Recent Submissions

  • MRI Radiomic Signature of White Matter Hyperintensities Is Associated With Clinical Phenotypes

    Bretzner, Martin; Bonkhoff, Anna K; Schirmer, Markus D; Hong, Sungmin; Dalca, Adrian V; Donahue, Kathleen L; Giese, Anne-Katrin; Etherton, Mark R; Rist, Pamela M; Nardin, Marco; et al. (Frontiers Media S.A., 2021-07-12)
    Objective: Neuroimaging measurements of brain structural integrity are thought to be surrogates for brain health, but precise assessments require dedicated advanced image acquisitions. By means of quantitatively describing conventional images, radiomic analyses hold potential for evaluating brain health. We sought to: (1) evaluate radiomics to assess brain structural integrity by predicting white matter hyperintensities burdens (WMH) and (2) uncover associations between predictive radiomic features and clinical phenotypes. Methods: We analyzed a multi-site cohort of 4,163 acute ischemic strokes (AIS) patients with T2-FLAIR MR images with total brain and WMH segmentations. Radiomic features were extracted from normal-appearing brain tissue (brain mask–WMH mask). Radiomics-based prediction of personalized WMH burden was done using ElasticNet linear regression. We built a radiomic signature of WMH with stable selected features predictive of WMH burden and then related this signature to clinical variables using canonical correlation analysis (CCA). Results: Radiomic features were predictive of WMH burden (R2 = 0.855 ± 0.011). Seven pairs of canonical variates (CV) significantly correlated the radiomics signature of WMH and clinical traits with respective canonical correlations of 0.81, 0.65, 0.42, 0.24, 0.20, 0.15, and 0.15 (FDR-corrected p-valuesCV1–6 < 0.001, p-valueCV7 = 0.012). The clinical CV1 was mainly influenced by age, CV2 by sex, CV3 by history of smoking and diabetes, CV4 by hypertension, CV5 by atrial fibrillation (AF) and diabetes, CV6 by coronary artery disease (CAD), and CV7 by CAD and diabetes. Conclusion: Radiomics extracted from T2-FLAIR images of AIS patients capture microstructural damage of the cerebral parenchyma and correlate with clinical phenotypes, suggesting different radiographical textural abnormalities per cardiovascular risk profile. Further research could evaluate radiomics to predict the progression of WMH and for the follow-up of stroke patients’ brain health.
  • Impact of Amerind ancestry and FADS genetic variation on omega-3 deficiency and cardiometabolic traits in Hispanic populations

    Yang, Chaojie; Hallmark, Brian; Chai, Jin Choul; O'Connor, Timothy D; Reynolds, Lindsay M; Wood, Alexis C; Seeds, Michael; Chen, Yii-Der Ida; Steffen, Lyn M; Tsai, Michael Y; et al. (Springer Nature, 2021-07-28)
    Long chain polyunsaturated fatty acids (LC-PUFAs) have critical signaling roles that regulate dyslipidemia and inflammation. Genetic variation in the FADS gene cluster accounts for a large portion of interindividual differences in circulating and tissue levels of LC-PUFAs, with the genotypes most strongly predictive of low LC-PUFA levels at strikingly higher frequencies in Amerind ancestry populations. In this study, we examined relationships between genetic ancestry and FADS variation in 1102 Hispanic American participants from the Multi-Ethnic Study of Atherosclerosis. We demonstrate strong negative associations between Amerind genetic ancestry and LC-PUFA levels. The FADS rs174537 single nucleotide polymorphism (SNP) accounted for much of the AI ancestry effect on LC-PUFAs, especially for low levels of n-3 LC-PUFAs. Rs174537 was also strongly associated with several metabolic, inflammatory and anthropomorphic traits including circulating triglycerides (TGs) and E-selectin in MESA Hispanics. Our study demonstrates that Amerind ancestry provides a useful and readily available tool to identify individuals most likely to have FADS-related n-3 LC-PUFA deficiencies and associated cardiovascular risk.
  • ECO-CollecTF: A Corpus of Annotated Evidence-Based Assertions in Biomedical Manuscripts

    Hobbs, Elizabeth T; Goralski, Stephen M; Mitchell, Ashley; Simpson, Andrew; Leka, Dorjan; Kotey, Emmanuel; Sekira, Matt; Munro, James B; Nadendla, Suvarna; Jackson, Rebecca; et al. (Frontiers Media S.A., 2021-07-13)
    Analysis of high-throughput experiments in the life sciences frequently relies upon standardized information about genes, gene products, and other biological entities. To provide this information, expert curators are increasingly relying on text mining tools to identify, extract and harmonize statements from biomedical journal articles that discuss findings of interest. For determining reliability of the statements, curators need the evidence used by the authors to support their assertions. It is important to annotate the evidence directly used by authors to qualify their findings rather than simply annotating mentions of experimental methods without the context of what findings they support. Text mining tools require tuning and adaptation to achieve accurate performance. Many annotated corpora exist to enable developing and tuning text mining tools; however, none currently provides annotations of evidence based on the extensive and widely used Evidence and Conclusion Ontology. We present the ECO-CollecTF corpus, a novel, freely available, biomedical corpus of 84 documents that captures high-quality, evidence-based statements annotated with the Evidence and Conclusion Ontology.
  • Phase I/II clinical trial of temsirolimus and lenalidomide in patients with relapsed and refractory lymphomas

    Major, Ajay; Kline, Justin; Karrison, Theodore G; Fishkin, Paul A S; Kimball, Amy S; Petrich, Adam M; Nattam, Sreenivasa; Rao, Krishna; Sleckman, Bethany G; Cohen, Kenneth; et al. (Ferrata Storti Foundation, 2021-07-29)
    The PI3K/Akt/mTOR (PAM) axis is constitutively activated in multiple lymphoma subtypes and is a promising therapeutic target. The mTOR inhibitor temsirolimus (TEM) and the immunomodulatory agent lenalidomide (LEN) have overlapping effects within the PAM axis with synergistic potential. This multicenter phase I/II study evaluated combination therapy with TEM/LEN in patients with relapsed and refractory lymphomas. Primary endpoints of the phase II study were rates of complete (CR) and overall response (ORR). There were 18 patients in the phase I dose-finding study, and TEM 25 mg weekly and LEN 20 mg on day 1 through day 21 every 28 days was established as the recommended phase II dose. An additional 93 patients were enrolled in the phase II component with three cohorts: diffuse large B-cell lymphoma (DLBCL, n=39), follicular lymphoma (FL, n=15), and an exploratory cohort of other lymphoma histologies with classical Hodgkin lymphoma (cHL) comprising the majority (n=39 total, n=20 with cHL). Patients were heavily pretreated with a median of 4 (range, 1-14) prior therapies and one-third with relapse following autologous stem cell transplantation (ASCT); patients with cHL had a median of 6 prior therapies. The FL cohort was closed prematurely due to slow accrual. ORR were 26% (13% CR) and 64% (18% CR) for the DLBCL and exploratory cohorts, respectively. ORR for cHL patients in the exploratory cohort, most of whom had relapsed after both brentuximab vedotin and ASCT, was 80% (35% CR). Eight cHL patients (40%) proceeded to allogeneic transplantation after TEM/LEN therapy. Grade ≥3 hematologic AEs were common. Three grade 5 AEs occurred. Combination therapy with TEM/LEN was feasible and demonstrated encouraging activity in heavily-pretreated lymphomas, particularly in relapsed/refractory cHL. identifier: NCT01076543.
  • Human Breast Milk Enhances Intestinal Mucosal Barrier Function and Innate Immunity in a Healthy Pediatric Human Enteroid Model

    Noel, Gaelle; In, Julie G; Lemme-Dumit, Jose M; DeVine, Lauren R; Cole, Robert N; Guerrerio, Anthony L; Campbell, James D; Kovbasnjuk, Olga; Pasetti, Marcela F (Frontiers Media S.A., 2021-07-13)
    Breastfeeding has been associated with long lasting health benefits. Nutrients and bioactive components of human breast milk promote cell growth, immune development, and shield the infant gut from insults and microbial threats. The molecular and cellular events involved in these processes are ill defined. We have established human pediatric enteroids and interrogated maternal milk's impact on epithelial cell maturation and function in comparison with commercial infant formula. Colostrum applied apically to pediatric enteroid monolayers reduced ion permeability, stimulated epithelial cell differentiation, and enhanced tight junction function by upregulating occludin. Breast milk heightened the production of antimicrobial peptide α-defensin 5 by goblet and Paneth cells, and modulated cytokine production, which abolished apical release of pro-inflammatory GM-CSF. These attributes were not found in commercial infant formula. Epithelial cells exposed to breast milk elevated apical and intracellular pIgR and enabled maternal IgA translocation. Proteomic data revealed a breast milk-induced molecular pattern associated with tissue remodeling and homeostasis. Using a novel ex vivo pediatric enteroid model, we have identified distinct cellular and molecular events involved in human milk-mediated improvement of human intestinal physiology and immunity.
  • Genome-wide association study of pancreatic fat: The Multiethnic Cohort Adiposity Phenotype Study

    Streicher, Samantha A; Lim, Unhee; Park, S Lani; Li, Yuqing; Sheng, Xin; Hom, Victor; Xia, Lucy; Pooler, Loreall; Shepherd, John; Loo, Lenora W M; et al. (Public Library of Science, 2021-07-30)
    Several studies have found associations between higher pancreatic fat content and adverse health outcomes, such as diabetes and the metabolic syndrome, but investigations into the genetic contributions to pancreatic fat are limited. This genome-wide association study, comprised of 804 participants with MRI-assessed pancreatic fat measurements, was conducted in the ethnically diverse Multiethnic Cohort-Adiposity Phenotype Study (MEC-APS). Two genetic variants reaching genome-wide significance, rs73449607 on chromosome 13q21.2 (Beta = -0.67, P = 4.50x10-8) and rs7996760 on chromosome 6q14 (Beta = -0.90, P = 4.91x10-8) were associated with percent pancreatic fat on the log scale. Rs73449607 was most common in the African American population (13%) and rs79967607 was most common in the European American population (6%). Rs73449607 was also associated with lower risk of type 2 diabetes (OR = 0.95, 95% CI = 0.89-1.00, P = 0.047) in the Population Architecture Genomics and Epidemiology (PAGE) Study and the DIAbetes Genetics Replication and Meta-analysis (DIAGRAM), which included substantial numbers of non-European ancestry participants (53,102 cases and 193,679 controls). Rs73449607 is located in an intergenic region between GSX1 and PLUTO, and rs79967607 is in intron 1 of EPM2A. PLUTO, a lncRNA, regulates transcription of an adjacent gene, PDX1, that controls beta-cell function in the mature pancreas, and EPM2A encodes the protein laforin, which plays a critical role in regulating glycogen production. If validated, these variants may suggest a genetic component for pancreatic fat and a common etiologic link between pancreatic fat and type 2 diabetes.
  • Public Perceptions of Physician Attire and Professionalism in the US

    Xun, Helen; Chen, Jonlin; Sun, Alexander H; Jenny, Hillary E; Liang, Fan; Steinberg, Jordan P (American Medical Association, 2021-07-30)
    Importance: In recent years, casual physician attire (fleece jackets and softshell jackets) has become increasingly popular, but to our knowledge, public perceptions of these garments have not been studied. Furthermore, gender biases may result in differing expectations and perceptions of female and male physicians and may be associated with patient rapport and trust building. Objective: To characterize public perceptions of casual physician attire and implicit gender biases in public assessment of physicians' professional attire. Design, setting, and participants: This survey study used a population-based survey administered via Amazon Mechanical Turk from May to June 2020 among individuals aged 18 years or older who were US residents and for whom English was the primary language. Intervention: Survey featuring photographs of a male or female model wearing various types of physician attire (white coat, business attire, and scrubs). Main outcomes and measures: Respondents' ratings of professionalism, experience, and friendliness of the male and female models in various attire and perceptions of the models' most likely health care profession. Preference scores for various outfits were calculated as the difference between the preference score for an outfit and the mean preference score for the outfit-role pairing. Results: Of 522 surveys completed, 487 were included for analysis; the mean (SD) age of respondents was 36.2 (12.4) years, 260 (53.4%) were female, and 372 (76.4%) were White individuals. Respondents perceived models of health care professionals wearing white coats vs those wearing fleece or softshell jackets as significantly more experienced (mean [SD] experience score: white coat, 4.9 [1.5]; fleece, 3.1 [1.5]; softshell, 3.1 [1.5]; P < .001) and professional (mean [SD] professionalism score: white coat, 4.9 [1.6]; fleece, 3.2 [1.5]; softshell, 3.3 [1.5]; P < .001). A white coat with scrubs attire was most preferred for surgeons (mean [SD] preference index: 1.3 [2.3]), whereas a white coat with business attire was preferred for family physicians and dermatologists (mean [SD] preference indexes, 1.6 [2.3] and 1.2 [2.3], respectively; P < .001). Regardless of outerwear, female models in business attire as inner wear were rated as less professional than male counterparts (mean [SD] professionalism score: male, 65.8 [25.4]; female, 56.2 [20.2]; P < .001). Both the male and the female model were identified by the greater number of respondents as a physician or surgeon; however, the female model vs the male model was mistaken by more respondents as a medical technician (39 [8.0] vs 16 [3.3%]; P < .005), physician assistant (56 [11.5%] vs 11 [2.3%]; P < .001), or nurse (161 [33.1%] vs 133 [27.3%]; P = .050). Conclusions and relevance: In this survey study, survey respondents rated physicians wearing casual attire as less professional and experienced than those wearing a white coat. Gender biases were found in impressions of professionalism, with female physicians' roles being more frequently misidentified. Understanding disparate public perceptions of physician apparel may inform interventions to address professional role confusion and cumulative career disadvantages for women in medicine.
  • Discovery of a Diverse Set of Bacteria That Build Their Cell Walls without the Canonical Peptidoglycan Polymerase aPBP

    Atwal, Sharanjeet; Chuenklin, Suthida; Bonder, Edward M; Flores, Juan; Gillespie, Joseph J; Driscoll, Timothy P; Salje, Jeanne (American Society for Microbiology, 2021-07-27)
    Peptidoglycan (PG) is a highly cross-linked peptide-glycan mesh that confers structural rigidity and shape to most bacterial cells. Polymerization of new PG is usually achieved by the concerted activity of two membrane-bound machineries, class-A penicillin binding proteins (aPBPs) and class-B penicillin binding proteins (bPBPs) in complex with shape, elongation, division, and sporulation (SEDS) proteins. Here, we have identified four phylogenetically distinct groups of bacteria that lack any identifiable aPBPs. We performed experiments on a panel of species within one of these groups, the Rickettsiales, and found that bacteria lacking aPBPs build a PG-like cell wall with minimal abundance and rigidity relative to cell walls of aPBP-containing bacteria. This reduced cell wall may have evolved to minimize the activation of host responses to pathogens and endosymbionts while retaining the minimal PG-biosynthesis machinery required for cell elongation and division. We term these "peptidoglycan-intermediate" bacteria, a cohort of host-associated species that includes some human pathogens. IMPORTANCE Peptidoglycan (PG) is a large, cross-linked polymer that forms the cell wall of most bacterial species and confers shape, rigidity, and protection from osmotic shock. It is also a potent stimulator of the immune response in animals. PG is normally polymerized by two groups of enzymes, aPBPs and bPBPs working together with shape, elongation, division, and sporulation (SEDS) proteins. We have identified a diverse set of host-associated bacteria that have selectively lost aPBP genes while retaining bPBP/SEDS and show that some of these build a minimal PG-like structure. It is expected that these minimal cell walls built in the absence of aPBPs improve the evolutionary fitness of host-associated bacteria, potentially through evasion of PG-recognition by the host immune system.

    Trastoy, Beatriz; Du, Jonathan J; Li, Chao; García-Alija, Mikel; Klontz, Erik H; Roberts, Blaine R; Donahue, Thomas C; Wang, Lai-Xi; Sundberg, Eric J; Guerin, Marcelo E (Elsevier Ltd., 2021-07-26)
    N-glycosylation is one of the most abundant post-translational modifications of proteins, essential for many physiological processes, including protein folding, protein stability, oligomerization and aggregation, and molecular recognition events. Defects in the N-glycosylation pathway cause diseases that are classified as congenital disorders of glycosylation. The ability to manipulate protein N-glycosylation is critical not only to our fundamental understanding of biology, but also for the development of new drugs for a wide range of human diseases. Chemoenzymatic synthesis using engineered endo-β-N-acetylglucosaminidases (ENGases) has been used extensively to modulate the chemistry of N-glycosylated proteins. However, defining the molecular mechanisms by which ENGases specifically recognize and process N-glycans remains a major challenge. Here we present the X-ray crystal structure of the ENGase EndoBT-3987 from Bacteroides thetaiotaomicron in complex with a hybrid type (Hy-type) glycan product. In combination with alanine scanning mutagenesis, molecular docking calculations and enzymatic activity measurements conducted on a chemically engineered monoclonal antibody substrate unveil two mechanisms for Hy-type recognition and processing by paradigmatic ENGases. Altogether, the experimental data provide pivotal insight into the molecular mechanism of substrate recognition and specificity for GH18 ENGases and further advance our understanding of chemoenzymatic synthesis and remodeling of homogeneous N-glycan glycoproteins.
  • Supporting scale-up of COVID-19 RT-PCR testing processes with discrete event simulation

    El Hage, Jad; Gravitt, Patti; Ravel, Jacques; Lahrichi, Nadia; Gralla, Erica (Public Library of Science, 2021-07-29)
    Testing is critical to mitigating the COVID-19 pandemic, but testing capacity has fallen short of the need in the United States and elsewhere, and long wait times have impeded rapid isolation of cases. Operational challenges such as supply problems and personnel shortages have led to these bottlenecks and inhibited the scale-up of testing to needed levels. This paper uses operational simulations to facilitate rapid scale-up of testing capacity during this public health emergency. Specifically, discrete event simulation models were developed to represent the RT-PCR testing process in a large University of Maryland testing center, which retrofitted high-throughput molecular testing capacity to meet pandemic demands in a partnership with the State of Maryland. The simulation models support analyses that identify process steps which create bottlenecks, and evaluate "what-if" scenarios for process changes that could expand testing capacity. This enables virtual experimentation to understand the trade-offs associated with different interventions that increase testing capacity, allowing the identification of solutions that have high leverage at a feasible and acceptable cost. For example, using a virucidal collection medium which enables safe discarding of swabs at the point of collection removed a time-consuming "deswabbing" step (a primary bottleneck in this laboratory) and nearly doubled the testing capacity. The models are also used to estimate the impact of demand variability on laboratory performance and the minimum equipment and personnel required to meet various target capacities, assisting in scale-up for any laboratories following the same process steps. In sum, the results demonstrate that by using simulation modeling of the operations of SARS-CoV-2 RT-PCR testing, preparedness planners are able to identify high-leverage process changes to increase testing capacity.
  • Impacts of Small RNAs and Their Chaperones on Bacterial Pathogenicity

    Djapgne, Louise; Oglesby, Amanda G (Frontiers Media S.A., 2021-07-12)
    Bacterial small RNAs (sRNAs) are critical post-transcriptional regulators that exert broad effects on cell physiology. One class of sRNAs, referred to as trans-acting sRNAs, base-pairs with mRNAs to cause changes in their stability or translation. Another class of sRNAs sequesters RNA-binding proteins that in turn modulate mRNA expression. RNA chaperones play key roles in these regulatory events by promoting base-pairing of sRNAs to mRNAs, increasing the stability of sRNAs, inducing conformational changes on mRNA targets upon binding, or by titrating sRNAs away from their primary targets. In pathogenic bacteria, sRNAs and their chaperones exert broad impacts on both cell physiology and virulence, highlighting the central role of these systems in pathogenesis. This review provides an overview of the growing number and roles of these chaperone proteins in sRNA regulation, highlighting how these proteins contribute to bacterial pathogenesis.
  • A Survey of Pharmacogenomics Testing Among Physicians, Pharmacists, and Researchers From China

    Guo, Chengxian; Hu, Biwen; Guo, Chengjun; Meng, Xiangguang; Kuang, Yun; Huang, Longjian; Wang, Danling; Xu, Kangwei; Zhao, Yanlin; Yang, Guoping; et al. (Frontiers Media S.A., 2021-07-12)
    To elucidate current domestic factors influencing pharmacogenomics (PGx) implementation and its future in China, we conducted a questionnaire survey on PGx applications and testing. A questionnaire-based survey was created on the popular online professional survey platform "Wenjuanxing" ( and performed via the social media platform WeChat. Among 422 participants, there were physicians (27.7%), pharmacists (31.3%), and researchers (41.0%). We found that less than 50% of physicians were aware of the importance of PGx in drug therapy, while over 50% of pharmacists and researchers recognized the importance. Only 38.5% of physicians, 40.9% of pharmacists, and 55.5% of researchers concurred that PGx analysis could lower the economic burdens for patients. However, most of the responders affirmed that PGx should be effectively implemented in clinical practices. A lack of sector standards, a lack of clinical research, and a lack of guidelines were found to be the major factors for hindering PGx clinical application. Among drugs associated with PGx assays, the most common were warfarin and clopidogrel. Although PGx research has advanced rapidly in recent years in mainland China, the clinical implementation of PGx has a long way to go.
  • Germ Cell Drivers: Transmission of Preconception Stress Across Generations

    Duffy, Korrina A; Bale, Tracy L; Epperson, C Neill (Frontiers Media S.A., 2021-07-12)
    Exposure to stress can accelerate maturation and hasten reproduction. Although potentially adaptive, the trade-off is higher risk for morbidity and mortality. In humans, the intergenerational effects of stress have been demonstrated, but the precise mechanisms are unknown. Strikingly, even if parental stress occurs prior to conception, as adults, their offspring show worse mental and physical health. Emerging evidence primarily from preclinical models suggests that epigenetic programming may encode preconception stress exposures in germ cells, potentially impacting the phenotype of the offspring. In this narrative review, we evaluate the strength of the evidence for this mechanism across animals and humans in both males and females. The strongest evidence comes from studies of male mice, in which paternal preconception stress is associated with a host of phenotypic changes in the offspring and stress-induced changes in the small non-coding RNA content in sperm have been implicated. Two recent studies in men provide evidence that some small non-coding RNAs in sperm are responsive to past and current stress, including some of the same ones identified in mice. Although preliminary evidence suggests that findings from mice may map onto men, the next steps will be (1) considering whether stress type, severity, duration, and developmental timing affect germ cell epigenetic markers, (2) determining whether germ cell epigenetic markers contribute to disease risk in the offspring of stress-exposed parents, and (3) overcoming methodological challenges in order to extend this research to females.
  • Mapping Evidence on Early Childhood Caries Prevalence: Complexity of Worldwide Data Reporting

    Abdelrahman, Marwa; Hsu, Kuei-Ling; Melo, Mary Anne; Dhar, Vineet; Tinanoff, Norman (Jaypee Brothers Medical Publishers, 2021)
    Objective: This review aims to identify variances and research gaps in the early childhood caries (ECC) prevalence within countries and the global community by mapping current evidence. Materials and methods: We performed a literature search in PubMed/MEDLINE and Web of Science to identify English-language, peer-reviewed epidemiologic studies published from January 1999 to January 2019. Abstracts and full-text articles were dual-screened based on predefined eligibility criteria. We classified outcomes by children's age and countries based on economic status. Ranges of reported caries prevalence and median values by country and age were calculated and evidence-mapped. Results: Out of 915 studies, 59 studies met the inclusion criteria. The most significant number of reports were from the USA, Brazil, and India. The ranges of prevalence (1-96%) among the studies were large. The calculated median caries prevalence values may better estimate countries' prevalence than the reported ranges. Early childhood caries prevalence's highest median values were found for South Korea studies (54%) for children <3-year-old and from Bosnia (81%) for children 3-6 years old. No apparent difference was found in the prevalence of ECC from developed and developing countries. Conclusion: This mapping review reflects the ranges and median values of ECC worldwide. Overall, the reported prevalence of ECC in most countries is very high. No apparent difference was found in the prevalence of ECC from developed and developing countries. Reported ranges of ECC, as well as heterogeneity and methodological issues, hamper comparisons across studies globally. Clinical significance: The global ECC prevalence ranges are extreme. Median data may provide a structure for future epidemiological studies to optimizing healthcare resources for caries interventions globally.
  • Comparison of the dosimetric accuracy of proton breast treatment plans delivered with SGRT and CBCT setups

    MacFarlane, Michael J; Jiang, Kai; Mundis, Michelle; Nichols, Elizabeth; Gopal, Arun; Chen, Shifeng; Biswal, Nrusingh C (Wiley-Blackwell, 2021-07-20)
    Purpose: To compare the dosimetric accuracy of surface-guided radiation therapy (SGRT) and cone-beam computed tomography (CBCT) setups in proton breast treatment plans. Methods: Data from 30 patients were retrospectively analyzed in this IRB-approved study. Patients were prescribed 4256–5040 cGy in 16–28 fractions. CBCT and AlignRT (SGRT; Vision RT Ltd.) were used for treatment setup during the first three fractions, then daily AlignRT and weekly CBCT thereafter. Each patient underwent a quality assurance CT (QA-CT) scan midway through the treatment course to assess anatomical and dosimetric changes. To emulate the SGRT and CBCT setups during treatment, the planning CT and QA-CT images were registered in two ways: (1) by registering the volume within the CTs covered by the CBCT field of view; and (2) by contouring and registering the surface surveyed by the AlignRT system. The original plan was copied onto these two datasets and the dose was recalculated. The clinical treatment volume (CTV): V95%; heart: V25Gy, V15Gy, and mean dose; and ipsilateral lung: V20Gy, V10Gy, and V5Gy, were recorded. Multi and univariate analyses of variance were performed to assess the differences in dose metric values between the planning CT and the SGRT and CBCT setups. Results: The CTV V95% and lung V20Gy, V10Gy, and V5Gy dose metrics were all significantly (p < 0.01) lower on the QA-CT in both the CBCT and SGRT setup. The differences were not clinically significant and were, on average, 1.4–1.6% lower for CTV V95% and 1.8%–6.0% lower for the lung dose metrics. When comparing the lung and CTV V95% dose metrics between the CBCT and SGRT setups, no significant difference was observed. This indicates that the SGRT setup provides similar dosimetric accuracy as CBCT. Conclusion: This study supports the daily use of SGRT systems for the accurate dose delivery of proton breast treatment plans.
  • Integrating 'Principles of Effective Intervention' into Domestic Violence Intervention Programs: New Opportunities for Change and Collaboration

    Radatz, Dana L; Richards, Tara N; Murphy, Christopher M; Nitsch, Lisa J; Green-Manning, Angelique; Brokmeier, Ann Marie; Holliday, Charvonne N (Springer Nature, 2021-07-12)
    Several evaluations and meta-analytic reviews have suggested that domestic violence (DV) treatment programs have only a modest impact on reducing DV recidivism. In response, a growing number of scholars and practitioners have called for the integration of evidence-based practices into DV treatment programming. In recent years, one leading approach has been to explore the infusion of the ‘principles of effective intervention (PEI),’ the prevailing evidence- based practice in correctional programming, into DV treatment. Findings from initial empirical studies from scholars and practitioners working to infuse the PEI into DV treatment programs have shown promise. This article provides an overview of the PEI and research exploring the integration of the PEI into DV treatment; a discussion on how these research findings can inform DV treatment programs interested in adopting a PEI framework; and practitioners’ perspectives on implementing programmatic changes and collaborating on evaluation research while also continuing to provide DV treatment. © 2021, Southern Criminal Justice Association.
  • Strategies to integrate genomic medicine into clinical care: Evidence from the IGNITE network

    Sperber, Nina R.; Dong, Olivia M.; Roberts, Megan C.; Dexter, Paul; Elsey, Amanda R.; Ginsburg, Geoffrey S.; Horowitz, Carol R.; Johnson, Julie A.; Levy, Kenneth D.; Ong, Henry; et al. (MDPI AG, 2021-07-08)
    The complexity of genomic medicine can be streamlined by implementing some form of clinical decision support (CDS) to guide clinicians in how to use and interpret personalized data; however, it is not yet clear which strategies are best suited for this purpose. In this study, we used implementation science to identify common strategies for applying provider-based CDS interventions across six genomic medicine clinical research projects funded by an NIH consortium. Each project’s strategies were elicited via a structured survey derived from a typology of implementation strategies, the Expert Recommendations for Implementing Change (ERIC), and follow-up interviews guided by both implementation strategy reporting criteria and a planning framework, RE-AIM, to obtain more detail about implementation strategies and desired outcomes. We found that, on average, the three pharmacogenomics implementation projects used more strategies than the disease-focused projects. Overall, projects had four implementation strategies in common; however, operationalization of each differed in accordance with each study’s implementation outcomes. These four common strategies may be important for precision medicine program implementation, and pharmacogenomics may require more integration into clinical care. Understanding how and why these strategies were successfully employed could be useful for others implementing genomic or precision medicine programs in different contexts. © 2021 by the authors.
  • Profiling variable-number tandem repeat variation across populations using repeat-pangenome graphs

    Lu, Tsung-Yu; Chaisson, Mark J P (Springer Nature, 2021-07-12)
    Variable number tandem repeats (VNTRs) are composed of consecutive repetitive DNA with hypervariable repeat count and composition. They include protein coding sequences and associations with clinical disorders. It has been difficult to incorporate VNTR analysis in disease studies that use short-read sequencing because the traditional approach of mapping to the human reference is less effective for repetitive and divergent sequences. In this work, we solve VNTR mapping for short reads with a repeat-pangenome graph (RPGG), a data structure that encodes both the population diversity and repeat structure of VNTR loci from multiple haplotype-resolved assemblies. We develop software to build a RPGG, and use the RPGG to estimate VNTR composition with short reads. We use this to discover VNTRs with length stratified by continental population, and expression quantitative trait loci, indicating that RPGG analysis of VNTRs will be critical for future studies of diversity and disease. © 2021, The Author(s).
  • Anti-SARS-CoV-2 immune responses in patients receiving an allogeneic stem cell or organ transplant

    Atanackovic, Djordje; Luetkens, Tim; Avila, Stephanie V.; Hardy, Nancy M.; Lutfi, Forat; Sanchez-Petitto, Gabriela; Mause, Erica Vander; Glynn, Nicole; Mannuel, Heather D.; Alkhaldi, Hanan; et al. (MDPI AG, 2021-07-03)
    Patients after autologous (autoSCT) and allogeneic stem cell transplantation (alloSCT) are at an increased risk of COVID-19-related morbidity and mortality, compounded by an immune system weakened by the underlying malignancy and prior treatments. Allogeneic transplantation, including stem cell and solid organ transplants, requires intensive immunosuppressive prophylaxis, which may further undermine the development of a protective vaccine-induced anti-viral immunity. Herein, we report on short- and long-term antiviral immune responses in two peri-stem cell transplant recipients and a third patient who received a COVID-19 vaccination after kidney transplantation. Our data indicate that: (1) patients post-alloSCT may be able to mount an anti-COVID-19 immune response; however, a sufficient time interval between transplant and exposure may be of critical importance; (2) alloSCT recipients with preexisting anti-SARS-CoV-2 immunity are at risk for losing protective humoral immunity following transplantation, particularly if the stem-cell donor lacks antiviral immunity, e.g., vaccine-derived immunity; and (3) some post-transplant patients are completely unable to build an immune response to a COVID-19 vaccine, perhaps based on the prophylactic suppression of T cell immunity.
  • Isolated Antineutrophil Cytoplasmic Antibody-Associated Coronary Vasculitis and Valvulitis

    Kim, Yoon Kook; Chekka, Praveen; Mysore, Manu; Childress, James; Alfaraidhy, Maha; Thomas, Afton; Taylor, Bradley; Mikdashi, Jamal; Liu, Stanley; Wang, Libin (Elsevier Inc., 2021-02-10)
    A 30-year-old woman presented with angina pectoris. Coronary angiography revealed severe stenosis in the left main and right coronary arteries that did not improve with intracoronary nitroglycerin. Coronary computed tomography angiography and positron emission tomography revealed coronary ostia inflammation and aortic root fat stranding. She was diagnosed with vasculitis and valvulitis and received immunotherapy and coronary bypass. (Level of Difficulty: Advanced.).

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