BackgroundElectronic cigarette (e-cigarette) use in the USA is increasing. As such, it is critical to understand who uses e-cigarettes, how e-cigarettes are used and what types of products are ...prevalent. This study assesses patterns of current e-cigarette use among daily and non-daily adult users in the 2013–2014 Population Assessment of Tobacco and Health (PATH) Study.MethodsWe examined the proportion of current adult e-cigarette users (n=3642) reporting infrequent use (use on ‘some days’ and use on 0–2 of the past 30 days), moderate use (use on ‘some days’ and use on >2 of the past 30 days) and daily use. We examined demographic characteristics, use of other tobacco products and e-cigarette product characteristics overall and by use category. Adjusted prevalence ratios (aPRs) were calculated using Poisson regression to assess correlates of daily e-cigarette use.ResultsAmong the 5.5% of adult current e-cigarette users in the PATH Study, 42.2% reported infrequent use, 36.5% reported moderate use and 21.3% reported daily use. Cigarette smokers who quit in the past year were more likely to report daily e-cigarette use, compared with current smokers (aPR=3.21, 95% CI=2.75 to 3.76). Those who reported using rechargeable or refillable devices were more likely to report daily use compared with those who did not use these devices (aPR=1.95, 95% CI=1.44 to 2.65 and aPR=2.10, 95% CI=1.75 to 2.52, respectively).ConclusionsThe majority of e-cigarette users in this study reported less than daily use. Compared with non-daily use, daily use was associated with being a former smoker; however, cross-sectional data limits our ability to establish the temporality or directionality of such associations.
Acute pancreatitis (AP) is a common and devastating inflammatory condition of the pancreas that is considered to be a paradigm of sterile inflammation leading to systemic multiple organ dysfunction ...syndrome (MODS) and death. Acute mortality from AP-MODS exceeds 20% (ref. 3), and the lifespans of those who survive the initial episode are typically shorter than those of the general population. There are no specific therapies available to protect individuals from AP-MODS. Here we show that kynurenine-3-monooxygenase (KMO), a key enzyme of tryptophan metabolism, is central to the pathogenesis of AP-MODS. We created a mouse strain that is deficient for Kmo (encoding KMO) and that has a robust biochemical phenotype that protects against extrapancreatic tissue injury to the lung, kidney and liver in experimental AP-MODS. A medicinal chemistry strategy based on modifications of the kynurenine substrate led to the discovery of the oxazolidinone GSK180 as a potent and specific inhibitor of KMO. The binding mode of the inhibitor in the active site was confirmed by X-ray co-crystallography at 3.2 Å resolution. Treatment with GSK180 resulted in rapid changes in the levels of kynurenine pathway metabolites in vivo, and it afforded therapeutic protection against MODS in a rat model of AP. Our findings establish KMO inhibition as a novel therapeutic strategy in the treatment of AP-MODS, and they open up a new area for drug discovery in critical illness.
Abstract
Background
Within-household transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been identified as one of the main sources of spread of coronavirus ...disease 2019 (COVID-19) after lockdown restrictions and self-isolation guidelines are implemented. Secondary attack rates among household contacts are estimated to be 5–10 times higher than among non-household contacts, but it is unclear which individuals are more prone to transmit infection within their households.
Methods
Using address matching, a cohort was assembled of all individuals with laboratory-confirmed COVID-19 residing in private households in Ontario, Canada. Descriptive analyses were performed to compare characteristics of cases in households that experienced secondary transmission versus those that did not. Logistic regression models were fit to determine index case characteristics and neighborhood characteristics associated with transmission.
Results
Between January and July 2020, there were 26 714 individuals with COVID-19 residing in 21 226 households. Longer testing delays (≥5 vs 0 days; odds ratio OR, 3.02; 95% confidence interval CI, 2.53–3.60) and male gender (OR, 1.28; 95% CI, 1.18–1.38) were associated with greater odds of household secondary transmission, while being a healthcare worker (OR, .56; 95% CI, .50–.62) was associated with lower odds of transmission. Neighborhoods with larger average family size and a higher proportion of households with multiple persons per room were also associated with greater odds of transmission.
Conclusions
It is important for individuals to get tested for SARS-CoV-2 infection as soon as symptoms appear, and to isolate away from household contacts; this is particularly important in neighborhoods with large family sizes and/or crowded households.
Odds of household transmission may be reduced by individuals seeking testing as soon as symptoms appear, and self-isolating outside the home or in a room alone, if possible.
The political-legal discourse of Indigenous rights continues to be separated from discussions of health care services in geographic scholarship, due to the ways in which political-legal, ...settler-colonial definitions of rights fail to take Indigenous understandings into account, as well as a distrust on the part of scholars of the limited and contingent notion of “rights.” While Indigenous rights, inherently tied in Canada to recognition by the settler-colonial state, have limited application in achieving social justice or decolonization for Indigenous peoples, we argue that Indigenous rights can be used as a complementary discourse to Indigenous resurgence, within broader discourses of Indigenous justice, to lend legal and political weight to arguments for cultural safety and human rights in health care. We draw on a study conducted with 50 Indigenous community members and 15 health services professionals in the northern city of Prince George, Canada, to elucidate how Indigenous peoples’ experiences in health care settings may be improved by giving attention to rights discourse and removing the geographic and identity-based limitations of Indigenous rights to health care in Canada.
To characterize the pharmacokinetics of a single oral dose (6 mg/kg) of mavacoxib in New Zealand White rabbits (Oryctolagus cuniculus) and to characterize any clinicopathologic effects with this ...medication and dose.
Six healthy, 4-month-old New Zealand White rabbits (3 male, 3 female).
Before drug administration, clinicopathologic samples were collected for baseline data (CBC, serum biochemical analyses, and urinalysis including urine protein-to-creatinine ratio). All 6 rabbits received a single oral dose (6 mg/kg) of mavacoxib. Clinicopathologic samples were collected at set time intervals to compare with the baseline. Plasma mavacoxib concentrations were determined using liquid chromatography with mass spectrometry, and pharmacokinetic analysis was performed using non-compartmental methods.
After a single oral dose, the maximum plasma concentration (Cmax; mean, range) was 854 (713-1040) ng/mL, the time to Cmax (tmax) was 0.36 (0.17-0.50) days, the area under the curve from 0 to the last measured time point (AUC0-last) was 2000 (1765-2307) days*ng/mL, the terminal half-life (t1/2) was 1.63 (1.30-2.26) days, and the terminal rate constant (λz) was 0.42 (0.31-0.53) days. All results for CBCs, serum biochemical analyses, urinalyses, and urine protein-to-creatinine ratios remained within published normal reference intervals.
This study determined that plasma concentrations reached target levels of 400 ng/mL for 48 hours in 3/6 rabbits at 6 mg/kg PO. In the remaining 3/6 rabbits, the plasma concentrations were 343-389 ng/mL at 48 hours, which is below the target concentration. Further research is needed to make a dosing recommendation, including a pharmacodynamic study and investigating pharmacokinetics at different doses and multiple doses.
Telomere length (TL) is associated with several aging-related diseases. Here, we present a DNA methylation estimator of TL (DNAmTL) based on 140 CpGs. Leukocyte DNAmTL is applicable across the entire ...age spectrum and is more strongly associated with age than measured leukocyte TL (LTL) (
-0.75 for DNAmTL versus
-0.35 for LTL). Leukocyte DNAmTL outperforms LTL in predicting: i) time-to-death (p=2.5E-20), ii) time-to-coronary heart disease (p=6.6E-5), iii) time-to-congestive heart failure (p=3.5E-6), and iv) association with smoking history (p=1.21E-17). These associations are further validated in large scale methylation data (n=10k samples) from the Framingham Heart Study, Women's Health Initiative, Jackson Heart Study, InChianti, Lothian Birth Cohorts, Twins UK, and Bogalusa Heart Study. Leukocyte DNAmTL is also associated with measures of physical fitness/functioning (p=0.029), age-at-menopause (p=0.039), dietary variables (omega 3, fish, vegetable intake), educational attainment (p=3.3E-8) and income (p=3.1E-5). Experiments in cultured somatic cells show that DNAmTL dynamics reflect in part cell replication rather than TL
. DNAmTL is not only an epigenetic biomarker of replicative history of cells, but a useful marker of age-related pathologies that are associated with it.
Discovering the molecular basis of mitochondrial respiratory chain disease is challenging given the large number of both mitochondrial and nuclear genes that are involved. We report a strategy of ...focused candidate gene prediction, high-throughput sequencing and experimental validation to uncover the molecular basis of mitochondrial complex I disorders. We created seven pools of DNA from a cohort of 103 cases and 42 healthy controls and then performed deep sequencing of 103 candidate genes to identify 151 rare variants that were predicted to affect protein function. We established genetic diagnoses in 13 of 60 previously unsolved cases using confirmatory experiments, including cDNA complementation to show that mutations in NUBPL and FOXRED1 can cause complex I deficiency. Our study illustrates how large-scale sequencing, coupled with functional prediction and experimental validation, can be used to identify causal mutations in individual cases.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
We assessed protection from coronavirus disease 2019 (COVID-19) vaccines and/or prior severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection against Omicron-associated severe outcomes ...during successive sublineage-predominant periods.
We used a test-negative design to estimate protection by vaccines and/or prior infection against hospitalization/death among community-dwelling, polymerase chain reaction (PCR)-tested adults aged ≥50 years in Ontario, Canada, between 2 January 2022 and 30 June 2023. Multivariable logistic regression was used to estimate the relative change in the odds of hospitalization/death with each vaccine dose (2-5) and/or prior PCR-confirmed SARS-CoV-2 infection (compared with unvaccinated, uninfected subjects) up to 15 months since the last vaccination or infection.
We included 18 526 cases with Omicron-associated severe outcomes and 90 778 test-negative controls. Vaccine protection was high during BA.1/BA.2 predominance but was generally <50% during periods of BA.4/BA.5 and BQ/XBB predominance without boosters. A third/fourth dose transiently increased protection during BA.4/BA.5 predominance (third-dose, 6-month: 68%, 95% confidence interval CI 63%-72%; fourth-dose, 6-month: 80%, 95% CI 77%-83%) but was lower and waned quickly during BQ/XBB predominance (third-dose, 6-month: 59%, 95% CI 48%-67%; 12-month: 49%, 95% CI 41%-56%; fourth-dose, 6-month: 62%, 95% CI 56%-68%, 12-months: 51%, 95% CI 41%-56%). Hybrid immunity conferred nearly 90% protection throughout BA.1/BA.2 and BA.4/BA.5 predominance but was reduced during BQ/XBB predominance (third-dose, 6-month: 60%, 95% CI 36%-75%; fourth-dose, 6-month: 63%, 95% CI 42%-76%). Protection was restored with a fifth dose (bivalent; 6-month: 91%, 95% CI 79%-96%). Prior infection alone did not confer lasting protection.
Protection from COVID-19 vaccines and/or prior SARS-CoV-2 infections against severe outcomes is reduced when immune-evasive variants/subvariants emerge and may also wane over time. Our findings support a variant-adapted booster vaccination strategy with periodic review.
Breaking beta: deconstructing the parasite transmission function McCallum, Hamish; Fenton, Andy; Hudson, Peter J. ...
Philosophical transactions of the Royal Society of London. Series B. Biological sciences,
05/2017, Letnik:
372, Številka:
1719
Journal Article
Recenzirano
Odprti dostop
Transmission is a fundamental step in the life cycle of every parasite but it is also one of the most challenging processes to model and quantify. In most host–parasite models, the transmission ...process is encapsulated by a single parameter β. Many different biological processes and interactions, acting on both hosts and infectious organisms, are subsumed in this single term. There are, however, at least two undesirable consequences of this high level of abstraction. First, nonlinearities and heterogeneities that can be critical to the dynamic behaviour of infections are poorly represented; second, estimating the transmission coefficient β from field data is often very difficult. In this paper, we present a conceptual model, which breaks the transmission process into its component parts. This deconstruction enables us to identify circumstances that generate nonlinearities in transmission, with potential implications for emergent transmission behaviour at individual and population scales. Such behaviour cannot be explained by the traditional linear transmission frameworks. The deconstruction also provides a clearer link to the empirical estimation of key components of transmission and enables the construction of flexible models that produce a unified understanding of the spread of both micro- and macro-parasite infectious disease agents.
This article is part of the themed issue ‘Opening the black box: re-examining the ecology and evolution of parasite transmission’.
Abstract
We estimated the effectiveness of booster doses of monovalent and bivalent mRNA COVID-19 vaccines against Omicron-associated severe outcomes among adults aged ≥50 years in Ontario, Canada. ...Monovalent and bivalent mRNA COVID-19 booster doses provided similar strong initial protection against severe outcomes. Uncertainty remains around waning of protection from these vaccines.
Shortly after bivalent mRNA COVID-19 vaccines were introduced, monovalent and bivalent booster doses provided similar strong initial protection against severe outcomes among Ontario community-dwelling adults aged ≥50 years. Uncertainty remains around waning of protection.
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