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Aims: The present analysis from the multicentre prospective Altshock-2 registry aims to better define clinical features, in-hospital course, and management of cardiogenic shock complicating acutely decompensated heart failure (ADHF-CS) as compared with that complicating acute myocardial infarction (AMI-CS)., Methods and Results: All patients with AMI-CS or ADHF-CS enrolled in the Altshock-2 registry between March 2020 and February 2022 were selected. The primary objective was the characterization of ADHF-CS patients as compared with AMI-CS. In-hospital length of stay and mortality were secondary endpoints. One-hundred-ninety of the 238 CS patients enrolled in the aforementioned period were considered for the present analysis: 101 AMI-CS (80% ST-elevated myocardial infarction and 20% non-ST-elevated myocardial infarction) and 89 ADHF-CS. As compared with AMI-CS, ADHF-CS patients were younger [63 (IQR 59-76) vs. 67 (IQR 54-73) years, P = 0.01], but presented with higher creatinine [1.6 (IQR 1.0-2.6) vs. 1.2 (IQR 1.0-1.4) mg/dL, P < 0.001], bilirubin [1.3 (IQR 0.9-2.3) vs. 0.6 (IQR 0.4-1.1) mg/dL, P = 0.01], and central venous pressure values [14 mmHg (IQR 8-12) vs. 10 mmHg (IQR 7-14),P = 0.01]. Norepinephrine was the most common catecholamine used in AMI-CS (79.3%), whereas epinephrine was used more commonly in ADHF-CS (65.5%); 75.8% vs. 46.6% received a temporary mechanical support in AMI-CS and ADHF-CS, respectively (P < 0.001). Length of hospital stay was longer in the latter [28 (IQR 13-48) vs. 17 (IQR 9-29) days, P = 0.001]. Heart replacement therapies were more frequently used in the ADHF-CS group (heart transplantation 13.5% vs. 0% and left ventricular assist device 11% vs. 2%, P < 0.01 and 0.01, respectively). In-hospital mortality was 41.1% (38.6% AMI-CS vs. 43.8% ADHF-CS, P = 0.5)., Conclusions: ADHF-CS is characterized by a higher prevalence of end-organ and biventricular dysfunction at presentation, a longer hospital length of stay, and higher need of heart replacement therapies when compared with AMI-CS. In-hospital mortality was similar between the two aetiologies. Our data warrant development of new management protocols focused on CS aetiology., (© 2023 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Several reports have described the autoimmune encephalitis' (AE) possible onset during pregnancy. In this systematic review, we summarize the available data on the diagnostic and therapeutic approach to AE during pregnancy, highlighting the associated maternal and fetal clinical outcomes. A systematic search of the literature was performed. The following databases were used: PubMed, Google Scholar, EMBASE, and CrossRef. The revision was registered on the PROSPERO platform (CRD42022336357). Forty-nine patients were included. AE onset was mainly observed during the first and the second trimester of pregnancy with psychiatric manifestations and seizures as main onset symptoms. CSF analysis showed AE-specific autoantibody positivity in 33 patients (anti-NMDA receptor as the most frequent). EEG generally showed normal findings. MRI revealed pathological findings in less than half of patients. Tumor screening was positive in 14 cases. First-line immunotherapy (single or combined) was generally employed while second line was administered in a minority of patients. Levetiracetam was the most used antiseizure medication. Cesarean section was performed in 18 women. Most of the women had an excellent early outcome after delivery but 22 showed persistent neurological deficits in long-term follow-up. Fetal outcome was positive in 33 cases, whereas 12 cases of fetal death were reported. A logistic regression showed that no variable significantly influenced the odds of good/bad maternal and fetal clinical outcome. Diagnosis and treatment of AE during pregnancy is challenging. The rate of miscarriage in women with AE seems to be higher than the general population. In addition, mothers may show long-term neurological deficits., (© 2023 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Background: Self-discharge is a risk factor for readmission and excess mortality. We assess the rate of self-discharge from the emergency department (ED) among presentations for acute recreational drug toxicity and identify factors associated with self-discharge., Methods: From the Euro-DEN Plus database of presentations to the ED with acute recreational drug toxicity, we extracted data from 11 centres in seven European countries from 2014 to 2017. Self-discharge was defined as taking one's own discharge or escaping from the ED before being medically cleared. We used multiple logistic regression analyses to look for factors associated with self-discharge., Results: Among 15,135 included presentations, 1807 (11.9%) self-discharged. Self-discharge rates varied from 1.7 to 17.1% between centres. Synthetic cannabinoids were associated with self-discharge, adjusted odds ratio 1.44 (95% confidence interval 1.10-1.89), as were heroin, 1.44 (1.26-1.64), agitation, 1.27 (1.10-1.46), and naloxone treatment, 1.27 (1.07-1.51), while sedation protected from self-discharge, 0.38 (0.30-0.48)., Conclusion: One in eight presentations self-discharged. There was a large variation in self-discharge rates across the participating centres, possibly partly reflecting different discharge procedures and practices. Measures to improve the management of agitation and cautious administration of naloxone to avoid opioid withdrawal symptoms may be approaches worth exploring to reduce self-discharge., (© 2023. The Author(s).)

Introduction: Long-term weakness is common in survivors of COVID-19-associated acute respiratory distress syndrome (CARDS). We longitudinally assessed the predictors of muscle weakness in patients evaluated 6 and 12 months after intensive care unit discharge with in-person visits., Methods: Muscle strength was measured by isometric maximal voluntary contraction (MVC) of the tibialis anterior muscle. Candidate predictors of muscle weakness were follow-up time, sex, age, mechanical ventilation duration, use of steroids in the intensive care unit, the compound muscle action potential of the tibialis anterior muscle (CMAP-TA-S100), a 6-min walk test, severe fatigue, depression and anxiety, post-traumatic stress disorder, cognitive assessment, and body mass index. We also compared the clinical tools currently available for the evaluation of muscle strength (handgrip strength and Medical Research Council sum score) and electrical neuromuscular function (simplified peroneal nerve test [PENT]) with more objective and robust measures of force (MVC) and electrophysiological evaluation of the neuromuscular function of the tibialis anterior muscle (CMAP-TA-S100) for their essential role in ankle control., Results: MVC improved at 12 months compared with 6 months. CMAP-TA-S100 ( P = 0.016) and the presence of severe fatigue ( P = 0.036) were independent predictors of MVC. MVC was strongly associated with handgrip strength, whereas CMAP-TA-S100 was strongly associated with PENT., Discussion: Electrical neuromuscular abnormalities and severe fatigue are independently associated with reduced MVC and can be used to predict the risk of long-term muscle weakness in CARDS survivors., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Benedini, Cogliati, Lulic-Kuryllo, Peli, Mombelli, Calza, Guarneri, Cudicio, Rizzardi, Bertoni, Gazzina, Renzi, Gitti, Rasulo, Goffi, Pozzi, Orizio, Negro, Latronico and Piva.)

Introduction: COVID-19 pandemic had a great impact on outcome in SARS-CoV-2 positive patients with ischemic stroke during the first wave in Italy. Few data are available on outcome stratified by sex., Methods: The Italian Society of Hospital Neuroscience conducted a multi-center, retrospective, observational study on neurological complications in COVID-19 patients with ischemic stroke. All the patients admitted from March 1st to April 30th, 2020 in 20 Neurology Units in Northern Italy were recruited. Demographical and clinical features, treatment and outcome data were compared focusing on sex differences., Results: 812 patients with ischemic stroke were enrolled, of whom 129 with COVID-19; males were 53.8%. In-hospital mortality in COVID-19 patients was 35.3% in males and 27.9% in females while 8.5% in male and 5.8% in female patients without COVID-19. SARS-CoV-2 positive patients had a higher frequency of stroke of undetermined etiology, than negative ones (32.8% vs 22.5%; p = 0.02), especially in females compared to males (36.1% vs 27.9%), albeit without statistical significance. Male patients with SARS-CoV-2 were more likely to require cPAP (30.9% vs 14.8%; p = 0.03), endotracheal tube (14.9% vs 3.3%; p = 0.02) and reperfusion strategies (29.4% vs 11.5%; p = 0.01) than females, as well as to have a higher CRP and D-dimer. These elements together with older age, a total anterior circulation stroke and lymphopenia were predictors of a worse outcome., Discussion: Our study detected some differences due to sex in ischemic stroke with and without COVID-19, supporting the possibility to perform sex analyses for SARS-CoV-2 positive patients for a better clinical management., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Implantable cardioverter-defibrillator (ICD) therapy is the most effective prophylactic strategy against sudden cardiac death (SCD) in patients with ischemic cardiomyopathy (ICM) and left ventricle ejection fraction (LVEF) ≤35% as detected by transthoracic echocardiograpgy (TTE). This approach has been recently questioned because of the low rate of ICD interventions in patients who received implantation and the not-negligible percentage of patients who experienced SCD despite not fulfilling criteria for implantation., Objectives: The DERIVATE-ICM registry (CarDiac MagnEtic Resonance for Primary Prevention Implantable CardioVerter DebrillAtor ThErapy; NCT03352648) is an international, multicenter, and multivendor study to assess the net reclassification improvement (NRI) for the indication of ICD implantation by the use of cardiac magnetic resonance (CMR) as compared to TTE in patients with ICM., Methods: A total of 861 patients with ICM (mean age 65 ± 11 years, 86% male) with chronic heart failure and TTE-LVEF <50% participated. Major adverse arrhythmic cardiac events (MAACE) were the primary endpoints., Results: During a median follow-up of 1,054 days, MAACE occurred in 88 (10.2%). Left ventricular end-diastolic volume index (HR: 1.007 [95% CI: 1.000-1.011]; P = 0.05), CMR-LVEF (HR: 0.972 [95% CI: 0.945-0.999]; P = 0.045) and late gadolinium enhancement (LGE) mass (HR: 1.010 [95% CI: 1.002-1.018]; P = 0.015) were independent predictors of MAACE. A multiparametric CMR weighted predictive derived score identifies subjects at high risk for MAACE compared with TTE-LVEF cutoff of 35% with a NRI of 31.7% (P = 0.007)., Conclusions: The DERIVATE-ICM registry is a large multicenter registry showing the additional value of CMR to stratify the risk for MAACE in a large cohort of patients with ICM compared with standard of care., Competing Interests: Funding Support and Author Disclosures The Italian Ministry of Health, Rome, Italy (RC 2017 R659/17-CCM698) has provided funding for this study. Dr De Cecco has received a grant from Siemens. Dr Pontone has received institutional fees from General Electric, Bracco, Heartflow, Medtronic, Bayer, and Bhoeringher. Dr Schwitter has received research support from Bayer Healthcare Switzerland. Dr Schoepf has received grants from Astellas, Bayer, General Electric, and Siemens Healthcare; personal fees from Guerbet; and speaking honoraria from Heartflow. Dr Varga-Szemes has received grants from Siemens Healthcare and personal fees from Elucid Bioimaging. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Hormone-receptor positive (HR+), Human-Epidermal-growth Factor negative (HER2-) breast cancer, including the Luminal A and the Luminal B subtypes, is the most common in women diagnosed with early-stage BC. Despite the advances in screening, surgery and therapies, recurrence still occurs. Therefore, it is important to identify early those factors that significantly impact the recurrence risk. Based on current evidence and their professional expertise, a Panel of oncologists discussed the definition of high risk of recurrence in early breast cancer. Histological grade, nodal involvement, genomic score, histological grade, tumor size, and Ki-67 proliferation index were rated as the most important factors to define the high risk in patients with early breast cancer. All these factors should be considered comprehensively to tailor the choice of treatment to the peculiar characteristics of each patient., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

In the maintenance phase of Associazione Italiana di Ematologia e Oncologia Pediatrica (AIEOP)- Berlin-Frankfurt-Muenster (BFM) acute lymphoblastic leukemia (ALL) 2009 protocol, mercaptopurine (MP) is given at the planned dose of 50 mg/m 2 /day; however, dose adjustments are routinely performed to target patients' white blood cells to the optimal range of 2,000-3,000 cells/μL. Pediatric patients with ALL (n = 290, age: median (1st-3rd quartile): 4.8 (3.0-8.1) years; boys: 56.9%) were enrolled mainly in 4 medium-large Italian pediatric hospitals; 14.1% of patients relapsed after a median (1st-3rd quartile) follow-up time of 4.43 (3.82-5.46) years from maintenance beginning. MP metabolites (thionucleotide (TGN) and methyl-derivatives (MMPN)) were measured in the erythrocytes of 387 blood samples of 200 patients by high performance liquid chromatography with ultraviolet detection. Single-nucleotide polymorphisms (SNPs; (rs1800462, rs1800460, and rs1142345 in TPMT gene, rs116855232 in NUDT15, rs1127354, rs7270101, rs6051702 in ITPA, and rs2413739 in PACSIN2) were characterized by Taqman SNP genotyping assays. Cox proportional hazard models did not show an impact of TGN levels and variability on relapse. In contrast, after multivariate analysis, relapse hazard ratio (HR) increased in children with ALL of the intermediate risk arm compared with those in standard risk arm (3.44, 95% confidence interval (CI), 1.31-9.05, P = 0.012), and in carriers of the PACSIN2 rs2413739 T allele compared with those with the CC genotype (heterozygotes CT: HR, 2.32, 95% CI, 0.90-5.97, P = 0.081; and homozygous TT: HR, 4.14, 95% CI, 1.54-11.11, P = 0.005). Future studies are needed to confirm the lack of impact of TGN levels and variability on relapse in the AIEOP-BFM ALL trials, and to clarify the mechanism of PACSIN2 rs2413739 on outcome., (© 2023 The Authors. Clinical Pharmacology & Therapeutics © 2023 American Society for Clinical Pharmacology and Therapeutics.)

Objectives: For COVID-19-related respiratory failure, noninvasive respiratory assistance via a high-flow nasal cannula (HFNC), helmet, and face-mask noninvasive ventilation is used. However, which of these options is most effective is yet to be determined. This study aimed to compare the three techniques of noninvasive respiratory support and to determine the superior technique., Design: A randomized control trial with permuted block randomization of nine cases per block for each parallel, open-labeled arm., Setting and Patients: Adult patients with COVID-19 with a Pa o2 /F io2 ratio of less than 300, admitted between February 4, 2021, and August 9, 2021, to three tertiary centers in Oman, were studied., Interventions: This study included three interventions: HFNC ( n = 47), helmet continuous positive airway pressure (CPAP; n = 52), and face-mask CPAP ( n = 52)., Measurements and Main Results: The endotracheal intubation rate and mortality at 28 and 90 days were measured as the primary and secondary outcomes, respectively. Of the 159 randomized patients, 151 were analyzed. The median age was 52 years, and 74% were men. The endotracheal intubation rates were 44%, 45%, and 46% ( p = 0.99), and the median intubation times were 7.0, 5.5, and 4.5 days ( p = 0.11) in the HFNC, face-mask CPAP, and helmet CPAP, respectively. In comparison to face-mask CPAP, the relative risk of intubation was 0.97 (95% CI, 0.63-1.49) for HFNC and 1.0 (95% CI 0.66-1.51) for helmet CPAP. The mortality rates were 23%, 32%, and 38% at 28 days ( p = 0.24) and 43%, 38%, and 40% ( p = 0.89) at 90 days for HFNC, face-mask CPAP, and helmet CPAP, respectively. The trial was stopped prematurely because of a decline in cases., Conclusions: This exploratory trial found no difference in intubation rate and mortality among the three intervention groups for the COVID-19 patients with hypoxemic respiratory failure; however, more evidence is needed to confirm these findings as the trial was aborted prematurely., Competing Interests: Dr. Al Hashim, Dr. Burad, Dr. Chandwani, Dr. R. Al Lawati, Dr. Al Balushi, Dr. S. Al Masroori, Mr. Al Siyabi, Dr. F. Al Lawati, Dr. Ahmed, Dr. Al Huraizi, Ms. Al Zaabi, Mr. Sebastian, and Dr. Al Busaidy received funding and support for this article research from the Medical Research Center, Sultan Qaboos University (EG/DVC/MRC/20/04). Dr. Al Reesi, Ms. Varghese, and Mr. Al Abri disclosed government work. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine and Wolters Kluwer Health, Inc.)

Background: The Italian Medicines Agency (AIFA) demands precise information on benefit/risk profile of home-based enzyme replacement therapy (ERT) for the treatment of patients with Pompe disease and Mucopolysaccharidosis type I (MPS I). This passage is necessary to obtain the authorization for ERT home therapy, even after the coronavirus disease-19 (COVID-19) pandemic period. This research intends to evaluate the safety, treatment satisfaction, and compliance of MPS I patients treated with laronidase (Aldurazyme®) and Pompe Disease patients treated with alglucosidase alfa (Myozyme®) in a homecare setting., Results: We report herein an early interim analysis of the HomERT (Home infusions of ERT) study, a multicenter, non-interventional, double-cohort study that retrospectively analyzed 38 patients from 14 sites in Italy: cohort A (Pompe disease - 32 patients) and cohort B (MPS I - 6 patients). Among the selected patients who started home therapy before enrollment, the average number of missed home-based infusions was 0.7 (1.3) in cohort A and 3.8 (6.4) in cohort B with no return to the hospital setting. Irrespective of the treatment location, 3 prior ADRs per cohort were reported. The majority of patients preferred home-based infusions (cohort A: 96.9%; cohort B: 100%): the main reason was attributed to treatment convenience (cohort A: 81.3%; cohort B: 83.3%). Despite the underlying conditions, most patients self-evaluated their health as "good" (cohort A: 50%; cohort B: 83.3%)., Conclusions: Evidence of favorable safety profile, improved treatment compliance and personal satisfaction validates the use of ERT with laronidase and alglucosidase alfa as a strong candidate for home therapy., (© 2023. The Author(s).)

Objectives: We aimed to investigate the use of sedation in patients with severe traumatic brain injury (TBI), focusing on the choice of sedative agent, dose, duration, and their association with clinical outcomes. Design: Multinational, multicentre, retrospective observational study. Settings: 14 trauma centres in Europe, Australia and the United Kingdom. Participants: A total of 262 adult patients with severe TBI and intracranial pressure monitoring. Main outcome measures: We described how sedative agents were used in this population. The primary outcome was 60-day mortality according to the use of different sedative agents. Secondary outcomes included intensive care unit and hospital length of stay, and the Extended Glasgow Outcome Scale at hospital discharge. Results: Propofol and midazolam were the most commonly used sedatives. Propofol was more common than midazolam as first line therapy (35.4% v 25.6% respectively). Patients treated with propofol had similar Acute Physiology and Chronic Health Evaluation (APACHE) II and International Mission for Prognosis and Analysis of Clinical Trials in Traumatic Brain Injury (IMPACT) scores to patients treated with midazolam, but lower Injury Severity Score (ISS) (median, 26 [IQR, 22-38] v 34 [IQR, 26-44]; P = 0.001). The use of propofol was more common in heavier patients, and midazolam use was strongly associated with opioid co-administration (OR, 12.9; 95% CI, 3.47-47.95; P < 0.001). Sixty-day mortality and hospital mortality were predicted by a higher IMPACT score ( P < 0.001) and a higher ISS ( P < 0.001), but, after adjustment, were not related to the choice of sedative agent. Conclusions: Propofol was used more often than midazolam, and large doses were common for both sedatives. The first choice was highly variable, was affected by injury severity, and was not independently associated with 60-day mortality., Competing Interests: All authors declare that they do not have any potential conflict of interest in relation to this manuscript., (© 2022 College of Intensive Care Medicine of Australia and New Zealand.)

Background and Objectives : Gastric neuroendocrine neoplasms (gNENs) represent rare but increasingly recognized tumors. They are distinguished into three main clinical types (type-1, type-2, and type-3) according to gastrin level and at histological evaluation in well-differentiated G1, G2, or G3 lesions, as well as poorly-differentiated lesions. Small type-1 and type-2 neoplasms with low proliferation indices demonstrated excellent survival without progression during an extended follow-up period, and for these reasons, active endoscopic observation or endoscopic resection are feasible options. On the other hand, surgery is the treatment of choice for more aggressive type-3, G3, or infiltrating neoplasms. The present study aims to comprehensively review and compare the available therapeutic strategies for gNENs. Materials and Methods : A computerized literature search was performed using relevant keywords to identify all of the pertinent articles with particular attention to gNEN endoscopic treatment. Results : In recent years, different endoscopic resective techniques (such as endoscopic mucosal dissection, modified endoscopic mucosal resection, and endoscopic full-thickness resection) have been developed, showing a high rate of complete resection for advanced and more aggressive lesions. Conclusions : Overall, gNENs represent a heterogeneous group of lesions with varying behavior which require personalized management. The non-operative approach for small type-1 gNENs seems to be feasible and should be promoted. A step-up approach with minimally invasive endoscopic therapies might be proposed, particularly for type-1 gNEN. On the other hand, it is important to recognize the negative prognostic factors in order to identify those rare cases requiring more aggressive approaches. A possible therapeutic algorithm for localized gNEN management is provided.

Objectives: To compare intensivist-diagnosed ventilator-associated pneumonia (iVAP) with four established definitions, assessing their agreement in detecting new episodes., Methods: A multi-centric prospective study on pulmonary microbiota was carried out in patients requiring mechanical ventilation (MV). Data collected were used to compare hypothetical VAP onset according to iVAP with the study consensus criteria, the European Centre for Disease Control and Prevention definition, and two versions of the latter adjusted for leukocyte count and fever., Results: In our cohort of 186 adult patients, iVAPs were 36.6% (68/186, 95% confidence interval 30.0-44.0%), with an incidence rate of 4.64/100 patient-MV-days, and median MV-day at diagnosis of 6. Forty-seven percent of patients (87/186) were identified as VAP by at least one criterion, with a median MV-day at diagnosis of 5. Agreement between intensivist judgement (iVAP/no-iVAP) and the criteria was highest for the study consensus criteria (50/87, 57.4%), but still one-third of iVAP were not identified and 9% of patients were identified as VAP contrary to intensivist diagnosis. VAP proportion differed between criteria (25.2-30.1%)., Conclusions: Caution is needed when evaluating studies describing VAP incidence. Pre-agreed criteria and definitions that capture VAP's evolving nature provide greater consistency, but new clinically driven definitions are needed to align surveillance and diagnostic criteria with clinical practice., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: The impact of sex in clinical and procedural outcomes in leadless pacemaker (LPM) patients has not yet been investigated., Objective: The purpose of this study was to investigate sex-related differences in patients undergoing LPM implantation., Methods: Consecutive patients enrolled in the i-LEAPER registry were analyzed. Comparisons between sexes were performed within the overall cohort using an adjusted analysis with 1:1 propensity matching for age and comorbidities. The primary outcome was the comparison of major complication rates. Sex-related differences regarding electrical performance and all-cause mortality during follow-up were deemed secondary outcomes., Results: In the overall population (n = 1179 patients; median age 80 years), 64.3% were men. After propensity matching, 738 patients with no significant baseline differences among groups were identified. During median follow-up of 25 [interquartile range 24-39] months, female sex was not associated with LPM-related major complications (hazard ratio [HR] 2.03; 95% confidence interval [CI] 0.70-5.84; P = .190) or all-cause mortality (HR 0.98; 95% CI 0.40-2.42; P = .960). LPM electrical performance results were comparable between groups, except for a higher pacing impedance in women at implant and during follow-up (24 months: 670 [550-800] Ω vs 616 [530-770] Ω; P = .014) that remained within normal limits., Conclusion: In a real-world setting, we found differences in sex-related referral patterns for LPM implantation with an underrepresentation of women, although major complication rate and LPM performance were comparable between sexes. Female patients showed higher impedance values, which had no impact on overall device performance. Electrical parameters remained within normal limits in both groups during the entire follow-up., (Copyright © 2023 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Introduction: Clinical trials confirmed the beneficial effects of adding pertuzumab (P) to the combination of trastuzumab-chemotherapy (TC) in the (neo)adjuvant setting of high-risk HER2-positive early breast cancer (HER2+BC). We evaluated the clinical, economic and societal impact of adding pertuzumab to neoadjuvant TC combination (TPC) in Italy., Methods: A cost-consequence analysis comparing TPC vs. TC was performed developing a cohort-based multi-state Markov model to estimate the clinical, societal and economic impact of the neoadjuvant therapy of TPC versus TC in HER2+BC at high-risk of recurrence. The model works on a cycle length of 1 month and 5-years-time horizon. Literature review-based data were used to populate the model. The following clinical and economic outcomes were estimated: cumulative incidence of loco-regional/distant recurrences, life of years and QALY and both direct and indirect costs (€). Finally, sensitivity analyses were performed., Results: TPC was associated with a 75,630 € saved of direct costs. Specifically, it was associated with an initial increase of treatment costs (+4.8%) followed by reduction of recurrence management cost (-20.4%). TPC was also associated with an indirect cost reduction of 1.40%, as well as decreased incidence of distant recurrence (-20.14%), days of work lost (-1.53%) and days lived with disability (-0.50%). Furthermore, TPC reported 10,47 QALY gained (+2.77%) compared to TC. The probability to achieve the pathological complete response (pCR) was the parameter that mostly affected the results in the sensitivity analysis., Conclusion: Our findings suggested that TPC combination could be a cost-saving option in patients with HER2+BC at high-risk of recurrence., Competing Interests: Declaration of competing interest AZ, MC, NLV, EM, ICA, SDC, AM, DG have no conflicts of interest to disclose. DG has received Honoraria from Novartis, Lilly, Roche, Pfizer, Istituto Gentili. Research funding from profit organizations as Astrazeneca, Novartis and Myriad. PAC has received a research grant from Baxalta now part of Shire, and speaking honoraria from Pfizer, Roche and Novartis. LGM has received grants and personal fees from Bayer AG, Boehringer Ingelheim, Pfizer and Daiichi-Sankyo. MN is employes of Novartis Pharma AG., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: To present clinical and instrumental sequelae after obstetric anal sphincter injuries (OASIS), evaluating correlations between intrapartum severity of lesions, postpartum symptoms, and sonographic and manometric findings; outcomes during subsequent deliveries were also evaluated., Methods: This retrospective study evaluated all consecutive women who sustained an OASIS between 2015 and 2020. Postpartum symptoms, anorectal manometry (ARM), and three-dimensional endoanal ultrasonography (3D-EAUS) were analyzed., Results: A total of 107 women underwent OASIS primary repair; 84 (78.5%) of them were asymptomatic after 1 month. The presence and severity of symptoms showed a great correlation with instrumental outcomes in terms of maximum resting pressure, squeeze pressure increment (SPI), circumferential extension of defect for both external anal sphincter (EAS) and internal anal sphincter (IAS), and EAS, IAS and total Starck scores. There was a significant correlation between ARM and 3D-EAUS findings, with the exception of SPI, for which the abnormalities were not predictable based on EAUS results., Conclusion: Both ARM and EAUS findings after OASIS are directly related to each other, and associated with symptoms. These instrumental tools may be useful for OASIS assessment and counseling., (© 2023 The Authors. International Journal of Gynecology & Obstetrics published by John Wiley & Sons Ltd on behalf of International Federation of Gynecology and Obstetrics.)

Historically, the admission of hematological patients in the ICU shortly after the start of a critical illness is associated with better survival rates. Early intensive interventions administered by MET could play a role in the management of hematological critically ill patients, eventually reducing the ICU admission rate. In this retrospective and monocentric study, we evaluate the safety and effectiveness of intensive treatments administered by the MET in a medical ward frame. The administered interventions were mainly helmet CPAP and pharmacological cardiovascular support. Frequent reassessment by the MET at least every 8 to 12 h was guaranteed. We analyzed data from 133 hematological patients who required MET intervention. In-hospital mortality was 38%; mortality does not increase in patients not immediately transferred to the ICU. Only three patients died without a former admission to the ICU; in these cases, mortality was not related to the acute illness. Moreover, 37% of patients overcame the critical episode in the hematological ward. Higher SOFA and MEWS scores were associated with a worse survival rate, while neutropenia and pharmacological immunosuppression were not. The MET approach seems to be safe and effective. SOFA and MEWS were confirmed to be effective tools for prognostication.

Competing Interests: VS received compensation for consulting services and/or speaking activities from AveXis, Cytokinetics, Italfarmaco, Liquidweb S.r.l., Novartis Pharma AG and Zambon. Receives or has received research supports form the Italian Ministry of Health, AriSLA, and E-Rare Joint Transnational Call. He is in the Editorial Board of Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, European Neurology, American Journal of Neurodegenerative Diseases, Frontiers in Neurology, and Exploration of Neuroprotective Therapy. NT received compensation for consulting services and/or speaking activities from Amylyx Pharmaceuticals, Italfarmaco and Zambon Biotech SA. He received research funding from the Italian Ministry of Health and AriSLA. He is Associate Editor for Frontiers in Aging Neuroscience. The remaining 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.

Background: The majority of NSTEMI burden resides outside high-income countries (HICs). We describe presentation, care, and outcomes of NSTEMI by country income classification., Methods and Results: Prospective cohort study including 2947 patients with NSTEMI from 287 centres in 59 countries, stratified by World Bank country income classification. Quality of care was evaluated based on 12 guideline-recommended care interventions. The all-or-none scoring composite performance measure was used to define receipt of optimal care. Outcomes included in-hospital acute heart failure, stroke/transient ischaemic attack, and death, and 30-day mortality. Patients admitted with NSTEMI in low to lower-middle-income countries (LLMICs), compared with patients in HICs, were younger, more commonly diabetic, and current smokers, but with a lower burden of other comorbidities, and 76.7% met very high risk criteria for an immediate invasive strategy. Invasive coronary angiography use increased with ascending income classification (LLMICs, 79.2%; upper middle income countries [UMICs], 83.7%; HICs, 91.0%), but overall care quality did not (≥80% of eligible interventions achieved: LLMICS, 64.8%; UMICs 69.6%; HICs 55.1%). Rates of acute heart failure (LLMICS, 21.3%; UMICs, 12.1%; HICs, 6.8%; P < 0.001), stroke/transient ischaemic attack (LLMICS: 2.5%; UMICs: 1.5%; HICs: 0.9%; P = 0.04), in-hospital mortality (LLMICS, 3.6%; UMICs: 2.8%; HICs: 1.0%; P < 0.001) and 30-day mortality (LLMICs, 4.9%; UMICs, 3.9%; HICs, 1.5%; P < 0.001) exhibited an inverse economic gradient., Conclusion: Patients with NSTEMI in LLMICs present with fewer comorbidities but a more advanced stage of acute disease, and have worse outcomes compared with HICs. A cardiovascular health narrative is needed to address this inequity across economic boundaries., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Extracorporeal membrane oxygenation (ECMO) is required for patients with refractory cardiac or respiratory failure. Inadequate securement of ECMO cannulae may lead to adverse events, ranging from line kinking to catastrophic accidents, such as air entrainment into the circuit or massive bleeding. Furthermore, the micro-motion of the cannulae at the entry site might increase the risk of local infections. Since 2015, we implemented a written protocol for management of ECMO cannulae and tubing, which specifically includes the securement of each cannula with three sutureless devices. The aim of the present study was to retrospectively assess cannulae micro-motion and the rate of bleeding events at the insertion site. Secondarily we aimed to evaluate the impact of prone positioning maneuvers during ECMO on these events. We performed a single-centre retrospective analysis of prospectively collected data on nursing care of ECMO cannulae. We included adult patients treated with veno-venous (V-V) or veno-arterial (V-A) ECMO between 2015 and 2018 in our general intensive care unit. The distance between the insertion site and the end of the wire-wound part of the cannula was recorded daily. Variations of this distance (defined as "cannula micro-motion") were recorded. Forty-five ECMO consecutive adult patients (40 V-V and 5 V-A) were included. No accidental cannula dislodgement was recorded. Median daily "cannula micro-motion" was 0.0 (-0.5 to 0.2) cm, without any significant difference between ECMO configuration, cannula type, and insertion site. Twelve patients (26%) presented at least one bleeding episode at cannula insertion site, none of which required surgical intervention. In the subgroup of patients who underwent prone positioning, no difference in cannulae micro-motion was recorded. An ECMO nursing protocol for cannulae management providing sutureless devices for cannula and tubing securement allows safe line stabilization, with the potential to reduce complications related to ECMO vascular access., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Gastric polyps represent an abnormal proliferation of the gastric mucosa. Chronic atrophic autoimmune gastritis (CAAG) targets parietal cells and results in hypo-achlorhydria and hypergastrinemia, which exerts a proliferative effect on the gastric mucosa., Aims: We investigate the incidence of gastric polyps in CAAG patients., Methods: This is a single-center retrospective study examining patients with confirmed CAAG from January 1990 until June 2022. Demographic, clinical, biochemical, and serological data were collected for each included patient. The histopathological characteristics of the detected polyps were recorded., Results: A total of 176 CAAG patients were included. Eighty-nine (50.5%) had 163 incidental polyps. Seventy-six patients (85%) had 130 non-endocrine lesions, among which 118 (90.7%) were inflammatory, 6 (4.6%) adenomatous, and 4 (3%) fundic; 33 patients (37%) had gastric neuroendocrine neoplasms (gNENs), and 21 (23.6%) both; one had MALToma and one gastric adenocarcinoma. Higher circulating levels of gastrin and chromogranin A were observed among patients with polyps (median 668 vs 893 pg/ml p = 0.0237, 146 vs 207 ng/ml p = 0.0027, respectively)., Conclusion: CAAG implies a high incidence of gNENs and exocrine lesions. Gastrin plays a possible trophic role on the mucosa. Further evidence is needed to validate its predictive role for increased polyp risk in CAAG., Competing Interests: Declaration of Competing Interest The Authors have no conflicts of interest to declare., (Copyright © 2023 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Introduction and Hypothesis: Pregnancy is a risk factor for urinary disorders, mainly in the third trimester. Lower urinary tract symptoms (LUTS) are often underreported by health care professionals and significantly impact the quality of life of pregnant women. Our objective is to analyse lower urinary tract function during the third trimester of pregnancy and assess the impact of traditional risk factors for pelvic floor dysfunctions on bladder health in pregnant women., Methods: This is a secondary analysis of a multicentre cross-sectional study. Third-trimester pregnant women aged 18 years or older anonymously filled in the "Italian Pelvic Floor Questionnaire for pregnant and postpartum women" questionnaire, validated for pelvic floor disorders in pregnancy and postpartum., Results: A total of 927 pregnant patients completed the questionnaire. Among them, 97.3% complained of at least one urinary disorder. Frequency was the symptom reported most often (77.3%), whereas nocturnal enuresis was the least reported (17%). Despite the high prevalence of LUTS in our sample, only 13.4% reported that they negatively impact their quality of life. Overweight and obesity, advanced maternal age, smoking, family history of pelvic floor disorders and poor pelvic floor contraction capacity were confirmed to be risk factors for the onset of LUTS, even in our population., Conclusions: Urinary symptoms are extremely common in the third trimester and significantly affect the quality of life of pregnant women. Since overweight, obesity, smoking and reduced pelvic floor contractility emerged as modifiable risk factors for the development of these symptoms, prevention and adequate counselling are cornerstones of pregnancy care., (© 2023. The International Urogynecological Association.)

Esketamine, the S-enantiomer of ketamine, has recently emerged as a therapy for treatment-resistant depression (TRD), showing both rapid antidepressant action and good efficacy and high safety. It is also indicated for the acute short-term treatment of psychiatric emergency due to major depressive disorder (MDD) and for depressive symptoms in adults with MDD with acute suicidal thoughts/behavior. We here provide preliminary insights on esketamine nasal spray (ESK-NS) effectiveness and safety among patients with a substance use disorder (SUD) within the sample of patients with TRD collected for the observational, retrospective, multicentre REAL-ESK study. Twenty-six subjects were retrospectively selected according to the presence of a SUD in comorbidity. Subjects enrolled completed the three different follow-up phases (T0/baseline, T1/after one month, and T2/after three months) and there were no dropouts. A decrease in Montgomery-Asberg depression rating scale (MADRS) scores was recorded, thus highlighting the antidepressant efficacy of ESK-NS (MADRS decreased from T0 to T1, t = 6.533, df=23, p<0.001, and from T1 to T2, t = 2.029, df=20, p = 0.056). Considering tolerability and safety issues, one or more side effects were reported by 19/26 subjects (73%) after treatment administration. All reported side effects were time-dependent and did not cause significant sequelae; among them, dissociative symptoms (38%) and sedation (26%) were the most frequently reported. Finally, no cases of abuse or misuse of ESK-NS were reported. Despite study limitations related to the inherent nature of the study, a limited number of patients, and a short follow-up period, ESK-NS showed to be effective and safe in patients diagnosed with TRD comorbid with a SUD., Competing Interests: Declaration of Competing Interest Giovanni Martinotti has been a consultant and/or a speaker and/or has received research grants from Angelini, Doc Generici, Janssen-Cilag, Lundbeck, Otsuka, Pfizer, Servier, and Recordati. Ileana Andriola was speaker at Janssen-sponsored conferences. Bernardo Dell'Osso has received lecture honoraria from Angelini, Lundbeck, Janssen, Pfizer, Neuraxpharm, Arcapharma, and Livanova. Antonio Vita received grant/research support and speaker/consultant fees from Angelini, Boheringer Ingelheim, Innovapharma, Janssen-Cilag, Lundbeck, Otsuka, Pfizer, Recordati, Roche, Rovi Pharma, and Takeda. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationship that could be construed as a potential conflict of interest., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Under-recognition of acute respiratory distress syndrome (ARDS) by clinicians is an important barrier to adoption of evidence-based practices such as low tidal volume ventilation. The burden created by the COVID-19 pandemic makes it even more critical to develop scalable data-driven tools to improve ARDS recognition. The objective of this study was to validate a tool for accurately estimating clinician ARDS recognition rates using discrete clinical characteristics easily available in electronic health records. We conducted a secondary analysis of 2,705 ARDS and 1,261 non-ARDS hypoxemic patients in the international LUNG SAFE cohort. The primary outcome was validation of a tool that estimates clinician ARDS recognition rates from health record data. Secondary outcomes included the relative impact of clinical characteristics on tidal volume delivery and clinician documentation of ARDS. In both ARDS and non-ARDS patients, greater height was associated with lower standardized tidal volume (mL/kg PBW) (ARDS: adjusted β = -4.1, 95% CI -4.5 --3.6; non-ARDS: β = -7.7, 95% CI -8.8 --6.7, P<0.00009 [where α = 0.01/111 with the Bonferroni correction]). Standardized tidal volume has already been normalized for patient height, and furthermore, height was not associated with clinician documentation of ARDS. Worsening hypoxemia was associated with both increased clinician documentation of ARDS (β = -0.074, 95% CI -0.093 --0.056, P<0.00009) and lower standardized tidal volume (β = 1.3, 95% CI 0.94-1.6, P<0.00009) in ARDS patients. Increasing chest imaging opacities, plateau pressure, and clinician documentation of ARDS also were associated with lower tidal volume in ARDS patients. Our EHR-based data-driven approach using height, gender, ARDS documentation, and lowest standardized tidal volume yielded estimates of clinician ARDS recognition rates of 54% for mild, 63% for moderate, and 73% for severe ARDS. Our tool replicated clinician-reported ARDS recognition in the LUNG SAFE study, enabling the identification of ARDS patients at high risk of being unrecognized. Our approach can be generalized to other conditions for which there is a need to increase adoption of evidence-based care., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: JL received consulting fees from Baxter Healthcare and Glaxosmithkline. The remaining authors have declared that no competing interests exist., (Copyright: © 2023 Bechel et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objectives: Rituximab has become the cornerstone of induction treatment in ANCA-associated vasculitis (AAV). B-cell depletion may increase the risk of hypogammaglobulinemia, potentially leading to severe infections. This study aims to assess factors associated with hypogammaglobulinemia in AAV patients treated with rituximab., Methods: This retrospective cohort study included AAV patients treated with rituximab induction in 14 European centres. Severe adverse events (SAEs) were defined as episodes requiring hospitalization or intravenous antibiotics, malignancies, or death. Linear and logistic regression were used to identify predictors of IgG levels and of the risk of hypogammaglobulinemia, defined as IgG ≤7 g/l at 6 months., Results: The study included 227 patients. IgG levels at 6 months were lower than baseline (P < 0.001). Patients requiring intravenous antibiotics during the first 6 months had lower IgG levels at 6 months (P = 0.004). Age [β (95% CI): -0.23 (-0.38, -0.08) per 10 years, P = 0.003], oral glucocorticoid dose at induction [β (95% CI): -0.37 (-0.51, -0.24) per sqrt-transformed mg prednisone, P < 0.001] and concomitant use of intravenous glucocorticoid pulses [β (95% CI): -0.88 (-1.73, -0.02), P = 0.044] were associated with IgG levels at 6 months. Hypogammaglobulinemia was identified in 97 (42.7%) patients. In multivariable logistic regression, factors associated with the risk of hypogammaglobulinemia were age [OR (95% CI): 1.46 (1.15, 1.86) per 10 years, P = 0.002] and oral glucocorticoid dose at induction [OR (95% CI): 1.52 (1.23, 1.89) per 10 mg prednisone, P < 0.001]., Conclusions: In AAV patients treated with rituximab, hypogammaglobulinemia at 6 months after induction is common, and lower IgG levels are associated with serious infections. The risk of hypogammaglobulinemia in these patients increases with age and higher glucocorticoid doses., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose: This work aimed to compare physical impairment in survivors of classic ARDS compared with COVID-19-associated ARDS (CARDS) survivors., Material and Methods: This is a prospective observational cohort study on 248 patients with CARDS and compared them with a historical cohort of 48 patients with classic ARDS. Physical performance was evaluated at 6 and 12 months after ICU discharge, using the Medical Research Council Scale (MRCss), 6-min walk test (6MWT), handgrip dynamometry (HGD), and fatigue severity score (FSS). We also assessed activities of daily living (ADLs) using the Barthel index., Results: At 6 months, patients with classic ARDS had lower HGD (estimated difference [ED]: 11.71 kg, p < 0.001; ED 31.9% of predicted value, p < 0.001), 6MWT distance (ED: 89.11 m, p < 0.001; ED 12.96% of predicted value, p = 0.032), and more frequent significant fatigue (OR 0.35, p = 0.046). At 12 months, patients with classic ARDS had lower HGD (ED: 9.08 kg, p = 0.0014; ED 25.9% of predicted value, p < 0.001) and no difference in terms of 6MWT and fatigue. At 12 months, patients with classic ARDS improved their MRCss (ED 2.50, p = 0.006) and HGD (ED: 4.13 kg, p = 0.002; ED 9.45% of predicted value, p = 0.005), while those with CARDS did not. Most patients in both groups regained independence in ADLs at 6 months. COVID-19 diagnosis was a significant independent predictor of better HGD (p < 0.0001) and 6MWT performance (p = 0.001), and lower prevalence of fatigue (p = 0.018)., Conclusions: Both classic ARDS and CARDS survivors experienced long-term impairments in physical functioning, confirming that post-intensive care syndrome remains a major legacy of critical illness. Surprisingly, however, persisting disability was more common in survivors of classic ARDS than in CARDS survivors. In fact, muscle strength measured with HGD was reduced in survivors of classic ARDS compared to CARDS patients at both 6 and 12 months. The 6MWT was reduced and fatigue was more common in classic ARDS compared to CARDS at 6 months but differences were no longer significant at 12 months. Most patients in both groups regained independent function in ADLs at 6 months., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Extracorporeal membrane oxygenation (ECMO) has been used in highly selected COVID-19 patients with severe respiratory failure. Scarce data exist on long-term outcomes of these patients. We performed a single-center prospective evaluation of consecutive COVID-19 ECMO patients successfully discharged from the intensive care unit between February 2020 and January 2022. Physical, cognitive and psychological outcome was assessed at 3, 6, and 12 months by in-person evaluation. All the 34 discharged patients (median age 49 years old) were alive at one year, and 25 of them were evaluated at the follow-up clinic. 67% of patients had muscle weakness, with improvement over time (p = 0.032). The percentage of patients able to return to work progressively increased, up to 86% at 1 year. 23% of patients experienced fatigue. Participation restriction improved over time for both physical (p = 0.050) and emotional (p = 0.005) problems. Cognitive impairment, anxiety, and depression occurred in 29%, 29%, and 23% of patients, respectively, with no changes over time. Health-related quality of life was good. In conclusion, COVID-19 ECMO patients suffer from significant long-term sequelae. However, multidimensional outcomes continued to improve over the follow-up time., Competing Interests: Disclosure: The authors have no conflicts of interest to report., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the ASAIO.)

Background: In China, lung cancer mainly affects the elderly population. Surgery remains the standard treatment for lung cancer in elderly patients, however, postoperative pulmonary complications (PPCs) are major contributors to morbidity and mortality following lung resection. This study aimed to identify perioperative predictors of PPCs among elderly patients undergoing pulmonary resection for lung cancer to provide evidence for better prevention and intervention for PPCs., Methods: A retrospective study was conducted with 456 patients (age >65 years) undergoing pulmonary resection for lung cancer in Yunnan, China from January 2016 to March 2019. Propensity score matching (PSM) was performed to compare preoperative data and clinical characteristics between the PPC and non-PPC groups, followed by binary logistic regression to evaluate predictors of PPCs., Results: Pulmonary complications occurred in 142/456 (31.1%) patients age >65 years, with pneumonia being the most common event (21.7%). Both PSM and binary logistic regression analysis identified American Society of Anesthesiologists (ASA) class II or those undergoing an open thoracotomy to help prevent the occurrence of PPCs., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-23-923/coif). JL is a robotic proctor for Intuitive Surgical and site principal investigator for clinical trials funded by Genentech and Novartis. The other authors have no conflicts of interest to declare., (2023 Journal of Thoracic Disease. All rights reserved.)

Idiopathic membranous nephropathy (IMN) is a pathologically defined disorder of the glomerulus, primarily responsible for nephrotic syndromes (NS) in nondiabetic adults. The underlying molecular mechanisms are still not completely clarified. To explore possible molecular and functional signatures, an optimised mass spectrometry (MS) method based on next-generation data-independent acquisition combined with ion-mobility was applied to serum of patients affected by IMN (n = 15) or by other glomerulopathies (PN) (n = 15). The statistical comparison highlighted a panel of 57 de-regulated proteins with a significant increase in lipoprotein-related proteins (APOC1, APOB, APOA1, APOL1 and LCAT) and a substantial quantitative alteration of key serpins (including A4, D1, A7, A6, F2, F1 and 1) possibly associated with IMN or NS and podocyte stress. A critical dysregulation in metabolisms of lipids (e.g., VLDL assembly and clearance) likely to be related to known hyperlipidemia in IMN, along with involvement of non-classical complement pathways and a putative enrolment of ficolin-2 in sustaining the activation of the lectin-mediated complement system have been pinpointed. Moreover, mannose receptor CD206 (MRC1-down in IMN) and biotinidase (BTD-up in IMN) are able alone to accurately distinguish IMN vs. PN. To conclude, our work provides key proteomic insights into the IMN complexity, opening the way to an efficient stratification of MN patients.

In polycythemia vera (PV), the prognostic relevance of an ELN-defined complete response (CR) to hydroxyurea (HU), the predictors of response, and patients' triggers for switching to ruxolitinib are uncertain. In a real-world analysis, we evaluated the predictors of response, their impact on the clinical outcomes of CR to HU, and the correlations between partial or no response (PR/NR) and a patient switching to ruxolitinib. Among 563 PV patients receiving HU for ≥12 months, 166 (29.5%) achieved CR, 264 achieved PR, and 133 achieved NR. In a multivariate analysis, the absence of splenomegaly ( p = 0.03), pruritus ( p = 0.002), and a median HU dose of ≥1 g/day ( p < 0.001) remained associated with CR. Adverse events were more frequent with a median HU dose of ≥1 g/day. Overall, 283 PR/NR patients (71.3%) continued HU, and 114 switched to ruxolitinib. In the 449 patients receiving only HU, rates of thrombosis, hemorrhages, progression, and overall survival were comparable among the CR, PR, and NR groups. Many PV patients received underdosed HU, leading to lower CR and toxicity rates. In addition, many patients continued HU despite a PR/NR; however, splenomegaly and other symptoms were the main drivers of an early switch. Better HU management, standardization of the criteria for and timing of responses to HU, and adequate intervention in poor responders should be advised.

Cerebral collaterals are recruited after arterial occlusion with a protective effect on tissue outcome in acute ischemic stroke. Head down tilt 15° (HDT15) is a simple, low cost and accessible procedure that could be applied as an emergency treatment, before recanalization therapies, with the aim to increase cerebral collateral flow. Spontaneously hypertensive rats have been shown to display anatomical differences in morphology and function of cerebral collaterals, compared to other rat strains, resulting in an overall poor collateral circulation. We investigate the efficacy and safety of HDT15 in spontaneously hypertensive (SHR) rats, which were considered as an animal stroke model with poor collaterals. Cerebral ischemia was induced by 90 minute endovascular occlusion of the middle cerebral artery (MCA). SHR rats were randomized to HDT15 or flat position (n = 19). HDT15 was applied 30 minutes after occlusion and lasted 60 minutes, until reperfusion. HDT15 application increased cerebral perfusion (+16.6% versus +6.1%; p = 0.0040) and resulted in a small reduction of infarct size (83.6 versus 107.1 mm 3 ; - 21.89%; p = 0.0272), but it was not associated with early neurological improvement, compared to flat position. Our study suggests that the response to HDT15 during MCA occlusion is dependent on baseline collaterals. Nonetheless, HDT15 promoted a mild improvement of cerebral hemodynamics even in subjects with poor collaterals, without safety concerns., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Increased intracranial pressure (ICP) is one of the most important modifiable and immediate threats to critically ill patients suffering from traumatic brain injury (TBI). Two hyperosmolar agents (HOAs), mannitol and hypertonic saline (HTS), are routinely used in clinical practice to treat increased ICP. We aimed to assess whether a preference for mannitol, HTS, or their combined use translated into differences in outcome. The Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) Study is a prospective multi-center cohort study. For this study, patients with TBI, admitted to the intensive care unit (ICU), treated with mannitol and/or HTS, and aged ≥16 years were included. Patients and centers were differentiated based on treatment preference with mannitol and/or HTS based on structured, data-driven criteria such as first administered HOA in the ICU. We assessed influence of center and patient characteristics in the choice of agent using adjusted multi-variate models. Further, we assessed the influence of HOA preference on outcome using adjusted ordinal and logistic regression models, and instrumental variable analyses. In total, 2056 patients were assessed. Of these, 502 (24%) patients received mannitol and/or HTS in the ICU. The first received HOA was HTS for 287 (57%) patients, mannitol for 149 (30%) patients, or both mannitol and HTS on the same day for 66 (13%) patients. Two unreactive pupils were more common in patients receiving both (13, 21%), compared with patients receiving HTS (40, 14%) or mannitol (22, 16%). Center, rather than patient characteristics, was independently associated with the preferred choice of HOA ( p -value <0.05). ICU mortality and 6-month outcome were similar between patients preferably treated with mannitol compared with HTS (odds ratio [OR] = 1.0, confidence interval [CI] = 0.4-2.2; OR = 0.9, CI = 0.5-1.6, respectively). Patients who received both also had a similar ICU mortality and 6-month outcome compared with patients receiving HTS (OR = 1.8, CI = 0.7-5.0; OR = 0.6, CI = 0.3-1.7, respectively). We found between-center variability regarding HOA preference. Moreover, we found that center is a more important driver of the choice of HOA than patient characteristics. However, our study indicates that this variability is an acceptable practice given absence of differences in outcomes associated with a specific HOA.

Aims and Objectives: To evaluate the impact of the professional transition of new graduate nurses during the COVID-19 pandemic., Background: The transition from the role of student to the professional role can be challenging for new graduate nurses for the acquisition of higher autonomy and responsibility. The COVID-19 pandemic impacted the quality of the professional transition., Design: This was a cross-sectional observational study following the Strengthening and Reporting of Observational Studies in Epidemiology checklist., Methods: One hundred and two nurses who graduated in three consecutive sessions (November 2019-pre-pandemic, March 2020-pandemic outbreak, and November 2020-2nd wave) in a north Italian university located in the most affected Italian region by the COVID-19 pandemic, completed an online survey assessing well-being, risk of burnout, resilience, perceived stigma, strengths and limitations and quality of the professional transition. The study was performed between March and May 2021., Results: 81.4% of participants described the professional transition as worse than expected, and new graduate nurses who worked in COVID-19 settings reported a more difficult transition to professional life. No differences emerged in burnout, mental well-being and perceived stigma between new graduate nurses who worked in COVID-19 settings and those who did not. Similarly, no differences emerged amongst the three graduated cohort sessions. The most commonly mentioned challenges faced during the transition were organisational aspects, suddenly acquired autonomy and lack of suitable coaching., Conclusion: New graduate nurses reported a challenging academic-professional transition, in particular, those who worked in COVID-19 settings. The mid- and long-term impact of experiencing an academic-professional transition in COVID-19 settings should be assessed and monitored., Relevance to Clinical Practice: The professional transition of new graduate students should be adequately planned and monitored, new graduates should be assisted to develop realistic expectations about the transition, and an adequate coaching period should be guaranteed all the more during health emergencies., (© 2022 The Authors. Journal of Clinical Nursing published by John Wiley & Sons Ltd.)

Advanced Therapy Medicinal Products (ATMPs) based on somatic cells expanded in vitro , with or without genetic modification, is a rapidly growing area of drug development, even more so following the marketing approval of several such products. ATMPs are produced according to Good Manufacturing Practice (GMP) in authorized laboratories. Potency assays are a fundamental aspect of the quality control of the end cell products and ideally could become useful biomarkers of efficacy in vivo . Here we summarize the state of the art with regard to potency assays used for the assessment of the quality of the major ATMPs used clinic settings. We also review the data available on biomarkers that may substitute more complex functional potency tests and predict the efficacy in vivo of these cell-based drugs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Capelli, Cuofano, Pavoni, Frigerio, Lisini, Nava, Quaroni, Colombo, Galli, Bezukladova, Panina-Bordignon, Gaipa, Comoli, Cossu, Martino, Biondi, Introna and Golay.)

Background: Patients with cytopenic myelofibrosis (MF) have more limited therapeutic options and poorer prognoses compared with patients with the myeloproliferative phenotype., Aims and Methods: Prognostic correlates of cytopenic phenotype were explored in 886 ruxolitinib-treated patients with primary/secondary MF (PMF/SMF) included in the RUX-MF retrospective study. Cytopenia was defined as: leukocyte count <4 × 10 9 /L and/or hemoglobin <11/<10 g/dL (males/females) and/or platelets <100 × 10 9 /L., Results: Overall, 407 (45.9%) patients had a cytopenic MF, including 249 (52.4%) with PMF. In multivariable analysis, high molecular risk mutations (p = .04), intermediate 2/high Dynamic International Prognostic Score System (p < .001) and intermediate 2/high Myelofibrosis Secondary to Polycythemia Vera and Essential Thrombocythemia Prognostic Model (p < .001) remained associated with cytopenic MF in the overall cohort, PMF, and SMF, respectively. Patients with cytopenia received lower average ruxolitinib at the starting (25.2 mg/day vs. 30.2 mg/day, p < .001) and overall doses (23.6 mg/day vs. 26.8 mg/day, p < .001) and achieved lower rates of spleen (26.5% vs. 34.1%, p = .04) and symptom (59.8% vs. 68.8%, p = .008) responses at 6 months compared with patients with the proliferative phenotype. Patients with cytopenia also had higher rates of thrombocytopenia at 3 months (31.1% vs. 18.8%, p < .001) but lower rates of anemia (65.6% vs. 57.7%, p = .02 at 3 months and 56.6% vs. 23.9% at 6 months, p < .001). After competing risk analysis, the cumulative incidence of ruxolitinib discontinuation at 5 years was 57% and 38% in patients with cytopenia and the proliferative phenotype (p < .001), whereas cumulative incidence of leukemic transformation was similar (p = .06). In Cox regression analysis adjusted for Dynamic International Prognostic Score System score, survival was significantly shorter in patients with cytopenia (p < .001)., Conclusions: Cytopenic MF has a lower probability of therapeutic success with ruxolitinib as monotherapy and worse outcome. These patients should be considered for alternative therapeutic strategies., (© 2023 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

The performance of viscoelastic coagulation monitor (VCM) compared with TEG 5000 (TEG) is unknown. In this multicenter study, the authors evaluated the agreement among VCM/TEG parameters and their relationship with standard coagulation tests in critically ill patients. Viscoelastic coagulation monitor, TEG, and laboratory samples were analyzed simultaneously. Viscoelastic coagulation monitor/TEG agreement was computed by Bland and Altman's plots, association with laboratory parameters was studied with Spearman's correlation coefficient and random-intercept linear models. One-hundred and twenty-seven patients enrolled, 320 paired observations: 210 (65.6%) under unfractioned heparin (UFH), 94 (29.4%) under low molecular weight heparin (LMWH), 16 (5.0%) no heparin. Under UFH prolonged clot formation times and reduced the amplitude of viscoelastic tracings on both devices, especially on TEG. The type of heparin affected the agreement between VCM/TEG homolog parameters. Reaction time (TEG-R) resulted 23.1 min longer than the homolog clotting time (VCM-CT) under UFH; maximum amplitude (TEG-MA) resulted 29.5 mm higher than maximum clot firmness (VCM-MCF) under LMWH. Weak correlation was observed between VCM-CT/TEG-R and activated partial thromboplastin time (aPTT)/anti-Xa; no correlation was found between VCM-alpha/TEG-angle and fibrinogen concentration. Viscoelastic coagulation monitor-MCF showed strong (LWMH) to moderate (UFH) correlation with platelet count, while TEG-MA only showed lower correlation. Viscoelastic coagulation monitor and TEG are differently affected by heparin. The platelet count is well represented by VCM-MCF even during UFH administration., Competing Interests: Disclosure: The authors have no conflicts of interest to report., (Copyright © ASAIO 2023.)

Background: Aim of the study was to collect information about emotional features in a sample of immigrant preadolescents in order to identify traits of emotional fragility or psychopathological risk factors., Methods: The sample consists of 1206 preadolescents (180 immigrants, 1026 Italian natives) attending the third year of the middle schools. In order to assess anxiety levels and the presence of depressive symptoms the Self-Administered Psychiatric Scale (SAFA-A) and the Children's Depression Inventory (CDI) were administered. Coping strategies and behavior problems were evaluated by the Coping Inventory for Stressful Situation (CISS) and the Youth Self Report scale (YRS). All teachers filled out the Teacher's Report Form (TRF). Parents were asked to fill out a form on social-demographic features and the Multidimensional Scale of Perceived Social Support (MSPSS)., Results: Immigration resulted a risk factor for development of anxiety (OR=0.702), depression (OR=0.644), internalizing problems (OR=0.685), behavior problems (OR=0.622) and total problems (OR=0.719). Teachers observed more behavior problems and lower competences in immigrants than natives. Immigrants relied significantly more often on emotion-oriented coping strategies to resolve stressful situation than natives (P=0.045). Analyzing the immigrants' sample, second generation children reported significantly higher levels in total competence (school, activity and relationship) than first generation ones (P≤00.1); on the contrary there were no significant differences between the two groups concerning other behavioral and emotional problems or the preferred coping style. Natives' families reported significantly higher levels of perceived support than immigrant ones., Conclusions: Our findings confirm the hypothesis that preadolescent immigrants are more at risk for psychopathological risk factors than native peers.

Neurological outcome after ischemic stroke depends on residual salvageable brain tissue at the time of recanalization. Head down tilt 15° (HDT15) was proven effective in reducing infarct size and improving functional outcome in rats with transient middle cerebral artery occlusion (t-MCAO) by increasing cerebral perfusion within the ischemic penumbra. In this pooled analysis, individual animal-level data from three experimental series were combined in a study population of 104 t-MCAO rats (45 in HDT15 group and 59 in flat position group). Co-primary outcomes were infarct size and functional outcome at 24 h in both groups. The secondary outcome was hemodynamic change induced by HDT15 in ischemic and non-ischemic hemispheres in a subgroup of animals. Infarct size at 24 h was smaller in HDT15 group than in flat position group (absolute mean difference 31.69 mm 3 , 95% CI 9.1-54.2, Cohen's d 0.56, p = 0.006). Functional outcome at 24 h was better in HDT15 group than in flat position group (median [IQR]: 13[10-16] vs. 11), with a shift in the distribution of the neurobehavioural scores in favour of HDT15. Mean cerebral perfusion in the ischemic hemisphere was higher during HDT15 than before its application (Perfusion Unit [P.U.], mean ± SD: 52.5 ± 19.52 P.U. vs. 41.25 ± 14.54 P.U., mean of differences 13.36, 95% CI 7.5-19.18, p = 0.0002). Mean cerebral perfusion in the non-ischemic hemisphere before and during HDT15 was unchanged (P.U., mean ± SD: 94.1 ± 33.8 P.U. vs. 100.25 ± 25.34 P.U., mean of differences 3.95, 95%, CI -1.9 to 9.6, p = 0.1576). This study confirmed that HDT15 improves the outcome in t-MCAO rats by promoting cerebral perfusion in the ischemic territory, without disrupting hemodynamics in non-ischemic areas., (© 2022 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Background: The aim of this study was to compare the costs and budget impact of adopting water vapor thermal therapy with the Rezūm™ System, for treatment of lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH) to transurethral resection of the prostate (TURP), from an Italian hospital healthcare perspective., Methods: A Markov model (4-year time horizon, 3-month cycle length), developed to support a submission to the National Institute of Health and Care Excellence (NICE) in England, was adapted to an Italian payer perspective. A cost minimization analysis was conducted, assuming equal efficacy between both therapies. Net difference in costs per patient was reported, considering procedure, adverse events and retreatment costs. Probabilistic and deterministic sensitivity analyses considered the uncertainty of the results. Population data and market share distribution assumptions were applied to a cohort of Italian patients treated in one year to report the budget and capacity impact of increased use of Rezūm., Results: Over 4 years, the costs per patient with Rezūm were €2072 compared to €2836 with TURP, resulting in net savings of €764. Sensitivity analyses showed that this conclusion was robust. Replacing 10% of TURP procedures with Rezūm generates cost-savings of € 7,139,549 over 4 years and saves 4671 theatre hours and 26,856 bed days in one year. Replacing 30% of BPH surgical procedures with Rezūm generates cost-savings to € 21,418,647 over 4 years, saves 14,012 theatre hours and 80,567 bed-days in one year., Conclusions: This analysis demonstrates that Rezūm is highly likely to be cost-saving compared to TURP from an Italian hospital healthcare perspective.

Introduction: Dysphagia is a swallowing disorder that affects 8% of the world population. However, data are lacking on its prevalence in a heterogeneous group of older patients. The aim of this study is to evaluate the prevalence of dysphagia at admission and at discharge, and its related factors, in particular delirium, in older patients admitted to a rehabilitation setting., Methods: Retrospective cohort study of patients 65 years and older admitted to a rehabilitation ward after an acute hospitalization. The presence of dysphagia at admission was screened with the 3OZ Test and confirmed by a speech-therapist. The association between clinical factors and dysphagia was investigated with a multivariate logistic regression analysis., Results: We included 1040 patients, (65% females, mean age 81.9 ± 7.2 years). The prevalence of dysphagia at admission was 14.8% and 12.8% at discharge, while the prevalence of delirium among patients with dysphagia was of 31.2% vs 6.4% among patients without dysphagia. The severity of dysphagia was moderate. In the multivariate logistic regression, delirium was associated with dysphagia at admission (OR 2.06; Confidence Interval, CI 1.08-3.23) along with a pre-hospital impairment in the Instrumental-Activities-of-Daily-Living (OR-1.26; CI - 1.1; - 1.10), a change in Barthel Index from pre-hospital to hospital admission (OR-1.02; CI - 1.01 to 1.04), comorbidity (OR 1.12; CI 0.94;1.29) and the number of antibiotics (OR-1.63; CI - 1.01;2.62)., Conclusion: Delirium was the main factor associated with dysphagia at rehabilitation admission. The study underlines the importance of screening dysphagia in delirious patients and warrants future studies to determine the changes in dysphagia prevalence according to delirium resolution., (© 2023. The Author(s), under exclusive licence to European Geriatric Medicine Society.)

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, characterized by asthma, eosinophilia and granulomatous or vasculitic involvement of several organs. The diagnosis and management of EGPA are often challenging and require an integrated, multidisciplinary approach. Current practice relies on recommendations and guidelines addressing the management of ANCA-associated vasculitis and not specifically developed for EGPA. Here, we present evidence-based, cross-discipline guidelines for the diagnosis and management of EGPA that reflect the substantial advances that have been made in the past few years in understanding the pathogenesis, clinical subphenotypes and differential diagnosis of the disease, as well as the availability of new treatment options. Developed by a panel of European experts on the basis of literature reviews and, where appropriate, expert opinion, the 16 statements and five overarching principles cover the diagnosis and staging, treatment, outcome and follow-up of EGPA. These recommendations are primarily intended to be used by healthcare professionals, pharmaceutical industries and drug regulatory authorities, to guide clinical practice and decision-making in EGPA. These guidelines are not intended to limit access to medications by healthcare agencies, nor to impose a fixed order on medication use., (© 2023. Springer Nature Limited.)

COVID-19 pandemic had a great impact on mental health, both in the general population and psychiatric patients. Little is known about the difference between these two populations in perceiving the pandemic as a traumatic event. The aim of the study was to compare psychiatric patients and healthy controls (HC) in terms of change over time of post-traumatic (PTSD) symptoms. Demographic and clinical variables were collected. Impact of Event Scale Revised (IES-R) scores were registered at T1 as lockdown period (March-April 2020) and T2 as restarting (May-June 2020). Descriptive analyses and linear regression models were performed. A total of 166 outpatients and 57 HC were recruited. Time (F = 15.76; p < 0.001) and diagnosis (F = 4.94; p < 0.001) had a significant effect on the change of IES-R scores, which resulted T1 > T2 (p < 0.001), except for subjects affected by Obsessive-Compulsive Disorder (OCD). Overall, IES-R scores were < in patients than in HC (p = 0.02), particularly in the schizophrenia (SKZ) subgroup (p < 0.001). IES-R scores of subjects with personality disorders (PDs) resulted to be > HC, although not statistically significant. The lockdown period was perceived as more traumatic than the reopening phase by both groups, with the exception of OCD patients, probably because of the clinical worsening associated with the urge of control against risks of contamination. Overall, HC reported more PTSD symptoms than psychiatric patients did, particularly SKZ ones. PD patients, in contrast, may be more vulnerable to PTSD symptoms probably as a result of poor coping skills. Together with OCD patients, subjects with PDs may need closer monitoring during the different phases of the pandemic. Trial Registration: ClinicalTrials.gov Identifier: NCT04694482.