KRIT1 loss of function causes a ROS-dependent upregulation of c-Jun

Loss-of-function mutations in the KRIT1 gene (CCM1) have been associated with the pathogenesis of cerebral cavernous malformations (CCM), a major cerebrovascular disease. However, KRIT1 functions and CCM pathogenetic mechanisms remain incompletely understood. Indeed, recent experiments in animal models have clearly demonstrated that the homozygous loss of KRIT1 is not sufficient to induce CCM lesions, suggesting that additional factors are necessary to cause CCM disease. Previously, we found that KRIT1 is involved in the maintenance of the intracellular reactive oxygen species (ROS) homeostasis to prevent ROS-induced cellular dysfunctions, including a reduced ability to maintain a quiescent state. Here, we show that KRIT1 loss of function leads to enhanced expression and phosphorylation of the redox-sensitive transcription factor c-Jun, as well as induction of its downstream target COX-2, in both cellular models and human CCM tissues. Furthermore, we demonstrate that c-Jun upregulation can be reversed by either KRIT1 re-expression or ROS scavenging, whereas KRIT1 overexpression prevents forced upregulation of c-Jun induced by oxidative stimuli. Taken together with the reported role of c-Jun in vascular dysfunctions triggered by oxidative stress, our findings shed new light on the molecular mechanisms underlying KRIT1 function and CCM pathogenesis

Cefiderocol treatment for carbapenem-resistant Acinetobacter baumannii infection in the ICU during the COVID-19 pandemic: a multicentre cohort study

open16noFunding: This study was carried out as part of our routine work and supported by internal funding.Objectives: To analyse the impact of cefiderocol use on outcome in patients admitted to the ICU for severe COVID-19 and further diagnosed with carbapenem-resistant Acinetobacter baumannii (CR-Ab) infection.Methods: Retrospective multicentre observational study was performed at four Italian hospitals, from January 2020 to April 2021. Adult patients admitted to ICU for severe COVID-19 and further diagnosed with CR-Ab infections were enrolled. Patients treated with cefiderocol, as compassionate use, for at least 72 h were compared with those receiving alternative regimens. Primary endpoint was all-cause 28 day mortality. The impact of cefiderocol on mortality was evaluated by multivariable Cox regression model.Results: In total, 107 patients were enrolled (76% male, median age 65 years). The median time from ICU admission to CR-Ab infection diagnosis was 14 (IQR 8-20) days, and the main types of CR-Ab infections were bloodstream infection (58%) and lower respiratory tract infection (41%). Cefiderocol was administered to 42 patients within a median of 2 (IQR 1-4) days after CR-Ab infection diagnosis and as monotherapy in all cases. The remaining patients received colistin, mostly (82%) administered as combination therapy. All-cause 28 day mortality rate was 57%, without differences between groups (cefiderocol 55% versus colistin 58% P = 0.70). In multivariable analysis, the independent risk factor for mortality was SOFA score (HR 1.24, 95% CI 1.15-1.38, P < 0.001). Cefiderocol was associated with a non-significant lower mortality risk (HR 0.64, 95% CI 0.38-1.08, P = 0.10).Conclusions: Our study confirms the potential role of cefiderocol in the treatment of CR-Ab infection, but larger clinical studies are needed.openPascale, Renato; Pasquini, Zeno; Bartoletti, Michele; Caiazzo, Luca; Fornaro, Giacomo; Bussini, Linda; Volpato, Francesca; Marchionni, Elisa; Rinaldi, Matteo; Trapani, Filippo; Temperoni, Chiara; Gaibani, Paolo; Ambretti, Simone; Barchiesi, Francesco; Viale, Pierluigi; Giannella, MaddalenaPascale, Renato; Pasquini, Zeno; Bartoletti, Michele; Caiazzo, Luca; Fornaro, Giacomo; Bussini, Linda; Volpato, Francesca; Marchionni, Elisa; Rinaldi, Matteo; Trapani, Filippo; Temperoni, Chiara; Gaibani, Paolo; Ambretti, Simone; Barchiesi, Francesco; Viale, Pierluigi; Giannella, Maddalen

Healthcare-associated infections and antimicrobial resistance in severe acquired brain injury: a retrospective multicenter study

BackgroundRecent studies underscore that healthcare-associated infections (HAIs) and multidrug-resistant (MDR) HAIs affect rehabilitation outcomes and hospital length of stay (LOS) for severe acquired brain injury (sABI).ObjectiveThis study aimed to estimate HAI incidence in different sABI rehabilitation settings and determine risk factors and HAI impact on neuromotor and cognitive recovery.MethodsWe conducted a retrospective multicenter study in two semi-intensive units (SICUs), two high-specialty post-acute units (PAUs), and one long-term care (LTC) rehabilitation facility. Data extraction was performed by experienced clinicians, using a structured Excel file and they agreed upon criteria for case definitions of healthcare. The main outcome measures were the HAI and MDR HAI incidence and the LOS, the functional recovery was measured using the Level of Cognitive Functioning and Disability Rating Scale.ResultsThere were 134 sABI participants. The calculation of the probability level was adjusted for three pairwise comparisons among settings (0.05/3 = 0.017). The HAI and MDR HAI incidences were significantly higher in SICU (3.7 and 1.3 per 100 person-days) than in other settings (LTC: 1.9, p = 0.034 and 0.5, p = 0.026; PAU: 1.2, p < 0.001 and 0.3, p < 0.001). HAI and MDR HAI risk variables included older age, an increased number of devices, and carbapenemase-producing Enterobacteriaceae (CPE) colonization, while a high prealbumin plasma value seemed to have a protective effect.ConclusionHAIs are related to longer LOS, and colonization is associated with poor prognosis and poor functional outcomes with reduced ability to achieve the cognitive capacity of self-care, employability, and independent living. The need to ensure the protection of non-colonized patients, especially those with severe disabilities on admission, is highlighted

Assessment of the economic performance of the seabream and seabass aquaculture industry in the European Union

Production of gilthead seabream (Sparus aurata) and European seabass (Dicentrarchus labrax) is the second most important aquaculture industry in the European Union in value terms. During the last 10 years, the industry has experienced a process of industry concentration with the aim to overcome efficiency and profitability issues. However, the economic performance of the companies is still in general rather poor. The present work analyzes the economic performance of EU seabream and seabass companies in the period 2008?2016. The work is the first study to analyze companies? profitability in the EU as a whole, by country and company size, using economic and financial data extracted from companies? annual accounts. Based on the results, the study discusses the improvement of production and business profitability in recent years and the different factors that may have caused it, as well as the challenges and threats that seabream and seabass companies will have to face in order to achieve economic sustainability.This research was undertaken under the MedAID project, which has received funding from the European Union's Horizon 2020 Research and Innovation Programme under grant agreement no 727315 (http://www.medaid-h2020.eu/)

The ESSO core curriculum committee update on surgical oncology

Introduction Surgical oncology is a defined specialty within the European Board of Surgery within the European Union of Medical Specialists (UEMS). Variation in training and specialization still occurs across Europe. There is a need to align the core knowledge needed to fulfil the criteria across subspecialities in surgical oncology. Material and methods The core curriculum, established in 2013, was developed with contributions from expert advisors from within the European Society of Surgical Oncology (ESSO), European Society for Radiotherapy and Oncology (ESTRO) and European Society of Medical Oncology (ESMO) and related subspeciality experts. Results The current version reiterates and updates the core curriculum structure needed for current and future candidates who plans to train for and eventually sit the European fellowship exam for the European Board of Surgery in Surgical Oncology. The content included is not intended to be exhaustive but, rather to give the candidate an idea of expectations and areas for in depth study, in addition to the practical requirements. The five elements included are: Basic principles of oncology; Disease site specific oncology; Generic clinical skills; Training recommendations, and, lastly; Eligibility for the EBSQ exam in Surgical Oncology. Conclusions As evidence-based care for cancer patients evolves through research into basic science, translational research and clinical trials, the core curriculum will evolve, mature and adapt to deliver continual improvements in cancer outcomes for patients

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Synthetic Cannabinoids: general aspects and screening analysis by HPLC-UV-Fl technique

I Cannabinoidi Sintetici (CS) occupano uno spazio rilevante nel contesto emergente delle Nuove Sostanze Psicoattive (NSP). Ad oggi, per la determinazione dei CS ci si avvale dell\u2019ausilio di strumentazioni all\u2019avanguardia, come tecniche di Cromatografia Liquida o Gassosa, accoppiate alla Spettrometria di Massa (LC/GC \u2013 MS). Nonostante questo approccio analitico abbia avuto grande successo nella determinazione di CS, sia nelle preparazioni clandestine che li contengono, che nei fluidi biologici di consumatori, si tratta comunque di strumentazioni molto costose e difficilmente fruibili per analisi di screening nei laboratori di routine. Lo scopo di questo progetto \ue8 stato lo sviluppo di un metodo analitico, basato sulla separazione cromatografica (in HPLC) associata ad una detection in UV e fluorescenza, per la determinazione di CS nelle miscele erbacee, ovvero nei cosiddetti \u201cHerbal blends\u201d. Per la parte sperimentale \ue8 stato impiegato un sistema HPLC-UV-FL cos\uec composto: Pompa HPLC LC-10AD (Shimadzu, Tokio); detector spettrofotometrico 875-UV Intelligent (Jasco, Japan); Fluorimetro RF10XAL (Shimadzu, Tokio)]. Nella fase separativa \ue8 stata utilizzata una colonna C18 a fase inversa [Discovery, 150 mm x 4.6 mm, 3 \u3bcm, (Supelco, PA, USA)]. Il modulo di comunicazione utilizzato \ue8 stato CBM-20A Prominence (Shimadzu) e il programma sul PC \u201cLabSolution\u201d (2008-2010, Shimadzu Corporation). Il metodo analitico si basa su una separazione isocratica e una fase mobile composta da METOH/H2O (87,20/12,80, v/v); il flusso di lavoro \ue8 stato impostato a 1 ml/min, la pressione si \ue8 mantenuta intorno ai 200 bar. La migliore lunghezza d\u2019onda di assorbimento, ottenuta per ottimizzazione delle condizioni sperimentali \ue8 229 nm, mentre per la maggior parte degli composti, si \ue8 ottenuto il migliore segnale in fluorescenza alle seguenti lunghezze d\u2019onda: 350 nm (eccitazione) e 425 nm (emissione). La preparazione del campione di miscela erbacea si basa su una semplice procedura estrattiva ( 4820 mg di campione sono stati incubati o.n. in 2 ml di metanolo, a temperatura ambiente). Nelle condizioni sperimentali descritte sono stati separati nove CS entro 10 minuti e col seguente ordine di eluizione: JWH-200, AM-694, JWH-015, JWH -250, JWH-073, JWH-018, JWH-081, JWH-019, JWH-210. Le prove di linearit\ue0 sono state eseguite considerando il range di concentrazione 1-10 \ub5M. I valori ottenuti per la sensibilit\ue0 vanno da 5.94 ng/ml (JWH-081) a 21.28 ng/ml (JWH-073). Il metodo \ue8 stato applicato all\u2019analisi di alcune miscele erbacee sequestrate in Smart Shops.Synthetic cannabinoids (SC) represent a very important side of the emerging and worrying phenomenon of the New Psychoactive substances (NPS). Currently, the determination of SC is based on the use of LC/GC \u2013 MS techniques. Although this analytical approach have been successfully applied to the determination of SC in both clandestine preparations and biological fluids, it is expensive and usually not suitable for the screening analysis in routine laboratories. Aim of this work was the development of a method based on a HPLC separation associated with a UV and FL detection, for the determination of SC in herbal mixtures. The experiments were performed using a HPLC-UV-FL system [LC-10AD HPLC Pump (Shimadzu, Tokio); Jasco 875-UV Intelligent Spectrophotometric detector (Jasco, Japan); RF10XAL Fluorescence detector (Shimadzu, Tokio)]. A reversed phase C18 column [Discovery, 150 mm x 4.6 mm, 3 \u3bcm, (Supelco, PA, USA)] was employed. The Communication Bus Module was a CBM-20A Prominence (Shimadzu) and the program on PC was \u201cLabSolution\u201d (2008-2010, Shimadzu Corporation). The separation was isocratic with a mobile phase composed by MEOH/H2O (87,20/12,80, v/v); the flow was set at 1 ml/min; the pressure was 48 200 bar. After optimization the best UV absorption scored at 229 nm, while, for the majority of the compounds, the best fluorescence signal was obtained at excitation wavelength = 350 nm and emission wavelength = 425 nm. The sample preparation of herbal mixtures was based on a simple extraction procedure ( 4820 mg of sample incubated o.n. in 2 ml of MEOH at room temperature). Under the described conditions, nine SC were separated within 10 minutes with the following elution sequence: JWH-200, AM-694, JWH-015, JWH -250, JWH-073, JWH-018, JWH-081, JWH-019, JWH-210. Linearity was tested in the 1-10 \ub5M concentration range. The analytical sensitivity ranged from 5.94 ng/ml (JWH-081) to 21.28 ng/ml (JWH-073). The method was successfully applied to the analysis of herbal mixtures seized at Smart Shops

Analisi tossicologiche sui lavoratori con mansioni a rischio: valutazione degli esami di conferma nel periodo 2009-2011

A seguito della recente introduzione della normativa in materia di accertamenti tossicologici su lavoratori con mansioni a rischio, il Laboratorio di Tossicologia dell'>Università di Verona, esegue a partire dal 2009, le analisi di "conferma" per i lavoratori dell'area veronese e vicentino sottoposti ad analisi di primo livello. A queste si aggiungono le analisi di "secondo livello". L'attività globalmente si può quantificare in 250 campioni/anno. Presso il nostro Istituto viene regolarmente svolta anche attività di interpretazione critica dei risultati critici o contestati, sulla base della criteriologia medico-legale e tossicologico-forense