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Andrea Spini,1 Luca L’Abbate,2 Ylenia Ingrasciotta,1 Giorgia Pellegrini,1 Massimo Carollo,1 Valentina Ientile,2 Olivia Leoni,3 Martina Zanforlini,4 Domenica Ancona,5 Paolo Stella,5 Anna Cavazzana,6 Angela Scapin,6 Sara Lopes,7 Valeria Belleudi,7 Gianluca Trifirò1 1Department of Diagnostics and Public Health, University of Verona, Verona, Italy; 2Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, Messina, Italy; 3Lombardy Regional Centre of Pharmacovigilance and Regional Epidemiologic Observatory, Milan, Italy; 4Azienda Regionale per l’Innovazione e gli Acquisti, S.p.A, Milan, Italy; 5Apulian Regional Health Department, Bari, Italy; 6Azienda Zero, Regione Veneto, Italy; 7Department of Epidemiology, Lazio Regional Health Service, Rome, ItalyCorrespondence: Gianluca Trifirò, Department of Diagnostics and Public Health, University of Verona, P. le L.A. Scuro 10, Verona, 37134, Italy, Tel +39 045 802 7679, Email gianluca.trifiro@univr.itPurpose: This research aimed to develop and validate a META-algorithm combining individual immune-mediated inflammatory disease (IMID)-specific algorithms to identify the exact IMID indications for incident biological drug users from claims data within the context of the Italian VALORE project.Methods and Patients: All subjects with at least one dispensing of TNF-alpha inhibitors, anti-interleukin agents, and selective immunosuppressants approved for IMIDs were identified from claims databases of Latium region in Italy (observation period: 2010– 2020). Validated coding algorithms for identifying individual IMIDs from claims databases were found from published literature and combined into a META-algorithm. Positive predictive value (PPV), sensitivity (Se), negative predictive value (NPV), specificity (Sp), and accuracy (Acc) were estimated for each indication against the electronic therapeutic plans (ETPs) of the Latium region as the reference standard. Lastly, the frequency of the indication of use across individual biologic drugs was compared with that reported in three other Italian regions (Lombardy, Apulia, and the Veneto region).Results: In total, 9755 incident biological drug users with a single IMID indication were identified. Using the newly developed META-algorithm, an indication of use was detected in 95% (n=9255) of the total cohort. The estimated Acc, Se, Sp, PPV, and NPV, against the reference standard were as follows: 0.96, 0.86, 0.97, 0.82, and 0.98 for Crohn’s disease, 0.96, 0.80, 0.98, 0.85, and 0.97 for ulcerative colitis, 0.93, 0.76, 0.99, 0.95, and 0.92 for rheumatoid arthritis, 0.97, 0.75, 0.99, 0.85, and 0.98 for spondylarthritis, and 0.91, 0.92, 0.91, 0.88, and 0.94 for psoriatic arthritis/psoriasis, respectively. Additionally, no substantial difference was observed in the frequency of indication of use by active ingredient among Latium and the other three Italian regions included in the study.Conclusion: The newly developed META-algorithm demonstrated high validity estimates in the Italian claims data and was capable of discriminating with good performance among the most frequent IMID indications.Plain Language Summary: In the claims database, the lack of information on the indication of use represents a well-known limitation for the conduct of observational studies. This study was conducted to develop and validate a META-algorithm that accurately identifies the exact indication for the use of biological drugs in treating various immune-mediated inflammatory diseases. Using claims databases from the Latium region, we developed and validated a META-algorithm. The META-algorithm combines disease-specific algorithms for different immune-mediated inflammatory diseases (ie, Crohn’s disease, ulcerative colitis, rheumatoid arthritis, spondyloarthritis, psoriasis, and psoriatic arthritis) and was tested against a reference standard (electronic therapeutic plans of the Lazio region). The META-algorithm reported high validity estimates and was able to distinguish with a good performance among the most frequent IMIDs as indications for use. Applying this META-algorithm may facilitate post-marketing surveillance of biological drugs such as TNF-alpha inhibitors, anti-interleukin, and selective immunosuppressants in specific therapeutic areas in an Italian setting.Keywords: immune-mediated inflammatory diseases, biological drugs, validation, claims data, META-algorithm, indication for use

Te paper reconstructs the profound intellectual connection between Piero Calamandrei and the brothers Carlo and Nello Rosselli, which began in the 1920s with the foundation of the Circolo di Cultura in Florence, and prosecuted through the collaboration with the underground newspaper Non Mollare, until the establishment of the Partito d’Azione that inherited the legacy of the Giustizia e Libertà movement founded by Carlo Rosselli in 1929. Particular attention is paid to the commemorative plaques dedicated by Calamandrei to the Rosselli brothers and to the ideas of liberal socialism, actively cultivated by the Florentine jurist in the Constituent Assembly.

A thick market external e ect is applied to a trading post model of N 3 commodities with transaction costs and distinct bid and ask prices. Anexistence theorem for general equilibrium with external e ects in the tradingpost model is stated and proved. Media of exchange occur endogenously asliquid commodities, characterized by a narrow bid/ask price spread. The thickmarket externality can lead to concentration of the endogenously determinedmedia of exchange towards an equilibrium with a single medium. In a class ofexamples, we show that if the households have su ciently heterogeneous tastesrelative to the size of the economy, the monetary equilibrium leads to higherconsumption than the barter equilibrium.

Abstract Autophagy is important for the removal, degradation and recycling of damaged organelles, proteins, and lipids through the degradative action of lysosomes. In addition to its catabolic function, autophagy is important in cancer and viral-mediated tumorigenesis, including Human Papillomavirus (HPV) positive cancers. HPV infection is a major risk factor in a subset of head and neck cancer (HNC), for which no targeted therapies are currently available. Herein, we assessed autophagy function in HPV-positive HNC. We showed that HPV-positive HNC cells presented a transcriptional and functional impairment of the autophagic process compared to HPV-negative cells, which were reactivated by knocking down HPV E6/E7 oncoproteins, the drivers of cellular transformation. We found that the oncoprotein c-MYC was stabilized and triggered in HPV-positive cell lines. This resulted in the reduced binding of the MiT/TFE transcription factors to their autophagy targets due to c-MYC competition. Thus, the knock-down of c-MYC induced the upregulation of autophagic and lysosomal genes in HPV-positive HNC cells, as well as the increase of autophagic markers at the protein level. Moreover, HPV oncoprotein E7 upregulated the expression of the phosphatase inhibitor CIP2A, accounting for c-MYC upregulation and stability in HPV+ HNC cells. CIP2A mRNA expression negatively correlated with autophagy gene expression in tumor tissues from HNC patients, showing, for the first time, its implication in a transcriptional autophagic context. Both CIP2A and c-MYC knock-down, as well as pharmacological downregulation of c-MYC, resulted in increased resistance to cisplatin treatment. Our results not only show a novel way by which HPV oncoproteins manipulate the host machinery but also provide more insights into the role of autophagy in chemoresistance, with possible implications for targeted HPV-positive HNC therapy.

Individuals with inflammatory bowel diseases (IBDs) have an increased risk of developing psychiatric comorbidities, including eating disorders (EDs). We aimed to investigate the potential association between key disease characteristics, including psychological features, and the development of EDs in a clinical sample of adolescents with IBDs. We enrolled 52 adolescents with IBDs, 83% of whom were in clinical remission, and systematically collected additional information on disease duration, the total number of relapses, the use of steroids, and the number of hospital admissions. All participants completed a validated psychometric battery assessing psychological symptoms (Symptom Checklist-90–Revised, SCL-90-R), alexithymia (Toronto Alexithymia Scale-20, TAS-20), and ED symptomatology (Eating Disorders Inventory-3rd edition, EDI-3). About one in ten patients (9.6%) reported Eating Disorder Risk scores higher than the cut-off on the EDI-3 subscale, specifically addressing the risk of developing EDs. According to the EDI-3 scores, the risk of developing EDs directly correlated with the number of total relapses of IBDs (p < 0.05). The TAS-total scores also correlated with the number of total relapses (p < 0.01), as well as with the number of steroid cycles (p < 0.05), the number of hospital admissions (p < 0.05), and overall disease duration (p < 0.05). Our findings suggest that disease relapses increase the risk of developing both EDs and alexithymia in adolescents with IBDs. The recurrence of disease relapses should be identified and screened early on to prevent the onset of psychiatric disorders, including EDs. Research should be conducted on larger samples with different IBD phenotypes to further investigate the characteristics of patients with IBDs at risk of developing EDs.

Andrea Spini,1 Luca L’Abbate,2 Ylenia Ingrasciotta,1 Giorgia Pellegrini,1 Massimo Carollo,1 Valentina Ientile,2 Olivia Leoni,3 Martina Zanforlini,4 Domenica Ancona,5 Paolo Stella,5 Anna Cavazzana,6 Angela Scapin,6 Sara Lopes,7 Valeria Belleudi,7 Gianluca Trifirò1 1Department of Diagnostics and Public Health, University of Verona, Verona, Italy; 2Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, Messina, Italy; 3Lombardy Regional Centre of Pharmacovigilance and Regional Epidemiologic Observatory, Milan, Italy; 4Azienda Regionale per l’Innovazione e gli Acquisti, S.p.A, Milan, Italy; 5Apulian Regional Health Department, Bari, Italy; 6Azienda Zero, Regione Veneto, Italy; 7Department of Epidemiology, Lazio Regional Health Service, Rome, ItalyCorrespondence: Gianluca Trifirò, Department of Diagnostics and Public Health, University of Verona, P. le L.A. Scuro 10, Verona, 37134, Italy, Tel +39 045 802 7679, Email gianluca.trifiro@univr.it

To date, no population-based studies have specifically explored the external validity of pivotal randomized clinical trials (RCTs) of biologics simultaneously for a broad spectrum of immuno-mediated inflammatory diseases (IMIDs). The aims of this study were, firstly, to compare the patients’ characteristics and median treatment duration of biologics approved for IMIDs between RCTs’ and real-world setting (RW); secondly, to assess the extent of biologic users treated for IMIDs in the real-world setting that would not have been eligible for inclusion into pivotal RCT for each indication of use. Using the Italian VALORE distributed database (66,639 incident biologic users), adult patients with IMIDs treated with biologics in the Italian real-world setting were substantially older (mean age ± SD: 50 ± 15 years) compared to those enrolled in pivotal RCTs (45 ± 15 years). In the real-world setting, certolizumab pegol was more commonly used by adult women with psoriasis/ankylosing spondylitis (F/M ratio: 1.8–1.9) compared to RCTs (F/M ratio: 0.5–0.6). The median treatment duration (weeks) of incident biologic users in RW was significantly higher than the duration of pivotal RCTs in almost all indications for use and most biologics (4–100 vs. 6–167). Furthermore, almost half (46.4%) of biologic users from RW settings would have been ineligible for inclusion in the respective indication-specific pivotal RCTs. The main reasons were: advanced age, recent history of cancer and presence of other concomitant IMIDs. These findings suggest that post-marketing surveillance of biologics should be prioritized for those patients.

During the COVID-19 pandemic, there have been multiple reports about an unforeseen surge in adolescents and young adults exhibiting sudden onset functional tic-like behaviors. This phenomenon has been mainly associated with the female gender and occasionally after exposure to social media content featuring similar patterns of functional tic-like behaviors. A significant portion of these individuals have been directed to specialist clinics for movement disorders with initial misdiagnoses of late-onset refractory Tourette syndrome. Distinguishing between rapid onset functional tic-like behaviors and neurodevelopmental tics as part of Tourette syndrome can be challenging; however, the differential diagnosis is facilitated by focusing on specific clinical and demographic factors, which we have explored in a systematic literature review. Compared to neurodevelopmental tics, functional tic-like behaviors typically present with a more abrupt and intense manifestation of symptoms, onset at a later age, higher prevalence among females, inability to suppress tics, coexisting anxiety and depression, and sometimes a history of exposure to social media content portraying tic-like behaviors of a similar nature. This novel manifestation of a functional neurological disorder may thus be viewed as an emerging neuropsychiatric condition potentially triggered/exacerbated by the psychosocial repercussions of the COVID-19 crisis.

RESUMO Buscou-se descrever como a automutilação é compreendida pelas instituições de ensino e quais são as ações realizadas frente ao fenômeno, a partir de uma revisão sistemática de literatura. Em busca no Portal BVS, SciELO e no Catálogo de Teses da Capes, utilizando os descritores automutilação, autolesão, comportamento autolesivo e comportamento autodestrutivo, selecionou-se 20 documentos que foram submetidos à análise de conteúdo. Identificou-se que os estudos são recentes, predominantemente qualitativos, influenciados pela Análise do Comportamento e Psicanálise, e desenvolvidos junto a adolescentes de escolas públicas. A automutilação foi compreendida como decorrente de condições fisiológicas, forma de dar sentido ao sofrimento, resultado de contágio social, tentativa de comunicação, manifestação de ideação suicida e comportamento de indivíduos com desenvolvimento atípico. Há poucos relatos de intervenção frente ao problema, abarcando práticas clínicas, preventivas e de formação profissional. Destaca-se a necessidade da ampliação de práticas nas escolas compreendendo a automutilação numa perspectiva social e coletiva.

IntroductionItalian administrative healthcare databases are frequently used for studies on real-world drug utilization. However, there is currently a lack of evidence on the accuracy of administrative data in describing the use of infusive antineoplastics. In this study, we used rituximab as a case study to investigate the validity of the regional administrative healthcare database of Tuscany (RAD) in describing the utilization of infusive antineoplastics.MethodsWe identified patients aged 18 years or older who had received ≥1 rituximab administration between 2011 and 2014 in the onco-haematology ward of the University Hospital of Siena. We retrieved this information from the Hospital Pharmacy Database (HPD-UHS) and linked the person-level information to RAD. Patients who had received ≥1dispensing of rituximab, single administration episodes, and patients treated for non-Hodgkin Lymphoma (nHL) or Chronic Lymphocytic Leukemia (CLL) were identified in RAD and validated using HPD-UHS as the reference standard. We identified the indications of use using algorithms based on diagnostic codes (ICD9CM codes, nHL=200*, 202*; CLL=204.1). We tested 22 algorithms of different complexity for each indication of use and calculated sensitivity and positive predictive value (PPV), with 95% confidence intervals (95%CI), as measures of validity.ResultsAccording to HPD-UHS, 307 patients received rituximab for nHL (N=174), CLL (N=21), or other unspecified indications (N=112) in the onco-haematology ward of the University Hospital of Siena. We identified 295 rituximab users in RAD (sensitivity=96.1%), but PPV could not be assessed due to missing information in RAD on dispensing hospital wards. We identified individual rituximab administration episodes with sensitivity=78.6% [95%CI: 76.4-80.6] and PPV=87.6% [95%CI: 86.1-89.2]. Sensitivity of algorithms tested for identifying nHL and CLL ranged from 87.7% to 91.9% for nHL and from 52.4% to 82.7% for CLL. PPV ranged from 64.7% to 66.1% for nHL and from 32.4% to 37.5% for CLL.DiscussionOur findings suggest that RAD is a very sensitive source of information for identifying patients who received rituximab for onco-haematological indications. Single administration episodes were identified with good-to-high accuracy. Patients receiving rituximab for nHL were identified with high sensitivity and acceptable PPV, while the validity for CLL was suboptimal.

Individuals with inflammatory bowel diseases (IBDs) have an increased risk of developing psychiatric comorbidities, including eating disorders (EDs). We aimed to investigate the potential association between key disease characteristics, including psychological features, and the development of EDs in a clinical sample of adolescents with IBDs. We enrolled 52 adolescents with IBDs, 83% of whom were in clinical remission, and systematically collected additional information on disease duration, the total number of relapses, the use of steroids, and the number of hospital admissions. All participants completed a validated psychometric battery assessing psychological symptoms (Symptom Checklist-90–Revised, SCL-90-R), alexithymia (Toronto Alexithymia Scale-20, TAS-20), and ED symptomatology (Eating Disorders Inventory-3rd edition, EDI-3). About one in ten patients (9.6%) reported Eating Disorder Risk scores higher than the cut-off on the EDI-3 subscale, specifically addressing the risk of developing EDs. According to the EDI-3 scores, the risk of developing EDs directly correlated with the number of total relapses of IBDs (p < 0.05). The TAS-total scores also correlated with the number of total relapses (p < 0.01), as well as with the number of steroid cycles (p < 0.05), the number of hospital admissions (p < 0.05), and overall disease duration (p < 0.05). Our findings suggest that disease relapses increase the risk of developing both EDs and alexithymia in adolescents with IBDs. The recurrence of disease relapses should be identified and screened early on to prevent the onset of psychiatric disorders, including EDs. Research should be conducted on larger samples with different IBD phenotypes to further investigate the characteristics of patients with IBDs at risk of developing EDs. [ABSTRACT FROM AUTHOR]

Child undernutrition and later-life non-communicable diseases (NCDs) are major global health issues. Literature suggests that undernutrition/famine exposure in childhood has immediate and long-term adverse health consequences. However, many studies have theoretical and methodological limitations. To add to the literature and overcome some of these limitations, we adopted a life course perspective and used more robust methods. We investigated the association between exposure to the 1959-1961 Chinese famine and later-life NCDs and if this association depends on: life stage at exposure, famine severity, and sex. We conducted a secondary data analysis of a large-scale, nationally representative, longitudinal study-the China Health and Retirement Longitudinal Study (2011-2018, 11,094 participants). We measured famine exposure/severity using self-reported experience, life stage using age at exposure, and health using the number of NCDs. We performed Poisson growth curve models. We obtained three findings. First, compared with unexposed participants, those exposed before age 18 had a higher risk of later-life NCDs, particularly if exposed in-utero (IRR = 1.90, 95% CI [1.70, 2.12], p < .001) and in the "first 1,000 days" of life (IRR = 1.86, 95% CI [1.73, 2.00], p < .001; for 0-6 months group, IRR = 1.95, 95% CI [1.67, 2.29], p < .001). Second, the famine effects among participants moderately and severely exposed were similar (IRR = 1.18, 95% CI [1.09, 1.28], p < .001 and IRR = 1.24, 95% CI [1.17, 1.32], p < .001). Third, the famine effects did not differ between females and males (IRR = 0.98, 95% CI [0.90, 1.07], p = .703). In an individual's life course, in-utero and the "first 1,000 days" are a particularly sensitive time period with marked long-term implications for NCDs if undernutrition/famine is experienced in this period. However, this window remains open until young adulthood. This highlights the need to invest more in preventing and treating child/adolescent undernutrition to tackle later-life NCDs.

Many factors may influence adaptation to critical life events such as divorce and bereavement in the second half of life, including having faced childhood adversity. However, pathways to reduced adaptation success are poorly understood. Self-continuity, an identity mechanism that incorporates life changes into a coherent life story, may contribute to better adaptation to adult critical life events, such as feeling less socially and emotionally lonely. We investigated the mediating role of self-continuity channeling the effects of childhood adversity on later life adaptation outcomes among individuals who had experienced divorce or bereavement. Data were derived from the longitudinal LIVES Intimate Partner Loss Study conducted in Switzerland from 2012 to 2016. The sample consisted of individuals who had experienced divorce (n = 416, Mage = 57.35) or bereavement (n = 339, Mage = 71.36) in later life, and a continuously married control group (n = 925, Mage = 67.04). Multilevel moderated mediations were used. Self-continuity mediated the effect of childhood adversity on emotional loneliness for all marital groups, but to a greater extent among divorcees. Self-continuity also mediated the effect of childhood adversity on social loneliness; however, this effect did not differ by marital group. In conclusion, childhood adversity was associated to greater loneliness in later life through self-continuity. Divorcees were the most impacted group regarding emotional loneliness, as they experienced lower levels of self-continuity. Interventions that aim to reinforce self-continuity may help overcome social and emotional loneliness, especially for individuals who have experienced the loss of their partner through divorce.

Abstract Background Recent developments in machine learning have shown its potential impact for clinical use such as risk prediction, prognosis, and treatment selection. However, relevant data are often scattered across different stakeholders and their use is regulated, e.g. by GDPR or HIPAA. As a concrete use-case, hospital Erasmus MC and health insurance company Achmea have data on individuals in the city of Rotterdam, which would in theory enable them to train a regression model in order to identify high-impact lifestyle factors for heart failure. However, privacy and confidentiality concerns make it unfeasible to exchange these data. Methods This article describes a solution where vertically-partitioned synthetic data of Achmea and of Erasmus MC are combined using Secure Multi-Party Computation. First, a secure inner join protocol takes place to securely determine the identifiers of the patients that are represented in both datasets. Then, a secure Lasso Regression model is trained on the securely combined data. The involved parties thus obtain the prediction model but no further information on the input data of the other parties. Results We implement our secure solution and describe its performance and scalability: we can train a prediction model on two datasets with 5000 records each and a total of 30 features in less than one hour, with a minimal difference from the results of standard (non-secure) methods. Conclusions This article shows that it is possible to combine datasets and train a Lasso regression model on this combination in a secure way. Such a solution thus further expands the potential of privacy-preserving data analysis in the medical domain.

Global repositories of postmarketing safety reports improve understanding of real-life drug toxicities, often not observed in clinical trials. The aim of this scoping review was to map the evidence from spontaneous reporting systems studies (SRSs) of antiangiogenic drugs (AADs) in cancer patients and highlight if the found disproportionality signals of adverse events (AEs) were validated and thus mentioned in the respective Summary of product Characteristics (SmPC). This scoping review was conducted according to PRISMA guidelines for scoping reviews. A knowledge gap on the safety of AADs was found: firstly, several cardiovascular AEs were not mentioned in the SmPCs and no pharmacovigilance studies were conducted despite the well-known safety concerns about these drugs on the cardiovascular system. Second, a disproportionality signal (not validated through causality assessment) of pericardial disease was found in the literature for axitinib with no mention in SmPC of the drug. Despite the exclusion of pharmacoepidemiological studies, we believe that this scoping review, which focuses on an entire class of drugs, could be considered as a novel approach to highlight possible safety concerns of drugs and as a guide for the conduction of a target postmarketing surveillance on AADs.