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An integrated system of three membrane bioreactors (MBRs) has been developed that cascades three different enzymatic reactions. The integrated system was applied to produce hydroxytyrosol acetate from oleuropein extracted from olive leaves. Different reactor configurations for each reaction were tested and individually optimized to select the MBR to ensure high conversion and continuous production of oleuropein aglycone (OA), hydroxytyrosol (HY) and hydroxytyrosol acetate (HA). Based on this study, the most performing configuration of the integrated system was identified. In the first reaction, oleuropein was converted to OA using a biocatalytic membrane reactor (BMR) with immobilized β-glucosidase in polymeric membranes (conversion 98%). The OA was then fed to another BMR, where it was converted to HY (conversion: 70%) by an immobilized mutant of the promiscuous hydrolase/acyltransferase (PestE) (from the thermophilic archaeon Pyrobaculum calidifontis VA1). The HY produced was then acetylated using PestE immobilized on magnetic nanoparticles in a multiphase MBR (conversion: 98%) and simultaneously extracted (extraction: 98%) in ethyl acetate. The work demonstrates that continuous cascade enzymatic reactions can be engineered using artificial membranes to tailor enzyme compartmentalization, mass transport and phase contact according to reaction requirements. Besides, environmental factors proved the sustainability of the integrated membrane bioreactive system., (© 2024 Wiley‐VCH GmbH.)

Background: Patients with previous recurrent pregnancy loss are subject to increased maternal anxiety and reduced antenatal attachment during the subsequent pregnancy. Maternal anxiety is associated with worse pregnancy and neonatal outcomes. Home ultrasound is a feasible tool with the potential to alleviate maternal anxiety by ensuring fetal well-being., Objective: This study aimed to investigate the impact of complementing standard prenatal care with twice-weekly telemedicine visits incorporating home ultrasound on maternal anxiety and antenatal attachment in individuals with a history of recurrent pregnancy loss., Study Design: In this randomized controlled trial, patients with a history of 2 or more prior abortions were randomized early in their subsequent pregnancy in a 1:1 ratio into either the control group, which received standard high-risk prenatal care, or the study group, which received additional twice-weekly home-ultrasound sessions. The home-ultrasound scans assessed fetal pulse, movements, and amniotic fluid volume, aiming to provide maternal reassurance. Patients performed the scans themselves using the Pulsenmore device, with real-time guidance from a physician. Maternal anxiety was assessed using the validated State-Trait Anxiety Inventory Scale (STAI-S) and the Revised Prenatal Distress Questionnaire (NuPDQ), while maternal attachment was measured with the validated Maternal Antenatal Attachment Scale (MAAS-2) at 3 time points during pregnancy. The primary outcome was the STAI-S score at the final prenatal visit. A sample size of 50 patients was calculated to detect a 20% difference in the primary outcome., Results: Of the 57 patients recruited, 50 completed the follow-up, 25 in each group. There were no significant differences in demographics between the groups. The primary outcome (STAI score at the last visit) was significantly lower in the device group compared to the control group (P=.037). In addition, the study group exhibited a greater reduction in STAI scores between the first and last visits (P=.045), and a significantly higher MAAS score at the end of the follow-up period (P=.046)., Conclusion: Integrating routine home-ultrasound telemedicine visits into prenatal care can significantly reduce maternal anxiety during pregnancy and contribute to greater maternal attachment in individuals with a history of recurrent pregnancy loss. These results emphasize the potential benefits of home ultrasound as a tool to alleviate anxiety, provide a sense of control, and foster a deeper maternal connection among pregnant individuals who have experienced previous pregnancy loss., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: To describe the construction and use of a percutaneous pelvic fixation model, evaluate its translational validity among fellowship-trained orthopedic trauma surgeons, and investigate the importance of specific criteria for effective competency-based assessment of pelvic fixation techniques., Methods: Five orthopedic trauma surgeons were asked to place percutaneous wires on a pelvic fixation model, including anterior column (antegrade/retrograde), posterior column (antegrade/retrograde), supra-acetabular, transsacral, and iliosacral. Evaluation criteria included successful wire placement, redirections, cortical breaches, procedure duration, radiation exposure, and quality of fluoroscopic views. Following completion, participants were provided a survey to rate the model., Results: There were no differences between approaches on successful screw placement, wire redirections, or fluoroscopic quality. Antegrade approaches to the anterior and posterior columns took longer (p = 0.008) and used more radiation (p = 0.02). There was also a trend toward more cortical breaches with the antegrade anterior column approach (p = 0.07). Median ratings among surgeons were 4 out of 5 for their overall impression and its accuracy in tactile response, positioning constraints, and fluoroscopic projections. Learning parameters considered most important to the progression of trainees (most to least important) were successful screw placement, corridor breaches, wire redirections, quality of fluoroscopic views, radiation exposure, and procedure duration., Conclusion: In being affordable, accessible, and realistic, this percutaneous pelvic fixation model represents an opportunity to advance orthopedic surgery education globally. Future research is needed to validate the findings of this pilot study and to expand upon how trainees should be evaluated within simulations and the operating room to optimize skill progression., (© 2023. The Author(s), under exclusive licence to Springer-Verlag France SAS, part of Springer Nature.)

Background: Breast Cancer (BC) prevention strategies range from lifestyle changes such as increasing physical activity and reducing body weight to preventive drugs like tamoxifen, known to reduce BC incidence in high-risk women. Sex Hormone Binding Globulin (SHBG) is related to BC risk due to its ability to bind circulating estradiol at high affinity and to regulate estradiol action. A study protocol is presented based on the assessment of the effect of different interventions such as tamoxifen at 10 mg every other day (LDT), intermittent caloric restriction (ICR) two days per week, lifestyle intervention (LI, step counter use) and their combination on the modulation of SHBG and several other biomarkers associated to BC., Methods: A randomized phase II biomarker study will be conducted in 4 Italian centers. Unaffected women aged between 18 and 70 years, carriers of a germline pathogenetic variant (BRCA1, BRCA2, PALB2, or other moderate penetrance genes), or with a >5% BC risk at 10 years (according to the Tyrer-Cuzick or the Breast Cancer Surveillance Consortium Risk models) or with a previous diagnosis of intraepithelial neoplasia will be eligible. A total of 200 participants will be randomized to one of the four arms: LDT; LDT + ICR; LI; LI + ICR. Interventions will span six months, with baseline and follow-up clinic visits and interim phone calls., Discussion: The aim of the study is to verify whether LDT increases circulating SHBG more than LI with or without ICR after 6 months. Secondary objectives include assessing HOMA-index, inflammatory markers, adiponectin/leptin ratio, quality of life (QoL), safety, toxicity, mammographic density, and changes in microbiome composition across groups. The study's innovation lies in its inclusion of diverse BC risk categories and combination of pharmaceutical and behavioral interventions, potentially enhancing intervention efficacy while balancing tamoxifen's side effects on QoL, especially menopausal symptoms., Trial Registration: EuCT number:2023-503994-39-00; Clinical trials.gov NCT06033092., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Guerrieri-Gonzaga 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.)

Background: In patients with cancer, lean body mass loss is frequent and associated with worse outcomes, including reduced treatment tolerance and survival. Bioelectrical impedance analysis (BIA) is a popular method for body composition assessment. We evaluated the value of BIA-derived body composition parameters in predicting mortality and, for the first time, dose-limiting toxicity (DLT)., Patients and Methods: We conducted a prospective multicenter (n = 12) observational study in adult patients with solid neoplastic disease and receiving primary systemic treatment. We collected information on BIA-derived parameters: phase angle (PhA) <5th percentile of age and gender-specific normative values; standardized PhA (SPA) <-1.65; Nutrigram® <660 mg/24 h/m and <510 mg/24 h/m for males and females, respectively. The primary outcome and the key secondary were 1-year mortality and DLT (any-type severe toxicity requiring a delay in systemic treatment administration or a reduction of its dosage), respectively., Results: In total, 640 patients were included. At 12 months, death occurred in 286 patients (47.6%). All BIA-derived body composition parameters were independently associated with death: SPA, hazard ratio (HR) = 1.59 [95% confidence interval (CI) 1.30-1.95] (P < 0.001); PhA, HR = 1.38 (95% CI 1.13-1.69) (P = 0.002); Nutrigram®, HR = 1.71 (95% CI 1.42-2.04) (P < 0.001). DLT occurred in 208 patients (32.5%) and body composition parameters were associated with this outcome, particularly SPA: odds ratio = 6.37 (95% CI 2.33-17.44) (P < 0.001)., Conclusions: The study confirmed that BIA-derived body composition parameters are independently associated not only with survival but also with DLT. Although our findings were limited to patients receiving first-line systemic treatment, the evidence reported may have important practice implications for the improvement of the clinical work-up of cancer patients., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Aims: Evidence on the epidemiology and prognostic significance of mitral regurgitation (MR) and tricuspid regurgitation (TR) in patients with cardiac amyloidosis (CA) is scarce., Methods and Results: Overall, 538 patients with either transthyretin (ATTR, n = 359) or immunoglobulin light-chain (AL, n = 179) CA were included at three Italian referral centres. Patients were stratified according to isolated or combined moderate/severe MR and TR. Overall, 240 patients (44.6%) had no significant MR/TR, 112 (20.8%) isolated MR, 66 (12.3%) isolated TR, and 120 (22.3%) combined MR/TR. The most common aetiologies were atrial functional MR, followed by primary infiltrative MR, and secondary TR due to right ventricular (RV) overload followed by atrial functional TR. Patients with isolated or combined MR/TR had a more frequent history of heart failure (HF) hospitalization and atrial fibrillation, worse symptoms, and higher levels of NT-proBNP as compared to those without MR/TR. They also presented more severe atrial enlargement, atrial peak longitudinal strain impairment, left ventricular (LV) and RV systolic dysfunction, and higher pulmonary artery systolic pressures. TR carried the most advanced features. After adjustment for age, sex, CA subtypes, laboratory, and echocardiographic markers of CA severity, isolated TR and combined MR/TR were independently associated with an increased risk of all-cause death or worsening HF events, compared to no significant MR/TR [adjusted HR 2.75 (1.78-4.24) and 2.31 (1.44-3.70), respectively]., Conclusion: In a large cohort of patients with CA, MR, and TR were common. Isolated TR and combined MR/TR were associated with worse prognosis regardless of CA aetiology, LV, and RV function, with TR carrying the highest risk., Competing Interests: Conflict of interest: D.T. none related to this work. Outside the present work: speaker fees from Alnylam, AstraZeneca, Boehringer Ingelheim, and Pfizer. A.A., V.C., G.V., and I.F. none related to this work. Outside this work: grants from Pfizer and Eidos. M.P. personal fees from Abbott Laboratories, AstraZeneca, Boehringer Ingelheim and Vifor Pharma, all outside the submitted work. M.M. none related to this work. Outside this work: personal fees of minimal amounts since January 2021 from Amgen, Livanova, and Vifor pharma as member of Executive or Data Monitoring Committees of sponsored clinical trials; from AstraZeneca, Bayer, Boehringer Ingelheim, Edwards Lifesciences, Roche Diagnostics for participation to advisory boards and/or speeches at sponsored meetings. M.A. none related to this work. Outside this work: speaker fees from Abbott Vascular and Edwards., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Palliative surgery (PS) is defined as any surgical procedure aimed at improving quality of life or relieving symptoms caused by an advanced or metastatic cancer. The involvement of patients, caregivers, and other professional figures is crucial for obtaining optimal symptom relief and avoiding complications. This study aims to evaluate the short-term outcome and related factors in patients undergoing PS., Patients and Methods: A retrospective analysis was performed in consecutive patients who underwent palliative gastrointestinal surgery at our surgical unit during the period June 2018 to May 2023. Demographic, clinical, pathological and follow-up data were collected from a prospectively maintained department database. The main outcomes were complications, symptoms palliation, symptoms recurrence and return to systemic chemotherapy. Standard statistical analysis was performed., Results: During the study period, 127 patients underwent palliative surgery. The Clavien-Dindo 3-5 complication rate and mortality rate were 19.7 % and 6 %, respectively. The resolution of symptoms was achieved in 109 patients (89 %). Successful symptom palliation was significantly related to the possibility of returning to systemic chemotherapy (SC) (OR 9.30 95 % CI 0.1.83-47.18, p 0.007). The only factor related to survival in multivariate analysis was the return to systemic chemotherapy (HR 0.25 95 % CI 0.15-0.42 0.001)., Conclusion: PS in selected patients is effective for symptom resolution and improving overall survival, if the result is making anticancer therapy possible. Prospective data collection is in any case warranted in every institution performing PS for the purpose of monitoring appropriateness and quality of surgical care., (© 2024 Published by Elsevier Ltd.)

Background: Immune thrombocytopenia (ITP) is an acquired immune-mediated bleeding disorder characterized by isolated thrombocytopenia. Its estimated yearly incidence in the pediatric population is 1.9-6.4/100,000. ITP in children is usually a self-limiting and benign disorder. The clinical management of children with ITP often remains controversial, as robust randomized trials on the management of this disorder are lacking. Treatments vary widely in clinical practice and existing guidelines from hematology societies on clinical management offer indications based largely on expert opinion rather than strong evidence., Materials and Methods: The Coagulative Disorder Working Group of the Italian Association of Pediatric Hematology and Oncology (AIEOP) developed this document to collect shared expert opinions on the management of newly diagnosed ITP, updating previous guidelines and providing recommendations to pediatricians. Each statement has been given a score expressing the strength of evidence, appropriateness and agreement among participants., Results: Clear-cut definitions of the clinical phases of the disease and clinical response are stated. Recommendations are given regarding the classification of bleeding symptoms, evaluation of bleeding risk, diagnosis, and prognostic factors. Specific recommendations for treatment include indications for first-line (intravenous immunoglobulins, steroids) and second-line (combined therapy, thrombopoietin receptor agonists, immunosuppressive drugs, rituximab) therapeutic agents, as well as hemorrhagic emergency and supportive treatment, including emergency splenectomy. The optimal follow-up schedule, the relation between ITP and vaccines and health-related quality-of-life issues are also discussed., Discussion: The panel achieved broad consensus on issues related to how to treat children with newly diagnosed ITP, providing a comprehensive review of all relevant clinical aspects.

Given the recent research on the application of eco-sustainable methods in organic chemistry, we have focused our attention on the derivatization processes for fundamental functional groups in organic chemistry, such as amino, hydroxyl and carbonyl groups. Protection reactions are needed to temporarily block a certain reactive site on a molecule. The use of green solvents in this context has made an excellent contribution to the development of eco-sustainable methods. In recent years, deep eutectic solvents (DESs) have had great success as a new class of green solvents used in various chemical applications, such as extraction or synthetic processes. These solvents are biodegradable and nontoxic. In this framework, a list of relevant works found in the literature is described, considering DESs to be a good alternative to classic toxic solvents in the protection reactions of important functional groups.

Introduction: The total number of cancer-related deaths and new cancer cases in 2020 was 19.3 billion and 10.8 billion, respectively. Therefore, prevention, diagnosis, and treatment of neoplastic disease, as well as management of comorbidities, are of paramount importance. In this regards, poor nutritional status and mental disorders are comorbidity conditions frequently observed in cancer patients. The aim of this study was to assess the association between malnutrition and anxiety in hospitalized adult cancer patients., Methods: This is a retrospective study. Nutrition Risk Screening (NRS) 2002, body mass index (BMI), daily calorie intake, and weight difference between admission and discharge were used to evaluate nutritional status. Anxiety was assessed with the Hospital Anxiety and Depression Scale (HADS-A). Ordered logistic and linear logistic regressions adjusted for sex and age were used to estimate the association between malnutrition and anxiety in cancer patients., Results: A total of 90 patients were included. Higher NRS risk [aβ = 0.85; 95% CI (0.28-1.42); p = 0.004], disease stage [aβ = 0.77; 95% CI (0.08-1.47); p = 0.029], and cachexia [aβ = 2.20; 95% CI (0.75-3.65); p = 0.003] were significantly associated with anxiety symptoms. Moreover, cancer site different than gastrointestinal cancers was associated with a lower risk of anxiety symptoms [aβ =  - 2.11; 95% CI (- 3.55/ - 0.66); p = 0.005]., Conclusion: In the current study, we found a relatively high rate of malnourished patients, indicating the importance of routinely assessing nutritional status and screening cancer patients for mental health issues. This approach could help physicians to treat both in a timely manner, thereby significantly reducing the burden of the disease and improving the quality of life of patients., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

A renewed understanding of eco-friendly principles is moving the industrial sector toward a shift in the utilization of less harmful solvents as a main strategy to improve manufacturing. Green analytical chemistry (GAC) has definitely paved the way for this transition by presenting green solvents to a larger audience. Among the most promising, surely DESs (deep eutectic solvents), NaDESs (natural deep eutectic solvents), HDESs (hydrophobic deep eutectic solvents), and HNaDESs (hydrophobic natural deep eutectic solvents), with their unique features, manifest a wide-range of applications, including their use as a means for the extraction of small bioactive compounds. In examining recent advancements, in this review, we want to focus our attention on some of the most interesting and novel 'solvent-free' extraction techniques, such as microwave-assisted extraction (MAE) and ultrasound-assisted extraction (UAE) in relation to the possibility of better exploiting DESs and NaDESs as plausible extracting solvents of the phenolic compounds (PCs) present in different matrices from olive oil components, such as virgin olive pomace, olive leaves and twigs, virgin and extra virgin olive oil (VOO and EVOO, respectively), and olive cake and olive mill wastewaters (OMWW). Therefore, the status of DESs and NaDESs is shown in terms of their nature, efficacy and selectivity in the extraction of bioactive phytochemicals such as secoiridoids, lignans, phenolic acids and alcohols. Related studies on experimental design and processes' optimization of the most promising DESs/NaDESs are also reviewed. In this framework, an extensive list of relevant works found in the literature is described to consider DESs/NaDESs as a suitable alternative to petrochemicals in cosmetics, pharmaceutical, or food applications.

The beneficial properties of extra virgin olive oil (EVOO) on lipids blood levels were recognized by the European Food Safety Authority (EFSA) with a health claim, specifically referring to EVOOs containing at least 5 mg of hydroxytyrosol and its secoiridoids derivatives per 20 g of oil. The main purpose of the work was to characterize the phenolic profile of two commercially available Calabrian monovarietal EVOOs ( Nocellara del Belice , VN; Dolce di Rossano , VDR), and to study the effect of one-year storage on secoiridoids composition, by monthly controls. A new UHPLC-ESI-HRMS method was developed and validated, thus facilitating the EFSA claim application and allowing producers to valorize their products. Seven biologically active compounds were chosen: tyrosol, hydroxytyrosol, oleocanthal, oleacein, oleuropein aglycone, verbascoside, and oleuropein. LODs and LOQs were 0.001-0.02 mg g -1 and 0.002-0.08 mg g -1 , respectively. The variation coefficients were ≤20% and the percentage of recovery was between 89-109%. During the 12-month storage period, the concentration of selected compounds ranged between 1258.78-1478.91 mg Kg -1 for VN, and 1408.22-2071.45 mg Kg -1 for VDR, with a decrease of 15% and 32% respectively. The method allows an accurate quantification of EVOO phenols thus being useful to certify the nutraceutical properties of olive oil.

Aims: To investigate the prognostic value of the right ventricle-to-pulmonary artery (RV-PA) coupling in patients with either transthyretin (ATTR) or immunoglobulin light-chain (AL) cardiac amyloidosis (CA)., Methods and Results: Overall, 283 patients with CA from 3 Italian high-volume centres were included (median age 76 years; 63% males; 53% with ATTR-CA, 47% with AL-CA). The RV-PA coupling was evaluated by using the tricuspid annular plane systolic excursion/pulmonary artery systolic pressure (TAPSE/PASP) ratio. The median value of TAPSE/PASP was 0.45 (0.33-0.63) mm/mmHg. Patients with a TAPSE/PASP ratio <0.45 were older, had lower systolic blood pressure, more severe symptoms, higher cardiac troponin and N-terminal pro-B-type natriuretic peptide levels, greater left ventricular (LV) thickness, and worse LV systolic and diastolic function. A TAPSE/PASP ratio <0.45 was independently associated with a higher risk of all-cause death or heart failure (HF) hospitalization [hazard ratio (HR) 1.98, 95% confidence interval (CI) 1.32-2.96; P = 0.001] and all-cause death (HR 2.18, 95% CI 1.31-3.62; P = 0.003). The TAPSE/PASP ratio reclassified the risk of both endpoints [net reclassification index 0.46 (95% CI 0.18-0.74) P = 0.001 and 0.49 (0.22-0.77) P < 0.001, respectively], while TAPSE or PASP alone did not (all P > 0.05). The prognostic impact of the TAPSE/PASP ratio was significant both in AL-CA patients (HR for the composite endpoint 2.47, 95% CI 1.58-3.85; P < 0.001) and in ATTR-CA (HR 1.81, 95% CI 1.11-2.95; P = 0.017). The receiver operating characteristic curve showed that the optimal cut-off for predicting prognosis was 0.47 mm/mmHg., Conclusion: In patients with CA, RV-PA coupling predicted the risk of mortality or HF hospitalization. The TAPSE/PASP ratio was more effective than TAPSE or PASP in predicting prognosis., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Very small case series of patients with apolipoprotein A1 (ApoA1) amyloidosis are available., Methods: We described the clinical and echocardiographic characteristics of individuals with the pathogenic APOA1 variant Leu75Pro (p. Leu99Pro), referred for cardiac screening., Results: We enrolled 189 subjects, 54% men, median age 55 years (interquartile range 42-67), 39% with concomitant renal disease and 31% with liver disease. Median left ventricular ejection fraction was 60% (55-66). Overall, these subjects did not show overt diastolic dysfunction nor left ventricular (LV) hypertrophy. Age correlated with interventricular septal (IVS) thickness ( r  = 0.484), LV mass index ( r  = 0.459), E/e' ( r  = 0.501), and right ventricular free wall thickness ( r  = 0.594) (all p  < 0.001). Some individuals displayed red flags for cardiac amyloidosis (CA), and 14% met non-invasive criteria for CA. Twenty-nine subjects died over 5.8 years (4.1-8.0), with 10 deaths for cardiovascular causes. Individuals meeting echocardiographic criteria for CA had a much higher risk of all-cause death ( p  = 0.009), cardiovascular death ( p  = 0.001), cardiovascular death or heart failure (HF) hospitalisation ( p  < 0.001). Subjects with both renal and liver involvement had a more prominent cardiac involvement, and shortest survival., Conclusions: Subjects with the APOA1 Leu75Pro variant displayed minor echocardiographic signs of cardiac involvement, but 14% met echocardiographic criteria for CA. Subjects with suspected CA had a worse outcome.

Background: The present multicenter retrospective study on eltrombopag administration in Italian children with chronic ITP aims to extend follow-up of our previous study., Materials and Methods: This retrospective multicenter study was conducted in 17 centers affiliated to the Italian Association of Pediatric Hematology and Oncology (AIEOP). Patients were classified into three subgroups: group 1 included patients who discontinued treatment due to a stable platelet count; group 2 included patients who discontinued treatment due to ineffectiveness; group 3 included patients who did not permanently discontinue treatment., Results: 56 patients were eligible for analysis. The median duration of eltrombopag treatment was 40 months (7-71 months). Twenty patients (36%) discontinued permanently eltrombopag. The reasons of permanent discontinuation were adverse effects ( n = 1), inefficacy ( n = 10), stable platelet count ( n = 9). All patients of group 1 maintained a durable response without additional treatments after eltrombopag discontinuation. We found that patients of group 2 were on treatment for less time (median treatment time: 13.5 months, min: 6.0 - max: 56.0) than patients of group 1 (median treatment time: 34 months, min: 16.0 - max: 62.0) ( p < 0.05). Patients of group 2 mostly did not achieve a stable platelet count in the first 6 months of treatment and underwent concomitant therapies during follow-up respect of group 1 and group 3 ( p < 0.01)., Conclusion: Our study found that the benefits of eltrombopag treatment, in terms of platelet count improvement and use of additional therapies, are identifiable from the first 6 months of treatment., 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 Giordano, Lassandro, Barone, Cesaro, Fotzi, Giona, Gorio, Maggio, Miano, Marzollo, Nardi, Pession, Ruggiero, Russo, Saracco, Spinelli, Tolva, Tornesello, Palladino and Del Vecchio.)

Study Design: Spinal cord decompression in thoracolumbar burst fractures is challenging. Development of minimally invasive approaches and the improvement in new magnification technologies allowed a better and safer surgical treatment for these complex spinal injuries. We reported our experience in the minimally invasive surgical treatment of thoracolumbar burst fractures with spinal cord compression supported by high-definition (HD) three-dimensional (3D) Video-assisted telescope operating monitor (VITOM) or exoscope., Objectives: To assess the role and potential advantages of exoscope in the minimally invasive surgery of traumatic thoracolumbar spinal cord compression comparing traditional magnification systems., Setting: The study was conducted in a Northern Italy Spinal Trauma Center., Methods: We reported 10 consecutive thoracolumbar (T11-L2) burst fractures associated with spinal cord compression treated with minimally invasive corpectomy and exoscope-assisted spinal decompression. Three main indicators were retrospectively analyzed: surgical time, blood loss, and intraoperative complications. The data were compared with those obtained from an equal sample of 10 procedures performed by the same surgeon with the same technique, but traditional microscope assisted. User impressions in terms of ergonomics, magnification, and image quality were rated differently., Results: A small reduction of surgical time and blood loss were observed in the exoscope assisted group. There were no intraoperative complications attributed to visualization mode or conversion to the traditional microscope in any procedure. In our experience the exoscope allowed a better magnification and image definition with better ergonomics and user-friendliness., Conclusions: In our preliminary experience the exoscope new technology is a safe and effective tool for spinal cord minimally invasive decompression in thoracolumbar burst fractures. The stereoscopic vision provided by 3D images seems to be crucial in hand eye coordination. There are clear advantages in terms of maneuverability, wide field of view, deep focus, and more comfortable posture for the spinal surgeon., (© 2022. The Author(s).)

Aim: The objective is to carry out an analysis of the system of residences in Health in Argentina from the Theory of Complexity, in order to improve the understanding of the reality of this system, allowing an analysis to be carried out from another perspective different from the traditional., Source and Synthesis of Data: In this review, the properties and characteristics of the residence system are analyzed according to the new paradigm of the Science of Complexity. For those who make decisions about the residential training of young professionals, full knowledge of the system in a holistic way and reflection on the characteristics of an open system applied to the residential system is of great importance and, it gives (or can give off) great benefits and possible improvements for those who live the day to day of these training programs., Conclusions: It is important to mention the ultimate benefit that knowledge of the study system analyzed here has or can have: the possibility of multidisciplinarity, as one more step in the evolution of this type of system., (Universidad Nacional de Córdoba)

Lock-in amplifiers (LIA) are widely used in laboratory environments to detect low-amplitude signals buried in noise as well as real and imaginary parts of a complex quantity. They are based on the technique of synchronous detection, where the signal of interest is modulated into a desired frequency, sent to the medium or device to be analyzed, and captured by a detector. The detector scheme relies on the concept of phase-sensitive detection, generally resulting in two components: in-phase and quadrature. This article shows a very simple and low computational-cost way to implement a dual-phase LIA, using readily available microcontrollers, running a simple and fast algorithm. Three examples of signal detection are presented (sound wave signal, impedance meter, and weak signal recovery) to point out the flexibility and capabilities of the proposed methodology., (© 2023 Author(s). Published under an exclusive license by AIP Publishing.)

An increasing awareness of the disease, new diagnostic tools and novel therapeutic opportunities have dramatically changed the management of patients with amyloid transthyretin cardiomyopathy (ATTR-CM). Supportive therapies have shown limited benefits, mostly related to diuretics for the relief from signs and symptoms of congestion in patients presenting heart failure (HF). On the other hand, huge advances in specific (disease-modifying) treatments occurred in the last years. Therapies targeting the amyloidogenic cascade include several pharmacological agents that inhibit hepatic synthesis of TTR, stabilize the tetramer, or disrupt fibrils. Tafamidis, a TTR stabilizer that demonstrated to prolong survival and improve quality of life in the ATTR-ACT trial, is currently the only approved drug for patients with ATTR-CM. The small interfering RNA (siRNA) patisiran and the antisense oligonucleotide (ASO) inotersen have been approved for the treatment of patients with hereditary ATTR polyneuropathy regardless of the presence of cardiac involvement, with patisiran also showing preliminary benefits on the cardiac phenotype. Ongoing phase III clinical trials are investigating another siRNA, vutrisiran, and a novel ASO formulation, eplontersen, in patients with ATTR-CM. CRISPR-Cas9 represents a promising strategy of genome editing to obtain a highly effective blockade of TTR gene expression., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor (AP) declared a past co-authorship with the authors (DT and MM)., (© 2023 Tomasoni, Bonfioli, Aimo, Adamo, Canepa, Inciardi, Lombardi, Nardi, Pagnesi, Riccardi, Vergaro, Vizzardi, Emdin and Metra.)

Aims: Cardiac amyloidosis (CA) is due to a deposition of amyloid fibrils in the heart causing an increase in wall thickness. A left ventricular (LV) wall thickness ≥12 mm plus at least one red flag should raise the suspicion of CA. As normal values of LV wall thickness are lower in women, the adoption or the same cut-off values for men and women could lead to underdiagnosis or delayed diagnosis in women. We investigated the relationship between LV wall thickness and the severity of cardiac involvement in women and men with transthyretin (ATTR) CA., Methods and Results: We evaluated 330 consecutive patients diagnosed with ATTR-CA at three centres (Pisa, n = 232; Brescia, n = 69; Trieste, n = 29). Interventricular septum (IVS) and posterior wall (PW) thickness values were lower in women (n = 53, 16%) than men, but most differences were abolished when indexing by body surface area (BSA), height, or height 2.7 , suggesting similar disease severity when accounting for the smaller body size of women. PW thickness indexed for height 2.7 was even higher in women. We also searched for correlations between IVS and PW thickness and other indicators of the severity of cardiac disease. IVS values indexed by height 2.7 displayed tighter associations with N-terminal pro-B-type natriuretic peptide values than non-indexed IVS values. Similarly, indexed values displayed closer relationships with relative wall thickness, E/e' ratio, and tricuspid annular plane systolic excursion., Conclusions: Indexed LV wall thickness values, particularly by height 2.7 , reflect more accurately the severity of cardiac involvement than non-indexed values., (© 2023 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Pancreatic cancer (PC) represents the 6th cause of cancer death. Although the aetiology of PC is not completely understood, numerous risk factors have been identified in association with this cancer, among them diet. However, little is known about the association between the Mediterranean Diet (MedDiet) and the risk of PC. For this reason, we conducted a systematic review with meta-analysis according to the PRISMA guidelines, searching on three databases (PubMed/MEDLINE, Scopus, and EMBASE). The protocol was registered in PROSPERO. Both fixed and random effect models were performed. The Effect size was reported as a hazard ratio (HR) with a 95% Confidence Interval (CI). A total of eight articles were included. The methodological quality of the included meta-analyses was high. Our results show that a higher adherence to the MedDiet is associated with a lower risk of PC [HR:0.82 (0.76-0.88) p < 0.001, based on 1,301,320 subjects]. The results were also confirmed in sensitivity and subgroups analyses (avoidance of potential overlapping effects, type of tools used to assess dietary intake and the diagnosis of PC, prevalence and incidence of PC risk, country where the studies took place, sex, and cancer site). Promoting a higher adherence to the MedDiet could be an effective approach to reduce the risk of PC.

Cancer patients are at risk of several comorbid conditions, including nutritional issues and mental health illnesses. The objective of the current study was to estimate the prevalence, upon hospital admission, of depression and malnutrition among adults with cancer. A retrospective chart review was conducted using health information collected as part of routine assistance. Nutritional status was measured through structured tools, including body mass index (BMI), Nutrition Risk Screening (NRS) 2002, and dietary intake needs. Depression was assessed with the Hospital Anxiety and Depression Scale (HAD). Cancer site, disease stage, length of hospitalization, age, and sex were also considered. Multivariate analyses were used to investigate the association between malnutrition and depression. In summary, our study reveals that malnutrition increases the risk of depression among cancer patients. The findings can also be used in clinical oncology for the implementation of appropriate prevention and treatment interventions in order to reduce the extent of depression and thus improve cancer patients' quality of life and survival rate., Competing Interests: The authors declare no conflicts of interest.

Olive Phenols (OPs) are known to be potent antioxidants and possess various bioactivities and health benefits. Epidemiological studies suggested that consumption of olive oil reduces the risk of different diseases exerting a protective effect against certain malignant tumors (prostate, breast, digestive tract, endothelium, etc.). However, extremely low absorption rate of olive phenolic compounds restricts their bioactivity. In this context, solid lipid nanoparticles (SLNs) are a promising solution because they provide higher drug stability and can incorporate both lipophilic and hydrophilic drugs. Interesting experimental results have been obtained using hydroxytyrosol oleate (HtyOle) as a main component of a nanoparticle delivery system containing oleuropein (OL), oleuropein aglycone (3,4-DHPEA-EA), or hydroxytyrosol itself (Hty). In this work, hydroxytyrosol oleate (HtyOle) and hydroxytyrosol oleate (HtyOle)-based solid lipid nanoparticles were prepared and characterized. In addition, we evaluatedin vitro their antioxidant activity by DPPH assays and by ROS formation using the SH-SY5Y cell line., 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 © 2022 Elsevier B.V. All rights reserved.)

A cross-sectional study was designed to assess the impact of a celebrity's announcement of having been diagnosed with pancreatic cancer on the volume of cancer-related research on the Internet. Global searches were carried out on Google Trends (GT) for the period from 1 January 2004 to 20 November 2022 (since data prior to 2004 were not available) using the search words Tumore del Pancreas (pancreatic cancer), Tumore neuroendocrino (neuroendocrine tumor), and Fedez (the name of a popular Italian rapper). The frequency of specific page views for Fedez, Tumore del pancreas, and Tumore neuroendocrino was collected via Wikipedia Trends data. Statistical analyses were carried out using the Pearson correlation coefficient (r). The GT data revealed a strong correlation (r = 0.83) while the Wikipedia Trends data indicated a moderate correlation (r = 0.37) for Tumore neuroendocrino and Tumore del pancreas. The search peaks for the GT and Wikipedia pages occur during the same time period. An association was found between the celebrity's announcement of his pancreatic cancer diagnosis and the volume of pancreatic-cancer-related online searches. Our findings demonstrate that media events and media coverage of health-related news can raise people's curiosity and desire for health information.

Oleuropein plays a key role as a pro-oxidant as well as an antioxidant in cancer. In this study, the activity of oleuropein, in an in vitro model of ovarian (OCCs) and breast cancer cells (BCCs) was investigated. Cell viability and cell death were analyzed. Oxidative stress was measured by CM-H2DCFDA flow cytometry assay. Mitochondrial dysfunction was evaluated based on mitochondrial reactive oxygen species (ROS) and GPX4 protein levels. Further, the effects on iron metabolism were analyzed by measuring the intracellular labile iron pool (LIP). We confirmed that high doses of oleuropein show anti-proliferative and pro-apoptotic activity on HEY and MCF-7 cells. Moreover, our results indicate that low doses of oleuropein impair cell viability without affecting the mortality of cells, and also decrease the LIP and ROS levels, keeping them unchanged in MCF-7 cells. For the first time, our data show that low doses of oleuropein reduce erastin-mediated cell death. Interestingly, oleuropein decreases the levels of intracellular ROS and LIP in OCCs treated with erastin. Noteworthily, we observed an increased amount of ROS scavenging enzyme GPX4 together with a consistent reduction in mitochondrial ROS, confirming a reduction in oxidative stress in this model.

Background: The incidence of the highly morbid and potentially lethal gangrenous cholecystitis was reportedly increased during the COVID-19 pandemic. The aim of the ChoCO-W study was to compare the clinical findings and outcomes of acute cholecystitis in patients who had COVID-19 disease with those who did not., Methods: Data were prospectively collected over 6 months (October 1, 2020, to April 30, 2021) with 1-month follow-up. In October 2020, Delta variant of SARS CoV-2 was isolated for the first time. Demographic and clinical data were analyzed and reported according to the STROBE guidelines. Baseline characteristics and clinical outcomes of patients who had COVID-19 were compared with those who did not., Results: A total of 2893 patients, from 42 countries, 218 centers, involved, with a median age of 61.3 (SD: 17.39) years were prospectively enrolled in this study; 1481 (51%) patients were males. One hundred and eighty (6.9%) patients were COVID-19 positive, while 2412 (93.1%) were negative. Concomitant preexisting diseases including cardiovascular diseases (p < 0.0001), diabetes (p < 0.0001), and severe chronic obstructive airway disease (p = 0.005) were significantly more frequent in the COVID-19 group. Markers of sepsis severity including ARDS (p < 0.0001), PIPAS score (p < 0.0001), WSES sepsis score (p < 0.0001), qSOFA (p < 0.0001), and Tokyo classification of severity of acute cholecystitis (p < 0.0001) were significantly higher in the COVID-19 group. The COVID-19 group had significantly higher postoperative complications (32.2% compared with 11.7%, p < 0.0001), longer mean hospital stay (13.21 compared with 6.51 days, p < 0.0001), and mortality rate (13.4% compared with 1.7%, p < 0.0001). The incidence of gangrenous cholecystitis was doubled in the COVID-19 group (40.7% compared with 22.3%). The mean wall thickness of the gallbladder was significantly higher in the COVID-19 group [6.32 (SD: 2.44) mm compared with 5.4 (SD: 3.45) mm; p < 0.0001]., Conclusions: The incidence of gangrenous cholecystitis is higher in COVID patients compared with non-COVID patients admitted to the emergency department with acute cholecystitis. Gangrenous cholecystitis in COVID patients is associated with high-grade Clavien-Dindo postoperative complications, longer hospital stay and higher mortality rate. The open cholecystectomy rate is higher in COVID compared with non -COVID patients. It is recommended to delay the surgical treatment in COVID patients, when it is possible, to decrease morbidity and mortality rates. COVID-19 infection and gangrenous cholecystistis are not absolute contraindications to perform laparoscopic cholecystectomy, in a case by case evaluation, in expert hands., (© 2022. The Author(s).)

Aims: The HFA-PEFF and H 2 FPEF scores have been developed to diagnose heart failure with preserved ejection fraction (HFpEF), and hold prognostic value. Their value in patients with HFpEF caused by cardiac amyloidosis (CA) has never been investigated., Methods and Results: We evaluated the diagnostic and prognostic value of the HFA-PEFF and H 2 FPEF scores in 304 patients from three cohorts with HFpEF caused by transthyretin CA (n = 160, 53%) or immunoglobulin light-chain CA (n = 144, 47%). A diagnosis of HFpEF was more likely using the HFA-PEFF score with 2 (1%), 71 (23%), and 231 (76%) patients ranked as having a low (0-1), intermediate (2-4), or high (5, 6) probability of HFpEF, respectively. Conversely, 36 (12%), 179 (59%) and 89 (29%) of patients ranked as having a low (0-1), intermediate (2-5), or high (6-9) probability of HFpEF using the H 2 FPEF score. During a median follow-up of 19 months (interquartile range 8-40), 132 (43%) patients died. The HFA-PEFF score, but not the H 2 FPEF score, predicted a high risk of all-cause death which remained significant after adjustment for age, AL-CA diagnosis, high-sensitivity troponin T, N-terminal pro-B-type natriuretic peptide, and echocardiographic parameters, including left ventricular global longitudinal strain, left ventricular diastolic function and right ventricular function (hazard ratio 1.51, 95% confidence interval 1.16-1.95, p = 0.002 for every 1-point increase in HFA-PEFF)., Conclusions: The HFA-PEFF score has a higher diagnostic utility in HFpEF caused by CA and holds independent prognostic value for all-cause mortality, while the H 2 FPEF score does not., (© 2022 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Pancreatic cancer (PC) represents the third leading cause of cancer death in 2020. Despite the fact that, in 2018, the World Cancer Research Fund report concluded that there is still a lack of evidence on the role of foods or diets and risk for PC, a flourishing body of evidence has been published and needs to be analyzed. For this reason, we conducted an umbrella review on the association between different dietary patterns/food components and PC. Data sources PubMed/MEDLINE, Scopus, Web of Science, EMBASE, and the Cochrane Collaboration were searched. The Joanna Briggs Institute Umbrella Review Methodology was used. The protocol was registered in PROSPERO. A total of 23 articles were included, covering a wide range of dietary patterns/food components: healthy/prudent dietary patterns ( n = 4), Mediterranean diets (MedDiet) ( n = 1), plant-based diets ( n = 2), the Dietary Inflammatory Index (DII) ( n = 2), western diets ( n = 2), and, lastly, unhealthy diets ( n = 2). Regarding dietary components, the following were assessed: total fruit ( n = 2), citrus fruit ( n = 1), total vegetables ( n = 2), cruciferous vegetables ( n = 1), red meat ( n = 6), processed meat ( n = 4), poultry ( n = 2), eggs ( n = 1), fish ( n = 5), whole grain ( n = 2), potato ( n = 1), and nuts ( n = 2). The methodological quality of the included meta-analyses was generally low or critically low. Although the strength of evidence was generally weak, convincing or suggestive evidence was found for a healthy/prudent, plant-based diet, fruit and vegetables, and lower risk of PC, whereas a high intake of red meat was associated with a higher risk of PC at a convincing level of evidence. Further studies are needed to confirm the role of the other dietary patterns/food components and the risk of PC.

Malnutrition is a common clinical and public health problem that can frequently affect patients in hospital and community settings. In particular, cancer-related malnutrition results from a combination of metabolic dysregulation and anorexia, caused both by the tumor itself and by its treatment. Patients with head-neck cancer, or with gastroesophageal, pancreatic, lung, and colorectal cancer, are particularly at risk of developing malnutrition, with a prevalence varying between 30 and 50% depending on tumor location and anti-cancer treatment complications. Prevention and adequate management of malnutrition is now considered an essential key point of therapeutic pathways of patients with cancer, with the aim to enhance their quality of life, reduce complications, and improve clinical outcomes. Oral nutritional supplements (ONS) are part of the nutritional therapy and represent an effective tool to address cancer-related malnutrition, as supported by growing literature data. However, patients' access to ONS - which is regulated by different national and regional policies in terms of reimbursement - is quite heterogeneous. This narrative review aims to summarize the current knowledge about the role of ONS in terms of cost-effectiveness in the management of actively treated patients with cancer, following surgery and/or radiotherapy/chemotherapy treatment and to present the position on this issue of the Alliance Against Cancer, the Italian National Oncology Network, coming up from a focused virtual roundtable of the Survivorship Care and Nutritional Support Working Group., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Early activation of palliative care for patients with advanced cancer is central in the treatment trajectory. At the Veneto Institute of Oncology, a simultaneous-care outpatient clinic (SCOC) has been active since 2014, where patients are evaluated by an oncologist together with a palliative care team. Recently, we reported on consecutive patients admitted at SCOC from 2018 to 2021 in terms of appropriateness, process, and outcome indicators. Here, we report further analysis in the same group of 753 patients, evaluating other parameters and the correlation between symptom intensity, gender, age, and survival., Methods: SCOC data were retrieved from a prospectively maintained database., Results: Among the patients, 42.2% were women, and the median age was 68 years, with 46.7% of patients aged ≥70 years. The most prevalent disease type was gastrointestinal cancer (75.2%), and 90.9% of the patients had metastatic disease. The median score for the distress thermometer was 4; the vast majority of the patients (98.6%) reported physical problems, and 69.4% presented emotional issues. Younger women demonstrated a significantly greater median distress than other patients (p=0.0018). Almost all symptoms had a higher prevalence on the 0-3 Edmonton Symptom Assessment Scale (ESAS) score, except for fatigue. About 43.8% of the patients received systemic anticancer treatment (SAT) in the last 60 days of life, 15.0% of whom received SAT in the last month and 3.1% in the last 2 weeks. For some symptoms, women frequently had more ESAS >3. Pain and nausea were significantly less reported by older patients compared with younger adults. Men had a lower risk of having MUST score ≥ 2 (p=0.0311). Men and older patients showed a lower prognosis awareness (p=0.0011 and p=0.0049, respectively). Older patients received less SAT within the last 30 days of life (p=0.0006) and had death risk decreased by 20.0%., Conclusion: Our study identified two subgroups of patients with advanced cancer who require special attention and support due to important symptoms' burden detected by Patient Reported Outcome Measures tests: women and younger adults. These categories of patients require special attention and should be provided early access at SCOC. The role of an oncologist remains crucial to intercept all patients in need of early palliative care and balancing trade-offs of anticancer treatment in advanced metastatic disease., 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 © 2022 Galiano, Schiavon, Nardi, Guglieri, Pambuku, Martino, Bolshinsky, Murgioni, Intini, Soldà, Marino, Daniel, De Toni, Pittarello, Chiusole, Prete, Bimbatti, Nappo, Caccese, Bergamo, Brunello, Lonardi and Zagonel.)

Purpose: PERSEUS-IT (NCT02289924) was a prospective, observational, 2-year study evaluating the effectiveness and treatment patterns of intravitreal aflibercept (IVT-AFL) in patients with neovascular age-related macular degeneration (nAMD) in routine clinical practice in Italy., Methods: Treatment-naïve patients with nAMD receiving IVT-AFL per routine clinical practice were enrolled. The primary endpoint was mean change in visual acuity (VA; decimals) from baseline to month (M) 12 and M24. Outcomes were evaluated for the overall study population and independently for the 2 treatment cohorts: regular (3 initial monthly doses, ≥ 7 injections by M12, and ≥ 4 injections between M12 and M24) and irregular (any other pattern)., Results: Of 813 patients enrolled, 709 were included in the full analysis set (FAS); VA assessments were available for 342 patients at M12 (FAS1Y, 140 regular and 202 irregular) and 233 patients at M24 (FAS2Y, 37 regular and 196 irregular). In the overall FAS, the mean ± SD change in VA from baseline to M12 and M24 was + 0.09 ± 0.24 and + 0.02 ± 0.25 decimals, and there was a statistically significant difference between the regular and irregular cohorts in both FAS1Y (p = 0.0034) and FAS2Y (p = 0.0222). Ocular treatment-emergent adverse events were reported in 4.1% (n = 33/810 [safety set]) of patients., Conclusion: In PERSEUS-IT, clinically relevant functional and anatomic improvements were observed within the first 12 months of IVT-AFL treatment in routine clinical practice in Italy in patients with treatment-naïve nAMD. These gains were generally maintained across the 2-year study. The safety profile of IVT-AFL was consistent with prior studies., Trial Registration Number: ClinicalTrials.gov Identifier: NCT02289924., Date of Registration: November 13, 2014., (© 2022. The Author(s).)

There is evidence of an association between cancer and certain types of altered eating behaviors, including orthorexia, food cravings, and food addiction. Given the growing interest in the topic throughout the scientific community we conducted a systematic review to summarize current evidence on the development of altered food behavior, including food addiction and cancer. The Cochrane Collaboration and the Meta-analysis Of Observational Studies in Epidemiology guidelines were followed to perform this systematic review. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement was used to report the process and results. The structured literature search was conducted on 19 April 2022, on PubMed/Medline and Scopus, combining free-text terms and medical subject headings. A total of seven articles were included once the selection process was completed. Food craving has been associated with different types of cancer in adults and young patients, as well as with orthorexia; conversely, compulsive eating has only been explored in patients with prolactinoma treated with dopamine agonists. This systematic review explored a new area of research that warrants further investigation. More research is required to better understand the relationship between cancer and food behavior.

Objective: To evaluate the effectiveness, treatment patterns and long-term safety of ranibizumab 0.5 mg in treatment-naïve patients with central retinal vein occlusion (CRVO) in a real-world setting., Methods: LUMINOUS, a 5-year, global, prospective, multicentre, multi-indication, observational, open-label study, recruited treatment naïve or prior treated patients who were treated as per the local ranibizumab label. Here, we report the mean change in visual acuity (VA; Early Treatment Diabetic Retinopathy Study [ETDRS] letters), treatment exposure over year (Y) 1 and 5-year safety in treatment-naïve CRVO patients., Results: At baseline, the mean age of treatment-naïve CRVO patients (n = 327) was 68.9 years, with a mean (Standard deviation [SD]) VA of 40.6 (23.9) letters. At Y1, patients (n = 144) had a mean (SD) VA gain from baseline of 10.8 (19.66) letters, with a mean (SD) of 5.4 (2.65) ranibizumab injections. Patients demonstrated mean (SD) VA gains of 2.7 (19.35), 11.6 (20.56), 13.9 (18.08), 11.1 (18.46) and 8.2 (24.86) letters with 1, 2-3, 4-5, 6-8 and >8 ranibizumab injections, respectively. Mean (SD) VA gains at Y1 in patients receiving loading (67.4%) and no loading dose (32.6%) was 11.9 (20.42) and 8.4 (17.99) letters, respectively. Over five years, the incidence of ocular/non-ocular adverse events (AEs) and serious AEs was 11.3%/8.6% and 1.2%/6.7%, respectively., Conclusions: These results demonstrate the effectiveness of ranibizumab in treatment-naïve CRVO patients at Y1 with clinically meaningful VA gains and no new safety findings over five years. These findings may help inform routine practice and enable better clinical management to achieve optimal visual outcomes., (© 2021. The Author(s).)

Tandem mass spectrometry is proposed to check lipid oxidation, a free radical-mediated phenomenon which effects oxidative deterioration in polyunsaturated fatty acids. Antioxidants are used by the food industry to delay the oxidation process. This process can be controlled by antioxidants, which may occur as natural constituents of foods or may be intentionally added to products. Synthetic antioxidants such as BHT, BHA, and propyl gallate have been extensively used as antioxidants in the industry. The worldwide tendency to avoid or minimize the use of synthetic food additives has prompted the replacement of synthetic antioxidants with natural analogues. The entire process can be supported by the detection and characterization of the reacting species by suitable application of electrospray tandem mass spectrometry under collision-induced dissociation (ESI-CID-MS/MS). Natural antioxidants were tested in this study to check the oxidative stability of algae oil when adding the natural additive. Results were observed in algae oil in situ using electrospray mass spectrometry in tandem with collision-induced dissociation tandem mass spectrometry (ESI-CID-MS/MS) and the POBN spin trapper. The results indicate that alpha-tocopherol is a better antioxidant.

The need to develop alternative methods or to use "green" solvents constitutes an essential strategy under the emerging field of green chemistry, particularly in the development of new synthetic strategies in the field of pharmaceutic industry. We report an eco-friendly method of synthesis of poly(2-ethyl-2-oxazoline)-palmitoylate (PEtOz-PA) using Er(OTf) 3 as Lewis's acid catalyst in 2-MeTHF. The novel biomolecule derivative was characterized to confirm palmitoyl group substitution and employed for the formulation, characterization, and antioxidant activity evaluation of curcumin-loaded polymeric micelles.

Introduction: Stroke-like syndrome (SLS) is a rare subacute neurological complication of intrathecal or high-dose (≥500 mg) Methotrexate (MTX) administration. Its clinical features, evoking acute cerebral ischaemia with fluctuating course symptoms and a possible spontaneous resolution, have elicited interest among the scientific community. However, many issues are still open on the underlying pathogenesis, clinical, and therapeutic management and long-term outcome., Materials and Methods: We retrospectively analyzed clinical, radiological and laboratory records of all patients diagnosed with SLS between 2011 and 2021 at 4 National referral centers for Pediatric Onco-Hematology. Patients with a latency period that was longer than 3 weeks between the last MTX administration of MTX and SLS onset were excluded from the analysis, as were those with unclear etiologies. We assessed symptom severity using a dedicated arbitrary scoring system. Eleven patients were included in the study., Results: The underlying disease was acute lymphoblastic leukemia type B in 10/11 patients, while fibroblastic osteosarcoma was present in a single subject. The median age at diagnosis was 11 years (range 4-34), and 64% of the patients were women. Symptoms occurred after a mean of 9.45 days (± 0.75) since the last MTX administration and lasted between 1 and 96 h. Clinical features included hemiplegia and/or cranial nerves palsy, paraesthesia, movement or speech disorders, and seizure. All patients underwent neuroimaging studies (CT and/or MRI) and EEG. The scoring system revealed an average of 4.9 points (± 2.3), with a median of 5 points (maximum 20 points). We detected a linear correlation between the severity of the disease and age in male patients., Conclusions: SLS is a rare, well-characterized complication of MTX administration. Despite the small sample, we have been able to confirm some of the previous findings in literature. We also identified a linear correlation between age and severity of the disease, which could improve the future clinical management., 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 © 2022 Santangelo, Bartolini, Nuzzi, Foiadelli, Michev, Mina, Trambusti, Fichera, Bonuccelli, Massimetti, Peroni, De Marco, Coccoli, Luti, Bernasconi, Nardi, Menconi, Casazza, Pruna, Mura, Marra, Zama, Striano, Cordelli, Battini and Orsini.)

Benefits of early palliative care referral in oncology are well-validated. At the Veneto Institute of Oncology-IRCCS, a simultaneous-care outpatient clinic (SCOC) has been active since 2014, where patients with advanced cancer are evaluated by an oncologist together with a palliative care team. We prospectively assessed SCOC patients’ characteristics and SCOC outcomes through internal procedure indicators. Data were retrieved from the SCOC prospectively maintained database. There were 753 eligible patients. The median age was 68 years; primary tumor sites were gastrointestinal (75.2%), genitourinary (15.0%) and other sites (9.8%). Predominant symptoms were psychological issues (69.4%), appetite loss (67.5%) and pain (65.9%). Dyspnea was reported in 53 patients (7%) in the referral form, while it was detected in 226 patients (34.2%) during SCOC visits (p < 0.0001). Median survival of patients after the SCOC visit was 7.3 months. Survival estimates by the referring oncologist were significantly different from the actual survival. Psychological intervention was deemed necessary and undertaken in 34.6% of patients, and nutritional support was undertaken in 37.9% of patients. Activation of palliative care services was prompted for 77.7% of patients. Out of 357 patients whose place of death is known, 69.2% died at home, in hospice or residential care. With regard to indicators’ assessment, the threshold was reached for 9 out of 11 parameters (81.8%) requested by the procedure. This study confirmed the importance of close collaboration between oncologists and palliative care teams in responding properly to cancer patients’ needs. The introduction of a procedure with indicators allowed punctual assessment of a team’s performance.

Purpose: The purpose of this paper is to present a new surgical technique to remove vitreous cortex remnants., Methods: Non-consecutive retrospective interventional case series., Results: When the posterior vitreous is split, its outermost layer may remain attached to the retina, developing vitreoschisis-induced vitreous cortex remnants (VCR). Their role in macular pathology etiopathogenesis has been well documented; however, recently, it has been proposed that VCR also play a crucial role in proliferative vitreoretinopathy and consequent retinal redetachment. The prevalence of VCR is underestimated because triamcinolone acetonide is not routinely used for vitreous staining. Vitreous cortex remnants (VCR) removal is challenging, and several surgical techniques have been proposed. However, they require sclerotomy enlargement, material that may not be readily available, and manual fashioning. Alternatively, a diamond-dusted membrane scraper (DDMS), already widely used in macular pathology treatment, can follow the contour of the retina, as it is a silicone tube, and remove VCR with its abrasive tip. A DDMS may also be introduced in the vitreous cavity through a standard trocar. Finally, the use of a DDMS provides predictable feedback, making the learning curve short. In this case series, 34 eyes affected by primary rhegmatogenous retinal detachment were enrolled. The retinal redetachment rate was 2.9% at six months of follow-up, below the average literature value of 21%. No adverse events were reported., Conclusion: A DDMS can be suitable for use in VCR removal, although further studies are warranted to understand the indications and extent of this surgical technique for improving the management of rhegmatogenous retinal detachment., (© 2021 The Authors. Acta Ophthalmologica published by John Wiley & Sons Ltd on behalf of Acta Ophthalmologica Scandinavica Foundation.)

Purpose: To evaluate the 10-year follow-up efficacy and safety of gold micro shunt (GMS) in patients with refractory glaucoma, and the potential risk factors for failure., Methods: Retrospective data analyses based on medical records from 55 patients who underwent GMS implant for refractory glaucoma between March 2007 and April 2008. The primary outcome measure was the cumulative probability of success defined as intraocular pressure (IOP) below 21 mmHg together with a 33% lowering of the baseline IOP with (qualified) or without (complete) topical medications, no reoperation for glaucoma or loss of light perception., Results: Mean IOP 10 years after the GMS implantation was 21.6 ± 5.1 mmHg with 2.7 ± 0.7 drugs. Qualified success was achieved in 8/55 patients (14.5%) with a mean of 2.9 ± 0.8 drugs at 5 years and in 2/55 patients (3.6%) with a mean of 2.7 ± 1.0 drugs at 10 years. None of the patients reached complete success at five years from surgery. The cumulative probability of complete success was 14%, 9% and 0% at 1, 2 and 5 years, respectively, and 72%, 67%, 36% and 3.6% at 1, 2, 5 and 10 years, respectively, for qualified success criterion. Baseline IOP for complete success, number of baseline medication for qualified success and age at the time of GMS implantation for both criteria were risk factors significantly associated with failure., Conclusion: A very low long-term survival rate of GMS in refractory glaucoma was found. Most patients did not reach the IOP success criteria of the study, even with the re-introduction of medications, leading to the need for further surgical procedures., (© 2021 The Authors. Acta Ophthalmologica published by John Wiley & Sons Ltd on behalf of Acta Ophthalmologica Scandinavica Foundation.)

The aim of this study was to determine if the risk of neurological injury to the inferior alveolar nerve (IAN) and the lingual nerve (LN) following the extraction of lower third molars is affected by the anesthetic modality (local anesthesia (LA) vs. general anesthesia (GA)). A systematic search was performed through the PubMed, Scopus, Cochrane Library, and Web of Science databases; furthermore, a manual search was performed by analyzing the references of full-text articles. From a total of 309 studies (collected after the removal of duplicates), 6 studies were selected. Of these, 4 reported a correlation between GA and nerve damage, while the other 2 did not show an obvious association. The level of bias in the studies was also calculated. Only 2 studies showed a medium risk of bias, while 4 studies showed a high risk of bias; no study showed a low risk of bias. Four of the 6 studies highlighted a higher incidence of IAN and LN injury following the extractions performed under GA. Although no scientific evidence is yet available, due to the scarcity and the limited quality of the studies in the literature, considering the risk–benefit ratio, LA should be the first choice in lower third molar surgery.

Posterior Reversible Encephalopathy Syndrome (PRES) is characterized by acute neurological symptoms with typical imaging features, primarily in the territories of the brain supplied by the posterior circulation, probably due to vasogenic edema. Both clinical and imaging features are generally reversible. We report a 13-year-old girl affected by Nodular Sclerosis Classical Hodgkin Lymphoma stage IIIB into complete remission, with a recurrence and autologous bone-marrow transplantation, who has been treated with an anti-CD30 monoclonal antibody, brentuximab-vedotin. The girl has suddenly presented a convulsive status epilepticus, that needed intubation and sedation. Therefore, an IV therapy with levetiracetam was started. Furthermore, the girl has presented high blood pressure and reduced kidney function. Brain MRI demonstrated a diffuse PRES-like disease, that went into regression after the first week. After another week, the girl presented a new prolonged generalized tonic clonic convulsive episode, that needed intubation and sedation and an association of clobazam and levetiracetam: a new brain MRI showed a recurrence of PRES-like lesions in addition to some signs of leukoencephalopathy with brain lactate accumulation on 1H-MRS, due to cerebral energetic failure. The girl also presented a refractory arterial hypertension. After 45 days of ICU hospitalization the patient has been discharged and followed up with neurological examinations. Brain MRI and brain 1H-MRS, 5 months after patient's discharge, showed incomplete regression of cerebral white matter signal abnormalities with MRS normalization.

The benzimidazole ring of the heterocyclic pharmacophores is one of the most widespread and studied systems in nature. The benzimidazole derivative synthesis study is a crucial point for the development of a clinically available benzimidazole-based drug. Here, we report a simple microwave assisted method for the synthesis of 1,2-disubstituted benzimidazoles. The combination of the molar ratio of N -phenyl- o -phenylenediamine:benzaldehyde (1:1) using microwave irradiation and only 1% mol of Er(OTf) 3 provides an efficient and environmental mild access to a diversity of benzimidazoles under solvent-free conditions. The proposed method allows for the obtainment of the desired products in a short time and with very high selectivity.

Objective: The extent to which mononuclear cells and TSH-receptor autoantibodies (TRAb) contribute to Graves' orbitopathy (GO) is not completely defined. Here we investigated the relationship between the immunohistochemical phenotype of orbital infiltrating cells and GO features in a large number of patients., Methods: We conducted an observational cohort study in 76 consecutive patients with GO (16 men and 60 women) who underwent orbital decompression over a period of 18 consecutive months. An ophthalmological evaluation was performed in all patients, as well as immunohistochemistry for CD3, CD4, CD8, CD56 (T-cell markers), CD25 (T and B-cell marker), CD20, CD19 (B-cell markers), and CD138 (plasmacell marker) in specimens collected at decompressive surgery., Results: Having established cutoff values for each marker, cell infiltrates were found in 60 patients (78.9%; CD3: 39.4%, CD4 55.2%, CD8 50%, CD56: 0%, CD25: 28.9%, CD20: 51.3%, CD19: 25%, CD138: 26.3%). Eleven (14.4%) stained exclusively for CD138 (plasmacells). Patients with CD4-positive mononuclear cells had a significantly greater GO clinical activity score (CAS) (mean difference 1.07, 95% CI - 0.33 to - 1.82, P = 0.004 by univariate, P = 0.05 by multivariate analysis). CAS as well as the remaining GO features were not affected significantly by the mononuclear cell subpopulations in multivariate analyses., Conclusions: Mononuclear cell infiltrates are present in the majority of GO patients, with a small percentage represented exclusively by plasmacells. CD4 cells exert a major role on GO activity. These findings may represent a further advancement in the comprehension of GO pathogenesis., (© 2021. Italian Society of Endocrinology (SIE).)

The careful mapping of photoinduced reversible-deactivation radical polymerizations (RDRP) is a prerequisite for their applications in soft matter materials design. Here, we probe the wavelength-dependent behavior of photochemically induced atom transfer radical polymerization (ATRP) using nanosecond pulsed-laser polymerization (PLP). The photochemical reactivities at identical photon fluxes of methyl acrylate in terms of conversion, number-average molecular weight, and dispersity of the resulting polymers are mapped against the absorption spectrum of the copper(II) catalyst in the range of 305-550 nm. We observe a red shift of the action spectrum relative to the absorption spectrum of the copper(II) catalyst. Both the number-average molecular weight and the dispersity show a wavelength dependence, while the molecular weight and conversion remain linearly correlated. The reported data allow the judicious selection of optimum wavelengths for photoATRP.

Objective: Graves' orbitopathy (GO) reflects an autoimmune response against antigens expressed by the thyroid and orbital tissues. Elimination of thyroid antigens may be beneficial for GO. Total thyroid ablation (TTA) [thyroidectomy (Tx), followed by 30 mCi of radioiodine] was shown to exert a beneficial effect on GO following intravenous glucocorticoids (ivGC) compared with Tx alone. Here, we investigated retrospectively whether TTA performed with a 15 mCi of radioiodine still maintains advantages over Tx., Methods: Thirty-two subjects, 13 treated with TTA (performed with 15 mCi of radioiodine) and 19 with Tx alone, all with moderately severe, active GO, treated with ivGC, were studied. The primary objective was the outcome of GO at 24 weeks based on a composite evaluation., Results: The two groups did not differ at baseline in terms of sex, age, smoking habits, TSH, anti-TSH receptor autoantibodies, GO duration and eye features. The proportion of GO responders at 24 weeks was greater in the TTA (61.5%) than in the Tx group (26.3%, P = 0.046). In contrast, GO outcome at 48 weeks did not differ between the two groups (69.2% vs 52.6% of responder in TTA and Tx group, respectively). The outcome of the individual GO features did not differ between the two groups both a 24 and 48 months., Conclusions: The advantage of total thyroid ablation seems to be a more rapid response for GO to ivGC treatment. Prospective, randomized studies in a larger number of subjects are needed to confirm our findings., (© 2021. The Author(s).)

The burden of pancreatic cancer varies greatly across countries, with the number of deaths, incident cases, and disability-adjusted life years more than doubling in recent years, and with high-income countries having the highest incidence and mortality rates. We conducted this systematic review with meta-analysis with the goal of summarizing the current evidence on dietary fiber intake and its role in reducing the risk of pancreatic cancer, given the importance of identifying risk factors. This systematic review followed the guidelines of the Cochrane Collaboration and the Meta-analysis of Observational Studies in Epidemiology and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020. The structured literature search was conducted on PubMed/Medline and Scopus, combining free text words and medical subject headings. Our review contained 18 records at the end of the process. Our results show that dietary fiber intake reduces the risk of pancreatic cancer. When the analysis was differentiated according to the type of fiber considered, sub-grouped by gender (reduction of around 60% among women), and when case-control studies were conducted, the strength of the association increased. Clinicians and policymakers should improve interventions to raise the population's awareness regarding the consumption of high-fiber diets, both in practice and in terms of public health policy.

Background: A protective action of statins on development of Graves' orbitopathy suggests that statins might be used for treatment of the disease. We aimed to assess the efficacy of the addition of a statin, atorvastatin, to intravenous glucocorticoids (ivGCs) on Graves' orbitopathy outcomes in patients with hypercholesterolaemia., Methods: We did a randomised, open-label, phase 2, adaptive, clinical trial at a single, tertiary, referral hospital in Pisa, Italy. Patients with moderate-to-severe, active Graves' orbitopathy, with a low-density lipoprotein cholesterol concentration between 2·97 and 4·88 mmol/L were eligible for inclusion. Patients were randomly assigned (1:1) in 11 blocks of eight, using a computer-based system, to the ST group or the NST group. The ST group received ivGCs (methylprednisolone 500 mg once a week for 6 weeks followed by 250 mg once a week for an additional six weeks) for 12 weeks and oral atorvastatin (20 mg once a day) for 24 weeks. The NST group only received the ivGC regimen. Patients were unmasked to group allocation; however, the ophthalmological investigator was masked to randomisation. The primary endpoint was the Graves' orbitopathy outcome (composite evaluation of exophthalmos, clinical activity score, eyelid aperture, and diplopia) at 24 weeks in the modified intention-to-treat (ITT) population (patients who attended the week 12 visit). Patients were considered responders when at least two of the following criteria were fulfilled in the most affected eye, without worsening in any of the same measures in both eyes: (1) reduction in exophthalmos of 2 mm or more, with no increase by 2 mm or more in the other eye; (2) reduction of clinical activity score by two or more points; (3) reduction in eyelid aperture by 2 mm or more, with no increase by 2 mm or more in the other eye; and (4) disappearance or improvement (change from constant to inconstant, intermittent, or absent, or from inconstant to intermittent or absent) of diplopia, and (5) improvement in visual acuity by 0·2 decimals or more. The trial is registered with EUDRACT, 2018-001317-33, and ClinicalTrials.gov, NCT03110848., Findings: Between June 1, 2020, and Nov 30, 2020, 119 patients were screened for inclusion, of whom 88 (74%) patients were enrolled and randomly assigned to one of the two treatment groups (44 [50%] to the ST group and 44 [50%] to the NST group). Eight (9%) patients did not attend the 12 week visit; 80 (91%) patients (18 [23%] men and 62 [78%] women) were included in the modified ITT population (41 [51%] in the ST group and 39 [49%] in the NST group]. The proportion of Graves' orbitopathy composite evaluation responders at 24 weeks was higher in the ST group (21 [51%] of 41 patients) than the NST group (11 [28%] of 39 patients; attributable risk 0·23 [95% CI 0·02-0·44]; p=0·042). 26 adverse events occurred in 21 (24%) of 88 patients in the safety population. One (2%) of 44 patients in each group required treatment discontinuation, with no serious adverse events and no difference between groups., Interpretation: Addition of oral atorvastatin to an ivGC regimen improved Graves' orbitopathy outcomes in patients with moderate-to-severe, active eye disease who were hypercholesterolaemic. Future phase 3 studies, which could potentially recruit patients regardless of low-density lipoprotein cholesterol concentration, are required to confirm this association., Funding: Associazione Allievi Endocrinologia Pisana., Competing Interests: Declaration of interest We declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: The purpose of this prospective study was to evaluate the efficacy and safety of the Ultrasound Cyclo Plasty (UCP) procedure using high-intensity focused ultrasound in surgery-naïve open-angle glaucoma patients., Methods: prospective, non-randomized, single-arm, multicenter clinical trial. Sixty-six eyes with primary open-angle glaucoma, intraocular pressure (IOP) ≥21 mmHg and with no history of filtering surgery were enrolled. Patients were treated by UCP with a therapy probe comprising six piezoelectric transducers, consecutively activated for 8 s each. Complete ophthalmic examination was performed before the procedure, 1 day after the procedure, and 1, 3, 6, 12, 18 and 24 months after the procedure. Primary outcomes were complete success (defined as IOP lowering from baseline ≥20% without additional glaucoma medications) and vision-threatening complications. Secondary outcomes were the presence of complications and the reduction of the number of medications used., Results: IOP was significantly reduced after one procedure ( p < 0.05), from a mean pre-operative value of 24.3 ± 2.9 mmHg (n = 2.3 hypotensive medications) to a mean value of 15.9 ± 3.6 mmHg (n = 2.2 hypotensive medications) at 2 years (mean IOP lowering of 33%). Surgical success was achieved in 74% of eyes. Notwithstanding side effects such as transient anterior chamber inflammation, refractive error changes, transient hypotony and macular edema, no major intra or post-operative complications such as phthisis, induced cataract, neovascularization or significant vision loss were observed., Conclusions: Ultrasound Cyclo Plasty is a valuable, effective and well-tolerated procedure to lower IOP in patients with open-angle glaucoma without previous filtering surgery.

We obtained data from Google Trends and Wikipedia in order to assess whether an analysis of Internet searches could provide information on the Internet users' behaviour/interest in diets. Differences in seasonality, year and before/during COVID-19 pandemic were assessed. From Wikipedia, we extracted the number of times a page is viewed by users, aggregated on monthly and seasonal bases. We also used Google Trends to evaluate the frequency of the users' web searches. The Mediterranean diet was the most frequently (33.9%), followed by the pescatarian diet (9.0%). Statistically, significant seasonal differences were found for the Mediterranean, vegetarian, Atkins, Scarsdale, and zone diets and pescetarianism. The most commonly searched diet and consequent diet-related queries on Google resulted to be: Dukan diet, Dukan and weight loss. Ketogenic, FODMAP and intermittent fasting diets were statistically more frequently searched during the pandemic compared with before. Our data show a different trend of searches based on the seasonality, year and the pandemic. These data could be useful for scientists, practitioners and policy makers because they can inform educational campaigns via the Internet, especially in periods when the population is more receptive.