Faculty Bibliography

Flaviviruses, represented by Zika and dengue virus (ZIKV and DENV), are widely present around the world and cause various diseases with serious consequences. However, no antiviral drugs have been clinically approved for use against them. Azelnidipine (ALP) is a dihydropyridine calcium channel blocker and has been approved for use as an antihypertensive drug. In the present study, ALP was found to show potent anti-flavivirus activities in vitro and in vivo. ALP effectively prevented the cytopathic effect induced by ZIKV and DENV and inhibited the production of viral RNA and viral protein in a dose-dependent manner. Moreover, treatment with 0.3 mg/kg of ALP protected 88.89% of mice from lethal challenge. Furthermore, using the time-of-drug-addition assay, the enzymatic inhibition assay, the molecular docking, and the surface plasmon resonance assay, we revealed that ALP acted at the replication stage of the viral infection cycle by targeting the viral RNA-dependent RNA polymerase. These findings highlight the potential for the use of ALP as an antiviral agent to combat flavivirus infections.

BACKGROUND: Midwives are a vital component of addressing maternal mortality crisis in the United States (US); however, there is scant understanding of the elements of midwifery practice that affect patient outcomes and the stability of the midwifery workforce in the country. This study investigates US midwives"™ perceptions of factors influencing their practice and willingness to stay in the profession. METHODS: We applied a pragmatic qualitative design using summative content analysis techniques to code 1,035 comments from a national sample of 2,887 certified nurse-midwives and certified midwives. Two coders identified categories and themes of midwives"™ perceptions of their practice environments, which were confirmed by an independent auditor. RESULTS: Eight themes emerged from the data: I love midwifery but"¦; feeling valued and respected"¦or not; workload; time and its consequences; the multilevel geography of midwifery practice; changes at odds with quality midwifery care; midwives withdrawing from practice to cope; and the ambiguity of "I just want to practice like a midwife." CONCLUSION: Midwives readily identified aspects of their practice environment that negatively impact quality of care and stability of the midwifery workforce, including not valuing midwives, high workload, regulatory restrictions, and moral distress; however, respondents expressed strong commitment to the profession of midwifery. The findings also demonstrated the lack of a universally accepted definition of midwifery care within respondents"™ professional communities and among respondents. Initiatives to increase integration of midwifery into the US perinatal health system will benefit from taking these findings into consideration.

It has been over 50 years since the Stonewall Inn Riots in June 1969, a seminal event for the lesbian, gay, bisexual, transgender, queer, intersex, and other sexual and gender-diverse minorities (LGBTQI+, or lesbian, gay, bisexual, transgender, queer, intersex, and everyone else) rights movement. However, sexual and gender minority (SGM) individuals still face discrimination and harassment due to their sexual orientation or gender identity. As such, the National Institute on Minority Health and Health Disparities has identified SGM communities as a "health disparity population." Broadly, there are higher rates of sexually transmitted infections, substance use and abuse, mental health conditions, obesity and eating disorders, certain cancers (breast, cervical, and anorectal), and cardiovascular disease in SGM communities. Transgender patients, especially those of color, are more likely to be uninsured, experience discrimination, and be denied health care than cisgender patients. In addition, SGM individuals have twice the risk of lifetime exposure to emotional, physical, and sexual trauma compared with heterosexuals. It is expected all these factors would negatively affect digestive health as well. This review summarizes the effects of social determinants of health and discrimination on health care access, highlights important digestive diseases to consider in the SGM population, and offers solutions to improve and prioritize the health of these communities. We aim to draw attention to SGM-specific issues that affect gastrointestinal health and spur research that is desperately lacking.

Introduction/UNASSIGNED:The combination of hydralazine-isosorbide dinitrate (H-ISDN) has potential as a heart failure (HF) therapy in the setting of maintenance dialysis. Methods/UNASSIGNED:In this retrospective study, we analyzed the efficacy of H-ISDN using United States Renal Data System (USRDS) data. We identified all adult patients with a history of HF on maintenance dialysis between January 1, 2011, and December 31, 2016, with at least 1 prescription for H-ISDN. Baseline characteristics, prescriptions, and outcomes were retrieved from institutional and physician claims. The primary outcome was death from any cause. Additional outcomes included cardiovascular death, sudden cardiac death, hospitalization for HF, an inpatient diagnosis of myocardial infarction (MI), or new-onset atrial fibrillation. Stabilized inverse probability weights were estimated using relevant baseline characteristics and were used in Cox proportional hazards regression. Results/UNASSIGNED:We identified 6306 patients who were treated with H-ISDN and 75,509 patients who did not receive H-ISDN. The crude all-cause mortality rate was lower in patients treated with H-ISDN (16.0 events/100 patient years [PYs]) than in nonusers (27.9/100-PY). H-ISDN use was independently associated with lower mortality: hazard ratio (HR) 0.48 (95% CI 0.43-0.54). Cardiovascular death and sudden cardiac death were less common among H-ISDN users than nonusers, Weighted HR was 0.62 (95% CI 0.53-0.71) and 0.62 (95% CI 0.52-0.73), respectively. In contrast, HF admission and MI were more frequent in patients treated with H-ISDN (195.5 and 18.0 events/100-PY) compared with nonusers (73.4 and 10.2 events/100-PY). Conclusion/UNASSIGNED:H-ISDN therapy may improve cardiovascular outcomes in maintenance dialysis patients with HF.

Type I interferon (IFN) is critical in our defense against viral infections. Increased type I IFN pathway activation is a genetic risk factor for systemic lupus erythematosus (SLE), and a number of common risk alleles contribute to the high IFN trait. We hypothesized that these common gain-of-function IFN pathway alleles may be associated with protection from mortality in acute COVID-19. We studied patients admitted with acute COVID-19 (756 European-American and 398 African-American ancestry). Ancestral backgrounds were analyzed separately, and mortality after acute COVID-19 was the primary outcome. In European-American ancestry, we found that a haplotype of interferon regulatory factor 5 (IRF5) and alleles of protein kinase cGMP-dependent 1 (PRKG1) were associated with mortality from COVID-19. Interestingly, these were much stronger risk factors in younger patients (OR=29.2 for PRKG1 in ages 45-54). Variants in the IRF7 and IRF8 genes were associated with mortality from COVID-19 in African-American subjects, and these genetic effects were more pronounced in older subjects. Combining genetic information with blood biomarker data such as C-reactive protein, troponin, and D-dimer resulted in significantly improved predictive capacity, and in both ancestral backgrounds the risk genotypes were most relevant in those with positive biomarkers (OR for death between 14 and 111 in high risk genetic/biomarker groups). This study confirms the critical role of the IFN pathway in defense against COVID-19 and viral infections, and supports the idea that some common SLE risk alleles exert protective effects in anti-viral immunity. BACKGROUND: We find that a number of IFN pathway lupus risk alleles significantly impact mortality following COVID-19 infection. These data support the idea that type I IFN pathway risk alleles for autoimmune disease may persist in high frequency in modern human populations due to a benefit in our defense against viral infections. TRANSLATIONAL SIGNIFICANCE: We develop multivariate prediction models which combine genetics and known biomarkers of severity to result in greatly improved prediction of mortality in acute COVID-19. The specific associated alleles provide some clues about key points in our defense against COVID-19.

This third paper in the "Confronting Racism in All Forms of Pain Research" series discusses adopting an antiracism framework across all pain research disciplines and highlights the significant benefits of doing so. We build upon the previous call to action and the proposed reframing of study designs articulated in the other papers in the series and seek to confront and eradicate racism through a shared commitment to change current research practices. Specifically, we emphasize the systematic disadvantage created by racialization (ie, the Eurocentric social and political process of ascribing racialized identities to a relationship, social practice, or group) and discuss how engaging communities in partnership can increase the participation of racialized groups in research studies and enrich the knowledge gained. Alongside this critical work, we indicate why diversifying the research environment (ie, research teams, labs, departments, and culture) enriches our scientific discovery and promotes recruitment and retention of participants from racialized groups. Finally, we recommend changes in reporting and dissemination practices so that we do not stigmatize or reproduce oppressive forms of power for racialized groups. Although this shift may be challenging in some cases, the increase in equity, generalizability, and credibility of the data produced will expand our knowledge and reflect the pain experiences of all communities more accurately. PERSPECTIVE: Perspective: In this third paper in our series, we advocate for a shared commitment toward an antiracism framework in pain research. We identify community partnerships, diversification of research environments, and changes to our dissemination practices as areas where oppressive forms of power can be reduced.

BACKGROUND & AIMS/OBJECTIVE:Colorectal cancer (CRC) incidence has decreased overall in the last several decades, but it has increased among younger adults. Prior studies have characterized this phenomenon in the United States (U.S.) using only a small subset of cases. We describe CRC incidence trends using high-quality data from 92% of the U.S. population, with an emphasis on those younger than 50 years. METHODS:We obtained 2001 to 2016 data from the U.S. Cancer Statistics database and analyzed CRC incidence for all age groups, with a focus on individuals diagnosed at ages 20 to 49 years (early-onset CRC). We compared incidence trends stratified by age, as well as by race/ethnicity, sex, region, anatomic site, and stage at diagnosis. RESULTS:We observed 191,659 cases of early-onset and 1,097,765 cases of late-onset CRC during the study period. Overall, CRC incidence increased in every age group from 20 to 54 years. Whites were the only racial group with a consistent increase in incidence across all younger ages, with the steepest rise seen after 2012. Hispanics also experienced smaller increases in incidence in most of the younger age groups. Asians/Pacific Islanders and blacks saw no increase in incidence in any age group in 2016, but blacks continued to have the highest incidence of CRC for every age group. Greater increase in early-onset CRC incidence was observed for males, left-sided tumors, and regional and distant disease. CONCLUSIONS:Early-onset CRC incidence increased overall from 2001 to 2016, but the trends were markedly different for whites, blacks, Asians/Pacific Islanders, and Hispanics. These results may inform future research on the risk factors underlying early-onset CRC.

AIM/OBJECTIVE:To study the relationship between Polish nurses' working conditions and their attitudes towards patient safety during the COVID-19 pandemic. BACKGROUND:Facing the COVID-19 pandemic, caused by the SARS-CoV-2 virus, healthcare worldwide has been reorganised. How these changes affected patient safety for hospitalised persons is not well understood. INTRODUCTION/BACKGROUND:Difficult working conditions related to the outbreak of the COVID-19 pandemic may affect the provision of safe and effective care by healthcare staff. METHODS:This observational research was performed on the group of 577 nurses working during the COVID-19 pandemic in isolation infection wards (n = 201) and non-infectious diseases wards (n = 376) in Polish hospitals. The evaluation of working conditions was performed with an author's questionnaire, while the evaluation of factors influencing attitudes towards safety of the hospitalised patients was performed using Safety Attitudes Questionnaire. The STROBE checklist was used to report this study. RESULTS:The procedures developed by management in advance for COVID-19 patient treatment had a statistically significant influence on nurses' 'evaluation of teamwork climate, safety climate, job satisfaction, perception of management and work conditions'. Providing management with the ability to perform a swab polymerase chain reaction SARS-CoV-2 test for hospital staff in the workplace, and psychological support from professionals and employers were statistically significant for higher ratings of 'teamwork climate, safety climate, job satisfaction, stress recognition, perception of management and work conditions' by the Polish nurses. Hospital workload during the COVID-19 pandemic was significantly correlated with lower evaluation of work conditions. DISCUSSION/CONCLUSIONS:Our study reinforces the existing literature on many fronts and demonstrates how even when operating under the COVID-19 pandemic conditions, some factors remain critical for fostering a culture of patient safety. Reinforcing patient safety practices is a imperative under these conditions. CONCLUSIONS AND IMPLICATIONS FOR NURSING/UNASSIGNED:Working conditions influence nurses' attitudes towards safety of the hospitalised patients. These are largely modifiable factors related to the workplace and include prior preparation of procedures, restrictions to extending daily work hours and psychological counselling for the staff.