To date, it has been challenging for clinicians and researchers alike to use the multiple outcome measures available to create a meaningful clinical picture and perform effective longitudinal ...follow-up. It has been found that instrumented gait analysis can provide information associated with a patient's performance and help to remedy the shortcomings of the currently available outcome measures. The goal of this methodological article is to set the background and justify a new outcome measure inspired by the motor control theories to analyze gait using spatiotemporal parameters. The method is applied in a population of individuals living with Friedreich's ataxia (FRDA), a neurodegenerative disease. The sample population consisted of 19 subjects, 11 to 65 years of age with FRDA, who either ambulated independently, with a cane, or with a rollator. Three scores based on the distance from healthy normative data were used: Organization Score, Variability Score, and an overall measurement, the Global Ambulation Score. The scores were then compared to the Scale for Assessment and Rating of Ataxia (SARA) Gait Score (SARA-GS), a clinical scale currently being used for gait analysis in FRDA. Organization Scores demonstrated a longitudinal deterioration in the gait characteristics from independent ambulators to those who ambulated with a rollator. Variability Scores mostly reflected dynamic instability, which became greater as the requirement of an ambulation aid or the switch from a cane to a rollator was imminent. The global value given by the Global Ambulation Score, which takes into consideration both the Organization Score, the Variability Score, and the level of assistive device, demonstrated a logarithmic relationship with the SARA-GS. Overall, these results highlight that both components introduced should be analyzed concurrently and suggest that the Global Ambulation Score may be a valuable outcome measure for longitudinal disease progression.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Gene therapy is a potential treatment for Friedreich ataxia, with multiple programs on the horizon. The purpose of this study was to collect opinions about gene therapy from individuals 14 years or ...older with Friedreich ataxia or parents/caregivers of Friedreich ataxia patients who were diagnosed as children 17 or younger. Participants were asked to complete a survey after reading brief educational materials regarding gene therapy. Most of the patients captured in this survey have an early-onset (classical) presentation of the disease. Participants expressed urgency in participating in gene therapy clinical trials despite the associated risks. About half of the respondents believed that gene therapy would cease progression or minimize symptoms, whereas nearly one-fourth expected to be cured. The survey also revealed how participants perceive their symptom burden, because a substantial majority reported that balance/walking issues most interfere with their quality of life and would be the symptom they would prioritize treating. Although not statistically significant, more caregivers prioritized treating cardiomyopathy than patients. This study provides valuable information on priorities, beliefs, and expectations regarding gene therapy and serves to guide future gene therapy opinion studies and gene therapy trial design.
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Corti and colleagues provided brief educational material and a Likert-style survey to patients and caregivers in the Friedreich ataxia community. This study provides valuable information on patient priorities, beliefs, and expectations regarding gene therapy and serves to guide future gene therapy opinion studies and gene therapy trial design.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract
Introduction
Population-wide genomic screening for CDC Tier-1 conditions offers the ability to identify the 1–2% of the US population at increased risk for Hereditary Breast and Ovarian ...Cancer, Lynch Syndrome, and Familial Hypercholesterolemia. Implementation of population-wide screening programs is highly complex, requiring engagement of diverse collaborators and implementation teams. Implementation science offers tools to promote integration of these programs through the identification of determinants of success and strategies to address potential barriers.
Methods
Prior to launching the program, we conducted a pre-implementation survey to assess anticipated barriers and facilitators to reach, effectiveness, adoption, implementation, and maintenance (RE-AIM), among 51 work group members (phase 1). During the first year of program implementation, we completed coding of 40 work group meetings guided by the Consolidated Framework for Implementation Research (CFIR) (phase 2). We matched the top barriers to implementation strategies identified during phase 2 using the CFIR-ERIC (Expert Recommendation for Implementing Change) matching tool.
Results
Staffing and workload concerns were listed as the top barrier in the pre-implementation phase of the program. Top barriers during implementation included adaptability (
n
= 8, 20%), complexity (
n
= 14, 35%), patient needs and resources (
n
= 9, 22.5%), compatibility (
n
= 11, 27.5%), and self-efficacy (
n
= 9, 22.5%). We identified 16 potential implementation strategies across six ERIC clusters to address these barriers and operationalized these strategies for our specific setting and program needs.
Conclusion
Our findings provide an example of successful use of the CFIR-ERIC tool to guide implementation of a population-wide genomic screening program.
Gene replacement therapy is a rational therapeutic strategy and clinical intervention for neurodegenerative disorders like Canavan disease, a leukodystrophy caused by biallelic mutations in the ...aspartoacylase (ASPA) gene. We aimed to investigate whether simultaneous intravenous (i.v.) and intracerebroventricular (i.c.v.) administration of rAAV9-CB6-ASPA provides a safe and effective therapeutic strategy in an open-label, individual-patient, expanded-access trial for Canavan disease. Immunomodulation was given prophylactically prior to adeno-associated virus (AAV) treatment to prevent an immune response to ASPA or the vector capsid. The patient served as his own control, and change from baseline was assessed by clinical pathology tests, vector genomes in the blood, antibodies against ASPA and AAV capsids, levels of cerebrospinal fluid (CSF) N-acetylaspartate (NAA), brain water content and morphology, clinical status, and motor function tests. Two years post treatment, the patient’s white matter myelination had increased, motor function was improved, and he remained free of typical severe epilepsy. NAA level was reduced at 3 months and remained stable up to 4 years post treatment. Immunomodulation prior to AAV exposure enables repeat dosing and has prevented an anti-transgene immune response. Dual-route administration of gene therapy may improve treatment outcomes.
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Byrne and colleagues demonstrated that simultaneous intravenous and intracerebroventricular administration of rAAV9-CB6-AspA in a single patient with Canavan disease is a safe approach to improve the patient’s white matter myelination and overall motor function. Prophylactic immunomodulation and the dual route of administration might have improved the outcome.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Friedreich's ataxia (FA) is an inherited disease that causes degeneration of the nervous system. Features of FA include proprioceptive and cerebellar deficits leading to impaired muscle coordination ...and, consequently, dysmetria in force and time of movement. The aim of this study is to characterize dysmetria and its association to disease severity. Also, we examine the neural mechanisms of dysmetria by quantifying the EMG burst area, duration, and time-to-peak of the agonist muscle. Twenty-seven individuals with FA and 13 healthy controls (HCs) performed the modified Functional Ataxia Rating Scale and goal-directed movements with the ankle. Dysmetria was quantified as position and time error during dorsiflexion. FA individuals exhibited greater time but not position error than HCs. Moreover, time error correlated with disease severity and was related to increased agonist EMG burst. Temporal dysmetria is associated to disease severity, likely due to altered activation of the agonist muscle.
For the first time, we quantified spatial and temporal dysmetria and its relation to disease severity in Friedreich's ataxia (FA). We found that FA individuals exhibit temporal but not spatial dysmetria relative to healthy controls. Temporal dysmetria correlated to disease severity in FA and was predicted from an altered activation of the agonist muscle. Therefore, these results provide novel evidence that FA exhibit temporal but not spatial dysmetria, which is different from previous findings on SCA6.
We use the implementation science framework RE-AIM (reach, effectiveness, adoption, implementation, and maintenance) to describe outcomes of In Our DNA SC, a population-wide genomic screening (PWGS) ...program. In Our DNA SC involves participation through clinical appointments, community events, or at home collection. Participants provide a saliva sample that is sequenced by Helix, and those with a pathogenic variant or likely pathogenic variant for CDC Tier 1 conditions are offered free genetic counseling. We assessed key outcomes among the first cohort of individuals recruited. Over 14 months, 20,478 participants enrolled, and 14,053 samples were collected. The majority selected at-home sample collection followed by clinical sample collection and collection at community events. Participants were predominately female, White (self-identified), non-Hispanic, and between the ages of 40–49. Participants enrolled through community events were the most racially diverse and the youngest. Half of those enrolled completed the program. We identified 137 individuals with pathogenic or likely pathogenic variants for CDC Tier 1 conditions. The majority (77.4%) agreed to genetic counseling, and of those that agreed, 80.2% completed counseling. Twelve clinics participated, and we conducted 108 collection events. Participants enrolled at home were most likely to return their sample for sequencing. Through this evaluation, we identified facilitators and barriers to implementation of our state-wide PWGS program. Standardized reporting using implementation science frameworks can help generalize strategies and improve the impact of PWGS.
We evaluated In Our DNA SC, a population-wide genomic screening program, through the RE-AIM framework. In 14 months, over 20,000 individuals enrolled, providing 14,053 samples. Pathogenic or likely pathogenic variants for a CDC Tier 1 condition were found in 137 individuals, with the majority of individuals agreeing to genetic counseling.
Abstract Researchers across the translational research continuum have emphasized the importance of integrating genomics into their research program. To date capacity and resources for genomics ...research have been limited; however, a recent population-wide genomic screening initiative launched at the Medical University of South Carolina in partnership with Helix has rapidly advanced the need to develop appropriate infrastructure for genomics research at our institution. We conducted a survey with researchers from across our institution (n = 36) to assess current knowledge about genomics health, barriers, and facilitators to uptake, and next steps to support translational research using genomics. We also completed 30-minute qualitative interviews with providers and researchers from diverse specialties (n = 8). Quantitative data were analyzed using descriptive analyses. A rapid assessment process was used to develop a preliminary understanding of each interviewee’s perspective. These interviews were transcribed and coded to extract themes. The codes included types of research, alignment with precision health, opportunities to incorporate precision health, examples of researchers in the field, barriers, and facilitators to uptake, educational activity suggestions, questions to be answered, and other observations. Themes from the surveys and interviews inform implementation strategies that are applicable not only to our institution, but also to other organizations interested in making genomic data available to researchers to support genomics-informed translational research.
The injured man, 69, was treated and released with nonserious injuries from Avera St. Luke's Hospital in Aberdeen, said Tim McCurdy, conservation officer with Game Fish & Parks, which is ...investigating the accident, which was two miles east of Cresbard.
Rita Louise Vollmer, the driver of a 1997 Lincoln Town Car, was westbound on South Dakota Highway 20 about 5:45 p.m. when she failed to stop at a railroad crossing and her vehicle collided with a ...northbound Burlington Northern-Santa Fe train, according to a report from the South Dakota Highway Patrol.
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