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(1) Background: The clinical implications of COVID-19 outbreaks following SARS-CoV-2 vaccination in immunocompromised recipients are a worldwide concern. Cancer patients on active treatment remain at an increased risk of developing breakthrough infections because of waning immunity and the emergence of SARS-CoV-2 variants. There is a paucity of data on the effects of COVID-19 outbreaks on long-term survival outcomes in this population. (2) Methods: We enrolled 230 cancer patients who were on active treatment for advanced disease and had received booster dosing of an mRNA-BNT162b2 vaccine as part of the Vax-On-Third trial between September 2021 and October 2021. Four weeks after the third immunization, IgG antibodies against the spike receptor domain of SARS-CoV-2 were tested in all patients. We prospectively evaluated the incidence of breakthrough infections and disease outcomes. The coprimary endpoints were the effects of antibody titers on the development of breakthrough infections and the impact of COVID-19 outbreaks on cancer treatment failure. (3) Results: At a median follow-up of 16.3 months (95% CI 14.5–17.0), 85 (37%) patients developed SARS-CoV-2 infection. Hospitalization was required in 11 patients (12.9%) and only 2 (2.3%) deaths related to COVID-19 outbreaks were observed. Median antibody titers were significantly lower in breakthrough cases than in non-cases (291 BAU/mL (95% CI 210–505) vs. 2798 BAU/mL (95% CI 2323–3613), p < 0.001). A serological titer cut-off below 803 BAU/mL was predictive of breakthrough infection. In multivariate testing, antibody titers and cytotoxic chemotherapy were independently associated with an increased risk of outbreaks. Time-to-treatment failure after booster dosing was significantly shorter in patients who contracted SARS-CoV-2 infection (3.1 months (95% CI 2.3–3.6) vs. 16.2 months (95% CI 14.3–17.0), p < 0.001) and had an antibody level below the cut-off (3.6 months (95% CI 3.0–4.5) vs. 14.6 months (95% CI 11.9–16.3), p < 0.001). A multivariate Cox regression model confirmed that both covariates independently had a worsening effect on time-to-treatment failure. (4) Conclusions: These data support the role of vaccine boosters in preventing the incidence and severity of COVID-19 outbreaks. Enhanced humoral immunity after the third vaccination significantly correlates with protection against breakthrough infections. Strategies aimed at restraining SARS-CoV-2 transmission in advanced cancer patients undergoing active treatment should be prioritized to mitigate the impact on disease outcomes.

This paper proposes an M-quantile regression approach to address the heterogeneity of the housing market in a modern European city. We show how M-quantile modelling is a rich and flexible tool for empirical market price data analysis, allowing us to obtain a robust estimation of the hedonic price function whilst accounting for different sources of heterogeneity in market prices. The suggested methodology can generally be used to analyse nonlinear interactions between prices and predictors. In particular, we develop a spatial semiparametric M-quantile model to capture both the potential nonlinear effects of the cultural environment on pricing and spatial trends. In both cases, nonlinearity is introduced into the model using appropriate bases functions. We show how the implicit price associated with the variable that measures cultural amenities can be determined in this semiparametric framework. Our findings show that the effect of several housing attributes and urban amenities differs significantly across the response distribution, suggesting that buyers of lower-priced properties behave differently than buyers of higher-priced properties.

Aim The aim of this study was to measure the prevalence of inadequate health literacy (HL) in a sample of family caregivers of older adults with dementia, and to assess the relationship of HL with characteristics of caregiver and persons with dementia. Methods The study followed a cross-sectional design. Persons with dementia and their family caregivers were enrolled in an outpatients’ geriatric memory clinic. For the caregivers, the following information was collected: socio-demographic data, level of HL, cognitive impairment (using the Mini-Cog). For persons with dementia, the following data were collected: socio-demographic data, functional status (using the Basic and Instrumental Activities of Daily Living), cognitive impairment (using the Mini Mental State Evaluation, and the Global Deterioration Scale) behavioral and psychological symptoms associated with dementia (assessed using the Neuropsychiatric Inventory). Results A total of 174 person with dementia/caregiver dyads were enrolled. About 45% of the caregivers presented a possibility or a high likelihood of inadequate HL. The percentage of caregivers with inadequate HL was higher among spousal caregivers than in offspring. Female gender, higher age and lower education were independent predictors of low HL. On multiple logistic regression analysis, persons with dementia assisted by caregivers with a high likelihood of limited HL presented higher risk of a more severe disease. Conclusion The results of this study suggest that the HL of dementia caregivers has to be included in the comprehensive geriatric assessment, to develop an appropriate individualized care plan. Moreover, public health interventions are needed to increase the HL of dementia caregivers.

Aim: Endoscopic discectomies provide several advantages over other techniques such as traditional open lumbar discectomy (OLD) including possibly decreased complications, shorter hospital stay and an earlier return to work. Methods: An electronic database search including MEDLINE/PubMed, EMBASE, Scopus, Cochrane Database of Systematic Reviews and Cochrane Controlled trials (CENTRAL) were reviewed for randomized controlled trials (RCTs) only. Results: A total of nine RCTs met inclusion criteria. Three showed benefit of endoscopic discectomy over the comparator with regards to pain relief, with the remaining six studies showing no difference in pain relief or function. Conclusion: Based on review of the nine included studies, we can conclude that endoscopic discectomy is as effective as other surgical techniques, and has additional benefits of lower complication rate and superior perioperative parameters.

In a previous work, authors have proposed a medico-legal definition of femicide as the murder due to the failure to recognize the right of self-determination of women. The aim of this paper was to apply the proposed definition to a cohort of cases to characterise femicides and female homicides and assess whether femicides can be considered a distinct entity or not. A comparison between female and male homicides was performed to assess common and distinctive features. Femicides were identified and compared to the cohort of non-femicide female murder. Results were compared to those reported in published forensic studies. Significant associations between female and male homicides were found for sex and partner/ex-partner offender, sex and indoor homicide and sex and asphyxia as dynamic of death emerged. A higher prevalence of indoor homicides and asphyxiation and of partner relationships were documented in female homicides. Gunshot, blunt injuries and cut wounds are well represented in both types of homicides. Most affected sites are back and chest in male homicides, and head, breasts, pubis, and limbs in female homicides. When comparing femicides and female homicides, a positive association between strangulation as harmful mean and a negative one between femicides and indoor homicides were found. Male and female homicides can be considered as two distinct victimological phenomena. Focusing on femicide allows to establish injuries and circumstantial patterns, that could represent evidence of a specific murder. More studies with a standardized data collection are needed to corroborate the theory of this paper.

Background: KRASG12C-mutated metastatic colorectal cancer (mCRC) has recently been recognized as a distinct druggable molecular entity; however, there are limited data on its sensitivity to standard chemotherapy. In the near future, the combination of chemotherapy plus a KRASG12C-inhibitor might become the standard of care; however, the optimal chemotherapy backbone is unknown. Methods: A multicentre retrospective analysis was conducted including KRASG12C-mutated mCRC patients treated with first-line FOLFIRI or FOLFOX +/− bevacizumab. Both unmatched and propensity-score-matched analysis (PSMA) were conducted, with PSMA controlling for: previous adjuvant chemotherapy, ECOG PS, use of bevacizumab in first line, timing of metastasis appearance, time from diagnosis to first-line start, number of metastatic sites, presence of mucinous component, gender, and age. Subgroup analyses were also performed to investigate subgroup treatment–effect interactions. KRASG12D-mutated patients were analysed as control. Results: One hundred and four patients treated with irinotecan-(N = 47) or oxaliplatin-based (N = 57) chemotherapy were included. In the unmatched population, objective response rate (ORR) and median (m) progression-free and overall survival (mPFS and mOS) were comparable between the treatment arms. However, a late (>12 months) PFS advantage was observed with irinotecan (HR 0.62, p = 0.02). In the PSMA-derived cohort, a significant improvement with irinotecan vs. oxaliplatin was observed for both PFS and OS: 12- and 24-month PFS rates of 55% vs. 31% and 40% vs. 0% (HR 0.40, p = 0.01) and mOS 37.9 vs. 21.7 months (HR 0.45, p = 0.045), respectively. According to the subgroup analysis, interaction effects between the presence of lung metastases and treatment groups were found in terms of PFS (p for interaction = 0.08) and OS (p for interaction = 0.03), with a higher benefit from irinotecan in patients without lung metastases. No difference between treatment groups was observed in the KRASG12D-mutated cohort (N = 153). Conclusions: First-line irinotecan-based regimens provided better survival results in KRASG12C-mutated mCRC patients and should be preferred over oxaliplatin. These findings should also be considered when investigating chemotherapy plus targeted agent combinations.

Background: Patients with refractory mCRC rarely undergo third-line or subsequent treatment. This strategy could negatively impact their survival. In this setting, regorafenib (R) and trifluridine/tipiracil (T) are two key new treatment options with statistically significant improvements in overall survival (OS), progression-free survival (PFS), and disease control with different tolerance profiles. This study aimed to retrospectively evaluate the efficacy and safety profiles of these agents in real-world practice. Materials and Methods: In 2012–2022, 866 patients diagnosed with mCRC who received sequential R and T (T/R, n = 146; R/T, n = 116]) or T (n = 325]) or R (n = 279) only were retrospectively recruited from 13 Italian cancer institutes. Results: The median OS is significantly longer in the R/T group (15.9 months) than in the T/R group (13.9 months) (p = 0.0194). The R/T sequence had a statistically significant advantage in the mPFS, which was 8.8 months with T/R vs. 11.2 months with R/T (p = 0.0005). We did not find significant differences in outcomes between groups receiving T or R only. A total of 582 grade 3/4 toxicities were recorded. The frequency of grade 3/4 hand-foot skin reactions was higher in the R/T sequence compared to the reverse sequence (37.3% vs. 7.4%) (p = 0.01), while grade 3/4 neutropenia was slightly lower in the R/T group than in the T/R group (66.2% vs. 78.2%) (p = 0.13). Toxicities in the non-sequential groups were similar and in line with previous studies. Conclusions: The R/T sequence resulted in a significantly longer OS and PFS and improved disease control compared with the reverse sequence. R and T given not sequentially have similar impacts on survival. More data are needed to define the best sequence and to explore the efficacy of sequential (T/R or R/T) treatment combined with molecular-targeted drugs.

Background: Since the beginning of the covid19 pandemic, clinical and demographic data showed that cancer patients are at high risk of developing severe consequences of Sars-Cov2 disease. For this reason, vaccination is strongly recommended, especially for patients on active treatment. Nevertheless, the efficacy of the Sars-Cov2 vaccine in cancer patients is not fully investigated. Our trial aim to explore the seroconversion in a large series of vaccinated cancer patients undergoing active treatment. Here we present a subgroup analysis concerning patients affected by breast cancer. Methods: The “VAX-on” is a single-center study that enrolled 366 cancer patients who underwent oncological treatment within the last six months. The study was approved by the ethics committee and all patients had to sign specific informed consent to be enrolled. Subjects were vaccinated against Sars-Cov2 with mRNA vaccine BNT162b2 (Comirnaty) - Pfizer BioNTech. Blood samples were obtained to quantify the production of specific anti-Spike IgG antibodies at day 21 from the first dose and at 6-8 weeks after the second dose. The antibody laboratory title cut-off of 50 U.A./mL defined the seroconversion. Results are shown as Mean and Standard Deviation for continuous variable, percentage (%) for categorical ones. The Mann-Whitney test or Chi-Square test were used to compare continuous or categorical groups, respectively. Results: A total of 100 patients with breast cancer were enrolled. Clinical and demographic data are summarized in Table 1. The median age was 60.5 years and the majority had an ECOG PS of 0 (75%). Almost all were women (97%), with advanced cancer in 60% of cases. In early or advanced setting 46% patients were treated with chemotherapy while 54% were on target therapy (also including monoclonal antibody and CDK4/6 inhibitors). The mean antibody title after the first dose of mRNA Comirnaty vaccine was 2185.03±9303.26 U.A./mL (M±SD), while after the second dose the mean antibody title rise to 6492.10±10425.95 (M±SD). After the first dose 61% of patients were considered as immunized, meanwhile after the second dose 86% of patients resulted immunized (defined as an antibody title >50 U.A./mL). In the 9 patients in treatment with steroids (prednisone > 10mg/die or equivalent), there was a trend to a decreased antibody development compared to patients without chronic use of steroids (p 0.06 and 0.05 after the first and second dose, respectively). Of interest, patients using G-CSF (12%) had a significant reduction in the production of Sars-Cov2 antibody after vaccination compared to patients who did not use them (p 0.02 and Table 1.Parameters *Gender (F) (%)97 (97.00)Age (yrs)60.55±11.94Advanced Stage (Yes) (%)60 (60.00)ECOGPS (%)075 (75.00)121 (21.00)24 (4.00)Setting (%)Other Therapy60 (60.00)Adjuvant & Neoadjuvant40 (40.00)Therapy (%)Other46 (46.00)Target54 (54.00)Last cycle 10 mg)/> 7 days9 (9.00)FANS last 7 days (Yes) (%)15 (15.00)G-CSF last 21 days (Yes) (%)12 (12.00)Previous Allergies (Yes) (%)19 (19.00)Antibody Title 1st Dose2185.03±9303.26Antibody Level 1st Dose (>50) (%)61 (62.89)Antibody Title 2nd Dose6492.10±10425.95Antibody Level 2nd Dose (>50) (%)86 (92.47) Citation Format: Agnese Fabbri, Eleonora Marrucci, Fabrizio Nelli, Marco Mazzotta, Angelo Onorato, Primi Francesca, Mario Giovanni Chilelli, Antonella Virtuoso, Carlo Signorelli, Julio R Giron Berrios, Marta Schirripa, Rossella Donghia, Enzo Maria Ruggeri. Evaluation of the effects of anticancer treatments in cancer patients undergoing SARS-COV2 vaccination (VAX-on study: Breast cancer subgroup analysis) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-11-02.

This figure shows the signal pathway of TLR1, TLR2, and TLR6. TLR1 and TLR6, each of which forms a heterodimer with TLR2, initiate MAPK or NFκB pathway through TAK1. MyD88: myeloid differentiation factor88, TRAF: TNF receptor-associated factor, IRAK: 　IL-1R associated kinase, TAK: TGFβ-activated kinase, TAB: TAK1-binding protein, MAPK: mitogen-activated protein kinase.

This table shows the association of each SNP and clinical outcome in TRIBE. The association between SNP and clinical outcome in FIRE-3 is also demonstrated when there are statistically significant associations in TRIBE.

Supplementary Table

Supplementary Figure S2

Purpose:BRAF mutations are grouped in activating RAS-independent signaling as monomers (class 1–V600E) or as dimers (class 2–codons 597/601), and RAS-dependent with impaired kinase activity (class 3–codons 594/596). Although clinical, pathologic, and molecular features of V600EBRAF-mutated metastatic colorectal cancer (mCRC) are well known, limited data are available from the two other classes.Experimental Design:Data from 117 patients with BRAF (92 class 1, 12 class 2, and 13 class 3)-mutated mCRC were collected. A total of 540 BRAF wt mCRCs were included as control. IHC profiling was performed to determine the consensus molecular subtypes (CMS), cytokeratin 7/20 profiles, tumor-infiltrating lymphocyte infiltration, and BM1/BM2 categorization. Overall survival (OS) and progression-free survival were evaluated by Kaplan–Meier and log-rank test.Results:Class 3 BRAF-mutated mCRC was more frequently left sided (P = 0.0028), pN0 (P = 0.0159), and without peritoneal metastases (P = 0.0176) compared with class 1, whereas class 2 cases were similar to class 1. Hazard ratio for OS, as compared with BRAF wt, was 2.38 [95% confidence interval (CI), 1.61–3.54] for class 1, 1.90 (95% CI, 0.85–4.26) for class 2, and 0.93 (95% CI, 0.51–1.69) for class 3 (P < 0.0001). Class 2 and 3 tumors were all assigned to CMS2-3. A higher median CD3/CD8-positive lymphocyte infiltration was observed in BRAF-mutated class 2 (P = 0.033) compared with class 3 cases.Conclusions:For the first time, different clinical and pathologic features and outcome data were reported according to the three BRAF mutation classes in mCRC. Specific targeted treatment strategies should be identified in the near future for such patients.

Purpose: Vitamin D exerts its inhibitory influence on colon cancer growth by inhibiting Wnt signaling and angiogenesis. We hypothesized that SNPs in genes involved in vitamin D transport, metabolism, and signaling are associated with outcome in metastatic colorectal cancer (mCRC) patients treated with first-line FOLFIRI and bevacizumab.Experimental Design: 522 mCRC patients enrolled in the FIRE-3 (discovery cohort) and TRIBE (validation set) trials treated with FOLFIRI/bevacizumab were included in this study. 278 patients receiving FOLFIRI and cetuximab (FIRE-3) served as a control cohort. Six SNPs in 6 genes (GC, CYP24A1, CYP27B1, VDR, DKK1, CST5) were analyzed.Results: In the discovery cohort, AA carriers of the GC rs4588 SNP encoding for the vitamin D–binding protein, and treated with FOLFIRI/bevacizumab had a shorter overall survival (OS) than those harboring any C allele (15.9 vs. 25.1 months) in both univariable (P = 0.001) and multivariable analyses (P = 0.047). This association was confirmed in the validation cohort in multivariable analysis (OS 18.1 vs. 26.2 months, HR, 1.83; P = 0.037). Interestingly, AA carriers in the control set exhibited a longer OS (48.0 vs. 25.2 months, HR, 0.50; P = 0.021). This association was further confirmed in a second validation cohort comprising refractory mCRC patients treated with cetuximab ± irinotecan (PFS 8.7 vs. 3.7 months) in univariable (P = 0.033) and multivariable analyses (P = 0.046).Conclusions: GC rs4588 SNP might serve as a predictive marker in mCRC patients treated with FOLFIRI/bevacizumab or FOLFIRI/cetuximab. Whereas AA carriers derive a survival benefit with FOLFIRI/cetuximab, treatment with FOLFIRI/bevacizumab is associated with a worse outcome. Clin Cancer Res; 24(4); 784–93. ©2017 AACR.

SNPs and clinical outcomes among patients with mCRC treated with first-line FOLFIRI/bevacizumab in FIRE-3 (discovery cohort)

Analyzed SNPs involved in vitamin D transport, metabolism and signaling. Overview on their functional significance and primer sequences

Supplementary Figure S1

Associations between GC rs4588 and clinical/molecular variables

Association between GC and VDR SNPs and clinical outcomes in the validation cohort 1 (TRIBE FOLFIRI/bevacizumab arm)

Supplementary Figure S3

BackgroundLabeling efficiency is a crucial parameter in fluorescence applications, especially when studying biomolecular interactions. Current approaches for estimating the yield of fluorescent labeling have critical drawbacks that usually lead them to be inaccurate or not quantitative.ResultsWe present a method to quantify fluorescent-labeling efficiency that addresses the critical issues marring existing approaches. The method operates in the same conditions of the target experiments by exploiting a ratiometric evaluation with two fluorophores used in sequential reactions. We show the ability of the protocol to extract reliable quantification for different fluorescent probes, reagents concentrations, reaction timing and to optimize labeling performance. As paradigm, we consider the labeling of the membrane-receptor TrkA through 4’-phosphopantetheinyl transferase Sfp in living cells, visualizing the results by TIRF microscopy. This investigation allows us to find conditions for demanding single and multi-color single-molecule studies requiring high degrees of labeling.ConclusionsThe developed method allows the quantitative determination and the optimization of staining efficiency in any labeling strategy based on stable reactions.

Single particle tracking (SPT) combined with total internal reflection fluorescence (TIRF) microscopy is an outstanding approach to decipher crucial molecular mechanisms on the cell membrane at the nanometric scale. In multicolor configurations it can even be the ideal tool to investigate interactions, but this is hindered by a number of experimental challenges. We systematically and quantitatively analyze the impact of all the necessary sub-elements of any SPT-TIRF setup on signal-to-noise ratio, especially in dynamic studies using minimally-invasive dyes for biomolecule labeling. We show that the dominant limiting factor is the autofluorescence originating from the commonly-used optical glass. We identify and test a different material and show a significant improvement of signal-to-noise ratio in a multichannel TIRF configuration employing the new glass covers. We also address the problem of photobleaching of fluorescent probes by presenting effective approaches suited to a multicolor implementation that requires simultaneous stabilization of multiple dyes. We apply the developed protocol to the analysis of p75 receptors labeled by two fluorophores on the membrane of living cells. Our strategy yields reliable, simultaneous two-color SPT, even for fast-diffusing receptors, enabling this study under conditions not accessible with standard experimental configurations. We argue that the present protocol can pave the way for multicolor super-resolved localization and tracking of single molecules by TIRF microscopy, much expanding the potential of SPT.

How does Classical Extensional Mereology (CEM) interact with time and modality? In its first-order logical setting, CEM does not have the formal tools to deal with these dimensions. Nonetheless, it is often charged with endorsing controversial metaphysical theses like mereological essentialism and mereological constantism. Allowing CEM to interact with quantified modal logic (QML) without adding any further mereological commitment clarifies which modal theorems CEM actually implies and eventually undercuts wrong-headed allegations against it. From the logical side, I endorse system KTB of modal logic with constant domain semantics, but several theorems are also provable with the adoption of weaker logics (like KT and even the simplest K). We will also be able to successfully simulate variable domain semantics via the procedure of existential relativisation. From the mereological side, I necessitate the ordering axioms and the strong-supplementation axiom, leaving the door open for four different alternatives to deal with the axiom of unrestricted composition. The mereological results emerging from this setting include the necessity of extensionality principles – which does not lead to mereological essentialism – and the existence of possible fusions even when an actualist version of unrestricted composition is adopted. In the final part of the thesis, I apply the main findings of modal extensional mereology to group membership. After showing why some standard objections are misguided, I argue that the standard account of social groups based on CEM fails to be satisfactory because it conceives group membership as just parthood. My proposal is to regard group membership as φ-parthood instead. Under this new account, social groups are not just mereological wholes, but mereological wholes with a specified understanding of the parthood relation. Endorsing this novel account allows us to retain an account of social groups based on CEM while avoiding the knockdown objections faced by the standard one.

The COVID-19 pandemic has heavily hit international economy giving a particular setback to the tourism sector. Between March and May 2020, during the first lockdown, and between October and December of the same year, during the second lockdown, a questionnaire was administrated in Italy, Greece and Great Britain. Through the questionnaire, people’s feelings and expectations of their desire to take a vacation were collected regarding the period of constraint due to the new coronavirus and the possible end of the pandemic, or the first government approved travel openings. In particular, the question of how long it would take to decide on a holiday, the type and duration, after the period of constriction due to the coronavirus was over, was asked. Both surveys, in the two different lockdown periods, showed the potential desire of tourists to leave relatively quickly, and to take forms of domestic tourism, characterized by small and short-lived trips. The favorite destination being the seaside.

The evolution of the Apennine wedge has seen the time-space migration of the forebulge, foredeep, thrust wedge, and back-arc extension phases in the wake of the Eastward rollback of the subducting Adria slab. In this framework, thrusting and post-orogenic extensional faulting have occurred in two parallel forelandward-migrating ribbons, with extensional deformation overprinting or partly exploiting anisotropies of the inherited thrust system. Here, we explore the tectonic framework and the timing of thrusting and subsequent negative inversion of the Circeo thrust, one of the major thrusts in the inner portion of the central Apennines, with the main aim to constrain the timing and mode of the compression to extension switch. Structural analysis, carbonate C and O and clumped isotopes analysis, X-ray diffraction of clay minerals, and U-Pb dating of calcite slickenfibers have been integrated with seismic interpretation, cross-section balancing, and 1D burial and thermal modeling. We show that the Circeo thrust developed during Langhian-Serravallian time. Its extensional reactivation is dated at the Serravallian, during the stacking of an underlying thrust slice, before the onset of Pliocene back-arc extension in the area. Combination of our data with the age of thrusts, extensional basins, and base of the foredeep infill of the central Apennines, demonstrates that forelandward migration of the foredeep-thrust system occurred at variable velocities. Accelerations and decelerations are synchronous, respectively, with the opening of the Liguro-Provençal and Tyrrhenian back-arc basins and with the interluding quiescent period., Tectonics, 42 (6), ISSN:1944-9194

Structural analysis coupled with geochemical study of syn-tectonic mineralizations unraveled the role of fluids during the polyphase tectonic evolution of the Val D’Agri, a seismically-active intermontane basin located in the Southern Apennines fold and thrust belt, hosting the largest onshore oil field in western Europe. In this basin, the structural control on present-day fluid circulation is still not well constrained. For this reason, the aim of this work is to reconstruct the Val d’Agri fault system (VAF) architecture and paleo-fluid circulation during the basin tectonic evolution. The VAF evolution was caused by non-coaxial polyphase stress regimes that can be summarized in: 1) Upper Miocene-Lower Pliocene compressional regime; 2) Upper Pliocene-Lower Pleistocene late orogenic strike-slip regime 3) Early Pleistocene-Present post-orogenic extensional regime. Based on new field work, mapping, and structural analysis, we recognized that the VAF is organized in different oriented faults sets. The main sets are N-S-, NE-SW-, and ESE-WNW-striking faults, where the last one has the higher degree of maturity. U-Pb dating of calcite slickenfibres highlighted the long-term tectonic history of these fault sets, with episodes of activation and reactivation of inherited faults. In particular, we recognize: N-S-striking normal faults that reactivated inherited Upper Miocene-Lower Pliocene thrusts; Upper Pleistocene NE-SW-striking normal-lateral faults; one Miocene ESE-WNW-striking normal-lateral fault, with also evidence of reactivation in more recent time. Clumped isotopes analysis together with optical and cathodoluminescence observations of about 50 syn-tectonic calcite mineralizations allowed us to link specific fluid pathways to the different stress regimes. Indeed, bed-parallel veins and mineralizations sampled along transpressive, transtensive, and normal fault sets show that: 1) during the Upper Miocene-Lower Pliocene compressive tectonic phase, fluid circulation occurred in a closed system, characterized by host-rock buffered fluids; 2) during Upper Pliocene-Lower Pleistocene late orogenic phase, fluid circulation occurred in an open system, characterized by meteoric water with low to moderate residence time; 3) during the Lower Pleistocene-Present extensional phase, fluid circulation occurred in an open system, characterized by the mixing of meteoric water and uprising deep high temperature fluids. We highlight that the reconstruction of paleo to present-day fluid circulation is a valid tool for assessing natural and induced seismic hazard in seismically active areas where hydrocarbons are exploited and fluids are injected into the crust, such as in the Val d'Agri basin.

Background Numerous research studies have looked into how the primary tumor location (PTL) affects patients' prognosis for colorectal cancer (CRC). Our research aimed to investigate the prognostic effects of PTL in patients with synchronous (SM) and metachronous (MM) colorectal cancer liver metastases (CRCLM). Material and methods From 2016 to 2021, we looked back at the records of patients at our institute who were affected by CRCLM. Results 109 patients were included, of whom 21.1% received CRCLM resection (R0=73.9%), with 57.7% having left-sided colon cancer (LCC) and 42.2% having right-sided colon cancer (RCC). SM predominated (69.7%). The median duration of follow-up was 21,3 months (95%CI=15,4-25,2). ≥5 hepatic metastases prevailed in the SM group (N=61; 83.5%). 21% of all patients underwent CRCLM resection (R0=78.2%). We observed a double rate of patients unresponsive to standard systemic antineoplastic treatments in the SM group (35.8% vs. 17.9% of the MM group) (p=0.27). We found a significantly longer median overall survival (OS) in patients with MM-LCC compared with the other groups (27.7 months; HR=0.3797; 95%CI=0.19-0.74; p=0.0205). The median OS, regardless of PTL, was higher in the MM group (16,5 months vs. 16,1 months; HR=0,29; 95%CI=0,13-0,67; p=0.0038) as well as progression-free survival (PFS) (11 months vs. 10,2 months; HR=0,61; 95%CI=0,33-1,12; p=0.11). Finally, in patients undergoing liver surgery, a noteworthy median OS was shown to be significantly in favor of patients with metachronous liver metastases from the primary left tumor (37.0 months; HR=0.47; 95%CI=0.11-1.96; p=0.0041). Conclusions Our real-life study demonstrated that patients with LCC, particularly MM-LCC, have the highest survival and that the timing of CRCLM should be a prognostic factor.

Background The aim of the study was to evaluate the trends of prevalence of several health risk behaviors (HRBs) and health conditions over a 10-years period in a representative sample of adolescents of Tuscany Region, Italy. Methods The study had a repeated cross-sectional design, data from the last four survey waves of EDIT surveillance (2008-2018) were used. EDIT surveillance investigates HRBs in a representative sample of students attending the upper secondary schools of Tuscany. Prevalence of 17 HRBs and health conditions were considered and analyzed by age, sex, and socioeconomic status (SES). Results A total of 21.943 students were surveyed from 2008 to 2018. Declining trends in the participation in smoking, cocaine use, driving under the influence of alcohol and drugs, and problem gambling were observed, while alcohol abuse and at-risk sexual behaviors remained unchanged or increased during the study period. During the most recent survey males resulted more frequently involved in most of the HRBs, while females more frequently reported physical inactivity, regular smoking and not using a condom. Female participation in smoking and alcohol abuse behaviors, fruit and vegetables consumption, and bullying worsened over the study period. Smoking, poor dietary habits, physical inactivity, high distress level, and obesity were more frequently observed in low SES students than in high SES students. Conclusions In conclusion findings showed various different tendencies in adolescent participation in HRBs over the course of the last decade; concerning trends in at-risk sexual behaviors and alcohol consumption and females’ risk-taking behavior on the rise require careful monitoring and intervention. Key messages • Distinct tendencies according to sex, socio-economic condition and specific health risk behavior were observed in adolescent participation in health risk behaviors over the course of the last decade. • Health promotion and prevention interventions tailored on specific health risk behaviors and population groups are needed.

The cell-cycle is a tightly orchestrated process where sequential steps guarantee cellular growth linked to a correct DNA replication. The entire cell division is controlled by cyclin-dependent kinases (CDKs). CDK activation is balanced by the activating cyclins and CDK inhibitors whose correct expression, accumulation and degradation schedule the time-flow through the cell cycle phases. Dysregulation of the cell cycle regulatory proteins causes the loss of a controlled cell division and is inevitably linked to neoplastic transformation. Due to their function as cell-cycle brakes, CDK inhibitors are considered as tumor suppressors. The CDK inhibitors p16INK4a and p15INK4b are among the most frequently altered genes in cancer, including hematopoietic malignancies. Aberrant cell cycle regulation in hematopoietic stem cells (HSCs) bears severe consequences on hematopoiesis and provokes hematological disorders with a broad array of symptoms. In this review, we focus on the importance and prevalence of deregulated CDK inhibitors in hematological malignancies.

Probe choice in single-molecule microscopy requires deeper evaluations than those adopted for less sensitive fluorescence microscopy studies. Indeed, fluorophore characteristics can alter or hide subtle phenomena observable at the single-molecule level, wasting the potential of the sophisticated instrumentation and algorithms developed for advanced single-molecule applications. There are different reasons for this, linked, e.g., to fluorophore aspecific interactions, brightness, photostability, blinking, and emission and excitation spectra. In particular, these spectra and the excitation source are interdependent, and the latter affects the autofluorescence of sample substrate, medium, and/or biological specimen. Here, we review these and other critical points for fluorophore selection in single-molecule microscopy. We also describe the possible kinds of fluorophores and the microscopy techniques based on single-molecule fluorescence. We explain the importance and impact of the various issues in fluorophore choice, and discuss how this can become more effective and decisive for increasingly demanding experiments in single- and multiple-color applications.

In space missions, medical control and any therapeutic suggestions are provided by control center on the ground. Indeed, although astronauts are highly trained, they need aid when performing 'complex' medical diagnosis or procedures. In general, medical imaging and plotting vs. time of physiological variables are routine medical procedures. Medical Imaging Techniques (MITs) are standard tools used by clinicians to diagnose, establish appropriate therapies, and/or plan for surgery. MITs consists of image acquisition, image transformation, and image visualization. Uncertainty affects each of these steps. It can degrade information and greatly influence doctors' decision making. In this article, we aim to summarize the current state of the art on the characterization of uncertainty existing in medical imaging. In addition, we briefly illustrate the open problems on the treatment of uncertainty in medical imaging.

To detecting delaminations in honeycomb structures, shearography has great capability. It is commonly used by the aerospace industries for non-destructive testing (NDT). In this paper, we describe a simple and inexpensive shearography system suitable for routine control of composite material. In particular, the system is suitable for detecting delamination deriving from impact at low-velocity (tool drop, bird-strike, runway debris, etc.).

Introduction Diabetes mellitus is a frequent co–morbidity in heart failure patients reaching a prevalence of about 35% and patients with diabetes mellitus are twice as likely as non–diabetics to develop heart failure. The presence of diabetes is associated with higher rates of cardiovascular morbidity and mortality. In recent years, the introduction of remote monitoring systems has allowed for more careful management of them, although there are no large studies demonstrating their effectiveness in terms of improving prognosis. The aim of our study was to evaluate the prognosis of patients with diabetes mellitus and heart failure undergoing remote monitoring. Methods All patients undergoing device implantation for heart failure in our Center were recruited into the study, and the incidence of events (new hospitalizations or hospitalizations) during the period from January 1, 2021 to December 31, 2021 was assessed. Patients were monitored, and direct telephone contact or contact with one of the family members was made for all of them. Data on clinical characteristics and drug therapy were recorded. Results A total of 240 patients (73±11 years, 81% male) of whom 74 were diabetic (73±11 years, 87% male) and 166 were nondiabetic (73±10 years, p=0.82, 80% male, p= 0.198) were enrolled in the study. The two groups had no statistically significant differences in terms of clinical characteristics (such as ejection fraction, NYHA class, presence of anemia, rate of wide QRS, or rate of defibrillator implantation) except for a higher incidence of coronary artery disease in diabetic patients (70%) and multivessel coronary disease (67%) than in non–diabetic patients (57% coronary artery disease p= 0.05, and 46% multivessel disease p= 0.02). There were no significant differences in terms of drugs with the exception of higher use of statins in the group of diabetic patients (84%) compared to non–diabetics (64%, p= 0.002). Diabetic patients had almost 4 times higher mortality rates than non–diabetic patients (22% and 6% respectively, p< 0.0001). Differently, hospitalization rates were not significantly different among diabetic patients (24%) compared with nondiabetic patients (28%, p= 0.58). Conclusions The association of diabetes mellitus and heart failure represents a dangerous combination associated with an increased incidence of death. Therefore, clinical monitoring strategies and intensity of drug therapy should be particularly implemented in diabetic patients.

Introduction The prevalence of heart failure in the general population in the idustrialized countries is estimated to be around 2%, a prevalence that increases with age until it reaches 10% at 70 aa of age. The disease is burdened by a high mortality rate and high expense related mainly to repeated hospitalizations. Patients with low ejection fraction heart failure are often implanted with devices, which have the ability to be monitored remotely. The Ministry of Health‘s 2017 annual report on hospitalization activity shows dramatic data: 60% of patients with heart failure are re–hospitalized within one year of discharge and in 14% of cases even within one month of discharge with an annual mortality rate of 18%. The aim of our study is to investigate whether remote monitoring allows improving the outcome of patients with heart failure in terms of reduction of hospitalizations and reduction of all–cause mortality. Materials and Methods In the year 2021, 241 patients with heart failure and reduced ejection fraction, implanted with devices of mean age 73 yr (+/– 11 yr) were remotely monitored in our center; Other population data: see Table 1. On the occasion of transmissions presenting with alarm events, our operational flow chart provides: first telephone contact and possible subsequent outpatient follow–up within 24 h working hours. Results During the year 2021, all–cause mortality in our population was 10.7% (26 patients), while re–hospitalizations were 70 (28.8%). As a result of alarms reported to remote monitoring, 83 patients were contacted whose therapy was changed or device reprogrammed. The causes of alarms were in order: reduced thoracic impedance, arrhythmic events, and reduced biventricular pacing rate. Conclusions The use of remote monitoring in heart failure patients and device wearers allows early and timely diagnosis of clinical changes that anticipate heart failure exacerbation and active intervention by modifying the clinical course, often avoiding hospitalization, with a significant social and economic impact. Thanks to the operational organization of our center, the management of remote monitoring has allowed a low rate of hospitalization and low mortality year compared with literature data.

An 82–years old female patient with history of hypertension, diagnosis of dilatative cardiomyopathy with normal coronary arteries and permanent atrial fibrillation (AF) was implanted with a dual chamber implantable cardioverter defibrillator (ICD), Guidant Ventak Prizm DR (Boston Scientific,Marlborough,USA) as a secondary prevention of sudden cardiac death in 2002. The ICD was electively replaced in 2005 and in 2010 with a Guidant, Vitality 2 DR (Boston Scientific,Marlborough,USA). In 2016, despite an optimized medical therapy, the patient experienced an episode of palpitation due to an AF with high ventricular response. Considering the difficulties of the heart rate management with the pharmacological therapy the patient underwent to an ablation of AV node. In 2017 we performed a third replacement of the ICD downgrading the system to a single chamber ICD, Fortify Assura VR (Abbott,Sylmar,USA) and providing the patient with a bedside–transmitter Merlin@home (Abbott,Sylmar,USA) The patient, followed for 4 years remotely, did not experience ventricular arrhythmias and the ventricular lead electrical parameters, including pacing and shock impedances, were stable and in the normal range. In March 2021 an alert of the Merlin system triggered an unscheduled transmission that showed several episodes of ventricular oversensing. The episodes revealed that an electrical interference inhibited the ventricular pacing causing episodes of asystole with a maximum duration of three seconds (Fig.1). Unexpectedly electrical parameters such as the pacing and shock impedances showed a stable and normal measurements (Fig .2), while the chest X–rays showed that the ventricular lead was kinked at 90–degrees below the clavicle evidencing a lead fracture (Fig.3). The patient was therefore implanted with a new ventricular lead avoiding inappropriate shocks and further episodes of asystole. The occurrence of a lead failure represents an insidious and potentially harmful event for the device implanted population, especially for ICD or pacemaker–dependent patients. The diagnosis of a lead failure is not easily predictable, and it is usually driven after a clinical event of inappropriate shock or unexplained syncope. Our case highlighted how Remote Monitoring is extremely helpful even more in this case of apparently correct functioning based on electric measurements.

Background Neuroendocrine differentiation has been extensively associated with worse prognosis and to mechanisms of therapy resistance in several epithelial cancers. A high prevalence of neuroendocrine differentiation was recently described in V600EBRAF-mutated (BRAFmt) metastatic colorectal cancers (mCRCs) but no data are available about its prognostic impact in this setting. Methods We assessed synaptophysin immunohistochemical expression in a multi-institutional series of 159 BRAFmt mCRCs with matched clinical and pathological information. Tumours were dichotomized as synaptophysin high and low. Overall survival (OS) and progression-free survival (PFS) were evaluated by Kaplan–Meier and log-rank tests. Results Thirty-five tumours (22.0%) showed any level of positivity for synaptophysin, and 18 (11.3%) were characterized by positivity in at least 20% of tumour cells. Four cases resulted 100% synaptophysin positive. The histotype of synaptophysin-positive tumours (i.e. ≥20%) was not otherwise specified in 11 cases (61.1%) and mucinous adenocarcinoma in 4 cases (22.2%). Four cases were DNA mismatch repair deficient (22.2%) and 7 (38.9%) were characterized by a high number of tumour-infiltrating lymphocytes. At multivariate analysis, high synaptophysin expression was a negative independent prognostic factor for both PFS (HR = 2.00, 95% confidence interval [CI] 1.21–3.33, p = 0.006) and OS (HR = 2.27, 95% CI 1.35–3.85, p = 0.001). Conclusions Among BRAFmt mCRCs, synaptophysin-positive tumours are characterized by worse PFS and OS. Further studies should investigate the molecular mechanisms involved in the acquisition of the neuroendocrine phenotype to identify novel-targeted treatment strategies.

Background The clinical implications of the third dose of coronavirus disease 2019 (COVID-19) vaccines in patients receiving immune checkpoint inhibitors (ICIs) are currently unknown. We performed a prospective analysis of the Vax-On-Third study to investigate the effects of antibody response on immune-related adverse events (irAEs) and disease outcomes. Methods Recipients of the booster dose of SARS-CoV-2 mRNA-BNT162b2 vaccine who had received at least one course of ICI treatment before vaccination for an advanced solid malignancy were eligible. Results The current analysis included 56 patients with metastatic disease (median age: 66 years; 71% male), most of whom had a lung cancer diagnosis and were being treated with pembrolizumab- or nivolumab-based regimens. The optimal cut-point antibody titer of 3424 AU/mL allowed a dichotomization of recipients into low-responders (Low-R

Summary Within a project co-funded by the Italian Ministry of Foreign Affairs, the final aim of which is to develop a WSN for smart monitoring of pesticides on agricultural land, the Italian and Serbian researchers have developed a hardware section of an electronic nose for pesticides. Since there are no specialized sensors which can smell the presence or absence of pesticides in the air, the electronic nose has been designed starting from an array of commercial gas sensors developed for other environmental applications. These sensors have a great advantage as they are COTS components. A measurement bench for testing the performance of the system has also been developed. Experimental tests have been conducted and the results have demonstrated the appropriateness of the idea. A test for calibration has been designed, as well, and it will be performed in the near future.

The rise of initiatives involving small towns at risk of depopulation offers the opportunity to empirically grasp different paths “to imagine a different future”. In particular, we focus on cultural strategies: interventions drawing on symbols to fight marginalizing trends and trigger processes of local development. Such strategies are tackled by comparing two case studies: the experimentation of the Sprar model of widespread reception for refugees and asylum seekers in a small village of Calabrian Appennino (Sant’Alessio d’Aspromonte) and the variety of social and cultural initiatives that welcome fragile social groups promoted by the association Nocetum in a former agricultural village situated between the rural area Parco Agricolo Sud Milano and Milan. The heterogeneity of the selected cases will make evident two recurring mechanisms: first, the fact that associative styles and organizational cultures are in both cases the result of multiple levels of negotiation, in which local leaders are engaged in many ways to implement the reputation of their interventions; second, it will be shown the ambiguous role played by the traditional collective representations concerning the analysed local communities, thus illustrating how such representations are unavoidable conditions for anyone promoting cultural strategies in those communities. Due strategie culturali tra marginalità e accoglienza Il moltiplicarsi di iniziative civiche e sociali che coinvolgono i piccoli centri a rischio di spopolamento offre l’occasione per verificare empiricamente la tenuta e il funzionamento di diverse ipotesi “per immaginare un futuro diverso”. Particolare rilievo assumono oggi le cosiddette strategie culturali: interventi che agiscono su rappresentazioni e simboli per contrastare tendenze marginalizzanti. Il contributo presenta e discute due studi di caso: la sperimentazione del modello Sprar di accoglienza diffusa per rifugiati e richiedenti asilo in un paese dell’Aspromonte reggino (Sant’Alessio) e l’azione di contrasto al degrado promossa dall’associazione Nocetum ai confini fra Milano e un’area rurale circostante. Il dialogo fra casi tanto diversi consente di evidenziare elementi ricorrenti nell’attivazione di strategie culturali di valorizzazione locale, relative alla forma di questi interventi, non al loro contenuto. In primo luogo, il fatto che culture organizzative e stili associativi dei soggetti che promuovono le azioni studiate sono il frutto di più livelli di negoziazione, legati alla capacità di imbastire percorsi di implementazione della propria reputazione. In secondo luogo, l’analisi evidenzia l’ambiguo ruolo giocato dalle rappresentazioni di cui i territori analizzati sono tradizionalmente stati oggetto e il loro porsi come condizioni locali ineludibili per chiunque voglia promuovere processi di valorizzazione attraverso strategie culturali.

Background: Radiofrequency ablation (RFA) of the medial branches of the dorsal rami has been reported to relieve facet joint–related back pain for 6 months to 1 year in 60% of patients. Although providing benefit in a significant proportion of patients, there remains a group of patients who do not experience any pain relief from RFA or experience only benefit from the ablation for a short period. Failure of RFA has been attributed to technical failure of coagulating the nerve or coagulation of a minimal section of the nerve, allowing for early reinnervation. Increasing the success rate and duration of relief may require techniques that increase the likelihood of successful nerve ablation over a relevant distance by maximizing lesion size. Objectives: The aim of this technical note is to detail a modification to the current commonly used lumbar medial branch radiofrequency (RF) denervation approach to increase lesion size. Study Design: This is a technical report describing a novel two-needle approach to lumbar RF medial branch denervation. Setting: Large private interventional pain management institute. Methods: A dual needle placement of two 10-mm active tip RF cannulas separated by 6 mm is used to optimally contact the superior articular process (SAP) from its ventral to dorsal borders, which encompasses the anticipated course of the medial branch nerves. Results: The described technique creates a lesion that we estimate to be 11.0-mm wide and 11.6-mm long along the course of the medial branch adjacent to the SAP ensuring adequate coverage and treatment. Limitations: This report does not encompass a systematic evaluation of the clinical safety and efficacy of the two-needle RFA approach. Future studies will have to assess the longterm efficacy and safety of the approach. Conclusions: The detailed two-needle approach to lumbar RF medial branch denervation appears to be promising in terms of projected treatment success by coagulating a large volume of tissue, in a cost- and time-efficient manner. Key words: Radiofrequency ablation, RFA, lumbar, medial branch, facet joint, pain, rhizotomy