Background
Upper respiratory tract infections (URTIs) are important triggers for asthma exacerbations. We hypothesized that inhalation of the anti‐viral cytokine, interferon (IFN)‐β, during URTI, ...could prevent these exacerbations.
Objective
To evaluate the efficacy of on‐demand inhaled IFN‐β1a (AZD9412) to prevent severe asthma exacerbations following symptomatic URTI.
Methods
This was a randomized, double‐blind, placebo‐controlled trial in which patients with severe asthma (GINA 4‐5; n = 121) reporting URTI symptoms were randomized to 14 days of once‐daily nebulized AZD9412 or placebo. The primary endpoint was severe exacerbations during treatment. Secondary endpoints included 6‐item asthma control questionnaire (ACQ‐6) and lung function. Exploratory biomarkers included IFN‐response markers in serum and sputum, blood leucocyte counts and serum inflammatory cytokines.
Results
Following a pre‐planned interim analysis, the trial was terminated early due to an unexpectedly low exacerbation rate. Asthma worsenings were generally mild and tended to peak at randomization, possibly contributing to the lack of benefit of AZD9412 on other asthma endpoints. Numerically, AZD9412 did not reduce severe exacerbation rate, ACQ‐6, asthma symptom scores or reliever medication use. AZD9412 improved lung function (morning peak expiratory flow; mPEF) by 19.7 L/min. Exploratory post hoc analyses indicated a greater mPEF improvement by AZD9412 in patients with high blood eosinophils (>0.3 × 109/L) at screening and low serum interleukin‐18 relative change at pre‐treatment baseline. Pharmacodynamic effect of AZD9412 was confirmed using IFN‐response markers.
Conclusions & Clinical Relevance
Colds did not have the impact on asthma patients that was expected and, due to the low exacerbation rate, the trial was stopped early. On‐demand AZD9412 treatment did not numerically reduce the number of exacerbations, but did attenuate URTI‐induced worsening of mPEF. Severe asthma patients with high blood eosinophils or low serum interleukin‐18 response are potential subgroups for further investigation of inhaled IFN‐β1a.
Acetaminophen is widely used as first-line therapy for chronic pain because of its perceived safety and the assumption that, unlike nonsteroidal anti-inflammatory drugs, it has little or no effect on ...blood pressure (BP). Although observational studies suggest that acetaminophen may increase BP, clinical trials are lacking. We, therefore, studied the effects of regular acetaminophen dosing on BP in individuals with hypertension.
In this double-blind, placebo-controlled, crossover study, 110 individuals were randomized to receive 1 g acetaminophen 4× daily or matched placebo for 2 weeks followed by a 2-week washout period before crossing over to the alternate treatment. At the beginning and end of each treatment period, 24-hour ambulatory BPs were measured. The primary outcome was a comparison of the change in mean daytime systolic BP from baseline to end of treatment between the placebo and acetaminophen arms.
One-hundred three patients completed both arms of the study. Regular acetaminophen, compared with placebo, resulted in a significant increase in mean daytime systolic BP (132.8±10.5 to 136.5±10.1 mm Hg acetaminophen vs 133.9±10.3 to 132.5±9.9 mm Hg placebo;
<0.0001) with a placebo-corrected increase of 4.7 mm Hg (95% CI, 2.9-6.6) and mean daytime diastolic BP (81.2±8.0 to 82.1±7.8 mm Hg acetaminophen vs 81.7±7.9 to 80.9±7.8 mm Hg placebo;
=0.005) with a placebo-corrected increase of 1.6 mm Hg (95% CI, 0.5-2.7). Similar findings were seen for 24-hour ambulatory and clinic BPs.
Regular daily intake of 4 g acetaminophen increases systolic BP in individuals with hypertension by ≈5 mm Hg when compared with placebo; this increases cardiovascular risk and calls into question the safety of regular acetaminophen use in this situation. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01997112. URL: https://www.clinicaltrialsregister.eu; Unique identifier: 2013-003204-40.
Context
The aim of the National Athletic Trainers' Association Inter-Association Task Force (NATA-IATF) preseason heat-acclimatization guidelines was to acclimatize high school athletes to the ...environment during the first 2 weeks of the preseason and reduce the risk of exertional heat illness.
Objective
To identify barriers and facilitators that high school athletic trainers (ATs) encountered when implementing the NATA-IATF guidelines.
Design
Qualitative study.
Setting
Individual phone interviews with all participants.
Patients or Other Participants
Thirty-three ATs (16 men, 17 women; age = 36.0 ± 12.0 years, athletic training experience = 12.9 ± 10.5 years) representing 19 states (4 with state mandates) were interviewed before data saturation was achieved. Participants were purposefully sampled from a larger investigation based on stratification of US Census region and preidentified high school compliance with the NATA-IATF guidelines.
Main Outcome Measure(s)
A cross-sectional, semistructured phone interview (6 steps) was conducted with each participant and then transcribed verbatim. A 7-person research team (5 coders, 2 auditors) coded the data into themes and categories, focusing on consensus of data placement to reduce bias and ensure accuracy.
Results
Facilitators and barriers that influenced successful guideline implementation were (1) perceived stakeholder access, (2) perceived stakeholder role, (3) capability and capacity, (4) school culture, (5) logistical support, (6) resources, (7) physical environment, and (8) consistency of the guidelines. Overall, participants discussed facilitators and barriers within each category based on their experiences and circumstances.
Conclusions
Athletic trainers faced numerous concerns regarding compliance with the NATA-IATF preseason heat-acclimatization guidelines. Multiple levels of influence should be targeted to improve implementation. These include intrapersonal factors by giving ATs the education and self-efficacy to support advocacy for implementation, interpersonal components by establishing strong collaborative networks for change, community and environmental factors by optimizing school culture and community resources for implementation, and policy aspects by establishing consistent guidelines across all bodies.
Although developmental theories and popular accounts suggest that midlife is a time of turmoil and change, longitudinal studies of personality traits have generally found stability of rank order and ...little or no change in mean levels. Using data from 2,274 men and women in their 40s retested after 6 to 9 years, the present study examined two hypotheses: (a) that retest correlations should be no higher than about .60 and (b) that there should be small decreases in Neuroticism, Extraversion, and Openness, and small increases in Agreeableness and Conscientiousness. The study also explored the effects of recalled life events on subsequent personality scores. Results did not support the first hypothesis; uncorrected retest correlations uniformly exceeded .60. This was true for all personality traits, including facets of Agreeableness and Conscientiousness not previously included in longitudinal studies. The hypothesized decreases in Neuroticism, Extraversion, and Openness were found, but Conscientiousness showed a small decrease instead of the predicted increase. Life events in general showed very little influence on the levels of personality traits, although some effects were seen for changes in job and marital status that warrant further research.
The present work describes the emulsifying properties of dried orange pulp fibers. Their surface activity is believed to originate from the proteins (∼8%) and pectins (∼35%), while the cellulose ...(>45%) enables the fibers to act as thickener. The surface activity of the dried fibers was compared to the one of their pre-activated counterparts. High pressure homogenization at 700 bar prior drying was used for this, which allowed obtaining significantly finer emulsions. Rheology of the emulsions demonstrated that at same fiber:water ratio, a critical concentration (c*) of 3.1 wt% was found when using pre-activated fibers. This corresponded well with the c* of suspensions without oil. The non-activated fiber emulsions had a much higher c*. Interestingly, no coalescence could be observed at room temperature during 2 weeks when G′ reached 345Pa. CLSM imaging demonstrated increased amounts of proteins at the oil-water interface in activated fiber emulsions, which explained their higher surface activity.
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•Opening of the plant cell wall matrix through homogenization leads to finer O/W emulsions.•The emulsification process will equally impact the oil droplets and the insoluble particles.•The endogenous proteins will migrate to the O/W interface once released from the matrix.•The cellulose network will provide long-term stability by thickening of the continuous phase.•Long-term stability is reached once a threshold G′ is obtained, independently from fiber history.
Fibromyalgia patients frequently report cognitive abnormalities. As the hippocampus plays an important role in learning and memory, we determined whether individuals with fibromyalgia had smaller ...hippocampal volume compared with healthy control participants.
T1-weighted structural magnetic resonance imaging (MRI) scans were acquired from 40 female participants with fibromyalgia and 22 female healthy controls. The volume of the hippocampus was estimated using the software FreeSurfer. An analysis of covariance model controlling for potentially confounding factors of age, whole brain size, MRI signal quality, and Beck Depression Inventory scores were used to determine significant group differences.
Fibromyalgia participants had significantly smaller hippocampi in both left (F1,56=4.55, P=0.037, η (2) p=0.08) and right hemispheres (F1,56=5.89, P=0.019, η (2) p=0.10). No significant effect of depression was observed in either left or right hemisphere hippocampal volume (P=0.813 and P=0.811, respectively).
Potential mechanisms for reduced hippocampal volume in fibromyalgia include abnormal glutamate excitatory neurotransmission and glucocorticoid dysfunction; these factors can lead to neuronal atrophy, through excitotoxicity, and disrupt neurogenesis in the hippocampus. Hippocampal atrophy may play a role in memory and cognitive complaints among fibromyalgia patients.
Objective
To investigate whether antidrug antibodies and/or drug non‐trough levels predict the long‐term treatment response in a large cohort of patients with rheumatoid arthritis (RA) treated with ...adalimumab or etanercept and to identify factors influencing antidrug antibody and drug levels to optimize future treatment decisions.
Methods
A total of 331 patients from an observational prospective cohort were selected (160 patients treated with adalimumab and 171 treated with etanercept). Antidrug antibody levels were measured by radioimmunoassay, and drug levels were measured by enzyme‐linked immunosorbent assay in 835 serial serum samples obtained 3, 6, and 12 months after initiation of therapy. The association between antidrug antibodies and drug non‐trough levels and the treatment response (change in the Disease Activity Score in 28 joints) was evaluated.
Results
Among patients who completed 12 months of followup, antidrug antibodies were detected in 24.8% of those receiving adalimumab (31 of 125) and in none of those receiving etanercept. At 3 months, antidrug antibody formation and low adalimumab levels were significant predictors of no response according to the European League Against Rheumatism (EULAR) criteria at 12 months (area under the receiver operating characteristic curve 0.71 95% confidence interval (95% CI) 0.57, 0.85). Antidrug antibody–positive patients received lower median dosages of methotrexate compared with antidrug antibody–negative patients (15 mg/week versus 20 mg/week; P = 0.01) and had a longer disease duration (14.0 versus 7.7 years; P = 0.03). The adalimumab level was the best predictor of change in the DAS28 at 12 months, after adjustment for confounders (regression coefficient 0.060 95% CI 0.015, 0.10, P = 0.009). Etanercept levels were associated with the EULAR response at 12 months (regression coefficient 0.088 95% CI 0.019, 0.16, P = 0.012); however, this difference was not significant after adjustment. A body mass index of ≥30 kg/m2 and poor adherence were associated with lower drug levels.
Conclusion
Pharmacologic testing in anti–tumor necrosis factor–treated patients is clinically useful even in the absence of trough levels. At 3 months, antidrug antibodies and low adalimumab levels are significant predictors of no response according to the EULAR criteria at 12 months.
Introduction: MicroRNA 122 (miR-122) is a new circulating biomarker for liver injury, which increases earlier than conventional markers in patients with acetaminophen hepatotoxicity. However, as ...co-ingestion of ethanol is common with drug overdose, a confounding effect of acute ethanol consumption on serum miR-122 must be examined. Methods: Blood was collected from healthy volunteers before and after recreational consumption of ethanol. Routine biochemistry and haematology measurements were performed, and serum miR-122 was measured by qPCR. The primary outcome was the difference in serum miR-122 with ethanol consumption. Results: We recruited 18 participants (72% male). Their mean serum ethanol concentration was 113 mg/dl (95% confidence interval CI 91-135 mg/dl) after consuming ethanol. Serum miR-122 increased from a mean of 71.3 million (95% CI 29.3-113.2 million) to 139.1 million (95% CI 62.6-215.7 million) copies/ml (2.2-fold increase). There was no significant difference in serum alanine aminotransferase activity before and after ethanol consumption. Conclusion: miR-122 increased with moderate ethanol consumption, but the fold change was modest. As increases with acetaminophen toxicity are 100- to 10 000-fold, moderate ethanol intoxication is unlikely to confound the use of this biomarker of hepatotoxicity.
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