Multimodal Analgesia's Impact on Opioid Use and Adverse Drug Effects in a Multihospital Health System.

Purpose:In addition to opioid abuse and dependency, opioid use can lead to opioid related adverse drug events (ORADEs). ORADEs are associated with increased length of stay, cost of care, 30-day readmission rate, and inpatient mortality. The addition of scheduled non-opioid analgesic medications has shown to be effective in reducing opioid utilization in post-surgical and trauma populations, but evidence in entire hospital patient populations is limited. The objective of this study was to determine the effects of a multimodal analgesia order set on opioid utilization and adverse drug events in adult hospitalized patients. Methods: This retrospective pre/post implementation analysis was conducted at 3 community hospitals and a level II trauma center between January 2016 and December 2019. Patients included were 18 years of age or older, admitted for greater than 24 hours, and had at least one opioid ordered during hospital admission. The primary outcome of this analysis was the average oral morphine milligram equivalents (MME) used on days 1 through 5 of hospitalization. Secondary outcomes included the percentage of hospitalized patients with an opioid ordered for analgesia who received a scheduled non-opioid analgesic medication, the average number of ORADEs recorded in nursing assessments on hospitalization days 1 through 5, length of stay, and mortality. Multimodal analgesic medications included acetaminophen, gabapentinoids, non-steroidal anti-inflammatory drugs, muscle relaxants, and transdermal lidocaine. Results: The pre- and post-groups included 86 535 patients and 85 194 patients, respectively. The average oral MMEs used on days 1 through 5 were lower in the post-group (P < .0001). Utilization of multimodal analgesia as measured by the percentage of patients with 1 or more scheduled multimodal analgesia agent ordered increased from 33% to 49% at the end of the analysis. Conclusion: Utilization of a multimodal analgesia order set was associated with a decrease in opioid use and an increase in multimodal analgesia use in an entire hospital adult population.

Autocrine TNF-α production supports CML stem and progenitor cell survival and enhances their proliferation.

Chronic myeloid leukemia (CML) stem cells are not dependent on BCR-ABL kinase for their survival, suggesting that kinase-independent mechanisms must contribute to their persistence. We observed that CML stem/progenitor cells (SPCs) produce tumor necrosis factor-α (TNF-α) in a kinase-independent fashion and at higher levels relative to their normal counterparts. We therefore investigated the role of TNF-α and found that it supports survival of CML SPCs by promoting nuclear factor κB/p65 pathway activity and expression of the interleukin 3 and granulocyte/macrophage-colony stimulating factor common ß-chain receptor. Furthermore, we demonstrate that in CML SPCs, inhibition of autocrine TNF-α signaling via a small-molecule TNF-α inhibitor induces apoptosis. Moreover TNF-α inhibition combined with nilotinib induces significantly more apoptosis relative to either treatment alone and a reduction in the absolute number of primitive quiescent CML stem cells. These results highlight a novel survival mechanism of CML SPCs and suggest a new putative therapeutic target for their eradication.

Genomic characterization implicates iAMP21 as a likely primary genetic event in childhood B-cell precursor acute lymphoblastic leukemia.

Intrachromosomal amplification of chromosome 21 (iAMP21) defines a distinct subgroup of childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL) that has a dismal outcome when treated with standard therapy. For improved diagnosis and risk stratification, the initiating genetic events need to be elucidated. To investigate the genetic basis of BCP-ALL, genomes of 94 iAMP21 patients were interrogated by arrays, FISH, and multiplex ligation-dependent probe amplification. Most copy number alterations targeted chromosome 21, reinforcing the complexity of this chromosome. The common region of amplification on chromosome 21 was refined to a 5.1-mb region that included RUNX1, miR-802, and genes mapping to the Down syndrome critical region. Recurrent abnormalities affecting genes in key pathways were identified: IKZF1 (22%), CDKN2A/B (17%), PAX5 (8%), ETV6 (19%), and RB1 (37%). Investigation of clonal architecture provided evidence that these abnormalities, and P2RY8-CRLF2, were secondary to chromosome 21 rearrangements. Patient outcome was uniformly poor with standard therapy irrespective of the presence or absence of these changes. This study has provided evidence that chromosome 21 instability is the only anomaly among those so far investigated that is common to all iAMP21 patients, and therefore the initiating event is likely to be found among the complex structural rearrangements of this abnormal chromosome.

Demographic, clinical, and outcome features of children with acute lymphoblastic leukemia and CRLF2 deregulation: results from the MRC ALL97 clinical trial.

Deregulated expression of CRLF2 (CRLF2-d) arises via its juxtaposition to the IGH@ enhancer or P2RY8 promoter. Among 865 BCP-ALL children treated on MRC ALL97, 52 (6%) had CRLF2-d, but it was more prevalent among Down syndrome patients (54%). P2RY8-CRLF2 (n = 43) was more frequent than IGH@-CRLF2 (n = 9). CRLF2-d was not associated with age, sex, or white cell count, but IGH@-CRLF2 patients were older than P2RY8-CRLF2 patients (median 8 vs 4 years, P = .0017). Patients with CRLF2-d were more likely to present with enlarged livers and spleens (38% vs 18%, P < .001). CRLF2-d was not seen in conjunction with established chromosomal translocations but 6 (12%) cases had high hyperdiploidy, and 5 (10%) had iAMP21. Univariate analysis suggested that CRLF2-d was associated with an inferior outcome: (event-free survival [EFS] hazard ratio 2.27 [95% confidence interval 1.48-3.47], P < .001; OS 3.69 [2.34-5.84], P < .001). However, multivariate analysis indicated that its effect was mediated by other risk factors such as cytogenetics and DS status (EFS 1.45 [0.88-2.39], P = .140; OS 1.90 [1.08-3.36], P = .027). Although the outcome of IGH@-CRLF2 patients appeared inferior compared with P2RY8-CRLF2 patients, the result was not significant (EFS 2.69 [1.15-6.31], P = .023; OS 2.86 [1.15-6.79], P = .021). Therefore, we concluded that patients with CRLF2-d should be classified into the intermediate cytogenetic risk group.

Genes commonly deleted in childhood B-cell precursor acute lymphoblastic leukemia: association with cytogenetics and clinical features.

In childhood B-cell precursor acute lymphoblastic leukemia, cytogenetics is important in diagnosis and as an indicator of response to therapy, thus playing a key role in risk stratification of patients for treatment. Little is known of the relationship between different cytogenetic subtypes in B-cell precursor acute lymphoblastic leukemia and the recently reported copy number abnormalities affecting significant leukemia associated genes. In a consecutive series of 1427 childhood B-cell precursor acute lymphoblastic leukemia patients, we have determined the incidence and type of copy number abnormalities using multiplex ligation-dependent probe amplification. We have shown strong links between certain deletions and cytogenetic subtypes, including the novel association between RB1 deletions and intrachromosomal amplification of chromosome 21. In this study, we characterized the different copy number abnormalities and show heterogeneity of PAX5 and IKZF1 deletions and the recurrent nature of RB1 deletions. Whole gene losses are often indicative of larger deletions, visible by conventional cytogenetics. An increased number of copy number abnormalities is associated with NCI high risk, specifically deletions of IKZF1 and CDKN2A/B, which occur more frequently among these patients. IKZF1 deletions and rearrangements of CRLF2 among patients with undefined karyotypes may point to the poor risk BCR-ABL1-like group. In conclusion, this study has demonstrated in a large representative cohort of children with B-cell precursor acute lymphoblastic leukemia that the pattern of copy number abnormalities is highly variable according to the primary genetic abnormality.

Pharmacist-driven epoetin alfa-epbx dosing for hospitalized patients.

PURPOSE: To determine the effectiveness of pharmacy consultation in managing epoetin alfa-epbx dosing for inpatients on hemodialysis. METHODS: This multisite, retrospective cohort study evaluated the implementation of an initial dose consultation for epoetin alfa-epbx by pharmacists. A pre-post cohort study evaluated patients from August 2020 through January 2021 and August 2021 through January 2022, respectively. Hospitalized patients were included if they were at least 18 years of age, received hemodialysis, and were administered an erythropoiesis-stimulating agent (ESA) for anemia due to chronic kidney disease. Patients were excluded for religious objections to receiving blood products or if patients were discharged or died before their first hemodialysis session. The primary outcome was the average epoetin alfa-epbx acquisition cost per patient. Secondary endpoints were the epoetin alfa-epbx overall pharmacy purchasing cost, the average dose, and the number of administered doses. A subgroup analysis was performed for patients in the post group with an outpatient ESA before admission to determine the epoetin alfa-epbx days saved. RESULTS: A total of 264 patients were included in the pre group, and 272 patients were included in the post group. The average acquisition cost was significantly lower in the post group ($1,681.77 vs $1,041.35, P < 0.0001). The overall pharmacy purchasing cost was also lower in the post group ($148,970.89 vs $127,873.25). The post group had a significantly lower average dose (13,694 vs 10,112 units, P = 0.0004), while the number of administered doses did not differ significantly between the groups (2.09 vs 1.79 doses, P = 0.0668). The subgroup analysis included 83 patients, which yielded 53 epoetin alfa-epbx days saved. CONCLUSION: Pharmacist-driven ESA dosing was associated with significant decreases in ESA average acquisition cost and average total dose per patient.

Retrospective assessment of general anesthesia-related challenges, morbidity, and death in snakes: 139 cases (2000-2022).

OBJECTIVE: To summarize the anesthetic events of snakes seen at a large university hospital, identify challenges with record keeping, and assess patient and anesthesia-related morbidity and death. SAMPLE: 139 anesthetic events were performed; only 106 cases had detailed anesthetic reports available for further analyses. PROCEDURES: Medical records of snakes that underwent general anesthesia between October 2000 and January 2022 were retrospectively reviewed. Only cases with complete anesthesia records were used to assess anesthetic parameters. Collected data included general patient details, diagnoses, procedures, premedication, induction, maintenance, monitoring, and recovery. RESULTS: A thorough review of the records identified issues or scenarios that resulted in poor record management as well as highlighted the most frequently used anesthetics in snakes. For premedication this was alfaxalone, butorphanol, and hydromorphone, whereas isoflurane, alfaxalone, or propofol were the most common with induction. Lastly, with maintenance, isoflurane was the most popular choice. Of the 139 cases performed, 127 animals recovered, 8 were euthanatized due to poor prognosis, and 4 failed to recover. All snakes that failed to recover had preexisting disease identified pre-, peri-, or postoperatively at necropsy. CLINICAL RELEVANCE: General anesthesia can be reliably and safely undertaken in snakes without severe preexisting disease. Efforts should be directed at identifying preexisting disease and maintaining and completing anesthesia records, and we recommend an auditing system to identify and correct issues as they arise.

Deregulated expression of cytokine receptor gene, CRLF2, is involved in lymphoid transformation in B-cell precursor acute lymphoblastic leukemia.

We report 2 novel, cryptic chromosomal abnormalities in precursor B-cell acute lymphoblastic leukemia (BCP-ALL): a translocation, either t(X;14)(p22;q32) or t(Y;14)(p11;q32), in 33 patients and an interstitial deletion, either del(X)(p22.33p22.33) or del(Y)(p11.32p11.32), in 64 patients, involving the pseudoautosomal region (PAR1) of the sex chromosomes. The incidence of these abnormalities was 5% in childhood ALL (0.8% with the translocation, 4.2% with the deletion). Patients with the translocation were older (median age, 16 years), whereas the patients with the deletion were younger (median age, 4 years). The 2 abnormalities result in deregulated expression of the cytokine receptor, cytokine receptor-like factor 2, CRLF2 (also known as thymic stromal-derived lymphopoietin receptor, TSLPR). Overexpression of CRLF2 was associated with activation of the JAK-STAT pathway in cell lines and transduced primary B-cell progenitors, sustaining their proliferation and indicating a causal role of CRLF2 overexpression in lymphoid transformation. In Down syndrome (DS) ALL and 2 non-DS BCP-ALL cell lines, CRLF2 deregulation was associated with mutations of the JAK2 pseudokinase domain, suggesting oncogenic cooperation as well as highlighting a link between non-DS ALL and JAK2 mutations.

The Canadian Clean Air Regulatory Agenda Mercury Science Program.

The Clean Air Regulatory Agenda (CARA) Mercury Science Program was developed to provide scientific information to support regulatory activities and accountability pertaining to atmospheric emissions of mercury in Canada. The first phase of the science program, entitled "Setting-the-Baseline", sought to achieve the following: identify key indicators of the state-of-the-Canadian environment with respect to the transport, fate and effects of mercury; define these indicators; and, understand the processes that relate these indicators to anthropogenic emissions of mercury. To achieve these outcomes, a consultative process was used to identify the scientific needs of the agenda for mercury; understand Canada's scientific capacity; and, develop a plan to fulfill these scientific needs. The science plan that emerged from this process was structured around the themes of atmospheric monitoring, landscape-based risk assessment, ecological risk assessment, ecosystem modeling, and trends. Implementation of the science plan necessitated a multi-disciplinary and extensively partnered program. To date, the CARA Mercury Science Program is producing coordinated science at the national-scale that aims to directly assess the effectiveness of the CARA for mercury and for many of Canada's other mercury-related policies.

Mercury in the Great Lakes region: bioaccumulation, spatiotemporal patterns, ecological risks, and policy.

This special issue examines bioaccumulation and risks of methylmercury in food webs, fish and wildlife in the Laurentian Great Lakes region of North America, and explores mercury policy in the region and elsewhere in the United States and Canada. A total of 35 papers emanated from a bi-national synthesis of multi-media data from monitoring programs and research investigations on mercury in aquatic and terrestrial biota, a 3-year effort involving more than 170 scientists and decision-makers from 55 different universities, non-governmental organizations, and governmental agencies. Over 290,000 fish mercury data points were compiled from monitoring programs and research investigations. The findings from this scientific synthesis indicate that (1) mercury remains a pollutant of major concern in the Great Lakes region, (2) that the scope and intensity of the problem is greater than previously recognized and (3) that after decades of declining mercury levels in fish and wildlife concentrations are now increasing in some species and areas. While the reasons behind these shifting trends require further study, they also underscore the need to identify information gaps and expand monitoring efforts to better track progress. This will be particularly important as new pollution prevention measures are implemented, as global sources increase, and as the region faces changing environmental conditions.

Increasing item engagement and decreasing automatically reinforced problem behavior within a modified competing stimulus assessment.

A competing stimulus assessment (CSA) is commonly used to identify leisure items for use in treatments designed to decrease automatically reinforced problem behavior. However, this type of assessment may not yield useful information if participants do not readily engage with leisure items. The purpose of this study was to evaluate a modified CSA that included additional treatment components (i.e., prompting, prompting plus differential reinforcement of alternative behavior). The modified CSA identified the treatment components and leisure items that were most effective for increasing leisure-item engagement and decreasing problem behavior for each participant. Modified CSA outcomes maintained during an extended treatment analysis in a natural setting and when intervention components were faded.

CD93 is expressed on chronic myeloid leukemia stem cells and identifies a quiescent population which persists after tyrosine kinase inhibitor therapy.

The introduction of BCR-ABL tyrosine kinase inhibitors has revolutionized the treatment of chronic myeloid leukemia (CML). A major clinical aim remains the identification and elimination of low-level disease persistence, termed "minimal residual disease". The phenomenon of disease persistence suggests that despite targeted therapeutic approaches, BCR-ABL-independent mechanisms exist which sustain the survival of leukemic stem cells (LSCs). Although other markers of a primitive CML LSC population have been identified in the preclinical setting, only CD26 appears to offer clinical utility. Here we demonstrate consistent and selective expression of CD93 on a lin-CD34+CD38-CD90+ CML LSC population and show in vitro and in vivo data to suggest increased stem cell characteristics, as well as robust engraftment in patient-derived xenograft models in comparison with a CD93- CML stem/progenitor cell population, which fails to engraft. Through bulk and single-cell analyses of selected stem cell and cell survival-specific genes, we confirmed the quiescent character and demonstrate their persistence in a population of CML patient samples who demonstrate molecular relapse on TKI withdrawal. Taken together, our results identify that CD93 is consistently and selectively expressed on a lin-CD34+CD38-CD90+ CML LSC population with stem cell characteristics and may be an important indicator in determining poor TKI responders.

Correction: CD93 is expressed on chronic myeloid leukemia stem cells and identifies a quiescent population which persists after tyrosine kinase inhibitor therapy.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Chronic myeloid leukaemia cells require the bone morphogenic protein pathway for cell cycle progression and self-renewal.

Leukaemic stem cell (LSC) persistence remains a major obstacle to curing chronic myeloid leukaemia (CML). The bone morphogenic protein (BMP) pathway is deregulated in CML, with altered expression and response to the BMP ligands shown to impact on LSC expansion and behaviour. In this study, we determined whether alterations in the BMP pathway gene signature had any predictive value for therapeutic response by profiling 60 CML samples at diagnosis from the UK SPIRIT2 trial and correlating the data to treatment response using the 18-month follow-up data. There was significant deregulation of several genes involved in the BMP pathway with ACV1C, INHBA, SMAD7, SNAIL1 and SMURF2 showing differential expression in relation to response. Therapeutic targeting of CML cells using BMP receptor inhibitors, in combination with tyrosine kinase inhibitor (TKI), indicate a synergistic mode of action. Furthermore, dual treatment resulted in altered cell cycle gene transcription and irreversible cell cycle arrest, along with increased apoptosis compared to single agents. Targeting CML CD34+ cells with BMP receptor inhibitors resulted in fewer cell divisions, reduced numbers of CD34+ cells and colony formation when compared to normal donor CD34+ cells, both in the presence and absence of BMP4. In an induced pluripotent stem cell (iPSC) model generated from CD34+ hematopoietic cells, we demonstrate altered cell cycle profiles and dynamics of ALK expression in CML-iPSCs in the presence and absence of BMP4 stimulation, when compared to normal iPSC. Moreover, dual targeting with TKI and BMP inhibitor prevented the self-renewal of CML-iPSC and increased meso-endodermal differentiation. These findings indicate that transformed stem cells may be more reliant on BMP signalling than normal stem cells. These changes offer a therapeutic window in CML, with intervention using BMP inhibitors in combination with TKI having the potential to target LSC self-renewal and improve long-term outcome for patients.

Improving Measures of Sexual and Gender Identity in English and Spanish to Identify LGBT Older Adults in Surveys.

PURPOSE: The goal of this research is to advance the study of health disparities faced by older sexual and gender minorities by assessing comprehension of and improving measures of sexual and gender identity in surveys. METHODS: Cognitive interviews were conducted by expert interviewers with 48 non-lesbian, gay, bisexual, and transgender (non-LGBT) and 9 LGBT older English and Spanish speakers. RESULTS: All respondents were able to answer questions about their sex assigned at birth and current gender identity successfully despite some cisgender respondents' lack of clear understanding of the transgender response option. On the contrary, while the vast majority of English speakers could answer the question about their sexual identity successfully, almost 60% of the non-LGBT Spanish speakers did not select the "heterosexual, that is, not gay (or lesbian)" response category. Qualitative probing of their response process pointed mainly to difficulties understanding the term "heterosexual," leading to their choosing "something else" or saying that they didn't know how to answer. A second round of testing of alternative response categories for the sexual identity question with Spanish speakers found a marked improvement when offered "not gay (or lesbian), that is, heterosexual" instead of beginning with the term "heterosexual." CONCLUSION: This research adds to our understanding of gender and sexual identity questions appropriate for population surveys with older adults. Inclusion of these measures in surveys is a crucial step in advancing insights into the needs of and disparities faced by LGBT older adults.

Design and Operation of the National Survey of Children's Health, 2011-2012.

Objectives This report presents the development, plan, and operation of the 2011-2012 National Survey of Children's Health, a module of the State and Local Area Integrated Telephone Survey, conducted by the National Center for Health Statistics. Funding was provided by the Maternal and Child Health Bureau, Health Resources and Services Administration. The survey was designed to produce national and state prevalence estimates of the physical and emotional health of children aged 0-17 years, as well as factors that may relate to child well-being including medical homes, family interactions, parental health, school and after-school experiences, and neighborhood characteristics.

Heterogeneous leukemia stem cells in myeloid blast phase chronic myeloid leukemia.

Chronic myeloid leukemia (CML) is an excellent model of the multistep processes in cancer. Initiating BCR-ABL mutations are required for the initial phase of the disease (chronic phase, CP-CML). Some CP-CML patients acquire additional mutation(s) that transforms CP-CML to poor prognosis, hard to treat, acute myeloid or lymphoid leukemia or blast phase CML (BP-CML). It is unclear where in the hemopoietic hierarchy additional mutations are acquired in BP-CML, how the hemopoietic hierarchy is altered as a consequence, and the cellular identity of the resulting leukemia-propagating stem cell (LSC) populations. Here, we show that myeloid BP-CML is associated with expanded populations that have the immunophenotype of normal progenitor populations that vary between patients. Serial transplantation in immunodeficient mice demonstrated functional LSCs reside in multiple populations with the immunophenotype of normal progenitor as well as stem cells. Multicolor fluorescence in situ hybridization detected serial acquisition of cytogenetic abnormalities of chromosome 17, associated with transformation to BP-CML, that is detected with equal frequency in all functional LSC compartments. New effective myeloid BP-CML therapies will likely have to target all these LSC populations.

Deregulated hedgehog pathway signaling is inhibited by the smoothened antagonist LDE225 (Sonidegib) in chronic phase chronic myeloid leukaemia.

Targeting the Hedgehog (Hh) pathway represents a potential leukaemia stem cell (LSC)-directed therapy which may compliment tyrosine kinase inhibitors (TKIs) to eradicate LSC in chronic phase (CP) chronic myeloid leukaemia (CML). We set out to elucidate the role of Hh signaling in CP-CML and determine if inhibition of Hh signaling, through inhibition of smoothened (SMO), was an effective strategy to target CP-CML LSC. Assessment of Hh pathway gene and protein expression demonstrated that the Hh pathway is activated in CD34(+) CP-CML stem/progenitor cells. LDE225 (Sonidegib), a small molecule, clinically investigated SMO inhibitor, used alone and in combination with nilotinib, inhibited the Hh pathway in CD34(+) CP-CML cells, reducing the number and self-renewal capacity of CML LSC in vitro. The combination had no effect on normal haemopoietic stem cells. When combined, LDE225 + nilotinib reduced CD34(+) CP-CML cell engraftment in NSG mice and, upon administration to EGFP(+) /SCLtTA/TRE-BCR-ABL mice, the combination enhanced survival with reduced leukaemia development in secondary transplant recipients. In conclusion, the Hh pathway is deregulated in CML stem and progenitor cells. We identify Hh pathway inhibition, in combination with nilotinib, as a potentially effective therapeutic strategy to improve responses in CP-CML by targeting both stem and progenitor cells.

Human papillomavirus vaccine uptake in boys and girls in a school-based vaccine delivery program in Prince Edward Island, Canada.

BACKGROUND: In 2013, Prince Edward Island was the first province to introduce HPV vaccine universally to grade six boys in a school-based program. Because uptake rates in boys are unknown in this type of vaccination program, uptake of HPV vaccination in boys was measured and compared with uptake rates in girls and then analyzed with factors such as county, urban-rural location of the school, and school board to identify where the vaccine program could be improved. METHODS: HPV vaccination records from the provincial childhood immunization registry in PEI were merged with Department of Education data containing all grade six girls and boys in PEI. Vaccine uptakes between years and between sexes were compared using two sample tests of proportions. Logistic regression modeling which accounted for the hierarchical nature of the data was used to analyze associations between factors and uptake rates. RESULTS: Although uptake was high in boys and girls, a significantly greater proportion of girls (85%) received all three doses of the HPV vaccine compared to boys (79%; p=0.004). The odds of grade six girls being fully vaccinated for HPV were 1.5 times greater than of grade six boys, and the odds of students in the English Language School Board receiving all three doses were more than twice as great as the odds of French Language School Board students. CONCLUSIONS: HPV vaccination for boys in PEI has had a successful launch, almost reaching the Canadian Immunization Committee recommendations of >80% for the early years of a program. PEI has a highly organized Public Health Nursing program that is involved in all childhood and school-based vaccinations in PEI and in this context very high coverage rates were obtained. Areas to target for improving uptake include the boys and the students in the French Language School Board.

Atmospheric mercury in the Canadian Arctic. Part II: insight from modeling.

A review of mercury in the Canadian Arctic with a focus on field measurements is presented in part I (see Steffen et al., this issue). Here we provide insights into the dynamics of mercury in the Canadian Arctic from new and published mercury modeling studies using Environment Canada's mercury model. The model simulations presented in this study use global anthropogenic emissions of mercury for the period 1995-2005. The most recent modeling estimate of the net gain of mercury from the atmosphere to the Arctic Ocean is 75 Mg year(-1) and the net gain to the terrestrial ecosystems north of 66.5° is 42 Mg year(-1). Model based annual export of riverine mercury from North American, Russian and all Arctic watersheds to the Arctic Ocean are in the range of 2.8-5.6, 12.7-25.4 and 15.5-31.0 Mg year(-1), respectively. Analysis of long-range transport events of Hg at Alert and Little Fox Lake monitoring sites indicates that Asia contributes the most ambient Hg to the Canadian Arctic followed by contributions from North America, Russia, and Europe. The largest anthropogenic Hg deposition to the Canadian Arctic is from East Asia followed by Europe (and Russia), North America, and South Asia. An examination of temporal trends of Hg using the model suggests that changes in meteorology and changes in anthropogenic emissions equally contribute to the decrease in surface air elemental mercury concentrations in the Canadian Arctic with an overall decline of ~12% from 1990 to 2005. A slow increase in net deposition of Hg is found in the Canadian Arctic in response to changes in meteorology. Changes in snowpack and sea-ice characteristics and increase in precipitation in the Arctic related with climate change are found to be primary causes for the meteorology-related changes in air concentrations and deposition of Hg in the region. The model estimates that under the emissions reduction scenario of worldwide implementation of the best emission control technologies by 2020, mercury deposition could potentially be reduced by 18-20% in the Canadian Arctic.