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Ugo Fedeli,1 Alfredo De Giorgi,2 Nicola Gennaro,1 Eliana Ferroni,1 Massimo Gallerani,3 Dimitri P Mikhailidis,4 Roberto Manfredini,2 Fabio Fabbian2 1Epidemiological Department, Veneto Region, 2Department of Medical Sciences, Clinica Medica Unit, School of Medicine, University of Ferrara, 3Department of Internal Medicine, University Hospital of Ferrara, Ferrara, Italy; 4Department of Clinical Biochemistry (Vascular Disease Prevention Clinic), University College London Medical School, London, UK Background: COPD is among the major causes of death, and it is associated with several comorbid conditions. Chronic kidney disease (CKD) is frequently diagnosed in older people living in Western societies and could impact COPD patients’ mortality. We evaluated the relationship between burden of comorbidities, CKD, and mortality in a population-based cohort of patients discharged with a diagnosis of COPD.Methods: A longitudinal cohort study was conducted evaluating 27,272 COPD patients. Recruitment of COPD subjects and identification of CKD and other comorbidities summarized by the Charlson comorbidity index (CCI) were based on claims data coded according to the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM). Severity of COPD was classified by hospital diagnosis or exemption from medical charges due to respiratory failure or previous hospitalizations for COPD. The impact of comorbidities on survival was assessed by Cox regression.Results: Less than 40% of patients were still alive at the end of a median follow-up of 37 months (17 months for patients who died and 56 months for those alive at the end of follow-up). After adjustment for age, gender, and severity score of COPD, CKD (hazard ratio =1.36, 95% confidence interval 1.30–1.42) independently from comorbidities summarized by the CCI was a significant risk factor for mortality.Conclusion: In spite of limitations due to the use of claims data, long-term survival of COPD patients was heavily affected by the presence of CKD and other comorbidities. Keywords: COPD, chronic kidney disease, Charlson comorbidity index, mortality, comorbidity

Automated in-vehicle systems and related human-machine interfaces can contribute to alleviating the workload of drivers. However, each new functionality can also introduce a new source of workload, due to the need to attend to new tasks and thus requires careful testing before being implemented in vehicles. Driving simulators have become a viable alternative to on-the-road tests, since they allow optimal experimental control and high safety. However, for each driving simulator to be a useful research tool, for each specific task an adequate correspondence must be established between the behavior in the simulator and the behavior on the road, namely, the simulator absolute and relative validity. In this study we investigated the validity of a driving-simulator-based experimental environment for research on mental workload measures by comparing behavioral and subjective measures of workload of the same large group of participants in a simulated and on-road driving task on the same route. Consistent with previous studies, mixed support was found for both types of validity, although results suggest that allowing more and/or longer familiarization sessions with the simulator may be needed to increase its validity. Simulator sickness also emerged as a critical issue for the generalizability of the results.

IntroductionPancreatic ductal adenocarcinoma (PDAC) represents the complexity of interaction between cancer and cells of the tumor microenvironment (TME). Immune cells affect tumor cell behavior, thus driving cancer progression. Cancer-associated fibroblasts (CAFs) are responsible of the desmoplastic and fibrotic reaction by regulating deposition and remodeling of extracellular matrix (ECM). As tumor-promoting cells abundant in PDAC ECM, CAFs represent promising targets for novel anticancer interventions. However, relevant clinical trials are hampered by the lack of specific markers and elusive differences among CAF subtypes. Indeed, while single-cell transcriptomic analyses have provided important information on the cellular constituents of PDACs and related molecular pathways, studies based on the identification of protein markers in tissues aimed at identifying CAF subtypes and new molecular targets result incomplete.MethodsHerein, we applied multiplexed Imaging Mass Cytometry (IMC) at single-cell resolution on 8 human PDAC tissues to depict the PDAC composing cells, and profiling immune cells, endothelial cells (ECs), as well as endocrine cells and tumor cells.ResultsWe focused on CAFs by characterizing up to 19 clusters distinguished by phenotype, spatiality, and interaction with immune and tumor cells. We report evidence that specific subtypes of CAFs (CAFs 10 and 11) predominantly are enriched at the tumor-stroma interface and closely associated with tumor cells. CAFs expressing different combinations of FAP, podoplanin and cadherin-11, were associated with a higher level of CA19-9. Moreover, we identified specific subsets of FAP+ and podoplanin+/cadherin-11+ CAFs enriched in patients with negative prognosis.DiscussionThe present study provides new general insights into the complexity of the PDAC microenvironment by defining phenotypic heterogeneities and spatial distributions of CAFs, thus suggesting different functions of their subtypes in the PDAC microenvironment.

Abstract Malignant bile duct obstruction is typically treated by biliary stenting, which however increases the risk of bacterial infections. Here, we analyzed the microbial content of the biliary stents from 56 patients finding widespread microbial colonization. Seventeen of 36 prevalent stent species are common oral microbiome members, associate with disease conditions when present in the gut, and include dozens of biofilm- and antimicrobial resistance-related genes. This work provides an overview of the microbial communities populating the stents.

IntroductionMetabolic reprogramming is a hallmark feature of pancreatic ductal adenocarcinoma (PDAC). A pancreatic juice (PJ) metabolic signature has been reported to be prognostic of oncological outcome for PDAC. Integration of PJ profiling with transcriptomic and spatial characterization of the tumor microenvironment would help in identifying PDACs with peculiar vulnerabilities.MethodsWe performed a transcriptomic analysis of 26 PDAC samples grouped into 3 metabolic clusters (M_CL) according to their PJ metabolic profile. We analyzed molecular subtypes and transcriptional differences. Validation was performed by multidimensional imaging on tumor slides.ResultsPancreatic juice metabolic profiling was associated with PDAC transcriptomic molecular subtypes (p=0.004). Tumors identified as M_CL1 exhibited a non-squamous molecular phenotype and demonstrated longer survival. Enrichment analysis revealed the upregulation of immune genes and pathways in M_CL1 samples compared to M_CL2, the group with worse prognosis, a difference confirmed by immunofluorescence on tissue slides. Enrichment analysis of 39 immune signatures by xCell confirmed decreased immune signatures in M_CL2 compared to M_CL1 and allowed a stratification of patients associated with longer survival.DiscussionPJ metabolic fingerprints reflect PDAC molecular subtypes and the immune microenvironment, confirming PJ as a promising source of biomarkers for personalized therapy.

Abstract Mitochondrial and lysosomal activities are crucial to maintain cellular homeostasis: optimal coordination is achieved at their membrane contact sites where distinct protein machineries regulate organelle network dynamics, ions and metabolites exchange. Here we describe a genetically encoded SPLICS reporter for short- and long- juxtapositions between mitochondria and lysosomes. We report the existence of narrow and wide lysosome-mitochondria contacts differently modulated by mitophagy, autophagy and genetic manipulation of tethering factors. The overexpression of α-synuclein (α-syn) reduces the apposition of mitochondria/lysosomes membranes and affects their privileged Ca2+ transfer, impinging on TFEB nuclear translocation. We observe enhanced TFEB nuclear translocation in α-syn-overexpressing cells. We propose that α-syn, by interfering with mitochondria/lysosomes tethering impacts on local Ca2+ regulated pathways, among which TFEB mediated signaling, and in turn mitochondrial and lysosomal function. Defects in mitochondria and lysosome represent a common hallmark of neurodegenerative diseases: targeting their communication could open therapeutic avenues.

Introduction: Infections caused by multidrug-resistant bacteria (MDR) occur more frequently after pancreaticoduodenectomy (PD) compared to other abdominal surgeries, and infective complications represent a major determinant of postoperative morbidity following PD. Preoperative biliary stent (PBS) placement often leads to biliary contamination, which plays a significant role in postoperative infections. The aim of this study is to evaluate the impact of MDR contamination on short-term postoperative outcomes in patients undergoing PD and to evaluate the relationship between MDR bacteria, PBS, and bile contamination. Methods: This is a retrospective study based on a prospectively maintained database including 825 consecutive patients who underwent pancreaticoduodenectomies (PDs). All procedures were performed by experienced pancreatic surgeons at a high-volume center and the patients were managed according to the same perioperative enhanced recovery protocol. Results: MDR bacteria were present in 17.5% of bile cultures, exclusively within the stented group. At the multivariate analysis, the development of major postoperative complications (MPC) was correlated with the presence of MDR bacteria in the bile (OR 1.66, 95% CI: 1.1–2.52; p = 0.02). MDR bacteria were detected early in the surgical drainage in 144 out of 825 patients (12.1%), with 72.2% having a previous biliary stent placement and 27.8% without stents (p < 0.001). Moreover, the development of an MPC was associated with the presence of MDR bacteria in the drainage (OR = 1.81, 95% CI: 1.21–2.73, p = 0.0042). Conclusions: We demonstrated that MDR contamination worsens the short-term outcomes of patients undergoing PDs. Specifically, when MDR bacteria are present in both the bile and drainage, there is a statistically significant increase in the incidence of major postoperative complications (MPC). Our data suggest that the majority of MDR surgical site infections stem from biliary contamination resulting from the placement of a preoperative biliary stent (PBS).

Abstract Tuberous Sclerosis Complex (TSC) is caused by TSC1 or TSC2 mutations, leading to hyperactivation of mechanistic target of rapamycin complex 1 (mTORC1) and lesions in multiple organs including lung (lymphangioleiomyomatosis) and kidney (angiomyolipoma and renal cell carcinoma). Previously, we found that TFEB is constitutively active in TSC. Here, we generated two mouse models of TSC in which kidney pathology is the primary phenotype. Knockout of TFEB rescues kidney pathology and overall survival, indicating that TFEB is the primary driver of renal disease in TSC. Importantly, increased mTORC1 activity in the TSC2 knockout kidneys is normalized by TFEB knockout. In TSC2-deficient cells, Rheb knockdown or Rapamycin treatment paradoxically increases TFEB phosphorylation at the mTORC1-sites and relocalizes TFEB from nucleus to cytoplasm. In mice, Rapamycin treatment normalizes lysosomal gene expression, similar to TFEB knockout, suggesting that Rapamycin’s benefit in TSC is TFEB-dependent. These results change the view of the mechanisms of mTORC1 hyperactivation in TSC and may lead to therapeutic avenues.

Increasing motorization represents a severe problem worldwide, also affecting the emission levels of the road network. Accordingly, congestion management has obtained growing importance because of its strong economic, social, and environmental implications. Macroscopic Fundamental Diagram (MFD) based traffic control is a popular and efficient approach in this scientific field. In our research work the urban network has been divided into homogeneous regions, each of them characterized by its own MFD, and they are regulated using a network-level control scheme. The proposed Multiobjective Model Predictive Control (M-MPC) takes into account the congestion and $CO_{2}$ emission levels of the urban network, modelled by the emerging Emission Macroscopic Fundamental Diagram (e-MFD). The applied strategy has been demonstrated in a realistic traffic scenario (Luxembourg City) using validated microscopic traffic simulation. According to the introduced multiobjective approach, the control method can better exploit the road network capacity while efficiently reducing traffic-induced emissions.

Several interdisciplinary studies have investigated the impact of Connected and Autonomous Vehicles (CAVs) on the performance of traffic networks, which expect positive effects. Nevertheless, there will be a transitional period during which both Human-Driven Vehicles (HDVs) and CAVs shall operate simultaneously. Adequate modeling of the interactions between CAVs and HDVs is vital to understand the mixed traffic dynamics. We propose a second-order macroscopic model by reconstructing the backward propagation speed of perturbation based on the dynamic headway distance between vehicles in mixed traffic. The proposed model is validated using microscopic simulations, and it replicates the given traffic scenarios subjected to assorted Penetration Rate (PR) of CAVs. The proposed model is employed to investigate the dynamics of mixed traffic. The results demonstrate that the average traffic velocity and the Level of Service (LOS) significantly improve with the increase in the PR of CAVs. Additionally, the performance of the proposed model is compared with the well-known Jiang-Qing-Zhu (JQZ) model, and it outperforms the JQZ model. The proposed model can be employed in traffic forecasting and real-time traffic control.

There are different cancers in the peri-ampullary region, including pancreatic ductal adenocarcinoma (PDAC), duodenum cancers (DCs), and ampullary adenocarcinoma (AAC). Here, significant morphological–molecular characterizations should be necessary for the distinction of primary tumours and classifications of their subtypes of cancers. The sub classification of AACs might include up to five different variants, according to different points of view, concerning the prevalence of the two more-cellular components found in the ampulla. In particular, regarding the AACs, the most important subtypes are represented by the intestinal (INT) and the pancreato-biliary (PB) ones. The subtyping of AACs is essential for diagnosis, and their identifications have been impacting clinical management responses to treatments and overall survival (os) after surgery. Pb is associated with a worse clinical outcome. Otherwise, the criteria, through which are possible to attribute its subtype classification, are not well established. A triage of immune markers represented by CK7, CK20, and CDX-2 seem to represent the best compromise in order to split the cohort of AAC patients in the INT and PB groups. The test of choice for the sub-classification of AACs is represented by the immuno-histochemical approach, in which its molecular classification acquires its diagnostic, predictive, and prognostic value for both the INT and PB patients.

Background. Survival after surgery for pancreatic ductal adenocarcinoma (PDAC) remains poor, due to early recurrence (ER) of the disease. A global definition of ER is lacking and different cut-off values (6, 8, and 12 months) have been adopted. The aims of this study were to define the optimal cut-off for the definition of ER and predictive factors for ER. Methods. Recurrence was recorded for all consecutive patients undergoing upfront surgery for PDAC at our institute between 2010 and 2017. Receiver operating characteristic (ROC) curves were utilized, to estimate the optimal cut-off for the definition of ER as a predictive factor for poor post-progression survival (PPS). To identify predictive factors of ER, univariable and multivariable logistic regression models were used. Results. Three hundred and fifty one cases were retrospectively evaluated. The recurrence rate was 76.9%. ER rates were 29.0%, 37.6%, and 47.6%, when adopting 6, 8, and 12 months as cut-offs, respectively. A significant difference in median PPS was only shown between ER and late recurrence using 12 months as cut-off (p = 0.005). In the multivariate analysis, a pre-operative value of CA 19-9 > 70.5 UI/L (OR 3.10 (1.41–6.81); p = 0.005) and the omission of adjuvant treatment (OR 0.18 (0.08–0.41); p < 0.001) were significant predictive factors of ER. Conclusions. A twelve-months cut-off should be adopted for the definition of ER. Almost 50% of upfront-resected patients presented ER, and it significantly affected the prognosis. A high preoperative value of CA 19-9 and the omission of adjuvant treatment were the only predictive factors for ER.

This paper handles the problem of controlling speed limits on freeways in a connected traffic environment to reduce traffic congestion and improve both the operational and environmental performance of the road network. In order to achieve this objective, we present a Variable Speed Limit (VSL) system that utilizes fuzzy logic, which adjusts the speed limits that connected vehicles must comply with by leveraging traffic data such as vehicle flow, occupancy, and speed obtained from loop detectors installed along the road. To evaluate the effectiveness of the proposed Fuzzy-based VSL system and its potential benefits compared to the conventional rule-based VSL system in terms of traffic congestion and environmental impact, we conducted a simulation analysis using the microscopic traffic simulator, VISSIM. Specifically, three simulation scenarios are taken into account: $i)$ no VSL, where the VSL system is not enabled; $ii)$ Rule-based VSL system, where a typical a decision tree-based system is considered; $iii)$ Fuzzy-based VSL system, where the herein proposed approach is appraised. The results demonstrate that the proposed approach enhances road efficiency by decreasing speed variation, increasing average speed and vehicle volume, and reducing fuel consumption.

TFEBexplorer is a comprehensive web-tool to study genes modulated by the transcription factor EB (TFEB), a master regulator of lysosomal biogenesis and autophagy, that integrates multiple datasets following genetic perturbation of TFEB with experimentally validated and bioinformatically-predicted binding sites across multiple species. Given one gene, or a set of genes of interest, in input (query), the results are displayed in different panels, each reporting results of experiments or bioinformatic analyses. TFEBdb is a unique resource for those interested in understanding the effect of TFEB on a set of genes of interest. The database offers an intuitive interface and results are displayed in an easy-to-interpret format offering information on the expression changes following inducible over-expression, knock-down and knock-out of TFEB across cell lines and species together with experimentally validated and bioinformatically predicted binding sites in the proximal promoter of the gene(s) of interest. The TFEBdb homepage can be found at http://tfeb.tigem.it. Abbreviations ChIP-seq: chromatin-immunoprecipitation followed by sequencing; CLEAR: Coordinated Lysosomal Expression and Regulation; DMEM: Dulbecco’s modified Eagle’s medium; FDR: False discovery rate; GEPs: gene expression profiles; PBS: phosphate-buffered saline; RMA: robust multiarray average TFEB: The transcription factor EB; TFEBdb: database; ToA: time of activation of the gene.

Gastrojejunostomy is the principal method of palliation for unresectable malignant gastric outlet obstructions (GOO). Gastrojejunostomy was traditionally performed as a surgical procedure with an open approach butrecently, notable progress in the development of minimally invasive procedures such as laparoscopic gastrojejunostomies have emerged. Additionally, advancements in endoscopic techniques, including endoscopic stenting (ES) and endoscopic ultrasound-guided gastroenterostomy (EUS-GE), are becoming more prominent. ES involves the placement of self-expandable metal stents (SEMS) to restore luminal patency. ES is commonly the first choice for patients deemed unfit for surgery or at high surgical risk. However, although ES leads to rapid improvement of symptoms, it carries limitations like higher stent dysfunction rates and the need for frequent re-interventions. Recently, EUS-GE has emerged as a potential alternative, combining the minimally invasive nature of the endoscopic approach with the long-lasting effects of a gastrojejunostomy. Having reviewed the advantages and disadvantages of these different techniques, this article aims to provide a comprehensive review regarding the management of unresectable malignant GOO.

Pancreatic surgery is extremely challenging and demands an extended learning curve to be executed with a low incidence of post-operative complications. The soft consistency of the human pancreas poses a primary challenge for pancreatic surgeons. This study aimed to analyze the preliminary mechanical characteristics of the human pancreas to develop a realistic synthetic phantom for surgical simulations in the near future. Pancreatic specimens, comprehensive of the pancreatic parenchyma and main pancreatic duct, were collected during pancreatic resections and analyzed through nano-bio-indentation (BioindenterTM UNHT3 Bio, Anton Paar GmbH, Graz, Austria) to measure the elastic modulus. Comparisons were made between slow and fast loading rates, immediate and post-freezing analyses, and multipoint indentations. The results demonstrated that a slow loading rate (30 μN/min), immediate analysis, and multipoint measurements are crucial for obtaining accurate values of the elastic modulus of the human pancreas (1.40 ± 0.47 kPa). In particular, the study revealed that analysis after freezing could impact the outcomes of the indentation. Moreover, the study suggested that both the pancreatic parenchyma and the main pancreatic duct should be analyzed to achieve a more precise and comprehensive definition of the. mechanical features of the pancreas. These preliminary findings represent the initial steps toward defining the consistency and mechanical characteristics of human pancreatic tissue with the goal of creating a realistic synthetic phantom.

Background and aimsBody composition parameters and immunonutritional indexes provide useful information on the nutritional and inflammatory status of patients. We sought to investigate whether they predict the postoperative outcome in patients with pancreatic cancer (PC) who received neoadjuvant therapy (NAT) and then pancreaticoduodenectomy.MethodsData from locally advanced PC patients who underwent NAT followed by pancreaticoduodenectomy between January 2012 and December 2019 in four high-volume institutions were collected retrospectively. Only patients with two available CT scans (before and after NAT) and immunonutritional indexes (before surgery) available were included. Body composition was assessed and immunonutritional indexes collected were: VAT, SAT, SMI, SMA, PLR, NLR, LMR, and PNI. The postoperative outcomes evaluated were overall morbidity (any complication occurring), major complications (Clavien-Dindo ≥ 3), and length of stay.ResultsOne hundred twenty-one patients met the inclusion criteria and constituted the study population. The median age at the diagnosis was 64 years (IQR16), and the median BMI was 24 kg/m2 (IQR 4.1). The median time between the two CT-scan examined was 188 days (IQR 48). Skeletal muscle index (SMI) decreased after NAT, with a median delta of −7.8 cm2/m2 (p < 0.05). Major complications occurred more frequently in patients with a lower pre-NAT SMI (p = 0.035) and in those who gained in subcutaneous adipose tissue (SAT) compartment during NAT (p = 0.043). Patients with a gain in SMI experienced fewer major postoperative complications (p = 0.002). The presence of Low muscle mass after NAT was associated with a longer hospital stay [Beta 5.1, 95%CI (1.5, 8.7), p = 0.006]. An increase in SMI from 35 to 40 cm2/m2 was a protective factor with respect to overall postoperative complications [OR 0.43, 95% (CI 0.21, 0.86), p < 0.001]. None of the immunonutritional indexes investigated predicted the postoperative outcome.ConclusionBody composition changes during NAT are associated with surgical outcome in PC patients who receive pancreaticoduodenectomy after NAT. An increase in SMI during NAT should be favored to ameliorate the postoperative outcome. Immunonutritional indexes did not show to be capable of predicting the surgical outcome.

Abstract Batten diseases (BDs) are a group of lysosomal storage disorders characterized by seizure, visual loss, and cognitive and motor deterioration. We discovered increased levels of globotriaosylceramide (Gb3) in cellular and murine models of CLN3 and CLN7 diseases and used fluorescent‐conjugated bacterial toxins to label Gb3 to develop a cell‐based high content imaging (HCI) screening assay for the repurposing of FDA‐approved compounds able to reduce this accumulation within BD cells. We found that tamoxifen reduced the lysosomal accumulation of Gb3 in CLN3 and CLN7 cell models, including neuronal progenitor cells (NPCs) from CLN7 patient‐derived induced pluripotent stem cells (iPSC). Here, tamoxifen exerts its action through a mechanism that involves activation of the transcription factor EB (TFEB), a master gene of lysosomal function and autophagy. In vivo administration of tamoxifen to the CLN7Δex2 mouse model reduced the accumulation of Gb3 and SCMAS, decreased neuroinflammation, and improved motor coordination. These data strongly suggest that tamoxifen may be a suitable drug to treat some types of Batten disease.

Abstract Background Serous cysto-adenoma (SCA) is a rare benign neoplasm of the pancreas. SCA can mimic other pancreatic lesions, such as neuroendocrine tumours. 68Gallium-DOTA-peptide Positron Emission Tomography (PET) is able to image in vivo the over-expression of the somatostatin receptors, playing an important role for the identification of neuroendocrine neoplasms. Case presentation We reported a case of 63-year-old man, with a solid lesion of 7 cm of diameter of the body–tail of the pancreas. Two fine-needle-aspirations (FNA) were inconclusive. A 68Ga-DOTA-peptide PET-CT revealed a pathological uptake of the pancreatic lesion. The diagnosis of a pancreatic neuroendocrine neoplasm was established and a laparoscopic distal splenopancreatectomy and cholecystectomy was performed. Final histopathological report revealed the presence of a micro-cystic SCA. Conclusions The current case firstly reports a pancreatic SCA showing increased radiopharmaceutical uptake at 68Ga-DOTA-peptide PET-CT images. This unexpected finding should be taken into account during the diagnostic algorithm of a pancreatic lesion, in order to minimize the risk of misdiagnosis and overtreatment of SCA.

BackgroundThe fourth type of multiple endocrine neoplasia (MEN) is known as a rare variant of MEN presenting a MEN1-like phenotype and originating from a germline mutation in CDKN1B. However, due to the small number of cases documented in the literature, the peculiar clinical features of MEN4 are still largely unknown, and clear indications about the clinical management of these patients are currently lacking. In order to widen our knowledge on MEN4 and to better typify the clinical features of this syndrome, we present two more cases of subjects with MEN4, and through a review of the current literature, we provide some possible indications on these patients’ management.Case PresentationThe first report is about a man who was diagnosed with a metastatic ileal G2-NET at the age of 34. Genetic analysis revealed the mutation p.I119T (c.356T>C) of exon 1 of CDKN1B, a mutation already reported in the literature in association with early-onset pituitary adenomas. The second report is about a 76-year-old woman with a multifocal pancreatic G1-NET. Genetic analysis identified the CDKN1B mutation c.482C>G (p.S161C), described here for the first time in association with MEN4 and currently classified as a variant of uncertain significance. Both patients underwent biochemical and imaging screening for MEN1-related diseases without any pathological findings.ConclusionsAccording to the cases reported in the literature, hyperparathyroidism is the most common clinical feature of MEN4, followed by pituitary adenoma and neuroendocrine tumors. However, MEN4 appears to be a variant of MEN with milder clinical features and later onset. Therefore, these patients might need a different and personalized approach in clinical management and a peculiar screening and follow-up strategy.

The choice of the most appropriate suture threads for pancreatic anastomoses may play an important role in reducing the incidence of post-operative pancreatic fistula (POPF). The literature on this topic is still not conclusive. The aim of this study was to analyze the mechanical characteristics of suture materials to find the best suture threads for pancreatic anastomoses. A single-axial electromagnetic actuation machine was used to obtain the stress–deformation relationship curves and to measure both the ultimate tensile strength (UTS) and the Young’s modulus at the 0–3% deformation range (E0–3) of four different suture materials (Poliglecaprone 25, Polydioxanone, Polyglactin 910, and Polypropylene) at baseline and after incubation in saline solution, bile, and pancreatic juice for 1, 3, and 7 days. Polydioxanone and Polypropylene showed stable values of UTS and E0–3 in all conditions. Polyglactin 910 presented significant UTS and E0–3 variations between different time intervals in all types of liquids analyzed. Poliglecaprone 25 lost half of its strength in all biological liquids analyzed but maintained low E0–3 values, which could reduce the risk of lacerations of soft tissues. These results suggest that Polydioxanone and Poliglecaprone 25 could be the best suture materials to use for pancreatic anastomoses. In vivo experiments will be organized to obtain further confirmations of this in vitro evidence.

Summary: The transcription factor EB (TFEB) has emerged as a master regulator of lysosomal biogenesis, exocytosis, and autophagy, promoting the clearance of substrates stored in cells. c-Abl is a tyrosine kinase that participates in cellular signaling in physiological and pathophysiological conditions. In this study, we explored the connection between c-Abl and TFEB. Here, we show that under pharmacological and genetic c-Abl inhibition, TFEB translocates into the nucleus promoting the expression of its target genes independently of its well-known regulator, mammalian target of rapamycin complex 1. Active c-Abl induces TFEB phosphorylation on tyrosine and the inhibition of this kinase promotes lysosomal biogenesis, autophagy, and exocytosis. c-Abl inhibition in Niemann-Pick type C (NPC) models, a neurodegenerative disease characterized by cholesterol accumulation in lysosomes, promotes a cholesterol-lowering effect in a TFEB-dependent manner. Thus, c-Abl is a TFEB regulator that mediates its tyrosine phosphorylation, and the inhibition of c-Abl activates TFEB promoting cholesterol clearance in NPC models.

In this paper, we present a robotic painting system whereby a team of mobile robots equipped with different color paints create pictorial compositions by leaving trails of color as they move throughout a canvas. We envision this system to be used by an external user who can control the concentration of different colors over the painting by specifying density maps associated with the desired colors over the painting domain, which may vary over time. The robots distribute themselves according to such color densities by means of a heterogeneous distributed coverage control paradigm, whereby only those robots equipped with the appropriate paint will track the corresponding color density function. The painting composition therefore arises as the integration of the motion trajectories of the robots, which lay paint as they move throughout the canvas tracking the color density functions. The proposed interactive painting system is evaluated on a team of mobile robots. Different experimental setups in terms of paint capabilities given to the robots highlight the effects and benefits of considering heterogeneous teams when the painting resources are limited.

On amino acid deprivation TFEB translocates from the cytoplasm to the nucleus. Here the authors identify a nuclear export signal in TFEB that is recognized by the exportin CRM1, and show that dual phosphorylation at S142 and S138 by mTOR accelerates export of TFEB.

IntroductionItaly became the second epicenter of the novel coronavirus disease 2019 (COVID-19) pandemic after China, surpassing by far China's death toll. The disease swept through Lombardy, which remained in lockdown for about two months, starting from the 8th of March. As of that day, the isolation measures taken in Lombardy were extended to the entire country. Here, assuming that effectively there was one case "zero" that introduced the virus to the region, we provide estimates for: (a) the day-zero of the outbreak in Lombardy, Italy; (b) the actual number of asymptomatic infected cases in the total population until March 8; (c) the basic (R0)and the effective reproduction number (Re) based on the estimation of the actual number of infected cases. To demonstrate the efficiency of the model and approach, we also provide a tentative forecast two months ahead of time, i.e. until May 4, the date on which relaxation of the measures commenced, on the basis of the COVID-19 Community Mobility Reports released by Google on March 29.MethodsTo deal with the uncertainty in the number of the actual asymptomatic infected cases in the total population Volpert et al. (2020), we address a modified compartmental Susceptible/ Exposed/ Infectious Asymptomatic/ Infected Symptomatic/ Recovered/ Dead (SEIIRD) model with two compartments of infectious persons: one modelling the cases in the population that are asymptomatic or experience very mild symptoms and another modelling the infected cases with mild to severe symptoms. The parameters of the model corresponding to the recovery period, the time from the onset of symptoms to death and the time from exposure to the time that an individual starts to be infectious, have been set as reported from clinical studies on COVID-19. For the estimation of the day-zero of the outbreak in Lombardy, as well as of the "effective" per-day transmission rate for which no clinical data are available, we have used the proposed SEIIRD simulator to fit the numbers of new daily cases from February 21 to the 8th of March. This was accomplished by solving a mixed-integer optimization problem. Based on the computed parameters, we also provide an estimation of the basic reproduction number R0 and the evolution of the effective reproduction number Re. To examine the efficiency of the model and approach, we ran the simulator to "forecast" the epidemic two months ahead of time, i.e. from March 8 to May 4. For this purpose, we considered the reduction in mobility in Lombardy as released on March 29 by Google COVID-19 Community Mobility Reports, and the effects of social distancing and of the very strict measures taken by the government on March 20 and March 21, 2020.ResultsBased on the proposed methodological procedure, we estimated that the expected day-zero was January 14 (min-max rage: January 5 to January 23, interquartile range: January 11 to January 18). The actual cumulative number of asymptomatic infected cases in the total population in Lombardy on March 8 was of the order of 15 times the confirmed cumulative number of infected cases, while the expected value of the basic reproduction number R0 was found to be 4.53 (min-max range: 4.40- 4.65). On May 4, the date on which relaxation of the measures commenced the effective reproduction number was found to be 0.987 (interquartiles: 0.857, 1.133). The model approximated adequately two months ahead of time the evolution of reported cases of infected until May 4, the day on which the phase I of the relaxation of measures was implemented over all of Italy. Furthermore the model predicted that until May 4, around 20% of the population in Lombardy has recovered (interquartile range: ∼10% to ∼30%).

Abstract Background One of the most important steps taken by Beyond Batten Disease Foundation in our quest to cure juvenile Batten (CLN3) disease is to understand the State of the Science. We believe that a strong understanding of where we are in our experimental understanding of the CLN3 gene, its regulation, gene product, protein structure, tissue distribution, biomarker use, and pathological responses to its deficiency, lays the groundwork for determining therapeutic action plans. Objectives To present an unbiased comprehensive reference tool of the experimental understanding of the CLN3 gene and gene product of the same name. Methods BBDF compiled all of the available CLN3 gene and protein data from biological databases, repositories of federally and privately funded projects, patent and trademark offices, science and technology journals, industrial drug and pipeline reports as well as clinical trial reports and with painstaking precision, validated the information together with experts in Batten disease, lysosomal storage disease, lysosome/endosome biology. Results The finished product is an indexed review of the CLN3 gene and protein which is not limited in page size or number of references, references all available primary experiments, and does not draw conclusions for the reader. Conclusions Revisiting the experimental history of a target gene and its product ensures that inaccuracies and contradictions come to light, long‐held beliefs and assumptions continue to be challenged, and information that was previously deemed inconsequential gets a second look. Compiling the information into one manuscript with all appropriate primary references provides quick clues to which studies have been completed under which conditions and what information has been reported. This compendium does not seek to replace original articles or subtopic reviews but provides an historical roadmap to completed works.

The new standards on energy saving for new and existing buildings have animated both researchers and technicians in recent years, aiming at reducing the dependence on fossil fuels, improving indoor comfort, and systems efficiency. In this scenario, special attention must be paid to historical buildings that need to preserve their key testimonial heritage within the society. This paper describes the design and realization stages of a pilot system based on a ground-coupled heat pump, operating both in heating and cooling modes, installed in the monumental site of Saints Marcellino and Festo (SM&F), in Naples, Southern Italy. This study aims to demonstrate that low-enthalpy geothermal systems can be employed as energy retrofit applications in buildings of historical, artistic, and cultural interest and, at the same time, to prove that the use of this technology allows achieving the objectives, set at global level by the current regulations, and requiring a reduction of carbon dioxide emissions (tCO2) of 53% compared to technology using fossil fuels.

An artificial ground freezing (AGF) technique in the horizontal direction has been employed in Naples (Italy), in order to ensure the stability and waterproofing of soil during the excavation of two tunnels in a real underground station. The artificial freezing technique consists of letting a coolant fluid, with a temperature lower than the surrounding ground, circulate inside probes positioned along the perimeter of the gallery. In this paper, the authors propose an efficient numerical model to analyze heat transfer during the whole excavation process for which this AGF technique was used. The model takes into account the water phase change process, and has been employed to analyze phenomena occurring in three cross sections of the galleries. The aim of the work is to analyze the thermal behavior of the ground during the freezing phases, to optimize the freezing process, and to evaluate the thickness of frozen wall obtained. The steps to realize the entire excavation of the tunnels, and the evolution of the frozen wall during the working phases, have been considered. In particular, the present model has allowed us to calculate the thickness of the frozen wall equal to 2.1 m after fourteen days of nitrogen feeding.