In recent decades, cyanobacteria harmful algal blooms (cyanoHABs) have increased in magnitude, frequency, and duration in freshwater ecosystems. CyanoHABs can impact water quality by the production ...of potent toxins known as cyanotoxins. Environmental exposure to cyanotoxins has been associated with severe illnesses in humans, domestic animals, and wildlife. However, the effects of sustained exposure to cyanotoxins on aquatic life are poorly understood. In this study, over 150 peer-reviewed articles were critically evaluated to better understand the ecotoxicity of 5 cyanotoxin classes (microcystins, cylindrospermopsin, anatoxin-a, saxitoxins, nodularin) on fish, amphibians, aquatic invertebrates, and birds exclusively feeding in freshwater habitats. The systemic review demonstrated that microcystins, and more specifically microcystin-LR, were the most studied cyanotoxins. Ecotoxicological investigations were typically conducted using a fish or aquatic invertebrate model, with mortality, bioaccumulation, and biochemical responses as the most frequently measured endpoints. After excluding the studies that did not meet our acceptability criteria, remaining studies were examined to identify the no-observed and lowest observed effect concentrations (NOEC and LOEC) for microcystins; the limited amount of data for other cyanotoxins did not allow for analysis. The published ecotoxicity data suggests that the U.S. EPA recreational water quality criteria for microcystin (8 μg/L) may be protective of acute toxicity in aquatic organisms but does not appear to protect against chronic toxicity. Individual U.S. states have developed more stringent recreational health-based thresholds, such as 0.8 μg/L in California. Comparisons of this threshold to the chronic NOEC and LOEC data indicate that more restrictive microcystins thresholds may be required to be protective of aquatic life. Additional research is needed to evaluate the sublethal effects of a wider array of microcystin congeners and other cyanotoxins on organisms relevant to U.S. watersheds to better support nationwide thresholds protective of aquatic life.
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•Ecotoxicological risk of cyanotoxins on aquatic life remains poorly understood.•There is limited toxicity data for most cyanotoxins classes and relevant species.•Thorough characterization of cyanotoxins could facilitate interpretation of ecotoxicity data.•U.S. recreational thresholds for microcystins may not be protective of aquatic life.
Assessing the impact of chemical contaminants on aquatic ecosystem health remains challenging due to complex exposure scenarios and the myriad of impact metrics to consider. To expand the breadth of ...compounds monitored and evaluate the potential hazard of environmental mixtures, cell-based bioassays (estrogen receptor alpha (ERα) and aryl hydrocarbon receptor (AhR)) and non-targeted chemical analyses with high resolution mass spectrometry (NTA-HRMS) were used to assess the quality of ∼70 marine sediment samples collected from 5 distinct coastal and offshore habitats of the Southern California Bight. AhR responses (<0.12–4.5 ng TCDD/g dry weight) were more frequently detectable and more variable than for ERα (<0.1–0.5 ng E2/g dry weight). The range of AhR and ERα responses increased by habitat as follows: Channel Islands < Mid-shelf < Marinas < Ports < Estuaries. The narrow range and magnitude of ERα screening response suggested limited potential for estrogenic impacts across sediments from all 5 habitats. The AhR response was positively correlated with total PAH and PCB concentrations and corresponded with a chemical score index representing the severity of metal and organic contamination. NTA-HRMS fingerprints generated in positive electrospray ionization mode were clearly distinguishable among coastal vs. offshore samples, with the greatest chemical complexity (n = 982 features detected) observed in estuarine sediment from a highly urbanized watershed (Los Angeles River). The concordance and complementary nature of bioscreening and NTA-HRMS results indicates their utility as holistic proxies for sediment quality, and when analyzed in conjunction with routine targeted chemical monitoring, show promise in identifying unexpected contaminants and novel toxicants.
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•First large-scale application of cell bioassay and non-targeted chemical analyses to assess coastal and marine sediments.•The aryl hydrocarbon receptor bioassays provided a means for efficient screening of sediment quality.•Cell bioassays coupled with non-targeted chemical analyses showed potential to identify unknown or unexpected toxicants.
The analysis of small particles, including extracellular vesicles and viruses, is contingent on their ability to scatter sufficient light to be detected. These detection methods include flow ...cytometry, nanoparticle tracking analysis, and single particle reflective image sensing. To standardize measurements and enable orthogonal comparisons between platforms, a quantifiable limit of detection is required. The main parameters that dictate the amount of light scattered by particles include size, morphology, and refractive index. To date, there has been a lack of accessible techniques for measuring the refractive index of nanoparticles at a single-particle level. Here, we demonstrate two methods of deriving a small particle refractive index using orthogonal measurements with commercially available platforms. These methods can be applied at either a single-particle or population level, enabling the integration of diameter and scattering cross section values to derive the refractive index using Mie theory.
Salt marshes are highly productive ecosystems which perform many valuable services including carbon sequestration, nutrient transformation, and mitigation of rough waters generated by storms. Coastal ...salt marshes currently face threats resulting from global climate change, including sea level rise (SLR). Coastal marshes have kept pace with historical SLR through elevation gain via sediment precipitation from tidal waters. In the coming century, sea level is expected to increase 5x-8x faster than the previous century. Since the rate of sedimentation is unlikely to increase with SLR, marshes are in danger of habitat loss via drowning and subsidence. The decomposing organisms in salt marsh sediments are essential to maintaining marsh plant health. The response of decomposing organisms to longer periods of inundation is unclear. To determine how the prokaryote and invertebrate communities may change in response to SLR, mesocosms were designed, which simulated different inundation intensities within the marsh. A gradient developed over the 10-month sampling period in which the most inundated sediments had significantly different communities than the driest sediments. The high inundation treatments were dominated by anaerobic prokaryotes and insect larvae, and sulfate reduction was the predominant decomposition processes. The ambient mesocosms (driest sediments) were dominated by aerobic prokaryotes and oligochaete worms. Aerobic processes such as leaf litter decay became the key decomposition processes in these sediments.
Reviewer Employment Research Grant Other Research Support Speakers' Bureau/Honoraria Expert Witness Ownership Interest Consultant/Advisory Board Other Vera Bittner University of Alabama at Birmingham ...Gilead: WISQ Studydagger; Roche-DAL-Outcomes Studydagger; GSK-Stability Trialdagger; NIH/Yale-VIRGO Registrydagger; NIH/Abbott-AIM HIGH trialdagger National Coordinator for the ALECARDIO trial (Roche)* None None None Pfizer* Immediate past president, National Lipid Association* Eliot A. Brinton University of Utah Abbottdagger; GSKdagger; Merckdagger None Abbottdagger; Daiichi-Sankyo*; GSKdagger; Kaneka*; Merckdagger; Takedadagger None None Abbott*; Amarin*; Atherotechdagger; Daiichi-Sankyo*; Essentialis*; GSK*; Merck*; Takeda* None Monique V. Chireau Duke University Duke Translational Research Institutedagger; Duke Clinical Research Unit* None None None None Chireau Consultant/Advisory Board, Templeton Foundation* None Jennifer Cummings Akron General Medical Center None None Sanofi Aventis*; Boston Scientific*; Medtronic*; St Jude* None None Corazon Consulting*; St Jude*; Medtronic* None Claire Duvernoy VA Healthcare System VA Cooperative Studies Program* Sanofi-Aventis* None None None None None Federico Gentile Centro Medico Diagnostico (Naples, Italy) None None None None None None None Suzanne Hughes Summa Health System (Akron, OH) None None None None None None None Courtney O. Jordan University of Minnesota None None None None None None None Sanjay Kaul Cedars-Sinai Medical Center Hoffman La Roche* None None None Johnson & Johnson* Hoffman La Roche*; FDA* None Mary McGrae McDermott Northwestern University NHLBIdagger None None None None None Contributing editor, JAMAdagger Laxmi S. Mehta Ohio State University None None None None None None None C. Venkata S. Ram Dallas Nephrology Associates None None None None None None None Rita F. Redberg UCSF Flight Attendant Medical Research Institute* None None None None GTAF*; FDA CVD Expert Panel* None Vincent L. Sorrell University of Arizona None None None None None None None Deborah Wesley Wake Forest University None None None None None None None * Reviewer Disclosures This table represents the relationships of reviewers that may be perceived as actual or reasonably perceived conflicts of interest as reported on the Disclosure Questionnaire, which all reviewers are required to complete and submit.
Introduction: First-line (1L) therapy for diffuse large B-cell lymphoma (DLBCL) can cure ~60% of patients (pts), but ~10-15% do not respond and 20-25% relapse. Salvage chemotherapy with autologous ...stem cell transplant (ASCT) is standard for ‘fit’ pts with relapsed or refractory (R/R) disease. However ~50% of pts are ineligible for transplant and most who undergo ASCT will relapse; for these pts options are extremely limited. Here we evaluated R/R DLBCL treatment patterns and outcomes for pts managed at a single UK center to create a detailed ‘real-world’ comparator for novel therapies.
Methods: A detailed retrospective analysis of medical records was undertaken for pts with DLBCL 2006-2017 and a R/R event 2011-2017. Additional eligibility criteria were: age ≥18 years; ≥1 prior anti-CD20 antibody-containing chemo-immunotherapy regimen; no history of high-grade transformation; and no lymphomatous CNS involvement. Pt characteristics, treatments, responses, and overall survival (OS) were reported by line (L) of therapy (2L, 3L, 4L+) in all pts and in refractory pts (defined as no response to or relapse within 6 months of last treatment).
Results: Of 2025 pts diagnosed with DLBCL 2006-2017, 89 fulfilled eligibility including a R/R event 2011-2017: 89, 63, and 41 received 2L, 3L, and 4L+ treatment. Median age at 2L was 66 years (range 58-72). 58.4% (n=52) were male and 64.0% (n=57) were stage III/IV; 49.4% (n=44) were ABC subtype and 29.2% (n=26) were GCB. Systemic 2L therapies (≥5% incidence) included R-DHAP (20.2%; n=18), R-GDP (20.2%; n=18), DHAP (10.1%; n=9), R-GCVP (7.9%; n=7), and gemcitabine (5.6%; n=5). In 2L, 23.6% (n=21) of pts underwent ASCT. With each line, regimens became more diverse, with increased use of experimental therapies. Overall response rate was 46.1% in 2L, 27.0% in 3L, and 9.8% in 4L+. In refractory pts, it was 34.8%, 21.2%, and 7.9% (Table). OS is shown in the Figure and Table; 2-year OS was 30.6% in all R/R pts and 20.5% in refractory pts. Median OS was reduced in pts with low ECOG performance status or high LDH. Two-year OS was 71.4% in transplanted pts (n=23) and 16.3% in non-transplanted pts.
Conclusions: Despite multiple treatment options, pts with R/R DLBCL have a very poor prognosis, highlighting the need for rapid introduction of more effective therapies. This can be facilitated by robust data such as these, which may be used for comparing outcomes of novel therapies with those expected at a given line of treatment in the ‘real world’, unrestricted by the requirements of a trial protocol. Results will be compared with those from the SCHOLAR-1 study (Crump et al. Blood 2017;130:1800-8) to provide greater clarity regarding R/R DLBCL treatment outcomes in the ‘real world’ setting.
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Radford:Seattle Genetics: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; ADC Therapeutics: Consultancy, Research Funding; AstraZeneca: Equity Ownership, Research Funding; GSK: Equity Ownership; BMS: Consultancy, Honoraria. Castro:F. Hoffmann-La Roche Ltd: Employment. Chaturvedi:Christie Hospital NHS Trust: Employment. Spielewoy:F. Hoffmann-La Roche Ltd: Employment. Gibb:Takeda: Research Funding. Surinach:Genesis Research: Employment. Shang:F.Hoffmann-La Roche AG: Employment. Wenger:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership.
“Atezolizumab (atezo) is a programmed death-ligand 1 (PD-L1) blocking antibody. In the United States, atezo is approved for treatment of pts with locally advanced or metastatic urothelial carcinoma who are: not eligible for cisplatin-containing chemotherapy (chemo) and whose tumors express PDL-1, or are not eligible for any platinum-containing chemo regardless of PD L1 status; or have disease progression during or following any platinum-containing chemo, or within 12 months of neoadjuvant or adjuvant chemo. Atezo is also approved: in combination with bevacizumab, paclitaxel and carboplatin for first-line treatment of pts with metastatic non-squamous non-small-cell lung carcinoma (NSCLC) with no EGFR or ALK genomic tumor aberrations, and for pts with metastatic NSCLC who have disease progression during or following platinum-containing chemo; in combination with paclitaxel protein-bound for the treatment of adults with unresectable locally advanced or metastatic triple-negative breast cancer whose tumors express PD-L1; and in combination with carboplatin and etoposide, for the first-line treatment of adults with extensive-stage small cell lung cancer. Atezo is not approved for treatment of pts with multiple myeloma.”
Some commonly used preventive interventions lacked clinical trial data for women, and it was unclear whether results of studies conducted in men could be generalized to women. Since the 2003 ...literature review, numerous clinical trials that have a bearing on CVD prevention in women have been completed (see Appendix). Reviewer Representation Research Grant Other Research Support Speakers' Bureau/ Honoraria Ownership Interest Consultant/ Advisory Board Other Jeffrey L. Anderson American College of Cardiology Foundation Clinical Expert Consensus Document Task Force None None Bristol-Myers Squibb*; Merck* None None None Vera Bittner American College of Cardiology Foundation Prevention Committee National Heart, Lung, and Blood Institutedagger; Pfizerdagger; Atherogenicsdagger; National Institutes of Health/Kosdagger None None None Pfizer*; Reliant*; CV Therapeutics* None Roger S. Blumenthal Johns Hopkins Hospital Pfizer*; Merck*; General Electric* None None None None None Ann Bolger American Heart Association None None None None None None Charles Bridges Society for Thoracic Surgeons None None None None None None Doug Campos-Outcalt American Academy of Family Physicians None None None None None None Vincent F. Carr American College of Cardiology Foundation Board of Governors None None None None None None James I. Cleeman National Heart, Lung and Blood Institute None None None None None None Darla E. Danford National Heart, Lung and Blood Institute None None None None None None Karen A. Donato National Heart, Lung and Blood Institute None None None None None None Mark J. Eisenberg American College of Cardiology Foundation Clinical Expert Consensus Document Task Force None None None None None None Victor Ferraris Society for Thoracic Surgeons Aventis*; THG Med Co*; Bayerdagger; BioMarindagger; Guilforddagger; Medtronicdagger None AstraZeneca*; Bayer*; NATA*; THG Med Co* None None None Valentin Fuster World Heart Federation None None None None Kereos*; Vasogen* GlaxoSmithKline Research & Education Foundation for Cardiovascular Disease* Deborah Grady American College of Physicians Eli Lilly* None None None None None Sharonne Hayes American Heart Association None None None None None None David Herrington American Heart Association None None None None None None Mark Hlaty American College of Cardiology Foundation Board of Trustees None None None None None None Suzanne Hughes American College of Cardiology Foundation Board of Trustees None None Biosite*; Kos*; Pfizer* None Guidant*; Johnson & Johnson*; Merck* Associate editor, Cardiosource Darwin Labarthe Centers for Disease Control and Prevention None None None None None None Robert Lichtenberg American College of Cardiology Foundation Board of Trustees None None None None None None Edward J. Roccella National Heart, Lung and Blood Institute None None None None None None Samuel J. Shubrooks, Jr American College of Cardiology Foundation Clinical Expert Consensus Document Task Force None None None None None None Cynthia Tracy American College of Cardiology Foundation Clinical Expert Consensus Document Task Force None None None None None None Janet S. Wright American College of Cardiology Foundation Board of Trustees None None None None None None Stanley Zinberg American College of Obstetricians and Gynecologists None None None None None None * Reviewer Disclosures This table represents the relationships of reviewers that may be perceived as actual or reasonably perceived conflicts of interest as reported on the Disclosure Questionnaire, which all reviewers are required to complete and submit.
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