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Role of Pilot Trials in RCT Quality and Feasibility
Get PDFLarge randomized controlled trials are crucial for assessing intervention efficacy but often fail or remain incomplete due to feasibility issues. Pilot trials may increase full-scale trial success but come with methodological challenges, including the debate over estimating efficacy. Design modifications post-pilot are common but their impact on feasibility is not fully understood. Furthermore, the association between pilot trials and the quality of full-scale trials is underexplored.
This meta-epidemiological study tackles these challenges by assembling two datasets. We searched PubMed for pilot trials published between 2005 and 2018 and their subsequent full-scale trials. The meta-analysis of the full-scale trials was then used to identify other full-scale trials on the same research topic but without a pilot trial.
In Paper 1, we analyzed 248 pairs of pilot and full-scale trials. Full-scale trials with a significant pilot trial were 2.72 times more likely to find a significant result for the primary efficacy outcome than those with a non-significant pilot trial. In 73% of the pairs, the pilot trial yielded a larger point estimate than the full-scale trial, yet in 87% of cases, the pilot's 95% confidence interval encompassed the full-scale point estimate. Paper 2 analyzed 249 pilot and full-scale trial pairs. Using feasibility progression criteria in pilot trials and maintaining the same masking status as the full-scale trial may improve the chances of successful screening, whereas adding extra content to the intervention, changing to active or more frequent control, and altering follow-up lengths and visits may decrease the chances of retaining participants in full-scale trials. In Paper 3, 58 full-scale trials with a pilot trial and 151 full-scale trials without were identified from 47 meta-analyses. A pilot trial's presence was associated with lower risk of bias in full-scale trial random sequence generation, allocation concealment, and participants/researchers masking, but not outcome assessment masking, incomplete outcome data, and selective reporting.
Pilot trials can offer early signals on intervention efficacy. Researchers and funders should weigh both the data from pilot trials and proposed design modifications when evaluating full-scale trials. Pilot trials may improve the quality of ensuing full-scale trials and warrant more frequent consideration
DYNAMIC PHENOMENA IN BIOLOGICAL SYSTEMS FROM: PROTEIN LIGAND INTERACTIONS TO REVERSIBLE DNA CROSS-LINKING
Get PDFThe first part of this thesis examines the flavin-dependent reductive dehalogenase iodotyrosine deiodinase (IYD). IYD scavenges iodide from iodotyrosines, side products of thyroid hormone biosynthesis. IYD has a dynamic active site lid that adopts a well folded alpha helix (closed conformation) in the presence of iodotyrosine. However, in the absence of substrate, or in the presence of 2-iodophenol (2IP) no electron density for the active site lid is observed. A network of polar and hydrogen bonding interactions between the substrate, enzyme and flavin is thought to be critical for lid closure, substrate selectivity and catalysis.
Surprisingly, with 19F NMR a phenolic ligand was found to induce a conformational change in the active site lid. Using Exchange spectroscopy (EXSY) ligand binding and lid closure were found to occur on the same timescale with 3-(trifluoromethoxy)tyrosine (CF3O-Tyr) and on slightly different timescales and 2.5-fold faster with a phenolic ligand. Thus, the lid does not discriminate between phenols and tyrosines but may prohibit binding of larger substrates such as the thyroid hormones T3 and T4 preventing a futile cycle in Chordata. This work is an initial foray into examining lid dynamics in IYD and can serve as a foundation for examining structural changes in the active site lid with the reduced enzyme.
The second part of this thesis examines reactive electrophilic intermediates quinone methides (QMs). QMs are a class of electrophilic intermediates frequently used in organic synthesis, and in biological applications. QMs are dynamic DNA cross-linkers capable of migrating along a DNA duplex. Previously T7GP4, a hexameric helicase, promoted cross-link release from a DNA duplex. When reversibly cross-linked DNA was challenged by Rep-X, a “super helicase”, cross-link release was not observed. A lack of release was not a result of the DNA sequence, the cross-link electronics, or the formation of a DNA protein cross-link additionally migration was also not observed. QM regeneration was then examined on two different timescales through the use of DNA nanopore technology, and with Rep-X. QM regeneration was not observed on either the second or minute timescales
Painting in Lucca in the Late Fifteenth Century: A Problem in Artistic Geography
No full textThis dissertation focuses on the painters active in Lucca in the late fifteenth century to examine how the art production in a region typically treated as “provincial” or “peripheral” can help us rethink the supremacy of a canonical “center.” Lucca is a suitable case study for this analysis because each of the city’s painters of this period—Baldassarre di Biagio (first doc. 1437; died 1482/84), Michele (doc. 1463-1521) and Sano Ciampanti (1474-1532/35), Vincenzo Frediani (1458-1505), Antonio Corsi (doc. 1465-1616) and Michelangelo di Pietro Membrini (ca 1461/64-1525)—emerged in scholarship as hypothetical “Masters” identified by connoisseurs on the detectable influences in their works. As a result, they have traditionally—and paradoxically—been cast as homogeneous eclectics whose styles derived from their more famous contemporaries, namely the two Florentines Domenico Ghirlandaio (1448-94) and Filippino Lippi (ca 1457-1504). I argue, however, that aside from being contradictory in its notion of a homogeneous eclecticism, this assessment minimizes the ambition and originality of Lucchese painting; it overlooks the dynamic patterns of mobility, dialogue and exchange evidenced in these painters’ works and archival biographies, the latter of which were all recovered from the Lucchese state archives in the mid-1980s. Moving beyond anachronistic and geographically-biased notions of unidirectional “influence,” this study emphasizes these artists’ idiosyncrasies and reconstructs key aspects of their creative environment (partnerships, imitation, patrons, travel). In historicizing their practice, it reveals the ways in which they critically engaged with each other and their foreign contemporaries. In expanding the rigid geographic borders of Italian Renaissance art history, this study ultimately demands a reconsideration of the notion of influence, how artistic style is tethered to location and how the term “eclecticism” is mobilized in the discipline of art history. The dissertation concludes with the first-ever catalogue raisonnés for each Lucchese painter active ca 1465-1525
The Effect of Limb Dynamics on Upper-Limb Amputee Motor Control and Learning in Physical and Virtual Reality
No full textWhile the motor capabilities of state-of-the-art upper-limb prosthetic devices have reached parity with those of a natural limb, the control strategies of such devices limit their adoption due to insufficient, unreliable performance. While recent work has focused on improving the accuracy or robustness of motor decoding platforms, these designs are agnostic to the effect simply wearing a prosthesis has on motor processing. In this thesis, Chapter 1 provides a brief overview of the motivation behind the work that will be discussed, while Chapter 2 provides a general overview of biomimetic control strategies for upper-limb prostheses. The chapters that follow provide an exploration of how the dynamic properties of the upper-limb influence motor processing of prosthesis users at several stages of computation. Chapter 3 details the relationship between quasistatic joint torques and the myoelectric features commonly used for pattern recognition-based control of a multiarticulated hand. Additionally, a decoding framework that leverages joint torque distributions as a relevancy filter is shown to provide robust prosthesis operation during untrained conditions with minimal initial training investment. Chapter 4 outlines a motor planning framework that minimizes the sum of absolute joint torques to predict upper-limb paths for individuals with and without an upper-limb amputation. The results show that an approximation of biomechanical energy expenditure is an accurate, robust, and efficient cost space in which upper-limb motor strategies can be generated. Finally, Chapter 5 explores the effect that the load of a prosthesis has on the effectiveness of motor rehabilitation conducted in a virtual environment. Results from this work pose significant doubts about standard clinical practices of gravity compensation and their effects on the efficiency of current rehabilitation protocols. In general, the work encapsulated in this thesis investigates the relationship between upper-limb dynamics and prosthesis motor control and leverages that relationship to enhance the experience for those operating a prosthetic device
PACIFIC PIVOT OR HALF STEP?: ANALYZING THE OBAMA ADMINISTRATION'S "PIVOT" TO ASIA
No full textIn 2011 the Obama Administration announced a re-orientation of American foreign policy toward the Asia-Pacific. This new strategy toward and prioritization of Asia – which had been prominent but informal throughout the administration’s early years from 2009-2012 – became known as the “Pivot.”
The Pivot enjoyed support from the American public, the Congress, and from Asian countries, who, with justification, felt ignored by American policymakers even as their economies grew rapidly in the 1990s and 2000s. The Pivot included a series of diplomatic, military, and economic efforts including military posture changes in Asia and completing free trade and investment agreements across the region. Despite several successes, the Pivot’s effects remained limited when the administration left office in 2017. Namely, the administration did not secure US membership in the much-heralded Trans-Pacific Partnership, despite cheerleading the pact for years nor significantly increase US Military force in Asia. Indeed, the military’s force posture, shipbuilding, equipment procurement, and doctrine showed little change despite administration promises. Through 2016 military spending and security assistance funding remained overwhelmingly focused on the Middle East and Afghanistan despite reductions in troop levels.
Shortcomings arose from structural issues with the administration’s implementation of the Pivot. Instead of an ongoing policy process, the administration relied largely on rhetoric from the President and Secretary of
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State to broadcast the Pivot, leaving the details to subalterns. Agencies and departments implemented the Pivot with varying degrees of alacrity and success. Complicating the Obama Administration’s efforts was increasing domestic partisanship which resulted in the 2013 Sequestration budget cuts. The disconnect between rhetoric and actions was apparent as early as the 2012 Scarborough Shoal conflict between the Philippines and China and China’s ensuing island-building campaign in the South China Sea. Left without clear guidance, when challenges occurred, such as the Russia’s 2014 invasion of Crimea, the rise of ISIS in late 2014, and Sequestration budget cuts from 2013 onward, the administration was unable to protect several Pivot-related initiatives from resource shortfalls, funding cuts, or lack of senior officials’ time.
Altogether, the administration’s failure to back up rhetoric with action prompted apprehension from American allies and partners. These implications and the frustration associated with the Pivot have clear lessons for policymakers
Characterizing the Biophysical Properties of Eukaryotic Type IIA Topoisomerase Liquid-Liquid Phase Separation
Get PDFType IIA topoisomerases are enzymes uniquely suited to resolve different topological problems in DNA. Type IIA topoisomerase activity relies on a strand-passage mechanism in which one double-stranded segment of DNA is physically transported through a transient, enzyme-mediated break in a second duplex. Strand passage is primarily facilitated by the catalytic core of the enzyme; however, eukaryotic type IIA topoisomerases (topo IIs) also possess an intrinsically disordered C-terminal domain (CTD) that has played an unknown part in this mechanism. Over the last several years, the intrinsically disordered regions of many proteins have been shown to facilitate the ability of macromolecules to locally concentrate and undergo liquid-liquid phase separation. In this thesis, I report on the discovery and characterization of the ability of eukaryotic topo IIs to undergo such a transition and highlight role of their CTD in this process.
In Chapter 2, I used ScTop2 as a model system to study various aspects of phase separation by topo II. Using a range of approaches, including fluorescence microscopy and biochemical assays, I unexpectedly found that phase separation in the presence of plasmid DNA drove the enzyme to shift the steady state distribution of DNA topological intermediates towards catenane production. When the ScTop2 CTD was removed from the core of the enzyme, I found that the topological distribution was instead shifted towards knot formation. This behavior was recapitulated with two different human type IIA topoisomerases, HsTOP2A and HsTOP2B, indicating that this behavior is universal for this enzyme family. A mechanism for how topo IIs can shift the steady state distributions of these different topological forms, along with insights into how these differing activities might have implications for topo II activity in vivo, are also discussed.
In Chapter 3, I describe unpublished findings that further characterize different dependencies and influences of phase separation on human topo IIs. Interestingly, I found several differences in phase separation behavior between HsTOP2 and HsTOP2β, such as the critical concentration required for phase separation and the dynamics of condensates in the presence of DNA. Using cross-linking mass spectrometry and mixing experiments, I also discovered that the CTD has an unexpected ability to interact with the core of the enzyme. Collectively, the data obtained during my thesis answers several long-standing questions about topo II mechanisms while paving the way for new research directions aimed at better understanding the role and functional impact of phase separation by this family of enzymes in vitro and in vivo
A Quantitative Synthesis of Outcomes of Educational Technology Approaches in K-12 Mathematics
No full textResearchers have consistently examined the effects of educational technology on K-12 students’ mathematics learning, but previous meta-analyses suffered from lax inclusion criteria, resulting in inflated effect sizes, and also treated educational technology as a method rather than a delivery mechanism. The aim of the present meta-analysis was to examine the effects of ed-tech on mathematics learning employing rigorous inclusion criteria and examining the effects of both study-related and program-related moderators. Preliminary results from a random-effects model revealed a significant, small effect for mathematics learning (g = +.12). Statistically significant moderators included study design, sample size, blended as compared to fully tech, fidelity of implementation, and personalization. The findings support the positive effects of educational technology, and also provide considerations for program evaluators in terms of study design, and for program developers in terms of intervention design.The research reported here was supported by the Institute of Education Sciences, U.S. Department of Education, though Grant R305A210186 to Johns Hopkins University. The opinions expressed are those of the authors and do not represent views of the Institute of the U.S. Department of Education
Using time activity data to study children’s exposure to chemical hazards: a scoping review
No full textTime activity data (TAD) is information describing the timing, duration, and/or frequency of human activities and is used to inform estimates of exposure to chemical hazards. Activity data can help researchers better understand exposure as activity dictates the exposure pathway and directly impacts exposure dose. Following a previously published systematic evidence map protocol with slight modifications, this review identified 44 studies collecting TAD to estimate children’s exposure to chemical hazards. After analysis, three themes emerged as common aims of studies within this body of literature: (1) quantifying inhalation-based exposures from specific macroactivities, (2) investigating non-dietary ingestion from microactivities, and (3) calculating dermal exposures associated with activities of varying scales. For children aged 6 months to 6 years, this review found that microactivities are well documented, but macroactivities are understudied. Conversely, older children's (6+ years old) macroactivity patterns are well studied, but there are very few microactivity studies. This review also highlights the need for better reporting of demographic information in TAD studies to identify understudied groups and address research gaps
Computational Study on the Hemodynamics of Bioprosthetic Pulmonary Valves in Patients with Repaired Tetralogy of Fallot
Get PDFPulmonary valve replacement (PVR) is the primary treatment option for pulmonary regurgitation, a pathology commonly found in patients with repaired tetralogy of Fallot. However, PVR requires the use of bioprosthetic valve implants, which have limited life spans, particularly in young people, due to structural valve deterioration. For this reason, patients with a need for PVR often undergo multiple valve replacements during their lifetimes, with each surgical approach increasing the attendant risks.
Ideal valve mechanics improve their durability. Pulmonary valves do not display a fibrous annulus as do other valves in the heart; thus, pulmonary valves can be implanted at multiple orientations and locations within the right ventricular outflow tract (RVOT). This anatomical feature results in considerably more degrees of freedom at the time of pulmonary valve replacement. We therefore hypothesized that implantation of pulmonary valves at an optimal orientation that results in favorable hemodynamics and valve dynamics would improve valve durability. Thus, determining the optimal orientation can produce a set of parameters for surgical guidance.
In this thesis, Computational Fluid Dynamics (CFD) simulations are performed using a sharp interface immersed-boundary-based flow solver which includes a dynamic valve leaflet model. Two sets of models are simulated, canonical models that contain idealized geometries of the pulmonary arteries as well as patient-specific models that have been acquired from CT and MR Angiogram image data. A valve implant measurement pipeline is also developed to quantify the extent to which a valve implant deviates from an ideal orientation.
With this measurement pipeline, 3 characteristic angles are determined which fully describe the valve orientation. With the idealized canonical models, the sensitivity of the hemodynamics and leaflet dynamics are described as a function of valve orientation. It is demonstrated that angular rotations have the smallest effect on the hemodynamics, while the in-plane and out-of-plane angles are responsible for increasing the extent of asymmetry in the branch arteries. These results also generalize to patient-specific simulations, where the ideal implant orientation improves the hemodynamics compared to the actual implant orientation
Why Shed the Shield? A Narrative-based Educational Campaign for Discontinuing Gonadal Shielding
Get PDFGonadal shielding, or placing a protective barrier between patients and a source of radiation to reduce exposure to the gonads, has long been a standard practice in diagnostic imaging. However, advances in technology and new evidence regarding radiation exposure have led to shielding gradually being discontinued at medical centers nationwide. Radiology technologists (RTs) are responsible for implementing “no-shield” policies at these centers, but the legacy status of shielding and conflicting guidance from healthcare professionals complicate messaging around shielding.
We created a visual narrative to convey the scientific rationale behind no-shield policies in an educational campaign for RTs. We recruited 41 professional RTs employed at Johns Hopkins to assess the animation. Learning was measured through a pre- and post-test and engagement was measured with Likert-scale surveys. Open response questions were analyzed qualitatively for themes.
We performed paired sample t-tests to check for differences in pre- and post-test scores. Our analysis found that scores significantly increased after RTs watched the animation (p = 0.00009). In the engagement survey, RTs generally agreed with positive statements about the animation’s content (attention, understanding, enjoyment).
Our study provides insight into the benefits of incorporating narrative-based animation into medical education campaigns. The narrative animation produced for this study will be available online and potentially distributed to hospitals for RT training as they adopt no-shield policies