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The aim of this study was to build and validate an artificial neural network (ANN) algorithm to predict sleep using data from a portable monitor (Biologix system) consisting of a high-resolution oximeter with built-in accelerometer plus smartphone application with snoring recording and cloud analysis. A total of 268 patients with suspected obstructive sleep apnea (OSA) were submitted to standard polysomnography (PSG) with simultaneous Biologix (age: 56 ± 11 years; body mass index: 30.9 ± 4.6 kg/m 2 , apnea-hypopnea index [AHI]: 35 ± 30 events/h). Biologix channels were input features for construction an ANN model to predict sleep. A k-fold cross-validation method (k=10) was applied, ensuring that all sleep studies (N=268; 246,265 epochs) were included in both training and testing across all iterations. The final ANN model, evaluated as the mean performance across all folds, resulted in a sensitivity, specificity and accuracy of 91.5%, 71.0% and 86.1%, respectively, for detecting sleep. As compared to the oxygen desaturation index (ODI) from Biologix without sleep prediction, the bias (mean difference) between PSG-AHI and Biologix-ODI with sleep prediction (Biologix-Sleep-ODI) decreased significantly (3.40 vs. 1.02 events/h, p<0.001). We conclude that sleep prediction by an ANN model using data from oximeter, accelerometer, and snoring is accurate and improves Biologix system OSA diagnostic precision. [ABSTRACT FROM AUTHOR]

A polymerase chain reaction (PCR) survey was performed at an amateur parrot breeding facility in Italy to investigate the presence and molecular characteristics of adenoviruses. Eighty psittacine birds, belonging to seven parrot species, were sampled by cloacal swabs; in addition, 15 livers were collected from specimens that were found dead. Seventy-two out of 95 samples collected were positive for adenoviruses, with a prevalence rate of 75.8%. All seven psittacine species tested positive for at least one genus of the family Adenoviridae; notably, adenoviral infection was found for the first time in the hooded parrot (Psephotellus dissimilis). Based on the sequences and phylogenetic analysis, 57 sequences were psittacine adenovirus 2, seven sequences were duck adenovirus 1 and two sequences were identified as psittacine adenovirus 5. The six remaining sequences showed low nucleotide and amino acid identity with the reference strains of accepted species or types, revealing the presence of novel adenoviruses belonging to the genera Aviadenovirus, Barthadenovirus and Siadenovirus. There were identical adenovirus sequences in both apparently healthy and dead birds suggesting that further investigation into the role and impact of these viruses on the health of psittacine birds is warranted. [ABSTRACT FROM AUTHOR]

Cannabidiol (CBD) has gained significant attention as a complementary and alternative medicine due to its promising therapeutic properties. However, CBD faces obstacles when administered orally due to its poor solubility in water, leading to limited absorption into the bloodstream and low and variable bioavailability. Therefore, the development of innovative delivery approaches that can enhance CBD's bioavailability, facilitate administration, and promote patient adherence is crucial. We propose a new approach for buccal delivery of CBD based on a self-assembling nanoemulsion (NE) made of a mixture of surfactants (Tween 80 and Labrasol) and medium chain triglycerides (MCTs). The NE formulation showed properties suitable for buccal administration, including appropriate size, CBD content, and surface properties, and, if compared to a CBD-MCT solution, it exhibited better control of administered doses, faster dissolution in buccal medium, and enhanced stability. The CBD-NE effectively released its active load within 5 h, remained stable even when diluted in simulated buccal fluids, and could be easily administered through a commercially available spray, providing consistent and reproducible doses of NE with optimized properties. In vitro permeation studies demonstrated that the CBD-NE facilitated swift and consistent permeation through the buccal mucosa, resulting in a higher concentration in the acceptor compartment compared to CBD-MCT. Furthermore, the in vivo study in mice showed that a single buccal administration of CBD-NE led to a quicker onset of action than a CBD solution in MCT, while maintaining the same plasma levels over time and leading to typically higher plasma concentrations compared to those usually achieved through oral administration. In conclusion, our CBD-NE represents a promising alternative formulation strategy for buccal CBD administration, overcoming the challenges associated with conventional formulations such as variable bioavailability and low control of administered doses. [ABSTRACT FROM AUTHOR]

Italy has a long history in beef production, with local breeds such as Marchigiana, Chianina, Romagnola, Maremmana, and Podolica which produce high-quality meat. Selection has improved meat production, precocity, growth ability and muscle development, but the genetic determinism of such traits is mostly unknown. Using 33K SNPs-data from young bulls (N = 4064) belonging to these five Italian breeds, we demonstrated that the Maremmana and Podolica rustic breeds are closely related, while the specialised Marchigiana, Chianina, and Romagnola breeds are more differentiated. A genome-wide association study for growth and muscle development traits (average daily gain during the performance test, weight at 1 year old, muscularity) was conducted in the five Italian breeds. Results indicated a region on chromosome 2, containing the myostatin gene (MSTN), which displayed significant genome-wide associations with muscularity in Marchigiana cattle, a breed in which the muscle hypertrophy phenotype is segregating. Moreover, a significant SNP on chromosome 14 was associated, in the Chianina breed, to muscularity. The identification of diverse genomic regions associated with conformation traits might increase our knowledge about the genomic basis of such traits in Italian beef cattle and, eventually, such information could be used to implement marker-assisted selection of young bulls tested in the performance test. [ABSTRACT FROM AUTHOR]

Fifty-seven Gallid alphaherpesvirus 2 (GaHV-2) isolates, collected during a 30-year period (1990–2019) from commercial poultry flocks affected by Marek's disease (MD), were molecularly characterised. The GaHV-2 meq gene was amplified and sequenced to evaluate the virus virulence, based on the number of PPPPs within the proline-rich repeats (PRRs) of its transactivation domain. The present illustration of virus virulence evaluation on a large scale of field virus isolates by molecular analysis exemplifies the practical benefit and usefulness of the molecular marker in commercial GaVH-2 isolates. The alternative assay of GaVH-2 virulence pathotyping is the classical Gold Standard ADOL method, which is difficult and impossible to employ on a large scale using the Specific Pathogen Free (SPF) chicks of the ADOL strains kept in isolators for two months. The phylogenetic analysis performed in the present study showed that the meq gene amino acid sequences of the 57 Israeli strains divide into 16 phylogenetic branches. The virulence evaluation was performed in comparison with 36 GaHV-2 prototype strains, previously characterised by the in vivo Gold Standard ADOL assay. The results obtained revealed that the GaHV-2 strains circulating in Israel have evolved into a higher virulence potential during the years, as the four-proline stretches number in the meq gene decreased over the investigated period, typically of very virulent virus prototypes. The present study supports the meq gene molecular markers for the assessment of field GaVH-2 strains virulence. [ABSTRACT FROM AUTHOR]

Treatment of lenalidomide refractory (Len-R) multiple myeloma (MM) patients still represents an unmet clinical need. In the last years, daratumumab-bortezomib-dexamethasone (D-VD) combination was extensively used in this setting, even though only a small fraction of Len-R patients was included in the pivotal trial. This real-life study aimed to evaluate the efficacy and safety of the D-VD regimen in a cohort that exclusively enrolled Len exposed or refractory MM patients. The study cohort included 57 patients affected by relapsed/refractory MM. All patients were previously exposed to Len, with 77.2% being refractory. The overall response rate (ORR) was 79.6% with 43% of cases obtaining at least a very good partial response (VGPR). The D-VD regimen showed a favorable safety profile, with low frequency of grade 3–4 adverse events, except for thrombocytopenia observed in 21.4% of patients. With a median follow-up of 13 months, median progression-free survival (PFS) was 17 months. No significant PFS differences were observed according to age, ISS, LDH levels, type of relapse, and high-risk FISH. Len exposed patients displayed a PFS advantage as compared to Len refractory patients (29 vs 16 months, p = 0.2876). Similarly, patients treated after Len maintenance showed a better outcome as compared to patients who had received a full-dose Len treatment (23 vs 13 months, p = 0.1728). In conclusion, our real-world data on D-VD combination showed remarkable efficacy in Len-R patients, placing this regimen as one of the standards of care to be properly taken into account in this MM setting. [ABSTRACT FROM AUTHOR]

Haemorrhagic enteritis is an economically significant disease reported in the majority of the countries where turkeys are raised intensively; it is caused by Turkey adenovirus 3 (TAdV-3). The aim of this study was to analyse and compare the ORF1 gene 3′ region from turkey haemorrhagic enteritis virus (THEV) vaccine-like and field strains in order to develop a molecular diagnostic method to differentiate the strains from each other. Eighty samples were analysed by sequencing and phylogenetic analyses using a new set of polymerase chain reaction (PCR) primers targeting a genomic region spanning the partial ORF1, hyd and partial IVa2 gene sequences. A commercial live vaccine was also included in the analysis. The results showed that 56 of the 80 sequences obtained in this study showed ≥99.8% nucleotide identity with the homologous vaccine strain sequence. Three non-synonymous mutations – ntA1274G (aaI425V), ntA1420C (aaQ473H) and ntG1485A (aaR495Q) – were detected in the THEV field strains but not in the vaccine strain. Phylogenetic analysis confirmed the clustering of the field and vaccine-like strains in different phylogenetic branches. In conclusion, the method employed in this study could be a useful tool towards making a correct diagnosis. The data could contribute to the knowledge of field distribution of THEV strains and increase the limited existing information available on native isolates around the world. [ABSTRACT FROM AUTHOR]

Objectives: Compassion science has been informed and guided by Buddhist perspectives, but has yet to fully account for certain key Buddhist ideas about compassion. Skillful means and fierce compassion represent two such ideas, both of which pertain to compassionate actions that may not always appear compassionate to recipients or observers. Methods: To better account for the variety of compassionate behavior evident in the Buddhist traditions, including but not limited to skillful means and fierce compassion, this paper reviews relevant theory and findings from compassion science through the lens of the Big Two Framework. The Big Two Framework distinguishes between two core dimensions of social cognition, namely communion (i.e., warmth, morality, and expressiveness) and agency (i.e., dominance, competence, and instrumentality). Results: The Big Two Framework's fundamental distinction between communion and agency appears useful for delineating forms of compassionate behavior. Additionally, the framework is helpful for considering behavior from actor versus recipient/observer perspectives, making it well-suited to account for compassionate actions that may not appear compassionate. Conclusions: Reflecting on compassion in relation to the Big Two maps a richer understanding of the social cognition underlying diverse forms of compassionate behavior and offers an empirically tractable framework and terminology for advancing research on understudied expressions of compassion. [ABSTRACT FROM AUTHOR]

Compassion science has been shaped and guided by Mahāyāna Buddhist conceptions of compassion, including the potential for compassion to be cultivated through contemplative practices and training. Despite these influences, important Buddhist perspectives and ideas about compassion are still underrepresented in the scientific literature. This Special Issue focuses on initiating a body of literature on skillful means, a foundational idea from Mahāyāna Buddhism pertaining to the enactment of compassion joined with wisdom. Arising from a seminal Think Tank centered around compassion and skillful means, scholars and trainers representing diverse perspectives were invited to contribute to a Special Issue introducing a variety of perspectives, insights, and approaches that may help to advance contemporary understanding, research, and training of compassion. This includes papers that examine skillful means within Buddhism and Christianity, empirical studies that draw on skillful means to motivate or frame tractable questions, theoretical papers that reflect on skillful means in relation to other topics in psychological science, and how common compassion practices may themselves serve as skillful means. Considered together, we believe the variety evident throughout this Special Issue highlights the potential of skillful means to serve as a broad and flexible concept that can inspire many new ideas and directions for the field. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study is to analyse the effect of BMI on clinical outcomes of cemented fixed-bearing lateral unicompartmental knee arthroplasty (UKA) on a 2- to 12-year follow-up. Methods: Between January 2010 and January 2020, a total of 103 lateral UKAs were implanted. The Oxford Knee Score (OKS) and the Western Ontario and McMaster University Osteoarthritis Index for pain, stiffness, function, and total score were administered to estimate patients' overall health status pre- and post-operatively. Results were considered good or excellent for WOMAC values > 85 points and OKS > 40 points. Survivorship, described with Kaplan–Meier method, was defined as the lack of revision at the latest follow-up. Complications or further operations were recorded. p values of < 0.05 were considered significant. Results: One hundred one lateral UKAs were assessed at a mean follow-up of 77.8 months. No patients underwent revision, but 2 patients (2, 0%) developed aseptic loosening of the implant 2 and 5 years after surgery but for clinical reasons neither undergo revision (5-year survivor 97.2%). Overall satisfaction was generally high, with excellent scores in all WOMAC subscales and OKS for all BMI groups. Considering the pain subscale (WOMAC pain), patients with normal weight and overweight achieve excellent results more frequently [10 (25.64%) vs 10 (23.81%) p = 0.026] than obese patients (n = 0); on the other hand, considering the quality of life (WOMAC QoL), obese patients most frequently reach excellent values, even statistically significant [n = 15 (75.00%) p = 0.040]. Conclusion: Although obesity has historically been described as a contraindication to UKA, improved outcomes with modern UKA implant designs have challenged this perception. Therefore, the classic contraindication of UKAs in patients with BMI > 30 kg/m2 may not be justified. According to the present study, lateral UKA patients with BMI > 30 kg/m2 had satisfactory patient-reported outcome measures compared to non-obese patients on a long term with survival rates comparable to medial UKA. Obese patients should not be excluded from the benefit of lateral UKA surgery. [ABSTRACT FROM AUTHOR]

Androgen deprivation therapies aimed to target prostate cancer (PrCa) are only partially successful given the occurrence of neuroendocrine PrCa (NEPrCa), a highly aggressive and highly metastatic form of PrCa, for which there is no effective therapeutic approach. Our group has demonstrated that while absent in prostate adenocarcinoma, the αVβ3 integrin expression is increased during PrCa progression toward NEPrCa. Here, we show a novel pathway activated by αVβ3 that promotes NE differentiation (NED). This novel pathway requires the expression of a GPI-linked surface molecule, NgR2, also known as Nogo-66 receptor homolog 1. We show here that NgR2 is upregulated by αVβ3, to which it associates; we also show that it promotes NED and anchorage-independent growth, as well as a motile phenotype of PrCa cells. Given our observations that high levels of αVβ3 and, as shown here, of NgR2 are detected in human and mouse NEPrCa, our findings appear to be highly relevant to this aggressive and metastatic subtype of PrCa. This study is novel because NgR2 role has only minimally been investigated in cancer and has instead predominantly been analyzed in neurons. These data thus pave new avenues toward a comprehensive mechanistic understanding of integrin-directed signaling during PrCa progression toward a NE phenotype. [ABSTRACT FROM AUTHOR]

In the last decades, mobile robotics has become a very interesting research topic in the field of robotics, mainly because of population ageing and the recent pandemic emergency caused by Covid-19. Against this context, the paper presents an overview on wheeled mobile robot (WMR), which have a central role in nowadays scenario. In particular, the paper describes the most commonly adopted locomotion strategies, perception systems, control architectures and navigation approaches. After having analyzed the state of the art, this paper focuses on the kinematics of three omnidirectional platforms: a four mecanum wheels robot (4WD), a three omni wheel platform (3WD) and a two swerve-drive system (2SWD). Through a dimensionless approach, these three platforms are compared to understand how their mobility is affected by the wheel speed limitations that are present in every practical application. This original comparison has not been already presented by the literature and it can be used to improve our understanding of the kinematics of these mobile robots and to guide the selection of the most appropriate locomotion system according to the specific application. [ABSTRACT FROM AUTHOR]

Backgrounds: Healthy volunteers play a key role in clinical trials and it is crucial to develop recruitment strategies that capitalise on their motivations and maximise their participation. The COVID-19 pandemic has shown the importance of finding motivated healthy volunteers for the development of new vaccines. Public registers represent a promising way to promote the participation of healthy volunteers in the research field, but their adoption is still limited. The current study aimed to explore the motivations of healthy volunteers to enrol in an Italian public register for clinical trials during the COVID-19 pandemic and their attitude toward participating in a phase 1 COVID-19 vaccine clinical trial. The impacts of different enrolling interview modalities (in person, by phone, by mail) on motivation, understanding of information and trust in researchers were also investigated. Methods: An online survey investigating experience with COVID-19, motivations to enrol, trust in researchers, political and healthcare authorities and pharmacological companies was presented to people applying as healthy volunteers in the public register for clinical trials at Phase 1 Unit Research Centre of ASST Monza, Italy, and considering to participate in a COVID-19 vaccine clinical trial. Data were collected in June 2021. Results: Altruistic motivations were the main driver for enrolling in the public register, while self-interested motivations were secondary. No gender differences were found. As for enrolling modalities, no differences emerged between in-person and interviews for motivation to enrol, understanding of information and trust in researchers. Email modality led to significantly lower volunteers' satisfaction and understanding of information but similar trust in research. Conclusions: This study supports the validity of different interview modalities (in person and by phone) for the enrolment of healthy volunteers for clinical trials and highlights the positive role of public registers for the recruitment procedures. [ABSTRACT FROM AUTHOR]

A biodegradable engineered nanoplatform combining anti-angiogenic activity and targeting of cancer cells to improve the anticancer activity of docetaxel (DTX) is here proposed. Indeed, we have developed biodegradable nanoparticles (NPs) of poly(ethylene glycol)-poly(ε-caprolactone), exposing on the surface both folate motifs (Fol) for recognition in cells overexpressing Folate receptor-α (FRα) and the anti-angiogenic hexapeptide aFLT1. NPs showed a size around 100 nm, the exposure of 60% of Fol moieties on the surface, and the ability to entrap DTX and sustain its release with time. NPs were stable in simulated biological fluids and slightly interacted with Fetal Bovine serum, especially in the formulation decorated with Fol and aFLT1. The presence of Fol on NPs did not impair the anti-angiogenic activity of aFLT1, as assessed by in vitro tube formation assay in HUVEC endothelial cells. In both 2D and 3D KB cell cultures in vitro, the cytotoxicity of DTX loaded in NPs was not significantly affected by Fol/aFLT1 double decoration compared to free DTX. Remarkably, NPs distributed differently in 3D multicellular spheroids of FRα-positive KB cancer cells depending on the type of ligand displayed on the surface. In particular, NPs unmodified on the surface were randomly distributed in the spheroid, whereas the presence of Fol promoted the accumulation in the outer rims of the spheroid. Finally, NPs with Fol and aFLT1 gave a uniform distribution throughout the spheroid structure. When tested in zebrafish embryos xenografted with KB cells, NPs displaying Fol/aFLT1 reduced DTX systemic toxicity and inhibited the growth of the tumor mass and associated vasculature synergistically. Overall, nanotechnology offers excellent ground for combining therapeutic concepts in cancer, paving the way to novel multifunctional nanopharmaceuticals decorated with bioactive elements that can significantly improve therapeutic outcomes. [ABSTRACT FROM AUTHOR]

Chronic lymphocytic leukemia (CLL) is an incurable disease characterized by an extremely variable clinical course. We have recently shown that high catalase (CAT) expression identifies patients with an aggressive clinical course. Elucidating mechanisms regulating CAT expression in CLL is preeminent to understand disease mechanisms and develop strategies for improving its clinical management. In this study, we investigated the role of the CAT promoter rs1001179 single nucleotide polymorphism (SNP) and of the CpG Island II methylation encompassing this SNP in the regulation of CAT expression in CLL. Leukemic cells harboring the rs1001179 SNP T allele exhibited a significantly higher CAT expression compared with cells bearing the CC genotype. CAT promoter harboring the T -but not C- allele was accessible to ETS-1 and GR-β transcription factors. Moreover, CLL cells exhibited lower methylation levels than normal B cells, in line with the higher CAT mRNA and protein expressed by CLL in comparison with normal B cells. Methylation levels at specific CpG sites negatively correlated with CAT levels in CLL cells. Inhibition of methyltransferase activity induced a significant increase in CAT levels, thus functionally validating the role of CpG methylation in regulating CAT expression in CLL. Finally, the CT/TT genotypes were associated with lower methylation and higher CAT levels, suggesting that the rs1001179 T allele and CpG methylation may interact in regulating CAT expression in CLL. This study identifies genetic and epigenetic mechanisms underlying differential expression of CAT, which could be of crucial relevance for the development of therapies targeting redox regulatory pathways in CLL. [ABSTRACT FROM AUTHOR]

It has recently emerged that drugs such as the mTOR inhibitor rapamycin (Rapa) may play a key role in the treatment of airway inflammation associated with lung diseases, such as chronic obstructive pulmonary disease, asthma, and cystic fibrosis. Nevertheless, Rapa clinical application is still prevented by its unfavorable chemical-physical properties, limited oral bioavailability, and adverse effects related to non-specific biodistribution. In this paper, the design and production of a novel formulation of Rapa based on nano into micro (NiM) particles are detailed. To achieve it, Rapa-loaded nanoparticles were produced by nanoprecipitation of an amphiphilic pegylated poly-ɛ-caprolactone/polyhydroxyethyl aspartamide graft copolymer. The obtained nanoparticles that showed a drug loading of 14.4 wt% (corresponding to an encapsulation efficiency of 82 wt%) did not interact with mucins and were able to release and protect Rapa from degradation in simulated lung and cell fluids. To allow their local administration to the lungs as a dry powder, particle engineering at micro-sized level was done by embedding nanoparticles into mannitol-based microparticles by spray drying. Obtained NiM particles had a mean diameter of about 2-µ, spherical shape and had good potential to be delivered to the lungs by a breath-activated dry powder inhalers. Rheological and turbidity experiments showed that these NiM particles can dissolve in lung simulated fluid and deliver the Rapa-loaded pegylated nanoparticles, which can diffuse through the mucus layer. [ABSTRACT FROM AUTHOR]

Background and purpose: Congenital portosystemic shunts (CPSS) are associated with multisystem complications, with the most common being liver tumors. The purpose of this study is to investigate the incidence of complications of CPSS, and to determine the natural history of liver tumors and their relationship with shunt closure. Methods: Single-center retrospective cohort study of patients with CPSS referred from 1990 to 2020. Data on demographics, laboratory, radiological and histological investigations, clinical evolution, and surgery were reviewed. Mann–Whitney for continuous data and Fisher's exact test for categorical data were used. A p value of 0.05 was considered significant. Results: 54 patients were investigated for CPSS with a median age of 1.1 years (IQR 0.2–11.8 years) at presentation—7 intrahepatic shunts resolved spontaneously and were excluded. Type 1 (without intrahepatic portal flow) had a higher rate of all hepatic tumors than Type 2 (partial intrahepatic portal flow) [18/22(82%) vs. 9/25(36%); p = 0.003); and malignant tumors (6/22(27%) vs 1/25(4%); (p = 0.04). Following shunt closure, 4/11(36%) of patients experienced partial and 3/11(27%) complete tumor regression. Pulmonary hypertension and hepatopulmonary syndrome affected 4(9%), and 3(6%) patients, respectively. Pulmonary complications affected 1 patient with Type 1 and 6 with Type 2 shunts (p = 0.1). Neurocognitive anomalies were identified in 16/47(34%) patients, 8/22(35%) with Type 1 shunts and 8/25(32%) with Type 2 shunts (p = 0.76). 9/47 (19%) required special needs schooling. Conclusions: Severity of portal venous deprivation (Type 1 CPSS) increases the risk of hepatic tumors and surgical closure is associated with a reduction in size or complete resolution of benign tumors. [ABSTRACT FROM AUTHOR]

This study considers a set of state-of-the-art seasonal forecasting systems (ECMWF, MF, UKMO, CMCC, DWD and the corresponding multi-model ensemble) and quantifies their added value (if any) in predicting seasonal and monthly temperature and precipitation anomalies over the Mediterranean region compared to a simple forecasting method based on the ERA5 climatology (CTRL) or the persistence of the ERA5 anomaly (PERS). This analysis considers two starting dates, May 1st and November 1st and the forecasts at lead times up to 6 months for each year in the period 1993–2014. Both deterministic and probabilistic metrics are employed to derive comprehensive information on the forecast quality in terms of association, reliability/resolution, discrimination, accuracy and sharpness. We find that temperature anomalies are better reproduced than precipitation anomalies with varying spatial patterns across different forecast systems. The Multi-Model Ensemble (MME) shows the best agreement in terms of anomaly correlation with ERA5 precipitation, while PERS provides the best results in terms of anomaly correlation with ERA5 temperature. Individual forecast systems and MME outperform CTRL in terms of accuracy of tercile-based forecasts up to lead time 5 months and in terms of discrimination up to lead time 2 months. All seasonal forecast systems also outperform elementary forecasts based on persistence in terms of accuracy and sharpness. [ABSTRACT FROM AUTHOR]

Immunotherapy is now the standard of care for advanced hepatocellular carcinoma (HCC), yet many patients fail to respond. A major unmet goal is the boosting of T-cells with both strong HCC reactivity and the protective advantages of tissue-resident memory T-cells (TRM). Here, we show that higher intratumoural frequencies of γδ T-cells, which have potential for HLA-unrestricted tumour reactivity, associate with enhanced HCC patient survival. We demonstrate that γδ T-cells exhibit bona fide tissue-residency in human liver and HCC, with γδTRM showing no egress from hepatic vasculature, persistence for >10 years and superior anti-tumour cytokine production. The Vγ9Vδ2 T-cell subset is selectively depleted in HCC but can efficiently target HCC cell lines sensitised to accumulate isopentenyl-pyrophosphate by the aminobisphosphonate Zoledronic acid. Aminobisphosphonate-based expansion of peripheral Vγ9Vδ2 T-cells recapitulates a TRM phenotype and boosts cytotoxic potential. Thus, our data suggest more universally effective HCC immunotherapy may be achieved by combining aminobisphosphonates to induce Vγ9Vδ2TRM capable of replenishing the depleted pool, with additional intratumoural delivery to sensitise HCC to Vγ9Vδ2TRM-based targeting. Many cancer immune therapy approaches depend on an HLA-restricted neoantigen-specific T cell response. AUs show here that Zoledronic acid can expand, and induce tumour recognition by, a population of tissue resident memory gamma-delta T cells associated with an efficient anti-tumour immune response in hepatocellular carcinoma. [ABSTRACT FROM AUTHOR]

Purpose: Colorectal cancer (CRC) can be classified according to the chromosomal-instability pathway (a microsatellite-stable (MSS) pathway) and the microsatellite-instability (MSI) pathway. Adjuvant therapy after surgery in advanced CRC is usually based on fluoropyrimidine 5-fluorouracil (5-FU) alone or combined with other agents. Controversy however remains on the use of 5-FU-based regimens in treating MSI-related tumours. Aims: To systematically investigate the relationship between tumour microsatellite profile and 5-year overall survival in patients with CRC treated with 5-FU. Methods: A systematic literature review of PubMed and Embase databases was conducted. Pre-specified criteria determined study inclusion/exclusion. The PRISMA and QUADAS-2 criteria were used to assess study suitability and quality respectively. Patients were categorised as having either MSI or MSS CRC. Overall 5-year survival was estimated from Kaplan–Meier curves. Publication bias was assessed using funnel-plots and Egger's test. Results: 1807 studies were identified, with meta-analysis performed using nine studies. 5-FU treated individuals with CRC who died at 5 years were found to be 0.31 times less likely to have MSI than those who were alive, although this was not statistically significant. There was an insufficient number of studies to enable subgroup analysis by stage. Conclusions: In this meta-analysis, MSI status does not alter 5-year survival of patients with CRC patients treated with adjuvant 5-FU, however there is significant heterogeneity in the design of individual studies in the data synthesis. More studies are necessary to clarify whether CRC patients with MSI CRC, in particular early stage, should be offered 5-FU based adjuvant chemotherapy. [ABSTRACT FROM AUTHOR]

The unstructured nature of Real-World (RW) data from onco-hematological patients and the scarce accessibility to integrated systems restrain the use of RW information for research purposes. Natural Language Processing (NLP) might help in transposing unstructured reports into standardized electronic health records. We exploited NLP to develop an automated tool, named ARGO (Automatic Record Generator for Onco-hematology) to recognize information from pathology reports and populate electronic case report forms (eCRFs) pre-implemented by REDCap. ARGO was applied to hemo-lymphopathology reports of diffuse large B-cell, follicular, and mantle cell lymphomas, and assessed for accuracy (A), precision (P), recall (R) and F1-score (F) on internal (n = 239) and external (n = 93) report series. 326 (98.2%) reports were converted into corresponding eCRFs. Overall, ARGO showed high performance in capturing (1) identification report number (all metrics > 90%), (2) biopsy date (all metrics > 90% in both series), (3) specimen type (86.6% and 91.4% of A, 98.5% and 100.0% of P, 92.5% and 95.5% of F, and 87.2% and 91.4% of R for internal and external series, respectively), (4) diagnosis (100% of P with A, R and F of 90% in both series). We developed and validated a generalizable tool that generates structured eCRFs from real-life pathology reports. [ABSTRACT FROM AUTHOR]

The purpose of this study was to determine whether zinc phosphate treatments of tomato plants (Solanum lycopersicum L.) can attenuate bacterial speck disease severity through reduction of Pseudomonas syringae pv. tomato (Pst) growth in planta and induce morphological and biochemical plant defence responses. Tomato plants were treated with 10 ppm (25.90 µM) zinc phosphate and then spray inoculated with strain DAPP-PG 215, race 0 of Pst. Disease symptoms were recorded as chlorosis and/or necrosis per leaf (%) and as numbers of necrotic spots. Soil treatments with zinc phosphate protected susceptible tomato plants against Pst, with reductions in both disease severity and pathogen growth in planta. The reduction of Pst growth in planta combined with significantly higher zinc levels in zinc-phosphate-treated plants indicated direct antimicrobial toxicity of this microelement, as also confirmed by in vitro assays. Morphological (i.e. callose apposition) and biochemical (i.e., expression of salicylic-acid-dependent pathogenesis-related protein PR1b1 gene) defence responses were induced by the zinc phosphate treatment, as demonstrated by histochemical and qPCR analyses, respectively. In conclusion, soil treatments with zinc phosphate can protect tomato plants against Pst attacks through direct antimicrobial activity and induction of morphological and biochemical plant defence responses. [ABSTRACT FROM AUTHOR]

This study provides valuable information on the levels of various trace metals (Pb, Cd, Hg, Zn, Cu, Cr) in meat products (baked ham, raw ham, mortadella, cured sausage, würstel, salami) from South Italy and calculates potential health risk toxicity associated with their consumption for the total population and for children. In the samples studied metal concentrations are within the permissible legal limits (Cd: 0.01–0.03 μg g−1 w.w., Hg: 0.01–0.02 μg g−1 w.w., Zn: 5.71–7.32 μg g−1 w.w., Cu: 1.08–1.21 μg g−1 w.w., Cr: 0.15–0.23 μg g−1 w.w.), except for Pb (Pb: 0.22–0.38 μg g−1 w.w.). The estimated intake values are within the provisional tolerable daily intake limits for toxic metals and recommended daily intake values for essential metals in both tested groups. The noncarcinogenic risk values of the individual metals indicate that there is no health risk, but their combined effects might constitute a potential risk for children. Furthermore, the cumulative cancer risk of all samples studied exceeds the recommended threshold risk limit (> 10−4) in both total population and children, indicating a risk of potential health problems for consumers especially for children, who are more vulnerable to toxic metal exposure. [ABSTRACT FROM AUTHOR]

The histological distinction between acute and chronic liver injury is a challenging aspect of liver histopathology. It is traditionally based on the interpretation of morphological changes to the extracellular matrix (ECM) at sites of hepatocyte loss using histochemical stains. Our aim was to investigate whether immunohistochemistry and multiplexing for collagen type (I & III) and elastic fibres and a modified Victoria blue method could be helpful. We studied 43 livers removed at transplantation for acute liver failure (ALF, 20 cases) or cirrhosis (23) plus 8 normal controls. In ALF the periportal ECM was normal in 2 cases, contained mainly collagen I associated with a ductular reaction in 6 cases, and delicate elastic strands in 11 cases. Periportal deposition of mainly collagen I and mature elastic fibres was observed in cirrhosis. In ALF the perisinusoidal ECM was intact in 4 cases, collapsed or condensed but of normal composition (predominantly collagen III) in 2 cases, and collapsed and condensed containing mostly collagen I in 17 cases (7 including delicate immature elastic strands). In contrast, bridging fibrous septa of cirrhosis contained abundant collagen 1 and bundles of mature elastin. We propose the use of a scale and the use of immunohistochemistry and multiplexing in additional to histochemical stains to characterise the ECM changes in acute and chronic liver injury. [ABSTRACT FROM AUTHOR]

Regulated cell proliferation is an effector mechanism of regeneration, whilst dysregulated cell proliferation is a feature of cancer. We have previously identified microRNA (miRNA) that regulate successful and failed human liver regeneration. We hypothesized that these regulators may directly modify tumor behavior. Here we show that inhibition of miRNAs -503 and -23a, alone or in combination, enhances tumor proliferation in hepatocyte and non-hepatocyte derived cancers in vitro, driving more aggressive tumor behavior in vivo. Inhibition of miRNA-152 caused induction of DNMT1, site-specific methylation with associated changes in gene expression and in vitro and in vivo growth inhibition. Enforced changes in expression of two miRNA recapitulating changes observed in failed regeneration led to complete growth inhibition of multi-lineage cancers in vivo. Our results indicate that regulation of regeneration and tumor aggressiveness are concordant and that miRNA-based inhibitors of regeneration may constitute a novel treatment strategy for human cancers. [ABSTRACT FROM AUTHOR]

In ecosystems, plants are continuously challenged by combined stress conditions more than by a single biotic or abiotic factor. Consequently, in recent years studies on plant relationships with multiple stresses have aroused increasing interest. Here, the impact of inoculation with fungal pathogens with different lifestyles on Arabidopsis plants response to the following infestation with the invasive crop pest Eurydema oleracea was investigated. In particular, as fungal pathogens the necrotroph Botrytis cinerea and the biotroph Golovinomyces orontii were used. Plants exposed to B. cinerea, but not to G. orontii, showed reduced herbivore feeding damage. This difference was associated to different hormonal pathways triggered by the pathogens: G. orontii only induced the salicylate-mediated pathway, while B. cinerea stimulated also the jasmonate-dependent signalling, which persisted for a long time providing a long-term defence to further herbivore attack. In particular, the lower susceptibility of B. cinerea-infected Arabidopsis plants to E. oleracea was related to the stimulation of the JA-induced pathway on the production of plant volatile compounds, since treatment with VOCs emitted by B. cinerea inoculated plants inhibited both insect plant choice and feeding damage. These results indicate that necrotrophic plant pathogenic fungi modulate host volatile emission, thus affecting plant response to subsequent insect, thereby increasing the knowledge on tripartite plant–microbe–insect interactions in nature. [ABSTRACT FROM AUTHOR]

Calcium is the most abundant mineral in the human body and is central to many physiological processes, including immune system activation and maintenance. Studies continue to reveal the intricacies of calcium signalling within the immune system. Perhaps the most well-understood mechanism of calcium influx into cells is store-operated calcium entry (SOCE), which occurs via calcium release-activated channels (CRACs). SOCE is central to the activation of immune system cells; however, more recent studies have demonstrated the crucial role of other calcium channels, including transient receptor potential (TRP) channels. In this review, we describe the expression and function of TRP channels within the immune system and outline associations with murine models of disease and human conditions. Therefore, highlighting the importance of TRP channels in disease and reviewing potential. The TRP channel family is significant, and its members have a continually growing number of cellular processes. Within the immune system, TRP channels are involved in a diverse range of functions including T and B cell receptor signalling and activation, antigen presentation by dendritic cells, neutrophil and macrophage bactericidal activity, and mast cell degranulation. Not surprisingly, these channels have been linked to many pathological conditions such as inflammatory bowel disease, chronic fatigue syndrome and myalgic encephalomyelitis, atherosclerosis, hypertension and atopy. [ABSTRACT FROM AUTHOR]

In the present study, we serosurveyed the exposure of 222 draft horses to different arboviruses in the city of Santa Fe, Argentina. Plaque reduction neutralization tests confirmed exposure to Fort Sherman virus (FSV), Saint Louis encephalitis virus (SLEV), West Nile virus (WNV), and Río Negro virus (RNV). Apparently, Western and Eastern equine encephalitis viruses did not circulate in the population tested. The confirmation of five seroconversions for WNV, FSV, and SLEV and the association between prevalence and age are indicative of recent circulation. These results highlight the importance of considering draft horses in arboviral surveillance in urban and rural areas of developing countries. [ABSTRACT FROM AUTHOR]

We believe we are now in a position to answer the question, "Are faces special?" inasmuch as this applies to the face inversion effect (better performance for upright vs inverted faces). Using a double-blind, between-subject design, in two experiments (n = 96) we applied a specific tDCS procedure targeting the Fp3 area while participants performed a matching-task with faces (Experiment 1a) or checkerboards from a familiar prototype-defined category (Experiment 1b). Anodal tDCS eliminated the checkerboard inversion effect reliably obtained in the sham group, but only reduced it for faces (although the reduction was significant). Thus, there is a component to the face inversion effect that we are not affecting with a tDCS procedure that can eliminate the checkerboard inversion effect. We suggest that the reduction reflects the loss of an expertise-based component in the face inversion effect, and the residual is due to a face-specific component of that effect. [ABSTRACT FROM AUTHOR]

The peribiliary glands are intramural or extramural structures with multiple functions related to bile secretion. The peribiliary glands can develop cystic alterations in several conditions, such as alcohol addiction. Peribiliary cysts can enlarge till being radiologically visible and mimic cancer. We studied 217 consecutive explanted livers for end-stage alcohol-related liver disease from the Pathology Unit of the Liver Unit at the King's College Hospital in Denmark Hill, with particular focus on peribiliary glands. Our cohort consisted of 31 females and 186 males, with a median age of 51 and of 56 years respectively. 92,2% had established cirrhosis, 73,3% had only alcohol-induced liver disease, whilst 26,7% had other co-morbidities. We found a mild ectasia of the peribiliary glands (<2 mm) in 37,8% and peribiliary cysts (> = 2 mm) in 22,6% of cases. The diameter of the peribiliary glands varied from 1 mm to 8 mm. Inflammation of the peribiliary glands was found in the majority of cases with dilatation (p value = 0,000). 4,6% of the peribiliary cysts had low-grade intraductal papillary neoplasm of the bile ducts confined to the peribiliary glands. Pancreatic heterotopia was found in 10,6% and associated with the presence of ectasia. Our findings fit with what is reported in literature, such as the alcohol-induced damage at the peribiliary glands. Moreover these results underline the possible role of peribiliary glands in the development of the intraductal papillary neoplasm of the bile ducts, the biliary counterpart of the branch type intraductal mucinous neoplasm of the pancreas. [ABSTRACT FROM AUTHOR]

A critical problem derived from airport operations is the environmental impact of runoff water. Airport runoff includes a complex mixture of pollutants, e.g., from deicing agents, that may affect negatively natural water bodies. This study assesses the spatial and temporal aquatic ecotoxicity of runoff water and possible aeroplane drift in a German airport. Over winter 2012–2013, from November to May, water samples were collected within the airport and surrounding area. These samples were analyzed using traditional physicochemical analysis and biotests with two aquatic organisms from different trophic levels, Lemna gibba and Aliivibrio fischeri. Overall, the samples examined in this study were relatively non-toxic to the tested organisms. The physicochemical parameters were mainly influenced by the sampling period being higher in colder months. In contrast, the ecotoxicity was influenced by the sampling site. For sites within the airport, a high correlation between the physicochemical parameters (EC and TOC) and toxicity in L. gibba was found. These correlations were not evident in samples taken outside the airport or when A. fischeri was used as a bioindicator. However, a pronounced seasonality has been observed, linked to the coldest months with average inhibition values of 50% in L. gibba and 25% in A. fischeri, particularly in January. Both biotests yielded differing results; therefore, more biotests should be included. However, L. gibba showed a good response with this type of water samples to be included in future studies together with detailed chemical analysis. The present study provides data to assess the potential ecotoxicological effects of airport runoff affected by winter operations. [ABSTRACT FROM AUTHOR]

The study of plant phenology has frequently been used to link phenological events to various factors, such as temperature or photoperiod. In the high-alpine environment, proper timing of the phenological cycle has always been crucial to overcome harsh conditions and potential extreme events (i.e. spring frosts) but little is known about the response dynamics of the vegetation, which could shape the alpine landscape in a future of changing climate. Alpine tundra vegetation is composed by an array of species belonging to different phytosociological optima and with various survival strategies, and snowbed communities are a relevant expression of such an extreme-climate adapted flora. We set eight permanent plots with each one in a snowbed located on the Cimalegna plateau in Northwestern Italy and then we selected 10 most recurring species among our plots, all typical of the alpine tundra environment and classified in 3 different pools: snowbed specialists, grassland species and rocky debris species. For 3 years we registered the phenophases of each species during the whole growing season using an adaptation of the BBCH scale. We later focused on the three most biologically relevant phenophases, i.e., flower buds visible, full flowering, and beginning of seed dispersion. Three important season-related variables were chosen to investigate their relationship with the phenological cycle of the studied species: (i) the Day Of Year (DOY), the progressive number of days starting from the 1st of January, used as a proxy of photoperiod, (ii) Days From Snow Melt (DFSM), selected to include the relevance of the snow dynamics, and (iii) Growing Degree Days (GDD), computed as a thermal sum. Our analysis highlighted that phenological development correlated better with DFSM and GDD than with DOY. Indeed, models showed that DOY was always a worse predictor since it failed to overcome interannual variations, while DFSM and marginally GDD were better suited to predict the phenological development of most of the species, despite differences in temperature and snowmelt date among the three years. Even if the response pattern to the three variables was mainly consistent for all the species, the timing of their phenological response was different. Indeed, species such as Salix herbacea and Ranunculus glacialis were always earlier in the achievement of the phenophases, while Agrostis rupestris and Euphrasia minima developed later and the remaining species showed an intermediate behavior. However, we did not detect significant differences among the three functional pools of species. [ABSTRACT FROM AUTHOR]

Introduction: Ten percent of cirrhotic patients are known to have a high risk of postoperative complications. Ninety percent of bariatric patients suffer from non-alcoholic fatty liver disease (NAFLD), and 50% of them may develop non-alcoholic steatohepatitis (NASH) which can progress to cirrhosis. The aim of this study was to assess whether the presence of cirrhosis at the time of bariatric surgery is associated with an increased rate and severity of short- and long-term cirrhotic complications. Methods: A cohort of 110 bariatric patients, between May 2003 and February 2018, who had undergone liver biopsy at the time of bariatric surgery were reassessed for histological outcome and divided into two groups based on the presence (C, n = 26) or absence (NC, n = 84) of cirrhosis. The NC group consisted of NASH (n = 49), NAFLD (n = 24) and non-NAFLD (n = 11) liver histology. Medical notes were retrospectively assessed for patient characteristics, development of 30-day postoperative complications, severity of complications (Clavien-Dindo (CD) classification) and length of stay. The C group was further assessed for long-term cirrhosis-related outcomes. Results: The C group was older (52 years vs 43 years) and had lower BMI (46 kg/m2 vs 52 kg/m2) and weight (126 kg vs 145 kg) compared to the NC group (p < 0.05). The C group had significantly higher overall complication rate (10/26 vs 14/84, p < 0.05) and severity of complications (CD class ≥ III, 12% vs 7%, p < 0.05) when compared to the NC group. The length of stay was similar between the two groups (5 days vs 4 days). The C group had significant improvement in model end-stage liver disease scores (7 vs 6, p < 0.01) with median follow-up of 4.5 years (range 2–11 years). There were no long-term cirrhosis-related complications or mortality in our studied cohort (0/26). Conclusion: Bariatric surgery in cirrhotic patients has a higher risk of immediate postoperative complications. Long-term cirrhosis-related complications or mortality was not increased in this small cohort. Preoperative identification of liver cirrhosis may be useful for risk stratification, optimisation and informed consent. Bariatric surgery in well-compensated cirrhotic patients may be used as an aid to improve long-term outcome. [ABSTRACT FROM AUTHOR]

We present an in silico characterization of the von Hippel–Lindau-like protein (VLP), the only known human paralog of the von Hippel–Lindau tumor suppressor protein (pVHL). Phylogenetic investigation showed VLP to be mostly conserved in upper mammals and specifically expressed in brain and testis. Structural analysis and molecular dynamics simulations show VLP to be very similar to pVHL three-dimensional organization and binding dynamics. In particular, conservation of elements at the protein interfaces suggests VLP to be a functional pVHL homolog potentially possessing multiple functions beyond HIF-1α-dependent binding activity. Our findings show that VLP may share at least seven interactors with pVHL, suggesting novel functional roles for this understudied human protein. These may occur at precise hypoxia levels where functional overlap with pVHL may permit a finer modulation of pVHL functions. [ABSTRACT FROM AUTHOR]

Congenital portosystemic shunt (CPSS) is a congenital anomaly resulting in partial or complete diversion of the portal blood into the systemic circulation. The literature on the histological changes in livers of patients with CPSS is limited. Liver histology of 22 consecutive patients managed in our institution between 2001 and 2016 was reviewed. Twenty-one patients were children at the time of diagnosis. Thirty-two specimens were available and consisted of three explant livers and 29 biopsy samples from 19 patients. Sixteen samples were from wedge biopsies taken at the time of shunt closure. Thirteen were from core needle biopsies taken during clinical work-up. A variable proportion of portal tracts contained prominent thin-walled channels (PTWCs) and arterio-biliary dyads. The proportion of portal tracts containing triads, arterio-biliary dyads and biliary monads varied considerably in the different samples. Dilated inlet venules, increase in the number of portal arteries or the presence of portal arteries of increased size, deposition of copper-associated protein, sinusoidal dilatation, capillarization and intralobular individual arteries were present. Physiological nuclear vacuolation of periportal hepatocytes was absent in most samples from our paediatric patients. Presence of PTWCs, arterial-biliary dyads, increased arterial profiles in portal tracts and lobule and lack of the physiological periportal vacuolated hepatocytes in children are the most characteristic histological changes of CPSS in the liver periphery. [ABSTRACT FROM AUTHOR]

Bird nest orientation is affected by environmental variables determined by their geographical position as well as microclimatic conditions. In closed-cup-nesting species, nests may be oriented to avoid adverse environmental extremes such as sun exposure, wind, and rainfall, although vegetal cover may provide extra protection generating random orientation patterns. Here, we assess nest entrance orientation in Rufous Hornero (Furnarius rufus) at 11 South American sites by comparing nests well covered by vegetation (> 75% covered) from those with less or non-external vegetal protection (< 25%). We estimated and compared mean entrance orientation between northern and southern locations and levels of vegetation cover using circular statistics (n = 1291). Additionally, the influence of geographical latitude and vegetation cover on nest orientation was evaluated using linear mixed models across sites with non-random nest-orientation patterns. Results showed differences in mean orientation values between covered and uncovered nests at most locations and directed entrance orientation for uncovered nests. On the other hand, the models indicate that nest entrance orientation is not affected by the joint effect of latitude and vegetation cover and high variability between locations. Local microclimatic conditions provided by the vegetation above nests are important determinants for nest orientation in the species, although additional information about local rainfall, wind, temperature, and nesting site availability may help to determine the factors affecting orientation in the species on a local level. [ABSTRACT FROM AUTHOR]

The investigation of the dynamics of national disciplinary profiles is at the forefront in quantitative investigations of science. We propose a new approach to investigate the complex interactions among scientific disciplinary profiles. The approach is based on recent pseudo-likelihood techniques introduced in the framework of machine learning and complex systems. We infer, in a Bayesian framework, the network topology and the related interdependencies among national disciplinary profiles. We analyse data extracted from the Incites database which relate to the national scientific production of most productive world countries at disciplinary level over the period 1992-2016. [ABSTRACT FROM AUTHOR]

Mindfulness, whether distinguished as a state, trait, or training, is central to a growing wave of interest in meditation. Theoretical development has been called for in order to clarify confusion about mindfulness from a scientific perspective. Ideally, such development will allow ingress for more traditional perspectives and guide inclusive research on the wider range of meditation practices. To address this call, we outline a new approach for understanding mindfulness and related meditative experience that accommodates diverse perspectives. In accord with other integrative approaches, we employ foundational psychological constructs (namely, attention, intention, and awareness) to understand mindfulness. In contrast to other theoretical perspectives, however, we utilize this foundation to derive novel psychological constructs needed to better explain mindfulness and important features of meditative experience more widely. The contemplative cognition framework integrates three attention-related processes entailed by a variety of contemplative practices: intended attention, attention to intention, and awareness of transient information. After delineating this set of three processes, we explain how they can cooperate to promote a contemplative range of metacognition about attention, intention, and awareness, as well as enhanced regulation of cognition, emotion, and behavior. The contemplative cognition framework (a) overcomes discrepancies in mindfulness research; (b) accounts for contextual and motivational aspects of training; (c) supports investigation from phenomenological, information processing, neurophysiological, and clinical perspectives; and (d) enables investigations on various contemplative states, traits, and practices to inform one another. This new approach has potential for advancing a more inclusive, productive, and theory-driven science of mindfulness and meditation. [ABSTRACT FROM AUTHOR]