP caused by nutrient supplies compared to those driven exclusively by meteorological data (MM). Particularly, we compared the performances of different RSM formulations – relying on the use of Fy760 or sPRI as a proxy for LUE and NDVI or MTCI as a fraction of absorbed photosynthetically active radiation (f APAR) – with those of classical MM. Results showed higher GPP in the N-fertilized experimental plots during the growing period. These differences in GPP disappeared in the drying period when senescence effects masked out potential differences due to plant N content. Consequently, although MTCI was closely related to the mean of plant N content across treatments (r2 D 0:86, p < 0:01), it was poorly related to GPP (r2 D 0:45, p < 0:05). On the contrary sPRI and Fy760 correlated well with GPP during the whole measurement period. Results revealed that the relationship between GPP and Fy760 is not unique across treatments, but it is affected by N availability. Results from a cross-validation analysis showed that MM (AICcv D 127, MEcv D 0:879) outperformed RSM (AICcv D 140, MEcv D 0:8737) when soil moisture was used to constrain the seasonal dynamic of LUE. However, residual analyses demonstrated that GPP predictions with MM are inaccurate whenever no climatic variable explicitly reveals nutrient-related changes in the LUE parameter. These results suggest that RSM is a valuable means to diagnose nutrient-induced effects on the photosynthetic activity.Trabajo financiado por: Alexander von Humboldt Foundation y la Max Planck Research AwardpeerReviewe

Effects of antiangiogenetic drugs on microcirculation and macrocirculation in patients with advanced-stage renal cancer

Adverse cardiovascular effects, including hypertension, were described in patients with different cancers treated with tyrosine kinase inhibitors (TKI). The mechanism of TKI-related hypertension is still debated. The aim of this work was to study the effects of TKI on blood pressure (BP), searching for a relationship with possible causative factors in patients with metastatic renal cell carcinoma. We included 29 patients in a prospective, observational study; 22 were treated with a first-line drug (sunitinib), while seven participated in the second-line treatment (axitinib or cabozantinib). Patients were investigated at the beginning of antiangiogenic therapy (T0) and at one (T1), three (T2), and six months (T3) after treatment. Patients were evaluated by office blood pressure (BP) and ultrasonography to measure flow-mediated dilatation (FMD), and carotid artery distensibility (cDC) by echocardiography and nailfold capillaroscopy. Plasma endothelin-1 (p-ET-1), urine nitrates, and proteins were also measured. At T1, systolic BP, along with U proteins and p-ET-1, increased significantly. In patients with a clinically significant increase in BP (defined as either the need for an antihypertensive drug or systolic blood pressure (SBP) T1\u207bT0 6510 and/or SBP 65140 mmHg and/or diastolic blood pressure (DBP) T1\u207bT0 655 and/or DBP 6590 mmHg), the urine nitrate concentration was lower at T0, whereas there were no differences in the p-ET-1 and U proteins. Seventeen participants showed changes in the capillaroscopic pattern at T1 with no association with BP increases. There were no differences in the FMD, cDC, and echocardiographic parameters. Our findings are consistent with those of previous studies about BP increases by TKI, and suggest a role of nitric oxide in BP maintenance in this population

The 2020 Italian Society of Arterial Hypertension (SIIA) practical guidelines for the management of primary aldosteronism

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The Long-Baseline Neutrino Experiment: Exploring Fundamental Symmetries of the Universe

The preponderance of matter over antimatter in the early Universe, the dynamics of the supernova bursts that produced the heavy elements necessary for life and whether protons eventually decay --- these mysteries at the forefront of particle physics and astrophysics are key to understanding the early evolution of our Universe, its current state and its eventual fate. The Long-Baseline Neutrino Experiment (LBNE) represents an extensively developed plan for a world-class experiment dedicated to addressing these questions. LBNE is conceived around three central components: (1) a new, high-intensity neutrino source generated from a megawatt-class proton accelerator at Fermi National Accelerator Laboratory, (2) a near neutrino detector just downstream of the source, and (3) a massive liquid argon time-projection chamber deployed as a far detector deep underground at the Sanford Underground Research Facility. This facility, located at the site of the former Homestake Mine in Lead, South Dakota, is approximately 1,300 km from the neutrino source at Fermilab -- a distance (baseline) that delivers optimal sensitivity to neutrino charge-parity symmetry violation and mass ordering effects. This ambitious yet cost-effective design incorporates scalability and flexibility and can accommodate a variety of upgrades and contributions. With its exceptional combination of experimental configuration, technical capabilities, and potential for transformative discoveries, LBNE promises to be a vital facility for the field of particle physics worldwide, providing physicists from around the globe with opportunities to collaborate in a twenty to thirty year program of exciting science. In this document we provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess.Comment: Major update of previous version. This is the reference document for LBNE science program and current status. Chapters 1, 3, and 9 provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess. 288 pages, 116 figure

Global patterns of care in advanced stage mycosis fungoides/Sezary syndrome: a multicenter retrospective follow-up study from the Cutaneous Lymphoma International Consortium

ABSTRACT Background Advanced-stage mycosis fungoides (MF)/Sezary syndrome (SS) patients are weighted by an unfavorable prognosis and share an unmet clinical need of effective treatments. International guidelines are available detailing treatment options for the different stages but without recommending treatments in any particular order due to lack of comparative trials. The aims of this second CLIC study were to retrospectively analyze the pattern of care worldwide for advanced-stage MF/SS patients, the distribution of treatments according to geographical areas (USA versus non-USA), and whether the heterogeneity of approaches has potential impact on survival. Patients and methods This study included 853 patients from 21 specialist centers (14 European, 4 USA, 1 each Australian, Brazilian, and Japanese). Results Heterogeneity of treatment approaches was found, with up to 24 different modalities or combinations used as first-line and 36% of patients receiving four or more treatments. Stage IIB disease was most frequently treated by total-skin-electron-beam radiotherapy, bexarotene and gemcitabine; erythrodermic and SS patients by extracorporeal photochemotherapy, and stage IVA2 by polychemotherapy. Significant differences were found between USA and non-USA centers, with bexarotene, photopheresis and histone deacetylase inhibitors most frequently prescribed for first-line treatment in USA while phototherapy, interferon, chlorambucil and gemcitabine in non-USA centers. These differences did not significantly impact on survival. However, when considering death and therapy change as competing risk events and the impact of first treatment line on both events, both monochemotherapy (SHR = 2.07) and polychemotherapy (SHR = 1.69) showed elevated relative risks. Conclusion This large multicenter retrospective study shows that there exist a large treatment heterogeneity in advanced MF/SS and differences between USA and non-USA centers but these were not related to survival, while our data reveal that chemotherapy as first treatment is associated with a higher risk of death and/or change of therapy and thus other therapeutic options should be preferable as first treatment approach

An explainable model of host genetic interactions linked to COVID-19 severity

We employed a multifaceted computational strategy to identify the genetic factors contributing to increased risk of severe COVID-19 infection from a Whole Exome Sequencing (WES) dataset of a cohort of 2000 Italian patients. We coupled a stratified k-fold screening, to rank variants more associated with severity, with the training of multiple supervised classifiers, to predict severity based on screened features. Feature importance analysis from tree-based models allowed us to identify 16 variants with the highest support which, together with age and gender covariates, were found to be most predictive of COVID-19 severity. When tested on a follow-up cohort, our ensemble of models predicted severity with high accuracy (ACC = 81.88%; AUCROC = 96%; MCC = 61.55%). Our model recapitulated a vast literature of emerging molecular mechanisms and genetic factors linked to COVID-19 response and extends previous landmark Genome-Wide Association Studies (GWAS). It revealed a network of interplaying genetic signatures converging on established immune system and inflammatory processes linked to viral infection response. It also identified additional processes cross-talking with immune pathways, such as GPCR signaling, which might offer additional opportunities for therapeutic intervention and patient stratification. Publicly available PheWAS datasets revealed that several variants were significantly associated with phenotypic traits such as "Respiratory or thoracic disease", supporting their link with COVID-19 severity outcome.A multifaceted computational strategy identifies 16 genetic variants contributing to increased risk of severe COVID-19 infection from a Whole Exome Sequencing dataset of a cohort of Italian patients

The polymorphism L412F in TLR3 inhibits autophagy and is a marker of severe COVID-19 in males

The polymorphism L412F in TLR3 has been associated with several infectious diseases. However, the mechanism underlying this association is still unexplored. Here, we show that the L412F polymorphism in TLR3 is a marker of severity in COVID-19. This association increases in the sub-cohort of males. Impaired macroautophagy/autophagy and reduced TNF/TNFα production was demonstrated in HEK293 cells transfected with TLR3L412F-encoding plasmid and stimulated with specific agonist poly(I:C). A statistically significant reduced survival at 28 days was shown in L412F COVID-19 patients treated with the autophagy-inhibitor hydroxychloroquine (p = 0.038). An increased frequency of autoimmune disorders such as co-morbidity was found in L412F COVID-19 males with specific class II HLA haplotypes prone to autoantigen presentation. Our analyses indicate that L412F polymorphism makes males at risk of severe COVID-19 and provides a rationale for reinterpreting clinical trials considering autophagy pathways. Abbreviations: AP: autophagosome; AUC: area under the curve; BafA1: bafilomycin A1; COVID-19: coronavirus disease-2019; HCQ: hydroxychloroquine; RAP: rapamycin; ROC: receiver operating characteristic; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; TLR: toll like receptor; TNF/TNF-α: tumor necrosis factor