Human activities introduce a variety of chemicals to the Laurentian Great Lakes including pesticides, pharmaceuticals, flame retardants, plasticizers, and solvents (collectively referred to as ...contaminants of emerging concern or CECs) potentially threatening the vitality of these valuable ecosystems. We conducted a basin-wide study to identify the presence of CECs and other chemicals of interest in 12 U.S. tributaries to the Laurentian Great Lakes during 2013 and 2014. A total of 292 surface-water and 80 sediment samples were collected and analyzed for approximately 200 chemicals. A total of 32 and 28 chemicals were detected in at least 30% of water and sediment samples, respectively. Concentrations ranged from 0.0284 (indole) to 72.2 (cholesterol) μg/L in water and 1.75 (diphenhydramine) to 20,800 μg/kg (fluoranthene) in sediment. Cluster analyses revealed chemicals that frequently co-occurred such as pharmaceuticals and flame retardants at sites receiving similar inputs such as wastewater treatment plant effluent. Comparison of environmental concentrations to water and sediment-quality benchmarks revealed that polycyclic aromatic hydrocarbon concentrations often exceeded benchmarks in both water and sediment. Additionally, bis(2-ethylhexyl) phthalate and dichlorvos concentrations exceeded water-quality benchmarks in several rivers. Results from this study can be used to understand organism exposure, prioritize river basins for future management efforts, and guide detailed assessments of factors influencing transport and fate of CECs in the Great Lakes Basin.
Large subsurface treatment systems (LSTS) and rapid infiltration basins (RIB) are preferred onsite wastewater treatments compared to direct discharge of treated wastewater to streams and adjacent ...facilities. Discharge of these wastewater treatments may result in contaminant loading to aquifers that also serve as drinking water sources downgradient from the discharge site. Until recently, few studies have characterized the contribution of micropollutants (e.g. pharmaceuticals, fragrances, flame retardants, etc.) to receiving aquifers. We conducted a pilot project to characterize the occurrence of micropollutants in groundwater downgradient from 7 on-site treatment systems in Minnesota, USA: 5 community LSTS and 2 municipal RIB. One downgradient monitoring well was sampled three times at each facility over one year. Of 223 micropollutants analyzed, 35 were detected. Total sample concentrations ranged from 90 to 4,039 ng/L. Sulfamethoxazole (antibiotic) was detected in all samples at concentrations from 7 to 965 ng/L. Other pharmaceuticals (0.12-1,000 ng/L), organophosphorus flame retardants (10-500 ng/L), and other anthropogenic chemicals (4-775 ng/L) were also detected. The numbers and concentrations of micropollutants detected were inversely related to dissolved oxygen and depth to water. Ratios of pharmaceutical concentrations to human-health screening values were <0.10 for most samples. However, concentrations of carbamazepine and sulfamethoxazole exceeded screening values at two sites. Study results illustrate that large on-site wastewater systems designed to discharge to permeable soil or shallow groundwater effectively deliver pharmaceuticals and other micropollutants to groundwater aquifers and could contribute micropollutants to drinking water via water supply wells.
Polycystic ovary syndrome (PCOS) is a common endocrine disorder, which is accompanied by a variety of comorbidities including metabolic, reproductive, and psychiatric disorders. Genome-wide ...association studies have identified several genetic variants that are associated with PCOS. However, these variants often occur outside of coding regions and require further investigation to understand their contribution to PCOS. A transcriptome-wide association study (TWAS) was performed to uncover heritable gene expression profiles that are associated with PCOS in two independent cohorts. Causal gene prioritization was subsequently performed and expression of genes prioritized through these analyses was examined in 49 PCOS patients and 30 controls. TWAS analyses revealed that increased expression of ARL14EP was significantly associated with PCOS risk in the discovery (P = 1.6 × 10
) and replication cohorts (P = 2.0 × 10
). Gene prioritization pipelines provided further evidence that ARL14EP is the most likely causal gene at this locus. ARL14EP gene expression was shown to be significantly different between PCOS cases and controls, after adjusting for body mass index, age and testosterone levels (P = 1.2 × 10
). This study has provided evidence for the role of ARL14EP in PCOS. Given that ARL14EP has been reported to play an important role in chromatin remodeling, variants affecting the expression of ARL14EP may also affect the expression of other genes that contribute to PCOS pathogenesis.
Induction of lipid-laden foamy macrophages is a cellular hallmark of tuberculosis (TB) disease, which involves the transformation of infected phagolysosomes from a site of killing into a ...nutrient-rich replicative niche. Here, we show that a terpenyl nucleoside shed from Mycobacterium tuberculosis, 1-tuberculosinyladenosine (1-TbAd), caused lysosomal maturation arrest and autophagy blockade, leading to lipid storage in M1 macrophages. Pure 1-TbAd, or infection with terpenyl nucleoside-producing M. tuberculosis, caused intralysosomal and peribacillary lipid storage patterns that matched both the molecules and subcellular locations known in foamy macrophages. Lipidomics showed that 1-TbAd induced storage of triacylglycerides and cholesterylesters and that 1-TbAd increased M. tuberculosis growth under conditions of restricted lipid access in macrophages. Furthermore, lipidomics identified 1-TbAd-induced lipid substrates that define Gaucher's disease, Wolman's disease, and other inborn lysosomal storage diseases. These data identify genetic and molecular causes of M. tuberculosis-induced lysosomal failure, leading to successful testing of an agonist of TRPML1 calcium channels that reverses lipid storage in cells. These data establish the host-directed cellular functions of an orphan effector molecule that promotes survival in macrophages, providing both an upstream cause and detailed picture of lysosome failure in foamy macrophages.
Numerous contaminants of emerging concern (CECs) typically occur in urban rivers. Wastewater effluents are a major source of many CECs. Urban runoff (stormwater) is a major urban water budget ...component and may constitute another major CEC pathway. Yet, stormwater-based CEC field studies are rare. This research investigated 384 CECs in 36 stormwater samples in Minneapolis-St. Paul, Minnesota, USA. Nine sampling sites included three large stormwater conveyances (pipes) and three paired iron-enhanced sand filters (IESFs; untreated inlets and treated outlets). The 123 detected compounds included commercial-consumer compounds, veterinary and human pharmaceuticals, lifestyle and personal care compounds, pesticides, and others. Thirty-one CECs were detected in ≥50% of samples. Individual samples contained a median of 35 targeted CECs (range: 18–54). Overall, median concentrations were ≥10 ng/L for 25 CECs and ≥100 ng/L for 9 CECs. Ranked, hierarchical linear modeling indicated significant seasonal- and site type-based concentration variability for 53 and 30 CECs, respectively, with observed patterns corresponding to CEC type, source, usage, and seasonal hydrology. A primarily warm-weather, diffuse, runoff-based profile included many herbicides. A second profile encompassed winter and/or late summer samples enriched with some recalcitrant, hydrophobic compounds (e.g., PAHs), especially at pipes, suggesting conservative, less runoff-dependent sources (e.g., sediments). A third profile, indicative of mixed conservative/non-runoff, runoff, and/or atmospheric sources and transport that collectively affect a variety of conditions, included various fungicides, lifestyle, non-prescription, and commercial-consumer CECs. Generally, pipe sites had large, diverse land-use catchments, and showed more frequent detections of diverse CECs, but often at lower concentrations; while untreated sites (with smaller, more residential-catchments) demonstrated greater detections of “pseudo-persistent” and other ubiquitous or residentially-associated CECs. Although untreated stormwater transports an array of CECs to receiving waters, IESF treatment significantly removed concentrations of 14 (29%) of the 48 most detected CECs; for these, median removal efficiencies were 26%–100%. Efficient removal of some hydrophobic (e.g., PAHs, bisphenol A) and polar-hydrophilic (e.g., caffeine, nicotine) compounds indicated particulate-bound contaminant filtration and for certain dissolved contaminants, sorption.
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•123 of 384 studied contaminants of emerging concern (CECs) detected in stormwater.•38 of 48 frequently detected CEC varied seasonally, and 18 varied by site type.•IESFs significantly removed concentrations of 14 of 48 frequently detected CECs.
Anthropogenic chemicals and their potential for adverse biological effects raise concern for aquatic ecosystem health in protected areas. During 2013–15, surface waters of four Midwestern United ...States national parks were sampled and analyzed for wastewater indicators, pharmaceuticals, personal care products, and pesticides. More chemicals and higher concentrations were detected at the two parks with greater urban influences (Mississippi National River and Recreation Area and Indiana Dunes National Lakeshore) than at the two more remote parks (Apostle Islands National Lakeshore and Isle Royale National Park). Atrazine (10–15ng/L) and N,N-diethyl-meta-toluamide (16–120ng/L) were the only chemicals detected in inland lakes of a remote island national park (Isle Royale National Park). Bisphenol A and organophosphate flame retardants were commonly detected at the other sampled parks. Gabapentin and simazine had the highest observed concentrations (>1000ng/L) in three and two samples, respectively. At the two parks with urban influences, metolachlor and simazine concentrations were similar to those reported for other major urban rivers in the United States. Environmental concentrations of detected chemicals were often orders of magnitude less than standards or reference values with three exceptions: (1) hydrochlorothiazide exceeded a human health-based screening value in seven samples, (2) estrone exceeded a predicted critical environmental concentration for fish pharmacological effects in one sample, and (3) simazine was approaching the 4000ng/L Maximum Contaminant Level in one sample even though this concentration is not expected to reflect peak pesticide use. Although few environmental concentrations were approaching or exceeded standards or reference values, concentrations were often in ranges reported to elicit effects in aquatic biota. Data from this study will assist in establishing a baseline for chemicals of concern in Midwestern national parks and highlight the need to better understand the sources, pathways, and potential adverse effects to aquatic systems in national parks.
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•Chemicals of concern were detected in surface waters of four U.S. national parks.•Gabapentin and metformin frequently occurred together.•Pesticides were detected at a higher rate than other chemicals analyzed.•Environmental concentrations rarely exceeded reference values or standards.•Chemicals detected at concentrations reported to elicit adverse effects to biota.
Post-COVID-19 condition (also known as long COVID) is an emerging chronic illness potentially affecting millions of people. We aimed to evaluate whether outpatient COVID-19 treatment with metformin, ...ivermectin, or fluvoxamine soon after SARS-CoV-2 infection could reduce the risk of long COVID.
We conducted a decentralised, randomised, quadruple-blind, parallel-group, phase 3 trial (COVID-OUT) at six sites in the USA. We included adults aged 30–85 years with overweight or obesity who had COVID-19 symptoms for fewer than 7 days and a documented SARS-CoV-2 positive PCR or antigen test within 3 days before enrolment. Participants were randomly assigned via 2 × 3 parallel factorial randomisation (1:1:1:1:1:1) to receive metformin plus ivermectin, metformin plus fluvoxamine, metformin plus placebo, ivermectin plus placebo, fluvoxamine plus placebo, or placebo plus placebo. Participants, investigators, care providers, and outcomes assessors were masked to study group assignment. The primary outcome was severe COVID-19 by day 14, and those data have been published previously. Because the trial was delivered remotely nationwide, the a priori primary sample was a modified intention-to-treat sample, meaning that participants who did not receive any dose of study treatment were excluded. Long COVID diagnosis by a medical provider was a prespecified, long-term secondary outcome. This trial is complete and is registered with ClinicalTrials.gov, NCT04510194.
Between Dec 30, 2020, and Jan 28, 2022, 6602 people were assessed for eligibility and 1431 were enrolled and randomly assigned. Of 1323 participants who received a dose of study treatment and were included in the modified intention-to-treat population, 1126 consented for long-term follow-up and completed at least one survey after the assessment for long COVID at day 180 (564 received metformin and 562 received matched placebo; a subset of participants in the metformin vs placebo trial were also randomly assigned to receive ivermectin or fluvoxamine). 1074 (95%) of 1126 participants completed at least 9 months of follow-up. 632 (56·1%) of 1126 participants were female and 494 (43·9%) were male; 44 (7·0%) of 632 women were pregnant. The median age was 45 years (IQR 37–54) and median BMI was 29·8 kg/m2 (IQR 27·0–34·2). Overall, 93 (8·3%) of 1126 participants reported receipt of a long COVID diagnosis by day 300. The cumulative incidence of long COVID by day 300 was 6·3% (95% CI 4·2–8·2) in participants who received metformin and 10·4% (7·8–12·9) in those who received identical metformin placebo (hazard ratio HR 0·59, 95% CI 0·39–0·89; p=0·012). The metformin beneficial effect was consistent across prespecified subgroups. When metformin was started within 3 days of symptom onset, the HR was 0·37 (95% CI 0·15–0·95). There was no effect on cumulative incidence of long COVID with ivermectin (HR 0·99, 95% CI 0·59–1·64) or fluvoxamine (1·36, 0·78–2·34) compared with placebo.
Outpatient treatment with metformin reduced long COVID incidence by about 41%, with an absolute reduction of 4·1%, compared with placebo. Metformin has clinical benefits when used as outpatient treatment for COVID-19 and is globally available, low-cost, and safe.
Parsemus Foundation; Rainwater Charitable Foundation; Fast Grants; UnitedHealth Group Foundation; National Institute of Diabetes, Digestive and Kidney Diseases; National Institutes of Health; and National Center for Advancing Translational Sciences.
Globally, over 200 million people are chronically exposed to arsenic (As) and/or manganese (Mn) from drinking water. We used machine-learning (ML) boosted regression tree (BRT) models to predict high ...As (>10 μg/L) and Mn (>300 μg/L) in groundwater from the glacial aquifer system (GLAC), which spans 25 states in the northern United States and provides drinking water to 30 million people. Our BRT models’ predictor variables (PVs) included recently developed three-dimensional estimates of a suite of groundwater age metrics, redox condition, and pH. We also demonstrated a successful approach to significantly improve ML prediction sensitivity for imbalanced data sets (small percentage of high values). We present predictions of the probability of high As and high Mn concentrations in groundwater, and uncertainty, at two nonuniform depth surfaces that represent moving median depths of GLAC domestic and public supply wells within the three-dimensional model domain. Predicted high likelihood of anoxic condition (high iron or low dissolved oxygen), predicted pH, relative well depth, several modeled groundwater age metrics, and hydrologic position were all PVs retained in both models; however, PV importance and influence differed between the models. High-As and high-Mn groundwater was predicted with high likelihood over large portions of the central part of the GLAC.
Background
Atrial fibrillation (AF) impacts performance and horse and jockey safety. Understanding the outcomes of AF identified postrace will better inform regulatory policy.
Hypothesis/Objectives
...To investigate the outcomes after episodes of AF identified postrace and determine whether affected horses are at increased risk of additional episodes compared to the general racing population.
Animals
Total of 4684 Thoroughbred racehorses.
Methods
Race records for Thoroughbred horses racing in Hong Kong from 2007 to 2017 were reviewed. Horses that performed below expectation were examined by cardiac auscultation and ECG. Incidence and recurrence of AF were compared between horses with and without a history of AF and between horses with paroxysmal and persistent episodes using Fisher's exact test.
Results
There were 96 135 race starts during the study. Atrial fibrillation was identified in 4.9% of horses, with an overall incidence of 2.7 episodes per 1000 starts. The incidence of AF in horses after any previous episode (12.8 per 1000 starts) was higher than for horses with no previous episode (2.4 per 1000 starts; odds ratio OR, 5.3; 95% confidence interval CI, 3.8‐7.6). Recurrence was seen in 64% of horses previously treated for persistent AF, which was higher than recurrence in horses with paroxysmal AF (23%; OR, 5.9; 95% CI, 1.6‐21.2). Median duration between episodes was 343 days (range, 34‐1065).
Conclusions and Clinical Importance
Thoroughbreds are at increased risk of recurrent AF after both paroxysmal and persistent episodes, but the duration of time between episodes varies widely. These findings support a substantial burden of AF among individual Thoroughbred racehorses.
Hip fracture has a devastating impact on individuals and is an increasing burden for health systems and society. Compared to usual care, increased physiotherapy provision has demonstrated efficacy in ...improving patient and health service outcomes in this population. However, physiotherapy workforce challenges prevent sustained implementation.
Our aim was to evaluate the safety, feasibility, acceptability, effectiveness and implementation cost of thrice daily physiotherapy for patients in the acute care setting after hip fracture at two public hospitals. We added twice-daily exercise implemented by an alternative workforce, to usual care consisting of daily mobility practice by a physiotherapist. Sites identified their preferred alternative workforce, with pre-registration physiotherapy students and allied health assistants chosen. We used a mixed methods approach, using the Consolidated Framework for Implementation Research (CFIR) as a determinant framework to guide implementation planning and data collection. We compared hospital length of stay data to a reference cohort.
We recruited 25 patients during the study period. Acute care hospital length of stay decreased from 11 days in the reference cohort to 8 days in the BOOST cohort (mean difference - 3.3 days, 95%CI -5.4 to -1.2 days, p = 0.003). Intervention fidelity was 72% indicating feasibility, no safety concerns were attributed to the intervention, and uptake was 96% of all eligible patients. The intervention was acceptable to patients, carers and healthcare providers. This intervention was cost-effective from the acute orthopaedic service perspective.
Higher daily frequency of physiotherapy can be safely, feasibly and effectively implemented by an alternative workforce for patients in the acute care setting following hip fracture surgery.
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