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1.  Treatment Use and Costs among Privately-Insured Youth with Bipolar Diagnoses 
Objectives
Recent evidence suggests that children are increasingly diagnosed with bipolar disorder, yet no studies have quantified treatment costs for pediatric patients. The objectives are to identify one-year health services utilization and treatment costs among youth with new bipolar diagnoses.
Methods
MarketScan administrative claims from 2005–2007 were used to construct a retrospective person-level cohort of children ages 0–17 to identify one-year health services utilization and costs among privately insured youth with bipolar diagnoses. Inpatient and outpatient services were categorized as mental health related and non-mental health related. Pharmacy costs were classified as psychotropic or non-psychotropic.
Results
In the sample (N=4,973), one-year mean reimbursements for health services were $10,372, and patient out-of-pocket spending $1,429 per child. Mental health services comprised 71% of all health care spending, with psychotropic medications and inpatient care contributing the largest proportions of total spending (24% and 27%, respectively).
Conclusions
The costs of care among privately insured children with bipolar disorder are similar to that of adults. However, spending on children is concentrated on mental health related services. Because private insurance plans have historically limited mental health service benefits, the concentration of spending on mental health services may place a greater burden on families for out of pocket payments. As mental health parity is adopted by private insurers it will be important to monitor the impact on patient utilization and costs of health services, particularly for children with severe mental illness.
doi:10.1176/appi.ps.201100516
PMCID: PMC4041154  PMID: 22855210
Bipolar Disorder; Utilization; Expenditures; Children; Pharmacotherapy; Epidemiology
2.  Confounding control in a non-experimental study of STAR*D data: Logistic regression balanced covariates better than boosted CART 
Annals of epidemiology  2013;23(4):204-209.
Purpose
Propensity scores, a powerful bias-reduction tool, can balance treatment groups on measured covariates in non-experimental studies. We demonstrate the use of multiple propensity score estimation methods to optimize covariate balance.
Methods
We used secondary data from 1,292 adults with non-psychotic major depressive disorder in the Sequenced Treatment Alternatives to Relieve Depression trial (2001–2004). After initial citalopram treatment failed, patient preference influenced assignment to medication augmentation (n=565) or switch (n=727). To reduce selection bias, we used boosted classification and regression trees (BCART) and logistic regression iteratively to identify two potentially optimal propensity scores. We assessed and compared covariate balance.
Results
After iterative selection of interaction terms to minimize imbalance, logistic regression yielded better balance than BCART (average standardized absolute mean difference across 47 covariates: 0.03 vs. 0.08, matching; 0.02 vs. 0.05, weighting).
Conclusions
Comparing multiple propensity score estimates is a pragmatic way to optimize balance. Logistic regression remains valuable for this purpose. Simulation studies are needed to compare propensity score models under varying conditions. Such studies should consider more flexible estimation methods, such as logistic models with automated selection of interactions or hybrid models using main effects logistic regression instead of a constant log-odds as the initial model for BCART.
doi:10.1016/j.annepidem.2013.01.004
PMCID: PMC3773847  PMID: 23419508
propensity score; statistics as topic; models, statistical; epidemiologic methods; estimation techniques
3.  Investigating differences in treatment effect estimates between propensity score matching and weighting: A demonstration using STAR*D trial data 
Purpose
The choice of propensity score (PS) implementation influences treatment effect estimates not only because different methods estimate different quantities, but also because different estimators respond in different ways to phenomena such as treatment effect heterogeneity and limited availability of potential matches. Using effectiveness data, we describe lessons learned from sensitivity analyses with matched and weighted estimates.
Methods
With subsample data (N=1,292) from Sequenced Treatment Alternatives to Relieve Depression, a 2001–2004 effectiveness trial of depression treatments, we implemented PS matching and weighting to estimate the treatment effect in the treated and conducted multiple sensitivity analyses.
Results
Matching and weighting both balanced covariates but yielded different samples and treatment effect estimates (matched RR 1.00, 95% CI:0.75–1.34; weighted RR 1.28, 95% CI:0.97–1.69). In sensitivity analyses, as increasing numbers of observations at both ends of the PS distribution were excluded from the weighted analysis, weighted estimates approached the matched estimate (weighted RR 1.04, 95% CI 0.77–1.39 after excluding all observations below the 5th percentile of the treated and above the 95th percentile of the untreated). Treatment appeared to have benefits only in the highest and lowest PS strata.
Conclusions
Matched and weighted estimates differed due to incomplete matching, sensitivity of weighted estimates to extreme observations, and possibly treatment effect heterogeneity. PS analysis requires identifying the population and treatment effect of interest, selecting an appropriate implementation method, and conducting and reporting sensitivity analyses. Weighted estimation especially should include sensitivity analyses relating to influential observations, such as those treated contrary to prediction.
doi:10.1002/pds.3396
PMCID: PMC3639482  PMID: 23280682
Propensity score; matching; weighting; comparative effectiveness research; treatment effect heterogeneity; treatment effect in the treated; sensitivity analysis
4.  Real-world utilization patterns and outcomes of colesevelam hcl in the ge electronic medical record 
Background
In randomized controlled trials (RCTs), colesevelam HCI, added to other anti-diabetic therapy, reduced hemoglobin A1C by approximately 0.3% to 0.4% over 16- to 26-weeks compared with an increase of approximately 0.1% to 0.2% for placebo, for a placebo-adjusted treatment effect of approximately 0.5%. Evidence on real-world effectiveness is unknown. This retrospective cohort study examined A1C changes following colesevelam HCL initiation in patients with diabetes, regardless of concomitant anti-diabetic medication use.
Methods
2000–2011 GE Centricity electronic medical records data were used to identify patients with type 2 diabetes mellitus (T2DM) aged 18 or older initiating colesevelam HCL. The sample was further restricted to uncontrolled patients with database activity ≥ 395 days before and after colesevelam HCL initiation, A1C > 7% during 90 days prior to starting colesevelam HCL, without prior use of bile acid sequestrants, and with at least one A1C result between 42 to 210 days after initiation. Three overlapping time intervals were created for A1C measurement, including 16-weeks, 26-weeks, and 52-weeks following therapy initiation. The last observed A1C lab measurement during each interval was used to define change from baseline. Mean change in A1C was examined using paired t-tests. Sensitivity analyses considered only patients who remained on colesevelam HCL through each respective measurement period, as well as the effect of concomitant diabetes medications.
Results
Of 1,709,393 patients in the GE database with T2DM, 1,747 met inclusion criteria. The cohort was 58% female, 38% age ≥ 65, and the majority was white. For the 16-week endpoint (N = 1,385), A1C dropped from a mean of 8.22% to 7.75% (mean change −0.47%; P < 0.0001). For the 26- and 52-week endpoints (N = 1,747), A1C dropped from a mean of 8.25% to 7.81% (mean change −0.44%; P < 0.0001) and 8.25% to 7.79% (mean change −0.46%; P < 0.0001), respectively. Sensitivity analyses showed that A1C reductions were of similar direction and magnitude for patients who remained on treatment, and for the subgroups of patients stratified by receipt of concomitant T2DM treatments.
Conclusions
The 0.44% to 0.47% A1C reduction observed in this study was similar to the reduction observed in RCTs, supporting the real-world effectiveness of colesevelam HCL in reducing A1C.
doi:10.1186/1472-6823-13-24
PMCID: PMC3750408  PMID: 23866087
5.  Statins are Associated with Reduced Use of Steroids in Inflammatory Bowel Disease: a Retrospective Cohort Study 
Inflammatory Bowel Diseases  2011;18(6):1048-1056.
Introduction
Statin medications have anti-inflammatory effects. We sought to determine whether statin use in persons with inflammatory bowel disease (IBD) was associated with reduced rates of steroid use or other markers of disease activity.
Methods
We performed a retrospective cohort study using administrative data. Statin users with IBD were compared to statin-unexposed IBD subjects. The primary outcome was an oral steroid prescription; secondary outcomes included anti-TNF initiation, hospitalization, or abdominal surgery. Cox proportional hazard models were used to estimate hazard ratios (HR) adjusted for potential confounders.
Results
The study cohort included 1,986 statin-exposed and 9,871 unexposed subjects. Statin use was associated with an 18% reduction in the rate of steroid initiation [HR 0.82 (95% CI 0.71, 0.94)]. A statistically significant result was seen with atorvastatin only [HR 0.76 (95% CI 0.60, 0.96)]. Statins were associated with a reduced rate of steroids in ulcerative colitis [HRs 0.75 (95% CI 0.62, 0.91)], but not in Crohn’s disease [HR 0.91 (95% CI 0.74, 1.12)]. Statin use was associated with reduced hazard of anti-TNF use [HR 0.72 (95% CI 0.46, 1.11)], abdominal surgery [HR 0.80 (95% CI 0.63, 1.02)], and hospitalization [HR 0.88 (95% CI 0.74, 1.05)], but these results did not reach statistical significance.
Conclusion
In this large retrospective cohort study, statin use amongst persons with IBD was associated with reduced use of oral steroids, particularly for UC. Prospective clinical trials are needed to confirm whether adjuvant treatment of IBD with statin drugs may spare immunosuppressant therapy or ameliorate flares.
doi:10.1002/ibd.21822
PMCID: PMC3213287  PMID: 21826766
Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammatory Bowel Diseases; Ulcerative Colitis; Crohn’s Disease; Glucocorticoids
6.  The Microaerophilic Microbiota of De-Novo Paediatric Inflammatory Bowel Disease: The BISCUIT Study 
PLoS ONE  2013;8(3):e58825.
Introduction
Children presenting for the first time with inflammatory bowel disease (IBD) offer a unique opportunity to study aetiological agents before the confounders of treatment. Microaerophilic bacteria can exploit the ecological niche of the intestinal epithelium; Helicobacter and Campylobacter are previously implicated in IBD pathogenesis. We set out to study these and other microaerophilic bacteria in de-novo paediatric IBD.
Patients and Methods
100 children undergoing colonoscopy were recruited including 44 treatment naïve de-novo IBD patients and 42 with normal colons. Colonic biopsies were subjected to microaerophilic culture with Gram-negative isolates then identified by sequencing. Biopsies were also PCR screened for the specific microaerophilic bacterial groups: Helicobacteraceae, Campylobacteraceae and Sutterella wadsworthensis.
Results
129 Gram-negative microaerophilic bacterial isolates were identified from 10 genera. The most frequently cultured was S. wadsworthensis (32 distinct isolates). Unusual Campylobacter were isolated from 8 subjects (including 3 C. concisus, 1 C. curvus, 1 C. lari, 1 C. rectus, 3 C. showae). No Helicobacter were cultured. When comparing IBD vs. normal colon control by PCR the prevalence figures were not significantly different (Helicobacter 11% vs. 12%, p = 1.00; Campylobacter 75% vs. 76%, p = 1.00; S. wadsworthensis 82% vs. 71%, p = 0.312).
Conclusions
This study offers a comprehensive overview of the microaerophilic microbiota of the paediatric colon including at IBD onset. Campylobacter appear to be surprisingly common, are not more strongly associated with IBD and can be isolated from around 8% of paediatric colonic biopsies. S. wadsworthensis appears to be a common commensal. Helicobacter species are relatively rare in the paediatric colon.
Trial Registration
This study is publically registered on the United Kingdom Clinical Research Network Portfolio (9633).
doi:10.1371/journal.pone.0058825
PMCID: PMC3595230  PMID: 23554935
7.  Does the presence of accompanying symptom clusters differentiate the comparative effectiveness of second-line medication strategies for treating depression? 
Depression and anxiety  2011;28(11):989-998.
Background
We explored whether clinical outcomes differ by treatment strategy following initial antidepressant treatment failure among patients with and without clinically relevant symptom clusters.
Methods
The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial was used to examine depression remission and response in patients with coexisting anxiety, atypical features, insomnia, and low energy. We applied propensity scoring to control for selection bias that precluded comparisons between augmentation and switch strategies in the original trial. Binomial regressions compared the likelihood of remission or response among patients with and without symptom clusters for switch versus augmentation strategies (n=269 per arm); augmentation strategy type (n=565); and switch strategy type (n=727).
Results
We found no statistically significant difference in remission or response rates between augmentation or switch strategies. However, symptom clusters did distinguish among augmentation and switch strategies, respectively. For patients with low energy, augmentation with buspirone was less likely to produce remission than augmentation with bupropion (remission Risk Ratio [RR]:0.54, 95% CI: 0.35–0.85, response RR:0.67, 95% CI 0.43, 1.03). Also, for patients with low energy, switching to venlafaxine or bupropion was less likely to produce remission than switching to sertraline (RR: 0.59, 95% CI: 0.36–0.97; RR: 0.63, 95% CI: 0.38–1.06, respectively).
Conclusions
Remission and response rates following initial antidepressant treatment failure did not differ by treatment strategy for patients with coexisting atypical symptoms or insomnia. However, some second-step treatments for depression may be more effective than others in the presence of coexisting low energy. Subsequent prospective testing is necessary to confirm these initial findings.
doi:10.1002/da.20898
PMCID: PMC3215789  PMID: 21898717
Depression; Antidepressant; Propensity Score; Symptom Cluster; Medication Selection
8.  Comparative effects of non-steroidal anti-inflammatory drugs (NSAIDs) on blood pressure in patients with hypertension 
Background
Nonsteroidal anti-inflammatory drugs (NSAIDs) may disrupt control of blood pressure in hypertensive patients and increase their risk of morbidity, mortality, and the costs of care. The objective of this study was to examine the association between incident use of NSAIDs and blood pressure in patients with hypertension.
Methods
We conducted a retrospective cohort study of adult hypertensive patients to determine the effects of their first prescription for NSAID on systolic blood pressure and antihypertensive drug intensification. Data were collected from an electronic medical record serving an academic general medicine practice in Indianapolis, Indiana, USA. Using propensity scores to minimize bias, we matched a cohort of 1,340 users of NSAIDs with 1,340 users of acetaminophen. Propensity score models included covariates likely to affect blood pressure or the use of NSAIDs. The study outcomes were the mean systolic blood pressure measurement after starting NSAIDs and changes in antihypertensive therapy.
Results
Compared to patients using acetaminophen, NSAID users had a 2 mmHg increase in systolic blood pressure (95% CI, 0.7 to 3.3). Ibuprofen was associated with a 3 mmHg increase in systolic blood pressure compared to naproxen (95% CI, 0.5 to 4.6), and a 5 mmHg increase compared to celecoxib (95% CI, 0.4 to 10). The systolic blood pressure increase was 3 mmHg in a subgroup of patients concomitantly prescribed angiotensin converting enzyme inhibitors or calcium channel blockers and 6 mmHg among those prescribed a beta-adrenergic blocker. Blood pressure changes in patients prescribed diuretics or multiple antihypertensives were not statistically significant.
Conclusion
Compared to acetaminophen, incident use of NSAIDs, particularly ibuprofen, is associated with a small increase in systolic blood pressure in hypertensive patients. Effects in patients prescribed diuretics or multiple antihypertensives are negligible.
doi:10.1186/1471-2261-12-93
PMCID: PMC3502533  PMID: 23092442
NSAIDs; Hypertension; Blood pressure; Propensity score
9.  Activation of fast skeletal muscle troponin as a potential therapeutic approach for treating neuromuscular diseases 
Nature medicine  2012;18(3):452-455.
Limited neuromuscular input results in muscle weakness in neuromuscular disease either because of a reduction in the density of muscle innervation, the rate of neuromuscular junction activation or the efficiency of synaptic transmission1. We developed a small molecule fast skeletal troponin activator, CK-2017357, as a means to increase muscle strength by amplifying the response of muscle when neuromuscular input is diminished secondary to a neuromuscular disease. Binding selectively to the fast skeletal troponin complex, CK-2017357 slows the rate of calcium release from troponin C and sensitizes muscle to calcium. As a consequence, the force-calcium relationship of muscle fibers shifts leftwards as does the force-frequency relationship of a nerve-muscle pair. In vitro and in vivo, CK-2017357 increases the production of force at sub-maximal stimulation rates. Importantly, we show that sensitization of the fast skeletal troponin complex to calcium improves muscle force and grip strength immediately after single doses of CK-2017357 in a model of neuromuscular disease, myasthenia gravis. Troponin activation may provide a new therapeutic approach to improve physical activity in diseases where neuromuscular function is compromised.
doi:10.1038/nm.2618
PMCID: PMC3296825  PMID: 22344294
10.  Interprofessional Education in Introductory Pharmacy Practice Experiences at US Colleges and Schools of Pharmacy 
Objective. To assess the extent to which US colleges and schools of pharmacy are incorporating interprofessional education into their introductory pharmacy practice experiences (IPPEs), and to identify barriers to implementation; characterize the format, structure, and assessment; and identify factors associated with incorporating interprofessional education in IPPEs.
Methods. An electronic survey of 116 US colleges and schools of pharmacy was conducted from March 2011 through May 2011.
Results. Interprofessional education is a stated curricular goal in 78% of colleges and schools and consistently occurred in IPPEs in 55%. Most colleges and schools that included interprofessional education in IPPEs (70%) used subjective measures to assess competencies, while 17.5% used standardized outcomes assessment instruments. Barriers cited by respondents from colleges and schools that had not implemented interprofessional education in IPPEs included a lack of access to sufficient healthcare facilities with interprofessional education opportunities (57%) and a lack of required personnel resources (52%).
Conclusions. Many US colleges and schools of pharmacy have incorporated interprofessional education into their IPPEs, but there is a need for further expansion of interprofessional education and better assessment related to achievement of interprofessional education competencies in IPPEs.
doi:10.5688/ajpe76580
PMCID: PMC3386031  PMID: 22761521
interprofessional education; interdisciplinary education; introductory pharmacy practice experiences; experiential education
11.  Risk of hyperkalemia associated with selective COX-2 inhibitors† 
Pharmacoepidemiology and drug safety  2010;19(11):1194-1198.
SUMMARY
Background
Selective cyclooxygenase-2 (COX-2) inhibitors have been linked to cardiac death. The mechanism for this adverse effect appears to be by ischemic insult; however another mechanism could involve hyperkalemia. The objective of this study was to determine the effects of selective COX-2 inhibitors and non-selective nonsteroidal anti-inflammatory drugs (NSAIDs) on serum potassium concentration and the electrocardiogram.
Methods
A retrospective cohort study was conducted using propensity score matching of patients from an inner-city academic medical center at Indianapolis, Indiana. Two hundred and two patients prescribed selective COX-2 inhibitors were matched to 202 patients prescribed non-selective NSAIDs using propensity scores methods. Outcomes included change in serum potassium concentration from baseline and the risk of an abnormal electrocardiogram.
Results
Compared to patients prescribed non-selective NSAIDs, those prescribed a selective COX-2 inhibitor had a higher risk of serum potassium increase greater than 5 mEq/L (OR, 2.56; 95%CI, 1.03–6.36). However, patients prescribed selective COX-2 inhibitors had no greater risk of electrocardiogram abnormality (OR, 1.16; 95%CI, 0.74–1.82).
Conclusions
Selective COX-2 inhibitors may have a greater risk of hyperkalemia than non-selective NSAIDs. This study was exploratory with small numbers of patients. Further studies are needed to confirm these results and any association with cardiovascular events.
doi:10.1002/pds.2011
PMCID: PMC3018679  PMID: 20842761
hyperkalemia; NSAIDs; selective COX-2 inhibitors; retrospective cohort study; propensity score
12.  Orally Administered Particular β-Glucan Modulates Tumor-capturing Dendritic Cells and Improves Anti-tumor T Cell Responses in Cancer 
Purpose
The beneficial properties of β-glucans have been recognized for centuries. Their proposed mechanisms of action in cancer therapy occur via stimulation of macrophages and priming of innate neutrophil complement receptor 3 (CR3) for eliciting CR3-dependent cellular cytotoxicity of iC3b-opsonized tumor cells. The current study is to investigate whether β-glucan therapy has any impact on anti-tumor adaptive T cell responses.
Experimental Design
We first examined the trafficking of orally administered particulate yeast-derived β-glucan and its interaction with dendritic cells (DCs) that captured tumor materials. Antigen-specific T cells were adoptively transferred into recipient mice to determine whether oral β-glucan therapy induces augmented T cell responses. Lewis lung carcinoma and RAM-S lymphoma models were used to test oral β-glucan therapeutic effect. Further mechanistic studies including tumor-infiltrating T cells and cytokine profiles within the tumor milieu were determined.
Results
Orally administered particulate β-glucan trafficked into spleen and lymph nodes and activated DCs that captured dying tumor cells in vivo, leading to the expansion and activation of antigen-specific CD4 and CD8 T cells. In addition, IFN-γ production of tumor-infiltrating T cells and CTL responses were significantly enhanced upon β-glucan treatment, which ultimately resulted in significantly reduced tumor burden. Moreover, β-glucan-treated tumors had significantly more DC infiltration with the activated phenotype and significant levels of Th1-biased cytokines within the tumor microenvironment.
Conclusions
These data highlight the ability of yeast-derived β-glucan to bridge innate and adaptive anti-tumor immunity and suggest that it can be used as an adjuvant for tumor immunotherapy.
doi:10.1158/1078-0432.CCR-10-0820
PMCID: PMC2970627  PMID: 20855461
13.  A Comprehensive Evaluation of Colonic Mucosal Isolates of Sutterella wadsworthensis from Inflammatory Bowel Disease 
PLoS ONE  2011;6(10):e27076.
Inflammatory bowel disease (IBD) arises in genetically susceptible individuals as a result of an unidentified environmental trigger, possibly a hitherto unknown bacterial pathogen. Twenty-six clinical isolates of Sutterella wadsworthensis were obtained from 134 adults and 61 pediatric patients undergoing colonoscopy, of whom 69 and 29 respectively had IBD. S. wadsworthensis was initially more frequently isolated from IBD subjects, hence this comprehensive study was undertaken to elucidate its role in IBD. Utilizing these samples, a newly designed PCR was developed, to study the prevalence of this bacterium in adult patients with ulcerative colitis (UC). Sutterella wadsworthensis was detected in 83.8% of adult patients with UC as opposed to 86.1% of control subjects (p = 0.64). Selected strains from IBD cases and controls were studied to elicit morphological, proteomic, genotypic and pathogenic differences. This study reports Scanning Electron Microscopy (SEM) appearances and characteristic MALDI-TOF MS protein profiles of S. wadsworthensis for the very first time. SEM showed that the bacterium is pleomorphic, existing in predominantly two morphological forms, long rods and coccobacilli. No differences were noted in the MALDI-TOF mass spectrometry proteomic analysis. There was no distinct clustering of strains identified from cases and controls on sequence analysis. Cytokine response after monocyte challenge with strains from patients with IBD and controls did not yield any significant differences. Our studies indicate that S. wadsworthensis is unlikely to play a role in the pathogenesis of IBD. Strains from cases of IBD could not be distinguished from those identified from controls.
doi:10.1371/journal.pone.0027076
PMCID: PMC3205041  PMID: 22073125
14.  Detection of Campylobacter concisus and Other Campylobacter Species in Colonic Biopsies from Adults with Ulcerative Colitis 
PLoS ONE  2011;6(6):e21490.
Introduction
The critical role of bacteria in the pathogenesis of ulcerative colitis (UC) is well recognized, but an individual causative microorganism has not been singled out so far. Campylobacter concisus and other non-jejuni species of Campylobacter have been implicated as putative aetiological agents in inflammatory bowel disease in children, but such studies have not been addressed in adults. This study investigated the prevalence of Campylobacter species in colonic biopsy samples from adults with UC and healthy controls.
Methods
Adult patients who were undergoing diagnostic colonoscopy were recruited for the study, which included 69 patients with histologically proven UC and 65 healthy controls. DNA was extracted from the biopsy samples and subjected to Campylobacter genus specific and Campylobacter concisus specific polymerase chain reaction and sequencing.
Results
Detection of all Campylobacter DNA utilising genus specific primers was significantly higher in cases of UC, with a prevalence of 73.9% (51/69) compared to 23.1% (15/65) in controls (p = 0.0001). Nested PCR for C. concisus DNA was positive in 33.3% (23/69) of biopsy samples from subjects with UC, which was significantly higher than the prevalence rate of 10.8% (7/65) from controls (p = 0.0019). Sequencing of the remaining Campylobacter positive samples revealed that Campylobacter ureolyticus was positive in 21.7% (15/69) of samples from UC subjects as opposed to 3.1% (2/65) in controls (p = 0.0013). Mixed Campylobacter species were more common in UC patients, 20.3% (14/69) as compared to controls 4.6% (3/65) (p = 0.0084).
Conclusion
The higher prevalence of Campylobacter genus and more specifically C. concisus and C. ureolyticus in biopsy samples from adults with UC suggests these genera of bacteria may be involved in the chronic inflammation that is characteristically seen in UC. To the best of our knowledge this is the first report of this association of C. concisus and C. ureolyticus with UC in adults.
doi:10.1371/journal.pone.0021490
PMCID: PMC3124515  PMID: 21738679
15.  Prescription Refill Records as a Screening Tool to Identify Antidepressant Non-Adherence 
Purpose
Non-adherence is a significant problem with antidepressants. Identifying patients at highest risk for discontinuing antidepressant treatment can be used to target clinical management. Accordingly, our purpose was to determine the shortest gap in medication supply that is predictive of discontinuation, while minimizing false positive results.
Methods
A retrospective cohort study of medical and prescription claims from a national health plan affiliated with i3 Innovus. Sensitivities, specificities, and positive and negative predictive values were calculated for gap lengths to assess how well they predicted discontinuation. Continuously insured individuals aged 18–65 with newly diagnosed major depression and an antidepressant prescription within 45 days of diagnosis were included. Gap length was defined as the maximum number of continuous days without medication supply during acute phase treatment. Discontinuation was defined as a continuous gap of 30 or more days between an expected refill and actual refill.
Results
Of 4,545 eligible patients, 73% discontinued antidepressant treatment during the study period. A maximum continuous gap of 14 days had a sensitivity of 87% and a specificity of 82% for predicting discontinuation. In analyses that varied the way gaps and discontinuation were defined, gap lengths between 8 and 19 days were highly predictive of discontinuation without exceeding a 20% false positive rate.
Conclusions
Based on administrative pharmacy records, screening for gaps in medication supply of at least 14 days can accurately identify 4 of every 5 patients at risk for discontinuing. This early indicator can be used to target clinical interventions.
doi:10.1002/pds.1881
PMCID: PMC3057376  PMID: 19998397
Adherence; screening; depression; prescription refills
16.  Enterohepatic Helicobacter in Ulcerative Colitis: Potential Pathogenic Entities? 
PLoS ONE  2011;6(2):e17184.
Background
Changes in bacterial populations termed “dysbiosis” are thought central to ulcerative colitis (UC) pathogenesis. In particular, the possibility that novel Helicobacter organisms play a role in human UC has been debated but not comprehensively investigated. The aim of this study was to develop a molecular approach to investigate the presence of Helicobacter organisms in adults with and without UC.
Methodology/Principal Findings
A dual molecular approach to detect Helicobacter was developed. Oligonucleotide probes against the genus Helicobacter were designed and optimised alongside a validation of published H. pylori probes. A comprehensive evaluation of Helicobacter genus and H. pylori PCR primers was also undertaken. The combined approach was then assessed in a range of gastrointestinal samples prior to assessment of a UC cohort. Archival colonic samples were available from 106 individuals for FISH analysis (57 with UC and 49 non-IBD controls). A further 118 individuals were collected prospectively for dual FISH and PCR analysis (86 UC and 32 non-IBD controls). An additional 27 non-IBD controls were available for PCR analysis. All Helicobacter PCR-positive samples were sequenced. The association between Helicobacter and each study group was statistically analysed using the Pearson Chi Squared 2 tailed test. Helicobacter genus PCR positivity was significantly higher in UC than controls (32 of 77 versus 11 of 59, p = 0.004). Sequence analysis indicated enterohepatic Helicobacter species prevalence was significantly higher in the UC group compared to the control group (30 of 77 versus 2 of 59, p<0.0001). PCR and FISH results were concordant in 74 (67.9%) of subjects. The majority of discordant results were attributable to a higher positivity rate with FISH than PCR.
Conclusions/Significance
Helicobacter organisms warrant consideration as potential pathogenic entities in UC. Isolation of these organisms from colonic tissue is needed to enable interrogation of pathogenicity against established criteria.
doi:10.1371/journal.pone.0017184
PMCID: PMC3044171  PMID: 21383845
17.  Preventing medication errors in long‐term care: results and evaluation of a large scale web‐based error reporting system 
Quality & Safety in Health Care  2007;16(4):297-302.
Objective
To describe the implementation and evaluation of a web‐based medication error reporting system.
Design
Evaluation study.
Setting
Long‐term care.
Participants
25 nursing homes in the US state of North Carolina.
Intervention
Detailed information about all medication errors occurring in a facility during a 1 year period was entered into a web‐based reporting system. An evaluation survey was conducted to assess usability and the potential for the system to prevent errors.
Main outcome measures
Number and specific characteristics of medication errors reported. A survey evaluating ease of use of the system and whether the participants thought it would help improve medication safety.
Results
23 (92%) sites entered 631 error reports for 2731 discrete error instances when weighted by the number of times the errors were repeated. 51 (8%) errors were classified as having a serious patient impact requiring monitoring/intervention or worse. The most common errors were dose omission (203, 32%), overdose (91, 14%), underdose (43, 7%), wrong patient (38, 6%), wrong product (38, 6%), and wrong strength (38, 6%). Errors most commonly occurred during medication administration (296, 47%) and were attributed to basic human error (402, 48%). Seven drugs were implicated in a third (175, 28%) of all errors: lorazepam, oxycodone, warfarin, furosemide, hydrocodone, insulin and fentanyl. 20 sites (86% of respondents) completed the evaluation survey and participants found the system easy to use and thought it would increase accuracy of reporting and improve patient safety.
Conclusions
The web‐based medication error reporting system was easy to use, with strong indications that it would be a valuable tool for preventing future errors.
doi:10.1136/qshc.2007.022483
PMCID: PMC2464957  PMID: 17693679
18.  Direct to consumer and physician promotion of tegaserod correlated with physician visits, diagnoses, and prescriptions 
Gastroenterology  2009;137(2):518-524.e2.
Background & Aims
Direct to consumer advertisement (DTCA) and physician promotion of drugs can influence patient and physician behaviors. We sought to determine the relationship between promotion of tegaserod and the number of office visits for abdominal pain, constipation, and bloating; diagnoses of irritable bowel syndrome (IBS); and tegaserod prescriptions.
Methods
We used an Integrated Promotional Services database to estimate tegaserod DTCA and promotion expenditures, The National Ambulatory/Hospital Medical Care Surveys (1997–2005) to estimate the number of ambulatory care visits for abdominal pain, constipation, and bloating and diagnoses of IBS, and IMS Health's National Prescription Audit Plus to estimate the number of prescriptions. We constructed segmented and multivariate regression models to analyze the data.
Results
In the 3 months immediately following the start of tegaserod DTCA, there was a significant increase in physician visits (by 1 million; 95% CI 0.5–1.6 million) and IBS diagnoses (by 397,025; 95% CI 3,909–790,141). Subsequently, the trend of visits and IBS diagnoses reduced. In multivariate analyses that examined the overall relationship of promotion with visits, diagnoses, and prescriptions, only the relationship between physician promotion and tegaserod prescribing was significant; every $1 million spent on physician promotion resulted in an additional 4,108 prescriptions (95% CI: 2,526–5,691).
Conclusions
The initial DTCA of tegaserod was associated with a significant, immediate increase in physician visits and IBS diagnoses. This trend reversed and in multivariate models, neither DTCA nor physician promotion correlated with visits or diagnoses. Physician promotion (though not DTCA) correlated with tegaserod prescription volume.
doi:10.1053/j.gastro.2009.05.005
PMCID: PMC2717184  PMID: 19445943
19.  Combined Yeast-derived β-Glucan with Anti-tumor Monoclonal Antibody for Cancer Immunotherapy 
β-Glucan is an immuno-stimulating agent that has been used to treat cancer and infectious disease for many years with varying and unpredictable efficacy. Recent studies have unraveled the action mode of yeast-derived β-glucan in combination with anti-tumor monoclonal antibodies (mAbs) in cancer therapy. It has demonstrated that particulate or large molecular weight soluble β-glucans are ingested and processed by macrophages. These macrophages secrete the active moiety that primes neutrophil complement receptor 3 (CR3) to kill iC3b-opsonized tumor cells. In vitro and in vivo data demonstrate that successful combination therapy requires complement activation and deposition on tumors and CR3 expression on granulocytes. Pre-clinical animal studies have demonstrated the efficacy of combined β-glucan with anti-tumor mAbs therapy in terms of tumor regression and long-term survival. Clinical trials are underway using anti-epidermal growth factor receptor mAb (Erbitux) in combination with β-glucan for metastatic colorectal cancer. This review provides a brief overview of this combination therapy in cancer and describes in detail the β-glucan composition and structure, mechanism of action, and preclinical studies in human carcinoma xenograft models. It is proposed that the addition of β-glucan will further improve the therapeutic efficacy of anti-tumor mAbs in cancer patients.
doi:10.1016/j.yexmp.2009.01.006
PMCID: PMC2685877  PMID: 19454271
β-glucan; anti-tumor monoclonal antibody; immunotherapy; complement; neutrophils; complement regulatory proteins
20.  Pre-Dialysis Chronic Kidney Disease: Evaluation of Quality of Life in Clinic Patients Receiving Comprehensive Anemia Care 
Background
Anemia is common in chronic kidney disease (CKD), and suboptimal management of anemia can lead to serious health complications and poor quality of life.
Objectives
1) To describe health-related and overall quality of life among patients entering a clinic focused on anemia management; 2) to compare their baseline quality of life with other relevant populations; 3) to explore predictors of quality of life prior to anemia management; and 4) to explore changes in quality of life over 1 year for patients managed in the clinic.
Methods
The Kidney Disease Quality of Life questionnaire – short form (KDQOL™-SF) was used to measure kidney disease specific and overall quality of life in a cohort of pre-dialysis CKD patients (n=79) enrolled in the clinic from January 2003 to September 2004. Baseline measures were compared to previously published measurements. The influence of demographic and clinical characteristics on baseline quality of life was explored. Changes in quality of life were evaluated over time.
Results
Patients with CKD entering the clinic had lower overall quality of life compared with estimates from the general US population (physical composite 35.7 vs. 48.4 and mental composite 46.0 vs. 50.2, respectively). Clinic patients had better kidney disease specific scores than patients with end stage kidney disease. General quality of life scores were similar regardless of kidney disease severity, with the exception of physical functioning which was lowest for patients with end-stage disease. Hemoglobin was the only factor predictive of quality of life. Over time, quality of life improved among patients managed in the CKD clinic, with statistically significant improvements in sleep (change of 6.2 ± 15.2; p < 0.05) and social function (change of 11.6 ± 27.7; p < 0.05).
Conclusions
Patients with anemia of chronic kidney disease reported reduced quality of life compared to populations without kidney disease, but better quality of life compared to populations with end stage kidney disease on dialysis. Quality of life generally improved among patients managed in the multidisciplinary anemia clinic.
doi:10.1016/j.sapharm.2008.06.004
PMCID: PMC2722114  PMID: 19524862
Quality of life; chronic kidney disease; anemia; SF-36; KDQOL; multidisciplinary
21.  Prevention of major depressive disorder relapse and recurrence with second-generation antidepressants: A systematic review and meta-analysis 
Objective
To review data on the efficacy and effectiveness of second-generation antidepressants for preventing major depression relapse and recurrence during continuation and maintenance phase treatment, respectively.
Methods
MEDLINE®, EMBASE, and PsychLit; the Cochrane Library; and the International Pharmaceutical Abstracts were searched from January 1980 through April 2007 for reviews, randomized controlled trials, meta-analyses, and observational studies. Two persons independently reviewed abstracts and full text articles using a structured data abstraction form to ensure consistency in appraisal and data extraction.
Findings
Four comparative trials and 23 placebo controlled trials that addressed relapse or recurrence prevention were included. Results of comparative trials have not demonstrated statistically significant differences between duloxetine and paroxetine, fluoxetine and sertraline, fluvoxamine and sertraline, and trazodone and venlafaxine. Pooled data for the class of second-generation antidepressants compared with placebo suggest a relatively large effect size that persists over time. The number needed to treat to prevent one additional relapse or recurrence is 5 (95% CI 4 to 6). Differences in the length of open-label treatment prior to randomization, drug type, and trial duration did not affect pooled estimates of relapse rates (P = 0.716, P = 0.507, and P = 0.480, respectively). Across all trials, 7% of patients randomized to active treatment and 5% of patients randomized to placebo discontinued treatment because of adverse events.
Conclusions
This review demonstrates the overall benefits of continuation- and maintenance-phase treatment of major depression with second-generation antidepressants, and stresses the need for additional studies on comparative differences among drugs.
doi:10.1176/appi.ps.59.10.1121
PMCID: PMC2840386  PMID: 18832497
Antidepressant; major depressive disorder; prevention; relapse; recurrence
22.  Controlling for Drug Dose in Systematic Review and Meta-Analysis: A Case Study of the Effect of Antidepressant Dose 
Purpose
To describe a method for quantitatively dealing with drug dose in comparative effectiveness reviews. Second-generation antidepressants are used as an example to illustrate this method, and to determine whether dose influences conclusions on comparative effectiveness.
Methods
Studies previously identified in a systematic review of second-generation antidepressants were included if data on drug dose were available. The usual dosing range for each drug was defined, and then used to create 2- and 3-level dose categories. Placebo-controlled data were used to calculate overall effect sizes for the drug class and effect sizes stratified by drug dose. Meta-regression tested the impact of dose on effect size. Weighted mean differences and risk ratios were calculated for comparative studies, stratifying by whether compared doses were equivalent.
Results
The dose classification method was able to identify dose-response trends in the context of meta-analysis. Compared to low dose studies, medium and high dose studies had a 1 to 2 point greater differential in mean HAM-D change (P<0.001). Dose was not a statistically significant predictor of categorical HAM-D response. Among comparative trials with non-equivalent doses, trends favored higher dose categories, but generally were not statistically significant.
Conclusions
A structured method for quantitatively dealing with drug dose in comparative effectiveness reviews is described, with application to the second-generation antidepressants. Dose-dependent reductions in HAM-D scores were identified, although differences did not translate into better response rates for higher doses. Dose equivalency was not a significant factor among comparative studies in second-generation antidepressants.
doi:10.1177/0272989X08323298
PMCID: PMC2657322  PMID: 19141788
meta-analysis; meta-regression; dose; dose-response; comparative effectiveness
23.  Efficacy and safety of anakinra for the treatment of rheumatoid arthritis: an update of the Oregon Drug Effectiveness Review Project 
Objective
To systematically review the general and comparative efficacy and safety of anakinra for rheumatoid arthritis.
Methods
We searched MEDLINE®, Embase, The Cochrane Library, and the International Pharmaceutical Abstracts from 1980 to April 2009. We manually searched reference lists of pertinent review articles and explored the Center for Drug Evaluation and Research database. For efficacy we included randomized controlled trials (RCTs) comparing anakinra with placebo or other biologics. For safety both experimental and observational studies were eligible. Two persons independently reviewed abstracts and full text articles and extracted relevant data.
Results
We included data from 3 RCTs comparing anakinra with placebo for rheumatoid arthritis (RA). The pooled relative risk (RR) of an ACR50 (American College of Rheumatology) response for anakinra compared with placebo is 2.28 (95% CI 1.41 to 3.67). Adjusted indirect comparisons of ACR50 response rates of anakinra and anti-TNF agents showed a RR of 0.67 (95% CI 0.38 to 1.17) favoring the anti-TNF drugs. This result did not reach statistical significance. For safety, we included 9 experimental and observational studies of 24 weeks to 3 years duration. Up to 30% of patients withdrew from the studies due to adverse events. 67.2% (95% CI 38.7 to 95.7) of patients experienced an injection site reaction.
Conclusions
Anakinra is an effective drug for treating RA. Indirect comparisons with adalimumab, etanercept and infliximab, however, showed a trend towards greater efficacy for the anti-TNF drugs. Anakinra also seems to be associated with comparably high rates of injection site reactions. These results should be taken into account when considering biologic therapy for patients with RA.
PMCID: PMC2802074  PMID: 20054439
anakinra; rheumatoid arthritis; infection
24.  Risk of Adverse Gastrointestinal Events from Inhaled Corticosteroids 
Pharmacotherapy  2008;28(11):1325-1334.
Study Objective
Previous studies suggest a risk of gastrointestinal events in patients prescribed oral corticosteroids, but gastrointestinal events have not commonly been documented in patients prescribed inhaled corticosteroids. We explored whether patients prescribed inhaled corticosteroids are at risk of adverse gastrointestinal effects.
Design
A retrospective cohort study was conducted using 25 years of electronic medical record data.
Setting
An urban health center with an academic affiliation.
Patients
The incidence of adverse gastrointestinal events in patients prescribed inhaled corticosteroids and albuterol (n = 7,156) was compared to those prescribed albuterol alone (n = 12,287).
Measurements and Main Results
Adverse gastrointestinal outcomes included events such as gastritis, ulcers, and bleeding. Cox proportional hazards models were used to determine the risk of adverse events controlling for possible confounders such as alcohol use or non-steroidal anti-inflammatory drug use. Adverse gastrointestinal events were observed in 461 (6.4%) patients prescribed inhaled corticosteroids and albuterol and in 302 (2.5%) patients prescribed only albuterol. Patients prescribed inhaled albuterol and inhaled corticosteroids had an increased risk of adverse gastrointestinal events compared to patients prescribed only albuterol [hazard ratio 1.26 (95% confidence interval 1.02 to 1.56)] after controlling for potential confounders. A prescription for a spacer device reduced this risk among patients prescribed inhaled steroid [hazard ratio 0.26 (95% confidence interval 0.20 to 0.34)].
Conclusions
Patients prescribed inhaled corticosteroids appear to have a slight risk of adverse gastrointestinal events that is mitigated in patients prescribed a spacer device.
doi:10.1592/phco.28.11.1325
PMCID: PMC2648528  PMID: 18956992
inhaled corticosteroids; gastrointestinal adverse events; spacer; obstructive airways disease
25.  Efficacy and Tolerability of Second-Generation Antidepressants in Social Anxiety Disorder 
A systematic review and meta-analysis was conducted to evaluate the comparative efficacy and tolerability of second-generation antidepressants in social anxiety disorder. Studies were identified by searching MEDLINE®, Embase, The Cochrane Library, PsychLit, and the International Pharmaceutical Abstracts from January 1980 through October 2006. Comparative evidence was summarized and indirect comparisons were made using network meta-analysis. Only three head-to-head trials were identified; comparative trials found only minimal differences in efficacy between escitalopram and paroxetine, and no statistically significant differences in efficacy between extended-release venlafaxine and paroxetine. Pooled evidence from 15 placebo-controlled trials suggests that escitalopram (relative benefit 1.3; 95% CI 1.2 to 1.5), paroxetine (relative benefit 1.9; 95% CI 1.5 to 2.3), sertraline (relative benefit 1.8; 95% CI 1.5 to 2.2), and venlafaxine (relative benefit 1.7; 95% CI 1.5 to 1.9) all produce significantly more responders than placebo; evidence favored fluvoxamine over placebo but was not significant (relative benefit 1.5; 95% CI 0.9 to 2.4). Network meta-analysis did not reveal differences in efficacy among drugs. Overall, fair evidence supports the efficacy of escitalopram, fluvoxamine, paroxetine, sertraline, and venlafaxine in social anxiety disorder. The drugs do not differ in efficacy, although their adverse event profiles do.
doi:10.1097/YIC.0b013e3282f4224a
PMCID: PMC2657552  PMID: 18408531
social anxiety disorder; social phobia; second-generation antidepressant; network meta-analysis; indirect comparison

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