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Background and aimsLipoprotein(a) [Lp(a)] is causally associated with aortic valve stenosis (AS) but Lp(a) testing among AS patients is not broadly incorporated into clinical practice. We evaluated trends in Lp(a) testing in an academic medical center.MethodsEducational efforts and adding Lp(a) to the lipid panel on the electronic medical record (EMR) and pre-procedure order sets were used to increase awareness of Lp(a) as a risk factor in AS. Medical records at University of California San Diego Health (UCSDH) were analyzed from 2010 to 2020 to define the yearly frequency of first time Lp(a) testing in patients with diagnosis codes for AS or undergoing transcatheter aortic valve replacement (TAVR).ResultsLp(a) testing for any indication increased over 5-fold from 2010 to 2020. A total of 3808 patients had a diagnosis of AS and 417 patients had TAVR. Lp(a) levels >30mg/dL were present in 37% of AS and 35% of TAVR patients. The rates of Lp(a) testing in AS and TAVR were 14.0% and 65.7%, respectively. In AS, Lp(a) testing increased over time from 8.5% in 2010, peaking at 24.2% in 2017, and declining to 13.9% in 2020 (p&nbsp

Objectives Evidence-based treatment protocols are currently lacking for immune-mediated necrotizing myopathy (IMNM). In this multicentre retrospective study, we examined baseline clinical characteristics and treatment variables that may predict short-term outcomes of patients with IMNM. Methods Muscle biopsies from the John Hunter Hospital and the Royal Adelaide Hospital obtained between 2012 and 2019 were reviewed at a single laboratory at South Australia Pathology. All biopsies with histological features of IMNM were identified. Demographics of study subjects, clinical information and myositis-specific antibody status were recorded along with muscle strength, serum creatine kinase (CK) and treatment regimens at baseline and 3 and 6 months. Primary outcome measures were muscle strength and serum CK at 3 and 6 months. Mixed-effects regression models in a Bayesian framework were performed using the R statistical package. Results Female sex, older age, initial prednisone dose and i.v. methylprednisolone were associated with greater improvement in serum CK. In patients with moderate–severe disease at baseline, early IVIG was associated with greater improvement in hip flexor strength at 6 months. Conclusion Early IVIG was associated with clinical improvement in the short-term follow-up in IMNM. Female sex, older age, initial oral prednisone dose and initial use of i.v. methylprednisolone were associated with better biochemical improvement.

In the international standard for system and software engineering ISO/IEC/IEEE 15288: 2015, the output of the stakeholder needs and the business or mission analysis technical processes are transformed into a technical view of the system by the system requirements definition process. In model-based systems engineering, functional needs can be modeled by use case diagrams. Intended outcomes of system requirements definition include resolution of disagreement about requirements, explicit agreement between stakeholders, and traceability. However, stakeholder needs are often elicited in a siloed manner and may be inconsistent. The lack of mathematically based systematic approaches for requirements definition poses a challenge to model-based transformation of needs into a technical view of the system that achieves agreement between stakeholders. This paper specifies and demonstrates mathematical frameworks for rationalizing and synthesizing functional needs that have been captured through an elicitation process. Benefits of this approach include but are not limited to supporting rigorous identification and resolution of disagreements and facilitating systematic analysis of change impact to achieve stakeholder agreement all with minimal intervention by the system engineers., Comment: Accepted version, to appear in IEEE Open Journal of Systems Engineering

Myositis is a known complication of chronic graft-vs-host disease (cGVHD) following allogeneic haematopoietic stem cell transplantation, but can be difficult to diagnose and manage. We present the case of a 57 year old man with cGVHD in whom the full manifestations of myositis were suppressed for some time, likely due to partial treatment of his condition with immunosuppression including ibrutinib. Though initial muscle biopsy showed necrotising myopathy without significant inflammation, on cessation of ibrutinib he developed increasing weakness and creatine kinase levels, with repeat muscle biopsy showing histological changes more in keeping with dermatomyositis. The close temporal correlation of his clinical course with commencement and cessation of ibrutinib suggests a potential role for ibrutinib in treating inflammatory myopathy in cGVHD.

This study investigates placebos and video games’ usefulness as psychological research tools. One proposed underlying mechanism of the placebo effect is participants’ expectations. Such expectation effects exist in sports psychology and healthcare domains, but inconsistent findings have emerged on whether similar effects impact a participants’ cognitive performance. Concurrently, using video games as task environments is an emerging methodology relating to expertise and large-scale behavioral data collection. Therefore, this study examines the expectancy effect induced by researcher instructions on in-game performance. The instructional expectancy condition for this study is in-game successes framed using emoting (e.g., emoting under the pretense of subsequent performance increases) versus a control group. Preliminary results showed no evidence of different in-game performance between expectancy conditions. Potential mechanisms that could have led to a lack of effect were discussed.

Virtual reality technology is constantly improving such that a virtual environment is more like a physical one. However, some research evidence suggest that certain virtual reality scenarios are less real than others to human observers (e.g., experience of falling from a high place) leading to potential limitations of using virtual reality as a research tool for certain tasks. Moreover, since the inception of VR research the terms presence and immersion have been somewhat convoluted and at times, even used interchangeably. Using a thematic content analysis based on seventeen articles, a theme for each term emerged. Presence is an experiential quality in virtual environments and immersion is associated with the technical aspects of a virtual system that aide the user in feeling a sense of presence. Several new technologies, as well as more traditional approaches are discussed as potential methods to improve of immersion, and therefore presence, in virtual reality.

In this third decade of systems engineering in the twenty-first century, it is important to develop and demonstrate practical methods to exploit machine-readable models in the engineering of systems. Substantial investment has been made in languages and modelling tools for developing models. A key problem is that system architects and engineers work in a multidisciplinary environment in which models are not the product of any one individual. This paper provides preliminary results of a formal approach to specify models and structure preserving transformations between them that support model synchronization. This is an important area of research and practice in software engineering. However, it is limited to synchronization at the code level of systems. This paper leverages previous research of the authors to define a core fractal for interpretation of concepts into model specifications and transformation between models. This fractal is used to extend the concept of synchronization of models to the system level and is demonstrated through a practical engineering example for an advanced driver assistance system., Accepted by the 8th IEEE International Symposium on Systems Engineering (ISSE 2022), Special Session on Theoretical Foundations of System Engineering (THEFOSE)

Growing interest in improving patient participation convenience and the feasible execution of clinical trials has increased demand for new approaches to leverage patient input in the protocol design process. This study builds on prior work conducted by the Tufts Center for the Study of Drug Development in collaboration with ZS. A comprehensive participant burden algorithm based on protocol procedures, participation requirements and lifestyle preferences was developed and tested. Clinical trial preferences and perceptions from 3002 global patients were analyzed to inform and derive the algorithm. It was next tested against a convenience sample of 266 completed protocols. Descriptive statistics, significance tests, and regression analyses were performed. Mean participant burden scores were highly associated with, and predictive (p

Investigate the clinical and functional implications of elevated CRABP2 expression in endometrial cancer (EC) patients.Patients were stratified into high and low CRABP2 expression groups using a decision tree classifier. Univariate and multivariate statistical analyses determined the prognostic and clinicopathological consequences of increased CRABP2 expression. A CRABP2 gene signature was generated using differential expression analysis, and analyzed using network-based approaches. The findings were validated in The Clinical Proteomic Tumor Analysis Consortium (CPTAC), a newly generated cohort of 120 endometrial tissues, and The Cancer Dependency Map (DepMap).60 (11%) patients in TCGA had high CRABP2 expression, whilst 468 (89%) had low expression. High expression was associated with serous EC, reduced overall survival, advanced stage and grade. Downstream retinoic acid receptors (RARG and RARA) were correlated with CRABP2 expression and were associated with worse prognosis in serous EC. The CRABP2 gene signature was enriched for Polycomb target gene sets, and was regulated by ELP3 and BMP7. BMP7 expression was increased in the CRABP2-high group, was associated with worse prognosis, and CRISPR-Cas9 screens revealed correlations in its cell-fitness score with CRABP2 following gene knockout. The opposite was true for ELP3, suggesting opposing effects from both master regulators.CRABP2 expression is associated with poor prognosis and advanced EC. The expression of RARA and RARG correlates with CRABP2 and are associated with worse prognosis in advanced histological subtypes. Polycomb target gene sets and two master regulators, ELP3 and BMP7, were identified as functionally relevant mechanisms driving aberrant CRABP2 expression.

ImportanceSafety and effectiveness studies of COVID-19 vaccines are being conducted using clinical data, including administrative claims. However, claims data only partially capture administered COVID-19 vaccine doses for numerous reasons, such as vaccination at sites that do not generate claims for reimbursement.ObjectiveTo evaluate the extent to which Immunization Information Systems (IIS) data linked to claims data enhances claims-based COVID-19 vaccine capture for a commercially insured population and to estimate the magnitude of misclassification of vaccinated individuals as having unvaccinated status in the linked IIS and claims data.Design, Setting, and ParticipantsThis cohort study used claims data from a commercial health insurance database and obtained vaccination data from IIS repositories in 11 US states. Participants were individuals younger than 65 years who resided in 1 of 11 states of interest and who were insured in health plans from December 1, 2020, through December 31, 2021.Main Outcomes and MeasuresEstimated proportion of individuals with at least 1 dose of any COVID-19 vaccine and proportion of individuals with a completed vaccine series based on general population guidelines. Vaccination status estimates were calculated and compared using claims data alone and linked IIS and claims data. Remaining misclassification of vaccination status was assessed by comparing linked IIS and claims data estimates with estimates from external surveillance data sources (Centers for Disease Control and Prevention [CDC] and state Department of Health [DOH]) and capture-recapture analysis.ResultsThis cohort study included 5 112 722 individuals (mean [SD] age, 33.5 [17.6] years; 2 618 098 females [51.2%]) from 11 states. Characteristics of those who received at least 1 vaccine dose and those who completed a vaccine series were similar to the overall study population. The proportion with at least 1 vaccine dose increased from 32.8% using claims data alone to 48.1% when the data were supplemented with IIS vaccination records. Vaccination estimates using linked IIS and claims data varied widely by state. The percentage of individuals who completed a vaccine series increased from 24.4% to 41.9% after the addition of IIS vaccine records and varied across states. The percentages of underrecording using linked IIS and claims data were 12.1% to 47.1% lower than those using CDC data, 9.1% to 46.9% lower than the state DOH, and 9.2% to 50.9% lower than capture-recapture analysis.Conclusion and RelevanceResults of this study suggested that supplementing COVID-19 claims records with IIS vaccination records substantially increased the number of individuals who were identified as vaccinated, yet potential underrecording remained. Improvements in reporting vaccination data to IIS infrastructures could allow frequent updates of vaccination status for all individuals and all vaccines.

The article discusses the Weiss dispute from a political economy perspective. It first sets this litigation in its wider context, namely the protracted transformation of the Economic and Monetary Union (EMU) over the last decade, a decade which has revealed the structural flaws in its design. It then briefly sketches the changing role of central banking, from a fixation on fighting inflation to a more recent focus on combating deflation. This helps to explain the problematic character of the Weiss rulings and the commentaries they have provoked, illustrating a general failure to consider the limits of law, the result of clinging to different parts of the EMU wreckage, on the assumption that the current constitutional framework remains viable. Finally, the article emphasizes the transformative potential of the Weiss saga. The judicial conflict lays bare the unsustainability of the present arrangements, and reveals the necessity of a choice between genuinely federal integration and coordinated dismantling of EMU.

Emotion is critical to human experience and is an integral part of perception, cognition, and behavior. While the mechanisms and precise measurement of emotion has been debated in the literature, researchers have theorized that emotion is related to activation across physiological, experiential, and behavioral response systems. This has important implications in human factors research and practice. Just as the cognitive task analysis was proposed to be used in tandem with hierarchical task analyses to account for cognitive components of a task, the current paper proposes a method to account for emotional components of a task. The emotion task analysis is proposed for the purpose of explicating emotion from an individual. Specifically, in order to account for emotional load and/or processes elicited during a task and to be used in tandem with previously established task analyses by usability/user experience researchers and human factors practitioners.

The development of head-mounted display virtual reality systems (e.g., Oculus Rift, HTC Vive) has resulted in an increasing need to represent the physical world while immersed in the virtual. Current research has focused on representing static objects in the physical room, but there has been little research into notifying VR users of changes in the environment. This study investigates how different sensory modalities affect noticeability and comprehension of notifications designed to alert head-mounted display users when a person enters his/her area of use. In addition, this study investigates how the use of an orientation type notification aids in perception of alerts that manifest outside a virtual reality users’ visual field. Results of a survey indicated that participants perceived the auditory modality as more effective regardless of notification type. An experiment corroborated these findings for the person notifications; however, the visual modality was in practice more effective for orientation notifications.

The Cherenkov Telescope Array (CTA) will be the next generation gamma-ray observatory and will be the major global instrument for very-high-energy astronomy over the next decade, offering 5 - 10 x better flux sensitivity than current generation gamma-ray telescopes. Each telescope will provide a snapshot of gamma-ray induced particle showers by capturing the induced Cherenkov emission at ground level. The simulation of such events provides images that can be used as training data for convolutional neural networks (CNNs) to determine the energy of the initial gamma rays. Compared to other state-of-the-art algorithms, analyses based on CNNs promise to further enhance the performance to be achieved by CTA. Pattern spectra are commonly used tools for image classification and provide the distributions of the shapes and sizes of various objects comprising an image. The use of relatively shallow CNNs on pattern spectra would automatically select relevant combinations of features within an image, taking advantage of the 2D nature of pattern spectra. In this work, we generate pattern spectra from simulated gamma-ray events instead of using the raw images themselves in order to train our CNN for energy reconstruction. This is different from other relevant learning and feature selection methods that have been tried in the past. Thereby, we aim to obtain a significantly faster and less computationally intensive algorithm, with minimal loss of performance., Comment: 14 pages, 4 figures, Proceedings of the 37th International Cosmic Ray Conference (ICRC 2021), Berlin, Germany

Contending with a continuously expanding volume and variety of clinical data poses challenges and opportunities for the industry and clinical data management organizations. Tufts CSDD conducted an online survey aimed at further quantifying and understanding the magnitude and impact that expanded data volume, sources and diversity are having on clinical trials. The survey was distributed between October and December 2019. Responses from a total of 149 individuals were included in the final analysis. The survey found that companies use or pilot from one to six different data sources with the majority of respondents using or piloting 3–4 different sources of data in their clinical trials. The results showed that average times to database lock have increased an average 5 days compared to a 2017 study, possibly as a result of managing an even larger number of data sources. Finally, three key mitigation strategies surfaced as techniques respondents used to tackle expanding data volume, sources, and diversity: the creation of a formalized data strategy, investment in new analytics tools and more sophisticated data technology infrastructures, and the development of new data science disciplines. Without further investments into infrastructure and developments of additional mitigation techniques in this area, database lock cycle times are likely to continue to increase as more and more data supporting a clinical trial are coming from nontraditional, CRF sources. Further research must be done into organizations who are handling these challenges appropriately.

Faster drug development times get new therapies to patients sooner and financially benefit drug developers by shortening the time between investment and returns and increasing the time on the market with intellectual property protection. The result is enhanced incentives to innovate. We provide a real-world example of the financial gains from quicker development using recent estimates of drug development costs, returns, and estimates of time reductions from an alternative early-stage drug development paradigm. We utilized data obtained from a drug development and manufacturing services organization to estimate the reduction in development time for drug sponsors from using an integrated platform of formulation development, real-time manufacturing, and clinical testing for 19 completed drug product development projects covering three key drug development activities (transitioning from first-in-human to proof-of-concept [FIH-PoC], modified release formulation development [MR], and enhanced solubility formulation development [ES]). A traditional drug development paradigm was taken as the base case and financial impacts of the alternative development program were determined relative to the base case. The total after-tax financial benefits of shorter development times from integrating formulation development, real-time manufacturing, and clinical testing when applied across a broad portfolio of investigational drugs ranged from $230.5 million to $290.1 million, $196.4 million to $247.5 million, and $102.6 million to $275.5 million, per approved new drug for FIH-PoC, MR, and ES applications, respectively (2018 dollars). For the data we examined, this integrated development model yielded substantial financial benefits over traditional drug development.

The vendor qualification assessment (VQA) process is regarded as expensive and time consuming but there is no quantitative data characterizing and benchmarking this process. The Tufts Center for the Study of Drug Development (Tufts CSDD)-in collaboration with the Avoca Group and 13 pharmaceutical, biotechnology and contract research organizations-conducted a survey of 120 unique companies to gather baseline data. The study results confirm that companies are investing substantial time and resources to support a high and growing volume of vendor qualifications and re-qualifications each year. The average total time to perform a vendor qualification is almost 5 months for single service providers and nearly 7 months for multi-service providers with wide variation within and between companies observed. Re-qualification cycle times are only marginally faster although, in theory, experience and familiarity with a given vendor should replace some assessment requirements. Significant differences were observed by company size and type. A high percentage of assessments-most notably those conducted by large companies-involve customized assessment areas. CROs are able to perform the VQA process significantly faster with fewer personnel. Based on the data provided, Tufts CSDD estimates that global drug developers spent about $375 million to perform approximately 25,000 new vendor qualifications and re-qualifications in 2018.

Background Subdural hygromas are excess fluid accumulations in the subdural compartment, likely occurring via tears in the arachnoid membrane causing cerebrospinal fluid (CSF) leakage into the subdural space. Treatment recommendations for spinal subdural hygromas are lacking. Case Description We report a case of a 30-year-old man who developed delayed-onset cauda equina syndrome after a motor vehicle accident. Magnetic resonance imaging of the thoracic and lumbar spine revealed a CSF intensity collection involving most of the thoracic spine and extending toward the distal end of the thecal sac with ventral displacement of the spinal cord and nerve roots. The patient was successfully treated using interventional radiology-guided lumbar puncture. Conclusions Posttraumatic spinal subdural hygromas are rare complications, as evidenced by the lack of literature and treatment guidelines. Using lumbar puncture, we demonstrate clinical and radiographic resolution of a traumatic subdural hygroma. This outcome suggests lumbar puncture may be an effective treatment modality for similar patients, and can potentially be used to avoid a more invasive surgical decompression.