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Abstract Stalagmites are useful archives in reconstructing paleoclimates: most paleoclimate studies used stalagmites that are distributed in specific locations and ages. We examined a stalagmite (GYM-1) collected from Nara Prefecture, central Japan, where limestone areas are limited. Applying 238U–234U method, the ages of GYM-1 were determined as 744 ± 70 to 677 ± 74 ka (based only on analytical uncertainties, 1σ). Even assuming a 10% uncertainty in the initial activity of 234U/238U, (234U/238U)0, this age could be still older than 460 ka. Temperatures calculated based on δD in the fluid inclusions and δ18O in the calcium carbonate ranged from 9.0 to 11.9 °C (10.8 ± 0.9 °C on average) or from 6.0 to 9.1 °C (7.9 ± 0.9 °C on average) depending on the equation. The estimated temperature suggests that GYM-1 formed during an interglacial period of the Middle Pleistocene. Synchronous behavior of isotopic values with lamination likely reflects seasonal temperature in a highly ventilated cave system.

Abstract Some of the largest magmatic-hydrothermal copper ore deposits and deposit clusters are associated with arc-oblique fault systems. Whether this structural context impacts the geochemistry of hydrothermal fluids, including their copper contents, remains unknown. Here, we investigate the copper concentration and helium isotope signature of geothermal fluids as modern analogs of hydrothermal ore deposits in the Andes of central-southern Chile. We show that fault systems broadly parallel to the regional stress field facilitate the early release of fluids from deep primitive magmas. By contrast, fault systems oblique to the regional stress field prevent the early escape of fluids and promote magmatic enrichment in copper, volatiles, and ligands, enhancing the potential to form copper deposits. We conclude that the orientation of fault systems actively influences the copper budget of ascending hydrothermal fluids, explaining the contrasting distribution of metals along distinct structures often observed in porphyry-epithermal systems and other types of magmatic-hydrothermal deposits.

Abstract In this contribution, we present some of the first data on the elemental signature of deep crustal fluids in a basalt-hosted, low-chloride magmatic-hydrothermal system. Down-hole fluid samples (850–1600 m) from wells in the Theistareykir and Krafla geothermal fields in the Northern Volcanic Zone of Iceland were combined with well-head samples of condensed vapor, cuttings of altered rock, and fresh basalt (being some of the first concentration data for volatile and semi-volatile elements (Sb, Tl, Bi, Cd and As) for this area of Iceland). Results show that the deep fluids are relatively enriched in base metals and (semi)-volatile metals (in particular Te, Hg, Re and Tl) compared to local basalt. We interpret this enrichment in volatile metals to reflect a significant element input from magma degassing. Boiling of this deep fluid results in a well-head fluid composition that is significantly depleted in most elements. This well-head fluid has a distinct elemental signature, including a depletion in Sb that is mirrored in the altered rocks, and a depletion in the base metals that shows their selective sequestration in scale minerals, likely sulphides. As expected, the element content and patterns in surface fluids can thus not be interpreted to directly reflect that of the deep reservoir fluid. The behaviour of elements in Theistareykir and Krafla fluids is consistent, and largely agrees with similar data obtained for the Reykjanes geothermal system in SW Iceland. We therefore posit that our results are representative for this geological setting and indicate a significant magmatic degassing cation input to deep fluids, variably modified by water–rock interaction.

Abstract The introgression of M. enterolobii resistance-related genes in guava breeding programs can be compromised by incompatibility among Psidium species. This study aimed to evaluate the female parent preference and genetic diversity of Psidium interspecific hybrids using morphoagronomic traits and resistance to M. enterolobii. There were evaluated cross successes and germination from crosses between accesses of P. cattleyanum, P. guineense and P. guajava and the genetic diversity by Ward-MLM method of hybrids according to descriptors developed for the genus. Crosses were more successful when P. cattleyanum was the female parent. Germination was more successful in crosses involving P. cattleyanum and P. guajava. Four groups were formed. The group IV clustered the most resistant genotypes, composed by genotypes of P. cattleyanum x P. guineense, while the group II was the most susceptible. The groups I and III grouped some genotypes of P. cattleyanum x P. guajava with low levels of susceptibility. There are preferences of female parent species among crosses. Some individuals of groups I and III can be used as source of resistance genes for the breeding program, due the presence of favorable alleles inherited from guava parent. The high susceptibility leads to reduction in root development.

Abstract The influence of refrigeration on the post-embryonic development of Chrysomya putoria larvae was evaluated, regarding its resistance in the logistics of storage and distribution in biotherapy. Previously sterilized larvae were submitted to four periods of storage under refrigeration (T1=12 h, T2=24 h, T3=48 h and T4=72 h) and control (without sterilization and refrigeration). Newly hatched larvae (0.200 g) were stored between 3 and 9ºC. After refrigeration, 40 neo-larvae (in triplicate) were transferred to 50 g of protein diet and incubated in an acclimatized chamber. There was a significant difference in the larval body mass (T1 and T2) and in the duration of larval, pupal and total development (T3 and T4). The sex ratios found in the four treatments did not differ from what was expected. Normality rates were 100% for all treatments. There was no significant difference between the Control, T1 and T2 treatments for larval, pupal and total viability. There was a significant difference between control (C) and T4 (larval viability), between C, T3 and T4 (pupa) and between C and T4 (total). C. putoria has resistance under refrigeration and storage of up to 56 h, presenting viability above 70% for use in biotherapy.

Dissipative Particle Dynamics (DPD) is a stochastic particle model that is able to simulate larger systems over longer time scales than atomistic modeling approaches by including the concept of coarse-graining. Whether standard DPD can cover the whole mesoscale by changing the level of coarse-graining is still an open issue. A scaling scheme originally developed by Füchslin et al. (2009) was here applied to interfacial systems as one of the most successful uses of the classical DPD method. In particular, equilibrium properties such as the interfacial tension were analyzed at different levels of coarse-graining for planar oil–water interfaces with and without surfactant. A scaling factor for the interfacial tension was found due to the combined effect of the scaling scheme and the coarse-graining parameterization. Although the level of molecular description was largely decreased, promising results showed that it is possible to conserve the interfacial tension trend at increasing surfactant concentrations, remarkably reducing modeling complexity. The same approach was also employed to simulate a droplet configuration. Both planar and droplet conformations were maintained, showing that typical domain formations of multi-component systems can be performed in DPD by means of the scaling procedure. Therefore, we explored the possibility of describing oil–water and oil–water–surfactant systems in standard DPD using a scaling scheme with the aim of highlighting its advantages and limitations.

Abstract Worldwide, forests are susceptible to fire. Forests with fire and selective logging interactions require monitoring and evaluation. This study evaluated the phytosociology and dynamics of tree vegetation in a disturbed forest (DF) and an undisturbed forest (UF) in selective logging areas affected by fire, in the Brazilian East Amazon. All trees with DBH ≥ 5 cm were measured and identified botanically in 93 plots (5 X 50 m) in the DF area and 58 plots (5 X 50 m) in the UF area, in 2010 (before logging), 2011, 2015 and 2017 (two years after the fire). Analysis of species and tree composition, diversity, similarity, mortality and recruitment were carried out. The fire affected the DF and UF areas in a similar proportion in terms of trees loss and basal area, intensifying the mortality rate. In the short term (2 years), the fire did not cause a significant reduction in species diversity, but there was a tendency towards a similarity loss in species composition in the area disturbed by logging. Subsequent assessments are necessary to understand the forest’s recovery mechanisms.

Abstract Six wells were continuously monitored in Hokkaido, northern Japan, to relate groundwater level changes to regional seismic activity. Groundwater level changes following the 2018 Hokkaido Eastern Iburi earthquake were detected in three of the six wells, even though they are located hundreds of kilometers from the epicenter. The groundwater level changes are qualitatively consistent with the volumetric strain induced by the earthquake. We analyzed groundwater level responses to the M2 tidal constituent before and after the earthquake, but related changes in amplitude and phase shifts remained within the usual variation. Observed coseismic change was explained by the response to the M2 tidal constituent component and the calculated volumetric strain for one of the wells, where groundwater level decreased. The observed change in the other two was found to be much greater than the corresponding estimates of the volumetric strain.

Records of volcanic activity are a key resource in volcano monitoring and hazard mitigation. The time period for which such records are available and the level of detail vary widely among volcanic centers and there is, therefore, a need for supplementary sources of this information. Here, we use growth-zoned gypsum as a mineral archive of the activity of Kawah Ijen volcano in East-Java, Indonesia. Gypsum precipitates where water seeps from the crater lake and hydrothermal system, and it has formed a 100 m long cascading plateau. A 19 cm plateau cross-section was analysed for minor and trace elements using laser-ablation ICP-MS. Absolute ages were assigned to this transect based on 210Pb dating. This 210Pb age model was corrected for variations in the 210Pb0 resulting from fluctuations in the volcanic radon flux by using 84Kr/36Ar and 132Xe/36Ar. The age model indicates that the transect covers a period from 1919 ± 12 to 2008 ± 0.2. Gypsum-fluid partition coefficients (D) permit the gypsum compositions to be converted to the concentrations in the fluid from which each growth zone grew. The D-values also show the compatibility of the elements in the gypsum structure, and identify the LREE, Sr, Pb, Tl, Ni, Co, Cu, Zn, Cd, Sb, Th, and Mo as least susceptible to contamination from rock fragment and mineral inclusions, and therefore as most reliable elements of the gypsum record. Compositional variability in the timeseries correlates with known element behavior in the Kawah Ijen system and shows three element groups: the LREE, Sr, and Pb that represent rock-leaching; Cu, Zn, and Cd, which have previously been linked to immiscible sulfide destabilization in a deep-seated basalt; and Sb, Tl, and As which point to a contribution from the shallow system and evolved magma. Moreover, the gypsum record shows that episodes of unrest and quiescence have a distinct compositional signature in Kawah Ijen seepage fluids, and can be distinguished. Thus, we show that gypsum is a sensitive recorder of volcanic activity and can provide detailed information on the state of the magmatic-hydrothermal system in the past.

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is responsible for causing Coronavirus Disease-2019 (COVID-19), a heterogeneous clinical condition that manifests varying symptom severity according to the demographic profile of the studied population. While many studies have focused on the spread of COVID-19 in large urban centers in Brazil, few have evaluated medium or small cities in the Northeast region. The aims of this study were: (i) to identify risk factors for mortality from SARS-CoV-2 infection, (ii) to evaluate the gene expression patterns of key immune response pathways using nasopharyngeal swabs of COVID-19 patients, and (iii) to identify the circulating SARS-CoV-2 variants in the residents of a medium-sized city in Northeast Brazil. A total of 783 patients infected with SARS-CoV-2 between May 2020 and August 2021 were included in this study. Clinical-epidemiological data from patients who died and those who survived were compared. Patients were also retrospectively divided into three groups based on disease severity: asymptomatic, mild, and moderate/severe. Samples were added to a qPCR array for analyses of 84 genes involved with immune response pathways and sequenced using the Oxford Nanopore MinION technology. Having pre-existing comorbidity; being male; having cardiovascular disease, diabetes, and/or chronic obstructive pulmonary disease; and PCR cycle threshold (Ct) values under 22 were identified as risk factors for mortality. Analysis of the expression profiles of inflammatory pathway genes showed that the greater the infection severity, the greater the activation of inflammatory pathways, triggering the cytokine storm and downregulating anti-inflammatory pathways. Viral genome analysis revealed the circulation of multiple lineages, such as B.1, B.1.1.28, Alpha, and Gamma, suggesting that multiple introduction events had occurred over time. This study’s findings help identify the specific strains and increase our understanding of the true state of local health. In addition, our data demonstrate that epidemiological and genomic surveillance together can help formulate public health strategies to guide governmental actions.

Carbon capture and storage (CCS) is considered a key technology for reducing CO2 emissions into the atmosphere. Nonetheless, there are concerns that if injected CO2 migrates in the crust, it may trigger slip of pre-existing faults. In order to test if this is the case, covariations of carbon, hydrogen, and oxygen isotopes of groundwater measured from Uenae well, southern Hokkaido, Japan are reported. This well is located 13 km away from the injection point of the Tomakomai CCS project and 21 km from the epicenter of September 6th, 2018 Hokkaido Eastern Iburi earthquake (M 6.7). Carbon isotope composition was constant from June 2015 to February 2018, and decreased significantly from April 2018 to November 2019, while total dissolved inorganic carbon (TDIC) content showed a corresponding increase. A decrease in radiocarbon and δ13C values suggests aquifer contamination by anthropogenic carbon, which could possibly be attributable to CCS-injected CO2. If such is the case, the CO2 enriched fluid may have initially migrated through permeable channels, blocking the fluid flow from the source region, increasing pore pressure in the focal region and triggering the natural earthquake where the brittle crust is already critically stressed.

Study region: An uplifted atoll of Minami-Daito Island, Japan. Study focus: Major ions and stable isotopes (δ2H and δ18O) of groundwater at fifteen observation wells, surface water at eight representative lakes and one seawater site were measured to unravel the dominant processes controlling the chemistry of water, its spatial distribution and to identify the salinization mechanism caused by long-term sea-level rise. New hydrological insights for the region: Rainfall is the main source for groundwater and lake water. Evaporation affects both the ion concentration and the stable isotopes of the lake water. Geochemical modeling suggests that freshwater-seawater mixing is the main process increasing concentrations of Na+, Cl−, Mg2+, and SO42−, whereas dissolution of calcite and dolomite increases concentrations of Ca2+, Mg2+, and HCO3− in groundwater. Fresh groundwater and lake water (i.e., Cl− < 500 mg/L) are largely distributed along a SW-NE direction, but they have been reduced since the 1970s. Sea-level rise causes an increase in the salinity of lake water by flowing through fractures being connected from lakes to the northern coast, then spreading to other lakes through the artificial channels built in the years.

Abstract There are no guava cultivars resistant to the Meloidogyne enterolobii; for this reason, genetic breeding has been performed by introgressing genes into the current cultivars through interspecific hybridization. We used 33 microsatellite markers for the genetic-molecular characterization of segregating populations of Psidium resistant to M. enterolobii, aiming at selection within and between populations for generation advancement in the guava breeding program. The average number of alleles per locus ranged from 1.60 to 2.09. Populations 1 (P. guineense × P. cattleyanum) and 5 (P. guajava × P. cattleyanum) obtained the greatest genetic diversity, which can be confirmed by the higher observed-heterozygosity values (0.422 and 0.312, respectively). Bayesian analysis showed that the populations were subdivided into three groups, agreeing with the number of groups observed by Nei’s genetic distance. The population obtained from the P. guineense × P. cattleyanum cross differed from the others with a clear structuring, whereas the P. guajava × P. cattleyanum and P. cattleyanum × P. guineense populations were the most similar between each other. The SSR markers were efficient in discriminating the populations, and individual 80 may be employed in future crosses with guava, allowing generation advancement in the guava breeding program aimed at resistance to M. enterolobii.

ABSTRACT The aim of this research was to evaluate the performance of Japanese quail (Coturnix coturnix japonica), with 94 (+49) days of age, through the production and quality of the eggs, with the birds kept in environments illuminated with LED lamps in the colors white, blue and red. The experimental design was a completely randomized design with three treatments (lamp colors) and seven replications. In the three environments, the relative air temperature averages can be considered above the thermal comfort zone for quails; however, the black globe temperature index, humidity and the thermal radiation load can be considered comfortable. The laying percentage of the birds kept under white LED was inferior to those maintained in the red LED. The feed intake, the feed conversion, the average weight and the egg quality were not affected by the different lamp colors (P

Computational Fluid Dynamics (CFD) can be used to simulate different parts of an industrial freeze-drying equipment and to properly design them; in particular data concerning the freeze-dryer chamber and the duct connecting the chamber with the condenser, with the valves and vanes eventually present are given here, and can be used to understand the behavior of the apparatus allowing an improved design. Pilot and large scale freeze-drying chambers have been considered; data of a detailed simulation of a complete pilot scale apparatus, including duct and condenser, are included. Data on conductance of an empty duct with different L/D ratio, on disk valves with different geometry, and on mushroom valve are presented. Velocity, pressure, temperature and composition fields are reported on selected planes for chambers and valves. Results of dynamic simulations are also presented, to evaluate possible performance of monitoring devices in the chamber. Some further data, with detailed interpretation and discussion of the presented data can be found in the related research article by Barresi et al. [1] and Marchisio et al. [2].

Here we evaluate the effects of different concentrations of the antibiotic ampicillin on the growth and development of Chrysomya putoria. Third-generation, first instar larvae (L1) reared on 60 grams of homogenate+agar 65% were treated with ampicillin sodium. The experiment consisted of four replicates (40 larvae/replicate) of each antibiotic concentration tested (T1: 466µg/mL ; T2: 81.33 mg/mL and T3: 166.66mg/mL) and a T4: control. The body mass of the mature larvae, after they abandoned the diet, were recorded in batches of five. The variation between the mean body mass of larvae and the duration of larval and pupal stages, and overall duration of the development, viability and normal rates were analyzed by ANOVA. There were no significant differences between the four treatments in the following parameters: body mass of larvae that discontinued the diet as well as the duration of larval, pupal, and total development. The sex ratios found in the four treatments did not differ from those expected. Normality rates were 100% for all treatments. There were no significant differences between treatments for larval and overall viability, but pupal viability differed significantly between T1 and the control, T1 and T2, and between the control and T3. The antibiotic did not appear to significantly alter the development of C. putoria.

Background and aim: Disease-modifying therapies (DMTs) used in multiple sclerosis (MS) have distinct safety profiles. In this paper, we report preliminary results of an on-going pharmacovigilance project (the FASM study). Results: Neurologists working at involved multiple sclerosis centers collected 272 Individual Case Safety Reports (ICSRs). Adverse drug reactions (ADRs) mainly occurred in adult patients and in a higher percentage of women compared to men. No difference was found in ADRs distribution by seriousness. The outcome was reported as favorable in 61% of ICSRs. Out of 272 ICSRs, almost 53% reported dimethyl fumarate, fingolimod and IFN beta 1a as suspected. These medications were commonly associated to the occurrence of ADRs related hematological, gastrointestinal, general, infective or cancer disorders. The median time to event (days) was 177 for dimethyl fumarate, 1058 for fingolimod and 413 for IFN beta 1a. The median time to event for the remaining suspected drugs was 226. Conclusion: We believe that our results, together with those that will be presented at the end of the study, may bring new knowledge concerning the safety profile of DMTs and their proper use. This will provide the opportunity to draw new recommendations both for neurologists and patients.

Two peat cores from two bogs were used to record changes in the atmospheric Pb accumulation rate (Pb AR) in Belgium during the Roman period. The two records were compared to assess the reliability of peat cores as archives of atmospheric Pb deposition and to establish histories of atmospheric emissions from anthropogenic sources. To address these issues we analyzed Pb concentration and its isotopes, using ICP-MS, LA-ICP-MS and MC-ICP-MS in two peat sections, spanning 1000 years each. Lead concentrations in the two cores range from 0.1 to 60 μg g−1, with the maxima between 15 and 60 μg g−1. The average natural background of Pb AR varies between 0.003 and 0.07 mg m−2 yr−1 and the maximum ranges from 0.7 to 1.2 mg m−2 yr−1 between 50 BC and AD 215. The highest Pb AR exceed the pre-Roman period values by a factor of 17–80. Pb isotopic composition indicates that mining and metallurgical activities were the predominant sources of pollution during the Roman period. The Pb AR and chronologies in the Belgian peat cores are consistent with those reported for other continental archives such as lake sediments, peat and ice cores.

The inflammatory process plays a major role in the prognosis of dengue. In this context, the eicosanoids may have considerable influence on the regulation of the Dengue virus-induced inflammatory process. To quantify the molecules involved in the cyclooxygenase and lipoxygenase pathways during Dengue virus infection, plasma levels of thromboxane A2, prostaglandin E2 and leukotriene B4; mRNA levels of thromboxane A2 synthase, prostaglandin E2 synthase, leukotriene A4 hydrolase, cyclooxygenase-2 and 5-lipoxygenase; and the levels of lipid bodies in peripheral blood leukocytes collected from IgM-positive and IgM-negative volunteers with mild dengue, and non-infected volunteers, were evaluated. Dengue virus infection increases the levels of thromboxane A2 in IgM-positive individuals as well as the amount of lipid bodies in monocytes in IgM-negative individuals. We suggest that increased levels of thromboxane A2 in IgM-positive individuals plays a protective role against the development of severe symptoms of dengue, such as vascular leakage.

The laminae of leaves optimize photosynthetic rates by serving as a platform for both light capture and gas exchange, while minimizing water losses associated with thermoregulation and transpiration. Many have speculated that plants maximize photosynthetic output and minimize associated costs through leaf size, complexity, and shape, but a unifying theory linking the plethora of observed leaf forms with the environment remains elusive. Additionally, the leaf itself is a plastic structure, responsive to its surroundings, further complicating the relationship. Despite extensive knowledge of the genetic mechanisms underlying angiosperm leaf development, little is known about how phenotypic plasticity and selective pressures converge to create the diversity of leaf shapes and sizes across lineages. Here, we use wild tomato accessions, collected from locales with diverse levels of foliar shade, temperature, and precipitation, as a model to assay the extent of shade avoidance in leaf traits and the degree to which these leaf traits correlate with environmental factors. We find that leaf size is correlated with measures of foliar shade across the wild tomato species sampled and that leaf size and serration correlate in a species-dependent fashion with temperature and precipitation. We use far-red induced changes in leaf length as a proxy measure of the shade avoidance response, and find that shade avoidance in leaves negatively correlates with the level of foliar shade recorded at the point of origin of an accession. The direction and magnitude of these correlations varies across the leaf series, suggesting that heterochronic and/or ontogenic programs are a mechanism by which selective pressures can alter leaf size and form. This study highlights the value of wild tomato accessions for studies of both morphological and light-regulated development of compound leaves, and promises to be useful in the future identification of genes regulating potentially adaptive plastic leaf traits.

Shade avoidance is an ecologically and molecularly well-understood set of plant developmental responses that occur when the ratio of red to far-red light (R:FR) is reduced as a result of foliar shade. Here, a genome-wide association study (GWAS) in Arabidopsis thaliana was used to identify variants underlying one of these responses: increased hypocotyl elongation. Four hypocotyl phenotypes were included in the study, including height in high R:FR conditions (simulated sun), height in low R:FR conditions (simulated shade), and two different indices of the response of height to low R:FR. GWAS results showed that variation in these traits is controlled by many loci of small to moderate effect. A known PHYC variant contributing to hypocotyl height variation was identified and lists of significantly associated genes were enriched in a priori candidates, suggesting that this GWAS was capable of generating meaningful results. Using metadata such as expression data, GO terms, and other annotation, we were also able to identify variants in candidate de novo genes. Patterns of significance among our four phenotypes allowed us to categorize associations into three groups: those that affected hypocotyl height without influencing shade avoidance, those that affected shade avoidance in a height-dependent fashion, and those that exerted specific control over shade avoidance. This grouping allowed for the development of explicit hypotheses about the genetics underlying shade avoidance variation. Additionally, the response to shade did not exhibit any marked geographic distribution, suggesting that variation in low R:FR-induced hypocotyl elongation may represent a response to local conditions.

Abstract Parkinson’s Disease (PD) exhibits heterogeneous cognitive deficits that may represent different cognitive phenotypes. While previous studies have described them in a “macro” manner, only one study has applied Network Analysis (NA) in PD. NA represents a model to explore relationships between cognitive abilities, aiding in understanding cognitive phenotypes. This study aims to verify whether the cognitive system undergoes reorganization in PD with Mild Cognitive Impairment (PD-MCI) patients. To explore this, a Level II cognitive assessment was administered to 275 PD patients, who were classified into two diagnostic categories: PD-Cognitive Unimpaired (CU) (n = 171) and PD-MCI (n = 104). NA was applied to construct Gaussian Graphical Models for each diagnostic group, where nodes represent cognitive tests and demographic factors, and edges represent their interconnections. The NA revealed substantial differences between the cognitive networks of PD-CU and PD-MCI patients. Specifically, the network of PD-MCI patients appears less sparse, with some weakened relationships between nodes. Overall, the results support the presence of a cognitive reorganization in PD-MCI patients, potentially indicating a functional compensation mechanism. In conclusion, this study enhances the understanding of the cognitive mechanisms underlying cognitive decline in patients with PD.

Abstract Nowadays the phenomenon of global warming is unequivocal, as confirmed by the latest reports of the IPCC and studies of the climate-change impacts on ecosystems, global economy, and populations. The effect of climate change on groundwater is a very relevant task especially for regions dependent chiefly on groundwater availability, as for the southern Italy. In such a territorial framework, to achieve a detailed hydro-climatological characterization, an Ensemble of 15 RCMs (E15) derived from the EURO-CORDEX project was analyzed considering two IPCC Representative Concentration Pathways (RCP4.5 and RCP8.5). The E15 was calibrated over the period (1950–1996) by a statistical comparison with data observed by the regional meteorological network managed by the former National Hydrological Service (SIMN), Department of Naples. The effects of climate change on air temperature (T), precipitation (P) and, consequently, on actual evapotranspiration (ETR) and effective precipitation Pe (P – ETR) were analyzed until 2100. The latter was considered as a proxy of groundwater recharge of the principal aquifer systems, represented chiefly by the karst aquifers. As a principal result, it was found that the E15 is basically able to reproduce the observed annual precipitation (OBSP) and mean annual air temperature (OBST), being characterized by a very similar frequency distribution. Accordingly, an inferential statistical approach was performed for calibrating E15 precipitation (E15P) and air temperature (E15T) based on the compensation of the difference with OBSP (+ 7%) and OBST (− 16%). The E15 projects a reduction in precipitation and an increase in air temperature under both RCPs, with a divergence point between the two scenarios occurring by about 2040. As a principal result, Pe shows declining trends for both RCP scenarios, reaching a decrease of the 11-yrs moving average down to − 20%, for RCP4.5, and − 50%, for RCP8.5, even if characterized by relevant inter-annual fluctuations.

Abstract Childhood adversity is associated with various clinical dimensions in psychosis; however, how genetic vulnerability shapes the adversity-associated psychopathological signature is yet to be studied. We studied data of 583 First Episode Psychosis (FEP) cases from the EU-GEI FEP case-control study, including Polygenic risk scores for major depressive disorder (MDD-PRS), bipolar disorder (BD-PRS) and schizophrenia (SZ-PRS); childhood adversity measured with the total score of the Childhood Trauma Questionnaire (CTQ); and positive, negative, depressive and manic psychopathological domains from a factor model of transdiagnostic dimensions. Genes and environment interactions were explored as a departure from a multiplicative effect of PRSs and total CTQ on each dimension. Analyses were adjusted for age, sex, 10 PCA, site of recruitment and for medication. A childhood adversity and PRS multiplicative interaction was observed between A) the CTQ and MDD-PRS on the predominance of positive (β = 0.42, 95% CI = [0.155, 0.682], p = 0.004); and depressive (β = 0.33, 95% CI = [0.071, 0.591], p = 0.013) dimensions; B) between the CTQ and BD-PRS on the positive dimension (β = 0.45, 95% CI = [0.106, 0.798], p = 0.010), and C) with the CTQ and SZ-PRS on the positive dimension (β = −0.34, 95% CI = [−0.660, −0.015], p = 0.040). Bonferroni corrected p-value of significance was set at 0.0125. In conclusion, despite being underpowered, this study suggests that genetic liability for MDD and BD may have a moderating effect on the sensibility of childhood adversity on depressive and positive psychotic dimensions. This supports the hypothesis of an affective pathway to psychosis in those exposed to childhood adversity.

Abstract Background Palliative care provided to frail and dying older persons in nursing homes results in intense emotions for residents and their relatives as well as for healthcare professionals. In France, scant attention has been given to how nursing home professionals manage their emotions when providing palliative care. This study analysed the emotional demands of providing palliative care in the nursing home context, the emotional strategies used by healthcare professionals to navigate such demands, and how these demands affect their emotional wellbeing. Methods This qualitative study used a multiple case study approach. We purposively selected nine nursing homes from three geographical provinces in France with diverse ownership statuses (public, private, associative). Individual interviews and focus group discussions were held with 93 healthcare professionals from various occupational groups employed in the participating nursing homes. Data was collected from April 2021 to September 2022 and was analysed using thematic content analysis. Results Data revealed that providing palliative care to dying residents within the nursing home context results in intertwined rewarding and exhausting emotional experiences for healthcare professionals. Professionals have to utilize multifaceted emotional strategies to navigate these experiences, including suppressing and modifying emotions and distancing themselves emotionally from residents to protect themselves from emotional suffering. Participants noted a lack of formal space to express emotions. Unrecognized emotional labour undermines the wellbeing of healthcare professionals in nursing homes, whereas acknowledging emotions enhances satisfaction and gives enhanced meaning to their crucial role in resident care. Conclusion Acknowledging emotional labour as an inevitable component of providing palliative care in nursing homes is critical to supporting healthcare professional wellbeing, resilience, and retention, which may ultimately improve the quality of care for dying residents. Ensuring quality care and supporting the emotional wellbeing of nursing home professionals requires an organisational culture that considers emotional expression a collective strength-building resource rather than an individual responsibility, in hopes of shaping a new culture that fully acknowledges their humanity alongside their professional skills. Trial registration ClinicalTrials.gov ID: NCT04708002; National registration: ID-RCB number: 2020-A01832-37, Registration date: 2020-12-03.

Abstract Breast cancer is the most frequent type of tumor in women and is characterized by variable outcomes due to its heterogeneity and the presence of many cancer cell-autonomous and –non-autonomous factors. A major determinant of breast cancer aggressiveness is represented by immune infiltration, which can support tumor development. In our work, we studied the role of mast cells in breast cancer and identified a novel activity in promoting the tumor-initiating properties of cancer cells. Mast cells are known to affect breast cancer prognosis, but show different effects according to the diverse subtypes. Starting from the observation that co-injection of mast cells with limiting concentrations of cancer cells increased their in vivo engraftment rate, we characterized the molecular mechanisms by which mast cells promote the tumor stem-like features. We provide evidence that mast cell heparanase plays a pivotal role since both its activity and the stimulation of mast cells with heparan sulfate, the product of heparanase activity, are crucial for this process. Moreover, the pharmacological inhibition of heparanase prevents the function of mast cells. Our data show that soluble factors released by mast cells favor the expression of estrogen receptor in a MUC1-dependent manner. The MUC1/estrogen receptor axis is eventually essential for cancer stem-like features, specifically in HER2-negative cells, and promotes the capability of cancer cells to form mammospheres and express stem-related genes, also reducing their sensitivity to tamoxifen administration. Altogether our findings describe a novel mechanism by which mast cells could increase the aggressiveness of breast cancer uncovering a molecular mechanism displaying differences based on the specific breast cancer subtype.

Abstract Tri-boson production together with vector-boson scattering is a privileged channel to study the electroweak structure of the Standard Model. Upcoming LHC running stages will allow to measure these processes at unprecedented accuracy and for all possible final states, which requires to push theory predictions to still unexplored frontiers. In this work we present the first calculation for the process pp → μ + μ − e+ ν ejj at the LHC in a tri-boson phase space. We evaluate the three LO contributions, namely the O $$ \mathcal{O} $$ (α 6), which contains the genuine tri-boson signature, along with the O $$ \mathcal{O} $$ (α s α 5) and O $$ \mathcal{O} $$ ( α s 2 $$ {\alpha}_{\textrm{s}}^2 $$ α 4), and the two O $$ \mathcal{O} $$ (α 7) and O $$ \mathcal{O} $$ (α s α 6) NLO corrections. The calculation is based on full Standard-Model matrix elements, including all resonant and non-resonant terms, complete spin correlations and interference effects. Integrated and differential cross sections are presented for a fiducial region inspired by High Luminosity LHC prospect studies. We find electroweak corrections of −14% for the fiducial cross section, almost twice as large as for other tri-boson processes.

Abstract The consumption of alcohol and caffeine affects the lives of billions of individuals worldwide. Although recent evidence indicates that caffeine impairs the reinforcing properties of alcohol, a characterization of its effects on alcohol-stimulated mesolimbic dopamine (DA) function was lacking. Acting as the pro-drug of salsolinol, alcohol excites DA neurons in the posterior ventral tegmental area (pVTA) and increases DA release in the nucleus accumbens shell (AcbSh). Here we show that caffeine, via antagonistic activity on A2A adenosine receptors (A2AR), prevents alcohol-dependent activation of mesolimbic DA function as assessed, in-vivo, by brain microdialysis of AcbSh DA and, in-vitro, by electrophysiological recordings of pVTA DA neuronal firing. Accordingly, while the A1R antagonist DPCPX fails to prevent the effects of alcohol on DA function, both caffeine and the A2AR antagonist SCH 58261 prevent alcohol-dependent pVTA generation of salsolinol and increase in AcbSh DA in-vivo, as well as alcohol-dependent excitation of pVTA DA neurons in-vitro. However, caffeine also prevents direct salsolinol- and morphine-stimulated DA function, suggesting that it can exert these inhibitory effects also independently from affecting alcohol-induced salsolinol formation or bioavailability. Finally, untargeted metabolomics of the pVTA showcases that caffeine antagonizes alcohol-mediated effects on molecules (e.g. phosphatidylcholines, fatty amides, carnitines) involved in lipid signaling and energy metabolism, which could represent an additional salsolinol-independent mechanism of caffeine in impairing alcohol-mediated stimulation of mesolimbic DA transmission. In conclusion, the outcomes of this study strengthen the potential of caffeine, as well as of A2AR antagonists, for future development of preventive/therapeutic strategies for alcohol use disorder.

Ischemic preconditioning (PC) induced by a sub-lethal cerebral insult triggers brain tolerance against a subsequent severe injury through diverse mechanisms, including the modulation of the immune system. Tumor necrosis factor (TNF)-α-stimulated gene 6 (TSG-6), a hyaluronate (HA)-binding protein, has recently been involved in the regulation of the neuroimmune response following ischemic stroke. Thus, we aimed at assessing whether the neuroprotective effects of ischemic PC involve the modulation of TSG-6 in a murine model of transient middle cerebral artery occlusion (MCAo). The expression of TSG-6 was significantly elevated in the ischemic cortex of mice subjected to 1 h MCAo followed by 24 h reperfusion, while this effect was further potentiated (p < 0.05 vs. MCAo) by pre-exposure to ischemic PC (i.e., 15 min MCAo) 72 h before. By immunofluorescence analysis, we detected TSG-6 expression mainly in astrocytes and myeloid cells populating the lesioned cerebral cortex, with a more intense signal in tissue from mice pre-exposed to ischemic PC. By contrast, levels of TSG-6 were reduced after 24 h of reperfusion in plasma (p < 0.05 vs. SHAM), but were dramatically elevated when severe ischemia (1 h MCAo) was preceded by ischemic PC (p < 0.001 vs. MCAo) that also resulted in significant neuroprotection. In conclusion, our data demonstrate that neuroprotection exerted by ischemic PC is associated with the elevation of TSG-6 protein levels both in the brain and in plasma, further underscoring the beneficial effects of this endogenous modulator of the immune system.

Abstract Measuring vector-boson scattering beyond the fully-leptonic final state is becoming possible at the LHC, which demands to have a solid control on the theory predictions for all final states of this class of processes. In this work we present a full off-shell leading-order calculation for the process pp → ℓ + ν ℓ + 4j in two fiducial regions which are particularly relevant for its experimental measurement. In addition to the fully electroweak order, i.e. O α 6 $$ \mathcal{O}\left({\alpha}^6\right) $$ , we complement our results with O α s α 5 $$ \mathcal{O}\left({\alpha}_{\textrm{s}}{\alpha}^5\right) $$ and O α s 2 α 4 $$ \mathcal{O}\left({\alpha}_{\textrm{s}}^2{\alpha}^4\right) $$ for inclusive predictions. At O α 6 $$ \mathcal{O}\left({\alpha}^6\right) $$ we present for the first time a systematic treatment of the process in double-pole approximation and we perform a detailed study of its range of validity by considering inclusive and differential predictions compared to the full off-shell calculation.

Abstract: Cleft lip and palate (CLP) represent the most frequently reported congenital anomaly affecting the craniofacial region. The aim of this study was to assess the output (in number of procedures) of the Brazilian hospitals accredited for the treatment of CLP patients, examine the referral flow of patients requiring this type of care, and ascertain the adequacy of the corresponding infrastructure of these healthcare facilities. Methodologically, the study used an observational, cross-sectional, and ecological design. Output data, categorized by state and macro-region, and patient referral flow records were accessible through the Outpatient Information System (SIA, in its Portuguese acronym) and the Hospital Information System (SIH, in Portuguese), respectively. Infrastructure assessment relied on data sourced from the National Register of Health Establishments (CNES, in Portuguese). Analysis encompassed data from 28 accredited hospitals. Concerning output metrics, the state of São Paulo ranked first in the number of procedures conducted. The establishments exhibiting the lowest output performance comprised six hospitals located in the Southeast region and two in the Center-West region. Examination of patient referral flow corroborated the concentration of procedures predominantly conducted in the Southeast, notably within São Paulo state. Infrastructure evaluation encompassed the following categories: physical facilities, diagnostic and therapeutic support services, equipment, and comprehensive multidisciplinary care services. The data showed that roughly 61% of the hospitals surveyed possessed less than half of the recommended items. The primary deficiency identified pertained to inadequacies in equipment availability. Conversely, the best outcomes were associated with diagnostic and therapeutic support services. It was concluded that enhancing hospital infrastructure is imperative for the amelioration of care provision to patients with CLP across all Brazilian states.

Background: One of the fundamental pillars of integrating a palliative approach in nursing home care is increasing professional competencies and institutional capacity. However, conventional training designs have been proven to fall short of supporting this integration. This paper details the results of a practice development intervention that used critical companionship as a learning design to facilitate the integration of a palliative approach in the care of nursing home residents in France. Objectives: This study aimed to explore the perceived outcomes of Padi-Palli critical companionship in supporting the integration of a palliative approach in the care of residents in nursing homes in France. Design: Qualitative multiple case study situated within a constructivist theoretic lens. Methods: This qualitative multiple case study is part of a larger interventional mixed-method study. Nurses with palliative care clinical expertise facilitated experiential learning with nursing home professionals for 10 months spread across three phases. At the end of the intervention, a purposive sampling method was used to select professionals from six nursing homes that participated, including leaders and critical companions. Focus groups and individual interviews were used to collect data between February 2023 and March 2024. Data analysis followed Braun and Clarke’s reflexive thematic analysis. Results: Four interrelated themes explained how Padi-Palli critical companionship enhanced the palliative care competencies of professionals, improved nursing home palliative care practices, supported organisational practices for palliative care and facilitated collaborative learning at the bedside. The collaborative and co-creative principles that informed the delivery of the Padi-Palli critical companionship program facilitated a culture shift towards integrating a palliative approach in resident care at individual, team and organisational levels. Conclusion: Critical companionship offers an innovative practice development approach that can support the delivery of timely palliative care for residents in nursing homes. Trial registration: ID-RCB 2020-A01832-37.

Introdução: A resistência antimicrobiana é considerada pala OMS uma crise global, a principal causa dessa resistência se dá devido ao uso excessivo e irracional de antimicrobianos. O programa stewardship foi criando com o objetivo de prevenir essa resistência além de, promover o uso racional de antimicrobianos no ambiente hospitalar. Objetivo: Esse estudo tem por objetivo avaliar o impacto da implementação do programa stewardship em um hospital público de médio porte. Método: Trata-se de um estudo transversal realizado através do monitoramento de 19 antimicrobianos de uso restrito prescritos para pacientes internados em um hospital público de médio porte no litoral sul do estado de são Paulo. A coleta de dados ocorreu entre os meses de janeiro e abril de 2024. Os dados foram obtidos através das intervenções farmacêuticas realizadas em conjunto com a equipe de infectologia no programa stewardship. Resultados: Ao longo dos quatro meses do programa stewardship foram analisadas 625 prescrições, através dessas analises foram realizadas 729 intervenções farmacêuticas que resultam em uma economia de total para o hospital de R$ 23.506,06 reais, além otimização do uso antimicrobianos. Conclusão: A implementação do programa stewardship em um hospital público tem gerando impactos positivos tanto para a economia hospitalar, quando para a promoção do uso racional de antimicrobianos, se mostrando uma estratégia promissora para a prevenção da resistência antimicrobiana no âmbito hospitalar.

O tumor ósseo multilobular é uma neoplasia primária rara em cães que acomete ossos chatos do crânio, potencialmente maligna, localmente invasiva e de crescimento lento. Normalmente atinge cães de raças de médio a grande porte e de meia idade a idosos. As alterações clínicas irão depender do comportamento biológico do tumor e estão associadas às estruturas que sofrem compressão pela massa. O objetivo deste trabalho foi relatar o caso de tumor ósseo multilobular craniano em uma cadela, sem raça definida, de nove anos de idade. A paciente apresentou o desenvolvimento progressivo de uma massa firme na região dorsal dos ossos frontais e parietais do crânio, que resultou em ceratoconjuntivite devido à tensão excessiva da pele na região palpebral. A radiografia craniana demonstrou a presença de uma massa de grande radiopacidade e aspecto granular. O exame citopatológico evidenciou achados sugestivos de tumor ósseo multilobular, optando-se pela excisão cirúrgica da massa. Foi realizada a excisão da neoplasia por meio da divulsão dos tecidos adjacentes e secção da neoplasia na base do crânio. Devido ao grau de invasividade do tumor não foi possível o estabelecimento de margem cirúrgica. O diagnóstico foi confirmado por meio do exame histopatológico. A paciente apresentou boa recuperação após a cirurgia, inclusive da lesão ocular, porém após cinco meses houve recidiva local da neoplasia. Uma segunda intervenção cirúrgica não foi possível, pois a paciente veio a óbito por intoxicação por bufotoxina. A remoção cirúrgica da neoplasia, mesmo com margens comprometidas, melhorou significativamente a qualidade de vida da paciente.

IntroductionThis study aimed to establish normative data for the Self-Administered Tasks Uncovering Risk of Neurodegeneration (SATURN), a brief computer-based test for global cognitive assessment through accuracy and response times on tasks related to memory, attention, temporal orientation, visuo-constructional abilities, math (calculation), executive functions, and reading speed.MethodsA sample of 323 Italian individuals with Montreal Cognitive Assessment (MoCA) equivalent score ≥1 (180 females; average age: 61.33 years; average education: 11.32 years), stratified by age, education, and sex, completed SATURN using PsychoPy, and a paper-and-pencil protocol consisting of Mini-Mental State Examination (MMSE) and MoCA. Data analyses included: (i) correlations between the total accuracy scores of SATURN and those of MMSE and MoCA; (ii) multiple regressions to determine the impact of sex, age, and education, along with the computation of adjusted scores; (iii) the calculation of inner and outer tolerance limits, equivalent scores, and the development of correction grids.ResultsThe mean total time on tasks was 6.72 ± 3.24 min. Age and education significantly influence the SATURN total accuracy, while sex influences the total time on tasks. Specific sociodemographic characteristics influence subdomain accuracies and times on task differently. For the adjusted SATURN total score, the outer limit corresponds to 16.56 out of 29.00 (cut-off), while the inner limit is 18.57. SATURN significantly correlates with MMSE and MoCA.DiscussionIn conclusion, SATURN is the first open-source digital tool for initial cognitive assessment in Italy, showing potential for self-administration in primary care, and remote administration. Future studies need to assess its sensitivity and specificity in detecting pathological cognitive decline.

O tumor ósseo multilobular é uma neoplasia primária rara em cães que acomete ossos chatos do crânio, potencialmente maligna, localmente invasiva e de crescimento lento. Normalmente atinge cães de raças de médio a grande porte e de meia idade a idosos. As alterações clínicas irão depender do comportamento biológico do tumor e estão associadas às estruturas que sofrem compressão pela massa. O objetivo deste trabalho foi relatar o caso de tumor ósseo multilobular craniano em uma cadela, sem raça definida, de nove anos de idade. A paciente apresentou o desenvolvimento progressivo de uma massa firme na região dorsal dos ossos frontais e parietais do crânio, que resultou em ceratoconjuntivite devido à tensão excessiva da pele na região palpebral. A radiografia craniana demonstrou a presença de uma massa de grande radiopacidade e aspecto granular. O exame citopatológico evidenciou achados sugestivos de tumor ósseo multilobular, optando-se pela excisão cirúrgica da massa. Foi realizada a excisão da neoplasia por meio da divulsão dos tecidos adjacentes e secção da neoplasia na base do crânio. Devido ao grau de invasividade do tumor não foi possível o estabelecimento de margem cirúrgica. O diagnóstico foi confirmado por meio do exame histopatológico. A paciente apresentou boa recuperação após a cirurgia, inclusive da lesão ocular, porém após cinco meses houve recidiva local da neoplasia. Uma segunda intervenção cirúrgica não foi possível, pois a paciente veio a óbito por intoxicação por bufotoxina. A remoção cirúrgica da neoplasia, mesmo com margens comprometidas, melhorou significativamente a qualidade de vida da paciente.

Abstract Polar‐orbiting satellites have significantly improved our understanding of the terrestrial carbon cycle, yet they are not designed to observe sub‐daily dynamics that can provide unique insight into carbon cycle processes. Geostationary satellites offer remote sensing capabilities at temporal resolutions of 5‐min, or even less. This study explores the use of geostationary satellite data acquired by the Geostationary Operational Environmental Satellite—R Series (GOES‐R) to estimate terrestrial gross primary productivity (GPP) and ecosystem respiration (RECO) using machine learning. We collected and processed data from 126 AmeriFlux eddy covariance towers in the Contiguous United States synchronized with imagery from the GOES‐R Advanced Baseline Imager (ABI) from 2017 to 2022 to develop ML models and assess their performance. Tree‐based ensemble regressions showed promising performance for predicting GPP (R2 of 0.70 ± 0.11 and RMSE of 4.04 ± 1.65 μmol m−2 s−1) and RECO (R2 of 0.77 ± 0.10 and RMSE of 0.90 ± 0.49 μmol m−2 s−1) on a half‐hourly time step using GOES‐R surface products and top‐of‐atmosphere observations. Our findings align with global efforts to utilize geostationary satellites to improve carbon flux estimation and provide insight into how to estimate terrestrial carbon dioxide fluxes in near‐real time.

Abstract Since spring 2022, the global epidemiology of the monkeypox virus (MPXV) has changed. The unprecedented increase of human clade II MPXV cases worldwide heightened concerns about this emerging zoonotic disease. We analysed the positivity rates, viral loads, infectiousness, and persistence of MPXV DNA for up to 4 months in several biological samples from 89 MPXV-confirmed cases. Our data showed that viral loads and positivity rates were higher during the first two weeks of symptoms for all sample types. Amongst no-skin-samples, respiratory specimens showed higher MPXV DNA levels and median time until viral clearance, suggesting their usefulness in supporting MPXV diagnosis, investigating asymptomatic patients, and monitoring viral shedding. Infectious virus was cultured from respiratory samples, semen, and stools, with high viral loads and collected within the first 10 days. Notably, only one saliva and one semen were found positive for viral DNA after 71 and 31 days from symptoms, respectively. The focus on bloodstream samples showed the best testing sensitivity in plasma, reporting the overall highest MPXV DNA detection rate and viral loads during the 3-week follow-up as compared to serum and whole-blood. The data here presented can be useful for MPXV diagnostics and a better understanding of the potential alternative routes of its onward transmission.

A convolutional neural network is trained on a large dataset of suitably randomized film profiles and corresponding elastic energy densities ρɛ, computed by the finite element method. The trained model provides quantitative predictions of ρɛ for arbitrary profiles, surrogating its explicit calculation, and is used for the time integration of partial differential equations describing the evolution of strained films. The close match found between the neural network predictions and the “ground-truth” evolutions obtained by the finite element method calculation of ρɛ, even after tens-of-thousands of integration time-steps, validates the approach. A substantial computational speed up without significant loss of accuracy is demonstrated, allowing for million-steps simulations of islands growth and coarsening. The intriguing possibility of extending the domain size is also discussed.

Virtual Reality (VR) technologies have entered many aspects of daily life (e.g., workplace, education, gaming). VR users report that time flows faster when immersed in a virtual environment. Such an effect is supported by recent scientific evidence (Mullen & Davidenko, 2021). Indeed, a familiarity effect could foster such a time compression effect. To investigate this possibility, a between-subject design was adopted: in one condition, participants explored a virtual environment through a head-mounted display (HMD), whereas in the control condition, participants explored the same environment through a standard monitor. Participants were all instructed to produce an interval of 4 minutes so that longer produced durations in an interval production task were evidence of underestimation. Adopting a prospective time estimation paradigm, the time intervals produced were compared between the two conditions. Results confirmed the time compression effect: participants in the VR condition reported longer produced intervals than participants in the control condition. Furthermore, the significant interaction with levels of prior experience with VR technologies suggests that time compression effects may be more pronounced for VR newcomers, thus favoring an interpretation in terms of familiarity. The present findings provide valuable insights into the perception of time in virtual environments, suggesting the importance of continued research in this emerging technology. Limits, implications, and the need for further research are finally discussed.

This work presents a technique to estimate on-line the global inertia of an electric power system by exploiting the footprint of the principal frequency system dynamics. This method can estimate the inertia provided as a whole by synchronous machines, as well as by converter-interfaced generators controlled to emulate the behavior of the former through virtual inertia. Probing tones are injected by a grid-forming converter-interfaced generator and its virtual rotor speed is used to extrapolate its footprint. As a result, the method requires neither measuring the active power exchange of each synchronous generator nor extrapolating their rotor speeds. Since the proposed technique is entirely data driven, it does not require any model of the power system generators/prime-movers/controllers and of the interconnecting grid. The method is comprehensively tested on a modified version of the IEEE 39-BUS system and a dynamic version of the IEEE 118-BUS system, both containing grid-forming converter-interfaced generators.

Summary: Brown adipose tissue (BAT) is mitochondria rich, enabling high oxidative metabolism for non-shivering thermogenesis. The release of large/small extracellular vesicles (EVs) containing mitochondria or mitochondrial fragments, termed mito-EVs, may support mitochondrial quality control or intercellular communication. We present a protocol to isolate and characterize mito-EVs. We detail steps for BAT processing, cell debris removal, differential centrifugation (dC), and mito-EV analysis by flow cytometry and immunoblotting assays.For complete details on the use and execution of this protocol, please refer to Rosina et al.1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Introduction: The gut microbiota (MB), although one of the main producers of Aβ in the body, in physiological conditions contributes to the maintainance of a healthy brain. Dysbiosis, the dysbalance between Gram-negative and Gram-positive bacteria in the MB increases Aβ production, contributing to the accumulation of Aβ plaques in the brain, the main histopathological hallmark of Alzheimer’s disease (AD). Administration of prebiotics and probiotics, maintaining or recovering gut-MB composition, could represent a nutraceutical strategy to prevent or reduce AD sympthomathology. Aim of this research was to evaluate whether treatment with pre- and probiotics could modify the histopathological signs of neurodegeneration in hippocampal CA1 and CA3 areas of a transgenic mouse model of AD (APP/PS1 mice). The hippocampus is one of the brain regions involved in AD.Methods: Tg mice and Wt littermates (Wt-T and Tg-T) were fed daily for 6 months from 2 months of age with a diet supplemented with prebiotics (a multi-extract of fibers and plant complexes, containing inulin/fruit-oligosaccharides) and probiotics (a 50%–50% mixture of Lactobacillus rhamnosus and Lactobacillus paracasei). Controls were Wt and Tg mice fed with a standard diet. Brain sections were immunostained for Aβ plaques, neurons, astrocytes, microglia, and inflammatory proteins that were evaluated qualitatively and quantitatively by immunofluorescence, confocal microscopy and digital imaging with ImageJ software.Results: Quantitative analyses demonstrated that: 1) The treatment with pre- and probiotics significantly decreased Aβ plaques in CA3, while in CA1 the reduction was not significant; 2) Neuronal damage in CA1 Stratum Pyramidalis was significantly prevented in Tg-T mice; no damage was found in CA3; 3) In both CA1 and CA3 the treatment significantly increased astrocytes density, and GFAP and IBA1 expression, especially around plaques; 4) Microglia reacted differently in CA1 and CA3: in CA3 of Tg-T mice there was a significant increase of CD68+ phagocytic microglia (ball-and-chain phenomic) and of CX3CR1 compared with CA1.Discussion: The higher microglia reactivity could be responsible for their more efficient scavenging activity towards Aβ plaques in CA3 in comparison to CA1. Treatment with pre- and probiotics, modifying many of the physiopathological hallmarks of AD, could be considered an effective nutraceutical strategy against AD symptomatology.

Study region: Avella Mts., southern Italy. Study focus: The paper is focused on groundwater of Avella Mts. This aquifer has been experiencing an increasing human pressure due to periods of drought and growth in groundwater extraction. A novel hydrogeological conceptual model was developed, and groundwater recharge was estimated by two approaches. The study was carried out by an in-depth literature review and a GIS-based analysis of geological and piezometric data, ground-based meteorological and remotely sensed data. New hydrological insights for the region: The new hydrogeological conceptual model allowed to reconstruct the aquifer lithology, its deep geometry, and, for the first time, groundwater flow scheme. Five groundwater basins were recognized with distinct outlets and subsurface outflows, suggesting a new aquifer compartmentalization in-series groundwater basins. Some basal springs are fed by autonomous basins with smaller extension, while other springs have dried up completely. The groundwater recharge varies from 7.30 to 6.90 m3/s as estimated by Turc formula and MODIS data, respectively; the values are comparable among them, confirming mutually the validity of approaches used. The comparison with previous studies highlights variations and changes for both the hydrogeological conceptual model and water balance, linked to natural and anthropogenic factors. The results obtained represent a way for supporting sustainable management of groundwater, waterwork systems security and groundwater-dependent ecosystems protection of a large sector of Campania region.

Background: Medical students are at high risk for mental disorders, and the COVID-19 pandemic might have exacerbated psychological distress. However, no data are available for the southern part of Italy. The SMS-ME (Sicilian Medical Students’ MEntal health) project aimed to estimate the prevalence of and predictors of depression, anxiety, stress, and suicidal ideation in a sample of Sicilian medical students. Methods: A web-based cross-sectional survey was carried out from September 2022 to December 2022. The study protocol investigated sociodemographic factors and clinical data including Depression, Anxiety, Stress Scale-21 (DASS-21), and a specific question addressing suicidal ideation frequency over the last six months. Multivariate regression models were assessed to examine the association between symptoms and relevant predictors and then regressed their residuals with suicidal thought frequency. Result: We collected 1,866 records (age=22.5, SD=3.4; 65.2 % females). One out of four students presented highly severe depression (25 %) and referred to the presence of some suicidal ideation in the six months preceding the interview (26.1 %). DASS-21 scores, especially depression (F(5, 1,828)=58.8, p = 6.59–57), increasingly predicted the frequency of suicidal thoughts when above the sample's mean. Limitations: The cross-sectional study design does not allow inferences on temporal relationships and the self-report strategy could be intrinsically biased by the person's feelings at the time of the interview. Conclusions: High prevalence of anxiety and depressive symptoms and suicidal thoughts were observed among Sicilian medical students. The DASS-21 was a good predictor for suicidal ideation that Universities could use as a simple tool to assess the need for psychological healthcare in this population.

Background and purpose: Radiotherapy plans with excessive complexity exhibit higher uncertainties and worse patient-specific quality assurance (PSQA) results, while the workload of measurement-based PSQA can impact the efficiency of the radiotherapy workflow. Machine Learning (ML) and Lean Six Sigma, a process optimization method, were implemented to adopt a targeted PSQA approach, aiming to reduce workload, risk of failures, and monitor complexity. Materials and methods: Lean Six Sigma was applied using DMAIC (define, measure, analyze, improve, and control) steps. Ten complexity metrics were computed for 69,811 volumetric modulated arc therapy (VMAT) arcs from 28,612 plans delivered in our Institute (2013–2021). Outlier complexities were defined as >95th-percentile of the historical distributions, stratified by treatment. An ML model was trained to predict the gamma passing rate (GPR-3 %/1mm) of an arc given its complexity. A decision support system was developed to monitor the complexity and expected GPR. Plans at risk of PSQA failure, either extremely complex or with average GPR

Summary: Background: The outcome of patients with metastatic tumors who discontinued immune checkpoint inhibitors (ICIs) not for progressive disease (PD) has been poorly explored. We performed a meta-analysis of all studies reporting the clinical outcome of patients who discontinued ICIs for reasons other than PD. Methods: We searched PubMed, Embase and Scopus databases, from the inception of each database to December 2023, for clinical trials (randomized or not) and observational studies assessing PD-(L)1 and CTLA-4 inhibitors in patients with metastatic solid tumors who discontinued treatment for reasons other than PD. Each study had to provide swimmer plots or Kaplan–Meier survival curves enabling the reconstruction of individual patient-level data on progression-free survival (PFS) following the discontinuation of immunotherapy. The primary endpoint was PFS from the date of treatment discontinuation overall and according to tumor histotype, type of treatment and reason of discontinuation. The Combersure’s method was used to estimate meta-analytical non-parametric summary survival curves assuming random effects at study level. Findings: Thirty-six studies (2180 patients) were included. The pooled median PFS (mPFS) was 24.7 months (95% CI, 18.8–30.6) and the PFS-rate at 12, 24, and 36 months was respectively 69.8% (95% CI, 63.1–77.3), 51.0% (95% CI, 43.4–59.8) and 34.0% (95% CI, 27.0–42.9). Univariable analysis showed that the mPFS was significantly longer for patients with melanoma (43.0 months), as compared with non-small cell lung cancer (NSCLC, 13.5 months) and renal cell carcinoma (RCC, 10.0 months; between-strata comparison test p-value < 0.001); for patients treated with anti-PD-(L)1 + anti-CTLA-4 as compared with anti-PD-(L)1 monotherapy (44.6 versus 19.9 months; p-value

Summary: Human genetic studies of critical COVID-19 pneumonia have revealed the essential role of type I interferon-dependent innate immunity to SARS-CoV-2 infection. Conversely, an association between the HLA-B∗15:01 allele and asymptomatic SARS-CoV-2 infection in unvaccinated individuals was recently reported, suggesting a contribution of pre-existing T cell-dependent adaptive immunity. We report a lack of association of classical HLA alleles, including HLA-B∗15:01, with pre-omicron asymptomatic SARS-CoV-2 infection in unvaccinated participants in a prospective population-based study in the United States (191 asymptomatic vs. 945 symptomatic COVID-19 cases). Moreover, we found no such association in the international COVID Human Genetic Effort cohort (206 asymptomatic vs. 574 mild or moderate COVID-19 cases and 1,625 severe or critical COVID-19 cases). Finally, in the Human Challenge Characterisation study, the three HLA-B∗15:01 individuals infected with SARS-CoV-2 developed symptoms. As with other acute primary infections studied, no classical HLA alleles favoring an asymptomatic course of SARS-CoV-2 infection were identified.