"It was one of those complicated cases": health practitioners' perspectives and practices of providing end-of-life care for people with profound intellectual and multiple disability.

BACKGROUND: Due to developments in health and social care, people with profound intellectual and multiple disability (PIMD) are living longer than ever before, meaning they are increasingly experiencing life-threatening health conditions requiring palliative care. Little is known about providing end-of-life care for people with PIMD. The aim of this study was to explore health practitioners' perspectives and practices relating to end-of-life decision-making and planning for people with PIMD. METHODS: Seven in-depth semi-structured interviews were conducted with health practitioners employed in a range of hospital and community services throughout Melbourne, Australia. Questions were designed to gather information about their experience, perceptions, and attitudes relating to people with PIMD during and at the end of their life. Each interview, ranging from 40 to 60 min in length, was audio recorded and transcribed. Inductive thematic analysis was used to analyse the data. RESULTS: Four main themes emerged: limited participation, bias, dignity, and quality of death. Health practitioners indicated that people with PIMD are frequently excluded from participating in decision-making related to end-of-life care. Participants discussed reasons for this exclusion including challenges with communication and cognition. Participants reported a need for additional support and guidance in providing care for people with PIMD at the end of life. Professional and family bias played a role in end-of-life decision-making for people with PIMD. Participants reported a disproportional focus by palliative care practitioners on physical as opposed to emotional and spiritual well-being for patients with PIMD at the end of life. Finally, participants reported that people with PIMD generally did not die in specialised palliative care settings, but in segregated supported living environments. CONCLUSIONS: Due to negative perceptions of a person with PIMD's decision-making capacity, people with PIMD are likely to be assessed as unable to express choice and preference regarding end-of-life care and are offered limited opportunity to be involved in their own end-of-life care. This research provides guidance for the development of training and professional development relating to people with PIMD at the end of life. It is hoped that this will increase the accessibility of end-of-life services for people with PIMD, ensuring that a respectful and dignified death can be a reality for all humankind regardless of disability.

Prioritization of Pesticides for Assessment of Risk to Aquatic Ecosystems in Canada and Identification of Knowledge Gaps.

Pesticides can enter aquatic environments via direct application, via overspray or drift during application, or by runoff or leaching from fields during rain events, where they can have unintended effects on non-target aquatic biota. As such, Fisheries and Oceans Canada identified a need to prioritize current-use pesticides based on potential risks towards fish, their prey species, and habitats in Canada. A literature review was conducted to: (1) Identify current-use pesticides of concern for Canadian marine and freshwater environments based on use and environmental presence in Canada, (2) Outline current knowledge on the biological effects of the pesticides of concern, and (3) Identify general data gaps specific to biological effects of pesticides on aquatic species. Prioritization was based upon recent sales data, measured concentrations in Canadian aquatic environments between 2000 and 2020, and inherent toxicity as represented by aquatic guideline values. Prioritization identified 55 pesticides for further research nationally. Based on rank, a sub-group of seven were chosen as the top-priority pesticides, including three herbicides (atrazine, diquat, and S-metolachlor), three insecticides (chlorpyrifos, clothianidin, and permethrin), and one fungicide (chlorothalonil). A number of knowledge gaps became apparent through this process, including gaps in our understanding of sub-lethal toxicity, environmental fate, species sensitivity distributions, and/or surface water concentrations for each of the active ingredients reviewed. More generally, we identified a need for more baseline fish and fish habitat data, ongoing environmental monitoring, development of marine and sediment-toxicity benchmarks, improved study design including sufficiently low method detection limits, and collaboration around accessible data reporting and management.

Targeted Endodontic Microsurgery: Implications of the Greater Palatine Artery.

INTRODUCTION: Targeted Endodontic Microsurgery (TEMS) combines trephine burs and 3D-printed guides to make flapless maxillary palatal root-end surgery possible. This study assessed the location of the greater palatine artery (GPA), the relationship of the GPA to maxillary molar root ends, and the feasibility of flapless palatal-approach TEMS. METHODS: Three endodontists analyzed 250 cone-beam computed tomographic images of maxillary molars for (1) transition morphology between the hard palate and the alveolar process adjacent to first and second molars as an indication of the most likely location of the GPA, (2) the superior-inferior relationship between the GPA and root ends, and (3) the feasibility of palatal-approach TEMS. RESULTS: Palatal transition morphology included 20% Spine, 72% Bridge, and 8% Smooth. GPA position as related to palatal root ends was classified as 34% superior, 40% adjacent, and 21% inferior. Five percent of classifications were undefined. TEMS was deemed feasible for 47% of maxillary first molars and 52% of second molars, and was significantly more feasible with GPAs superior to palatal root ends. Reasons for infeasibility included GPA proximity and unfavorable resection angle or level. Maxillary first molar palatal roots were 11.13 ± 2.68 mm from the greater palatine foramen (GPF) and 2.37 ± 1.46 mm from the GPA. Second molar palatal roots were 4.94 ± 2.55 mm from the GPF and 2.53 ± 1.77 mm from the GPA. CONCLUSIONS: Palatal transition morphology and GPA position adjacent to maxillary molars, as manifested in cone-beam computed tomographic coronal views, suggested maxillary palatal root TEMS could be accomplished with a 2-mm safety margin in 47% of first molars and 52% of second molars. Historical paradigms that do not consider flapless palatal surgical approaches may need to be revised.

FEV1 is a stronger mortality predictor than FVC in patients with moderate COPD and with an increased risk for cardiovascular disease.

Purpose: Chronic obstructive pulmonary disease (COPD) is one of the leading causes of death worldwide. Impaired lung function is associated with heightened risk for death, cardiovascular events, and COPD exacerbations. However, it is unclear if forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) differ in predictive value. Patients and Methods: Data from 16,485 participants in the Study to Understand Mortality and Morbidity (SUMMIT) in COPD were analyzed. Patients were grouped into quintiles for each lung function parameter (FEV1 %predicted, FVC %predicted, FEV1/FVC). The four highest quintiles (Q2-Q5) were compared to the lowest (Q1) to assess their relationship with all-cause mortality, cardiovascular events, and moderate-to-severe and severe exacerbations. Cox-regression was used, adjusted for age, sex, ethnicity, body-mass index, smoking status, previous exacerbations, cardiovascular disease, treatment, and modified Medical Research Council dyspnea score. Results: Compared to Q1 (<53.5% FEV1 predicted), increasing FEV1 quintiles (Q2 53.5-457.5% predicted, Q3 57.5-461.6% predicted, Q4 61.6-465.8% predicted, and Q5 ≥65.8%) were all associated with significantly decreased all-cause mortality (20% (4-34%), 28% (13-40%), 23% (7-36%), and 30% (15-42%) risk reduction, respectively). In contrast, a significant risk reduction (21% (4-35%)) was seen only between Q1 and Q5 quintiles of FVC. Neither FEV1 nor FVC was associated with cardiovascular risk. Increased FEV1 and FEV1/FVC quintiles were also associated with the reduction of moderate-to-severe and severe exacerbations while, surprisingly, the highest FVC quintile was related to the heightened exacerbation risk (28% (8-52%) risk increase). Conclusion: Our results suggest that FEV1 is a stronger predictor for all-cause mortality than FVC in moderate COPD patients with heightened cardiovascular risk and that subjects with moderate COPD have very different risks.

Anthropogenic factors affecting wildlife species status outcomes: why the fixation on pesticides?

Most Americans are at least three generations removed from the farm, thereby at least three generations removed from the reality of where their food comes from. Not surprisingly, there are many misconceptions about modern food production, including the potential collateral environmental damage attributed to agriculture, particularly the application of pesticides. However, the implication of conventional agriculture in the broader narrative of wildlife species status outcomes (SSOs) lacks context and relativity. Since the dawn of civilization, humans have had a profound impact on their environment. Originating as hunter-gatherer societies, our ancient ancestors initially exploited anything that could be consumed or brought to bear. With the advent of the "first proto-farmers," humans began manipulating their environments to maximize available resources. Urban centers propagated and flourished proximal to agricultural origins, where modern societies have been built primarily on an abundance of food. As societies "developed," and continue to develop, an inevitable economic transition occurs from agriculture to industry/service predominance, culminating in a corresponding shift in land use. Developed countries have typically experienced maximal expansion of the agricultural frontier, where farmland is now steadily eroding by a proverbial flood of urban development. In contrast, in developing countries, this shift in economic development has not yet fully manifested and the agricultural footprint continues to expand at the expense of native habitats. Thus, the relative influence of "agriculture" on SSOs, in terms of land use, is primarily dependent on economic developmental status, which can be, at least in part, ameliorated via technology by increasing yield from existing land. Moreover, in addition to the land use challenge, there are multiple other factors affecting wildlife SSOs, including a figurative plague of invasive species, a literal plague of disease, a barrage of buildings, bumpers, grilles, and windshields to collide with, light pollution to confuse cues with, poachers to contend with, and even more complicated factors such as climate change. Being an easy target does not mean pesticides are the right target, and this fixation can potentially detract from public awareness regarding the primary drivers affecting SSOs as well as the opportunity to proactively address them. So, relatively speaking, how do these other factors compare to "pesticides" in terms of driving SSOs? Moreover, why is the popular media so fixated on the pesticide narrative? Based on the available evidence, this manuscript attempts to address these questions from a holistic and relative perspective within the context of land use change, economic development, population growth, and associated implications of global connectivity and commerce.

Photodegradation of bitumen-derived organics in oil sands process-affected water.

The chemical composition of water-soluble organics in oil sands process-affected water (OSPW) is primarily composed of natural constituents of bitumen that are solubilized and concentrated during aqueous extraction of oil sands. OSPW organics are persistent and acutely toxic, and a leading remediation strategy is long-term ageing in end-pit lakes, despite limited data available on its photochemical fate. Here, direct photolysis of whole OSPW, or of its constituent fractions, was examined at environmentally relevant wavelengths (>290 nm) in bench-top studies. Changes in the chemical profiles of whole OSPW, acid- (AEO), and base-extractable organics (BEO) were characterized by liquid chromatography with ultra-high resolution mass spectrometry in negative (-) and positive (+) ionization modes. Following 18 d of irradiation, photolysis reduced the total ion intensity in all samples in both modes. The most photo-labile species included the O2-, O3-, O4-, O2S-, and O4S- chemical classes, which were depleted in whole OSPW by 93-100% after only 5 d. In positive mode, detected species were more recalcitrant than those detected in negative mode, with an average reduction across all heteroatomic classes of 75 ± 11.0% after 18 d. Estimated environmental half-lives for heteroatomic classes ranged from 57 d (O4S-) to 545 d (O3N+), with a greater recalcitrance for classes detected in positive mode compared to negative mode. Under field conditions in end-pit lakes, natural photolysis may be an important mechanism for effective OSPW remediation, and we suggest that future end-pit lakes be shallow to maximize light penetration and natural photolysis in ageing OSPW.

Early Effects of Cyclophosphamide, Methotrexate, and 5-Fluorouracil on Neuronal Morphology and Hippocampal-Dependent Behavior in a Murine Model.

Breast cancer (BC) is the most common cancer among women. Fortunately, BC survival rates have increased because the implementation of adjuvant chemotherapy leading to a growing population of survivors. However, chemotherapy-induced cognitive impairments (CICIs) affect up to 75% of BC survivors and may be driven by inflammation and oxidative stress. Chemotherapy-induced cognitive impairments can persist 20 years and hinder survivors' quality of life. To identify early effects of CMF administration in mice, we chose to evaluate adult female mice at 2-week postchemotherapy. Mice received weekly IP administration of CMF (or saline) for 4 weeks, completed behavioral testing, and were sacrificed 2 weeks following their final CMF injection. Behavioral results indicated long-term memory (LTM) impairments postchemotherapy, but did not reveal short-term memory deficits. Dendritic morphology and spine data found increases in overall spine density within CA1 basal and CA3 basal dendrites, but no changes in DG, CA1 apical, or CA3 apical dendrites. Further analysis revealed decreases in arborization across the hippocampus (DG, CA1 apical and basal, CA3 apical and basal). These physiological changes within the hippocampus correlate with our behavioral data indicating LTM impairments following CMF administration in female mice 2-week postchemotherapy. Hippocampal cytokine analysis identified decreases in IL-1α, IL-1ß, IL-3, IL-10, and TNF-α levels.

Otherwise Healthy 15-Month-Old With Rapid-Onset Soft Tissue Swelling.

Necrotizing soft tissue infections are a serious medical emergency that involve necrosis within the soft tissue space including the dermis, subcutaneous tissue, superficial fascia, deep fascia, and muscle. Inciting factors include recent varicella infection, omphalitis, trauma, intramuscular injections, perianal trauma, and surgery. Unlike adult cases, children presenting with necrotizing soft tissue infections are more likely to be immunocompetent and without underlying chronic illnesses. Although rare in children, familiarity with the clinical manifestations of necrotizing soft tissue infections is essential for early diagnosis and surgical debridement, as significant mortality is associated with advanced disease.

The agro-enabled urban revolution, pesticides, politics, and popular culture: a case study of land use, birds, and insecticides in the USA.

Urbanization is an inevitable process in human civilization. When populations expand, socio-economic and political dynamics typically shift from agricultural predominance to one of industry and services. Accordingly, agrarian societies transform from diffuse rural communities to dense urban centers. By 2050, the world's population is projected to reach 9.1 billion, with the urban population growing from 50 to 70%. Inevitably, this ever-expanding urban frontier encroaches along the human-ecological interface, creating a challenge for conservation and biodiversity. For the past 30 years, agricultural cropland area in the USA has remained fairly constant, despite significant population growth over the same time period. Thus, agricultural production in America has more than kept pace with rapid population growth and global export demand without increasing the farmland footprint at the expense of wildlife habitat. This is primarily due to considerable advances made in pesticide development, safety, and regulation, coupled with soil conservation and genetically modified crops. Still, the potential contribution of agriculture to ecosystem impairment remains contentious, particularly with regard to current use of pesticides. Recently, significant focus has been placed on the state of bird populations in the USA. Many species are considered imperiled, and this is often attributed in the popular media to pesticide use. However, focusing solely on the agricultural/chemical story as a significant driver of species viability and ecological risk within the broader biodiversity and conservation narrative lacks context and perspective. Moreover, the hypothesis that pesticides are indirectly affecting bird population status via reductions in food resources should be considered with caution and within the context of other likely causes. This work explores the dynamics between historical land use, human-controlled activity, and bird population trends from a holistic perspective within the USA. The aim is to provide context, developed from a relative comparison of potential contributing factors, in order to help inform discussion and foster dialogue between industry, academia, government, non-governmental organizations, and the public.

Late Effects of 16O-Particle Radiation on Female Social and Cognitive Behavior and Hippocampal Physiology.

The radiation environment in space remains a major concern for manned space exploration, as there is currently no shielding material capable of fully protecting flight crews. Additionally, there is growing concern for the social and cognitive welfare of astronauts, due to prolonged radiation exposure and confinement they will experience on a mission to Mars. In this artice, we report on the late effects of 16O-particle radiation on social and cognitive behavior and neuronal morphology in the hippocampus of adult female mice. Six-month-old mice received 16O-particle whole-body irradiation at doses of either 0.25 or 0.1 Gy (600 MeV/n; 18-33 cGy/min) at the NASA's Space Radiation Laboratory in Upton, NY. At nine months postirradiation, the animals underwent behavioral testing in the three-chamber sociability, novel object recognition and Y-maze paradigms. Exposure to 0.1 or 0.25 Gy 16O significantly impaired object memory, a 0.25 Gy dose impaired social novelty learning, but neither dosage impaired short-term spatial memory. We observed significant decreases in mushroom spine density and dendrite morphology in the dentate gyrus, cornu ammonis 3, 2 and 1 of the hippocampus, which are critical areas for object novelty and sociability processing. Our data suggest exposure to 16O modulates hippocampal pyramidal and granular neurons and induces behavioral deficits at a time point of nine months after exposure in females.

Effects of thioTEPA chemotherapy on cognition and motor coordination.

Cancer survivorship has increased greatly as therapies have become more advanced and effective. Thus, we must now focus on improving the quality of life of patients after treatment. After chemotherapy, many patients experience chemotherapy-induced cognitive decline, indicating a need to investigate pathologies associated with this condition. In this study, we addressed cognitive impairment after thioTEPA treatment by assessing behavior and assaying cytokine production and the structure of dendrites in the hippocampus. Male mice were given three intraperitoneal injections of thioTEPA. Five weeks later, the mice underwent behavior testing, and brains were collected for Golgi staining and cytokine analysis. Behavior tests included y-maze and Morris water maze and licking behavioral task. Cytokines measured include: IL-1α, IL-1ß, IL-2, IL-3, IL-4, IL-5, IL-10, IL-12p70, MCP-1, TNF-α, GMCSF, and RANTES. We observed decreased memory retention in behavioral tasks. Also, dendritic arborization and length were decreased after chemotherapy treatment. Finally, thioTEPA decreased cytokine production in animals treated with chemotherapy, compared to saline-treated controls. Here, we used a mouse model to correlate the decreases in dendritic complexity and inflammatory cytokine production with cognitive impairment after chemotherapy.

Effects of Cyclophosphamide and/or Doxorubicin in a Murine Model of Postchemotherapy Cognitive Impairment.

Postchemotherapy cognitive impairment, or PCCI, is a common complaint, particularly among breast cancer patients. However, the exact nature of PCCI appears complex. To model the human condition, ovariectomized C57BL/6J mice were treated intravenous weekly for 4 weeks with saline, 2 mg/kg doxorubicin (DOX), 50 mg/kg cyclophosphamide (CYP), or DOX + CYP. For the subsequent 10 weeks, mice were assessed on several behavioral tests, including those measuring spatial learning and memory. After sacrifice, hippocampal spine density and morphology in the dentate gyrus, CA1, and CA3 regions were measured. Additionally, hippocampal levels of total glutathione, glutathione disulfide, MnSOD, CuZnSOD, and cytokines were measured. Body weight decreased in all groups during treatment, but recovered post-treatment. Most behaviors were unaffected by drug treatment: Open field activity, motor coordination, grip strength, water maze and Barnes maze performance, buried food test performance, and novel object and object location recognition tests. There were some significant effects of CYP and DOX + CYP treatment during the initial test of home cage behavior, but these did not persist into the second and third test times. Density of stubby spines, but not mushroom or thin spines, in the dentate gyrus was significantly decreased in the DOX, CYP, and DOX + CYP treatment groups. There were no significant effects in the CA1 or CA3 regions. CuZnSOD levels were significantly increased in DOX + CYP-treated mice; other hippocampal antioxidant levels were unaffected. Most cytokines showed no treatment-related effects, but IL-1ß, IL-6, and IL-12 were slightly reduced in mice treated with DOX + CYP. Although the animal model, route of exposure, and DOX and CYP doses used here were reflective of human exposure, there were only sporadic effects due to chemotherapeutic treatment.

Changes in cognition and dendritic complexity following intrathecal methotrexate and cytarabine treatment in a juvenile murine model.

Acute lymphoblastic leukemia (ALL) is the most prevalent childhood cancer and accounts for 26.8% of cancer diagnoses among children, worldwide-approximately 3000 children each year. While advancements in treating ALL have led to a remission rate of more than 90%, many survivors experience adverse neurocognitive and/or neurobehavioral effects as a result of intrathecal chemotherapy. Methotrexate (MTX) is commonly administered with cytosine arabinoside (AraC, cytarabine) during intrathecal chemotherapy for ALL. To date, few studies exist that test the cognitive effects of intrathecal injections of MTX/AraC on juvenile populations. The purpose of our study was to investigate the combined effects of MTX/AraC on cognition and dendritic structure in the hippocampus in juvenile male mice. Twenty, 21-day-old male C57BL/6 mice were used in this study; 10 mice received intrathecal MTX/AraC treatment, and 10 were given intrathecal saline injections. Five weeks after injections, we tested the animals' hippocampus-dependent cognitive performance in the Morris water maze. After the first day of hidden-platform training, we observed that the mice that received MTX/AraC treatment showed signs of significant impairment in spatial memory retention. MTX/AraC treatment significantly compromised the dendritic architecture and reduced mushroom spine density in the dorsal ganglion (DG), CA1, and CA3 areas of the hippocampus. The present data provided evidence that MTX/AraC compromised the dendritic architecture and impaired hippocampal dependent cognition. This could provide insight into chemotherapy-induced cognitive decline in juvenile patients treated for ALL.

Fluticasone furoate and vilanterol and survival in chronic obstructive pulmonary disease with heightened cardiovascular risk (SUMMIT): a double-blind randomised controlled trial.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) often coexists with cardiovascular disease. Treatments for airflow limitation might improve survival and both respiratory and cardiovascular outcomes. The aim of this study was to assess whether inhaled treatment with a combined treatment of the corticosteroid, fluticasone furoate, and the long-acting ß agonist, vilanterol could improve survival compared with placebo in patients with moderate COPD and heightened cardiovascular risk. METHODS: In this double-blind randomised controlled trial (SUMMIT) done in 1368 centres in 43 countries, eligible patients were aged 40-80 years and had a post-bronchodilator forced expiratory volume in 1 s (FEV1) between 50% and 70% of the predicted value, a ratio of post-bronchodilator FEV1 to forced vital capacity (FVC) of 0·70 or less, a smoking history of at least 10 pack-years, and a score of 2 or greater on the modified Medical Research Council dyspnoea scale. Patients had to have a history, or be at increased risk, of cardiovascular disease. Enrolled patients were randomly assigned (1:1:1:1) through a centralised randomisation service in permuted blocks to receive once daily inhaled placebo, fluticasone furoate (100 µg), vilanterol (25 µg), or the combination of fluticasone furoate (100 µg) and vilanterol (25 µg). The primary outcome was all-cause mortality, and secondary outcomes were on-treatment rate of decline in forced expiratory volume in 1 s (FEV1) and a composite of cardiovascular events. Safety analyses were performed on the safety population (all patients who took at least one dose of study drug) and efficacy analyses were performed on the intention-to-treat population (safety population minus sites excluded with Good Clinical Practice violations). This study is registered with ClinicalTrials.gov, number NCT01313676. FINDINGS: Between Jan 24, 2011, and March 12, 2014, 23 835 patients were screened, of whom 16 590 were randomised. 16 485 patients were included in the intention-to-treat efficacy population; 4111 in the placebo group, 4135 in the fluticasone furoate group, 4118 in the vilanterol group, and 4121 in the combination group. Compared with placebo, all-cause mortality was unaffected by combination therapy (hazard ratio [HR] 0·88 [95% CI 0·74-1·04]; 12% relative reduction; p=0·137) or the components (fluticasone furoate, HR 0·91 [0·77-1·08]; p=0·284; vilanterol, 0·96 [0·81-1·14]; p=0·655), and therefore secondary outcomes should be interpreted with caution. Rate of decline in FEV1 was reduced by combination therapy (38 mL per year [SE 2·4] vs 46 mL per year [2·5] for placebo, difference 8 mL per year [95% CI 1-15]) with similar findings for fluticasone furoate (difference 8 mL per year [95% CI 1-14]), but not vilanterol (difference -2 mL per year [95% CI -8 to 5]). Combination therapy had no effect on composite cardiovascular events (HR 0·93 [95% CI 0·75-1·14]) with similar findings for fluticasone furoate (0·90 [0·72-1·11]) and vilanterol (0·99 [0·80-1·22]). All treatments reduced the rate of moderate and severe exacerbation. No reported excess risks of pneumonia (5% in the placebo group, 6% in the combination group, 5% in the fluticasone furoate group, and 4% in the vilanterol group) or adverse cardiac events (17% in the placebo group, 18% in the combination group, and 17% in the fluticasone furoate group, and 17% in the vilanterol group) were noted in the treatment groups. INTERPRETATION: In patients with moderate COPD and heightened cardiovascular risk, treatment with fluticasone furoate and vilanterol did not affect mortality or cardiovascular outcomes, reduced exacerbations, and was well tolerated. Fluticasone furoate, alone or in combination with vilanterol, seemed to reduce FEV1 decline. FUNDING: GlaxoSmithKline.

Lenalidomide Enhances Immune Checkpoint Blockade-Induced Immune Response in Multiple Myeloma.

PURPOSE: PD-1/PD-L1 signaling promotes tumor growth while inhibiting effector cell-mediated antitumor immune responses. Here, we assessed the impact of single and dual blockade of PD-1/PD-L1, alone or in combination with lenalidomide, on accessory and immune cell function as well as multiple myeloma cell growth in the bone marrow (BM) milieu. EXPERIMENTAL DESIGN: Surface expression of PD-1 on immune effector cells, and PD-L1 expression on CD138(+) multiple myeloma cells and myeloid-derived suppressor cells (MDSC) were determined in BM from newly diagnosed (ND) multiple myeloma and relapsed/refractory (RR) multiple myeloma versus healthy donor (HD). We defined the impact of single and dual blockade of PD-1/PD-L1, alone and with lenalidomide, on autologous anti-multiple myeloma immune response and tumor cell growth. RESULTS: Both ND and RR patient multiple myeloma cells have increased PD-L1 mRNA and surface expression compared with HD. There is also a significant increase in PD-1 expression on effector cells in multiple myeloma. Importantly, PD-1/PD-L1 blockade abrogates BM stromal cell (BMSC)-induced multiple myeloma growth, and combined blockade of PD-1/PD-L1 with lenalidomide further inhibits BMSC-induced tumor growth. These effects are associated with induction of intracellular expression of IFNγ and granzyme B in effector cells. Importantly, PD-L1 expression in multiple myeloma is higher on MDSC than on antigen-presenting cells, and PD-1/PD-L1 blockade inhibits MDSC-mediated multiple myeloma growth. Finally, lenalidomide with PD-1/PD-L1 blockade inhibits MDSC-mediated immune suppression. CONCLUSIONS: Our data therefore demonstrate that checkpoint signaling plays an important role in providing the tumor-promoting, immune-suppressive microenvironment in multiple myeloma, and that PD-1/PD-L1 blockade induces anti-multiple myeloma immune response that can be enhanced by lenalidomide, providing the framework for clinical evaluation of combination therapy.

Toxicity of oil and dispersed oil on juvenile mud crabs, Rhithropanopeus harrisii.

In order to simulate an offshore oil spill event, we assessed the acute toxicity of the non-dispersed and the chemically dispersed water-accommodated fraction (WAF) of crude oil using Louisiana sweet crude and Corexit(®) 9500A with juvenile Harris mud crabs (Rhithropanopeus harrisii), an important Gulf of Mexico benthic crustacean. The chemical dispersion of crude oil significantly increased acute toxicity of the WAF in juvenile mud crabs compared to naturally dispersed oil. The majority of the mortality in the chemically dispersed treatments occurred within 24 h. While higher concentrations of chemically dispersed WAF had no survivors, at lower concentrations surviving juvenile crabs displayed no long-term effects. These results suggest that if the juvenile crabs survive initial exposure, acute exposure to dispersed or non-dispersed crude oil may not induce long-term effects.

Effects of exposure to oil sands process-affected water from experimental reclamation ponds on Chironomus dilutus.

Effective detoxification of oil sands process-affected water (OSPW) is one issue associated with bitumen extraction in the Alberta oil sands. It has been suggested that reclamation ponds can be used to passively treat OSPW, potentially allowing for its safe return to the environment. In this study, OSPW was sampled in two batches (A and B) from the Syncrude Canada Ltd. West In-Pit (WIP) settling pond and from three experimental reclamation ponds - Big Pit, FE5, and TPW. Acute (10 d) and chronic (until adult emergence) exposures of Chironomus dilutus larvae to OSPW were conducted and survival, growth, development, and behavior were assessed. Masses of larvae exposed to WIP-OSPW were 64-77% less than the freshwater control (p < 0.001). Similarly, chronic exposure to WIP-OSPW resulted in significantly (p < 0.05) less pupation than in the freshwater control, with 31% (A) and 71% (B) less pupation of larvae exposed to WIP-OSPW. Rates of emergence were significantly less for larvae exposed to WIP-OSPW, with only 13% (A) and 8% (B) of larvae emerging as adults when exposed to WIP-OSPW, compared to 81% in the freshwater control (p < 0.0001). Pupation and emergence rates were significantly less in TPW than freshwater control (p < 0.05), but there were no differences observed in Big Pit or FE5. Lesser toxicity was observed in reclaimed OSPW compared to fresh OSPW and this coincided with lesser concentrations of NAs. The results presented are consistent with the hypothesis that an organic fraction is the cause of the toxicity of OSPW toward C. dilutus and that OSPW aged in reclamation ponds retains toxicity and therefore, more aggressive, targeted treatment of OSPW is required to accelerate decreases.

The impact of metallic coagulants on the removal of organic compounds from oil sands process-affected water.

Coagulation/flocculation (CF) by use of alum and cationic polymer polyDADMAC, was performed as a pretreatment for remediation of oil sands process-affected water (OSPW). Various factors were investigated and the process was optimized to improve efficiency of removal of organic carbon and turbidity. Destabilization of the particles occurred through charge neutralization by adsorption of hydroxide precipitates. Scanning electron microscope images revealed that the resultant flocs were compact. The CF process significantly reduced concentrations of naphthenic acids (NAs) and oxidized NAs by 37 and 86%, respectively, demonstrating the applicability of CF pretreatment to remove a persistent and toxic organic fraction from OSPW. Concentrations of vanadium and barium were decreased by 67-78% and 42-63%, respectively. Analysis of surface functional groups on flocs also confirmed the removal of the NAs compounds. Flocculation with cationic polymer compared to alum, caused toxicity toward the benthic invertebrate, Chironoums dilutus, thus application of the polymer should be limited.