IntroductionSocial skills training interventions for children with autism spectrum disorder (ASD) typically focus on a skills deficit model rather than building on existing skills or encouraging the ...child to seek their own solutions. LEGO-based therapy is a child-oriented intervention to help improve social interactional skills and reduce isolation. The therapy is designed for school-age children with ASD and uses group-based play in a school setting to encourage peer relationships and social learning. Despite the reported potential benefits of LEGO-based therapy in a prior randomised controlled trial (RCT) and its adoption by many schools, the evidence to support its effectiveness on the social and emotional well-being of children with ASD is limited and includes no assessment of cost-effectiveness.Methods and analysisThis multicentre, pragmatic, cluster RCT will randomise 240 participants (aged 7–15 years) with a clinical diagnosis of ASD to receive usual care or LEGO-based therapy with usual care. Cluster randomisation will be conducted on a school level, randomising each school as opposed to each individual child within a school. All prospective participants will be screened for eligibility before assenting to the study (with parents giving informed consent on behalf of their child). All participants will be followed up at 20 and 52 weeks after randomisation to assess for social, emotional and behavioural changes. The primary outcome measure is the social skills subscale of the Social Skills Improvement System completed by a teacher or teaching assistant associated with participating children at the 20-week follow-up time point.Ethics and disseminationEthics approval has been obtained via the University of York Research Ethics Committee. The results of the trial will be submitted for publication in a peer-reviewed journal and will be disseminated to participating families, education practitioners and the third sector including voluntary and community organisations.Trial registration number ISRCTN64852382; Pre-results.
The negative experience of large-scale collective farms during the Soviet period, whose primary function was to benefit the state as opposed to the individual small farmer, remains in the psyche of ...farmers throughout Central and Eastern Europe (CEE), serving as a disincentive to collaborate. This perspective clashes with a rapidly changing global marketplace, which demands large volumes of high-quality products to meet the needs of consumers. Using the Mennonite Economic Development Associates' (MEDA) Ukraine Horticulture Development Project (UHDP) as a case study, this article demonstrates that, introduced using a culturally sensitive approach and with the right market-based incentives, informal and formal methods of collective action can result in important benefits for small farmers in terms of increased incomes, stronger market position, and strengthened community alliances.
Tensor-based analysis of genetic influences on brain integrity using DTI in 100 twins Lee, Agatha D; Leporé, Natasha; Brun, Caroline ...
Medical image computing and computer-assisted intervention : MICCAI ... International Conference on Medical Image Computing and Computer-Assisted Intervention,
2009, Letnik:
12, Številka:
Pt 1
Journal Article, Conference Proceeding
Recenzirano
Odprti dostop
Information from the full diffusion tensor (DT) was used to compute voxel-wise genetic contributions to brain fiber microstructure. First, we designed a new multivariate intraclass correlation ...formula in the log-Euclidean framework. We then analyzed used the full multivariate structure of the tensor in a multivariate version of a voxel-wise maximum-likelihood structural equation model (SEM) that computes the variance contributions in the DTs from genetic (A), common environmental (C) and unique environmental (E) factors. Our algorithm was tested on DT images from 25 identical and 25 fraternal twin pairs. After linear and fluid registration to a mean template, we computed the intraclass correlation and Falconer's heritability statistic for several scalar DT-derived measures and for the full multivariate tensors. Covariance matrices were found from the DTs, and inputted into SEM. Analyzing the full DT enhanced the detection of A and C effects. This approach should empower imaging genetics studies that use DTI.
Purpose: Genetic counselors (GCs) increasingly play key roles in advancing genomic medicine through innovative research. Here, we examine one large cohort of GCs’ evolving contributions to the ...literature, with the goal of facilitating worldwide professional development for GCs through scholarly activities. Methods: Publications were cataloged by members of the Section of Genetic Counseling (Section), established at the Children’s Hospital of Philadelphia and the University of Pennsylvania in 2014, including publication year, journal, impact factor, and author position. Data were organized using the “My Bibliography” tool on the National Center for Biotechnology Information website and a Research Electronic Data Capture database created to initially collect manuscripts published through 30 June 2020. A subsequent survey captured publications through 5 February 2024. Results: An amount of 52 of 120 (43%) GCs shared their curriculum vitae/papers. 992 unique publications were identified from 1986 to 2024. Since 2013, no less than 32 papers were published annually by Section members and no less than 10 GCs contributed to publications yearly. Impact factors typically averaged >5.0 per year. Areas of foci diversified considerably since 2015. Conclusions: Here, we establish that GCs indeed contribute to scholarly work as evidenced by the number of publications alone. The establishment of an academic home may have contributed, given publications increased concurrent to launching the Section, providing a model for organizing GCs at institutions nationally and internationally. Highlighting such achievements will foster the expansion of GC roles in the era of precision genomic medicine and therapy. Considering ways to support GCs towards expanding these activities is equally important.
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Background: Hemophilia A therapy is currently based on intravenous administration of exogenous FVIII protein either on demand to treat bleeding or prophylactically to prevent bleeding. Prophylaxis ...has revolutionized health outcomes in hemophilia by significantly reducing the frequency of bleeding, preventing the development of arthropathy, improving health-related quality of life and enabling affected individuals to increase participation in physical activities enhancing psychosocial outcomes. The burden of repetitive infusions and the time required to perform them may be partially responsible for a strikingly high rate of non-compliance. A recent multi-center study revealed only 43% of individuals with hemophilia adhered to their prophylactic regimen (Schrijvers 2016) putting improved outcomes in jeopardy. Recombinant adeno-associated viral (rAAV) vectors have been in development for >25 years. No major safety concerns have emerged in the >100 previously conducted rAAV gene transfer clinical trials. A single administration of rAAV vector encoding human coagulation F8 or F9 gene may result in sustained expression of therapeutic factor activity levels sufficient to reduce or eliminate the need for exogenous factor infusions (Pasi 2017; George 2017).
Objectives: 1) To safely obtain consistent, predictable and sustained FVIII activity (FVIII:C) >12% adequate to prevent spontaneous bleeding without the need for prophylactic FVIII infusions, manipulation of normal coagulant or anticoagulant pathways or increased thrombotic risk; 2) Minimize a dose-dependent capsid immune response by using the lowest possible vector dose that produces clinically relevant improvements in FVIII:C.
Methods: SPK-8011 is a recombinant AAV vector composed of a bio-engineered capsid (AAV-Spark200) with liver specific enhanced tropism and a codon-optimized expression cassette that encodes the SQ-FVIII variant of a B-domain-deleted (BDD) human F8 gene (Lind 1995). This Phase 1/2 study is an open-label, non-randomized, dose-escalation study of SPK-8011 with a starting dose of 5x1011 vg/kg. The study is evaluating the safety, tolerability and efficacy of a single intravenous infusion of SPK-8011 in up to 18 adult men with hemophilia A (endogenous FVIII activity levels ≤2% of normal). Data on bleeding and factor infusions in the year prior to enrollment are retrospectively compiled. Laboratory values, bleeding frequency, and FVIII consumption are prospectively evaluated following vector infusion.
Results: As of 8/1/17, we infused 3 subjects with SPK-8011, two at a dose of 5 x1011 vg/kg and one at a dose of 1x1012 vg/kg. Infused subjects were adult males ages 34-52 years with baseline FVIII:C <1% and Spark200 NAb titer of <1:1. The two participants infused with a vector dose of 5x1011 vg/kg have FVIII:C of 11% and 14% at 23 and 12 weeks, respectively, after infusion (Figure 1). Subject 3 is two-weeks post infusion with 1x1012 vg/kg and has not yet reached peak steady-state transgene expression. No subjects have experienced hepatic transaminase elevation, a decline in FVIII:C or required steroid intervention. ELISPOT reactivity to Spark200 capsid peptides revealed a transient low-level positivity to two different AAV peptides at week 3 and 4 in the second subject. By week 5 all ELISPOTs were negative. The positive ELISPOTs were not associated with a decrease in FVIII:C or increase in hepatic transaminases. No participants have developed a FVIII inhibitor. All subjects have discontinued FVIII prophylaxis. In the cumulative 258 days of follow up, there have been no vector or procedure-related adverse events.
Conclusion: Our preliminary results from the ongoing Phase 1/2 study of SPK-8011 demonstrate FVIII:C levels in the range of 12%, sufficient in the trial to date to prevent spontaneous bleeding without the need for exogenous factor infusions, and with no evidence of a cellular immune response to transduced hepatocytes. Therapeutic transgene-derived FVIII:C was achieved at a 120-fold lower vector dose than that previously reported (Pasi 2017) in another ongoing AAV gene transfer trial for hemophilia A. Transduction in the participant dosed at 1x1012 vg/kg tracks at higher levels than observed at the same time point for participants in the low dose cohort, providing early evidence of a dose-response. No adverse events or safety concerns have been observed in the first 258 days of subject exposure to SPK-8011.
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George:Spark Therapeutics: Other: Principal Investigator of Ongoing Phase I/II Gene Therapy Trials for Hemophilia A and B; Pfizer: Consultancy. Ragni:Alnylam, CSL Behring, BAYER, Biomarin, Biomarin, Bioverativ, Genetech/Roche, Pfizer, Shire, SPARK: Research Funding; A Anylam, Biomarin, Bioverativ, Shire: Honoraria. Cuker:Spark Therapeutics: Research Funding; T2 Biosystems: Research Funding. Cole:Spark Therapeutics: Employment. Wright:Spark Therapeutics: Employment, Equity Ownership, Patents & Royalties. Chen:Spark Therapeutics: Employment. Hui:Spark Therapeutics: Employment, Equity Ownership. Wachtel:Spark Therapeutics: Employment. Takefman:Spark Therapeutics: Employment. Couto:Spark Therapeutics: Employment. Reape:Spark Therapeutics: Employment. Carr:Spark Therapeutics: Employment. Anguela:Spark Therapeutics: Employment, Equity Ownership, Patents & Royalties. High:Spark Therapeutics: Employment, Equity Ownership, Patents & Royalties.
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Background: Prior work demonstrated long term expression of factor IX (mean FIX:C ~5.1%) after AAV8-mediated gene transfer in hemophilia B (Nathwani et al., 2014), but transgene-derived FIX:C fell ...short of trough values obtained by long-acting FIX prophylaxis (Santagostino et al . 2016) and natural history data supporting levels of ~12% sufficiently eliminate spontaneous hemarthroses (den Uijl et al. 2011). We developed an efficient capsid and expression cassette that could be administered at low doses to achieve FIX:C adequate to prevent bleeding without use of exogenous FIX. Here we report 1 year follow up data in 7 subjects following SPK-9001 infusion at a dose of 5 x 1011vg/kg. These data represent the largest cohort of hemophilia B subjects treated with gene transfer using the same vector and dose with available 1 year follow up data. We additionally report observations of subject baseline pre-vector characteristics relative to steady-state transgene-derived FIX:C and clinical outcomes.
Objective: To obtain long term transgene-derived FIX:C > 12% able to prevent spontaneous bleeding without the need for prophylactic FIX infusions with consistent and predictable results among all subjects, irrespective of baseline characteristics.
Methods: The study vector, SPK-9001, consists of a liver specific, bioengineered AAV capsid (Spark100) and a single-stranded codon optimized expression cassette encoding FIX-Padua. FIX-Padua is a naturally occurring variant that confers ~8-12-fold greater specific activity compared to wild-type FIX (Simioni et al. 2009, Crudele et al. 2015). Subject baseline characteristics were determined at study screening. FIX:C and clinical data were prospectively collected after vector infusion.
Results: To date, 7 subjects completed 1 year follow up after SPK-9001 infusion at a dose of 5 x1011 vg/kg. No subjects developed a FIX inhibitor or experienced vector related adverse events (AEs). Subject mean FIX:C following vector infusion through 52 weeks is outlined in figure 1. Subjects were males ages 18-52 yrs with FIX:C ≤2%. One subject had a Spark 100 neutralizing antibody (NAb) of 1:1 and the remaining were <1:1. Five patients were CRM+ and 2 were CRM-. The FIX:C at steady state, defined as the average of all values measured starting at week 12, for the 5 CRM+ subjects was 32.3±11.0% (mean±SD) and 21.0±5.7% for the 2 CRM- subjects. However, the analysis is confounded by a 1:1 NAb in one CRM- subject and partial loss of FIX:C due to immune response in one of the CRM+ subjects. Steady state FIX:C for the 6 subjects with <1:1 NAb was 31.1±10.3% and 17% for the one subject with NAb 1:1. FIX:C in subjects with a history of HCV and stage 1-2 liver fibrosis (29.7±12.7%), was comparable to that of subjects with no history of HCV (28.2±10.2%). FIX:C in the one patient with HCV exposure on HIV anti-retroviral therapy did not differ from other participants (25% vs. 29.7%±11.7%). All subjects discontinued prophylaxis at vector infusion. One subject self-reported bleeding that was incongruent with the remaining cohort, including those with the similar vector-derived FIX:C and baseline hemophilic arthropathy, who did not experience bleeding events or require factor (Table 1). The 1 subject (subject 7) who experienced a suspected capsid immune response had no known baseline characteristics that differed from the cohort; the subject completed a course of steroids, had a stable, sustained FIX:C of 14% and did not experience bleeding post vector. All subjects reported significantly improved quality of life (QoL) at 1-year (p<0.023).
Conclusion: As of 8/1/17, we report the highest, most consistent and sustained vector derived FIX:C following gene transfer. Despite heterogenous baseline characteristics, all subjects achieved consistent clinical results, including no vector related AEs, improved QoL, termination of prophylaxis, near complete elimination of bleeding and factor use. Low grade liver fibrosis and prior HCV exposure did not appear to affect steady-state FIX:C. Individual subject data may imply effects of CRM status and NAb titer on achieved FIX, but the current dataset is too small to define the relationship. In summary, these preliminary data suggest SPK-9001 safely, consistently, and independent of subject baseline characteristics, achieved FIX:C able to substantially ameliorate clinical manifestations of hemophilia.
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George:Pfizer: Consultancy; Spark Therapeutics: Other: Principal Investigator of Ongoing Phase I/II Gene Therapy Trials for Hemophilia A and B. Ducore:Octapharma: Research Funding; Bayer, Shire, HemaBiologics, Bioverativ, Octapharma, Spark Therapeutics: Other: Advisory board. Cuker:T2 Biosystems: Research Funding; Spark Therapeutics: Research Funding. Von Mackensen:LFB: Honoraria. McGuinn:Shire / Baxalta, Spark, Biogen, Roche/Genetehc: Research Funding; Shire/Baxalta: Consultancy. Wright:Spark Therapeutics: Employment, Equity Ownership, Patents & Royalties. Dasen:Spark Therapeutics: Employment. Barber:Spark Therapeutics: Employment. Chen:Spark Therapeutics: Employment. Hui:Spark Therapeutics: Employment. Patel:Spark Therapeutics: Employment. Liu:Spark Therapeutics: Employment. Wachtel:Spark Therapeutics: Employment. Takefman:Spark Therapeutics: Employment. Couto:Spark Therapeutics: Employment. Reape:Spark Therapeutics: Employment. Carr:Spark Therapeutics: Employment. Anguela:Spark Therapeutics: Employment, Equity Ownership, Patents & Royalties. High:Spark Therapeutics: Employment, Equity Ownership, Patents & Royalties.
Abstract
Purpose: The use of simulated learning environments to develop clinical skills is gaining momentum in speech-language pathology training programs. The aim of the current study was to examine ...the benefits of adding Human Patient Simulation (HPS) into the university curriculum in the area of paediatric dysphagia.
Method: University students enrolled in a mandatory dysphagia course (n = 29) completed two, 2-hour HPS scenarios: (a) performing a clinical feeding assessment with a medically complex infant; and (b) conducting a clinical swallow examination (CSE) with a child with a tracheostomy. Scenarios covered technical and non-technical skills in paediatric dysphagia management. Surveys relating to students' perceived knowledge, skills, confidence and levels of anxiety were conducted: (a) pre-lectures; (b) post-lectures, but pre-HPS; and (c) post-HPS. A fourth survey was completed following clinical placements with real clients.
Result: Results demonstrate significant additive value in knowledge, skills and confidence obtained through HPS. Anxiety about working clinically reduced following HPS. Students rated simulation as very useful in preparing for clinical practice. Post-clinic, students indicated that HPS was an important component in their preparation to work as a clinician.
Conclusion: This trial supports the benefits of incorporating HPS as part of clinical preparation for paediatric dysphagia management.
Abstract Introduction An exposed knee prosthesis is a limb threatening condition. Our unit manages such cases according to a multidisciplinary orthoplastic protocol. Whilst early prosthetic joint ...infection with dehiscence may be managed by Debridement, Antibiotics and Implant Retention (DAIR) and soft tissue coverage, the majority of these cases are chronic and in our unit are managed by Debridement, Explantation, Antibiotics (spacer and systemic) and Flap (DEAF). Patients and methods We report our experience of managing 17 of these challenging cases, 16 DEAFs and one DAIR and flap. Outcomes were assessed clinically and using the 36-item Short Form Health Survey (SF-36). Results The mean time from arthroplasty to presentation in our unit was 19 months (range: 0.5–80). Whilst an open knee replacement is by definition ‘infected’, significant microbiological growth from deep tissue/fluid samples was only detected in fourteen patients (82%) Five patients (29.4%) subsequently underwent an amputation. Of these five, three patients were extensor deficient at presentation. At follow up, health-related quality of life scoring using the Short Form-36 demonstrated poor physical function and highlighted differences in emotional function and pain levels between patients whose limbs were salvaged and patients who underwent amputation. Conclusion An exposed total knee prosthesis is a devastating complication, which despite our multidisciplinary salvage approach, has a high rate (5/17 = 29%) of amputation in this series. Quality of life in this patient group is poor irrespective of limb salvage. Salvage surgery was associated with worse pain, but better emotional profile than patients with an above knee amputation.
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