PMC21 PATIENT-REPORTED OUTCOMES IN PRODUCT DEVELOPMENT GUIDANCE

Medina Campeny, XavierHomenatge a Mercè Rodoreda amb una reproducció del personatge de la Colometa, a la Plaça del Diamant, novel·la de l'escriptora. Al 1984 es va posar provisionalment a la pl. Rius i Taulet. Al 1990 es va traslladar a l'actual emplaçament

Recent environmental changes in the area of La Maddalena Harbour (Sardinia, Italy): data from mollusks and benthic foraminifera

Mollusks and benthic foraminifera are reliable tools to paleo-environmental reconstructions because they commonly occur in most marine habitats and are sensitive to major and short-lived changes of environmental drivers, induced by both natural and anthropogenic events. Their community structure provides useful information about the characteristics of their habitat and some species are sensitive to specific environmental controls. Features such as changes in species composition and community, or variation in test morphology provide evidence of fluctuation of several environmental factors. Therefore, both mollusks and benthic foraminifera can be used as an efficient method for identifying the history and ecological trajectory of marine ecosystems. This study focuses on the macro- (mollusks) and micropaleontological (benthic foraminifera) study of a 3 m long sediment core collected in the former military arsenal of the La Maddalena harbor (N Sardinia, Italy), at a depth of 15 m. The core site is located on the S-E coast of La Maddalena island, that underwent a complex history of human occupation along with natural environmental evolution and human-derived pressures. We aimed to reconstruct the main environmental changes recorded in the fossil benthic communities along the core, and to propose the most likely factors that caused these changes. Both mollusks and benthic foraminifera have been picked from the core, identified at genus/species level and counted. Ecological indications for each species have been extracted from literature. Univariate and multivariate statistics have been applied to highlight the community dynamics. More than 90 species of benthic foraminifera have been identified, and 101 mollusk species (846 specimens). The foraminifera diversity indices show a general reduction from the first 50 cm downcore. This slight decline is accompanied by changes in foraminiferal assemblages. The results concerning changes in foraminiferal species composition, their abundance and biodiversity, supported by statistical analyses (cluster analysis), allowed identification of three major foraminiferal associations corresponding to different marine coastal settings. The same results have been obtained by using mollusks and their ecological significance in the framework of benthic marine bionomics. Species are related to infralittoral vegetated bottom such as Posidonia meadows (HP) or photophilous algae through the core, but with variation in percentage of abundance, and HP species decreases from the bottom to the top, whereas species related to muddy bottom follow the opposite trend (coastal detritic mud, deep mud). This testifies that the area underwent a progressive reduction of Posidonia meadows and light-loving algae with a shift toward muddy bottoms, possibly related to the effect of the intensive renovation works of the harbor area. Moreover, radiocarbon dating obtained from Cerithium specimens indicated that the sedimentation rate increases in the upper portion of the core, according to the ecological signal reconstructed by the analysis of the mollusk assemblage

Natural vs. Anthropic influence on the multidecadal shoreline changes of mediterranean urban beaches: Lessons from the Gulf of Cagliari (Sardinia)

Urban Mediterranean beaches are often characterized by a fragile and unstable equilibrium that can be easily altered by ongoing climate change and by the increase in human pressure. This may pose serious threats to the survival of beach systems that cannot accommodate these modifications. In this paper, the spatio-temporal shift of the shoreline was investigated along two urban beaches in the Gulf of Cagliari (Poetto and Giorgino; southern Sardinia, western Mediterranean Sea) across a time frame of 62 years (1954–2016). The Digital Shoreline Analysis System (DSAS) ArcGIS™ extension was used to extract different statistical parameters which allowed us to quantify the erosion and accretion rates. These data were further examined in relation to a number of anthropic and natural forcings in order to disentangle the factors controlling shoreline evolution. Eight sectors with interchanging net erosive and accretion trends were identified along the Poetto and Giorgino beaches. In six decades, some sectors of the two study sites appeared to have undergone great shoreline modification as a result of the intense anthropogenic activities impacting these coastal areas. The westernmost portions of both beaches were found to be the most vulnerable to erosion processes; such conditions were likely controlled by the interplaying of local hydrodynamics and by the intense coastal development which affected these sectors. The highest retreat rates (mean end point rate (EPR) = −0.51/year) were recorded in the western limit of Giorgino beach. Along the western limit of Poetto beach, EPR erosion rates (mean EPR = −2.92/year) considerably increased in the years after the artificial beach nourishment carried out in 2002, suggesting that the majority of the nourished material was lost offshore or partly redistributed along the beach. Coastal structures, urban development, river catchment modification, industrial and port activities, beach cleaning and touristic and recreational activities have been identified as the ongoing causes of coastal alteration. If these factors remain constant, under projected climate change scenarios, these beaches are at risk of further increased flooding and erosion. In this context, the application of DSAS appeared as an essential tool, supporting a monitoring system able to provide understanding and, potentially, predictions of the short-to long-term evolution of these beach systems

Homeostatic control of slow vacuolar channels by luminal cations and evaluation of the channel-mediated tonoplast Ca2+ fluxes in situ

Ca2+, Mg2+, and K+ activities in red beet (Beta vulgaris L.) vacuoles were evaluated using conventional ion-selective microelectrodes and, in the case of Ca2+, by non-invasive ion flux measurements (MIFE) as well. The mean vacuolar Ca2+ activity was ∼0.2 mM. Modulation of the slow vacuolar (SV) channel voltage dependence by Ca2+ in the absence and presence of other cations at their physiological concentrations was studied by patch-clamp in excised tonoplast patches. Lowering pH at the vacuolar side from 7.5 to 5.5 (at zero vacuolar Ca2+) did not affect the channel voltage dependence, but abolished sensitivity to luminal Ca2+ within a physiological range of concentrations (0.1–1.0 mM). Aggregation of the physiological vacuolar Na+ (60 mM) and Mg2+ (8 mM) concentrations also results in the SV channel becoming almost insensitive to vacuolar Ca2+ variation in a range from nanomoles to 0.1 mM. At physiological cation concentrations at the vacuolar side, cytosolic Ca2+ activates the SV channel in a voltage-independent manner with Kd=0.7–1.5 μM. Comparison of the vacuolar Ca2+ fluxes measured by both the MIFE technique and from estimating the SV channel activity in attached patches, suggests that, at resting membrane potentials, even at elevated (20 μM) cytosolic Ca2+, only 0.5% of SV channels are open. This mediates a Ca2+ release of only a few pA per vacuole (∼0.1 pA per single SV channel). Overall, our data suggest that the release of Ca2+ through SV channels makes little contribution to a global cytosolic Ca2+ signal

A multi-dating approach to age-modelling long continental records: The 135 ka El Cañizar de Villarquemado sequence (NE Spain)

Under embargo until: 2021-06-23We present a multidisciplinary dating approach - including radiocarbon, Uranium/Thorium series (U/Th), paleomagnetism, single-grain optically stimulated luminescence (OSL), polymineral fine-grain infrared stimulated luminescence (IRSL) and tephrochronology - used for the development of an age model for the Cañizar de Villarquemado sequence (VIL) for the last ca. 135 ka. We describe the protocols used for each technique and discuss the positive and negative results, as well as their implications for interpreting the VIL sequence and for dating similar terrestrial records. In spite of the negative results of some techniques, particularly due to the absence of adequate sample material or insufficient analytical precision, the multi-technique strategy employed here is essential to maximize the chances of obtaining robust age models in terrestrial sequences. The final Bayesian age model for VIL sequence includes 16 AMS 14C ages, 9 single-grain quartz OSL ages and 5 previously published polymineral fine-grain IRSL ages, and the accuracy and resolution of the model are improved by incorporating information related to changes in accumulation rate, as revealed by detailed sedimentological analyses. The main paleohydrological and vegetation changes in the sequence are coherent with global Marine Isotope Stage (MIS) 6 to 1 transitions since the penultimate Termination, although some regional idiosyncrasies are evident, such as higher moisture variability than expected, an abrupt inception of the last glacial cycle and a resilient response of vegetation in Mediterranean continental Iberia in both Terminations.acceptedVersio

The Interplay between PolyQ and Protein Context Delays Aggregation by Forming a Reservoir of Protofibrils

Polyglutamine (polyQ) diseases are inherited neurodegenerative disorders caused by the expansion of CAG codon repeats, which code for polyQ in the corresponding gene products. These diseases are associated with the presence of amyloid-like protein aggregates, induced by polyQ expansion. It has been suggested that the soluble aggregates rather than the mature fibrillar aggregates are the toxic species, and that the aggregation properties of polyQ can be strongly modulated by the surrounding protein context. To assess the importance of the protein carrier in polyQ aggregation, we have studied the misfolding pathway and the kinetics of aggregation of polyQ of lengths above (Q41) and below (Q22) the pathological threshold fused to the well-characterized protein carrier glutathione S-transferase (GST). This protein, chosen as a model system, is per se able to misfold and aggregate irreversibly, thus mimicking the behaviour of domains of naturally occurring polyQ proteins. We prove that, while it is generally accepted that the aggregation kinetics of polyQ depend on its length and are faster for longer polyQ tracts, the presence of GST alters the polyQ aggregation pathway and reverses this trend. Aggregation occurs through formation of a reservoir of soluble intermediates whose populations and kinetic stabilities increase with polyQ length. Our results provide a new model that explains the toxicity of expanded polyQ proteins, in which the interplay between polyQ regions and other aggregation-prone domains plays a key role in determining the aggregation pathway

Patient-reported outcomes in metastatic castration-resistant prostate cancer

Many novel therapies are available for use in patients with metastatic castration-resistant prostate cancer (mCRPC), some of which convey substantial progression-free survival and overall survival benefits. Delaying disease progression and providing palliation of symptoms are primary therapeutic aims of treating patients with mCRPC; therefore, ensuring that the benefit-to-harm ratios are acceptable to patients, through systematic measurement of patient-reported outcomes (PROs) using validated tools, is vital. In this Perspectives, we appraised the published reports from clinical trials testing treatments of mCRPC over the past 5 years and found that PROs were either not being measured routinely, or if used, were often not reported adequately, thus hampering evaluation of the true effects of many of these treatments on patients' quality of life. Improvements are needed because data collected directly from patients, not just physician-collected safety data and adverse events, are crucial to inform clinical decision-making on treatment options