Comprehensive assessment of chemical residues in surface and wastewater using passive sampling, chemical, biological, and fish behavioral assays.

Effluents from ten full-scale municipal wastewater treatment plants (WWTPs) that discharge into the Hudson River, surface waters, and wild-caught fish samples were analyzed using liquid chromatography with tandem mass spectrometry (LC/MS/MS) to examine the influence of wastewater discharge on the concentrations of contaminants of emerging concern (CECs) and their ecological impacts on fish. Analysis was based on targeted detection of 41 pharmaceuticals, and non-targeted analysis (suspect screening) of CECs. Biological effects of treated WWTP effluents were assessed using a larval zebrafish (Danio rerio) swimming behavior assay. Concentrations of residues in surface waters were determined in grab samples and polar organic chemical integrative samplers (POCIS). In addition, vitellogenin peptides, used as biomarkers of endocrine disruption, were quantified using LC/MS/MS in the wild-caught fish plasma samples. Overall, 94 chemical residues were identified, including 63 pharmaceuticals, 10 industrial chemicals, and 21 pesticides. Eight targeted pharmaceuticals were detected in 100% of effluent samples with median detections of: bupropion (194 ng/L), carbamazepine (91 ng/L), ciprofloxacin (190 ng/L), citalopram (172 ng/L), desvenlafaxine (667 ng/L), iopamidol (3790 ng/L), primidone (86 ng/L), and venlafaxine (231 ng/L). Over 30 chemical residues were detected in wild-caught fish tissues. Notably, zebrafish larvae exposed to chemical extracts of effluents from 9 of 10 WWTPs, in at least one season, were significantly hyperactive. Vitellogenin expression in male or immature fish occurred 2.8 times more frequently in fish collected from the Hudson River as compared to a reference site receiving no direct effluent input. Due to the low concentrations of pharmaceuticals detected in effluents, it is likely that chemicals other than pharmaceuticals measured are responsible for the behavioral changes observed. The combined use of POCIS and non-target analysis demonstrated significant increase in the chemical coverage for CEC detection, providing a better insight on the impacts of WWTP effluents and agricultural practices on surface water quality.

Acute respiratory viral adverse events during use of antirheumatic disease therapies: A scoping review.

INTRODUCTION: COVID-19 is an acute respiratory viral infection that threatens people worldwide, including people with rheumatic disease, although it remains unclear to what extent various antirheumatic disease therapies increase susceptibility to complications of viral respiratory infections. OBJECTIVE: The present study undertakes a scoping review of available evidence regarding the frequency and severity of acute respiratory viral adverse events related to antirheumatic disease therapies. METHODS: Online databases were used to identify, since database inception, studies reporting primary data on acute respiratory viral infections in patients utilizing antirheumatic disease therapies. Independent reviewer pairs charted data from eligible studies using a standardized data abstraction tool. RESULTS: A total of 180 studies were eligible for qualitative analysis. While acknowledging that the extant literature has a lack of specificity in reporting of acute viral infections or complications thereof, the data suggest that use of glucocorticoids, JAK inhibitors (especially high-dose), TNF inhibitors, and anti-IL-17 agents may be associated with an increased frequency of respiratory viral events. Available data suggest no increased frequency or risk of respiratory viral events with NSAIDs, hydroxychloroquine, sulfasalazine, methotrexate, azathioprine, mycophenolate mofetil, cyclophosphamide, or apremilast. One large cohort study demonstrated an association with leflunomide use and increased risk of acute viral respiratory events compared to non-use. CONCLUSION: This scoping review identified that some medication classes may confer increased risk of acute respiratory viral infections. However, definitive data are lacking and future studies should address this knowledge gap.

Comparative transcriptomics implicate mitochondrial and neurodevelopmental impairments in larval zebrafish (Danio rerio) exposed to two selective serotonin reuptake inhibitors (SSRIs).

Pharmaceuticals and personal care products are emerging contaminants that are increasingly detected in the environment worldwide. Certain classes of pharmaceuticals, such as selective serotonin reuptake inhibitors (SSRIs), are a major environmental concern due to their widespread use and the fact that these compounds are designed to have biological effects at low doses. A complication in predicting toxic effects of SSRIs in nontarget organisms is that their mechanism of action is not fully understood. To better understand the potential toxic effects of SSRIs, we employed an ultra-low input RNA-sequencing method to identify potential pathways that are affected by early exposure to two SSRIs (fluoxetine and paroxetine). We exposed wildtype zebrafish (Danio rerio) embryos to 100 µg/L of either fluoxetine or paroxetine for 6 days before extracting and sequencing mRNA from individual larval brains. Differential gene expression analysis identified 1550 genes that were significantly affected by SSRI exposure with a core set of 138 genes altered by both SSRIs. Weighted gene co-expression network analysis identified 7 modules of genes whose expression patterns were significantly correlated with SSRI exposure. Functional enrichment analysis of differentially expressed genes as well as network module genes repeatedly identified various terms associated with mitochondrial and neuronal structures, mitochondrial respiration, and neurodevelopmental processes. The enrichment of these terms indicates that toxic effects of SSRI exposure are likely caused by mitochondrial dysfunction and subsequent neurodevelopmental effects. To our knowledge, this is the first effort to study the tissue-specific transcriptomic effects of SSRIs in developing zebrafish, providing specific, high resolution molecular data regarding the sublethal effects of SSRI exposure.

Association of body mass index on disease activity in axial spondyloarthritis: systematic review and meta-analysis.

OBJECTIVES: In axial spondyloarthritis (axSpA), higher body mass index (BMI) is associated with worse outcomes including response to biologics. Further clarity is needed on whether BMI is associated with disease activity overall, independent of treatment response. We performed a systematic review and meta-analysis to assess the association between BMI and disease activity as reported by the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) or Ankylosing Spondylitis Disease Activity Score (ASDAS) in axSpA. METHODS: We systematically searched for studies evaluating BMI and disease activity as the exposure and outcome of interest, respectively, in axSpA. Using random effects models, we estimated summary standardised mean differences (SMDs) and 95% CIs of BASDAI or ASDAS, comparing obese (BMI>30 kg/m2) or overweight/obese (BMI>25 kg/m2) individuals to those with normal BMI (18.5-24.9 kg/m2). RESULTS: Twelve studies were included in the meta-analysis. Among all studies reporting the BASDAI at baseline, the pooled SMD of the BASDAI for those with an obese or overweight/obese BMI compared to a normal BMI was 0.38 (95% CI 0.21 to 0.55, I2 =75.2%), indicating a significant association of higher BMI with higher BASDAI score. The pooled SMD of the ASDAS for those with an obese or overweight/obese BMI compared to a normal BMI was 0.40 (95% CI 0.27 to 0.54, I2=0%). Findings were robust across subgroup analyses. CONCLUSION: These results demonstrate an association between an overweight/obese BMI and higher disease activity in studies of axSpA. Future longitudinal studies of BMI and disease activity should assess how this association changes over time.

Early Initiation of Tocilizumab in Clinically Isolated Aortitis.

Clinically isolated aortitis can arise from infectious or inflammatory etiologies. Glucocorticoids are the first-line therapy for inflammatory causes of aortitis such as large-vessel vasculitis. However, prolonged steroids use is associated with numerous side effects. We present a case of a 60-year-old woman with clinically isolated aortitis who received early treatment with tocilizumab to avoid prolonged steroid use.

Pharmacist-managed titration of urate-lowering therapy to streamline gout management.

The treat-to-target approach for serum uric acid is the recommended model in gout management according to the 2012 American College of Rheumatology (ACR) guidelines. Adherence to urate-lowering therapy (ULT) can be difficult for patients due to barriers, which include medication burden, financial hardship, and lack of medical literacy. Our aim was to create a pharmacist-managed referral for the titration of ULT to target serum uric acid (sUA) levels in a complex patient population. We utilized a clinical database to query patients seen at a rheumatology clinic over a 12-month period with an ICD-10 diagnosis for gout. The referral criteria were indications for ULT per the 2012 ACR guidelines. Rheumatology providers, consisting of attendings, fellows, and a physician assistant, were asked to refer the identified patients to the pharmacist-managed titration program. The intervention group consisted of 19 referred patients and the control group consisted of 28 non-referred patients. The baseline sUA (median (IQR)) at the time of referral was 8.8 (2) mg/dL for the intervention group and 7.6 (2.8) mg/dL for the control group (p = 0.2). At the end of the study period, the sUA was 6.1 (1.4) mg/dL for the intervention group and 6.8 (3.2) mg/dL for the control group (p = 0.08). At the end of the study period, 6 of 19 (32%) intervention group and 7 of 28 (25%) control group were at goal (p = 0.3). A newly instituted pharmacist-managed titration program was able to achieve lower average sUA levels in referred patients compared to demographically similar individuals who received standard gout management.

Varying the exposure period and duration of neuroactive pharmaceuticals and their metabolites modulates effects on the visual motor response in zebrafish (Danio rerio) larvae.

Pharmaceuticals and personal care products are emerging contaminants that are increasingly detected in surface waters around the world. Despite the rise in environmental detections, measured concentrations are still typically low, raising the importance of environmental risk assessments that focus on ecologically relevant sublethal endpoints, such as altered behavior. Neuroactive pharmaceuticals, like mental health medications, pain killers, etc., may be particularly potent in this regard as they are specifically designed to cause behavioral changes without causing physiologic impairment in mammalian systems. We screened 15 different popular neuroactive pharmaceuticals, ranging from antidepressants (including 3 major antidepressant metabolites), anxiety medications, and pain killers, under three different exposure scenarios (repeated, late acute and early transient exposure) to look for behavioral effects in larval zebrafish using the visual motor response (VMR). Drugs were screened at 0, 1, 10, and 100 µg/L in the repeated exposure scenario, and at 0 and 100 µg/L in the late acute and early transient exposure scenarios. Eight of the 15 compounds tested, specifically the antidepressants amitriptyline, fluoxetine, nor-fluoxetine, paroxetine, sertraline, nor-sertraline, venlafaxine, and the antipsychotic drug haloperidol decreased swimming activity by 25% to 40% under repeated exposure conditions. Five of the compounds (amitriptyline, fluoxetine, nor-fluoxetine, paroxetine, and sertraline) also significantly decreased activity by 17% to 31% in the late acute exposure paradigm. Three compounds (fluoxetine, paroxetine and venlafaxine) significantly altered swimming activity with early transient exposure, however creating a hyperactive response and increasing activity from 24% to 28%, while haloperidol significantly decreased activity by 31%. This paper is, to our knowledge, the first to screen so many neuroactive pharmaceuticals, including major metabolites, in parallel under multiple exposure conditions. We show that antidepressants most consistently alter VMR swimming activity. Additionally, we show that major antidepressant metabolites can potentially alter behavior as much as their parent compounds. Furthermore, we show that the magnitude and direction of behavioral effect is dependent on the exposure duration and period, indicating that a more diverse experimental approach might be needed to more accurately assess the risk these compounds pose to the environment.

Effect of a combined education and eHealth programme on the control of oral anticoagulation patients (PORTALS study): a parallel cohort design in Dutch primary care.

OBJECTIVES: To analyse the effect on therapeutic control and self-management skills of the implementation of self-management programmes, including eHealth by e-learning versus group training. SETTING: Primary Care Thrombosis Service Center. PARTICIPANTS: Of the 247 oral anticoagulation therapy (OAT) patients, 63 started self-management by e-learning, 74 self-management by group training and 110 received usual care. INTERVENTION AND METHODS: Parallel cohort design with two randomised self-management groups (e-learning and group training) and a group receiving usual care. The effect of implementation of self-management on time in therapeutic range (TTR) was analysed with multilevel linear regression modelling. Usage of a supporting eHealth platform and the impact on self-efficacy (Generalised Self-Efficacy Scale (GSES)) and education level were analysed with linear regression analysis. After intervention, TTR was measured in three time periods of 6 months. MAIN OUTCOME MEASURES: (1) TTR, severe complications,(2) usage of an eHealth platform,(3) GSES, education level. RESULTS: Analysis showed no significant differences in TTR between the three time periods (p=0.520), the three groups (p=0.460) or the groups over time (p=0.263). Comparison of e-learning and group training showed no significant differences in TTR between the time periods (p=0.614), the groups (p=0.460) or the groups over time (p=0.263). No association was found between GSES and TTR (p=0.717) or education level and TTR (p=0.107). No significant difference was found between the self-management groups in usage of the platform (0-6 months p=0.571; 6-12 months p=0.866; 12-18 months p=0.260). The percentage of complications was low in all groups (3.2%; 1.4%; 0%). CONCLUSIONS: No differences were found between OAT patients trained by e-learning or by a group course regarding therapeutic control (TTR) and usage of a supporting eHealth platform. The TTR was similar in self-management and regular care patients. With adequate e-learning or group training, self-management seems safe and reliable for a selected proportion of motivated vitamin K antagonist patients. TRIAL REGISTRATION NUMBER: NTR3947.

Managed Bumble Bees (Bombus impatiens) (Hymenoptera: Apidae) Caged With Blueberry Bushes at High Density Did Not Increase Fruit Set or Fruit Weight Compared to Open Pollination.

Highbush blueberry (Vaccinium corymbosum L.) is an important crop grown throughout Florida. Currently, most blueberry growers use honey bees (Apis mellifera L.) to provide pollination services for highbush blueberries even though bumble bees (Bombus spp.) have been shown to be more efficient at pollinating blueberries on a per bee basis. In general, contribution of bumble bees to the pollination of commercial highbush blueberries in Florida is unknown. Herein, we determined if managed bumble bees could contribute to highbush blueberry pollination. There were four treatments in this study: two treatments of caged commercial bumble bee (Bombus impatiens Cresson) colonies (low and high weight hives), a treatment excluding all pollinators, and a final treatment which allowed all pollinators (managed and wild pollinators) in the area have access to the plot. All treatments were located within a highbush blueberry field containing two cultivars of blooming plants, 'Emerald' and 'Millennia', with each cage containing 16 mature blueberry plants. We gathered data on fruit set, berry weight, and number of seeds produced per berry. When pollinators were excluded, fruit set was significantly lower in both cultivars (<8%) compared to that in all of the other treatments (>58%). Berry weight was not significantly different among the treatments, and the number of seeds per berry did not show a clear response. This study emphasizes the importance of bumble bees as an effective pollinator of blueberries and the potential beneficial implications of the addition of bumble bees in commercial blueberry greenhouses or high tunnels.

Hypoxia Enhances the Toxicity of Corexit EC9500A and Chemically Dispersed Southern Louisiana Sweet Crude Oil (MC-242) to Sheepshead Minnow (Cyprinodon variegatus) Larvae.

Oil exploration and production activities are common in the northern Gulf of Mexico as well as many other coastal and near coastal areas worldwide. Seasonal hypoxia is also a common feature in the Northern Gulf, and many other coastal areas, which is likely to increase in severity and extent with continuing anthropogenic nutrient inputs. Hypoxia has well established physiological effects on many organisms, and it has been shown to enhance the toxicity of polycyclic aromatic hydrocarbons (persistent components of petroleum) in fish. The goal of this study was to examine the combined effects of hypoxia and exposure to contaminants associated with oil spills. We evaluated the effects of short term (48 hr) exposures to Corexit EC9500A, water accommodated fractions (WAF), and chemically enhanced water accommodated fractions (CEWAF) prepared from Southern Louisiana Sweet Crude Oil (MC 242) on survival of sheepshead minnow (Cyprinodon variegatus) larvae held under normoxic (ambient air) or hypoxic (2 mg/L O2) conditions. Results demonstrated that hypoxia significantly enhances mortality observed in response to Corexit or CEWAF solutions. In the latter case, significant interactions between the two stressors were also observed. Our data supports the need to further evaluate the combined stresses imparted by hypoxia and exposure to petroleum hydrocarbons and dispersants.

Oil and fatty acid contents in seed of Citrullus lanatus Schrad.

Intact seed of 475 genebank accessions of Citrullus ( C. lanatus var. lanatus and C. lanatus var. citroides) were analyzed for percent oil content using TD-NMR. Extracts from whole seed of 96 accessions of C. lanatus (30 var. citroides, 33 var. lanatus, and 33 egusi), C. colocynthis (n = 3), C. ecirrhosus (n = 1), C. rehmii (n = 1), and Benincasa fistulosa (n = 3) were also analyzed for their fatty acids content. Among the materials analyzed, seed oil content varied from 14.8 to 43.5%. Mean seed oil content in egusi types of C. lanatus was significantly higher (mean = 35.6%) than that of either var. lanatus (mean = 23.2%) or var. citroides (mean = 22.6%). Egusi types of C. lanatus had a significantly lower hull/kernel ratio when compared to other C. lanatus var. lanatus or C. lanatus var. citroides. The principal fatty acid in all C. lanatus materials examined was linoleic acid (43.6-73%). High levels of linoleic acid were also present in the materials of C. colocynthis (71%), C. ecirrhosus (62.7%), C. rehmii (75.8%), and B. fistulosa (73.2%), which were included for comparative purposes. Most all samples contained traces (<0.5%) of arachidonic acid. The data presented provide novel information on the range in oil content and variability in the concentrations of individual fatty acids present in a diverse array of C. lanatus, and its related species, germplasm.

Seed oil and fatty acid content in okra (Abelmoschus esculentus) and related species.

Approximately 1100 genebank accessions of okra (Abelmoschus esculentus) and 540 additional accessions that included six of its related species-A. caillei, A. crinitis, A. esculentus, A. ficulneus, A. manihot, A. moschatus and A. tuberculatus-were evaluated for seed oil content using time domain NMR (TD-NMR). Oil content in seed of A. caillei, A. esculentus, A. ficulneus, A. manihot, A. moschatus and A. tuberculatus was in the ranges 2.51-13.61%, 12.36-21.56%, 6.62-16.7%, 16.1-22.0%, 10.3-19.8% and 10.8-23.2%, respectively. Accession PI639680 (A. tuberculatus) had the highest seed oil content (∼23%). Accessions of A. esculentus with high seed oil content included PI nos. PI274350 (21.5%), PI538082 (20.9%) and PI538097 (20.9%). Values for the three accessions of A. manihot with the highest seed oil content were PI nos. PI639673 (20.4%), PI639674 (20.9%) and PI639675 (21.9%), all representing var. tetraphyllus. Average percent seed oil in materials of A. esculentus from Turkey and Sudan (17.35% and 17.36%, respectively) exceeded the averages of materials from other locations. Ninety-eight accessions (total of six species) were also examined for fatty acid composition. Values of linoleic acid ranged from 23.6-50.65% in A. esculentus. However, mean linoleic acid concentrations were highest in A. tuberculatus and A. ficulneus. Concentrations of palmitic acid were significantly higher in A. esculentus (range of 10.3-36.35%) when compared to that of other species, and reached a maximum in PI489800 Concentrations of palmitic acid were also high in A. caillei (mean = ∼30%). Levels of oleic acid were highest in A. manihot, A. manihot var. tetraphyllus and A. moschatus.

A simple, innovative surgical-instruction tool.

In the present report, we demonstrate the utility of a knitting needle as a device to improve the teaching of surgical principals and practice. Although we emphasize obstetric and gynecologic surgery, these techniques can easily be applied to other surgical specialties.

The increasing recalcitrance of smokers in clinical trials.

It has been suggested that a consequence of the declining prevalence of smoking in the United States over the past 25 years is that the population of remaining smokers is becoming more difficult to treat. That is, compared to smokers of years past, today's smokers are more likely to be highly nicotine dependent, have comorbid psychiatric and substance abuse disorders, have less education, and be of lower economic status. If this is indeed the case, there should be found declining abstinence rates in published clinical trials, when the type of treatment is held constant. To test this hypothesis, a literature search was conducted for group-administered multicomponent smoking cessation trials that emphasized coping skills training. Twenty-three studies published between 1977 and 1996 were identified. As predicted, robust negative correlations were found between year of publication and end-of-treatment abstinence rates. Using point-prevalence abstinence rates from later follow-up points produced somewhat weaker associations. Controlling for the use of biochemical verification or nicotine replacement therapies did not alter the findings. In summary, the efficacy of clinical trials--with treatment held constant--appears to be declining. One possible cause is the increasing recalcitrance of those individuals who continue to smoke despite social, regulatory, and medical pressures to quit.

X-ray crystallographic analysis of pokeweed antiviral protein-II after reductive methylation of lysine residues.

Pokeweed antiviral protein II (PAP-II) is a naturally occurring protein isolated from early summer leaves of the pokeweed plant (Phytolacca americana). PAP-II belongs to a family of ribosome-inactivating proteins which catalytically deadenylate ribosomal and viral RNA. The chemical modification of PAP-II by reductive methylation of its lysine residues significantly improved the crystal quality for X-ray diffraction studies. Hexagonal crystals of the modified PAP-II, with unit cell parameters a = b = 92.51 A, c = 79.05 A, were obtained using 1.8 M Na/K phosphate as the precipitant. These crystals contained one enzyme molecule per asymmetric unit and diffracted up to 2.4 A, when exposed to a synchroton source.

X-ray crystallographic analysis of the structural basis for the interactions of pokeweed antiviral protein with its active site inhibitor and ribosomal RNA substrate analogs.

The pokeweed antiviral protein (PAP) belongs to a family of ribosome-inactivating proteins (RIP), which depurinate ribosomal RNA through their site-specific N-glycosidase activity. We report low temperature, three-dimensional structures of PAP co-crystallized with adenyl-guanosine (ApG) and adenyl-cytosine-cytosine (ApCpC). Crystal structures of 2.0-2.1 A resolution revealed that both ApG or ApCpC nucleotides are cleaved by PAP, leaving only the adenine base clearly visible in the active site pocket of PAP. ApCpC does not resemble any known natural substrate for any ribosome-inactivating proteins and its cleavage by PAP provides unprecedented evidence for a broad spectrum N-glycosidase activity of PAP toward adenine-containing single stranded RNA. We also report the analysis of a 2.1 A crystal structure of PAP complexed with the RIP inhibitor pteoric acid. The pterin ring is strongly bound in the active site, forming four hydrogen bonds with active site residues and one hydrogen bond with the coordinated water molecule. The second 180 degrees rotation conformation of pterin ring can form only three hydrogen bonds in the active site and is less energetically favorable. The benzoate moiety is parallel to the protein surface of PAP and forms only one hydrogen bond with the guanido group of Arg135.