Markers of physical functioning and neuromuscular fatigue for the post-discharge follow-up of subjects already assisted in intensive care for COVID-19 and non-communicable diseases.

L'insorgenza di malattie non trasmissibili con incidenza neuromuscolare e il prolungato ricovero in terapia intensiva comportano implicazioni negative sulla capacità funzionale e l'autonomia dei pazienti. Queste alterazioni sono causate da fattori come l'immobilità prolungata, l'infiammazione sistemica, le disfunzioni neuromuscolari e gli effetti diretti della patologia stessa. Ciò porta a fatica e debolezza muscolare, contribuendo a un significativo declino nelle abilità motorie, ostacolando il recupero e peggiorando la qualità della vita dei pazienti. Le principali disfunzioni motorie si manifestano con l’alterata deambulazione, limitando l'autonomia nelle attività quotidiane. Tali disfunzioni sono causate dalla compromissione delle vie motorie del sistema nervoso e si manifestano già durante la fase acuta della malattia, peggiorando successivamente con il suo evolversi. Tale quadro clinico è aggravato ulteriormente dalla conseguente inattività fisica, favorita dalle condizioni psicofisiche dei singoli. Di conseguenza, tutto ciò incide notevolmente sulle proprietà contrattili dei muscoli, portando ad alterazioni critiche che influenzano la capacità del sistema nervoso centrale e periferico di reclutare e modulare l'attività delle unità motorie. Date le complessità associate a queste considerazioni, diventa fondamentale identificare marcatori in grado di quantificare e caratterizzare l’alterazione della capacità funzionale e l’insorgenza della debolezza muscolare e della fatica. Ciò faciliterebbe una diagnosi precoce e, in modo cruciale, il monitoraggio continuo di tali problematiche. Pertanto, l'obiettivo primario di questa ricerca di Dottorato è identificare e analizzare marcatori in grado di supportare efficacemente gli operatori sanitari nella progettazione e nell'implementazione di approcci terapeutici personalizzati per accelerare il recupero di questi individui. Nonostante, infatti, la pratica clinica attualmente in uso negli ospedali offra continui miglioramenti, questa presenta ancora delle limitazioni. Sebbene le valutazioni attualmente impiegate riescano ad identificare la presenza di fatica e debolezza muscolare nei pazienti post-ricovero in terapia intensiva o in soggetti affetti da malattie non trasmissibili, non riescono tuttavia ad indagare a fondo su quali siano le effettive cause che innescano la perdita della forza muscolare o ad esaminare in modo esaustivo i fattori centrali e/o periferici che contribuiscono all'insorgenza della fatica. Per colmare in modo esaustivo questa lacuna, lo studio ha condotto un'ampia ricerca combinando l'elettromiografia di superficie con la capacità di generare forza muscolare in diverse condizioni patologiche, includendo attivazioni muscolari sia volontarie che indotte elettricamente. Il muscolo oggetto di studio è stato il tibiale anteriore, scelto per il suo ruolo cruciale nella biomeccanica della deambulazione e quindi fondamentale per il mantenimento dell’autonomia motoria. I risultati hanno mostrato che le variazioni nella forza e nei parametri delle unità motorie possono servire da indicatori per le alterazioni neuromuscolari e il recupero progressivo, facilitando il monitoraggio a breve e lungo termine. Questo studio ha quindi un'importanza fondamentale per le popolazioni coinvolte e può suggerire approcci più ampi per la gestione delle alterazioni neuromuscolari in diversi contesti clinici. In particolare, sottolinea l'importanza di programmi di riabilitazione personalizzati e soggettivati alle esigenze specifiche di ciascun individuo.The onset of non-communicable neuromuscular diseases and prolonged stays in the intensive care unit have deep implications for physical functioning and neuromuscular health. These repercussions arise from muscle deconditioning, systemic inflammation, and the direct impact of the pathology. Moreover, resulting fatigue and acquired muscle weakness contribute to reduced muscular performance, significantly hampering recovery and diminishing overall quality of life. The predominant motor impairments observed in these patients primarily manifest in their ability to perform correct walking, substantially limiting their independent execution of daily activities. This compromised excitability in descending motor pathways becomes evident during the acute phase of the disease and intensifies as the condition progresses chronically, exacerbated by prolonged physical inactivity. Consequently, this significantly affects the muscle's contractile properties, leading to critical alterations that influence the nervous systems' capacity to recruit and modulate the activity of motor units, the fundamental functional units responsible for planning, executing, and maintaining motor gestures. Given these considerations, it becomes crucial to identify markers that enable the quantification and characterization of physical functioning impairment, muscle weakness and fatigue. This would facilitate early diagnosis and, crucially, the ongoing monitoring of these issues. Thus, the primary goal of this PhD research is to identify and analyze markers that can effectively support healthcare practitioners in devising and delivering personalized therapeutic approaches to expedite the recovery of these individuals. The overarching objective is to optimize the current clinical practice commonly employed in hospitals. Despite ongoing refinements, these practices still exhibit limitations. While standard assessments succeed in identifying the presence of fatigue and muscle weakness in ICU patients or those afflicted by non-communicable diseases, they fall short of investigating the root causes of muscle strength deterioration or thoroughly probing the central and/or peripheral factors contributing to the emergence of pathological fatigue. To comprehensively bridge this existing gap, the study undertook an extensive exploration by measuring concurrent joint torques and surface electromyography across various pathological conditions, encompassing both voluntary and electrically induced muscle activations. The focal point was the tibialis anterior muscle, chosen for its pivotal role in gait patterns and consequential influence on individual autonomy. The presented results were mainly achieved through the decomposition of signals recorded using the High-Density Surface EMG technique. This technique enabled the analysis of individual motor units recruited during motor tasks administered to patients within the studied populations. The process of data collection and analysis revealed that variations in muscle strength values and motor unit parameters can serve as indicators of neuromuscular system alterations and progressive recovery. These factors are pivotal for subsequent follow-up procedures. Indeed, by establishing a robust framework of markers, is possible to contribute to the development of evidence-based protocols that enhance the post-discharge care of these individuals. This study is not only pivotal for these specific cohorts but also holds the potential to inform broader strategies for managing physical impairment and neuromuscular challenges in diverse clinical settings. Notably, the study highlights that hospitalization in intensive care, as well as the onset of non-communicable pathologies with high motor impact, leads to specific alterations in parameters of both central and peripheral neuromuscular pathways. This underscores the imperative for devising personalized rehabilitation regimens tailored to each patient's needs

Neuropsychiatric symptoms in Systemic Lupus Erythematosus: mixed methods analysis of patient-derived attributional evidence in the international INSPIRE project

Objective: Attribution of neuropsychiatric symptoms in systemic lupus erythematosus (SLE) relies heavily on clinician assessment. Limited clinic time, variable knowledge and symptom under-reporting contribute to discordance between clinician assessments and patient symptoms. We obtained attributional data directly from patients and clinicians in order to estimate and compare potential levels of direct attribution to SLE of multiple neuropsychiatric symptoms using different patient-derived measures. Methods: Quantitative and qualitative data analysed included: the prevalence and frequency of neuropsychiatric symptoms, response to corticosteroids and concurrence of neuropsychiatric symptoms with non-neuropsychiatric SLE disease activity. SLE patients were also compared with controls and inflammatory arthritis (IA) patients to explore the attributability of neuropsychiatric symptoms to the direct disease effects on the brain/nervous system. Results: We recruited 2817 participants, including 400 clinicians. SLE patients (n = 609) reported significantly higher prevalences of neuropsychiatric symptoms than controls (n = 463) and IA patients (n = 489). SLE and IA patients' quantitative data demonstrated multiple neuropsychiatric symptoms relapsing/remitting with other disease symptoms such as joint pain. Over 45% of SLE patients reported resolution/improvement of fatigue, positive sensory symptoms, severe headache, and cognitive dysfunction with corticosteroids. Evidence of direct attributability in SLE was highest for hallucinations and severe headache. SLE patients had greater reported improvement from corticosteroids (p= 0.008), and greater relapsing-remitting with disease activity (P < 0.001) in the comparisons with IA patients for severe headache. Clinicians and patients reported insufficient time to discuss patient-reported attributional evidence. Symptoms viewed as indirectly related/non-attributable were often less prioritized for discussion and treatment. Conclusion: We found evidence indicating varying levels of direct attributability of both common and previously unexplored neuropsychiatric symptoms in SLE patients, with hallucinations and severe headache assessed as the most directly attributable. There may also be-currently under-estimated-direct effects on the nervous system in IA and other systemic rheumatological diseases

Animal spirits, bankruptcies, and monetary policy effectiveness in a hybrid macroeconomic agent-based financial accelerator model

This paper develops a hybrid model with an agent-based financial accelerator framework embedded in a standard new Keynesian economy. It explores the interactions between the financial accelerator and the credit market, focusing on the effects of bankruptcy. The paper replicates credit-market relationships, modeling various credit crunch scenarios. It uncovers endogenous fluctuations and "animal spirits" in entrepreneurs' expectations, driving investment and production decisions. Notably, higher pro-cyclical leverage can have destabilizing effects in the presence of small shocks, increasing entrepreneurs' bankruptcies. The results suggest that monetary policy's effectiveness in stabilizing fluctuations depends on factors such as heterogeneity, bounded rationality, and heuristic updating mechanisms. Moderate monetary policies perform better in terms of economic growth with moderate-to-low volatility, while aggressive policies on inflation assist bounded rational agents in reducing errors in investment decisions and default rates, fostering a more stable macroeconomic environment. Increasing forecasting options introduces diversification among entrepreneurs, reducing volatility and stabilizing investments. More options mitigate investment fluctuations, acting as a counterbalance to prevailing market sentiments. Over time, individuals weakly adhering to trends or adopting contrarian approaches come to dominate the population of entrepreneurs, enhancing the overall stability of investment decisions

Federalizing process europeo e sussidiarietà: la cooperazione tra autorità di controllo nella trasformazione digitale

Una delle tematiche, di particolare attualità, approfondita dal prof. Caravita nell’ambito del progetto Jean Monnet Chair 2020, porta il titolo “The European Path of Artificial Intelligence (EPAI)”. Questo filone di ricerca si inserisce nel solco di precedenti studi che fanno dell’Unione Europea il leit motiv, e va quindi letto quale coerente ed ulteriore sviluppo del Suo pensiero sul federalizing process europeo e sulla sussidiarietà. Il contributo, prendendo le mosse da questa “intersezione tematica”, tra trasformazione digitale, federalizing process europeo e sussidiarietà, “crocevia” attraverso cui si snodano le dinamiche qualificanti il processo di integrazione europea, pone il focus sulla cooperazione rafforzata che a livello europeo si va realizzando tra autorità competenti, con specifico riguardo alla transizione digitale. Su tali basi viene quindi a rafforzarsi la "terza matrice" del processo eurounitario (transgovernativa, in aggiunta alle matrici comunitaria e intergovernativa) che trova nel principio di sussidiarietà il proprio fondamento

Role of the repeat expansion size in predicting age of onset and severity in RFC1 disease

RFC1 disease, caused by biallelic repeat expansion in RFC1, is clinically heterogeneous in terms of age of onset, disease progression and phenotype. We investigated the role of the repeat size in influencing clinical variables in RFC1 disease. We also assessed the presence and role of meiotic and somatic instability of the repeat. In this study, we identified 553 patients carrying biallelic RFC1 expansions and measured the repeat expansion size in 392 cases. Pearson's coefficient was calculated to assess the correlation between the repeat size and age at disease onset. A Cox model with robust cluster standard errors was adopted to describe the effect of repeat size on age at disease onset, on age at onset of each individual symptoms, and on disease progression. A quasi-Poisson regression model was used to analyse the relationship between phenotype and repeat size. We performed multivariate linear regression to assess the association of the repeat size with the degree of cerebellar atrophy. Meiotic stability was assessed by Southern blotting on first-degree relatives of 27 probands. Finally, somatic instability was investigated by optical genome mapping on cerebellar and frontal cortex and unaffected peripheral tissue from four post-mortem cases. A larger repeat size of both smaller and larger allele was associated with an earlier age at neurological onset [smaller allele hazard ratio (HR) = 2.06, P < 0.001; larger allele HR = 1.53, P < 0.001] and with a higher hazard of developing disabling symptoms, such as dysarthria or dysphagia (smaller allele HR = 3.40, P < 0.001; larger allele HR = 1.71, P = 0.002) or loss of independent walking (smaller allele HR = 2.78, P < 0.001; larger allele HR = 1.60; P < 0.001) earlier in disease course. Patients with more complex phenotypes carried larger expansions [smaller allele: complex neuropathy rate ratio (RR) = 1.30, P = 0.003; cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) RR = 1.34, P < 0.001; larger allele: complex neuropathy RR = 1.33, P = 0.008; CANVAS RR = 1.31, P = 0.009]. Furthermore, larger repeat expansions in the smaller allele were associated with more pronounced cerebellar vermis atrophy (lobules I-V β =-1.06, P < 0.001; lobules VI-VII β =-0.34, P = 0.005). The repeat did not show significant instability during vertical transmission and across different tissues and brain regions. RFC1 repeat size, particularly of the smaller allele, is one of the determinants of variability in RFC1 disease and represents a key prognostic factor to predict disease onset, phenotype and severity. Assessing the repeat size is warranted as part of the diagnostic test for RFC1 expansion

On the Existence and Stability of 2D Compressible Current-Vortex Sheets

We study the existence and the stability of two-dimensional current-vortex sheets in ideal compressible magnetohydrodynamics. Under a suitable stability condition for the background state, we show that the linearized current-vortex sheets problem obeys an energy estimate in anisotropic weighted Sobolev spaces with a loss of derivatives. Then we establish the local-in-time existence and nonlinear stability of current-vortex sheets by a suitable Nash–Moser iteration, provided the stability condition is satisfied at each point of the initial discontinuity. This survey paper presents our recent results in Morando et al. (Arch. Rational Mech. Anal. 247, 50 (2023))

High with low: Harnessing the power of demand-side solutions for high wellbeing with low energy and material demand

The authors are all devoted energy system and sustainability transformation scholars, who collaborate regularly and actively at global and local levels to advance the knowledge space of demand-side solutions and policies. They are members of a growing bottom-up initiative, the Energy Demand Changes Induced by Technological and Social Innovations (EDITS) network (https://iiasa.ac.at/projects/edits), which builds on various research disciplines to facilitate advances in modeling, data compilation, and analysis of the scope and breadth of the potential contributions of demand-side solutions for climate change mitigation, improved wellbeing for all, and sustainability, complementing supply-side solutions for decarbonizing the energy and material systems