Application of a Clinical Workflow May Lead to Increased Diagnostic Precision in Hereditary Spastic Paraplegias and Cerebellar Ataxias: A Single Center Experience

The molecular characterization of Hereditary Spastic Paraplegias (HSP) and inherited cerebellar ataxias (CA) is challenged by their clinical and molecular heterogeneity. The recent application of Next Generation Sequencing (NGS) technologies is increasing the diagnostic rate, which can be influenced by patients\u2019 selection. To assess if a clinical diagnosis of CA/HSP received in a third-level reference center might impact the molecular diagnostic yield, we retrospectively evaluated the molecular diagnostic rate reached in our center on 192 unrelated families (90 HSP and 102 CA) (i) before NGS and (ii) with the use of NGS gene panels. Overall, 46.3% of families received a genetic diagnosis by first-tier individual gene screening: 43.3% HSP and 50% spinocerebellar ataxias (SCA). The diagnostic rate was 56.7% in AD-HSP, 55.5% in AR-HSP, and 21.2% in sporadic HSP. On the other hand, 75% AD-, 52% AR- and 33% sporadic CA were diagnosed. So far, 32 patients (24 CA and 8 HSP) were further assessed by NGS gene panels, and 34.4% were diagnosed, including 29.2% CA and 50% HSP patients. Eleven novel gene variants classified as (likely) pathogenic were identified. Our results support the role of experienced clinicians in the diagnostic assessment and the clinical research of CA and HSP even in the next generation era

Clinical-Genetic Features Influencing Disability in Spastic Paraplegia Type 4: A Cross-sectional Study by the Italian DAISY Network

Background and objectives: Hereditary spastic paraplegias (HSPs) are a group of inherited rare neurologic disorders characterized by length-dependent degeneration of the corticospinal tracts and dorsal columns, whose prominent clinical feature is represented by spastic gait. Spastic paraplegia type 4 (SPG4, SPAST-HSP) is the most common form. We present both clinical and molecular findings of a large cohort of patients, with the aim of (1) defining the clinical spectrum of SPAST-HSP in Italy; (2) describing their molecular features; and (3) assessing genotype-phenotype correlations to identify features associated with worse disability. Methods: A cross-sectional retrospective study with molecular and clinical data collected in an anonymized database was performed. Results: A total of 723 Italian patients with SPAST-HSP (58% men) from 316 families, with a median age at onset of 35 years, were included. Penetrance was 97.8%, with men showing higher Spastic Paraplegia Rating Scale (SPRS) scores (19.67 ± 12.58 vs 16.15 ± 12.61, p = 0.009). In 26.6% of patients with SPAST-HSP, we observed a complicated phenotype, mainly including intellectual disability (8%), polyneuropathy (6.7%), and cognitive decline (6.5%). Late-onset cases seemed to progress more rapidly, and patients with a longer disease course displayed a more severe neurologic disability, with higher SPATAX (3.61 ± 1.46 vs 2.71 ± 1.20, p < 0.001) and SPRS scores (22.63 ± 11.81 vs 12.40 ± 8.83, p < 0.001). Overall, 186 different variants in the SPAST gene were recorded, of which 48 were novel. Patients with SPAST-HSP harboring missense variants displayed intellectual disability (14.5% vs 4.4%, p < 0.001) more frequently, whereas patients with truncating variants presented more commonly cognitive decline (9.7% vs 2.6%, p = 0.001), cerebral atrophy (11.2% vs 3.4%, p = 0.003), lower limb spasticity (61.5% vs 44.5%), urinary symptoms (50.0% vs 31.3%, p < 0.001), and sensorimotor polyneuropathy (11.1% vs 1.1%, p < 0.001). Increasing disease duration (DD) and abnormal motor evoked potentials (MEPs) were also associated with increased likelihood of worse disability (SPATAX score>3). Discussion: The SPAST-HSP phenotypic spectrum in Italian patients confirms a predominantly pure form of HSP with mild-to-moderate disability in 75% of cases, and slight prevalence of men, who appeared more severely affected. Early-onset cases with intellectual disability were more frequent among patients carrying missense SPAST variants, whereas patients with truncating variants showed a more complicated disease. Both longer DD and altered MEPs are associated with worse disability

Research and Definition of Car Accident Scenarios for Roadway Safety Management of S:s: 372 "Telesina".

The present paper has been developed on traffic, car accident and geometric data surveyed on the 61 kms of the italian rural road SS (Strada Statale) 372 “Telesina”. The SS 372 starts from the motorway exit of Caianello, located on the Rome - Naples highway and ends in the town of Benevento. It has a variable cross section but in average it is about 9 m wide. The road alignment is typical of rural roads running in the hilly countryside of Campania region, southern Italy. The vertical alignment is made with several crests among upgrades but their values are lower than 3,5%; in the final part of the track heading Benevento there is just one 7% upgrade. All along the track there are many motorway exits made on different levels with small lenght acceleration and deceleration lanes. Car accident data related to a 11 year period ranging from 1993 to 2003 have been collected and analysed from Police reports. The resulting database is made of about 180 accidents. The ANAS statistics on 3 sections of the road track have been collected too, being ANAS the Italian society deputed to the management of most part of rural roads. So, it has been possible to share the whole track in 3 parts. The ADT (Average Daily Traffic) has been supposed to be constant within each part of the road. The preliminary general analyses done on the whole track showed not so high accident indexes. Nevertheless, the successive scenario research showed some specific matters. First, a database of the road has been built. The database has been shared in three parts: 1) geometric data; 2) traffic data; 3) accident data. The first part has been built with the help of the existing topographic data: the whole track has been summarized with specific regard to horizontal and vertical alignment and location of motorway exits. The second part has been built on ANAS data as previously stated. The third part has been built on the police data. Accident location, traffic and road pavement conditions have been filed. Finally, a matrix data in which the following quantities have been associated to every accident has been built: “heading (to Benevento or Caianello) of the car which caused the accident, extracted from part 3; light conditions (day or night) at the moment of the accident, extracted from part 3; road pavement conditions (wet or dry) at the moment of the accident, extracted from part 3; horizontal alignment (curve or tangent), vertical alignment (positive, negative or plan) in the area of the accident, extracted from part 1 and finally the sight distance of the point in which the car accident happened (yes or no) calculated with informations provided from parts 1 and 3. Part 2 data have been just used to share the road into three homogeneous traffic conditions. Not all components have been used to build scenarios. Finally, 96 different possible scenarios have been built. As soon as each scenario has been characterized on the temporal and spatial point of view their hazardousness has been evaluated with the accident index. Results showed that all 3 most dangerous scenarios included the component “lack of passing sight distance”. Details showed that the first and most dangerous scenario is made with the following components: “daytime, wet, curve, lack of passing sight distance”; the second one “daytime, dry, curve, lack of passing sight distance”. So, it seems clear that the component ”lack of passing sight distance” has a prevalent influence on the hazardousness of scenarios; in order to improve safety it should be necessary to work on this component for instance by enlarging the shoulders of the road or making adequate excavation in curve

A methodogy for air route planning: the case NAP - NYC

The entrance in service of wide body aircraft at the beginning of the 70's and the effect of the air transport liberalization are probably the main reasons for the increase of air traffic. The interest of airlines and airport management come up in this context with the aim of planning new air routes. The analysis of the demand of the existing flights, through the use of mathematical models, represents the initial stage of a planning process. Many researches have been developed in this field. In the present paper the convenience of direct air links, without intermediary landings between Naples and New York has been examined. The technique followed is that of simulating the choice behaviour of the passengers through the use of a Logit Model. As to the qualifications characterizing each available alternative we have developed 3 different hypothesis. In the first we have considered: the time of transportation, the fare, the frequency and a variable concerning the quality of the service offered. In the second hypotheses the transporta¬tion time and the frequency only have been taken into account. Finally in the third, we have considered a change in the fourth variable, believing it to be necessary to simulate the probability that a passenger might not find seats available on an certain journey. The next phase concerned the model calibration on the existing situation of the air link between Naples and New York, determining the capacity of the mathematical model in reproducing the present situation. Then, we have assumed the existence of the direct link between Naples and New York through the alternative of a true journey and a hypothetical one, obtaining the flows on all the journeys of the network. It has been showed that the alternative of direct transportation without intermediary landings would be the most attended one. However, the profitability for the airline under determined fare and frequency hypotheses should be expected as from 2004

The Savone bridge on the SS 7 “Appia”: real time and topographic monitoring of thermal strain

The Savone bridge is located along the SS 7 rural road “Appia” in the southern territory of Francolise town (Caserta county). It overpasses the Savone river and it is about 150 m long. It has been built in the first part of the 50s and now it shows some problems that have been decided to investigate. Specifically, it has been observed that one of the 8 expansion joints located on the bridge was not correctly positioned. In other words, there was a too high and irregular displacement between the 2 faces of the joint. So, it was time to ask if the whole expansion joint had to be redone or the problem could be located elsewhere. In order to understand what could it be happened, it was decided to put the expansion joint under control via two different methods: a classic topographical way and an innovative real time way. With respect to the first way, 2 reference points were placed across the joint. The space between the faces has been read 6 times with different outside temperature values. This work was also useful to the second because it had to calibrated. The real time monitoring consisted of 4 displacement sensors placed at the 4 ends of the bridge deck and 1 temperature sensor. The sensors read the displacements and temperature 6 times per day for a 6 months period. The data were collected in a central unit and it was possible to download them by a simple click on the computer desktop. In fact, an innovative GSM connection between the central unit and a remote one has been provided. This was the true “real time” monitoring as in every connection it was possible to read the sensors and to become aware of the passing of a car or a truck (excessive or low displacement). Finally, lots of data have been collected. They have been first calibrated with the topographical survey and then correlated with the temperature sensor data with a normalization standard. Results showed that 3 over 4 sensor ends had an erratic behavior. So, it was demonstrated the problem was not located only on the expansion joint itself but also on the lower bearing devices of the bridge

La valutazione del funzionamento mentale, della personalità e del processo terapeutico in adolescenza: uno studio single case

Le ricerche empiriche su processo e esito delle psicoterapie in adolescenza sono piuttosto limitate nonostante l’ampia letteratura clinica (Shirk,Russell, 1996; Kazdin, 2000, 2004; Fonagy, Target, Cottrell, Philips, Kurtz, 2002). Questo studio si propone di fornire un inquadramento diagnostico del funzionamento mentale, dei pattern/disturbi di personalità e dei pattern sintomatici di un ragazzo preadolescente di 12 anni attraverso la classificazione PDM (sezione bambini e adolescenti; PDM Task Force, 2008) e di valutare i cambiamenti nel suo funzionamento della personalità e i fattori terapeutici attivi nella psicoterapia psicodinamicamente orientata, durata due anni, cui si è sottoposto. Abbiamo analizzato 12 trascritti di sedute, ricavati da diversi momenti della terapia (iniziale, centrale e conclusivo), con una batteria di strumenti che include: • la Shedler–Westen Assessment Procedure–200 per adolescenti (SWAP-200-A; Westen, Shedler, Durrett,Glass, Martens, 2003; Lingiardi, 2009) per la valutazione della personalità sana e patologica; • l’Adolescent Psychotherapy Q-set (APQ; Calderon, Midgley, Schneider, Target, 2012) per la valutazione del processo terapeutico (applicato per la prima volta in Italia). I risultati derivati da un’analisi qualitativa e quantitativa evidenziano come l’impiego di specifiche strategie di intervento sia associato a un aumento nelle capacità di funzionamento sano del paziente. Le implicazioni cliniche dello studio saranno argomentate e discusse

Neurological Erdheim–Chester Disease Manifesting with Subacute or Progressive Cerebellar Ataxia: Novel Case Series and Review of the Literature

Neurological involvement is relatively common in Erdheim–Chester disease (ECD), a rare clonal disorder of histiocytic myeloid precursors characterized by multisystem involvement. In ECD patients, neurological symptoms can occur either at onset or during the disease course and may lead to various degrees of neurological disability or affect patients’ life expectancy. The clinical neurological presentation of ECD often consists of cerebellar symptoms, showing either a subacute or progressive course. In this latter case, patients manifest with a slowly progressive cerebellar ataxia, variably associated with other non-specific neurological signs, infratentorial leukoencephalopathy, and cerebellar atrophy, possibly mimicking either adult-onset degenerative or immune-mediated ataxia. In such cases, diagnosis of ECD may be particularly challenging, yet some peculiar features are helpful to address it. Here, we retrospectively describe four novel ECD patients, all manifesting cerebellar symptoms at onset. In two cases, slow disease progression and associated brain MRI features simulated a degenerative cerebellar ataxia. Three patients received a definite diagnosis of histiocytosis, whereas one case lacked histology confirmation, although clinical diagnostic features were strongly suggestive. Our findings regarding existing literature data focused on neurological ECD will be also discussed to highlight those diagnostic clues helpful to address diagnosis