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Background: Phelan–McDermid syndrome (PMD) is usually not only caused by 22q13.3 deletion but also pathogenic variants (mutations) of SHANK3 gene. PMD is characterized by global intellectual disability, severely delayed or absent speech, and features of autism spectrum disorder and susceptibility to psychotic behavior. Here, we describe a neurocognitive follow-up and genetic etiology for two siblings with PMD. Methods: Comparative genomic hybridization (CGH) array test was normal and no 22q13.3 deletion was observed. For this reason, whole exome sequencing (WES) analyzed the siblings’ and the parents’ DNA sample. Results: The results of the siblings strongly suggest that the SHANK3 gene variant c.2313+1G>A is pathogenic and PMD can be inherited from a mosaic father for this gene variant. Both siblings learned new skills until puberty but experienced a neuropsychiatric disaster after the age of 14 years experienced neurocognitive decline and it was sharp for one of the siblings. Conclusions: The long-term observations are sparse in PMD and SHANK3 mutations. This is the neurocognitive follow-up from childhood to middle ages, where a sharp neurocognitive decline was observed. We conclude that progressive neuropsychiatric symptoms in adolescence are a universal clinical clue for PMD diagnosis and an underlying SHANK3 splicing site mutation.

BACKGROUND: Plasma-derived (pd) or recombinant (r) therapeutic factor VIII proteins (FVIIIs) are infused to arrest/prevent bleeding in patients with hemophilia A (PWHA). However, FVIIIs are neutralized if anti-FVIII-antibodies (inhibitors) develop. Accumulating evidence suggests that pdFVIIIs with von Willebrand factor (VWF) are less immunogenic than rFVIIIs and that distinct rFVIIIs are differentially immunogenic. Since inhibitor development is T-helper-cell-dependent, human leukocyte antigen (HLA)-class-II (HLAcII) molecules constitute an important early determinant. OBJECTIVES: Use dendritic cell (DC)-protein processing/presentation assays with mass-spectrometric and peptide-proteomic analyses to quantify the DP-bound, DQ-bound, and DR-bound FVIII-derived peptides in individual HLAcII repertoires and compare the immunogenic potential of six distinct FVIIIs based on their measured peptide counts. PATIENTS/METHODS: Monocyte-derived DCs from normal donors and/or PWHA were cultured with either: Mix-rFVIII, a VWF-free equimolar mixture of a full-length (FL)-rFVIII [Advate® (Takeda)] and four distinct B-domain-deleted (BDD)-rFVIIIs [Xyntha® (Pfizer), NovoEight® (Novo-Nordisk), Nuwiq® (Octapharma), and Afstyla® (CSL Behring GmBH)]; a pdFVIII + pdVWF [Beriate® (CSL Behring GmBH)]; Advate ± pdVWF; Afstyla ± pdVWF; and Xyntha + pdVWF. RESULTS: We showed that (i) Beriate had a significantly lower immunogenic potential than Advate ± pdVWF, Afstyla - pdVWF, and Mix-rFVIII; (ii) distinct FVIIIs differed significantly in their immunogenic potential in that, in addition to (i), Afstyla + pdVWF had a significantly lower immunogenic potential than Beriate, while the immunogenic potential of Beriate was not significantly different from that of Xyntha + pdVWF; and (iii) rFVIIIs with pdVWF had significantly lower immunogenic potentials than the same rFVIIIs without pdVWF. CONCLUSIONS: Our results provide HLAcII peptidomic level explanations for several important clinical observations

Background: Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability. The aim of our longitudinal study was to describe ageing‐related cognitive changes in men with FXS. Method: A neuropsychologist determined the raw scores (RSs) of 19 men with FXS twice with the Leiter International Performance Scale at an average interval of 22 years. The ages of the participants at baseline ranged from 16 to 50 (mean 27) years. Results: At follow‐up, the RSs improved in two men, remained the same in two men and declined in 15 men. Overall, the RS of the study group deteriorated by an average 4 points in RSs (p < 0.001). Conclusion: Cognitive ageing in men with FXS started earlier than that in men in the general population; in many cases, cognitive ageing in men with FXS began before middle age, usually without any medical or other underlying cause.

Background: Williams syndrome (WBS) is a genetic multisystem disorder. The main symptom is borderline (intelligence quotient, IQ 70–79) or abnormally low intelligence (IQ < 70). According to earlier studies young individuals with WBS demonstrate generally a slightly higher verbal IQ (VIQ) compared to performance/nonverbal IQ (PIQ). WBS was recognized as a distinct entity already about 60 years ago, but still cognition in adults with WBS is poorly known. Methods: We followed 25 adults (age at baseline 19–68, median 38) with genetically confirmed WBS for about 20 years. The study subjects underwent medical and neuropsychological assessments at the baseline and at the end of follow‐up. Results: The mean VIQ remained quite stable from early adulthood up to 40 years of age after which it declined. The mean PIQ kept on improving from early adulthood until 50 years of age after which it gradually declined. At the end of the study, all study subjects had at least two longstanding health problems out of which hypertension, psychiatric disorder, and scoliosis or kyphosis occurred most frequently. At end of the study, two patients suffered from vascular dementia. Seven patients died during the follow‐up. Conclusions: In adults with WBS, the course of cognition is uneven across the cognitive profile. Their verbal functions both develop and deteriorate earlier than performance/nonverbal functions. Frequent somatic co‐morbidities may increase risk to shortened life span.

We describe here the clinical outcome of four women with epilepsy with eyelid myoclonia (aged 21–53 years). All patients had an uneventful early history, normal physical growth and appearance and no comorbid sensory or motor disability and normal brain magnetic resonance imaging finding. Two women were moderately and one mildly intellectually disabled and one showed a low-average intelligence. The overall well-being of the patients was hampered by psychiatric or various somatic comorbidities and related psychosocial problems. The three women with an intellectual disability had been treated with narrow-spectrum antiepileptic drugs and one also with vigabatrin during childhood and adolescence. The patient with a low-average intelligence had been on broad-spectrum antiepileptic medication (i.e. valproate and ethosuximide) since the epilepsy diagnosis but she has had compliance problems. Based on these cases, the cognitive deficits in patients with epilepsy with eyelid myoclonia may occur more commonly than what has been thought hitherto. We discuss the role of narrow-spectrum antiepileptic drugs as a contributing factor to poor seizure control and an impaired intelligence.

Immunogenicity is an important consideration in the licensure of a therapeutic protein because the development of neutralizing anti-drug antibodies (ADAs) can affect both safety and efficacy. Neoantigens introduced by bioengineering of a protein drug are a particular cause for concern. The development of a bioengineered recombinant factor VIIa (rFVIIa) analog was discontinued after phase 3 trials because of the development of ADAs. The unmodified parent molecule (rFVIIa), on the other hand, has been successfully used as a drug for more than two decades with no reports of immunogenicity in congenital hemophilia patients with inhibitors.We used computational and experimental methods to demonstrate that the observed ADAs could have been elicited by neoepitopes in the engineered protein. The human leukocyte antigen type of the patients who developed ADAs is consistent with this hypothesis of a neoepitope-driven immune response, a finding that might have implications for the preclinical screening of therapeutic protein analogs.

Neutralizing antibodies (inhibitors) to replacement factor VIII (FVIII, either plasma derived or recombinant) impair the effective management of hemophilia A. Individuals with hemophilia A due to major deletions of the FVIII gene (F8) lack antigenically cross-reactive material in their plasma ("CRM-negative"), and the prevalence of inhibitors in these individuals may be as high as 90%. Conversely, individuals with hemophilia A caused by F8 missense mutations are CRM-positive, and their overall prevalence of inhibitors is <10% (ref. 2). Individuals with the F8 intron 22 inversion (found in ∼50% of individuals with severe hemophilia A) have been grouped with the former on the basis of their genetic defect and CRM-negative status. However, only ∼20% of these individuals develop inhibitors. Here we demonstrate that the levels of F8 mRNA and intracellular FVIII protein in B lymphoblastoid cells and liver biopsies from individuals with the intron 22 inversion are comparable to those in healthy controls. These results support the hypothesis that most individuals with the intron 22 inversion are tolerized to FVIII and thus do not develop inhibitors. Furthermore, we developed a new pharmacogenetic algorithm that permits the stratification of inhibitor risk for individuals and subpopulations by predicting the immunogenicity of replacement FVIII using, as input, the number of putative T cell epitopes in the infused protein and the competence of major histocompatibility complex class II molecules to present such epitopes. This algorithm showed statistically significant accuracy in predicting the presence of inhibitors in 25 unrelated individuals with the intron 22 inversion.

Neutralizing antibodies (inhibitors) to replacement factor VIII (FVIII, either plasma derived or recombinant) impair the effective management of hemophilia A. Individuals with hemophilia A due to major deletions of the FVIII gene (F8) lack antigenically cross-reactive material in their plasma ("CRM-negative"), and the prevalence of inhibitors in these individuals may be as high as 90%. Conversely, individuals with hemophilia A caused by F8 missense mutations are CRM-positive, and their overall prevalence of inhibitors is <10% (ref. 2). Individuals with the F8 intron 22 inversion (found in ∼50% of individuals with severe hemophilia A) have been grouped with the former on the basis of their genetic defect and CRM-negative status. However, only ∼20% of these individuals develop inhibitors. Here we demonstrate that the levels of F8 mRNA and intracellular FVIII protein in B lymphoblastoid cells and liver biopsies from individuals with the intron 22 inversion are comparable to those in healthy controls. These results support the hypothesis that most individuals with the intron 22 inversion are tolerized to FVIII and thus do not develop inhibitors. Furthermore, we developed a new pharmacogenetic algorithm that permits the stratification of inhibitor risk for individuals and subpopulations by predicting the immunogenicity of replacement FVIII using, as input, the number of putative T cell epitopes in the infused protein and the competence of major histocompatibility complex class II molecules to present such epitopes. This algorithm showed statistically significant accuracy in predicting the presence of inhibitors in 25 unrelated individuals with the intron 22 inversion.

Neutralizing antibodies (inhibitors) to replacement factor VIII (FVIII, either plasma derived or recombinant) impair the effective management of hemophilia A1. Individuals with hemophilia A due to major deletions of the FVIII gene (F8) lack antigenically cross-reactive material in their plasma (“CRM-negative”), and the prevalence of inhibitors in these individuals may be as high as 90%. Conversely, individuals with hemophilia A caused by F8 missense mutations are CRM-positive, and their overall prevalence of inhibitors is <10% (ref. 2). Individuals with the F8 intron 22 inversion (found in ~50% of individuals with severe hemophilia A) have been grouped with the former on the basis of their genetic defect and CRM-negative status. However, only ~20% of these individuals develop inhibitors3. Here we demonstrate that the levels of F8 mRNA and intracellular FVIII protein in B lymphoblastoid cells and liver biopsies from individuals with the intron 22 inversion are comparable to those in healthy controls. These results support the hypothesis that most individuals with the intron 22 inversion are tolerized to FVIII and thus do not develop inhibitors. Furthermore, we developed a new pharmacogenetic algorithm that permits the stratification of inhibitor risk for individuals and subpopulations by predicting the immunogenicity of replacement FVIII using, as input, the number of putative T cell epitopes in the infused protein and the competence of major histocompatibility complex class II molecules to present such epitopes. This algorithm showed statistically significant accuracy in predicting the presence of inhibitors in 25 unrelated individuals with the intron 22 inversion.

This master's thesis focuses on loads on superstructures of steel pedestrian bridge caused by vehicle impact, using a truck with loading crane as the colliding object. Simple calculation formulas and FEM models have been made to evaluate the impact load. Impact loads given in Euro code are based on the assumption that the bridge is completely rigid and immovable. This assumption holds reasonably well for massive concrete bridges but not for lightweight bridges, hence the need to examine the impact load magnitudes for steel pedestrian bridges. Impact load magnitude is affected by the mass distributions and rigidities of both the vehicle and the bridge, as well as vehicle velocity, damping, changes in geometry, nature of the contact surface and energy losses resulting from a collision. The short duration of collisions, in the order of magnitude of 0,1 s, makes impact load difficult to determine. In addition, determining the impact load under transient loading conditions is not straightforward; therefore, the load needs to be established with both dynamic and static models. The thesis studies a number of different dynamic FEM models. The models were used to determine displacements of bridges after which the dynamic contribution was removed, and the equivalent static displacements were determined by using the static point loads. Dynamic FEM models take into account the plastic behaviour of the material and geometric non-linearity of the structure. The material model used (in the models) was elastic-perfectly plastic. Calculation sheets were made with mathematical program to compare the FEM results. Finally, obtained collision loads were compared with loads given in Euro code and with bridge model capacities. Furthermore, preliminary cost estimates were calculated for different structural solutions. The results show that in collisions into pedestrian bridges, the biggest stresses are concentrated on the supports., Työssä on tutkittu törmäyksen aiheuttamia kuormia teräksisen kevyen liikenteen sillan päällysrakenteeseen. Törmäävänä objektina työssä on käytetty kuormausnosturilla varustettua kuorma-autoa. Työssä on esitelty yksinkertaisia laskukaavoja sekä FEM-malleja törmäyksessä syntyvän voiman määrittämiseen. Eurokoodin antamat törmäyskuormat perustuvat oletukseen, että silta on täysin jäykkä sekä liikkumaton. Tämä oletus pätee kohtalaisen hyvin massiivisiin betonisiltoihin, muttei kevytrakenteisiin siltoihin. Tästä syystä nähtiin tarpeelliseksi tutkia törmäyskuormien suuruuksia teräksisillä kevyen liikenteen silloilla. Törmäyskuorman suuruuteen vaikuttaa ajoneuvon sekä sillan massajakaumat, jäykkyydet, ajoneuvon nopeus, vaimennukset, geometrian muutokset, kontaktipinta sekä törmäyksessä syntyvät energiahäviöt. Törmäyksen lyhyt kesto, joka on suuruusluokkaa 0,1 s, tekee myös törmäyskuorman määrittämisen vaikeaksi. Lisäksi törmäyksen aiheuttaman voiman määrittäminen tilapäisessä kuormituksessa ei ole suoraviivaista, joten kuorma joudutaan määrittämään sekä dynaamisen, että staattisen mallin avulla. Työssä tutkittiin lukuisia erilaisia dynaamisia FEM-malleja. Mallien avulla määritettiin siltojen siirtymät. Tämän jälkeen malleista poistettiin dynaaminen osuus ja määritettiin staattisten pistekuormien avulla dynaamista siirtymää vastaava törmäyskuorma. Dynaamisissa FEM-malleissa on huomioitu materiaalin plastinen käyttäytyminen sekä rakenteen geometrinen epälineaarisuus. Materiaalimallina käytettiin ideaalista kimmoplastista mallia. Työssä johdettujen dynaamisten kaavojen avulla luotiin laskentapohja matematiikkaohjelmalla FEM-tuloksien rinnalle. Lopuksi saatuja törmäyskuormia verrattiin eurokoodin antamiin törmäyskuormiin sekä siltamallien kapasiteetteihin. Eri rakenneratkaisuista laadittiin myös alustava kustannusarvio. Tuloksista pystytään päättelemään, että suurimmat jännitykset törmäyksissä kevyen liikenteen siltaan ovat tukialueilla.

This study focuses on the interacting performance effects of marketing and sales activities. Literature review draws together relevant research relating to this topic and thus, concentrates on marketing performance and marketing-sales relationship. Both of the fields have received only limited attention in the earlier literature. A fresh approach called Fuzzy Set Qualitative Comparative Analysis (FS/QCA) is used as an approach and as a methodology in this study. FS/QCA assists in explicating the causal link between marketing and sales activities and performance. Configurations of marketing and sales activities can affect marketing performance in various ways, as it is demonstrated in this study. The case company is a Finnish company called Aalto University Executive Education Ltd (Aalto EE), which offers executive education services. This study focuses on the business area of Open programs and Forums. The data for the empirical part is obtained mainly through interviews, observation, and by collecting data from the case company’s electronic data sources. The most important contribution of this study is that it disentangles the relationship between the performance outcomes and the configurations of marketing and sales activities at Aalto EE. This study also demonstrates that FS/QCA can be implemented in marketing context and it can explain marketing outcomes. The results confirm that a single activity can affect the examined outcome differently when it’s part of a different configuration. Sales e-mail campaigns represent an important marketing activity for the case company, which is why there is a separate ‘mini-study’ on these. Depending on the type of the examined program, some configurations seemed to be more effective than others in reaching the sales targets; and thus, the cases were divided into two separate groups. The success of the sales of the programs in one group was highly contingent on the success of various marketing activities. Especially high sales e

http://www.sil.org/resources/archives/19630

Poster promoting the first Gay Pride Parade of Bahia. It depicts two anonimous, stick-figures holding hands and running. Sponsered by GGB (Grupo Gay da Bahia), USAID, Prudence, Pathfinder, DST Aids, UNESCO, Prefeitura de Salvador, Bahia and the Ministério da Saude.

Mariano Pistofilo es seud. de Demetrio Sauna, Sign.: A-T\p4\s, X\p6\s, Antep