Kinetics Study of the Reactions of 4-Methyl-2-Pentanone and m-Ethyl Toluene with Hydroxyl Radicals between 240 and 340 K and 1-8 Torr Using the Relative Rate/Discharge Flow/Mass Spectrometry Technique.

The kinetics of reactions of 4-methyl-2-pentanone (MIBK) and m-ethyl toluene (MET) with hydroxyl radicals has been studied at a total pressure of 1-8 Torr and 240-340 K using the RR/DF/MS technique. The rate constant for the reaction of MIBK with the hydroxyl radical was found to be essentially pressure-independent in the range of 1-3 Torr. The rate constant for MET reaction with the hydroxyl radical increased with pressure at 1-5 Torr, and a high pressure limit was reached at 5 Torr. At 298 K, rate constants (in cm3 molecule-1 s-1) of kMIBK+OH(298 K) = (1.25 ± 0.21) × 10-11 and kMET+OH(298 K) = (2.05 ± 0.23) × 10-11 were determined with n-nonane as the reference compound, while kMIBK+OH(298 K) = (1.25 ± 0.11) × 10-11 and kMET+OH(298 K) = (1.88 ± 0.17) × 10-11 were obtained with 1,4-dioxane as the reference compound, where kMIBK+OH was measured at 1 Torr and kMET+OH was measured at 5 Torr. The rate constant of MIBK reaction with the hydroxyl radical was found to be negatively dependent on temperature at 240-340 K, with an Arrhenius expression of kMIBK+OH(T) = (2.00 ± 0.07) × 10-12 exp[(535 ± 11)/T] cm3 molecule-1 s-1. The rate constant of MET reaction with the hydroxyl radicals was also found to negatively depend on temperature at 240-340 K but with nonlinear behavior in the Arrhenius plot.

Brief Report: Single-nucleotide polymorphisms in VKORC1 are risk factors for systemic lupus erythematosus in Asians.

OBJECTIVE: The increased risk of thrombosis in systemic lupus erythematosus (SLE) may be partially explained by interrelated genetic pathways for thrombosis and SLE. The present study was undertaken to investigate whether 33 established and novel single-nucleotide polymorphisms (SNPs) in 20 genes involved in hemostasis pathways that have been associated with deep venous thrombosis (DVT) in the general population are risk factors for SLE among Asian subjects. METHODS: Patients in the discovery cohort were enrolled in 1 of 2 North American SLE cohorts. Patients in the replication cohort were enrolled in 1 of 4 Asian or 2 North American cohorts. We first genotyped 263 Asian patients with SLE and 357 healthy Asian control subjects for 33 SNPs in the discovery phase, and then genotyped 5 SNPs in up to an additional 1,496 patients and 993 controls in the replication phase. Patients were compared to controls for bivariate association with minor alleles. Principal components analysis was used to control for intra-Asian ancestry in the replication cohort. RESULTS: Two genetic variants in the gene VKORC1 were highly significant in both the discovery and replication cohorts: rs9934438 (in the discovery cohort, odds ratio [OR] 2.45, P=2×10(-9); in the replication cohort, OR 1.54, P=4×10(-6)) and rs9923231 (in the discovery cohort, OR 2.40, P=6×10(-9); in the replication cohort, OR 1.53, P=5×10(-6)). These associations were significant in the replication cohort after adjustment for intra-Asian ancestry: for rs9934438, OR 1.34, P=0.0029; for rs9923231, OR 1.34, P=0.0032. CONCLUSION: Genetic variants in VKORC1, which are involved in vitamin K reduction and associated with DVT, correlate with SLE development in Asian subjects. These results suggest that there may be intersecting genetic pathways for the development of SLE and thrombosis.

Prevalence and whole-genome sequencing characterization of Salmonella in urban karst groundwater and predominantly groundwater-fed surface waters for serotypes and antimicrobial resistance.

Karst aquifers provide a significant source of drinking water around the world; however, they are prone to bacterial contamination. We investigated the prevalence, serotypes, and antimicrobial resistance genes (ARGs) of Salmonella in urban karst groundwater and groundwater-fed surface waters. Weekly water samples (n = 443) were collected from nine groundwater sites and the Barren River in Bowling Green, KY. Additionally, cross-sectional samples were collected from 45 sites, including groundwaters and two rivers, in Tampa, FL. Salmonella was detected in 14.5% of Bowling Green samples resulting in 176 isolates representing 18 serotypes. Two (4.4%) of the Tampa samples were positive yielding eight isolates representing two serotypes. In Bowling Green, Salmonella prevalence varied by sampling site, week, month, and season, with the highest prevalence in surface water in the month of November and during summer. Salmonella Newport was the most common serotype detected. Nine of the serotypes detected in the study were among the top 20 serotypes commonly associated with human infections in the United States. Isolates were clustered with human clinical isolates, or isolates obtained from food animals, suggesting the importance of humans and agricultural practices as a source of water contamination. ARGs were detected in 12.5% (n = 176) of the Bowling Green isolates; overall, 81.8% (n = 22) of these were multidrug-resistant (resistance to ≥3 antimicrobial classes). Notably, the four Salmonella Agona isolates were resistant to four antimicrobial classes, mercury, and quaternary ammonium compounds. Seasonality and the widespread occurrence of Salmonella both in the groundwater and groundwater-fed surface waters is a potential risk to public health.

Occurrence and prevalence of antimicrobial resistance in urban karst groundwater systems based on targeted resistome analysis.

Antimicrobial resistance (AMR) is a global crisis threatening human, animal, and environmental health. The natural environment, specifically water resources, has been recognized as a reservoir and dissemination pathway for AMR; however, urban karst aquifer systems have been overlooked. This is a concern as these aquifer systems provide drinking water to about 10 % of the global population; yet, the urban influence on the resistome in these vulnerable aquifers is sparingly explored. This study used high-throughput qPCR to determine the occurrence and relative abundance of antimicrobial resistant genes (ARG) in a developing urban karst groundwater system in Bowling Green, KY. Ten sites throughout the city were sampled weekly and analyzed for 85 ARGs, as well as seven microbial source tracking (MST) genes for human and animal sources, providing a spatiotemporal understanding of the resistome in urban karst groundwater. To further understand ARGs in this environment, potential drivers (landuse, karst feature type, season, source of fecal pollution) were considered in relation to the resistome relative abundance. The MST markers highlighted a prominent human influence to the resistome in this karst setting. The concentration of targeted genes varied between the sample weeks, but all targeted ARGs were prevalent throughout the aquifer regardless of karst feature type or season, with high concentrations captured for sulfonamide (sul1), quaternary ammonium compound (qacE), and aminoglycoside (strB) antimicrobial classes. Higher prevalence and relative abundance were detected during the summer and fall seasons, as well as at the spring features. Linear discriminant analysis suggested that karst feature type had higher influence on ARGs in the aquifer compared to season and the source of fecal pollution had the least influence. These findings can contribute to the development of effective management and mitigation strategies for AMR.

Antimicrobial Resistance and Environmental Health: A Water Stewardship Framework for Global and National Action.

Antimicrobial resistance (AMR) is a global health crisis that affects all life on Earth. In 2015, the World Health Organization developed guidance to combat AMR in accordance with a One Health framework considering human, animal, and environment sectors of planetary health. This study reviewed global guidance and 25 National Action Plans to evaluate thematic priorities in One Health AMR approaches using a novel framework that additionally facilitated the identification of water-related stewardship gaps, as water resources are recognized as the primary environmental AMR reservoir and dissemination pathway. This review found that global and national stewardship primarily focuses on mitigating antibiotic use in the human and animal sectors, overlooking environmental drivers, particularly diverse environmental waters. The findings of this study highlight the need to broaden the scope of water-related AMR concerns beyond water, sanitation, and hygiene (WASH) infrastructure for water supply and wastewater treatment, and account for environmental waters in AMR development and dissemination, particularly in low-income countries where half a billion people rely on environmental waters to meet daily needs. Equitably accounting for water environments, supplies, and waste in AMR prevention, mitigation, surveillance, and innovation can significantly enhance the integration of environmental objectives in One Health AMR stewardship.

A Rapid Review of Environmental Health Gaps in Antimicrobial Resistance and Water-Related Research from 1990-2020.

Antimicrobial resistance (AMR) is a pervasive global health threat linked to human antimicrobial misuse and abuse, food production, and broader environmental contamination. While global agencies promote a multi-sectoral One Health system approach to equitably combat human, animal, and environmental health AMR risks, it is widely acknowledged that the human and animal sectors dominate discussions. Given this disproportionate focus, identification of critical research gaps is needed to develop stewardship plans that equitably address One Health AMR threats. This review used natural language processing and term frequency algorithms to classify 12,638 records from 1990-2020 thematically in order to highlight sectoral prioritization and gaps. It also specifically assessed water-related gaps as water is recognized as both a primary environmental dissemination pathway and key means of intervention. Drawing from systemic health and integrated water management lenses, this review found that themes related to plant, wildlife, and environmental-related AMR threats-in particular, the role that environmental (ambient) waters play in AMR development, transmission, and spread-are under-prioritized as compared to human and food animal health concerns regardless of geographic region or income level. Further prioritization of these themes is needed to strengthen the environmental dimension of One Health AMR responses and systemically protect global health.

Genetics research in systemic lupus erythematosus for clinicians: methodology, progress, and controversies.

PURPOSE OF REVIEW: Clinical journals are reporting genetic associations with systemic lupus erythematosus (SLE) with increasing frequency. Interpreting these studies is difficult for clinicians without rigorous training in epidemiology, statistics, and genetics. In this review, we discuss basic issues important to understanding and contextualizing new genetic association studies. We, therefore, highlight literature related to methodology as well as recent genetic discoveries in SLE. RECENT FINDINGS: Functional single nucleotide polymorphisms (SNPs) and/or haplotypes have now been identified for ITGAM, PTPN22, and IRF5, and several additional loci have been highlighted in recent genome-wide association studies in SLE. Recent work also indicates that several regions within the extended major histocompatibility complex contribute independently to SLE risk. Evidence of additive statistical interaction has been found between IRF5 and TYK2, IRF5, and STAT4, and between NAT2 and exposure to tobacco smoke. SUMMARY: Many new genes have been associated with SLE susceptibility, revealing insight into SLE pathophysiology. Current research is focusing on further refining the initial genetic association results and extending this work to non-European populations. Research is also expanding beyond SNP associations to investigate the contribution of copy number variants (CNVs) and DNA methylation to SLE risk.

Incidence of lymphoma in patients with rheumatoid arthritis: a systematic review of the literature.

To our knowledge, this review is the most broad and only systematic survey to date of the rheumatology, oncology, and epidemiology literature to determine the prevalence of lymphoma in patients with rheumatoid arthritis (RA). This survey is analyzed to determine whether the association between RA and increased lymphoma risk is a result of the risks conferred by medications used to treat RA or a result of the disease itself. PubMed was searched for articles from 1964 to May 2007 using the Medical Subject Heading terms "arthritis, rheumatoid, and lymphoma." Twenty-six studies met inclusion and exclusion criteria and are included for review. Most studies confirmed an approximate 2-fold increase in lymphoma incidence in patients with RA. Contrary to a widely held belief about medication toxicity in RA, most studies did not reveal a statistically significant increased risk of lymphoma with methotrexate or azathioprine. An increased lymphoma incidence with tumor necrosis factor-alpha inhibitors was suggested; however, follow-up in the studies considered was too short to definitively determine increased risk. Most studies differed in which medications they evaluated in determining their impact on lymphoma risk, making studies difficult to compare. Confounding by disease severity (patients with the most severe disease are treated with the strongest medications) in most studies makes the association between lymphoma risk and medications and/or disease severity difficult to assess. Recent work suggests that it is the disease itself, not its treatment, that is associated with increased risk of lymphoma in patients with RA.

Sexual harassment and feeding inhibition between two invasive dengue vectors.

Two invasive mosquitoes, Aedes aegypti and Aedes albopictus, have been interacting during the course of a rapid range expansion by A. albopictus. We investigated the potential for interspecific feeding interference by male mosquitoes interacting with females within and between these species. A. aegypti feeding on both sugar and blood was suppressed when females of this species were exposed to A. albopictus males, but no change was observed when exposed to conspecifics. A. albopictus feeding was not affected by males of either species. The potential consequences of these behaviors are discussed within the context of other known interspecific effects, all of which appear to favor the displacement of A. aegypti by A. albopictus.

A polymorphism in TLR2 is associated with arterial thrombosis in a multiethnic population of patients with systemic lupus erythematosus.

OBJECTIVE: Thrombosis is a serious complication of systemic lupus erythematosus (SLE). Studies that have investigated the genetics of thrombosis in SLE are limited. We undertook this study to assess the association of previously implicated candidate genes, particularly Toll-like receptor (TLR) genes, with pathogenesis of thrombosis. METHODS: We genotyped 3,587 SLE patients from 3 multiethnic populations for 77 single-nucleotide polymorphisms (SNPs) in 10 genes, primarily in TLRs 2, 4, 7, and 9, and we also genotyped 64 ancestry-informative markers (AIMs). We first analyzed association with arterial and venous thrombosis in the combined population via logistic regression, adjusting for top principal components of the AIMs and other covariates. We also subjected an associated SNP, rs893629, to meta-analysis (after stratification by ethnicity and study population) to confirm the association and to test for study population or ethnicity effects. RESULTS: In the combined analysis, the SNP rs893629 in the KIAA0922/TLR2 region was significantly associated with arterial thrombosis (logistic P = 6.4 × 10(-5) , false discovery rate P = 0.0044). Two additional SNPs in TLR2 were also suggestive: rs1816702 (logistic P = 0.002) and rs4235232 (logistic P = 0.009). In the meta-analysis by study population, the odds ratio (OR) for arterial thrombosis with rs893629 was 2.44 (95% confidence interval 1.58-3.76), without evidence for heterogeneity (P = 0.78). By ethnicity, the effect was most significant among African Americans (OR 2.42, P = 3.5 × 10(-4) ) and European Americans (OR 3.47, P = 0.024). CONCLUSION: TLR2 gene variation is associated with thrombosis in SLE, particularly among African Americans and European Americans. There was no evidence of association among Hispanics, and results in Asian Americans were limited due to insufficient sample size. These results may help elucidate the pathogenesis of this important clinical manifestation.

Longitudinal study of the impact of incident organ manifestations and increased disease activity on work loss among persons with systemic lupus erythematosus.

OBJECTIVE: There is increasing evidence of the impact of systemic lupus erythematosus (SLE) on employment, but few studies have had sufficient sample size and longitudinal followup to estimate the impact of specific manifestations or of increasing disease activity on employment. METHODS: Data were derived from the University of California, San Francisco, Lupus Outcomes Study, a longitudinal cohort of 1,204 persons with SLE sampled between 2002 and 2009. Of the 1,204 persons, 484 were working at baseline and had at least 1 followup interview. We used the Kaplan-Meier method to estimate the time between onset of thrombotic, neuropsychiatric, or musculoskeletal manifestations, or of increased disease activity, and work loss. We used Cox proportional hazards regression to estimate the risk of work loss associated with the onset of specific manifestations, the number of manifestations, and increased activity, with and without adjustment for sociodemographic, employment, and SLE duration characteristics. RESULTS: By 4 years of followup, 57%, 34%, and 38% of those with thrombotic, musculoskeletal, and neuropsychiatric manifestations, respectively, had stopped working, as had 42% of those with increased disease activity. On a bivariable basis, the risk of work loss was significantly higher among persons ages 55-64 years and those with increased disease activity and each kind of manifestation. In multivariable analysis, older age, shorter job tenure, thrombotic and musculoskeletal manifestations, greater number of manifestations, and high levels of activity increased the risk of work loss. CONCLUSION: Incident thrombosis and musculoskeletal manifestations, multiple manifestations, and increased disease activity are associated with the risk of work loss in SLE.

Cardiovascular disease and cognitive dysfunction in systemic lupus erythematosus.

OBJECTIVE: Cognitive dysfunction and cardiovascular disease are common and debilitating manifestations of systemic lupus erythematosus (SLE). In this study, we evaluated the relationship between cardiovascular events, traditional cardiovascular risk factors, and SLE-specific risk factors as predictors of cognitive dysfunction in a large cohort of participants with SLE. METHODS: Subjects included 694 participants from the Lupus Outcomes Study (LOS), a longitudinal study of SLE outcomes based on an annual telephone survey querying demographic and clinical variables. The Hopkins Verbal Learning Test-Revised and the Controlled Oral Word Association Test were administered to assess cognitive function. Multiple logistic regression was used to identify cardiovascular events (myocardial infarction, stroke), traditional cardiovascular risk factors (hypertension, hyperlipidemia, diabetes mellitus, obesity, smoking), and SLE-specific risk factors (antiphospholipid antibodies [aPL], disease activity, disease duration) associated with cognitive impairment in year 7 of the LOS. RESULTS: The prevalence of cognitive impairment as measured by verbal memory and verbal fluency metrics was 15%. In adjusted multiple logistic regression analyses, aPL (odds ratio [OR] 2.10, 95% confidence interval [95% CI] 1.3-3.41), hypertension (OR 2.06, 95% CI 1.19-3.56), and a history of stroke (OR 2.27, 95% CI 1.16-4.43) were significantly associated with cognitive dysfunction. In additional analyses evaluating the association between these predictors and severity of cognitive impairment, stroke was significantly more prevalent in participants with severe impairment when compared to those with mild or moderate impairment (P = 0.036). CONCLUSION: These results suggest that the presence of aPL, hypertension, and stroke are key variables associated with cognitive impairment, which may aid in identification of patients at greatest risk.

Genetic risk factors for thrombosis in systemic lupus erythematosus.

OBJECTIVE: Thrombosis is a serious complication of systemic lupus erythematosus (SLE). We investigated whether genetic variants implicated in thrombosis pathways are associated with thrombosis among 2 ethnically diverse SLE cohorts. METHODS: Our discovery cohort consisted of 1698 patients with SLE enrolled in the University of California, San Francisco, Lupus Genetics Project and our replication cohort included 1361 patients with SLE enrolled in the PROFILE cohort. Patients fulfilled American College of Rheumatology SLE criteria, and data relevant to thrombosis were available. Thirty-three single nucleotide polymorphisms (SNP) previously shown to be associated with risk of deep venous thrombosis in the general population or implicated in thrombosis pathways were genotyped and tested for association with thrombosis in bivariate allelic analyses. SNP with p < 0.1 in the bivariate analyses were further tested in multivariable logistic regression models adjusted for age, sex, disease duration, antiphospholipid antibody status, smoking, nephritis, and medications. RESULTS: In the discovery cohort, 23% of patients with SLE experienced a thrombotic event. SNP in the following genes demonstrated association with thrombosis risk overall in the discovery or replication cohorts and were assessed using metaanalytic methods: factor V Leiden (FVL) rs6025 (OR 1.85, p = 0.02) and methylenetetrahydrofolate reductase (MTHFR) rs1801133 (OR 0.75, p = 0.04) in whites, and fibrinogen gamma (FGG) rs2066865 (OR 1.91, p = 0.01) in Hispanic Americans. SNP in these genes showed association with venous thrombosis risk in whites: MTHFR rs1801131 (OR 1.51, p = 0.01), MTHFR rs1801133 (OR 0.70, p = 0.04), FVL rs6025 (OR 2.69, p = 0.002), and FGG rs2066865 (OR 1.49, p = 0.02) in whites. A SNP in FGG rs2066865 (OR 2.19, p = 0.003) demonstrated association with arterial thrombosis risk in Hispanics. CONCLUSION: Our results implicate specific genetic risk factors for thrombosis in patients with SLE and suggest that genetic risk for thrombosis differs across ethnic groups.

Contraceptive counseling and use among women with systemic lupus erythematosus: a gap in health care quality?

OBJECTIVE: Disease activity and medication use can complicate pregnancies in patients with systemic lupus erythematosus (SLE). We therefore examined contraceptive counseling and use among women in the University of California, San Francisco Lupus Outcomes Study. METHODS: In 2008, we queried participants regarding their pregnancy intentions, contraceptive use, and receipt of contraceptive counseling. Premenopausal women age <45 years who were sexually active with men were considered at risk of pregnancy. We compared self-reported rates of contraceptive counseling and use stratified by treatment with teratogenic medications and by history of thrombosis or antiphospholipid antibodies (aPL), using chi-square tests. We used logistic regression models to examine predictors of contraceptive counseling and use. RESULTS: Among 206 women, 86 were at risk for unplanned pregnancy. Most (59%) had not received contraceptive counseling in the last year, 22% reported inconsistent contraceptive use, and 53% depended solely on barrier methods. Intrauterine device contraceptives (IUDs) were used by 13%. Women using potentially teratogenic medications were no more likely to have received contraceptive counseling, to have used contraception consistently, or to have used more effective contraceptives. A history of thrombosis or aPL did not account for low rates of hormonal methods. Four women with a history of thrombosis or aPL were using estrogen-containing contraceptives. CONCLUSION: Most women at risk for unplanned pregnancy reported no contraceptive counseling in the past year, despite common use of potentially teratogenic medications. Many relied upon contraceptive methods with high failure rates; few used IUDs. Some were inappropriately using estrogen-containing contraceptives. These findings suggest the need to improve the provision of contraceptive services to women with SLE.

Systematic review and metaanalysis of patient self-report versus trained assessor joint counts in rheumatoid arthritis.

OBJECTIVE: Patient self-report outcomes and physician-performed joint counts are important measures of disease activity and treatment response. This metaanalysis examines the degree of concordance in joint counts between trained assessors and patients with rheumatoid arthritis (RA). METHODS: Studies eligible for inclusion met the following criteria: English language; compared patient with trained assessor joint counts; peer-reviewed; and RA diagnosis determined by board-certified or board-eligible specialist or met 1987 American College of Rheumatology criteria. We searched PubMed and Embase to identify articles between 1966 and January 1, 2008. We compared measures of correlation between patients and assessors for either tender/painful or swollen joint counts. We used metaanalysis methods to calculate summary correlation estimates. RESULTS: We retrieved 462 articles and 18 were included. Self-report joint counts were obtained by a text and/or mannequin (picture) format. The summary estimates for the Pearson correlation coefficients for tender joint counts were 0.61 (0.47 lower, 0.75 upper) and for swollen joint counts 0.44 (0.15, 0.73). Summary results for the Spearman correlation coefficients were 0.60 (0.30, 0.90) for tender joint counts and 0.54 (0.35, 0.73) for swollen joint counts. CONCLUSION: A self-report tender joint count has moderate to marked correlation with those performed by a trained assessor. In contrast, swollen joint counts demonstrate lower levels of correlation. Future research should explore whether integrating self-report tender joint counts into routine care can improve efficiency and quality of care, while directly involving patients in assessment of RA disease activity.