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Abstract Climate change is restructuring natural ecosystems. The direct impacts of these events on biodiversity and community structure are widely documented, but the impacts on the genetic variation of populations remains largely unknown. We monitored populations of Acropora coral on a remote coral reef system in northwest Australia for two decades and through multiple cycles of impact and recovery. We combined these demographic data with a temporal genetic dataset of a common broadcast spawning corymbose Acropora to explore the spatial and temporal patterns of connectivity underlying recovery. Our data show that broad-scale dispersal and post-recruitment survival drive recovery from recurrent disturbances, including mass bleaching and mortality. Consequently, genetic diversity and associated patterns of connectivity are maintained through time in the broader metapopulation. The results highlight an inherent resilience in these globally threatened species of coral and showcase their ability to cope with multiple disturbances, given enough time to recover is permitted.

Abstract Although clinical examination still represents the gold standard for the differential diagnosis of prolonged disorders of consciousness (pDoC), the introduction of innovative markers is essential for diagnosis and prognosis, due to the problem of covert cognition. We evaluated the brain-derived neurotrophic factor protein (BDNF) and the soluble cell adhesion molecules proteins (CAMs) in a cohort of prolonged disorders of consciousness patients to identify a possible application in the clinical context. Furthermore, peripheral blood determinations were correlated with imaging parameters such as white matter hyperintensities (WMH), cranial standardized uptake value (cSUV), electroencephalography (EEG) data and clinical setting. Our results, although preliminary, identify BDNF as a possible blood marker for the diagnosis of pDoC (p value 0.001), the soluble CAMs proteins CD44, Vcam-1, E-selectin (p value

Abstract No prospective data were available prior to 2021 to inform selection between combination BRAF and MEK inhibition versus dual blockade of programmed cell death protein-1 (PD-1) and cytotoxic T lymphocyte antigen-4 (CTLA-4) as first-line treatment options for BRAFV600-mutant melanoma. SECOMBIT (NCT02631447) was a randomized, three-arm, noncomparative phase II trial in which patients were randomized to one of two sequences with immunotherapy or targeted therapy first, with a third arm in which an 8-week induction course of targeted therapy followed by a planned switch to immunotherapy was the first treatment. BRAF/MEK inhibitors were encorafenib plus binimetinib and checkpoint inhibitors ipilimumab plus nivolumab. Primary outcome of overall survival was previously reported, demonstrating improved survival with immunotherapy administered until progression and followed by BRAF/MEK inhibition. Here we report 4-year survival outcomes, confirming long-term benefit with first-line immunotherapy. We also describe preliminary results of predefined biomarkers analyses that identify a trend toward improved 4-year overall survival and total progression-free survival in patients with loss-of-function mutations affecting JAK or low baseline levels of serum interferon gamma (IFNy). These long-term survival outcomes confirm immunotherapy as the preferred first-line treatment approach for most patients with BRAFV600-mutant metastatic melanoma, and the biomarker analyses are hypothesis-generating for future investigations of predictors of durable benefit with dual checkpoint blockade and targeted therapy.

In this paper, we present a comprehensive investigation of the challenges of Monocular Visual Simultaneous Localization and Mapping (vSLAM) methods for underwater robots. While significant progress has beenmade in state estimation methods that utilize visual data in the past decade, most evaluations have been limited to controlled indoor and urban environments, where impressive performance was demonstrated. However, these techniques have not been extensively tested in extremely challenging conditions, such as underwater scenarios where factors such as water and light conditions, robot path, and depth can greatly impact algorithm performance. Hence, our evaluation is conducted in real-world AUV scenarios as well as laboratory settings which provide precise external reference. A focus is laid on understanding the impact of environmental conditions, such as optical properties of the water and illumination scenarios, on the performance of monocular vSLAM methods. To this end, we first show that all methods perform very well in air and subsequently investigate the degradation of their performance in ever more challenging underwater environments. The final goal of this study is to identify techniques that can improve accuracy and robustness of SLAM methods in such conditions. To achieve this goal, we investigate the potential of image enhancement techniques to improve the quality of input images used by the SLAM methods, specifically in low visibility and extreme lighting scenarios in scattering media. We present a first evaluation on calibration maneuvers and simple image restoration techniques to determine their ability to enable or enhance the performance of monocular SLAM methods in underwater environments.

Objective. To report cross-sectionally serum levels of 25-hydroxyvitamin D [25(OH)D] in women living in Italy within 12 months from breast cancer (BC) diagnosis. Methods. Baseline data were obtained from 394 women diagnosed with primary BC, enrolled from 2016 to 2019 in a lifestyle trial conducted in Italy. Subjects’ characteristics were compared between two 25(OH)D concentrations (hypovitaminosis D30, and ≥35 versus

Abstract Behavioral assessments during the clinical evaluation in prolonged disorders of consciousness patients could be not sufficient for a correct diagnosis and prognostication. To this aim, we used an innovative approach, involving the ultra-sensitive determination of biological markers, correlating them with imaging parameters to investigate the prolonged disorders of consciousness (pDoC).We assessed the serum concentration of neurofilament light chain(NF-L) and glial fibrillary acidic protein (GFAP) in pDoC (n = 16), and healthy controls (HC, n = 6) as well as several clinical imaging parameters such as Fractional Anisotropy (FA), Whole Brain SUV, and White Matter Hyperintensities volumes (WMH) using PET-MRI acquisition. As for differential diagnosis task, only the imaging WMH volume was able to discriminate between vegetative state/unresponsive wakefulness syndrome (VS/UWS), and minimally conscious state (MCS) patients (p-value

Abstract Background Studies carried out in vitro and in a mouse model have shown that BRAF inhibitors enhance the effects of IFN-α on BRAFV600E melanoma cells through the inhibition of ERK. Therefore, the combination of vemurafenib and IFN-α in patients with BRAFV600E melanoma may provide therapeutic benefits; MEK inhibition may prevent the reactivation of the MAPK pathway induced by BRAF inhibitor resistance. Patients and methods In a phase I study, adult patients with advanced BRAFV600-mutated melanoma were treated with vemurafenib + PEG-IFN-α-2b or vemurafenib + cobimetinib + PEG-IFN-α-2b, to assess the safety of the combination and the upregulation of IFN-α/β receptor-1 (IFNAR1). Results Eight patients were treated; 59 adverse events with four serious ones (three related to study treatments) were reported. Patients with a pre-treatment IFNAR1 expression on ≤ 35% melanoma cells had a median progression-free survival of 12.0 months (range: 5.6–18.4 months) and a median overall survival of 31.0 months (range: 19.8–42.2 months), while patients with a pre-treatment IFNAR1 expression on > 35% of melanoma cells had a median progression-free survival of 4.0 months (range: 0–8.8; p = 0.03), and a median overall survival of 5 months (p = 0.02). Following treatment, responders had higher levels of growth-suppressor genes, including GAS1 and DUSP1, and genes involved in a metabolically robust immune response, including FAP. Conclusion Our study supports the overall safety of the vemurafenib + PEG-IFN-α-2b + cobimetinib combination. IFNAR1 expression levels correlated with response to treatment, including survival. Vemurafenib + PEG-IFN-α-2b + cobimetinib would have difficulty finding a niche in the current treatment scenario for advanced melanoma, but we speculate that our findings may contribute to identify subjects particularly responsive to treatment. Trial registration: The study was registered at clinicaltrials.gov (NCT01959633). Registered 10 October 2013, https://clinicaltrials.gov/ct2/show/NCT01959633

Abstract Association of immunotherapy and/or chemotherapy and/or targeted therapy, in sequence or as single therapies, may induce osteonecrosis of the jaw. Multidisciplinary team management of these patients should be provided.

Abstract Background PD-1 blocking agents, such as nivolumab, have demonstrated clear anti-tumor effects and clinical benefits in a subset of patients with advanced malignancies. Nonetheless, more efforts are needed to identify reliable biomarkers for outcome, to correctly select patients who will benefit from anti-PD-1 treatment. The aim of this study was to investigate the role of peripheral CD8+T cells expressing CD73, involved in the generation of the immune suppressive molecule adenosine, in predicting outcome after nivolumab treatment in advanced melanoma patients. Methods PBMCs from 100 melanoma patients treated with nivolumab were collected at National Cancer Institute “G. Pascale” of Naples. Frequencies of CD8+ lymphocytes phenotypes were assessed by flow cytometry at baseline before nivolumab treatment, along with clinical characteristics and blood count parameters. Healthy controls (n = 20) were also analysed. Percentages of baseline T cells expressing PD-1 and CD73 were correlated with outcome after nivolumab treatment. Results Melanoma patients presented a lower frequency of total circulating CD8+ lymphocytes than control subjects (p = 0.008). Patients with low baseline percentage of circulating CD8+PD-1+CD73+ lymphocytes (

Abstract The therapeutic landscape in metastatic melanoma has changed dramatically in the last decade, with the success of immune checkpoint inhibitors resulting in durable responses for a large number of patients. For patients with BRAF mutations, combinations of BRAF and MEK inhibitors demonstrated response rates and benefit comparable to those from immune checkpoint inhibitors, providing the rationale for sequential treatment with targeted and immunotherapies and raising the question of optimal treatment sequencing. Biomarkers for the selection of anti-PD-1 therapy in BRAF wild type (BRAF WT) and in BRAF mutated (BRAF MUT) patients help development of alternative treatments for patients unlikely to benefit, and might lead to better understanding of the interaction of checkpoint inhibition and targeted therapy. In this paper we evaluate the performance of a previously developed serum proteomic test, BDX008, in metastatic melanoma patients treated with anti-PD-1 agents and investigate the role of BRAF mutation status. BDX008, a pre-treatment proteomic test associated with acute phase reactants, wound healing and complement activation, stratifies patients into two groups, BDX008+ and BDX008-, with better and worse outcomes on immunotherapy. Serum samples were available from 71 patients treated with anti-PD1 inhibitors; 25 patients had BRAF mutations, 39 were wild type. Overall, BDX008+ patients had significantly better overall survival (OS) (HR = 0.50, P = 0.016) and a trend for better progression-free survival (PFS) (HR = 0.61, P = 0.060) than BDX008- patients. BDX008 classification was statistically significant in the analyses adjusted for mutation status, LDH, and line of treatment (P = 0.009 for OS and 0.031 for PFS). BRAF WT BDX008+ patients had markedly long median OS of 32.5 months and 53% landmark 2 years survival, with statistically significantly superior OS as compared to BDX008- patients (HR = 0.41, P = 0.032). The difference between BDX008+ and BDX008- in PFS in BRAF WT patients and in OS and PFS in BRAF MUT patients did not reach statistical significance, though numerically was consistent with overall results. The test demonstrated significant interaction with neutrophil-to-lymphocyte ratio (NLR) (PFS P = 0.041, OS P = 0.004). BDX008 as a biomarker selecting for benefit from immune checkpoint blockade, especially in patients with wild type BRAF and in subgroups with low NLR, warrants further evaluation.

Abstract Background Aβ1-42 peptide abnormal production is associated with the development and maintenance of neuroinflammation and oxidative stress in brains from Alzheimer disease (AD) patients. Suppression of neuroinflammation may then represent a suitable therapeutic target in AD. We evaluated the efficacy of IFNβ1a in attenuating cognitive impairment and inflammation in an animal model of AD. Methods A rat model of AD was obtained by intra-hippocampal injection of Aβ1-42 peptide (23 μg/2 μl). After 6 days, 3.6 μg of IFNβ1a was given subcutaneously (s.c.) for 12 days. Using the novel object recognition (NOR) test, we evaluated changes in cognitive function. Measurement of pro-inflammatory or anti-inflammatory cytokines, reactive oxygen species (ROS), and SOD activity levels was performed in the hippocampus. Data were evaluated by one-way ANOVA with Fisher’s Protected Least Significant Difference (PLSD) test. Results We showed that treatment with IFNβ1a was able to reverse memory impairment and to counteract microglia activation and upregulation of pro-inflammatory cytokines (IL-6, IL-1β) in the hippocampus of Aβ1-42-injected rats. The anti-inflammatory cytokine IL-10, significantly reduced in the Aβ1-42 animals, recovered to control levels following IFNβ1a treatment. IFNβ1a also reduced ROS and lipids peroxidation and increased SOD1 protein levels in the hippocampus of Aβ1-42-injected rats. Conclusion This study shows that IFNβ1a is able to reverse the inflammatory and cognitive effects of intra-hippocampal Aβ1-42 in the rat. Given the role played by inflammation in AD pathogenesis and the established efficacy of IFNβ1a in the treatment of inflammatory diseases of the central nervous system such as multiple sclerosis, its use may be a viable strategy to inhibit the pro-inflammatory cytokine and oxidative stress cascade associated with Aβ deposition in the hippocampus of AD patients.

Checkpoint inhibitors can cause an imbalance in immune tolerance that may clinically manifest as immune-related adverse events (irAEs). These events may involve many organs and tissues, including the skin, gastrointestinal (GI) tract, liver, endocrine system, kidneys, central nervous system (CNS), eyes and lungs. The incidence of irAEs appears to be lower with anti-programmed death antigen-1/programmed death antigen-ligand-1 agents than with the anti-cytotoxic T-lymphocyte-associated protein-4 antibody ipilimumab. Combined immunotherapy does not appear to be associated with novel safety signals compared with monotherapy, but more organs may be involved. Increased experience and the use of algorithms for the most common irAEs have resulted in severe toxicity and related deaths being reduced. However, continuous vigilance, especially regarding less common events, is needed to better characterize the wide spectrum of clinical manifestations.

Abstract Background Nivolumab is an anti-PD1 checkpoint inhibitor active in patients with advanced melanoma and as adjuvant therapy in high-risk metastatic melanoma patients. Methods In this single-center retrospective analysis, we investigated the CD73 enzyme activity in patients with metastatic melanoma stage IV and its correlation with the response to nivolumab. The soluble CD73 (sCD73) enzyme activity was measured in the serum of 37 melanoma patients before receiving nivolumab and the Harrel’s C index was used to find the best cut-off for this biomarker. The multivariate Cox proportional hazard model was used to evaluate the prognostic value of CD73 enzyme activity for survival and progression-free survival. Results Our results show that high levels of sCD73 enzyme activity were significantly associated with poor overall survival and progression-free survival in patients with metastatic melanoma. The median progression–free survival was 2.6 months [95% confidence interval (CI) 1.9–3.3] in patients with high sCD73 enzyme activity (> 27.8 pmol/min/mg protein), and 14.2 months (95% CI 4.6–23.8) in patients with lower CD73 enzyme activity, when patients were follow-up for a median of 24 months range. The median overall survival was not reached in patients with low sCD73 activity (

El objetivo de este estudio fue analizar y describir la situación actual de la calidad en las organizaciones deportivas de gestión de instalaciones deportivas españolas. De un total de 5.065 registradas bajo el código nacional de actividades económicas 9311, se procedió al estudio pormenorizado de cada una de las organizaciones a través de la observación sistemática, para finalmente seleccionar a 35 organizaciones con certificación de calidad ISO9001, ISO14001, OHSAS 18001y EFQM. Los resultados muestran una escasa implantación de calidad en las organizaciones de gestión de instalaciones deportivas, siendo las certificaciones con mayor implantación, el sistema de gestión de calidad (ISO 9001) y el sistema de gestión medioambiental (ISO 14001).

Las estrategias nutricionales durante la fase de recuperación del deportista son fundamentales. Uno de los principales objetivos de la recuperación es la reposición del glucógeno muscular. Este aspecto se hace más importante cuando los deportistas se enfrentan a entrenamientos intensos o eventos competitivos con cortos periodos de recuperación. Además, la manipulación deliberada de su disponibilidad puede mejorar las adaptaciones moleculares al entrenamiento. La presente revisión tiene por objetivo informar sobre los aspectos fisiológicos básicos de esta situación, así como conocer el momento del consumo, la cantidad, el tipo y la interacción de diferentes nutrientes con los hidratos de carbono, para poder maximizar o jugar con la reposición del mismo en función de las necesidades y/o las estrategias planteadas. El glucógeno ya no debe ser visto como un simple almacén de energía sino como una molécula que puede desencadenar numerosos procesos celulares importantes para el deportista.

Background: Tumor microenvironment may have a key role in providing immunological markers that can help predict clinical response to treatment with checkpoint inhibitors. We investigated whether the baseline expression of PD-L1 in advanced melanoma patients treated with ipilimumab may correlate with clinical outcome. Methods: PD-L1 expression was assessed in 114 patients with advanced melanoma treated with ipilimumab and, in a cohort of 77 patients, a comprehensive assessment using multispectral imaging to assess the presence and distribution of CD3+, CD8+, CD163+, FOXP3+ and PD-L1+ cells inside and at periphery of the tumor was performed. Results: PD-L1 status alone was not a predictive biomarker for response or survival. There was an association between clinical benefit from ipilimumab therapy with the coexistence of low densities of CD8+ and high densities of CD163+ PD-L1+ cells at the periphery of the tumor. Conclusions: To explain the association of this peculiar microenvironment with clinical benefit from ipilimumab, we proposed a model where baseline CD8 cells levels are low due to inhibitory effect of Tregs and to pro-tumor activity of TAM M2 (CD163+ PD-L1+ cells). Ipilimumab treatment causes a decrease of Treg cells, mediated by ADCC from macrophages, with a concomitant change in TAM polarization that switches from M2 to M1 with a subsequent attraction of CD8 cells and the increase of antitumor response.

There is no information on how organisms influence hydrostructural properties of constructed Technosols and how such influence will be affected by the parent-material composition factor. In a laboratory experiment, parent materials, which were excavated deep horizons of soils and green waste compost (GWC), were mixed at six levels of GWC (from 0 to 50 %). Each mixture was set up in the presence/absence of plants and/or earthworms, in a full factorial design (n = 96). After 21 weeks, hydrostructural properties of constructed Technosols were characterized by soil shrinkage curves. Organisms explained the variance of hydrostructural characteristics (19 %) a little better than parent-material composition (14 %). The interaction between the effects of organisms and parent-material composition explained the variance far better (39 %) than each single factor. To summarize, compost and plants played a positive role in increasing available water in macropores and micropores; plants were extending the positive effect of compost up to 40 and 50 % GWC. Earthworms affected the void ratio for mixtures from 0 to 30 % GWC and available water in micropores, but not in macropores. Earthworms also acted synergistically with plants by increasing their root biomass, resulting in positive effects on available water in macropores. Organisms and their interaction with parent materials positively affected the hydrostructural properties of constructed Technosols, with potential positive consequences on resistance to drought or compaction. Considering organisms when creating Technosols could be a promising approach to improve their fertility.

La gestión de la deuda en las organizaciones deportivas es una variable determinante para la supervivencia de éstas, la falta de control puede afectar al buen funcionamiento de una entidad. Según los datos existentes, las organizaciones que gestionan campos de golf gozan de una buena situación económica. Por ello, el propósito del presente estudio fue conocer el estado y evolución de la deuda de las empresas deportivas que participan en el deporte del golf no competitivo. Para ello, se seleccionó una muestra de 93 organizaciones de todo el territorio Español, con una antigüedad media de 20,08 años. Para la obtención de los datos se utilizó la información económica del Sistema de Análisis de Balances Ibéricos de la pasada década. Los hallazgos obtenidos en el presente estudio nos llevan a conocer que la deuda media de las organizaciones ha aumentado en el 70,5% de los casos después de una década. A pesar de la buena salud económica y al aumento de sus ingresos por explotación y total de activos en el período de estudio, podemos afirmar que la deuda de estas organizaciones ha aumentado exponencialmente entre el 2005-2015.

Esta investigación aborda a partir de la Teoría de la Generalizabilidad (TG) la optimización de recursos en la gestión deportiva. Se utilizó una estructura de diseño compuesta por las facetas usuarios (U), actividades (A), escalas (E) e ítems (I), siguiendo un diseño no ortogonal, parcialmente anidado y multifaceta dentro del Modelo General Lineal (GLM). Los 537 participantes (32.11 ± 11.11 años) cumplimentaron el Cuestionario de Evaluación de la Calidad Percibida en Servicios Deportivos obteniendo resultados excelentes de fiabilidad (ξρ²(δ) > 0.98) y generalizabilidad (ξρ²(Δ) > 0.98). La optimización mostró que con una reducción del número de participantes a la mitad y con un menor número de actividades evaluadas, obtenemos un alto grado de generalización al mismo tiempo que se reduce el número total de observaciones de cara a futuros registros, lo que facilitará la evaluación del servicio deportivo de manera más eficiente.

Checkpoint inhibitors have improved survival for patients with melanoma, non-small-cell lung cancer (NSCLC), bladder, head and neck and other cancers. Antibodies against PD-L1, including atezolizumab, avelumab and durvalumab, are also being developed and have been approved for various cancers. Compared with anti-CTLA-4 drugs, studies with anti-PD-1/PD-L1 agents have suggested higher response rates and improved survival. Targeting PD-L1 rather than PD-1 may also theoretically offer further benefit, with the potential for improved efficacy and reduced toxicity, although this has not been clearly shown by clinical experience to date. Anti-PD-L1 agents have shown good efficacy and manageable toxicity in several tumor types.

Despite the success of immune checkpoint blockade in melanoma, the majority of patients do not respond. We hypothesized that the T and NK cell subset frequencies and expression levels of their receptors may predict responses and clinical outcome of anti-CTLA-4 treatment. We thus characterized the NK and T cell phenotype, as well as serum levels of several cytokines in 67 melanoma patients recruited in Italy and Sweden, using samples drawn prior to and during treatment. Survival correlated with low expression of the inhibitory receptor TIM-3 on circulating T and NK cells prior to and during treatment and with the increased frequency of mature circulating NK cells (defined as CD3−CD56dim CD16+) during treatment. Survival also correlated with low levels of IL-15 in the serum. Functional experiments in vitro demonstrated that sustained exposure to IL-15 enhanced the expression of PD-1 and TIM-3 on both T and NK cells, indicating a causative link between high IL-15 levels and enhanced expression of TIM-3 on these cells. Receptor blockade of TIM-3 improved NK cell-mediated elimination of melanoma metastasis cell lines in vitro. These observations may lead to the development of novel biomarkers to predict patient response to checkpoint blockade treatment. They also suggest that induction of additional checkpoints is a possibility that needs to be considered when treating melanoma patients with IL-15.

In everyday life people are simultaneously exposed to several annoying sources (sounds, vibrations and odours), which emerge from background of considerable variability of land uses, infrastructures, residential patterns, topography, meteorology condition, and standards quality of life. The European Union has provided in recent years (and is going to update) several tools to harmonize noise mapping methodologies and relative Noise Action Plans through directives and guidelines. Unfortunately the same efforts have not been put in the harmonization of approaches in other annoying sources like odours. As a consequence, each European Member State at national or even at local level defined its own direct or indirect approach to limit odour impacts, usually considerably different one from the others. The most common approach to deal with noise impact at a policy, economic and strategy level is the use of priority indices focused to highlight areas more sensitive and where mitigation actions will be more advisable or urgent. Locations that for their specific land use are more sensitive to noise impacts (e.g. residential areas) are generally also sensitive to odour impacts. According these, the aim of the present research is to provide a brief review of the most used European strategies in noise action plans end try to extend their approaches for the definition of a nuisance action plan, able to control both odour and noise. Paper present a possible implementation of integrated nuisances action plan in the municipality of Palma Campania (Campania Region, Italy). The analysis underlines that is possible define, under the same set of nuisance indicators, the degree of sensitivity of areas according to population, land uses, levels of exposures and/or distance from the annoying sources. Nuisance acceptability levels are then definable according to the sensitivity degree of the locations. Factors related to vibrations and visual perception of the landscape can further contribute to control total sensorial annoyance in the land planning.