Phenotypic profiling of solute carriers characterizes serine transport in cancer.

Serine is a vital amino acid in tumorigenesis. While cells can perform de novo serine synthesis, most transformed cells rely on serine uptake to meet their increased biosynthetic requirements. Solute carriers (SLCs), a family of transmembrane nutrient transport proteins, are the gatekeepers of amino acid acquisition and exchange in mammalian cells and are emerging as anticancer therapeutic targets; however, the SLCs that mediate serine transport in cancer cells remain unknown. Here we perform an arrayed RNAi screen of SLC-encoding genes while monitoring amino acid consumption and cell proliferation in colorectal cancer cells using metabolomics and high-throughput imaging. We identify SLC6A14 and SLC25A15 as major cytoplasmic and mitochondrial serine transporters, respectively. We also observe that SLC12A4 facilitates serine uptake. Dual targeting of SLC6A14 and either SLC25A15 or SLC12A4 diminishes serine uptake and growth of colorectal cancer cells in vitro and in vivo, particularly in cells with compromised de novo serine biosynthesis. Our results provide insight into the mechanisms that contribute to serine uptake and intracellular handling.

LC-MS Approach to Decipher a Light Chain Chromatographic Peak Splitting of a Monoclonal Antibody.

PURPOSE: Monoclonal antibodies (mAbs), like other protein therapeutics, are prone to various forms of degradation, some of which are difficult to distinguish from the native form yet may alter potency. A generalizable LC-MS approach was developed to enable quantitative analysis of isoAsp. In-depth understanding of product quality attributes (PQAs) enables optimization of the manufacturing process, better formulation selection, and decreases risk associated with product handling in the clinic or during shipment. METHODS: Reversed-phase chromatographic peak splitting was observed when a mAb was exposed to elevated temperatures. Multiple LC-MS based methods were applied to identify the reason for peak splitting. The approach involved the use of complementary HPLC columns, multiple enzymatic digestions and different MS/MS ion dissociation methods. In addition, mAb potency was measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: The split peaks had identical masses, and the root cause of the peak splitting was identified as isomerization of an aspartic acid located in the complementarity-determining region (CDR) of the light chain. And the early eluting and late eluting peaks were collected and performed enzymatic digestion to confirm the isoAsp enrichment in the early eluting peak. In addition, decreased potency was observed in the same heat-stressed sample, and the increased isoAsp levels in the CDR correlate well with a decrease of potency. CONCLUSION: Liquid chromatography-mass spectrometry (LC-MS) has been utilized extensively to assess PQAs of biological therapeutics. In this study, a generalizable LC-MS-based approach was developed to enable identification and quantitation of the isoAsp-containing peptides.

Sensitisation of cancer cells to radiotherapy by serine and glycine starvation.

BACKGROUND: Cellular metabolism is an integral component of cellular adaptation to stress, playing a pivotal role in the resistance of cancer cells to various treatment modalities, including radiotherapy. In response to radiotherapy, cancer cells engage antioxidant and DNA repair mechanisms which mitigate and remove DNA damage, facilitating cancer cell survival. Given the reliance of these resistance mechanisms on amino acid metabolism, we hypothesised that controlling the exogenous availability of the non-essential amino acids serine and glycine would radiosensitise cancer cells. METHODS: We exposed colorectal, breast and pancreatic cancer cell lines/organoids to radiation in vitro and in vivo in the presence and absence of exogenous serine and glycine. We performed phenotypic assays for DNA damage, cell cycle, ROS levels and cell death, combined with a high-resolution untargeted LCMS metabolomics and RNA-Seq. RESULTS: Serine and glycine restriction sensitised a range of cancer cell lines, patient-derived organoids and syngeneic mouse tumour models to radiotherapy. Comprehensive metabolomic and transcriptomic analysis of central carbon metabolism revealed that amino acid restriction impacted not only antioxidant response and nucleotide synthesis but had a marked inhibitory effect on the TCA cycle. CONCLUSION: Dietary restriction of serine and glycine is a viable radio-sensitisation strategy in cancer.

Immune-regulated IDO1-dependent tryptophan metabolism is source of one-carbon units for pancreatic cancer and stellate cells.

Cancer cells adapt their metabolism to support elevated energetic and anabolic demands of proliferation. Folate-dependent one-carbon metabolism is a critical metabolic process underpinning cellular proliferation supplying carbons for the synthesis of nucleotides incorporated into DNA and RNA. Recent research has focused on the nutrients that supply one-carbons to the folate cycle, particularly serine. Tryptophan is a theoretical source of one-carbon units through metabolism by IDO1, an enzyme intensively investigated in the context of tumor immune evasion. Using in vitro and in vivo pancreatic cancer models, we show that IDO1 expression is highly context dependent, influenced by attachment-independent growth and the canonical activator IFNγ. In IDO1-expressing cancer cells, tryptophan is a bona fide one-carbon donor for purine nucleotide synthesis in vitro and in vivo. Furthermore, we show that cancer cells release tryptophan-derived formate, which can be used by pancreatic stellate cells to support purine nucleotide synthesis.

Polyamine pathway activity promotes cysteine essentiality in cancer cells.

Cancer cells have high demands for non-essential amino acids (NEAAs), which are precursors for anabolic and antioxidant pathways that support cell survival and proliferation. It is well-established that cancer cells consume the NEAA cysteine, and that cysteine deprivation can induce cell death; however, the specific factors governing acute sensitivity to cysteine starvation are poorly characterized. Here, we show that that neither expression of enzymes for cysteine synthesis nor availability of the primary precursor methionine correlated with acute sensitivity to cysteine starvation. We observed a strong correlation between efflux of the methionine-derived metabolite methylthioadenosine (MTA) and sensitivity to cysteine starvation. MTA efflux results from genetic deletion of methylthioadenosine phosphorylase (MTAP), which is frequently deleted in cancers. We show that MTAP loss upregulates polyamine metabolism which, concurrently with cysteine withdrawal, promotes elevated reactive oxygen species and prevents cell survival. Our results reveal an unexplored metabolic weakness at the intersection of polyamine and cysteine metabolism.

Use of 13C315N1-Serine or 13C515N1-Methionine for Studying Methylation Dynamics in Cancer Cell Metabolism and Epigenetics.

Tracing the fate of carbon-13 (13C) labeled metabolites within cells by liquid chromatography mass spectrometry (LCMS) is a powerful analytical technique used for many years in the study of cell metabolism. Conventional experiments using LCMS and labeled nutrients tend to track the incorporation of 13C from exogenous nutrients (such as amino acids) into other, relatively proximal, cellular metabolites. Several labs have extended this technique to track transfer of 13C from the metabolite pool onto macromolecules, such as DNA, where methylation acts as an important functional modification. Here we describe a complete method that integrates previously established techniques to simultaneously track the use of 13C-serine or 13C-methionine into metabolite pools of the methionine cycle and into methylation of DNA and RNA. Given the ability to track methyl-transfer in a time-dependent way, this technique can provide temporal information about active methyl-transfer as well as quantification of total DNA/RNA methylation levels.

Repeat emergency department visits by nursing home residents: a cohort study using health administrative data.

BACKGROUND: Nursing home (NH) residents are frequent users of emergency departments (ED) and while prior research suggests that repeat visits are common, there is little data describing this phenomenon. Our objectives were to describe repeat ED visits over one year, identify risk factors for repeat use, and characterize "frequent" ED visitors. METHODS: Using provincial administrative data from Ontario, Canada, we identified all NH residents 65 years or older who visited an ED at least once between January 1 and March 31, 2010 and then followed them for one year to capture all additional ED visits. Frequent ED visitors were defined as those who had 3 or more repeat ED visits. We used logistic regression to estimate risk factors for any repeat ED visit and for being a frequent visitor and Andersen-Gill regression to estimate risk factors for the rate of repeat ED visits. RESULTS: In a cohort of 25,653 residents (mean age 84.5 (SD = 7.5) years, 68.2% female), 48.8% had at least one repeat ED visit. Residents who experienced a repeat ED visit were generally similar to others but they tended to be slightly younger, have a higher proportion male, and a higher proportion with minimal cognitive or physical impairment. Risk factors for a repeat ED visit included: being male (adjusted odds ratio 1.27, (95% confidence interval 1.19-1.36)), diagnoses such as diabetes (AOR 1.28 (1.19-1.37)) and congestive heart failure (1.26 (1.16-1.37)), while severe cognitive impairment (AOR 0.92 (0.84-0.99)) and 5 or more chronic conditions (AOR 0.82 (0.71-0.95)) appeared protective. Eleven percent of residents were identified as frequent ED visitors, and they were more often younger then 75 years, male, and less likely to have Alzheimer's disease or other dementias than non-frequent visitors. CONCLUSIONS: Repeat ED visits were common among NH residents but a relatively small group accounted for the largest number of visits. Although there were few clear defining characteristics, our findings suggest that medically complex residents and younger residents without cognitive impairments are at risk for such outcomes.

Postdischarge service utilisation and outcomes among Chinese and South Asian psychiatric inpatients in Ontario, Canada: a population-based cohort study.

OBJECTIVE: We sought to examine the short-term and long-term impacts of psychiatric hospitalisations among patients of Chinese and South Asian origin. DESIGN: Retrospective population-based cohort study using linked health administrative data. SETTING: We examined all adult psychiatric inpatients discharged between 1 April 2006 and 31 March 2014 in Ontario, Canada, who were classified as Chinese, South Asian and all other ethnicities (ie, 'general population') using a validated algorithm. We identified 2552 Chinese, 2439 South Asian and 127 142 general population patients. PRIMARY AND SECONDARY OUTCOME MEASURES: We examined psychiatric severity measures at admission and discharge and performed multivariable logistic regression analyses to examine 30-day, 180-day and 365-day postdischarge service utilisation and outcomes, comparing each of the ethnic groups with the reference population, after adjustment for age, sex, income, education, marital status, immigration status, community size and discharge diagnosis. RESULTS: Despite presenting to hospital with greater illness severity, Asian psychiatric inpatients had shorter lengths of hospital stay and greater absolute improvements in mental health and functional status at discharge compared with other inpatients. After hospitalisation, Chinese patients were more likely to visit psychiatrists and South Asian patients were more likely to seek mental healthcare from general practitioners. They were also less likely to have a psychiatric readmission or die 1 year following hospitalisation (adjusted ORChinese=0.87; 95% CI 0.79 to 0.97; adjusted ORSouth Asian=0.82, 95% CI 0.73 to 0.91). Findings were consistent across genders, psychiatric diagnoses and immigrant groups. CONCLUSION: Once hospitalised, patients of Chinese and South Asian origin fared as well as or better than general population patients at discharge and following discharge, and had a positive trajectory of psychiatric service utilisation.

Impact of Physician Follow-Up Care on Psychiatric Readmission Rates in a Population-Based Sample of Patients With Schizophrenia.

OBJECTIVE: The study evaluated the association between physician follow-up within 30 days after hospital discharge and psychiatric readmission within the subsequent 180 days. METHODS: Among inpatients with schizophrenia who were discharged between 2007 and 2012 in Ontario (N=19,132), those who had a 30-day follow-up visit with a primary care physician (PCP) only, a psychiatrist only, or both were compared with a no-follow-up group. The primary outcome was psychiatric readmission in the subsequent 180 days. Secondary analyses stratified the sample on the basis of readmission risk at discharge. RESULTS: About 65% of patients had follow-up care within 30 days postdischarge. Psychiatric readmission rates were similar among patients with any physician follow-up and significantly lower than among those with no follow-up (26%): PCP only: 22%; adjusted hazard ratio [aHR]=.88, 95% confidence interval [CI]=.81-.96; psychiatrist only, 22%; aHR=.84, CI=.77-.90; both, 21%, aHR=.82, CI=.75-.90). In stratified analyses, 66% of patients were in the category at highest risk of psychiatric readmission, and the effect of follow-up with any physician was significant for these patients, compared with high-readmission risk patients with no follow-up, who had a 29% readmission rate (PCP only, 20% readmission rate, aHR=.85, CI=.77-.94; psychiatrist only, 29%, aHR=.84, CI=.77-.92; both, 17%, aHR=.81, CI=.73-.90). DISCUSSION: Timely physician follow-up was associated with reduced risk of psychiatric readmissions, with the greatest reduction among patients at high risk of readmission. Because more than one-third of patients had no physician visit within 30 days postdischarge, improving physician follow-up may help reduce psychiatric readmission rates.

Autophagy acts through TRAF3 and RELB to regulate gene expression via antagonism of SMAD proteins.

Macroautophagy can regulate cell signalling and tumorigenesis via elusive molecular mechanisms. We establish a RAS mutant cancer cell model where the autophagy gene ATG5 is dispensable in A549 cells in vitro, yet promotes tumorigenesis in mice. ATG5 represses transcriptional activation by the TGFß-SMAD gene regulatory pathway. However, autophagy does not terminate cytosolic signal transduction by TGFß. Instead, we use proteomics to identify selective degradation of the signalling scaffold TRAF3. TRAF3 autophagy is driven by RAS and results in activation of the NF-κB family member RELB. We show that RELB represses TGFß target promoters independently of DNA binding at NF-κB recognition sequences, instead binding with SMAD family member(s) at SMAD-response elements. Thus, autophagy antagonises TGFß gene expression. Finally, autophagy-deficient A549 cells regain tumorigenicity upon SMAD4 knockdown. Thus, at least in this setting, a physiologic function for autophagic regulation of gene expression is tumour growth.

Serine and Functional Metabolites in Cancer.

Folate metabolism functions to supply one-carbon units that are vital for a range of biochemical reactions. Cancer cells can utilise serine as a major source of one-carbon units, rendering them dependent upon extracellular serine uptake or de novo serine synthesis for maximal growth and proliferation. One-carbon units are required for the production of critical cellular components, such as nucleotides, which enable cancer cells to maintain high proliferate rates. Of recent interest, one-carbon metabolism contributes to the biosynthesis and recycling of functional metabolites, such as ATP, S-adenosyl-methionine (SAM), and NAD(P)H, with important downstream consequences for cancer cell survival. In this review, we describe recent advances in our understanding of the importance of one-carbon metabolism in cancer, focussing upon the routes through which cancer cells obtain and use one-carbon units.

One-carbon metabolism in cancer.

Cells require one-carbon units for nucleotide synthesis, methylation and reductive metabolism, and these pathways support the high proliferative rate of cancer cells. As such, anti-folates, drugs that target one-carbon metabolism, have long been used in the treatment of cancer. Amino acids, such as serine are a major one-carbon source, and cancer cells are particularly susceptible to deprivation of one-carbon units by serine restriction or inhibition of de novo serine synthesis. Recent work has also begun to decipher the specific pathways and sub-cellular compartments that are important for one-carbon metabolism in cancer cells. In this review we summarise the historical understanding of one-carbon metabolism in cancer, describe the recent findings regarding the generation and usage of one-carbon units and explore possible future therapeutics that could exploit the dependency of cancer cells on one-carbon metabolism.

Insulin pump use and discontinuation in children and teens: a population-based cohort study in Ontario, Canada.

OBJECTIVE: To describe insulin pump use by youth since introduction of universal funding in Ontario, Canada and to explore the relationship between pump use and pediatric diabetes center characteristics and the relationship between discontinuation and center and patient characteristics. RESEARCH DESIGN AND METHODS: Observational, population-based cohort study of youth with type 1 diabetes (<19 yr) who received pump funding from 2006 to 2013 (n = 3700). We linked 2012 survey data from 33 pediatric diabetes centers to health administrative databases. We tested the relationship between center-level pump uptake and center characteristics (center type, physician model, and availability of 24-h support) using an adjusted negative binomial model; we studied center- and patient-level factors (socioeconomic status and baseline glycemic control) associated with discontinuation using a Cox proportional hazards model with generalized estimating equations. RESULTS: Pump users were more likely to be in the highest income quintile than non-pump users (29.6 vs. 19.1%, p < 0.0001). In 2012, mean percent pump use was 38.0% with variability across centers. There was no association between uptake and center characteristics. Discontinuation was low (0.42/100 person-yr) and was associated with being followed at a small community center [hazard ratio (HR): 2.24 (1.05-4.76)] and being more deprived [HR: 2.36 (1.14-1.48)]. Older age was associated with a lower rate of discontinuation [HR: 0.31 (0.14-0.66)]. CONCLUSIONS: Rates of pump use have increased since 2006 and discontinuation is rare. Large variation in uptake across centers was not explained by the factors we examined but may reflect variation in patient populations or practice patterns, and should be further explored.

Inhaled Long-acting Anticholinergics and Urinary Tract Infection in Individuals with COPD.

Inhaled, long-acting anticholinergic medication (LAA), commonly used for moderate-to-severe chronic obstructive pulmonary disease (COPD), has been shown to decrease COPD hospitalizations, emergency department visits, and acute exacerbations but has also been associated with urinary tract infection (UTI) in a prior meta-analysis. The objective of this study was to verify if there was an association between LAA and UTI in older individuals with COPD. A population-based, real-world cohort study using health administrative data from Ontario, Canada was conducted. Incidence of UTI was compared between older people with physician-diagnosed COPD, who were new users of inhaled long-acting anticholinergics and new users of inhaled corticosteroids-a reference medication used in similar clinical settings that has no known association with UTI. Propensity score matching was used to minimize the effects of confounding. An overall association between LAA and various measures of UTI in older individuals was not found. However, in a priori defined stratified analyses, men newly initiated on LAA were 75% more likely to develop a UTI than men newly started on an inhaled corticosteroid (hazard ratio 1.75; 95% confidence interval 1.05-2.92). No significant association was seen in women. In conclusion, older men with COPD newly started on LAA are at increased risk of UTI. Men considering an inhaled LAA should be informed of this risk and, if they decide to take it, be provided with appropriate monitoring.

Variation in Emergency Department Transfer Rates from Nursing Homes in Ontario, Canada.

BACKGROUND: Nursing home (NH) residents are frequently transferred to the emergency department (ED) but there is little data on inter-facility variation, which has implications for intervention planning and implementation. OBJECTIVES: To describe variation in ED transfer rates (TRs) across NHs and the association with NH characteristics. DESIGN/SETTING: Retrospective cohort study using linked administrative data from Ontario. PARTICIPANTS: 71,780 residents of 604 NHs in 2010 and followed for one year. MEASUREMENTS: Funnel plots were used to identify high transfer NHs and logistic regression to test the association with NH location, size, ownership and historical ED transfer rate. RESULTS: One-year ED transfer rates ranged from 4.3% to 58.6% (mean 28.4%); 115 (19%) NHs were considered high. Being within five minutes of an ED, larger size and high historical ED transfer rate were associated with being a high ED transfer home. CONCLUSION: There was substantial variation across NHs. Consideration of characteristics such as proximity to an ED may be important in the development and targeting of different interventions for NHs.

Low socioeconomic status is associated with adverse events in children and teens on insulin pumps under a universal access program: a population-based cohort study.

OBJECTIVE: To describe adverse events in pediatric insulin pump users since universal funding in Ontario and to explore the role of socioeconomic status and 24-hour support. RESEARCH DESIGN AND METHODS: Population-based cohort study of youth (<19 years) with type 1 diabetes (n=3193) under a universal access program in Ontario, Canada, from 2006 to 2013. We linked 2012 survey data from 33 pediatric diabetes centers to health administrative databases. The relationship between patient and center-level characteristics and time to first diabetic ketoacidosis (DKA) admission or death was tested using a Cox proportional hazards model and the rate of diabetes-related emergency department visits and hospitalizations with a Poisson model, both using generalized estimating equations. RESULTS: The rate of DKA was 5.28/100 person-years and mortality 0.033/100 person-years. Compared with the least deprived quintile, the risk of DKA or death for those in the most deprived quintile was significantly higher (HR 1.58, 95% CI 1.05 to 2.38) as was the rate of diabetes-related acute care use (RR 1.60, 95% CI 1.27 to 2.00). 24-hour support was not associated with these outcomes. Higher glycated hemoglobin, prior DKA, older age, and higher nursing patient load were associated with a higher risk of DKA or death. CONCLUSIONS: The safety profile of pump therapy in the context of universal funding is similar to other jurisdictions and unrelated to 24-hour support. Several factors including higher deprivation were associated with an increased risk of adverse events and could be used to inform the design of interventions aimed at preventing poor outcomes in high-risk individuals.

Ethnic Differences in Mental Illness Severity: A Population-Based Study of Chinese and South Asian Patients in Ontario, Canada.

OBJECTIVE: Little is known about the sociocultural determinants of mental illness at hospital presentation. Our objective was to examine ethnic differences in illness severity at hospital admission among Chinese, South Asian, and the general population living in Ontario, Canada. METHODS: We conducted a large, population-based, cross-sectional study of psychiatric inpatients aged from 19 to 105 years who were discharged between 2006 and 2014. A total of 133,588 patients were classified as Chinese (n = 2,582), South Asian (n = 2,452), or the reference group (n = 128,554) using a validated surnames algorithm (specificity: 99.7%). Diagnoses were based on DSM-IV criteria. We examined the association between ethnicity and 4 measures of disease severity: involuntary admissions, aggressive behaviors, and the number and frequency of positive symptoms (ie, hallucinations, command hallucinations, delusions, and abnormal thought process) (Positive Symptoms Scale, Resident Assessment Instrument-Mental Health [RAI-MH]). RESULTS: After adjusting for sociodemographic characteristics, immigration status, and discharge diagnosis, Chinese patients had greater odds of involuntary admissions (odds ratio [OR] = 1.79; 95% CI, 1.64-1.95) and exhibiting severe aggressive behaviors (OR = 1.36; 95% CI, 1.23-1.51) and ≥ 3 positive symptoms (OR = 1.39; 95% CI, 1.24-1.56) compared to the general population. South Asian ethnicity was also an independent predictor of most illness severity measures. The association between Chinese ethnicity and illness severity was consistent across sex, diagnostic and immigrant categories, and first-episode hospitalization. CONCLUSIONS: Chinese and South Asian ethnicities are independent predictors of illness severity at hospital presentation. Understanding the role of patient, family, and health system factors in determining the threshold for hospitalization is an important future step in informing culturally specific care for these large and growing populations worldwide.

Variability in Antibiotic Use Across Nursing Homes and the Risk of Antibiotic-Related Adverse Outcomes for Individual Residents.

IMPORTANCE: Antibiotics are frequently and often inappropriately prescribed to patients in nursing homes. These antibiotics pose direct risks to recipients and indirect risks to others residing in the home. OBJECTIVE: To examine whether living in a nursing home with high antibiotic use is associated with an increased risk of antibiotic-related adverse outcomes for individual residents. DESIGN, SETTING, AND PARTICIPANTS: In this longitudinal open-cohort study performed from January 1, 2010, through December 31, 2011, we studied 110,656 older adults residing in 607 nursing homes in Ontario, Canada. EXPOSURES: Nursing home-level antibiotic use was defined as use-days per 1000 resident-days, and facilities were classified as high, medium, and low use according to tertile of use. Multivariable logistic regression modeling was performed to assess the effect of nursing home-level antibiotic use on the individual risk of antibiotic-related adverse outcomes. MAIN OUTCOMES AND MEASURES: Antibiotic-related harms included Clostridium difficile, diarrhea or gastroenteritis, antibiotic-resistant organisms (which can directly affect recipients and indirectly affect nonrecipients), allergic reactions, and general medication adverse events (which can affect only recipients). RESULTS: Antibiotics were provided on 2,783,000 of 50,953,000 resident-days in nursing homes (55 antibiotic-days per 1000 resident-days). Antibiotic use was highly variable across homes, ranging from 20.4 to 192.9 antibiotic-days per 1000 resident-days. Antibiotic-related adverse events were more common (13.3%) in residents of high-use homes than among residents of medium-use (12.4%) or low-use homes (11.4%) (P < .001); this trend persisted even among the residents who did not receive antibiotic treatments. The primary analysis indicated that residence in a high-use nursing home was associated with an increased risk of a resident experiencing an antibiotic-related adverse event (adjusted odds ratio, 1.24; 95% CI, 1.07-1.42; P = .003). A sensitivity analysis examining nursing home-level antibiotic use as a continuous variable confirmed an increased risk of resident-level antibiotic-related harms (adjusted odds ratio, 1.004 per additional day of nursing home antibiotic use; 95% CI, 1.001-1.006; P = .01). CONCLUSIONS AND RELEVANCE: Antibiotic use is highly variable across nursing homes; residents of high-use homes are exposed to an increased risk of antibiotic-related harms even if they have not directly received these agents. Antibiotic stewardship is needed to improve the safety of all nursing home residents.

Impact of mindfulness-based cognitive therapy on health care utilization: a population-based controlled comparison.

OBJECTIVE: Elevated rates of mood and anxiety disorders among high utilizers of health care have been suggested as one driver of increased service use. We compared the impact of Mindfulness Based Cognitive Therapy (MBCT), a structured group treatment, on the rates of health care utilization with matched control participants receiving non-MBCT group therapy. METHODS: Using Ontario health administrative data, we created a retrospective cohort of population-based patients receiving MBCT and an age- and gender-matched (3:1) cohort of non-MBCT group therapy controls. Subjects were recruited between 2003 and 2010 and stratified according to high/low rates of primary care utilization, with the high utilization cohort being the cohort of interest. The primary outcome was a reduction in an aggregate measure of non-mental health utilization comprising Emergency Department, non-mental health primary care, and non-psychiatrist specialist visits. RESULTS: There were 10,633 MBCT recipients, 4851 (46%) of whom were high utilizers. The proportion of high utilizers was 13,274 (45%, N=29,795) for non-MBCT group therapy controls. Among high utilizers, there was a significant reduction in non-mental health utilization among MBCT recipients compared to non-MBCT group therapy recipients (0.55 (0.21-0.89)) suggesting that for every two MBCT patients treated, there is a reduction in 1 non-mental health visit. CONCLUSION: Among high utilizers of primary care, MBCT reduced non-mental health care utilization 1year post-therapy compared to non-MBCT, group therapy controls. The reductions suggest that MBCT, an established treatment modality for a variety of mental illnesses, has the added benefit of reducing distress-related high health care utilization.

Influenza and seasonal patterns of hospital use by older adults in long-term care and community settings in Ontario, Canada.

OBJECTIVES: We compared seasonal influenza hospital use among older adults in long-term care (LTC) and community settings. METHODS: We used provincial administrative data from Ontario to identify all emergency department (ED) visits and hospital admissions for pneumonia and influenza among adults older than 65 years between 2002 and 2008. We used sentinel laboratory reports to define influenza and summer seasons and estimated mean annual event rates and influenza-associated rates. RESULTS: Mean annual pneumonia and influenza ED visit rates were higher in LTC than the community (rate ratio [RR] for influenza season = 3.9; 95% confidence interval [CI] = 3.8, 4.0; for summer = 4.9; 95% CI = 4.8, 5.1) but this was attenuated in influenza-associated rates (RR = 2.4; 95% CI = 2.1, 2.8). The proportion of pneumonia and influenza ED visits attributable to seasonal influenza was 17% (15%-20%) in LTC and 28% (27%-29%) in the community. Results for hospital admissions were comparable. CONCLUSIONS: We found high rates of hospital use from LTC but evidence of lower impact of circulating influenza in the community. This differential impact of circulating influenza between the 2 environments may result from different influenza control policies.