Organic Matter Sources, Composition, and Quality in Rivers and Experimental Streams

Organic matter (OM) is often considered the “currency” for ecosystem processes, such as respiration and primary production. OM in aquatic ecosystems is derived from multiple sources, and is a complex mixture of thousands of different chemical constituents. Therefore, it is difficult to identify all the sources of OM that enter and exit aquatic ecosystems. As humans develop undisturbed land, the rate at which terrestrial OM (e.g.soil and plants) and associated nutrients (e.g.nitrogen) enters rivers has increased. Increased nutrients may lead to increased primary production from aquatic plants and algae, potentially causing eutrophication and harmful algal blooms. In this study, I identified and characterized different sources of OM in four watersheds of Northeastern Utah with multiple land covers such as cities, forests, and crops. I expected OM in watersheds with human-altered land cover would have more OM produced instream by algae and other primary producers, than OM in less disturbed watersheds, which typically have OM from terrestrial sources. I found that OM at river sites with high human impact had high amounts of OM from instream primary production, but there was also OM produced in-steam at sites with low human impact. The greatest differences in OM across watersheds was due to wastewater treatment effluent. I also measured microbial consumption rates of algal derived and terrestrially derived DOM in experimental streams to quantify how much faster algal derived OM was consumed than terrestrial OM. I found algal derived OM was consumed extremely fast, so fast that realistic measurements of its consumption in some river ecosystems may not be possible. It is important to identify and characterize sources of OM to rivers, so watershed manager scan devise effective OM reduction plans appropriate for the constituent of concern unique to that watershed or region. Constituents of concern associated with OM include pathogens affiliated with manure, toxins in harmful algal blooms, metals, and pharmaceuticals from wastewater treatment effluent. Each pollutant requires a unique mitigation strategy and therefore the first step to pollution mitigation is source identification

Organic Matter is a Mixture of Terrestrial, Autochthonous, and Wastewater Effluent in an Urban River

Terrestrially derived organic matter (OM) is known to dominate the OM pool in reference watersheds. Urban watersheds are known to receive large OM loads compared to reference watersheds, but the proportion of terrestrial, autochthonous, and anthropogenic (e.g., wastewater effluent) sources of OM in urban watersheds remains unknown. Organic matter was identified as a pollutant of concern in the Jordan River, an urban river in the Salt Lake Basin, U.S.A. Our objective was to identify autochthonous, terrestrial, and anthropogenic sources of three size-classes of OM to the Jordan River to inform OM reduction strategies within the watershed. Samples of coarse particulate OM (CPOM), fine particulate OM (FPOM), and dissolved OM (DOM) were analyzed for stable isotopes of carbon, nitrogen, and hydrogen. Stable isotope values of OM were used for Bayesian and graphical gradient-based mixing models to identify autochthonous, terrestrial, and anthropogenic sources. Fluorescent properties of DOM were also used to characterize the sources and composition of DOM. CPOM was primarily terrestrially derived with increased autochthonous inputs from macrophytes in warm months. FPOM was a mixture of terrestrial, autochthonous, and wastewater effluent throughout the year. DOM was primarily from wastewater effluent as well as DOM with isotope signatures unique to DOM from Utah Lake. Characterization of OM in urban rivers will help inform conceptual models of OM dynamics and load management in urban ecosystems

Towards More Realistic Estimates of DOM Decay in Streams: Incubation Methods, Light, and Non-Additive Effects

Dissolved organic matter (DOM) is the largest pool of organic matter in aquatic ecosystems and is a primary substrate for microbial respiration in streams. However, understanding the controls on DOM processing by microbes remains limited, and DOM decay rates remain largely unconstrained. Many DOM decay rates are quantified with bioassays in dark bottles, which may underestimate DOM decay in streams because these bioassays do not include a benthic zone and do not account for abiotic factors of DOM loss, such as photodegradation and volatilization. We measured decay of labile and semi-labile DOM over 3 d in experimental streams and bottle bioassays. Incubations included 3 types of labile DOM (algal, light-degraded soil, and light-degraded plant leachates) and 2 types of semi-labile DOM (plant and soil leachates). We also quantified decay rates when labile and semi-labile DOM were mixed to test for non-additive effects, or priming, of semi-labile DOM by labile DOM. We converted dissolved organic carbon (DOC) decay rates to half-lives and uptake velocities and compared these metrics to previous studies that quantified DOC loss in bioassays or real streams. Percent DOC lost over time, or biodegradable DOC, was greater in experimental streams than in bioassays. DOC decay rates and uptake velocities did not differ between bioassays and experimental streams but were lower than in real streams. Mixing of labile and semi-labile DOM resulted in both positive and negative non-additive effects. Consistent non-additive effects were difficult to quantify because decay rates were not constant over the course of each incubation, as shown by faster decay rates calculated over the first 6 h of incubation compared to \u3e70 h. Decay rates of leachates from natural substrates (e.g., algae and soil) incubated over short periods of time (hours–days) are needed for models that aim to quantify organic matter transformation in aquatic ecosystems with short residence times, such as rivers and streams

Updated Guidance Regarding The Risk ofAllergic Reactions to COVID-19 Vaccines and Recommended Evaluation and Management: A GRADE Assessment, and International Consensus Approach

This guidance updates 2021 GRADE (Grading of Recommendations Assessment, Development and Evaluation) recommendations regarding immediate allergic reactions following coronavirus disease 2019 (COVID-19) vaccines and addresses revaccinating individuals with first-dose allergic reactions and allergy testing to determine revaccination outcomes. Recent meta-analyses assessed the incidence of severe allergic reactions to initial COVID-19 vaccination, risk of mRNA-COVID-19 revaccination after an initial reaction, and diagnostic accuracy of COVID-19 vaccine and vaccine excipient testing in predicting reactions. GRADE methods informed rating the certainty of evidence and strength of recommendations. A modified Delphi panel consisting of experts in allergy, anaphylaxis, vaccinology, infectious diseases, emergency medicine, and primary care from Australia, Canada, Europe, Japan, South Africa, the United Kingdom, and the United States formed the recommendations. We recommend vaccination for persons without COVID-19 vaccine excipient allergy and revaccination after a prior immediate allergic reaction. We suggest against \u3e 15-minute postvaccination observation. We recommend against mRNA vaccine or excipient skin testing to predict outcomes. We suggest revaccination of persons with an immediate allergic reaction to the mRNA vaccine or excipients be performed by a person with vaccine allergy expertise in a properly equipped setting. We suggest against premedication, split-dosing, or special precautions because of a comorbid allergic history

The SANAD II study of the effectiveness and cost-effectiveness of levetiracetam, zonisamide, or lamotrigine for newly diagnosed focal epilepsy: an open-label, non-inferiority, multicentre, phase 4, randomised controlled trial

Background: Levetiracetam and zonisamide are licensed as monotherapy for patients with focal epilepsy, but there is uncertainty as to whether they should be recommended as first-line treatments because of insufficient evidence of clinical effectiveness and cost-effectiveness. We aimed to assess the long-term clinical effectiveness and cost-effectiveness of levetiracetam and zonisamide compared with lamotrigine in people with newly diagnosed focal epilepsy. Methods: This randomised, open-label, controlled trial compared levetiracetam and zonisamide with lamotrigine as first-line treatment for patients with newly diagnosed focal epilepsy. Adult and paediatric neurology services across the UK recruited participants aged 5 years or older (with no upper age limit) with two or more unprovoked focal seizures. Participants were randomly allocated (1:1:1) using a minimisation programme with a random element utilising factor to receive lamotrigine, levetiracetam, or zonisamide. Participants and investigators were not masked and were aware of treatment allocation. SANAD II was designed to assess non-inferiority of both levetiracetam and zonisamide to lamotrigine for the primary outcome of time to 12-month remission. Anti-seizure medications were taken orally and for participants aged 12 years or older the initial advised maintenance doses were lamotrigine 50 mg (morning) and 100 mg (evening), levetiracetam 500 mg twice per day, and zonisamide 100 mg twice per day. For children aged between 5 and 12 years the initial daily maintenance doses advised were lamotrigine 1·5 mg/kg twice per day, levetiracetam 20 mg/kg twice per day, and zonisamide 2·5 mg/kg twice per day. All participants were included in the intention-to-treat (ITT) analysis. The per-protocol (PP) analysis excluded participants with major protocol deviations and those who were subsequently diagnosed as not having epilepsy. Safety analysis included all participants who received one dose of any study drug. The non-inferiority limit was a hazard ratio (HR) of 1·329, which equates to an absolute difference of 10%. A HR greater than 1 indicated that an event was more likely on lamotrigine. The trial is registered with the ISRCTN registry, 30294119 (EudraCt number: 2012-001884-64). Findings: 990 participants were recruited between May 2, 2013, and June 20, 2017, and followed up for a further 2 years. Patients were randomly assigned to receive lamotrigine (n=330), levetiracetam (n=332), or zonisamide (n=328). The ITT analysis included all participants and the PP analysis included 324 participants randomly assigned to lamotrigine, 320 participants randomly assigned to levetiracetam, and 315 participants randomly assigned to zonisamide. Levetiracetam did not meet the criteria for non-inferiority in the ITT analysis of time to 12-month remission versus lamotrigine (HR 1·18; 97·5% CI 0·95–1·47) but zonisamide did meet the criteria for non-inferiority in the ITT analysis versus lamotrigine (1·03; 0·83–1·28). The PP analysis showed that 12-month remission was superior with lamotrigine than both levetiracetam (HR 1·32 [97·5% CI 1·05 to 1·66]) and zonisamide (HR 1·37 [1·08–1·73]). There were 37 deaths during the trial. Adverse reactions were reported by 108 (33%) participants who started lamotrigine, 144 (44%) participants who started levetiracetam, and 146 (45%) participants who started zonisamide. Lamotrigine was superior in the cost-utility analysis, with a higher net health benefit of 1·403 QALYs (97·5% central range 1·319–1·458) compared with 1·222 (1·110–1·283) for levetiracetam and 1·232 (1·112, 1·307) for zonisamide at a cost-effectiveness threshold of £20 000 per QALY. Cost-effectiveness was based on differences between treatment groups in costs and QALYs. Interpretation: These findings do not support the use of levetiracetam or zonisamide as first-line treatments for patients with focal epilepsy. Lamotrigine should remain a first-line treatment for patients with focal epilepsy and should be the standard treatment in future trials. Funding: National Institute for Health Research Health Technology Assessment programme

The SANAD II study of the effectiveness and cost-effectiveness of valproate versus levetiracetam for newly diagnosed generalised and unclassifiable epilepsy: an open-label, non-inferiority, multicentre, phase 4, randomised controlled trial

Background: Valproate is a first-line treatment for patients with newly diagnosed idiopathic generalised or difficult to classify epilepsy, but not for women of child-bearing potential because of teratogenicity. Levetiracetam is increasingly prescribed for these patient populations despite scarcity of evidence of clinical effectiveness or cost-effectiveness. We aimed to compare the long-term clinical effectiveness and cost-effectiveness of levetiracetam compared with valproate in participants with newly diagnosed generalised or unclassifiable epilepsy. Methods: We did an open-label, randomised controlled trial to compare levetiracetam with valproate as first-line treatment for patients with generalised or unclassified epilepsy. Adult and paediatric neurology services (69 centres overall) across the UK recruited participants aged 5 years or older (with no upper age limit) with two or more unprovoked generalised or unclassifiable seizures. Participants were randomly allocated (1:1) to receive either levetiracetam or valproate, using a minimisation programme with a random element utilising factors. Participants and investigators were aware of treatment allocation. For participants aged 12 years or older, the initial advised maintenance doses were 500 mg twice per day for levetiracetam and valproate, and for children aged 5–12 years, the initial daily maintenance doses advised were 25 mg/kg for valproate and 40 mg/kg for levetiracetam. All drugs were administered orally. SANAD II was designed to assess the non-inferiority of levetiracetam compared with valproate for the primary outcome time to 12-month remission. The non-inferiority limit was a hazard ratio (HR) of 1·314, which equates to an absolute difference of 10%. A HR greater than 1 indicated that an event was more likely on valproate. All participants were included in the intention-to-treat (ITT) analysis. Per-protocol (PP) analyses excluded participants with major protocol deviations and those who were subsequently diagnosed as not having epilepsy. Safety analyses included all participants who received one dose of any study drug. This trial is registered with the ISRCTN registry, 30294119 (EudraCt number: 2012-001884-64). Findings: 520 participants were recruited between April 30, 2013, and Aug 2, 2016, and followed up for a further 2 years. 260 participants were randomly allocated to receive levetiracetam and 260 participants to receive valproate. The ITT analysis included all participants and the PP analysis included 255 participants randomly allocated to valproate and 254 randomly allocated to levetiracetam. Median age of participants was 13·9 years (range 5·0–94·4), 65% were male and 35% were female, 397 participants had generalised epilepsy, and 123 unclassified epilepsy. Levetiracetam did not meet the criteria for non-inferiority in the ITT analysis of time to 12-month remission (HR 1·19 [95% CI 0·96–1·47]); non-inferiority margin 1·314. The PP analysis showed that the 12-month remission was superior with valproate than with levetiracetam. There were two deaths, one in each group, that were unrelated to trial treatments. Adverse reactions were reported by 96 (37%) participants randomly assigned to valproate and 107 (42%) participants randomly assigned to levetiracetam. Levetiracetam was dominated by valproate in the cost-utility analysis, with a negative incremental net health benefit of −0·040 (95% central range −0·175 to 0·037) and a probability of 0·17 of being cost-effectiveness at a threshold of £20 000 per quality-adjusted life-year. Cost-effectiveness was based on differences between treatment groups in costs and quality-adjusted life-years. Interpretation: Compared with valproate, levetiracetam was found to be neither clinically effective nor cost-effective. For girls and women of child-bearing potential, these results inform discussions about benefit and harm of avoiding valproate. Funding: National Institute for Health Research Health Technology Assessment Programme

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Filtering with a Drill Pump: An Efficient and Cost Effective Method to Collect Suspended Sediment and Filtrate

Water quality monitoring programs across multiple disciplines use total suspended solids (TSS), and volatile suspended solids (VSS), to assess potential impairments of surface water and groundwater. While previous methods for instream filtering have been developed, the need for rapid, cost-effective, high volume sampling has increased with the need to verify and supplement data produced by sondes and instantaneous data loggers. We present an efficient method to filter water instream with a portable drill pump that results in reduced sample processing time, and potentially reduced error associated with sample transportation, preservation, contamination, and homogenization. This technical note outlines the advantages of filtering instream vs. in the laboratory. It also compares TSS and VSS concentrations filtered with a drill pump vs. standard filtration methods with a vacuum pump as outlined by USEPA methods 160.2 and 160.4. Samples were collected at 4 sites and filtered in the field, or transported to the laboratory and filtered within 12 or 24 h of collection. Overall TSS and VSS samples filtered instream with a drill pump vs. in the laboratory produced similar concentrations with a similar range in variability for each method. Sample filtering with a drill pump decreased processing time by five minutes per sample