Research Spotlight

Chen, X., Sheng, L., Ma, J., Qi, D., Li, X., Wang, Z., Wu, Z., Wong, L., Huang, J. H., Wu, E., Ma, Q. and Zhang, D. (2022). “4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone provokes progression from chronic pancreatitis to pancreatic intraepithelial neoplasia.” iScience 25(1): 103647.

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The risk of pancreatic cancer is higher among people who are cigarette smokers than among non-smokers; however, the action mechanisms of cigarette metabolites are not yet fully understood. In this study, we investigated the effect of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in cigarette smoking on chronic pancreatitis and pancreatic cancer as well as the biological mechanism of NNK causing malignant transformation. We show that smoking may promote Kras mutation and P16 promoter methylation from clinical samples and NNK markedly facilitates the growth and migration of pancreatic cancer cells via the activation of Sonic Hedgehog signaling. We demonstrate that NNK promotes acinar-to-ductal metastasis and pancreatic intraepithelial neoplasia in rats with chronic pancreatitis, accompanied by desmoplastic reaction and Gli1 overexpression. Together, we here present evidence that NNK provokes the progression of chronic pancreatitis toward pancreatic cancer and highlight potential strategies and targets for early prevention of pancreatic cancer and its therapeutics.

da Graca, B., Bennett, M. M., Powers, M. B., Gottlieb, R. L., Waddimba, A. C. and Warren, A. M. (2022). “Psychological differences in adults with and without a COVID-19 diagnosis.” J Ment Health: 1-8.

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BACKGROUND: Substantial evidence is emerging regarding the broad societal and psychological impacts of the COVID-19 pandemic, but little is known about whether infected individuals are differently affected. AIM: We evaluated psychological differences between individuals who do vs. do not report testing positive for COVID-19. METHODS: An online survey was offered to adults (≥18 years) who were diagnosed with COVID-19 by a provider within a large integrated-delivery healthcare system, enrolled in COVID-19-related clinical trials at the healthcare system, or responded to targeted local distribution. Measures assessed included the 8-item Patient Health Questionnaire depression scale, Generalized Anxiety Disorder 7-item Scale, and Posttraumatic Diagnostic Scale for DSM-5. RESULTS: Of 487 respondents, 43% reported testing positive for COVID-19, including 11% requiring hospitalization. Overall rates of general anxiety disorder and posttraumatic stress were 34% and 16%, respectively, with no significant differences between groups. Prevalence of depression was higher among respondents reporting a positive COVID-19 test (52% vs. 31%). This difference persisted after controlling for respondent characteristics (odds ratio = 3.7, p < 0.01). CONCLUSIONS: People who report testing positive for COVID-19, even those not requiring hospitalization, have increased risk for depression. Mental health care screening and services should be offered to individuals testing positive, facilitating early intervention.

Kling, C. E., Perkins, J. D., Biggins, S. W., Wall, A. E. and Reyes, J. D. (2022). “Building a Utility-based Liver Allocation Model in Preparation for Continuous Distribution.” Transplant Direct 8(2): e1282.

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BACKGROUND: The current model for end-stage liver disease-based liver allocation system in the United States prioritizes sickest patients first at the expense of long-term graft survival. In a continuous distribution model, a measure of posttransplant survival will also be included. We aimed to use mathematical optimization to match donors and recipients based on quality to examine the potential impact of an allocation system designed to maximize long-term graft survival. METHODS: Cox proportional hazard models using organ procurement and transplantation network data from 2008 to 2012 were used to place donors and waitlist candidates into 5 groups of increasing risk for graft loss (1-lowest to 5-highest). A mixed integer programming optimization model was then used to generate allocation rules that maximized graft survival at 5 and 8 y. RESULTS: Allocation based on mathematical optimization improved 5-y survival by 7.5% (78.2% versus 70.7% in historic cohort) avoiding 2271 graft losses, and 8-y survival by 9% (71.8% versus 62.8%) avoiding 2725 graft losses. Long-term graft survival for recipients within a quality group is highly dependent on donor quality. All candidates in groups 1 and 2 and 43% of group 3 were transplanted, whereas none of the candidates in groups 4 and 5 were transplanted. CONCLUSIONS: Long-term graft survival can be improved using a model that allocates livers based on both donor and recipient quality, and the interaction between donor and recipient quality is an important predictor of graft survival. Considerations for incorporation into a continuous distribution model are discussed.

Wall, A. E., Fiedler, A., Karp, S., Shah, A. and Testa, G. (2022). “Applying the ethical framework for donation after circulatory death to thoracic normothermic regional perfusion procedures.” Am J Transplant.

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The novel approach of thoracic normothermic regional perfusion (TA-NRP) for in-situ preservation of organs prior to removal presents a new series of ethical questions about donation after circulatory determination of death (DCD) procedures. This manuscript describes the framework used for the analysis of ethical acceptability of DCD donation and analyzes the specific practice of TA-NRP DCD within that framework to demonstrate that TA-NRP DCD can be performed within the ethical boundaries of DCD donation. We argue that TA-NRP DCD organ procurements meet the ethical standards of informed consent, non-maleficence, adherence to the dead donor rule, and irreversibility, and as such, are ethically acceptable. We also describe the potential benefits of TA-NRP DCD procedures that result from higher organ yields and better recipient outcomes. Finally, we call for open and transparent support of TA-NRP DCD by professional organizations as a necessary cornerstone for the advancement of TA-NRP DCD procedures.

Jarman, M., Bennett, M. M., Louis, J. M., Clark, R., Tolia, V. N. and Ahmad, K. A. (2022). “Changing Tocolytic Exposures Among Neonatal Intensive Care Unit Admitted Preterm Infants.” Am J Perinatol.

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OBJECTIVE: Since 2010, the American College of Obstetrics and Gynecology have released three committee opinions to recommend and re-affirm the utility of magnesium sulfate for neuroprotection and later for tocolysis to achieve antenatal steroid course completion in preterm labor. We sought to determine changes in antenatal magnesium sulfate exposure and other tocolytic agents for pregnancies resulting in NICU-admitted preterm infants. STUDY DESIGN: Using the Pediatrix Clinical Data Warehouse, we evaluated all inborn infants delivered between 22 to 33 weeks’ gestation and admitted to the intensive care units from 2009 to 2018. We classified patients based on antenatal exposure to tocolytic medications: calcium channel blockers (nifedipine and amlodipine), betamimimetics (terbutaline, theophylline, and ritrodine), prostaglandin inhibitors (indomethacin) and magnesium sulfate. RESULTS: A total of 190,884 patients met inclusion criteria. During the study period, magnesium sulfate exposure increased from 27.6% to 57.7% of births while betamimetic exposure decreased from 10.2% to 5.2%. Increasing magnesium sulfate exposure over time was seen at all gestational ages examined and magnesium exposure was most common between 24 and 31 weeks’ gestation. By 2017-2018, 70.5% of 24 to 29 weeks’ gestation NICU infants received exposure to at least one tocolytic agent while this remained at 53.7% of 32 to 33 weeks’ NICU admitted infants (figure 3). Antenatal steroid exposure increased from 74.8% to 87.4% during the study period. CONCLUSION: For NICU admitted preterm infants, prenatal exposure patterns to tocolytic agents has shifted since 2009 with prenatal magnesium sulfate exposure increasing significantly. Antenatal steroid exposure has risen concurrently. Exposure to tocolytic agents is highest amongst preterm infants born between 24 and 29 weeks’ gestation.