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There has been continuous progress in diabetes management over the last few decades, not least due to the widespread dissemination of continuous glucose monitoring (CGM) and automated insulin delivery systems. These technological advances have radically changed the daily lives of people living with diabetes, improving the quality of life of both children and their families. Despite this, hypoglycemia remains the primary side-effect of insulin therapy. Based on a systematic review of the available scientific evidence, this paper aims to provide evidence-based recommendations for recognizing, risk stratifying, treating, and managing patients with hypoglycemia. The objective of these recommendations is to unify the behavior of pediatric diabetologists with respect to the timely recognition and prevention of hypoglycemic episodes and the correct treatment of hypoglycemia, especially in patients using CGM or advanced hybrid closed-loop systems. All authors have long experience in the specialty and are members of the Italian Society of Pediatric Endocrinology and Diabetology. The goal of treating hypoglycemia is to raise blood glucose above 70 mg/dL (3.9 mmol/L) and to prevent further decreases. Oral glucose at a dose of 0.3 g/kg (0.1 g/kg for children using “smart pumps” or hybrid closed loop systems in automated mode) is the preferred treatment for the conscious individual with blood glucose

Background and Aims: Hypoalbuminemia, as defined by serum albumin (SA) levels ≤35 g/L, is associated to venous and arterial thrombosis in general population and in patients at risk of cardiovascular disease. It is unknown if SA ≤35 g/L is also associated to portal vein thrombosis (PVT) in cirrhosis. Methods: Cirrhotic patients enrolled in the Portal vein thrombosis Relevance On Liver cirrhosis: Italian Venous thrombotic Events Registry (PRO-LIVER) study (n = 753), were followed-up for 2 years to assess the risk of PVT, that was diagnosed by Doppler ultrasonography. Child-Pugh classes, Model for End-Stage Liver Disease score, presence of hepatocellular carcinoma and laboratory variables including SA, D-dimer, and high-sensitivity C-reactive protein (hs-CRP) were measured at baseline. Results: SA ≤35 g/L was detected in 52% of patients. A logistic multivariate regression analysis showed that higher Child-Pugh class, hepatocellular carcinoma and thrombocytopenia were significantly associated to SA ≤35 g/L. In a subgroup of patients where data regarding hs-CRP and D-dimer were available, SA ≤35 g/L was inversely associated with hs-CRP and D-dimer. During the follow-up, a total of 61 patients experienced PVT. A Kaplan Meier survival analysis showed SA ≤35 g/L was associated to increased risk of PVT compared to SA >35 g/L (P = .005). A multivariate Cox proportional hazards regression analysis showed that male sex, lower platelet count, and SA ≤35 g/L remained associated to PVT after adjusting for confounding factors. Conclusion: Cirrhotic patients with SA ≤35 g/L are at higher risk of experiencing PVT compared to those with SA >35 g/L and could be considered as potential candidates to anticoagulant prophylaxis for PVT prevention.

Rosaria Di Lorenzo,1 Matteo Reami,2 Diego Dragone,1 Martina Morgante,1 Giulia Panini,1 Sergio Rovesti,3 Tommaso Filippini,3,4 Silvia Ferrari,3,5 Paola Ferri3 1Mental Health Department and Drug Abuse, AUSL-Modena, Modena, Italy; 2School of Medicine & Surgery, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy; 3Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy; 4School of Public Health, University of California Berkeley, Berkeley, CA, USA; 5Mental Health Department and Drug Abuse, AUSL-IRCCS Reggio Emilia, Reggio Emilia, ItalyCorrespondence: Rosaria Di Lorenzo, Mental Health Department and Drug Abuse, SPDC in OCSAE, via P. Giardini, 1355, Baggiovara, Modena, 41126, Italy, Tel +393355410018, Email saradilorenzo1@alice.it; r.dilorenzo@ausl.mo.itPurpose: We evaluated the differences between demographic (age, sex, nationality, employment, housing, schooling, support administrator), clinical (hospitalization reason, aggressive behaviour, length of hospitalization, psychiatric diagnosis and comorbidities, psychiatric medications, discharge destination, “revolving door” hospitalizations) and environmental (pre-and pandemic period) variables in voluntary (VHs) and involuntary hospitalizations (IHs) in an acute psychiatric ward during a 6-year period.Patients and Methods: We retrospectively collected the selected variables concerning the hospitalizations of subjects over 18 years of age in the Service for Psychiatric Diagnosis and Care of Mental Health and Drug Abuse Department in Modena from 01/01/2017 to 31/12/2022.Results: We observed a progressive and sharp reduction in the number of VHs (n = 1800; 61.41%) during the pandemic and a stability of IHs (n = 1131; 38.59%), which in 2022 became prevalent. We highlighted the following differences between VHs and IHs: an increase in hospitalization length in IHs (14.25 mean days ± 15.89 SD) in comparison with VHs (8.78 mean days ± 13.88 SD), which increased more during the pandemic; an increase in aggressive behavior in IHs, especially during the pandemic (Pearson Chi2 = 90.80; p = 0.000); a prevalence of schizophrenia and bipolar disorders (Pearson Chi2 = 283.63; p = 0.000) and more frequent maladaptive social conditions among subjects in IHs.Conclusion: During the 6-year observation period, we underscored a trend of increasingly reduced recourse to VHs, whereas IHs increased even in the pandemic. Our results suggest that IHs in Psychiatry represented an extreme measure for treating the most severe psychopathological situations such as schizophrenia and bipolar disorders, characterized by aggressive behaviour and precarious social conditions, which needed longer stay than VHs, especially during the pandemic.Keywords: nonadherence to treatment, involuntary psychiatric hospitalizations, pandemic, revolving door

The Situationsethik began to be a source of concern for the Roman authority only at the beginning of the 1950s when some Catholic authors promoted a morality that, in evaluating an act, took greater account of the context rather than the universal moral law. Through the examination of the archival material of the former Holy Office, it was possible to reconstruct the stages of the path that led the ‘Suprema’ to carry out severe investigations on some scholars (Fuchs, Michel, Leclercq, Tiberghien) and to the promulgation of the Instructio of 1956 with which the ethica situationis was condemned.

Andrea Ferrari,1 Pablo Berlanga,2 Susanne Andrea Gatz,3 Reineke A Schoot,4 Max M van Noesel,4,5 Shushan Hovsepyan,6 Stefano Chiaravalli,1 Luca Bergamaschi,1 Veronique Minard-Colin,2 Nadege Corradini,7 Rita Alaggio,8 Patrizia Gasparini,9 Bernadette Brennan,10 Michela Casanova,1 Sandro Pasquali,11,12 Daniel Orbach13 1Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; 2Department of Pediatric and Adolescent Oncology, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, France; 3Cancer Research UK Clinical Trials Unit, Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK; 4Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands; 5Division Imaging & Cancer, University Medical Center Utrecht, Utrecht, the Netherlands; 6Pediatric Cancer and Blood Disorders Center of Armenia, Yerevan, Armenia; 7Department of Pediatric Hematology and Oncology-IHOPe, Léon Bérard Center, Lyon, France; 8Pathology Department, Ospedale Pediatrico Bambino Gesù IRCCS, Roma, Italy; 9Tumor Genomics Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; 10Pediatric Oncology, Royal Manchester Children’s Hospital, Manchester, UK; 11Molecular Pharmacology Unit, Department of Applied Research and Technological Development, Molecular Pharmacology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; 12Sarcoma Service, Department of Surgery, Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; 13SIREDO Oncology Center(Care, Innovation and Research for Children, Adolescents and Young Adults with Cancer), Institut Curie, PSL University, Paris, FranceCorrespondence: Andrea Ferrari, Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Via G. Venezian, Milano, MI, 1 20133, Italy, Tel +39 02 23902588, Fax +39 02 23902648, Email andrea.ferrari@istitutotumori.mi.itAbstract: While the overall prognosis is generally quite satisfactory in children, adolescents and young adults with localised synovial sarcoma at first diagnosis, the outcome remains poor for patients after relapse. Conversely to the front-line standardised treatment options, patients with relapse generally have an individualised approach and to date, there is still a lack of consensus regarding standard treatment approaches. Studies on relapsed synovial sarcoma were able to identify some prognostic variables that influence post-relapse survival, in order to plan risk-adapted salvage protocols. Treatment proposals must consider previous first-line treatments, potential toxicities, and the possibility of achieving an adequate local treatment by new surgery and/or re-irradiation. Effective second-line drug therapies are urgently needed. Notably, experimental treatments such as adoptive engineered TCR-T cell immunotherapy seem promising in adults and are currently under validation also in paediatric patients.Keywords: synovial sarcoma, relapse, second line therapy, surgery, new agents, TCR-T cell therapy, children

Sabina Vennarini,1 Francesca Colombo,1,2 Alfredo Mirandola,3 Stefano Chiaravalli,4 Ester Orlandi,5 Maura Massimino,4 Michela Casanova,4 Andrea Ferrari4 1Pediatric Radiotherapy Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy; 2Department of Oncology and Hemato-Oncology (DIPO), University of Milan, Milan, Italy; 3Medical Physics Unit, Clinical Department, National Center for Oncological Hadrontherapy (CNAO), Pavia, Italy; 4Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milano, Italy; 5Radiation Oncology Unit, Clinical Department, National Center for Oncological Hadrontherapy (CNAO), Pavia, ItalyCorrespondence: Andrea Ferrari, Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale Tumori, Via G. Venezian, Milano, MI, 1 20133, Italy, Tel +39 02 23902588, Fax +39 02 23902648, Email andrea.ferrari@istitutotumori.mi.itAbstract: This paper offers an insight into the use of Proton Beam Therapy (PBT) in paediatric patients with rhabdomyosarcoma (RMS). This paper provides a comprehensive analysis of the literature, investigating comparative photon-proton dosimetry, outcome, and toxicity. In the complex and multimodal scenario of the treatment of RMS, clear evidence of the therapeutic superiority of PBT compared to other modern photon techniques has not yet been demonstrated; however, PBT can be considered an excellent treatment option, in particular for young children and patients with specific primary sites, such as the head and neck area (and especially the parameningeal regions), genito-urinary, pelvic, and paravertebral regions. The unique depth-dose characteristics of protons can be exploited to achieve significant reductions in normal tissue doses and may allow an escalation of tumour doses and greater sparing of normal tissues, thus potentially improving local control while at the same time reducing toxicity and improving quality of life. However, access of children with RMS (and more in general with solid tumors) to PBT remains a challenge, due to the limited number of available proton therapy installations.Keywords: rhabdomyosarcoma, pediatric, proton beam therapy, local treatment, radiotherapy

The Complete Works of Álvaro de Campos (New Directions, 2023), brings together the poetry and prose of Fernando Pessoa’s most prolific heteronym in English translation in a single book for the first time. More importantly, it features a large number of texts previously unavailable in English. The digital dossier presented here serves as an addendum to the U. S. edition which was abridged to attract a larger anglophone readership. This digital dossier in translation includes all the poems in the Tinta-da-china Poetry Annex section, as well as a large selection of Campos’ prose texts unpublished during Pessoa’s lifetime. Some facsimiles of these texts are also reproduced here for the first time.

Introduction Lung cancer (LC) is the most common cause of cancer-related deaths worldwide. Its early detection can be achieved with a CT scan. Two large randomised trials proved the efficacy of low-dose CT (LDCT)-based lung cancer screening (LCS) in high-risk populations. The decrease in specific mortality is 20%–25%.Nonetheless, implementing LCS on a large scale faces obstacles due to the low number of thoracic radiologists and CT scans available for the eligible population and the high frequency of false-positive screening results and the long period of indeterminacy of nodules that can reach up to 24 months, which is a source of prolonged anxiety and multiple costly examinations with possible side effects.Deep learning, an artificial intelligence solution has shown promising results in retrospective trials detecting lung nodules and characterising them. However, until now no prospective studies have demonstrated their importance in a real-life setting.Methods and analysis This open-label randomised controlled study focuses on LCS for patients aged 50–80 years, who smoked more than 20 pack-years, whether active or quit smoking less than 15 years ago. Its objective is to determine whether assisting a multidisciplinary team (MDT) with a 3D convolutional network-based analysis of screening chest CT scans accelerates the definitive classification of nodules into malignant or benign. 2722 patients will be included with the aim to demonstrate a 3-month reduction in the delay between lung nodule detection and its definitive classification into benign or malignant.Ethics and dissemination The sponsor of this study is the University Hospital of Nice. The study was approved for France by the ethical committee CPP (Comités de Protection des Personnes) Sud-Ouest et outre-mer III (No. 2022-A01543-40) and the Agence Nationale du Medicament et des produits de Santé (Ministry of Health) in December 2023. The findings of the trial will be disseminated through peer-reviewed journals and national and international conference presentations.Trial registration number NCT05704920.

Benoîte Mery,1,2,* Christine Ménétrier-Caux,2,3,* Laure Montané,4 Pierre-Etienne Heudel,1 Isabelle Ray-Coquard,1 Thomas Bachelot,1 Olfa Derbel,5 Paule Augereau,6 Isabelle Treilleux,2,7 Justine Berthet,2,3 Axelle Nkodia,3 Christine Bardin-Dit-Courageot,3 Valery Attignon,8 Anthony Ferrari,9 Gwenaele Garin,4 David Perol,4 Christophe Caux,2,3 Bertrand Dubois,2,3,* Olivier Trédan1,2,* 1Department of Medical Oncology, Centre Léon Bérard, Lyon, France; 2Inserm U1052, CNRS 5286, Cancer Research Center of Lyon, Université Claude Bernard Lyon 1, Lyon, France; 3Laboratory of Cancer Immunotherapy of LYON (LICL), Centre Léon Bérard, Lyon, France; 4Clinical Research Platform (DRCI), Centre Léon Bérard, Lyon, France; 5Department of Medical Oncology, Hôpital Privé Jean-Mermoz, Lyon, France; 6Department of Medical Oncology, Institut de Cancérologie de L’ouest- Paul Papin, Angers, France; 7Biopathology Department, Centre Léon Bérard, Lyon, France; 8Genomic of Cancer Platform, Centre Léon Bérard, Lyon, France; 9Gilles Thomas Bioinformatics Platform, Synergie Lyon Cancer Foundation, Centre Léon Bérard, Lyon, France*These authors contributed equally to this workCorrespondence: Benoîte Mery, Department of Medical Oncology, Centre Léon Bérard, 28 Rue Laennec, Lyon, 69008, France, Tel +33 4 78 78 26 44, Fax +33 4 78 78 27 15, Email Benoite.mery@lyon.unicancer.frPurpose: Metastatic endocrine-resistant breast cancer (MBC) is a disease with poor prognosis and few treatment options. Low lymphocyte count is associated with limited overall survival. In a prospective cohort of lymphopenic patients with HER-2 negative MBC, we assessed the clinical and biological impact of pembrolizumab combined with metronomic cyclophosphamide.Experimental Design: This multicenter Phase II study evaluated the safety and clinical activity of pembrolizumab (intravenous (IV), 200mg, every 3 weeks) combined with metronomic cyclophosphamide (50mg/day, per os) in lymphopenic adult patients with HER2-negative MBC previously treated by at least one line of chemotherapy in this setting according to a Simon’s minimax two-stage design. Blood and tumor samples were collected to assess the impact of the combined treatment on circulating immune cells and the tumor immune microenvironment through multiparametric flow cytometry and multiplex immunofluorescence analyses. Primary endpoint was the clinical benefit rate at 6 months of treatment (CBR-6M). Secondary endpoints were objective response rate (ORR), duration of response, progression free survival (PFS), and overall survival (OS).Results: Two out of the twenty treated patients presented clinical benefit (one Tumor Mutational Burden (TMB)-high patient with complete response (CR) and one patient with objective response (OR) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST V1.1) associated with a strong increase of cytokine-producing and proliferating CD4+ T cells and higher CD8+ T cells to macrophage ratios in the tumor. This impact on CD4+ and CD8+ T cell polyfunctionality was still observed more than one year for the patient with CR. A decreased in their absolute number of CD4+ and CD8+ memory T cells was observed in other patients.Conclusion: Pembrolizumab combined with metronomic cyclophosphamide was well tolerated, and displayed limited anti-tumoral activity in lymphopenic MBC. Correlative translational data of our trial advocates for additional studies with other chemotherapy combinations.Keywords: metastatic breast cancer, lymphopenia, immunotherapy, chemotherapy, immunomonitoring

A 50-year-old patient was referred to our service for the investigation of oropharynx cancer and was diagnosed with squamous cell carcinoma. Although there were no signs of distant metastasis, the disease was given as unresectable. The patient was treated with induction chemotherapy followed by chemoradiotherapy. After a trauma episode, the patient had pain in the right hand, being investigated with magnetic resonance, which demonstrated lesion of soft parts and bone structures. Additionally, in staging examinations, pulmonary metastasis was observed. Of the patients with oropharynx squamous carcinoma, approximately 15 to 20% develop metastases throughout the course of the disease, and metastases in soft parts are rare (less than 10% of those with known distance disease).

A tailor-made health plan is a set of recommendations for a farmer to achieve and maintain a high health and welfare status. Tailored to each farm, it is intended to be an effective way of triggering change. This study aimed to assess the effectiveness of tailor-made health plans in pig farms, designed in various situations after a systematic biosecurity and herd health audit. An intervention study was carried out in 20 farrow-to-finish pig farms. An initial standardized audit and discussion between the farm veterinarian and the farmer resulted in a specific plan. Compliance with recommendations was monitored during 8 months. Changes in health, performances and antimicrobial use were monitored. We defined two categories of plans: i) 14 plans targeting a given health disorder present in a farm; ii) 17 plans to improve prevention, not targeting a specific health disorder (a farm could have both types of plans). A small number of priority recommendations were made per farm. In 18 farms, farmers implemented 1 to 4 recommendations (none in 2 farms). Of the 17 non-disorder-specific plans, 11 were considered effective (>50% recommendations implemented), 3 intermediate (at least one but less than half of the recommendations implemented) and 3 ineffective (no implementation). Of the 14 disorder-specific plans, 9 were followed with full or good compliance (>50% recommendations implemented), 2 with intermediate compliance (1 recommendation implemented out of 2) and 3 with no compliance (no recommendation implemented). When at least one recommendation was implemented, change in clinical, performance and antimicrobial use indicators was assessed if a biological association with the disorder was deemed plausible and if their initial value showed room for improvement. Improvement was evidenced 4/9, 1/6 and 1/6 times for these indicators, respectively. Independently, veterinarians concluded that 8/14 plans were effective. Overall, tailor-made health plans were effective in triggering changes in farm management. Three key points were identified for future assessments of the effectiveness of tailor-made health plans. Compliance should be the first indicator of assessment. Outcome indicators and their monitoring periods should be adapted to each farm and to the targeted health disorder. Indicators should be combined to have a holistic description of the evolution of a health disorder. Further research is needed to identify how to select indicators to combine and how to combine them, according to health disorders.