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Objectives: Respiratory syncytial virus (RSV) is a frequent cause of acute lower respiratory infection in children, imposing a substantial economic burden on healthcare systems. This systematic review aimed to assess the economic burden and healthcare utilisation of RSV in children aged 0-59 months in Italy., Study Design: Systematic review., Methods: A systematic search of PubMed, Embase, Scopus, and the International HTA Database, including studies published in English or Italian, was conducted between January 2000 and July 2022. Inclusion criteria required studies to be conducted in Italy and provide data on the economic costs and healthcare resource utilisation related to RSV infections., Results: Out of 20,845 records screened, 18 articles met the inclusion criteria. Only one study provided comprehensive data on RSV disease costs, including hospitalisation, diagnostic tests, and medical procedures for infants with RSV-bronchiolitis. The mean cost per inpatient was higher for RSV-positive children (€5753.43 ± €2041.62) than that for RSV-negative children. Additionally, five studies reported a median length of hospital stay of 5 days for RSV-infected children, and four studies indicated a higher frequency of intensive care unit admissions for RSV-infected children than for those with other viral infections., Conclusions: This is the first systematic review to examine the economic burden and healthcare utilisation of RSV in children aged 0-59 months in Italy. While limited data were available, the findings underscore the urgency to conduct further research and gather additional evidence on the costs and healthcare resource utilisation associated with RSV infections. Such efforts are essential for informing the development of effective prevention strategies for paediatric RSV infections in Italy., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Myelodysplastic Syndromes, a heterogeneous group of hematological disorders, are characterized by abnormalities in phosphoinositide-dependent signaling, epigenetic regulators, apoptosis, and cytokine interactions within the bone marrow microenvironment, contributing to disease pathogenesis and neoplastic growth. Comprehensive knowledge of these pathways is crucial for the development of innovative therapies that aim to restore normal apoptosis and improve patient outcomes., Competing Interests: Declaration of competing interest The authors have not conflicts of interest to declare., (Copyright © 2024. Published by Elsevier Ltd.)

Background: The aims of this study were to quantify the histological improvement and its risk factors in patients with NASH enrolled in the placebo arms of randomized controlled trials (RCTs), and to indirectly compare the effect of several investigational drugs for NASH on validated histological outcomes., Data Synthesis: A comprehensive search was conducted to detect phase 2 and 3 RCTs comparing pharmacological interventions in patients with NASH. According to Food and Drug Administration (FDA) recommendations, primary outcomes included: 1) NASH resolution without worsening of fibrosis; 2) At least 1-point reduction in fibrosis without worsening of NASH. Meta-analysis and meta-regressions were conducted on placebo arms, while network meta-analysis was performed on intervention arms. A total of 15 RCTs met the eligibility criteria. The meta-analysis on placebo arms showed a pooled estimate rate of 17% (95%C.I. 12%-23%;I 2  = 86%; p < 0.01) for NASH resolution without worsening of fibrosis and of 21% (95%C.I. 13%-31%;I 2  = 84%; p < 0.01) for ≥1stage improvement of fibrosis without worsening of NASH. Phase 3 (vs Phase 2)RCTs, older age and higher AST levels were significantly associated with progression of liver disease by univariate meta-regression. At network meta-analysis, Semaglutide (P-score 0.906), Pioglitazione alone (score 0.890) and plus Vitamin E (0.826) had the highest probability of being ranked the most effective intervention for NASH resolution without worsening of fibrosis, while Aldafermin (0.776), Lanifibranor (0.773) and Obeticholic acid (0.771) had the highest probability to achieve ≥1 stage of fibrosis improvement without worsening of NASH., Conclusion: This study confirms the heterogeneity of histological progression of untreated patients with NASH and provides evidence to stratify patients according to identified risk factors in future RCTs of combination therapies. PROSPERO CRD42021287205., Competing Interests: Declaration of competing interest None., (Copyright © 2022 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Introduction: Systemic sclerosis (SSc) is characterized by a complex etiopathogenesis encompassing both host genetic and environmental -infectious/toxic- factors responsible for altered fibrogenesis and diffuse microangiopathy. A wide spectrum of clinical phenotypes may be observed in patients' populations from different geographical areas. We investigated the prevalence of specific clinical and serological phenotypes in patients with definite SSc enrolled at tertiary referral centres in different Italian geographical macro-areas. The observed findings were compared with those reported in the world literature., Materials and Methods: The clinical features of 1538 patients (161 M, 10.5%; mean age 59.8 ± 26.9 yrs.; mean disease duration 8.9 ± 7.7 yrs) with definite SSc recruited in 38 tertiary referral centres of the SPRING (Systemic sclerosis Progression INvestiGation Group) registry promoted by Italian Society of Rheumatology (SIR) were obtained and clustered according to Italian geographical macroareas., Results: Patients living in Southern Italy were characterized by more severe clinical and/or serological SSc phenotypes compared to those in Northern and Central Italy; namely, they show increased percentages of diffuse cutaneous SSc, digital ulcers, sicca syndrome, muscle involvement, arthritis, cardiopulmonary symptoms, interstitial lung involvement at HRCT, as well increased prevalence of serum anti-Scl70 autoantibodies. In the same SSc population immunusppressive drugs were frequently employed. The review of the literature underlined the geographical heterogeneity of SSc phenotypes, even if the observed findings are scarcely comparable due to the variability of methodological approaches., Conclusion: The phenotypical differences among SSc patients' subgroups from Italian macro-areas might be correlated to genetic/environmental co-factors, and possibly to a not equally distributed national network of information and healthcare facilities., 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. Published by Elsevier B.V.)

Breast conserving surgery (BCS) plus radiation therapy (RT) or mastectomy have shown comparable oncological outcomes in early-stage breast cancer and are considered standard of care treatments. Postmastectomy radiation therapy (PMRT) targeted to both the chest wall and regional lymph nodes is recommended in high-risk patients. Oncoplastic breast conserving surgery (OBCS) represents a significant recent improvement in breast surgery. Nevertheless, it represents a challenge for radiation oncologists as it triggers different decision-making strategies related to treatment volume definition and target delineation. Hence, the choice of the best combination and timing when offering RT to breast cancer patients who underwent or are planned to undergo reconstruction procedures should be carefully evaluated and based on individual considerations. We present an Italian expert Delphi Consensus statements and critical review, led by a core group of all the professional profiles involved in the management of breast cancer patients undergoing reconstructive procedures and RT. The report was structured as to consider the main recommendations on breast reconstruction and RT and analyse the current open issues deserving investigation and consensus. We used a three key-phases and a Delphi process. The final expert panel of 40 colleagues selected key topics as identified by the core group of the project. A final consensus on 26 key statements on RT and breast reconstruction after three rounds of the Delphi voting process and harmonisation was reached. An accompanying critical review of available literature was summarized. A clear communication and cooperation between surgeon and radiation oncologist is of paramount relevance both in the setting of breast reconstruction following mastectomy when PMRT is planned and when extensive glandular rearrangements as OBCS is performed. A shared-decision making, relying on outcome-based and patient-centred considerations, is essential, while waiting for higher level-of-evidence data., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The rapid onset and worldwide spread of the COVID-19 epidemic (caused by SARS-CoV-2 coronavirus) has been associated with a profound impact in clinical practice also in the hematologic setting. First of all, given the immunosuppressive effect of many therapies that are normally administered to patients with hematological diseases, with a consequent increased risk of contracting a more severe viral infection, it has been necessary to reconsider in each individual patient the urgency and priority of the treatments foreseen by the normal standards of care. In particular, as regards allogeneic (and to a lesser extent autologous) hematopoietic cell transplantation and CAR T-cell therapy, specific recommendations have been issued by the transplant community on the criteria to be used to decide whether or not to postpone these procedures and on the clinical management of recipients and donors exposed to COVID-19. As to cytotoxic chemotherapy and other antineoplastic therapies, criteria have been proposed to decide, in the various clinical situations, which treatments were not deferrable and which instead could be postponed or replaced by less aggressive therapies. In the outpatient clinics, various organizational solutions for telemedicine have been adopted, resorting to telephone interviews and/or Information Technology, with the aim of reducing the influx of patients while maintaining an adequate control of their clinical condition. The collection of blood by the transfusion centers has been the subject of organizational measures, in order to avoid the transmission of COVID 19 while maintaining a sufficient blood collection for clinical needs. Finally, some hematologic laboratory alterations have been identified, such as thrombocytopenia, lymphopenia and coagulation abnormalities, useful for the prognostic evaluation of infected patients., (Copyright © 2020. Published by Elsevier Ltd.)

Background & Aims: Hepatocyte polarity is essential for the development of bile canaliculi and for safely transporting bile and waste products from the liver. Functional studies of autologous mutated proteins in the context of the polarized hepatocyte have been challenging because of the lack of appropriate cell models. The aims of this study were to obtain a patient-specific hepatocyte model that recapitulated hepatocyte polarity and to employ this model to study endogenous mutant proteins in liver diseases that involve hepatocyte polarity., Methods: Urine cell-derived pluripotent stem cells, taken from a patient with a homozygous mutation in ATP7B and a patient with a heterozygous mutation, were differentiated towards hepatocyte-like cells (hiHeps). HiHeps were also derived from a patient with MEDNIK syndrome., Results: Polarized hiHeps that formed in vivo-like bile canaliculi could be generated from embryonic and patient urine cell-derived pluripotent stem cells. HiHeps recapitulated polarized protein trafficking processes, exemplified by the Cu 2+ -induced redistribution of the copper transporter protein ATP7B to the bile canalicular domain. We demonstrated that, in contrast to the current dogma, the most frequent yet enigmatic Wilson disease-causing ATP7B-H1069Q mutation per se did not preclude trafficking of ATP7B to the trans-Golgi Network. Instead, it prevented its Cu 2+ -induced polarized redistribution to the bile canalicular domain, which could not be reversed by pharmacological folding chaperones. Finally, we demonstrate that hiHeps from a patient with MEDNIK syndrome, suffering from liver copper overload of unclear etiology, showed no defect in the Cu 2+ -induced redistribution of ATP7B to the bile canaliculi., Conclusions: Functional cell polarity can be achieved in patient pluripotent stem cell-derived hiHeps, enabling, for the first time, the study of the endogenous mutant proteins, patient-specific pathogenesis and drug responses for diseases where hepatocyte polarity is a key factor., Lay Summary: This study demonstrates that cells that are isolated from urine can be reprogrammed in a dish towards hepatocytes that display architectural characteristics similar to those seen in the intact liver. The application of this methodology to cells from patients diagnosed with inherited copper metabolism-related liver diseases (that is, Wilson disease and MEDNIK syndrome) revealed unexpected and novel insights into patient mutation-specific disease mechanisms and drug responses., (Copyright © 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Purpose: Timely training was urgently needed at the onset of the 2014 Ebola virus disease epidemic. Massive open online courses (MOOCs) have grown in popularity, though little is known about their utility in time-sensitive situations, including infectious disease outbreaks., Methods: We created the first English language massive open online course on Ebola virus disease. Designed by a team representing various units of Emory University and six partner institutions, the six module course was aimed at a global general audience but also relevant for health care professionals., Results: Over 7,000 learners from 170 countries participated in the initial course offering. More than a third of learners were from emerging economies, including seven percent from Africa, and another 13% from countries outside the United States who received individuals requiring treatment for Ebola virus disease., Conclusions: Creating and producing the first English language MOOC on EVD in a short time period required effective collaboration and strong coordination between subject matter and course development experts from Emory. Through these collaborative efforts, the development team was able to provide urgently needed training and educational materials while the epidemic of EVD continued to radiate through West Africa., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Platinum-based chemoradiation (CCRT) is the standard treatment for Locally Advanced Head and Neck Squamous-Cell Carcinoma (LAHNSCC). Cetuximab/RT (CET/RT) is an alternative treatment option to CCRT. The efficacy of induction chemotherapy (IC) followed by chemoradiation compared to chemoradiation alone has not been demonstrated in randomized clinical trials. The goals of this phase II-III trial were to assess: (i) the overall survival (OS) of IC versus no-induction (no-IC) and (ii) the Grade 3-4 in-field mucosal toxicity of CCRT versus CET/RT. The present paper focuses on the analysis of efficacy., Materials and Methods: Patients with LAHNSCC were randomized to receive concomitant treatment alone [CCRT (Arm A1) or CET/RT (Arm A2)], or three cycles of induction docetaxel/cisplatin/5 fluorouracil (TPF) followed by CCRT (Arm B1) or followed by CET/RT (Arm B2). The superiority hypothesis of OS comparison of IC versus no-IC (Arms B1 + B2 versus A1 + A2) required 204 deaths to detect an absolute 3-year OS difference of 12% (HR 0.675, with 80% power at two-sided 5% significance level)., Results: 414 out of 421 patients were finally analyzed: 206 in the IC and 208 in the no-IC arm. Six patients were excluded because of major violation and one because of metastatic disease at diagnosis. With a median follow-up of 44.8 months, OS was significantly higher in the IC arm (HR 0.74; 95% CI 0.56-0.97; P = 0.031). Complete Responses (P = 0.0028), Progression Free Survival (P = 0.013) and the Loco-regional Control (P = 0.036) were also significantly higher in the IC arm. Compliance to concomitant treatments was not affected by induction TPF., Conclusions: IC followed by concomitant treatment improved the outcome of patients with LAHNSCC without compromising compliance to the concomitant treatments. The degree of the benefit of IC could be different according to the type of the subsequent concomitant strategy., Clinical Trial Number: NCT01086826, www.clinicaltrials.gov., (© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objective: Arthritis, myositis and interstitial lung disease (ILD) constitute the classic clinical triad of anti-synthetase syndrome (ASSD). These patients experience other accompanying features, such as Raynaud's phenomenon, fever or mechanic's hands. Most ASSD patients develop the complete triad during the follow-up. In the present study we aimed to determine whether the subsequent appearance of accompanying features may suggest the development of triad findings lacking at the onset in anti-Jo1 positive ASSD patients., Methods: Anti-Jo1 positive patients presenting with incomplete ASSD (no >2 classic triad features) were assessed. Clinical characteristics and clusters of disease manifestations were retrospectively collected and analyzed in a large international multicenter cohort of ASSD patients., Results: 165 patients (123 women) with incomplete ASSD were identified. Ninety-five patients (57.5%) developed new classic triad manifestations after 15months median (IQR 9-51) and 40 (24%) developed new accompanying features after 19months median (IQR 6-56) from disease onset. During the follow-up, the ex-novo occurrence of triad features was observed in 32 out of 40 patients (80%) with new accompanying findings and in 63 out of 125 patients (50.5%) without new accompanying findings (p=0.002). In patients with at least one new accompanying feature the odds ratio for the occurrence of new triad manifestations was 3.94 with respect to patients not developing ex-novo accompanying findings (95% CI 1.68-9.21, p=0.002)., Conclusion: Anti-Jo1 ASSD patients with incomplete forms at disease onset are at high risk for the subsequent occurrence of lacking classic triad findings. Although all ASSD patients should be carefully assessed for the occurrence of new triad features, a closer follow-up should be considered in the subgroup of patients developing ex novo accompanying findings. These patients, indeed, have near four-fold increased risk for new classic triad manifestation occurrence with respect to patients not presenting ex novo accompanying findings., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Aims: To determine the incidence of cancer treatment-induced diarrhoea in patients submitted to irradiation., Methods: Forty-five Italian radiation oncology departments took part in this prospective observational study and a total of 1020 patients were enrolled. The accrual lasted three consecutive weeks; evaluation was based on diary cards filled in daily by patients during radiotherapy and one week after cessation. Diary cards recorded both the onset and intensity of diarrhoea., Results: A total of 1004 patients were eligible for this analysis. 147/1004 (14.6%) patients had diarrhoea. The median minimum number of daily events was 1 (range 1-7) with a median maximum events of 3 (range 1-23). 82/147 patients (56.2%) had a drug prescription for diarrhoea. In the evaluation of the onset of diarrhoea, in multivariate analysis, we found the following factors to be statistically significant predictors of an increased likelihood of diarrhoea: primitive tumour site, therapeutic purpose and field size., Conclusions: Patients with abdominal-pelvic cancer, treated with curative purpose and using large field sizes are at high risk of cancer treatment-induced diarrhoea. Diarrhoea was also observed in patients treated at other sites. In this population group there is the need for more stringent monitoring during the delivery of radiation therapy., (Copyright © 2013 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Preeclampsia, affecting 5-8% of pregnancies, is the main cause of fetal-maternal mortality and morbidity. The differential diagnosis with chronic kidney disease (CKD) is a challenge owing to the overlapping clinical features. No biomarker has been found to discriminate between the two conditions. Here, we tested whether maternal serum levels of placental growth factor (PlGF) and soluble FMS-like tyrosine kinase-1 (sFlt-1), markers of preeclampsia, could be used to discriminate between 34 patients with preeclampsia, 23 patients with CKD during pregnancy, and 38 healthy pregnant women. Serum levels of PlGF and sFlt-1 were determined during the third trimester by commercially available immunoassays. In preeclampsia, sFlt-1 levels were significantly increased in comparison with that in CKD and in the control women. Serum levels of PlGF in preeclampsia were significantly decreased relative to both controls and patients with CKD. The sFlt-1 to PlGF ratio was significantly increased in preeclampsia (median 436) compared with controls (median 9.4) and CKD (median 4.0). No differences were found between controls and patients with CKD. Thus, our study suggests that it is possible to discriminate between preeclampsia and CKD during pregnancy by determining maternal serum levels of sFlt-1 and PlGF and their ratio.

Thirteen patients with acute myeloid leukemia, 5 with active disease, 2 in molecular relapse, and 6 in morphologic complete remission (CR; median age, 62 years; range, 53-73 years) received highly purified CD56(+)CD3(-) natural killer (NK) cells from haploidentical killer immunoglobulin-like receptor-ligand mismatched donors after fludarabine/cyclophosphamide immunosuppressive chemotherapy, followed by IL-2. The median number of infused NK cells was 2.74 × 10(6)/Kg. T cells were < 10(5)/Kg. No NK cell-related toxicity, including GVHD, was observed. One of the 5 patients with active disease achieved transient CR, whereas 4 of 5 patients had no clinical benefit. Both patients in molecular relapse achieved CR that lasted for 9 and 4 months, respectively. Three of 6 patients in CR are disease free after 34, 32, and 18 months. After infusion, donor NK cells were found in the peripheral blood of all evaluable patients (peak value on day 10). They were also detected in BM in some cases. Donor-versus-recipient alloreactive NK cells were shown in vivo by the detection of donor-derived NK clones that killed recipient's targets. Adoptively transferred NK cells were alloreactive against recipient's cells, including leukemia. In conclusion, infusion of purified NK cells is feasible in elderly patients with high-risk acute myeloid leukemia. This trial was registered at www.clinicaltrial.gov as NCT00799799.

Background Aims: Procedures for cardiomyocyte differentiation of mouse embryonic stem cells (mESCs) utilize different amounts of serum. Because the serum composition is unknown, unambiguous characterization of the differentiation process is biased. All reported serum-free protocols used for compound testing provide serum throughout the differentiation process. We report on an embryoid body (EB)-based procedure for cardiomyocyte differentiation of mESCs in which serum is provided only in the earliest step (hanging drop, 0-2 days)., Methods: To assess cardiomyocyte differentiation, we generated an mESCs clone that expressed green fluorescence protein (GFP) under the control of the myosin light chain 2v (MLC2v) promoter. To define the lowest serum concentration required for efficient induction of cardiomyocyte differentiation, EBs were formed in presence of 5% (S5), 10% (S10) and 15% (S15) serum until day 2, then switched to a serum-free medium., Results: Analysis of cardiac-specific transcripts on day 6 of differentiation showed that 10% (S10) was the minimum amount of serum for efficient continuation of cultures under serum-free conditions. Spontaneously beating foci were detected in 90.0 ± 5.5% of S10 EBs on day 7 of differentiation, and cardiomyocyte markers were expressed from day 8 of differentiation (MLC2v-driven GFP; α-myosin heavy chain). Dose-response curves to isoproterenol showed that the beating rate increased by 113.0 ± 39.4%, with a concentration for half-maximal effect (EC(50)) of 25.7 nm., Conclusions: The development of functional cardiomyocytes from mESCs is not affected by serum withdrawal after EBs formation. This culture system represents a new model for cardiomyocyte differentiation of mESCs to assess the effects of compounds on the process of cardiomyogenesis.

Invasive urinary tumors are relatively rare and their treatment may cause important changes in urinary, sexual, and social functions. A systematic review of external radiation therapy studies in urinary cancers has been carried out. This synthesis of the literature is based on data from meta-analysis, randomized and prospective trials, and retrospective studies. There are few controlled clinical trials using adjuvant or radical radiotherapy +/- chemotherapy in kidney, ureter, and urethra cancers; there are several reports of muscle-invasive bladder cancer using multimodality treatment: intravesical surgery and neo-adjuvant chemotherapy to radiotherapy or concomitant radiochemotherapy with organ preservation. The conclusions reached for renal cancer are controversial; urethra and ureter cancers data are few and inconclusive; sufficient data now exist in literature to demonstrate that conservative management with organ preservation, for muscle-invasive bladder cancer, is a valid alternative to radical cystectomy, viewed as the gold standard.

cripto is the original member of the family of EGF-CFC genes, recently recognized as novel extracellular factors essential for vertebrate development. During the early stages of mouse gastrulation, cripto mRNA is detected in mesodermal cells; later, cripto mRNA is detected only in the truncus arteriosus of the developing heart. Here we describe the in vivo distribution of Cripto protein throughout mouse embryo development and show that cripto mRNA and protein colocalize. By means of immunofluorescence analysis and biochemical characterization, we show that Cripto is a membrane-bound protein anchored to the lipid bilayer by a glycosylphosphatidylinositol (GPI) moiety. We suggest that presentation of Cripto on the cell surface via a GPI-linkage is important in determining the spatial specificity of cell-cell interactions that play a critical role in the early patterning of the embryo.

A high-performance liquid chromatographic method for the determination of picotamide in human plasma and urine is described. After addition of an internal standard (bamifylline), the plasma and urine samples were subjected to liquid-liquid extraction and clean-up procedures. The final extracts were evaporated to dryness and the resulting residues were reconstituted in 100 microliters of methanol-water (50:50, v/v) and chromatographed on a LiChrosorb RP-SELECT B reversed-phase column coupled to an ultraviolet detector monitored at 230 nm. Chromatographic analysis takes about 10 min per sample. The assay was linear over a wide range and has a limit of detection of 0.005 and 0.1 micrograms/ml in plasma and urine, respectively. It was selective for picotamide, accurate and robust and thus suitable for routine assays after therapeutic doses of picotamide.