Prevalence of Fabry disease and GLA variants in young patients with acute stroke: The challenge to widen the screening. The Fabry-Stroke Italian Registry.

BACKGROUND: Fabry disease (FD) is a treatable X-linked lysosomal storage disorder caused by GLA gene variants leading to alpha-galactosidase A deficiency. FD is a rare cause of stroke, and it is still controversial whether in stroke patients FD should be searched from the beginning or at the end of the diagnostic workup (in cryptogenic strokes). METHODS: Fabry-Stroke Italian Registry is a prospective, multicentric screening involving 33 stroke units. FD was sought by measuring α-galactosidase A activity (males) and by genetic tests (males with reduced enzyme activity and females) in patients aged 18-60 years hospitalized for TIA, ischemic stroke, or intracerebral hemorrhage. We diagnosed FD in patients with 1) already known pathogenic GLA variants; 2) novel GLA variants if additional clinical, laboratory, or family-derived criteria were present. RESULTS: Out of 1906 patients, we found a GLA variant in 15 (0.79%; 95%CI 0.44-1.29) with a certain FD diagnosis in 3 (0.16%; 95%CI 0.03-0.46) patients, none of whom had hemorrhage. We identified 1 novel pathogenic GLA variant. Ischemic stroke etiologies in carriers of GLA variants were: cardioaortic embolism (33%), small artery occlusion (27%), other causes (20%), and undetermined (20%). Mild severity, recurrence, previous TIA, acroparesthesias, hearing loss, and small artery occlusion were predictors of GLA variant. CONCLUSION: In this large multicenter cohort the frequency of FD and GLA variants was consistent with previous reports. Limiting the screening for GLA variants to patients with cryptogenic stroke may miss up to 80% of diagnoses. Some easily recognizable clinical features could help select patients for FD screening.

Impulsivity Traits in Parkinson's Disease: A Systematic Review and Meta-Analysis.

Background: In Parkinson's disease (PD), impulsivity as a personality trait may be linked to the risk of developing impulse control disorders (ICDs) during dopaminergic therapy. However, studies evaluating differences in trait impulsivity between patients with PD and healthy controls or between patients with PD with and without ICDs reported partly inconsistent findings. Objectives: We conducted a systematic review and meta-analysis (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) of studies comparing Barratt Impulsiveness Scale (BIS-11) scores between patients with PD and healthy controls and between patients with PD with and without ICDs. Methods: Eligible studies were identified through a systematic search in 3 databases. Mean differences with 95% confidence intervals (CIs) for BIS-11 total and subscale scores were separately calculated for studies comparing patients with PD and healthy controls and patients with PD with and without ICDs. Meta-regressions were performed to explore sources of heterogeneity (percentage of men, age, disease duration, and levodopa equivalent daily dose). Results: A total of 40 studies were included in the quantitative analyses. BIS-11 total scores were significantly higher in patients with PD compared with healthy controls (mean difference 2.43; 95% CI, 1.03, 3.83), and in patients with PD with active ICDs compared with patients without ICDs (6.62; 95% CI, 5.01, 8.23). No significant moderators emerged by meta-regression analyses. Conclusions: The present meta-analysis supports that impulsivity, as a personality trait, may characterize patients with PD, even in the absence of ICDs. Moreover, these data corroborate findings of clinical studies reporting higher levels of trait impulsivity in PD patients with ICDs compared with patients without ICDs.

Jupiter Science Enabled by ESA's Jupiter Icy Moons Explorer.

ESA's Jupiter Icy Moons Explorer (JUICE) will provide a detailed investigation of the Jovian system in the 2030s, combining a suite of state-of-the-art instruments with an orbital tour tailored to maximise observing opportunities. We review the Jupiter science enabled by the JUICE mission, building on the legacy of discoveries from the Galileo, Cassini, and Juno missions, alongside ground- and space-based observatories. We focus on remote sensing of the climate, meteorology, and chemistry of the atmosphere and auroras from the cloud-forming weather layer, through the upper troposphere, into the stratosphere and ionosphere. The Jupiter orbital tour provides a wealth of opportunities for atmospheric and auroral science: global perspectives with its near-equatorial and inclined phases, sampling all phase angles from dayside to nightside, and investigating phenomena evolving on timescales from minutes to months. The remote sensing payload spans far-UV spectroscopy (50-210 nm), visible imaging (340-1080 nm), visible/near-infrared spectroscopy (0.49-5.56 µm), and sub-millimetre sounding (near 530-625 GHz and 1067-1275 GHz). This is coupled to radio, stellar, and solar occultation opportunities to explore the atmosphere at high vertical resolution; and radio and plasma wave measurements of electric discharges in the Jovian atmosphere and auroras. Cross-disciplinary scientific investigations enable JUICE to explore coupling processes in giant planet atmospheres, to show how the atmosphere is connected to (i) the deep circulation and composition of the hydrogen-dominated interior; and (ii) to the currents and charged particle environments of the external magnetosphere. JUICE will provide a comprehensive characterisation of the atmosphere and auroras of this archetypal giant planet.

Incidence and Long-term Functional Outcome of Neurologic Disorders in Hospitalized Patients With COVID-19 Infected With Pre-Omicron Variants.

BACKGROUND AND OBJECTIVES: A variety of neurologic disorders have been reported as presentations or complications of coronavirus disease 2019 (COVID-19) infection. The objective of this study was to determine their incidence dynamics and long-term functional outcome. METHODS: The Neuro-COVID Italy study was a multicenter, observational, cohort study with ambispective recruitment and prospective follow-up. Consecutive hospitalized patients presenting new neurologic disorders associated with COVID-19 infection (neuro-COVID), independently from respiratory severity, were systematically screened and actively recruited by neurology specialists in 38 centers in Italy and the Republic of San Marino. The primary outcomes were incidence of neuro-COVID cases during the first 70 weeks of the pandemic (March 2020-June 2021) and long-term functional outcome at 6 months, categorized as full recovery, mild symptoms, disabling symptoms, or death. RESULTS: Among 52,759 hospitalized patients with COVID-19, 1,865 patients presenting 2,881 new neurologic disorders associated with COVID-19 infection (neuro-COVID) were recruited. The incidence of neuro-COVID cases significantly declined over time, comparing the first 3 pandemic waves (8.4%, 95% CI 7.9-8.9; 5.0%, 95% CI 4.7-5.3; 3.3%, 95% CI 3.0-3.6, respectively; p = 0.027). The most frequent neurologic disorders were acute encephalopathy (25.2%), hyposmia-hypogeusia (20.2%), acute ischemic stroke (18.4%), and cognitive impairment (13.7%). The onset of neurologic disorders was more common in the prodromic phase (44.3%) or during the acute respiratory illness (40.9%), except for cognitive impairment whose onset prevailed during recovery (48.4%). A good functional outcome was achieved by most patients with neuro-COVID (64.6%) during follow-up (median 6.7 months), and the proportion of good outcome increased throughout the study period (r = 0.29, 95% CI 0.05-0.50; p = 0.019). Mild residual symptoms were frequently reported (28.1%) while disabling symptoms were common only in stroke survivors (47.6%). DISCUSSION: Incidence of COVID-associated neurologic disorders decreased during the prevaccination phase of the pandemic. Long-term functional outcome was favorable in most neuro-COVID disorders, although mild symptoms commonly lasted more than 6 months after infection.

Tumour growth control: analysis of alternative approaches.

In this work we address the problem of tumour growth control by properly exploiting a low-dimensional model that grounds on the Chemical Reaction Network (CRN) formalism. Originally conceived to work both in deterministic and stochastic frameworks, it is shown that, except for the case of very low number of tumour cells, the deterministic approach is appropriate to characterize the system behaviour, especially for control planning purposes. Two alternative control approaches are here investigated. One trivially assumes a constant infusion of external drug administration, the other is designed according to a state-feedback control scheme, with complete or partial knowledge of the state. Pros and cons of both control laws are investigated, showing that the tumour size at the beginning of the therapy plays a role of paramount importance for fixed infusion therapies, whilst only state-feedback laws can eradicate arbitrarily large tumours.

Time-dependent recovery of brain hypometabolism in neuro-COVID-19 patients.

PURPOSE: We evaluated brain metabolic dysfunctions and associations with neurological and biological parameters in acute, subacute and chronic COVID-19 phases to provide deeper insights into the pathophysiology of the disease. METHODS: Twenty-six patients with neurological symptoms (neuro-COVID-19) and [18F]FDG-PET were included. Seven patients were acute (< 1 month (m) after onset), 12 subacute (4 ≥ 1-m, 4 ≥ 2-m and 4 ≥ 3-m) and 7 with neuro-post-COVID-19 (3 ≥ 5-m and 4 ≥ 7-9-m). One patient was evaluated longitudinally (acute and 5-m). Brain hypo- and hypermetabolism were analysed at single-subject and group levels. Correlations between severity/extent of brain hypo- and hypermetabolism and biological (oxygen saturation and C-reactive protein) and clinical variables (global cognition and Body Mass Index) were assessed. RESULTS: The "fronto-insular cortex" emerged as the hypometabolic hallmark of neuro-COVID-19. Acute patients showed the most severe hypometabolism affecting several cortical regions. Three-m and 5-m patients showed a progressive reduction of hypometabolism, with limited frontal clusters. After 7-9 months, no brain hypometabolism was detected. The patient evaluated longitudinally showed a diffuse brain hypometabolism in the acute phase, almost recovered after 5 months. Brain hypometabolism correlated with cognitive dysfunction, low blood saturation and high inflammatory status. Hypermetabolism in the brainstem, cerebellum, hippocampus and amygdala persisted over time and correlated with inflammation status. CONCLUSION: Synergistic effects of systemic virus-mediated inflammation and transient hypoxia yield a dysfunction of the fronto-insular cortex, a signature of CNS involvement in neuro-COVID-19. This brain dysfunction is likely to be transient and almost reversible. The long-lasting brain hypermetabolism seems to reflect persistent inflammation processes.

Impulsivity traits and awareness of motor intention in Parkinson's disease: a proof-of-concept study.

INTRODUCTION: In patients with Parkinson's disease (PD), impulsivity is still a matter of investigation. It has been hypothesized that impulsive personality traits may favour impulse control disorder (ICD) onset during dopaminergic therapy. In healthy subjects, a relationship between the awareness of motor intention and impulsive personality traits assessed by the Barratt impulsivity scale (BIS-11) has been reported. The aim of this study was to evaluate the relationship between the awareness of voluntary action and impulsivity traits in PD. METHODS: Twenty-eight PD patients (stages I-III on the Hoehn and Yahr scale) underwent an impulsivity trait assessment by the BIS-11 scale and a task based on the Libet's clock. Participants were requested to perform a self-initiated movement and report the time they first feel their intention to move (W-judgement) or the time of the actual movement (M-judgement). RESULTS: In patients with higher BIS-11 scores, the time lag between the W-judgement and the actual movement was significantly lower than in patients with lower BIS-11. No difference emerged in the M-judgement. CONCLUSION: Data suggest that also in PD patients, the impulsive personality trait is related to a "delayed" awareness of motor intention and therefore to a shorter interval to allow a conscious "veto" of the impending action. Characterization of the temporal profile of awareness of motor intention could prove useful in identifying PD patients at risk of developing ICDs during dopaminergic treatment.

Fabry-Stroke Italian Registry (FSIR): a nationwide, prospective, observational study about incidence and characteristics of Fabry-related stroke in young-adults. Presentation of the study protocol.

BACKGROUND: TIA and stroke, both ischemic and hemorrhagic, may complicate Fabry disease at young-adult age and be the first manifestation that comes to the clinician's attention. No definite indications have yet been elaborated to guide neurologists in Fabry disease diagnostics. In current practice, it is usually sought in case of cryptogenic strokes (while Fabry-related strokes can also occur by classical pathogenic mechanisms) or through screening programs in young cerebrovascular populations. Data on recurrence and secondary prevention of Fabry's stroke are scanty. METHODS: The study had a prospective observational design involving 33 Italian neurological Stroke Units. Considering the incidence of TIA/stroke in the European population aged < 60 years and the frequency of Fabry disease in this category (as foreseen by a pilot study held at the Careggi University-Hospital, Florence), we planned to screen for Fabry disease a total of 1740 < 60-year-old individuals hospitalized for TIA, ischemic, or hemorrhagic stroke. We investigated TIA and stroke pathogenesis through internationally validated scales and we gathered information on possible early signs of Fabry disease among all cerebrovascular patients. Every patient was tested for Fabry disease through dried blood spot analysis. Patients who received Fabry disease diagnosis underwent a 12-month follow-up to monitor stroke recurrence and multi-system progression after the cerebrovascular event. DISCUSSION: The potential implications of this study are as follows: (i) to add information about the yield of systematic screening for Fabry disease in a prospective large cohort of acute cerebrovascular patients; (ii) to deepen knowledge of clinical, pathophysiological, and prognostic characteristics of Fabry-related stroke.

Optimal design of lock-down and reopening policies for early-stage epidemics through SIR-D models.

The diffusion of COVID-19 represents a real threat for the health and economic system of a country. Therefore the governments have to adopt fast containment measures in order to stop its spread and to prevent the related devastating consequences. In this paper, a technique is proposed to optimally design the lock-down and reopening policies so as to minimize an aggregate cost function accounting for the number of individuals that decease due to the spread of COVID-19. A constraint on the maximal number of concomitant infected patients is also taken into account in order to prevent the collapse of the health system. The optimal procedure is built on the basis of a simple SIR model that describes the outbreak of a generic disease, without attempting to accurately reproduce all the COVID-19 epidemic features. This modeling choice is motivated by the fact that the containing measurements are actuated during the very first period of the outbreak, when the characteristics of the new emergent disease are not known but timely containment actions are required. In fact, as a consequence of dealing with poor preliminary data, the simplest modeling choice is able to reduce unidentifiability problems. Further, the relative simplicity of this model allows to compute explicitly its solutions and to derive closed-form expressions for the maximum number of infected and for the steady-state value of deceased individuals. These expressions can be then used to design static optimization problems so to determine the (open-loop) optimal lock-down and reopening policies for early-stage epidemics accounting for both the health and economic costs.

Mixture distributions in a stochastic gene expression model with delayed feedback: a WKB approximation approach.

Noise in gene expression can be substantively affected by the presence of production delay. Here we consider a mathematical model with bursty production of protein, a one-step production delay (the passage of which activates the protein), and feedback in the frequency of bursts. We specifically focus on examining the steady-state behaviour of the model in the slow-activation (i.e. large-delay) regime. Using a formal asymptotic approach, we derive an autonomous ordinary differential equation for the inactive protein that applies in the slow-activation regime. If the differential equation is monostable, the steady-state distribution of the inactive (active) protein is approximated by a single Gaussian (Poisson) mode located at the globally stable fixed point of the differential equation. If the differential equation is bistable (due to cooperative positive feedback), the steady-state distribution of the inactive (active) protein is approximated by a mixture of Gaussian (Poisson) modes located at the stable fixed points; the weights of the modes are determined from a WKB approximation to the stationary distribution. The asymptotic results are compared to numerical solutions of the chemical master equation.

Epilepsy and brain channelopathies from infancy to adulthood.

Genetic brain channelopathies result from inherited or de novo mutations of genes encoding ion channel subunits within the central nervous system. Most neurological channelopathies arise in childhood with paroxysmal or episodic symptoms, likely because of a transient impairment of homeostatic mechanisms regulating membrane excitability, and the prototypical expression of this impairment is epilepsy. Migraine, episodic ataxia and alternating hemiplegia can also occur, as well as chronic phenotypes, such as spinocerebellar ataxias, intellectual disability and autism spectrum disorder. Voltage-gated and ligand-gated channels may be involved. In most cases, a single gene may be associated with a phenotypical spectrum that shows variable expressivity. Different clinical features may arise at different ages and the adult phenotype may be remarkably modified from the syndrome onset in childhood or adolescence. Recognizing the prominent phenotypical traits of brain channelopathies is essential to perform appropriate diagnostic investigations and to provide the better care not only in the paediatric setting but also for adult patients and their caregivers. Herein, we provide an overview of genetic brain channelopathies associated with epilepsy, highlight the different molecular mechanisms and describe the different clinical characteristics which may prompt the clinician to suspect specific syndromes and to possibly establish tailored treatments.

Optical design of the High Resolution Imaging Channel of SIMBIO-SYS: publisher's note.

This publisher's note corrects several sections in Appl. Opt.58, 4059 (2019)1559-128X10.1364/AO.58.004059.

Optical design of the High Resolution Imaging Channel of SIMBIO-SYS.

This paper describes the optical design of the High Resolution Imaging Channel (HRIC), which is part of the spectrometers and imagers for the Mercury Planetary Orbiter BepiColombo Integrated Observatory SYStem (SIMBIO-SYS) suite, for imaging and spectroscopic investigation of Mercury. The optical design has been optimized to achieve the stringent scientific requirement of 5 m ground sampling at 400 km from the planet's surface in the harsh Mercury environment.

Hypertension, seizures, and epilepsy: a review on pathophysiology and management.

BACKGROUND: Epilepsy and hypertension are common chronic conditions, both showing high prevalence in older age groups. This review outlines current experimental and clinical evidence on both direct and indirect role of hypertension in epileptogenesis and discusses the principles of drug treatment in patients with hypertension and epilepsy. METHODS: We selected English-written articles on epilepsy, hypertension, stroke, and cerebrovascular disease until December, 2018. RESULTS: Renin-angiotensin system might play a central role in the direct interaction between hypertension and epilepsy, but other mechanisms may be contemplated. Large-artery stroke, small vessel disease and posterior reversible leukoencephalopathy syndrome are hypertension-related brain lesions able to determine epilepsy by indirect mechanisms. The role of hypertension as an independent risk factor for post-stroke epilepsy has not been demonstrated. The role of hypertension-related small vessel disease in adult-onset epilepsy has been demonstrated. Posterior reversible encephalopathy syndrome is an acute condition, often caused by a hypertensive crisis, associated with the occurrence of acute symptomatic seizures. Chronic antiepileptic treatment should consider the risk of drug-drug interactions with antihypertensives. CONCLUSIONS: Current evidence from preclinical and clinical studies supports the vision that hypertension may be a cause of seizures and epilepsy through direct or indirect mechanisms. In both post-stroke epilepsy and small vessel disease-associated epilepsy, chronic antiepileptic treatment is recommended. In posterior reversible encephalopathy syndrome blood pressure must be rapidly lowered and prompt antiepileptic treatment should be initiated.

Closed-loop control of tumor growth by means of anti-angiogenic administration.

A tumor growth model accounting for angiogenic stimulation and inhibition is here considered, and a closed-loop control law is presented with the aim of tumor volume reduction by means of anti-angiogenic administration. To this end the output-feedback linearization theory is exploited, with the feedback designed on the basis of a state observer for nonlinear systems. Measurements are supposed to be acquired at discrete sampling times, and a novel theoretical development in the area of time-delay systems is applied in order to derive a continuous-time observer in spite of the presence of sampled measurements. The overall control scheme allows to set independently the control and the observer parameters thanks to the structural properties of the tumor growth model. Simulations are carried out in order to mimic a real experimental framework on mice. These results seem extremely promising: they provide very good performances according to the measurements sampling interval suggested by the experimental literature, and show a noticeable level of robustness against the observer initial estimate, as well as against the uncertainties affecting the model parameters.

Frequency of drug combinations between enzyme-inducing first-generation antiepileptic drugs and inducible drugs in patients with epilepsy.

OBJECTIVE: The objective of the study was to systematically assess, through the analysis of administrative data, the frequency of combinations of first-generation enzyme-inducing (EI) antiepileptic drugs (AEDs) with drugs frequently prescribed in patients with epilepsy whose metabolism is induced by EIAEDs. METHODS: From the population of Tuscany (a region in Italy of about 3,750,000 habitants), patients who had been treated with at least one first-generation EIAEDs (carbamazepine, phenytoin, phenobarbital, and primidone) and had received prescriptions of an inducible non-AED (NON-AED) included in a prespecified list of 103 inducible drugs were identified. RESULTS: At the index date, 9221 patients with epilepsy were treated with at least one traditional EIAED, and there were 2538 drug combinations between EIAEDs and NON-AEDs, which may result in potentially serious clinical consequences, and 3317 combinations with NON-AEDs that have their metabolism consistently increased. CONCLUSIONS: Patients with epilepsy treated with traditional EIAEDs are at a very high risk of drug interactions.

Challenges in the treatment of convulsive status epilepticus.

Convulsive status epilepticus (CSE) is a medical emergency associated with high mortality and morbidity. The most recent definition of CSE is a convulsive seizure lasting more than 5min or consecutive seizures without recovery of consciousness. In adults, for the treatment of the early stages of CSE, diazepam, lorazepam or midazolam are the most common treatments, although the choice of agent seems less important than rapid treatment. Midazolam, when administered intramuscularly (best evidence), buccally, or nasally, is effective and safe in the pre-hospital setting. The antiepileptic drugs, phenytoin, valproate, levetiracetam and, more recently lacosamide, are used in CSE that persists after first-line treatments (established CSE). Phenytoin is more difficult to administer and is less well tolerated. Evidence of the efficacy of lacosamide is scarce. Anaesthetics are the drugs of choice for the treatment of refractory CSE (not responding to second-line drugs). Midazolam seems to be the best tolerated and is the most often used drug, followed by propofol and thiopental (pentobarbital in the USA). A few studies indicate that ketamine is effective with the possible advantage that it can be co-administered with other anaesthetics, such as midazolam or propofol. CSE becomes super-refractory after more than 24h of appropriate treatments and may last weeks. Several anaesthetics have been proposed but evidence is scarce. Autoimmune refractory CSE has been recently identified, and early treatment with immuno-modulatory agents (corticosteroids and IV immunoglobulins and also second-line agents such as cyclophosphamide and rituximab followed by chronic immunosuppressive treatment) is now recommended by many experts.

Identification of prevalent patients with epilepsy using administrative data: the Tuscany experience.

Overall prevalence of epilepsy ranges from 4 to 10 cases per 1000. Italy lacks recent epidemiological studies on large populations. In the present study, prevalence of epilepsy has been assessed in Tuscany, an Italian Region with 3,750,000 habitants, implementing an algorithm based on administrative data from the Regional Information Health System. To identify patients with epilepsy, we used at least one the following criteria: (a) at least one EEG and at least two dispensations of any antiepileptic drug (AEDS) at a minimum distance of 12 months; (b) at least two dispensations of one "specific" AED (authorized for use only for patients with epilepsy) at a minimum distance of 12 months; and (c) hospital admission for epilepsy or recurrent relapses (cod. ICD-IX-345.*). This algorithm was validated through comparison with lists of true patients with epilepsy and subjects without neurological disorders (gold standard). 35,950 cases were identified. Total crude prevalence was 9.6/1000. Prevalence increased in older patients up to 16/1000 without gender differences. Overall sensitivity of the algorithm was 87.3%, and specificity was 99.9%. This algorithm identifies patients with epilepsy with acceptable sensitivity and specificity and can be used to assess the burden of disease and for monitoring health services.

Impact of negative feedback in metabolic noise propagation.

Synthetic biology combines different branches of biology and engineering aimed at designing synthetic biological circuits able to replicate emergent properties useful for the biotechnology industry, human health and environment. The role of negative feedback in noise propagation for a basic enzymatic reaction scheme is investigated. Two feedback control schemes on enzyme expression are considered: one from the final product of the pathway activity, the other from the enzyme accumulation. Both schemes are designed to provide the same steady-state average values of the involved players, in order to evaluate the feedback performances according to the same working mode. Computations are carried out numerically and analytically, the latter allowing to infer information on which model parameter setting leads to a more efficient noise attenuation, according to the chosen scheme. In addition to highlighting the role of the feedback in providing a substantial noise reduction, our investigation concludes that the effect of feedback is enhanced by increasing the promoter sensitivity for both schemes. A further interesting biological insight is that an increase in the promoter sensitivity provides more benefits to the feedback from the product with respect to the feedback from the enzyme, in terms of enlarging the parameter design space.