Mechanism of 6-Hydroxynicotinate 3-Monooxygenase, a Flavin-Dependent Decarboxylative Hydroxylase Involved in Bacterial Nicotinic Acid Degradation.

6-Hydroxynicotinate 3-monooxygenase (NicC) is a Group A FAD-dependent monooxygenase that catalyzes the decarboxylative hydroxylation of 6-hydroxynicotinic acid (6-HNA) to 2,5-dihydroxypyridine (2,5-DHP) with concomitant oxidation of NADH in nicotinic acid degradation by aerobic bacteria. Two mechanisms for the decarboxylative hydroxylation half-reaction have been proposed [Hicks, K., et al. (2016) Biochemistry 55, 3432-3446]. Results with Bordetella bronchiseptica RB50 NicC here show that a homocyclic analogue of 6-HNA, 4-hydroxybenzoic acid (4-HBA), is decarboxylated and hydroxylated by NicC with a 420-fold lower catalytic efficiency than is 6-HNA. The 13( V/ K), measured with wild-type NicC by isotope ratio mass spectrometry following the natural abundance of 13C in the CO2 product, is inverse for both 6-HNA (0.9989 ± 0.0002) and 4-HBA (0.9942 ± 0.0004) and becomes negligible (0.9999 ± 0.0004) for 5-chloro-6-HNA, an analogue that is 10-fold more catalytically efficient than 6-HNA. Covalently bound 6-HNA complexes of NicC are not observed by mass spectrometry. Comparative steady-state kinetic and Kd6HNA analyses of active site NicC variants (C202A, H211A, H302A, H47E, Y215F, and Y225F) identify Tyr215 and His47 as critical determinants both of 6-HNA binding ( KdY215F/ KdWT > 240; KdH47E/ KdWT > 350) and in coupling rates of 2,5-DHP and NAD+ product formation ([2,5-DHP]/[NAD+] = 1.00 (WT), 0.005 (Y215F), and 0.07 (H47E)]. Results of these functional analyses are in accord with an electrophilic aromatic substitution reaction mechanism in which His47-Tyr215 may serve as the general base to catalyze substrate hydroxylation and refine the structural model for substrate binding by NicC.

Oral nitrite restores age-dependent phenotypes in eNOS-null mice.

Alterations in the synthesis and bioavailability of NO are central to the pathogenesis of cardiovascular and metabolic disorders. Although endothelial NO synthase-derived (eNOS-derived) NO affects mitochondrial long-chain fatty acid ß-oxidation, the pathophysiological significance of this regulation remains unclear. Accordingly, we determined the contributions of eNOS/NO signaling in the adaptive metabolic responses to fasting and in age-induced metabolic dysfunction. Four-month-old eNOS-/- mice are glucose intolerant and exhibit serum dyslipidemia and decreased capacity to oxidize fatty acids. However, during fasting, eNOS-/- mice redirect acetyl-CoA to ketogenesis to elevate circulating levels of ß-hydroxybutyrate similar to wild-type mice. Treatment of 4-month-old eNOS-/- mice with nitrite for 10 days corrected the hypertension and serum hyperlipidemia and normalized the rate of fatty acid oxidation. Fourteen-month-old eNOS-/- mice exhibited metabolic derangements, resulting in reduced utilization of fat to generate energy, lower resting metabolic activity, and diminished physical activity. Seven-month administration of nitrite to eNOS-/- mice reversed the age-dependent metabolic derangements and restored physical activity. While the eNOS/NO signaling is not essential for the metabolic adaptation to fasting, it is critical for regulating systemic metabolic homeostasis in aging. The development of age-dependent metabolic disorder is prevented by low-dose replenishment of bioactive NO.

Micro-cultural customization of organ donation propagation messages.

OBJECTIVE: Organ transplantation is plagued by limited availability of organs. This study investigated the effect of messages promoting organ donation which were customized according to the language-defined micro-cultures in Switzerland. METHODS: Community-, informative-, and emotional-oriented messages were carried by conventional flyers. A 3 × 3 between-subjects experiment was conducted with short- and long-term willingness to donate, long-term signing of organ donation card and long-term interpersonal communication on organ donation as outcome variables. RESULTS: The culturally customized interventions appeared to have no immediate effect and consequently no differential effect on willingness to donate organs and on signing a donor card. Among the Swiss Germans, of the three messages, the community-oriented one instigated less interpersonal communication. CONCLUSION: Findings are consistent with a mechanism in which the message does not have an immediate effect on willingness to donate organs but motivates further thought and related behaviors that lead to higher commitment and later increased willingness to donate. PRACTICE IMPLICATIONS: Targeting not only the message but also the objective that drives the messages must be considered. Campaigns should include elements that build on the unfolding commitment process to promote the follow-up actions that lead to greater willingness.

An empirical test of the Health Empowerment Model: Does patient empowerment moderate the effect of health literacy on health status?

OBJECTIVE: The Health Empowerment Model (Schulz & Nakamoto, 2013) advocates that the effects of health literacy and empowerment are intertwined on health outcomes. This study aims to test this assumption in the context of health status as a patient outcome. METHODS: A cross-sectional study was conducted with a sample of 302 participants between June and December 2015. The participants' health literacy (using the NVS and S-TOFHLA tests), empowerment and self-reported health status were assessed. RESULTS: The participants having a high level of patient empowerment and concurrent adequate health literacy (the so-called 'effective self-managers') reported better health status compared to patients who had either lower health literacy and/or lower empowerment scores (P<0.05). Moreover, the meaningfulness (b=0.053, t(297)=2.29, P=0.02) and competence (b=0.07, t(297)=2.47, P=0.01) sub-dimensions of patient empowerment moderated the effect of the NVS on current health status. CONCLUSION: The study provides evidence for the independence of health literacy and empowerment and partial evidence for their interaction predicting health status. PRACTICE IMPLICATIONS: Our findings highlight that health literacy and patient empowerment (in particular its competence and meaningfulness sub-facets) are crucial patient-related variables, to be taken into consideration simultaneously, during screening and health promotion campaigns fostering health status in the general population.

The doctor-patient relationship and patient resilience in chronic pain: A qualitative approach to patients' perspectives.

OBJECTIVES: To study patients' perspectives about the role of the doctor-patient relationship in promoting the resilience process. METHODS: We conducted in-depth interviews with 20 chronic pain patients. Using open-ended questions, the interviews explored aspects of the doctor-patient relationship that impacted the patients' perceptions of their resilience. Thematic analysis built on an inductive, adaptive approach to data coding was employed to organize a representation of key factors affecting resilience. RESULTS: The themes emerging from the interviews inform us about how the different aspects of the doctor-patient relationship can promote patient resilience in chronic pain. Three main themes emerged: the doctor providing psychological support, promoting patients' health literacy related to chronic pain and its treatment, and empowering the patients to cooperate in finding the right treatment. This fosters patients' direct outcomes (feeling validated, health literate, and empowered), which, in turn, lead to adaptive coping responses and day-to-day disease management. These direct outcomes are crucial for patients to maintain socially and personally meaningful activities and their functional (physical) capacity. DISCUSSION: A doctor-patient relationship following the precepts of the patient-centered care is a significant resource that can lead to increased patient resilience. Thus, future interventions promoting patient resilience might consider addressing the doctor-patient relationship.

Is patient empowerment the key to promote adherence? A systematic review of the relationship between self-efficacy, health locus of control and medication adherence.

BACKGROUND: Current health policies emphasize the need for an equitable doctor-patient relationship, and this requires a certain level of patient empowerment. However, a systematic review of the empirical evidence on how empowerment affects medication adherence-the extent to which patients follow the physician's prescription of medication intake-is still missing. The goal of this systematic review is to sum up current state-of-the-art knowledge concerning the relationship between patient empowerment and medication adherence across medical conditions. As our conceptualization defines health locus of control and self-efficacy as being crucial components of empowerment, we explored the relationship between these two constructs and medication adherence. METHODS: Relevant studies were retrieved through a comprehensive search of Medline and PsychINFO databases (1967 to 2017). In total, 4903 publications were identified. After applying inclusion and exclusion criteria and quality assessment, 154 articles were deemed relevant. Peer-reviewed articles, written in English, addressing the relationship between empowerment (predictor) and medication adherence (outcome) were included. FINDINGS: High levels of self-efficacy and Internal Health Locus of Control are consistently found to promote medication adherence. External control dimensions were found to have mainly negative (Chance and God attributed control beliefs) or ambiguous (Powerful others attributed control beliefs) links to adherence, except for Doctor Health Locus of Control which had a positive association with medication adherence. To fully capture how health locus of control dimensions influence medication adherence, the interaction between the sub-dimensions and the attitudinal symmetry between the doctor and patient, regarding the patient's control over the disease management, can provide promising new alternatives. DISCUSSION: The beneficial effect of patients' high internal and concurrent physician-attributed control beliefs suggests that a so-called "joint empowerment" approach can be suitable in order to foster medication adherence, enabling us to address the question of control as a versatile component in the doctor-patient relationship.

Intentional and Unintentional Medication Non-Adherence in Hypertension: The Role of Health Literacy, Empowerment and Medication Beliefs.

BACKGROUND: Medication non-adherence is a major public health issue, creating obstacles to effective treatment of hypertension. Examining the underlying factors of deliberate and non-deliberate non-adherence is crucial to address this problem. Thus, the goal of the present study is to assess the socio-demographic, clinical and psychological determinants of intentional and unintentional non-adherence. DESIGN AND METHODS: A cross-sectional survey was conducted between March, 2015 and April, 2016. The sample consisted of hypertension patients holding at least one medical prescription (N=109). Measurements assessed patients' medication adherence, health literacy, empowerment, self-efficacy, medication beliefs, and patients' acceptance of their doctor's advice, socio-demographic and clinical characteristics. RESULTS: Patients who occasionally engaged in either intentional or unintentional non-adherence reported to have lower adherence selfefficacy, higher medication concern beliefs, lower meaningfulness scores and were less likely to accept the doctor's treatment recommendations. Patients who occasionally engaged in unintentional nonadherence were younger and had experienced more side effects compared to completely adherent patients. Adherence self-efficacy was a mediator of the effect of health literacy on patients' medication adherence and acceptance of the doctor's advice was a covariate. CONCLUSIONS: Regarding the research implications, health literacy and adherence self-efficacy should be assessed simultaneously when investigating the factors of non-adherence. Regarding the practical implications, adherence could be increased if physicians i) doublecheck whether their patients accept the treatment advice given and ii) if they address patients' concerns about medications. These steps could be especially important for patients characterized with lower self-efficacy, as they are more likely to engage in occasional nonadherence.

The effect of social support features and gamification on a Web-based intervention for rheumatoid arthritis patients: randomized controlled trial.

BACKGROUND: Rheumatoid arthritis (RA) is chronic systematic disease that affects people during the most productive period of their lives. Web-based health interventions have been effective in many studies; however, there is little evidence and few studies showing the effectiveness of online social support and especially gamification on patients' behavioral and health outcomes. OBJECTIVE: The aim of this study was to look into the effects of a Web-based intervention that included online social support features and gamification on physical activity, health care utilization, medication overuse, empowerment, and RA knowledge of RA patients. The effect of gamification on website use was also investigated. METHODS: We conducted a 5-arm parallel randomized controlled trial for RA patients in Ticino (Italian-speaking part of Switzerland). A total of 157 patients were recruited through brochures left with physicians and were randomly allocated to 1 of 4 experimental conditions with different types of access to online social support and gamification features and a control group that had no access to the website. Data were collected at 3 time points through questionnaires at baseline, posttest 2 months later, and at follow-up after another 2 months. Primary outcomes were physical activity, health care utilization, and medication overuse; secondary outcomes included empowerment and RA knowledge. All outcomes were self-reported. Intention-to-treat analysis was followed and multilevel linear mixed models were used to study the change of outcomes over time. RESULTS: The best-fit multilevel models (growth curve models) that described the change in the primary outcomes over the course of the intervention included time and empowerment as time-variant predictors. The growth curve analyses of experimental conditions were compared to the control group. Physical activity increased over time for patients having access to social support sections plus gaming (unstandardized beta coefficient [B]=3.39, P=.02). Health care utilization showed a significant decrease for patients accessing social support features (B=-0.41, P=.01) and patients accessing both social support features and gaming (B=-0.33, P=.03). Patients who had access to either social support sections or the gaming experience of the website gained more empowerment (B=2.59, P=.03; B=2.29, P=.05; respectively). Patients who were offered a gamified experience used the website more often than the ones without gaming (t91=-2.41, P=.02; U=812, P=.02). CONCLUSIONS: The Web-based intervention had a positive impact (more desirable outcomes) on intervention groups compared to the control group. Social support sections on the website decreased health care utilization and medication overuse and increased empowerment. Gamification alone or with social support increased physical activity and empowerment and decreased health care utilization. This study provides evidence demonstrating the potential positive effect of gamification and online social support on health and behavioral outcomes. TRIAL REGISTRATION: International Standard Randomized Controlled Trial Number (ISRCTN): 57366516; http://www.controlled-trials. com/ISRCTN57366516 (Archived by webcite at http://www.webcitation.org/6PBvvAvvV).

The impact of search engine selection and sorting criteria on vaccination beliefs and attitudes: two experiments manipulating Google output.

BACKGROUND: During the past 2 decades, the Internet has evolved to become a necessity in our daily lives. The selection and sorting algorithms of search engines exert tremendous influence over the global spread of information and other communication processes. OBJECTIVE: This study is concerned with demonstrating the influence of selection and sorting/ranking criteria operating in search engines on users' knowledge, beliefs, and attitudes of websites about vaccination. In particular, it is to compare the effects of search engines that deliver websites emphasizing on the pro side of vaccination with those focusing on the con side and with normal Google as a control group. METHOD: We conducted 2 online experiments using manipulated search engines. A pilot study was to verify the existence of dangerous health literacy in connection with searching and using health information on the Internet by exploring the effect of 2 manipulated search engines that yielded either pro or con vaccination sites only, with a group receiving normal Google as control. A pre-post test design was used; participants were American marketing students enrolled in a study-abroad program in Lugano, Switzerland. The second experiment manipulated the search engine by applying different ratios of con versus pro vaccination webpages displayed in the search results. Participants were recruited from Amazon's Mechanical Turk platform where it was published as a human intelligence task (HIT). RESULTS: Both experiments showed knowledge highest in the group offered only pro vaccination sites (Z=-2.088, P=.03; Kruskal-Wallis H test [H5]=11.30, P=.04). They acknowledged the importance/benefits (Z=-2.326, P=.02; H5=11.34, P=.04) and effectiveness (Z=-2.230, P=.03) of vaccination more, whereas groups offered antivaccination sites only showed increased concern about effects (Z=-2.582, P=.01; H5=16.88, P=.005) and harmful health outcomes (Z=-2.200, P=.02) of vaccination. Normal Google users perceived information quality to be positive despite a small effect on knowledge and a negative effect on their beliefs and attitudes toward vaccination and willingness to recommend the information (χ²5=14.1, P=.01). More exposure to antivaccination websites lowered participants' knowledge (J=4783.5, z=-2.142, P=.03) increased their fear of side effects (J=6496, z=2.724, P=.006), and lowered their acknowledgment of benefits (J=4805, z=-2.067, P=.03). CONCLUSION: The selection and sorting/ranking criteria of search engines play a vital role in online health information seeking. Search engines delivering websites containing credible and evidence-based medical information impact positively Internet users seeking health information. Whereas sites retrieved by biased search engines create some opinion change in users. These effects are apparently independent of users' site credibility and evaluation judgments. Users are affected beneficially or detrimentally but are unaware, suggesting they are not consciously perceptive of indicators that steer them toward the credible sources or away from the dangerous ones. In this sense, the online health information seeker is flying blind.

Patient behavior and the benefits of artificial intelligence: the perils of "dangerous" literacy and illusory patient empowerment.

OBJECTIVE: Artificial intelligence can provide important support of patient health. However, limits to realized benefits can arise as patients assume an active role in their health decisions. METHODS: Distinguishing the concepts of health literacy and patient empowerment, we analyze conditions that bias patient use of the Internet and limit access to and impact of artificial intelligence. RESULTS: Improving health literacy in the face of the Internet requires significant guidance. Patients must be directed toward the appropriate tools and also provided with key background knowledge enabling them to use the tools and capitalize on the artificial intelligence technology. CONCLUSION: Benefits of tools employing artificial intelligence to promote health cannot be realized without recognizing and addressing the patients' desires, expectations, and limitations that impact their Internet behavior. In order to benefit from artificial intelligence, patients need a substantial level of background knowledge and skill in information use-i.e., health literacy. PRACTICE IMPLICATIONS: It is critical that health professionals respond to patient search for information on the Internet, first by guiding their search to relevant, authoritative, and responsive sources, and second by educating patients about how to interpret the information they are likely to encounter.

Health literacy and patient empowerment in health communication: the importance of separating conjoined twins.

OBJECTIVE: Patient empowerment and health literacy have both been studied empirically, but they have hardly ever been explicitly linked. METHODS: Pertinent literature from the development of both concepts was studied, drawing not only on health care literature, but also on management research. RESULTS: This article argues that it is important to recognize that the concepts are distinct, both conceptually and empirically. At the same time, the impacts of health literacy and patient empowerment are deeply intertwined. High literacy does not necessarily entail empowerment and vice versa, and mismatches of the two can have deleterious consequences. High levels of health literacy without a corresponding high degree of patient empowerment creates an unnecessary dependence of patients on health professionals, while a high degree of empowerment without a corresponding degree of health literacy poses the risk of dangerous health choices. CONCLUSION: We discuss the importance of carefully conceptualizing both approaches, the implications for their measurement and the design of health interventions. PRACTICE IMPLICATIONS: Communication programs must include the empowerment that motivates consumers to engage and the literacy that enables them to make informed and reasoned choices.

Differential effects of health knowledge and health empowerment over patients' self-management and health outcomes: a cross-sectional evaluation.

OBJECTIVE: The role of health knowledge and empowerment in explaining behavioral and health outcomes was treated in depth in the literature, but the combined effect of these constructs has been somehow neglected. This study presents an empirical, a priori, cross-sectional evaluation of the differential effects of health knowledge and empowerment on patients' self-management and health outcomes. METHODS: This study relies on a cross-sectional design involving a total of 209 Fibromyalgia patients. Structural Equation Modeling techniques were employed to analyze the model relationships. RESULTS: Knowledge and three empowerment dimensions were found to positively impact health outcomes. However, these relationships were not mediated by self-management. Self-management, operationalized in terms of physical exercise and drug intake, was found to be a strong predictor of health outcomes. CONCLUSION: Despite the lack of support for the mediating role of self-management, a strong impact of knowledge and empowerment over health outcomes was observed. Theories of health literacy and empowerment may benefit from this result by integrating both dimensions in an overall model of behavioral and health outcomes change. PRACTICE IMPLICATIONS: Results from this study suggest that health interventions targeted to chronic patients should focus simultaneously on knowledge and empowerment, rather than favoring one of these individual constructs.

Prescription drug fatalities among women in rural Virginia: a study of medical examiner cases.

OBJECTIVE: To evaluate female drug overdose deaths from the Office of the Chief Medical Examiner, Western Virginia (1997-2003) for demographics, medical history, toxicology results, and prescribed medications. DESIGN: Autopsy reports, death investigations, and hospital/physician notes were reviewed for 330 fatal drug poisonings among women. Data were evaluated with both qualitative and quantitative methods. RESULTS: Most decedents were Caucasian (95 percent), their average age was 42.8 years, and the predominant manner and cause of death was accidental and polydrug toxicity, respectively. Drugs were identified on toxicology or assigned as a cause of death in all 330 cases. The three most common drug classes detected on toxicology were opioids (n = 239; 72.4 percent), antidepressants (n = 201; 60.9 percent), and sedative/anxiolytic/muscle relaxant (SAMR) (n = 161; 48.8 percent) with all three drug classes detected in 89 (27 percent) cases. Illicit drugs identified included cocaine (n = 33; 10 percent) and heroin (n = 3; 0.9 percent). Prescriptions for opioids, SAMR, and antidepressants were found in decedent name in 48 percent, 67.1 percent, and 58 percent of cases, respectively, and 46.1 percent of cases were prescribed at least one medication from each of those three drug classes. CONCLUSION: Although many decedents held prescriptions, and often for multiple drugs, toxicological findings indicate the frequent presence of other therapeutic drugs in the absence of a prescription. Moreover, many of these cases held simultaneous prescriptions for which there are known drug interactions. It is likely that misuse, fatal medication errors, abuse, and addiction were factors in the increased numbers of these deaths. Interventions to prevent prescription overdose deaths must involve education of both physicians and patients.

Opioid deaths in rural Virginia: a description of the high prevalence of accidental fatalities involving prescribed medications.

In rural Virginia, drug overdose deaths increased 300% from 1997 to 2003. Polydrug deaths predominate (57.9%) in this review of 893 medical examiner cases. Prescription opioids (74.0%), antidepressants (49.0%), and benzodiazepines (39.3%) were more prevalent than illicit drugs. Two-thirds of decedents were 35-54 years old; 37% were female. When compared to western Virginia metropolitan cases, polydrug abuse was more common, specific medication combinations were found, the death rate per population was higher, and fewer illicit drugs were detected. These rural prescription overdose deaths differ from urban illicit drug deaths, suggesting the need for different strategies in prevention, treatment, and intervention by clinicians and policymakers.

The rabbit in the hat: dubious argumentation and the persuasive effects of prescription drug advertising (DTCA).

There is an ongoing global debate over the potential benefits and risks of allowing direct-to-consumer advertising of prescription medicines (DTCA). The core of this debate concerns the identification of DTCA either as a beneficial procedure to be promoted or as a damaging procedure to be abolished. Economic data on DTCA suggest that this form of advertising has an impact on consumers. Based on this premise, we explore the use of argumentation theory to inquire into the reasons for this success. In particular, by combining perspectives from argumentation theory and marketing research this paper aims to test the hypothesis of whether DTCA presents information framed in potentially misleading, but persuasive, argumentative structures. We highlight and discuss the results of two studies designed to assess whether readers perceive DTCA as argumentative and, if so, which explicit and implicit elements provide groundings for the inference that consumers draw from the ads. The analysis highlights the presence in DTCA of dubious arguments (fallacies and distracting claims) that may go unnoticed. Also, it illustrates the nature of readers' wrong assumptions that arise independently from the contents of the ads. These factors seem to influence the level of the self-perceived persuasiveness of DTCA.

Prescription drug abuse among prisoners in rural Southwestern Virginia.

Non-medical use of prescription medications is on the rise across the U.S., particularly in rural areas. In this study of 233 prisoners and probationers in southwestern Virginia, we add to an emerging profile of individuals abusing prescription medications. In this retrospective review of 2000-2004 augmented Addiction Severity Index data, those abusing prescription medications reported increased illicit drug and alcohol abuse, poly-drug abuse, psychiatric problems, and arrests for property crimes. Forty percent reported abuse of OxyContin, a drug implicated in a number of deaths in this region. Compared to non-users, OxyContin users were younger, more likely to be female, and more likely to abuse benzodiazepines, methadone, cocaine, and heroin. Longevity of abuse of these other drugs belies suggestions that OxyContin was acting as a "gateway" drug leading naïve users into addiction and risk of death.

More than nation and knowledge: cultural micro-diversity and organ donation in Switzerland.

OBJECTIVE: While recent studies of organ donation have recognized cultural factors, most analyses in developed countries have focused on awareness as the critical constraint. The present paper examines this assumption and assesses the number of potential organ donors as well as their knowledge and attitudes regarding organ donation. METHODS: We conducted a telephone survey of 1509 adults using a stratified random sample of the main three language groups (German, French, and Italian) in Switzerland with oversampling of the Italian language group to compensate for its relatively small size. Because our analyses are performed separately on each language group, the oversampling does not distort our findings. RESULTS: The three language groups display substantial differences with respect to patterns of knowledge, motives, and concerns underlying their willingness to donate organs--differences that persist even in the context of strong national identity, relatively homogeneous cultural background, and the public good nature of organ donation. CONCLUSION: The results demonstrate a need to consider and address cultural factors and barriers when designing organ donation campaigns. PRACTICE IMPLICATIONS: Centrally designed organ donation campaigns are not likely to be effective and efficient. Message strategies should rather be tailored to different (micro-) cultural groups.