Default and Control Networks Connectivity Dynamics Track the Stream of Affect at Multiple Timescales

In everyday life, the stream of affect results from the interaction between past experiences, expectations and the unfolding of events. How the brain represents the relationship between time and affect has been hardly explored, as it requires modeling the complexity of everyday life in the laboratory setting. Movies condense into hours a multitude of emotional responses, synchronized across subjects and characterized by temporal dynamics alike real-world experiences. Here, we use time-varying intersubject brain synchronization and real-time behavioral reports to test whether connectivity dynamics track changes in affect during movie watching. The results show that polarity and intensity of experiences relate to the connectivity of the default mode and control networks and converge in the right temporoparietal cortex. We validate these results in two experiments including four independent samples, two movies and alternative analysis workflows. Finally, we reveal chronotopic connectivity maps within the temporoparietal and prefrontal cortex, where adjacent areas preferentially encode affect at specific timescales

Riluzole use in presence of contraindications in adults affected by amyotrophic lateral sclerosis and its off-label use in other motor neuron diseases: Findings from an Italian multicentre study (the {CAESAR} project)

Background: This analysis describes the use of riluzole in amyotrophic lateral sclerosis (ALS) individuals with contraindications and off-label use for subjects with other motor neuron diseases (o-MND) in the Italian regions of Latium, Tuscany and Umbria.Methods: A cohort of adults with ALS prescribed with riluzole during the years 2016–2019 was enrolled from administrative healthcare databases, excluding subjects with o-MND in the preceding 5 years. Being affected by ALS for more than 5 years, presence of tracheostomy, renal or hepatic failure were considered as contraindications to the use of riluzole. A cohort of adults with o-MND was enrolled in 2016–2019 for whom off-label use of riluzole was retrieved up to 4 years, analysing over the time differences related to sex.Results: Among 206 ALS individuals prescribed with riluzole in Latium, 336 in Tuscany and 60 in Umbria, less than 1% were diagnosed with ALS for more than 5 years. Less than 2% were tracheotomised or affected by hepatic failure. Renal failure was documented for 1.9%, 2.7%, and 5.0% of ALS individuals in Latium, Tuscany and Umbria. The o-MND cohort comprised 264 subjects in Latium, 222 in Tuscany, and 66 in Umbria. Non-negligible off-label riluzole use was observed: 8.5%, 33.0%, and 4.2% in females, and 19.9%, 26.5% and 2.4% in males in Latium, Tuscany and Umbria.Discussion: Riluzole use in ALS individuals in the presence of contraindications is rare, with slightly higher numbers in presence of renal failure. Off-label use in o-MND was found to be non-negligible, with variations between sexes

Assessing disease activity of rheumatoid arthritis patients and drug-utilization patterns of biologic disease-modifying antirheumatic drugs in the Tuscany region, Italy

Introduction: The disease activity associated with the drug-utilization patterns of biologic Disease Modifying Anti-Rheumatic Drugs (DMARDs) is poorly investigated in real-world studies on rheumatoid arthritis (RA) patients. To investigate the relationship between biologic DMARD initiation/discontinuations in RA patients identified in the healthcare administrative databases of Tuscany and the Disease Activity Score 28 (DAS28) reported in the medical charts.Methods: This retrospective population-based study included RA’s first-ever biologic DMARD users of the Pisa University Hospital from 2014 to 2016. Patients were followed up until 31 December 2019. We evaluated the DAS28 recorded before (T0) and after (T1) the biologic DMARD initiation and before (TD0) and after (TD1) discontinuations. Patients were classified as “off-target” (DAS28 > 3.2) or “in-target” (DAS28 ≤ 3.2). We described the disease activity trends at initiation and discontinuation.Results: Ninety-five users were included (73 women, mean age 59.6). Among 70 patients (74%) with at least three DAS28 measures, 28 (40.0%) were off-target at T0 and 38 (54.3%) in-target at T1. Thirty-three (47%) patients had at least one discontinuation, among those with at least three DAS28 assessments. In the disease activity trend, disease stability or improvement was observed in 28 out of 37 (75.7%) patients at initiation and in 24 out of 37 (64.9%) at discontinuation.Discussion: Biologic DMARD discontinuations identified in the healthcare administrative databasese of Tuscany are frequently observed in situations of controlled RA disease. Further studies are warranted to confirm that these events can be used in studies using healthcare administrative databases as proxies of treatment effectiveness

Farmaci di origine marina: panoramica sulle molecole gia' in uso e in studio clinico

L’obiettivo di questa tesi è presentare una panoramica sui farmaci di origine marina che attualmente sono disponibili in commercio o che sono in una delle 3 fasi di studio clinico. I composti naturali sono da sempre fondamentali per la scoperta e lo sviluppo di nuovi farmaci. Sono composti naturali o loro derivati alcuni dei pilastri della terapia farmacologica nell’ambito delle principali patologie: tumori, infezioni, dolore, malattie metaboliche e cardiovascolari, ecc. La fonte principale di composti naturali è sempre stato l’ambiente terrestre, in quanto più accessibile ed estremamente ricco di molecole biologicamente attive. Lo sviluppo di resistenza farmacologica alle terapie tradizionali e le difficoltà riscontrate nel trattamento di molte patologie ha portato ad ampliare l’orizzonte della ricerca farmacologica all’ambiente marino. Questo è stato possibile grazie a nuovi mezzi per l’esplorazione subacquea, a nuove conoscenze sulla biologia e la genomica, e allo sviluppo delle biotecnologie. Se è il regno vegetale ad avere un ruolo di primo piano nell’ambiente terrestre per l’enorme varietà di metaboliti secondari che offrono, nell’ambiente marino sono soprattutto gli animali ad aver attirato l’attenzione dei ricercatori. Gli animali marini invertebrati, spesso sessili o con una mobilità molto limitata, si avvalgono della produzione di metaboliti secondari, similmente alle piante, per espletare gran parte delle loro relazioni ecologiche. Si tratta di un patrimonio immenso di molecole biologicamente attive, spesso con caratteristiche uniche, frutto della enorme variabilità di habitat e specie che si trovano nella componente della biosfera più vasta e varia e allo stesso tempo più inesplorata. Molti di questi composti sono prodotti da microrganismi simbionti con l’animale superiore dalla quale sono state isolate per la prima volta. Si tratta spesso di potenti tossine prodotte dagli organismi eterotrofi marini a scopo difensivo o predatorio a causa della forte competizione ecologica a cui sono sottoposti e non è un caso che la maggior parte delle molecole in studio e in uso clinico siano agenti citotossici con attività antitumorale. La tesi è suddivisa in 4 capitoli, uno per ogni fase di studio clinico e uno per i farmaci in commercio. Nel primo capitolo vengono illustrate l’origine e le caratteristiche principali dei farmaci già in uso clinico, dai derivati delle spongosine al brentuximab vedotin, l’ultimo farmaco di origine marina approvato dall’EMA (2012) ed il primo anticorpo coniugato (ADC) con una tossina marina. Nei capitoli successivi vengono presentati i farmaci di origine marina attualmente in studio clinico, illustrando l’origine, le caratteristiche principali e alcuni dei trials clinici che li riguardano. La gran parte di questi farmaci sono ADC, anticorpi monoclonali coniugati con tossine derivate dalla dolastatina 10, isolata dalla lumaca marina Dolabella auricolaria, di cui Il brentuximab vedotin, illustrato nel primo capitolo, ne rappresenta il capostipite. La strategia alla base della costruzione degli ADC è il poter veicolare agenti citotossici estremamente potenti nei tessuti malati senza che siano coinvolti i tessuti sani. Gli ADC costituiscono un importante fronte di ricerca per la terapia antitumorale e le tossine marine si stanno dimostrando agenti antitumorali efficaci e adatti alla coniugazione con anticorpi monoclonali. Dei 41 farmaci illustrati in questa panoramica, 26 di essi sono ADC costituiti da anticorpi monoclonali diretti contro antigeni sovra-espressi nei tessuti tumorali, coniugati con un agente citotossico di origine marina. Molti di trials clinici illustrati in questa panoramica sono attualmente in corso e si attendono i risultati nei prossimi anni

From Life in the Sea to the Clinic: The Marine Drugs Approved and under Clinical Trial

In the last decades Blue Growth policy in european and non-european countries produced a great impulse in applied marine sciences, comprehending the research of new bioactive molecules in marine organisms. These organisms are a great source of natural compounds with unique features resulting from the huge variability of marine habitats and species living in them. Most of the marine compounds in use and in clinical trials are drugs for cancer therapy and many of them are conjugated to antibody to form antibody-drug conjugates (ADCs). Severe pain, viral infections, hypertriglyceridemia, obesity, Alzheimer’s and other CNS diseases are further target conditions for these pharmaceuticals. This review summarizes the state-of-the-art marine drugs focusing on the most successful results in the fast expanding field of marine pharmacology

Exploring pharmacological approaches for managing cytokine storm associated with pneumonia and acute respiratory distress syndrome in COVID-19 patients

Sars-CoV-2 complications include pneumonia and acute respiratory distress syndrome (ARDS), which require intensive care unit admission. These conditions have rapidly overwhelmed healthcare systems, with detrimental effects on the quality of care and increased mortality. Social isolation strategies have been implemented worldwide with the aim of reducing hospital pressure. Among therapeutic strategies, the use of immunomodulating drugs, to improve prognosis, seems promising. Particularly, since pneumonia and ARDS are associated with a cytokine storm, drugs belonging to therapeutic classes as anti-IL-6, anti-TNF, and JAK inhibitors are currently studied. In this article, we discuss the potential advantages of the most promising pharmacological approaches

Investigating a Signal of Acquired Hemophilia Associated with COVID-19 Vaccination: A Systematic Case Review

Acquired hemophilia A (AHA), a rare but life-threatening disorder, most commonly occurs in older people and during pregnancy. During the coronavirus disease 2019 (COVID-19) vaccination campaign, an unexpected number of newly diagnosed AHA patients have been identified in clinical practice that were temporally related to COVID-19 vaccination. We present the result of a signal detection analysis aimed at exploring a possible association between COVID-19 immunization and occurrence of AHA. A disproportionality analysis on the World Health Organization (WHO) database was performed to investigate the presence of a signal of risk for AHA associated with COVID-19 vaccines. Reports of AHA associated with any COVID-19 vaccine included in the WHO database were then integrated with those available on the Food and Drug Administration Vaccine Adverse Events Reporting System and those published in the medical literature. The WHO database included 146 reports of AHA. The information component (IC) was significant for the association of AHA with all COVID-19 vaccines (IC025: 1.1) and with the vaccine product BNT162b2 (IC025: 1.6). After duplicate exclusion, 96 unique cases of AHA following COVID-19 vaccines have been reviewed. Median time to diagnosis was 18 days and 40% of cases documented the occurrence after the second dose. Overall, in 57% of the investigated cases, a preexisting condition predisposing to AHA was excluded. About 22% of cases occurred in subjects with age ≤65 years and there was no case associated with pregnancy. Mortality was 11%. Although we cannot exclude that the unexpected frequency of AHA diagnosis can be explained by a detection bias, the signal for COVID-19 vaccine-related AHA is robust and deserves further investigations

An interesting question of Pompe disease. A case report

Glycogenosis type II or Pompe disease is an inherited autosomal recessive disorder known in 3 different clinical forms (infantile, juvenile and adult). We report on a case diagnosed as a classic infantile form with the worst outcome of all 3 described, if we had followed and executed a correct and complete diagnostic pathway. A 7 months old female child was admitted for fever and dyspnoea. At chest auscultation weepings and weezings were found; on the cardiac apex a murmur due to mitralic failure was retrieved. The thorax X-ray showed a greatly increased heart shadow with a cardiothoracic index of 0.75. ECG showed high voltages and signs of bilateral ventricular hypertrophy. Cardiac ultrasonography confirmed the presence of a big heart with an enormous swollen left ventricle and a severe mitralic failure. The clinical diagnosis of infantile Pompe disease was confirmed by the almost total absence of cellular acid α-glucosidase activity but we couldn't perform the assay because of the rapid exitus of our patient, which occurred before gtycogen storage disease II was suspected. So, we tried to compare our case with others reported in the literature in order to ratify our diagnostic hypothesis. The contribution of genetic counseling practiced on all the couples at risk remains useful every time that a certain diagnosis is made

Drug-Utilization, Healthcare Facilities Accesses and Costs of the First Generation of JAK Inhibitors in Rheumatoid Arthritis

: This study is aimed at describing tofacitinib and baricitinib users by characterizing their prescription and healthcare histories, drug and healthcare utilization patterns, and direct costs from a healthcare system perspective. This retrospective cohort study was performed using Tuscan administrative healthcare databases, which selected two groups of Janus kinase inhibitors (JAKi) incident users (index date) from 1st January 2018 to 31 December 2019 and from 1 January 2018 to 30 June 2019. We included patients ≥18 years old, at least 10 years of data, and six months of follow-up. In the first analysis, we describe mean time, standard deviation (SD), from the first-ever disease-modifying antirheumatic drug (DMARD) to the JAKi, and costs of healthcare facilities and drugs in the 5 years preceding the index date. In the second analysis, we assessed Emergency Department (ED) accesses and hospitalizations for any causes, visits, and costs in the follow-up. In the first analysis, 363 incident JAKi users were included (mean age 61.5, SD 13.6; females 80.7%, baricitinib 78.5%, tofacitinib 21.5%). The time to the first JAKi was 7.2 years (SD 3.3). The mean costs from the fifth to the second year before JAKi increased from 4325 € (0; 24,265) to 5259 € (0; 41,630) per patient/year, driven by hospitalizations. We included 221 incident JAKi users in the second analysis. We observed 109 ED accesses, 39 hospitalizations, and 64 visits. Injury and poisoning (18.3%) and skin (13.8%) caused ED accesses, and cardiovascular (69.2%) and musculoskeletal (64.1%) caused hospitalizations. The mean costs were 4819 € (607.5; 50,493) per patient, mostly due to JAKi. In conclusion, the JAKi introduction in therapy occurred in compliance with RA guidelines and the increase in costs observed could be due to a possible selective prescription