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The shallow landslides constitute a consistent current hazard that could increase in the future, especially in the Mediterranean areas. Regional scale hazard maps involving runout estimation are not yet particularly widespread. The study was conducted with the aim of testing a debris flows risk assessment process starting from the runout analysis of a debris flows dataset triggered by the event of October 1, 2009.Preliminary results highlight how the procedure permit to produce a runout hazard assessment in the valley areas where the more important and vulnerable exposed elements are situated. Despite the obvious limitations, the process appears particularly useful to address the public administration demand for simple tools to manage and direct regional planning.

Aim: This guideline (GL) is aimed at providing a reference for the management of non-functioning, benign thyroid nodules causing local symptoms in adults outside of pregnancy. Methods: This GL has been developed following the methods described in the Manual of the National Guideline System. For each question, the panel appointed by Associazione Medici Endocrinology(AME) identified potentially relevant outcomes, which were then rated for their impact on therapeutic choices. Only outcomes classified as “critical” and “important” were considered in the systematic review of evidence and only those classified as “critical” were considered in the formulation of recommendations. Results: The present GL contains recommendations about the respective roles of surgery and minimally invasive treatments for the management of benign symptomatic thyroid nodules. We suggest hemithyroidectomy plus isthmectomy as the first-choice surgical treatment, provided that clinically significant disease is not present in the contralateral thyroid lobe. Total thyroidectomy should be considered for patients with clinically significant disease in the contralateral thyroid lobe. We suggest considering thermo-ablation as an alternative option to surgery for patients with a symptomatic, solid, benign, single, or dominant thyroid nodule. These recommendations apply to outpatients, either in primary care or when referred to specialists. Conclusion: The present GL is directed to endocrinologists, surgeons, and interventional radiologists working in hospitals, in territorial services, or private practice, general practitioners, and patients. The available data suggest that the implementation of this GL recommendations will result in the progressive reduction of surgical procedures for benign thyroid nodular disease, with a decreased number of admissions to surgical departments for non-malignant conditions and more rapid access to patients with thyroid cancer. Importantly, a reduction of indirect costs due to long-term replacement therapy and the management of surgical complications may also be speculated.

Frequency-domain full-waveform inversion (FWI) is potentially amenable to efficient processing of full-azimuth long-offset stationary-recording seabed acquisition carried out with a sparse layout of ocean-bottom nodes (OBNs) and broadband sources because the inversion can be performed with a few discrete frequencies. However, computing the solution of the forward (boundary-value) problem efficiently in the frequency domain with linear algebra solvers remains a challenge for large computational domains involving tens to hundreds of millions of parameters. We illustrate the feasibility of 3D frequency-domain FWI with a subset of the 2015/2016 Gorgon OBN data set in the North West Shelf, Australia. We solve the forward problem with the massively parallel multifrontal direct solver MUMPS, which includes four key features to reach high computational efficiency: an efficient parallelism combining message-passing interface and multithreading, block low-rank compression, mixed-precision arithmetic, and efficient processing of sparse sources. The Gorgon subdata set involves 650 OBNs that are processed as reciprocal sources and 400,000 sources. Monoparameter FWI for vertical wavespeed is performed in the viscoacoustic vertically transverse isotropic approximation with a classical frequency continuation approach proceeding from a starting frequency of 1.7 Hz to a final frequency of 13 Hz. The target covers an area ranging from 260 km2 (frequency ≥ 8.5 Hz) to 705 km2 (frequency ≤ 8.5 Hz) for a maximum depth of 8 km. Compared to the starting model, FWI dramatically improves the reconstruction of the bounding faults of the Gorgon horst at reservoir depths as well as several intrahorst faults and several horizons of the Mungaroo Formation down to a depth of 7 km. Seismic modeling reveals a good kinematic agreement between recorded and simulated data, but amplitude mismatches between the recorded and simulated reflection from the reservoir suggest elastic effects. Therefore, future works involve multiparameter reconstruction for density and attenuation before considering elastic FWI from hydrophone and geophone data.

Background: Up to 6% of patients (pts) with HER2 positive (pos) metastatic breast cancer (MBC) experience a radiologic complete response (rCR) to a first line of therapy, but these results mostly derive from dated and/or limited cohorts. Aim of this study was to define the clinico-pathological characteristics of HER2 positive (pos) MBC pts experiencing a rCR. Methods: Pts were selected from the database of the GIM14 study (NCT02284581) and classified according to the best radiologic response obtained to the first line chemotherapy (CT) and upon time-to-treatment-failure (TTF). rCR was defined as complete response (CR) with a TTF > 3 months. The association across variables was tested through logistic regression and their prognostic impact in terms of overall survival (OS) was estimated using the Kaplan-Meier method and compared using the log-rank test. Results: Of the 3,423 pts included in the GIM14 study, 814 had HER2 pos MBC. After exclusion of pts treated with first line endocrine therapy and/or with TTF < 3 months, 656 pts were included in the present analysis, of which 96 (14.6%) experienced a rCR. Instead, the best response was a partial response for 295 pts (45.0%), stable disease for 221 pts (33.7%), and progression for 44 pts (6.7%). Most pts (59.8%) presented de novo MBC; 379 pts (57.8%) had visceral metastases (mets), 609 pts (92.8%) did not have central nervous system (CNS) involvement and 318 pts (48.5%) had only 1 site of distant mets. Also, 445 pts (67.9%) had hormone receptor (HR) pos disease, a HER2 3+ score at immunohistochemistry (IHC) was present in 59.8% of cases versus 40.2% with HER2 2+ at IHC and in situ hybridization (ISH) + disease. Taxanes were the main CT backbone (489 pts, 74.5%), 341 pts (52.0%) had received a Trastuzumab-Pertuzumab doublet. At multivariable analysis, higher odds of experiencing a rCR were reported for presence of non-visceral mets (OR 1.87, 95%CI 1.10-3.17), low number of metastatic sites (OR 2.42, 95%CI 0.80-7.33 for 1 site only) and HER2 3+ score at IHC (OR 1.80, 95%CI 1.09-2.98). Disease-free interval (DFI) was associated to rCR at univariable but not at multivariable analysis. HR status, CT backbone and type of anti-HER2 regimen were not associated with rCR neither at univariable nor at multivariable analysis. Median follow-up was 76.2 months. Amongst pts with TTF>12 months, those with rCR had a significantly higher OS compared to those not experiencing a rCR (median OS 133 and 90 months, respectively; p=0.0191). OS rates in pts with TTF ≥ 12 months were 97.8% at 2-year follow-up and 59.4% at 5-year follow-up. Instead, in pts with TTF ≥ 60 months, OS rates were 76.7% at 10-year follow-up. Amongst the 96 pts experiencing a CR, 38 had a rCR with TTF between 12 and 60 months, while 22 pts had a rCR with a TTF ≥ 60 months. The remaining pts had a CR with a TTF < 12 months. Pts with HR negative (neg) disease were found to be more likely to experience a rCR with a with TTF between 12 and 60 months, whilst pts with HR pos disease had a higher probability to experience a rCR with a TTF ≥ 60 months (p=0.0074). Pts with HER2 3+ score at IHC had a higher probability to achieve a rCR with a TTF ≥ 12 months compared to pts with HER2 2+ score at IHC and ISH + (p=0.0216). Age at diagnosis, menopausal status, DFI, number and site of mets, CT backbone and anti-HER2 therapy did not influence the duration of the rCR obtained. Conclusions: This study characterized a real-world cohort of HER2 positive MBC patients experiencing radiologic complete response to a first line treatment. Based on these results a clinical trial focused on liquid biopsy-based minimal residual disease is being designed. Novel anti-HER2 agents are gaining momentum as ever increasingly effective treatments and future de-escalation strategies after complete response will represent a growing need. Citation Format: Linda Cucciniello, Eva Blondeaux, Claudia Bighin, Simona Gasparro, Stefania Russo, Arianna Dri, Palma Pugliese, Andrea Fontana, Giuseppe Naso, Antonella Ferzi, Ferdinando Riccardi, Valentina Sini, Luca Boni, Alessandra Fabi, Filippo Montemurro, Michelino De Laurentiis, Grazia Arpino, Lucia Del Mastro, Lorenzo Gerratana, Fabio Puglisi. Assessing the clinico-pathological characteristics of HER2 positive metastatic breast cancer patients experiencing radiologic complete response in a nationwide cohort [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-11-04.

With the aim to promote a fast and effective characterization of the sound environment in educational facilities and an adequate classroom acoustics design, this work provides a basic measurement protocol which consists of a minimum number of parameters and positions to be considered. The present study involved 29 primary-school classrooms where background noise level during silent and group activities, reverberation time, speech clarity, useful-to-detrimental ratio and speech levels have been acquired in occupied condition along the main axis and in one or two offset positions. Two cut-off values of maximum reverberation time to ensure optimal acoustic conditions in the case of moderate and severe requirements, respectively, were assumed equal to 0.8 s and 0.6 s, according to literature and subjective data. For each cut-off value, classrooms were divided in two consistent groups either if they were compliant or non-compliant with such requirements, respectively. Given the strong correlation among the measured quantities, cut-off values were also identified for the other acoustical parameters. The main result of the work suggests that more convenient parameters, such as clarity in the central location of the classroom, can be used beyond reverberation time, which implies a more laborious measurement procedure.

To determine whether the Veterans Health Administration’s (VHA) hepatitis C (HCV) treatment campaign reached marginalized populations, we compared HCV care by previous incarceration status with Veterans Aging Cohort Study data. Of those with and those without previous incarceration, respectively, 40% and 21% had detectable HCV, 59% and 65% underwent treatment (P = .07); 92% and 94% of those who completed treatment achieved sustained virologic response. The VHA HCV treatment effort was successful and other systems should replicate those efforts. (Am J Public Health. 2023;113(2):162–165. https://doi.org/10.2105/AJPH.2022.307152 )

As with past pandemics of influenza, COVID-19 tore through US prisons and jails; however, the COVID-19 pandemic, uniquely, has led to more health research on carceral systems than has been seen to date. Herein, we review the data on its impact on incarcerated people, correctional officers, health systems, and surrounding communities. We searched medical, sociological, and criminology databases from March 2020 through February 2022 for studies examining the intersection of COVID-19, prisons and jails, and health outcomes, including COVID-19 incidence, prevalence, hospitalizations, and vaccination. Our scoping review identified 77 studies—the bulk of which focus on disease epidemiology in carceral systems, with a small minority that focuses on the efficacy or effectiveness of prevention and mitigation efforts, including testing, vaccination, and efforts to depopulate correctional facilities. We highlight areas for future research, including the experiences of incarcerated people and correctional staff, unanticipated health effects of prolonged quarantine, excess deaths due to delays in healthcare, and experimental studies on vaccine uptake and testing in correctional staff. These studies will enable a fuller understanding of COVID-19 and help stem future pandemics.

En mayo de 2019 comenzó una disputa entre dos localidades cordobesas por los restos corporales (reliquias) del cura Brochero (1840-1914), declarado santo en octubre de 2016. La municipalidad de Villa Santa Rosa, su lugar de nacimiento, aprobó una resolución solicitando el traslado allí de sus reliquias, situadas en Villa Cura Brochero. En este trabajo veremos que en tanto “objetos poderosos” las reliquias de los santos han sido a lo largo de la historia motivo de interés de las comunidades por poseerlas. Asimismo, luego de mencionar la importancia simbólica y afectiva que las reliquias tienen dentro del movimiento brocheriano, daremos cuenta de esta querella recuperando diferentes voces. Finalizamos señalando que este conflicto pone de manifiesto la importancia que las reliquias poseen en lo que respecta a la legitimidad simbólica que aportan, los lazos comunales que articulan y la relevancia económica que tienen para las comunidades que las poseen.

The development of the internet-of-things requires cheap, light, small and reliable true random number generator (TRNG) circuits to encrypt the data—generated by objects or humans—before transmitting them. However, all current solutions consume too much power and require a relatively large battery, hindering the integration of TRNG circuits on most objects. Here we fabricated a TRNG circuit by exploiting stable random telegraph noise (RTN) current signals produced by memristors made of two-dimensional (2D) multi-layered hexagonal boron nitride (h-BN) grown by chemical vapor deposition and coupled with inkjet-printed Ag electrodes. When biased at small constant voltages (≤70 mV), the Ag/h-BN/Ag memristors exhibit RTN signals with very low power consumption (∼5.25 nW) and a relatively high current on/off ratio (∼2) for long periods (>1 hour). We constructed TRNG circuits connecting an h-BN memristor to a small, light and cheap commercial microcontroller, producing a highly-stochastic, high-throughput signal (up to 7.8 Mbit s−1) even if the RTN at the input gets interrupted for long times up to 20 s, and if the stochasticity of the RTN signal is reduced. Our study presents the first full hardware implementation of 2Dmaterial- based TRNGs, enabled by the unique stability and figures of merit of the RTN signals in h-BN based memristors., Ministry of Science and Technology, China 2019YFE0124200 2018YFE0100800, National Natural Science Foundation of China (NSFC) 61874075, Collaborative Innovation Centre of Suzhou Nano Science and Technology, Priority Academic Program Development of Jiangsu Higher Education Institutions, 111 Project from the State Administration of Foreign Experts Affairs of China, King Abdullah University of Science & Technology, Ministerio de Ciencia, Tecnologia e Innovacion (MINCyT) PICT 2016/0579 PME 2015-0196 PICTE 2018-0192 UTN-FRBA CCUTIBA4764TC MATUNBA4936 CCUTNBA5182 CCUTNBA6615

The suffix array, perhaps the most important data structure in modern string processing, is often augmented with the longest common prefix (LCP) array which stores the lengths of the LCPs for lexicographically adjacent suffixes of a string. Together the two arrays are roughly equivalent to the suffix tree with the LCP array representing the tree shape. In order to better understand the combinatorics of LCP arrays, we consider the problem of inferring a string from an LCP array, i.e., determining whether a given array of integers is a valid LCP array, and if it is, reconstructing some string or all strings with that LCP array. There are recent studies of inferring a string from a suffix tree shape but using significantly more information (in the form of suffix links) than is available in the LCP array. We provide two main results. (1) We describe two algorithms for inferring strings from an LCP array when we allow a generalized form of LCP array defined for a multiset of cyclic strings: a linear time algorithm for binary alphabet and a general algorithm with polynomial time complexity for a constant alphabet size. (2) We prove that determining whether a given integer array is a valid LCP array is NP-complete when we require more restricted forms of LCP array defined for a single cyclic or non-cyclic string or a multiset of non-cyclic strings. The result holds whether or not the alphabet is restricted to be binary. In combination, the two results show that the generalized form of LCP array for a multiset of cyclic strings is fundamentally different from the other more restricted forms.

Iron-sulfur (Fe-S) clusters are cofactors essential for life. Though the proteins that function in the assembly of Fe-S clusters are well known, details of the molecular mechanism are less well established. The Isc (Iron-sulfur cluster) biogenesis apparatus is widespread in bacteria and is the closest homologue to the human system. Mutations in certain components of the human system lead to disease, and so further studies of this system could be important for developing strategies for medical treatments. We have studied two core components of the Isc biogenesis system: IscS, a cysteine desulfurase; and IscU, a scaffold protein on which clusters are built before subsequent transfer onto recipient apo-proteins. Fe2+-binding, sulfur transfer, and formation of a [2Fe-2S] was followed by a range of techniques, including time-resolved mass spectrometry, and intermediate and product species were unambiguously identified through isotopic substitution experiments using 57Fe and 34S. Under cluster synthesis conditions, sulfur adducts and the [2Fe-2S] cluster product readily accumulated on IscU, but iron adducts (other than the cluster itself) were not observed at physiologically relevant Fe2+ concentrations. Our data indicate that either Fe2+ or sulfur transfer can occur first, but that the transfer of sulfane sulfur (S0) to IscU must occur first if Zn2+ is bound to IscU, suggesting that it is the key step that initiates cluster assembly. Following this, [2Fe-2S] cluster formation is a largely concerted reaction once Fe2+ is introduced.

A phytosociological study on the gypsicolous bryophyte communities of Sicily was carried out. The surveyed communities are: Tortuletum revolventis, Trichostomo crispuli-Tortuletum revolventis, Crossidio squamiferi-Aloinetum aloidis of the order Barbuletalia unguiculatae, and Crossidio crassinervis-Tortuletum obtusatae of the order Tortulo brevissimae-Aloinetalia bifrontis. The associations were examined from a synecological, synhierarchical and chorological point of view. A life form and life strategy analysis of all communities reflect the response of plant functional types towards the environmental demands. Only one life strategy dominates the communities; acrocarpous, turf-forming colonists clearly prevail on gypsum outcrops, subject to drought stress. They provide the main functional type within pioneering communities and communities of first successional stages. The keystone characters outlined ensure a successful dispersal, establishment and habitat maintenance of the species and associations.

Immune checkpoint inhibitors have significantly improved the therapeutic scenario of many different advanced malignancies and could be an effective treatment strategy in synchronous or metachronous tumors. The authors describe the clinical case of a patient who experienced a long-lasting response of his metastatic renal cell carcinoma and an optimal response of his locally advanced cutaneous squamous cell carcinoma to immunotherapy. The systemic treatment was chosen based on a literature review of several clinical reports, since there was no prospective study on anti-PD-1 blockade activity in cutaneous squamous cell carcinoma when the patient started the treatment. This clinical case supports the growing evidence for immunotherapy as a valid treatment option across different types of advanced tumors.Immunotherapy is an effective treatment strategy across different cancer types and could be a valid treatment strategy in patients with multiple malignant tumors. In this scenario, in fact, the main challenge is to choose a systemic treatment which could be active on both tumors with an acceptable toxicity profile. The authors report the clinical case of a patient with metastatic renal cell carcinoma and a disfiguring cutaneous cancer of the zygomatic region who experienced a durable response of the renal tumor and almost a complete clinical response of the cutaneous cancer.

Although adrenocortical carcinoma (ACC) during pregnancy is rare, a retrospective review of a case series at our hospital revealed that almost one third of our patients were women in childbearing age. Given that the age of maternity is increasing, dealing with a tumor diagnosis during pregnancy and the need for fertility planning in cancer survivors is likely to become more frequent.We thus carried out a case-based discussion regarding: i) diagnosing and treating an ACC during pregnancy; ii) patients conceiving while on mitotane; iii) ACC survivors with a maternal desire.In each of these cases, it is important to provide patients with sufficient information, to offer medical advice and psychological support, to personalize treatments in accordance with the wishes of the patient and her relatives, and to collaborate with other specialists since a multidisciplinary expert team is required to manage each case individually.

Initial access in millimeter-wave (mmW) wireless is critical toward successful realization of the fifth-generation (5G) wireless networks and beyond. Limited bandwidth in existing standards and use of phase-shifters in analog/hybrid phased-antenna arrays (PAA) are not suited for these emerging standards demanding low-latency direction finding. This work proposes a reconfigurable true-time-delay (TTD) based spatial signal processor (SSP) with frequency-division beam training methodology and wideband beam-squint less data communications. Discrete-time delay compensated clocking technique is used to support 800~MHz bandwidth with a large unity-gain bandwidth ring-amplifier (RAMP)-based signal combiner. To extensively characterize the proposed SSP across different SSP modes and frequency-angle pairs, an automated testbed is developed using computer-vision techniques that significantly speeds up the testing progress and minimize possible human errors. Using seven levels of time-interleaving for each of the 4 antenna elements, the TTD SSP has a delay range of 3.8 ns over 800 MHz and achieves unique frequency-to-angle mapping in the beamtraining mode with nearly 12 dB frequency-independent gain in the beamforming mode. The SSP is prototyped in 65nm CMOS with an area of 1.98mm$^2$ consuming only 29 mW excluding buffers. Further, an error vector magnitude (EVM) of 9.8% is realized for 16-QAM modulation at a speed of 122.8 Mb/s.

Background: In the era of targeted therapies, chemotherapy (CT) is still a valuable treatment option for patients (pts) with HER2 negative metastatic breast cancer (MBC). The identification of predictive and prognostic markers might improve treatment response and survival. Here we investigated the role of tumor subtypes, circulating tumor cells (CTCs), and mutations in genes or pathways of interest, in predicting response to CT and prognosis of HER2 negative MBC pts within AARES trial. Methods: AARES is an open label multicentric randomised phase 2 trial comparing a DNA-damaging (arm A: cisplatin 25 mg/m2/day, day 1-3 + cyclophosphamide 600 mg/m2 day 1) versus (vs) a non-DNA-damaging (arm B: capecitabine 1000 mg/m2 bid/day, day 1-14 + vinorelbine 60 mg/m2/day, day 1,8) CT regimen in pts with HER2 negative MBC. Archival tumor tissue samples and blood samples were collected at baseline. The Cell SearchTM system was used for CTCs isolation and enumeration and a cut-off of 5 CTC/7,5 ml was used. Tumor subtypes were based on locally assessed hormone receptors and HER2 status. The luminal-like subtype (Lum) was defined by ER or PR positivity, while the triple negative subtype (TN) by ER, PR, and HER2 negativity. Tissue samples were used for DNA extraction and next generation sequencing analysis using a target enrichment panel of 170 genes (TruSight 170, Illumina). Primary endpoint was objective response rate (ORR) assessed for the two treatment arms. Progression free survival (PFS) and overall survival (OS) were evaluated as secondary endpoints, and estimated with the Kaplan-Meier method. ORR, PFS and OS were correlated with CTC counts, tumor subtypes, and mutational status of genes/pathway of interest (PIK3CA, TP53, BRCA1, BRCA2, PI3K/AKT pathway (PI3K/AKT)). Results: AARES enrolled 102 pts from 2011 to 2016 across 9 Italian centers. Of these, 77 pts were evaluable for ORR. Median follow up was 32 months. Overall, median age was 57. The majority of pts had Lum tumors (73%), while 27% had TN. 86% of pts had visceral metastases, and 52% had 3 or more metastatic sites. 48% of pts received the study treatment as 1st line, 32% as 2nd line, and 19% as 3rd line. Out of the 77 pts with ORR data, 41 (53%) were CTC- and 36 (47%) CTC+. A larger proportion of pts with Lum tumors were CTC+ (54% n=30), while TN tumors were mainly CTC- (71% n=15). 49 pts had adequate tumor tissue for sequencing analysis. TP53 mutations (mut) were found in 33% of pts, BRCA1/2 mut in 14%, PIK3CA mut in 35%, and PI3K/AKT mut in 47%. ORR was 24% and 37% in arm A vs arm B, respectively (p= 0.2), and no difference in ORR was observed by tumor subtypes (Lum vs TN), and CTCs count (+ vs -). PFS and OS were assessable on the whole population (n=102) and did not significantly differ by treatment arms. Median OS (mOS) was higher in Lum pts compared to TN (24 months (mo) vs 15.4 mo, p=0.048) while median PFS (mPFS) did not differ according to tumor subtypes (p=0.28). Overall, CTCs count was not significantly associated with mPFS or OS however in pts with TN tumors and CTC-, mPFS and mOS were significantly longer (mPFS: 4.44 mo vs 2.56 mo in CTC- and CTC+ subgroups, respectively, p=0.00087 and mOS: 22.07 mo vs 3.57 mo in CTC- and CTC+ subgroups, respectively, p< 0.0001). On the other hand, no differences were observed in Lum pts categorized according to CTC status (p=0.83 for mPFS, p=0.54 for mOS). Finally, pts with PI3K/AKT mut had a significantly worse PFS compared to wild type in the overall population (p=0.0091) as well as in Lum (p=0.034) and TN pts (p=0.0052). Conclusions: CTCs and tumor subtypes were not predictive of response to CT regimens in HER2 negative MBC pts. A number of CTC >5 in TN MBC, and mutations in the PI3K/AKT pathway, identified a subgroup of pts with worse prognosis, potentially candidates for alternative treatments. Further studies are needed to confirm these results in a larger population. Citation Format: Emanuela Risi, Marta Pestrin, Chiara Biagioni, Dario Romagnoli, Ilenia Migliaccio, Francesca Galardi, Francesca De Luca, Matteo Benelli, Erica Moretti, Giuseppina Sanna, Luca Livraghi, Silvia Cappadona, Roberta Di Marsico, Domenico Amoroso, Angelo Martignetti, Angela S. Ribecco, Elena Rota Caremoli, Luigi Coltelli, Fabio Puglisi, Luca Malorni, Laura Biganzoli. Circulating tumor cells, immunohistochemical subtypes, and genes mutation as prognostic markers in HER2 negative metastatic breast cancer patients candidates to chemotherapy [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-05-45.

The results of the 4th National Report for the Italian flora under the 92/43/EEC ‘Habitats’ Directive are presented. The outcomes showed a general negative conservation status for plant species, with the worst situation being in the Mediterranean bioregion. At the National level, significant monitoring and conservation activities are required.

Tyrosine kinase inhibitors (TKIs) are the backbone of the systemic treatment for patients with metastatic renal cell carcinoma (mRCC). TKIs such as pazopanib and cabozantinib can interact with other drugs concomitantly administered, particularly with proton-pump inhibitors (PPIs), possibly impacting the effectiveness of the anticancer treatment and patients outcome. Few data are available about this interaction. We conducted a multicenter retrospective observational data collection of patients with mRCC treated with pazopanib or cabozantinib between January 2012 and December 2020 in nine Italian centers. Univariate and multivariate analyses were performed. The aim was to describe the impact of baseline concomitant PPIs on the outcome of patients to pazopanib and cabozantinib in terms of response, progression-free survival (PFS) and overall survival (OS), toxicity, and treatment compliance. The use of PPI in our study population (301 patients) significantly influenced the effectiveness of TKIs with worse PFS (16.3 vs. 9.9 months; P0.001) and OS (30.6 vs. 18.4 months; P = 0.013) in patients taking PPI at TKI initiation. This detrimental effect was maintained both in the pazopanib and cabozantinib groups. The use of PPI influenced the toxicity and TKI treatment compliance with a reduction of dose or schedule modifications, and treatment interruptions in the population taking PPIs. Our study demonstrates that the use of PPIs can significantly influence the outcome and compliance of patients with mRCC to TKI treatment, suggesting the importance of a more careful selection of patients who need a gastroprotective therapy, avoiding indiscriminate use of PPIs.

Objective. Perforation of the gallbladder (PG) is a dreaded complication of an acute cholecystitis and is associated with increased morbidity and mortality. Cholecystocutaneous abscess (CCA) is an extremely rare complication. There is usually a history of cholecystolithiasis or neglected chronic gallbladder disease. We report a case of perforated gallbladder into the abdominal wall. Methods. A 65-year-old female, obese, was admitted to our department complaining of right upper quadrant abdominal pain. The diagnosis of acute cholecystitis was based on the clinical picture, laboratory test, and ultrasound findings. She was treated with oral antibiotics for 10 days and readmitted due to a painful, erythematous mass on the right subcostal region. An abdominal computed tomography showed the presence of a subparietal formation in communication with the gallbladder, and a gallbladder perforation was postulated. The treatment consisted of percutaneous drainage of the abdominal wall abscess followed by laparoscopic cholecystectomy in a two-stage protocol. Anatomical pathology analysis found chronic inflammation and excluded malignancy. The postoperative follow-up was uneventful. Discussion. This case demonstrates a very rare presentation of PG that created an abscess into the muscles of the abdominal wall. This kind of PG is rarely seen due to medicine improvements. When the conditions of the patient are good, rather than perform immediate surgery that could lead to serious complications, we propose a two-stage approach. Conclusion. CCA is a possible complication of gallbladder’s pathology that all surgeons have to know. There is no standard baseline management for this pathology, due to the few numbers of cases and to the differences in the quality of the patients’ illness. We suggest a two-stage approach with drainage of the abscess followed by laparoscopic cholecystectomy with abscess debridement.

There is a clear correlation between gut microbiota, diet, and metabolic outcomes. A diet high in fiber has been shown to decrease inflammation, increase insulin sensitivity, and reduce dyslipidemias whereas a diet high in fat and sugar leads to dyslipidemia, insulin resistance, and low-grade inflammation. There is recent evidence suggesting that the human gut microbiota has a significant role in the development or the resolution of metabolic syndrome (MetS) and associated conditions. Leading a stressful, sedentary lifestyle with limited or no physical activity and consuming an unhealthy diet high in saturated fat, simple carbohydrates, and sodium and low in dietary fiber and in high-quality protein are some of the contributing factors. Unhealthy diets have been shown to induce alterations in the gut microbiota and contribute to the pathogenesis of MetS by altering microbiota composition and disrupting the intestinal barrier, which leads to low-grade systemic inflammation. In contrast, healthy diets can lead to changes in microbiota that increase gut barrier function and increase the production of anti-inflammatory biomarkers. This review aims at providing a more in-depth discussion of diet-induced dysbiosis of the gut microbiota and its effect on MetS. Here, we discuss the possible mechanisms involved in the development of the metabolic biomarkers that define MetS, with an emphasis on the role of sugar and dietary fiber in microbiome-mediated changes in low-grade systemic inflammation and metabolic dysfunction.

The advent of immune checkpoint inhibitors in combination with multitarget tyrosine kinase inhibitors has become a standard first-line treatment for metastatic renal cell cancer. Along with survival improvement, new toxicities have emerged. Such adverse events are still complex to be managed and some of them are rare and could be insidious or even fatal. Medical oncologists dispose of guidelines about the management of toxicities from immune checkpoint inhibitors but not for combinations. Therefore, it is still difficult to properly attribute and manage additive or overlapping adverse events. We report two clinical cases regarding rare treatment-related endocrine toxicities—hypophysitis and thyroiditis—with particular focus on their management. To this purpose, immune checkpoint-related toxicities guidelines represent the starting point. However, their implementation with additional measures is needed, considering the increasing complexity of current clinical scenarios. The goal is to correctly recognize adverse events and address side effects, so as not to discontinue effective treatments. We, therefore, aim at discussing the points of proper management of toxicities and individuating potential areas of improvement.

Tumour markers have no established role in the monitoring of the course of metastatic breast cancer during antineoplastic therapy, yet cancer antigen 15.3 (CA15.3) and carcinoembryonic antigen (CEA) are commonly used in clinical practice to aid in the early detection of progression of disease (PD). In our multicentre, prospective, real-life study, we enrolled 142 consecutive patients with advanced breast cancer receiving endocrine therapy in combination with a CDK4/6 inhibitor from January 2017 to October 2020; 75 patients had PD at the time of database closure. We measured serum marker concentrations at regular 4-month intervals together with radiological tumour response assessments and in cases of clinical suspicion of PD. Appropriate descriptive and inferential statistical methods were used to analyse serum marker level trends amongst prespecified subgroups and at specific time points (baseline, best radiologically documented tumour response and first detection of PD) in the subpopulation of patients with PD at the time of database closure. Notably, the median time from treatment initiation to best tumour response was 4.4 months. We evaluated the presence of an association between baseline CA15.3 and CEA levels and prespecified clinical characteristics but found no clinically meaningful correlation. We assessed marker level variations at the time of best radiologically documented disease response and PD: in the subgroup of patients who responded to treatment before progressing, we detected a statistically significant correlation with tumour marker variation between the time of best response and progression; this finding was not confirmed in the subgroup of patients that did not benefit from treatment. In conclusion, serum tumour marker flares can be useful in the early diagnosis of PD but should not be used as the sole factor prompting a change in treatment strategy without radiological confirmation.

The spread of COVID-19 led countries around the world to adopt lockdown measures of varying stringency, with the purpose of restricting the movement of people. However, the effectiveness of these measures on mobility has been markedly different. Employing a difference-in-differences design, we analyse the effectiveness of movement restrictions across different countries. We disentangle the role of regulation (stringency measures) from the role of people's knowledge about the spread of COVID-19. We proxy COVID-19 knowledge by using Google Trends data on the term "Covid". We find that lockdown measures have a higher impact on mobility the more people learn about COVID-19. This finding is driven by countries with low levels of trust in institutions and low levels of education.

Converging translational and clinical research strongly indicates that altered immune and inflammatory homeostasis (neuroinflammation) plays a critical pathophysiological role in Alzheimer's disease (AD), across the clinical continuum. A dualistic role of neuroinflammation may account for a complex biological phenomenon, representing a potential pharmacological target. Emerging blood-based pathophysiological biomarkers, such as cytokines (Cyt) and interleukins (ILs), have been studied as indicators of neuroinflammation in AD. However, inconsistent results have been reported probably due to a lack of standardization of assays with methodological and analytical differences. We used machine-learning and a cross-validation-based statical workflow to explore and analyze the potential impact of key biological factors, such as age, sex, and apolipoprotein-E (APOE) genotype (the major genetic risk factor for late-onset AD) on Cyt. A set of Cyt was selected based on previous literature, and we investigated any potential association in a pooled cohort of cognitively healthy, mild cognitive impairment (MCI), and AD-like dementia patients. We also performed explorative analyses to extrapolate preliminary clinical insights. We found a robust sex effect on IL12 and an APOE-related difference in IL10, with the latter being also related to the presence of advanced cognitive decline. IL1β was the variable most significantly associated with MCI-to-dementia conversion over a 2.5 year-clinical follow-up. Although preliminary, our data support further clinical research to understand whether plasma Cyt may represent reliable and noninvasive tools serving the investigation of neuroimmune and inflammatory dynamics in AD and to foster biomarker-guided pathway-based therapeutic approaches, within the precision medicine development framework.

The cancer disparities between people with incarceration histories compared to those who do not have those histories are vast. Opportunities for bolstering cancer equity among those impacted by mass incarceration exist in criminal legal system policy, carceral, community, and public health linkages, better cancer prevention, screening, and treatment services in carceral settings, expansion of health insurance, education of professionals, and use of carceral sites for health promotion and transition to community care. Clinicians, researchers, persons with a history of incarceration, carceral administrators, policymakers, and community advocates could play a cancer equity role in each of these areas. Raising awareness and setting a cancer equity plan of action is critical to reducing cancer disparities among those affected by mass incarceration.

A main concern of agriculture is to improve plant nutrient efficiency to enhance crop yield and quality, and at the same time to decrease the environmental impact caused by the lixiviation of excess N fertilizer application. The aim of this study was to evaluate the potential use of biopolymers (BPs), obtained by alkaline hydrolysis of the solid anaerobic digestate of municipal biowastes, in order to face up these main concerns of agriculture. The experimental trials involved the application of BPs (at 50 and 150 kg/ha) alone or mixed with different amounts (100%, 60% and 0%) of mineral fertilizer (MF). Three different controls were routinely included in the experimental trials (MF 100%, 60% and 0%). The effect of BPs on lettuce was evaluated by monitoring growth parameters (fresh and dry weights of shoot and root, nitrogen use efficiency), and the N-flux in plant-soil system, taking into account the nitrate leached due to over irrigation events. The activities of enzymes involved in the nitrogen uptake (nitrate reductase, glutamate synthase and glutamine synthase), and the nitrogen form accumulated in the plant tissues (total N, protein and NO3−) were evaluated. The results show that the application to the soil of 150 kg/ha BPs allows to increase lettuce growth and nitrogen use efficiency, trough stimulation of N-metabolism and accumulation of proteins, and hence to reduce the use of MF by 40%, thus decreasing the nitrate leaching. These findings suggest that the use of BPs as biostimulant greatly contributes to reduce the consumption of mineral fertilizers, and to mitigate the environmental impact caused by nutrients leaching, according to European common agricultural policy, that encourages R&D of new bioproducts for sustainable eco-friendly agriculture.

The geodynamic framework of Mount Etna volcano (Italy) is characterised by two superimposed tectonic domains: a compressional one, oriented N-S, and an extensional one, oriented approximately WNW-ESE. The combination of these two domains and the volcano activity, has generated a complex system of faults prevalently on the eastern flank of the volcano. The eastern flank is the most active area of the volcano in terms of deformation and seismicity. The velocities there are at least one order of magnitude greater than in the rest of the volcano flanks due to the eastward sliding of the eastern flank.The monitoring and analysis of the acceleration occurring on the eastern flank of Mount Etna is the keystone to understand the volcano-tectonic dynamics that, apart from the tectonic and magmatic processes, involves the instability of this flank in a densely inhabited area.In order to monitor the deformation, Istituto Nazionale Geofisica e Vulcanologia – Osservatorio Etneo (INGV-OE) and the GeoDynamic & GeoMatic Laboratory of the University of Catania integrate GNSS and InSAR products with twofold objective: to characterize the dynamics of the area and to analyse the deformation transients, this last in view of a possible use in the framework of an alert system.Here, we analyse the ground deformation that occurred between 2016 and 2019 across the faults of the south-eastern flank of Mount Etna. On the south-eastern flank the deformation is accommodated by several faults which have different kinematics and behaviours. We discriminate the deformation transient and the activity of the Belpasso-Ognina lineament, Tremestieri, Trecastagni, San Gregorio-Acitrezza, Linera, Nizzeti and Fiandaca faults. The latter generated the 26 December 2018 earthquake, two days after the eruption of 24 December, which induced a clear post seismic deformation, detected by GNSS and InSAR data. In particular, we discriminate the deformation occurred along the San Gregorio-Acitrezza fault, which is accommodated by the Nizzeti fault, and we analyse the post seismic deformation along the Linera fault. We analyse the Slow Slip Events (SSE) that are observed in the GNSS and InSAR time series in the vicinity of the Acitrezza fault and we quantify and discuss the tectonic origin of the Belpasso-Ognina lineament that we interpreted as a tear fault.

Measuring how the surface deforms in time and space plays a crucial role, not only for understanding volcanic mechanisms, but also for hazard assessment, risk mitigation and supporting crisis management. Mount Etna, one of the most active volcanoes in the world, with a growing population in its vicinity, has experienced an intense period of activity in recent years, mainly characterized by continuous degassing and recurring lava fountains. Due to this activity, continuous deformation can be observed at Mount Etna.The summit craters showed brisk activity in the last months of 2020, accompanied by increasing seismicity. A period of paroxysms started in December 2020 and intensified in February 2021, with brief but violent eruptive lava-fountaining episodes, that continued throughout all the year. The focus of this study is to understand the dynamics of the near-surface feeding system by constraining the sources responsible for the observed paroxysms. To localize and describe the time-dependent ground deformation, we examine surface deformation at Mount Etna by means of an Interferometric Synthetic Aperture Radar time series analysis utilizing Sentinel-1 data between the second half of 2020 and the end of 2021. The onset of the paroxysms was preceded by an inflation period and deflation episodes were observed during the paroxysms period, which suggests a link between the volcano activity and the observed deformation. The findings may contribute to the discussion on the distribution and dynamics of magma reservoirs that form Mount Etna's conduit system and its interaction with the local tectonic regime.

O cálcio (Ca2+), um dos íons envolvidos no complexo funcionamento do coração, é também considerado o mais importante pelo fato de ser o ativador direto dos miofilamentos que causam a contração. O seu fluxo irregular é uma das principais causas de arritmias cardíacas e disfunção contráctil. Nesse sentido, a formulação de novos modelos matemáticos e computacionais de miócito ventricular de mamífero aporta ferramentas importantes para entender os mecanismos de liberação de Ca2+e analisar de forma detalhada as causas dos diversos tipos de arritmia cardíaca. O objetivo desse trabalho é apresentar um modelo de compartimentos para o miócito ventricular de rato, fundamentado no modelo de Shannon et al. (2004) e a partir desse modelo desenvolver a ferramenta computacional Cardio Junction que pode ser acessada no endereço: https://cardiolab.ifspguarulhos.edu.br/, uma plataforma online para simulação, desenvolvida na linguagem de programação Python. Para avaliação da plataforma foram realizados testes de validação do modelo para o transiente de Ca2+e força de contração, além de simulações envolvendo a aplicação do fármaco (SS-68). O modelo e a aplicação WEB foram ajustados para uma melhor reprodução do fenômeno em estudo, e o sistema deve contribuir com as pesquisas dessa área bem como servir de base para complementar o ensino dos princípios básicos da eletrofisiologia cardíaca.

Background Heavy metals (HMs) phytoremediation is a well-recognized protocol to remove toxic elements from the soil. As known, arbuscular mycorrhizal fungi (AMF) enhance the plants' growth responses. The idea of the present study was to assay the response of lavender plants to HMs stress under AMF inoculation. We hypothesized that mycorrhiza will enhance the phytoremediation and simultaneously reduce the harmful effects of heavy HMs. So, lavender (Lavandula angustifolia L.) plants were inoculated with AMF (0 and 5 g Kg−1 soil) under Pb [150 and 225 mg kg−1 soil from Pb (NO3)2] and Ni [220 and 330 mg kg−1 soil from Ni (NO3)2] pollution, in the greenhouse conditions. The control treatment was plants not treated with AMF and HMs. Doing this, the root colonization, HMs uptake, enzymatic and non-enzymatic antioxidants pool, MDA, proline, total phenolics (TPC), flavonoids (TFC), anthocyanins, and essential oil (EO) components were evaluated. Results According to the findings, the AMF inoculation enhanced shoot and root Pb and Ni content, antioxidant enzymes activity, the total antioxidant activity by DPPH and FRAP methods, TPC, TFC, anthocyanins, and H2O2 content in the lavender plants subjected to Pb and Ni stress. Moreover, the highest (28.91%) and the least (15.81%) percentages of borneol were identified in the lavender plants subjected to AMF under 150 mg kg−1 of Pb and the control plants without AMF application, respectively. Furthermore, the top 1,8-cineole (12.75%) content was recorded in AMF-inoculated plants. Conclusions The overall results verify that AMF inoculation can be a reliable methodology to enhance the phytoremediation of Pb and Ni by lavender plants while maintaining reliable growth potential. The treatments improved the main EO constituents content, especially under moderate HMs stress conditions. With more detailed studies, the results will be advisable for the extension section for the phytoremediation of polluted soils.

Activation of ryanodine receptors on the sarcoplasmic reticulum are well known to cause subcellular rapid Ca2+ events that are commonly referred to as Ca2+ sparks. These Ca2+ spark events regulate vascular reactivity through activation of potassium channels on the plasma membrane. Intracellular Ca2+ signals are commonly examined using fluorescent imaging approaches using high speed confocal microscopes. Over the past two decades, analysis of these events has advanced from visual observation and manual analysis by trained observers to more automated approaches. The purpose of the current study was to test whether fully automated approaches could accurately detect Ca2+ sparks in line-scan images and analyze spatial and temporal aspects to the events. This evaluation was addressed by re-analyzing a published “gold standard” dataset, where original analysis was performed through experimenter guided analysis of Ca2+ signals from recordings made in pulmonary arterial myocytes of en face arterial preparations. Ca2+ sparks were detected and analyzed automatically post-hoc using a customized Ca2+ spark analysis program, Sparklab 5.8. Increasing the threshold for detection led to incremental decreases in the percentage of cells with activity and the firing frequency. Raising the threshold also impacted the PPV, sensitivity and false discovery rate, which was examined through comparison to visually observed Ca2+ spark events. Interestingly, changing the threshold had little impact on spatial and temporal aspects of the Ca2+ spark events. Overall, automated Ca2+ spark detection and analysis with Sparklab 5.8 is expected to greatly improve experimental workflow and can be well optimized with low false discovery rates and reasonable levels of sensitivity. NIH R01HL155295, R01HL149608 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Before birth, the pulmonary vasculature is relatively constricted and has reduced blood flow. The vasculature dilates with birth, and blood flow and oxygenation increase. Pulmonary arterial dilation during birth is related to activation of large conductance potassium channels and Ca2+ spark events through activation of ryanodine receptors (RyR) on the sarcoplasmic reticulum. This coupled mechanism is driven by activation of L-type Ca2+ channels, which stimulate RyRs. Long-term maternal hypoxia increases oxidative stress in neonatal pulmonary arteries, which may arise from the mitochondria. There is also disruption of Ca2+ sparks and pulmonary hypertension in newborn lambs. Long-term MitoQ usage, an antioxidant that targets the mitochondria, can reduce oxidative stress levels and improve vascular function due to hypoxic stress. We hypothesize that hypoxia induced reactive oxygen species generated through disruption of mitochondrial function dysregulates Ca2+ spark activity, underlying functional problems due to long term hypoxic stress. This study aims to analyze and understand whether MitoQ treatment can recover Ca2+ spark activity. To address this hypothesis, pulmonary arterial myocytes of control (N=11 normoxic, 2 hypoxic) and MitoQ treated newborn sheep (N=2 normoxic, 5 hypoxic) were examined in the presence and absence of membrane depolarization with 30 mM potassium (30K). The intracellular Ca2+ was recorded in the myocytes of isolated pulmonary arteries that were loaded with Fluo-4 using line-scan techniques on a confocal microscope. Ca2+ spark activity was analyzed using automated customized software (Sparklab). In comparison to our previously published work, the basal spark activity was generally high in both normoxic and hypoxic groups, but the MitoQ normoxic group had lower activity. MitoQ treatment did not modify Ca2+ spark activity in any group. Use of the newly designed automated detection software may underlie differences as compared to our published work. The lack of an effect of MitoQ on spark activity parallels the ineffectiveness of acute antioxidant treatment in our other pilot studies on fetal pulmonary arteries. Overall, additional studies are required to resolve the discrepancies between our current and previous work. NIH R01HL155295 and R01HL149608, NSF Grant MRI-DBI 0923559 and the Loma Linda University School of Medicine This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

PURPOSE As the continuation beyond progression (BP) of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) is becoming increasingly attractive for the treatment of patients with hormone receptor (HR)–positive, human epidermal growth factor receptor 2 (HER2)–negative metastatic breast cancer (MBC), the definition of resistance factors is crucial. The aim of the study was to investigate the impact of CDK 4/6i BP and to explore potential genomic stratification factors. MATERIALS AND METHODS We retrospectively analyzed a multi-institutional cohort of patients with HR-positive HER2-negative MBC characterized for circulating tumor DNA through next-generation sequencing before treatment start. Differences across subgroups were analyzed by chi-square test, and survival was tested by univariable and multivariable Cox regression. Further correction was applied by propensity score matching. RESULTS Among the 214 patients previously exposed to CDK4/6i, 172 were treated with non–CDK4/6i-based treatment (non-CDK) and 42 with CDK4/6i BP. Multivariable analysis showed a significant impact of CDK4/6i BP, TP53 single-nucleotide variants, liver involvement, and treatment line on both progression-free survival (PFS) and overall survival (OS). Propensity score matching confirmed the prognostic role of CDK4/6i BP both for PFS and OS. The favorable impact of CDK4/6i BP was consistent across all subgroups, and a differential benefit was suggested for ESR1-mutated patients. ESR1 and RB1 mutations were more represented in the CDK4/6i BP subgroup with respect to CDK4/6i upfront. CONCLUSION The study highlighted a significant prognostic impact of the CDK4/6i BP strategy with a potential added benefit in patients with ESR1 mutations suggesting the need for an extensive biomarker characterization.