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The CACHE challenges are a series of prospective benchmarking exercises to evaluate progress in the field of computational hit-finding. Here we report the results of the inaugural CACHE challenge in which 23 computational teams each selected up to 100 commercially available compounds that they predicted would bind to the WDR domain of the Parkinson's disease target LRRK2, a domain with no known ligand and only an apo structure in the PDB. The lack of known binding data and presumably low druggability of the target is a challenge to computational hit finding methods. Of the 1955 molecules predicted by participants in Round 1 of the challenge, 73 were found to bind to LRRK2 in an SPR assay with a K D lower than 150 μM. These 73 molecules were advanced to the Round 2 hit expansion phase, where computational teams each selected up to 50 analogs. Binding was observed in two orthogonal assays for seven chemically diverse series, with affinities ranging from 18 to 140 μM. The seven successful computational workflows varied in their screening strategies and techniques. Three used molecular dynamics to produce a conformational ensemble of the targeted site, three included a fragment docking step, three implemented a generative design strategy and five used one or more deep learning steps. CACHE #1 reflects a highly exploratory phase in computational drug design where participants adopted strikingly diverging screening strategies. Machine learning-accelerated methods achieved similar results to brute force (e.g., exhaustive) docking. First-in-class, experimentally confirmed compounds were rare and weakly potent, indicating that recent advances are not sufficient to effectively address challenging targets.

Background: Multiple techniques exist for the preoperative localization of small, deeply located solid or subsolid pulmonary nodules to guide limited thoracoscopic resection. This study aims to conduct a multi-institutional comparison of three different tomography-guided tracers' methods. Methods: A retrospective multicenter cross-sectional study was conducted. All patients suitable for CT-guided tracers with microcoil (GROUP1, n = 58), hook wire (GROUP2, n = 86), or bioabsorbable hydrogel plug (GROUP3, n = 33) were scheduled for video-assisted thoracoscopic wedge resection. Outcome variables: successful nodule localization, safety, and the feasibility of the tracers' placement. A χ 2 test or Fisher's test for expected numbers less than five and a Kruskal-Wallis test were used to analyze the categorical and continuous variables, respectively. For the power calculations, we used G*Power version 3.1.9.6. Results: One hundred seventy-seven patients underwent the localization and resection of 177 nodules detected with three different CT-guided tracers. A significant difference was recorded for cancer history ( p = 0.030), respiratory function, Charlson comorbidity index ( p = 0.018), lesion type ( p < 0.0001), distance from pleura surface ( p < 0.0001), and time between preoperative CT-guided tracers and surgical procedures ( p < 0.0001). Four post-procedural complications were recorded and in GROUP2, four cases of tracer dislocations occurred. Finally, hook wire group was associated with the shortest surgical time (93 min, p = 0.001). Conclusions: All methods were feasible and efficient, resulting in a 100% success rate for the microcoils and the bioabsorbable hydrogel plugs and a 94.2% success rate for the hook wires. Our results highlight the need to choose a technique that is less stressful for the patient and helps the surgeon by extending the approach to deep nodules and resecting over the course of several days from deployment.

The article considers a large class of delayed neural networks (NNs) with extended memristors obeying the Stanford model. This is a widely used and popular model that accurately describes the switching dynamics of real nonvolatile memristor devices implemented in nanotechnology. The article studies via the Lyapunov method complete stability (CS), i.e., convergence of trajectories in the presence of multiple equilibrium points (EPs), for delayed NNs with Stanford memristors. The obtained conditions for CS are robust with respect to variations of the interconnections and they hold for any value of the concentrated delay. Moreover, they can be checked either numerically, via a linear matrix inequality (LMI), or analytically, via the concept of Lyapunov diagonally stable (LDS) matrices. The conditions ensure that at the end of the transient capacitor voltages and NN power vanish. In turn, this leads to advantages in terms of power consumption. This notwithstanding, the nonvolatile memristors can retain the result of computation in accordance with the in-memory computing principle. The results are verified and illustrated via numerical simulations. From a methodological viewpoint, the article faces new challenges to prove CS since due to the presence of nonvolatile memristors the NNs possess a continuum of nonisolated EPs. Also, for physical reasons, the memristor state variables are constrained to lie in some given intervals so that the dynamics of the NNs need to be modeled via a class of differential inclusions named differential variational inequalities.

Bovine mastitis is one of the main inflammatory diseases that can affect the udder during lactation. Somatic cell counts and sometimes microbiological tests are routinely adopted during monitoring diagnostics in dairy herds. However, subclinical mastitis is challenging to identify, reducing the possibility of early treatments. The main aim of this study was to investigate the miRNome profile of extracellular vesicles isolated from milk as potential biomarkers of subclinical mastitis. Milk samples were collected from a total of 60 dairy cows during routine monitoring tests. Small RNA sequencing technology was applied to extracellular vesicles of milk samples collected from cows classified according to the somatic cell count to identify differences in the miRNome between mastitic and healthy cows. A total of 1997 miRNAs were differentially expressed between both groups. Among them, 68 miRNAs whose FDRs were < 0.05 were mostly downregulated, with only one upregulated miRNA (i.e., miR-361). Functional analysis revealed that miR-455-3p, miR-503-3p, miR-1301-3p and miR-361-5p are involved in the regulation of several biological processes related to mastitis, including immune system-related processes. This study suggests the involvement of extracellular vesicle-derived miRNAs in the regulation of mastitis. Moreover, these findings provide evidence that miRNAs from milk extracellular vesicles can be used to identify biomarkers of mastitis. However, further studies must be conducted to validate these miRNAs, especially for subclinical diagnosis., (© 2024. The Author(s).)

Background: Neurodevelopmental disorder with dysmorphic facies and distal limb anomalies (NEDDFL) is associated to BPTF gene haploinsufficiency. Epilepsy was not included in the initial descriptions of NEDDFL, but emerging evidence indicates that epileptic seizures occur in some affected individuals. This study aims to investigate the electroclinical epilepsy features in individuals with NEDDFL., Methods: We enrolled individuals with BPTF-related seizures or interictal epileptiform discharges (IEDs) on electroencephalography (EEG). Demographic, clinical, genetic, raw EEG, and neuroimaging data as well as response to antiseizure medication were assessed., Results: We studied 11 individuals with a null variant in BPTF, including five previously unpublished ones. Median age at last observation was 9 years (range: 4 to 43 years). Eight individuals had epilepsy, one had a single unprovoked seizure, and two showed IEDs only. Key features included (1) early childhood epilepsy onset (median 4 years, range: 10 months to 7 years), (2) well-organized EEG background (all cases) and brief bursts of spikes and slow waves (50% of individuals), and (3) developmental delay preceding seizure onset. Spectrum of epilepsy severity varied from drug-resistant epilepsy (27%) to isolated IEDs without seizures (18%). Levetiracetam was widely used and reduced seizure frequency in 67% of the cases., Conclusions: Our study provides the first characterization of BPTF-related epilepsy. Early-childhood-onset epilepsy occurs in 19% of subjects, all presenting with a well-organized EEG background associated with generalized interictal epileptiform abnormalities in half of these cases. Drug resistance is rare., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Posttranslational modifications can enhance immunogenicity of self-proteins. In several conditions, including hypertension, systemic lupus erythematosus, and heart failure, isolevuglandins (IsoLGs) are formed by lipid peroxidation and covalently bond with protein lysine residues. Here, we show that the murine class I major histocompatibility complex (MHC-I) variant H-2Db uniquely presents isoLG-modified peptides and developed a computational pipeline that identifies structural features for MHC-I accommodation of such peptides. We identified isoLG-adducted peptides from renal proteins, including sodium glucose transporter 2, cadherin 16, Kelch domain-containing protein 7A, and solute carrier family 23, that are recognized by CD8+ T cells in tissues of hypertensive mice, induce T cell proliferation in vitro, and prime hypertension after adoptive transfer. Finally, we find patterns of isoLG-adducted antigen restriction in class I human leukocyte antigens that are similar to those in murine analogs. Thus, we have used a combined computational and experimental approach to define likely antigenic peptides in hypertension.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. The aim of this study was to compare overall survival between open and minimally invasive radical hysterectomy with participants followed for 4.5 years. The primary objective was to evaluate whether minimally invasive surgery was noninferior in disease-free survival (DFS) to abdominal radical hysterectomy. Secondary outcomes included overall survival. Sample size was based on DFS of 90% at 4.5 years and 7.2% noninferiority margin for minimally invasive surgery. A total of 631 patients were enrolled: 319 assigned to minimally invasive and 312 to open surgery. Of these, 289 (90.6%) patients underwent minimally invasive surgery and 274 (87.8%) patients open surgery. At 4.5 years, DFS was 85.0% in the minimally invasive group and 96% in the open group (difference of -11.1; 95% CI, -15.8 to -6.3; P = .95 for noninferiority). Minimally invasive surgery was associated with lower rate of DFS compared with open surgery (hazard ratio [HR], 3.91 [95% CI, 2.02 to 7.58]; P < .001). Rate of overall survival at 4.5 years was 90.6% versus 96.2% for the minimally invasive and open surgery groups, respectively (HR for death of any cause = 2.71 [95% CI, 1.32 to 5.59]; P = .007). Given higher recurrence rate and worse overall survival with minimally invasive surgery, an open approach should be standard of care.

The fusion of traditional chemical descriptors with Graph Neural Networks (GNNs) offers a compelling strategy for enhancing ligand-based virtual screening methodologies. A comprehensive evaluation revealed that the benefits derived from this integrative strategy vary significantly among different GNNs. Specifically, while GCN and SchNet demonstrate pronounced improvements by incorporating descriptors, SphereNet exhibits only marginal enhancement. Intriguingly, despite SphereNet's modest gain, all three models-GCN, SchNet, and SphereNet-achieve comparable performance levels when leveraging this combination strategy. This observation underscores a pivotal insight: sophisticated GNN architectures may be substituted with simpler counterparts without sacrificing efficacy, provided that they are augmented with descriptors. Furthermore, our analysis reveals a set of expert-crafted descriptors' robustness in scaffold-split scenarios, frequently outperforming the combined GNN-descriptor models. Given the critical importance of scaffold splitting in accurately mimicking real-world drug discovery contexts, this finding accentuates an imperative for GNN researchers to innovate models that can adeptly navigate and predict within such frameworks. Our work not only validates the potential of integrating descriptors with GNNs in advancing ligand-based virtual screening but also illuminates pathways for future enhancements in model development and application. Our implementation can be found at https://github.com/meilerlab/gnn-descriptor., Competing Interests: Conflict of Interest Authors have no conflict of interest to declare.

Quartz Crystal Microbalances (QCMs) are versatile sensors employed in various fields, from environmental monitoring to biomedical applications, owing mainly to their very high sensitivity. However, the assessment of their metrological performance, including the impact of conditioning circuits, digital processing algorithms, and working conditions, is a complex and novel area of study. The purpose of this work is to investigate and understand the measurement errors associated with different QCM measurement techniques, specifically focusing on the influence of conditioning electronic circuits. Through a tailored and novel experimental setup, two measurement architectures-a Quartz Crystal Microbalance with dissipation monitoring (QCM-D) system and an oscillator-based QCM-R system-were compared under the same mechanical load conditions. Through rigorous experimentation and signal processing techniques, the study elucidated the complexities of accurately assessing QCM parameters, especially in liquid environments and under large mechanical loads. The comparison between the two different techniques allows for highlighting the critical aspects of the measurement techniques. The experimental results were discussed and interpreted based on models allowing for a deep understanding of the measurement problems encountered with QCM-based measurement systems. The performance of the different techniques was derived, showing that while the QCM-D technique exhibited higher accuracy, the QCM-R technique offered greater precision with a simpler design. This research advances our understanding of QCM-based measurements, providing insights for designing robust measurement systems adaptable to diverse conditions, thus enhancing their effectiveness in various applications.

Introduction: Diet is one of the main factors influencing the intestinal microbiota in horses, yet a systematic characterization of the microbiota along the length of the digestive tract in clinically healthy horses, homogenous for age and breed and receiving a specific diet is lacking., Methods: The study used 16S rRNA amplicon sequencing to characterize the microbiota of the intestinal tracts of 19 healthy Bardigiano horses of 14.3  ±  0.7  months of age fed one of two diets. Nine horses received a high-starch diet (HS), and ten horses received a high-fiber diet (HF). After 129  days, the horses were slaughtered, and samples were collected from the different intestinal tract compartments., Results and Discussion: The microbiota alpha diversity indices were lower in the caecum, pelvic flexure and right dorsal colon of the horses fed the HS diet (False Discovery Rate, FDR  <  0.05). The values of beta diversity indicated significant compositional differences between the studied intestinal tract compartments according to the diet received (FDR  <  0.05). At the lower taxonomic level (genus or family), the HS diet was associated with a higher relative frequency of Enterobacteriaceae within the small intestine (jejunum and duodenum) (FDR  <  0.05). Within the hindgut (caecum and sternal flexure), the HS diet was associated with lower relative frequencies (i.e., a smaller core community) of bacteria belonging to Fibrobacteraceae and Prevotellaceae (FDR  <  0.05). Moreover, horses fed the HS diet displayed a higher relative abundance of Streptococcus in the caecum (FDR  <  0.05) and Fusobacterium in the sternal flexure (FDR  <  0.05), both of which are pathogenic bacteria responsible for inflammation diseases. Samples collected from the pelvic flexure and rectum of horses fed the HS diet showed significantly higher relative frequencies of Succinivibrionaceae (FDR  <  0.05) - amylolytic bacteria associated with acidosis. The relative frequencies of the Lachnospiraceae and Ruminococcaceae were lower in the feces collected from the rectum of horses receiving the HS diet vs. HF diet, indicating smaller core communities of these bacteria (FDR  <  0.05). Fibrous diets should be promoted to prevent dysbiosis of the microbiota associated with high-starch diet., Competing Interests: 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 Raspa, Chessa, Bergero, Sacchi, Ferrocino, Cocolin, Corvaglia, Moretti, Cavallini and Valle.)

Purpose: In radiotherapy it is often necessary to transfer a patient's DICOM (Digital Imaging and COmmunications in Medicine) dataset from one system to another for re-treatment, plan-summation or registration purposes. The aim of the study is to evaluate effects of dataset transfer between treatment planning systems., Materials and Methods: Twenty-five patients treated in a 0.35T MR-Linac (MRidian, ViewRay) for locally-advanced pancreatic cancer were enrolled. For each patient, a nominal dose distribution was optimized on the planning MRI. Each plan was daily re-optimized if needed to match the anatomy and exported from MRIdian-TPS (ViewRay Inc.) to Eclipse-TPS (Siemens-Varian). A comparison between the two TPSs was performed considering the PTV and OARs volumes (cc), as well as dose coverages and clinical constraints., Results: From the twenty-five enrolled patients, 139 plans were included in the data comparison. The median values of percentage PTV volume variation are 10.8 % for each fraction, while percentage differences of PTV coverage have a mean value of -1.4 %. The median values of the percentage OARs volume variation are 16.0 %, 7.0 %, 10.4 % and 8.5 % for duodenum, stomach, small and large bowel, respectively. The percentage variations of the dose constraints are 41.0 %, 52.7 % and 49.8 % for duodenum, stomach and small bowel, respectively., Conclusions: This study has demonstrated a non-negligible variation in size and dosimetric parameters when datasets are transferred between TPSs. Such variations should be clinically considered. Investigations are focused on DICOM structure algorithm employed by the TPSs during the transfer to understand the cause of such variations., 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. Published by Elsevier Ltd.)

As the number of determined and predicted protein structures and the size of druglike 'make-on-demand' libraries soar, the time-consuming nature of structure-based computer-aided drug design calls for innovative computational algorithms. De novo drug design introduces in silico heuristics to accelerate searching in the vast chemical space. This review focuses on recent advances in structure-based de novo drug design, ranging from conventional fragment-based methods, evolutionary algorithms, and Metropolis Monte Carlo methods to deep generative models. Due to the historical limitation of de novo drug design generating readily available drug-like molecules, we highlight the synthetic accessibility efforts in each category and the benchmarking strategies taken to validate the proposed framework.

The emergence of insecticide resistance in arbovirus vectors is putting the focus on the development of new strategies for control. In this regard, the exploitation of Wolbachia endosymbionts is receiving increasing attention due to its demonstrated effectiveness in reducing the vectorial capacity of Aedes mosquitoes. Here, we describe the establishment of a naïve Wolbachia infection in a wild Aedes albopictus population of eastern Spain through a hybridization approach to obtain males capable of sterilizing wild females. The obtained lines were compared with the Wolbachia donor, Ae. albopictus AR w P, previously artificially infected with Wolbachia w Pip, regarding immature and adult survival, female fecundity, egg fertility, and level of induced sterility. Our results did not show significant differences between lines in any of the biological parameters analyzed, indicating the full suitability of the hybrids to be used as a control tool against Ae. albopictus . In particular, hybrid males induced 99.9% sterility in the eggs of wild females without the need for any preliminary treatment. Being harmless to non-target organisms and the environment, the use of this bacterium for the control of Ae. albopictus deserves further exploration. This is especially relevant in areas such as eastern Spain, where this mosquito species has recently spread and may represent a serious threat due to its competence as a vector for dengue, chikungunya, and Zika viruses.

Nonalcoholic fatty liver disease (NAFLD) exponentially affects the global healthcare burden, and it is currently gaining increasing interest in relation to its potential impact on central nervous system (CNS) diseases, especially concerning cognitive deterioration and dementias. Overall, scientific research nowadays extends to different levels, exploring NAFLD's putative proinflammatory mechanism of such dysmetabolic conditions, spreading out from the liver to a multisystemic involvement. The aim of this review is to analyze the most recent scientific literature on cognitive involvement in NAFLD, as well as understand its underlying potential background processes, i.e., neuroinflammation, the role of microbiota in the brain-liver-gut axis, hyperammonemia neurotoxicity, insulin resistance, free fatty acids, and vitamins.

Post-translational modifications (PTMs) of proteins play a vital role in their function and stability. These modifications influence protein folding, signaling, protein-protein interactions, enzyme activity, binding affinity, aggregation, degradation, and much more. To date, over 400 types of PTMs have been described, representing chemical diversity well beyond the genetically encoded amino acids. Such modifications pose a challenge to the successful design of proteins, but also represent a major opportunity to diversify the protein engineering toolbox. To this end, we first trained artificial neural networks (ANNs) to predict eighteen of the most abundant PTMs, including protein glycosylation, phosphorylation, methylation, and deamidation. In a second step, these models were implemented inside the computational protein modeling suite Rosetta, which allows flexible combination with existing protocols to model the modified sites and understand their impact on protein stability as well as function. Lastly, we developed a new design protocol that either maximizes or minimizes the predicted probability of a particular site being modified. We find that this combination of ANN prediction and structure-based design can enable the modification of existing, as well as the introduction of novel, PTMs. The potential applications of our work include, but are not limited to, glycan masking of epitopes, strengthening protein-protein interactions through phosphorylation, as well as protecting proteins from deamidation liabilities. These applications are especially important for the design of new protein therapeutics where PTMs can drastically change the therapeutic properties of a protein. Our work adds novel tools to Rosetta's protein engineering toolbox that allow for the rational design of PTMs., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Ertelt et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Pyrenean Mountain Dog (PMD) is an ancient dog breed firstly described in XIV century in the Pyrenees Region and nowadays diffused both in Europe and in the US. Hereditary Cataract (HC), defined as the inherited opacity of the lens, involves clinical signs ranging from reduced vision to glaucoma. A molecular basis of HC was firstly described in Staffordshire Bull Terriers and then reported in multiple canine breeds. The HC-associated variation is a single nucleotide deletion in HSF4 gene that introduces a premature stop codon (c.962del, p.Ala321*). Multifocal Retinopathy 1 (MR) is an ocular disorder characterized by multiple areas of retinal degeneration, caused in various dog breeds (including PMD) by a single nucleotide variant (SNV) in BEST1 gene that generates a premature stop codon (c.73G>A, p.Arg25*). Degenerative Myelopathy (DM) is an adult-onset, progressive neurodegenerative disease and it is associated to a SNV in SOD1 gene causing a change in aminoacidic sequence of the protein (c.118G>A, p.Glu40Lys). This causative variant has been described in various dog breeds, including PMD. Aim of this study was to determine the allele frequencies for the abovementioned three genetic diseases in the Italian breeding PMD population. The survey found no dogs carrying the allele (deletion) associated with HC, while three dogs (6 %) were heterozygous (G/A) for the MR-associated variant, and seven dogs (13 %) were heterozygous (G/A) for the DM-associated alteration, indicating that the variant alleles frequency were 0  %, 3 %, and 7 %, respectively. Appropriate mating management is suggested for the prevention of genetic diseases spreading in the PMD population., Competing Interests: Declaration of Competing Interest None of the authors has any financial or personal relationships that could inappropriately influence or bias the content of the paper., (Copyright © 2023. Published by Elsevier Inc.)

The accurate diagnosis of bone metastasis, a condition in which cancer cells have spread to the bone, is essential for optimal patient care and outcome. This review provides a detailed overview of the current medical imaging techniques used to detect and diagnose this critical condition focusing on three cardinal imaging modalities: positron emission tomography (PET), single photon emission computed tomography (SPECT) and magnetic resonance imaging (MRI). Each of these techniques has unique advantages: PET/CT combines functional imaging with anatomical imaging, allowing precise localization of metabolic abnormalities; the SPECT/CT offers a wider range of radiopharmaceuticals for visualizing specific receptors and metabolic pathways; MRI stands out for its unparalleled ability to produce high-resolution images of bone marrow structures. However, as this paper shows, each modality has its own limitations. The comprehensive analysis does not stop at the technical aspects, but ventures into the wider implications of these techniques in a clinical setting. By understanding the synergies and shortcomings of these modalities, healthcare professionals can make diagnostic and therapeutic decisions. Furthermore, at a time when medical technology is evolving at a breakneck pace, this review casts a speculative eye towards future advances in the field of bone metastasis imaging, bridging the current state with future possibilities. Such insights are essential for both clinicians and researchers navigating the complex landscape of bone metastasis diagnosis.

Objectives: The objectives of this study were to investigate the c.1024G>T SNP in the TRPV4 gene in Scottish Straight and Fold cats, and to evaluate the pattern of skeletal phenotype and the evolution of radiological signs of Scottish Fold osteochondrodysplasia (SFOCD) over time in heterozygous subjects., Methods: DNA was obtained from blood samples of 17 cats (Scottish Fold: n = 12; Scottish Straight: n = 5) and subsequently genotyped by sequencing in a 249 bp region of the TRPV4 gene (exon 6), including the known c.1024G>T causative mutation for osteochondrodysplasia. Orthopaedic and radiographic analyses were performed on animals carrying the mutant allele., Results: Genotyping by sequencing confirmed that all and only the Scottish Fold cats carried the mutant allele in a heterozygous asset. Furthermore, two other exon variants, already described in the literature as silent variants, were found in some of the sampled cats. Comparative orthogonal radiographic views of the shoulder, elbow, carpus, hip, stifle and tarsus were obtained. A mediolateral projection of the thoracic and lumbar column was also performed. Three out of four cats were clinically and radiographically examined again 1.5 years later., Conclusions and Relevance: Although the presence of the mutant allele in all the tested Scottish Fold cats was confirmed, only 1/12 showed clinical signs of SFOCD. Furthermore, no cats in the 1.5-year follow-up showed skeletal changes. Although significant, the c.1024G>T mutation in the TRPV4 gene, supposedly, is not the only cause or risk of developing SFOCD., Competing Interests: Conflict of interestThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Introduction: Contouring of gas pockets is a time consuming step in the workflow of adaptive radiotherapy. We would like to better understand which gas pockets electronic densitiy should be used and the dosimetric impact on adaptive MRgRT treatment., Materials and Methods: 21 CT scans of patients undergoing SBRT were retrospectively evaluated. Anatomical structures were contoured: Gross Tumour Volume (GTV), stomach (ST), small bowel (SB), large bowel (LB), gas pockets (GAS) and gas in each organ respectively STG, SBG, LBG. Average HU in GAS was converted in RED, the obtained value has been named as Gastrointestinal Gas RED (GIGED). Differences of average HU in GAS, STG, SBG and LBG were computed. Three treatment plans were calculated editing the GAS volume RED that was overwritten with: air RED (0.0012), water RED (1.000), GIGED, generating respectively APLAN, WPLAN and the GPLAN. 2-D dose distributions were analyzed by gamma analysis. Parameter called active gas volume (AGV) was calculated as the intersection of GAS with the isodose of 5% of prescription dose., Results: Average HU value contained in GAS results to be equal to -620. No significative difference was noted between the average HU of gas in different organ at risk. Value of Gamma Passing Rate (GPR) anticorrelates with the AGV for each plan comparison and the threshold value for GPR to fall below 90% is 41, 60 and 139 cc for WPLANvsAPLAN, GPLANvsAPLAN and WPLANvsGPLAN respectively., Discussions: GIGED is the right RED for Gastrointestinal Gas. Novel AGV is a useful parameter to evaluate the effect of gas pocket on dose distribution., Competing Interests: 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 © 2023 Nardini, Meffe, Galetto, Boldrini, Chiloiro, Romano, Panza, Bevacqua, Turco, Votta, Capotosti, Moretti, Gambacorta, Indovina and Placidi.)

Abstract: In a 51-year-old woman affected by breast cancer, hepatic recurrence of disease was managed by concurrent 90 Y-labeled glass microsphere embolization (transarterial radioembolization) and radiofrequency thermoablation. Intention-to-treat target, candidate to radioembolization, was in the IV hepatic segment; another lesion, managed with radiofrequency thermoablation, was in the VI-VII hepatic segment. Concomitant correction of a duodenocephalopancreatic shunting was performed as well. Thermoablation did not interfere with distribution of 99m Tc-macroaggregated albumin and 90 Y-labeled microspheres to the target and healthy liver. At our knowledge, this is the first report that combines 2 locoregional procedures in different hepatic segments on the same day., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Psychology and neuroscience are concerned with the study of behavior, of internal cognitive processes, and their neural foundations. However, most laboratory studies use constrained experimental settings that greatly limit the range of behaviors that can be expressed. While focusing on restricted settings ensures methodological control, it risks impoverishing the object of study: by restricting behavior, we might miss key aspects of cognitive and neural functions. In this article, we argue that psychology and neuroscience should increasingly adopt innovative experimental designs, measurement methods, analysis techniques and sophisticated computational models to probe rich, ecologically valid forms of behavior, including social behavior. We discuss the challenges of studying rich forms of behavior as well as the novel opportunities offered by state-of-the-art methodologies and new sensing technologies, and we highlight the importance of developing sophisticated formal models. We exemplify our arguments by reviewing some recent streams of research in psychology, neuroscience and other fields (e.g., sports analytics, ethology and robotics) that have addressed rich forms of behavior in a model-based manner. We hope that these "success cases" will encourage psychologists and neuroscientists to extend their toolbox of techniques with sophisticated behavioral models - and to use them to study rich forms of behavior as well as the cognitive and neural processes that they engage., 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 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Incompatible insect technique (IIT) is a population suppression approach based on the release of males with manipulated Wolbachia infection inducing egg inviability in wild females. We here present results of multiple field releases of incompatible ARwP males carried out in 2019 in a 2.7-ha green area within urban Rome (Italy) to assess the effect on Aedes albopictus egg viability. Data are compared with results obtained in 2018, when the approach was tested for the first time in Europe., Results: An average of 4674 ARwP males were released weekly for 7 weeks, resulting in a mean ARwP:wild male ratio of 1.1:1 (versus 0.7:1 in 2018). Egg-viability dynamics in ovitraps significantly varied between treated and control sites, with an estimated overall reduction of 35% (versus 15% in 2018). The estimated proportion of females classified as mated with ARwP males was 41.8% and the viability rate of eggs laid by these females (9.5%) was on average significantly lower than that of females only mated with wild males (87.8%); however, high variability in fertility was observed. Values of ARwP male competitiveness were 0.36 and 0.73 based on the overall viability rate of eggs in ovitraps and on female fertility, respectively; thus, well above the conventional 0.2 threshold for an effective suppressive impact in the field., Conclusions: Results further support the potential of IIT as a tool to contribute to Ae. albopictus control in the urban context, stressing the need for larger field trials to evaluate the cost-efficacy of the approach in temperate regions. © 2023 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry., (© 2023 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.)

Introduction: interventional radiology workers are potentially exposed to high levels of ionizing radiation, therefore preventive dose estimation is mandatory for the correct risk classification of staff. Effective dose (ED) is a radiation protection quantity strictly related to the secondary air kerma ( K S ), using appropriate multiplicative conversion factors (ICRP 106). The aim of this work is to evaluate the accuracy of K S estimated from physically measurable quantities such as dose-area product (DAP) or fluoroscopy time (FT)., Methods: radiological units ( n = 4) were characterized in terms of primary beam air kerma and DAP-meter response, consequently defining a DAP-meter correction factor (CF) for each unit. K S , scattered from an anthropomorphic phantom and measured by a digital multimeter, was then compared with the value estimated from DAP and FT. Different combinations of tube voltages, field sizes, current and scattering angles were used to simulate the variation of working conditions. Further measurements were performed to estimate the couch transmission factor for different phantom placements on the operational couch, defining a CF as the mean transmission factor., Results: when no CFs were applied, the measured K S showed a median percentage difference of between 33.8% and 115.7% with respect to K S evaluated from DAP, and between -46.3% and 101.8% for K S evaluated from FT. By contrast, when previously defined CFs were applied to the evaluated K S , the median percentage difference between the measured K S and the value evaluated from DAP ranged from between -7.94% and 15.0%, and between -66.2% and 17.2% for that evaluated from FT., Conclusion: when appropriate CF are applied, the preventive ED estimation from the median DAP value seems to be more conservative and easier to obtain with respect to the one obtained from the FT value. Further measurements should be performed with a personal dosimeter during routine activities to assess the proper K S to ED conversion factor., (© 2023 Society for Radiological Protection. Published on behalf of SRP by IOP Publishing Limited. All rights reserved.)

The human gut microbiome plays a crucial role in human health and has been a focus of increasing research in recent years. Omics-based methods, such as metagenomics, metatranscriptomics, and metabolomics, are commonly used to study the gut microbiome because they provide high-throughput and high-resolution data. The vast amount of data generated by these methods has led to the development of computational methods for data processing and analysis, with machine learning becoming a powerful and widely used tool in this field. Despite the promising results of machine learning-based approaches for analyzing the association between microbiota and disease, there are several unmet challenges. Small sample sizes, disproportionate label distribution, inconsistent experimental protocols, or a lack of access to relevant metadata can all contribute to a lack of reproducibility and translational application into everyday clinical practice. These pitfalls can lead to false models, resulting in misinterpretation biases for microbe-disease correlations. Recent efforts to address these challenges include the construction of human gut microbiota data repositories, improved data transparency guidelines, and more accessible machine learning frameworks; implementation of these efforts has facilitated a shift in the field from observational association studies to experimental causal inference and clinical intervention.

Background: Transarterial Radioembolization (TARE) is a widespread radiation therapy for unresectable hepatic lesions, but a clear understanding of the dose-response link is still missing. The aim of this preliminary study is to investigate the role of both dosimetric and clinical parameters as classifiers or predictors of response and survival for TARE in hepatic tumors and to present possible response cut-off., Methods: 20 patients treated with glass or resin microspheres according to a personalized workflow were included. Dosimetric parameters were extracted from personalized absorbed dose maps obtained from the convolution of 90Y PET images with 90Y voxel S-values., Results: D 95 ≥ 104 Gy and tumor mean absorbed dose MADt ≥ 229 Gy were found to be optimal cut-off values for complete response, while D 30 ≥ 180 Gy and MAD t ≥ 117 Gy were selected as cut-off values for at least partial response and predicted better survival. Clinical parameters Alanine Transaminase (ALT) and Model for End-Stage Liver Disease (MELD) didn't show sufficient classification capability for response or survival., Concusion: These preliminary results highlight the importance of an accurate dosimetric evaluation and suggest a cautious approach when considering clinical indicators. Dosimetric cut-off values could be a support tool in both planning and post-treatment phases. Larger multi-centric randomized trials, with standardized methods regarding patient selection, response criteria, Regions of Interest definition, dosimetric approach and activity planning are needed to confirm these promising results., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Purpose: To evaluate the feasibility of comprehensive automation of an intra-cranial proton treatment planning., Materials and Methods: Class solution (CS) beam configuration selection allows the user to identify predefined beam configuration based on target localization; automatic CS (aCS) will then explore all the possible CS beam geometries. Ten patients, already used for the evaluation of the automatic selection of the beam configuration, have been also employed to training an algorithm based on the computation of a benchmark dose exploit automatic general planning solution (GPS) optimization with a wish list approach for the planning optimization. An independent cohort of ten patients has been then used for the evaluation step between the clinical and the GPS plan in terms of dosimetric quality of plans and the time needed to generate a plan., Results: The definition of a beam configuration requires on average 22 min (range 9-29 min). The average time for GPS plan generation is 18 min (range 7-26 min). Median dose differences (GPS-Manual) for each OAR constraints are: brainstem -1.60 Gy, left cochlea -1.22 Gy, right cochlea -1.42 Gy, left eye 0.55 Gy, right eye -2.33 Gy, optic chiasm -1.87 Gy, left optic nerve -4.45 Gy, right optic nerve -2.48 Gy and optic tract -0.31 Gy. Dosimetric CS and aCS plan evaluation shows a slightly worsening of the OARs values except for the optic tract and optic chiasm for both CS and aCS, where better results have been observed., Conclusion: This study has shown the feasibility and implementation of the automatic planning system for intracranial tumors. The method developed in this work is ready to be implemented in a clinical workflow., 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 Associazione Italiana di Fisica Medica e Sanitaria. Published by Elsevier Ltd. All rights reserved.)

Computation methods that predict the binding of peptides to MHC-I are important tools for screening and identifying immunogenic antigens and have the potential to accelerate vaccine and drug development. However, most available tools are sequence-based and optimized only for peptides containing the twenty canonical amino acids. This omits a large number of peptides containing non-canonical amino acids (NCAA), or residues that undergo varied post-translational modifications such as glycosylation or phosphorylation. These modifications fundamentally alter peptide immunogenicity. Similarly, existing structure-based methods are biased towards canonical peptide backbone structures, which may or may not be preserved when NCAAs are present. Rosetta FlexPepDock ab-initio is a structure-based computational protocol able to evaluate peptide-receptor interaction where no prior information of the peptide backbone is known. We benchmarked FlexPepDock ab-initio for docking canonical peptides to MHC-I, and illustrate for the first time the method's ability to accurately model MHC-I bound epitopes containing NCAAs. FlexPepDock ab-initio protocol was able to recapitulate near-native structures (≤1.5Å) in the top lowest-energy models for 20 out of 25 cases in our initial benchmark. Using known experimental binding affinities of twenty peptides derived from an influenza-derived peptide, we showed that FlexPepDock protocol is able to predict relative binding affinity as Rosetta energies correlate well with experimental values (r = 0.59, p = 0.006). ROC analysis revealed 80% true positive and a 40% false positive rate, with a prediction power of 93%. Finally, we demonstrate the protocol's ability to accurately recapitulate HLA-A*02:01 bound phosphopeptide backbone structures and relative binding affinity changes, the theoretical structure of the lymphocytic choriomeningitis derived glycosylated peptide GP392 bound to MHC-I H-2Db, and isolevuglandin-adducted peptides. The ability to use non-canonical amino acids in the Rosetta FlexPepDock protocol may provide useful insight into critical amino acid positions where the post-translational modification modulates immunologic responses., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Bloodworth et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Celiac disease (CD) is a complex multi-organ disease with a high prevalence of extra-intestinal involvement, including neurological and psychiatric manifestations, such as cerebellar ataxia, peripheral neuropathy, epilepsy, headache, cognitive impairment, and depression. However, the mechanisms behind the neurological involvement in CD remain controversial. Recent evidence shows these can be related to gluten-mediated pathogenesis, including antibody cross-reaction, deposition of immune-complex, direct neurotoxicity, and in severe cases, vitamins or nutrients deficiency. Here, we have summarized new evidence related to gut microbiota and the so-called "gut-liver-brain axis" involved in CD-related neurological manifestations. Additionally, there has yet to be an agreement on whether serological or neurophysiological findings can effectively early diagnose and properly monitor CD-associated neurological involvement; notably, most of them can revert to normal with a rigorous gluten-free diet. Moving from a molecular level to a symptom-based approach, clinical, serological, and neurophysiology data might help to disentangle the many-faceted interactions between the gut and brain in CD. Eventually, the identification of multimodal biomarkers might help diagnose, monitor, and improve the quality of life of patients with "neuroCD".

Since the very beginning of the coronavirus disease 2019 (COVID-19) pandemic in early 2020, it was evident that patients with cardiovascular disease (CVD) were at an increased risk of developing severe illness, and complications spanning cerebrovascular disorders, dysrhythmias, acute coronary syndrome, ischemic and non-ischemic heart disease, pericarditis, myocarditis, heart failure, thromboembolic disease, stroke, and death. Underlying these was excessive systemic inflammation and coagulopathy due to SARS-COV-2 infection, the effects of which also continued long-term as evidenced by post-COVID-19 cardiovascular complications. The acute and chronic cardiovascular effects of COVID-19 occurred even among those who were not hospitalized and had no previous CVD or those with mild symptoms. This comprehensive review summarizes the current understanding of molecular mechanisms triggered by the SARS-CoV-2 virus on various cells that express the angiotensin-converting enzyme 2, leading to endothelial dysfunction, inflammation, myocarditis, impaired coagulation, myocardial infarction, arrhythmia and a multisystem inflammatory syndrome in children or Kawasaki-like disease., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Parkinson's disease (PD), the fastest-growing movement disorder, is still challenged by the unavailability of disease-modifying therapy. Mildly elevated levels of unconjugated bilirubin (UCB, PubChem CID 5280352) have been shown to be protective against several extra-CNS diseases, and the effect is attributed to its well-known anti-oxidant and anti-inflammatory capability. We explored the neuroprotective effect of low concentrations of UCB (from 0.5 to 4 µM) in our PD model based on organotypic brain cultures of substantia nigra (OBCs-SN) challenged with a low dose of rotenone (Rot). UCB at 0.5 and 1 µM fully protects against the loss of TH + (dopaminergic) neurons (DOPAn). The alteration in oxidative stress is involved in TH + positive neuron demise induced by Rot, but is not the key player in UCB-conferred protection. On the contrary, inflammation, specifically tumor necrosis factor alpha (TNF-α), was found to be the key to UCB protection against DOPAn sufferance. Further work will be needed to introduce the use of UCB into clinical settings, but determining that TNF-α plays a key role in PD may be crucial in designing therapeutic options.

Introduction: Hepatocellular carcinoma (HCC) is the sixth most diagnosed malignancy and the fourth leading cause of cancer-related death worldwide, with poor overall survival despite available curative treatments. One of the most crucial factors influencing survival in HCC is recurrence. The current study aims to determine factors associated with early recurrence of HCC in patients with BCLC Stage 0 or Stage A treated with surgical resection or local ablation. Materials and Methods: We retrospectively enrolled 58 consecutive patients diagnosed with HCC within BCLC Stage 0 or Stage A and treated either by surgical resection or local ablation with maximum nodule diameter < 50 mm. In the first year of follow-up after treatment, imaging was performed regularly one month after treatment and then every three months. Each case was discussed collectively by the Liver Multidisciplinary Group to decide diagnosis, treatment, follow-up, and disease recurrence. Variables resulting in statistically significant difference were then studied by Cox regression analysis; univariately and then multivariately based on forward stepwise Cox regression. Results are represented in hazard ratio (H.R.) with 95% confidence interval (C.I.). Results: There was no statistically significant difference in recurrence rates (34.8 vs. 45.7%, log-rank test, p = 0.274) between patients undergoing surgical resection and local ablation, respectively. Early recurrence was associated with male gender (HR 2.5, 95% C.I. 1.9−3.1), nodule diameter > 20 mm (HR 4.5, 95% C.I. 3.9−5.1), platelet count < 125 × 103 cell/mm3 (HR 1.6, 95% C.I. 1.2−1.9), platelet-lymphocyte ratio < 95 (HR 2.1, 95% C.I. 1.7−2.6), lymphocyte-monocyte ratio < 2.5 (HR 1.9, 95% C.I. 1.4−2.5), and neutrophil-lymphocyte ratio > 2 (HR 2.7, 95% C.I. 2.2−3.3). Discussion and Conclusions: Our results are in line with the current literature. Male gender and tumor nodule dimension are the main risk factors associated with early HCC recurrence. Platelet count and other combined scores can be used as predictive tools for early HCC recurrence, although more studies are needed to define cut-offs.

The follicle-stimulating hormone receptor (FSHR) belongs to the glycoprotein hormone receptors, a subfamily of G-protein-coupled receptors (GPCRs). FSHR is involved in reproductive processes such as gonadal development and maturation. Structurally, the extensive extracellular domain, which contains the hormone-binding site and is linked to the transmembrane domain by the hinge region (HR), is characteristic for these receptors. How this HR is involved in hormone binding and signal transduction is still an open question. We combined in vitro and in situ chemical crosslinking, disulfide pattern analysis, and mutation data with molecular modeling to generate experimentally driven full-length models. These models provide insights into the interface, important side-chain interactions, and activation mechanism. The interface indicates a strong involvement of the connecting loop. A major rearrangement of the HR seems implausible due to the tight arrangement and fixation by disulfide bonds. The models are expected to allow for testable hypotheses about signal transduction and drug development for GPHRs., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

. A model of continuity of care for not residents through medical-nursing teleconsultation in a Hub & Spoke network., Introduction: The Seasonal Continuity of Care (CAS) is a service of the Bergamo Health Protection Agency that provides medical and healthcare services, guaranteeing outpatient or home care to Italian and foreign tourists and seasonal workers during the months of July and August. The Covid-19 pandemic and the shortage of doctors made it impossible to provide the service in 2021 as in previous summer seasons., Aims: To activate a CAS service with the involvement of nurses., Methods: A "Hub-Spoke" network model was activated; nurses in the Spoke sites, with the patient in attendance, through teleconsultation by video call, made remote contact with a doctor in the Hub., Results: In the 3 Spoke CASs, from 2 to 22 August 2021, 274 services (of which 14.3% were teleconsultations between the nurse at the Spoke CAS site and the doctor at the Hub site) and 162 repeat prescription requests were made. Teleconsultation was mainly performed for patients with acute pathology (71.8%), mainly for arthralgia and fever. In the majority of cases, it was sufficient to answer to the needs of the patient (87.2%); a small number of cases were referred to a doctor's appointment (10.3%) or to Emergency Department (2.6%)., Conclusions: Nurse triage reduced the time of medical visits, allowing more patients to be taken care of. The need for digital infrastructure, training and integration with district services emerged.

Introduction: Due to scant literature and the absence of high-level evidence, the treatment of vulvar cancer is even more challenging in countries facing limited resources, where direct application of international guidelines is difficult. Recommendations from a panel of experts convened to address some of these challenges were developed., Methods: The panel met in Rio de Janeiro in September 2019 during the International Gynecological Cancer Society congress and was composed of specialists from countries in Africa, Asia, Eastern Europe, Latin America, and the Middle East. The panel addressed 62 questions and provided recommendations for the management of early, locally advanced, recurrent, and/or metastatic vulvar cancer. Consensus was defined as at least 75% of the voting members selecting a particular recommendation, whereas a majority vote was considered when one option garnered between 50.0% and 74.9% of votes. Resource limitation was defined as any issues limiting access to qualified surgeons, contemporary imaging or radiation-oncology techniques, antineoplastic drugs, or funding for the provision of contemporary medical care., Results: Consensus was reached for nine of 62 (14.5%) questions presented to the panel, whereas a majority vote was reached for 29 (46.7%) additional questions. For the remaining questions, there was considerable heterogeneity in the recommendations., Conclusion: The development of guidelines focusing on areas of the world facing more severe resource limitations may improve medical practice and patient care., Competing Interests: 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 © 2022 Maluf, Zibetti, Paulino, de Melo, Racy, Ferrigno, Uson Junior, Ribeiro, Moretti, Sadalla, Nogueira Rodrigues, Carvalho, Baiocchi, Callegaro-Filho and Angioli.)

Discovering novel risk and prognostic factors for COVID-19 may help not only in reducing severity and mortality but also in creating targeted therapies considering patients’ individual features. Liver fibrosis is considered a complication in Non-alcoholic Fatty Liver Disease (NAFLD), it is a feature of steatohepatitis (NASH), and it has already been related to an increased risk for a wide range of diseases. Here, we aimed to define if any parameter assessing metabolic status has predictive power in identifying inpatients at risk for poorer prognosis and an increased mortality from COVID-19. This retrospective study was conducted at the Sub-Intensive Medicine Care Unit of the Presidio Maxi-Emergenze Fiera del Levante, Azienda Ospedaliero-Universitaria Policlinico di Bari, Italy. We evaluated 271 inpatients with moderate-to-severe SARS-CoV-2-related respiratory failure by comparing biochemical features and non-invasive liver fibrosis scores among discharged, transferred to Intensive Care Units (ICU) and non-survivor patients. Moreover, by performing ROC curves, we defined cut-off values to predict mortality and disease severity for each score. We found that non-invasive scores of liver fibrosis, obtained at day of admission, such as AAR (p < 0.001), FIB-4 and mFIB-4, FORNS, and AARPRI (p < 0.05) strongly predict not only in-hospital mortality but also the length of hospitalization and eventual admission to ICU. FIB-4 was the best score to identify non-survivor patients (sensitivity of 80% and specificity of 63%) and predict the need for ICU or mortality (71% of sensitivity and 65% of specificity), with a cut-off value of 1.94. Therefore, we present the predictive power and the cut-off values of several liver fibrosis scores here for disease severity and mortality in SARS-CoV-2 in-patients and we proposed the use of the present scores to identify ab initio the clinical therapeutic and diagnostic protocols for high-risk patients.

Heifers are a fundamental resource on farms, and their importance is reflected in both farm management and economy. Therefore, the selection of heifers to be reared on a farm should be carefully performed to select only the best animals. Genomic selection is available nowadays to evaluate animals in a fast and economic way. However, it is mainly used on the sire line and on performance traits. Ten farms were selected based on their 5-year records of average somatic cell count and evenly classified into high (>300,000 cells/mL) and low somatic cell count (<150,000 cells/mL). Genomic indexes (regarding both wellness and productive traits) were evaluated in 157 Italian Holstein heifers reared in the selected ten farms (90 from high-cells farms and 67 from low-cells ones). Linear mixed models were fitted to analyze the effects of the abovementioned genomic indexes on related phenotypes. Results have shown that farms classified into low somatic cell count had an overall better animal genomic pool compared to high somatic cell count ones. Additionally, the results shown in this study highlighted a difference in wellness genomic indexes in animals from farms with either a high or a low average somatic cell count. Applying genomic tools directly to heifer selection could improve economic aspects related to herd turnover.

Introduction: Nearly 85% of cervical cancer new cases are diagnosed in limited resources countries. Although several strategies have been proposed to reduce the disease burden, challenges remain to provide the best possible care. We report recommendations from an expert consensus meeting convened to address from prevention to management of cervical cancer in limited resources countries., Methods: The expert panel, composed by invited specialists from 38 developing countries in Africa, Asia, Eastern Europe, Latin America, and the Middle East, convened in Rio de Janeiro in September 2019, during the Global Meeting of the International Gynecological Cancer Society (IGCS). Panel members considered the published scientific evidence and their practical experience on the topics, as well as the perceived cost-effectiveness of, and access to, the available interventions. The focus of the recommendations was on geographic regions rather than entire countries because medical practice varies considerably in the countries represented. Resource limitation was qualified as limited access to qualified surgeons, contemporary imaging or radiation-oncology techniques, antineoplastic drugs, or overall funding for provision of state-of-the-art care. Consensus was defined as at least 75% of the voting members selecting a particular answer of the multiple-choice questionnaire, whereas the majority vote was considered as 50% to 74.9%., Results: Consensus was reached for 25 of the 121 (20.7%) questions, whereas for 54 (44.6%) questions there was one option garnering between 50% to 74.9% of votes (majority votes). For the remaining questions, considerable heterogeneity in responses was observed., Discussion: The implementation of international guidelines is challenging in countries with resource limitations or unique health-care landscapes. The development of guidelines by the health care providers in those regions is more reflective of the reality on the ground and may improve medical practice and patient care. However, challenges remain toward achieving that goal at political, economic, social, and medical levels., Competing Interests: 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 © 2022 Maluf, Dal Molin, de Melo, Paulino, Racy, Ferrigno, Uson Junior, Ribeiro, Moretti, Sadalla, Nogueira-Rodrigues, Carvalho, Baiocchi, Callegaro-Filho and Abu-Rustum.)

In the present context of growing antimicrobial resistance (AMR) concern, understanding the distribution of AMR determinants in food matrices such as milk is crucial to protect consumers and maintain high food safety standards. Herein, the resistome of different dairy farms was investigated through a shotgun metagenomic sequencing approach, taking advantage of in-line milk filters as promising tools. The application of both the reads-based and the assembly-based approaches has allowed the identification of numerous AMR determinants, enabling a comprehensive resolution of the resistome. Notably most of the species harboring AMR genes were predicted to be Gram-negative genera, namely Enterobacter, Acinetobacter, Escherichia, and Pseudomonas, pointing out the role of these bacteria as reservoirs of AMR determinants. In this context, the use of de novo assembly has allowed a more holistic AMR detection strategy, while the reads-based approach has enabled the detection of AMR genes from low abundance bacteria, usually undetectable by assembly-based methods. The application of both reads-based and assembly-based approaches, despite being computationally demanding, has facilitated the comprehensive characterization of a food chain resistome, while also allowing the construction of complete metagenome assembled genomes and the investigation of mobile genetic elements. Our findings suggest that milk filters can successfully be used to investigate the resistome of bulk tank milk through the application of the shotgun metagenomic sequencing. In accordance with our results, raw milk can be considered a source of AMR bacteria and genes; this points out the importance of properly informing food business operators about the risk associated with poor hygiene practices in the dairy production environment and consumers of the potential microbial food safety risks derived from raw milk products consumption. Translating these findings as risk assessment outputs heralds the next generation of food safety controls., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

In this paper, an FPGA (Field Programmable Gate Array)-based digital architecture for the measurement of quartz crystal microbalance (QCM) oscillating frequency of transient responses, i.e., in QCM-D (QCM and Dissipation) applications, is presented. The measurement system is conceived for operations in liquid, with short QCM transient responses due to the large mechanical load. The proposed solution allows for avoiding the complex processing systems typically required by the QCM-D techniques and grants frequency resolutions better than 1 ppm. The core of the architecture is a reciprocal digital frequency meter, combined with the preprocessing of the QCM signal through mixing operations, such as a step-down of the input frequency and reducing the measurement error. The measurement error is further reduced through averaging. Different strategies are proposed to implement the proposed measurement solution, comprising an all-digital circuit and mixed analog/digital ones. The performance of the proposed architectures is theoretically derived, compared, and analyzed by means of experimental data obtained considering 10 MHz QCMs and 200 μs long transient responses. A frequency resolution of about 240 ppb, which corresponds to a Sauerbrey mass resolution of 8 ng/cm 2 , is obtained for the all-digital solution, whereas for the mixed solution the resolution halves to 120 ppb, with a measurement time of about one second over 100 repetitions.

Small ruminant lentiviruses (SRLV) belong to the Retroviridae family and can cause various diseases. One of the most impacting diseases is visna-maedi, a complex disease characterized by long latencies and chronic progressive inflammatory events affecting the nervous system, lungs, mammary gland, and articular joints. A single nucleotide polymorphism (rs408593969, c.103G>A, missense mutation E35K) in the ovine transmembrane protein gene 154 (TMEM154) was identified as protective against small ruminant lentivirus infection in different herds worldwide. However, there is evidence in the scientific literature of a breed-specificity of this protective effect and, furthermore, there are still limited studies regarding the association between the animal genotype and the infecting virus genotype. Thus, the aim of this study was to further investigate the association between the animal genotype for the suggested protective mutation and the infecting virus genotype, in three different sheep breeds reared in northern Italy. The results obtained only partially confirmed the data available in the literature, as the protective effect was confirmed only for SRLV genotype A clusters, while other genotypes (namely B and E) infected AA and GA animals. Further studies with an experimental infection of specific virus genotypes in hosts with specific genotypes are required to confirm the larger number of cases the results obtained in this study., (© 2022. The Author(s).)

Volcanic ash exposure can lead to significant health risks. Damage to the respiratory and pulmonary systems are the most evident toxic side effects although the causes of these symptoms remain unclear. Conversely, the effects on other organs remain largely under-explored, limiting our understanding of the long-term volcanic ash-related risk at the whole-body scale. The metallome i.e. metal concentrations and isotopic compositions within the body, is suspected to be affected by volcanic ash exposure, having thus the potential for capturing some specificities of ash toxicity. However, the means by and extent to which the metallome is affected at the entire body scale and how the consequent chemical and isotopic deregulations correlate with pathophysiological dysfunctions are currently poorly understood. Here, we adopt a transdisciplinary approach combining high precision chemical analyses (major and trace element concentrations) and CuZn isotope measurements in seven organs and two biological fluids of isogenic mice (C57BL/6) exposed to eruption products from La Soufrière de Guadeloupe (Eastern Carribean), in tandem with biological parameters including physiological and morphological data. Based on principal component analysis, we show that after one month of exposure to volcanic ash deposits, the mice metallome; originally organ-specific and isotopically-typified, is highly disrupted as shown for example by heavy metal accumulation in testis (e.g., Fe, Zn) and Cu, Zn isotopic divergence in liver, intestine and blood. These metallomic variations are correlated with early testicular defects and might reflect the warning signs of premature (entero)hepatic impairments that may seriously affect fertility and favor the emergence of liver diseases after prolonged exposure. Monitoring the temporal evolution of the Cu and Zn isotope compositions seems to be a promising technique to identify the main biological processes and vital functions that are vulnerable to environmental volcanogenic pollutants although this will require further validation on human subjects., 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.)

NAFLD is the most common cause of abnormality in liver function tests. NAFLD is considered a potential cardiovascular risk factor and is linked to cardiovascular risk factors such as obesity, hypertension, type 2 diabetes, and dyslipidemia. Few previous studies have investigated whether NAFLD could be independently associated with cognitive impairment. The current study aims to find a possible role of NAFLD in the development of subcortical vascular dementia (sVaD). We considered NAFLD as a possible independent vascular risk factor or, considering its metabolic role, associated with other commonly accepted sVaD risk factors, i.e., lack of folate, vitamin B12, and vitamin D-OH25, and increased levels of homocysteine. We studied 319 patients diagnosed with sVaD. All patients underwent an abdominal ultrasound examination to classify steatosis into four levels (1-none up to 4-severe). sVaD patients were divided into two groups according to the presence or absence of NAFLD. Our results demonstrated a strong correlation between NAFLD and sVaD. Patients with the two comorbidities had worse neuropsychological outcomes and a worse metabolic profile. We also found a robust relationship between NAFLD and severe vitamin B12, folate, vitamin D hypovitaminosis, and higher hyperhomocysteinemia levels. This way, it is evident that NAFLD contributes to a more severe metabolic pathway. However, the strong relationship with the three parameters (B12, folate and vitamin D, and homocysteinemia) suggests that NAFLD can contribute to a proinflammatory condition.

Food authentication in local breeds has important implications from both an economic and a qualitative point of view. Meat products from autochthonous breeds are of premium value, but can easily incur fraudulent or accidental substitution or mislabeling. The aim of this study was to identify a small number of SNPs using the Illumina PorcineSNP60 BeadChip for breed traceability, in particular of the Italian Nero Siciliano pig and its derived products. A panel of 12 SNPs was sufficient to discriminate Nero Siciliano pig from cosmopolitan breeds and wild boars. After adding 8 SNPs, the final panel of 20 SNPs allowed us to discriminate all the breeds involved in the study, to correctly assign each individual to its breed, and, moreover, to discriminate Nero Siciliano from first-generation hybrids. Almost all livestock breeds are being genotyped with medium- or high-density SNP panels, providing a large amount of information for many applications. Here, we proposed a method to select a reduced SNP panel to be used for the traceability of pig breeds.

Small-vessel disease (SVD), also known as microvascular endothelial dysfunction, is a disorder with negative consequences for various organs such as the heart and brain. Impaired dilatation and constriction of small vessels in the heart lead to reduced blood flow and ischemia independently of coronary artery disease (CAD) and are associated with major cardiac events. SVD is usually a silent form of subcortical vascular burden in the brain with various clinical manifestations, such as silent-lacunar-ischemic events and confluent white-matter hyperintensities. Imaging techniques are the main help for clinicians to diagnose cardiac and brain SVD correctly. Markers of inflammation, such as C-reactive protein, tumor-necrosis-factor α, and interleukin 6, provide insight into the disease and markers that negatively influence nitric-oxide bioavailability and promote oxidative stress. Unfortunately, the therapeutic approach against SVD is still not well-defined. In the last decades, various antioxidants, oxidative stress inhibitors, and superoxide scavengers have been the target of extensive investigations due to their potential therapeutic effect, but with unsatisfactory results. In clinical practice, traditional anti-ischemic and risk-reduction therapies for CAD are currently in use for SVD treatment.

Small vessel disease (SVD) is one of the most frequent pathological conditions which lead to dementia. Biochemical and neuroimaging might help correctly identify the clinical diagnosis of this relevant brain disease. The microvascular alterations which underlie SVD have common origins, similar cognitive outcomes, and common vascular risk factors. Nevertheless, the arteriolosclerosis process, which underlines SVD development, is based on different mechanisms, not all completely understood, which start from a chronic hypoperfusion state and pass through a chronic brain inflammatory condition, inducing a significant endothelium activation and a consequent tissue remodeling action. In a recent review, we focused on the pathophysiology of SVD, which is complex, involving genetic conditions and different co-morbidities (i.e., diabetes, chronic hypoxia condition, and obesity). Currently, many points still remain unclear and discordant. In this paper, we wanted to focus on new biomarkers, which can be the expression of the endothelial dysfunction, or of the oxidative damage, which could be employed as markers of disease progression or for future targets of therapies. Therefore, we described the altered response to the endothelium-derived nitric oxide-vasodilators (ENOV), prostacyclin, C-reactive proteins, and endothelium-derived hyperpolarizing factors (EDHF). At the same time, due to the concomitant endothelial activation and chronic neuroinflammatory status, we described hypoxia-endothelial-related markers, such as HIF 1 alpha, VEGFR2, and neuroglobin, and MMPs. We also described blood-brain barrier disruption biomarkers and imaging techniques, which can also describe perivascular spaces enlargement and dysfunction. More studies should be necessary, in order to implement these results and give them a clinical benefit.

Background: Releasing considerable numbers of radiation-sterilized males is a promising strategy to suppress mosquito vectors. However, releases may also include small percentages of biting females, which translate to non-negligible numbers when releases are large. Currently, the effects of irradiation on host-seeking and host-biting behaviors have not been exhaustively investigated. Information is also lacking regarding the effects of sterilizing treatment on the endosymbiotic bacterium Wolbachia, which is known to affect the vector competence of infected mosquitos., Methods: To ascertain the effects of irradiation on females, the pupae of two Aedes albopictus strains, differing in their natural or artificial Wolbachia infection type, and Aedes aegypti-which is not infected by Wolbachia-were treated with various doses of X-rays and monitored for key fitness parameters and biting behavior over a period of 2 weeks. The effect of radiation on Wolbachia was investigated by quantitative polymerase chain reaction (qPCR) and fluorescence in situ hybridization (FISH) analysis., Results: Partial Aedes albopictus female sterility was achieved at 28 Gy, but the number of weekly bites more than doubled compared to that of the controls. Radiation doses of 35 and 45 Gy completely inhibited progeny production but did not significantly affect the survival or flight ability of Ae. albopictus females and caused a tripling of the number of bites per female per week (compared to untreated controls). These results were also confirmed in Ae. aegypti after treatment at 50 Gy. Wolbachia density decreased significantly in 45-Gy-irradiated females, with the greatest decreases in the early irradiation group (26 ± 2-h-old pupae). Wolbachia density also decreased as adults aged. This trend was confirmed in ovaries but not in extra-ovarian tissues. FISH analysis showed a strongly reduced Wolbachia-specific fluorescence in the ovaries of 13 ± 1-day-old females., Conclusions: These results suggest that, under sterile insect technique (SIT) programs, the vector capacity of a target population could increase with the frequency of the irradiated females co-released with the sterile males due to an increased biting rate. In the context of successful suppression, the related safety issues are expected to be generally negligible, but they should be conservatively evaluated when large-scale programs relying on imperfect sexing and high overflooding release ratios are run for long periods in areas endemic for arboviral diseases. Also, the effects of irradiation on the vector competence deserve further investigation., (© 2022. The Author(s).)

Vitamin D is a hormone with both genomic and non-genomic actions. It exerts its activity by binding vitamin D receptor (VDR), which belongs to the superfamily of nuclear receptors and ligand-activated transcription factors. Since VDR has been found in various tissues, it has been estimated that it regulates approximately 3% of the human genome. Several recent studies have shown pleiotropic effects of vitamin D in various processes such as cellular proliferation, differentiation, DNA repair and apoptosis and its involvement in different pathophysiological conditions as inflammation, diabetes mellitus, and anemia. It has been suggested that vitamin D could play an important role in neurodegenerative and cardiovascular disorders. Moderate to strong associations between lower serum vitamin D concentrations and stroke and cardiovascular events have been identified in different analytic approaches, even after controlling for traditional demographic and lifestyle covariates. The mechanisms behind the associations between vitamin D and cerebrovascular and cardiologic profiles have been widely examined both in animal and human studies. Optimization of vitamin D levels in human subjects may improve insulin sensitivity and beta-cell function and lower levels of inflammatory markers. Moreover, it has been demonstrated that altered gene expression of VDR and 1,25D3-membrane-associated rapid response steroid-binding (1,25D3-MARRS) receptor influences the role of vitamin D within neurons and allows them to be more prone to degeneration. This review summarizes the current understanding of the molecular mechanisms underlying vitamin D signaling and the consequences of vitamin D deficiency in neurodegenerative and cardiovascular disorders., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The liver is the primary site of drug metabolism, which can be altered by a variety of diseases affecting the liver parenchyma, especially in patients with liver cirrhosis. The use of antibiotics in patients with cirrhosis is usually a matter of concern for physicians, given the lack of practical knowledge for drug choice and eventual dose adjustments in several clinical scenarios. The aim of the current narrative review is to report, as broadly as possible, basic, and practical knowledge that any physician should have when approaching a patient with liver cirrhosis and an ongoing infection to efficiently choose the best antibiotic therapy.