Evaluating MedDRA-to-ICD terminology mappings.

BACKGROUND: In this era of big data, data harmonization is an important step to ensure reproducible, scalable, and collaborative research. Thus, terminology mapping is a necessary step to harmonize heterogeneous data. Take the Medical Dictionary for Regulatory Activities (MedDRA) and International Classification of Diseases (ICD) for example, the mapping between them is essential for drug safety and pharmacovigilance research. Our main objective is to provide a quantitative and qualitative analysis of the mapping status between MedDRA and ICD. We focus on evaluating the current mapping status between MedDRA and ICD through the Unified Medical Language System (UMLS) and Observational Medical Outcomes Partnership Common Data Model (OMOP CDM). We summarized the current mapping statistics and evaluated the quality of the current MedDRA-ICD mapping; for unmapped terms, we used our self-developed algorithm to rank the best possible mapping candidates for additional mapping coverage. RESULTS: The identified MedDRA-ICD mapped pairs cover 27.23% of the overall MedDRA preferred terms (PT). The systematic quality analysis demonstrated that, among the mapped pairs provided by UMLS, only 51.44% are considered an exact match. For the 2400 sampled unmapped terms, 56 of the 2400 MedDRA Preferred Terms (PT) could have exact match terms from ICD. CONCLUSION: Some of the mapped pairs between MedDRA and ICD are not exact matches due to differences in granularity and focus. For 72% of the unmapped PT terms, the identified exact match pairs illustrate the possibility of identifying additional mapped pairs. Referring to its own mapping standard, some of the unmapped terms should qualify for the expansion of MedDRA to ICD mapping in UMLS.

Fluorogenic monomer activation for protein-initiated atom transfer radical polymerization.

Fluorogenic atom transfer radical polymerization (ATRP) directly detects initiator-dependent polymer formation, as initially non-fluorescent polycyclic aromatic probe monomers reveal visible fluorescence upon polymerization in real time. Advancement of this initial proof-of-concept toward biodetection applications requires both a more detailed mechanistic understanding of probe fluorescence activation, and the ability to initiate fluorogenic polymerization directly from a biomolecule surface. Here, we show that simple monomer hydrogenation, independent of polymerization, reveals probe fluorescence, supporting the critical role of covalent enone attachment in fluorogenic probe quenching and subsequent fluorescence activation. We next demonstrate bioorthogonal, protein-initiated fluorogenic ATRP by the surface conjugation and characterization of protein-initiator conjugates of a model protein, bovine serum albumin (BSA). Fluorogenic ATRP from initiator-modified protein allows for real-time visualization of polymer formation with negligible background fluorescence from unmodified BSA controls. We further probe the bioorthogonality of this fluorogenic ATRP assay by assessing polymer formation in a complex biological environment, spiked with fetal bovine serum. Taken together, we demonstrate the potential of aqueous fluorogenic ATRP as a robust, bioorthogonal method for biomolecular-initiated polymerization by real-time fluorescence activation.

Trichodysplasia spinulosa polyomavirus small T antigen synergistically modulates S6 protein translation and DNA damage response pathways to shape host cell environment.

TSPyV is a viral agent linked to Trichodysplasia spinulosa, a disfiguring human skin disease which presents with hyperkeratotic spicule eruption in immunocompromised hosts. This proliferative disease state requires extensive modulation of the host cell environment. While the small T (sT) antigen of TSPyV has been postulated to cause widespread cellular perturbation, its specific substrates and their mechanistic connection are unclear. To identify the cellular substrates and pathways perturbed by TSPyV sT and propose a nuanced model that reconciles the multiple arms of TSPyV pathogenesis, changes in expression of several proteins and phospho-proteins in TSPyV sT expressing and TSPyV sT deletion mutant-expressing cell lysates were interrogated using Western blot assays. TSPyV sT expression exploits the DNA damage response pathway, by inducing hyperphosphorylation of ATM and 53BP1 and upregulation of BMI-1. Concurrently, sT dysregulates the S6 protein translation pathway via hyperphosphorylation of CDC2, p70 S6 kinase, S6, and PP1α. The S6S244/247 and p-PP1αT320 phospho-forms are points of overlap between the DDR and S6 networks. We propose a mechanistic rationale for previous reports positioning sT antigen as the key driver of TSPyV pathogenesis. We illuminate novel targets in the S6 and DDR pathways and recognize a potential synergy between these pathways. TSPyV may sensitize the cell to both unrestricted translation and genomic instability. This multi-pronged infection model may inform future therapeutic modalities against TSPyV and possibly other viruses with overlapping host substrates.

Trends and predictors of preterm birth among Asian Americans by ethnicity, 1992-2018.

BACKGROUND: In an increasingly diverse United States (US) population, racial disparities in preterm birth outcomes continue to widen. OBJECTIVE: In this study, we examined temporal trends and risk of preterm birth among Asian American women over a quarter century (1992-2018). STUDY DESIGN: This is a retrospective cohort study using the 1992-2018 Natality data files. We conducted joinpoint regression analyses to examine trends in preterm birth among Asian Americans and non-Hispanic (NH) Whites. Bivariate and multivariable analyses were used to identify risk factors associated with preterm birth among Asian Americans and their ethnic sub-groups as compared to NH-Whites. RESULTS: There were a total of 251,278 preterm births among Asian American women, corresponding to a rate of 10.0%, which was relatively stable over time. The incidence of extremely, very and moderate-to-late preterm birth among Asian Americans was 0.4%, 0.9% and 8.7% respectively. Overall, Asian American women exhibited lower adjusted odds (OR = 0.92; 95% CI: 0.88-0.97) of preterm birth than their NH-White counterparts. Comparing Asian American subgroups to NH-Whites, Filipinas and Vietnamese mothers had increased adjusted odds, whereas Chinese, Korean, Japanese and Asian Indian women showed decreased adjusted odds for preterm birth. CONCLUSION: The risk of preterm birth varied among the ethnic subgroups of Asian Americans in the United States. Future studies should explore the socio-cultural and environmental nuances that might explain these differences.

Can quality keep up with quantity-Longitudinal trends in research output for the dermatology residency match.

Dermatology is one of the most competitive specialties to match into and continually draws high-achieving medical students. According to National Residency Match Program data, applicants reported an increasing number of total research products throughout the past decade. To better contextualize this trajectory, our study investigates the specific types of research items underlying this trend and the impact of applicant-specific and program-specific factors on research output. Names of matched dermatology applicants from 2009, 2011, 2014, 2016, and 2018 were collected and searched on PubMed and Google Scholar to analyze research output. Applicants were further stratified by sex, PhD status, medical school attended, geography of matched program, domestic/international status, and whether they had a home dermatology program. Matched applicants reported a mean of 7.6 research products per applicant in 2018 and, of those products, had a mean of 2.55 peer-reviewed publications per applicant. This discrepancy was observed in other years. Matched applicants from the top 20 schools and applicants from men had a significantly higher mean of peer-reviewed publications. We observed that research volume did not impact an applicant's likelihood of matching to his/her home institution. The upward trend in total research products may be misleading, because applicants increasingly resort to nonindexed research (eg, abstracts, presentations, chapters) to be competitive for dermatology residency. We also observed preliminary evidence of certain applicant-specific factors (eg, attending a top 20 medical school, sex) correlating to increased applicant publications. There is a need for a more stringent and holistic method of evaluating applicant research.

Trends and predictors of eclampsia among singleton and multiple gestations in the United States, 1989-2018.

OBJECTIVE: To examine temporal trends of eclampsia by plurality in the US spanning three decades (1989-2018); and to investigate risk factors for eclampsia among singleton and multiple pregnancies in the US during the study period. STUDY DESIGN: We conducted a retrospective cohort study using the Natality data files, including information on all births within the gestational age of 20-42 weeks from 1989 through 2018. We used joinpoint regression analysis to evaluate trends in rates of eclampsia over the study period. We employed logistic regression models to examine the association between plurality and eclampsia after adjusting for socio-demographic and gestational factors. MAIN OUTCOME MEASURES: The primary outcome was eclampsia among singleton and multiple pregnancies. FINDINGS: There was a 2.8% (95% CI: -5.4, -0.1) average annual reduction in eclampsia rates among singletons, whereas among multiples there was a decline of about 3.7% (95% CI: -6.4, -1.0) annually. Mothers with multiple pregnancies had three-fold increased adjusted odds (OR = 95% CI: 2.95-3.21) of experiencing eclampsia when compared to those with singleton gestations. Non-Hispanic (NH) Black mothers with singletons had 37% greater adjusted odds of developing eclampsia than their NH-White peers (95%CI: 1.33-1.42). CONCLUSION: There was an overall decreasing trend in eclampsia incidence in the US from 1989 to 2018, regardless of plurality. The occurrence of eclampsia was associated with plurality, race/ethnicity, maternal age and maternal BMI. Given the heterogeneity in clinical presentations of eclampsia, personalized/standardized risk prediction models are needed to enable consistent diagnosis and timely intervention.

Pregnancy outcomes among Asian Americans of advanced maternal age, 1992-2018.

AIM: The trend of delayed childbearing has implications for the increasing national burden of adverse perinatal outcomes across vulnerable racial-ethnic groups. The objective of this study was to investigate age-adjusted risk for adverse maternal-fetal outcomes among Asian Americans of advanced maternal age (≥35 years). METHODS: This was a retrospective cohort study using the 1992-2018 Natality data files. We calculated the prevalence of maternal-fetal outcomes: maternal diabetes, hypertensive disorders of pregnancy (HDP), C-section, small-for-gestational age (SGA), large-for-gestational age (LGA), and preterm birth. Adjusted binomial logistic regression was created to evaluate the association between maternal race/ethnicity and each of the maternal-fetal outcomes. RESULTS: Compared with non-Hispanic Whites, Asian American women had reduced odds of diabetes, HDP, and LGA babies and increased odds of preterm birth, C-section delivery, and SGA, irrespective of the advanced maternal age group. The odds of developing specific adverse outcomes by advanced maternal age varied by Asian American ethnic subgrouping. DISCUSSION: The risk of maternal-fetal outcomes varied among the ethnic subgroups of Asian Americans in the United States. Future studies should explore the sociocultural and environmental nuances that might explain these differences.

Effects of ß-HPV on DNA damage response pathways to drive carcinogenesis: a review.

The DDR is a complex signaling network responsible for the preservation of genomic integrity. Beta human papillomaviruses (ß-HPVs) are able to destabilize the host genome by attenuating the DDR machinery at the molecular scale following expression of the oncogenes E6 and E7. In the event of ß-HPV infection, the E6- and E7-mediated inhibition of the DDR enhances the oncogenicity of UV-induced mutations to enable carcinogenesis in an otherwise immunocompetent host, marking an important mechanistic divergence from the alpha genus of HPVs. In this review, we summarize recent updates to build upon the 'hit-and-run' hypothesis of ß-HPV pathomechanism and highlight strain-dependent variations. Simultaneously, we illuminate points within the ß-HPV-DDR interface that may unravel new insights for HPV viral genetics, genus-specific mechanistic models, and developments in targeted molecular therapy of ß-HPV-related cancers.

Temporal trends in preterm birth phenotypes by plurality: Black-White disparity over half a century.

OBJECTIVE: To examine trends in rates of preterm birth by race and plurality; to evaluate the association between race, plurality, and phenotypes of preterm birth. STUDY DESIGN: Temporal trends analyses for preterm birth by race and plurality were performed for the years 1971-2018. Adjusted logistic regression models were utilized to evaluate the association between race, plurality, and phenotypes of preterm birth. RESULTS: We observed that 1105,266 (0.7%), 1901,604 (1.2%), and 14,769,746 (9.3%) births belonged to extreme preterm, very preterm, and moderate-to-late preterm categories, respectively. We also observed that the risk of extreme preterm (RR: 2.69, 95% CI: 2.642-2.75) was highest for Black mothers as compared to White mothers. CONCLUSION: Over the study period, preterm births disproportionately impacted Black mothers as well as pregnancies of higher plurality. With the persistence of racial disparities and growing trend of delayed childbearing and multiple pregnancies, targeted intervention is necessitated toward these vulnerable subgroups.

Commentary: Pharmacologic Correlates that Address the Clinicopathobiology of COVID-19.

COVID-19 could remain a pandemic until we get a SARS-CoV-2 vaccine to immunize the world population. In the interim, we have the opportunity to consider its clinicopathobiology in the context of the pharmacologic correlates available from the existing medical literature to prevent the COVID-19 infected patient from progressing into a fatal stage. This commentary serves as a forum for that end and suggests relatively non-toxic therapies that could be applied in a combinatorial fashion for consideration by the physicians and their patients with COVID-19 infection.

Human polyomavirus modulation of the host DNA damage response.

The human DNA damage response (DDR) is a complex signaling network constituting many factors responsible for the preservation of genomic integrity. Human polyomaviruses (HPyVs) are able to harness the DDR machinery during their infectious cycle by expressing an array of tumor (T) antigens. These molecular interactions between human polyomavirus T antigens and the DDR create conditions that promote viral replication at the expense of host genomic stability to cause disease as well as carcinogenesis in the cases of the Merkel cell polyomavirus and BK polyomavirus. This review focuses on the six HPyVs with disease association, emphasizing strain-dependent differences in their selective manipulation of the DDR. Appreciation of the HPyV-DDR interface at a molecular scale is conducive to the development of novel therapeutic approaches.

Fluorogenic atom transfer radical polymerization in aqueous media as a strategy for detection.

The development of novel approaches to signal amplification in aqueous media could enable new diagnostic platforms for the detection of water-soluble analytes, including biomolecules. This paper describes a fluorogenic polymerization approach to amplify initiator signal by the detection of visible fluorescence upon polymerization in real-time. Fluorogenic monomers were synthesized and co-polymerized by atom transfer radical polymerization (ATRP) in water to reveal increasing polymer fluorescence as a function of both reaction time and initiator concentration. Optimization of the fluorogenic ATRP reaction conditions allowed for the quantitative detection of a small-molecule initiator as a model analyte over a broad linear concentration range (pM to mM). Raising the reaction temperature from 30 °C to 60 °C facilitated sensitive initiator detection at sub-picomolar concentrations in as little as 1 h of polymerization. This method was then applied to the detection of streptavidin as a model biological analyte by fluorogenic polymerization from a designed biotinylated ATRP initiator. Taken together, these studies represent the first example of a fluorogenic ATRP reaction and establish fluorogenic polymerization as a promising approach for the direct detection of aqueous analytes and biomolecular recognition events.