Child Maltreatment History, Deployment-Related Traumatic Events, and Past 12-Month Cannabis Use Among Veterans in Canada.

OBJECTIVE: Cannabis use among veterans in Canada is an understudied public health priority. The current study examined cannabis use prevalence and the relationships between child maltreatment histories and deployment-related traumatic events (DRTEs) with past 12-month cannabis use including sex differences among Canadian veterans. METHOD: Data were drawn from the 2018 Canadian Armed Forces Members and Veterans Mental Health Follow-up Survey (response rate 68.7%; veterans only n = 1,992). Five child maltreatment types and 9 types of DRTEs were assessed in relation to the past 12-month cannabis use. RESULTS: The prevalence of lifetime and past 12-month cannabis use was 49.4% and 16.7%, respectively. Females were less likely than males to report lifetime cannabis use (41.9% vs. 50.4%; odds ratio [OR] 0.71; 95% CI, - 0.59 to 0.86). No sex differences were noted for past 12-month cannabis use (14.1% vs. 17.0%; OR 0.80; 95% CI, 0.60 to 1.07). Physical abuse, sexual abuse, neglect, any child maltreatment, most individual DRTEs, and any DRTE were associated with increased odds of past 12-month cannabis use after adjusting for sociodemographic and military variables. Some models were attenuated and/or nonsignificant after further adjustments for mental disorders and chronic pain conditions. Sex did not statistically significantly moderate these relationships. Cumulative effects of having experienced both child maltreatment and DRTEs compared to DRTEs alone increased the odds of past 12-month cannabis use. Statistically significant interaction effects between child maltreatment history and DRTE on cannabis use were not found. CONCLUSIONS: Child maltreatment histories and DRTEs increased the likelihood of past 12-month cannabis use among Canadian veterans. A history of child maltreatment, compared to DRTEs, indicated a more robust relationship. Understanding the links between child maltreatment, DRTEs, and cannabis use along with mental disorders and chronic pain conditions is important for developing interventions and improving health outcomes among veterans.

Adherence to Psychotropic Medication Before and During COVID-19: A Population-Wide Retrospective Observational Study.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic and associated public health measures have shifted the way people access health care. We aimed to study the effects of the COVID-19 pandemic on psychotropic medication adherence. METHODS: A retrospective cohort study using administrative data from the Manitoba Centre for Health Policy Manitoba Population Research Data Repository was conducted. Outpatients who received at least 1 prescription for an antidepressant, antipsychotic, anxiolytic/sedative-hypnotic, cannabinoid, lithium, or stimulants from 2015 to 2020 in Manitoba, Canada, were included. Adherence was measured using the proportion of individuals with a mean possession ratio of ≥0.8 over each quarter. Each quarter of 2020 after COVID-19-related health measures were implemented was compared with the expected trend using autoregression models for time series data plus indicator variables. Odds ratio of drug discontinuation among those previously adherent in 2020 was compared with each respective quarter of 2019. RESULTS: There were 1,394,885 individuals in the study population in the first quarter of 2020 (mean [SD] age, 38.9 [23.4] years; 50.3% female), with 36.1% having a psychiatric diagnosis in the preceding 5 years. Compared with the expected trend, increases in the proportions of individuals adherent to antidepressants and stimulants were observed in the fourth quarter (October-December) of 2020 (both P < 0.001). Increases in the proportions of individuals with anxiolytic and cannabinoid adherence were observed in the third quarter (July-September) of 2020 (both P < 0.05), whereas a decrease was seen with stimulants in the same quarter ( P < 0.0001). No significant changes were observed for antipsychotics. All drug classes except lithium had decreases in drug discontinuation in previously adherent patients during the pandemic compared with 2019. CONCLUSIONS: Improved adherence to most psychotropic medications in the 9 months after public health restrictions were enacted was observed. Patients who were already adherent to their psychotropic medications were less likely to discontinue them during the pandemic.

Nobiletin Prevents High-Fat Diet-Induced Dysregulation of Intestinal Lipid Metabolism and Attenuates Postprandial Lipemia.

OBJECTIVE: Nobiletin is a dietary flavonoid that improves insulin resistance and atherosclerosis in mice with metabolic dysfunction. Dysregulation of intestinal lipoprotein metabolism contributes to atherogenesis. The objective of the study was to determine if nobiletin targets the intestine to improve metabolic dysregulation in both male and female mice. Approach and Results: Triglyceride-rich lipoprotein (TRL) secretion, intracellular triglyceride kinetics, and intestinal morphology were determined in male and female LDL (low-density lipoprotein) receptor knockout (Ldlr-/-), and male wild-type mice fed a standard laboratory diet or high-fat, high-cholesterol (HFHC) diet ± nobiletin using an olive oil gavage, radiotracers, and electron microscopy. Nobiletin attenuated postprandial TRL levels in plasma and enhanced TRL clearance. Nobiletin reduced fasting jejunal triglyceride accumulation through accelerated TRL secretion and lower jejunal fatty acid synthesis with no impact on fatty acid oxidation. Fasting-refeeding experiments revealed that nobiletin led to higher levels of phosphorylated AKT (protein kinase B) and FoxO1 (forkhead box O1) and normal Srebf1c expression indicating increased insulin sensitivity. Intestinal length and weight were diminished by HFHC feeding and restored by nobiletin. Both fasting and postprandial plasma GLP-1 (glucagon-like peptide-1; and likely GLP-2) were elevated in response to nobiletin. Treatment with a GLP-2 receptor antagonist, GLP-2(3-33), reduced villus length in HFHC-fed mice but did not impact TRL secretion in any diet group. In contrast to males, nobiletin did not improve postprandial lipid parameters in female mice. CONCLUSIONS: Nobiletin opposed the effects of the HFHC diet by normalizing intestinal de novo lipogenesis through improved insulin sensitivity. Nobiletin prevents postprandial lipemia because the enhanced TRL clearance more than compensates for increased TRL secretion.

Global change scenarios in coastal river deltas and their sustainable development implications.

Deltas play a critical role in the ambition to achieve global sustainable development given their relatively large shares in population and productive croplands, as well as their precarious low-lying position between upstream river basin development and rising seas. The large pressures on these systems risk undermining the persistence of delta societies, economies, and ecosystems. We analyse possible future development in 49 deltas around the globe under the Shared Socio-economic and Representative Concentration Pathways until 2100. Population density, urban fraction, and total and irrigated cropland fraction are three to twelve times greater in these deltas, on average, than in the rest of the world. Maximum river water discharges are projected to increase by 11-33 % and river sediment discharges are projected to decrease 26-37 % on average, depending on the scenario. Regional sea-level rise reaches almost 1.0 m by 2100 for certain deltas in the worst-case scenario, increasing to almost 2.0 m of relative rise considering land subsidence. Extreme sea levels could be much higher still-reaching over 4.0 m by 2100 for six of the 49 deltas analysed. Socio-economic conditions to support adaptation are the weakest among deltas with the greatest pressures, compounding the challenge of sustainable development. Asian and African deltas stand out as having heightened socio-economic challenges-huge population and land use pressures in most Asian deltas and the Nile delta; low capacity for adaptation in most African deltas and the Irrawaddy delta. Although, deltas in other parts of the world are not immune from these and other pressures, either. Because of unique pressures and processes operating in deltas, as in other "hotspots" such as small islands, mountains, and semi-arid areas, we recommend greater consideration and conceptualisation of environmental processes in global sustainable development agendas and in the Integrated Assessment Models used to guide global policy.

Prevalence and Correlates of Military Sexual Trauma in Service Members and Veterans: Results From the 2018 Canadian Armed Forces Members and Veterans Mental Health Follow-up Survey.

INTRODUCTION: Military sexual trauma (MST) is an ongoing problem. We used a 2002 population-based sample, followed up in 2018, to examine: (1) the prevalence of MST and non-MST in male and female currently serving members and veterans of the Canadian Armed Forces, and (2) demographic and military correlates of MST and non-MST. METHODS: Data came from the 2018 Canadian Armed Forces Members and Veterans Mental Health Follow-up Survey (n = 2,941, ages 33 years + ). Individuals endorsing sexual trauma were stratified into MST and non-MST and compared to individuals with no sexual trauma. The prevalence of lifetime MST was computed, and correlates of sexual trauma were examined using multinomial regression analyses. RESULTS: The overall prevalence of MST was 44.6% in females and 4.8% in males. Estimates were comparable between currently serving members and veterans. In adjusted models in both sexes, MST was more likely among younger individuals (i.e., 33-49 years), and MST and non-MST were more likely in those reporting more non-sexual traumatic events. Among females, MST and non-MST were more likely in those reporting lower household income, non-MST was less likely among Officers, and MST was more likely among those with a deployment history and serving in an air environment. Unwanted sexual touching by a Canadian military member or employee was the most prevalent type and context of MST. INTERPRETATION: A high prevalence of MST was observed in a follow-up sample of Canadian Armed Forces members and veterans. Results may inform further research as well as MST prevention efforts.

Neuroticism as a moderator of symptom-related distress and depression in 4 noncancer end-of-life populations.

OBJECTIVES: Neuroticism is a significant predictor of adverse psychological outcomes in patients with cancer. Less is known about how this relationship manifests in those with noncancer illness at the end-of-life (EOL). The objective of this study was to examine the impact of neuroticism as a moderator of physical symptoms and development of depression in patients with amyotrophic lateral sclerosis (ALS), chronic obstructive pulmonary disease (COPD), end-stage renal disease (ESRD), and frailty in the last 6 months of life. METHODS: We met this objective using secondary data collected in the Dignity and Distress across End-of-Life Populations study. The data included N = 404 patients with ALS (N = 101), COPD (N = 100), ESRD (N = 101), and frailty (N = 102) in the estimated last 6 months of life, with a range of illness-related symptoms, assessed longitudinally at 2 time points. We examined neuroticism as a moderator of illness-related symptoms at Time 1 (∼6 months before death) and depression at Time 2 (∼3 months before death) using ordinary least squares regression. RESULTS: Results revealed that neuroticism significantly moderated the relationship between the following symptoms and depression measured 3 months later: drowsiness, fatigue, shortness of breath, wellbeing (ALS); drowsiness, trouble sleeping, will to live, activity (COPD); constipation (ESRD); and weakness and will to live (frailty). SIGNIFICANCE OF RESULTS: These findings suggest that neuroticism represents a vulnerability factor that either attenuates or amplifies the relationship of specific illness and depressive symptoms in these noncancer illness groups at the EOL. Identifying those high in neuroticism may provide insight into patient populations that require special care at the EOL.

Aligning research with policy and practice for sustainable agricultural land systems in Europe.

Agriculture is widely recognized as critical to achieving the Sustainable Development Goals (SDGs), but researchers, policymakers, and practitioners have multiple, often conflicting yet poorly documented priorities on how agriculture could or should support achieving the SDGs. Here, we assess consensus and divergence in priorities for agricultural systems among research, policy, and practice perspectives and discuss the implications for research on trade-offs among competing goals. We analyzed the priorities given to 239 environmental and social drivers, management choices, and outcomes of agricultural systems from 69 research articles, the SDGs and four EU policies, and seven agricultural sustainability assessment tools aimed at farmers. We found all three perspectives recognize 32 variables as key to agricultural systems, providing a shared area of focus for agriculture's contribution to the SDGs. However, 207 variables appear in only one or two perspectives, implying that potential trade-offs may be overlooked if evaluated from only one perspective. We identified four approaches to agricultural land systems research in Europe that omit most of the variables considered important from policy and practice perspectives. We posit that the four approaches reflect prevailing paradigms of research design and data analysis and suggest future research design should consider including the 32 shared variables as a starting point for more policy- and practice-relevant research. Our identification of shared priorities from different perspectives and attention to environmental and social domains and the functional role of system components provide a concrete basis to encourage codesigned and systems-based research approaches to guide agriculture's contribution to the SDGs.

Developing an Alternative Version of the Epworth Sleepiness Scale to Assess Daytime Sleepiness in Adults with Physical or Mental Disabilities.

INTRODUCTION: Excessive daytime sleepiness (EDS) is a frequent symptom with many possible causes, and many of these can be treated. EDS and its underlying causes have been associated with various negative health consequences. Recognition of EDS is thus an important public health concern. The concept of EDS is, however, not yet well defined, and different measures are used to diagnose EDS. The Epworth Sleepiness Scale (ESS) is the most widely used tool to assess daytime sleepiness in a broad range of populations. Its applicability in patients exhibiting physical or mental disabilities, like older multimorbid patients, is limited, since the ESS was not developed and validated in this patient group. METHODS: Within an expert study with 35 sleep medicine experts and a pilot study with 52 geriatric in-patients, who frequently exhibit physical or mental disabilities, and patients' close relatives, we adapted the original ESS to develop an alternative version to assess daytime sleepiness in adults with physical or mental disabilities (ESS-ALT). RESULTS: In this adapted version, items 3 (sitting inactively in a public place) and 8 (sleepy in traffic) were replaced by 2 new items (sitting in a waiting room, sitting and eating a meal) and an interview format was used. This ESS-ALT achieved fewer missing responses (23 vs. 73%) and a higher level of internal consistency (Cronbach's α = 0.64 vs. 0.23) than the original ESS while keeping its somnificity structure. CONCLUSION: The ESS-ALT achieves better psychometric properties than the original ESS for individuals with physical or mental disabilities.

Course and Predictors of Major Depressive Disorder in the Canadian Armed Forces Members and Veterans Mental Health Follow-up Survey: Cours et Prédicteurs du Trouble de Dépression Majeure Dans l'Enquête de Suivi Sur la Santé Mentale Auprès Des Membres des Forces Armées Canadiennes et des ex-Militaires.

OBJECTIVES: The present report is the first study of Canadian military personnel to use longitudinal survey data to identify factors that determine major depressive episodes (MDEs) over a period of 16 years. METHODS: The study used data from the Canadian Armed Forces Members and Veterans Mental Health Follow-up Survey (CAFVMHS) collected in 2018 (n = 2,941, response rate 68.7%) and linked baseline data from the same participants that were collected in 2002 when they were Canadian Regular Force members. The study used structured interviews to identify 5 common Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition mental disorders and collected demographic data, as well as information about traumatic experiences, childhood adversities, work stress, and potential resilience factors. Respondents were divided into 4 possible MDE courses: No Disorder, Remitting, New Onset, and Persistent/Recurrent. Relative risk ratios (RRRs) from multinomial regression models were used to evaluate determinants of these outcomes. RESULTS: A history of anxiety disorders and post-traumatic stress disorder (RRRs: 1.50 to 20.55), mental health service utilization (RRRs: 1.70 to 12.34), veteran status (RRRs: 1.64 to 2.15), deployment-associated traumatic events (RRRs: 1.71 to 2.27), sexual traumas (RRRs: 1.91 to 2.93), other traumas (RRRs: 1.67 to 2.64), childhood adversities (RRRs: 1.39 to 1.97), avoidance coping (RRRs 1.09 to 1.49), higher frequency of religious attendance (RRRs: 1.54 to 1.61), and work stress (RRRs: 1.05 to 1.10) were associated with MDE courses in most analyses. Problem-focused coping (RRRs: 0.73 to 0.91) and social support (RRRs: 0.95 to 0.98) were associated with protection against MDEs. CONCLUSIONS: The time periods following deployment and trauma exposure and during the transition from active duty to veteran status are particularly relevant for vulnerability to depression in military members. Interventions that enhance problem-focused coping and social support may be protective against MDEs in military members.

Course and Predictors of Posttraumatic Stress Disorder in the Canadian Armed Forces: A Nationally Representative, 16-Year Follow-up Study: Cours et prédicteurs du trouble de stress post-traumatique dans les Forces armées canadiennes: une étude de suivi de 16 ans nationalement représentative.

OBJECTIVE: This study examined baseline risk and protective predictors and interim correlates of the persistence/recurrence, remission, and onset of posttraumatic stress disorder (PTSD) in a 16-year prospective, nationally representative sample of Canadian Forces members and veterans. METHODS: The 2018 Canadian Armed Forces Members and Veterans Mental Health Follow-up Survey is a prospective study of 2,941 regular force service members and veterans who participated in the 2002 Canadian Community Health Survey on Mental Health and Wellbeing: Canadian Forces Supplement (n = 5,155; ages 15 to 64 years; response rate 68%). PTSD diagnoses in 2002 and 2018 were used to create 4 groups: (1) no lifetime, (2) remitted, (3) new onset, and (4) persistent/recurrent PTSD. Multinomial regressions were conducted to identify predictors of PTSD courses. RESULTS: Female sex, being a junior noncommissioned member (vs. officer), and land (vs. air) operations in 2002 were associated with all PTSD courses relative to no lifetime PTSD (relative risk ratio [RRR] range: 1.28 to 3.65). After adjusting for sociodemographic variables, baseline predictors of all PTSD courses included lifetime mental disorder, history of mental health care utilization, all trauma type categories (deployment-associated, sexual, "other"), and the number of lifetime traumatic events (RRR range: 1.14 to 8.95). New ("since 2002") traumas, transitioning to veteran status, and alcohol dependence were mostly associated with the new onset and persistent/recurrent PTSD courses (RRR range: 1.79 to 4.31), while mental health care utilization and greater avoidance coping were associated with all PTSD courses (RRR range: 1.10 to 17.87). Protective factors for several PTSD courses at one or both time points included social support, social network size, and problem-focused coping (RRR range: 0.71 to 0.98). CONCLUSIONS: This is the first population-based survey to examine the longitudinal course of PTSD in Canadian Forces members. Prevention and intervention programs focused on bolstering social support and active coping strategies as possible protective factors/correlates may help mitigate the development and persistence of PTSD.

Association of Child Maltreatment and Deployment-related Traumatic Experiences with Mental Disorders in Active Duty Service Members and Veterans of the Canadian Armed Forces: Association de la Maltraitance des Enfants et des Expériences Traumatisantes Liées au Déploiement Avec les Troubles Mentaux Chez les Membres du Service Actif et Les Anciens Combattants des Forces Armées Canadiennes.

OBJECTIVE: Mental health among military personnel is an important public health priority. It is known that military personnel experience a high prevalence of child maltreatment and deployment-related traumatic events (DRTEs) and both are related to mental health outcomes. However, few, if any, studies have examined the cumulative and interactive effects of child maltreatment and DRTEs on mental health disorders in a sample of active duty service members and military veterans. METHODS: Data were from the Canadian Armed Forces (CAF) Members and Veterans Mental Health Follow-up Survey collected in 2018 (N = 2,941, response rate = 68.7%), a 16-year follow-up survey of CAF Regular Force members interviewed in 2002. Five types of child maltreatment and 10 types of DTREs were assessed for impact on mental health. Mental disorders included past 12-month generalized anxiety disorder (GAD), panic disorder, social phobia, and major depressive episode (MDE). Past 12-month symptoms of posttraumatic stress disorder (PTSD) were also examined. RESULTS: The prevalence of any exposure to child maltreatment and DRTEs was 62.5% and 68.6%, respectively. All types of child maltreatment were associated with increased odds of past 12-month PTSD symptoms and mental disorders with the exception of physical abuse and GAD as well as childhood exposure to intimate partner violence and panic disorder. Cumulative effects of having experienced both child maltreatment and DRTEs increased the odds of past 12-month PTSD symptoms, GAD, social phobia, and MDE. No interaction effects were significant. CONCLUSIONS: The prevalence of a child maltreatment history is high among active Canadian military and veterans. As well, child maltreatment may increase the likelihood of mental disorders across the life span. This may be especially true for individuals who also experience DRTEs. Understanding these relationships may provide insight into developing effective interventions for military personnel and veteran mental health outcomes.

Rationale and Methodology of the 2018 Canadian Armed Forces Members and Veterans Mental Health Follow-up Survey (CAFVMHS): A 16-year Follow-up Survey: Raison D'être Et Méthodologie De L'enquête De Suivi Sur La Santé Mentale Des Membres Des Forces Armées Canadiennes Et Des Anciens Combattants, 2018 (ESSMFACM).

OBJECTIVE: Knowledge is limited regarding the longitudinal course and predictors of mental health problems, suicide, and physical health outcomes among military and veterans. Statistics Canada, in collaboration with researchers at the University of Manitoba and an international team, conducted the Canadian Armed Forces Members and Veterans Mental Health Follow-Up Survey (CAFVMHS). Herein, we describe the rationale and methods of this important survey. METHOD: The CAFVMHS is a longitudinal survey design with 2 time points (2002 and 2018). Regular Force military personnel who participated in the first Canadian Community Health Survey Cycle 1.2-Mental Health and Well-Being, Canadian Forces Supplement (CCHS-CFS) in 2002 (N = 5,155) were reinterviewed in 2018 (n = 2,941). The World Mental Health Survey-Composite International Diagnostic Interview was used with the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) criteria. RESULTS: The CAFVMHS includes 2,941 respondents (66% veterans; 34% active duty) and includes data on mental disorder diagnoses, physical health conditions, substance use, medication use, general health, mental health services, perceived need for care, social support, moral injury, deployment experiences, stress, physical activity, military-related sexual assault, childhood experiences, and military and sociodemographic information. CONCLUSIONS: The CAFVMHS provides a unique opportunity to further understand the health and well-being of military personnel in Canada over time to inform intervention and prevention strategies and improve outcomes. The data are available through the Statistics Canada Research Data Centres across Canada and can be used cross-sectionally or be longitudinally linked to the 2002 CCHS-CFS data.

Lifetime Prevalence and Comorbidity of Mental Disorders in the Two-wave 2002-2018 Canadian Armed Forces Members and Veterans Mental Health Follow-up Survey (CAFVMHS): Prévalence et Comorbidité de Durée de vie Des Troubles Mentaux Dans l'Enquête de Suivi Sur la Santé Mentale Auprès des Membres des Forces Armées Canadiennes et Des ex-Militaires (ESSMFACM) en Deux Cycles de 2002 à 2018.

OBJECTIVE: The current study used the Canadian Armed Forces Members and Veterans Mental Health Follow-up Survey (CAFVMHS) to (1) examine the incidence and prevalence of mental disorders and (2) estimate the comorbidity of mental disorders over the follow-up period. METHOD: The CAFVMHS (2018) is a longitudinal study with two time points of assessment. The sample is comprised of 2,941 Canadian Forces members and veterans who participated in the 2002 Canadian Community Health Survey: Canadian Forces Supplement. The World Health Organization Composite International Diagnostic Interview (WHO-CIDI) was utilized to diagnose Diagnostic and Statistical Manual-IV post-traumatic stress disorder (PTSD), major depressive episode (MDE), generalized anxiety disorder, social anxiety disorder (SAD), and alcohol abuse and dependence. Self-report health professional diagnoses were assessed for attention deficit hyperactivity disorder (ADHD), mania, obsessive compulsive disorder (OCD), and personality disorder. We established weighted prevalence of mental disorders and examined the association between mental disorders using logistic regression. RESULTS: In 2018, lifetime prevalence of any WHO-CIDI-based or self-reported mental disorder was 58.1%. Lifetime prevalence of any mood or anxiety disorder or PTSD was 54.0% in 2018. MDE (39.9%), SAD (25.7%), and PTSD (21.4%) were the most common mental disorders. There was a substantial increase in new onset or recurrence/persistence of mental disorders between the two measurement points (16-year assessment gap); 2002-2018 period prevalences were 43.5% for mood and anxiety disorder and 16.8% for alcohol abuse or dependence. The prevalence of self-reported ADHD, OCD, any personality disorder, and mania were 3.3%, 3.0%, 0.8%, and 0.8%, respectively. Comorbidity between mental disorders increased over the follow-up. CONCLUSIONS: This study demonstrates a high burden of mental disorders among a large Canadian military and veteran cohort. These findings underscore the importance of prevention and intervention strategies to reduce the burden of mental disorders and alcohol use disorders in these populations.

The citrus flavonoid nobiletin confers protection from metabolic dysregulation in high-fat-fed mice independent of AMPK.

Obesity, dyslipidemia, and insulin resistance, the increasingly common metabolic syndrome, are risk factors for CVD and type 2 diabetes that warrant novel therapeutic interventions. The flavonoid nobiletin displays potent lipid-lowering and insulin-sensitizing properties in mice with metabolic dysfunction. However, the mechanisms by which nobiletin mediates metabolic protection are not clearly established. The central role of AMP-activated protein kinase (AMPK) as an energy sensor suggests that AMPK is a target of nobiletin. We tested the hypothesis that metabolic protection by nobiletin required phosphorylation of AMPK and acetyl-CoA carboxylase (ACC) in mouse hepatocytes, in mice deficient in hepatic AMPK (Ampkß1-/-), in mice incapable of inhibitory phosphorylation of ACC (AccDKI), and in mice with adipocyte-specific AMPK deficiency (iß1ß2AKO). We fed mice a high-fat/high-cholesterol diet with or without nobiletin. Nobiletin increased phosphorylation of AMPK and ACC in primary mouse hepatocytes, which was associated with increased FA oxidation and attenuated FA synthesis. Despite loss of ACC phosphorylation in Ampkß1-/- hepatocytes, nobiletin suppressed FA synthesis and enhanced FA oxidation. Acute injection of nobiletin into mice did not increase phosphorylation of either AMPK or ACC in liver. In mice fed a high-fat diet, nobiletin robustly prevented obesity, hepatic steatosis, dyslipidemia, and insulin resistance, and it improved energy expenditure in Ampkß1-/-, AccDKI, and iß1ß2AKO mice to the same extent as in WT controls. Thus, the beneficial metabolic effects of nobiletin in vivo are conferred independently of hepatic or adipocyte AMPK activation. These studies further underscore the therapeutic potential of nobiletin and begin to clarify possible mechanisms.

PCSK9: Regulation and Target for Drug Development for Dyslipidemia.

Proprotein convertase subtilisin/kexin type-9 (PCSK9) is a secreted zymogen expressed primarily in the liver. PCSK9 circulates in plasma, binds to cell surface low-density lipoprotein (LDL) receptors, is internalized, and then targets the receptors to lysosomal degradation. Studies of naturally occurring PCSK9 gene variants that caused extreme plasma LDL cholesterol (LDL-C) deviations and altered atherosclerosis risk unleashed a torrent of biological and pharmacological research. Rapid progress in understanding the physiological regulation of PCSK9 was soon translated into commercially available biological inhibitors of PCSK9 that reduced LDL-C levels and likely also cardiovascular outcomes. Here we review the swift evolution of PCSK9 from novel gene to drug target, to animal and human testing, and finally to outcome trials and clinical applications. In addition, we explore how the genetics-guided path to PCSK9 inhibitor development exemplifies a new paradigm in pharmacology. Finally, we consider some potential challenges as PCSK9 inhibition becomes established in the clinic.

Bempedoic acid: effects on lipoprotein metabolism and atherosclerosis.

PURPOSE OF REVIEW: Bempedoic acid has emerged as a potent inhibitor of ATP-citrate lyase (ACLY), a target for the reduction of LDL cholesterol (LDL-C). We review the impact of bempedoic acid treatment on lipoprotein metabolism and atherosclerosis in preclinical models and patients with hypercholesterolemia. RECENT FINDINGS: The liver-specific activation of bempedoic acid inhibits ACLY, a key enzyme linking glucose catabolism to lipogenesis by catalyzing the formation of acetyl-CoA from mitochondrial-derived citrate for de novo synthesis of fatty acids and cholesterol. Adenosine monophosphate-activated protein kinase activation by bempedoic acid is not required for its lipid-regulating effects in vivo. Mendelian randomization of large human study cohorts has validated ACLY inhibition as a target for LDL-C lowering and atheroprotection. In rodents, bempedoic acid decreases plasma cholesterol and triglycerides, and prevents hepatic steatosis. In apolipoprotein E-deficient (Apoe) mice, LDL receptor-deficient (Ldlr) mice and LDLR-deficient miniature pigs, bempedoic acid reduces LDL-C and attenuates atherosclerosis. LDLR expression and activity are increased in primary human hepatocytes and in Apoe mouse liver treated with bempedoic acid suggesting a mechanism for LDL-C lowering, although additional pathways are likely involved. Phase 2 and 3 clinical trials revealed that bempedoic acid effectively lowers LDL-C as monotherapy, combined with ezetimibe, added to statin therapy and in statin-intolerant hypercholesterolemic patients. Treatment does not affect plasma concentrations of triglyceride or other lipoproteins. SUMMARY: The LDL-C-lowering and attenuated atherosclerosis in animal models and reduced LDL-C in hypercholesterolemic patients has validated ACLY inhibition as a therapeutic strategy. Positive results from phase 3 long-term cardiovascular outcome trials in high-risk patients are required for bempedoic acid to be approved for prevention of atherosclerosis.

Bempedoic Acid Lowers Low-Density Lipoprotein Cholesterol and Attenuates Atherosclerosis in Low-Density Lipoprotein Receptor-Deficient (LDLR+/- and LDLR-/-) Yucatan Miniature Pigs.

OBJECTIVE: Bempedoic acid (BemA; ETC-1002) is a novel drug that targets hepatic ATP-citrate lyase to reduce cholesterol biosynthesis. In phase 2 studies, BemA lowers elevated low-density lipoprotein cholesterol (LDL-C) in hypercholesterolemic patients. In the present study, we tested the ability of BemA to decrease plasma cholesterol and LDL-C and attenuate atherosclerosis in a large animal model of familial hypercholesterolemia. APPROACH AND RESULTS: Gene targeting has been used to generate Yucatan miniature pigs heterozygous (LDLR+/-) or homozygous (LDLR-/-) for LDL receptor deficiency (ExeGen). LDLR+/- and LDLR-/- pigs were fed a high-fat, cholesterol-containing diet (34% kcal fat; 0.2% cholesterol) and orally administered placebo or BemA for 160 days. In LDLR+/- pigs, compared with placebo, BemA decreased plasma cholesterol and LDL-C up to 40% and 61%, respectively. In LDLR-/- pigs, in which plasma cholesterol and LDL-C were 5-fold higher than in LDLR+/- pigs, BemA decreased plasma cholesterol and LDL-C up to 27% and 29%, respectively. Plasma levels of triglycerides and high-density lipoprotein cholesterol, fasting glucose and insulin, and liver lipids were unaffected by treatment in either genotype. In the aorta of LDLR+/- pigs, BemA robustly attenuated en face raised lesion area (-58%) and left anterior descending coronary artery cross-sectional lesion area (-40%). In LDLR-/- pigs, in which lesions were substantially more advanced, BemA decreased aortic lesion area (-47%) and left anterior descending coronary artery lesion area (-48%). CONCLUSIONS: In a large animal model of LDLR deficiency and atherosclerosis, long-term treatment with BemA reduces LDL-C and attenuates the development of aortic and coronary atherosclerosis in both LDLR+/- and LDLR-/- miniature pigs.

Correcting for Body Surface Area Identifies the True Prevalence of Abdominal Aortic Aneurysm in Screened Women.

OBJECTIVE: Recently, the prevalence of abdominal aortic aneurysm (AAA) using screening strategies based on elevated cardiovascular disease (CVD) risk was reported. AAA was defined as a diameter ≥30 mm, with prevalence of 6.1% and 1.8% in men and women respectively, consistent with the widely reported AAA predominant prevalence in males. Given the obvious differences in body size between sexes this study aimed to re-evaluate the expanded CVD risk based AAA screening dataset to determine the effect of body size on sex specific AAA prevalence. METHODS: Absolute (26 and 30 mm) and relative (aortic size index [ASI] equals the maximum infrarenal aorta diameter (cm) divided by body surface area (m2), ASI ≥ 1.5) thresholds were used to assess targeted AAA screening groups (n = 4115) and compared with a self reported healthy elderly control group (n = 800). RESULTS: Male AAA prevalence was the same using either the 30 mm or ASI ≥1.5 aneurysm definitions (5.7%). In females, AAA prevalence was significantly different between the 30 mm (2.4%) and ASI ≥ 1.5 (4.5%) or the 26 mm (4.4%) thresholds. CONCLUSION: The results suggest the purported male predominance in AAA prevalence is primarily an artefact of body size differences. When aortic size is adjusted for body surface area there is only a modest sex difference in AAA prevalence. This observation has potential implications in the context of the ongoing discussion regarding AAA screening in women.

Prevalence of Mental Disorders and Suicidality in Canadian Provinces.

OBJECTIVE: There is limited information to guide health-care service providers and policy makers on the burden of mental disorders and addictions across the Canadian provinces. This study compares interprovincial prevalence of major depressive disorder (MDD), bipolar disorder, generalized anxiety disorder (GAD), alcohol use disorder, substance use disorders, and suicidality. METHOD: Data were extracted from the 2012 Canadian Community Health Survey-Mental Health (n = 25,113), a representative sample of Canadians over the age of 15 years across all provinces. Cross tabulations and logistic regression were used to determine the prevalence and odds of the above disorders for each province. Adjustments for provincial sociodemographic factors were performed. RESULTS: The past-year prevalence of all measured mental disorders and suicidality, excluding GAD, demonstrated significant interprovincial differences. Manitoba exhibited the highest prevalence of any mental disorder (13.6%), reflecting high prevalence of MDD and alcohol use disorder compared to the other provinces (7.0% and 3.8%, respectively). Nova Scotia exhibited the highest prevalence of substance use disorders (2.9%). Quebec and Prince Edward Island exhibited the lowest prevalence of any mental disorder (8.5% and 7.7%, respectively). Manitoba also exhibited the highest prevalence of suicidal ideation (5.1%); however, British Columbia and Ontario exhibited the highest prevalence of suicidal planning (1.4% and 1.3%, respectively), and Ontario alone exhibited the highest prevalence of suicide attempts (0.7%). CONCLUSIONS: Significant interprovincial differences were found in the past-year prevalence of mental disorders and suicidality in Canada. More research is necessary to explore these differences and how they impact the need for mental health services.

Prevalence and risk factors for chronic kidney disease in primary health care in the southern region of New Zealand.

AIM: While the prevalence of end stage kidney disease in New Zealand (NZ) is well defined, the prevalence of chronic kidney disease (CKD) in NZ is unknown. To estimate the prevalence of and risk factors for CKD in the southern region of New Zealand. METHODS: A retrospective electronic health record cohort study using data from the Southern Primary Care register covering 94% of the population. Patients, 20 years or older were identified and linked to laboratory results for serum creatinine and urinary albumin excretion. Chronic kidney disease was defined as an estimated glomerular filtration rate of less than 60 mL/min per 1.73 m2 (G3-5) or the presence of albuminuria of greater than 3 mg/mmol (A2-3). Diabetes was identified from a national virtual diabetes database. From this, we estimated the prevalence of CKD by age, gender, ethnicity, deprivation and the presence of diabetes mellitus. RESULTS: Of a total adult population of 211 980, 159 799 had a serum creatinine checked and 27 905 had an estimate of albuminuria. The estimated prevalence of CKD was 11.8%. 6.3% of total population had CKD stage G3a, 2.4% G3b, 0.8% G4, 0.2% G5, 1.8% A2 albuminuria and 0.3% A3 albuminuria. Increasing age, female sex, ethnic group, social deprivation and diabetes mellitus were associated with an increased risk of CKD. 11 351 patients had a diagnosis of diabetes mellitus and were almost universally tested (99.3%) for CKD. The presence of albuminuria was strongly correlated with ethnic group, male sex and living in a deprived area. The retrospective electronic health record study with associated selection and testing bias are potential limitations of the present study. CONCLUSION: Chronic kidney disease prevalence in this region appears to be similar to other reported populations. The majority of those at risk for CKD were tested for reduced eGFR. The presence of albuminuria, an integral component of CKD diagnostic criteria, was under utilized in the non-diabetic population.