Management of Patients With Sepsis in Canadian Community Emergency Departments: A Retrospective Multicenter Observational Study.

BACKGROUND: Sepsis is a life-threatening syndrome and a leading cause of morbidity and mortality representing significant financial burden on the health-care system. Early identification and intervention is crucial to maximizing positive outcomes. We studied a quality improvement initiative with the aim of reviewing the initial management of patients with sepsis in Canadian community emergency departments, to identify areas for improving the delivery of sepsis care. We present a retrospective, multicenter, observational study during 2011 to 2015 in the community setting. METHODS: We collected data on baseline characteristics, clinical management metrics (triage-to-physician-assessment time, triage-to-lactate-drawn time, triage-to-antibiotic time, and volume of fluids administered within the first 6 hours of triage), and outcomes (intensive care unit [ICU] admission, in-hospital mortality) from a regional database. RESULTS: A total of 2056 patients were analyzed. The median triage-to-physician-assessment time was 50 minutes (interquartile range [IQR]: 25-104), triage-to-lactate-drawn time was 50 minutes (IQR: 63-94), and triage-to-antibiotics time was 129 minutes (IQR: 70-221). The median total amount of fluid administered within 6 hours of triage was 2.0 L (IQR: 1.5-3.0). The ICU admission rate was 36% and in-hospital mortality was 25%. We also observed a higher ICU admission rate (51% vs 24%) and in-hospital mortality (44% vs 14%) in those with higher lactate concentration (≥4 vs ≤2 mmol/L), independent of other sepsis-related parameters. CONCLUSION: Time-to-physician-assessment, time-to-lactate-drawn, time-to-antibiotics, and fluid resuscitation in community emergency departments could be improved. Future quality improvement interventions are required to optimize management of patients with sepsis. Elevated lactate concentration was also independently associated with ICU admission rate and in-hospital mortality rate.

Hepatitis C Core-Antigen Testing from Dried Blood Spots.

In order to expand hepatitis C virus (HCV) screening, a change in the diagnostic paradigm is warranted to improve accessibility and decrease costs, such as utilizing dried blood spot (DBS) collection. In our study, blood from 68 patients with chronic HCV infection was spotted onto DBS cards and stored at the following temperatures for one week: -80 °C, 4 °C, 21 °C, 37 °C, and alternating 37 °C and 4 °C; to assess whether temperature change during transportation would affect sensitivity. Sample was eluted from the DBS cards and tested for HCV antibodies (HCV-Ab) and HCV core antigen (core-Ag). HCV-Abs were detected from 68/68 DBS samples at -80 °C, 4 °C, 21 °C, and 67/68 at 37 °C and alternating 37 °C and 4 °C. Sensitivity of core-Ag was as follows: 94% (-80 °C), 94% (4 °C), 91% (21 °C), 93% (37 °C), and 93% (37 °C/4 °C). Not only did temperature not greatly affect sensitivity, but sensitivities are higher than previously reported, and support the use of this assay as an alternative to HCV RNA. We then completed a head-to-head comparison (n = 49) of venous versus capillary samples, and one versus two DBS. No difference in core-Ag sensitivity was observed by sample type, but there was an improvement when using two spots. We conclude that HCV-Abs and core-Ag testing from DBS cards has high diagnostic accuracy and could be considered as an alternative to HCV RNA in certain settings.

Cost Effectiveness of Hepatocellular Carcinoma Surveillance After a Sustained Virologic Response to Therapy in Patients With Hepatitis C Virus Infection and Advanced Fibrosis.

BACKGROUND & AIMS: Hepatitis C virus (HCV)-related cirrhosis increases the risk for hepatocellular carcinoma (HCC). After a sustained virologic response (SVR) to anti-HCV therapy, the risk of HCC is reduced but not eliminated. Recent developments in antiviral therapy have increased rates of SVR markedly. Guidelines recommend indefinite biannual ultrasound surveillance after SVR for patients with advanced fibrosis before treatment. Surveillance for HCC is cost effective before anti-HCV treatment; we investigated whether it remains so after SVR. METHODS: We developed a Markov model to evaluate the cost effectiveness of biannual or annual HCC ultrasound surveillance vs no surveillance in 50-year-old patients with advanced fibrosis after an SVR to anti-HCV therapy. Parameter values were obtained from publications and expert opinions. Primary outcomes were quality-adjusted life-years (QALYs), costs, and the incremental cost-effectiveness ratios (ICERs). RESULTS: With a constant 0.5% annual incidence of HCC, biannual and annual surveillance resulted in ICERs of $106,792 and $72,105 per QALY, respectively, with high false-positive rates. When surveillance was limited to patients with cirrhosis, but not F3 fibrosis, biannual surveillance likely was cost effective, with ICERs of $48,729 and $43,229 per QALY after treatment with interferon and direct-acting antiviral agents, respectively. In patients with F3 fibrosis, the incidence of HCC was 0.3% to 0.4% per year, leading to an ICER of $188,157 per QALY for biannual surveillance. If HCC incidence increases with age, surveillance becomes more cost effective but remains below willingness-to-pay thresholds only for patients with cirrhosis or with pretreatment aspartate aminotransferase to platelet ratio index greater than 2.0 or FIB-4 measurements greater than 3.25. Sensitivity analyses identified HCC incidence and transition rate to symptomatic disease without surveillance as factors that affect cost effectiveness. CONCLUSIONS: In a Markov model, we found HCC surveillance after an SVR to HCV treatment to be cost effective for patients with cirrhosis, but not for patients with F3 fibrosis.

HCV core antigen as an alternative to HCV RNA testing in the era of direct-acting antivirals: retrospective screening and diagnostic cohort studies.

BACKGROUND: Direct-acting antivirals for chronic hepatitis C (HCV) infection have reduced the need for on-treatment HCV RNA monitoring. We assessed the accuracy and cost implications of using HCV core antigen testing to replace HCV RNA testing for confirmation of diagnosis, on-treatment monitoring, and determination of sustained virological response (SVR). METHODS: In a retrospective screening cohort study, de-identified residual serum from unselected samples were obtained from commercial laboratories in Ontario, Canada. Samples from each 5-year age-sex band from birth years 1945-74 collected from Aug 1, 2014, to Feb 28, 2015, were included. All samples that tested positive for HCV antibodies, and 10% of samples that tested negative for HCV antibodies, were tested for HCV core antigen and HCV RNA. A retrospective clinical cohort study was also done using blood samples from patients with confirmed HCV infection collected at four tertiary academic centres: one in Canada, two in Germany, and one in the USA. For assessment of SVR, we included samples from patients who started direct-acting antiviral-based treatment (excluding telaprevir and boceprevir) with or without peginterferon, ribavirin, or both, from Jan 1, 2014, to March 31, 2015. To ensure inclusion of adequate numbers for analysis, patients who relapsed after any treatment regimen were included. Serum samples included in the study were from baseline, week 4 on-treatment (only for patients treated with direct-acting antivirals), end of treatment, and week 12 or 24 of follow-up. The sensitivity and specificity of core antigen testing as a diagnostic tool was assessed in the screening cohort, using HCV RNA as a reference. The sensitivity and specificity of core antigen testing as well as its concordance with HCV RNA testing in the clinical cohort was assessed at baseline, week 4 on-treatment, and at weeks 12 or 24 after the end of treatment in patients undergoing therapy with direct-acting antivirals. The cost-effectiveness of core antigen testing with and without confirmatory HCV RNA testing for negative samples was also assessed. FINDINGS: From 10 006 samples in the screening cohort, 75 of 80 viraemic (HCV RNA-positive) samples tested positive for HCV core antigen (sensitivity 94%, 95% CI 86-98), and none of the 993 HCV RNA-negative samples tested positive for HCV core antigen (specificity 100%, 95% CI 94-100). The five viraemic samples that tested negative for HCV core antigen had low corresponding HCV RNA concentrations. In the clinical cohort, two (1%) of 202 baseline samples tested negative for HCV core antigen; one had a low HCV RNA concentration (468 IU/mL), the other had a high HCV RNA concentration (>2 000 000 IU/mL). By week 4 of treatment, HCV core antigen concentrations decreased in all patients but were not predictive of SVR. Although there was good concordance between HCV RNA and HCV core antigen results at 12 weeks after the end of treatment (r=0·97; p<0·0001), three of the 148 patients who achieved SVR at 12 weeks tested HCV core antigen positive. 12 weeks after the end of treatment, HCV core antigen was undetectable in one (1%) of 71 samples from patients who were identified as having relapsed according to HCV RNA detection. On-treatment and end-of-treatment testing of core antigen or HCV RNA provided little clinical value. The use of HCV core antigen testing as a confirmatory diagnostic strategy was cost saving relative to HCV RNA testing, with a reduction of CAD$0·29-3·70 per patient screened depending on whether HCV RNA testing was used to confirm HCV core antigen-negative results. INTERPRETATION: These data support the use of HCV core antigen testing to document HCV viraemia in a cost-saving diagnostic algorithm. In a treatment setting, HCV core antigen testing can be used instead of HCV RNA testing for diagnosis and documentation of treatment adherence, but it might not be adequate to determine SVR. This approach might improve access to care, particularly in low-income and middle-income countries. FUNDING: Abbott Diagnostics and Toronto Centre for Liver Disease.

Wait Time for Curative Intent Radio Frequency Ablation is Associated with Increased Mortality in Patients with Early Stage Hepatocellular Carcinoma.

INTRODUCTION: Radiofrequency ablation (RFA) is a recommended curative intent treatment option for patients with early stage hepatocellular carcinoma (HCC). We investigated if wait times for RFA were associated with residual tumor, tumor recurrence, need for liver transplantation, or death. MATERIAL AND METHODS: We conducted a retrospective study of patients diagnosed with HCC between January 2010 and December 2013 presenting to University Health Network (UHN) in Toronto, Canada. All patients receiving curative intent RFA for HCC were included. Multivariable Cox regression was used to determine if wait times were associated with clinical outcomes. RESULTS: 219 patients were included in the study. 72.6% were male and the median age was 62.7 years (IQR 55.6-71). Median tumor size at diagnosis was 21.5 mm (IQR 17-26); median MELD was 8.7 (IQR 7.2-11.4) and 57.1% were Barcelona stage 0. The cause of liver disease was viral hepatitis in 73.5% (Hepatitis B and C). The median time from HCC diagnosis to RFA treatment was 96 days (IQR 75-139). In multivariate analysis, wait time was not associated with requiring liver transplant or tumor recurrence, however, each incremental 30-day wait time was associated with an increased risk of residual tumor (HR = 1.09; 95% CI 1.01-1.19; p = 0.033) as well as death (HR = 1.23; 95% CI 1.11-1.36; p ≤ 0.001). CONCLUSION: Incremental 30-day wait times are associated with a 9% increased risk of residual tumor and a 23% increased risk of death. We have identified system gaps where quality improvement measures can be implemented to reduce wait times and allocate resources for future RFA treatment, which may improve both quality and efficiency of HCC care.

Psychosocial predictors of quality of life and weight loss two years after bariatric surgery: Results from the Toronto Bari-PSYCH study.

OBJECTIVES: Studies exploring the impact of pre-surgery psychiatric status as a predictor of health related quality of life (QOL) after bariatric surgery have been limited to short-term follow-up and variable use of psychosocial measures. We examined the effect of pre-operative psychiatric factors on QOL and weight loss 2-years after surgery. METHODS: 156 patients participated in this prospective cohort study, the Toronto Bariatric Psychosocial Cohort Study, between 2010 and 2014. Patients were assessed pre-surgery for demographic factors, weight, psychiatric diagnosis using the MINI International Neuropsychiatric Interview and symptom measures for QOL, depression and anxiety at pre-surgery and at 1 and 2years post-surgery. RESULTS: At 2-years post-bariatric surgery, patients experienced a significant decrease in mean weight (-48.43kg, 95% [-51.1, -45.76]) and an increase only in physical QOL (+18.91, 95% [17.01, 20.82]) scores as compared to pre-surgery. Multivariate regression analysis identified pre-surgery physical QOL score (p<0.001), younger age (p=0.005), and a history of a mood disorder as significant predictors of physical QOL. Only a history of a mood disorder (p=0.032) significantly predicted mental QOL (p=0.006). Pre-surgery weight (p<0.001) and a history of a mood disorder (p=0.047) were significant predictors of weight loss 2-years post-surgery. CONCLUSIONS: Bariatric surgery had a sustained impact on physical QOL but not mental QOL at 2-years post-surgery. A history of mood disorder unexpectedly increased physical QOL scores and weight loss following surgery. Further research is needed to determine if these results are due to bariatric surgery candidate selection within this program.

Toronto HCC risk index: A validated scoring system to predict 10-year risk of HCC in patients with cirrhosis.

BACKGROUND & AIMS: Current guidelines recommend biannual surveillance for hepatocellular carcinoma (HCC) in all patients with cirrhosis, regardless of etiology. However, HCC incidence is not well established for many causes of cirrhosis. We aimed to assess the disease-specific incidence of HCC in a large cohort of patients with cirrhosis and to develop a scoring system to predict HCC risk. METHODS: A derivation cohort of patients with cirrhosis diagnosed by biopsy or non-invasive measures was identified through retrospective chart review. The disease-specific incidence of HCC was calculated according to etiology of cirrhosis. Factors associated with HCC were identified through multivariable Cox regression and used to develop a scoring system to predict HCC risk. The scoring system was evaluated in an external cohort for validation. RESULTS: Of 2,079 patients with cirrhosis and ≥6months follow-up, 226 (10.8%) developed HCC. The 10-year cumulative incidence of HCC varied by etiologic category from 22% in patients with viral hepatitis, to 16% in those with steatohepatitis and 5% in those with autoimmune liver disease (p<0.001). By multivariable Cox regression, age, sex, etiology and platelets were associated with HCC. Points were assigned in proportion to each hazard ratio to create the Toronto HCC Risk Index (THRI). The 10-year cumulative HCC incidence was 3%, 10% and 32% in the low-risk (<120points), medium-risk (120-240) and high-risk (>240) groups respectively, values that remained consistent after internal validation. External validation was performed on a cohort of patients with primary biliary cirrhosis, hepatitis B viral and hepatitis C viral cirrhosis (n=1,144), with similar predictive ability (Harrell's c statistic 0.77) in the validation and derivation cohorts. CONCLUSION: HCC incidence varies markedly by etiology of cirrhosis. The THRI, using readily available clinical and laboratory parameters, has good predictive ability for HCC in patients with cirrhosis, and has been validated in an external cohort. This risk score may help to guide recommendations regarding HCC surveillance among patients with cirrhosis. LAY SUMMARY: HCC incidence varies markedly depending on the underlying cause of cirrhosis. Herein, using readily available clinical and laboratory parameters we describe a risk score, THRI, which has a good predictive ability for HCC in patients with cirrhosis, and has been validated in an external cohort. This risk score may help to guide recommendations regarding HCC surveillance among patients with cirrhosis.

Efficacy and Safety of Direct Acting Antivirals for the Treatment of Mixed Cryoglobulinemia.

OBJECTIVES: Mixed cryoglobulinemia is strongly associated with hepatitis C virus (HCV) infection and ranges from being asymptomatic to causing life-threatening vasculitis. In those with symptoms, treatment with pegylated interferon (pegIFN) and ribavirin (RBV) reduces mortality. However, few data are available on the safety and efficacy of antiviral therapy with direct acting antivirals (DAAs) in the treatment of HCV-related cryoglobulinemia. METHODS: Patients treated for HCV-related cryoglobulinemia with DAA±pegIFN were retrospectively evaluated at a tertiary care center. Primary outcomes were virological, immunological, and clinical response. Complete (normalization), partial (>50% reduction), or non-response (<50% reduction) were used to describe change in cryocrit or vasculitic manifestations at week 12 post treatment. Side effects, hospitalizations, and decompensating events were recorded. RESULTS: Eighteen symptomatic and 65 asymptomatic patients were reviewed (61% male, median age 58 years) including 10 with severe/life-threatening vasculitis. Sixty-six (79.5%) patients received pegIFN-free therapy. Sustained virological response (SVR) was attained in 16 (88.9%) symptomatic and 59 (90.8%) asymptomatic patients. Cryoglobulins disappeared in 5 (29.4%) symptomatic and 27 (52.9%) asymptomatic patients. Of symptomatic patients with SVR, clinical response was complete in 7 (38.8%) and partial response in 4 (22.2%). Of the 5 viral relapsers, 1 had a complete response during therapy with no symptomatic recurrence, while the other patients had no clinical response. Among 7 with severe vasculitis, 6 achieved SVR but only 1 had a complete clinical response, with 3 showing a partial response and 2 showing no improvement. All four with life-threatening vasculitis required plasmapheresis and three received rituximab. All achieved SVR leading to partial clinical response in two, but no response in two. Skin manifestations (39% reduction) were most likely to completely resolve with lower responses seen in renal (11.2% reduction) and neurological symptoms (11.1%). Eighty-two (98.8%) patients completed therapy, with 19 (22.8%) reporting adverse events. Hospitalization for decompensation or worsening vasculitis occurred in five (6.0%) and four (22.2) patients respectively. CONCLUSIONS: DAAs resulted in high rates of SVR in patients with cryoglobulinemia. Safety and tolerability were excellent; however, most patients did not have a complete clinical or immunological response, suggesting a delay to clinical response particularly in those with severe/life-threatening vasculitis. Further follow-up will be required to determine if clinical improvement continues after viral clearance.

Psychosocial predictors of patient adherence to disease-modifying therapies for multiple sclerosis.

OBJECTIVES: Our aim was to identify the impact of psychosocial predictors, specifically relationship style, depressive symptoms, anxiety symptoms, cognitive impairment, and culture-specific disease beliefs, on treatment adherence for multiple sclerosis (MS) patients. METHODS: In this cross-sectional observational study, patients from two MS clinics in Saudi Arabia completed self-reported questionnaires focused on MS treatment adherence, physical symptom burden, relationship style, cultural beliefs, depressive symptoms, anxiety, and cognitive impairment. RESULTS: A total of 163 MS patients participated, 81.6% of them were female, and the mean age of the patients was 31.6 years. Mean patient-reported adherence to their MS treatment regimen was 79.47%±25.26%. Multivariate linear regression analysis only identified patients' belief that their MS was due to "supernatural" forces as being significantly negatively associated with MS medication adherence. CONCLUSION: This study demonstrates the importance of cultural interpretations to MS medication adherence in comparison to psychosocial factors. Education and family involvement in the treatment planning may address this issue and warrant further research.

Large-scale genome-wide association studies and meta-analyses of longitudinal change in adult lung function.

BACKGROUND: Genome-wide association studies (GWAS) have identified numerous loci influencing cross-sectional lung function, but less is known about genes influencing longitudinal change in lung function. METHODS: We performed GWAS of the rate of change in forced expiratory volume in the first second (FEV1) in 14 longitudinal, population-based cohort studies comprising 27,249 adults of European ancestry using linear mixed effects model and combined cohort-specific results using fixed effect meta-analysis to identify novel genetic loci associated with longitudinal change in lung function. Gene expression analyses were subsequently performed for identified genetic loci. As a secondary aim, we estimated the mean rate of decline in FEV1 by smoking pattern, irrespective of genotypes, across these 14 studies using meta-analysis. RESULTS: The overall meta-analysis produced suggestive evidence for association at the novel IL16/STARD5/TMC3 locus on chromosome 15 (P  =  5.71 × 10(-7)). In addition, meta-analysis using the five cohorts with ≥3 FEV1 measurements per participant identified the novel ME3 locus on chromosome 11 (P  =  2.18 × 10(-8)) at genome-wide significance. Neither locus was associated with FEV1 decline in two additional cohort studies. We confirmed gene expression of IL16, STARD5, and ME3 in multiple lung tissues. Publicly available microarray data confirmed differential expression of all three genes in lung samples from COPD patients compared with controls. Irrespective of genotypes, the combined estimate for FEV1 decline was 26.9, 29.2 and 35.7 mL/year in never, former, and persistent smokers, respectively. CONCLUSIONS: In this large-scale GWAS, we identified two novel genetic loci in association with the rate of change in FEV1 that harbor candidate genes with biologically plausible functional links to lung function.

Modification of the relationship of the apolipoprotein E ε4 allele to the risk of Alzheimer disease and neurofibrillary tangle density by sleep.

IMPORTANCE: The apolipoprotein E (APOE [GenBank, 348; OMIM, 107741]) ε4 allele is a common and well-established genetic risk factor for Alzheimer disease (AD). Sleep consolidation is also associated with AD risk, and previous work suggests that APOE genotype and sleep may interact to influence cognitive function. OBJECTIVE: To determine whether better sleep consolidation attenuates the relationship of the APOE genotype to the risk of incident AD and the burden of AD pathology. DESIGN, SETTING, AND PARTICIPANTS: A prospective longitudinal cohort study with up to 6 years of follow-up was conducted. Participants included 698 community-dwelling older adults without dementia (mean age, 81.7 years; 77% women) in the Rush Memory and Aging Project. EXPOSURES: We used up to 10 days of actigraphic recording to quantify the degree of sleep consolidation and ascertained APOE genotype. MAIN OUTCOMES AND MEASURES: Participants underwent annual evaluation for AD during a follow-up period of up to 6 years. Autopsies were performed on 201 participants who died, and ß-amyloid (Aß) and neurofibrillary tangles were identified by immunohistochemistry and quantified. RESULTS: During the follow-up period, 98 individuals developed AD. In a series of Cox proportional hazards regression models, better sleep consolidation attenuated the effect of the ε4 allele on the risk of incident AD (hazard ratio, 0.67; 95% CI, 0.46-0.97; P = .04 per allele per 1-SD increase in sleep consolidation). In a series of linear mixed-effect models, better sleep consolidation also attenuated the effect of the ε4 allele on the annual rate of cognitive decline. In individuals who died, better sleep consolidation attenuated the effect of the ε4 allele on neurofibrillary tangle density (interaction estimate, -0.42; SE = 0.17; P = .02), which accounted for the effect of sleep consolidation on the association between APOE genotype and cognition proximate to death. CONCLUSIONS AND RELEVANCE: Better sleep consolidation attenuates the effect of APOE genotype on incident AD and development of neurofibrillary tangle pathology. Assessment of sleep consolidation may identify APOE+ individuals at high risk for incident AD, and interventions to enhance sleep consolidation should be studied as potentially useful means to reduce the risk of AD and development of neurofibrillary tangles in APOE ε4+ individuals.

Sleep Fragmentation and the Risk of Incident Alzheimer's Disease and Cognitive Decline in Older Persons.

OBJECTIVE: Cross-sectional studies suggest that sleep fragmentation is associated with cognitive performance in older adults. We tested the hypothesis that sleep fragmentation is associated with incident Alzheimer's disease (AD) and the rate of cognitive decline in older adults. DESIGN: Prospective cohort study. SETTING: Community-based. PARTICIPANTS: 737 community dwelling older adults without dementia. MEASUREMENTS AND RESULTS: Sleep fragmentation was quantified from up to 10 consecutive days of actigraphy. Subjects underwent annual evaluation for AD with 19 neuropsychological tests. Over a follow-up period of up to 6 years (mean 3.3 years), 97 individuals developed AD. In a Cox proportional hazards model controlling for age, sex, and education, a higher level of sleep fragmentation was associated with an increased risk of AD (HR = 1.22, 95%CI 1.03-1.44, P = 0.02 per 1SD increase in sleep fragmentation). An individual with high sleep fragmentation (90th percentile) had a 1.5-fold risk of developing AD as compared with someone with low sleep fragmentation (10th percentile). The association of sleep fragmentation with incident AD did not vary along demographic lines and was unchanged after controlling for potential confounders including total daily rest time, chronic medical conditions, and the use of common medications which can affect sleep. In a linear mixed effect analysis, a 0.01 unit increase in sleep fragmentation was associated with a 22% increase in the annual rate of cognitive decline relative to the average rate of decline in the cohort (Estimate = -0.016, SE = 0.007, P = 0.03). CONCLUSIONS: Sleep fragmentation in older adults is associated with incident AD and the rate of cognitive decline. CITATION: Lim ASP; Kowgier M; Yu L; Buchman AS; Bennett DA. Sleep fragmentation and the risk of incident alzheimer's disease and cognitive decline in older persons. SLEEP 2013;36(7):1027-1032.

Association of genetic loci with sleep apnea in European Americans and African-Americans: the Candidate Gene Association Resource (CARe).

Although obstructive sleep apnea (OSA) is known to have a strong familial basis, no genetic polymorphisms influencing apnea risk have been identified in cross-cohort analyses. We utilized the National Heart, Lung, and Blood Institute (NHLBI) Candidate Gene Association Resource (CARe) to identify sleep apnea susceptibility loci. Using a panel of 46,449 polymorphisms from roughly 2,100 candidate genes on a customized Illumina iSelect chip, we tested for association with the apnea hypopnea index (AHI) as well as moderate to severe OSA (AHI≥15) in 3,551 participants of the Cleveland Family Study and two cohorts participating in the Sleep Heart Health Study.Among 647 African-Americans, rs11126184 in the pleckstrin (PLEK) gene was associated with OSA while rs7030789 in the lysophosphatidic acid receptor 1 (LPAR1) gene was associated with AHI using a chip-wide significance threshold of p-value<2×10(-6). Among 2,904 individuals of European ancestry, rs1409986 in the prostaglandin E2 receptor (PTGER3) gene was significantly associated with OSA. Consistency of effects between rs7030789 and rs1409986 in LPAR1 and PTGER3 and apnea phenotypes were observed in independent clinic-based cohorts.Novel genetic loci for apnea phenotypes were identified through the use of customized gene chips and meta-analyses of cohort data with replication in clinic-based samples. The identified SNPs all lie in genes associated with inflammation suggesting inflammation may play a role in OSA pathogenesis.

Predictors of patient self-ratings of quality of life in Alzheimer disease: cross-sectional results from the Canadian Alzheimer's Disease Quality of Life Study.

OBJECTIVES: To assess whether the core symptoms of Alzheimer disease (AD) consistently predict patient self-rated quality of life (QOL) as assessed by a variety of QOL measures in a large national sample of AD patients. DESIGN: Cross-sectional. SETTING: Fifteen dementia and geriatric clinics across Canada. PARTICIPANTS: Community-living patients with AD (n = 370) with Mini-Mental State Exam (MMSE) scores greater than 10. MEASUREMENTS: Patients rated their QOL by using two utility indexes, the European QOL-5 Dimensions and the Quality of Well-Being Scale, a global QOL Visual Analog Scale, and the disease-specific QOL-AD instrument. Cognition was assessed with the AD Assessment Scale-Cognitive subscale and MMSE, function with the Disability Assessment for Dementia, and behavioral and psychological symptoms with the Neuropsychiatric Inventory and the Geriatric Depression Scale (GDS). One-way analysis of variance and fully adjusted multiple linear regression were used to assess the relationship between core dementia symptoms and QOL ratings. RESULTS: The QOL measures had only small-to-moderate correlations with each other. For all QOL measures, patient ratings were significantly lower among patients with more depressive symptoms. In multivariable analyses, the GDS score was the only significant independent predictor of patient self-ratings for all four QOL measures. CONCLUSIONS: Self-rated symptoms of depression were a consistent independent predictor of patient-rated QOL across diverse QOL measures, while performance-based measures of cognition and informant-based functional status were not. These findings confirm the importance of identifying and treating depression in patients with AD and endorse the use of measures of self-rated depressive symptoms and QOL as outcomes in AD clinical trials.

Predictors of family caregiver ratings of patient quality of life in Alzheimer disease: cross-sectional results from the Canadian Alzheimer's Disease Quality of Life Study.

OBJECTIVES: To assess whether the core symptoms of Alzheimer disease (AD) and caregiver factors consistently predict family caregiver ratings of patient quality of life (QOL) as assessed by a variety of QOL measures in a large national sample. DESIGN: : Cross-sectional. SETTING: Fifteen dementia and geriatric clinics across Canada. PARTICIPANTS: : Family caregivers (n = 412) of community-living patients with AD of all severities. MEASUREMENTS: Caregiver ratings of patient QOL using three utility indexes, the European Quality of Life-5 Dimensions, Quality of Well-Being Scale and Health Utilities Index; a global QOL visual analogue scale; a disease-specific measure, the Quality of Life-Alzheimer's Disease; and a generic health status measure, the Short Form-36. Patient cognition was assessed with the cognitive subscale of the Alzheimer's Disease Assessment Scale and Mini-Mental State Examination, function with the Disability Assessment for Dementia, and behavioral and psychological symptoms with the Neuropsychiatric Inventory and the Geriatric Depression Scale. Caregiver burden was assessed with the Zarit Burden Interview and caregiver depression with the Center for Epidemiologic Studies Depression scale. One-way analysis of variance and fully adjusted multiple linear regression were used to assess the relationship between patient dementia symptom and caregiver variables with QOL ratings. RESULTS: In multivariable analyses, caregiver ratings of patient function and depressive symptoms were the only consistent independent predictors of caregiver-rated QOL across the QOL measures. CONCLUSIONS: Caregiver ratings of patient function and depression were consistent independent predictors of caregiver-rated QOL, using a spectrum of QOL measures, while measures of patient cognition and caregiver burden and depression were not. These findings support the continued use of caregiver ratings as an important source of information about patient QOL and endorse the inclusion in AD clinical trials of caregiver-rated measures of patient function, depression, and QOL.

Are occasional smokers a heterogeneous group? An exploratory study.

BACKGROUND: Occasional smokers represent an important segment of all smokers and have been described to be a heterogeneous group in terms of past experience and likelihood of maintaining nondaily smoking behavior. METHODS: In the prospective Ontario Tobacco Survey, 408 occasional smokers were followed for a year. Characteristics of subgroups of occasional smokers, as suggested by previous literature, were studied for personal and smoking behavior group differences. Agglomerative hierarchical clustering was also used to empirically identify subgroups of occasional smokers using average linkage. Smoking status at 1-year follow-up was examined overall and by the identified subgroups to determine if any were useful predictors of persistent status as nondaily smoking and likelihood of smoking cessation. RESULTS: Significant differences were seen among the subgroups of occasional smokers suggested in previous studies including the number of quit attempts, setting a firm quit date, and whether or not participants cared others knew they smoked in descriptive analyses. Exploratory cluster analysis suggested 4 clusters of occasional smokers based on differences in age, perceived addiction, and history of daily smoking. Subgroups based on participants' history of smoking, self-reported addiction level, and empirically identified cluster subgroups resulted in significant differences of smoking status at 1-year follow-up. CONCLUSIONS: This study suggests that occasional smokers may be a heterogeneous group with different subgroups characterized by age, accumulated smoking experience and smoking pattern, as well as factors associated with the likelihood of quitting altogether, over time, and perceived addiction.

Tenofovir and entecavir are the most effective antiviral agents for chronic hepatitis B: a systematic review and Bayesian meta-analyses.

BACKGROUND & AIMS: The relative efficacies of licensed antiviral therapies for treatment-naive chronic hepatitis B (CHB) infection in randomized controlled trials have not been determined. We evaluated the relative efficacies of the first 12 months of CHB treatments. METHODS: Drugs evaluated were lamivudine, pegylated interferon, adefovir, entecavir, telbivudine, and tenofovir, as monotherapies and combination therapies, in treatment-naive individuals. Databases were searched for randomized controlled trials of the first 12 months of therapy in hepatitis B e antigen (HBeAg)-positive and/or HBeAg-negative patients with CHB published in English before October 31, 2009. Bayesian mixed treatment comparisons were used to calculate the odds ratios, including 95% credible intervals and predicted probabilities of surrogate outcomes to determine the relative effects of each treatment. RESULTS: In HBeAg-positive patients, tenofovir was most effective in inducing undetectable levels of HBV DNA (predicted probability, 88%), normalization of alanine aminotransferase (ALT) levels (66%), HBeAg seroconversion (20%), and hepatitis B surface antigen loss (5%); it ranked third in histologic improvement of the liver (53%). Entecavir was most effective in improving liver histology (56%), second for inducing undetectable levels of HBV DNA (61%) and normalization of ALT levels (70%), and third in loss of hepatitis B surface antigen (1%). In HBeAg-negative patients, tenofovir was the most effective in inducing undetectable levels of HBV DNA (94%) and improving liver histology (65%); it ranked second for normalization of ALT levels (73%). CONCLUSIONS: In the first year of treatment for CHB, tenofovir and entecavir are the most potent oral antiviral agents for HBeAg-positive patients; tenofovir is most effective for HBeAg-negative patients.

Determining optimal sample sizes for multi-stage randomized clinical trials using value of information methods.

BACKGROUND: Traditional sample size calculations for randomized clinical trials depend on somewhat arbitrarily chosen factors, such as Type I and II errors. An effectiveness trial (otherwise known as a pragmatic trial or management trial) is essentially an effort to inform decision-making, i.e., should treatment be adopted over standard? Taking a societal perspective and using Bayesian decision theory, Willan and Pinto (Stat. Med. 2005; 24:1791-1806 and Stat. Med. 2006; 25:720) show how to determine the sample size that maximizes the expected net gain, i.e., the difference between the cost of doing the trial and the value of the information gained from the results. METHODS: These methods are extended to include multi-stage adaptive designs, with a solution given for a two-stage design. The methods are applied to two examples. RESULTS: As demonstrated by the two examples, substantial increases in the expected net gain (ENG) can be realized by using multi-stage adaptive designs based on expected value of information methods. In addition, the expected sample size and total cost may be reduced. LIMITATIONS: Exact solutions have been provided for the two-stage design. Solutions for higher-order designs may prove to be prohibitively complex and approximate solutions may be required. CONCLUSIONS: The use of multi-stage adaptive designs for randomized clinical trials based on expected value of sample information methods leads to substantial gains in the ENG and reductions in the expected sample size and total cost.

Cost-effectiveness analysis of a multinational RCT with a binary measure of effectiveness and an interacting covariate.

In a recent multinational randomized clinical trial, 1356 patients from 14 countries were randomized between two arms. The primary measure of effectiveness was 30-day survival. Health care utilization was collected on all patients and was combined with a single country's price weights to provide patient-level cost data. The purpose of this paper is to report the results of the cost-effectiveness analysis for the country that provided the cost weights, so as to provide a case study for illustrating recently proposed methodologies that account for skewed cost data, the between-country variation in treatment effects, possible interactions between treatment and baseline covariates, and the difficulty of estimated adjusted risk differences. A hierarchal model is used to account for the two sources of variation (between country and between patients, within a country). The model, which uses gamma distributions for cost data and recent methods for estimating adjusted risk differences, provides overall and country-specific estimates of treatment effects. Model estimation is facilitated by Markov chain Monte Carlo methods using the WinBUGS software. In addition, the theory of expected value of information is used to determine if the data provided by the trial are sufficient for decision making.