Quantification of Dynamic Model Validation Metrics Using Uncertainty Propagation from Requirements

The Space Launch System, NASA's new large launch vehicle for long range space exploration, is presently in the final design and construction phases, with the first launch scheduled for 2019. A dynamic model of the system has been created and is critical for calculation of interface loads and natural frequencies and mode shapes for guidance, navigation, and control (GNC). Because of the program and schedule constraints, a single modal test of the SLS will be performed while bolted down to the Mobile Launch Pad just before the first launch. A Monte Carlo and optimization scheme will be performed to create thousands of possible models based on given dispersions in model properties and to determine which model best fits the natural frequencies and mode shapes from modal test. However, the question still remains as to whether this model is acceptable for the loads and GNC requirements. An uncertainty propagation and quantification (UP and UQ) technique to develop a quantitative set of validation metrics that is based on the flight requirements has therefore been developed and is discussed in this paper. There has been considerable research on UQ and UP and validation in the literature, but very little on propagating the uncertainties from requirements, so most validation metrics are "rules-of-thumb;" this research seeks to come up with more reason-based metrics. One of the main assumptions used to achieve this task is that the uncertainty in the modeling of the fixed boundary condition is accurate, so therefore that same uncertainty can be used in propagating the fixed-test configuration to the free-free actual configuration. The second main technique applied here is the usage of the limit-state formulation to quantify the final probabilistic parameters and to compare them with the requirements. These techniques are explored with a simple lumped spring-mass system and a simplified SLS model. When completed, it is anticipated that this requirements-based validation metric will provide a quantified confidence and probability of success for the final SLS dynamics model, which will be critical for a successful launch program, and can be applied in the many other industries where an accurate dynamic model is required

Phenotypic diversity in an international Cure VCP Disease registry

BACKGROUND: Dominant mutations in valosin-containing protein (VCP) gene cause an adult onset inclusion body myopathy, Paget\u27s disease of bone, and frontotemporal dementia also termed multisystem proteinopathy (MSP). The genotype-phenotype relationships in VCP-related MSP are still being defined; in order to understand this better, we investigated the phenotypic diversity and patterns of weakness in the Cure VCP Disease Patient Registry. METHODS: Cure VCP Disease, Inc. was founded in 2018 for the purpose of connecting patients with VCP gene mutations and researchers to help advance treatments and cures. Cure VCP Disease Patient Registry is maintained by Coordination of Rare Diseases at Sanford. The results of two questionnaires with a 5-point Likert scale questions regarding to patients\u27 disease onset, symptoms, and daily life were obtained from 59 participants (28 males and 31 females) between June 2018 and May 2020. Independent of the registry, 22 patients were examined at the Cure VCP Disease annual patient conference in 2019. RESULTS: In the questionnaires of the registry, fifty-three patients (90%) reported that they were with inclusion body myopathy, 17 patients (29%) with Paget\u27s disease of bone, eight patients (14%) with dementia, two patients (3%) with amyotrophic lateral sclerosis, and a patient with parkinsonism. Thirteen patients (22%) reported dysphagia and 25 patients (42%) reported dyspnea on exertion. A self-reported functional rating scale for motor function identified challenges with sit to stand (72%), walking (67%), and climbing stairs (85%). Thirty-five (59%) patients in the registry answered that their quality of life is more than good. As for the weakness pattern of the 22 patients who were evaluated at the Cure VCP Disease annual conference, 50% of patients had facial weakness, 55% had scapular winging, 68% had upper proximal weakness, 41% had upper distal weakness, 77% had lower proximal, and 64% had lower distal weakness. CONCLUSIONS: The Cure VCP Disease Patient Registry is useful for deepening the understanding of patient daily life, which would be a basis to develop appropriate clinical outcome measures. The registry data is consistent with previous studies evaluating VCP patients in the clinical setting. Patient advocacy groups are essential in developing and maintaining disease registries

Optimizing Hybrid Plate Fixation with a Locked, Oblique End Screw in Osteoporotic Fractures

Background The end screw in a fracture plate creates the greatest resistance to bending. For osteoporotic fractures treated with plates, there is some question as to the optimal screw insertion technique for the screw farthest from the fracture. A locked, oblique end screw was previously shown to increase resistance to periprosthetic fracture. It is unknown, however, how this end screw configuration would resist pullout when subjected to bending. Methods Narrow, low contact 3.5 mm locking compression plates with 6 and 12 holes were anchored to simulated bone material with material properties representing osteoporotic bone. Four configurations were evaluated for the end screw: perpendicular and angulated 30 degrees away from the fracture for both non-locked and locked screws (n=6 per group). The constructs were subjected to 3 point bending until the peak load and finally total construct failure was achieved. Results Peak force, stiffness, energy to peak load, and the failure mode of each construct were determined. All four 12-hole construct groups failed by gross plastic bending deformation of the plate at the fulcrum past a previously established clinically relevant limit for failure (15°). All 12-hole plate constructs failed at statistically higher loads and energy than any of the 6-hole plate constructs, with the exception of the 6-hole locked, oblique construct. Conclusion The locked, oblique end screw provides equivalent pull out strength for 3.5 mm low contact plates regardless of plate length. Combined with its resistance to periprosthetic fracture, this end screw configuration appears to be the best option for the construct integrity of hybrid plating for osteoporotic fractures. Clinical Relevance Osteoporotic fractures are challenging to treat. The current study and the existing literature show that resistance to both bending loads and refracture at the end of a plate are minimized with a locked screw angled away from the fracture

Evaluation of Average and Maximum Heart Rate of Wrist-worn Wearable Technology Devices During Trail Running

It has been estimated that there are 20 million people who participate in trail running, and these numbers are expected to increase by 15% each year. Our laboratory group has conducted studies on the validity of wearable technology watches and heart rate (HR) during trail running. The previous generation devices were mostly inaccurate, and a limitation was that reliability was not measured. PURPOSE: To determine both validity and reliability in newer models of wearable devices during trail running. METHODS: Seventeen participants (F = 7) ran on the Thunderbird Gardens Lightning Switch trail in Cedar City, UT. Demographic characteristics: Age = 25 (9) years (mean [standard deviation]), ht = 168 (9) cm, mass = 72 (14) kg. Two Garmin Instincts and two Polar Vantage M2s were evaluated, along with the Polar H10 chest strap as the criterion measure. Participants ran out on the trail for 10-minutes, and then returned to the trailhead. Maximum HR and average HR were measured during the run. Data were analyzed for validity (Mean Absolute Percent Error [MAPE] and Lin’s Concordance [CCC]) and reliability (Coefficient of Variation [CV] and Intraclass Correlation Coefficient [ICC]). Predetermined thresholds were: MAPE0.70, CV0.70. RESULTS: The Garmin Instinct met the threshold for both reliability tests for average and maximum HR (see table). The Garmin Instinct and Polar Vantage met the threshold for both validity tests for maximum HR. CONCLUSION: In order for a device to be considered valid, it must meet the predetermined thresholds for both validity and reliability. These results indicate that only the Garmin Instinct is valid and reliable, but only for measuring maximum HR. This is challenging for those who wish to track their HR while trail running, because neither of the studied devices were valid and reliable for maximum and average HR

Efficacy of a Single Image-Guided Corticosteroid Injection for Glenohumeral Arthritis

Background There is limited data available on the efficacy of cortisone injection for glenohumeral osteoarthritis (GHOA). The amount and longevity of pain relief provided by a single cortisone injection is unclear. Additionally, it remains uncertain how the severity of radiographic GHOA and patient reported function and pain levels impact the efficacy of injection. Therefore, we sought to describe relief provided by a single, image guided glenohumeral injection for patients with GHOA. Additionally, we hypothesized that patients with more severe radiographic GHOA and poorer baseline shoulder function would require earlier secondary intervention. Methods Patients with symptomatic GHOA who elected to receive a corticosteroid injection for pain relief were prospectively enrolled. A phone interview was conducted to record baseline OSS and VAS scores prior to the injection, as well as at months 1, 2, 3, 4, 6, 9, and 12. Endpoints were designated when patients required a second injection, progressed to surgery, or reached month 12. Patients were grouped by their respective baseline OSS (mild, moderate/severe) and Samilson-Prieto radiographic classification (mild, moderate, severe) for analysis. Results Thirty shoulders (29 patients) were analyzed. 52% of patients were male. The average age of 66.1 years. No significant difference was seen in overall survival (defined as no additional intervention) between groups based on either OSS or Samilson-Prieto grades. Additionally, OSS and VAS scores at each follow-up were compared to baseline. For the entire cohort, a clinically significant difference was seen between baseline and months 1-4 for OSS and between baseline and months 1-4, 6,9, and 12 for VAS. Discussion This study aimed to determine the efficacy of corticosteroid injections for GHOA. There were no differences in the need for secondary interventions in this population based on severity of either the OSS or the Samilson-Prieto radiographic classification. However, patients with more severe shoulder dysfunction based on OSS did experience a statistically significant greater symptomatic relief compared with patients with milder dysfunction. Additionally, following a single injection, patients in this cohort experienced statistically and clinically relevant improvements in shoulder function and pain up to 4 months post-injection

Environmental cues and constraints affecting the seasonality of dominant calanoid copepods in brackish, coastal waters: a case study of Acartia, Temora and Eurytemora species in the south-west Baltic

Information on physiological rates and tolerances helps one gain a cause-and-effect understanding of the role that some environmental (bottom–up) factors play in regulating the seasonality and productivity of key species. We combined the results of laboratory experiments on reproductive success and field time series data on adult abundance to explore factors controlling the seasonality of Acartia spp., Eurytemora affinis and Temora longicornis, key copepods of brackish, coastal and temperate environments. Patterns in laboratory and field data were discussed using a metabolic framework that included the effects of ‘controlling’, ‘masking’ and ‘directive’ environmental factors. Over a 5-year period, changes in adult abundance within two south-west Baltic field sites (Kiel Fjord Pier, 54°19′89N, 10°09′06E, 12–21 psu, and North/Baltic Sea Canal NOK, 54°20′45N, 9°57′02E, 4–10 psu) were evaluated with respect to changes in temperature, salinity, day length and chlorophyll a concentration. Acartia spp. dominated the copepod assemblage at both sites (up to 16,764 and 21,771 females m−3 at NOK and Pier) and was 4 to 10 times more abundant than E. affinis (to 2,939 m−3 at NOK) and T. longicornis (to 1,959 m−3 at Pier), respectively. Species-specific salinity tolerance explains differences in adult abundance between sampling sites whereas phenological differences among species are best explained by the influence of species-specific thermal windows and prey requirements supporting survival and egg production. Multiple intrinsic and extrinsic (environmental) factors influence the production of different egg types (normal and resting), regulate life-history strategies and influence match–mismatch dynamics

Epidermal Growth Factor Receptor Activation in Glioblastoma through Novel Missense Mutations in the Extracellular Domain

Background: Protein tyrosine kinases are important regulators of cellular homeostasis with tightly controlled catalytic activity. Mutations in kinase-encoding genes can relieve the autoinhibitory constraints on kinase activity, can promote malignant transformation, and appear to be a major determinant of response to kinase inhibitor therapy. Missense mutations in the EGFR kinase domain, for example, have recently been identified in patients who showed clinical responses to EGFR kinase inhibitor therapy. Methods and Findings: Encouraged by the promising clinical activity of epidermal growth factor receptor (EGFR) kinase inhibitors in treating glioblastoma in humans, we have sequenced the complete EGFR coding sequence in glioma tumor samples and cell lines. We identified novel missense mutations in the extracellular domain of EGFR in 13.6% (18/132) of glioblastomas and 12.5% (1/ 8) of glioblastoma cell lines. These EGFR mutations were associated with increased EGFR gene dosage and conferred anchorage-independent growth and tumorigenicity to NIH-3T3 cells. Cells transformed by expression of these EGFR mutants were sensitive to small-molecule EGFR kinase inhibitors. Conclusions: Our results suggest extracellular missense mutations as a novel mechanism for oncogenic EGFR activation and may help identify patients who can benefit from EGFR kinase inhibitors for treatment of glioblastoma

Reforming Fiscal Institutions in Resource-Rich Arab Economies: Policy Proposals

This paper traces the evolution of fiscal institutions of Resource Rich Arab Economies (RRAEs) over time since their pre-oil days, through the discovery of oil to their build-up of oil exports. It then identifies challenges faced by RRAEs and variations in their severity among the different countries over time. Finally, it articulates specific policy reforms, which, if implemented successfully, could help to overcome these challenges. In some cases, however, these policy proposals may give rise to important trade-offs that will have to be evaluated carefully in individual cases

Epidermal Growth Factor Receptor Activation in Glioblastoma through Novel Missense Mutations in the Extracellular Domain

BACKGROUND: Protein tyrosine kinases are important regulators of cellular homeostasis with tightly controlled catalytic activity. Mutations in kinase-encoding genes can relieve the autoinhibitory constraints on kinase activity, can promote malignant transformation, and appear to be a major determinant of response to kinase inhibitor therapy. Missense mutations in the EGFR kinase domain, for example, have recently been identified in patients who showed clinical responses to EGFR kinase inhibitor therapy. METHODS AND FINDINGS: Encouraged by the promising clinical activity of epidermal growth factor receptor (EGFR) kinase inhibitors in treating glioblastoma in humans, we have sequenced the complete EGFR coding sequence in glioma tumor samples and cell lines. We identified novel missense mutations in the extracellular domain of EGFR in 13.6% (18/132) of glioblastomas and 12.5% (1/8) of glioblastoma cell lines. These EGFR mutations were associated with increased EGFR gene dosage and conferred anchorage-independent growth and tumorigenicity to NIH-3T3 cells. Cells transformed by expression of these EGFR mutants were sensitive to small-molecule EGFR kinase inhibitors. CONCLUSIONS: Our results suggest extracellular missense mutations as a novel mechanism for oncogenic EGFR activation and may help identify patients who can benefit from EGFR kinase inhibitors for treatment of glioblastoma