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Many studies have explored the extraction of bioactive compounds from different onion solid wastes, such as bulb, skin, and peel. However, onion leaves have received limited attention despite their potential as a valuable source of nutraceutical compounds. This study aimed to valorise, for the first time, the agricultural waste in the form of spring onion leaves (CN, Cipollotto Nocerino) to obtain antioxidant-rich polyphenolic extracts. A Box-Behnken design (BBD) was used to assess the impact of microwave-assisted extraction (MAE) variables (temperature, time, extraction volume, and ethanol concentration) on total polyphenol content (TPC) measured by Folin-Ciocalteu method and the antioxidant power determined by FRAP assay. Response surface methodology (RSM) was applied, and regression equations, analysis of variance, and 3D response curves were developed. Our results highlighted that the TPC values range from 0.76 to 1.43 mg GAE g -1 dw, while the FRAP values range from 8.25 to 14.80 mmol Fe(II)E g -1 dw. The optimal extraction conditions predicted by the model were 60 °C, 22 min, ethanol concentration 51% (v/v), and solvent volume 11 mL. These conditions resulted in TPC and FRAP values of 1.35 mg GAE g -1 dw and 14.02 mmol Fe(II)E g -1 dw, respectively. Furthermore, the extract obtained under optimized conditions was characterized by UHPLC-ESI-Orbitrap-MS analysis. LC/MS-MS platform allowed us to tentatively identify various compounds belonging to the class of flavonoids, saponins, fatty acids, and lipids. Finally, the ability of CN optimal extract to inhibit the intracellular reactive oxygen species (ROS) release in a hepatocarcinoma cell line using an H 2 O 2 -induced oxidative stress model, was evaluated. The results highlighted the potential of CN extract as a valuable source of polyphenols with significant antioxidant properties, suitable for various applications in the food and pharmaceutical industries., (© 2023. Springer Nature Limited.)

Noninvasive identification of active myocardial inflammation in patients with cardiac sarcoidosis plays a key role in management but remains elusive. T2 mapping is a proposed solution, but the added value of quantitative myocardial T2 mapping for active cardiac sarcoidosis is unknown. Retrospective cohort analysis of 56 sequential patients with biopsy-confirmed extracardiac sarcoidosis who underwent cardiac MRI for myocardial T2 mapping. The presence or absence of active myocardial inflammation in patients with CS was defined using a modified Japanese circulation society criteria within one month of MRI. Myocardial T2 values were obtained for the 16 standard American Heart Association left ventricular segments. The best model was selected using logistic regression. Receiver operating characteristic curves and dominance analysis were used to evaluate the diagnostic performance and variable importance. Of the 56 sarcoidosis patients included, 14 met criteria for active myocardial inflammation. Mean basal T2 value was the best performing model for the diagnosis of active myocardial inflammation in CS patients (pR2 = 0.493, AUC = 0.918, 95% CI 0.835-1). Mean basal T2 value > 50.8 ms was the most accurate threshold (accuracy = 0.911). Mean basal T2 value + JCS criteria was significantly more accurate than JCS criteria alone (AUC = 0.981 vs. 0.887, p = 0.017). Quantitative regional T2 values are independent predictors of active myocardial inflammation in CS and may add additional discriminatory capability to JCS criteria for active disease., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

Background: Four-dimensional (4D) flow MRI allows for the quantification of complex flow patterns; however, its clinical use is limited by its inherently long acquisition time. Compressed sensing (CS) is an acceleration technique that provides substantial reduction in acquisition time., Purpose: To compare intracardiac flow measurements between conventional and CS-based highly accelerated 4D flow acquisitions., Study Type: Prospective., Subjects: Fifty healthy volunteers (28.0 ± 7.1 years, 24 males)., Field Strength/sequence: Whole heart time-resolved 3D gradient echo with three-directional velocity encoding (4D flow) with conventional parallel imaging (factor 3) as well as CS (factor 7.7) acceleration at 3 T., Assessment: 4D flow MRI data were postprocessed by applying a valve tracking algorithm. Acquisition times, flow volumes (mL/cycle) and diastolic function parameters (ratio of early to late diastolic left ventricular peak velocities [E/A] and ratio of early mitral inflow velocity to mitral annular early diastolic velocity [E/e']) were quantified by two readers., Statistical Tests: Paired-samples t-test and Wilcoxon rank sum test to compare measurements. Pearson correlation coefficient (r), Bland-Altman-analysis (BA) and intraclass correlation coefficient (ICC) to evaluate agreement between techniques and readers. A P value < 0.05 was considered statistically significant., Results: A significant improvement in acquisition time was observed using CS vs. conventional accelerated acquisition (6.7 ± 1.3 vs. 12.0 ± 1.3 min). Net forward flow measurements for all valves showed good correlation (r > 0.81) and agreement (ICCs > 0.89) between conventional and CS acceleration, with 3.3%-8.3% underestimation by the CS technique. Evaluation of diastolic function showed 3.2%-17.6% error: E/A 2.2 [1.9-2.4] (conventional) vs. 2.3 [2.0-2.6] (CS), BA bias 0.08 [-0.81-0.96], ICC 0.82; and E/e' 4.6 [3.9-5.4] (conventional) vs. 3.8 [3.4-4.3] (CS), BA bias -0.90 [-2.31-0.50], ICC 0.89., Data Conclusion: Analysis of intracardiac flow patterns and evaluation of diastolic function using a highly accelerated 4D flow sequence prototype is feasible, but it shows underestimation of flow measurements by approximately 10%., Evidence Level: 2 TECHNICAL EFFICACY: Stage 1., (© 2022 The Authors. Journal of Magnetic Resonance Imaging published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Acute pancreatitis (AP) is a potentially life-threatening illness characterized by an exacerbated inflammatory response with limited options for pharmacological treatment. Here, we describe the rational development of a library of soluble epoxide hydrolase (sEH) inhibitors for the treatment of AP. Synthesized compounds were screened in vitro for their sEH inhibitory potency and selectivity, and the results were rationalized by means of molecular modeling studies. The most potent compounds were studied in vitro for their pharmacokinetic profile, where compound 28 emerged as a promising lead. In fact, compound 28 demonstrated a remarkable in vivo efficacy in reducing the inflammatory damage in cerulein-induced AP in mice. Targeted metabololipidomic analysis further substantiated sEH inhibition as a molecular mechanism of the compound underlying anti-AP activity in vivo . Finally, pharmacokinetic assessment demonstrated a suitable profile of 28 in vivo . Collectively, compound 28 displays strong effectiveness as sEH inhibitor with potential for pharmacological AP treatment.

Background: The coronavirus disease 2019 (COVID-19) pandemic and associated public health measures have shifted the way people access health care. We aimed to study the effects of the COVID-19 pandemic on psychotropic medication adherence., Methods: A retrospective cohort study using administrative data from the Manitoba Centre for Health Policy Manitoba Population Research Data Repository was conducted. Outpatients who received at least 1 prescription for an antidepressant, antipsychotic, anxiolytic/sedative-hypnotic, cannabinoid, lithium, or stimulants from 2015 to 2020 in Manitoba, Canada, were included. Adherence was measured using the proportion of individuals with a mean possession ratio of ≥0.8 over each quarter. Each quarter of 2020 after COVID-19-related health measures were implemented was compared with the expected trend using autoregression models for time series data plus indicator variables. Odds ratio of drug discontinuation among those previously adherent in 2020 was compared with each respective quarter of 2019., Results: There were 1,394,885 individuals in the study population in the first quarter of 2020 (mean [SD] age, 38.9 [23.4] years; 50.3% female), with 36.1% having a psychiatric diagnosis in the preceding 5 years. Compared with the expected trend, increases in the proportions of individuals adherent to antidepressants and stimulants were observed in the fourth quarter (October-December) of 2020 (both P < 0.001). Increases in the proportions of individuals with anxiolytic and cannabinoid adherence were observed in the third quarter (July-September) of 2020 (both P < 0.05), whereas a decrease was seen with stimulants in the same quarter ( P < 0.0001). No significant changes were observed for antipsychotics. All drug classes except lithium had decreases in drug discontinuation in previously adherent patients during the pandemic compared with 2019., Conclusions: Improved adherence to most psychotropic medications in the 9 months after public health restrictions were enacted was observed. Patients who were already adherent to their psychotropic medications were less likely to discontinue them during the pandemic., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Human Activity Recognition (HAR) is a complex problem in deep learning, and One-Dimensional Convolutional Neural Networks (1D CNNs) have emerged as a popular approach for addressing it. These networks efficiently learn features from data that can be utilized to classify human activities with high performance. However, understanding and explaining the features learned by these networks remains a challenge. This paper presents a novel eXplainable Artificial Intelligence (XAI) method for generating visual explanations of features learned by one-dimensional CNNs in its training process, utilizing t-Distributed Stochastic Neighbor Embedding (t-SNE). By applying this method, we provide insights into the decision-making process through visualizing the information obtained from the model's deepest layer before classification. Our results demonstrate that the learned features from one dataset can be applied to differentiate human activities in other datasets. Our trained networks achieved high performance on two public databases, with 0.98 accuracy on the SHO dataset and 0.93 accuracy on the HAPT dataset. The visualization method proposed in this work offers a powerful means to detect bias issues or explain incorrect predictions. This work introduces a new type of XAI application, enhancing the reliability and practicality of CNN models in real-world scenarios.

We consider a generic class of gene circuits affected by nonlinear extrinsic noise. To address this nonlinearity we introduce a general perturbative methodology based on assuming timescale separation between noise and gene dynamics, with fluctuations exhibiting a large but finite correlation time. We apply this methodology to the case of the toggle switch, and by considering biologically relevant log-normal fluctuations, we find that the system exhibits noise-induced transitions. The system becomes bimodal in regions of the parameter space where it would be deterministically monostable. We show that by including higher order corrections our methodology allows one to obtain correct predictions for the occurrence of transitions even for not so large correlation time of the fluctuations, thereby overcoming limitations of previous theoretical approaches. Interestingly we find that at intermediate noise intensities the noise-induced transition in the toggle switch affects one of the genes involved, but not the other one.

Lung cancer remains the leading cause of cancer deaths worldwide. International societies have promoted the molecular analysis of MET proto-oncogene, receptor tyrosine kinase ( MET ) exon 14 skipping for the clinical stratification of non-small cell lung cancer (NSCLC) patients. Different technical approaches are available to detect MET exon 14 skipping in routine practice. Here, the technical performance and reproducibility of testing strategies for MET exon 14 skipping carried out in various centers were evaluated. In this retrospective study, each institution received a set ( n = 10) of a customized artificial formalin-fixed paraffin-embedded (FFPE) cell line (Custom MET ex14 skipping FFPE block) that harbored the MET exon 14 skipping mutation (Seracare Life Sciences, Milford, MA, USA), which was previously validated by the Predictive Molecular Pathology Laboratory at the University of Naples Federico II. Each participating institution managed the reference slides according to their internal routine workflow. MET exon 14 skipping was successfully detected by all participating institutions. Molecular analysis highlighted a median Cq cut off of 29.3 (ranging from 27.1 to 30.7) and 2514 (ranging from 160 to 7526) read counts for real-time polymerase chain reaction (RT-PCR) and NGS-based analyses, respectively. Artificial reference slides were a valid tool to harmonize technical workflows in the evaluation of MET exon 14 skipping molecular alterations in routine practice.

Purpose: The aim of this study was to evaluate strategies to reduce contrast media volumes for coronary computed tomography (CT) angiography on a clinical first-generation dual-source photon-counting detector (PCD)-CT system using a dynamic circulation phantom., Materials and Methods: Coronary CT angiograph is an established method for the assessment of coronary artery disease that relies on the administration of iodinated contrast media. Reduction of contrast media volumes while maintaining diagnostic image quality is desirable. In this study, a dynamic phantom containing a 3-dimensional-printed model of the thoracic aorta and coronary arteries was evaluated using a clinical contrast injection protocol with stepwise reduced contrast agent concentrations (100%, 75%, 50%, 40%, 30%, and 20% contrast media content of the same 50 mL bolus, resulting in iodine delivery rates of 1.5, 1.1, 0.7, 0.6, 0.4 and 0.3 gl/s) on a first-generation, dual-source PCD-CT. Polychromatic images (T3D) and virtual monoenergetic images were reconstructed in the range of 40 to 70 keV in 5-keV steps. Attenuation and noise were measured in the coronary arteries and background material and the contrast-to-noise ratio (CNR) were calculated. Attenuation of 350 HU and a CNR of the reference protocol at 70 keV were regarded as sufficient for simulation of diagnostic purposes. Vessel sharpness and noise power spectra were analyzed for the aforementioned reconstructions., Results: The standard clinical contrast protocol (bolus with 100% contrast) yielded diagnostic coronary artery attenuation for all tested reconstructions (>398 HU). A 50% reduction in contrast media concentration demonstrated sufficient attenuation of the coronary arteries at 40 to 55 keV (>366 HU). Virtual monoenergetic image reconstructions of 40 to 45 and 40 keV allowed satisfactory attenuation of the coronary arteries for contrast concentrations of 40% and 30% of the original protocol. A reduction of contrast agent concentration to 20% of the initial concentration provided insufficient attenuation in the target vessels for all reconstructions. The highest CNR was found for virtual monoenergetic reconstructions at 40 keV for all contrast media injection protocols, yielding a sufficient CNR at a 50% reduction of contrast agent concentration., Conclusions: Using virtual monoenergetic image reconstructions at 40 keV on a dual-source PCD-CT system, contrast media concentration could be reduced by 50% to obtain diagnostic attenuation and objective image quality for coronary CT angiography in a dynamic vessel phantom. These initial feasibility study results have to be validated in clinical studies., Competing Interests: Conflicts of interest and sources of funding: This work was supported by a research grant from Siemens Healthineers. U. Joseph Schoepf receives institutional research support and/or personal fees from Bayer, Bracco, Elucid Bioimaging, Guerbet, HeartFlow, Inc, Keya Medical, and Siemens. Akos Varga-Szemes receives institutional research support and/or personal fees from Bayer, Elucid Bioimaging, and Siemens. Tilman Emrich received a speaker fee and travel support from Siemens Medical Solutions USA Inc. Jim O’Doherty is an employee of Siemens Medical Solutions USA Inc. Thomas Allmendinger, Tristan Nowak, Bernhard Schmidt, and Thomas Flohr are employees of Siemens Healthineers., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

T-cell acute lymphoblastic leukemia (T-ALL) is a challenging pediatric and adult haematologic disease still associated with an unsatisfactory cure rate. Unlike B-ALL, the availability of novel therapeutic options to definitively improve the life expectancy for relapsed/resistant patients is poor. Indeed, the shared expression of surface targets among normal and neoplastic T-cells still limits the efficacy and may induce fratricide effects, hampering the use of innovative immunotherapeutic strategies. However, novel monoclonal antibodies, bispecific T-cell engagers (BTCEs), and chimeric antigen receptors (CAR) T-cells recently showed encouraging results and some of them are in an advanced stage of pre-clinical development or are currently under investigation in clinical trials. Here, we review this exciting scenario focusing on most relevant advances, challenges, and perspectives of the emerging landscape of immunotherapy of T-cell malignancies., (© 2023. The Author(s).)

Purpose: The aim of this study was to evaluate coronary computed tomography angiography (CCTA)-based in vitro and in vivo coronary artery calcium scoring (CACS) using a novel virtual noniodine reconstruction (PureCalcium) on a clinical first-generation photon-counting detector-computed tomography system compared with virtual noncontrast (VNC) reconstructions and true noncontrast (TNC) acquisitions., Materials and Methods: Although CACS and CCTA are well-established techniques for the assessment of coronary artery disease, they are complementary acquisitions, translating into increased scan time and patient radiation dose. Hence, accurate CACS derived from a single CCTA acquisition would be highly desirable. In this study, CACS based on PureCalcium, VNC, and TNC, reconstructions was evaluated in a CACS phantom and in 67 patients (70 [59/80] years, 58.2% male) undergoing CCTA on a first-generation photon counting detector-computed tomography system. Coronary artery calcium scores were quantified for the 3 reconstructions and compared using Wilcoxon test. Agreement was evaluated by Pearson and Spearman correlation and Bland-Altman analysis. Classification of coronary artery calcium score categories (0, 1-10, 11-100, 101-400, and >400) was compared using Cohen κ ., Results: Phantom studies demonstrated strong agreement between CACS PureCalcium and CACS TNC (60.7 ± 90.6 vs 67.3 ± 88.3, P = 0.01, r = 0.98, intraclass correlation [ICC] = 0.98; mean bias, 6.6; limits of agreement [LoA], -39.8/26.6), whereas CACS VNC showed a significant underestimation (42.4 ± 75.3 vs 67.3 ± 88.3, P < 0.001, r = 0.94, ICC = 0.89; mean bias, 24.9; LoA, -87.1/37.2). In vivo comparison confirmed a high correlation but revealed an underestimation of CACS PureCalcium (169.3 [0.7/969.4] vs 232.2 [26.5/1112.2], P < 0.001, r = 0.97, ICC = 0.98; mean bias, -113.5; LoA, -470.2/243.2). In comparison, CACS VNC showed a similarly high correlation, but a substantially larger underestimation (24.3 [0/272.3] vs 232.2 [26.5/1112.2], P < 0.001, r = 0.97, ICC = 0.54; mean bias, -551.6; LoA, -2037.5/934.4). CACS PureCalcium showed superior agreement of CACS classification ( κ = 0.88) than CACS VNC ( κ = 0.60)., Conclusions: The accuracy of CACS quantification and classification based on PureCalcium reconstructions of CCTA outperforms CACS derived from VNC reconstructions., Competing Interests: Conflicts of interest and sources of funding: U. Joseph Schoepf receives institutional research support and / or personal fees from Bayer, Bracco, Elucid Bioimaging, Guerbet, HeartFlow, and Siemens. Akos Varga-Szemes receives institutional research support and / or personal fees from Elucid Bioimaging and Siemens. Tilman Emrich received a speaker fee and travel support from Siemens Medical Solutions USA Inc. Jim O’Doherty is a employee of Siemens Medical Solutions USA Inc. Thomas Allmendinger, Tristan Nowak, Bernhard Schmidt and Thomas Flohr are employees of Siemens Healthineers, (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Rationale and Objectives: The burden of coronavirus disease 2019 (COVID-19) airspace opacities is time consuming and challenging to quantify on computed tomography. The purpose of this study was to evaluate the ability of a deep convolutional neural network (dCNN) to predict inpatient outcomes associated with COVID-19 pneumonia., Materials and Methods: A previously trained dCNN was tested on an external validation cohort of 241 patients who presented to the emergency department and received a chest computed tomography scan, 93 with COVID-19 and 168 without. Airspace opacity scoring systems were defined by the extent of airspace opacity in each lobe, totaled across the entire lungs. Expert and dCNN scores were concurrently evaluated for interobserver agreement, while both dCNN identified airspace opacity scoring and raw opacity values were used in the prediction of COVID-19 diagnosis and inpatient outcomes., Results: Interobserver agreement for airspace opacity scoring was 0.892 (95% CI 0.834-0.930). Probability of each outcome behaved as a logistic function of the opacity scoring (25% intensive care unit admission at score of 13/25, 25% intubation at 17/25, and 25% mortality at 20/25). Length of hospitalization, intensive care unit stay, and intubation were associated with larger airspace opacity score (p = 0.032, 0.039, 0.036, respectively)., Conclusion: The tested dCNN was highly predictive of inpatient outcomes, performs at a near expert level, and provides added value for clinicians in terms of prognostication and disease severity., (Copyright © 2022 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Due to wearables' popularity, human activity recognition (HAR) plays a significant role in people's routines. Many deep learning (DL) approaches have studied HAR to classify human activities. Previous studies employ two HAR validation approaches: subject-dependent (SD) and subject-independent (SI). Using accelerometer data, this paper shows how to generate visual explanations about the trained models' decision making on both HAR and biometric user identification (BUI) tasks and the correlation between them. We adapted gradient-weighted class activation mapping (grad-CAM) to one-dimensional convolutional neural networks (CNN) architectures to produce visual explanations of HAR and BUI models. Our proposed networks achieved 0.978 and 0.755 accuracy, employing both SD and SI. The proposed BUI network achieved 0.937 average accuracy. We demonstrate that HAR's high performance with SD comes not only from physical activity learning but also from learning an individual's signature, as in BUI models. Our experiments show that CNN focuses on larger signal sections in BUI, while HAR focuses on smaller signal segments. We also use the grad-CAM technique to identify database bias problems, such as signal discontinuities. Combining explainable techniques with deep learning can help models design, avoid results overestimation, find bias problems, and improve generalization capability.

Background: Airspace disease as seen on chest X-rays is an important point in triage for patients initially presenting to the emergency department with suspected COVID-19 infection. The purpose of this study is to evaluate a previously trained interpretable deep learning algorithm for the diagnosis and prognosis of COVID-19 pneumonia from chest X-rays obtained in the ED., Methods: This retrospective study included 2456 (50% RT-PCR positive for COVID-19) adult patients who received both a chest X-ray and SARS-CoV-2 RT-PCR test from January 2020 to March of 2021 in the emergency department at a single U.S., Institution: A total of 2000 patients were included as an additional training cohort and 456 patients in the randomized internal holdout testing cohort for a previously trained Siemens AI-Radiology Companion deep learning convolutional neural network algorithm. Three cardiothoracic fellowship-trained radiologists systematically evaluated each chest X-ray and generated an airspace disease area-based severity score which was compared against the same score produced by artificial intelligence. The interobserver agreement, diagnostic accuracy, and predictive capability for inpatient outcomes were assessed. Principal statistical tests used in this study include both univariate and multivariate logistic regression., Results: Overall ICC was 0.820 (95% CI 0.790-0.840). The diagnostic AUC for SARS-CoV-2 RT-PCR positivity was 0.890 (95% CI 0.861-0.920) for the neural network and 0.936 (95% CI 0.918-0.960) for radiologists. Airspace opacities score by AI alone predicted ICU admission (AUC = 0.870) and mortality (0.829) in all patients. Addition of age and BMI into a multivariate log model improved mortality prediction (AUC = 0.906)., Conclusion: The deep learning algorithm provides an accurate and interpretable assessment of the disease burden in COVID-19 pneumonia on chest radiographs. The reported severity scores correlate with expert assessment and accurately predicts important clinical outcomes. The algorithm contributes additional prognostic information not currently incorporated into patient management., (© 2022. The Author(s).)

Thiazolidinediones (TZDs) are potent PPARγ agonists that have been shown to attenuate alveolar simplification after prolonged hyperoxia in term rodent models of bronchopulmonary dysplasia. However, the pulmonary outcomes of postnatal TZDs have not been investigated in preterm animal models. Here, we first investigated the PPARγ selectivity, epithelial permeability, and lung tissue binding of three types of TZDs in vitro (rosiglitazone (RGZ), pioglitazone, and DRF-2546), followed by an in vivo study in preterm rabbits exposed to hyperoxia (95% oxygen) to investigate the pharmacokinetics and the pulmonary outcomes of daily RGZ administration. In addition, blood lipids and a comparative lung proteomics analysis were also performed on Day 7. All TZDs showed high epithelial permeability through Caco-2 monolayers and high plasma and lung tissue binding; however, RGZ showed the highest affinity for PPARγ. The pharmacokinetic profiling of RGZ (1 mg/kg) revealed an equivalent biodistribution after either intratracheal or intraperitoneal administration, with detectable levels in lungs and plasma after 24 h. However, daily RGZ doses of 1 mg/kg did not improve lung function in preterm rabbits exposed to hyperoxia, and daily 10 mg/kg doses were even associated with a significant lung function worsening, which could be partially explained by the upregulation of lung inflammation and lipid metabolism pathways revealed by the proteomic analysis. Notably, daily postnatal RGZ produced an aberrant modulation of serum lipids, particularly in rabbit pups treated with the 10 mg/kg dose. In conclusion, daily postnatal RGZ did not improve lung function and caused dyslipidemia in preterm rabbits exposed to hyperoxia.

Background: Acute stroke care has greatly improved in recent decades. However, the increasing stroke mortality in low-to-middle income countries suggests that progress has not been reached completely by these populations. Here we present the analysis of the hospital phase of the first population-based stroke surveillance study. Methods: A daily hospital surveillance method was used to identify adult patients with acute stroke during 18 months in six hospitals. We abstracted data on demographics, vascular risk factors, neuroimaging-confirmed stroke types, and clinical data. Results: A total of 1361 adults with acute stroke were identified (mean age 69.2 years; 52% women) with transient ischemic attack (5.5%), acute ischemic stroke (68.6%), intracerebral hemorrhage (23.1%), cerebral venous thrombosis (0.2%), and undetermined stroke (2.6%). The main risk factors were hypertension (80.7%) and diabetes mellitus (47.6%). The usage rate of thrombolysis was 3.6%, in spite of the fact that 37.2% of acute ischemic stroke patients arrived in <4.5 h. The 30-day case fatality rate was 32.6%, higher in hemorrhagic than ischemic stroke. Conclusion: We identified limitations in acute stroke care in the Mexico City, including neuroimaging availability and thrombolysis usage. The door-to-door phase will help to depict the acute stroke burden in Mexico.

Objectives: Epicardial adipose tissue (EAT) from coronary CT angiography (CCTA) is strongly associated with coronary artery disease (CAD). We investigated the additive value of EAT volume to coronary plaque quantification and CT-derived fractional flow reserve (CT-FFR) to predict lesion-specific ischemia., Methods: Patients (n = 128, 60.6 ± 10.5 years, 61% male) with suspected CAD who had undergone invasive coronary angiography (ICA) and CCTA were retrospectively analyzed. EAT volume and plaque measures were derived from CCTA using a semi-automatic software approach, while CT-FFR was calculated using a machine learning algorithm. The predictive value and discriminatory power of EAT volume, plaque measures, and CT-FFR to identify ischemic CAD were assessed using invasive FFR as the reference standard., Results: Fifty-five of 152 lesions showed ischemic CAD by invasive FFR. EAT volume, CCTA ≥ 50% stenosis, and CT-FFR were significantly different in lesions with and without hemodynamic significance (all p < 0.05). Multivariate analysis revealed predictive value for lesion-specific ischemia of these parameters: EAT volume (OR 2.93, p = 0.021), CCTA ≥ 50% (OR 4.56, p = 0.002), and CT-FFR (OR 6.74, p < 0.001). ROC analysis demonstrated incremental discriminatory value with the addition of EAT volume to plaque measures alone (AUC 0.84 vs. 0.62, p < 0.05). CT-FFR (AUC 0.89) showed slightly superior performance over EAT volume with plaque measures (AUC 0.84), however without significant difference (p > 0.05)., Conclusions: EAT volume is significantly associated with ischemic CAD. The combination of EAT volume with plaque quantification demonstrates a predictive value for lesion-specific ischemia similar to that of CT-FFR. Thus, EAT may aid in the identification of hemodynamically significant coronary stenosis., Key Points: • CT-derived EAT volume quantification demonstrates high discriminatory power to identify lesion-specific ischemia. • EAT volume shows incremental diagnostic performance over CCTA-derived plaque measures in detecting lesion-specific ischemia. • A combination of plaque measures with EAT volume provides a similar discriminatory value for detecting lesion-specific ischemia compared to CT-FFR., (© 2022. The Author(s), under exclusive licence to European Society of Radiology.)

The identification of novel inhaled p38α/β mitogen-activated protein kinases (MAPK) (MAPK14/11) inhibitors suitable for the treatment of pulmonary inflammatory conditions has been described. A rational drug design approach started from the identification of a novel tetrahydronaphthalene series, characterized by nanomolar inhibition of p38α with selectivity over p38γ and p38δ isoforms. SAR optimization of 1c is outlined, where improvements in potency against p38α and ligand-enzyme dissociation kinetics led to several compounds showing pronounced anti-inflammatory effects in vitro (inhibition of TNFα release). Targeting of the defined physicochemical properties allowed the identification of compounds 3h , 4e , and 4f , which showed, upon intratracheal instillation, low plasma levels, prolonged lung retention, and anti-inflammatory effects in a rat acute model of a bacterial endotoxin-induced pulmonary inflammation. Compound 4e , in particular, displayed remarkable efficacy and duration of action and was selected for progression in disease models of asthma and chronic obstructive pulmonary disease (COPD).

Background: Penile cancer (PC) is an extremely rare malignancy, and the patients at advanced stages have currently limited treatment options with disappointing results. Immune checkpoint inhibitors anti-programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) are currently changing the treatment of several tumors. Furthermore, the microsatellite instability (MSI) and the deficient mismatch repair system (dMMR) proteins represent predictive biomarkers for response to immune checkpoint therapy. Until present, few data have been reported related to PD-L1 expression and MSI in PC. The main aim of our study was the evaluation of PD-L1 expression in tumor cells (TCs) and tumor-infiltrating lymphocytes (TILs) in immune cells and the analysis of dMMR/MSI status in a large series of PCs., Methods: A series of 72 PC, including 65 usual squamous cell carcinoma (USCC), 1 verrucous, 4 basaloid, 1 warty, and 1 mixed (warty-basaloid), was collected. Immunohistochemistry (IHC) was performed to assess PD-L1 expression using two different anti-PD-L1 antibodies (clone SP263 and SP142 Ventana) and MMR proteins expression using anti-MLH1, anti-PMS2, anti-MSH2, and anti-MSH6 antibodies. PCR analysis was performed for the detection of MSI status., Results: Of the 72 PC cases analyzed by IHC, 45 (62.5%) cases were TC positive and 57 (79%) cases were combined positive score (CPS) using PDL1 SP263. In our cohort, TILs were present in 62 out of 72 cases (86.1%), 47 (75.8%) out of 62 cases showed positivity to PDL1 clone SP142. In our series, 59 cases (82%) had pMMR, 12 cases (16.7%) had lo-paMMR, and only 1 case (1.3%) had MMR. PCR results showed that only one case lo-paMMR was MSI-H, and the case dMMR by IHC not confirmed MSI status., Conclusion: Our findings showed that PD-L1 expression and MSI status represent frequent biological events in this tumor suggesting a rationale for a new frontier in the treatment of patients with PC based on the immune checkpoint inhibitors., 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. The handling editor AM declared a shared affiliation with the authors FFe, GA at the time of review., (Copyright © 2022 Montella, Sabetta, Ronchi, De Sio, Arcaniolo, De Vita, Tirino, Caputo, D’Antonio, Fiorentino, Facchini, Lauro, Perdonà, Ventriglia, Aquino, Feroce, Borges Dos Reis, Neder, Brunelli, Franco and Zito Marino.)

The Helping to End Addiction Long-term Initiative (NIH HEAL Initiative) is an aggressive trans-NIH effort to speed solutions to stem the national opioid public health crisis, including through improved pain management. Toward this end, the NIH HEAL Initiative launched a common data element (CDE) program to ensure that NIH-funded clinical pain research studies would collect data in a standardized way. NIH HEAL Initiative staff launched a process to determine which pain-related core domains should be assessed by every clinical pain study and what questionnaires are required to ensure that the data is collected uniformly. The process involved multiple literature reviews, and consultation with experts inside and outside of NIH and the investigators conducting studies funded by the initiative. Ultimately, 9 core pain domains, and questionnaires to measure them, were chosen for studies examining acute pain and chronic pain in adults and pediatric populations. These were augmented with dozens of study-specific supplemental questionnaires to enable uniform data collection methods of outcomes outside of the core domains. The selection of core domains will ensure that valuable clinical pain data generated by the initiative is standardized, useable for secondary data analysis, and useful for guiding future research, clinical practice decisions, and policymaking. PERSPECTIVE: The NIH HEAL Initiative launched a common data element program to ensure that NIH-funded clinical pain research studies would collect data in a standardized way. Nine core pain domains and questionnaires to measure them were chosen for studies examining acute pain and chronic pain in adults and pediatric populations., (Published by Elsevier Inc.)

Toll-like receptors (TLRs) regulate innate and adaptive immune responses. Moreover, TLRs can induce a pro-survival and pro-proliferation response in tumor cells. This study aims to investigate the expression of TLR4 in the epithelium surrounding oral squamous cell carcinomas (OSCC) in relation to its inflammatory microenvironment. This study included 150 human samples: 30 normal oral control (NOC), 38 non-lichenoid epithelium surrounding OSCC (NLE-OSCC), 28 lichenoid epithelium surrounding OSCC (LE-OSCC), 30 OSCC ex-non oral lichenoid lesion (OSCC Ex-NOLL), and 24 OSCC ex-oral lichenoid lesion (OSCC Ex-OLL). TLR4 expression was investigated by immunohistochemistry and the percentage of positive cells was quantified. In addition, a semiquantitative analysis of staining intensity was performed. Immunohistochemical analysis revealed that TLR4 is strongly upregulated in LE-OSCC as compared to normal control epithelium and NLE-OSCC. TLR4 expression was associated with the inflammatory environment, since the percentage of positive cells increases from NOC and NLE-OSCC to LE-OSCC, reaching the highest value in OSCC Ex-OLL. TLR4 was detected in the basal third of the epithelium in NLE-OSCC, while in LE-OSCC, TLR4 expression reached the intermediate layer. These results demonstrated that an inflammatory microenvironment can upregulate TLR4, which may boost tumor development.

Background: Determination of the total number and size of all pulmonary metastases on chest CT is time-consuming and as such has been understudied as an independent metric for disease assessment. A novel artificial intelligence (AI) model may allow for automated detection, size determination, and quantification of the number of pulmonary metastases on chest CT., Objective: To investigate the utility of a novel AI program applied to initial staging chest CT in breast cancer patients in risk assessment of mortality and survival., Methods: Retrospective imaging data from a cohort of 226 subjects with breast cancer was assessed by the novel AI program and the results validated by blinded readers. Mean clinical follow-up was 2.5 years for outcomes including cancer-related death and development of extrapulmonary metastatic disease. AI measurements including total number of pulmonary metastases and maximum nodule size were assessed by Cox-proportional hazard modeling and adjusted survival., Results: 752 lung nodules were identified by the AI program, 689 of which were identified in 168 subjects having confirmed lung metastases (Lmet+) and 63 were identified in 58 subjects without confirmed lung metastases (Lmet-). When compared to the reader assessment, AI had a per-patient sensitivity, specificity, PPV and NPV of 0.952, 0.639, 0.878, and 0.830. Mortality in the Lmet + group was four times greater compared to the Lmet-group (p = 0.002). In a multivariate analysis, total lung nodule count by AI had a high correlation with overall mortality (OR 1.11 (range 1.07-1.15), p < 0.001) with an AUC of 0.811 (R2 = 0.226, p < 0.0001). When total lung nodule count and maximum nodule diameter were combined there was an AUC of 0.826 (R2 = 0.243, p < 0.001)., Conclusion: Automated AI-based detection of lung metastases in breast cancer patients at initial staging chest CT performed well at identifying pulmonary metastases and demonstrated strong correlation between the total number and maximum size of lung metastases with future mortality., Clinical Impact: As a component of precision medicine, AI-based measurements at the time of initial staging may improve prediction of which breast cancer patients will have negative future outcomes., Competing Interests: The authors declare the following conflict of interests: Philipp Hoelzer and Pooyan Sahbaee are employed by Siemens Healthcare. Jeremy Burt received research grants from Siemens Healthcare; owner YellowDot Innovations. U Joseph Schoepf received research grants from Siemens Healthcare., (© 2022 Published by Elsevier Ltd.)

Among deregulated microRNAs (miRs) in human malignancies, miR-221 has been widely investigated for its oncogenic role and as a promising biomarker. Moreover, recent evidence suggests miR-221 as a fine-tuner of chronic liver injury and inflammation-related events. Available information also supports the potential of miR-221 silencing as promising therapeutic intervention. In this systematic review, we selected papers from the principal databases (PubMed, MedLine, Medscape, ASCO, ESMO) between January 2012 and December 2020, using the keywords "miR-221" and the specific keywords related to the most important hematologic and solid malignancies, and some non-malignant diseases, to define and characterize deregulated miR-221 as a valuable therapeutic target in the modern vision of molecular medicine. We found a major role of miR-221 in this view., Competing Interests: The authors declare no competing interests., (© 2022 The Authors.)

We consider the effect of non-constant parameters on the human-forest interaction logistic model coupled with human technological growth introduced in [1]. In recent years in fact, a decrease in human population growth rate has emerged which can be measured to about 1.7% drop per year since 1960 value, which coincides with latest UN projections for next decades up to year 2100 [2]. We therefore consider here the effect of decreasing human population growth-rate on the aforementioned model and we evaluate its effect on the probability of survival of human civilization without going through a catastrophic population collapse. We find that for realistic values of the human population carrying capacity of the earth (measured by the parameter β) this decrease would not affect previous results, leading to a low probability of avoiding a catastrophic collapse. For larger more optimistic values of β instead, a decrease in growth-rate would tilt the probability in favor of a positive outcome, i.e. from 10-20% up to even 95% likelihood of avoiding collapse., Competing Interests: No potential conflict of interest was reported by the authors., (© 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

The objective of this study was to determine if certified electronic health record technology (CEHRT) can be used to identify and refer patients with prediabetes to lifestyle change programs (LCPs) recognized by the National Diabetes Prevention Program (DPP). This pilot utilized a prediabetes registry, patient portal, and clinical decision support to increase referrals. Data from 36 primary care providers showed 4930 patients were eligible for DPP LCP, 293 referrals were generated, compared to 20 referrals in the baseline period, and 116 patients enrolled. Referral to enrollment conversion rates were 41% in the study period and 69% in the post-study 1-year period. CEHRT functionalities can support systematic identification and management of prediabetes. The referral rate increased 7-fold compared to the baseline period, with high referral to enrollment conversion rates. CEHRT coupled with active provider engagement can serve as a tool to identify prediabetes patients and facilitate LCP referrals and enrollment., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Medical Informatics Association.)

Fault tolerance in IoT systems is challenging to overcome due to its complexity, dynamicity, and heterogeneity. IoT systems are typically designed and constructed in layers. Every layer has its requirements and fault tolerance strategies. However, errors in one layer can propagate and cause effects on others. Thus, it is impractical to consider a centralized fault tolerance approach for an entire system. Consequently, it is vital to consider multiple layers in order to enable collaboration and information exchange when addressing fault tolerance. The purpose of this study is to propose a multi-layer fault tolerance approach, granting interconnection among IoT system layers, allowing information exchange and collaboration in order to attain the property of dependability. Therefore, we define an event-driven framework called FaTEMa (Fault Tolerance Event Manager) that creates a dedicated fault-related communication channel in order to propagate events across the levels of the system. The implemented framework assist with error detection and continued service. Additionally, it offers extension points to support heterogeneous communication protocols and evolve new capabilities. Our empirical results show that introducing FaTEMa provided improvements to the error detection and error resolution time, consequently improving system availability. In addition, the use of Fatema provided a reliability improvement and a reduction in the number of failures produced.

Trypanosomiases and leishmaniases are neglected tropical diseases that have been spreading to previously non-affected areas in recent years. Identification of new chemotherapeutics is needed as there are no vaccines and the currently available treatment options are highly toxic and often ineffective. The causative agents for these diseases are the protozoan parasites of the Trypanosomatidae family, and they alternate between invertebrate and vertebrate hosts during their life cycles. Hence, these parasites must be able to adapt to different environments and compete with their hosts for several essential compounds, such as amino acids, vitamins, ions, carbohydrates, and lipids. Among these nutrients, lipids and fatty acids (FAs) are essential for parasite survival. Trypanosomatids require massive amounts of FAs, and they can either synthesize FAs de novo or scavenge them from the host. Moreover, FAs are the major energy source during specific life cycle stages of T. brucei, T. cruzi , and Leishmania . Therefore, considering the distinctive features of FAs metabolism in trypanosomatids, these pathways could be exploited for the development of novel antiparasitic drugs. In this review, we highlight specific aspects of lipid and FA metabolism in the protozoan parasites T. brucei, T. cruzi, and Leishmania spp., as well as the pathways that have been explored for the development of new chemotherapies., Competing Interests: Conflict of 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: © 2021 Parreira de Aquino et al.)

In Washington, DC, 2% of residents are living with HIV, with 15.3% of them experiencing homelessness. Additionally, over half of DC-area renters are paying over 30% of their income for housing. The primary objective of this study was to describe HIV outcomes at initial intake at Housing Counseling Services (HCS). This retrospective study included adults with HIV completing HCS intake between 2015 and 2018 and linked HCS data with DC Department of Health (DOH) HIV/AIDS, Hepatitis, STD, and TB Administration (HAHSTA) surveillance data. Proportions of individuals with retention in care (RIC) and viral suppression (VS) were compared across client subgroups using chi-square or rank sum tests. The sample of 734 participants was mostly male (67%), Non-Hispanic Black (89%), had MSM as the HIV transmission risk factor (44%) and had rental housing (60%). Most participants (634/734, 86%) were RIC at HCS intake. A majority of participants (477/621 or 77%) had VS at intake. Older age was associated with VS (p = 0.0007). Homeless individuals (with intake from the street) were less likely to be VS (4.8% vs. 11.1%, p < 0.0045). Our results suggest that PWH who have unstable housing or who are homeless may need additional support services for maintaining RIC and VS, as the proportion meeting those benchmarks was not at goal when they sought services at HCS., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.)

Background There are considerable differences in the prevalence of coronary artery disease (CAD) and its cardiovascular risk factors between men and women. Due to the significance of gender as a factor that potentially affects cardiovascular disorders and patient outcomes, the present study aimed to assess the baseline characteristics and outcomes of CAD patients in terms of gender distribution. Methods All consecutive patients diagnosed with ST-elevation myocardial infarction (MI) who had undergone primary percutaneous coronary intervention (PCI) in the previous two years in a comprehensive cardiology center were included. Data were retrospectively collected from the hospital record files. Color Doppler echocardiography, valvular involvement, and the type of coronary vessel involvement were also evaluated. Results In total, 557 consecutive patients (437 men and 120 women) were included with a mean age of 59.37 ± 26.23 years and 64.07 ± 11.60 years for men and women, respectively (p = 0.004). The prevalence of mitral regurgitation (MR) and tricuspid regurgitation (TR) was significantly higher among women than men. Conclusion Female patients who suffered from CAD and underwent PCI were older than men. Also, ischemic mitral regurgitation (MR) and tricuspid regurgitation (TR) were more prevalent among women, while smoking was more prevalent among men., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Heydari et al.)

Chromosomal rearrangements involving BCL2, BCL6 and MYC are commonly found in the most frequent B cell lymphomas, namely follicular lymphomas (FLs) and diffuse large B-cell lymphomas (DLBCLs). Particularly, BCL2-rearrangement represents a diagnostic hallmark in FLs, whereas MYC translocation can occur simultaneously with BCL2 and/or BCL6 rearrangements, defining a specific category of DLBCLs with a poorer prognosis. In this study, we aim to validate the diagnostic performance of multiplex BCL2/BCL6 FISH approach in formalin-fixed paraffin-embedded FLs and DBCLs and cytological samples of DLBCL comparing to the classic set of single break-apart probes. We collected a series of lymphomas, including 85 DLBCLs, 45 FLs and 36 other B-cell lymphoma histotypes and 16 cytological samples of DLBCLs. MYC, BCL2 and BCL6 rearrangements were previously assessed by a classic FISH test using single break-apart probes. All samples were analysed by a multiplex FISH assay. In the FL series, 38 cases showed BCL2-R; in the DLBCLs series, MYC-R was detected in 21 out of 85 DLBCL patients, BCL2-R in 10 out of 85 and BCL6-R in 33 out of 85. In the DLBCL cytological series, MYC-R was detected in 4 out of 16, BCL2-R in 4 out of 16 and BCL6-R in 1 out of 16. Notably, in FFPE, 13 double-hit lymphomas (DHLs) and 3 triple-hit lymphomas (THLs) were detected; in the cytological series, only 3 DHL cases were observed. The dual BCL2/BCL6 FISH probe test results were fully concordant with the results obtained using classic BCL2 and BCL6 single break apart. Particularly, multiplex FISH to simultaneously detect BCL2-R and BCL6-R on a single slide could find a wide application in the characterisation of double- and triple-hit DLBCLs., (© 2021. The Author(s).)

This study explored the associations between family (mother and father support), peers, and individual factors (self-efficacy) and how these relationships influence HIV attitudes among African American males 12 to 19 years of age, with an average age of 16 years. For this study, we used restricted data obtained from Wave I of the National Longitudinal Study of Adolescent to Adult Health (ADD Health). Descriptive statistics suggest that most of the sample had negative attitudes towards HIV. Bivariate regression analysis followed by a linear regression analysis was conducted to identify the factors that were associated with HIV attitudes. Major findings from regression analysis indicate that mother support, father support, self-efficacy, and age, predicted HIV attitudes. Mother support positively predicted positive HIV attitudes and surprisingly, father support negatively predicted HIV attitudes. Our findings can be used to better inform HIV prevention and intervention programs to help Black males stay healthy., Competing Interests: Declaration of Conflicting Interests The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NENs) are rare diseases occurring in the gastrointestinal tract and pancreas. They are characterized by the loss of epithelial tubular gland elements, and by the increased expression of neuroendocrine markers. GEP-NENs are subdivided into two histo-pathological types, gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs) and gastro-entero-pancreatic neuroendocrine carcinomas (GEP-NECs). According to WHO 2017 and 2019 classification criteria are graded and staged in four categories, NET-G1, NET-G2, NET-G3, and NEC-G3. The molecular characterization of these tumors can be fundamental for the identification of new diagnostic, prognostic and predictive biomarkers. The main purpose of this study was to analyze the expression of the paralogous 13 HOX genes, normally involved in embryogenic development and frequently deregulated in human cancers, and of the HOX regulating lncRNA HOTAIR in GEP-NENs. The expression of HOX genes is gradually lost in the transition from GEP NET G1 to NET/NEC G3 tumors, while HOTAIR expression, inversely correlated with HOX genes expression and weakly expressed in low-grade GEP NENs, becomes aberrant in NET G3 and NEC G3 categories. Our data highlights their potential role in the molecular stratification of GEP-NENs by suggesting new prognostic markers and potential therapeutic targets.

In this paper, we study the basic problem of a charged particle in a stochastic magnetic field. We consider dichotomous fluctuations of the magnetic field where the sojourn time in one of the two states are distributed according to a given waiting-time distribution either with Poisson or non-Poisson statistics, including as well the case of distributions with diverging mean time between changes of the field, corresponding to an ergodicity breaking condition. We provide analytical and numerical results for all cases evaluating the average and the second moment of the position and velocity of the particle. We show that the field fluctuations induce diffusion of the charge with either normal or anomalous properties, depending on the statistics of the fluctuations, with distinct regimes from those observed, e.g., in standard Continuous-Time Random Walk models.

Glycosphingolipids are important components of the plasma membrane where they modulate the activities of membrane proteins including signalling receptors. Glycosphingolipid synthesis relies on competing reactions catalysed by Golgi-resident enzymes during the passage of substrates through the Golgi cisternae. The glycosphingolipid metabolic output is determined by the position and levels of the enzymes within the Golgi stack, but the mechanisms that coordinate the intra-Golgi localisation of the enzymes are poorly understood. Here, we show that a group of sequentially-acting enzymes operating at the branchpoint among glycosphingolipid synthetic pathways binds the Golgi-localised oncoprotein GOLPH3. GOLPH3 sorts these enzymes into vesicles for intra-Golgi retro-transport, acting as a component of the cisternal maturation mechanism. Through these effects, GOLPH3 controls the sub-Golgi localisation and the lysosomal degradation rate of specific enzymes. Increased GOLPH3 levels, as those observed in tumours, alter glycosphingolipid synthesis and plasma membrane composition thereby promoting mitogenic signalling and cell proliferation. These data have medical implications as they outline a novel oncogenic mechanism of action for GOLPH3 based on glycosphingolipid metabolism., (© 2021 The Authors.)

Background: The high-risk human papillomavirus (HPV) infection represents one of the main etiologic pathways of penile carcinogenesis in approximately 30-50 % of cases. Several techniques for the detection of HPV are currently available including Polymerase chain reaction-based techniques, DNA and RNA in situ hybridization (ISH), p16 immunohistochemistry (IHC). The multiplex HPV RNA ISH/p16 IHC is a novel technique for the simultaneous detection of HPV E6/E7 transcripts and p16INK4a overexpression on the same slide in a single assay. The main aim of this study was to evaluate the discrepancy of p16 IHC expression relatively to HPV RNA ISH in penile cancer tissue., Methods: We collected a series of 60 PCs. HPV has been analysed through the RNA ISH, p16 IHC and the multiplex HPV RNA ISH/p16 IHC., Results: The multiplex HPV RNA ISH /p16 IHC results in the series were in complete agreement with the previous results obtained through the classic p16 IHC and HPV RNA scope carried out on two different slides. The multiplex HPV RNA ISH /p16 IHC showed that HPV positivity in our series is more frequently in usual squamous cell carcinoma than in special histotypes (19 out of 60 - 15 %- versus 6 out of 60 - 10 %-), in high-grade than in moderate/low grade carcinomas (6 out of 60 - 10 %- versus 4 out of 60 - 6.7 %-). In addition, our data revealed that in 5 out of 20 cases with p16 high intensity expression is not associated with HPV RNA ISH positivity., Conclusions: Our findings emphasize that the use of p16 as a surrogate of HPV positivity was unsuccessful in approximatively 8 % of cases analysed in our series. Indeed, p16 IHC showed a sensitivity of 100 % and a specificity of 71 %, with a positive predictive value (PPV) of 54 % and a negative predictive value of 100 %; when considering high intensity, p16 IHC showed a sensitivity of 100 %, a specificity of 89 %, with a PPV of 75 % and NPV of 100 %. Since HPV positivity could represent a relevant prognostic and predictive value, the correct characterization offered by this approach appears to be of paramount importance.

Background: Artificial intelligence (AI) in diagnostic radiology is undergoing rapid development. Its potential utility to improve diagnostic performance for cardiopulmonary events is widely recognized, but the accuracy and precision have yet to be demonstrated in the context of current screening modalities. Here, we present findings on the performance of an AI convolutional neural network (CNN) prototype (AI-RAD Companion, Siemens Healthineers) that automatically detects pulmonary nodules and quantifies coronary artery calcium volume (CACV) on low-dose chest CT (LDCT), and compare results to expert radiologists. We also correlate AI findings with adverse cardiopulmonary outcomes in a retrospective cohort of 117 patients who underwent LDCT., Methods: A total of 117 patients were enrolled in this study. Two CNNs were used to identify lung nodules and CACV on LDCT scans. All subjects were used for lung nodule analysis, and 96 subjects met the criteria for coronary artery calcium volume analysis. Interobserver concordance was measured using ICC and Cohen's kappa. Multivariate logistic regression and partial least squares regression were used for outcomes analysis., Results: Agreement of the AI findings with experts was excellent (CACV ICC = 0.904, lung nodules Cohen's kappa = 0.846) with high sensitivity and specificity (CACV: sensitivity = .929, specificity = .960; lung nodules: sensitivity = 1, specificity = 0.708). The AI findings improved the prediction of major cardiopulmonary outcomes at 1-year follow-up including major adverse cardiac events and lung cancer (AUC MACE  = 0.911, AUC Lung Cancer  = 0.942)., Conclusion: We conclude the AI prototype rapidly and accurately identifies significant risk factors for cardiopulmonary disease on standard screening low-dose chest CT. This information can be used to improve diagnostic ability, facilitate intervention, improve morbidity and mortality, and decrease healthcare costs. There is also potential application in countries with limited numbers of cardiothoracic radiologists.

There is a global concern with the escalating number of patients at hospitals caused mainly by population aging, chronic diseases, and recently by the COVID-19 outbreak. To smooth this challenge, IoT emerges as an encouraging paradigm because it provides the scalability required for this purpose, supporting continuous and reliable health monitoring on a global scale. Based on this context, an IoT-based healthcare platform to provide remote monitoring for patients in a critical situation was proposed in the authors' previous works. Therefore, this paper aims to extend the platform by integrating wearable and unobtrusive sensors to monitor patients with coronavirus disease. Furthermore, we report a real deployment of our approach in an intensive care unit for COVID-19 patients in Brazil., (This work is licensed under a Creative Commons Attribution 4.0 License. For more information, see https://creativecommons.org/licenses/by/4.0/.)

Non-coding RNA transcripts originating from Ultraconserved Regions (UCRs) have tissue-specific expression and play relevant roles in the pathophysiology of multiple cancer types. Among them, we recently identified and characterized the ultra-conserved-transcript-8+ (uc.8+), whose levels correlate with grading and staging of bladder cancer. Here, to validate uc.8+ as a potential biomarker in bladder cancer, we assessed its expression and subcellular localization by using tissue microarray on 73 human bladder cancer specimens. We quantified uc.8+ by in-situ hybridization and correlated its expression levels with clinical characteristics and patient survival. The analysis of subcellular localization indicated the simultaneous presence of uc.8+ in the cytoplasm and nucleus of cells from the Low-Grade group, whereas a prevalent cytoplasmic localization was observed in samples from the High-Grade group, supporting the hypothesis of uc.8+ nuclear-to-cytoplasmic translocation in most malignant tumor forms. Moreover, analysis of uc.8+ expression and subcellular localization in tumor-surrounding stroma revealed a marked down-regulation of uc.8+ levels compared to the paired (adjacent) tumor region. Finally, deep machine-learning approaches identified nucleotide sequences associated with uc.8+ localization in nucleus and/or cytoplasm, allowing to predict possible RNA binding proteins associated with uc.8+, recognizing also sequences involved in mRNA cytoplasm-translocation. Our model suggests uc.8+ subcellular localization as a potential prognostic biomarker for bladder cancer.

There is a strong relationship between metabolic state and susceptibility to Mycobacterium tuberculosis (MTB) infection, with energy metabolism setting the basis for an exaggerated immuno-inflammatory response, which concurs with MTB pathogenesis. Herein, we show that controlled caloric restriction (CR), not leading to malnutrition, protects susceptible DBA/2 mice against pulmonary MTB infection by reducing bacterial load, lung immunopathology, and generation of foam cells, an MTB reservoir in lung granulomas. Mechanistically, CR induced a metabolic shift toward glycolysis, and decreased both fatty acid oxidation and mTOR activity associated with induction of autophagy in immune cells. An integrated multi-omics approach revealed a specific CR-induced metabolomic, transcriptomic, and proteomic signature leading to reduced lung damage and protective remodeling of lung interstitial tightness able to limit MTB spreading. Our data propose CR as a feasible immunometabolic manipulation to control MTB infection, and this approach offers an unexpected strategy to boost immunity against MTB., Competing Interests: Declaration of Interests Authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

During academic clinical suspensions related to the COVID-19 pandemic, a group of medical students in Washington, D.C. collaborated with a local federally qualified health center to launch a free COVID-19 testing site to increase access to testing in the community. The patients who accessed the testing site were predominantly Black/African American and Hispanic/Latino, some of whom were uninsured or without access to testing or a timely physician's referral. In this article, medical students reflect on their experiences at this testing site and provide commentary on how existing racial and socioeconomic health disparities have been exacerbated by the COVID-19 pandemic. While under the extremely unusual circumstance of a suspension from their clinical rotations, medical students elaborate on the lessons learned from this experience and the continued work required to engage deeply in the issues of equality and racial justice now and in the future.

Background: Renal cell carcinoma (RCC) constitutes 3% of all cancers, with a higher incidence in patients with age between 60 and 70 years. RCC frequently present as a metastatic tumor at diagnosis, and bones represent one of the most frequent sites. Many cases, mainly in young patients, includes the Xp11 translocation RCC. The cytological diagnosis of Xp11 translocation RCC in adult population it is rarely performed, likely for the morphological overlap with other adult renal cell carcinoma subtypes., Methods: We retrospectively analyze a series of 92 adult patients with metastatic bone tumors, diagnosed on fine-needle aspiration cytology (FNAC) samples, focusing mainly on the cytological, immunophenotypic and molecular features of Xp11 translocation RCC., Results: In our series 6 of 92 (6.5%) cases were metastatic RCC (mRCC), among them 2 cases were metastasis from Xp11translocation RCC. Those cases showed a bloody background, with several groups of atypical cells arranged in syncytial groups or in papillary groups composed by atypical cells with abundant cytoplasm, with scattered clear cells. TFE3 was positive on immunocytochemical analysis and specific translocation t(Xp11.23) was detected by FISH analysis., Conclusions: In adult patients with mRCC, it is necessary to consider also Xp11 translocation RCC among the diagnostic hypotheses. FNAC represents a valid tool to investigate bone lesions but cytological features of Xp11 translocation RCC are still poorly described and must necessarily be better defined., (© 2020 Wiley Periodicals LLC.)

In humans, soft tissue spindle cell sarcomas (STSCS) grading is considered a useful parameter in determining prognosis and therapy, and it is recognized as an important prognostic factor in canine STSCS. The purpose of this study was to assess the utility and the accuracy of a cytologic grading system on fine needle aspiration cytology (FNAC) smears of canine and feline cutaneous and subcutaneous STSCS .Thirty-three cases of cytologically diagnosed STSCS were included. The smears and their tumour sections were cytologically and histologically graded, according to established methods in human oncology.Canine STSCS showed a cyto/histologic concordance in 12/20 cases (60%). Concordance was observed in 4/8 (50%) of grade 1, in 8/12 (67%) of grade 2, and in 0 cases of grade 3. Feline STSCS showed concordance in 11/13 cases (85%). Concordance was observed in 5/6 (83%) of grade 1, in 4/4 (100%) of grade 2, and in 2/3 (66.6%) of grade 3 cases. The overall concordance in the entire canine and feline population was 70%. The gradewise concordance was 65% in grade 1, 75% in grade 2, and 66% in grade 3 cases. The overall concordance is similar to that reported in humans. Although a wider population is required to strengthen our findings, these results suggest that cytologic grading of STSCSs may be a useful tool for therapeutic and prognostic evaluations in dogs and cats., Competing Interests: CONFLICT OF INTEREST The authors declare that they have no conflict of interest, (Copyright © 2020 Elsevier Inc. All rights reserved.)

Extrinsic noise-induced transitions to bimodal dynamics have been largely investigated in a variety of chemical, physical, and biological systems. In the standard approach in physical and chemical systems, the key properties that make these systems mathematically tractable are that the noise appears linearly in the dynamical equations, and it is assumed Gaussian and white. In biology, the Gaussian approximation has been successful in specific systems, but the relevant noise being usually non-Gaussian, non-white, and nonlinear poses serious limitations to its general applicability. Here we revisit the fundamental features of linear Gaussian noise, pinpoint its limitations, and review recent new approaches based on nonlinear bounded noises, which highlight novel mechanisms to account for transitions to bimodal behaviour. We do this by considering a simple but fundamental gene expression model, the repressed gene, which is characterized by linear and nonlinear dependencies on external parameters. We then review a general methodology introduced recently, so-called nonlinear noise filtering, which allows the investigation of linear, nonlinear, Gaussian and non-Gaussian noises. We also present a derivation of it, which highlights its dynamical origin. Testing the methodology on the repressed gene confirms that the emergence of noise-induced transitions appears to be strongly dependent on the type of noise adopted, and on the degree of nonlinearity present in the system.

Epithelial-Mesenchymal Transition (EMT) and angiogenesis are crucial events for development of aggressive and often fatal Oral Squamous Cell Carcinomas (OSCCs). Both promote cancer progression and metastasis development, but while the former induces the loss of E-cadherin expression and, hence cadherin switching; the latter produces hematic blood vessel neo-formation and contribute to OSCC cell growth, tumor mass development, and dissemination. Cyclooxygenase-2 (COX-2) has an important role, not only in angiogenic mechanisms, but also in favoring cancer invasion. Indeed it decreases the expression of E-cadherin and leads to phenotypic changes in epithelial cells (EMT) enhancing their carcinogenic potential. Our aim is to evaluate the interplay between E-cadherin cytoplasmic delocalization, COX-2 up-regulation and COX-2 induced neo-angiogenesis in 120 cases of OSCC. We have analyzed the distribution and the number of neo-formed endothelial buds surrounding infiltrating cells that express COX-2, as well as the neo-formed vessels in chronic inflammatory infiltrate, which surround the tumor. A double immunostaining method was employed in order to verify co-localization of endothelial cell marker (CD34) and COX-2. IHC has also been used to assess E-cadherin expression. Our data demonstrate that the OSCC cells, which lose membranous E-cadherin staining, acquiring a cytoplasmic delocalization, overexpress COX-2. Moreover, we find a new CD34+ vessel formation (sprouting angiogenesis). Only basaloid type of OSCC showes low level of COX-2 expression together with very low level of neo-angiogenesis and consequent tumor necrosis. The well-known anti-metastatic effect of certain COX-2 inhibitors suggests that these molecules might have clinical utility in the management of advanced cancers.

Background: The Anaplastic Lymphoma Kinase (ALK) gene is known to be affected by several genetic alterations, such as rearrangement, amplification and point mutation. The main goal of this study was to comprehensively analyze ALK amplification ( ALK -A) and ALK gene copy number gain ( ALK-CNG ) in a large cohort of non-small-cell lung cancer (NSCLC) patients in order to evaluate the effects on mRNA and protein expression. Methods: ALK locus number status was evaluated in 578 NSCLC cases by fluorescence in situ hybridization (FISH). In addition, ALK immunohistochemistry and ALK mRNA in situ hybridization were performed. Results: Out of 578 cases, 17 cases showed ALK -A. In addition, 14 cases presented AL K-CNG and 72 cases presented chromosome 2 polyploidy. None of those carrying ALK -A and -CNG showed either ALK immunohistochemical expression or ALK mRNA expression through in situ hybridization. We observed a high frequency of extra copies of the ALK gene. Conclusions : Our findings demonstrated that ALK -A is not involved in mRNA production and consequently is not involved in protein production; these findings support the hypothesis that ALK -A might not play a role in the pathogenesis of NSCLC, underlining the absence of a specific clinical application.

Mechanochemistry is an alternative for sustainable solvent-free processes that has taken the big step to become, in the near future, a useful synthetic method for academia and the fine chemical industry. The apparatus available, based on ball milling systems possessing several optimizable variables, requires too many control and optimization experiments to ensure reproducibility, which has limited its widespread utilization so far. Herein, we describe the development of an automatic mechanochemical single-screw device consisting of an electrical motor, a drill, and a drill chamber. The applicability and versatility of the new device are demonstrated by the implementation of di- and multicomponent chemical reactions with high reproducibility, using mechanical action exclusively. As examples, chalcones, dihydropyrimidinones, dihydropyrimidinethiones, pyrazoline, and porphyrins, were synthesized with high yields. The unprecedented sustainability is demonstrated by comparison of EcoScale and E -factor values of these processes with those previously described in the literature., Competing Interests: The authors declare no competing financial interest., (Copyright © 2020 American Chemical Society.)

In this paper we afford a quantitative analysis of the sustainability of current world population growth in relation to the parallel deforestation process adopting a statistical point of view. We consider a simplified model based on a stochastic growth process driven by a continuous time random walk, which depicts the technological evolution of human kind, in conjunction with a deterministic generalised logistic model for humans-forest interaction and we evaluate the probability of avoiding the self-destruction of our civilisation. Based on the current resource consumption rates and best estimate of technological rate growth our study shows that we have very low probability, less than 10% in most optimistic estimate, to survive without facing a catastrophic collapse.