Therapeutic effects of FGF21 mimetic bFKB1 on MASH and atherosclerosis in Ldlr-/-.Leiden mice.

Fibroblast growth factor 21 (FGF21) is a promising target for treatment of obesity-associated diseases including metabolic dysfunction-associated steatohepatitis (MASH) and atherosclerosis. We evaluated the effects of the bispecific anti-FGF21-ß klotho (KLB) agonist antibody bFKB1 in a preclinical model of MASH and atherosclerosis. Low-density lipoprotein receptor knockout (Ldlr-/-).Leiden mice received a high-fat diet for 20 weeks, followed by treatment with an isotype control antibody or bFKB1 for 12 weeks. Effects on plasma risk markers and (histo)pathology of liver, adipose tissue, and heart were evaluated alongside hepatic transcriptomics analysis. bFKB1 lowered body weight (-21%) and adipose tissue mass (-22%) without reducing food intake. The treatment also improved plasma insulin (-80%), cholesterol (-48%), triglycerides (-76%), alanine transaminase (ALT: -79%), and liver weight (-43%). Hepatic steatosis and inflammation were strongly reduced (macrovesicular steatosis -34%; microvesicular steatosis -100%; inflammation -74%) and while the total amount of fibrosis was not affected, bFKB1 did decrease new collagen formation (-49%). Correspondingly, hepatic transcriptomics and pathway analysis revealed the mechanistic background underlying these histological improvements, demonstrating broad inactivation of inflammatory and profibrotic transcriptional programs by bFKB1. In epididymal white adipose tissue, bFKB1 reduced adipocyte size (-16%) and inflammation (-52%) and induced browning, signified by increased uncoupling protein-1 (UCP1) protein expression (8.5-fold increase). In the vasculature, bFKB1 had anti-atherogenic effects, lowering total atherosclerotic lesion area (-38%). bFKB1 has strong beneficial metabolic effects associated with a reduction in hepatic steatosis, inflammation, and atherosclerosis. Analysis of new collagen formation and profibrotic transcriptional programs indicate that bFKB1 treatment may have antifibrotic potential in a longer treatment duration as well.

Antibody-mediated activation of the FGFR1/Klothoß complex corrects metabolic dysfunction and alters food preference in obese humans.

Fibroblast growth factor 21 (FGF21) controls metabolic organ homeostasis and eating/drinking behavior via FGF receptor 1/Klothoß (FGFR1/KLB) complexes expressed in adipocytes, pancreatic acinar cells, and the nervous system in mice. Chronic administration of recombinant FGF21 or engineered variants improves metabolic health in rodents, nonhuman primates, and humans; however, the rapid turnover of these molecules limits therapeutic utility. Here we show that the bispecific anti-FGFR1/KLB agonist antibody BFKB8488A induced marked weight loss in obese cynomolgus monkeys while elevating serum adiponectin and the adipose expression of FGFR1 target genes, demonstrating its action as an FGF21 mimetic. In a randomized, placebo-controlled, single ascending-dose study in overweight/obese human participants, subcutaneous BFKB8488A injection caused transient body weight reduction, sustained improvement in cardiometabolic parameters, and a trend toward reduction in preference for sweet taste and carbohydrate intake. These data suggest that specific activation of the FGFR1/KLB complex in humans can be used as therapy for obesity-related metabolic defects.

Effects of inhaled JAK inhibitor GDC-4379 on exhaled nitric oxide and peripheral biomarkers of inflammation.

BACKGROUND: Janus Kinases (JAKs) mediate activity of many asthma-relevant cytokines. GDC-0214, an inhaled small molecule JAK1 inhibitor, has previously been shown to reduce fractional exhaled nitric oxide (FeNO) in patients with mild asthma, but required an excessive number of inhalations. AIM: To assess whether GDC-4379, a new inhaled JAK inhibitor, reduces FeNO and peripheral biomarkers of inflammation. METHODS: This study assessed the activity of GDC-4379 in a double-blind, randomized, placebo-controlled, Phase 1 study in patients with mild asthma. Participants included adults (18-65y) with a diagnosis of asthma for ≥6 months, forced expiratory volume in 1 s (FEV1)> 70% predicted, FeNO >40 ppb, using as-needed short-acting beta-agonist medication only. Four sequential, 14-day, ascending-dose cohorts (10 mg QD, 30 mg QD, 40 mg BID, and 80 mg QD) of 12 participants each were randomized 2:1 to GDC-4379 or placebo. The primary activity outcome was percent change from baseline (CFB) in FeNO to Day 14 compared to the pooled placebo group. Safety, tolerability, pharmacokinetics, and pharmacodynamic biomarkers, including blood eosinophils, serum CCL17, and serum CCL18, were also assessed. RESULTS: Of 48 enrolled participants, the mean age was 25 years and 54% were female. Median (range) FeNO at baseline was 79 (41-222) ppb. GDC-4379 treatment led to dose-dependent reductions in FeNO. Compared to placebo, mean (95% CI) percent CFB in FeNO to Day 14 was: -6 (-43, 32) at 10 mg QD, -26 (-53, 2) at 30 mg QD, -55 (-78, -32) at 40 mg BID and -52 (-72, -32) at 80 mg QD. Dose-dependent reductions in blood eosinophils and serum CCL17 were also observed. Higher plasma drug concentrations corresponded with greater FeNO reductions. No serious AEs occurred. The majority of AEs were mild to moderate. The most common AEs were headache and oropharyngeal pain. Minor changes in neutrophils were noted at 80 mg QD, but were not considered clinically meaningful. CONCLUSIONS: In patients with mild asthma, 14-day treatment with GDC-4379 reduced FeNO levels and peripheral biomarkers of inflammation. Treatment was well tolerated without any major safety concerns. AUSTRALIAN NEW ZEALAND CLINICAL TRIALS REGISTRY: ACTRN12619000227190.

Smoking Susceptibility in Canadian Adolescent Electronic-Cigarette Users.

Background: E-cigarette use is increasing among Canadian youth, with experimentation especially prevalent among never-smoking youth. Among this group, there is concern e-cigarette use contributes to future initiation of smoking through a gateway effect. However, e-cigarette use and smoking share many common risk factors; a postulated mechanism to explain the apparent causal pathway from e-cigarette use to smoking initiation in previously smoking-naïve youth. A better understanding of the relationships between smoking susceptibility and e-cigarette use among never-smoking youth is needed. Purpose/objectives: The primary aim of this study was to gain a deeper understanding of the risk factors associated with smoking susceptibility in youth who have recently used e-cigarettes. Methods: This study used data (n = 40,363) from the 2018/2019 Canadian Student Tobacco Alcohol and Drug Use Survey (CSTADS) to compare the risk factor profiles of susceptible and non-susceptible never-smoking e-cigarette users, as well as susceptible and non-susceptible never-smoking youth who have never used an e-cigarette. Results: E-cigarette use, independent of susceptibility status, was associated with a sociodemographic and behavioral risk factor profile likely to confer a higher risk of initiating smoking. Among e-cigarette users, smoking susceptibility was associated with more smoking risk factors. Conclusions/importance: Study findings support a common risk-factor model, rather than e-cigarette use itself, to explain differences in the likelihood of smoking initiation among e-cigarette users. E-cigarette use and smoking initiation may be interchangeable outcomes amongst those with smoking risk factors. The risks of e-cigarette use, and their regulatory status, need to be balanced with their potential as harm reduction tools.

Expectations for Return to Work Predict Return to Work in Workers with Low Back Pain: An Individual Participant Data (IPD) Meta-Analysis.

Purpose Low back pain is associated with disability and lost productivity due to inability of workers to return to work. Personal recovery expectation beliefs may be associated with return to work outcomes in those with low back pain at high risk for chronic disability. We aimed to (1) assess whether workers' expectations for return to work, following a low back pain episode, are associated with subsequent return to work; and (2) explore the relationships between return to work expectations and other prognostic factors in their association with work outcomes.Methods We conducted an Individual Participant Data (IPD) meta-analysis using data from five prospective cohort studies identified by a Cochrane prognostic factor review. A one-stage IPD meta-analysis approach was applied. Multi-level mixed effects models were used to determine the unadjusted and adjusted associations between expectations and return to work (logistic regression) and time to return to work (parametric survival models with Weibull distribution).Results The final dataset included 2302 participants. Positive expectations for return to work were associated with return to work at follow-up in both unadjusted (Odds Ratio (OR) 2.95; 95% Confidence Interval (CI) 2.21, 3.95) (n = 2071) and comprehensively adjusted (OR 2.01; 95% CI 1.46, 2.77) (n = 1109) models. Similar findings were identified for shorter length of time to return to work in both unadjusted (HR 2.40; 95% CI 2.09, 2.75) (n = 1156) and minimally adjusted (HR 2.43; 95% CI 2.12, 2.79) (n = 1154) models.Conclusions Results suggest workers with low expectations for return to work are at increased risk for long-term work disability.

Inhaled JAK inhibitor GDC-0214 reduces exhaled nitric oxide in patients with mild asthma: A randomized, controlled, proof-of-activity trial.

BACKGROUND: The Janus kinase (JAK) pathway mediates the activity of many asthma-relevant cytokines, including IL-4 and IL-13. GDC-0214 is a potent, inhaled, small-molecule JAK inhibitor being developed for the treatment of asthma. OBJECTIVE: We sought to determine whether GDC-0214 reduces fractional exhaled nitric oxide (Feno), a JAK1-dependent biomarker of airway inflammation, in patients with mild asthma. METHODS: We conducted a double-blind, randomized, placebo-controlled, phase 1 proof-of-activity study in adults with mild asthma and Feno higher than 40 parts per billion (ppb). Subjects were randomized 2:1 (GDC-0214:placebo) into 4 sequential ascending-dose cohorts (1 mg once daily [QD], 4 mg QD, 15 mg QD, or 15 mg twice daily). All subjects received 4 days of blinded placebo, then 10 days of either active drug or placebo. The primary outcome was placebo-corrected percent reduction in Feno from baseline to day 14. Baseline was defined as the average Feno during the blinded placebo period. Pharmacokinetics, safety, and tolerability were also assessed. RESULTS: Thirty-six subjects (mean age, 28 years; 54% females) were enrolled. Mean Feno at baseline across all subjects was 93 ± 43 ppb. At day 14, placebo-corrected difference in Feno was -23% (95% CI, -37.3 to -9) for 15 mg QD and -42% (95% CI, -57 to -27.4) for 15 mg twice daily. Higher plasma exposure was associated with greater Feno reduction. No dose-limiting adverse events, serious adverse events, or treatment discontinuations occurred. There were no major imbalances in adverse events or laboratory findings, or evidence of systemic JAK inhibition. CONCLUSIONS: GDC-0214, an inhaled JAK inhibitor, caused dose-dependent reductions in Feno in mild asthma and was well tolerated without evidence of systemic toxicity.

Health Care Provider Utilization of Prescription Monitoring Programs: A Systematic Review and Meta-Analysis.

OBJECTIVE: To synthesize the literature on the proportion of health care providers who access and use prescription monitoring program data in their practice, as well as associated barriers to the use of such data. DESIGN: We performed a systematic review using a standard systematic review method with meta-analysis and qualitative meta-summary. We included full-published peer-reviewed reports of study data, as well as theses and dissertations. METHODS: We identified relevant quantitative and qualitative studies. We synthesized outcomes related to prescription monitoring program data use (i.e., ever used, frequency of use). We pooled the proportion of health care providers who had ever used prescription monitoring program data by using random effects models, and we used meta-summary methodology to identify prescription monitoring program use barriers. RESULTS: Fifty-three studies were included in our review, all from the United States. Of these, 46 reported on prescription monitoring program use and 32 reported on barriers. The pooled proportion of health care providers who had ever used prescription monitoring program data was 0.57 (95% confidence interval: 0.48-0.66). Common barriers to prescription monitoring program data use included time constraints and administrative burdens, low perceived value of prescription monitoring program data, and problems with prescription monitoring program system usability. CONCLUSIONS: Our study found that health care providers underutilize prescription monitoring program data and that many barriers exist to prescription monitoring program data use.

Prescription medication use as a risk factor for motor vehicle collisions: a responsibility study.

INTRODUCTION: Previous studies on the effect of prescription medications on MVCs are sparse, not readily applicable to real-world driving and/or subject to strong selection bias. This study examines whether the presence of prescription medication in drivers' blood is associated with being responsible for MVC. METHODS: This modified case-control study with responsibility analysis compares MVC responsibility rates among drivers with detectable levels of six classes of prescription medications (anticonvulsants, antidepressants, antihistamines, antipsychotics, benzodiazepines, opioids) versus those without. Data were collected between January 2010 and July 2016 from emergency departments in British Columbia, Canada. Collision responsibility was assessed using a validated and automated scoring of police collision reports. Multivariable logistic regression was used to determine OR of responsibility (analysed in 2018-2019). RESULTS: Unadjusted regression models show a significant association between anticonvulsants (OR 1.92; 95% CI 1.20 to 3.09; p=0.007), antipsychotics (OR 5.00; 95% CI 1.16 to 21.63; p=0.03) and benzodiazepines (OR 2.99; 95% CI 1.56 to 5.75; p=0.001) with collision responsibility. Fully adjusted models show a significant association between benzodiazepines with collision responsibility (aOR 2.29; 95% CI 1.16 to 4.53; p=0.02) after controlling for driver characteristics, blood alcohol and Δ-9-tetrahydrocannabinol concentrations, and the presence of other prescription medications. Antidepressants, antihistamines and opioids exhibited no significant associations. CONCLUSION: There is a moderate increase in the risk of a responsible collision among drivers with detectable levels of benzodiazepines in blood. Physicians and pharmacists should consider collision risk when prescribing or dispensing benzodiazepines. Public education about benzodiazepine use and driving and change to traffic policy and enforcement measures are warranted.

Exercise treatment effect modifiers in persistent low back pain: an individual participant data meta-analysis of 3514 participants from 27 randomised controlled trials.

BACKGROUND: Low back pain is one of the leading causes of disability worldwide. Exercise therapy is widely recommended to treat persistent non-specific low back pain. While evidence suggests exercise is, on average, moderately effective, there remains uncertainty about which individuals might benefit the most from exercise. METHODS: In parallel with a Cochrane review update, we requested individual participant data (IPD) from high-quality randomised clinical trials of adults with our two primary outcomes of interest, pain and functional limitations, and calculated global recovery. We compiled a master data set including baseline participant characteristics, exercise and comparison characteristics, and outcomes at short-term, moderate-term and long-term follow-up. We conducted descriptive analyses and one-stage IPD meta-analysis using multilevel mixed-effects regression of the overall treatment effect and prespecified potential treatment effect modifiers. RESULTS: We received IPD for 27 trials (3514 participants). For studies included in this analysis, compared with no treatment/usual care, exercise therapy on average reduced pain (mean effect/100 (95% CI) -10.7 (-14.1 to -7.4)), a result compatible with a clinically important 20% smallest worthwhile effect. Exercise therapy reduced functional limitations with a clinically important 23% improvement (mean effect/100 (95% CI) -10.2 (-13.2 to -7.3)) at short-term follow-up. Not having heavy physical demands at work and medication use for low back pain were potential treatment effect modifiers-these were associated with superior exercise outcomes relative to non-exercise comparisons. Lower body mass index was also associated with better outcomes in exercise compared with no treatment/usual care. This study was limited by inconsistent availability and measurement of participant characteristics. CONCLUSIONS: This study provides potentially useful information to help treat patients and design future studies of exercise interventions that are better matched to specific subgroups. PROTOCOL PUBLICATION: https://doi.org/10.1186/2046-4053-1-64.

Individual recovery expectations and prognosis of outcomes in non-specific low back pain: prognostic factor review.

BACKGROUND: Low back pain is costly and disabling. Prognostic factor evidence can help healthcare providers and patients understand likely prognosis, inform the development of prediction models to identify subgroups, and may inform new treatment strategies. Recent studies have suggested that people who have poor expectations for recovery experience more back pain disability, but study results have differed. OBJECTIVES: To synthesise evidence on the association between recovery expectations and disability outcomes in adults with low back pain, and explore sources of heterogeneity. SEARCH METHODS: The search strategy included broad and focused electronic searches of MEDLINE, Embase, CINAHL, and PsycINFO to 12 March 2019, reference list searches of relevant reviews and included studies, and citation searches of relevant expectation measurement tools. SELECTION CRITERIA: We included low back pain prognosis studies from any setting assessing general, self-efficacy, and treatment expectations (measured dichotomously and continuously on a 0 - 10 scale), and their association with work participation, clinically important recovery, functional limitations, or pain intensity outcomes at short (3 months), medium (6 months), long (12 months), and very long (> 16 months) follow-up. DATA COLLECTION AND ANALYSIS: We extracted study characteristics and all reported estimates of unadjusted and adjusted associations between expectations and related outcomes. Two review authors independently assessed risks of bias using the Quality in Prognosis Studies (QUIPS) tool. We conducted narrative syntheses and meta-analyses when appropriate unadjusted or adjusted estimates were available. Two review authors independently graded and reported the overall quality of evidence. MAIN RESULTS: We screened 4635 unique citations to include 60 studies (30,530 participants). Thirty-five studies were conducted in Europe, 21 in North America, and four in Australia. Study populations were mostly chronic (37%), from healthcare (62%) or occupational settings (26%). General expectation was the most common type of recovery expectation measured (70%); 16 studies measured more than one type of expectation. Usable data for syntheses were available for 52 studies (87% of studies; 28,885 participants). We found moderate-quality evidence that positive recovery expectations are strongly associated with better work participation (narrative synthesis: 21 studies; meta-analysis: 12 studies, 4777 participants: odds ratio (OR) 2.43, 95% confidence interval (CI) 1.64 to 3.62), and low-quality evidence for clinically important recovery outcomes (narrative synthesis: 12 studies; meta-analysis: 5 studies, 1820 participants: OR 1.89, 95% CI 1.49 to 2.41), both at follow-up times closest to 12 months, using adjusted data. The association of recovery expectations with other outcomes of interest, including functional limitations (narrative synthesis: 10 studies; meta-analysis: 3 studies, 1435 participants: OR 1.40, 95% CI 0.85 to 2.31) and pain intensity (narrative synthesis: 9 studies; meta-analysis: 3 studies, 1555 participants: OR 1.15, 95% CI 1.08 to 1.23) outcomes at follow-up times closest to 12 months using adjusted data, is less certain, achieving very low- and low-quality evidence, respectively. No studies reported statistically significant or clinically important negative associations between recovery expectations and any low back pain outcome. AUTHORS' CONCLUSIONS: We found that individual recovery expectations are probably strongly associated with future work participation (moderate-quality evidence) and may be associated with clinically important recovery outcomes (low-quality evidence). The association of recovery expectations with other outcomes of interest is less certain. Our findings suggest that recovery expectations should be considered in future studies, to improve prognosis and management of low back pain.

Evidence Base Update on the Treatment of Early Childhood Anxiety and Related Problems.

The controlled evaluation of treatments for early childhood anxiety and related problems has been a relatively recent area of investigation, and accordingly, trials examining early childhood anxiety treatment have not been well represented in existing systematic reviews of youth anxiety treatments. This Evidence Base Update provides the first systematic review of evidence supporting interventions specifically for the treatment of early childhood anxiety and related problems. Thirty articles testing 38 treatments in samples with mean age < 7.9 years (N = 2,228 children) met inclusion criteria. We applied Southam-Gerow and Prinstein's (2014) review criteria, which classifies families of treatments according to one of five levels of empirical support-Well-Established, Probably Efficacious, Possibly Efficacious, Experimental, and of Questionable Efficacy. We found family-based cognitive-behavioral therapy (CBT) to be a Well-Established treatment, and Group Parent CBT and Group Parent CBT + Group Child CBT to both be Probably Efficacious treatments. In contrast, play therapy and attachment-based therapy are still only Experimental treatments for early childhood anxiety, relaxation training has Questionable Efficacy, and there is no evidence to date to speak to the efficacy of individual child CBT and/or medication in younger anxious children. All 3 currently supported interventions for early childhood anxiety entail exposure-based CBT with significant parental involvement. This conclusion meaningfully differs from conclusions for treating anxiety in older childhood that highlight the well-established efficacy of individual child CBT and/or medication and that question whether parental involvement in treatment enhances outcomes.

The effectiveness of prescription drug monitoring programs at reducing opioid-related harms and consequences: a systematic review.

BACKGROUND: In order to address the opioid crisis in North America, many regions have adopted preventative strategies, such as prescription drug monitoring programs (PDMPs). PDMPs aim to increase patient safety by certifying that opioids are prescribed in appropriate quantities. We aimed to synthesize the literature on changes in opioid-related harms and consequences, an important measure of PDMP effectiveness. METHODS: We completed a systematic review. We conducted a narrative synthesis of opioid-related harms and consequences from PDMP implementation. Outcomes were grouped into categories by theme: opioid dependence, opioid-related care outcomes, opioid-related adverse events, and opioid-related legal and crime outcomes. RESULTS: We included a total of 22 studies (49 PDMPs) in our review. Two studies reported on illicit and problematic use but found no significant associations with PDMP status. Eight studies examined the association between PDMP status and opioid-related care outcomes, of which two found that treatment admissions for prescriptions opioids were lower in states with PDMP programs (p < 0.05). Of the thirteen studies that reported on opioid-related adverse events, two found significant (p < 0.001 and p < 0.05) but conflicting results with one finding a decrease in opioid-related overdose deaths after PDMP implementation and the other an increase. Lastly, two studies found no statistically significant association between PDMP status and opioid-related legal and crime outcomes (crime rates, identification of potential dealers, and diversion). CONCLUSION: Our study found limited evidence to support overall associations between PDMPs and reductions in opioid-related consequences. However, this should not detract from the value of PDMPs' larger role of improving opioid prescribing.

Correction to: Galcanezumab in episodic migraine: subgroup analyses of efficacy by high versus low frequency of migraine headaches in phase 3 studies (EVOLVE-1 & EVOLVE-2).

After publication of our article [1] we were notified that the data presented in the upper row of Fig. 7 was inadvertently the least square mean change from baseline (standard error) at Month 6 rather than the overall average of Month 3 and Month 6. The figure legend and discussion of the data in the text were and are correct. The error was only in the upper row of Fig. 7. The legend for Fig. 7 did not require revision.

Galcanezumab in episodic migraine: subgroup analyses of efficacy by high versus low frequency of migraine headaches in phase 3 studies (EVOLVE-1 & EVOLVE-2).

BACKGROUND: Patients with high-frequency episodic migraine (HFEM) have a greater disease burden than those with low-frequency episodic migraine (LFEM). Acute treatment overuse increases the risk of migraine chronification in patients with HFEM. Galcanezumab, a humanized monoclonal antibody binding calcitonin gene-related peptide (CGRP), is effective for migraine prevention with a favorable safety profile. Here, we investigate whether there are differences in galcanezumab efficacy in patients with LFEM or with HFEM. METHODS: Data were pooled from two double-blind, placebo-controlled phase 3 trials; EVOLVE-1 and EVOLVE-2. Patients were 18-65 years old, experienced 4-14 monthly migraine headache days (MHDs) for ≥1 year prior, with onset at < 50 years of age. Migraine headaches were tracked via electronic patient-reported outcome system and randomization was stratified by low (LFEM; 4-7 monthly MHDs) or high (HFEM; 8-14 monthly MHDs) frequency. Subgroup analysis compared the HFEM and LFEM subgroups with a linear or generalized linear mixed model repeated measures approach. RESULTS: The intent-to-treat patients (N = 1773) had a mean age of 41.3 years, were mostly white (75%), female (85%), and 66% of patients had HFEM. In both the LFEM and HFEM subgroups, the overall (Months 1-6) and monthly changes from baseline in monthly MHDs and monthly MHDs with acute medication use compared with placebo were statistically significantly reduced for galcanezumab 120-mg and 240-mg. Galcanezumab (120-mg and 240-mg) significantly decreased the overall and monthly MHDs with nausea and/or vomiting, and with photophobia and phonophobia versus placebo in patients with LFEM or HFEM. In both subgroups, the mean overall (Months 1-6) and monthly percentages of patients with ≥50%, ≥75%, and 100% reduction in monthly MHDs from baseline were statistically significantly greater in patients receiving either dose of galcanezumab versus placebo. Galcanezumab (120-mg and 240-mg) significantly improved the Migraine-Specific Quality of Life Questionnaire role function-restrictive domain score as well as the Migraine Disability Assessment total score versus placebo for patients with LFEM or HFEM. There were no significant subgroup-by-treatment interactions. CONCLUSIONS: Galcanezumab was as effective in patients with HFEM as in those with LFEM. Associated symptoms, quality of life, and disability were similarly improved in patients with HFEM or LFEM. TRIAL REGISTRATION: NCT02614183 , NCT02614196 .

Behavioural responses to infrasonic particle acceleration in cuttlefish.

Attacks by aquatic predators generate frontal water disturbances characterised by low-frequency gradients in pressure and particle motion. Low-frequency hearing is highly developed in cephalopods. Thus, we examined behavioural responses in juvenile cuttlefish to infrasonic accelerations mimicking main aspects of the hydrodynamic signals created by predators. In the experimental set-up, animals and their surrounding water moved as a unit to minimise lateral line activation and to allow examination of the contribution by the inner ear. Behavioural responses were tested in light versus darkness and after food deprivation following a 'simulated' hunting opportunity. At low acceleration levels, colour change threshold at 3, 5 and 9 Hz was 0.028, 0.038 and 0.035 m s-2, respectively. At higher stimulus levels, jet-propulsed escape responses thresholds in daylight were 0.043, 0.065 and 0.069 m s-2 at 3, 5 and 9 Hz, respectively, and not significantly different from the corresponding darkness thresholds of 0.043, 0.071 and 0.064 m s-2 In a simulated hunting mode, escape thresholds were significantly higher at 3 Hz (0.118 m s-2) but not at 9 Hz (0.134 m s-2). Escape responses were directional, and overall followed the direction of the initial particle acceleration, with mean escape angles from 313 to 33 deg for all three experiments. Thus, in the wild, particle acceleration might cause escape responses directed away from striking predators but towards suction-feeding predators. We suggest that cuttlefish jet-propulsed escape behaviour has evolved to be elicited by the early hydrodynamic disturbances generated during predator encounters, and that the inner ear plays an essential role in the acoustic escape responses.

Driving under the influence behaviours among high school students who mix alcohol with energy drinks.

Alcohol and energy drinks are commonly used substances by youth in Canada, and are often mixed (AmED). While several studies have shown that AmED can have dangerous effects, less well understood is how AmED is associated with driving under the influence of either alcohol or drugs. This study sought to determine whether youth who use AmED were more likely to engage in driving, or being a passenger of a driver, under the influence of alcohol or cannabis compared to youth who use either alcohol or energy drinks alone. This study used data from grade 10-12 students who took part in the 2014/2015 Canadian Student Tobacco, Alcohol and Drugs Survey (N=17,450). The association of past-year AmED use with past-30day: driving under the influence of alcohol or cannabis, and riding with an alcohol- or cannabis-influenced driver, was assessed using logistic regression. One in four youth had consumed AmED in the previous 12months. AmED users were more likely to engage in all risk behaviours except riding with a drinking driver, relative to youth who only consumed alcohol. No association was observed for youth who consumed alcohol and energy drinks on separate occasions. Youth who use AmED demonstrate a higher risk profile for driving under the influence of alcohol or cannabis, than youth who use alcohol alone. Future research should explore the biopsychosocial pathways that may explain why using energy drinks enhances the already heightened risk posed by alcohol on other health-related behaviours such as driving under the influence.

Changes of loggerhead turtle (Caretta caretta) dive behavior associated with tropical storm passage during the inter-nesting period.

To improve conservation strategies for threatened sea turtles, more knowledge on their ecology, behavior, and how they cope with severe and changing weather conditions is needed. Satellite and animal motion datalogging tags were used to study the inter-nesting behavior of two female loggerhead turtles in the Gulf of Mexico, which regularly has hurricanes and tropical storms during nesting season. We contrast the behavioral patterns and swimming energetics of these two turtles, the first tracked in calm weather and the second tracked before, during and after a tropical storm. Turtle 1 was highly active and swam at the surface or submerged 95% of the time during the entire inter-nesting period, with a high estimated specific oxygen consumption rate (0.95 ml min-1 kg-0.83). Turtle 2 was inactive for most of the first 9 days of the inter-nesting period, during which she rested at the bottom (80% of the time) with low estimated oxygen consumption (0.62 ml min-1 kg-0.83). Midway through the inter-nesting period, turtle 2 encountered a tropical storm and became highly active (swimming 88% of the time during and 95% after the storm). Her oxygen consumption increased significantly to 0.97 ml min-1 kg-0.83 during and 0.98 ml min-1 kg-0.83 after the storm. However, despite the tropical storm, turtle 2 returned to the nesting beach, where she successfully re-nested 75 m from her previous nest. Thus, the tropical storm had a minor effect on this female's individual nesting success, even though the storm caused 90% loss nests at Casey Key.

Rfx6 directs islet formation and insulin production in mice and humans.

Insulin from the beta-cells of the pancreatic islets of Langerhans controls energy homeostasis in vertebrates, and its deficiency causes diabetes mellitus. During embryonic development, the transcription factor neurogenin 3 (Neurog3) initiates the differentiation of the beta-cells and other islet cell types from pancreatic endoderm, but the genetic program that subsequently completes this differentiation remains incompletely understood. Here we show that the transcription factor Rfx6 directs islet cell differentiation downstream of Neurog3. Mice lacking Rfx6 failed to generate any of the normal islet cell types except for pancreatic-polypeptide-producing cells. In human infants with a similar autosomal recessive syndrome of neonatal diabetes, genetic mapping and subsequent sequencing identified mutations in the human RFX6 gene. These studies demonstrate a unique position for Rfx6 in the hierarchy of factors that coordinate pancreatic islet development in both mice and humans. Rfx6 could prove useful in efforts to generate beta-cells for patients with diabetes.

Why do older people oppose physician-assisted dying? A qualitative study.

BACKGROUND: Physician-assisted dying at the end of life has become a significant issue of public discussion. While legally available in a number of countries and jurisdictions, it remains controversial and illegal in New Zealand. AIM: The study aimed to explore the reasons some healthy older New Zealanders oppose physician-assisted dying in order to inform current debate. DESIGN: Recorded interviews were transcribed and analysed by the authors after some edits had been made by respondents. SETTING/PARTICIPANTS: In all, 11 older participants (over 65 years) who responded to advertisements placed in Grey Power magazines and a University of Auckland email list were interviewed for around 1 h and asked a number of open-ended questions. RESULTS: Four central themes opposing physician-assisted dying were identified from the interviews: one's personal experience with health care and dying and death, religious reasoning and beliefs, slippery slope worries and concern about potential abuses if physician-assisted dying were legalised. CONCLUSIONS: An important finding of the study suggests that how some older individuals think about physician-assisted dying is strongly influenced by their past experiences of dying and death. While some participants had witnessed good, well-managed dying and death experiences which confirmed for them the view that physician-assisted dying was unnecessary, those who had witnessed poor dying and death experiences opposed physician-assisted dying on the grounds that such practices could come to be abused by others.

Operationalizing Equity-centered Implementation Through Person-centered Care Capacity-building with HIV Service Organizations: The SUSTAIN Approach.

Capacity-building in trauma-informed care and harm reduction approaches with Southern HIV service organizations must be implemented in ways that foster trust and spur organizational change. Using an equity-centered implementation science framework, this study examines implementation strategies of the SUSTAIN COMPASS Coordinating Center's person-centered care (PCC) capacity-building interventions. METHODS: Fifty-eight (58) in-depth qualitative interviews with staff (N=116) who received PCC capacity-building were analyzed using modified grounded theory. RESULTS: Analysis identified four factors of equity-centered implementation that facilitated PCC capacity-building implementation. 1) Innovation factors: SUSTAIN models PCC approaches when implementing PCC capacity-building. 2) Inner factors: SUSTAIN employs PCC approaches. 3) Outer factors: SUSTAIN highlights socio-political factors that may influence PCC implementation. 4) Bridging factors: SUSTAIN facilitates partnerships to promote PCC learning and sustainability. CONCLUSION: SUSTAIN PCC capacity-building advances health equity through operationalizing personcentered care in capacity-building implementation.