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Le possibili distinzioni dei termini femmicidio e femminicidio riguardano significati politico-giuridici, ma possono anche voler indicare le diverse modalità di approccio allo studio. Mentre il femmicidio ci parla della natura del delitto di genere, specificando che tale fenomeno è anche un fatto sociale, contestualizzato e delineato dalla cultura di riferimento, il femminicidio viene inteso quale categoria generale della violenza contro le donne, estendendosi a qualsiasi forma di violenza di genere volta ad annientare la soggettività femminile dal punto di vista fisico, psicologico ed anche economico, contemperando anche le forme di violenza domestica e assistita. La legge n. 119 del 2013 ha introdotto nel settore del diritto penale sostanziale e processuale una serie di misure, preventive e repressive, volte a combattere la violenza contro le donne per motivi di genere. Questa disposizione normativa va ad aggiungersi alla precedente tutela penale della legge n. 66 del 1996 che introdusse già numerose novità sul tema, ma da sole non sufficienti per prevenire e reprimere il cosiddetto delitto in questione. Résumé Toute distinction entre les mots fémicide et féminicide implique certaines considérations politiques et juridiques, mais elles peuvent aussi dénoter les différentes façons d’aborder cette question. Le fémicide désigne la nature de la criminalité fondée sur le genre, précisant que ce phénomène est aussi un fait social qui est mis en contexte et décrit par le cadre de référence culturel. Le féminicide est une catégorie générale relative aux violences faites aux femmes. Ce mot fait également référence à tout type de violence fondée sur le genre visant à anéantir la subjectivité féminine d’un point de vue physique, psychologique et économique, en incluant aussi tout type de violence domestique et le phénomène des enfants témoins. Dans le domaine du droit pénal et de procédure pénale italien, la loi n°199/2013 introduit un ensemble de mesures préventives et punitives pour lutter contre toutes les formes de violences fondées sur le genre à l’égard des femmes. Cette loi est un ajout à la loi n°66/1996 qui avait déjà apporté de nombreux changements, mais ils seuls ne suffisaient pas pour prévenir et lutter contre les différent types de crimes susmentionnés. Abstract Any distinction between the words femicide and feminicide involves some political and legal considerations, but also exposes analysis of the different ways of approaching this issue. Femicide refers to the nature of gender crime, specifying that this phenomenon is also a social fact which is put into context and outlined by the cultural reference framework. Feminicide is a general category covering violence against women. It refers also to any kind of gender violence aimed at annihilating female subjectivity from a physical, psychological and economic point of view. The word feminicide also includes any kind of domestic violence and the phenomenon of children’s exposure to that aspect of domestic violence. In the field of Italian criminal law and substantive criminal law, the law n° 199 of 2013 introduced a set of preventive and punitive measures against all forms of gender-based violence against women. This law is an addition to the law n° 66 of 1996 which had already included many changes, but they alone were not sufficient to prevent and fight against the aforementioned different types of crimes.

Approximately 5% of Alzheimer's disease patients develop symptoms before age 65 (early-onset Alzheimer's disease), with either sporadic (sporadic early-onset Alzheimer's disease) or dominantly inherited (dominantly inherited Alzheimer's disease) presentations. Both sporadic early-onset Alzheimer's disease and dominantly inherited Alzheimer's disease are characterized by brain amyloid-β accumulation, tau tangles, hypometabolism and neurodegeneration, but differences in topography and magnitude of these pathological changes are not fully elucidated. In this study, we directly compared patterns of amyloid-β plaque deposition and glucose hypometabolism in sporadic early-onset Alzheimer's disease and dominantly inherited Alzheimer's disease individuals. Our analysis included 134 symptomatic sporadic early-onset Alzheimer's disease amyloid-Positron Emission Tomography (PET)-positive cases from the University of California, San Francisco, Alzheimer's Disease Research Center (mean ± SD age 59.7 ± 5.6 years), 89 symptomatic dominantly inherited Alzheimer's disease cases (age 45.8 ± 9.3 years) and 102 cognitively unimpaired non-mutation carriers from the Dominantly Inherited Alzheimer Network study (age 44.9 ± 9.2). Each group underwent clinical and cognitive examinations, 11C-labelled Pittsburgh Compound B-PET and structural MRI. 18F-Fluorodeoxyglucose-PET was also available for most participants. Positron Emission Tomography scans from both studies were uniformly processed to obtain a standardized uptake value ratio (PIB50-70 cerebellar grey reference and FDG30-60 pons reference) images. Statistical analyses included pairwise global and voxelwise group comparisons and group-independent component analyses. Analyses were performed also adjusting for covariates including age, sex, Mini-Mental State Examination, apolipoprotein ε4 status and average composite cortical of standardized uptake value ratio. Compared with dominantly inherited Alzheimer's disease, sporadic early-onset Alzheimer's disease participants were older at age of onset (mean ± SD, 54.8 ± 8.2 versus 41.9 ± 8.2, Cohen's d = 1.91), with more years of education (16.4 ± 2.8 versus 13.5 ± 3.2, d = 1) and more likely to be apolipoprotein ε4 carriers (54.6% ε4 versus 28.1%, Cramer's V = 0.26), but similar Mini-Mental State Examination (20.6 ± 6.1 versus 21.2 ± 7.4, d = 0.08). Sporadic early-onset Alzheimer's disease had higher global cortical Pittsburgh Compound B-PET binding (mean ± SD standardized uptake value ratio, 1.92 ± 0.29 versus 1.58 ± 0.44, d = 0.96) and greater global cortical 18F-fluorodeoxyglucose-PET hypometabolism (mean ± SD standardized uptake value ratio, 1.32 ± 0.1 versus 1.39 ± 0.19, d = 0.48) compared with dominantly inherited Alzheimer's disease. Fully adjusted comparisons demonstrated relatively higher Pittsburgh Compound B-PET standardized uptake value ratio in the medial occipital, thalami, basal ganglia and medial/dorsal frontal regions in dominantly inherited Alzheimer's disease versus sporadic early-onset Alzheimer's disease. Sporadic early-onset Alzheimer's disease showed relatively greater 18F-fluorodeoxyglucose-PET hypometabolism in Alzheimer's disease signature temporoparietal regions and caudate nuclei, whereas dominantly inherited Alzheimer's disease showed relatively greater hypometabolism in frontal white matter and pericentral regions. Independent component analyses largely replicated these findings by highlighting common and unique Pittsburgh Compound B-PET and 18F-fluorodeoxyglucose-PET binding patterns. In summary, our findings suggest both common and distinct patterns of amyloid and glucose hypometabolism in sporadic and dominantly inherited early-onset Alzheimer's disease.

BACKGROUND AND OBJECTIVES: Cavum septum pellucidum (CSP) is a common but nonspecific MRI finding in individuals with prior head trauma. The type and extent of head trauma related to CSP, CSP features specific to head trauma, and the impact of brain atrophy on CSP are unknown. We evaluated CSP cross-sectionally and longitudinally in healthy and clinically impaired older adults who underwent detailed lifetime head trauma characterization. METHODS: This is an observational cohort study of University of California, San Francisco Memory and Aging Center participants (healthy controls [HCs], those with Alzheimer disease or related dementias [ADRDs], subset with traumatic encephalopathy syndrome [TES]). We characterized traumatic brain injury (TBI) and repetitive head impacts (RHI) through contact/collision sports. Study groups were no RHI/TBI, prior TBI only, prior RHI only, and prior RHI + TBI. We additionally looked within TBI (1, 2, or 3+) and RHI (1-4, 5-10, and 11+ years). All underwent baseline MRI, and 67% completed a second MRI (median follow-up = 5.4 years). CSP measures included grade (0-4) and length (millimeters). Groups were compared on likelihood of CSP (logistic regression, odds ratios [ORs]) and whether CSP length discriminated groups (area under the curve [AUC]). RESULTS: Our sample included 266 participants (N = 160 HCs, N = 106 with ADRD or TES; age 66.8 ± 8.2 years, 45.3% female). Overall, 123 (49.8%) participants had no RHI/TBI, 52 (21.1%) had TBI only, 41 (16.6%) had RHI only, 31 (12.6%) had RHI + TBI, and 20 were classified as those with TES (7.5%). Compared with no RHI/TBI, RHI + TBI (OR 3.11 [1.23-7.88]) and TES (OR 11.6 [2.46-54.8]) had greater odds of CSP. Approximately 5-10 years (OR 2.96 [1.13-7.77]) and 11+ years of RHI (OR 3.14 [1.06-9.31]) had higher odds of CSP. CSP length modestly discriminated participants with 5-10 years (AUC 0.63 [0.51-0.75]) and 11+ years of prior RHI (AUC 0.69 [0.55-0.84]) from no RHI/TBI (cut point = 6 mm). Strongest effects were noted in analyses of American football participation. Longitudinally, CSP grade was unchanged in 165 (91.7%), and length was unchanged in 171 (95.5%) participants. DISCUSSION: Among older adults with and without neurodegenerative disease, risk of CSP is driven more by duration (years) of RHI, especially American football, than number of TBI. CSP length (≥6 mm) is relatively specific to individuals who have had substantial prior RHI. Neurodegenerative disease and progressive atrophy do not clearly influence development or worsening of CSP.

Approximately 5% of Alzheimer's disease cases have an early age at onset (

Early-onset Alzheimer's disease (AD) is highly heritable, yet only 10% of cases are associated with known pathogenic mutations. For early-onset AD patients without an identified autosomal dominant cause, we hypothesized that their early-onset disease reflects further enrichment of the common risk-conferring single nucleotide polymorphisms associated with late-onset AD. We applied a previously validated polygenic hazard score for late-onset AD to 193 consecutive patients diagnosed at our tertiary dementia referral center with symptomatic early-onset AD. For comparison, we included 179 participants with late-onset AD and 70 healthy controls. Polygenic hazard scores were similar in early- versus late-onset AD. The polygenic hazard score was not associated with age-of-onset or disease biomarkers within early-onset AD. Early-onset AD does not represent an extreme enrichment of the common single nucleotide polymorphisms associated with late-onset AD. Further exploration of novel genetic risk factors of this highly heritable disease is warranted.Highlights: There is a unique genetic architecture of early- versus late-onset Alzheimer's disease (AD).Late-onset AD polygenic risk is not an explanation for early-onset AD.Polygenic risk of late-onset AD does not predict early-onset AD biology.Unique genetic architecture of early- versus late-onset AD parallels AD heterogeneity.

Abstract Ischemia with non-obstructive coronary artery (INOCA) is a common cause of hospital admissions, leading to negative outcomes and reduced quality of life. Central to its pathophysiology is endothelial dysfunction, which contributes to myocardial ischemia despite the absence of significant coronary artery blockage. Addressing endothelial dysfunction is essential in managing INOCA to alleviate symptoms and prevent cardiovascular events. Recent studies have identified diabetes mellitus (DM) as a significant factor exacerbating INOCA complications by promoting endothelial impairment and coronary microvascular dysfunction. MicroRNAs (miRNAs) have emerged as potential biomarkers and therapeutic targets in various biological processes, including endothelial dysfunction and cardiovascular diseases. However, research on miRNA biomarkers in INOCA patients is sparse. In this study, we examined a panel of circulating miRNAs involved in the regulation of endothelial function in INOCA patients with and without DM. We analyzed miRNA expression using RT-qPCR in a cohort of consecutive INOCA patients undergoing percutaneous coronary intervention. We detected a significant dysregulation of miR-363-5p and miR-92a-3p in INOCA patients with DM compared to those without DM, indicating their role as biomarkers for predicting and monitoring endothelial dysfunction in INOCA patients with DM.

Abstract In recent years, the exploration of the therapeutic potential of Salvia has gained considerable attention, leading to a growing number of scientific studies emphasizing its pharmacological properties. Despite this, therapeutic applications of Salvia remain underexploited, requiring further investigation. Iran is a major center for sage diversity in Asia, boasting 60 Salvia species, 17 of which are unique to the area. This study aimed to comprehensively explore and compare the extracts of 102 Salvia samples belonging to 20 distinct Salvia species from Iran, providing a deeper understanding of their specific polyphenol content and, consequently, their antioxidant capabilities and potential therapeutic uses. All samples were analyzed to determine the contents of total phenolics, total flavonoids, total tannin, photosynthetic pigments, and ascorbic acid, along with their antioxidant activity. These data were then combined with the forty distinct chemical fingerprints identified by ultrafast high-pressure liquid chromatography coupled with high-resolution mass spectrometry. Multivariate data analysis was employed to find correlations and differences among the huge number of data obtained and to identify Salvia species with similar phytochemical and/or antioxidant properties. The results show that each Salvia species is characterized by a distinct class of polyphenols recognized for their antidiabetic, anti-inflammatory, cardioprotective and neuroprotective properties. Overall, our findings reveal the potential of some Salvia species for targeted therapeutic applications and provide a rational basis for the development of Salvia-derived nutraceuticals, ultimately improving the prospects for the use of Salvia in medicine.

Abstract Plastic foams, near-ubiquitous in everyday life and industry, show properties that depend primarily on density. Density measurement, although straightforward in principle, is not always easy. As such, while several methods are available, plastic foam industry is not yet supported with a standard technique that effectively enables to control density maps. To overcome this issue, this paper proposes Terahertz (THz) time-of-flight imaging using normal reflection measurements as a fast, relatively cheap, contactless, non-destructive and non-dangerous way to map plastic foam density, based on the expected relationship between density and refractive index. The approach is demonstrated in the case of polypropylene foams. First, the relationship between the estimated effective refractive index and the polypropylene foam density is derived by characterizing a set of carefully crafted samples having uniform density in the range 70–900 kg/m3. The obtained calibration curve subtends a linear relationship between the density and the refractive index in the range of interest. This relationship is validated against a set of test samples, whose estimated average densities are consistent with the nominal ones, with an absolute error lower than 10 kg/m3 and a percentage error on the estimate of 5%. Exploiting the calibration curve, it is possible to build quantitative images depicting the spatial distribution of the sample density. THz images are able to reveal the non-uniform density distribution of some samples, which cannot be appreciated from visual inspection. Finally, the complex spatial density pattern of a graded foam sample is characterized and quantitatively compared with the density map obtained via X-ray microscopy. The comparison confirms that the proposed THz approach successfully determines the density pattern with an accuracy and a spatial scale variability compliant with those commonly required for plastic foam density estimate.

Abstract Although physical models are improving our understanding of the crustal processes that lead to large earthquakes, observing their preparatory phases is still challenging. We show that the spatio-temporal evolution of the ground motion of small magnitude earthquakes can shed light on the preparatory phase of three main earthquakes that occurred in central Italy between 2016 and 2017. We analyze systematic deviations of peak ground accelerations generated by each earthquake from the values predicted by a reference ground motion model calibrated for background seismicity and refer to such deviations as event-specific ground motion anomalies (eGMAs). The eGMA temporal behavior indicates that during the activation phase of the main earthquakes, the ground shaking level deviates, positively or negatively, from the values expected for the background seismicity. eGMA can be exploited as beacons of stress change and help to monitor the mechanical state of the crust and the nucleation of large earthquakes.

Abstract Background Maximizing the efficiency to screen amyloid-positive individuals in asymptomatic and non-demented aged population using blood-based biomarkers is essential for future success of clinical trials in the early stage of Alzheimer’s disease (AD). In this study, we elucidate the utility of combination of plasma amyloid-β (Aβ)-related biomarkers and tau phosphorylated at threonine 217 (p-tau217) to predict abnormal Aβ-positron emission tomography (PET) in the preclinical and prodromal AD. Methods We designed the cross-sectional study including two ethnically distinct cohorts, the Japanese trial-ready cohort for preclinica and prodromal AD (J-TRC) and the Swedish BioFINDER study. J-TRC included 474 non-demented individuals (CDR 0: 331, CDR 0.5: 143). Participants underwent plasma Aβ and p-tau217 assessments, and Aβ-PET imaging. Findings in J-TRC were replicated in the BioFINDER cohort including 177 participants (cognitively unimpaired: 114, mild cognitive impairment: 63). In both cohorts, plasma Aβ(1-42) (Aβ42) and Aβ(1-40) (Aβ40) were measured using immunoprecipitation-MALDI TOF mass spectrometry (Shimadzu), and p-tau217 was measured with an immunoassay on the Meso Scale Discovery platform (Eli Lilly). Results Aβ-PET was abnormal in 81 participants from J-TRC and 71 participants from BioFINDER. Plasma Aβ42/Aβ40 ratio and p-tau217 individually showed moderate to high accuracies when detecting abnormal Aβ-PET scans, which were improved by combining plasma biomarkers and by including age, sex and APOE genotype in the models. In J-TRC, the highest AUCs were observed for the models combining p-tau217/Aβ42 ratio, APOE, age, sex in the whole cohort (AUC = 0.936), combining p-tau217, Aβ42/Aβ40 ratio, APOE, age, sex in the CDR 0 group (AUC = 0.948), and combining p-tau217/Aβ42 ratio, APOE, age, sex in the CDR 0.5 group (AUC = 0.955), respectively. Each subgroup results were replicated in BioFINDER, where the highest AUCs were seen for models combining p-tau217, Aβ42/40 ratio, APOE, age, sex in cognitively unimpaired (AUC = 0.938), and p-tau217/Aβ42 ratio, APOE, age, sex in mild cognitive impairment (AUC = 0.914). Conclusions Combination of plasma Aβ-related biomarkers and p-tau217 exhibits high performance when predicting Aβ-PET positivity. Adding basic clinical information (i.e., age, sex, APOE ε genotype) improved the prediction in preclinical AD, but not in prodromal AD. Combination of Aβ-related biomarkers and p-tau217 could be highly useful for pre-screening of participants in clinical trials of preclinical and prodromal AD.

Anderson–Fabry disease (AFD) is a lysosomal storage disorder, depending on defects in alpha galactosidase A activity, due to a mutation in the galactosidase alpha gene. Cardiovascular involvement represents the leading cause of death in AFD. Cardiac imaging plays a key role in the evaluation and management of AFD patients. Echocardiography is the first-line imaging modality for the identification of the typical features of AFD cardiomyopathy. Advanced echocardiography that allows assessment of myocardial deformation has provided insights into the cardiac functional status of AFD patients. The present review highlights the value and the perspectives of advanced ultrasound imaging in AFD.

BackgroundPlasma phosphorylated tau (p-tau) has emerged as a promising biomarker for Alzheimer's disease (AD). Studies have reported strong associations between p-tau and tau-PET that are mainly driven by differences between amyloid-positive and amyloid-negative patients. However, the relationship between p-tau and tau-PET is less characterized within cognitively impaired patients with a biomarker-supported diagnosis of AD. We conducted a head-to-head comparison between plasma p-tau217 and tau-PET in patients at the clinical stage of AD and further assessed their relationships with demographic, clinical, and biomarker variables.MethodsWe retrospectively included 87 amyloid-positive patients diagnosed with MCI or dementia due to AD who underwent structural MRI, amyloid-PET (11C-PIB), tau-PET (18F-flortaucipir, FTP), and blood draw assessments within 1 year (age = 66 ± 10, 48% female). Amyloid-PET was quantified in Centiloids (CL) while cortical tau-PET binding was measured using standardized uptake value ratios (SUVRs) referenced against inferior cerebellar cortex. Plasma p-tau217 concentrations were measured using an electrochemiluminescence-based assay on the Meso Scale Discovery platform. MRI-derived cortical volume was quantified with FreeSurfer. Mini-Mental State Examination (MMSE) scores were available at baseline (n = 85) and follow-up visits (n = 28; 1.5 ± 0.7 years).ResultsPlasma p-tau217 and cortical FTP-SUVR were correlated (r = 0.61, p

Ground-based high resolution observations of downward longwave irradiance (DLI), surface air temperature, water vapor surface partial pressure and column amount, zenith sky infrared (IR) radiance in the atmospheric window, and all-sky camera images are regularly obtained at the Thule High Arctic Atmospheric Observatory (THAAO, 76.5° N, 68.8° W), northwestern Greenland. The datasets for the years 2017 and 2018 have been used to assess the performance of different empirical formulas used to infer clear sky DLI. An algorithm to identify clear sky observations has been developed, based on value, variability, and persistence of zenith sky IR radiance. Seventeen different formulas to estimate DLI have been tested against the THAAO dataset, using the originally determined coefficients. The formulas that combine information on total column water vapor and surface air temperature appear to perform better than others, with a mean bias with respect to the measured DLI smaller than 1 W m−2 and a root mean squared error (RMSE) around 6 W m−2. Unexpectedly, some formulas specifically developed for the Arctic are found to produce poor statistical results. This is attributed partly to limitations in the originally used dataset, which does not cover a whole year or is relative to very specific condition (i.e., the presence of an ice sheet). As expected, the bias displays a significant improvement when the coefficients of the different formulas are calculated using the THAAO dataset. The presence of 2 full years of data allows the determination and the applicability of the coefficients for singular years and the evaluation of results. The smallest values of the bias and RMSE reach 0.1 and 5 W m−2, respectively. Overall, the best results are found for formulas that use both surface parameters and total water vapor column content, and have been developed from global datasets. Conversely, formulas that express the atmospheric emissivity as a linear function of the logarithm of the column integrated water vapor appear to reproduce poorly the observations at THAAO.

Abstract Glioblastoma (GBM) remains a deadly tumor. Treatment with chemo-radiotherapy and corticosteroids is known to impair the functionality of lymphocytes, potentially compromising the development of autologous CAR T cell therapies. We here generated pre-clinical investigations of autologous anti-GD2 CAR T cells tested against 2D and 3D models of GBM primary cells. We detected a robust antitumor effect, highlighting the feasibility of developing an autologous anti-GD2 CAR T cell-based therapy for GBM patients.

Abstract Background Impaired cerebrospinal fluid (CSF) dynamics is involved in the pathophysiology of neurodegenerative diseases of the central nervous system and the optic nerve (ON), including Alzheimer’s and Parkinson’s disease, as well as frontotemporal dementia. The smallness and intricate architecture of the optic nerve subarachnoid space (ONSAS) hamper accurate measurements of CSF dynamics in this space, and effects of geometrical changes due to pathophysiological processes remain unclear. The aim of this study is to investigate CSF dynamics and its response to structural alterations of the ONSAS, from first principles, with supercomputers. Methods Large-scale in-silico investigations were performed by means of computational fluid dynamics (CFD) analysis. High-order direct numerical simulations (DNS) have been carried out on ONSAS geometry at a resolution of 1.625 μm/pixel. Morphological changes on the ONSAS microstructure have been examined in relation to CSF pressure gradient (CSFPG) and wall strain rate, a quantitative proxy for mass transfer of solutes. Results A physiological flow speed of 0.5 mm/s is achieved by imposing a hydrostatic pressure gradient of 0.37–0.67 Pa/mm across the ONSAS structure. At constant volumetric rate, the relationship between pressure gradient and CSF-accessible volume is well captured by an exponential curve. The ONSAS microstructure exhibits superior mass transfer compared to other geometrical shapes considered. An ONSAS featuring no microstructure displays a threefold smaller surface area, and a 17-fold decrease in mass transfer rate. Moreover, ONSAS trabeculae seem key players in mass transfer. Conclusions The present analysis suggests that a pressure drop of 0.1–0.2 mmHg over 4 cm is sufficient to steadily drive CSF through the entire subarachnoid space. Despite low hydraulic resistance, great heterogeneity in flow speeds puts certain areas of the ONSAS at risk of stagnation. Alterations of the ONSAS architecture aimed at mimicking pathological conditions highlight direct relationships between CSF volume and drainage capability. Compared to the morphological manipulations considered herein, the original ONSAS architecture seems optimized towards providing maximum mass transfer across a wide range of pressure gradients and volumetric rates, with emphasis on trabecular structures. This might shed light on pathophysiological processes leading to damage associated with insufficient CSF flow in patients with optic nerve compartment syndrome.

Abstract Introduction Biomarker testing is mandatory for the clinical management of patients with advanced non-small cell lung cancer (NSCLC). Myriads of technical platforms are now available for biomarker analysis with differences in terms of multiplexing capability, analytical sensitivity, and turnaround time (TAT). We evaluated the technical performance of the diagnostic workflows of 24 representative Italian institutions performing molecular tests on a series of artificial reference specimens built to mimic routine diagnostic samples. Methods Sample sets of eight slides from cell blocks of artificial reference specimens harboring exon 19 EGFR (epidermal growth factor receptor) p.E746_AT50del, exon 2 KRAS (Kirsten rat sarcoma viral oncogene homologue) p.G12C, ROS1 (c-ros oncogene 1)-unknown gene fusion, and MET (MET proto-oncogene, receptor tyrosine kinase) Δ exon 14 skipping were distributed to each participating institution. Two independent cell block specimens were validated by the University of Naples Federico II before shipment. Methodological and molecular data from reference specimens were annotated. Results Overall, a median DNA concentration of 3.3 ng/µL (range 0.1–10.0 ng/µL) and 13.4 ng/µL (range 2.0–45.8 ng/µL) were obtained with automated and manual technical procedures, respectively. RNA concentrations of 5.7 ng/µL (range 0.2–11.9 ng/µL) and 9.3 ng/µL (range 0.5–18.0 ng/µL) were also detected. KRAS exon 2 p.G12C, EGFR exon 19 p.E736_A750del hotspot mutations, and ROS1 aberrant transcripts were identified in all tested cases, whereas 15 out of 16 (93.7%) centers detected MET exon 14 skipping mutation. Conclusions Optimized technical workflows are crucial in the decision-making strategy of patients with NSCLC. Artificial reference specimens enable optimization of diagnostic workflows for predictive molecular analysis in routine clinical practice.

The Arctic climate is influenced by the interaction of shortwave (SW) and longwave (LW) radiation with the atmosphere and the surface. The comprehensive evolution of the Surface Radiative Fluxes (SRF) on different time scales is of paramount importance to understanding the complex mechanisms governing the Arctic climate. However, only a few sites located in the Arctic region provide long-term time series of SRF allowing for capturing of the seasonality of atmospheric and surface parameters and for carrying out validation of satellite products and/or reanalyses. This paper presents the daily and monthly SRF record collected at the Thule High Arctic Atmospheric Observatory (THAAO, 76.5∘ N, 68.8∘ W), in North-Western Greenland. The downwelling components of the SW (DSI) and the LW (DLI) irradiances have been measured at THAAO since 2009, whereas the collection of the upwelling SW (USI) and LW (ULI) irradiance was started in 2016, together with additional measurements, such as meteorological parameters and column water vapour. The datasets of DSI (Meloni et al., 2022a; https://doi.org/10.13127/thaao/dsi), USI (Meloni et al., 2022b; https://doi.org/10.13127/thaao/usi), DLI (Meloni et al., 2022c; https://doi.org/10.13127/thaao/dli), ULI (Meloni et al., 2022d; https://doi.org/10.13127/thaao/uli), and near-surface air temperature (Muscari et al., 2018; https://doi.org/10.13127/thaao/met), can be accessed through the THAAO web site (https://www.thuleatmos-it.it/data, last access: 16 January 2024). The DSI is absent (solar zenith angle ≥90∘) from 29 October to 13 February, assuming maxima in June (monthly mean of 277.0 Wm−2), when it is about half of the total incoming irradiance. The USI maximum occurs in May (132.4 Wm−2) owing to the combination of moderately high DSI values and high albedo. The shortwave surface albedo (A) assumes an average of 0.16 during summer, when the surface is free of snow. Differently, during months of snow-covered surface, when solar radiation allows A to be estimated, its values are greater than 0.6. A large interannual variability is observed in May and September, months characterized by rapidly changing surface conditions, having a link with air temperature anomalies. The DLI and ULI maxima occur in July and August, and the minima in February and March. ULI is always larger than DLI and shows a wider annual cycle. ULI is well described by a fourth-order polynomial fit to the air temperature (R2>0.99 for monthly data and R2>0.97 for daily data). The Surface Radiation Budget (SRB) is positive from April to August, when absorption of solar radiation exceeds the infrared net cooling, with a maximum value of 153.2 Wm−2 in June. From November to February, during the polar night, the LW net flux varies between −34.5 and −43.0 Wm−2. In March and September, the negative LW net flux overcomes the positive SW contribution, producing a negative SRB. The THAAO measurements show clear evidence of the influence of several regional weather/climate events, that appear strongly linked with SRF anomalies. These anomalies were found, for example, during summer 2012, when a large ice melting event took place over Greenland, and during winter 2019–2020, which was extraordinarily cold in the Arctic region.

Abstract Background The early management of polytrauma patients with traumatic spinal cord injury (tSCI) is a major challenge. Sparse data is available to provide optimal care in this scenario and worldwide variability in clinical practice has been documented in recent studies. Methods A multidisciplinary consensus panel of physicians selected for their established clinical and scientific expertise in the acute management of tSCI polytrauma patients with different specializations was established. The World Society of Emergency Surgery (WSES) and the European Association of Neurosurgical Societies (EANS) endorsed the consensus, and a modified Delphi approach was adopted. Results A total of 17 statements were proposed and discussed. A consensus was reached generating 17 recommendations (16 strong and 1 weak). Conclusions This consensus provides practical recommendations to support a clinician’s decision making in the management of tSCI polytrauma patients.

A novel class of compounds designed to hit two anti-tumour targets, G-quadruplex structures and human carbonic anhydrases (hCAs) IX and XII is proposed. The induction/stabilisation of G-quadruplex structures by small molecules has emerged as an anticancer strategy, disrupting telomere maintenance and reducing oncogene expression. hCAs IX and XII are well-established anti-tumour targets, upregulated in many hypoxic tumours and contributing to metastasis. The ligands reported feature a berberine G-quadruplex stabiliser scaffold connected to a moiety inhibiting hCAs IX and XII. In vitro experiments showed that our compounds selectively stabilise G-quadruplex structures and inhibit hCAs IX and XII. The crystal structure of a telomeric G-quadruplex in complex with one of these ligands was obtained, shedding light on the ligand/target interaction mode. The most promising ligands showed significant cytotoxicity against CA IX-positive HeLa cancer cells in hypoxia, and the ability to stabilise G-quadruplexes within tumour cells.

Early-onset (age < 65) Alzheimer's disease is associated with greater non-amnestic cognitive symptoms and neuropathological burden than late-onset disease. It is not fully understood whether these groups also differ in the associations between molecular pathology, neurodegeneration and cognitive performance. We studied amyloid-positive patients with early-onset (n = 60, mean age 58 ± 4, MMSE 21 ± 6, 58% female) and late-onset (n = 53, mean age 74 ± 6, MMSE 23 ± 5, 45% female) Alzheimer's disease who underwent neurological evaluation, neuropsychological testing, 11C-Pittsburgh compound B PET (amyloid-PET) and 18F-flortaucipir PET (tau-PET). 18F-fluorodeoxyglucose PET (brain glucose metabolism PET) was also available in 74% (n = 84) of participants. Composite scores for episodic memory, semantic memory, language, executive function and visuospatial domains were calculated based on cognitively unimpaired controls. Voxel-wise regressions evaluated correlations between PET biomarkers and cognitive scores and early-onset versus late-onset differences were tested with a PET × Age group interaction. Mediation analyses estimated direct and indirect (18F-fluorodeoxyglucose mediated) local associations between 18F-flortaucipir binding and cognitive scores in domain-specific regions of interest. We found that early-onset patients had higher 18F-flortaucipir binding in parietal, lateral temporal and lateral frontal cortex; more severe 18F-fluorodeoxyglucose hypometabolism in the precuneus and angular gyrus; and greater 11C-Pittsburgh compound B binding in occipital regions compared to late-onset patients. In our primary analyses, PET-cognition correlations did not meaningfully differ between age groups.18F-flortaucipir and 18F-fluorodeoxyglucose, but not 11C-Pittsburgh compound B, were significantly associated with cognition in expected domain-specific patterns in both age groups (e.g. left perisylvian/language, frontal/executive, occipital/visuospatial). 18F-fluorodeoxyglucose mediated the relationship between 18F-flortaucipir and cognition in both age groups across all domains except episodic memory in late-onset patients. Additional direct effects of 18F-flortaucipir were observed for executive function in all age groups, language in early-onset Alzheimer's disease and in the total sample and visuospatial function in the total sample. In conclusion, tau and neurodegeneration, but not amyloid, were similarly associated with cognition in both early and late-onset Alzheimer's disease. Tau had an association with cognition independent of neurodegeneration in language, executive and visuospatial functions in the total sample. Our findings support tau PET as a biomarker that captures both the clinical severity and molecular pathology specific to Alzheimer's disease across the broad spectrum of ages and clinical phenotypes in Alzheimer's disease.

Summary: 2′3′-cyclic guanosine monophosphate–adenosine monophosphate (cGAMP) is the endogenous agonist of STING; as such, cGAMP has powerful immunostimulatory activity, due to its capacity to stimulate type I interferon-mediated immunity. Recent evidence indicates that cancer cells, under certain conditions, can release cGAMP extracellularly, a phenomenon currently considered important for therapeutic responses and tumor rejection. Nonetheless, the mechanisms that regulate cGAMP activity in the extracellular environment are still largely unexplored.In this work, we collected evidence demonstrating that CD38 glycohydrolase can inhibit extracellular cGAMP activity through its direct binding.We firstly used different cell lines and clinical samples to demonstrate a link between CD38 and extracellular cGAMP activity; we then performed extensive in silico molecular modeling and cell-free biochemical assays to show a direct interaction between the catalytic pocket of CD38 and cGAMP. Altogether, our findings expand the current knowledge about the regulation of cGAMP activity.