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Purpose To compare the effect of trehalose 3%/hyaluronic acid 0.15% vs hyaluronic acid 0.15% eyedrops in reducing ocular surface inflammation after cataract surgery. Setting Perugia, Italy. Design Randomized, prospective study. Methods Patients with healthy ocular surface were enrolled. Tear break-up time (TBUT), Schirmer test, corneal fluorescein staining (CFS), ocular surface disease index (OSDI) and in vivo confocal microscopy (IVCM) were performed preoperatively and at 1 months, 4 months, and 8 months postoperatively. Patients were randomly assigned to receive trehalose 3%/hyaluronic acid 0.15% eyedrops (Group A), hyaluronic acid 0.15% eyedrops (Group B), or no treatment (Group C). Results 98 patients were randomized as follows: 33 in Group A, 33 in Group B, and 32 in Group C. Schirmer test increased at 1-month follow-up in Group A and unchanged in Groups B and C. TBUT and CFS increased at 1-month follow-up in Group A and after 8 months in Groups B and C. OSDI score decreased at 1-month follow-up in Group A and at in Groups B and C. IVCM showed a reduction in the number of nerve fibers of the subbasal nerve plexus at 1 month in all groups and progressively increased to preoperative levels at 4 months in Group A, and at 8 months in Groups B and C. Tortuosity and reflectivity of subbasal plexus progressively decreased to became significant at 4-month follow-up in Group A whereas increased at 1-month follow-up and become normal at 8-month follow-up in Groups B and C. Langerhans cells and activated stromal keratocytes were higher in Groups B and C throughout the follow-up with a significantly lower density of hyperreflective stromal cells in Group A. Conclusions Trehalose 3%/hyaluronic acid 0.15% eyedrops were effective in reducing inflammation and dry-eye symptoms.

PURPOSE The aim of this study was to qualitatively and quantitatively assess the effect of osteotomy preparation by conventional, subtractive, or osseodensification instrumentation on osteotomies, treated with or without endosteal implants, and healing capacity. MATERIALS AND METHODS Seven sheep were used, and 56 osteotomies were made in the left and right ilium of the sheep (n = 8/sheep [4 per side/time point (3 and 6 weeks)]). Two different instrumentation techniques were used: (1) conventional/regular drilling in a three-step series of a 2-mm pilot and 3.2-mm and 3.8-mm twist drills and (2) osseodensification drilling with a Densah Bur 2.0-mm pilot and 2.8-mm and 3.8-mm multi-fluted tapered burs. Drilling was performed at 1,100 rpm with saline irrigation. RESULTS Qualitative histomorphometric evaluation of the osteotomies after 3 and 6 weeks did not indicate any healing impairment due to the instrumentation. In all samples, histologic examination suggested bone remodeling and growth (empty and treated with an implant), irrespective of preparation technique. Osteotomies prepared using the osseodensification instrumentation showed the existence of bone chips autografted into the trabecular spaces along the length of the osteotomy wall. CONCLUSION The osseodensification group yielded higher osseointegration rates, as distinguished through qualitative assessment, bone-to-implant contact, and bone-area-fraction occupancy, indicating an increased osteogenic potential in osteotomies prepared using the osseodensification technique.

Purpose of review The present review aims at describing recent advances in therapeutic strategies for the treatment of benign esophageal strictures in children. We discuss current knowledge and practice on esophageal dilations, which are still the mainstream of treatment. We present new evidence about adjuvant treatments for recurrent and refractory strictures, including endoscopic incisional therapy, esophageal stenting, intralesional or topical mytomicin C and intralesional, systemic or topical steroids. Recent findings Current evidence on esophageal dilations is not sufficient to establish superiority of one of the available techniques, especially the use of balloon or bougie dilators, but a prospective international cohort study on anastomotic stricture in esophageal atresia is underway to address this issue. Recurrent and refractory strictures still represent a challenge, since none of the adjuvant pharmacological and mechanical interventions has shown to be enough feasible, effective and safe to revolutionize clinical practice. Summary In the last couple of years, several encouraging results have been published on management of esophageal strictures in children. Further research is needed, hopefully directed toward secure, easily reproducible and minimally invasive measures.

First published online: 28 January 2020 Recent years have been tainted by market practices that continuously expose us, as consumers, to new risks and threats. We have become accustomed, and sometimes even resigned, to businesses monitoring our activities, examining our data, and even meddling with our choices. Artificial Intelligence (AI) is often depicted as a weapon in the hands of businesses and blamed for allowing this to happen. In this paper, we envision a paradigm shift, where AI technologies are brought to the side of consumers and their organizations, with the aim of building an efficient and effective counter-power. AI-powered tools can support a massive-scale automated analysis of textual and audiovisual data, as well as code, for the benefit of consumers and their organizations. This in turn can lead to a better oversight of business activities, help consumers exercise their rights, and enable the civil society to mitigate information overload. We discuss the societal, political, and technological challenges that stand before that vision.

Purpose Prospective, randomised, open-label, comparative study to evaluate efficacy of trehalose/sodium hyaluronate eye drops for post-operative discomfort and tear film stability in patients undergoing cataract surgery. Methods Patients with healthy ocular surface, subclinical, or mild dry eye were enrolled. Tear breakup time (TBUT), Schirmer test, dry eye symptoms, corneal fluorescein staining (CFS), and ocular surface disease (OSDI) evaluation were performed pre-operatively and at two and four weeks after surgery. Patients were assigned to receive trehalose/sodium hyaluronate eye drops b.i.d (Group A), or 0.9% unpreserved sodium chloride eye drops b.i.d for 4 weeks (Group B). Results One hundred and thirty-five patients were randomised, 66 patients in Group A (73.2 ± 4.5 years) and 69 patients in Group B (74.3 ± 3.8 years), 60.8% females. Fifteen patients (8 Group A) were lost at follow-up. Pre-operatively, no between-group differences were observed, and TBUT increased in Group A between the pre-operative and 2 and 4 week evaluations and was higher in group A than in Group B at 4 weeks. Schirmer test and CFS showed an improvement only in Group A four weeks post-operatively. In Group A an improvement was observed after two and four weeks in foreign body and puncture sensation, whilst a difference in blinking discomfort was observed after four weeks. In Group B we observed an improvement in puncture sensation two and four weeks after surgery. Mean OSDI scores differences between the two groups were significant at four weeks. Conclusions Trehalose/sodium hyaluronate eye drops were effective in reducing signs and symptoms of dry eye and improving tear film stability

Background Data on ERAS for gastrectomy are scarce, and the majority of the studies come from Eastern countries. Patients in the West are older and suffer from more advanced tumors that impair their clinical condition and often require neoadjuvant treatment. This retrospective study assessed the feasibility and safety of an Enhanced Recovery After Surgery (ERAS) protocol for gastrectomy in a Western center. Methods We conducted a single-center study of 351 patients operated for gastric cancer: 103, operated from January 2015 to December 2016, followed the standard pathway, while 248, operated from January 2017 to December 2019, followed the ERAS program. The primary outcomes considered were length of hospital stay (LOS) and direct costs. Secondary outcomes were 90-day morbidity and mortality, readmission rate, and compliance with ERAS items. A propensity score (PS) was built on confounding variables. Results Compliance with ERAS items after the program was ≥ 70%. Univariable analysis evidenced a 2-day median reduction in LOS and a median cost reduction of €826 per patient in the ERAS group. PS-based multivariable analysis confirmed a significant, 2-day decrease in median LOS and a €1097 saving after ERAS introduction. Ninety-day mortality decreased slightly in ERAS group, while complications and readmissions did not change significantly. When complications were included in the multivariable analysis, ERAS retained its significance, although the effects on LOS and cost were blunted to a median reduction of 1 day and €775, respectively. Conclusions ERAS for gastrectomy improved patients’ recovery and reduced hospital costs without changes in morbidity, mortality, or readmission.

BACKGROUNDPatients with coronavirus disease 2019 (COVID-19) develop pneumonia generally associated with lymphopenia and a severe inflammatory response due to uncontrolled cytokine release. These mediators are transcriptionally regulated by the JAK/STAT signaling pathways, which can be disabled by small molecules.METHODSWe treated a group of patients (n = 20) with baricitinib according to an off-label use of the drug. The study was designed as an observational, longitudinal trial and approved by the local ethics committee. The patients were treated with 4 mg baricitinib twice daily for 2 days, followed by 4 mg per day for the remaining 7 days. Changes in the immune phenotype and expression of phosphorylated STAT3 (p-STAT3) in blood cells were evaluated and correlated with serum-derived cytokine levels and antibodies against severe acute respiratory syndrome-coronavirus 2 (anti-SARS-CoV-2). In a single treated patient, we also evaluated the alteration of myeloid cell functional activity.RESULTSWe provide evidence that patients treated with baricitinib had a marked reduction in serum levels of IL-6, IL-1β, and TNF-α, a rapid recovery of circulating T and B cell frequencies, and increased antibody production against the SARS-CoV-2 spike protein, all of which were clinically associated with a reduction in the need for oxygen therapy and a progressive increase in the P/F (PaO2, oxygen partial pressure/FiO2, fraction of inspired oxygen) ratio.CONCLUSIONThese data suggest that baricitinib prevented the progression to a severe, extreme form of the viral disease by modulating the patients' immune landscape and that these changes were associated with a safer, more favorable clinical outcome for patients with COVID-19 pneumonia.TRIAL REGISTRATIONClinicalTrials.gov NCT04438629.FUNDINGThis work was supported by the Fondazione Cariverona (ENACT Project) and the Fondazione TIM.

BACKGROUND/PURPOSE The utilization of three-dimensionally (3D)-printed bioceramic scaffolds composed of beta-tricalcium phosphate in conjunction with dipyridamole have shown to be effective in the osteogenesis of critical bone defects in both skeletally immature and mature animals. Furthermore, previous studies have proven the dura and pericranium's osteogenic capacity in the presence of 3D-printed scaffolds; however, the effect galea aponeurotica on osteogenesis in the presence of 3D scaffolds remains unclear. METHOD/DESCRIPTION Critical-sized (11 mm) bilateral calvarial defects were created in 35-day old rabbits (n = 7). Two different 3D scaffolds were created, with one side of the calvaria being treated with a solid nonporous cap and the other with a fully porous cap. The solid cap feature was designed with the intention of preventing communication of the galea and the ossification site, while the porous cap permitted such communication. The rabbits were euthanized 8 weeks postoperatively. Calvaria were analyzed using microcomputed tomography, 3D reconstruction, and nondecalcified histologic sectioning in order assess differences in bone growth between the two types of scaffolding. RESULTS Scaffolds with the solid (nonporous) cap yielded greater percent bone volume (P = 0.012) as well as a greater percent potential bone (P = 0.001) compared with the scaffolds with a porous cap. The scaffolds with porous caps also exhibited a greater percent volume of soft tissue (P

Purpose To evaluate the safety and efficacy of corneal collagen cross-linking (CXL) performed on overlaying a corneal lenticule to thin recipient corneas of progressive keratoconus (KC) patients. Methods In this study were enrolled eyes of patients affected by progressive KC with a minimum corneal thickness less than 400 µm, after overlaying a lenticule of human corneal stroma prepared with the femtosecond laser. The lenticules used were 100 µm thick and of 8.5 mm diameter in all the cases. Both the host cornea and the lenticules were subjected to epithelial debridement. CXL was carried out according to the standard protocol. Visual acuity, refraction, slit-lamp examination, endothelial cell density, pachymetry and keratometry, anterior segment tomography (AS-OCT) and confocal microscopy were evaluated preoperatively and at 1, 3, 6 and 12 months postoperatively. Results CXL was performed in 10 eyes of 8 patients (main age 23), corneal thickness range 379–414 µm, mean 387.6 µm. One patient was lost at follow-up. In all other cases, visual acuity and the endothelial cell density remained stable over a 12-month follow-up. Preoperative mean K1 and mean K2 were 46.91 ± 1.9 and 50.75 ± 2.93, respectively, and at 12 months mean K1 was 47.36 ± 2.66 and mean K2 50.53 ± 3.35. The AS-OCT clearly showed a demarcation line in all patients at 1, 3 (mean depth 283 µm and 267 µm, respectively) and in some cases at 6 months. Reduced keratocyte density and stromal oedema were observed immediately up to 1 month after treatment, while a slight subepithelial haze was present at 1-month and completely disappeared by 6 months. Conclusion This new technique seems to offer a therapeutic opportunity for young patients suffering from progressive KC with very thin corneas, in which the standard treatment is not indicate, and delay or avoid the need for a corneal transplant.

Literature has reported that up to 50% of dental implants may be affected by peri-implantitis, a bacteria-induced chronic inflammatory process, which promotes osteoclast-mediated bone resorption and inhibits bone formation, leading to progressive bone loss around implants. Current evidence points toward an increased risk for the development of peri-implantitis in both obesity/metabolic syndrome (MetS) and diabetes mellitus (DM) conditions relative to the healthy population. Currently, there is no effective treatment for peri-implantitis and the 50% prevalence in MetS and DM, along with its predicted increase in the worldwide population, presents a major concern in implant dentistry as hyperglycemic conditions are associated with bone-healing impairment; this may be through dysfunction of osteocalcin-induced glucose metabolism. The MetS/DM proinflammatory systemic condition and altered immune/microbiome response affect both catabolic and anabolic events of bone-healing that include increased osteoclastogenesis and compromised osteoblast activity, which could be explained by the dysfunction of insulin receptor that led to activation of signals related with osteoblast differentiation. Furthermore, chronic hyperglycemia along with associated micro- and macro-vascular ailments leads to delayed/impaired wound healing due to activation of pathways that are particularly important in initiating events linked to inflammation, oxidative stress, and cell apoptosis; this may be through deactivation of AKT/PKB protein, which possesses a pivotal role in drive survival and eNOS signaling. This review presents an overview of the local and systemic mechanisms synergistically affecting bone-healing impairment in MetS/DM individuals, as well as a rationale for hierarchical animal model selection, in an effort to characterize peri-implantitis disease and treatment.

Lumbar fusion is a procedure associated with several indications, but screw failure remains a major complication, with an incidence ranging 10% to 50%. Several solutions have been proposed, ranging from more efficient screw geometry to enhance bone quality, conversely, drilling instrumentation have not been thoroughly explored. The conventional instrumentation (regular [R]) techniques render the bony spicules excavated impractical, while additive techniques (osseodensification [OD]) compact them against the osteotomy walls and predispose them as nucleating surfaces/sites for new bone. This work presents a case-controlled split model for in vivo/ex vivo comparison of R vs OD osteotomy instrumentation in posterior lumbar fixation in an ovine model to determine feasibility and potential advantages of the OD drilling technique in terms of mechanical and histomorphology outcomes. Eight pedicle screws measuring 4.5 mm × 45 mm were installed in each lumbar spine of eight adult sheep (four per side). The left side underwent R instrumentation, while the right underwent OD drilling. The animals were killed at 6- and 12-week and the vertebrae removed. Pullout strength and non-decalcified histologic analysis were performed. Significant mechanical stability differences were observed between OD and R groups at 6- (387 N vs 292 N) and 12-week (312 N vs 212 N) time points. Morphometric analysis did not detect significant differences in bone area fraction occupancy between R and OD groups, while it is to note that OD showed increased presence of bone spiculae. Mechanical pullout testing demonstrated that OD drilling provided higher degrees of implant anchoring as a function of time, whereas a significant reduction was observed for the R group.

Background Three-dimensionally-printed bioceramic scaffolds composed of β-tricalcium phosphate delivering the osteogenic agent dipyridamole can heal critically sized calvarial defects in skeletally mature translational models. However, this construct has yet to be applied to growing craniofacial models. In this study, the authors implanted three-dimensionally-printed bioceramic/dipyridamole scaffolds in a growing calvaria animal model and evaluated bone growth as a function of geometric scaffold design and dipyridamole concentration. Potential adverse effects on the growing suture were also evaluated. Methods Bilateral calvarial defects (10 mm) were created in 5-week-old (approximately 1.1 kg) New Zealand White rabbits (n = 16 analyzed). Three-dimensionally-printed bioceramic scaffolds were constructed in quadrant form composed of varying pore dimensions (220, 330, and 500 μm). Each scaffold was coated with collagen and soaked in varying concentrations of dipyridamole (100, 1000, and 10,000 μM). Controls consisted of empty defects. Animals were killed 8 weeks postoperatively. Calvariae were analyzed using micro-computed tomography, three-dimensional reconstruction, and nondecalcified histologic sectioning. Results Scaffold-induced bone growth was statistically greater than bone growth in empty defects (p = 0.02). Large scaffold pores, 500 μm, coated in 1000 μM dipyridamole yielded the most bone growth and lowest degree of scaffold presence within the defect. Histology showed vascularized woven and lamellar bone along with initial formation of vascular canals within the scaffold lattice. Micro-computed tomographic and histologic analysis revealed patent calvarial sutures without evidence of ectopic bone formation across all dipyridamole concentrations. Conclusion The authors present an effective pediatric bone tissue-engineering scaffold design and dipyridamole concentration that is effective in augmentation of calvarial bone generation while preserving cranial suture patency.

What Is Known - Endoscopy Training is becoming an integral part of Paediatric Gastroenterology Training within Europe. - There is a great degree of variation between European endoscopy training in terms of duration, content, procedural volume, assessment during and at the end of training. What Is New? - Achievement of milestones in training more accurately assesses competency compared with procedural number. - Train the trainers’ courses and educational material,such as e-learning and endoscopy simulator training improve a structuredapproachinendoscopy teaching. - Cooperation with the National Paediatric Gastroenterology, Hepatology and Nutrition Societies in Europe will facilitate dissemination, discussion and implementation of results of this position paper.

This study investigates a comprehensive model of bone regeneration capacity of dypiridamole-loaded 3D-printed bioceramic (DIPY-3DPBC) scaffolds composed of 100% beta-tricalcium phosphate (β –TCP) in an immature rabbit model through the time of facial maturity. The efficacy of this construct was compared to autologous bone graft, the clinical standard of care in pediatric craniofacial reconstruction, with attention paid to volume of regenerated bone by 3D reconstruction, histologic and mechanical properties of regenerated bone, and long-term safety regarding potential craniofacial growth restriction. Additionally, long-term degradation of scaffold constructs was evaluated. At 24 weeks in vivo, DIPY-3DPBC scaffolds demonstrated volumetrically significant osteogenic regeneration of calvarial and alveolar defects comparable to autogenous bone graft with favorable biodegradation of the bioactive ceramic component in vivo. Characterization of regenerated bone reveals osteogenesis of organized, vascularized bone with histologic and mechanical characteristics comparable to native bone. Radiographic and histologic analyses were consistent with patent craniofacial sutures. Lastly, through application of 3D morphometric facial surface analysis, our results support that DIPY-3DPBC scaffolds do not cause premature closure of sutures and preserve normal craniofacial growth. Based on this novel evaluation model, this DIPY-3DPBC scaffold strategy is a promising candidate as a safe, efficacious pediatric bone tissue engineering strategy.

Background and aims Ionizing radiation exposure during endoscopic retrograde cholangiopancreatography (ERCP) is an important quality issue especially in children. We aim to identify factors associated with extended fluoroscopy time (FT) in children undergoing ERCP. Methods ERCP on children ≤18 years from 15 centers were entered prospectively into a REDCap database from 5/2014 until 5/2018. Data were retrospectively evaluated for outcome and quality measures. A univariate and step-wise linear regression analysis was performed to identify factors associated with increased FT. Results 1073 ERCPs performed in 816 unique patients met inclusion criteria. Median age was 12.2 years (IQR 9.3-15.8). 767 (71%) patients had native papillae. The median FT was 120 seconds (IQR 60-240). Factors associated with increased FT included procedures performed on patients with chronic pancreatitis, ERCPs with ASGE difficulty grade ≥3, ERCPs performed by Pediatric Gastroenterologist (GI) with Adult GI supervision, and ERCPs performed at non-free standing children's hospitals. Hispanic ethnicity was the only factor associated with lower FT. Conclusion Several factors were associated with prolonged FTs in pediatric ERCP that differed from adult studies. This underscores that adult quality indicators cannot always be translated to pediatric patients. This data can better identify children with higher risk for radiation exposure and improve quality outcomes during pediatric ERCP. An infographic is available for this article at:http://links.lww.com/MPG/C570.

With over one million new cases (n = 1,033,701) and 782,685 deaths in 2018, gastric cancer (GC) ranks fifth for incidence and third for mortality among cancers worldwide. Most cancers have sporadic origin (90%) while a small proportion (10%) show a family component or hereditary syndromes. GC arises, in most cases, from the interaction of genetic and environmental components and 89% of cases worldwide are caused by chronic infections with Helicobacter pylori. Screening strategies aimed at reducing the mortality of GC are standardized in Asian countries, but there are currently no well-defined screening programs in the West. Consequently, in those countries without national guidelines for screening programs, an adequate prevention strategy could be developed by stratifying the population for relevant risk factors and directing the most appropriate diagnostic tests to high-risk individuals. Here we propose a risk stratification model for GC development, analysing the main risk factors and suggesting a screening strategy that could be effective in Western countries. In conclusion, a strategy that combines adequate risk stratification with gastroscopy on pre-selected individuals and gastric pre-cancer surveillance could lead to an increase in early diagnosis and hopefully in patient survival and quality of life.

BACKGROUND β-Tricalcium phosphate (β-TCP) is one of the most common synthetic bone grafting materials utilized in craniofacial reconstruction; however, it is limited by a slow degradation rate. The aim of this study was to leverage 3-dimensional (3D) printing in an effort to accelerate the degradation kinetics of β-TCP. METHODS Twenty-two 1-month-old New Zealand white rabbits underwent creation of calvarial and alveolar defects, repaired with 3D-printed β-TCP scaffolds coated with 1000 μM of osteogenic agent dipyridamole. Rabbits were euthanized after 2, 6, and 18 months after surgical intervention. Bone regeneration, scaffold degradation, and bone mechanical properties were quantified. RESULTS Histological analysis confirmed the generation of vascularized and organized bone. Microcomputed tomography analysis from 2 to 18 months demonstrated decreased scaffold volume within calvarial (23.6% ± 2.5%, 5.1% ± 2.2%; P < 0.001) and alveolar (21.5% ± 2.2%, 0.2% ± 1.9%; P < 0.001) defects, with degradation rates of 54.6%/year and 90.5%/year, respectively. Scaffold-inducted bone generation within the defect was volumetrically similar to native bone in the calvarium (55.7% ± 6.9% vs 46.7% ± 6.8%; P = 0.064) and alveolus (31.4% ± 7.1% vs 33.8% ± 3.7%; P = 0.337). Mechanical properties between regenerated and native bone were similar. CONCLUSIONS Our study demonstrates an improved degradation profile and replacement of absorbed β-TCP with vascularized, organized bone through 3D printing and addition of an osteogenic agent. This novel additive manufacturing and tissue engineering protocol has implications to the future of craniofacial skeletal reconstruction as a safe and efficacious bone tissue engineering method.

Background Work‐related lower airway symptoms (WR‐LAS), rhinitis (WRR), and asthma (WRA) are very common among bakers, due to airborne exposure to wheat flour and multigrain. Limited data is available regarding fractional exhaled nitric oxide (FeNO) in bakers in relation to respiratory burden and occupational sensitization in a real‐life situation. Objective To analyze FeNO levels in relation to WRR, WR‐LAS, and WRA with regard to allergic sensitization to occupational allergen in bakers. Methods Cross‐sectional, observational study of 174 bakers employed in traditional small bakeries in the Verona District. Subjects did FeNO measurements, spirometry, methacholine challenge, and skin prick test to common inhalant aeroallergens and bakeries occupational allergens. Results FeNO levels were higher in subjects sensitized to occupational allergens compared with bakers not sensitized to occupational allergens (22.8 ppb (18.9, 27.6) vs. 12.0 ppb (9.9, 14.5), p

A randomized clinical trial showed that trastuzumab, added to traditional chemotherapy, significantly improved overall survival in human epidermal growth factor receptor 2 (HER2)-overexpressing metastatic gastric cancer patients. This population-based study aimed at evaluating both the clinical and economic impact of trastuzumab in a real-world setting. By using the healthcare utilization databases of Lombardy, Italy, a cohort of patients newly diagnosed with metastatic gastric cancer during the period 2011&ndash, 2016 was selected. Among these, patients initially treated with either trastuzumab-based chemotherapy or standard chemotherapy alone were followed up until death, migration in other regions or June 2018. Overall survival and average cumulative costs were estimated and compared between the two treatment arms. Among the 1198 metastatic gastric cancer patients who started therapy within six months after metastasis detection, 87 were initially treated with trastuzumab-based chemotherapy and 1111 with standard chemotherapy. Median overall survival and restricted mean survival were 10.2 and 7.4 months, and 14.9 and 11.4 months, respectively, in the two treatment arms. The adjusted hazard ratio of death was 0.73 (95% CI 0.57&ndash, 0.93). The average per capita cumulative healthcare costs were, respectively, EUR 39,337 and 26,504, corresponding to an incremental cost-effectiveness ratio of EUR 43,998 for each year of survival gained. Our study shows that adding trastuzumab to conventional chemotherapy is effective and cost-effective.

Deep learning is bringing remarkable contributions to the field of argumentation mining, but the existing approaches still need to fill the gap toward performing advanced reasoning tasks. In this position paper, we posit that neural-symbolic and statistical relational learning could play a crucial role in the integration of symbolic and sub-symbolic methods to achieve this goal.

We study annotation projection in text classification problems where source documents are published in multiple languages and may not be an exact translation of one another. In particular, we focus on the detection of unfair clauses in privacy policies and terms of service. We present the first English-German parallel asymmetric corpus for the task at hand. We study and compare several language-agnostic sentence-level projection methods. Our results indicate that a combination of word embeddings and dynamic time warping performs best.

As ML applications are becoming ever more pervasive, fully-trained systems are made increasingly available to a wide public, allowing end-users to submit queries with their own data, and to efficiently retrieve results. With increasingly sophisticated such services, a new challenge is how to scale up to evergrowing user bases. In this paper, we present a distributed architecture that could be exploited to parallelize a typical ML system pipeline. We propose a case study consisting of a text mining service and discuss how the method can be generalized to many similar applications. We demonstrate the significance of the computational gain boosted by the distributed architecture by way of an extensive experimental evaluation., This is the open access arXiv preprint also available at https://arxiv.org/abs/2005.14080. The article's final version appeared in Future Generation Computer Systems 105 (2020) 275-286, DOI: 10.1016/j.future.2019.11.042

Foreign body and caustic ingestions in children are usually the most common clinical challenges for emergency physicians, general pediatricians and pediatric gastroenterologists. Management of these conditions often requires different levels of expertise and competence. Endoscopy is often necessary but there is a high risk of misusing this tool with incorrect timing and indications. The imprecise clinical history frequently leaves clinicians uncertain about timing and nature of the ingestion. Few clinical guidelines regarding management of these ingestions in children have been published, none of which from the Italian Society of Pediatric Gastroenterology, Hepatology and Nutrition (SIGENP). An expert panel of Italian endoscopists was convened by the SIGENP Endoscopy Working Group to produce the present article that outlines practical clinical approaches to the pediatric patient with a variety of foreign body and caustic ingestions. The Italian Association of Hospital Gastroenterologists and Endoscopists (AIGO) has also endorsed the project since many adult endoscopists usually manage children with these conditions. Differently from the other published guidelines, the proposed one focuses on the role of the endoscopists (regardless of whether they are adult or pediatric gastroenterologists) in the diagnostic process of children with foreign body and caustic ingestions.

There is no shortage of opinions on the impact of artificial intelligence and deep learning. We invited authors of Comment and Perspective articles that we published in roughly the first half of 2019 to look back at the year and give their thoughts on how the issue they wrote about developed.

Head and neck liposarcomas are rare entities accounting for less than 5% of all liposarcomas. The primary orbital location is even rarer, with about 40 cases described in the English literature. According with the widely accepted classification of Enzinger and Weis there are 5 histologic variants of liposarcomas: well differentiated, myxoid, dedifferentiated, round cell and pleomorphic. The first two are considered low-grade and display a favourable prognosis (>90% 5-year DSS and OS), whereas the dedifferentiated, round cell, and pleomorphic are defined high-grade and burdened with poorer prognosis (5-year DSS ranging 45–73%). Dedifferentiated liposarcomas (DDL) of the head and neck region are exceedingly rare, therefore there are scattered and contrasting data regarding their clinical history, treatment modality, and prognosis. We presented a case of DDL arising in the the left orbit (fourth case of primary orbital DDL described), free from disease after 5-year follow-up. Clinical history, treatment, and characteristics of the presented case were described and discussed in the light of how reported in the literature, in the attempt to bring further insight in the nature and management of this rare pathological entity. Keywords: Dedifferentiated liposarcoma, Head and neck, Orbit

Oxytocin is widely used after child delivery for preventing postpartum haemorrhage. Rather high level of spinal block for for Caesarean section has a disadvantage of frequent arterial hypotension. The aim of our study was to assess maternal circulation after mini-dose (0.5 IU) oxytocin administered before, not after, delivery. Methods. Spinal anaesthesia (L3, hyperbaric 0.5% bupivacaine, 13.5 mg) for Caesarean section was performed in 80 women, randomly divided into study (n=40) and control (n=40) groups. In the study group, oxytocin (0.5 IU, slow intravenous bolus) was administered immediately after anaesthesia performance. In both groups, after delivery the slow oxytocin bolus was administered (4.5 IU in study and 5 IU in control group), then another 5 IU were infused in normal saline over 20-25 min. Results. During anaesthesia, minimal systolic arterial pressure (M±SD) in the study group (107±11 Torr) was significantly (p

BACKGROUND Autologous bone grafts remain a standard of care for the reconstruction of large bony defects, but limitations persist. The authors explored the bone regenerative capacity of customized, three-dimensionally printed bioactive ceramic scaffolds with dipyridamole, an adenosine A2A receptor indirect agonist known to enhance bone formation. METHODS Critical-size bony defects (10-mm height, 10-mm length, full-thickness) were created at the mandibular rami of rabbits (n = 15). Defects were replaced by a custom-to-defect, three-dimensionally printed bioactive ceramic scaffold composed of β-tricalcium phosphate. Scaffolds were uncoated (control), collagen-coated, or immersed in 100 μM dipyridamole. At 8 weeks, animals were euthanized and the rami retrieved. Bone growth was assessed exclusively within scaffold pores, and evaluated by micro-computed tomography/advanced reconstruction software. Micro-computed tomographic quantification was calculated. Nondecalcified histology was performed. A general linear mixed model was performed to compare group means and 95 percent confidence intervals. RESULTS Qualitative analysis did not show an inflammatory response. The control and collagen groups (12.3 ± 8.3 percent and 6.9 ± 8.3 percent bone occupancy of free space, respectively) had less bone growth, whereas the most bone growth was in the dipyridamole group (26.9 ± 10.7 percent); the difference was statistically significant (dipyridamole versus control, p < 0.03; dipyridamole versus collagen, p < 0.01 ). There was significantly more residual scaffold material for the collagen group relative to the dipyridamole group (p < 0.015), whereas the control group presented intermediate values (nonsignificant relative to both collagen and dipyridamole). Highly cellular and vascularized intramembranous-like bone healing was observed in all groups. CONCLUSION Dipyridamole significantly increased the three-dimensionally printed bioactive ceramic scaffold's ability to regenerate bone in a thin bone defect environment.

Background Cirrhosis for biliary atresia (BA) is associated with risk of gastrointestinal bleeding (GB) from gastroesophageal varices due to portal hypertension. Primary prophylaxis of GB is controversial in children who are candidates for liver transplantation (LT). The aim of the study was to define the management of gastroesophageal varices and to identify the benefit of primary prophylaxis for GB in BA children waiting for LT. Methods A retrospective single-center study including all BA children listed for LT in 2008–2016. Clinical, endoscopical, and biochemical data were analyzed. Results Of 82 children, 50 (61%) did not receive primary prophylaxis and did not present any episode of bleeding, 16 (19.5%) underwent primary prophylaxis, and 16 (19.5%) presented spontaneous GB and received secondary prophylaxis. Children without primary prophylaxis and GB were younger than patients with primary prophylaxis and those with GB (7.7 years [range, 4.1–37.9 years] vs 11.2 years [range, 5.1–43 years]; P = .03 vs 10.7 years [range, 6.9–39.9 years], respectively; P = .004). Seventy-five percent of GB occurred in children older than 8 months. Fifteen (93.8%) children with GB presented esophageal varices (grade III = 10 [62.5%]) and 10 (62.5%) required endoscopic treatments, consisting mainly of sclerotherapy. Median time to LT was similar for children with or without bleeding (2 months [range, 0–17.7 months] vs 2.2 months [0–17.9 months], respectively; P = .89). After 45.5 months (range, 13.7–105.5 months) of follow-up, the overall patient survival was 97.6%. At the intention-to-treat analysis, the survival rate was 100% for patients without bleeding episode and 87.5% for children with GB (P = .16). Conclusions Despite the risk of GB being not clinically predictable in children with BA waiting for LT, our experience suggests that primary prophylaxis of GB might be unnecessary in children younger than 6 months, while it should be considered in older children. Thus, the occurrence of GB does not delay the timing of transplantation.

The Arabian Peninsula is strategic for investigations centered on the early structuring of modern humans in the wake of the out-of-Africa migration. Despite its poor climatic conditions for the recovery of ancient human DNA evidence, the availability of both genomic data from neighboring ancient specimens and informative statistical tools allow modeling the ancestry of local modern populations. We applied this approach to a data set of 741,000 variants screened in 291 Arabians and 78 Iranians, and obtained insightful evidence. The west-east axis was a strong forcer of population structure in the Peninsula, and, more importantly, there were clear continuums throughout time linking western Arabia with the Levant, and eastern Arabia with Iran and the Caucasus. Eastern Arabians also displayed the highest levels of the basal Eurasian lineage of all tested modern-day populations, a signal that was maintained even after correcting for a possible bias due to a recent sub-Saharan African input in their genomes. Not surprisingly, eastern Arabians were also the ones with highest similarity with Iberomaurusians, who were, so far, the best proxy for the basal Eurasians amongst the known ancient specimens. The basal Eurasian lineage is the signature of ancient non-Africans who diverged from the common European-eastern Asian pool before 50,000 years ago, prior to the later interbred with Neanderthals. Our results appear to indicate that the exposed basin of the Arabo-Persian Gulf was the possible home of basal Eurasians, a scenario to be further investigated by searching ancient Arabian human specimens.

Venous malformation (VM) is the most common type among vascular malformations classified by the International Society for the Study of Vascular Anomalies. Most VMs are sporadic (94%), caused in 40% of cases by somatic mutation of TEK gene. VMs can be cutaneous, visceral, or combined. Visceral involvement is rare, and gastrointestinal (GI) tract is the most common localization. Visceral VMs, usually asymptomatic, may manifest with bleeding, anemia, and consumptive coagulopathy, which sometimes require an emergency treatment. Our aim is to study the possible GI involvement in patients with only one cutaneous VM. We analyzed a series of six patients who presented with a single cutaneous VM and have subsequently manifested intestinal involvement at our reference center for vascular anomalies since 2010. In our patients, cutaneous VMs were located on lower or upper limbs, and GI involvement manifested from 3 to 10 years after skin diagnosis. Our experience urges to early diagnose a GI involvement also in patients with only one skin VM and to prevent severe complications. A multidisciplinary approach is mandatory for the diagnosis and treatment of these patients.

Background and Objective: Guided bone regeneration allows new bone formation in anatomical sites showing defects preventing implant rehabilitation. Material and Methods: The present case series reported the outcomes of five patients treated with customized titanium meshes manufactured with a digital workflow for achieving bone regeneration at future implant sites. A significant gain in both width and thickness was achieved for all patients. Results: From a radiographic point of view (CBTC), satisfactory results were reached both in horizontal and vertical defects. An average horizontal gain of 3.6 &plusmn, 0.8 mm and a vertical gain of 5.2 &plusmn, 1.1 mm. Conclusions: The findings from this study suggest that customized titanium meshes represent a valid method to pursue guided bone regeneration in horizontal, vertical or combined defects. Particular attention must be paid by the surgeon in the packaging of the flap according to a correct method called the &ldquo, poncho&rdquo, technique in order to reduce the most frequent complication that is the exposure of the mesh even if a partial exposure of one mesh does not compromise the final outcome of both the reconstruction and the healing of the implants.

Background Although pathological complete response (pCR) after multimodal treatment for esophageal cancer is associated to the best prognosis, recurrence may occur in 20–40% of cases. The present study investigated the recurrence pattern and predictive factors of recurrence after pCR in patients with esophageal cancer. Methods In this study, 427 patients received preoperative treatment for either esophageal squamous cell carcinoma (SCC) or adenocarcinoma at Verona University Hospital between 2000 and 2018. Of these, 145 patients (34%) achieved a pCR. Long-term prognosis, recurrence pattern, and risk factors for relapse in pCR patients were analysed. Results During a median follow-up of 52 months, 37 relapses (25.5%) occurred, mostly at distant level (n = 28). Nearly all locoregional relapses (8/9) were detected in SCC cases. The 5-year overall survival and cancer-related survival were 71.7% (95% confidence interval [CI] 62.6–78.9%) and 77.5% (95% CI 68.5–84.2%) respectively. Male sex, higher body mass index, and cT4 were significant risk factors for recurrence at univariate analysis. The multivariate analysis confirmed the role of cT4 as predictor of recurrence only in SCCs. Conclusions Esophageal cancer recurs in about one-fourth of pCR cases. A fair number of local recurrences occurs in SCCs, but the main problem is the systemic disease control. According to our analysis, SCCs patients with cT4 stage have an increased risk to recur, so they should be managed differently by a personalized approach in terms of adjuvant treatment and follow-up.

Purpose The aim of the present study was to systematically analyze how a multifactorial surgical instrumentation approach affects osseointegration on both narrow-diameter and wide-diameter short implants. Materials and Methods Twelve skeletally mature female sheep were used in the study along with 144 plateau-root-form healing chamber titanium (Ti-6Al-4V) implants (Bicon LLC, Boston, MA), evenly distributed between narrow (3.5 mm) and wide (6.0 mm) diameters. The presence or the absence of irrigation, different drilling speeds, and 2 time points quantifying bone-implant contact (BIC) and bone area fraction occupancy (BAFO) to evaluate the osteogenic parameters around the implants. Results There were no signs of inflammation, infection, or failure of the implants observed at either healing period. The narrow 3.5-mm implant, at 6 weeks, yielded significant differences in terms of BIC at a drilling speed of 50 rotations per minute (RPM), with higher values of the samples using irrigation (30.6 ± 6.1%) compared with those without (19.7 ± 6.1%). No statistical differences were detected for 500 and 1,000 RPM with or without irrigation. The wide 6-mm diameter implant showed differences with respect to drilling speed, 500 and 1,000 RPM, with higher values associated with samples subjected to irrigation. BAFO results, for both diameters, only detected statistical differences between the 2 times (3 vs 6 weeks); no statistical differences were detected when evaluating as a function of time, drilling speed, and irrigation. Conclusions Surgical instrumentation variables (ie, drilling speed [RPM] and irrigation) yielded to be more of an effect for BIC at longer healing time (6 weeks) for the wider implants. Furthermore, deploying narrow or wide plateau-root-form implants, where conditions allow, has shown to be a safe alternative, considering the high BIC and BAFO values observed, independent of irrigation.

BACKGROUND: The European Society for Paediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) position paper from 2015 on percutaneous endoscopic gastrostomy (PEG) required updating in the light of recent clinical knowledge and data published in medical journals since 2014. METHODS: A systematic review of medical literature from 2014 to 2020 was carried out. Consensus on the content of the manuscript, including recommendations, was achieved by the authors through electronic and virtual means. The expert opinion of the authors is also expressed in the manuscript when there was a lack of good scientific evidence regarding PEGs in children in the literature. RESULTS: The authors recommend that the indication for a PEG be individualized, and that the decision for PEG insertion is arrived at by a multidisciplinary team (MDT) having considered all appropriate circumstances. Well timed enteral nutrition is optimal to treat faltering growth to avoid complications of malnutrition and body composition. Timing, device choice and method of insertion is dependent on the local expertise and after due consideration with the MDT and family. Major complications such as inadvertent bowel perforation should be avoided by attention to good technique and by ensuring the appropriate experience of the operating team. Feeding can be initiated as early as 3 hours after tube placement in a stable child with iso-osmolar feeds of standard polymeric formula. Low-profile devices can be inserted initially using the single-stage procedure or after 2-3 months by replacing a standard PEG tube, in those requiring longer-term feeding. Having had a period of non-use and reliance upon oral intake for growth and weight gain-typically 8-12 weeks-a PEG may then safely be removed after due consultation. In the event of non-closure of the fistula the most successful method for closing it, to date, has been a surgical procedure, but the Over-The-Scope-Clip (OTSC) has recently been used with considerable success in this scenario. CONCLUSIONS: A multidisciplinary approach is mandatory for the best possible treatment of children with PEGs. Morbidity and mortality are minimized through team decisions on indications for insertion, adequate planning and preparation before the procedure, subsequent monitoring of patients, timing of the change to low-profile devices, management of any complications, and optimal timing of removal of the PEG.

BACKGROUND AND AIMS The aim of this project was to evaluate the current practice of D2 in Europe. MATERIALS AND METHODS In the first part of the study, 18 European high volume gastric cancer centres completed a questionnaire, designed to evaluate their preferred lymphadenectomy in a series of clinical scenarios. Surgeon compliance with international guidelines for lymphadenectomy was evaluated. In the second part, information on 381 gastrectomies performed for primary gastric cancer by participating surgeons from January to December 2015, was retrospectively collected. RESULTS Surgical choice in clinical scenarios was affected by tumour stage and to a lesser extent, site and histotype. In particular, in early gastric cancer with diffuse histology D2 was recommended by >70% of surgeons, while this percentage dropped to 44% in intestinal histotypes. When surgeons selected a D2 dissection, the procedure was rarely fully compliant with the Japanese guidelines. In the review of gastrectomy experience an adequate number of nodes (≥15 nodes) was retrieved in 97% after D2. The number of retrieved nodes varied with median values ranging from 17 to 35 (p

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Purpose To investigate the effect of cyclosporine on corneal ultrastructure and on major signs and symptoms of patients with dry eye disease.Patients and methods In this prospective cohort study, patients with dry eye disease were treated with a drop of cyclosporine 0.05% twice daily. Clinical evaluation was carried out at baseline and at months 1, 3, and 6. All patients completed the Ocular Surface Disease Index (OSDI) questionnaire, and tear film break-up time (BUT), fluorescein and lissamine green staining, and Schirmer test were carried out. In vivo confocal microscopy was also performed and epithelial cellular density, keratocyte activation, and subbasal plexus morphology were assessed.Results A total of 40 patients completed the study. After 6 months, OSDI, BUT, and fluorescein and lissamine green staining showed a clinically significant improvement. During the 6-month follow-up, density of intermediate epithelial cells increased from 1969.5 +/- 85.4 cell/mm(2) to 4881.2 +/- 75.7 cell/mm(2) (P

Attention is an increasingly popular mechanism used in a wide range of neural architectures. The mechanism itself has been realized in a variety of formats. However, because of the fast-paced advances in this domain, a systematic overview of attention is still missing. In this article, we define a unified model for attention architectures in natural language processing, with a focus on those designed to work with vector representations of the textual data. We propose a taxonomy of attention models according to four dimensions: the representation of the input, the compatibility function, the distribution function, and the multiplicity of the input and/or output. We present the examples of how prior information can be exploited in attention models and discuss ongoing research efforts and open challenges in the area, providing the first extensive categorization of the vast body of literature in this exciting domain., Comment: 18 pages, 8 figures

This article provides an overview of the fundamentals related to agent-oriented paradigm and Multi Agent Systems (MASs). Specifically, in the first part, the definition of agent and its main features are reported. The second section discusses multi-agent systems and their main features by focusing on the concepts of automation, coordination, norms and emerging behavior which characterize a MAS. Finally, in the sections third and forth, two main ways to approach and use such paradigm for developing respectively agent-based simulations and agent-based software, by breaking down the leading and most renowned reference software platforms, are discussed.

A population in a natural crossroad within Europe reveals multiple ancient contributions and substantial population structure., European populations display low genetic differentiation as the result of long-term blending of their ancient founding ancestries. However, it is unclear how the combination of ancient ancestries related to early foragers, Neolithic farmers, and Bronze Age nomadic pastoralists can explain the distribution of genetic variation across Europe. Populations in natural crossroads like the Italian peninsula are expected to recapitulate the continental diversity, but have been systematically understudied. Here, we characterize the ancestry profiles of Italian populations using a genome-wide dataset representative of modern and ancient samples from across Italy, Europe, and the rest of the world. Italian genomes capture several ancient signatures, including a non–steppe contribution derived ultimately from the Caucasus. Differences in ancestry composition, as the result of migration and admixture, have generated in Italy the largest degree of population structure detected so far in the continent, as well as shaping the amount of Neanderthal DNA in modern-day populations.

The management of suspected choledocholithiasis remains a challenge in pediatric endoscopy. Several recommendations are available for adult patients; however, it is unknown which pediatric patients are most likely to benefit from ERCP for evaluation of choledocholithiasis. The primary aim of this study was to evaluate adult-based criteria in the evaluation of pediatric patients with choledocholithiasis. A secondary aim was to evaluate the role of conjugated (or direct) bilirubin to improve the sensitivity of detecting choledocholithiasis.This was a prospective multicenter study in pediatric patients as part of the Pediatric ERCP Database Initiative (PEDI) with additional post-hoc analysis of updated guidelines. Patients 19 years of age undergoing ERCP for suspected choledocholithiasis or gallstone pancreatitis were enrolled at participating sites.Ninety-five patients were enrolled (69 with choledocholithiasis confirmed at ERCP and 26 with no stones at ERCP). Adverse event rates were similar in both groups. Specificity ranged from 27% to 91% using adult guidelines, but a sensitivity of only 20% to 69%. The were no significant differences between the 2 groups using preprocedure transabdominal US (P = 1.0). Significant differences between groups were identified using either the total or conjugated bilirubin (P = .02). There was also a significant difference between the stone and no-stone groups when conjugated bilirubin was dichotomized to2 mg/dL (P = .03).Abdominal imaging and laboratory indices may be used to predict pediatric choledocholithiasis with varying sensitivity and specificity. Pediatric-specific guidelines may allow for improved stone prediction compared with existing adult recommendations.

Objective To analyze the findings of both multichannel intraluminal impedance with pH (MII-pH) and endoscopy/histopathology in children with esophageal atresia at age 1 year, according to current recommendations for the evaluation of gastroesophageal reflux disease (GERD) in esophageal atresia. Study design We retrospectively reviewed both MII-pH and endoscopy/histopathology performed in 1-year-old children with esophageal atresia who were followed up in accordance with international recommendations. Demographic data and clinical characteristics were also reviewed to investigate factors associated with abnormal GERD investigations. Results In our study cohort of 48 children with esophageal atresia, microscopic esophagitis was found in 33 (69%) and pathological esophageal acid exposure on MII-pH was detected in 12 (25%). Among baseline variables, only the presence of long-gap esophageal atresia was associated with abnormal MII-pH. Distal baseline impedance was significantly lower in patients with microscopic esophagitis, and it showed a very good diagnostic performance in predicting histological changes. Conclusions Histological esophagitis is highly prevalent at 1 year after esophageal atresia repair, but our results do not support a definitive causative role of acid-induced GERD. Instead, they support the hypothesis that chronic stasis in the dysmotile esophagus might lead to histological changes. MII-pH may be a helpful tool in selecting patients who need closer endoscopic surveillance and/or benefit from acid suppression.

This study sought to estimate patient-reported outcomes and compare quality-of-life (QOL) measures between patients electing for either open reduction internal fixation (ORIF) or closed reduction with intermaxillary fixation (CRIMF).This was a retrospective cohort study of patients with unilateral condyle fractures who had undergone either ORIF or CRIMF at the New York University Tisch Hospital and Bellevue Hospital Center. The primary study predictor was treatment choice (ORIF or CRIMF). Other study predictors were patient age, gender, and the presence of any other coexisting facial fractures. The 9 study outcomes were derived from an 11-item postoperative QOL questionnaire evaluating self-reported perceptions of pain and function. Univariate comparisons and multivariate regression models were calculated.A total of 38 patients (21 CRIMF and 17 ORIF) comprised the study sample. All patients were eligible for either ORIF or CRIMF, and the choice of treatment was decided through shared decision making after a comprehensive discussion of risks and benefits. With respect to pain outcomes, patients who underwent ORIF reported lower overall pain scores at 2 weeks (P .01) and 2 months (P = .01), less mastication pain at 3 months (P = .01), and a lower rate of persistent headaches after 6 weeks (P = .04). With respect to functional outcomes, patients who underwent ORIF reported better range of motion at 3 months (P = .01), less treatment-related weight loss (P = .01), and more ease when performing physical (P .01) and work-related (P .01) activities. In the multivariate regression models, ORIF was independently associated with decreased pain at 2 weeks (P .01) and decreased difficulty in obtaining nutrition (P .01), performing physical activities (P = .02), and performing work-related activities (P .01).Patients who underwent ORIF appeared to experience subjective favorable pain and functional QOL outcomes. Given the clinical controversy, the choice of treatment should synthesize patient-reported outcomes and be approached through shared decision making.

Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related mortality among adults in developed countries. The discovery of the most common genetic alterations as well as the development of organoid models of pancreatic cancer have provided insight into the fundamental pathways driving tumor progression from a normal cell to non-invasive precursor lesion and finally to widely metastatic disease, offering new opportunities for identifying the key driver of cancer evolution. Obesity is one of the most serious public health challenges of the 21st century. Several epidemiological studies have shown the positive association between obesity and cancer-related morbidity/mortality, as well as poorer prognosis and treatment outcome. Despite strong evidence indicates a link between obesity and cancer incidence, the molecular basis of the initiating events remains largely elusive. This is mainly due to the lack of an accurate and reliable model of pancreatic carcinogenesis that mimics human obesity-associated PDAC, making data interpretation difficult and often confusing. Here we propose a feasible and manageable organoid-based preclinical tool to study the effects of obesity on pancreatic carcinogenesis. Therefore, we tracked the effects of obesity on the natural evolution of PDAC in a genetically defined transplantable model of the syngeneic murine pancreatic preneoplastic lesion (mP) and tumor (mT) derived-organoids that recapitulates the progression of human disease from early preinvasive lesions to metastatic disease. Our results suggest that organoid-derived transplant in obese mice represents a suitable system to study early steps of pancreatic carcinogenesis and supports the hypothesis that inflammation induced by obesity stimulates tumor progression and metastatization during pancreatic carcinogenesis.

To evaluate efficacy of a microemulsion of fatty acids of the ω-3 series on the regeneration of the sub-epithelial corneal nerve plexus in patients with keratoconus after epi-off cross-linking. In this prospective study, we recruited 40 patients, 18 females, mean age 28 years (range 22–37), who were randomly divided in two groups. Group A, 20 patients, after cross-linking were treated with a microemulsion of fatty acids of the ω-3 series. Group B were treated with hyaluronic acid (0.15%)-based tear substitute. Nerve tortuosity, reflectivity and density were examined with in vivo confocal microscopy. Ocular surface disease index (OSDI) questionnaire at the preoperative and at each follow-up visit (1, 3 and 6 months) after treatment was completed. No significant difference between the two groups was noted at 1 month in terms of nerve density and OSDI. A statistically significant difference between the two groups was detected at 3 months in terms of nerve fibers density (6 ± 0.82 in Group A and 1 ± 0.51 in Group B, P = 0.0001). Reflectivity and tortuosity of the fibers did not show significant differences between the two groups at any time point. At 1 month, OSDI average value in group A and in group B was 31.5 ± 1.94 and 30 ± 1.96, at 3 months 13 ± 1.71 and 28 ± 1.83, and at 6 months 10.5 ± 1.87 and 9.0 ± 1.81, respectively. The use of a microemulsion of fatty acids appears to ensure a faster regeneration of nerve fibers in patients undergoing epi-off cross-linking.

Umbria is located in Central Italy and took the name from its ancient inhabitants, the Umbri, whose origins are still debated. Here, we investigated the mitochondrial DNA (mtDNA) variation of 545 present-day Umbrians (with 198 entire mitogenomes) and 28 pre-Roman individuals (obtaining 19 ancient mtDNAs) excavated from the necropolis of Plestia. We found a rather homogeneous distribution of western Eurasian lineages across the region, with few notable exceptions. Contemporary inhabitants of the eastern part, delimited by the Tiber River and the Apennine Mountains, manifest a peculiar mitochondrial proximity to central-eastern Europeans, mainly due to haplogroups U4 and U5a, and an overrepresentation of J (30%) similar to the pre-Roman remains, also excavated in East Umbria. Local genetic continuities are further attested to by six terminal branches (H1e1, J1c3, J2b1, U2e2a, U8b1b1 and K1a4a) shared between ancient and modern mitogenomes. Eventually, we identified multiple inputs from various population sources that likely shaped the mitochondrial gene pool of ancient Umbri over time, since early Neolithic, including gene flows with central-eastern Europe. This diachronic mtDNA portrait of Umbria fits well with the genome-wide population structure identified on the entire peninsula and with historical sources that list the Umbri among the most ancient Italic populations. We are grateful to Soprintendenza Archeologia, Belle Arti e Paesaggio dell’Umbria, to Istituto Comprensivo Statale Foligno 5 (Perugia) and to all the volunteers who generously participated in this survey and made this research possible. We thank our colleagues Prof. Fausto Panara and Dr. Livia Lucentini with whom we have been discussing the feasibility and the first steps of this project, and Prof. Cristina Cereda, Dr. Gaetano Grieco, Dr. Marialuisa Valente, Dr. Nicole Huber and Jannika Oeke for technical support. We would like to thank the two anonymous reviewers for their suggestions and thoughtful comments. This research received support from: the Italian Ministry of Education, University and Research projects FIR2012 RBFR126B8I (to AO and AA), PRIN2017 20174BTC4R (to AA); Dipartimenti di Eccellenza Program (2018–2022)—Department of Biology and Biotechnology “L. Spallanzani,” University of Pavia (to AA, AO, OS and AT) and Department of Biology, University of Florence (to DC); the Fondazione Cariplo (project no. 2018–2045 to AA, AO and AT); the Fon-dazione Carifol (2008 to AA) and the Tiroler Wissenschaftsfonds (TWF) (UNI-404/1998) (to MB).