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The Italian pig farming industry is unique in its focus on raising heavy pigs primarily for the production of high-quality dry-cured hams. These products require pigs to be slaughtered at a live weight of around 170 kg at 9 months of age. The primary breeds used in this system are Italian Duroc, Italian Landrace, and Italian Large White which are crossed to produce lines that meet standard requirements. Over the past four decades, selection and breeding programmes for these breeds have been subjected to distinct selective pressures to highlight the characteristics of each breed. In this study, we investigated the genome of these breeds by analysing high-density single nucleotide polymorphism data from over 9 000 pigs to scan for signatures of selection using four different methods, two within breeds and two across breeds. This allowed to identify the genomic regions that differentiate these breeds as well as any relevant genes and biological terms. On a global scale, we found that the Italian Duroc breed exhibited a higher genetic differentiation from the Italian Landrace and Italian Large White breeds, with a pairwise F ST value of 0.20 compared with the 0.13 between Italian Landrace and Italian Large White. This may reflect either their different origins or the different breeding goals, which are more similar for the Italian Landrace and Italian Large White breeds. Despite these genetic differences at a global level, few signatures of selection regions reached complete fixation, possibly due to challenges in detecting selection linked to quantitative polygenic traits. The differences among the three breeds are confirmed by the low level of overlap in the regions detected. Genetic enrichment analyses of the three breeds revealed pathways and genes related to various productive traits associated with growth and fat deposition. This may indicate a common selection direction aimed at enhancing specific production traits, though different biological mechanisms are likely targeted by the same directional selection in these three breeds. Therefore, these genes may play a critical role in determining the distinctive characteristics of Italian Duroc, Italian Landrace, and Italian Large White, and potentially influence the traits in crossbred pigs derived from them. Overall, the insights gained from this study will contribute to understanding how directional selection has shaped the genome of these heavy pig breeds and to better address selection strategies aimed at enhancing the meat processing industry linked with dry-cured ham production chains., (Copyright © 2024. Published by Elsevier B.V.)

Cytomegalovirus (CMV) infection is associated with poor kidney transplant outcomes. While innate and adaptive immune cells have been implicated in its prevention, an in-depth characterization of the in vivo kinetics of multiple cell subsets and their role in protecting against CMV infection has not been achieved. Here, we performed high-dimensional immune phenotyping by mass cytometry, and functional assays, on 112 serially collected samples from CMV seropositive kidney transplant recipients. Advanced unsupervised deep learning analysis was used to assess immune cell populations that significantly correlated with prevention against CMV infection and anti-viral immune function. Prior to infection, kidney transplant recipients who developed CMV infection showed significantly lower CMV-specific cell-mediated immune (CMI) frequencies than those that did not. A broad diversity of circulating cell subsets within innate and adaptive immune compartments were associated with CMV infection or protective CMV-specific CMI. While percentages of CMV (tetramer-stained)-specific T cells associated with high CMI responses and clinical protection, circulating CD3 + CD8 mid CD56 + NK-T cells overall strongly associated with low CMI and subsequent infection. However, three NK-T cell subsets sharing the CD11b surface marker associated with CMV protection and correlated with strong anti-viral CMI frequencies in vitro. These data were validated in two external independent cohorts of kidney transplant recipients. Thus, we newly describe the kinetics of a novel NK-T cell subset that may have a protective role in post-transplantation CMV infection. Our findings pave the way to more mechanistic studies aimed at understanding the function of these cells in protection against CMV infection., (Copyright © 2024 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Immunotherapy with immune checkpoint inhibitors (ICI) is increasingly employed in oncology. National and international endocrine and oncologic scientific societies have provided guidelines for the management of endocrine immune-related adverse events. However, guidelines recommendations differ according to the specific filed, particularly pertaining to recommendations for the timing of endocrine testing. In this position paper, a panel of experts of the Italian Association of Medical Oncology (AIOM), Italian Association of Medical Diabetologists (AMD), Italian Society of Diabetology (SID), Italian Society of Endocrinology (SIE), and Italian Society of Pharmacology (SIF) offers a critical multidisciplinary consensus for a clear, simple, useful, and easily applicable endocrine-metabolic assessment checklist for cancer patients on immunotherapy., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: V.R. has received a travel grant from Androlabs. M.G. has received honoraria for speaker fees and/or travel grants for scientific meetings from AAA, AstraZeneca, Boehringer-Ingelheim, Bruno Farm., Eli-Lilly, IBSA, Lifescan, Mundipharma, Novo Nordisk and Sanofi, and served on scientific advisory panels for Boehringer-Ingelheim, Merck Sharp & Dohme and Novo Nordisk. S.F. serves on the scientific advisory board of, has a consulting relationship with and reports receiving support for travel expenses from Novartis, Teva, Roche, BMS, Lilly and Ipsen. R.D. serves on the scientific advisory board and has a consulting relationship with Ipsen, Novartis, Pfizer, Sanofi Genzyme, AstraZeneca, Janssen, Gilead, Lilly, Gilead, EUSA Pharma; and reports support for travel, accommodation and expenses from Ipsen and Sanofi Genzyme. F.G. has served as an advisor for AstraZeneca, Eli Lilly and Novo Nordisk; has served as a research investigator for Eli Lilly and Roche Diabetes Care; has served as a speaker for AstraZeneca and Eli Lilly; has served as a consultant for AstraZeneca, Boehringer Ingelheim, Eli Lilly, Merck Sharp & Dohme, Novo Nordisk, Roche Diabetes Care and Sanofi; and has received grants from Eli Lilly, Lifescan and Roche Diabetes Care. N.S. received fees for consulting from Roche, Lilly, Servier. All other authors declare no conflict of interest. All other authors have declared no conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Adolescent binge alcohol drinking is a serious health concern contributing to adult alcohol abuse often associated with anxiety disorders. We have used adolescent intermittent ethanol (AIE) administration as a model of binge drinking in rats in order to explore its long-term effect on the basolateral amygdala (BLA) responsiveness to alcohol and anxiety-like behavior. AIE increased the number of BLA c-Fos positive cells in adult Wistar rats and anxiety-like behavior assessed by the open field test (OFT). Additionally, in adult female rats receiving AIE BLA over expression of miR-182 was found. Therefore, our results indicate that alcohol consumption during adolescence can lead to enduring changes in anxiety-like behavior and BLA susceptibility to alcohol that may be mediated by sex-dependent epigenetic changes. These results contribute to understanding the mechanisms involved in the development of alcohol use disorders (AUD) and anxiety-related disorders., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Carbon sequestration in soils is a strategy to mitigate climate change and promote sustainable soil management. Since the European Union (EU) stimulates the reduction of greenhouse gases (GHG) from the atmosphere, the necessity to explore innovative approaches to sequester carbon in agricultural landscapes is becoming urgent. Carbon Farming (CF) has emerged as a promising program to mitigate climate change in agriculture but there is still a lack of agreement on which tools can be used to calculate Soil Organic Carbon (SOC) dynamics in this context. Using the RothC model a spatial analysis of SOC in the agricultural parcels of Flanders, Belgium was performed. Two among the various CF practices were simulated: a use of cover crops (CC) and the most common crop rotations adopted in the area, enriched with the use of cover crops. The performances of the model were evaluated and compared to other studies in areas with similar climate and environments. The selected CF practices can mitigate the carbon emissions from agricultural soils up to 60 % of the current projections. The most sensitive variables in the RothC model that affect the final total SOC, and thus determining the model outcome, are the Business As Usual (BAU) carbon inputs and the initial carbon content. For these variables the Pearson Correlation Coefficient with the change in SOC reached values of -0.78 and -0.50 respectively. To achieve net carbon sequestration in the agricultural soils of Flanders, Belgium, more effective solutions need to be evaluated. Furthermore, a larger amount and accessibility of data are required to reach better modelling performances., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Inserting cerebrospinal fluid diversion devices such as external ventricular drains (EVDs) and ventriculoperitoneal shunts (VPSs) is a critical procedure. Unfortunately, complications such as catheter misplacement, dislocation, or infection can occur. Various surgical strategies aim to reduce these risks. One recent innovation is the "catheter-locking device-assisted" technique for EVD surgery. In this study, we examined its application in a larger group of cases encompassing both EVDs and VPSs over a 30-month period, with a focus on these complications., Methods: All adult patients who underwent a shunt procedure for noninfectious hydrocephalus at our institution from January 2021 to June 2023 were reviewed. We compared complications between those treated with the "standard" technique (subgroup A) and those managed with the "catheter-locking device-assisted" approach (subgroup B)., Results: In the EVD surgical group (initial procedures, n = 161), 6 patients (3.7%) required reoperation owing to the catheter misplacement caused by inadvertent migration of the ventricular catheter within the operating room ("early" migration), while 11 patients (6.8%) experienced unintentional postoperative dislodgement ("delayed" migration). Seven patients (4.3%) developed an EVD-related infection after an average duration of 7.4 days. None of these complications were observed in subgroup B patients (P < 0.05). Among VPS patients (n = 137), 4 (2.9%), all in subgroup A, required reoperation due to intraoperative migration of the catheter (P = 0.121); no other complications were identified., Conclusions: The "catheter-locking device-assisted" technique may significantly decrease the occurrence of the most common EVD complications and can also prove beneficial in VPS surgery. However, further investigation is necessary., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Transfusions are extremely frequent after cardiac surgery, and they have a considerable economic burden and impact on outcomes. Optimal patient blood management could play a fundamental role in reducing the rate of transfusion and Jehovah's Witnesses (JW) represent the ideal surrogate study population. This meta-analysis compares outcomes of JWs and non-JWs' patients undergoing cardiac surgery, assessing the safety of a bloodless cardiac surgery. A scoping review was conducted using a search strategy for studies assessing outcomes of JW undergoing cardiac surgery. The primary outcome was perioperative mortality, and a random-effects meta-analysis was performed. Ten studies were included in our meta-analysis, involving 780 JW patients refusing any type of transfusion ("JW") and 1182 patients accepting transfusion if needed ("non-JW"). 86% of non-JW patients received at least 1 transfusion. There was no significant difference in terms of perioperative mortality (OR 0.91; 95% CI 0.55-1.52; p = 0.72). The volume blood loss was significantly less in the JW (p = 0.001), while the rate of reoperation for bleeding was also lower, but not statistically significative, in the JW (p = 0.16). Both preoperative and postoperative hemoglobin and hematocrit were significantly higher in the JW. Therefore, we concluded that bloodless cardiac surgery is safe and early outcomes are similar between JW and non-JW patients: optimal patient blood management is fundamental in guarantying these results. Further studies are needed to assess if a limitation of transfusion could have a positive long-term impact on outcomes., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Diagnostic histopathology faces increasing demands due to aging populations and expanding healthcare programs. Semi-automated diagnostic systems employing deep learning methods are one approach to alleviate this pressure. The learning models for histopathology are inherently complex and opaque from the user's perspective. Hence different methods have been developed to interpret their behavior. However, relatively limited attention has been devoted to the connection between interpretation methods and the knowledge of experienced pathologists. The main contribution of this paper is a method for comparing morphological patterns used by expert pathologists to detect cancer with the patterns identified as important for inference of learning models. Given the patch-based nature of processing large-scale histopathological imaging, we have been able to show statistically that the VGG16 model could utilize all the structures that are observable by the pathologist, given the patch size and scan resolution. The results show that the neural network approach to recognizing prostatic cancer is similar to that of a pathologist at medium optical resolution. The saliency maps identified several prevailing histomorphological features characterizing carcinoma, e.g., single-layered epithelium, small lumina, and hyperchromatic nuclei with halo. A convincing finding was the recognition of their mimickers in non-neoplastic tissue. The method can also identify differences, i.e., standard patterns not used by the learning models and new patterns not yet used by pathologists. Saliency maps provide added value for automated digital pathology to analyze and fine-tune deep learning systems and improve trust in computer-based decisions., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Co-author, Petr HOLUB, is serving as an guest editor for the special issue of the journal., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

AI development in biotechnology relies on high-quality data to train and validate algorithms. The FAIR principles (Findable, Accessible, Interoperable, and Reusable) and regulatory frameworks such as the In Vitro Diagnostic Regulation (IVDR) and the Medical Device Regulation (MDR) specify requirements on specimen and data provenance to ensure the quality and traceability of data used in AI development. In this paper, a framework is presented for recording and publishing provenance information to meet these requirements. The framework is based on the use of standardized models and protocols, such as the W3C PROV model and the ISO 23494 series, to capture and record provenance information at various stages of the data generation and analysis process. The framework and use case illustrate the role of provenance information in supporting the development of high-quality AI algorithms in biotechnology. Finally, the principles of the framework are illustrated in a simple computational pathology use case, showing how specimen and data provenance can be used in the development and documentation of an AI algorithm. The use case demonstrates the importance of managing and integrating distributed provenance information and highlights the complex task of considering factors such as semantic interoperability, confidentiality, and the verification of authenticity and integrity., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. This work does not raise any ethical issues., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Cancer management has significantly evolved in recent years, focusing on a multidisciplinary team approach to provide the best possible patient care and address the various comorbidities, toxicities, and complications that may arise during the patient's treatment journey. The co-occurrence of diabetes and cancer presents a significant challenge for health care professionals worldwide. Management of these conditions requires a holistic approach to improve patients' overall health, treatment outcomes, and quality of life, preventing diabetes complications and cancer treatment side-effects. In this article, a multidisciplinary panel of experts from different Italian scientific societies provide a critical overview of the co-management of cancer and diabetes, with an increasing focus on identifying a novel specialty field, 'diabeto-oncology', and suggest new co-management models of cancer patients with diabetes to improve their care. To better support cancer patients with diabetes and ensure high levels of coordinated care between oncologists and diabetologists, 'diabeto-oncology' could represent a new specialized field that combines specific expertise, skills, and training., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Thoracic endovascular aortic repair (TEVAR) has become a standard treatment for acute and chronic thoracic aorta diseases. We analyzed long-term outcomes and risk factors of TEVAR procedures according to the aortic pathology., Methods: Demographics, indications, technical details, and outcomes of patients undergoing TEVAR procedures in our institutions were prospectively collected and retrospectively analyzed. Overall survival was determined using Kaplan-Meier methods while log-rank tests were used to compare the survival between groups. Cox regression analysis was used to identify risk factors., Results: Between June 2002 and April 2020, 116 patients underwent TEVAR for different thoracic aorta diseases. Among them, 47 patients (41%) underwent TEVAR for aneurysmatic aortic disease, 26 (22%) for type-B aortic dissection, 23 (20%) for penetrating aortic ulcer, 11 (9%) after previous type-A dissection treatment, and 9 (8%) for traumatic aortic injury. Patients with posttraumatic aortic injury were younger (P < 0.01) with less hypertension (P < 0.01), diabetes (P < 0.01), and prior cardiac surgery (P < 0.01). Survival was different based on indication for TEVAR (log rank 0.024). Patients after previous type-A dissection treatment had the worst survival rate (50% at 5 years) while survival for aneurysmatic aortic disease was 55% at 5 years. No late death occurred in the traumatic group. Cox-regression model identified independent predictors for mortality: age (hazard ratio [HR]: 1.05, 95% confidence interval [CI]: 1.01-1.09, P = 0.006), male gender (HR: 3.2, 95% CI: 1.1-9.2, P = 0.028), moderate chronic obstructive pulmonary disease (HR: 2.1, 95% CI: 1.02-4.55, P = 0.043), previous cardiac surgery (HR: 2.1, 95% CI: 1.008-4.5, P = 0.048), and treatment indication for aneurysm (HR: 2.6, 95% CI: 1.2-5.2, P = 0.008)., Conclusions: TEVAR is a safe and effective procedure with excellent long-term results in case of traumatic aortic injury. The overall long-term survival is affected by aortic pathology, associated comorbidities, gender, and previous cardiac surgery., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Neointimal hyperplasia and lumen irregularities are major contributors to vein graft failure and the use of VEST (R) should prevent this. In this review, we aim to evaluate the angiographic outcomes of externally supported vein grafts. Medline, Embase and Cochrane Library were systematically reviewed for randomized clinical trials published by August 2022. The primary outcome was graft failure. Secondary outcomes included graft ectasia, intimal hyperplasia area and thickness, and graft nonuniformity. Odds ratios (OR) for dichotomous variables and mean difference (MD) for continuous variables with 95% confidence intervals (CI) were pooled using a fixed-effects model. Three randomized controlled trials with a total of 437 patients were included with follow-up ranging from 1 to 2 years. The odds of graft failure were similar in the 2 groups (OR 1.22; 95%CI 0.88-1.71; I² = 0%). Intimal hyperplasia area [MD -0.77 mm 2 ; 95%CI -1.10 to -0.45; I 2  = 0%] and thickness [MD -0.06 mm; 95% CI -0.08 to -0.04; I 2 =0%] were significantly lower in the VEST group. Fitzgibbon Patency Scale of II or III (representing angiographic conduit nonuniformity; OR 0.67; 95%CI 0.48-0.94; I 2  = 0%) and graft ectasia (OR 0.53; 95%CI 0.32-0.88; I 2  = 33%) were also significantly lower in the VEST group. At short-term follow-up, VEST does not seem to reduce the incidence of graft failure, although it is associated with attenuation of intimal hyperplasia and nonuniformity. Longer angiographic follow-up is warranted to determine whether these positive effects might translate into a positive effect in graft failure and in long-term clinical outcomes., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Increasing evidence suggests that patients with diabetes, particularly type 2 diabetes (T2D), are characterized by an increased risk of developing different types of cancer, so cancer could be proposed as a new T2D-related complication. On the other hand, cancer may also increase the risk of developing new-onset diabetes, mainly caused by anticancer therapies. Hyperinsulinemia, hyperglycemia, and chronic inflammation typical of T2D could represent possible mechanisms involved in cancer development in diabetic patients. MicroRNAs (miRNAs) are a subset of non-coding RNAs, ⁓22 nucleotides in length, which control the post-transcriptional regulation of gene expression through both translational repression and messenger RNA degradation. Of note, miRNAs have multiple target genes and alteration of their expression has been reported in multiple diseases, including T2D and cancer. Accordingly, specific miRNA-regulated pathways are involved in the pathogenesis of both conditions. In this review, a panel of experts from the Italian Association of Medical Oncology (AIOM), Italian Association of Medical Diabetologists (AMD), Italian Society of Diabetology (SID), Italian Society of Endocrinology (SIE), and Italian Society of Pharmacology (SIF) provide a critical view of the evidence about the involvement of miRNAs in the pathophysiology of both T2D and cancer, trying to identify the shared miRNA signature and pathways able to explain the strong correlation between the two conditions, as well as to envision new common pharmacological approaches., Competing Interests: Disclosure The authors have declared no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Of-Pis1 is a potent piscidin antimicrobial peptide (AMP), recently isolated from rock bream (Oplegnathus fasciatus). This rich in histidines and glycines 24-amino acid peptide displays high and broad antimicrobial activity and no significant hemolytic toxicity against human erythrocytes, suggesting low toxicity. To better understand the mechanism of action of Of-Pis1 and its potential selectivity, using NMR and CD spectroscopies, we studied the interaction with eukaryotic and procaryotic membranes and membrane models. Anionic sodium dodecyl sulfate (SDS) and lipopolysaccharide (LPS) micelles were used to mimic procaryotic membranes, while zwitterionic dodecyl phosphocholine (DPC) was used as eukaryotic membrane surrogate. In an aqueous environment, Of-Pis1 adopts a flexible random coil conformation. In DPC and SDS instead, the N-terminal region of Of-Pis1 forms an amphipathic α-helix with the non-polar face in close contact with the micelles. Slower solvent exchange and higher pK a s of the histidine residues in SDS than in DPC suggest that Of-Pis1 interacts more tightly with SDS. Of-Pis1 also binds tightly and structurally perturbs LPS micelles. Of-Pis1 interacts with both Escherichia coli and mammalian cell membranes, but only in the presence of Escherichia coli membranes it populates the helical conformation. Furthermore, ligand-based NMR experiments support a tighter and more specific interaction with bacterial than with eukaryotic membranes. Overall, these data clearly show the selective interaction of this broadly active AMP with bacterial over eukaryotic membranes. The conformational information is discussed in terms of Of-Pis1 amino acid sequence and composition to provide insights useful to design more potent and selective AMPs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Aim: In 2019, the Italian Society of Diabetology and the Italian Association of Clinical Diabetologists nominated an expert panel to develop guidelines for drug treatment of type 2 diabetes. This expert panel, after identifying the effects of glucose-lowering agents on major adverse cardiovascular events (MACEs), all-cause mortality, and hospitalization for heart failure (HHF) as critical outcomes, decided to perform a systematic review and meta-analysis on the effect of insulin with this respect., Data Synthesis: A MEDLINE database search was performed to identify all RCTs, up to June 1st, 2021, with duration≥52 weeks, in which insulin was compared with either placebo or active comparators. The principal endpoints were MACE and HHF (restricted for RCT reporting MACEs within their outcomes), all-cause mortality (irrespective of the inclusion of MACEs among the pre-specified outcomes). Mantel-Haenszel odds ratio (MH-OR) with 95% Confidence Interval (95% CI) was calculated for all the endpoints considered. Six RCTs (enrolling 8091 patients and 10,139 in the insulin and control group, respectively) were included in the analysis for MACEs and HF, and 18 in that for all-cause mortality (9760 and 11,694 patients in the insulin and control group, respectively). Treatment with insulin neither significantly increased nor reduced the risk of MACE, all-cause mortality, and HHF in comparison with placebo/active comparators (MH-OR: 1.09, 95% CI 0.97-1.23; 0.99, 95% CI 0.91, 1.08; and 0.90, 95% CI 0.78, 1.04, respectively)., Conclusions: This meta-analysis showed no significant effects of insulin on incident MACE, all-cause mortality, and HHF., Competing Interests: Declaration of competing interest MM has received speaking fees from Astra Zeneca, Bristol Myers Squibb, Boehringer-Ingelheim, Eli-Lilly, Merck, Novo Nordisk, Sanofi, and Novartis and research grants from Bristol Myers Squibb; EM has received consultancy fees from Merck and Novartis speaking fees from Astra Zeneca, Bristol Myers Squibb, Boehringer-Ingelheim, Eli-Lilly, Merck, Novo Nordisk, Sanofi, and Novartis and research grants from Merck, Novartis, and Takeda. AG has received speaking fees and/or advisory board invitations from Abbott, Astra Zeneca, Boehringer-Ingelheim, Eli Lilly, MSD, Mundipharma, Novo-Nordisk, Sanofi. BN was an employee of NovoNordisk. The other authors did not report any relevant conflicts of interest. All the authors approved the final version of this manuscript. Dr. Edoardo Mannucci is the person who takes full responsibility for the work as a whole, including the study design, access to data, and the decision to submit and publish the manuscript., (Copyright © 2022 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Aim: In 2019, the Italian Society of Diabetology and the Italian Association of Clinical Diabetologists nominated an expert panel to develop guidelines for drug treatment of type 2 diabetes. After identifying the effects of glucose-lowering agents on major adverse cardiovascular events (MACEs), all-cause mortality, and hospitalization for heart failure (HHF) as critical outcomes, the experts decided to perform a systematic review and meta-analysis on the effect of pioglitazone with this respect., Data Synthesis: A MEDLINE database search was performed to identify RCTs, up to June 1st, 2021, with duration≥52 weeks, in which pioglitazone was compared with either placebo or active comparators. The principal endpoints were MACE and HHF (restricted for RCT reporting MACEs within their outcomes), all-cause mortality (irrespective of the inclusion of MACEs among the pre-specified outcomes). Mantel-Haenszel odds ratio (MH-OR) with 95% Confidence Interval (95% CI) was calculated for all the endpoints considered. Eight RCTs were included in the analysis for MACEs and HF (5048 and 5117 patients in the pioglitazone and control group, respectively), and 24 in that for all-cause mortality (10,682 and 9674 patients). Pioglitazone neither significantly increased nor reduced the risk of MACE, all-cause mortality, and HHF in comparison with placebo/active comparators (MH-OR: 0.90, 95% CI 0.78-1.03, 0.91, 95% CI 0.77, 1.09, and 1.16, 95% CI 0.73, 1.83, respectively). Pioglitazone was associated with a significant reduction of MACE in patients with prior cardiovascular events (MH-OR 0.84, 95% CI 0.72-0.99)., Conclusions: This meta-analysis showed no significant effects of pioglitazone on incident MACE, all-cause mortality, and HHF., Competing Interests: Declaration of competing interest MM has received speaking fees from Astra Zeneca, Bristol Myers Squibb, Boehringer-Ingelheim, Eli-Lilly, Merck, Novo Nordisk, Sanofi, and Novartis and research grants from Bristol Myers Squibb; EM has received consultancy fees from Merck and Novartis speaking fees from Astra Zeneca, Bristol Myers Squibb, Boehringer-Ingelheim, Eli-Lilly, Merck, Novo Nordisk, Sanofi, and Novartis and research grants from Merck, Novartis, and Takeda. AG has received speaking fees and/or advisory board invitations from Abbott, Astra Zeneca, Boehringer-Ingelheim, Eli Lilly, MSD, Mundipharma, Novo-Nordisk, Sanofi. The other authors did not report any relevant conflicts of interest. All the authors approved the final version of this manuscript. Dr. Edoardo Mannucci is the person who takes full responsibility for the work as a whole, including the study design, access to data, and the decision to submit and publish the manuscript., (Copyright © 2021 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Nuclear Magnetic Resonance (NMR) based metabolomic analysis of whole saliva has provided potential diagnostic biomarkers for numerous human diseases contributing to a better understanding of their mechanisms. However, a comprehensive interpretation of the significance of metabolites in whole, parotid, and submandibular/sublingual saliva subtypes is still missing. Precision and reproducibility of sample preparation is an essential step. Here, we present a simple and efficient protocol for saliva 1 H-NMR metabolic profiling. This procedure has been specifically designed and optimized for the identification and quantification of low concentration metabolites (as low as 1.1 μM) and is suitable for all the saliva subtypes., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose To estimate the prevalence of current and past COVID-19 in Ohio adults. Methods We used stratified, probability-proportionate-to-size cluster sampling. During July 2020, we enrolled 727 randomly-sampled adult English- and Spanish-speaking participants through a household survey. Participants provided nasopharyngeal swabs and blood samples to detect current and past COVID-19. We used Bayesian latent class models with multilevel regression and poststratification to calculate the adjusted prevalence of current and past COVID-19. We accounted for the potential effects of non-ignorable non-response bias. Results The estimated statewide prevalence of current COVID-19 was 0.9% (95% credible interval: 0.1%-2.0%), corresponding to ∼85,000 prevalent infections (95% credible interval: 6,300-177,000) in Ohio adults during the study period. The estimated statewide prevalence of past COVID-19 was 1.3% (95% credible interval: 0.2%-2.7%), corresponding to ∼118,000 Ohio adults (95% credible interval: 22,000-240,000). Estimates did not change meaningfully due to non-response bias. Conclusions Total COVID-19 cases in Ohio in July 2020 were approximately 3.5 times as high as diagnosed cases. The lack of broad COVID-19 screening in the United States early in the pandemic resulted in a paucity of population-representative prevalence data, limiting the ability to measure the effects of statewide control efforts., (Copyright © 2021. Published by Elsevier Inc.)

Aim: Patient education is an essential component of the treatment of type 2 diabetes mellitus (T2DM). The present meta-analysis was aimed at verifying the efficacy of group-based versus individual education for self-management in patients with T2DM., Data Synthesis: A Medline and Embase search up to January 1st, 2021, was performed, including Randomized Controlled Trials (RCT) with duration>6 months, enrolling patients with T2DM and comparing individual-based with group-based educational programs. The primary outcome was endpoint HbA1c; secondary endpoints were lipid profile, body weight, blood pressure, patients' adherence/knowledge, and quality of life. The weighed difference in means (WMD) and Mantel-Haenzel Odds Ratio (MH-OR), with 95% Confidence Interval (CI), were calculated. We retrieved 14 RCT. No significant between-group difference in HbA1c (WMD -0.39[-0.89; 0.09] mmol/mol, p = 0.11) was observed. At metaregression analyses, longer trial duration, higher baseline mean age and duration of diabetes, and lower baseline HbA1c were correlated with greater efficacy of group-based programs in reducing HbA1c. When analyzed separately, trials excluding insulin-treated patients showed a significant reduction of HbA1c in favor of group education., Conclusions: In patients with T2DM, group education has similar efficacy as individual education on glucose control. Group programs are associated with an improved quality of life and patients' knowledge., Prospero and Osf Registration: ID243149., Competing Interests: Declaration of competing interest EM has received consultancy fees from Merck and Novartis speaking fees from Astra Zeneca, Bristol Myers Squibb, Boehringer-Ingelheim, Eli-Lilly, Merck, Novo Nordisk, Sanofi, and Novartis, and research grants from Merck, Novartis, and Takeda. MM has received speaking fees from Astra Zeneca, Bristol Myers Squibb, Boehringer-Ingelheim, Eli-Lilly, Merck, Novo Nordisk, Sanofi, and Novartis and research grants from Bristol Myers Squibb; AB, BDA, MG, MLM, MT and AG have no relevant conflicts of interest to declare. All the authors approved the final version of this manuscript. Dr. Edoardo Mannucci is the person who takes full responsibility for the work as a whole, including the study design, access to data, and the decision to submit and publish the manuscript., (Copyright © 2021 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Purpose: With the increase in the aging population, the level of frailty has become an important metric for assessing preoperative patient risk. Although medical and surgical specialties continue to adopt and standardize the use of frailty instruments, few studies within the plastic surgery literature have utilized such instruments to predict poor postoperative outcomes. The purpose of this article is two-fold: (1) to provide a comprehensive review of the existing frailty instruments and (2) to summarise the existing evidence regarding the role of pre-operative frailty assessments on peri‑operative morbidity and mortality in plastic surgery., Methods: This systematic review was registered a priori on the Open Science Framework (https://osf.io/vfzw8). A computerized database search of Ovid MEDLINE, EMBASE, and Cochrane was performed from database inception to December 13, 2020. All articles that examined the effect of preoperative patient frailty on perioperative morbidity and mortality outcomes following plastic surgery interventions were included for data extraction., Results: From the 11 studies included in this review, ten unique frailty instruments were identified. The modified Frailty Index (mFI) and the Fried Frailty Index (FFI) were the most commonly reported frailty measurement tools; however, the FRAIL scale was the only outcome measure identified to be valid, reliable, and responsive to change. Regardless of the frailty measure used, nearly all studies reported that worse surgical outcomes were associated with a higher patient frailty score., Conclusion: There is a strong association between higher frailty scores and worse postoperative outcomes in plastic surgery. The FRAIL scale is a clinimetrically sound frailty instrument that should be used in all patients to assess perioperative risk in plastic surgery., Competing Interests: Declaration of Competing Interest Dr. Achilles Thoma may receive royalties from the sale of his book “Evidence-Based Medicine: A Guide to Understanding and Interpreting the Surgical Literature” published with Springer Nature in 2019. No other authors have any conflicts of interest to disclose., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Aim: Alpha-glucosidase inhibitors are approved drugs for treating type 2 diabetes (T2DM); however, their effects on mortality and cardiovascular safety are unclear. This meta-analysis was aimed at evaluating the effects of alpha-glucosidase inhibitors on all-cause mortality and major cardiovascular events (MACE)., Data Synthesis: A Medline, Embase, Cochrane database searching for alpha-glucosidase inhibitors was performed up to July 1st, 2021. All randomized controlled trials (RCT) with a duration ≥52 weeks and comparing the effects of alpha-glucosidase inhibitors with placebo or active drugs were collected. Further inclusion criteria were: RCT reporting MACE within their primary outcome, or as pre-defined secondary outcome; and RCT enrolling at least 100 patients with T2DM. Mantel-Haenszel odds ratio (MH-OR) with 95% confidence intervals were calculated for the aforementioned outcomes. A total of eight RCTs, enrolling 1124 and 908 patients on alpha-glucosidase inhibitors and comparators, respectively, were identified. No trials reported information on MACE. Treatment with alpha-glucosidase inhibitors was not associated with a significant increase of all-cause mortality compared with other therapies or no therapy/placebo (MH-OR 0.76 [0.28; 2.05])., Conclusions: The evidence of beneficial or detrimental effects of alpha-glucosidase inhibitors on all-cause mortality and cardiovascular events is not sufficient to draw any conclusions., Competing Interests: Declaration of competing interest MM has received speaking fees from Astra Zeneca, Bristol Myers Squibb, Boehringer-Ingelheim, Eli-Lilly, Merck, Novo Nordisk, Sanofi, and Novartis and research grants from Bristol Myers Squibb; EM has received consultancy fees from Merck and Novartis speaking fees from Astra Zeneca, Bristol Myers Squibb, Boehringer-Ingelheim, Eli-Lilly, Merck, Novo Nordisk, Sanofi, and Novartis and research grants from Merck, Novartis, and Takeda. All the other authors have no conflict of interests to declare. All the authors approved the final version of the manuscript. Dr. Edoardo Mannucci is the person who takes full responsibility for the work as a whole, including the study design, access to data, and the decision to submit and publish the manuscript., (Copyright © 2021 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Aims: Meta-analyses of randomized trials on Dipeptidyl Peptidase-4 inhibitors (DPP4i) reported discordant results on major cardiovascular events (MACE), mortality, and heart failure. Aim of this meta-analysis of randomized trials is the assessment of the cardiovascular safety of DPP4i., Data Synthesis: A Medline, Embase, Cochrane database search for sitagliptin, vildagliptin, omarigliptin, saxagliptin, alogliptin, trelagliptin, anagliptin, linagliptin, gemigliptin, evogliptin, and teneligliptin was performed up to up January 1st, 2020. All trials with a duration ≥24 weeks and comparing the effects of DPP4i with placebo or active drugs were collected. Mantel-Haenszel odds ratio (MH-OR) with 95% Confidence Interval (95% CI) was calculated for all outcomes defined above. A total of 182 eligible trials were identified. DPP-4i were not associated with an increased risk of MACE (MH-OR 0.99 [0.93, 1.04]), all-cause mortality (MH-OR 0.99 [0.93, 1.06]), and heart failure (MH-OR 1.05 [0.96, 1.15]) with no significant differences across individual molecules, except for saxagliptin, which was associated with an increased risk of heart failure., Conclusions: As a class, DPP4i are not associated with any increase or reduction of MACE, all-cause mortality, and heart failure. Saxagliptin seems to be associated with an increased risk of hospitalization for heart failure., Competing Interests: Declaration of competing interest BN is presently an employee of Novo Nordisk; CM, MG, and AG have no conflicts of interest to declare; MM has received speaking fees from Astra Zeneca, Bristol Myers Squibb, Boehringer-Ingelheim, Eli-Lilly, Merck, Novo Nordisk, Sanofi, and Novartis and research grants from Bristol Myers Squibb; EM has received consultancy fees from Merck and Novartis, speaking fees from Astra Zeneca, Bristol Myers Squibb, Boehringer-Ingelheim, Eli-Lilly, Merck, Novo Nordisk, Sanofi, and Novartis, and research grants from Merck, Novartis, and Takeda. All the authors approved the final version of this manuscript. Dr. Matteo Monami is the person who takes full responsibility for the work as a whole, including the study design, access to data, and the decision to submit and publish the manuscript., (Copyright © 2021 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Pancreatic cancer (PC) is a common cause of cancer-related death, due to difficulties in detecting early-stage disease, to its aggressive behaviour, and to poor response to systemic therapy. Therefore, developing strategies for early diagnosis of resectable PC is critical for improving survival. Diabetes mellitus is another major public health problem worldwide. Furthermore, diabetes can represent both a risk factor and a consequence of PC: nowadays, the relationship between these two diseases is considered a high priority for research. New-onset diabetes can be an early manifestation of PC, especially in a thin adult without a family history of diabetes. However, even if targeted screening for patients at higher risk of PC could be a promising approach, this is not recommended in asymptomatic adults with new-onset diabetes, due to the much higher incidence of hyperglycaemia than PC and to the lack of a safe and affordable PC screening test. Prompted by a well-established and productive multidisciplinary cooperation, the Italian Association of Medical Oncology (AIOM), the Italian Medical Diabetologists Association (AMD), the Italian Society of Endocrinology (SIE), and the Italian Society of Pharmacology (SIF) here review available evidence on the mechanisms linking diabetes and PC, addressing the feasibility of screening for early PC in patients with diabetes, and sharing a set of update statements with the aim of providing a state-of-the-art overview and a decision aid tool for daily clinical practice., Competing Interests: Disclosure SA has served as a consultant for Menarini. GB has served as consultant for Roche, Servier, Celgene, Ipsen, Sanofi, Merck Serono. NS has served as a consultant for Merck Sharp & Dohme, Roche, Isheo, Iquvia. All other authors have declared no conflicts of interest., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Most anticancer molecules are administered in body-size-based dosing schedules, bringing up unsolved issues regarding pharmacokinetic data in heavy patients. The worldwide spread of obesity has not been matched by improved methods and strategies for tailored drug dosage in this population. The weight or body surface area (BSA)-based approaches may fail to fully reflect the complexity of the anthropometric features besides obesity in cancer patients suffering from sarcopenia. Likewise, there is a lack of pharmacokinetic data on obese patients for the majority of chemotherapeutic agents as well as for new target drugs and immunotherapy. Therefore, although the available findings point to the role of dose intensity in cancer treatment, and support full weight-based dosing, empirical dose capping often occurs in clinical practice in order to avoid toxicity. Thus a panel of experts of the Associazione Italiana Oncologia Medica (AIOM), Associazione Medici Diabetologi (AMD), Società Italiana Endocrinologia (SIE), and Società Italiana Farmacologia (SIF), provides here a consensus statement for appropriate cytotoxic chemotherapy and new biological cancer drug dosing in obese patients., Competing Interests: Disclosure NS has served as consultant for Celgene and Isheo. GB has served as consultant for Roche, Servier, Celgene, Ipsen, Sanofi, Merck Serono. All other authors have declared no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Among their various functions, the members of the cerato-platanin family can stimulate plants' defense responses and induce resistance against microbial pathogens. Recent results suggest that conserved loops, also involved in chitin binding, might be a structural motif central for their eliciting activity. Here, we focus on cerato-platanin and its orthologous cerato-populin, searching for a rationale of their diverse efficiency to elicit plants' defense and to interact with oligosaccharides. A 3D model of cerato-populin has been generated by homology modeling using the NMR-derived cerato-platanin structure as template, and it has been validated by fitting with residual dipolar couplings. Loops β1-β2 and β2-β3 have been indicated as important for some CPPs members to express their biological function. When compared to cerato-platanin, in cerato-populin they present two mutations and an insertion that significantly modify their electrostatic surface. NMR relaxation experiments point to a reduced conformational plasticity of cerato-populin loops with respect to the ones of cerato-platanin. The different electrostatic surface of the loops combined with a distinct network of intra-molecular interactions are expected to be factors that, by leading to a diverse spatial organization and dissimilar collective motions, can regulate the eliciting efficacy of the two proteins and their affinity for oligosaccharides., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Volume overload and fluid congestion are a fundamental issue in the assessment and management of patients with heart failure (HF). Recent studies have found that in acute decompensated heart failure (ADHF), right and left-sided pressures generally start to increase before any notable weight changes take place preceding an admission. ADHF may be a problem of volume redistribution among different vascular compartments instead of, or in addition to, fluid shift from the interstitial compartment. Thus, identifying heterogeneity of volume overload would allow guidance of tailored therapy. A comprehensive evaluation of congestive HF needs to take into account myriad parameters, including physical examination, echocardiographic values, and biomarker serum changes. Furthermore, potentially useful diagnostic tools include bioimpedance to measure intercompartmental fluid shifts, and evaluation of ultrasound lung comets to detect extravascular lung water., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objectives: The aim of this study was to evaluate early results of valve-in-valve (ViV) transcatheter aortic valve replacement (TAVR) versus redo surgical aortic valve replacement (SAVR) for structural valve degeneration (SVD)., Background: ViV TAVR has been increasingly used for SVD, but it remains unknown whether it produces better or at least comparable results as redo SAVR., Methods: Observational studies comparing ViV TAVR and redo SAVR were identified in a systematic search of published research. Random-effects meta-analysis was performed, comparing clinical outcomes between the 2 groups., Results: Twelve publications including a total of 16,207 patients (ViV TAVR, n = 8,048; redo SAVR, n = 8,159) were included from studies published from 2015 to 2020. In the pooled analysis, ViV TAVR was associated with lower rates of 30-day mortality overall (odds ratio [OR]: 0.53; 95% confidence interval [CI]: 0.32 to 0.87; p = 0.017) and for matched populations (OR: 0.419; 95% CI: 0.278 to 0.632; p = 0.003), stroke (OR: 0.65; 95% CI: 0.55 to 0.76; p < 0.001), permanent pacemaker implantation (OR: 0.73; 95% CI: 0.22 to 2.43; p = 0.536), and major bleeding (OR: 0.49; 95% CI: 0.26 to 0.93; p = 0.034), as well as with shorter hospital stay (OR: -3.30; 95% CI: -4.52 to -2.08; p < 0.001). In contrast, ViV TAVR was associated with higher rates of myocardial infarction (OR: 1.50; 95% CI: 1.01 to 2.23; p = 0.045) and severe patient-prosthesis mismatch (OR: 4.63; 95% CI: 3.05 to 7.03; p < 0.001). The search revealed an important lack of comparative studies with long-term results., Conclusions: ViV TAVR is a valuable option in the treatment of patients with SVD because of its lower incidence of post-operative complications and better early survival compared with redo SAVR. However, ViV TAVR is associated with higher rates of myocardial infarction and severe patient-prosthesis mismatch., Competing Interests: Author Disclosures Dr. Pibarot has echocardiography Core Laboratory contracts with Edwards Lifesciences, for which he receives no direct compensation. Dr. Clavel has computed tomography Core Laboratory contract with Edwards Lifesciences, for which she receives no direct compensation and received research grant from Medtronic. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Purpose: In the thumb carpometacarpal (CMC) joint osteoarthritis (OA) literature, there is substantial heterogeneity in outcome and outcome measure reporting. This could be rectified by a standardized core outcome set (COS). This study aimed to identify a comprehensive list of outcomes and outcome measures for thumb CMC joint OA, which represents the first step in developing a COS., Methods: A computerized search of MEDLINE, EMBASE, Cochrane, and CINAHL was performed to identify randomized controlled trials, as well as observational studies involving at least 50 participants aged greater than 18 years undergoing surgery for thumb CMC joint OA. Reported outcomes and outcome measures were extracted from these trials and summarized., Results: This search yielded 3,498 unique articles, 97 of which were used for analysis. A total of 33 unique outcomes and 25 unique outcome measures were identified. The most frequently used outcomes were complications (78), postoperative pain (73), radiologic outcomes (64), and grip strength (63). Within each reported outcome, there was substantial variation in how the outcome was measured. Of the 25 unique outcome measures, 10 were validated. Of the remaining 15, 12 were created ad hoc by the author. The Disabilities of the Arm, Shoulder, and Hand questionnaire was the most commonly reported outcome measure (34%)., Conclusions: There is a lack of consensus on critical outcomes after surgery for thumb CMC joint OA. A standardized COS created by stakeholder consensus would improve the consistency and therefore the quality of future research., Clinical Relevance: This systematic review of outcomes represents the first step in developing a core outcome set for thumb CMC joint OA., (Copyright © 2021 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.)

Purpose: Comparison between studies assessing outcomes after surgical treatment of cubital tunnel syndrome (CuTS) has proven to be difficult owing to variations in outcome reporting. This study aimed to identify outcomes and outcome measures used to evaluate postoperative results for CuTS., Methods: We performed computerized database searches of MEDLINE and EMBASE. Studies with 20 or more patients aged 18 and older who were undergoing medial epicondylectomy, endoscopic decompression, open simple decompression, or decompression with subcutaneous, submuscular, or intramuscular transposition for ulnar neuropathy at the elbow were included. Outcomes and outcome measures were extracted and tabulated., Results: Of the 101 studies included, 45 unique outcomes and 31 postoperative outcome measures were identified. These included 7 condition-specific, clinician-reported instruments; 4 condition-specific, clinician-reported instruments; 8 patient-reported, generic instruments; 11 clinician-generated instruments; and one utility measure. Outcome measures were divided into 6 unique domains. Overall, 60% of studies used condition-specific outcome measures. The frequency of any condition-specific outcome measure ranged from 1% to 37% of included studies., Conclusions: There is marked heterogeneity in outcomes and outcome measures used to assess CuTS. A standardized core outcome set is needed to compare results of various techniques of cubital tunnel decompression., Clinical Relevance: This study builds on the existing literature to support the notion that there is marked heterogeneity in outcomes and outcome measures used to assess CuTS. The authors believe that a future standardized set of core outcomes is needed to limit heterogeneity among studies assessing postoperative outcomes in CuTS to compare these interventions more easily and pool results in the form of systematic reviews and meta-analyses., (Copyright © 2020 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.)

Single nucleotide polymorphism (SNP) genotyping tools, which can analyse thousands of SNPs covering the whole genome, have opened new opportunities to estimate the inbreeding level of animals directly using genome information. One of the most commonly used genomic inbreeding measures considers the proportion of the autosomal genome covered by runs of homozygosity (ROH), which are defined as continuous and uninterrupted chromosome portions showing homozygosity at all loci. In this study, we analysed the distribution of ROH in three commercial pig breeds (Italian Large White, n = 1968; Italian Duroc, n = 573; and Italian Landrace, n = 46) and four autochthonous breeds (Apulo-Calabrese, n = 90; Casertana, n = 90; Cinta Senese, n = 38; and Nero Siciliano, n = 48) raised in Italy, using SNP data generated from Illumina PorcineSNP60 BeadChip. We calculated ROH-based inbreeding coefficients (FROH) using ROH of different minimum length (1, 2, 4, 8, 16 Mbp) and compared them with several other genomic inbreeding coefficients (including the difference between observed and expected number of homozygous genotypes (FHOM)) and correlated all these genomic-based measures with the pedigree inbreeding coefficient (FPED) calculated for the pigs of some of these breeds. Autochthonous breeds had larger mean size of ROH than all three commercial breeds. FHOM was highly correlated (0.671 to 0.985) with FROH measures in all breeds. Apulo-Calabrese and Casertana had the highest FROH values considering all ROH minimum lengths (ranging from 0.273 to 0.189 and from 0.226 to 0.152, moving from ROH of minimum size of 1 Mbp (FROH1) to 16 Mbp (FROH16)), whereas the lowest FROH values were for Nero Siciliano (from 0.072 to 0.051) and Italian Large White (from 0.117 to 0.042). FROH decreased as the minimum length of ROH increased for all breeds. Italian Duroc had the highest correlations between all FROH measures and FPED (from 0.514 to 0.523) and between FHOM and FPED (0.485). Among all analysed breeds, Cinta Senese had the lowest correlation between FROH and FPED. This might be due to the imperfect measure of FPED, which, mainly in local breeds raised in extensive production systems, cannot consider a higher level of pedigree errors and a potential higher relatedness of the founder population. It appeared that ROH better captured inbreeding information in the analysed breeds and could complement pedigree-based inbreeding coefficients for the management of these genetic resources.

Ham weight loss at first salting (HWLFS) is a meat quality parameter used to assess the suitability of the hams for salting and seasoning. The relationships between HWLFS and 17 performance, carcass and raw ham quality parameters were investigated in 260 performance tested Italian Large White heavy pigs. HWLFS was affected by slaughter day and visible intermuscular fat of trimmed hams whereas sex did not affect its variability. Residual correlations of HWLFS with backfat thickness (BFT; r = -0.51) and lean cuts (LC; r = +0.51) were stronger than with ham weight at trimming (r = +0.40) and after first salting (r = +0.37). Significant correlations of HWLFS with fresh ham quality traits ranged from +0.16 to -0.25. BFT, LC and pH 24h were the main predictors of HWLFS in the regression model. Results from this study indicated that higher ham fat coverage and pH 24h and lower LC could reduce HWLFS of green hams for Protected Designation of Origin products., Competing Interests: Declaration of competing interest The authors declare that they do not have competing interests., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: In head and neck squamous cell carcinoma (HNSCC) 30% of cN0 patients have occult metastasis. LN invasion is a major prognostic factor. Sentinel lymph node (SLN) is an option for cN0 neck management. One-step nucleic acid amplification (OSNA) used to analyze SLN in breast cancer is also a candidate to get more reliable intraoperative HNSCC lymph node (LN) staging., Objective: To compare OSNA analysis to pathological analysis in cN0 HNSCC., Materials and Methods: 157 LN from 26 cN0 HNSCC patients were prospectively analyzed (6.3LN/patient). Exclusion criteria were previous surgery or radiotherapy. Each node was cut into 4 equal pieces alternatively sent to pathological analysis and OSNA technique. IHC CK19 was performed on the primary tumor biopsy and RT-qPCR of CK19, PVA and EPCAM on the LN lysate of discordant cases., Results: OSNA was able to provide intraoperative result in all patients. OSNA detected 21 metastases. There were 139 concordant LN (88.5%). There were 18 initial discordant LN (11.5%), 13 (8.3%) were OSNA positive/pathological analysis negative, 5 (3.2%) were OSNA negative/pathological analysis positive. After elimination of allocation bias, false negative rate was 1.3%, sensitivity and specificity were 90% and 95.6%, PPV and NPV were 75% and 98.5%., Conclusion: Our results suggest that OSNA should be considered to improve SNB analysis both for increasing micro metastasis diagnosis and offer extemporaneous results. Study registered under clinicaltrials.gov database number NCT02852343., Competing Interests: Declaration of Competing Interest This work was funded by the Translational Research Committee of the Teaching Hospital of Rennes, France. Sysmex®, Kobe, Japan provided the OSNA reagent., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Single nucleotide polymorphisms (SNPs) able to describe population differences can be used for important applications in livestock, including breed assignment of individual animals, authentication of mono-breed products and parentage verification among several other applications. To identify the most discriminating SNPs among thousands of markers in the available commercial SNP chip tools, several methods have been used. Random forest (RF) is a machine learning technique that has been proposed for this purpose. In this study, we used RF to analyse PorcineSNP60 BeadChip array genotyping data obtained from a total of 2737 pigs of 7 Italian pig breeds (3 cosmopolitan-derived breeds: Italian Large White, Italian Duroc and Italian Landrace, and 4 autochthonous breeds: Apulo-Calabrese, Casertana, Cinta Senese and Nero Siciliano) to identify breed informative and reduced SNP panels using the mean decrease in the Gini Index and the Mean Decrease in Accuracy parameters with stability evaluation. Other reduced informative SNP panels were obtained using Delta, Fixation index and principal component analysis statistics, and their performances were compared with those obtained using the RF-defined panels using the RF classification method and its derived Out Of Bag rates and correct prediction proportions. Therefore, the performances of a total of six reduced panels were evaluated. The correct assignment of the animals to its breed was close to 100% for all tested approaches. Porcine chromosome 8 harboured the largest number of selected SNPs across all panels. Many SNPs were included in genomic regions in which previous studies identified signatures of selection or genes (e.g. ESR1, KITL and LCORL) that could contribute to explain, at least in part, phenotypically or economically relevant traits that might differentiate cosmopolitan and autochthonous pig breeds. Random forest used as preselection statistics highlighted informative SNPs that were not the same as those identified by other methods. This might be due to specific features of this machine learning methodology. It will be interesting to explore if the adaptation of RF methods for the identification of selection signature regions could be able to describe population-specific features that are not captured by other approaches.

Uterine cancer is the 6th leading cause of cancer death amongst American women. Most uterine cancers are endometrial carcinomas (ECs), which are classified into histological subtypes including endometrioid, serous, and clear cell ECs. Somatic copy number alterations (SCNAs) are frequent in serous EC, infrequent in endometrioid ECs, and poorly defined in clear cell ECs. The purpose of this study was to evaluate the occurrence of SCNAs in clinically diagnosed clear cell ECs. Paired tumor-normal DNAs for 51 ECs were hybridized to Illumina Infinium HumanHap650Y or Human660W-Quad Beadchips. Copy number calls were made using the Hidden Markov Model based SNP-FASST2 segmentation algorithm within Nexus Copy Number software (v.6.1). High-level SCNAs were defined as gain of ≥5 copies or homozygous deletion, both <10Mb. GISTIC 1.0, in Nexus, was used to identify statistically significant SCNAs, corrected for multiple testing. One or more high-level SCNAs were detected in 50% of 6 clear cell ECs, 78.6% of 28 serous ECs, and 17.6% of 17 endometrioid ECs. A positive association was found between high-level SCNAs and TP53 mutation across ECs (two-tailed p value<0.0001). Classifying tumors according to POLE, MSI, and TP53 status yielded four molecular subgroups; copy number altered tumors were more frequent in the TP53-mutated subgroup (95.8%) than in the unspecified subgroup (22.2%), and absent from the POLE and MSI subgroups. In conclusion, our study provides evidence of inter-tumor heterogeneity in the extent to which SCNAs occur in clinically diagnosed clear cell EC, and across molecular subgroups of EC. The co-occurrence of high-level SCNAs and TP53 mutations in some clear cell ECs is consistent with the view that a subset of clinically diagnosed clear cell ECs have molecular similarities to serous ECs., (Copyright © 2019. Published by Elsevier Inc.)

The efficiency of calcium phosphate (CaP) bone substitutes can be improved by tuning their resorption rate. The influence of both crystal orientation and ion doping on resorption is here investigated for beta-tricalcium phosphate (β-TCP). Non-doped and Mg-doped (1 and 6 mol%) sintered β-TCP samples were immersed in acidic solution (pH 4.4) to mimic the environmental conditions found underneath active osteoclasts. The surfaces of β-TCP samples were observed after acid-etching and compared to surfaces after osteoclastic resorption assays. β-TCP grains exhibited similar patterns with characteristic intra-crystalline pillars after acid-etching and after cell-mediated resorption. Electron BackScatter Diffraction analyses, coupled with Scanning Electron Microscopy, Inductively Coupled Plasma-Mass Spectrometry and X-Ray Diffraction, demonstrated the influence of both grain orientation and doping on the process and kinetics of resorption. Grains with c-axis nearly perpendicular to the surface were preferentially etched in non-doped β-TCP samples, whereas all grains with simple axis (a, b or c) nearly normal to the surface were etched in 6 mol% Mg-doped samples. In addition, both the dissolution rate and the percentage of etched surface were lower in Mg-doped specimens. Finally, the alignment direction of the intra-crystalline pillars was correlated with the preferential direction for dissolution. STATEMENT OF SIGNIFICANCE: The present work focuses on the resorption behavior of calcium phosphate bioceramics. A simple and cost-effective alternative to osteoclast culture was implemented to identify which material features drive resorption. For the first time, it was demonstrated that crystal orientation, measured by Electron Backscatter Diffraction, is the discriminating factor between grains, which resorbed first, and grains, which resorbed slower. It also elucidated how resorption kinetics can be tuned by doping β-tricalcium phosphate with ions of interest. Doping with magnesium impacted lattice parameters. Therefore, the crystal orientations, which preferentially resorbed, changed, explaining the solubility decrease. These important findings pave the way for the design of optimized bone graft substitutes with tailored resorption kinetics., (Copyright © 2019 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

In 1988, two unrelated papers reported the discovery of peptide vectors with innate cell translocation properties, setting the ground for a new area of research that over the years has grown into considerable therapeutic potential. The vectors, named cell-penetrating peptides (CPPs), constitute a now large and diversified family, sharing the extraordinary ability to diffuse unaltered across cell membranes while ferrying diverse associated cargos. Such properties have made CPPs ideal tools for delivery of nucleic acids, proteins and other therapeutic/diagnostic molecules to cells and tissues via covalent conjugation or complexation. This year 2018 marks the 30 th anniversary of a peptide research landmark opening new perspectives in drug delivery. Given its vastness, exhaustive coverage of the main features and accomplishments in the CPP field is virtually impossible. Hence this manuscript, after saluting the above 30 th jubilee, focuses by necessity on the most recent contributions, providing a comprehensive list of recognized CPPs and their latest-reported applications over the last two years. In addition, it thoroughly reviews three areas of peptide vector research of particular interest to us, namely (i) efficient transport of low-bioavailability drugs into the brain; (ii) CPP-delivered disruptors of G protein-coupled receptor (GPCRs) heteromers related to several disorders, and (iii) CPP-mediated delivery of useful but poorly internalized drugs into parasites., (Copyright © 2018. Published by Elsevier Inc.)