Polaris Research Articles

Cultural adaptation, validity and reliability of the Turkish version of north star ambulatory assessment.

The North Star Ambulatory Assessment (NSAA) is a functional motor outcome measure originally developed for patients with Duchenne muscular dystrophy (DMD). The aim of this study was to perform the cultural adaptation and investigate the validity and reliability of the Turkish version of the NSAA (T-NSAA) in DMD. After translation process, internal consistency, interrater and test-retest reliability of the NSAA were determined by using the Cronbach Alpha Coefficient and Intraclass Correlation Coefficient (ICC), respectively. Absolute reliability was determined by using the Standard Error of Measurement (SEM) with minimal detectable change at 95% limits of confidence (MDC95). Lower limb functionality of children was evaluated by Vignos Lower Extremity Scale (VLERS). To establish convergent validity, the correlations between T-NSAA and Motor Function Measure (MFM-32), 6-minute walk test (6-MWT), and VLERS were analyzed by using the Spearman's correlation coefficient. The study was completed with 86 patients with DMD whose age were mean 104.56 ± 24.66 months. The internal consistency (Cronbach's α = 0.94), intra-reliability (ICC = 0.977) and inter-reliability (ICC = 0.972) of T-NSAA were excellent. SEM and MDC values were low indicating satisfactory absolute agreement (< %10). The T-NSAA had strong correlations with the MFM-total score, 6-MWT, and VLERS (p < 0.01). T-NSAA is a valid and reliable tool to assess ambulatory status of Turkish-speaking DMD population. NCT05549999, Date of registration: September 19, 2022.

AAV gene therapy for Duchenne muscular dystrophy: the EMBARK phase 3 randomized trial.

Duchenne muscular dystrophy (DMD) is a rare, X-linked neuromuscular disease caused by pathogenic variants in the DMD gene that result in the absence of functional dystrophin, beginning at birth and leading to progressive impaired motor function, loss of ambulation and life-threatening cardiorespiratory complications. Delandistrogene moxeparvovec, an adeno-associated rh74-viral vector-based gene therapy, addresses absent functional dystrophin in DMD. Here the phase 3 EMBARK study aimed to assess the efficacy and safety of delandistrogene moxeparvovec in patients with DMD. Ambulatory males with DMD, ≥4 years to <8 years of age, were randomized and stratified by age group and North Star Ambulatory Assessment (NSAA) score to single-administration intravenous delandistrogene moxeparvovec (1.33 × 1014 vector genomes per kilogram; n = 63) or placebo (n = 62). At week 52, the primary endpoint, change from baseline in NSAA score, was not met (least squares mean 2.57 (delandistrogene moxeparvovec) versus 1.92 (placebo) points; between-group difference, 0.65; 95% confidence interval (CI), -0.45, 1.74; P = 0.2441). Secondary efficacy endpoints included mean micro-dystrophin expression at week 12: 34.29% (treated) versus 0.00% (placebo). Other secondary efficacy endpoints at week 52 (between-group differences (95% CI)) included: Time to Rise (-0.64 (-1.06, -0.23)), 10-meter Walk/Run (-0.42 (-0.71, -0.13)), stride velocity 95th centile (0.10 (0.00, 0.19)), 100-meter Walk/Run (-3.29 (-8.28, 1.70)), time to ascend 4 steps (-0.36 (-0.71, -0.01)), PROMIS Mobility and Upper Extremity (0.05 (-0.08, 0.19); -0.04 (-0.24, 0.17)) and number of NSAA skills gained/improved (0.19 (-0.67, 1.06)). In total, 674 adverse events were recorded with delandistrogene moxeparvovec and 514 with placebo. There were no deaths, discontinuations or clinically significant complement-mediated adverse events; 7 patients (11.1%) experienced 10 treatment-related serious adverse events. Delandistrogene moxeparvovec did not lead to a significant improvement in NSAA score at week 52. Some of the secondary endpoints numerically favored treatment, although no statistical significance can be claimed. Safety was manageable and consistent with previous delandistrogene moxeparvovec trials. ClinicalTrials.gov: NCT05096221.

Orientation method based on lunar hour angle

Abstract Astronomical orientation is a crucial technique for obtaining high-precision azimuths. However, at night, this often relies on the North Star, which can be challenging to locate and identify. An orientation method is proposed based on the lunar hour angle as an alternative. By applying theories from astronomy and geodesy, we conduct an in-depth study of the key points and calculation steps for using a theodolite to measure the moon. By observing the moon’s edge and center and combining this with the observer’s geographic location and observation time, we calculate the lunar hour angle to determine the true north azimuth. To improve computational efficiency, an application has been developed to assist with observation and data processing. Practical applications and tests have validated the feasibility and effectiveness of this lunar hour angle-based orientation method. This method addresses the limitations of traditional North Star orientation, offering an efficient and convenient approach to orientation.

322P Rasch evaluation of North Star Ambulatory Assessment and North Star Assessment for limb-girdle type muscular dystrophies in Becker muscular dystrophy

322P Rasch evaluation of North Star Ambulatory Assessment and North Star Assessment for limb-girdle type muscular dystrophies in Becker muscular dystrophy

383P A qualitative evaluation of meaningful change on the north star ambulatory assessment and performance of upper limb in Duchenne muscular dystrophy

383P A qualitative evaluation of meaningful change on the north star ambulatory assessment and performance of upper limb in Duchenne muscular dystrophy

394P Longitudinal changes in the North Star Ambulatory Assessment and leg muscle fat fraction in DMD

394P Longitudinal changes in the North Star Ambulatory Assessment and leg muscle fat fraction in DMD

381P Survey results for use of the Performance of the Upper Limb Module in patients with Duchenne muscular dystrophy: UK North Star national registry

381P Survey results for use of the Performance of the Upper Limb Module in patients with Duchenne muscular dystrophy: UK North Star national registry

375P Relationship between Pediatric Outcomes Data Collection Instrument (PODCI) and North Star Ambulatory Assessment (NSAA)

375P Relationship between Pediatric Outcomes Data Collection Instrument (PODCI) and North Star Ambulatory Assessment (NSAA)

Efficacy and Safety of Vamorolone in Duchenne Muscular Dystrophy: A Systematic Review.

Vamorolone has recently been approved for the management of Duchenne muscular dystrophy to replace glucocorticosteroids, which theoretically have more side effects. However, its efficacy and safety profile is unclear. We aimed to assess the efficacy of vamorolone in Duchenne muscular dystrophy through the 6-minute walk test (6MWT), the North Star Ambulatory Assessment (NSAA), time to stand velocity (TTSTAND), time to run 10 m (TTRW), time to climb four stairs (TTCLIMB) and a safety profile. A systematic search was conducted in MEDLINE, Scopus, Web of Science and the Cochrane Library from inception to June 2024 (PROSPERO: CRD42024558413) for studies evaluating the effect or safety profile of vamorolone in a population with Duchenne muscular dystrophy on 6MWT, NSAA and TTSTAND. TTRW, TTCLIMB and a safety profile were included. The risk of bias was assessed using the Cochrane Collaboration's risk of bias tool (RoB2) and the Quality Assessment Tool for Before-After (Pre-Post) Studies with No Control Group from the US National Institutes of Health National Heart, Lung, and Blood Institute, depending on the type of design. Results were expressed as mean differences or proportions with 95% confidence intervals (CIs), depending on the outcome. Six studies with a total of 145 individuals with Duchenne muscular dystrophy and a baseline age between 4.7 and 5.5 years were included in the systematic review. Overall, the most effective dose was 6 mg/kg/day. At 24 weeks, this dose showed a statistically significant effect compared with the untreated cohorts of 41.60 m (95% CI 14.30, 68.90) on the 6MWT, 3.57 points (95% CI 1.89, 5.25) on the NSAA, 0.06 events/s (95% CI 0.02, 0.10) on the TTSTAND, approximately 0.25 m/s on the TTRW and 0.04 (95% CI -0.00, 0.08) to 0.07 events/s (95% CI 0.03, 0.11) on the TTCLIMB. There was some discrepancy in the statistical significance of some studies, although the direction of the effect was usually similar. In general, the effect was maintained in the extension studies. Adverse events were less frequent than in historical cohorts treated with glucocorticoids. Finally, the risk of bias in the included studies was low. According to our results, vamorolone offers a statistically and clinically significant benefit in the management of Duchenne muscular dystrophy, with fewer side effects than glucocorticoids. However, the number of studies limits the interpretability and generalisability of these data, requiring more studies with more participants to perform a meta-analysis.

Skeletal muscle symptoms and quantitative MRI in females with dystrophinopathy.

The dystrophinopathies primarily affect males; however, female carriers of pathogenic dystrophin variants can develop skeletal muscle symptoms. This study aimed to evaluate muscle involvement and symptoms in females with dystrophinopathy using quantitative magnetic resonance imaging (MRI), functional assessments, and patient-reported outcomes. Controls and females with dystrophinopathy with muscle symptoms of pain, weakness, fatigue, or excessive tightness were enrolled in this cross-sectional study. Participants underwent lower extremity MRI to quantify muscle inflammation, replacement by fat, and disease asymmetry. Cardiac MRI, functional ability, muscle symptoms, and serum creatine kinase levels were also evaluated. Six pediatric females with dystrophinopathy (mean age: 11.7 years), 11 adult females with dystrophinopathy (mean age: 41.3 years), and seven controls enrolled. The mean fat fraction was increased in females with dystrophinopathy compared to controls in the soleus (0.11 vs. 0.03, p = .0272) and vastus lateralis (0.16 vs. 0.03, p = .004). Magnetic resonance spectroscopy water T2, indicative of muscle inflammation, was elevated in the soleus and/or vastus lateralis in 11 of 17 individuals. North Star Ambulatory Assessment score was lower in the dystrophinopathy group compared to controls (29 vs. 34 points, p = .0428). From cardiac MRI, left ventricle T1 relaxation times were elevated in females with dystrophinopathy compared to controls (1311 ± 55 vs. 1263 ± 25 ms, p < .05), but ejection fraction and circumferential strain did not differ. Symptomatic females with dystrophinopathy quantitatively demonstrate muscle replacement by fat and inflammation, along with impairments in functional ability and cardiac function. Additional research is needed to evaluate how symptoms and muscle involvement change longitudinally.

Understanding North Star Ambulatory Assessment total scores and their implications for standards of care using observational data

NorthStar Ambulatory Assessment (NSAA) total score (TS) is an ordinal scale to evaluate disease progression and treatment response in ambulatory Duchenne Muscular Dystrophy individuals. Clinical management according to standard of care could be enhanced by understanding how changes in the TS could inform standards of care. Here we describe the associated item performance patterns in the NorthStar Database for ranges of NSAA TS and its timed tests (10 metre walk/run and rise from floor ). We then compare these patterns depending on whether a participant is on an improving/stable (≤2-point loss in the prior year) or declining (>2-point loss in the prior year) trend. These TS and trends are subsequently linked and referenced to therapy standards of care. We included 761 participants from the UK NorthStar observational clinical database between 5-16 years, who were on steroids. Differences and trends in item ability, compensations, and times can suggest specific disease complications and lead towards anticipatory therapy recommendations. Families and therapists can benefit from using the TS and trend to guide therapy management.

Reductions in functional muscle mass and ability to ambulate in Duchenne muscular dystrophy from ages 4 to 24 years.

Duchenne muscular dystrophy (DMD) results in a progressive loss of functional skeletal muscle mass (MM) and replacement with fibrofatty tissue. Accurate evaluation of MM in DMD patients has not previously been available. Our objective was to measure MM using the D3creatine (D3Cr) dilution method and determine its relationship with strength and functional capacity in patients with DMD over a wide range of ages. Subjects were recruited for participation in a 12month, longitudinal, observational study. Here, we report the baseline data. A 20mg dose of D3Cr dissolved in water was ingested by 92 patients with DMD (ages 4-25years) followed later with a fasting urine sample. Enrichment of D3creatinine was determined by liquid chromatography-mass spectrometry analysis. The North Star Ambulatory Assessment (NSAA) total score was determined for ambulatory participants, and the Performance of Upper Limb (PUL 2.0) total score and grip strength for all participants. We observed a significant age-associated increase in body weight along with a substantial decrease in MM/body weight (%MM). MM and %MM were associated with PUL score (r=0.517, P<0.0001 and r=0.764, P<0.0001 respectively). The age-associated decrease in MM and %MM was strongly associated with ambulatory status. We observed very little overlap in %MM between ambulant and non-ambulant subjects, suggesting a threshold of 18-22% associated with loss of ambulation. MM is substantially diminished with advancing age and is highly related to clinically meaningful functional status. The D3Cr dilution method may provide a biomarker of disease progression and therapeutic efficacy in patients with DMD or other neuromuscular disorders. KEY POINTS: The non-invasive D3creatine dilution method provides novel data on whole body functional muscle mass (MM) in a wide range of ages in patients with DMD and reveals profoundly low functional MM in older non-ambulant patients. The difference in %MM between ambulant and non-ambulant subjects suggests a threshold for loss of ambulatory ability between 18 and 22% MM. The data suggest that as functional MM declines with age, maintaining a lower body weight may help to conserve ambulatory ability.

The Impact of Postural and Anthropometric Properties of Foot and Ankle on Physical Performance and Ambulation of Patients with Duchenne Muscular Dystrophy.

Abnormal foot anthropometry and posture of patients with Duchenne Muscular Dystrophy (DMD) can be considered as possible risk factors for performance and ambulation. It was aimed to examine the effects of foot posture and anthropometric characteristics, which deteriorated from the early period, on ambulation and performance of patients with DMD. The foot arch height (FAH), the metatarsal width (MW), subtalar pronation angle, and ankle limitation degree (ALD) were evaluated to determine the foot anthropometric characteristics of the patients. Foot Posture Index-6 (FPI-6) was used to evaluate foot posture. The performance of the patients was determined by the 6-minute walk test (6MWT), the 10-meter walk test (10MWT), and ascend/descend a standard 4-step test, and the ambulation was determined by the North Star Ambulatory Assessment (NSAA). Spearman's correlation coefficient was calculated to assess the relationship between foot anthropometric characteristics and posture, and performance and ambulation. The sample consisted of 48 patients with DMD aged 5.5 to 12 years. Both of the right and left foot FPI-6 scores were associated with all parameters, except descending 4-step. The left FAH was associated with 6MWT and NSAA, and the left MW was associated with 6MWT. The ALD of right foot was associated with 6MWT, ascending/descending 4 steps, and NSAA, and left ankle limitation was associated with NSAA (p<0.05). There was no relationship between other parameters. These findings suggest that postural disorders in the foot and ankle may contribute to the decrease in performance and ambulation in patients with DMD.

Large scale serum proteomics identifies proteins associated with performance decline and clinical milestones in Duchenne muscular dystrophy.

Serum biomarkers are promising minimally invasive outcome measures in clinical studies in Duchenne muscular dystrophy (DMD). However, biomarkers strongly associated with clinical progression and predicting performance decline are lacking. In this study we aimed to identify serum biomarkers associated with clinical performance and able to predict clinical milestones in DMD. Towards this aim we present a retrospective multi-center cohort study including serum samples and clinical data collected in research participants with DMD as part of a natural history study at the University of Florida (UF) and real-world observations at Leiden University Medical Center (LUMC) between 2009-2022. The 7K SomaScan® assay was used to analyse protein levels in in individual serum samples. Serum biomarkers predicted age at loss of ambulation (LoA), age at loss of overhead reach (OHR) and age at loss of hand to mouth function (HTM). Secondary outcomes were the association of biomarkers with age, corticosteroid (CS) usage, and clinical performance based on the North Star Ambulatory Assessment (NSAA), 10 meter run velocity (10mrv), 6 minute walk (6MWT) and Performance of the Upper Limb (PUL2.0). A total of 716 serum samples were collected in 79 participants at UF and 74 at LUMC (mean[SD] age; 10.9[3.2] vs 8.4[3.4]). 244 serum proteins showed an association with CS usage in both cohorts independent of CS type and regimen, including MMP3 and IGLL1. 318 probes (corresponding to 294 proteins) showed significant associations with NSAA, 10mrv, 6MWT and/or PUL2.0 across both cohorts. The expression of 38 probes corresponding to 36 proteins such as RGMA, EHMT2, ART3, ANTXR2 and DLK1 was associated with risk of both lower and upper limb clinical milestones in both the LUMC and UF cohort. In conclusion, multiple biomarkers were associated with CS use, motor function and upper lower and upper limb disease milestones in DMD. These biomarkers were validated across two independent cohorts, increasing their likelihood of translation for use within the broader DMD population.

"If you cannot measure it, you cannot improve it". Outcome measures in Duchenne Muscular Dystrophy: current and future perspectives.

Duchenne Muscular Dystrophy (DMD) is an X-linked recessive neuromuscular disorder primarily affecting males, caused by mutations in the dystrophin gene. The absence of dystrophin protein leads to progressive skeletal muscle degeneration. Recent advances in the therapeutic landscape underscore the need to identify appropriate outcome measures to assess treatment efficacy in ambulant and non-ambulant DMD patients, across clinical and research settings. This is essential for accurately evaluating new treatments and attributing therapeutic benefits.It is crucial to establish a robust correlation between outcome scores and disease progression patterns. This task is challenging since functional test performance may be influenced by different patient's characteristics, including the physiological evolution of the neurodevelopment together with the disease progression. While widely used DMD outcomes such as the North Star Ambulatory Assessment, the 6-Minute Walking Test, the 4 stairs climbed, and the Performance of the Upper Limb exhibit reliability and validity, their clinical significance is influenced by the wide phenotype and progression variability of the disease.We present and discuss the features (relevance, quantifiability, validity, objectivity, reliability, sensitivity, specificity, precision) of available DMD outcome measures, including new potential measures that may be provided by digital tools and artificial intelligence.

The NCCB Case Example: Reflections on a Successful Fourteen-Year CBPR Partnership

The Newark Community Collaborative Board (NCCB) is in its fourteenth year of operation with nine successful research projects and more than six million dollars in funding. The NCCB began with a community needs assessment in Newark, New Jersey, that led to the subsequent establishment of a community collaborative board (CCB) of consumers, researchers, service providers, and residents committed to advocating for health equity through community engagement and research informed by critical thinking. This paper explores the NCCB’s history and processes that allowed conducting community-based participatory research (CBPR) to reduce inequities related to social determinants of health (SDH). This conceptual manuscript draws on data from NCCB meeting minutes and a group interview with three of the five founding members. We detail the collaborative process used to develop and assess Community Wise, a multilevel, group-based intervention designed to reduce substance use among formerly incarcerated men in Newark, funded by the National Institutes of Health. Review of documentation and interview transcripts revealed the following key ingredients for success: 1) Having a north star; 2) Functional diversity; 3) Challenges as learning opportunities; 4) Board structure and healthy relationships; and 5) Funding and resources. The NCCB has undergone multiple transformations, including a name change to the New Jersey Critical Consciousness Collaborative Board (NJ-3CB), representing its growth from being a small local board to becoming part of a network of community collaborative boards across the United States and a chapter of the global campaign against racism. These and future transitions will help sustain the collaborative journey.

Finding a North Star: Lessons in space law for the Nuclear Regime

Finding a North Star: Lessons in space law for the Nuclear Regime

High-Resolution Iodine-Enhanced Micro-Computed Tomography of Intact Human Hearts for Detailed Coronary Microvasculature Analyses.

Identifying the detailed anatomies of the coronary microvasculature remains an area of research; one needs to develop methods for non-destructive, high-resolution, three-dimensional imaging of these vessels for computational modeling. Currently employed Micro-Computed Tomography (Micro-CT) protocols for vasa vasorum analyses require organ dissection and, in most cases, non-clearable contrast agents. Here, we describe a method developed for a non-destructive, economical means to achieve high-resolution images of the human coronary microvasculature without organ dissection. Formalin-fixed human hearts were cannulated using venogram balloon catheters, which were then fixed into the specimen's aortic root. The canulated hearts, protected by a polyethylene bag, were placed in radiolucent containers filled with insulating polyurethane foam to reduce movement. For vasculature staining, iodine potassium iodide (IKI, Lugol's solution; 6.3% Potassium Iodide, 4.1% Iodide) was injected. Contrast distributions were monitored using a North Star Imaging X3000 micro-CT scanner with low-radiation settings, followed by high-radiation scanning (3600 rad, 60 kV, 900 mA) for the final high-resolution imaging. We successfully imaged four intact human hearts presenting with chronic total coronary occlusions of the right coronary artery. This imaging enabled detailed analyses of the vasa vasorum surrounding stenosed and occluded segments. After imaging, the hearts were cleared of iodine and excess polyurethane foam and returned to their initial formalin-fixed state for indefinite storage. Conclusions: the described methodologies allow for the non-destructive, high-resolution micro-CT imaging of coronary microvasculature in intact human hearts, paving the way for detailed computational 3D microvascular reconstructions with a macrovascular context.

Meaningful changes in motor function in Duchenne muscular dystrophy (DMD): A multi-center study.

Evaluations of treatment efficacy in Duchenne muscular dystrophy (DMD), a rare genetic disease that results in progressive muscle wasting, require an understanding of the 'meaningfulness' of changes in functional measures. We estimated the minimal detectable change (MDC) for selected motor function measures in ambulatory DMD, i.e., the minimal degree of measured change needed to be confident that true underlying change has occurred rather than transient variation or measurement error. MDC estimates were compared across multiple data sources, representing >1000 DMD patients in clinical trials and real-world clinical practice settings. Included patients were ambulatory, aged ≥4 to <18 years and receiving steroids. Minimal clinically important differences (MCIDs) for worsening were also estimated. Estimated MDC thresholds for >80% confidence in true change were 2.8 units for the North Star Ambulatory Assessment (NSAA) total score, 1.3 seconds for the 4-stair climb (4SC) completion time, 0.36 stairs/second for 4SC velocity and 36.3 meters for the 6-minute walk distance (6MWD). MDC estimates were similar across clinical trial and real-world data sources, and tended to be slightly larger than MCIDs for these measures. The identified thresholds can be used to inform endpoint definitions, or as benchmarks for monitoring individual changes in motor function in ambulatory DMD.

تحديد عائد الاستثمارات الأمنية للشركات التقنية الناشئة

تعتبر الشركات الناشئة في مجال التكنولوجيا بالغة الأهمية في النهوض بالمبادرات الرقمية في العديد من البلدان التي تخضع لأجندة الدولة الذكية. وبالتالي ، فإن الشركات الناشئة في مجال التكنولوجيا هي بائعون وموردون للخدمات للمنظمات الكبيرة مثل القطاع الحكومي والشركات متعددة الجنسيات والمؤسسات المالية. على هذا النحو ، أصبحت الشركات الناشئة سريعًا نواقل هجوم للجناة الخبثاء للدخول عبر الأبواب الخلفية إلى المؤسسات الكبيرة. ومع ذلك ، لا تزال الشركات الناشئة حكيمة في إنفاقها على الأمن السيبراني لأن نجمها الشمالي هو توليد الإيرادات من خلال تقديم خدماتها والحد الأدنى من المنتجات القابلة للتطبيق (MVP) لعملائها. تقترح هذه الدراسة عائدًا معززًا على الاستثمار الأمني (ROSI) والذي يساعد الشركات الناشئة في مجال التكنولوجيا على حساب العائد على الاستثمار الأمني وتبرير ميزانيتها للإنفاق على الأمن السيبراني على الرغم من وجود نماذج حالية لحساب عائد الاستثمارات المخصصة لنفقات الأمن السيبراني ، إلا أنها معقدة نوعًا ما ولا تعطي وضوحًا للإدارة من حيث القيمة النقدية للإنفاق على الأمن السيبراني. علاوة على ذلك ، لا تلبي النماذج الحالية ديناميكيات وفروق الشركات الناشئة في مجال التكنولوجيا. يوفر النموذج المحسّن أيضًا للشركات الناشئة في مجال التكنولوجيا القدرة على تعديل استثماراتها في مجال الأمن السيبراني بشكل مناسب بناءً على حسابات قيم الحد الأدنى (الأدنى) والحد الأقصى (الأقصى) لمؤشر ROSI. تم التحقق من صحة نموذج ROSI المقترح والمحسّن من قبل 5 من خبراء الأمن السيبراني الذين اتفقوا على أهمية وضرورة النموذج الذي سيتم تطبيقه على الشركات الناشئة في مجال التكنولوجيا. تتيح نتائج دراسة الحالة الخاصة بشركة FinTech الناشئة حساب Min و Max ROSI لتبرير العائد على الاستثمارات الأمنية وتزويد الشركة الناشئة بالقدرة على ضبط الإنفاق على الأمن السيبراني وفقًا لذلك.