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Discusses the importance of attitudinal correctness rather than political correctness in dealing with the handicapped. Loss of focus on behavioral and attitudinal correctness due to the emphasis on political correctness; Public attitudes as the prevailing obstacle to the handicapped's place in the world; Need for attitudinal education of the entire population; Combination of activism and educational efforts.

Space weather driven atmospheric density variations affect low Earth orbit (LEO) satellites during all phases of their operational lifetime. Rocket launches, re-entry events and space debris are also similarly affected. A better understanding of space weather processes and their impact on atmospheric density is thus critical for satellite operations as well as for safety issues. The Horizon 2020 project Space Weather Atmosphere Model and Indices (SWAMI) project, which started in January 2018, aims to enhance this understanding by: Developing improved neutral atmosphere and thermosphere models, and combining these models to produce a new whole atmosphere model. Developing new geomagnetic activity indices with higher time cadence to enable better representation of thermospheric variability in the models, and improving the forecast of these indices. The project stands out by providing an integrated approach to the satellite neutral environment, in which the main space weather drivers are addressed together with model improvement. The outcomes of SWAMI will provide a pathway to improved space weather services as the project will not only address the science issues, but also the transition of models into operational services. The project aims to develop a unique new whole atmosphere model, by extending and blending the Unified Model (UM), which is the Met Office weather and climate model, and the Drag Temperature Model (DTM), which is a semi-empirical model which covers the 120–1500 km altitude range. A user-focused operational tool for satellite applications shall be developed based on this. In addition, improved geomagnetic indices shall be developed and shall be used in the UM and DTM for enhanced nowcast and forecast capability. In this paper, we report on progress with SWAMI to date. The UM has been extended from its original upper boundary of 85 km to run stably and accurately with a 135 km lid. Developments to the UM radiation scheme to enable accurate performance in the mesosphere and lower thermosphere are described. These include addition of non-local thermodynamic equilibrium effects and extension to include the far ultraviolet and extreme ultraviolet. DTM has been re-developed using a more accurate neutral density observation database than has been used in the past. In addition, we describe an algorithm to develop a new version of DTM driven by geomagnetic indices with a 60 minute cadence (denoted Hp60) rather than 3-hourly Kp indices (and corresponding ap indices). The development of the Hp60 index, and the Hp30 and Hp90 indices, which are similar to Hp60 but with 30 minute and 90 minute cadences, respectively, is described, as is the development and testing of neural network and other machine learning methods applied to the forecast of geomagnetic indices.

Background and Purpose: Pitt-Hopkins syndrome (PTHS) is a rare neurodevelopmental disorder caused by deletions/variants in the TCF4 gene. Seizures may be present in up to half of the patients, leading to a more severe disease burden. This study aims to analyse the electroclinical phenotype, treatment options, and long-term outcomes of epilepsy in PTHS., Methods: A multicentre observational cohort study was performed, and the electroclinical data of PTHS individuals affected by epileptic seizures were retrospectively reviewed and analysed., Results: The series includes 21 patients (11 female) with a median age at seizure onset of 2 years (range = 0.5-8). The median time of follow-up was 7.9 years (range = 2-27). Both generalized and focal epilepsies were present at the same prevalence (42.8%), whereas a minority of patients presented developmental and epileptic encephalopathies (14.4%). At the long-term follow-up, 42.8% achieved seizure freedom, whereas 42.8% developed drug-resistant epilepsy (DRE). The age at seizure onset was found to be an independent predictor for seizure outcome; in this regard, patients having seizure onset after the age of 2 years were more prone to achieve seizure freedom (odds ratio = 0.04, 95% confidence interval = 0.003-0.53; p = 0.01). During evolution, seizures tended to settle down, and even in patients with DRE, seizures tended to persist at a lower frequency and appeared to be more easily manageable over time., Conclusions: This study provides new insight into the natural history of epilepsy in PTHS. Better characterization of epileptic phenotype and prompt tailored treatment improve overall management and quality of life., (© 2021 European Academy of Neurology.)

Aim: To better characterize the clinical phenotype of Poirier-Bienvenu neurodevelopmental syndrome (OMIM ID: 618,732) due to pathogenic variants of the CSNK2B gene., Method: We reviewed the electro-clinical and developmental data of all 14 patients with de novo mutations of the CSNK2B gene reported in the literature and describe a further individual with a novel CSNK2B pathogenic variant., Results: Clustered generalized tonic-clonic or myoclonic seizures with onset before the age of 18 months and delayed neurodevelopment were present in more than 75% of patients. Epilepsy was pharmaco-resistant in 40%. All the individuals (27%) with normal neurological development had pharmaco-sensitive epilepsy. The severity of cognitive and motor impairments was higher in the group with pharmaco-resistant epilepsy, and a statistically significant correlation between seizure control and the severity of cognitive impairment was documented (χ2(3) = 9.44; p = .024) INTERPRETATION: Early seizure onset, clustered seizures and delayed development in both males and females were early clinical markers in most patients with CSNK2B mutations. The entity of neurodevelopmental abnormalities was related to epilepsy severity. Prospective studies are required to better assess the relationship between epilepsy and developmental outcomes in this condition., (Copyright © 2021 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Background: Epilepsy is a main feature of Mowat Wilson Syndrome (MWS), a congenital malformation syndrome caused by ZEB2 variants. The aim of this study was to investigate the long-term evolution of the electroclinical phenotype of MWS in a large population., Methods: Forty-individuals with a genetically confirmed diagnosis were enrolled. Three age groups were identified (t1 = 0-4; t2 = 5-12; t3 = >13 years); clinical data and EEG records were collected, analyzed, and compared for age group. Video-EEG recorded seizures were reviewed., Results: Thirty-six of 40 individuals had epilepsy, of whom 35/35 aged >5 years. Almost all (35/36) presented focal seizures at onset (mean age at onset 3.4 ± 2.3 SD) that persisted, reduced in frequency, in 7/22 individuals after the age of 13. Absences occurred in 22/36 (mean age at onset 7.2 ± 0.9 SD); no one had absences before 6 and over 16 years old. Paroxysmal interictal abnormalities in sleep also followed an age-dependent evolution with a significant increase in frequency at school age (p = 0.002) and a reduction during adolescence (p = 0.008). Electrical Status Epilepticus during Sleep occurred in 14/36 (13/14 aged 5-13 years old at onset). Seven focal seizure ictal video-EEGs were collected: all were long-lasting and more visible clinical signs were often preceded by prolonged electrical and/or subtle (erratic head and eye orientation) seizures. Valproic acid was confirmed as the most widely used and effective drug, followed by levetiracetam., Conclusions: Epilepsy is a major sign of MWS with a characteristic, age-dependent, electroclinical pattern. Improvement with adolescence/adulthood is usually observed. Our data strengthen the hypothesis of a GABAergic transmission imbalance underlying ZEB2-related epilepsy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: We aimed to delineate the phenotypic spectrum and long-term outcome of individuals with KCNB1 encephalopathy., Methods: We collected genetic, clinical, electroencephalographic, and imaging data of individuals with KCNB1 pathogenic variants recruited through an international collaboration, with the support of the family association "KCNB1 France." Patients were classified as having developmental and epileptic encephalopathy (DEE) or developmental encephalopathy (DE). In addition, we reviewed published cases and provided the long-term outcome in patients older than 12 years from our series and from literature., Results: Our series included 36 patients (21 males, median age = 10 years, range = 1.6 months-34 years). Twenty patients (56%) had DEE with infantile onset seizures (seizure onset = 10 months, range = 10 days-3.5 years), whereas 16 (33%) had DE with late onset epilepsy in 10 (seizure onset = 5 years, range = 18 months-25 years) and without epilepsy in six. Cognitive impairment was more severe in individuals with DEE compared to those with DE. Analysis of 73 individuals with KCNB1 pathogenic variants (36 from our series and 37 published individuals in nine reports) showed developmental delay in all with severe to profound intellectual disability in 67% (n = 41/61) and autistic features in 56% (n = 32/57). Long-term outcome in 22 individuals older than 12 years (14 in our series and eight published individuals) showed poor cognitive, psychiatric, and behavioral outcome. Epilepsy course was variable. Missense variants were associated with more frequent and more severe epilepsy compared to truncating variants., Significance: Our study describes the phenotypic spectrum of KCNB1 encephalopathy, which varies from severe DEE to DE with or without epilepsy. Although cognitive impairment is worse in patients with DEE, long-term outcome is poor for most and missense variants are associated with more severe epilepsy outcome. Further understanding of disease mechanisms should facilitate the development of targeted therapies, much needed to improve the neurodevelopmental prognosis., (© 2020 International League Against Epilepsy.)

Intellectual disability (ID) and autism spectrum disorder (ASD) are clinically and genetically heterogeneous diseases. Recent whole exome sequencing studies indicated that genes associated with different neurological diseases are shared across disorders and converge on common functional pathways. Using the Ion Torrent platform, we developed a low-cost next-generation sequencing gene panel that has been transferred into clinical practice, replacing single disease-gene analyses for the early diagnosis of individuals with ID/ASD. The gene panel was designed using an innovative in silico approach based on disease networks and mining data from public resources to score disease-gene associations. We analyzed 150 unrelated individuals with ID and/or ASD and a confident diagnosis has been reached in 26 cases (17%). Likely pathogenic mutations have been identified in another 15 patients, reaching a total diagnostic yield of 27%. Our data also support the pathogenic role of genes recently proposed to be involved in ASD. Although many of the identified variants need further investigation to be considered disease-causing, our results indicate the efficiency of the targeted gene panel on the identification of novel and rare variants in patients with ID and ASD., (© 2019 Wiley Periodicals, Inc.)

Fragile-X-syndrome is the most common cause of inherited intellectual disability. Epilepsy is reported to occur in 10-20% of individuals with Fragile-X-syndrome. A frequent seizure/electroencephalogram (EEG) pattern resembles that of benign rolandic epilepsy. We describe the clinical features, EEG findings and evolution in three patients affected by Fragile-X-syndrome and epilepsy mimicking Panayiotopoulos syndrome. Age at seizure onset was between 4 and about 7 years. Seizures pattern comprised a constellation of autonomic symptoms with unilateral deviation of the eyes and ictal syncope. Duration of the seizures could be brief or lengthy. Interictal EEGs revealed functional multifocal abnormalities. The evolution was benign in all patients with seizures remission before the age of 14. This observation expands the spectrum of benign epileptic phenotypes present in Fragile-X-syndrome and may be quite helpful in guiding anticonvulsant management and counseling families as to expectations regarding seizure remission., (© 2017 Wiley Periodicals, Inc.)

Aim: Mowat-Wilson Syndrome (MWS) is a genetic rare disease. Epilepsy is present in 70-75% of Patients and an age-dependent electroclinical pattern has been described. Up to date, there are studies with overnight sleep EEGs, probably because of the severe intellectual disability (ID) and hyperactivity of these Patients. Our purpose was to verify the hypothesis that MWS Patients might have electrical status epilepticus in slow wave sleep (ESES pattern)., Methods: A retrospective analysis of anamnestic and electrographic data was performed on 7 consecutive MWS Patients followed between 2007 and 2016. Only Patients with at least one overnight sleep EEG were included in the study., Results: Five out of 7 Patients had overnight sleep EEG studies and were included in this study. All of them had an anterior ESES pattern with spike-and-wave index>85%. The architecture of sleep was abnormal. An ESES related regression of cognitive and motor functions with impact on daily activities (ESES-related syndrome) was demonstrated in 3 out of 5 (60%) Patients. In two Patients marked improvement of cognitive and motor performances was observed when the epileptiform activity during sleep was successfully controlled or it was spontaneously reduced., Conclusions: The clinical significance of the ESES pattern is hard to assess in MWS Patients due to severe ID, but changing in behaviour or in motor and cognitive functions should mandate sleep EEG investigation and, if ESES is present, an appropriate treatment should be tried. Furthermore, overnight sleep EEG recordings, if regularly performed in the follow up, might help to understand if ESES pattern hampers the cognitive and communicative profile in MWS., (Copyright © 2017 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

In epileptic encephalopathies (EE), interictal epileptiform discharges (IEDs) contribute to cognitive impairment. The EE process has been studied in a patient affected by epilepsy with occipital calcification and celiac disease (CEC syndrome) by combining the administration of brain area stimulus specific (visual and auditory) reaction times (RT) during continuous EEG monitoring with the off-line reconstruction of auditory and visual evoked potentials (EP). Visual RT and VEP were abnormal only if recorded concomitantly to the IEDs. Auditory RT and EP were normal. When the EE process is going on, IEDs transiently disrupt aspects of cortical functioning, contributing to the cognitive impairment.

Background and Study Aims: To determine long-term outcome after treatment with an intragastric balloon for 6 months, with no structured weight maintenance program offered after balloon removal., Patients and Methods: 100 consecutive overweight/obese individuals (mean body mass index [BMI] 35.0 +/- 5.6 kg/m (2)) were prospectively followed after endoscopic implantation of a saline-filled intragastric balloon; 97 completed final follow-up at a mean of 4.8 +/- 1.6 years. Successful intragastric balloon therapy was defined as weight loss at 6 months of > or = 10 % of weight at baseline, that remained > or = 10 % until 2.5 years, without bariatric surgery. All analyses followed intention-to-treat principles., Results: At 6 months, mean weight loss was 12.6 +/- 8.3 kg, 63 individuals had > or = 10 % baseline weight loss; no severe morbidity was detected. During the first and second years following intragastric balloon removal, mean body mass increased by 4.2 +/- 6.8 and 2.3 +/- 6.0 kg, respectively ( P < 0.001 for both year-on-year comparisons). At 2.5 years, intragastric balloon therapy had been successful in 24 participants. At final follow-up (4.8 +/- 1.6 years), 28 had > or = 10 % baseline weight loss, 35 had undergone bariatric surgery (60 % had preoperative mass higher than baseline), and 3 were lost to follow-up; the 34 remaining had lost 1.5 +/- 5.8 kg compared with baseline. During follow-up, 13 had a second intragastric balloon implanted and 13 took sibutramine for short periods., Conclusion: Intragastric balloon therapy was relatively innocuous and associated with successful weight loss and maintenance at 2.5 years in a quarter of participants. It represents a valid option for weight loss.

The potassium orthophosphate added to the media with developing actinomycetes inhibits the nonactin macrotetrolide antibiotic but causes the increase of mycelium growth. The degree of inhibition depends on the quantity of orthophosphate and almost doesn't depend on the time of its adding to the actinomycetes culture. The degree of phosphorus consumption by actinomycetes is higher, the more its content in the media. The antibiotic synthesis takes place during the phosphorus consumption but not after its exhaustion from the media.

The effect of potassium orthophosphate on growth of the mycelium, its ATP contents and biosynthesis of the macrotetrolide antibiotic nonactin by Str. chrysomallus var. macrotetrolidi was studied. Direct dependence of the ATP contents in the mycelium on the amount of the phosphate added to the medium and consumed by the developing actinomycete was shown. Changes in the intracellular content of ATP depended also on the mycelium age. It was characterized by two peaks. Hemin was detected in the actinomycete mycelium. Its levels were sufficiently high and depended on the mycelium age and cultivation conditions, in particular on the phosphate content in the medium. Higher levels of nonactin biosynthesis were characteristic of the mycelium with lower contents of ATP, proteins and hemin. Intensive production of the antibiotic proceeded at the background of decreasing levels of ATP in the mycelium.