Using preliminary data and prospective power analyses for mid-stream revision of projected group and subgroup sizes in pragmatic patient-centered outcomes research

Pragmatic clinical trials are commonly used in patient-centered outcomes research to assess heterogeneity of treatment effects. Patient-Centered Outcomes Research Institute (PCORI) methodology standards for assessing heterogeneity of treatment effects are extremely rigorous, but their implementation in real-world settings can be difficult. Predicting recruitment effectiveness and subgroup characteristics is often challenging and may require mid-stream revision of projected group and subgroup sizes. Yet, little real-world data are available to demonstrate methodologically valid approaches to address situations where such revisions are necessary. These data were used for mid-stream revision of group and subgroup sizes in the Management of Diabetes in Everyday Life (MODEL) clinical trial. The planned number of randomized participants retained over the one-year study period was reduced from 800 to 581 due to recruitment difficulties among potential participants residing in rural areas. Prospective power analyses are based on the revised target of 581 participants retained and the proportions of 167 participants with various key baseline characteristics, who had been randomized in MODEL by January 2018, as reported to the Patient Center Outcomes Research Institute (PCORI) and the MODEL Data Safety and Monitoring Committee. Power calculations are based on two-sided t-tests with type-I error rates of 0.05 and the assumption that effect sizes will range from small (standardized difference = 0.36) to medium (= 0.50). The primary outcome variables are how many days in the previous week participants 1) ate healthy meals, 2) participated in at least 30 minutes of physical activity, and 3) took medications as prescribed. The POWER procedure of SAS 9.4 was used for all analyses. These data, along with the approach, can assist statisticians as they plan future pragmatic clinical trials evaluating heterogeneity of treatment effects. These data can help inform investigators, conducting patient-centered outcomes research, as they define subgroups for either confirmatory analyses for testing heterogeneity of treatment effects or for exploratory analyses where estimation of confidence bounds may be useful for generating future hypotheses. (This work was supported through a Patient-Centered Outcomes Research Institute (PCORI) Project Program Award (SC15-1503-28336), www.ClinicalTrials.gov and Identifier: NCT02957513 [1].

A Competency-based Approach to Faculty Development

Background—Faculty development at the Virginia Commonwealth University School of Medicine (VCU SOM) has previously focused on enhancing teaching and learning in the medical and clinical education settings. While this work is important, this narrow focus does not address all facets a faculty member’s role. To broaden their programming, the VCU SOM faculty development team adopted a competency-based approach to the development and planning of faculty development activities. Summary of work—The Senior Associate Dean for Faculty Affairs completed a research project focused on successful medical faculty who promote through the tenure process and advance in their careers. She identified the following categories for success: teaching, service, scholarship, advancing, and leadership. Each of these categories contains action-focused competencies that align with career progression addressing early, mid, and late career stages. The faculty development team adopted the identified competencies to their curriculum development and planning processes. Summary of results—The results of this adoption have been clearer goals for learners, a mapped structure for faculty development activities, and a broader range of topics offered that align with career stages. Discussion—Faculty development activities are now categorized into five (5) categories: Teach, Lead, Serve, Discover, and Advance with each category color coded for easy recognition in event marketing materials. A new logo reflecting these competency categories is now included on all Office of Faculty Affairs communications. Faculty are beginning to recognize and register for activities they need for promotion, tenure, and advancement. Conclusions—The adoption of the competencies for success from the Senior Associate Dean’s study has enriched faculty development offerings providing a recognizable structure allowing faculty to easily identify competency areas for development

Structure-function analysis of the Bacillus megaterium GerUD spore germinant receptor protein.

Germination of Bacillus spores is triggered by the interaction of germinant molecules with specialized receptor proteins localized to the spore inner membrane. Germinant receptors (GRs) are comprised typically of three interacting protein subunits, each of which is essential for receptor function. At least some GRs appear to have a fourth component, referred to as a D-subunit protein. A number of D-subunit proteins were shown previously to be capable of modulating the activity of associated GRs. Here, we investigate the topology and structure-function relationships of the Bacillus megaterium QM B1551 GerUD protein, which is associated with the GerU GR. The presented data demonstrate that GerUD can be subjected to relatively extensive structural modifications while retaining function. Indeed, the presence of either of the two transmembrane spanning domains is sufficient to modulate an efficient GerU-mediated germinative response. The precise function of D-subunit proteins has yet to be established, although they may act as molecular chaperones within the spore inner-membrane environment.S.G was the recipient of a RA Fisher bursary award from Gonville and Caius College, University of Cambridge. X.Z is the recipient of an EPSRC Doctoral Training Grant.This is the final version of the article. It was first available from OUP via http://dx.doi.org/10.1093/femsle/fnv21

New interleukin-15 superagonist (IL-15SA) significantly enhances graft-versus-tumor activity.

Interleukin-15 (IL-15) is a potent cytokine that increases CD8+ T and NK cell numbers and function in experimental models. However, obstacles remain in using IL-15 therapeutically, specifically its low potency and short in vivo half-life. To help overcome this, a new IL-15 superagonist complex comprised of an IL-15N72D mutation and IL-15RαSu/Fc fusion (IL-15SA, also known as ALT-803) was developed. IL-15SA exhibits a significantly longer serum half-life and increased in vivo activity against various tumors. Herein, we evaluated the effects of IL-15SA in recipients of allogeneic hematopoietic stem cell transplantation. Weekly administration of IL-15SA to transplant recipients significantly increased the number of CD8+ T cells (specifically CD44+ memory/activated phenotype) and NK cells. Intracellular IFN-γ and TNF-α secretion by CD8+ T cells increased in the IL-15SA-treated group. IL-15SA also upregulated NKG2D expression on CD8+ T cells. Moreover, IL-15SA enhanced proliferation and cytokine secretion of adoptively transferred CFSE-labeled T cells in syngeneic and allogeneic models by specifically stimulating the slowly proliferative and nonproliferative cells into actively proliferating cells.We then evaluated IL-15SA\u27s effects on anti-tumor activity against murine mastocytoma (P815) and murine B cell lymphoma (A20). IL-15SA enhanced graft-versus-tumor (GVT) activity in these tumors following T cell infusion. Interestingly, IL-15 SA administration provided GVT activity against A20 lymphoma cells in the murine donor leukocyte infusion (DLI) model without increasing graft versus host disease. In conclusion, IL-15SA could be a highly potent T- cell lymphoid growth factor and novel immunotherapeutic agent to complement stem cell transplantation and adoptive immunotherapy

An analysis of the thermal interaction between components in power converter applications

Accurately predicting the temperature of semiconductor devices is very important in the initial design of power electronics converter. RC thermal models derived from well-known methods have some ability to predict the temperature. However, the accuracy is boundary condition specific, hence, these methods cannot be used in the reliability analysis. To make the thermal model more accurate and robust the factors contributing to discrepancies need to be analyzed carefully. These are power-module-materials’ non-linear properties, thermal grease layer and the cooling system (i.e., liquid-cooled cold plate). In this work, estimation of accurate RC parameters from FEA thermal model is demonstrated in COMSOL. The electrical model having temperature dependent power loss model is coupled to refined thermal model and solved in a circuit simulator, PLECS. The proposed method is applied in two applications: assessing thermal interaction between IGBTs and anti-parallel diodes in a half-bridge power module, and assessing thermal interaction among the discrete switches in an interleaved bidirectional DC-DC converter. Results show that the impact of material non-linearity, thermal grease layer and cooling boundary conditions are significant for accurate prediction of IGBT and diode temperatures. The proposed model is consistent to FEA results and differs by 2-6.5% comparing to the experimental results

Can Birth Weight Influence the Development of Neonatal Abstinence Syndrome?

Background: Neonatal Abstinence Syndrome (NAS), a manifestation of the widespread opioid epidemic, has plagued our country, and particularly the region of Northeast Tennessee, for quite some time now. One question among many that seems to baffle almost everyone involved in research on the topic at hand is that why do only 35-40% of opioid exposed pregnancies result in NAS requiring medication while sparing the rest. Is there some discriminatory factor other than in utero opioid exposure involved? Thus, in light of this knowledge, we wanted to investigate whether birth weight at the time of delivery can influence the development of NAS; that is, are neonates of a low birth weight or high birth weight (with respect to gestational age thresholds) more likely to develop NAS. Methods: Therefore, we conducted a retrospective chart analysis of all deliveries within the Mountain States Health Alliance System over a 5 years period between July 1, 2011- June 30, 2016 at all 5 delivery sites in Northeast Tennessee and Southwest Virginia (N=18,728). Out of this sample size, we identified 2,392 at-term newborns as positive for prenatal opioid exposure, and then we stratified them into 2 categories: birth weight ≤3.5kg (proxy for low or average birth weight with respect to gestational age thresholds) and birth weight ≥3.5kg (proxy for high birth weight with respect to gestational age thresholds). Thereafter, we ran SPSS statistical analyses involving chi square, t tests, and logistic regression to assess whether one birth weight group was more likely to have a higher incidence rate of NAS compared to the other birth weight group. Results: We found that even after controlling for significant confounders such as marital status, race, and pregnancy smoking, benzodiazepine, and marijuana use, infants who were in the low to average birth weight group (≤3.5kg in this study) were almost twice as likely (statistically significant adjusted odds ratio of 1.95) to develop NAS compared to infants who were in the high birth weight group (≥3.5kg in this study). Our study helps shed some important light on the discriminatory factors for NAS development, with birth weight being a significantly associated clinical factor as we now know. Discussion & Implications: Unfortunately, the mechanism for the transport of opioids across the placenta is complicated, and poorly understood. There may be more ‘unbound or free opioids’ available in infants of low to average birth weight (with respect to gestational age thresholds) compared to infants of high birth weight (with respect to gestational age thresholds) resulting in a higher incidence of NAS in the former population. It is more of a speculation rather than a conclusion to explain the results of our study. However, being equipped with this knowledge that opioid exposed neonates of low to average birth weight (with respect to gestational age thresholds) have a higher risk of developing NAS will allow physicians to identify infants with a higher risk for NAS early, and this will subsequently lead to better outcomes and reduced severity in cases of NAS

Identifying olanzapine induced liver injury in the setting of acute hepatitis C: A case report

Olanzapine is linked to asymptomatic, transient elevations of liver aminotransferases but is historically thought to rarely cause significant hepatotoxicity. Underlying liver disease is a risk factor for drug-induced liver injury and may complicate the differential diagnosis of acute transaminitis in patients taking medications associated with hepatotoxicity. Ms L presented with 2 months of new psychotic symptoms resulting in hospitalizations. Although psychosis previously improved with haloperidol, she reported symptoms concerning for akathisia. Restlessness improved and psychotic symptoms resolved after initiation of olanzapine. Concurrently, her alanine aminotransferase (ALT) was elevated, prompting further workup and new diagnosis of acute hepatitis C. Over the course of hospitalization, her ALT increased exponentially. Initially attributed solely to acute hepatitis C infection, ALT rapidly decreased after holding olanzapine, implying it was contributing to her liver injury. Subsequently, given her prior response, haloperidol was retrialed with close monitoring for adverse effects. Her subjective restlessness was treated with additional agents, and she was then transitioned to monthly haloperidol decanoate injections to further assist her adherence. Prior to discharge, she had resolution of psychosis and transaminitis. Olanzapine may contribute to hepatotoxicity with concurrent viral hepatitis, and clarity can be obtained by a trial of stopping the suspected medication. Furthermore, olanzapine, when combined with underlying liver disease, may have an additive effect on liver injury, resulting in accelerated elevations in liver aminotransferases

Data-driven prognostics for smart qualification testing of electronic products

A flaw or drift from expected operational performance in one electronic module or component may affect the reliability of the entire upper-level electronic product or system. Therefore, it is important to ensure the required quality of each individual electronic part through qualification testing specified using standards or user requirements. Qualification testing is time-consuming and comes at a substantial cost for product manufacturers. Many electronics manufacturers have access to large historical sets of qualification testing data from their products which may hold information to enable optimization of the respective qualification procedures. In this paper, techniques from the domain of computational intelligence are applied. The development of data-driven models capable to forecast accurately and in-line the end result of a sequence of qualification tests is discussed and presented. Data-driven prognostics models are developed using test data of the electronic module by Neural Network (NN) and Support Vector Machine (SVM) techniques. The performances of the models in predicting the qualification outcomes (pass or fail) are assessed