Tobacco quitline performance: Comparing the impacts of early cessation and proactive re-engagement on callers' smoking status at follow-up at 12 months.

INTRODUCTION: While tobacco Quitlines are effective in the promotion of smoking cessation, the majority of callers who wish to quit still fail to do so. The aim of this study was to determine if 12-month tobacco Quitline smoking cessation rates could be improved with re-engagement of callers whose first Quitline treatment failed to establish abstinence. METHODS: In an adaptive trial, 614 adult smokers, who were active duty, retired, and family of military personnel with TRICARE insurance who called a tobacco Quitline, received a previously evaluated and efficacious four-session tobacco cessation intervention with nicotine replacement therapy (NRT). At the scheduled follow-up at 3 months, callers who had not yet achieved abstinence were offered the opportunity to re-engage. This resulted in three caller groups: 1) those who were abstinent, 2) those who were still smoking but willing to re-engage with an additional Quitline treatment; and 3) individuals who were still smoking but declined re-engagement. A propensity score-adjusted logistic regression model was generated to compare past-7-day point prevalence abstinence at 12 months post Quitline consultation. RESULTS: Using a propensity score adjusted logistic regression model, comparison of the three groups resulted in higher odds of past-7-day point prevalence abstinence at follow-up at 12 months for those who were abstinent at 3 months compared to those who re-engaged (OR=9.6; 95% CI: 5.2-17.8; Bonferroni adjusted p<0.0001), and relative to those who declined re-engagement (OR=13.4; 95% CI: 6.8-26.3; Bonferroni adjusted p<0.0001). There was no statistically significant difference in smoking abstinence between smokers at 3 months who re-engaged and those who declined re-engagement (OR=1.39; 95% CI: 0.68-2.85). CONCLUSIONS: Tobacco Quitlines seeking to select a single initiative by which to maximize abstinence at follow-up at 12 months may benefit from diverting additional resources from the re-engagement of callers whose initial quit attempt failed, toward changes which increase callers' probability of success within the first 3 months of treatment. TRIAL REGISTRATION: This study is registered at clinicaltrials.gov (NCT02201810).

Partnerships as an Avenue to Translate Emerging Disease Ecology of SARS-CoV-2 to Agricultural Groups.

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and associated coronavirus disease 19 (COVID-19) has brought farmers and farmworkers the designation of "essential", while placing them into heightened vulnerability for the disease. Many factors diminish access to education and prevention technologies emerging to combat COVID-19. For farmers, advanced age and rural location play a part. Farmworkers encounter numerous additional barriers including language and cultural differences, socioeconomic pressures, and immigration status. The unusual persistence and multiple transmission pathways of SARS-CoV-2 emerging from ongoing scientific study require customization of otherwise standard prevention messaging to farmers and farmworkers to prevent infection and disease exacerbation. AgriSafe Network and Migrant Clinicians Network, both national organizations and major stakeholders in agricultural health, are on the front lines of translating science into practical prevention strategies for those providing health services to farmworkers and farmers. The partnerships pursued provide a blueprint for quickly translating emerging disease ecology to support the health of agricultural populations during the COVID-19 pandemic.

Structure-Dependent Modulation of Substrate Binding and Biodegradation Activity of Pirin Proteins toward Plant Flavonols.

Pirin is a nonheme metalloprotein that occurs widely in human tissues and is highly conserved across all taxa. Pirin proteins typically function as nuclear transcription regulators, but two Pirin orthologs, YhhW (from Escherichia coli) and hPirin (from humans) were revealed to possess enzymatic activity of degrading quercetin. The exact role of Pirin homologues and their catalytic specificity remain poorly understood. In this work, by screening against a panel of plant flavonoids, we found that both Pirins catalyze the oxidative degradation of a wide spectrum of flavonol analogues and release carbon monoxide (CO) in the process. This shows that Pirin acts on a broad range of substrates and could represent a novel dietary source of CO in vivo. Although the kinetic profiles differ substantially between two Pirins, the identified substrate structures all share a 2,3-double bond and 3-hydroxyl and 4-oxo groups on their "flavonol backbone," which contribute to the specific enzyme-substrate interaction. While hPirin is iron-dependent, YhhW is identified as a novel nickel-containing dioxygenase member of the bicupin family. Besides the expanded Pirin activity, we present the crystal structures of the native Ni-YhhW and tag-free Fe-hPirin, revealing the distinctive differences occurring at the metal-binding site. In addition, YhhW features a flexible Ω-loop near the catalytic cavity, which may help stabilize the reaction intermediates via a Ni-flavonol complex. The structure-dependent modulation of substrate binding to the catalytic cavity adds to understanding the differential dispositions of natural flavonols by human and bacterial Pirins.

Wildfire Associated Health Risks Impacting Farmers and Ranchers.

The incidence of large, uncontained wildfires in North America has increased in recent years, significantly impacting both urban and agriculturally-focused areas. The physical damage and health pressures left in the wake of uncontrolled fires has especially devastated farm and ranch operators in affected areas, prompting concern from the community of healthcare providers and advocates servicing this specialized occupational population. The AgriSafe Network, a leading health advocacy organization centered in agricultural health, conducted an interactive webinar with nationally recognized knowledge thought leaders as a response to this crisis. Results identified primary, action-critical issues as an initiatives roadmap for future focused precision research and targeted educational efforts. Think tank initiatives provide intelligible guidance that can lead to tractable interventions for agricultural populations effected by wildfires.

Quantifying the relationship between patient characteristics and involvement in developing and implementing a treatment plan.

OBJECTIVE: Improving the patient-physician relationship through patient involvement in the care may lead to improved patient safety and better health outcomes. There exists a gap in knowledge in identifying factors that affect self-reported patient involvement in individualized treatment plans. The objectives of this study were to 1) describe patients' perceptions of their involvement in the creation and implementation of their treatment plans and 2) determine if patient involvement varied by medical condition or demographic characteristics. METHODS: This study was a cross-sectional analysis of data from the "Quality of Care" module of the 2008 Health and Retirement Study (HRS). The individuals of HRS surveys were older than 50 years. One-way analyses of variance were conducted to determine differences between patient characteristics and involvement in creating a treatment plan. A linear regression was conducted to determine predictors of the summed involvement score. RESULTS: Average summed scores for each domain (shared decision-making, counseling, and follow-up) and overall involvement scores were ~50%. Linear regression showed that being non-White, older age, and diagnosed with a psychiatric condition or diabetes were predictors of increased self-reported involvement in the development and communication of a patient's treatment plan. CONCLUSION: Age, race, and having diabetes or a psychiatric condition were the major predictors affecting patient involvement in care, although overall involvement in care was low for all groups. PRACTICE IMPLICATIONS: Patient involvement in care was lower than expected and should be further studied to determine the effects of involvement on health outcomes.

Function coupling of otoferlin with GAD65 acts to modulate GABAergic activity.

Otoferlin, an integral membrane protein implicated in a late stage of exocytosis, has been reported to play a critical role in hearing although the underlying mechanisms remain elusive. However, its widespread tissue distribution infers a more ubiquitous role in synaptic vesicle trafficking. Glutamate, an excitatory neurotransmitter, is converted to its inhibitory counterpart, γ-aminobutyric acid (GABA), by L-glutamic acid decarboxylase (GAD), which exists in soluble (GAD67) and membrane-bound (GAD65) forms. For the first time, we have revealed a close association between otoferlin and GAD65 in both HEK293 and neuronal cells, including SH-SY5Y neuroblastoma and primary rat hippocampus cells, showing a direct interaction between GAD65 and otoferlin's C2 domains. In primary rat hippocampus cells, otoferlin and GAD65 co-localized in a punctate pattern within the cell body, as well as in the axon along the path of vesicular traffic. Significantly, GABA is virtually abolished in otoferlin-knockdown neuronal cells whereas otoferlin overexpression markedly increases endogenous GABA. GABA attenuation in otoferlin-knockdown primary cells is correlated with diminished L-type calcium current. This previously unknown and close correlation demonstrates that otoferlin, through GAD65, modulates GABAergic activity. The discovery of otoferlin-GAD65 functional coupling provides a new avenue for understanding the molecular mechanism by which otoferlin functions in neurological pathways.

MLN8054, a small-molecule inhibitor of Aurora A, causes spindle pole and chromosome congression defects leading to aneuploidy.

Aurora A kinase plays an essential role in the proper assembly and function of the mitotic spindle, as its perturbation causes defects in centrosome separation, spindle pole organization, and chromosome congression. Moreover, Aurora A disruption leads to cell death via a mechanism that involves aneuploidy generation. However, the link between the immediate functional consequences of Aurora A inhibition and the development of aneuploidy is not clearly defined. In this study, we delineate the sequence of events that lead to aneuploidy following Aurora A inhibition using MLN8054, a selective Aurora A small-molecule inhibitor. Human tumor cells treated with MLN8054 show a high incidence of abnormal mitotic spindles, often with unseparated centrosomes. Although these spindle defects result in mitotic delays, cells ultimately divide at a frequency near that of untreated cells. We show that many of the spindles in the dividing cells are bipolar, although they lack centrosomes at one or more spindle poles. MLN8054-treated cells frequently show alignment defects during metaphase, lagging chromosomes in anaphase, and chromatin bridges during telophase. Consistent with the chromosome segregation defects, cells treated with MLN8054 develop aneuploidy over time. Taken together, these results suggest that Aurora A inhibition kills tumor cells through the development of deleterious aneuploidy.

A phenotype-sensitizing Apoe-deficient genetic background reveals novel atherosclerosis predisposition loci in the mouse.

Therapeutic intervention for atherosclerosis has predominantly concentrated on regulating cholesterol levels; however, these therapeutics are not efficacious for all patients, suggesting that other factors are involved. This study was initiated to identify mechanisms that regulate atherosclerosis predisposition in mice other than cholesterol level regulation. To do so we performed quantitative trait locus analysis using two inbred strains that each carry the atherosclerosis phenotype-sensitizing Apoe deficiency and that have been shown to have widely disparate predilection to atherosclerotic lesion formation. One highly significant locus on chromosome 10 (LOD = 7.8) accounted for 19% of the variance in lesion area independent of cholesterol. Two additional suggestive loci were identified on chromosomes 14 (LOD = 3.2) and 19 (LOD = 3.2), each accounting for 7-8% of the lesion variance. In all, five statistically significant and suggestive loci affecting lesion size but not lipoprotein levels were identified. Many of these were recapitulated in an independent confirmatory cross. In summary, two independently performed crosses between C57BL/6 and FVB/N Apoe-deficient mice have revealed several previously unreported atherosclerosis susceptibility loci that are distinct from loci linked to lipoprotein levels.