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Development and validation of a unifying pre-treatment decision tool for intracranial and extracranial metastasis-directed radiotherapy.
No full textBackgroundThough metastasis-directed therapy (MDT) has the potential to improve overall survival (OS), appropriate patient selection remains challenging. We aimed to develop a model predictive of OS to refine patient selection for clinical trials and MDT.Patients and methodsWe assembled a multi-institutional cohort of patients treated with MDT (stereotactic body radiation therapy, radiosurgery, and whole brain radiation therapy). Candidate variables for recursive partitioning analysis were selected per prior studies: ECOG performance status, time from primary diagnosis, number of additional non-target organ systems involved (NOS), and intracranial metastases.ResultsA database of 1,362 patients was assembled with 424 intracranial, 352 lung, and 607 spinal treatments (n=1,383). Treatments were split into training (TC) (70%, n=968) and internal validation (IVC) (30%, n=415) cohorts. The TC had median ECOG of 0 (interquartile range [IQR]: 0-1), NOS of 1 (IQR: 0-1), and OS of 18 months (IQR: 7-35). The resulting model components and weights were: ECOG = 0, 1, and > 1 (0, 1, and 2); 0, 1, and > 1 NOS (0, 1, and 2); and intracranial target (2), with lower scores indicating more favorable OS. The model demonstrated high concordance in the TC (0.72) and IVC (0.72). The score also demonstrated high concordance for each target site (spine, brain, and lung).ConclusionThis pre-treatment decision tool represents a unifying model for both intracranial and extracranial disease and identifies patients with the longest survival after MDT who may benefit most from aggressive local therapy. Carefully selected patients may benefit from MDT even in the presence of intracranial disease, and this model may help guide patient selection for MDT
Human Norovirus Aptamer Exhibits High Degree of Target Conformation-Dependent Binding Similar to That of Receptors and Discriminates Particle Functionality.
No full textAlthough two in vitro cultivation methods have been reported, discrimination of infectious human norovirus particles for study of viral inactivation is still a challenge, as both rely on reverse transcriptase quantitative PCR. Histo-blood group antigen (HBGA) binding assays serve as a proxy for estimation of infectious particles; however, they are costly and difficult to purify/modify. Some evidence suggests that certain nucleic acid aptamers only bind intact target proteins, thus displaying a high degree of conformation-dependent binding. The objective of this proof-of-concept study was to characterize the degree of conformation-dependent binding a human norovirus aptamer, M6-2, displayed with the capsid of the norovirus GII.4 Sydney (SYV) strain as a model. SYV capsids were exposed to heat, and aptamer, receptor (HBGA), and antibody binding was assessed. M6-2 and the receptor displayed similarly little target sequence-dependent binding (2.0% ± 1.3% and 0.5% ± 1.2% signal, respectively) compared to that of NS14 (26.4% ± 3.9%). The decay rates calculated with M6-2 and the receptor were also not statistically significantly different (P > 0.05), and dynamic light scattering and electron microscopy confirmed these observations. Ligand docking simulations revealed multiple distinct contacts of M6-2 in the N-terminal P1 and P2 domains of the viral capsid, with some residues close to receptor binding residues. These data suggest that single-stranded DNA aptamers like M6-2 display a high degree of target conformation-dependent binding. It is the first time nucleic acid aptamers have had this characteristic utilized and investigated to discern the infectivity status of viral particles, and the data suggest that other aptamers may show promise as valuable ligands in the study of other fastidious microorganisms. IMPORTANCE Human noroviruses impose a considerable health burden globally. However, study of their inactivation is still challenging with currently reported cell culture models, as discrimination of infectious viral particles is still difficult. Traditionally, the ability of particles to bind putative carbohydrate receptors is conducted as a proxy for infectivity, but these receptors are inconsistent, expensive, and hard to purify/modify. We report a hitherto unexplored property of a different type of ligand, a nucleic acid aptamer, to mimic receptor binding behavior and assess capsid functionality for a selected strain of norovirus. These emerging ligands are cheaper, more stable, and easily synthesized/modified. The previously unutilized characteristic reported here demonstrates the fundamental potential of aptamers to serve as valuable, accessible tools for any microorganism that is difficult to cultivate/study. Therefore, this novel concept suggests a new use for aptamers that is of great value to the microbiological community-specifically that involving fastidious microbes
Three-column osteotomy for correction of cervical and cervicothoracic deformities: alignment changes and early complications in a multicenter prospective series of 23 patients.
No full textPurposeThree-column osteotomy (3CO), including pedicle subtraction osteotomy (PSO) and vertebral column resection (VCR), can provide powerful alignment correction for adult cervical deformity (ACD). Our objective was to assess alignment changes and early complications associated with 3CO for ACD.MethodsACD patients treated with 3CO with minimum 90-day follow-up were identified from a prospectively collected multicenter ACD database. Complications within 90-days of surgery and pre- and postoperative radiographs were collected.ResultsAll 23 ACD patients treated with 3CO (14 PSO/9 VCR) had minimum 90-day follow-up (mean age 62.3 years, previous cervical/cervicothoracic instrumentation in 52.2% and thoracic/thoracolumbar instrumentation in 47.8%). The primary diagnosis was kyphosis in 91.3% and coronal deformity in 8.7%. The mean number of fusion levels was 12 (range 6-18). The most common 3CO levels were T1 (39.1%), T2 (30.4%) and T3 (21.7%). Eighteen (12 major/6 minor) complications affected 13 (56.5%) patients. The most common complications were neurologic deficit (17.4%), wound infection (8.7%), distal junctional kyphosis (DJK 8.7%), and cardiorespiratory failure (8.7%). Three (13.0%) patients required re-operation within 90-days (1 each for nerve root motor deficit, DJK, and implant pain/prominence). Cervical alignment improved significantly following 3CO, including cervical lordosis (-2.8° to -12.9°, p = 0.036), C2-7 sagittal vertical axis (64.6-42.3 mm, p ConclusionsAmong 23 ACD patients treated with 3CO, cervical alignment improved significantly following surgery. Thirteen (56.5%) patients had at least one complication. The most common complications were neurologic deficit, infection, DJK, and cardiorespiratory failure
Antibacterial Utilization for Febrile Illnesses and Laboratory-Confirmed Bloodstream Infections in Northern Tanzania.
No full textBackgroundWe describe antibacterial use in light of microbiology data and treatment guidelines for common febrile syndromes in Moshi, Tanzania.MethodsWe compared data from 2 hospital-based prospective cohort studies, cohort 1 (2011-2014) and cohort 2 (2016-2019), that enrolled febrile children and adults. A study team member administered a standardized questionnaire, performed a physical examination, and collected blood cultures. Participants with bloodstream infection (BSI) were categorized as receiving effective or ineffective therapy based upon antimicrobial susceptibility interpretations. Antibacterials prescribed for treatment of pneumonia, urinary tract infection (UTI), or presumed sepsis were compared with World Health Organization and Tanzania Standard Treatment Guidelines. We used descriptive statistics and logistic regression to describe antibacterial use.ResultsAmong participants, 430 of 1043 (41.2%) and 501 of 1132 (44.3%) reported antibacterial use prior to admission in cohorts 1 and 2, respectively. During admission, 930 of 1043 (89.2%) received antibacterials in cohort 1 and 1060 of 1132 (93.6%) in cohort 2. Inpatient use of ceftriaxone, metronidazole, and ampicillin increased between cohorts (P ≤ .002 for each). BSI was detected in 38 (3.6%) participants in cohort 1 and 47 (4.2%) in cohort 2. Of 85 participants with BSI, 81 (95.3%) had complete data and 52 (64.2%) were prescribed effective antibacterials. Guideline-consistent therapy in cohort 1 and cohort 2 was as follows: pneumonia, 87.4% and 56.8%; UTI, 87.6% and 69.0%; sepsis, 84.4% and 61.2% (P ≤ .001 for each).ConclusionsReceipt of antibacterials for febrile illness was common. While guideline-consistent prescribing increased over time, more than one-third of participants with BSI received ineffective antibacterials
Accessibility Improvement for the North Carolina Coastal Reserve
No full textThe N.C. Coastal Reserve and National Estuarine Research Reserve have 10 sites located around North Carolina that provide the public with recreational, educational, and research experiences within the ecosystems that they manage and preserve. To improve accessibility, this study reviews current accessibility at Reserve sites, provides broad legal background about accessibility in the U.S., provides Reserve history and use goals, and offers recommendations for accessibility improvement for each site where improvement is possible. These recommendations include product recommendations, product cost estimates, site-specific recommendations, and recommendations that apply to all, or most, Reserve sites. Final recommendations include a range of different costs, timeframes, and requirements to implement
A Virtual Reality Application: Creating an Alternative Immersive Experience for Dunhuang Mogao Cave Visitors
No full textAs the largest cave of Buddhist art with thousands of murals spanning ten dynasties, the Dunhuang Mogao cave has been described as a “peerless cave” because of its fabulous frescos and handcrafted delicate sculptures. However, tourism and in-cave human activities had damaged the frescos; only a few caves are now open with limited accessibility for global visitors and the public. In addition, Dunhuang Cave authorities set strict rules to exclude some people, such as people in wheelchairs, to protect the murals and sculptures from possible damage. This thesis project aims to address this problem by modeling how digital environments might provide universal access to the cave by marginalized and excluded groups. The thesis project includes two separate digital sections: a Unity VR (Virtual Reality) immersive experience and a web-based Story Map with a three-dimensional view of selected murals. The thesis project not only provides an immersive experience for worldwide visitors but also unlocks the door for the possibilities of preserving cultural heritage by using innovative digital methods. Through the use of Maya and Steam, the Unity game engine can be used to curate a virtual space by placing the audience into well-textured 3D cave models, while the web-based story map can be used to contextualize basic background knowledge and provides a comprehensive text explanation of the Silk Road and Buddhist culture to inform the user’s understanding of what they are seeing. Overall, this thesis demonstrates endeavors to discover more possibilities and opportunities for historical and cultural heritage protection while not losing access.</p
Diversity of undergraduates in STEM courses: individual and demographic differences in changes in self-efficacy, epistemic beliefs, and intrapersonal attribute profiles
No full textAcross undergraduate STEM learning contexts in several countries, students’ intrapersonal attributes of epistemic beliefs, self-efficacy beliefs, intrinsic motivation, and sense of identity have been found to influence learning and to change in response to educational practices. However, research can mask individual and demographic differences in student's attributes that may moderate or mediate the relationship between educational practices and learning outcomes. We employed variable-centered and person-centered methods to examine individual and demographic differences in changes in students’ intrapersonal attributes and patterns of interrelationship among attributes with a study sample of students (N = 4,500) in 14 STEM undergraduate courses (8 biology, 4 chemistry, and 2 statistics) at three research universities in the United States. Variable-centered analyses revealed overall increases in students’ science self-efficacy beliefs and epistemic beliefs even though these outcomes were not intentionally targeted as learning objectives. However, person-centered analyses indicated that not all students experienced these gains. For example, self-identified Asian/Pacific Islander and Black students were more likely to be members of groups demonstrating a decrease in science self-efficacy, whereas Asian/Pacific Islander students and men were less likely to be members of the subgroup with consistently evaluativist epistemic beliefs and higher GPAs. Using latent profile analysis (LPA), we identified five distinct student profiles that reflected different patterns of interrelationship of epistemic beliefs, science and writing self-efficacy beliefs, and science identity. We discuss the implications of these findings for educational practices, particularly with regard to intentionally fostering diverse students’ self-efficacy, sense of identity, and adaptive epistemic beliefs
Sabbath Rest(oration): Reframing the Purpose and Witness of an Eschatological Sabbath-keeping Community
No full textABSTRACTThis thesis touches on several massive themes within Christian theology, including questions of ecclesiology, eschatology, soteriology, and missiology. Yet it is grounded in a very real and practical question. What definition of the church should guide me, as the senior pastor of an incredibly diverse Sabbath-keeping local church in the Seventh-day Adventism denomination,as we develop the strategic vision for this next season of ministry, and decide how we want to fund those goals. What should the “markers” of the church be?In order to help narrow my focus, I will explore this question in four parts. In Chapter 1, I provide a brief history of Seventh-day Adventism, with a specific focus on the development of the doctrine of the Sabbath and the doctrine of the church, such as it is. In Chapter 2, I turn more directly to various models of the church. Using Avery Dulles as a conversation partner in hiswork Models of the Church, I examine Adventism in the light of some of the most prominent models and note which of these Adventism seems to lean towards. I then recommend a new eschatological understanding of the church that I believe could be uniquely well-suited for Adventism.In Chapter 3 I turn to the question of the Sabbath. Given that Sabbath-keeping is considered a marker of faithfulness for most Seventh-day Adventists, I propose that the biblical Sabbath has always been about more than humanity’s faithfulness, and that the Sabbath should be seen instead primarily as a pointer to the purpose and faithfulness of God. Drawing from Sigve Tonstad’s book The Lost Meaning of the Seventh Day, I suggest a reframed understanding of the Sabbath that includes seeing the Sabbath as an indicator of God’s future purpose promised from the very beginning of creation. I suggest that the Sabbath can best be seen as a promise, grounded in the past, pointing to the future, that shapes and directs the present.Finally, in Chapter 4, I consider how the idea of the “church as foretaste” and “Sabbath as promise” could shape the lived reality of a local community, and recommend some practices that we as a local church could explore that would help us better embody the coming kingdom of God.Questions about the nature, purpose, and mission of the church have been asked and answered and asked again for generations. Most recently, the coronavirus pandemic has caused the longest disruption to the regular rhythms and practices of the church in recent memory. Clergy and laity alike are wondering, as we imagine what a post-pandemic life will look like, justwhat impact this new reality will have on the church, which practices will stay the same, and which will shift. A season of new beginnings is an excellent time to reconsider old assumptions, and to recalibrate where needed.It is my hope that this thesis will be helpful in three ways. First, I hope for it to be helpful on the local church level, especially for Sabbath-keeping churches interested in a reframed perspective on the Sabbath that moves it beyond a question of obedience, to a question of meaning, liberation, and purpose. Secondly, I hope to contribute to the much needed and growing conversation within Seventh-day Adventism regarding Adventist ecclesiology. Over the past two decades, Adventist scholars have become increasingly convinced of the need to further develop our ecclesiology, but it is still a relatively recent field of study within the denomination. This thesis will offer a reframed understanding of Sabbath-keeping that is linked to an eschatologically-shaped ecclesiology. Finally, I hope this thesis will have something to offer to the broader Christian community. The biblical concept of the Sabbath has experienced something of a renaissance in the wider Christian conversations over the past half-century. The Sabbath has been linked to creation and as a potential response to the environmental crisis; to economics, debt relief and jubilee; and to emancipation, messianic ethics, and spiritual formation. Yet while many of these Christian authors draw on themes inherent in the biblical Sabbath, very few of them have lived in communities already profoundly shaped by its counter-cultural power. We as Adventists are deeply indebted to the gift of the Sabbath; it is my hope that our lived reality can provide inspiration to others.</p
Isolation, purification and in vitro differentiation of cytotrophoblast cells from human term placenta.
No full textBackgroundThe syncytialization of cytotrophoblast cells to syncytiotrophoblast is central to human placental transport and hormone production. Many techniques for in vitro study of this process have been proposed and new investigators to the field may find the literature in the field daunting. Here, we present a straightforward and reliable method to establish this important model using modern but readily available tools and reagents.MethodsVillous cytotrophoblast cells are obtained from term placenta using mild enzymatic degradation, Percoll gradient centrifugation, negative magnetic cell sorting using an antibody against classical major histocompatibility complex molecules and in vitro culture on a matrix-coated growth surface.ResultsThe purity of isolated cytotrophoblast cells exceeds 98 % as assessed by cytokeratin-7 expression using flow cytometry. Contamination by mesenchymal cells, extravillous trophoblast cells, leukocytes, Hofbauer and endothelial cells is minimized (less than 2 % when analyzed for vimentin, HLA-G, CD45, CD163 and CD31 using flow cytometry). Isolated cytotrophoblast cells began to aggregate into monolayers of mononucleated cells within about 12 h of plating. By 72 h in culture, most cytotrophoblast cells have differentiated into syncytiotrophoblast as demonstrated by a loss of intercellular E-cadherin expression upon fusion into multinucleated syncytia. After 72 h in culture, nearly every cultured cell expresses syncytiotrophoblast markers, including cytokeratin-7, human chorionic gonadotropin-β (β-hCG) and the fusion-related proteins glial cell missing-1 (GCM-1) and syncytin.ConclusionsWe present an efficient and reliable method for isolating of cytotrophoblast cells with high purity and complete differentiation into syncytiotrophoblast in vitro
