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Background and Objectives: The diagnosis of anaphylaxis comprehensively depends on both situational information and laboratory investigations. For this purpose, serum tryptase concentration is examined as an indicator of systemic mast cell mediator release, linked to an underlying anaphylactic process. Increased levels of tryptase may occur in some events different from anaphylaxis, but usually information from crime scene investigations is lacking and autoptic findings are not specific. For legal reasons, it is required to achieve a definite diagnosis of mast cell degranulation that can lead to a certain diagnosis of death from anaphylaxis. Immunohistochemistry seems to be a relatively simple, reliable, and easily repeatable method that can assist the forensic pathologist in the differential diagnosis of death from anaphylaxis. Materials and Methods: This work provides an overview of the current literature on immunohistochemical methods useful in the determination process of anaphylactic-related deaths. A systematic search, according to the PRISMA statement, was performed in databases to identify studies investigating immunohistochemical targets related to anaphylaxis death. Results: This work underscores the importance of anaphylaxis mediators such as tryptase, CD117, and chymase in the immunohistochemical analysis of anaphylactic deaths. Conclusions: According to the reviewed literature, the diagnosis of death due to anaphylaxis should depend not just on the suspicion of an anaphylactic reaction but also on confirming mast cell degranulation through the identification of IHC positivity for inflammatory mediators, particularly in the respiratory tract.

Healthcare-related homicidal cases are not novel within the medical–legal landscape, but investigations are often made difficult with the scarcity of material evidence related to the crime. For this reason, it is necessary to carefully analyze the clinical documentation and employ ancillary forensic resources such as radiology, histopathology, and toxicology. In the presented scenario, the observation of 14 deaths from abnormal bleeding in a First-Level Italian Hospital revealed the administration of massive doses of heparin by a nurse. On behalf of the Judicial Authority, a multidisciplinary medical team investigated the case through the following steps: a thorough review of the clinical documentation, exhumation of the bodies belonging to the deceased patients, performing PMCT and autopsy, and collecting tissue samples for histopathological, immunohistochemical, and toxicological investigations. All the analyzed cases have been characterized by the observation of fatal hemorrhagic episodes not explained with the clinical conditions of the patients, confirmed using autopsy observations and the histological demonstration of the vitality of the lesions. However, due to the limited availability of biological material for the toxicological analysis, the indirect evidence from hematological analyses in hospitalized patients was crucial in demonstrating heparin overdose and its link to the recorded deaths. The present scenario demonstrates the fundamental importance of a multidisciplinary approach to cases of judicial interest related to the healthcare context. Therefore, the illustrated methodologies can be interpreted as an operational framework for similar future cases.

Background: Defensive medicine is characterized by medical decisions made primarily as a precaution against potential malpractice claims. For psychiatrists, professional responsibility encompasses not only the appropriateness of diagnosis and treatment but also the effects of their interventions on patients and their behaviors. Objective: To investigate the socio-demographic, educational, and occupational characteristics and work-related attitudes that may serve as predictors of defensive medicine among Italian psychiatrists. This research extends the results of a previous analysis based on a national survey. Methods: A secondary analysis of the database of a national survey on attitudes and behaviors of Italian psychiatrists regarding defensive medicine and professional liability was performed for this study. Results: Among 254 surveyed psychiatrists, 153 admitted to practicing defensive medicine, while 101 had this attitude with less than half of their patients. The first group was predominantly comprised of women (p = 0.014), who were younger in age (43.34 y 9.89 vs. 48.81 y 11.66, p < 0.001) and had fewer years of professional experience (12.09 y ± 9.8 vs. 17.46 y ± 11.2, p < 0.001). There were no significant differences in prior involvement in complaints (p = 0.876) or the usual place of work (p = 0.818). The most prominent predictors for practicing defensive medicine were (1) considering guidelines and good clinical practices not only for their clinical efficacy but also or exclusively for reducing the risk of legal complaints for professional liability (OR = 3.62; 95%CI, 1.75–7.49), and (2) hospitalizing patients with violent intentions even if not warranted according to their mental state (OR = 2.28; 95%CI, 1.50–3.46, p < 0.001). Prioritizing protection from professional liability over patients’ actual needs in prescribing or adjusting drug dosages and in involuntary hospitalization, as well as prescribing lower dosages than recommended for pregnant patients, were identified as additional predictors. Finally, years of professional experience exhibited a protective function against defensive practices. Conclusions: Psychiatrists advocate the need to implement a ‘risk management culture’ and the provision of more balanced duties in order to ensure ethical and evidence-based care to their patients. A particular source of concern stems from their professional responsibility towards not only the health of patients but also their behavior. However, these aspects conflict with a limited potential for assessment and intervention based on effective clinical tools. A reform of professional liability that considers the specificities of patients cared for by mental health services could contribute to reducing the risk of defensive medicine.

Abstract The mitochondrial uncoupling protein 2 (UCP2) plays a protective function in the vascular disease of both animal models and humans. UCP2 downregulation upon high-salt feeding favors vascular dysfunction in knock-out mice, and accelerates cerebrovascular and renal damage in the stroke-prone spontaneously hypertensive rat. Overexpression of UCP2 counteracts the negative effects of high-salt feeding in both animal models. We tested in vitro the ability of UCP2 to stimulate autophagy and mitophagy as a mechanism mediating its protective effects upon high-salt exposure in endothelial and renal tubular cells. UCP2 silencing reduced autophagy and mitophagy, whereas the opposite was true upon UCP2 overexpression. High-salt exposure increased level of reactive oxygen species (ROS), UCP2, autophagy and autophagic flux in both endothelial and renal tubular cells. In contrast, high-salt was unable to induce autophagy and autophagic flux in UCP2-silenced cells, concomitantly with excessive ROS accumulation. The addition of an autophagy inducer, Tat-Beclin 1, rescued the viability of UCP2-silenced cells even when exposed to high-salt. In summary, UCP2 mediated the interaction between high-salt-induced oxidative stress and autophagy to preserve viability of both endothelial and renal tubular cells. In the presence of excessive ROS accumulation (achieved upon UCP2 silencing and high-salt exposure of silenced cells) autophagy was turned off. In this condition, an exogenous autophagy inducer rescued the cellular damage induced by excess ROS level. Our data confirm the protective role of UCP2 toward high-salt-induced vascular and renal injury, and they underscore the role of autophagy/mitophagy as a mechanism counteracting the high-salt-induced oxidative stress damage.

Attraverso una sorta di ‘viaggio nel tempo’, questo lavoro vuole darsi il compito di presentare un breve aggiornamento sui più recenti sviluppi del concetto di ‘cura del soggetto’ in psicoanalisi. In particolare, si pone qui l’accento sulla visione terapeutica che caratterizzava gli albori di questa disciplina, sostanzialmente orientata in senso unidirezionale dal terapeuta al paziente, e sul suo passaggio alla prospettiva attualmente invece dominante, che è diversa in quanto si fonda invece sul concetto di ‘mutualità’. In tale più recente visione, i cambiamenti nel tempo dell’assetto psichico del paziente traggono origine dai cambiamenti che il paziente stesso ha, per lo più inconsapevolmente, a sua volta prodotto nel tempo nell’assetto psichico del terapeuta che si è occupato e si sta occupando di lui. Tutto ciò sulla base di concetti e modelli che sono entrati nella sfera di interesse delle psicoanalisi soltanto in questi ultimi decenni, quali ad esempio la ‘Teoria del caos’ e le varie teorie sistemiche che si sono sviluppate a partire dalla ‘Teoria generale dei sistemi’ di Ludwig Von Bertalanffy sino ai più recenti modelli di interpretazione dei ‘Sistemi complessi dinamici non lineari’.

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Natural Killer (NK) cells are key innate effectors of antiviral immune response, and their activity changes in ageing and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Here, we investigated the age-related changes of NK cell phenotype and function during SARS-CoV-2 infection, by comparing adult and elderly patients both requiring mechanical ventilation. Adult patients had a reduced number of total NK cells, while elderly showed a peculiar skewing of NK cell subsets towards the CD56lowCD16high and CD56neg phenotypes, expressing activation markers and check-point inhibitory receptors. Although NK cell degranulation ability is significantly compromised in both cohorts, IFN-γ production is impaired only in adult patients in a TGF-β−dependent manner. This inhibitory effect was associated with a shorter hospitalization time of adult patients suggesting a role for TGF-β in preventing an excessive NK cell activation and systemic inflammation. Our data highlight an age-dependent role of NK cells in shaping SARS-CoV-2 infection toward a pathophysiological evolution.

Health care professionals, be they researchers, clinicians or educators, routinely face the need to find and apply best evidence in the context of complex situations. In order to navigate an increasingly large body of evidence advanced information literacy skills are required. More than simply a set of skills, information literacy is an approach that makes possible all other professional activities and goals in evidence-based practice (EBP). The Association for College and Research Libraries (ACRL) recognized this by shifting focus from information literacy competencies to overarching ideas or frames. While it is unlikely that healthcare organizations and accreditation bodies will rescind specific competencies, it is important for educators to recognise and explore the overarching ideas identified by the ACRL Framework, and perhaps identify and engage with other foundational ideas unique to healthcare. Workshops and lectures that teach linear strategies using easy-to-teach examples do not teach skills that students can easily apply to real and complex scenarios requiring critical thinking and iterative strategies. The use of pedagogical approaches such as inquiry-based learning (IBL) have historically been useful in this regard. We have successfully used IBL at the McGill Ingram School of Nursing to teach EBP competencies and engage with higher-level concepts.

Glioblastoma is an aggressive brain tumor with an average life expectancy between 14 and 16 months after diagnosis. The Ki-67 labeling index (LI), a measure of cellular proliferation, is emerging as a prognostic marker in GBM. In this study, we investigated the ultrastructure of glioblastoma tissue from 9 patients with the same molecular profile (adult IDH wild-type glioblastoma, wild-type ATRX, and positive for TP53 expression, GFAP expression, and EGFR overexpression) to find possible ultrastructural features to be used as biomarkers and correlated with the only parameter that differs among our samples, the Ki-67 LI. Our main results were the visualization of the anatomical basis of astrocyte-endothelial cells crosstalk; the ultrastructural in situ imaging of clusters of hyperactivated microglia cells (MsEVs); the ultrastructural in situ imaging of microglia cells storing lipid vesicles (MsLVs); the ultrastructural in situ imaging of neoplastic cells mitophagy (NCsM). The statistical analysis of our data indicated that MsEVs and MsLVs correlate with the Ki-67 LI value. We can thus assume they are good candidates to be considered morphological biomarkers correlating to Ki-67 LI. The role of NCsM instead must be further evaluated. Our study findings demonstrate that by combining ultrastructural characteristics with molecular information, we can discover biomarkers that have the potential to enhance diagnostic precision, aid in treatment decision-making, identify targets for therapy, and enable personalized treatment plans tailored to each patient. However, further research with larger sample sizes is needed to validate these findings and fully utilize the potential of ultrastructural analysis in managing glioblastoma.

The incidence of heart valve disease (HVD) has been rising over the last few decades, mainly due to the increasing average age of the general population, and mitral valve (MV) disease is the second most prevalent HVD after calcific aortic stenosis, but MV disease is a heterogeneous group of different pathophysiological diseases. It is widely proven that regular physical activity reduces all-cause mortality rates, and exercise prescription is part of the medical recommendations for patients affected by cardiovascular diseases. However, changes in hemodynamic balance during physical exercise (including the increase in heart rate, preload, or afterload) could favor the progression of the MV disease and potentially trigger major cardiac events. In young patients with HVD, it is therefore important to define criteria for allowing competitive sport or exercise prescription, balancing the positive effects as well as the potential risks. This review focuses on mitral valve disease pathophysiology, diagnosis, risk stratification, exercise prescription, and competitive sport participation selection, and offers an overview of the principal mitral valve diseases with the aim of encouraging physicians to embody exercise in their daily practice when appropriate.

Autoimmune heart disease is a non-random condition characterised by immune system-mediated aggression against cardiac tissue. Cardiac changes often exhibit nonspecific features and, if unrecognised, can result in fatal outcomes even among seemingly healthy young individuals. In the absence of reliable medical history, the primary challenge lies in differentiating between the various cardiopathies. Numerous immunohistochemical and genetic studies have endeavoured to characterise distinct types of cardiopathies, facilitating their differentiation during autopsy examinations. However, the presence of a standardised protocol that forensic pathologists can employ to guide their investigations would be beneficial. Hence, this summary aims to present the spectrum of autoimmune cardiopathies, including emerging insights such as SARS-CoV-2-induced cardiopathies, and proposes the utilisation of practical tools, such as blood markers, to aid forensic pathologists in their routine practice.

Background Monitoring toxicities among patients receiving immune checkpoint inhibitors using patient-reported outcome measures (PROMs) is relatively recent. This scoping review aims to guide decision making in the development of PROMs programs for patients receiving immune checkpoint inhibitor therapy. Methods Four electronic databases were searched from inception to January 2024. Data on PROM programs for patients receiving immune checkpoint inhibitors (eg, PROMs used, frequency) were extracted. Two authors with established interrater reliability screened titles, abstracts, and full texts. A narrative synthesis identified patterns in the data. Results A total of 22 articles described 16 unique multicomponent, electronic PROM programs for patients receiving immune checkpoint inhibitor therapy, mainly developed for remote monitoring of toxicities between appointments. Patients typically completed 18-26 items from the Patient-Reported Outcomes Common Terminology Criteria for Adverse Events (PRO-CTCAE) or Common Terminology Criteria for Adverse Events (CTCAE) weekly, with high adherence and satisfaction. Commonly monitored symptoms were diarrhea, fatigue, shortness of breath, cough, nausea, decreased appetite, rash, joint pain, pain, and mood. Other features of PROMs programs included clinician alerts, with some programs only flagging symptoms that had an impact on treatment. Some programs also or only sent alerts to patients to contact their clinicians and gave access to symptom management information. In terms of efficacy, the only consistent finding was an increase in quality of life. Conclusions The findings of this scoping review provide some indication as to which components of a PROM program are promising. However, as the evidence base for using PROMs among patients receiving immune checkpoint inhibitors is growing, many questions remain, including which symptoms to monitor, using which PROM, and at what frequency. More trials are needed to answer these questions and to determine how best to implement PROMs among patients receiving immune checkpoint inhibitor in clinical practice. [ABSTRACT FROM AUTHOR]

Death from falls accounts for a significant number of injuries and fatalities globally, often linked to suicides, workplace accidents, or substance abuse, and rarely to homicidal causes. Injuries from falls vary based on height, impact point, and surface struck, with severe trauma often seen, including visceral ruptures, organ lacerations, and complex fractures. Even minimal external injuries can mask severe internal damage, such as multiple organ ruptures, organ tears, and large vessel lacerations. Blunt cardiac injuries, which occur in 5% to 50% of falls, are significant, especially in falls over 6 m. In 70% of the cases, cardiac rupture is observed at the level of the posterior wall of the heart and occurs due to a contusive action on the heart during the diastolic filling phase. We report a case of a 29-year-old man (weight 95 kg) who died from an 11-meter fall. He had a history of cardiac surgery for the transposition of the great vessels, and an autopsy revealed extensive cardiac rupture, likely worsened by fibrotic adhesions anchoring the heart to the pericardium. Toxicological investigations on peripheral blood showed BAC > 2.58 g/L. Heart scars, macro- and microscopically as a deposit of fibrous tissue, due to previous surgery, may have contributed to the extent of the lesion, suggesting the need for further study on post-operative tissue changes and their effects on trauma from falls. [ABSTRACT FROM AUTHOR]

In this pilot study, we assessed the role of autophagy in Crohn's Disease (CD), particularly in patients with a stenosing phenotype. Through the analysis of biopsied specimens from 36 patients, including 11 controls and 25 CD patients, categorized into inflammatory and stenosing groups, we identified a significant reduction in the autophagosomal marker Lc3b-II in patients with active inflammation and stenosis. This was paralleled by an increase in oxidative stress markers, including sNOX2-dp and H2O2, and a decrease in the antioxidant capacity measured by HBA, suggesting an imbalance in autophagy and oxidative stress mechanisms. Additionally, our findings show a correlation between autophagy markers and oxidative stress levels, indicating that autophagy dysfunction may play a pivotal role in CD and in the progression of a stenosing disease phenotype, by failing to eliminate detrimental molecules and pathogenic bacteria, thereby promoting fibrosis. This study is the first to demonstrate in vivo autophagy inhibition in stenosing CD patients and suggests that stimulating autophagic processes could offer a new avenue for the prevention and treatment of intestinal fibrosis in CD. Our results highlight the importance of exploring the interactions between autophagy, the fibrotic process, and the inflammatory cascade, opening avenues for potential therapeutic interventions in CD management. [ABSTRACT FROM AUTHOR]

Low-grade endotoxemia by lipopolysaccharide (LPS) has been detected in COVID-19 and could favor thrombosis via eliciting a pro-inflammatory and pro-coagulant state. The aim of this study was to analyze the mechanism accounting for low-grade endotoxemia and its relationship with oxidative stress and clotting activation thrombosis in COVID-19. We measured serum levels of sNOX2-dp, zonulin, LPS, D-dimer, and albumin in 175 patients with COVID-19, classified as having or not acute respiratory distress syndrome (ARDS), and 50 healthy subjects. Baseline levels of sNOX2-dp, LPS, zonulin, D-dimer, albumin, and hs-CRP were significantly higher in COVID-19 compared to controls. In COVID-19 patients with ARDS, sNOX2-dp, LPS, zonulin, D-dimer, and hs-CRP were significantly higher compared to COVID-19 patients without ARDS. Conversely, concentration of albumin was lower in patients with ARDS compared with those without ARDS and inversely associated with LPS. In the COVID-19 cohort, the number of patients with ARDS progressively increased according to sNOX2-dp and LPS quartiles; a significant correlation between LPS and sNOX2-dp and LPS and D-dimer was detected in COVID-19. In a multivariable logistic regression model, LPS/albumin levels and D-dimer predicted thrombotic events. In COVID-19 patients, LPS is significantly associated with a hypercoagulation state and disease severity. In vitro, LPS can increase endothelial oxidative stress and coagulation biomarkers that were reduced by the treatment with albumin. In conclusion, impaired gut barrier permeability, increased NOX2 activation, and low serum albumin may account for low-grade endotoxemia and may be implicated in thrombotic events in COVID-19. [ABSTRACT FROM AUTHOR]

Background. Oxidative stress and inflammation are typically implied in atherosclerosis pathogenesis and progression, especially in coronary artery disease (CAD). Our objective was to investigate the oxidative stress and inflammation burden directly associated with atherosclerotic plaque in patients with stable coronary disease undergoing coronary artery bypass graft (CABG) surgery. Specifically, markers of oxidative stress and inflammation were compared in blood samples obtained from the atherosclerotic left anterior descending artery (LAD) and blood samples obtained from the healthy left internal thoracic artery (LITA), used as a bypass graft, within the same patient. Methods. Twenty patients scheduled for off-pump CABG were enrolled. Blood samples were collected from the LITA below anastomosis and the LAD below the stenosis. Samples were analysed for oxidative stress (sNOXdp, H2O2, NO) and inflammation markers (TNFα, IL-6, IL-1β, IL-10). Results. The analysis showed a significant increase in oxidative stress burden in the LAD as compared to LITA, as indicated by higher sNOX2-dp and H2O2 levels and lower NO levels (p < 0.01). Also, pro-inflammatory cytokines were increased in the LAD as compared to the LITA, as indicated by higher TNFα and IL-6 amounts (p < 0.01). On the other hand, no significant differences could be seen regarding IL-1β and IL-10 levels between the two groups. Conclusions. The oxidative stress and inflammatory burden are specifically enhanced in the LAD artery of stable coronary patients compared to systemic blood from the LITA of stable coronary patients. [ABSTRACT FROM AUTHOR]