Polychlorinated biphenyl and polybrominated diphenyl ether profiles vary with feeding ecology and marine rearing distribution among 10 Chinook salmon (Oncorhynchus tshawytscha) stocks in the North Pacific Ocean.

Chinook salmon (Oncorhynchus tshawytscha) along the west coast of North America have experienced significant declines in abundance and body size over recent decades due to several anthropogenic stressors. Understanding the reasons underlying the relatively high levels of persistent organic pollutants (POPs) in Chinook stocks is an important need, as it informs recovery planning for this foundation species, as well for the Chinook-dependent Resident killer whales (Orcinus orca, RKW) of British Columbia (Canada) and Washington State (USA). We evaluated the influence of stock-related differences in feeding ecology, using stable isotopes, and marine rearing ground on the concentrations and patterns of polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs) in Chinook salmon. A principal components analysis (PCA) revealed a clear divergence of PCB and PBDE congener patterns between Chinook with a nearshore rearing distribution ('shelf resident') versus a more offshore distribution. Shelf resident Chinook had 12-fold higher PCB concentrations and 46-fold higher PBDE concentrations relative to offshore stocks. Shelf resident Chinook had PCB and PBDE profiles that were heavier and dominated by more bioaccumulative congeners, respectively. The higher δ13C and δ15N in shelf resident Chinook compared to the offshore rearing stocks, and their different marine distributions explain the large divergence in contaminant levels and profiles, with shelf resident stocks being heavily influenced by land-based sources of industrial contamination. Results provide compelling new insight into the drivers of contaminant accumulation in Chinook salmon, raise important questions about the consequences for their health, and explain a major pathway to the heavily POP-contaminated Resident killer whales that consume them.

The role of sleep in the link between cannabis use and memory function: evidence from a cross-sectional study.

Background: It is known that cannabis use affects memory and sleep problems independently. However, to date, how memory and sleep problems may interact as a result of cannabis use remains unknown.Objectives: We performed a secondary analysis of existing data to determine whether sleep quality mediates the association between cannabis use and memory and whether sex moderated these effects.Methods: A total of 141 adults with cannabis use disorder (CUD) (83 men) and 87 without CUD (39 men) participated in this study. Outcome measures included self-reported sleep problems from the past 7 days (Marijuana Withdrawal Checklist), learning and memory performance via the short visual object learning task (sVOLT), short visual object learning task delayed (sVOLTd), and verbal memory via the N-back. Bootstrapped mediation and moderated mediation analyses were run to test if sleep quality mediated the association between cannabis use and memory outcomes and whether sex moderated these effects, respectively.Results: Sleep quality mediated the effect of group (i.e. adults with and without CUD) on sVOLT efficiency scores (indirect effect ß = -.08, 95% CI [-0.14, -0.04]) and sVOLTd efficiency scores (indirect effect ß = -.09, 95% CI [-0.14, -0.04]), where greater sleep difficulties was associated with poorer memory performance (decreased efficiency scores). Sex did not moderate these relationships.Conclusion: These initial findings of a mediating role of sleep in the association between CUD and visual learning memory highlight potential critical downstream effects of disrupted sleep in those with CUD and suggest the importance of investigating sleep in CUD.

Regulation of mouse exploratory behaviour by irradiance and cone-opponent signals.

BACKGROUND: Animal survival depends on the ability to adjust behaviour according to environmental conditions. The circadian system plays a key role in this capability, with diel changes in the quantity (irradiance) and spectral content ('colour') of ambient illumination providing signals of time-of-day that regulate the timing of rest and activity. Light also exerts much more immediate effects on behaviour, however, that are equally important in shaping daily activity patterns. Hence, nocturnal mammals will actively avoid light and dramatically reduce their activity when light cannot be avoided. The sensory mechanisms underlying these acute effects of light are incompletely understood, particularly the importance of colour. RESULTS: To define sensory mechanisms controlling mouse behaviour, we used photoreceptor-isolating stimuli and mice with altered cone spectral sensitivity (Opn1mwR), lacking melanopsin (Opn1mwR; Opn4-/-) or cone phototransduction (Cnga3-/-) in assays of light-avoidance and activity suppression. In addition to roles for melanopsin-dependent irradiance signals, we find a major influence of spectral content in both cases. Hence, remarkably, selective increases in S-cone irradiance (producing a blue-shift in spectrum replicating twilight) drive light-seeking behaviour and promote activity. These effects are opposed by signals from longer-wavelength sensitive cones, indicating a true spectrally-opponent mechanism. Using c-Fos-mapping and multielectrode electrophysiology, we further show these effects are associated with a selective cone-opponent modulation of neural activity in the key brain site implicated in acute effects of light on behaviour, the subparaventricular zone. CONCLUSIONS: Collectively, these data reveal a mechanism whereby blue-shifts in the spectrum of environmental illumination, such as during twilight, promote mouse exploratory behaviour.

Temperature-controlled Laminar Airflow (TLA) in symptomatic severe asthma - a post hoc analysis of severe exacerbations, quality of life and health economics.

PURPOSE: Uncontrolled severe asthma constitutes a major economic burden to society. Add-ons to standard inhaled treatments include inexpensive oral corticosteroids and expensive biologics. Nocturnal treatment with Temperature-controlled Laminar Airflow (TLA; Airsonett®) could be an effective, safe and cheaper alternative. The potential of TLA in reducing severe asthma exacerbations was addressed in a recent randomised placebo-controlled trial (RCT) in patients with severe asthma (Global Initiative for Asthma (GINA) step 4/5), but the results were inconclusive. We re-analysed the RCT with severe exacerbations stratified by the level of baseline asthma symptoms and Quality of Life. METHODS: More uncontrolled patients, defined by Asthma Control Questionnaire 7 (ACQ7) > 3, EuroQoL 5-Dimension Questionnaire Visual Analogue Scale (EQ5D-VAS) ≤ 65 and Asthma Quality of Life Questionnaire (AQLQ) ≤ 4 were selected for re-analysis. The rates of severe asthma exacerbations, changes in QoL and health-economics were analysed and compared between TLA and placebo. RESULTS: The study population included 226 patients (113 TLA / 113 placebo.) The rates of severe asthma exacerbations were reduced by 33, 31 and 25% (p = 0.083, 0.073, 0.180) for TLA compared to placebo, dependent on selected control measures (ACQ7, EQ5D-VAS, AQLQ, respectively). For patients with less control defined by AQLQ≤4, the difference in mean AQLQ0-12M between TLA and placebo was 0.31, 0.33, 0.26 (p = 0.085, 0.034, 0.150), dependent on selected covariate (AQLQ, EQ5D-VAS, ACQ7, respectively). For patients with poor control defined by ACQ7 > 3, the difference in EQ5D-5 L utility scores between TLA and placebo was significant at 9 and 12 months with a cost-effective ICER. The results from the original study did not demonstrate these differences. CONCLUSION: This post hoc analysis demonstrated an effect of TLA over placebo on severe exacerbations, asthma control and health economics in a subgroup of patients with more symptomatic severe allergic asthma. The results are consistent with the present recommendations for TLA. However, these differences were not demonstrated in the full study. Several explanations for the different outcomes have been outlined, which should be addressed in future studies. FUNDING: NIHR Health Technology Assessment Programme and Portsmouth Hospitals NHS Trust.

Association Between Minimum Inhibitory Concentration, Beta-lactamase Genes and Mortality for Patients Treated With Piperacillin/Tazobactam or Meropenem From the MERINO Study.

INTRODUCTION: This study aims to assess the association of piperacillin/tazobactam and meropenem minimum inhibitory concentration (MIC) and beta-lactam resistance genes with mortality in the MERINO trial. METHODS: Blood culture isolates from enrolled patients were tested by broth microdilution and whole genome sequencing at a central laboratory. Multivariate logistic regression was performed to account for confounders. Absolute risk increase for 30-day mortality between treatment groups was calculated for the primary analysis (PA) and the microbiologic assessable (MA) populations. RESULTS: In total, 320 isolates from 379 enrolled patients were available with susceptibility to piperacillin/tazobactam 94% and meropenem 100%. The piperacillin/tazobactam nonsusceptible breakpoint (MIC >16 mg/L) best predicted 30-day mortality after accounting for confounders (odds ratio 14.9, 95% confidence interval [CI] 2.8-87.2). The absolute risk increase for 30-day mortality for patients treated with piperacillin/tazobactam compared with meropenem was 9% (95% CI 3%-15%) and 8% (95% CI 2%-15%) for the original PA population and the post hoc MA populations, which reduced to 5% (95% CI -1% to 10%) after excluding strains with piperacillin/tazobactam MIC values >16 mg/L. Isolates coharboring extended spectrum ß-lactamase (ESBL) and OXA-1 genes were associated with elevated piperacillin/tazobactam MICs and the highest risk increase in 30-day mortality of 14% (95% CI 2%-28%). CONCLUSIONS: After excluding nonsusceptible strains, the 30-day mortality difference from the MERINO trial was less pronounced for piperacillin/tazobactam. Poor reliability in susceptibility testing performance for piperacillin/tazobactam and the high prevalence of OXA coharboring ESBLs suggests that meropenem remains the preferred choice for definitive treatment of ceftriaxone nonsusceptible Escherichia coli and Klebsiella.

The relationship between diabetes and depressive symptoms in men with or at risk of HIV infection.

OBJECTIVES: The aim of the study was to compare the prevalence of comorbid diabetes and depressive symptoms in men living with HIV (MLWH) with that in men without HIV infection and to determine associations between glycaemic control and depressive symptoms. METHODS: Participants included 920 MLWH and 840 men without HIV infection from the Multicenter AIDS Cohort Study (MACS) with available data regarding glycaemic status [categorized as normal for fasting blood glucose (FBG) < 100 mg/dL, prediabetes for FBG 100-125 mg/dL, and diabetes, defined by self-report, diabetes medication use or FBG ≥ 126 mg/dL on at least two consecutive visits, with diabetes classified as controlled if Hemoglobin A1c (HbA1C) < 7.5% and uncontrolled if HbA1C ≥ 7.5%]. Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression (CES-D) score, with CES-D ≥ 16 scores classified as elevated depressive symptoms. A modified Poisson regression model with robust variance was used and adjusted for covariates including HIV serostatus. RESULTS: Compared to men without HIV infection, MLWH had a higher mean CES-D score, but a similar prevalence of diabetes (11.3% versus 12.8%, respectively; P = 0.33). The concomitant prevalence of diabetes and elevated depressive symptoms did not differ by HIV serostatus (P = 0.215). In an adjusted analysis, men with uncontrolled diabetes had a greater prevalence of depressive symptoms compared to men with normoglycaemia (prevalence ratio = 1.43; 95% confidence interval 1.11, 1.84). The association between glycaemic status and depressive symptoms did not differ by HIV serostatus (P = 0.22 for interaction). CONCLUSIONS: Both controlled and uncontrolled diabetes were independently associated with a greater prevalence of depressive symptoms, regardless of HIV serostatus. These results highlight the importance of identifying depression in people with diabetes.

Testosterone use and shorter electrocardiographic QT interval duration in men living with and without HIV.

OBJECTIVES: Testosterone usage (T-use) may alter risk factors for sudden cardiac death in men living with HIV (MLWH). Electrocardiographic QT interval prolongation, which could potentiate ventricular arrhythmias, has previously been associated with HIV infection and, separately, with low testosterone levels. We investigated whether T-use shortens the QT interval duration in MLWH and HIV-uninfected men. METHODS: We utilized data from the Multicenter AIDS Cohort Study, a prospective, longitudinal study of HIV infection among men who have sex with men. Multivariable linear regression analyses were used to evaluate associations between T-use and corrected QT interval (QTc) duration. RESULTS: Testosterone usage was more common in MLWH compared with HIV-uninfected men (19% vs. 9%). In a multivariable regression analysis, T-use was associated with a 5.7 ms shorter QT interval [95% confidence interval (CI): -9.5 to -1.9; P = 0.003). Furthermore, stronger associations were observed for prolonged duration of T-use and recent timing of T-use. CONCLUSIONS: This study is the first known analysis of T-use and QTc interval in MLWH. Overall, our data demonstrate that recent T-use is associated with a shorter QTc interval. Increased T-use duration above a threshold of ≥ 50% of visits in the preceding 5 years was associated with a shorter QTc interval while lesser T-use duration was not.

The MOBILISE study: utilisation of ambulatory pumps in the inpatient setting to administer continuous antibiotic infusions-a randomised controlled trial.

In the inpatient setting, antibiotics are generally administered via bedside pumps with multiple daily dosing. Utilisation of a continuous antibiotic infusion (CAI) instead might have patient and nursing satisfaction, workflow efficiencies and infection control benefits. We aimed to study the utilisation of CAI in the inpatient setting for routine antibiotic administration. Patients receiving a peripherally inserted central venous catheter (PICC) for antibiotic administration were screened for the study. The patients were randomised to either (1) standard pump and intermittent antibiotic administration (IAA) or (2) CAI via an ambulatory pump. An accelerometer placed on the ankle was used to assess patient activity. Nursing and patient satisfaction surveys were also carried out. Forty patients met the study criteria for enrolment with 21 patients being enrolled in the CAI arm of the study. One hundred and five days of accelerometer recordings were available for analysis. The geometric mean activity was 45 min/day in the standard arm and 64 min/day in the CAI arm. This represented a 42% (95% CI: -14 to 133%, p = 0.16) difference in activity between the two groups. Nursing staff reported that they spent less time throughout their shift attending the antibiotic line or pump in patients who were in the CAI arm of the study (p < 0.001). In addition, patients in this arm of the study were more likely to recommend this method of administration of antibiotics to a family member (p =0.0001). The MOBILISE study showed nursing and patient satisfaction when CAI were utilised in the inpatient setting. A statistically non-significant difference in mobility was seen. The trial was registered (28/03/2018) with the Australia New Zealand Clinical Trials Registry (ACTRN12618000452291).

Subclinical cardiovascular disease in HIV controller and long-term nonprogressor populations.

OBJECTIVES: Elite controllers (ECs), viraemic controllers (VCs), and long-term nonprogressors (LTNPs) control HIV viral replication or maintain CD4 T-cell counts without antiretroviral therapy, but may have increased cardiovascular disease (CVD) risk compared to HIV-uninfected persons. We evaluated subclinical carotid and coronary atherosclerosis and inflammatory biomarker levels among HIV controllers, LTNPs and noncontrollers and HIV-uninfected individuals in the Multicenter AIDS Cohort Study (MACS) and the Women's Interagency HIV Study (WIHS). METHODS: We measured carotid plaque presence and common carotid artery intima-media thickness (IMT) in 1729 women and 1308 men, and the presence of coronary artery calcium and plaque in a subgroup of men. Associations between HIV control category and carotid and coronary plaque prevalences were assessed by multivariable regression analyses adjusting for demographics and CVD risk factors. Serum inflammatory biomarker concentrations [soluble CD163 (sCD163), soluble CD14 (sCD14), galectin-3 (Gal-3), galectin-3 binding protein (Gal-3BP) and interleukin (IL)-6] were measured and associations with HIV control category assessed. RESULTS: We included 135 HIV controllers (30 ECs) and 135 LTNPs in the study. Carotid plaque prevalence and carotid IMT were similar in HIV controllers, LTNPs and HIV-uninfected individuals. HIV controllers and LTNPs had lower prevalences of carotid plaque compared to viraemic HIV-infected individuals. The prevalence of coronary atherosclerosis was similar in HIV controllers/LTNPs compared to HIV-uninfected and viraemic HIV-infected men. Controllers and LTNPs had higher concentrations of sCD163 and sCD14 compared to HIV-uninfected persons. CONCLUSIONS: Subclinical CVD was similar in HIV controllers, LTNPs and HIV-uninfected individuals despite elevated levels of some inflammatory biomarkers. Future studies of HIV controllers and LTNPs are needed to characterize the risk of CVD among HIV-infected persons.

Patient-reported burden of hereditary angioedema: findings from a patient survey in the United States.

BACKGROUND: Hereditary angioedema (HAE) with C1-inhibitor deficiency is associated with painful, potentially fatal attacks affecting subcutaneous or submucosal tissues. OBJECTIVE: To evaluate HAE burden from the patients' perspective. METHODS: This was a noninterventional survey of patients with HAE in the United States, conducted from March 17 to April 28, 2017. Patients were recruited through the US Hereditary Angioedema Association. Key eligibility criteria included the following: (1) aged 18 years and older, (2) self-reported physician diagnosis of HAE type I or II, (3) 1 or more HAE attacks or prodromal symptoms within the last year, and (4) receipt of HAE medication for an attack within the last 2 years. Descriptive analyses were conducted. RESULTS: A total of 445 patients completed the survey. Most patients (92.8%) were aged 18 to 64 years with HAE type I (78.4%) and had a positive family history (78.4%). Mean (SD) ages at symptom onset and diagnosis were 12.5 (9.1) and 20.1 (13.7) years, respectively. Most patients (78.7%) experienced an attack within the past month. The abdomen (58.0%) and extremities (46.1%) were commonly affected sites; pain (73.9%) and abdominal (57.0%) and nonabdominal (55.1%) swelling were frequently reported symptoms. Most patients (68.5%) had received or were currently receiving long-term prophylaxis. Most patients (88.8%) reported visiting allergists or immunologists, whereas 9.2% visited emergency departments or urgent care clinics. Per the Hospital Anxiety and Depression Scale, 49.9% and 24.0% of respondents had anxiety and depression, respectively. Mean Hereditary Angioedema-Quality of Life scores were generally lower with higher attack frequency. General health was "poor" or "fair" for 24.8% of patients. Mean (SD) percentage impairments were 5.9% (14.1%) for absenteeism, 23.0% (25.8%) for presenteeism, 25.4% (28.1%) for work productivity loss, and 31.8% (29.7%) for activity impairment. CONCLUSION: Despite treatment advances, patients with HAE in the United States continue to have a high burden of illness.