Characterizing the Features of Mitotic Figures Using a Conditional Diffusion Probabilistic Model

Mitotic figure detection in histology images is a hard-to-define, yet clinically significant task, where labels are generated with pathologist interpretations and where there is no ``gold-standard'' independent ground-truth. However, it is well-established that these interpretation based labels are often unreliable, in part, due to differences in expertise levels and human subjectivity. In this paper, our goal is to shed light on the inherent uncertainty of mitosis labels and characterize the mitotic figure classification task in a human interpretable manner. We train a probabilistic diffusion model to synthesize patches of cell nuclei for a given mitosis label condition. Using this model, we can then generate a sequence of synthetic images that correspond to the same nucleus transitioning into the mitotic state. This allows us to identify different image features associated with mitosis, such as cytoplasm granularity, nuclear density, nuclear irregularity and high contrast between the nucleus and the cell body. Our approach offers a new tool for pathologists to interpret and communicate the features driving the decision to recognize a mitotic figure.Comment: Accepted for Deep Generative Models Workshop at Medical Image Computing and Computer Assisted Intervention (MICCAI) 202

Coral recovery in the central Maldives archipelago since the last major mass-bleaching, in 1998

Increasing frequency and severity of disturbances is causing global degradation of coral reef ecosystems. This study examined temporal changes in live coral cover and coral composition in the central Maldives from 1997 to 2016, encompassing two bleaching events, a tsunami, and an outbreak of Acanthaster planci. We also examined the contemporary size structure for five dominant coral taxa (tabular Acropora, Acropora muricata, Acropora humilis, Pocillopora spp, and massive Porites). Total coral cover increased throughout the study period, with marked increases following the 1998 mass-bleaching. The relative abundance of key genera has changed through time, where Acropora and Pocillopora (which are highly susceptible to bleaching) were under-represented following 1998 mass-bleaching but increased until outbreaks of A. planci in 2015. The contemporary size-structure for all coral taxa was dominated by larger colonies with peaked distributions suggesting that recent disturbances had a disproportionate impact on smaller colonies, or that recruitment is currently limited. This may suggest that coral resilience has been compromised by recent disturbances, and further bleaching (expected in 2016) could lead to highly protracted recovery times. We showed that Maldivian reefs recovered following the 1998 mass-bleaching event, but it took up to a decade, and ongoing disturbances may be eroding reef resilience

Downside: The perpetrator of violence in the representations of social and health professionals

Gender-based violence is a widespread phenomenon and pandemic that affects women’s lives. Many interventions have been activated for perpetrators, but the dropout rate is still high. In order to draw up guidelines for responsibly and sustainably dealing with the phenomenon, this study is aimed at investigating the professionals’ perception of the perpetrator as a useful element in designing innovative intervention policies. Open interviews were carried out with welfare and health professionals and the Grounded Theory Methodology was used to analyze the collected data. These results detect attitudes of social health personnel and their feelings of impotence towards gender-based perpetrators because of the emergence of an inevitable repetitiveness of the violent behavior, as well as the “normality of violence” in a patriarchal culture and its “transversality”. This reflective knowledge allows for the opportunity to develop best transformative attitudes toward the phenomenon. According to the results, it is urgent to establish an active and convinced alliance with the healthy part of the man, through specific prevention paths, in order to activate an authentic motivation for change and its sustainability

Tolerogenic Effect Elicited by Protein Fraction Derived From Different Formulas for Dietary Treatment of Cow’s Milk Allergy in Human Cells

Several formulas are available for the dietary treatment of cow’s milk allergy (CMA). Clinical data suggest potentially different effect on immune tolerance elicited by these formulas. We aimed to comparatively evaluate the tolerogenic effect elicited by the protein fraction of different formulas available for the dietary treatment of CMA. Five formulas were compared: extensively hydrolyzed whey formula (EHWF), extensively hydrolyzed casein formula (EHCF), hydrolyzed rice formula (HRF), soy formula (SF), and amino acid-based formula (AAF). The formulas were reconstituted in water according to the manufacturer’s instructions and subjected to an in vitro infant gut simulated digestion using a sequential gastric and duodenal static model. Protein fraction was then purified and used for the experiments on non-immune and immune components of tolerance network in human enterocytes and in peripheral mononuclear blood cells (PBMCs). We assessed epithelial layer permeability and tight junction proteins (occludin and zonula occludens-1, ZO-1), mucin 5AC, IL-33, and thymic stromal lymphopoietin (TSLP) in human enterocytes. In addition, Th1/Th2 cytokine response and Tregs activation were investigated in PBMCs from IgE-mediated CMA infants. EHCF-derived protein fraction positively modulated the expression of gut barrier components (mucin 5AC, occludin and ZO-1) in human enterocytes, while SF was able to stimulate the expression of occludin only. EHWF and HRF protein fractions elicited a significant increase in TSLP production, while IL-33 release was significantly increased by HRF and SF protein fractions in human enterocytes. Only EHCF-derived protein fraction elicited an increase of the tolerogenic cytokines production (IL-10, IFN-γ) and of activated CD4+FoxP3+ Treg number, through NFAT, AP1, and Nf-Kb1 pathway. The effect paralleled with an up-regulation of FoxP3 demethylation rate. Protein fraction from all the study formulas was unable to induce Th2 cytokines production. The results suggest a different regulatory action on tolerogenic mechanisms elicited by protein fraction from different formulas commonly used for CMA management. EHCF-derived protein fraction was able to elicit tolerogenic effect through at least in part an epigenetic modulation of FoxP3 gene. These results could explain the different clinical effects observed on immune tolerance acquisition in CMA patients and on allergy prevention in children at risk for atopy observed using EHCF

Ultrasound-assessed lung aeration correlates with respiratory system compliance in adults and neonates with acute hypoxemic restrictive respiratory failure: an observational prospective study

Background: Lung ultrasound allows lung aeration to be assessed through dedicated lung ultrasound scores (LUS). Despite LUS have been validated using several techniques, scanty data exist about the relationships between LUS and compliance of the respiratory system (Crs) in restrictive respiratory failure. Aim of this study was to investigate the relationship between LUS and Crs in neonates and adults affected by acute hypoxemic restrictive respiratory failure, as well as the effect of patients' age on this relationship. Methods: Observational, cross-sectional, international, patho-physiology, bi-center study recruiting invasively ventilated, adults and neonates with acute respiratory distress syndrome (ARDS), neonatal ARDS (NARDS) or respiratory distress syndrome (RDS) due to primary surfactant deficiency. Subjects without lung disease (NLD) and ventilated for extra-pulmonary conditions were recruited as controls. LUS, Crs and resistances (Rrs) of the respiratory system were measured within 1 h from each other. Results: Forty adults and fifty-six neonates were recruited. LUS was higher in ARDS, NARDS and RDS and lower in control subjects (overall p < 0.001), while Crs was lower in ARDS, NARDS and RDS and higher in control subjects (overall p < 0.001), without differences between adults and neonates. LUS and Crs were correlated in adults [r = - 0.86 (95% CI - 0.93; - 0.76), p < 0.001] and neonates [r = - 0.76 (95% CI - 0.85; - 0.62), p < 0.001]. Correlations remained significant among subgroups with different causes of respiratory failure; LUS and Rrs were not correlated. Multivariate analyses confirmed the association between LUS and Crs both in adults [B = - 2.8 (95% CI - 4.9; - 0.6), p = 0.012] and neonates [B = - 0.045 (95% CI - 0.07; - 0.02), p = 0.001]. Conclusions: Lung aeration and compliance of the respiratory system are significantly and inversely correlated irrespective of patients' age. A restrictive respiratory failure has the same ultrasound appearance and mechanical characteristics in adults and neonates

High exposure to advanced glycation End-products could facilitate the occurrence of pediatric Eosinophilic Esophagitis

Eosinophilic esophagitis (EoE) is a major cause of upper gastrointestinal morbidity in the pediatric age. It has been hypothesized that the interaction between genetic and environmental factors (i.e., dietary habits) may induce the development of EoE. Among dietary factors, it has been postulated that advanced glycation end-products (AGEs), present at high level in ultra-processed foods (UPFs), could be involved in the pathogenesis of several inflammatory diseases, including food allergy. AGEs are ligands to the RAGE receptor and, mimicking signals provoked by tissue damage, are capable to increase tissue permeability, inflammation and Th2 response. We aimed to evaluate the potential pathogenic role elicited by AGEs in pediatric EoE

B-cell-depleted patients with persistent SARS-CoV-2 infection: combination therapy or monotherapy? A real-world experience

Objectives: The aim of the study was to describe a cohort of B-cell-depleted immunocompromised (IC) patients with prolonged or relapsing COVID-19 treated with monotherapy or combination therapy. Methods: This is a multicenter observational retrospective study conducted on IC patients consecutively hospitalized with a prolonged or relapsing SARS-CoV-2 infection from November 2020 to January 2023. IC COVID-19 subjects were stratified according to the monotherapy or combination anti-SARS-CoV-2 therapy received. Results: Eighty-eight patients were enrolled, 19 under monotherapy and 69 under combination therapy. The study population had a history of immunosuppression (median of 2 B-cells/mm3, IQR 1–24 cells), and residual hypogammaglobulinemia was observed in 55 patients. A reduced length of hospitalization and time to negative SARS-CoV-2 molecular nasopharyngeal swab (NPS) in the combination versus monotherapy group was observed. In the univariable and multivariable analyses, the percentage change in the rate of days to NPS negativity showed a significant reduction in patients receiving combination therapy compared to those receiving monotherapy. Conclusion: In IC persistent COVID-19 patients, it is essential to explore new therapeutic strategies such as combination multi-target therapy (antiviral or double antiviral plus antibody-based therapies) to avoid persistent viral shedding and/or severe SARS-CoV-2 infection

Early improvement of glycaemic control after virus clearance in patients with chronic hepatitis C and severe liver fibrosis: a cohort study

HCV has been recognized as the cause of chronic hepatitis C (CHC) since 1990. CHC is associated with progressive liver damage and extrahepatic conditions. Direct antiviral agents (DAAs), approved in 2014, have shown effectiveness in eradicating HCV in most patients. However, little is known about the effect of viral eradication on hepatic and extra-hepatic damage. We performed a historical cohort study of patients with HCV-related liver diseases who achieved SVR from March 2015 to October 2016 at INMI Lazzaro Spallanzani liver Unit in Rome (Italy). Repeated measures of glycaemia were analysed through a multilevel analysis framework to assess short time kinetics of blood glucose level at different times after therapy and for different levels of HCV viremia. The analysis included 205 patients. A model assessing temporal kinetics and variation of glycaemia according to HCV viremia provided evidence that blood glucose levels significantly dropped in patients with diabetes achieving SVR. Most of the variations occurred at 3-5 weeks of therapy (-17.96 mg/dL; p<0.001) and in coincidence with HCV clearance (-13.92 mg/dL; p<0.001). A weak, non-statistically significant reduction was observed in normoglycemic patients. Our study provides evidence that DAAs therapy may significantly improve glycaemic control in patients with CHC achieving SVR even when liver diseases are already established