Epidemiology of seropositive myasthenia gravis in Sardinia: A population-based study in the district of Sassari.

INTRODUCTION/AIMS: The global incidence and prevalence of myasthenia gravis (MG) range between 6-31/million and 10-37/100,000, respectively. Sardinia is a high-risk region for different immune-mediated disorders, but the epidemiology of MG remains unclear. We determined the epidemiology of MG with acetylcholine receptor (AChR)-immunoglobulin G (IgG) and muscle-specific tyrosine kinase (MuSK)-IgG in the district of Sassari (North-Western Sardinia; population, 325,288). METHODS: From the laboratory of the University Hospital of Sassari (reference for AChR/MuSK-IgG testing in Sardinia since 1998) and the main neurology units in Sardinia, we retrospectively identified MG patients with (1) AChR-IgG and/or MuSK-IgG positivity by radioimmunoprecipitation assay; and (2) residency in the district of Sassari. Incidence (January 2010-December 2019) and prevalence (December 31, 2019) were calculated. RESULTS: A total of 202 patients were included (incident, 107; prevalent, 180). Antibody specificities were AChR (n = 187 [93%]) and MuSK (n = 15 [7%]). The crude MG incidence (95% confidence interval) was 32.6 (26.8-39.2)/million, while prevalence was 55.3 (47.7-63.9)/100,000. After age-standardization to the world population, incidence decreased to 18.4 (14.3-22.5)/million, while prevalence decreased to 31.6 (26.1-37.0)/100,000. Among incident cases, age strata (years) at MG onset were: <18 (2%), 18-49 (14%), 50-64 (21%), and ≥65 (63%). DISCUSSION: Sardinia is a high-risk region for MG, with a prevalence that exceeds the European threshold for rare disease. Identification of the environmental and genetic determinants of this risk may improve our understanding of disease pathophysiology.

A simplified math approach to predict ICU beds and mortality rate for hospital emergency planning under Covid-19 pandemic.

The different stages of Covid-19 pandemic can be described by two key-variables: ICU patients and deaths in hospitals. We propose simple models that can be used by medical doctors and decision makers to predict the trends on both short-term and long-term horizons. Daily updates of the models with real data allow forecasting some key indicators for decision-making (an Excel file in the Supplemental material allows computing them). These are beds allocation, residence time, doubling time, rate of renewal, maximum daily rate of change (positive/negative), halfway points, maximum plateaus, asymptotic conditions, and dates and time intervals when some key thresholds are overtaken. Doubling time of ICU beds for Covid-19 emergency can be as low as 2-3 days at the outbreak of the pandemic. The models allow identifying the possible departure of the phenomenon from the predicted trend and thus can play the role of early warning systems and describe further outbreaks.

Different routes and formulations of melatonin in critically ill patients. A pharmacokinetic randomized study.

BACKGROUND AND OBJECTIVES: Critically ill patients present reduced endogenous melatonin blood levels, and they might benefit from its exogenous supplementation. The aim of this research was to evaluate the feasibility of different routes of administration and drug formulations of melatonin. The efficiency of absorption was assessed as well as the adequacy in achieving and maintaining the physiological nocturnal blood peak. METHODS: Twenty-one high-risk critically ill patients were randomly assigned to receive melatonin either: (a) per os, as a standard tablet (ST-OS), (b) per os, as a suspension in solid lipid nanoparticles (SLN-OS) or c) transdermal (TD), by applying a jellified melatonin microemulsion (µE) on the skin (µE-TD). SLN-OS and µE-TD were lipid-based colloidal systems. The endogenous melatonin blood values were observed for 24 hours; subsequently, melatonin 3 mg was administered and pharmacokinetics was studied for 24 hours further. RESULTS: In both groups that received ST-OS and SLN-OS, the median time-to-peak blood concentration was 0.5 hours; however, the area under the curve (AUC) after administration of SLN-OS was significantly higher than after ST-OS (157386 [65732-193653] vs 44441 [22319-90705] pg/mL*hours, P = 0.048). µE-TD presented a delayed time-to-peak blood concentration (4 hours), a lower bioavailability (AUC: 3142 [1344-14573] pg/mL*hours) and reached pharmacological peak concentration (388 [132-1583] pg/mL). CONCLUSIONS: SLN-melatonin enterally administered offers favourable pharmacokinetics in critically ill patients, with higher bioavailability with respect to the standard formulation; µE-TD provided effective pharmacological blood levels, with a time-concentration profile more similar to the physiological melatonin pattern.

A physiologically based model for tramadol pharmacokinetics in horses.

This work proposes an application of a minimal complexity physiologically based pharmacokinetic model to predict tramadol concentration vs time profiles in horses. Tramadol is an opioid analgesic also used for veterinary treatments. Researchers and medical doctors can profit from the application of mathematical models as supporting tools to optimize the pharmacological treatment of animal species. The proposed model is based on physiology but adopts the minimal compartmental architecture necessary to describe the experimental data. The model features a system of ordinary differential equations, where most of the model parameters are either assigned or individualized for a given horse, using literature data and correlations. Conversely, residual parameters, whose value is unknown, are regressed exploiting experimental data. The model proved capable of simulating pharmacokinetic profiles with accuracy. In addition, it provides further insights on un-observable tramadol data, as for instance tramadol concentration in the liver or hepatic metabolism and renal excretion extent.

Neuropathy and levodopa in Parkinson's disease: evidence from a multicenter study.

The objectives of this study were to evaluate the risk of neuropathy in patients with Parkinson's disease (PD) and to evaluate the role of levodopa exposure as a potential risk factor. A multicenter study of 330 patients with PD and 137 healthy controls with a comparable age distribution was performed. With respect to levodopa exposure, 144 patients had long exposure (≥ 3 years) to levodopa (LELD), 103 patients had short exposure (<3 years) to levodopa (SELD), and 83 patients had no exposure to levodopa (NOLD). Nerve function was evaluated using the reduced total neuropathy score. Right sural sensory antidromic and peroneal motor nerve conduction studies were performed by neurophysiologists who were blinded to the existence of neuropathy clinical features or PD treatment. Overall, 19.40% of patients in the LELD group, 6.80% in the SELD group, 4.82% in the NOLD group, and 8.76% in the control group were diagnosed with neuropathy (axonal, predominantly sensory). Multivariate logistic analysis indicated that the risk of neuropathy was not influenced by disease duration, severity, or sex. The risk of neuropathy increased by approximately 8% for each year of age (P < 0.001; odds ratio [OR], 1.08; 95% confidence interval [CI], 1.037-1.128). The risk of neuropathy was 2.38 higher in the LELD group than in the control group (P = 0.022; OR, 2.38; 95% CI, 1.130-5.014). In a comparison between patients with and without neuropathy (Student's t test), the levodopa dose was higher (P < 0.0001), serum vitamin B12 levels were lower (P = 0.0102), and homocysteine levels were higher (P < 0.001) in the patients with neuropathy. Our results demonstrate that the duration of exposure to levodopa, along with age, is the main risk factor for the development of neuropathy. Screening for homocysteine and vitamin B12 levels and clinical-neurophysiological monitoring for neuropathy may be advisable in patients with PD who are receiving treatment with levodopa.

A minimal physiologically based pharmacokinetic model for high-dose methotrexate.

PURPOSE: High-dose methotrexate (HDMTX) is administered for the treatment of a variety of malignant tumors. Wide intra- and inter-individual variabilities characterize the pharmacokinetics of MTX, which is mostly excreted renally. HDMTX dosages are prescribed as a function of body surface area whereas dose adjustments depending on renal function are not well defined. We develop a population pharmacokinetic model with a physiological description of renal excretion as the basis for clinical tools able to suggest model-informed dosages and support therapeutic monitoring. METHODS: This article presents a minimal physiologically based pharmacokinetic (PBPK) model for HDMTX, which specifically accounts for individual characteristics such as body weight, height, gender, age, hematocrit, and serum creatinine to provide individualized predictions. The model supplies a detailed and mechanistic description of capillary and cellular exchanges between plasma, interstitial fluid, and intracellular fluid compartments, and focuses on an individualized description of renal excretion. RESULTS: The minimal PBPK model is identified and validated with a literature dataset based on Chinese patients suffering from primary central nervous system lymphoma. A comparison with a pharmacokinetic model from the literature suggests that the proposed model provides improved predictions. Remarkably, the model does not present any significant bias in a wide range of degrees of renal function. CONCLUSION: Results show that model predictions can capture the wide intra- and inter-individual variability of HDMTX, and highlight the role played by the individual degree of renal function. The proposed model can be the basis for the development of clinical decision-support systems for individualized dosages and therapeutic monitoring.

Restless legs syndrome in multiple sclerosis: a case-control study.

The aim of our study was to explore restless legs syndrome (RLS) frequency in multiple sclerosis (MS)-patients and establish whether RLS could be a symptom of MS. Over a period of 1 year, we consecutively enrolled 202 MS-patients and 212 healthy controls, matched for sex and age, in a case-control study. All of them filled in a structured questionnaire according to IRLSSG criteria. Those patients who fit the diagnostic criteria were subsequently examined by a neurologist to verify the effective presence of RLS. A total of 91 MS-patients (45%) responded positively to the questionnaires. The diagnosis of RLS was carried out in 29 subjects (14.4%). Among the healthy controls, a definite diagnosis of RLS was achieved only in 6 subjects (2.8%). The risk of MS patients to present RLS was significantly higher (OR.5.76 P:0.00002) than the general population. None of them was affected by other medical conditions related to RLS developing. The 62 remaining patients presented numbness and weakness of the legs not suggestive of RLS. Our findings confirm a significant correlation between MS and RLS. In our opinion, MS must be definitively included among RLS causes.

Accidents involving liquids: a step ahead in modeling pool spreading, evaporation and burning.

The manuscript focuses on the modeling of industrial accidents involving liquid substances, i.e. liquid pools. The paper discusses how to improve Webber's model (1990) for evaluating the liquid pool dynamics in terms of spreading (onto land and water) and evaporation rates. In particular, our attention was devoted to the following points: friction term in presence of film boiling; evaluation of the friction velocity; determination of the wind profile index; evaluation of the conductive heat flux; the pool radius dynamics; turbulent mixing onto water; dispersion model input data. The paper presents, also, how to couple the proposed model to the pool burning dynamics. This allows simulating the burning of a spreading pool. Thanks to its prompt response in terms of CPU time, the proposed model is helpful not only under risk assessment or under emergency preparedness, but also during accident response. A comparison between experimental data and the model predictions validates the model effectiveness in simulating real accidental events.

Physiologically-based pharmacokinetic simulations in pharmacotherapy: selection of the optimal administration route for exogenous melatonin.

The benefits of melatonin on human body are drawing increasing attention from several researchers in different fields. While its role as cure for sleep disturbances (e.g., jet lag, insomnia) is well documented and established, new functions in physiological and pathophysiological processes are emerging. To investigate these effects, there is need for the characterization of melatonin transport processes in the body and resulting pharmacokinetics. Although recent works propose physiologically-based pharmacokinetic modelling of melatonin, no work has yet highlighted the potential of PBPK simulations to shed light on melatonin pharmacokinetic aspects and discrimination among administration routes. This paper presents, validates, and discusses a versatile PBPK model featuring different ways of administration and compares the resulting pharmacokinetic profiles of intravenous, oral, and transdermal administration, with the goal of understanding which is the optimal route to achieve either physiological and/or supraphysiological melatonin levels.

On pool spreading around tanks: geometrical considerations.

The paper discusses a straightforward approach for evaluating the distance covered by a spreading liquid pool, when the axisymmetric hypothesis is no longer valid. This distance is evaluated by a three-steps methodology: the pre-processing of input data (bund radius, if present, and radial velocity); the simulation of pool spreading by a model based on the axisymmetric hypothesis; and the post-processing of results. The paper reports some geometrical correlations to pre- and post-process the data, with regard to four case-studies. Some numerical examples are also presented to prove that the pre-processed input data and post-processed results differ from those based on the axisymmetric hypothesis. Finally, we validate our modeling approach with the experimental data of Cronin and Evans [P.S. Cronin, J.A. Evans, A series of experiments to study the spreading of liquid pools with different bund arrangements, HSE Contract Research Report 405/2002, Advantica Technologies Limited, 2002].

A physiologically-based model to predict individual pharmacokinetics and pharmacodynamics of remifentanil.

Remifentanil based anesthesia is nowadays spread worldwide. This drug is characterized by a rapid onset of the analgesic effects, but also by a rapid onset of the side effects. For this reason, the knowledge of the remifentanil concentration in the human body is a key topic in anesthesiology. The aims of this work are to propose and validate a physiologically based pharmacokinetic model capable to predict both the pharmacokinetics and pharmacodynamics of remifentanil, and to take into account the inter-individual differences among the patients (such as height and body mass). The blood concentration of remifentanil has been successfully simulated and compared with experimental literature data. The pharmacodynamics, in terms of effect of remifentanil on minute ventilation and electroencephalogram, has been implemented in this model. Moreover, the remifentanil concentration in various organs and tissues is predicted, which is a significant improvement with respect to the traditional compartmental models. The availability of the model makes possible the prediction of the effects of remifentanil administration, also accounting for individual parameters.

Innovations and Improvements in Pharmacokinetic Models Based on Physiology.

BACKGROUND: Accompanied by significant improvements of modeling techniques and computational methods in medical sciences, the last thirty years saw the flourishing of pharmacokinetic models for applications in the pharmacometric field. In particular, physiologically based pharmacokinetic (PBPK) models, grounded on a mechanistic foundation, have been applied to explore a multiplicity of aspects with possible applications in patient care and new drugs development, as in the case of siRNA therapies. METHOD: This article summarizes the features we recently introduced in PBPK modeling within a threeyear research project funded by Italian Research Ministry. Four major points are detailed: (i) the mathematical formulation of the model, which allows modulating its complexity as a function of the administration route and active principle; (ii) a dedicated parameter of the PBPK model quantifies the drugprotein binding, which affects the active principle distribution; (iii) the gall bladder compartment and the bile enterohepatic circulation process; (iv) the coupling of the pharmacokinetic and pharmacodynamic models to produce an overall understanding of the drug effects on mammalian body. RESULTS: The proposed model is applied to two separate endovenous (remifentanil) and oral (sorafenib) drug administrations. The resulting PBPK simulations are consistent with the literature experimental data. Blood concentration predictability is confirmed in multiple reference subjects. Furthermore, in case of sorafenib administration in mice, it is possible to evaluate the drug concentration in the liver and reproduce the effects of the enterohepatic circulation. Finally, a preliminary application of the coupling of the pharmacokinetic/pharmacodynamic models is presented and discussed.

Engineering approaches in siRNA delivery.

siRNAs are very potent drug molecules, able to silence genes involved in pathologies development. siRNAs have virtually an unlimited therapeutic potential, particularly for the treatment of inflammatory diseases. However, their use in clinical practice is limited because of their unfavorable properties to interact and not to degrade in physiological environments. In particular they are large macromolecules, negatively charged, which undergo rapid degradation by plasmatic enzymes, are subject to fast renal clearance/hepatic sequestration, and can hardly cross cellular membranes. These aspects seriously impair siRNAs as therapeutics. As in all the other fields of science, siRNAs management can be advantaged by physical-mathematical descriptions (modeling) in order to clarify the involved phenomena from the preparative step of dosage systems to the description of drug-body interactions, which allows improving the design of delivery systems/processes/therapies. This review analyzes a few mathematical modeling approaches currently adopted to describe the siRNAs delivery, the main procedures in siRNAs vectors' production processes and siRNAs vectors' release from hydrogels, and the modeling of pharmacokinetics of siRNAs vectors. Furthermore, the use of physical models to study the siRNAs vectors' fate in blood stream and in the tissues is presented. The general view depicts a framework maybe not yet usable in therapeutics, but with promising possibilities for forthcoming applications.

Chemical Engineering in the "BIO" World.

Modern Chemical Engineering was born around the end of the 19th century in Great Britain, Germany, and the USA, the most industrialized countries at that time. Milton C. Whitaker, in 1914, affirmed that the difference between Chemistry and Chemical Engineering lies in the capability of chemical engineers to transfer laboratory findings to the industrial level. Since then, Chemical Engineering underwent huge transformations determining the detachment from the original Chemistry nest. The beginning of the sixties of the 20th century saw the development of a new branch of Chemical Engineering baptized Biomedical Engineering by Peppas and Langer and that now we can name Biological Engineering. Interestingly, although Biological Engineering focused on completely different topics from Chemical Engineering ones, it resorted to the same theoretical tools such as, for instance, mass, energy and momentum balances. Thus, the birth of Biological Engineering may be considered as a Darwinian evolution of Chemical Engineering similar to that experienced by mammals which, returning to water, used legs and arms to swim. From 1960 on, Biological Engineering underwent a considerable evolution as witnessed by the great variety of topics covered such as hemodialysis, release of synthetic drugs, artificial organs and, more recently, delivery of small interfering RNAs (siRNA). This review, based on the activities developed in the frame of our PRIN 2010-11 (20109PLMH2) project, tries to recount origins and evolution of Chemical Engineering illustrating several examples of recent and successful applications in the biological field. This, in turn, may stimulate the discussion about the Chemical Engineering students curriculum studiorum update.

The Viareggio LPG railway accident: event reconstruction and modeling.

This manuscript describes in detail the LPG accident occurred in Viareggio on June 2009 and its modeling. The accident investigation highlighted the uncertainty and complexity of assessing and modeling what happened in the congested environment close to the Viareggio railway station. Nonetheless, the analysis allowed comprehending the sequence of events, the way they influenced each other, and the different possible paths/evolutions. The paper describes suitable models for the quantitative assessment of the consequences of the most probable accidental dynamics and its outcomes. The main finding is that after about 80 s from the beginning of the release the dense-gas cloud reached the surrounding houses that were destroyed successively by internal explosions. This fact has two main implications. First, it shows that the adopted modeling framework can give a correct picture of what happened in Viareggio. Second, it confirms the need to develop effective mitigation measures because, in case of this kind of accidents, there is no time to apply any protective emergency plans/actions.

Emergencies in parkinsonism: akinetic crisis, life-threatening dyskinesias, and polyneuropathy during L-Dopa gel treatment.

This article reviews literature on three emergencies in Parkinson's disease (PD): Akinetic crisis, severe dyskinesias or life-threatening dyskinesias, and polyneuropathy during duodenal L-Dopa gel infusion treatment. Akinetic crisis is also known as Parkinsonian hyperpyrexia, Neuroleptic-like malignant syndrome, Acute akinesia, and Malignant syndrome in parkinsonism. It appears in 0.3% of PD patients/year, and is characterized in the most severe cases by total akinesia with dysphagia, hyperthermia, dysautonomia, increment of muscle enzymes and alterations of mental status, but it may also appear in less severe forms ("forme frusta"). At difference with the continuum of motor hypokinesias observed in PD it is characterized by transient (in cases with favorable outcome) unresponsiveness to rescue drugs. Life-supporting measures are mandatory in patients affected by this emergency. Severe dyskinesia, or life-threatening dyskinesia, is due to increased dopaminergic stimulation (either by the patient or by the prescriber): when it appears the level of dopaminomimetic stimulation should be reduced. Polyneuropathy during duodenal L-Dopa gel infusion is a recently described complication, attributed to the onset of Guillain-Barré syndromes. However, hemapheresis was not effective in some reported cases, and recent evidence suggests that Vitamin B12 deficiency or direct high-dose chronic L-Dopa toxicity might play a role in its origin.

Electroneurography index based on nerve conduction study data: method and findings in control subjects.

We developed a summary score of data obtained from nerve conduction studies (NCS). The principle of such approach is that when a nonrandom trend to lower amplitudes or conduction velocities is present, it may be revealed by a summary nerve conduction score. In a group of normal subjects, peroneal, sural, ulnar, and superficial radial nerves were studied; age- and height-related F-wave and soleus H-reflex latencies were also examined. Z-scores of distal latencies, amplitudes, conduction velocities, F-wave latencies, and H-index were averaged in order to obtain three electroneurography (ENG) indices: a simple arithmetic (ENG index 1) and two weighted means (index 2 and index 3), assigning a double or triple weight to lower limb z-scores. Reference limits were established using multiple regression equations of ENG indices against age and height. This technique could be useful in providing a better cut-off between normal and diseased populations and in improving test-retest variability of NCS when follow-up studies are required.