MPYS, also known as STING and MITA, is an interferon (IFN)β stimulator essential for host defense against RNA, DNA viruses and intracellular bacteria. MPYS also facilitates the adjuvant activity of ...DNA vaccines. Here, we report identification of a distinct human MPYS haplotype that contains three non-synonymous single nucleotide polymorphisms (SNPs), R71H-G230A-R293Q (thus, named the HAQ haplotype). We estimate, in two cohorts (1,074 individuals), that ∼3% of Americans are homozygous for this HAQ haplotype. HAQ MPYS exhibits a > 90% loss in the ability to stimulate IFNβ production. Furthermore, fibroblasts and macrophage cells expressing HAQ are defective in Listeria monocytogenes infection-induced IFNβ production. Lastly, we find that the loss of IFNβ activity is due primarily to the R71H and R293Q SNPs in HAQ. We hypothesize that individuals carrying HAQ may exhibit heightened susceptibility to viral infection and respond poorly to DNA vaccines.
In many space, astrophysical, and laboratory plasmas the energy contained in the magnetic field or plasma flow exceeds the thermal energy. Magnetic field ( ) annihilation, often enabled by magnetic ...reconnection, transfers magnetic energy to particles. Shocks transfer bulk flow energy to particles. If there is a sufficiently large energy transfer, strong turbulence ( / B ∼ 1) develops, which, in turn, can result in nonthermal acceleration. In this article, we investigate acceleration in a finite-sized region of strong turbulence driven by magnetic reconnection with analytical modeling and test-particle simulations. This research is based on detailed observations in the Earth's magnetotail. We find that the primary transfer of magnetic energy to particle energy is advanced by large-amplitude electric field structures ( ) generated by the strong turbulence. To no surprise, ion energization is dominated by intense DC , near the ion cyclotron frequency (fci), and/or variations at scales near the ion gyroradius. Electron energization comes from higher-frequency . The turbulent cascade continuously regenerates near fci and higher frequencies. Importantly, the turbulence also creates magnetic depletions that can trap particles and considerably increase their dwell time in regions of strong energization, which substantially enhances nonthermal acceleration. Moreover, energization is primarily perpendicular to , so particles have difficulty escaping regions of depleted , which can lead to near runaway acceleration. We discuss how this process may be active in large-scale settings such as supernova shells and may contribute, at least in in part, to the development of the cosmic ray spectrum.
Patient self-reports are the primary method for capturing the experience of pain, and diaries are often used to collect patient self-reports. This study was designed to determine if momentary ...monitoring of pain with an electronic diary affected pain levels over time, if it affected weekly recall of pain, and if daily sampling density affected compliance rates and patients' reactions to the study. Ninety-one patients with chronic pain were randomized into four groups with differing levels of momentary monitoring over 2 weeks. Little support was found for reactivity defined as temporal shifts in pain over the study or as changes in recalled weekly pain due to momentary monitoring. Compliance with the electronic diary protocol was 94% or better, and was not related to sampling density. Patients reported little difficulty with the diary procedures and were not unduly burdened by the protocol.
Although systemic lupus erythematosus is associated with premature myocardial infarction, the prevalence of underlying atherosclerosis and its relation to traditional risk factors for cardiovascular ...disease and lupus-related factors have not been examined in a case-control study.
In 197 patients with lupus and 197 matched controls, we performed carotid ultrasonography, echocardiography, and an assessment for risk factors for cardiovascular disease. The patients were also evaluated with respect to their clinical and serologic features, inflammatory mediators, and disease treatment.
The risk factors for cardiovascular disease were similar among patients and controls. Atherosclerosis (carotid plaque) was more prevalent among patients than the controls (37.1 percent vs. 15.2 percent, P<0.001). In multivariate analysis, only older age, the presence of systemic lupus erythematosus (odds ratio, 4.8; 95 percent confidence interval, 2.6 to 8.7), and a higher serum cholesterol level were independently related to the presence of plaque. As compared with patients without plaque, patients with plaque were older, had a longer duration of disease and more disease-related damage, and were less likely to have multiple autoantibodies or to have been treated with prednisone, cyclophosphamide, or hydroxychloroquine. In multivariate analyses including patients with lupus, independent predictors of plaque were a longer duration of disease, a higher damage-index score, a lower incidence of the use of cyclophosphamide, and the absence of anti-Smith antibodies.
Atherosclerosis occurs prematurely in patients with systemic lupus erythematosus and is independent of traditional risk factors for cardiovascular disease. The clinical profile of patients with lupus and atherosclerosis suggests a role for disease-related factors in atherogenesis and underscores the need for trials of more focused and effective antiinflammatory therapy.
INTRODUCTIONThere is considerable controversy about the development of dependence among e-cigarette users. This study describes the average amount of time using e-cigarettes before dependence ...milestones emerge and the differences in developing dependence between e-cigarette users who smoke cigarettes compared to those who do not.METHODSAdolescents and young adults aged 16-25 living in Canada were recruited into an online survey in 2021. Current (past-month) e-cigarette users completed 15 items assessing dependence from the Penn-State Electronic Cigarette Dependence Index and the E-cigarette Dependence Scale for a total of 12 behavioural (e.g., difficulty refraining from vaping) and 3 frequency (e.g., using e-cigarette daily, weekly, or monthly) indicators of dependence milestones. Number of years after e-cigarette onset at which the cumulative probability of attaining each milestone was 25 % was computed.RESULTSAmong 1205 participants, most (80.6 %) were female, 73.7 % were Caucasian, and 49.7 % resided in Ontario. Ten of the 12 e-cigarette use milestones were attained by 25 % of respondents 2 years after starting vaping except for daily cigarette use (2.5 years after onset) and waking at night to vape (5.6 years after onset). Within the entire study population, frequency milestones (weekly, monthly, daily e-cigarette use) were attained faster by ever-smokers (hazard ratio compared to attainment by never-smokers: 1.12, 1.21, and 1.28 respectively), whereas for at least monthly users, behavioural milestones were attained faster by never-smokers.DISCUSSIONMany current e-cigarette users developed symptoms of e-cigarette dependence between two and five years since onset. Never smokers may be at higher risk of becoming e-cigarette dependent since they attained e-cigarette dependence milestones faster than smokers.
Disordered breathing during sleep is associated with acute, unfavorable effects on cardiovascular physiology, but few studies have examined its postulated association with cardiovascular disease ...(CVD). We examined the cross-sectional association between sleep- disordered breathing and self-reported CVD in 6,424 free-living individuals who underwent overnight, unattended polysomnography at home. Sleep-disordered breathing was quantified by the apnea-hypopnea index (AHI)-the average number of apneas and hypopneas per hour of sleep. Mild to moderate disordered breathing during sleep was highly prevalent in the sample (median AHI: 4.4; interquartile range: 1.3 to 11.0). A total of 1,023 participants (16%) reported at least one manifestation of CVD (myocardial infarction, angina, coronary revascularization procedure, heart failure, or stroke). The multivariable-adjusted relative odds (95% CI) of prevalent CVD for the second, third, and fourth quartiles of the AHI (versus the first) were 0.98 (0.77-1.24), 1.28 (1.02-1.61), and 1.42 (1.13-1.78), respectively. Sleep-disordered breathing was associated more strongly with self-reported heart failure and stroke than with self-reported coronary heart disease: the relative odds (95% CI) of heart failure, stroke, and coronary heart disease (upper versus lower AHI quartile) were 2.38 (1.22-4.62), 1.58 (1.02- 2.46), and 1.27 (0.99-1.62), respectively. These findings are compatible with modest to moderate effects of sleep-disordered breathing on heterogeneous manifestations of CVD within a range of AHI values that are considered normal or only mildly elevated.
Ambulatory blood pressure may be higher or lower than clinic blood pressure. Attention has focused on "white coat hypertension" (normal ambulatory blood pressure elevated in the clinic). The converse ...phenomenon of high ambulatory blood pressure but normal office blood pressure-"white coat normotension"-has not been studied.
To assess whether white coat normotension (awake ambulatory blood pressure > 134/90 mm Hg and clinic blood pressure < 140/90 mm Hg) is associated with target organ damage.
Cross-sectional observational study.
University hospital hypertension center and participant work sites.
295 clinically normotensive adults and 64 patients with sustained hypertension (elevated clinic and ambulatory blood pressure).
Target organ abnormalities were measured by echocardiography and arterial ultrasonography in 61 patients with white coat normotension, 234 with sustained normotension (normal clinic and ambulatory blood pressure), and 64 with sustained hypertension.
Patients with white coat normotension were older; had higher body mass indices, serum creatinine concentrations, and glucose levels; and a higher prevalence of current smokers. Left ventricular mass index and relative wall thickness were higher by 13 g/m2 (CI, 8 to 18 g/m2) and by 0.03 (CI, 0.01 to 0.04), respectively, in patients with white coat normotension compared with those who had sustained normotension. Patients with white coat normotension and those with sustained hypertension did not differ significantly for left ventricular mass index (4 g/m2 CI, - 3 to 10 g/m2) or relative wall thickness (0.01 CI, -0.01 to 0.03). The prevalence of discrete atherosclerotic plaques was similar in patients with white coat normotension (17 of 61, or 28% CI, 17% to 39%) and those with sustained hypertension (17 of 64, or 27% CI, 16% to 38%), but the difference lost significance after adjustment for age.
White coat normotension is associated with left ventricular mass and carotid wall thickness similar to those in sustained hypertension. The association of white coat normotension with prognostically important target organ damage may partly explain the ability of high normal left ventricular mass and high normal clinic blood pressure to predict subsequent hypertension and cardiovascular events in patients with clinical normotension.
Patients were instructed to complete daily entries at 10 am, 4 pm, and 8 pm within 15 minutes of the target times. With the electronic diary, entries could not be initiated outside the designated 30 ...minute windows. We considered paper diary entries to be compliant if they were made within the 30 minute windows. A more liberal secondary outcome allowed a 90 minute window around the target times. Reported compliance was based on the time and date that patients recorded on their paper diary cards.
It remains uncertain whether abnormal dipping patterns of nocturnal blood pressure influence the prognosis for stroke. We studied stroke events in 575 older Japanese patients with sustained ...hypertension determined by ambulatory blood pressure monitoring (without medication). They were subclassified by their nocturnal systolic blood pressure fall (97 extreme-dippers, with >/=20% nocturnal systolic blood pressure fall; 230 dippers, with >/=10% but <20% fall; 185 nondippers, with >/=0% but <10% fall; and 63 reverse-dippers, with <0% fall) and were followed prospectively for an average duration of 41 months. Baseline brain magnetic resonance imaging (MRI) disclosed that the percentages with multiple silent cerebral infarct were 53% in extreme-dippers, 29% in dippers, 41% in nondippers, and 49% in reverse-dippers. There was a J-shaped relationship between dipping status and stroke incidence (extreme-dippers, 12%; dippers, 6.1%; nondippers, 7.6%; and reverse-dippers, 22%), and this remained significant in a Cox regression analysis after controlling for age, gender, body mass index, 24-hour systolic blood pressure, and antihypertensive medication. Intracranial hemorrhage was more common in reverse-dippers (29% of strokes) than in other subgroups (7.7% of strokes, P=0.04). In the extreme-dipper group, 27% of strokes were ischemic strokes that occurred during sleep (versus 8.6% of strokes in the other 3 subgroups, P=0.11). In conclusion, in older Japanese hypertensive patients, extreme dipping of nocturnal blood pressure may be related to silent and clinical cerebral ischemia through hypoperfusion during sleep or an exaggerated morning rise of blood pressure, whereas reverse dipping may pose a risk for intracranial hemorrhage.
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