Developmental arsenic exposure impairs cognition, directly targets DNMT3A, and reduces DNA methylation.

Developmental arsenic exposure has been associated with cognitive deficits in epidemiological studies, but the underlying mechanisms remain poorly understood. Here, we establish a mouse model of developmental arsenic exposure exhibiting deficits of recognition and spatial memory in the offspring. These deficits are associated with genome-wide DNA hypomethylation and abnormal expression of cognition-related genes in the hippocampus. Arsenic atoms directly bind to the cysteine-rich ADD domain of DNA methyltransferase 3A (DNMT3A), triggering ubiquitin- and proteasome-mediated degradation of DNMT3A in different cellular contexts. DNMT3A degradation leads to genome-wide DNA hypomethylation in mouse embryonic fibroblasts but not in non-embryonic cell lines. Treatment with metformin, a first-line antidiabetic agent reported to increase DNA methylation, ameliorates the behavioral deficits and normalizes the aberrant expression of cognition-related genes and DNA methylation in the hippocampus of arsenic-exposed offspring. Our study establishes a DNA hypomethylation effect of developmental arsenic exposure and proposes a potential treatment against cognitive deficits in the offspring of pregnant women in arsenic-contaminated areas.

Validation of a Tool to Evaluate Nursing Students' Electronic Health Record Competency in Simulation.

AIM: The aim of the study was to establish reliability and validity of the Competency Assessment in Simulation of Electronic Health Records (CASE) tool. BACKGROUND: Effective teaching and learning practices, including valid and reliable assessment of students' electronic health record (EHR) competency, contribute to safe, high-quality, efficient nursing care. METHOD: The study used a mixed-methods design to test reliability and validity of the CASE tool. RESULTS: A nationally representative sample of faculty from universities representing 27 states provided scores for videos using the CASE tool. Forty-seven participants completed the first scoring survey; 22 of the 47 participants (47%) completed the second-round scoring. Intraclass correlation for the final score between the first and second responses shows the consistency of test-retest reliability (ICC = .78, p < .001). CONCLUSION: The CASE tool provided evidence of validity and reliability in evaluating EHR competency in simulation.

A maternity care home model of enhanced prenatal care to reduce preterm birth rate and NICU use.

BACKGROUND: Centers for Medicare & Medicaid Services (CMS) funded 182 US health care sites to reduce preterm birth rates by enhancing prenatal care for at-risk women. As a funded site, the enhanced prenatal care maternity care home (MCH) model was implemented from 2013 to 2018 for 1042 Medicaid-eligible pregnant women. METHODS: This retrospective study evaluated the impact of enhanced services on preterm birth risk reduction. Certified community health workers provided enhanced services from enrollment through six weeks postpartum. Participants attending enhanced intake and third-trimester prenatal visits comprised the Active Group (N = 632). Participants missing third-trimester visits, but participating in enhanced intake and postpartum visits, comprised the Inactive Group (N = 128). Lost Group participants attended only intake visits (N = 282). Data were collected through CMS-developed intake, third-trimester, postpartum, and exit forms. Descriptive analysis, analysis of variance, and the chi-square tests analyzed the impact of risk factors, participant characteristics, and program participation on birth outcomes. RESULTS: Active Group compared with Inactive and Lost Group participants experienced significantly lower preterm birth rates (7.64% vs 22.48% and 15.82%, P < 0.001) and therefore a significantly lower NICU admission rate compared with Inactive and Lost Groups (2.82% vs 11.85% and 5.47%, P < 0.001). CONCLUSIONS: The MCH model of enhanced prenatal care reduced preterm birth and NICU admission rates for Active Group participants. The Black Active Group participant preterm birth rate was not significantly different than other Active Group rates, but was lower than Black Inactive and Lost Group rates.

Exploring Strategies to Build Resiliency in Nurses During Work Hours.

OBJECTIVE: This pilot study investigated increasing nurse resiliency utilizing a toolkit of stress-reducing interventions on medical-surgical units at 4 hospitals. BACKGROUND: Resiliency-building activities are time consuming and undertaken outside work hours. Although the activities show a positive impact on resilience, researchers investigated whether similar results could be achieved where nurses experience work stress. METHODS: This quasi-experimental pretest and posttest interventional study used a within-subjects design. Provided toolkits included written instructions to carry out the study. Nurses completed surveys at baseline, at 10 time points over a 6-week period, and at study conclusion. RESULTS: The Connor-Davidson Resilience Scale-10 scores increased significantly at follow-up (P < .02). Self-reported stress levels decreased over the 10 shifts with continued use of the interventions. CONCLUSION: Using stress-reducing interventions during work decreased stress and increased resiliency, thereby offering nurse leaders additional options to promote a healthy workforce at the bedside.

Building nurse resilience in the workplace.

AIMS: The aims of the study were 1) to replicate the research based on the pilot study; 2) to increase resilience in nurses working on all units at four hospitals and 3) to determine which interventions were preferred and most effective. BACKGROUND: Work stress mediates resilience and resilience moderates work stress. Resilience building activities in the literature are often time consuming, complex and done outside work hours. This study investigated use of portable, accessible and brief interventions by nurses to decrease stress and increase resilience during work hours. METHODS: This study used a cross sectional, longitudinal, repeated measures survey design. The study took place in October 2018 to January 2019. Toolkits included written instructions for completing the study protocol, and six activities. Nurses completed surveys at baseline, at 10 time points over a four- to six-week period, and at study conclusion. RESULTS: Connor-Davidson Resilience Scale-10 instrument scores showed resilience increased significantly at four weeks and the effect continued at three months (p < .02). Self-reported stress levels decreased over the study period and nurses self-selected to continue use of the interventions. CONCLUSION: The interventions used during work hours decreased self-reported stress and increased resilience. Nurse leaders may easily adopt these options to promote a less stressed workforce. Resilience can increase the ability of nurses to tolerate high stress in the workplace, which may decrease burnout and turnover. In the pandemic, resilience is even more important as hospitals struggle to retain nurses.

Interpersonal Violence: What Undergraduate Nursing Students Know.

A program evaluation of undergraduate nursing curricula content was completed and survey developed to assess undergraduate nursing students' knowledge about interpersonal violence. Students electively answered a 43-question survey regarding interpersonal violence as a public health problem. The sample included 104 traditional and accelerated undergraduate nursing students. Increasing scores during undergraduate program enrollment suggests that students receive some content on violence from the undergraduate curriculum. This study provides data about curricular deficits and proposes content revisions to prepare nursing students to address violence in patient populations.

Arabidopsis CPK6 positively regulates ABA signaling and drought tolerance through phosphorylating ABA-responsive element-binding factors.

Abscisic acid (ABA) regulates numerous developmental processes and drought tolerance in plants. Calcium-dependent protein kinases (CPKs) are important Ca2+ sensors playing crucial roles in plant growth and development as well as responses to stresses. However, the molecular mechanisms of many CPKs in ABA signaling and drought tolerance remain largely unknown. Here we combined protein interaction studies, and biochemical and genetic approaches to identify and characterize substrates that were phosphorylated by CPK6 and elucidated the mechanism that underlines the role of CPK6 in ABA signaling and drought tolerance. The expression of CPK6 is induced by ABA and dehydration. Two cpk6 T-DNA insertion mutants are insensitive to ABA during seed germination and root elongation of seedlings; in contrast, overexpression of CPK6 showed the opposite phenotype. Moreover, CPK6-overexpressing lines showed enhanced drought tolerance. CPK6 interacts with and phosphorylates a subset of core ABA signaling-related transcription factors, ABA-responsive element-binding factors (ABFs/AREBs), and enhances their transcriptional activities. The phosphorylation sites in ABF3 and ABI5 were also identified through MS and mutational analyses. Taken together, we present evidence that CPK6 mediates ABA signaling and drought tolerance through phosphorylating ABFs/AREBs. This work thus uncovers a rather conserved mechanism of calcium-dependent Ser/Thr kinases in ABA signaling.

Neuroprotective Effects of Four Phenylethanoid Glycosides on H2O2-Induced Apoptosis on PC12 Cells via the Nrf2/ARE Pathway.

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key transcription factor against oxidative stress and neurodegenerative disorders. Phenylethanoid glycosides (PhGs; salidroside, acteoside, isoacteoside, and echinacoside) exhibit antioxidant and neuroprotective bioactivities. This study was performed to investigate the neuroprotective effect and molecular mechanism of PhGs. PhGs pretreatment significantly suppressed H2O2-induced cytotoxicity in PC12 cells by triggering the nuclear translocation of Nrf2 and reversing the downregulated protein expression of heme oxygenase 1 (HO-1), NAD(P)H quinone oxidoreductase 1 (NQO1), glutamate cysteine ligase-catalytic subunit (GCLC), and glutamate-cysteine ligase modifier subunit (GCLM). Nrf2 siRNA or HO-1 inhibitor zinc protoporphyrin (ZnPP) reduced the neuroprotective effect. PhGs showed potential interaction with the Nrf2 binding site in Kelch-like ECH-association protein 1 (Keap1). This result may support the hypothesis that PhGs are activators of Nrf2. We demonstrated the potential binding between PhGs and the Keap1-activated Nrf2/ARE pathway, and that PhGs with more glycosides had enhanced effects.

Effects of Health Insurance Among Patients on Hepatitis C Treatment Along the Texas-Mexico Border.

The incidence and prevalence of hepatitis C virus (HCV) is steadily increasing across the world. Increasing morbidity and mortality rates associated with HCV are influencing research on treatment outcomes. The purpose of this project was to examine the effect of health insurance status and office visit compliance on sustained virologic response (SVR) in adult patients living along the Texas-Mexico border treated for HCV and who received dual or triple medication therapy between January 2010 and August 2013. The objective of this project was to determine whether there is an association between health insurance status, and/or office visit compliance, and SVR. We conducted a longitudinal retrospective chart review pilot study of patients who underwent treatment with dual and triple therapy in a border community in Texas. Results revealed that lack of insurance did not affect SVR in the Texas Tech University Health Sciences Center El Paso-based clinic setting due to enrollment into a managed healthcare program. Providing a financial benefit may improve treatment compliance of HCV-infected individuals, reduce overall cost, and improve the patient's quality of life.

Effects of Recording Food Intake Using Cell Phone Camera Pictures on Energy Intake and Food Choice.

BACKGROUND: The well-documented increases in obesity and unhealthy dietary practices substantiate the need for evidence-based tools that can help people improve their dietary habits. The current spread of mobile phone-embedded cameras offers new opportunities for recording food intake. Moreover, the act of taking pictures of food consumed may enhance visual consciousness of food choice and quantity. The present study aimed to assess the effect of using cell phone pictures to record food intake on energy intake and food choice in college students. The effectiveness and acceptability of cell phone picture-based diet recording also was assessed. METHODS: A repeated measures crossover design was used. One group of participants entered their food intake online during 3 days based on their memory, although a second group recorded their food intake using cell phone pictures as their reference. Participants then crossed over to complete 3 more days of diet recording using the alternate method. Focus groups were conducted to obtain feedback on the effectiveness and acceptability of cell phone picture-based diet recording. RESULTS: Intake of meat and vegetable servings were significantly higher in the memory period compared with the cell phone period, regardless of the order. Results from the focus group indicated a positive attitude toward the use of cell phone pictures in recording food intake and an increased awareness of food choice and portion size. LINKING EVIDENCE TO ACTION: Cell phone pictures may be an easy, relevant, and accessible method of diet self-monitoring when aiming at dietary changes. Future trials should combine this technique with healthy eating education.

Effectiveness of a Technology-Based Intervention to Teach Evidence-Based Practice: The EBR Tool.

BACKGROUND: As the world becomes increasingly digital, advances in technology have changed how students access evidence-based information. Research suggests that students overestimate their ability to locate quality online research and lack the skills needed to evaluate the scientific literature. Clinical nurses report relying on personal experience to answer clinical questions rather than searching evidence-based sources. To address the problem, a web-based, evidence-based research (EBR) tool that is usable from a computer, smartphone, or iPad was developed and tested. The purpose of the EBR tool is to guide students through the basic steps needed to locate and critically appraise the online scientific literature while linking users to quality electronic resources to support evidence-based practice (EBP). METHODS: Testing of the tool took place in a mixed-method, quasi-experimental, and two-population randomized controlled trial (RCT) design in a U.S. and Middle East university. RESULTS: A statistically significant improvement in overall research skills was supported in the quasi-experimental nursing student group and RCT nutrition student group using the EBR tool. A statistically significant proportional difference was supported in the RCT nutrition and PharmD intervention groups in participants' ability to distinguish the credibility of online source materials compared with controls. The majority of participants could correctly apply PICOTS to a case study when using the tool. CONCLUSIONS: The data from this preliminary study suggests that the EBR tool enhanced student overall research skills and selected EBP skills while generating data for assessment of learning outcomes. LINKING EVIDENCE TO ACTION: The EBR tool places evidence-based resources at the fingertips of users by addressing some of the most commonly cited barriers to research utilization while exposing users to information and online literacy standards of practice, meeting a growing need within nursing curricula.

Eight-year outcomes of a program for early prevention of cardiovascular events: a growth-curve analysis.

BACKGROUND: Early identification of cardiovascular diseases allows us to prevent the progression of these diseases. The Bale/Doneen Method, a prevention and treatment program for heart attacks and ischemic strokes, has been adopted nationally in primary care and specialty clinics. OBJECTIVES: The main purpose of this study was to evaluate the effect of the Bale/Doneen Method on lipoproteins and carotid intima-media thickness (IMT) for cardiovascular disease prevention and reduction. A secondary purpose was to illustrate the use of latent growth-curve analysis in studying trajectories of clinical outcomes and biomarkers in individual patients over time. METHOD: This retrospective analysis is based on 576 patients at a nurse-managed ambulatory clinic who received the heart attack prevention and treatment program from 2000 to 2008. All patients were white; 61% were men; mean age was 55.5 years. Outcome measures include hemoglobin A1c, fasting blood sugar, plaque burden score (PBS), high-density lipoprotein, low-density lipoprotein (LDL), mean carotid artery IMT, and lipoprotein-associated phospholipase A2 test results. Latent growth-curve analysis was used in modeling changes in these outcome measures. RESULTS: On average, mean IMT score decreased by 0.01 per year (P < .001), PBS decreased by 0.17 per year (P < .001), LDL decreased by 5.19 per year (P < .001), and lipoprotein-associated phospholipase A2 decreased by 3.6 per year (P < .05). Hemoglobin A1c increased by 0.04 per year (P < .001). Significant sex and age differences in the initial level and/or rate of change of mean IMT, PBS, fasting blood sugar, high-density lipoprotein, and LDL scores were found. DISCUSSION: The current findings suggest that the Bale/Doneen Method is effective in generating a positive effect on the atherosclerotic disease process by achieving regression of disease in the carotid arteries.

Decitabine induces IRF7-mediated immune responses in p53-mutated triple-negative breast cancer: a clinical and translational study.

p53 is mutated in half of cancer cases. However, no p53-targeting drugs have been approved. Here, we reposition decitabine for triple-negative breast cancer (TNBC), a subtype with frequent p53 mutations and extremely poor prognosis. In a retrospective study on tissue microarrays with 132 TNBC cases, DNMT1 overexpression was associated with p53 mutations (P = 0.037) and poor overall survival (OS) (P = 0.010). In a prospective DEciTabinE and Carboplatin in TNBC (DETECT) trial (NCT03295552), decitabine with carboplatin produced an objective response rate (ORR) of 42% in 12 patients with stage IV TNBC. Among the 9 trialed patients with available TP53 sequencing results, the 6 patients with p53 mutations had higher ORR (3/6 vs. 0/3) and better OS (16.0 vs. 4.0 months) than the patients with wild-type p53. In a mechanistic study, isogenic TNBC cell lines harboring DETECT-derived p53 mutations exhibited higher DNMT1 expression and decitabine sensitivity than the cell line with wild-type p53. In the DETECT trial, decitabine induced strong immune responses featuring the striking upregulation of the innate immune player IRF7 in the p53-mutated TNBC cell line (upregulation by 16-fold) and the most responsive patient with TNBC. Our integrative studies reveal the potential of repurposing decitabine for the treatment of p53-mutated TNBC and suggest IRF7 as a potential biomarker for decitabine-based treatments.

Characterization of the generic mutant p53-rescue compounds in a broad range of assays.

Dozens of compounds that rescue tumor-associated mutant p53 have been reported. Xiao et al. perform 10 assays to evaluate effectiveness of the mutant p53-rescue compounds side-by-side but do not detect reliable rescue in any assay for the evaluated compounds, except for ATO and its analog PAT.

Effectiveness of cell phones and mypyramidtracker.gov to estimate fruit and vegetable intake.

AIM AND BACKGROUND: Inadequate fruit and vegetable intake is linked to leading causes of global mortality and rise in obesity. Measuring fruit and vegetable intake is problematic. Advances in cell phone technologies may improve the accuracy and ease of recording diet. This study tested the effectiveness of using cell phones with digital pictures to prompt memory and mypyramidtracker.gov to estimate self-reported fruit and vegetable intake in 69 college students. METHODS: A repeated measures design was used. Focus groups provided feedback on the acceptability, usability, and feasibility of cell phones for diet recording in this population. RESULTS: A statistically significant difference in fruit and vegetable scores, F(1, 58)=4.64, p=.04, was supported between cell phone use for short-term memory prompt and mypyramidtracker.gov alone. CONCLUSIONS: Cell phone pictures improved memory and accuracy of recall when using an online self-reported interactive diet record and was considered an easy, relevant, and accessible way to record diet.

Interprofessional Collaborative Practice: Management of Chronic Disease and Mental Health Issues in Primary Care.

This case study describes the process of implementing and evaluating an interprofessional collaborative practice (IPCP) program for primary care and behavioral health integration focused on chronic disease management. The result was a strong IPCP program in a nurse-led federally qualified health center serving medically underserved populations. The IPCP program at the Larry Combest Community Health and Wellness Center at the Texas Tech University Health Sciences Center spanned >10 years of planning, development, and implementation, supported by demonstration, grants, and cooperative grants from the Health Resources and Services Administration. The program launched 3 projects: a patient navigation program, an IPCP program for chronic disease management, and a program for primary care and behavioral health integration. We established 3 evaluation domains to track the outcomes of the program: TeamSTEPPS education outcomes (Team Strategies and Tools to Enhance Performance and Patient Safety), process/service measures, and patient clinical and behavioral measures. TeamSTEPPS outcomes were evaluated before and after training on a 5-point Likert scale (1 = strongly disagree, 5 = strongly agree). Mean (SD) scores increased significantly in team structure (4.2 [0.9] vs 4.7 [0.5]; P < .001), situation monitoring (4.2 [0.8] vs 4.6 [0.5]; P = .002), and communication (4.1 [0.8] vs 4.5 [0.5]; P = .001). From 2014 to 2020, the rate of depression screening and follow-up improved from 16% to 91%, and the hypertension control rate improved from 50% to 62%. Lessons learned include recognizing partner contributions and the worth of each team member. Our program evolved with the help of networks, champions, and collaborative partners. Program outcomes show the positive impact of a team-based IPCP model on health outcomes among medically underserved populations.

AcGlcAs: A Novel P53-Targeting Arsenical with Potent Cellular Uptake and Cancer Cell Selectivity.

Arsenic trioxide (ATO) targets PML/RARα and leads to miraculous success in treating acute promyelocytic leukemia. Notably, ATO also targets p53, the most frequently mutated protein in cancers, through a similar binding mechanism. However, p53-targeting ATO trials are challenging due to the poor cellular uptake and cancer selectivity of ATO. Here, we analyzed the structure-activity relationship of arsenicals and rationally developed a novel arsenical (designated AcGlcAs) by conjugating arsenic to sulfur atoms and tetraacetyl-ß-d-thioglucose. AcGlcAs exhibited remarkable cellular uptake through a thiol-mediated pathway (maximally 127-fold higher than ATO), thereby potently targeting PML/RARα and mutant p53. Among the 55 tested cell lines, AcGlcAs preferentially killed cancer lines rather than normal lines. In preclinical studies, AcGlcAs significantly extended the survival of mice bearing a xenograft tumor with p53 mutation while showing high plasma stability and oral bioavailability. Thus, AcGlcAs is a potential clinical candidate for precisely treating numerous p53-mutated cancers.

Arsenic trioxide extends survival of Li-Fraumeni syndrome mimicking mouse.

Li-Fraumeni syndrome (LFS) is characterized by germline mutations occurring on one allele of genome guardian TP53. It is a severe cancer predisposition syndrome with a poor prognosis, partly due to the frequent development of subsequent primary tumors following DNA-damaging therapies. Here we explored, for the first time, the effectiveness of mutant p53 rescue compound in treating LFS-mimicking mice harboring a deleterious p53 mutation. Among the ten p53 hotspot mutations in IARC LFS cohorts, R282W is one of the mutations predicting the poorest survival prognosis and the earliest tumor onset. Among the six clinical-stage mutant p53 rescue compounds, arsenic trioxide (ATO) effectively restored transactivation activity to p53-R282W. We thus constructed a heterozygous Trp53 R279W (corresponding to human R282W) mouse model for the ATO treatment study. The p53R279W/+ (W/+) mice exhibited tumor onset and overall survival well mimicking the ones of human LFS. Further, 35 mg/L ATO addition in drink water significantly extended the median survival of W/+ mice (from 460 to 596 days, hazard ratio = 0.4003, P = 0.0008). In the isolated tumors from ATO-treated W/+ mice, the representative p53 targets including Cdkn1a, Mdm2, and Tigar were significantly upregulated, accompanying with a decreased level of the proliferation marker Ki67 and increased level of apoptosis marker TUNEL. Together, the non-genotoxic treatment of p53 rescue compound ATO holds promise as an alternative for LFS therapeutic.

Diverse rescue potencies of p53 mutations to ATO are predetermined by intrinsic mutational properties.

Tumor suppressor p53 is inactivated by thousands of heterogeneous mutations in cancer, but their individual druggability remains largely elusive. Here, we evaluated 800 common p53 mutants for their rescue potencies by the representative generic rescue compound arsenic trioxide (ATO) in terms of transactivation activity, cell growth inhibition, and mouse tumor-suppressive activities. The rescue potencies were mainly determined by the solvent accessibility of the mutated residue, a key factor determining whether a mutation is a structural one, and the temperature sensitivity, the ability to reassemble the wild-type DNA binding surface at a low temperature, of the mutant protein. A total of 390 p53 mutants were rescued to varying degrees and thus were termed as type 1, type 2a, and type 2b mutations, depending on the degree to which they were rescued. The 33 type 1 mutations were rescued to amounts comparable to the wild type. In PDX mouse trials, ATO preferentially inhibited growth of tumors harboring type 1 and type 2a mutants. In an ATO clinical trial, we report the first-in-human mutant p53 reactivation in a patient harboring the type 1 V272M mutant. In 47 cell lines derived from 10 cancer types, ATO preferentially and effectively rescued type 1 and type 2a mutants, supporting the broad applicability of ATO in rescuing mutant p53. Our study provides the scientific and clinical communities with a resource of the druggabilities of numerous p53 mutations (www.rescuep53.net) and proposes a conceptual p53-targeting strategy based on individual mutant alleles rather than mutation type.

Transformacion Para Salud: a patient navigation model for chronic disease self-management.

Increased cost of chronic illnesses in United States is an urgent call to develop a cost effective approach to improve chronic disease self-management, especially among vulnerable populations. An emerging role for professionals and paraprofessionals is the patient navigator. We present an example of a conceptual framework, Transformation for Health, developed to underpin the training of certified community health workers (CHW) to deliver health care, preventive services, and health education for underserved populations to promote chronic disease self-management. Transformacion Para Salud (TPS), a patient navigation model for chronic disease self-management, was a two year demonstration program to develop a culturally sensitive intervention to facilitate patient behavior changes. Patients involved in the TPS intervention showed improvements in clinical and behavioral outcomes after twelve months of intervention. This article describes the conceptual basis and implementation of the TPS and discusses program evaluation, specific intervention outcomes, and implications for practice. Use of CHWs in the patient navigator role demonstrated a cost effective method to improve access to quality, cost-effective, primary health care services as well as to facilitate chronic disease self-management.