Vitamin C, vitamin E, ß-carotene and risk of Parkinson's disease: a systematic review and dose-response meta-analysis of observational studies.

OBJECTIVE: This study aimed to explore the relationship between the intake of vitamin C, vitamin E and ß-carotene, and the risk of Parkinson's disease (PD). METHODS: Web of Science, Embase, PubMed, Cochrane library, CNKI, and WanFang databases were searched from inception to 29 August 2022 for observational studies reporting the odds ratios (ORs) or relative risks (RRs) or hazard ratios (HRs) and 95% confidence intervals (CIs) of PD by Vitamin C/Vitamin E/ß-carotene intake. Random-effects models, publication bias assessment, subgroup, sensitivity and dose-response analyses were performed, using.Stata version 12.0. RESULTS: A total of 13 studies were included. There was no significant association between high-dose vitamin C intake and the risk of PD compared with low-dose vitamin C intake (RR = 0.98, 95%CI:0.89,1.08). Compared with low-dose intake, high-dose intake of vitamin E can prevent the risk of PD (RR = 0.87, 95%CI:0.77,0.99). Compared with lower ß-carotene intake, there was a borderline non-significant correlation between higher intake and PD risk (RR = 0.91, 95%CI:0.82,1.01), and high dose ß-carotene intake was found to be associated with a lower risk of PD in women (RR = 0.78, 95%CI:0.64,0.96). CONCLUSION: This study shows that vitamin E intake can reduce the risk of PD and play a preventive role.

Safety of baclofen versus tizanidine for older adults with musculoskeletal pain.

BACKGROUND: Baclofen and tizanidine are both muscle relaxants that carry the risk for neuropsychiatric events in older adults but there is a lack of data directly comparing their safety. This study aimed to investigate the relative risk between these two medications in causing injury and delirium in older adults. METHODS: This was a retrospective cohort study that was completed in an integrated healthcare system in the United States and included patients aged 65 years or older who started baclofen or tizanidine for the treatment of musculoskeletal pain from January 2016 through December 2018. Outcomes included new incidence of injury (concussion, contusion, dislocation, fall, fracture, or other injuries) and delirium. The cohort was followed from the initiation of therapy until the first occurrence of any of the following events: end of the index drug exposure, end of health plan membership, death, or the study end date of December 31st, 2019. Descriptive statistics were used to compare baseline patient characteristics between baclofen and tizanidine treatment groups. Cox proportional hazards model was used to calculate adjusted hazard ratios (HRs) with 95% confidence intervals. RESULTS: The final study cohort included 12,101 and 6,027 older adults in the baclofen and tizanidine group respectively (mean age 72.2 ± 6.2 years old, 59% female). Older adults newly started on baclofen had a greater risk of injury (HR = 1.54, 95% CI = 1.21-1.96, P = < 0.001) and delirium (HR = 3.33, 95% CI = 2.11-5.26, p = <0.001) compared to those started on tizanidine. CONCLUSION: The results of this study suggest that baclofen is associated with higher incidences of injury and delirium compared to tizanidine when used for the treatment of musculoskeletal pain. Future studies should investigate if these risks are dose-related and include a comparison group not exposed to either drug.

Study on syndrome rules of stagnated heat in liver and stomach of non-erosive reflux disease based on microecology of tongue coating.

INTRODUCTION: At present, the pathogenesis of non-erosive reflux disease (NERD) is still unclear, and proton pump inhibitors are the main treatment drug. However, the effect is limited. Traditional Chinese medicine treatment of NERD has advantages. Stagnated heat in liver and stomach syndrome is the most important traditional Chinese medicine syndrome type of this disease. Tongue diagnosis is an important basis for the diagnosis of stagnated heat in liver and stomach syndrome. The microecology of tongue coating suggests the occurrence and development of disease. The purpose of this study aims to clarify the regular changes of tongue coating microecology in stagnated heat in liver and stomach syndrome of NERD. METHODS AND ANALYSIS: This is a cross-sectional clinical trial. This study is divided into NERD stagnated heat in liver and stomach syndrome group, qi stagnation, and phlegm obstruction syndrome control group and normal control group, with 20 cases in each group. Tongue coating samples will be collected from 3 groups, and 16SrRNA gene sequencing technology will be used to detect the genome of tongue coating flora in patients with NERD with stagnated heat in liver and stomach syndrome, control group with qi stagnation and phlegm obstruction syndrome and normal control group. The main outcome measures are the distribution, diversity, and richness of the tongue flora in patients and healthy controls. DISCUSSION: The results of this study will clarify the internal relationship between NERD stagnated heat in liver and stomach syndrome and the microecological changes in tongue coating.

Real world outcomes related to providing an annual supply of short-acting hormonal contraceptives.

OBJECTIVE: To compare pregnancy rates among women provided a 12-month supply or less than a 12-month supply of short-acting hormonal contraceptives. STUDY DESIGN: This retrospective cohort study examined data from an integrated health plan in California, collected about people aged 10-50 years, who filled at least one contraceptive prescription between January 2017 and September 2018. We examined outcomes following index contraceptive prescriptions for up to 15 months, end of membership, initiation of a long-acting contraceptive, or death, whichever occurred first. We compared rates per 100 person years of observation of: pregnancy, receipt of emergency contraception (EC), and contraceptive refills more than 12 months after the index prescription. We used multivariable logistic regression to control for demographics and baseline clinical variables when comparing provision of a 12-month to a smaller supply. RESULTS: We identified 1689 members who received a 12-month supply of short-acting hormonal contraception and 352,624 women who received less than a 12-month supply. Those who received a 12-month supply were less likely to receive EC (1.3 vs 2.1 per 100 person years, p = 0.04) or have documentation of pregnancy (1.7 vs 2.7 per 100 person-years, p = 0.02), and more likely to refill the contraceptive more than 1 year after the index prescription (99.4% vs 63.9%, p < 0.01). Among new starts, the adjusted odds ratio (OR) of pregnancy was 0.50 (95% CI 0.27-0.94) among women who received a 12-month supply vs. those were not. CONCLUSION: Members of an integrated healthcare system who received a 12-month supply of short-acting hormonal contraceptives are less likely to become pregnant within the following year. IMPLICATIONS: Offering a 12-month supply of short-acting hormonal contraceptives may reduce rates of undesired pregnancy.

Cardiovascular and kidney outcomes of spironolactone or eplerenone in combination with ACEI/ARBs in patients with diabetic kidney disease.

BACKGROUND: Mineralocorticoid receptor antagonist (MRA) when combined with either angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) may provide additional benefits of cardiovascular and kidney disease risk reduction in patients with diabetic kidney disease (DKD) and hypertension. We evaluated the effectiveness of combination therapy (MRAs, either spironolactone or eplerenone, plus ACEI/ARB) compared with monotherapy (ACEI/ARB only) in patients with DKD and hypertension. METHODS: Retrospective cohort study was performed in patients (age ≥ 18 years) with hypertension, diabetes, and albuminuria between 2008 and 2018 within an integrated health system. MRA with ACEI/ARB compared to ACEI/ARB alone was evaluated on composite of cardiovascular events, progression to end-stage kidney disease, or all-cause mortality. Hyperkalemia was compared as a safety outcome. RESULTS: We identified 1282 patients who received MRAs with ACEI/ARBs and 5484 patients who received ACEI/ARBs alone. Median exposure time for combination therapy was 126 days. The rates per 100 person-years of cardiovascular, kidney, or all-cause mortality outcomes were 12.2 and 9.2 for combination therapy and monotherapy, respectively (hazard ratios = 1.24, 95% Confidence Interval (CI):0.94, 1.63). Patients receiving combination therapy had greater reduction in urine albumin-to-creatinine ratio compared with monotherapy (Mean reduction: 823 and 585 mg/g; p < 0.001, respectively). Hyperkalemia was more frequent in combination therapy versus monotherapy (22.3 vs. 10.9 per 100 person-years for combination and monotherapy, respectively; hazard ratios = 1.78, 95%CI: 1.42, 2.24). CONCLUSIONS: Among patients with DKD and hypertension, the short-term use of MRAs, either spironolactone or eplerenone, in combination with ACEI/ARBs, was not associated with lower risk of cardiovascular or kidney outcomes compared with ACEI/ARB monotherapy. The risk of hyperkalemia and the short duration of combination therapy may suggest a real-world clinical challenge for MRA with ACEI/ARB combination therapy.

Application of vermicompost and biochar suppresses Fusarium root rot of replanted American ginseng.

Soil sterilization integrated with agronomic measures is an effective method to reduce soilborne replant diseases. However, the effect of vermicompost or biochar application after soil sterilization on soilborne diseases is poorly understood. A pot experiment was conducted in American ginseng to investigate the effects of vermicompost (VF), biochar (BF), and a combination of vermicompost and biochar (VBF) applied after soil sterilization on the incidence of Fusarium root rot using natural recovery (F) as control. After one growing season, the disease index of root rot, the phenolic acids, and the microbial communities of American ginseng rhizosphere soil were analyzed. The disease index of VF, BF, and VBF decreased by 33.32%, 19.03%, and 80.96%, respectively, compared with F. The highest bacterial richness and diversity were observed in the rhizosphere soil of VBF. Besides, VF and VBF significantly increased the relative abundance of beneficial bacteria (Pseudomonas, Lysobacter, and Chryseolinea) in the rhizosphere soil. Higher concentrations of vanillin, one of the phenolic acids in the roots exudates, were recorded in the rhizosphere soils of BF and VBF. The vanillin concentration showed a significant negative correlation with the disease index. To conclude, vermicompost improved the beneficial bacteria of the rhizosphere soil, while biochar regulated the allelopathic effect of the phenolic acids. The study proposes a combined application of biochar and vermicompost to the rhizosphere soil to control Fusarium root rot of replanted American ginseng effectively. KEY POINTS: Vermicompost improves the relative abundance of rhizosphere beneficial bacteria. Biochar inhibits the degradation of phenolic acids by adsorption. The combination of vermicompost and biochar enhances the disease control effect.

Patterns of Care and Treatment Outcomes for Outpatient Daptomycin-Containing Regimens in Osteomyelitis.

BACKGROUND: Use of daptomycin at doses ≥ 6 mg/kg for treatment of osteomyelitis is increasing in clinical practice; unfortunately, limited data are available to guide optimal dosing and duration. The objective of this study was to assess daptomycin dosing and duration regimens for osteomyelitis treatment. METHODS: This was a retrospective, multi-site, cohort study conducted in an integrated healthcare delivery system. Nonpregnant patients ≥ 18 years of age with osteomyelitis diagnosed between November 1, 2003 and June 30, 2011, ≥ 2 weeks outpatient daptomycin therapy, and ≥ 1 month of follow-up were included. Daptomycin doses < 6 mg/kg and ≥ 6 mg/kg at durations of < 6 weeks and ≥ 6 weeks were examined with univariate and multivariate analyses to assess treatment success and all-cause mortality. RESULTS: A total of 247 patients were included, with 39 (15.8%), 37 (15.0%), 107 (43.3%), and 64 (25.9%) receiving < 6 mg/kg and ≥ 6 weeks, < 6 mg/kg and < 6 weeks, ≥ 6 mg/kg and ≥ 6 weeks, and ≥ 6 mg/kg and < 6 weeks of daptomycin therapy, respectively. Patients had a mean age of 58 years and had received prior vancomycin therapy (65.6%). Patients receiving < 6 weeks of therapy were less likely to experience treatment success compared with ≥ 6 weeks (41.5% vs 25.3%, adjusted odds ratio = 0.55; 95% confidence interval = 0.31-0.98) independent of duration. There were no differences across groups in mortality after adjustment. CONCLUSION: In a diverse clinical population, daptomycin for treatment of osteomyelitis of 6 weeks or longer duration was associated with success independent of dose. This finding supports longer treatment with daptomycin as a first-line agent in antimicrobial stewardship initiatives.

Retrospective Cohort Study Comparing Infliximab-dyyb and Infliximab in Biologic-Naive Patients With Inflammatory Bowel Disease in the United States.

Background: Real-world assessments of biosimilars are needed to understand their effectiveness and safety in practice settings that may differ from those seen in clinical trials or healthcare systems in different countries. To assess the effectiveness and safety of a biosimilar (infliximab-dyyb) and its reference product (infliximab) in patients with inflammatory bowel disease (IBD) in the United States. Methods: We conducted a retrospective cohort study of biologic-naive patients with IBD who started treatment with infliximab-dyyb or infliximab. The study included 3206 patients identified through electronic health records in a US integrated healthcare delivery system. The effectiveness outcome was a composite of IBD-related surgery, IBD-related emergency room visit, and IBD-related hospitalization within 12 months of initiation. Safety outcomes included incidence of any or serious infection, cancer, acute liver dysfunction, and tuberculosis. We used a non-inferiority test with an upper-limit margin of 10% to analyze effectiveness. Doubly robust methods incorporating Cox proportional hazard regression with standardized inverse probability of treatment weighting were used to analyze both effectiveness and safety outcomes. Results: The composite effectiveness outcome occurred in 107 of 870 patients (12.3%) in the infliximab-dyyb and 379 of 2336 patients (16.2%) in the infliximab groups. Infliximab-dyyb was non-inferior (P < .01) and was not different (hazard ratio [HR] 0.81; confidence interval [CI] 0.65-1.01; P = .06) to infliximab. Safety outcomes were not different between infliximab-dyyb and infliximab for any infections (HR 1.01; CI 0.86-1.17; P = .95), serious infections (HR 0.83; CI 0.54-1.26; P = .38), cancers (HR 0.83; CI 0.44-1.54; P = .55), and tuberculosis (HR 0.59; CI 0.10-3.55; P = .57). Conclusions: Initiation of infliximab-dyyb was non-inferior to infliximab among biologic-naive patients with IBD in an US integrated healthcare delivery system.

Morphine-mediated release of miR-138 in astrocyte-derived extracellular vesicles promotes microglial activation.

Opioids, such as morphine, are the mainstay for the management of postsurgical pain. Over the last decade there has been a dramatic increase in deaths related to opioid overdose. While opioid abuse has been shown to result in increased neuroinflammation, mechanism(s) underlying this process, remain less understood. In recent years, microRNAs have emerged as key mediators of gene expression regulating both paracrine signaling and cellular crosstalk. MiRNAs constitute the extracellular vesicle (EV) cargo and can shuttle from the donor to the recipient cells. Exposure of human primary astrocytes to morphine resulted in induction and release of miR-138 in the EVs isolated from conditioned media of cultured astrocytes. Released EVs were, in turn, taken up by the microglia, leading to activation of these latter cells. Interestingly, activation of microglia involved binding of the GUUGUGU motif of miR138 to the endosomal toll like receptor (TLR)7, leading, in turn, to cellular activation. These findings were further corroborated in vivo in wildtype mice wherein morphine administration resulted in increased microglial activation in the thalamus. In TLR7-/- mice on the other hand, morphine failed to induce microglial activation. These findings have ramifications for the development of EV-loaded anti-miRNAs as therapeutics for alleviating neuroinflammation in opioids abusers.

Bisphosphonate Treatment Beyond 5 Years and Hip Fracture Risk in Older Women.

Importance: Clinical trials have demonstrated the antifracture efficacy of bisphosphonate drugs for the first 3 to 5 years of therapy. However, the efficacy of continuing bisphosphonate for as long as 10 years is uncertain. Objective: To examine the association of discontinuing bisphosphonate at study entry, discontinuing at 2 years, and continuing for 5 additional years with the risk of hip fracture among women who had completed 5 years of bisphosphonate treatment at study entry. Design, Setting, and Participants: This cohort study included women who were members of Kaiser Permanente Northern and Southern California, 2 integrated health care delivery systems, and who had initiated oral bisphosphonate and completed 5 years of treatment by January 1, 2002, to September 30, 2014. Data analysis was conducted from January 2018 to August 2020. Exposure: Discontinuation of bisphosphonate at study entry (within a 6-month grace period), discontinuation at 2 years (within a 6-month grace period), and continuation for 5 additional years. Main Outcomes and Measures: The outcome was hip fracture determined by principal hospital discharge diagnoses. Demographic, clinical, and pharmacological data were ascertained from electronic health records. Results: Among 29 685 women (median [interquartile range] age, 71 [64-77] years; 17 778 [60%] non-Hispanic White individuals), 507 incident hip fractures were identified. Compared with bisphosphonate discontinuation at study entry, there were no differences in the cumulative incidence (ie, risk) of hip fracture if women remained on therapy for 2 additional years (5-year risk difference [RD], -2.2 per 1000 individuals; 95% CI, -20.3 to 15.9 per 1000 individuals) or if women continued therapy for 5 additional years (5-year RD, 3.8 per 1000 individuals; 95% CI, -7.4 to 15.0 per 1000 individuals). While 5-year differences in hip fracture risk comparing continuation for 5 additional years with discontinuation at 2 additional years were not statistically significant (5-year RD, 6.0 per 1000 individuals; 95% CI, -9.9 to 22.0 per 1000 individuals), interim hip fracture risk appeared lower if women discontinued after 2 additional years (3-year RD, 2.8 per 1000 individuals; 95% CI, 1.3 to 4.3 per 1000 individuals; 4-year RD, 9.3 per 1000 individuals; 95% CI, 6.3 to 12.3 per 1000 individuals) but not without a 6-month grace period to define discontinuation. Conclusions and Relevance: In this study of women treated with bisphosphonate for 5 years, hip fracture risk did not differ if they discontinued treatment compared with continuing treatment for 5 additional years. If women continued for 2 additional years and then discontinued, their risk appeared lower than continuing for 5 additional years. Discontinuation at other times and fracture rates during intervening years should be further studied.

Evaluation of a Pharmacist-Managed Nonsteroidal Anti-Inflammatory Drugs Deprescribing Program in an Integrated Health Care System.

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used to treat symptoms of chronic inflammatory diseases such as osteoarthritis and rheumatoid arthritis; however, they are also associated with various adverse effects, including gastrointestinal (GI) bleeding and renal harm. As patients get older, some medications may no longer be beneficial or may even cause harm. Deprescribing is defined as the planned and supervised process of dose reduction or discontinuation of medications. While there are studies showing that deprescribing strategies with several classes of medications positively affects outcomes in elderly patients, there is a lack of strong evidence and guidance to deprescribe NSAIDs. OBJECTIVE: To evaluate the effectiveness, safety, and economic impact of pharmacists deprescribing NSAIDs under the guidance of a standardized deprescribing program compared with usual care within an integrated health care system. METHODS: This retrospective, propensity score-matched cohort study included patients aged ≥ 65 years who were eligible for the NSAID deprescribing program from July 2016 to June 2018. Those patients in the deprescribing group were assessed by pharmacists and had their medications deprescribed. Patients who were eligible for the deprescribing program but did not receive any interventions were matched to the deprescribed group using propensity score matching at a 4:1 ratio and became the usual care group. Patients were followed for 6 months, until end of membership, or until death, whichever occurred first. The effectiveness and safety outcomes included rates of 3 adverse events: GI bleeds, acute kidney injuries (AKI), and exacerbation of pain triggering a hospitalization or emergency room visit. The economic outcome was the change in monthly NSAID cost. Descriptive statistics, t-tests, chi-square tests, and conditional logistic regression models were used for analysis. RESULTS: There were 431 patients in the deprescribed group and 1,724 patients in the usual care group, with similar baseline characteristics after propensity score matching. The adjusted results showed no significant difference between the deprescribed and usual care groups for GI bleed events (OR = 0.65, 95% CI = 0.36-1.16, P = 0.15) and AKI (OR = 0.53, 95% CI = 0.24-1.16, P = 0.11). The deprescribed group experienced a significant 2-fold decrease in the odds of exacerbation of pain versus the deprescribed group (OR = 0.50, 95% CI = 0.33-0.77, P < 0.01). Finally, there was no significant difference in the change in monthly NSAIDs costs between the 2 groups (median change, IQR: -$0.29, -$2.37 to -$0.11 for deprescribed group; -$0.23, -2.59 to 0.00 for usual care group, P = 0.054). CONCLUSIONS: Although this study did not find any difference in the rate of GI bleed or AKI, we found a significant decrease in the rate of exacerbation of pain in the deprescribed group versus the usual care group. This result suggests that deprescribing NSAIDs did not cause harm during the 6-month follow-up. Further long-term studies are necessary to validate these outcomes. DISCLOSURES: No funding was provided to support this research study. The authors of this study have no actual or potential conflicts of interest to report. Parts of this study were presented in a nonreviewed resident poster at the AMCP Managed Care and Specialty Pharmacy Annual Meeting; March 25-28, 2019; San Diego, CA.

Correction to: Effectiveness of Switching from Reference Product Infliximab to Infliximab-Dyyb in Patients with Inflammatory Bowel Disease in an Integrated Healthcare System in the United States: A Retrospective, Propensity Score-Matched, Non-Inferiority Cohort Study.

The article Effectiveness of Switching from Reference Product Infliximab to Infliximab-Dyyb in Patients with Inflammatory Bowel Disease in an Integrated Healthcare System in the United States: A Retrospective, Propensity Score-Matched, Non-Inferiority Cohort Study, written by Stephanie L. Ho, Fang Niu, Suresh Pola, Fernando S. Velayos, Xian Ning and Rita L. Hui, was originally published electronically on 26 February 2020 without open access.

Effectiveness of Switching from Reference Product Infliximab to Infliximab-Dyyb in Patients with Inflammatory Bowel Disease in an Integrated Healthcare System in the United States: A Retrospective, Propensity Score-Matched, Non-Inferiority Cohort Study.

PURPOSE: The aim was to compare outcomes in adult patients with inflammatory bowel disease (IBD) who switched to infliximab-dyyb with those who remained on reference product (RP) infliximab in the United States (US) in a retrospective, propensity score-matched, non-inferiority cohort trial. METHODS: This study was a retrospective, non-inferiority study conducted within a US integrated healthcare system and included adult patients with a confirmed diagnosis of Crohn's disease or ulcerative colitis. A 1:1 propensity score matching was utilized to match patients who switched to infliximab-dyyb during the period April 2016-March 2018 to patients who remained on RP infliximab. The non-inferiority margin was set at + 10% of the upper limit. The primary outcome was a composite measure of disease worsening requiring acute care after the index date of switching to infliximab-dyyb or continuing RP infliximab. Disease worsening requiring acute care was defined as any IBD-related emergency room visit, hospitalization, or surgery. The secondary outcome was the composite measure of disease worsening requiring acute care or treatment failure. A switch to another biologic or tofacitinib was a proxy for treatment failure. All patients were followed for up to 9 months. RESULTS: After propensity score matching, the matched cohort included 1409 patients in the infliximab-dyyb group and 1409 patients in the RP infliximab group. The overall mean age (± standard deviation) was 47.7 ± 17.0 years, 50.9% of patients were of male gender, and 51.8% of patients had Crohn's disease, while the remainder of the cohort had ulcerative colitis. There were 144 patients (10.2%) in the infliximab-dyyb group and 245 patients (17.4%) in the RP infliximab group who experienced disease worsening requiring acute care (P < 0.01 for non-inferiority). There were 347 patients (24.6%) in the infliximab-dyyb group who experienced disease worsening requiring acute care or treatment failure compared to 375 patients (26.6%) who remained on RP infliximab (P < 0.01 for non-inferiority). CONCLUSION: There was no increased risk of (1) disease worsening requiring acute care or (2) disease worsening requiring acute care or treatment failure in patients with IBD who switched from RP infliximab to infliximab-dyyb when compared to patients who remained on RP infliximab in this US population. Infliximab-dyyb is an option for patients with IBD who need to use RP infliximab.

Immune-related Adverse Effects Associated with Programmed Death-1 Inhibitor Therapy in the Treatment of Non-Small Cell Lung Cancer: Incidence, Management, and Effect on Outcomes.

BACKGROUND: The programmed death 1 (PD-1) inhibitors may improve survival outcomes of non-small cell lung cancer (NSCLC) patients but are associated with immune-related adverse effects (IRAEs). Management of IRAEs may include immunosuppression (ie, corticosteroids), but there is concern that this may affect efficacy. This study evaluated the influence of IRAEs and immunosuppression for IRAEs on survival outcomes of NSCLC patients treated with PD-1 inhibitors (pembrolizumab and nivolumab). METHODS: We retrospectively examined data from Kaiser Permanente Southern and Northern California members diagnosed with NSCLC who received a PD-1 inhibitor from March 1, 2011 to September 30, 2016. Our primary goal was to evaluate the effects and management of IRAEs on survival with PD-1 inhibitors. Electronic database records were used to identify the occurrence of IRAEs, medication utilization, and death. Cox proportional hazard models were used to evaluate variables for association with increased risk of death. RESULTS: A total of 662 patients were included in the study (median age = 68 years) (interquartile range 61-74). IRAEs were identified in 18% of patients, of which 62% received immunosuppression. Median overall survival was 10 months (interquartile range = 4 months to not reached). Adjusting for covariates, use of immunosuppression during PD-1 inhibitor treatment was not associated with a significantly higher risk of death (hazard ratio = 1.04, 95% confidence interval = 0.84-1.29), whereas corticosteroid use before initiating PD-1 inhibitor therapy was (hazard ratio = 1.48, 95% confidence interval = 1.14-1.91). CONCLUSIONS: In a large, real-world cohort from an integrated healthcare system, use of corticosteroids prior to PD-1 inhibitors was associated with worse survival outcomes, whereas concomitant treatment was not.

Evaluation of Dipeptidyl Peptidase-4 Inhibitors versus Thiazolidinediones or Insulin in Patients with Type 2 Diabetes Uncontrolled with Metformin and a Sulfonylurea in a Real-World Setting.

BACKGROUND: Guidelines do not make clear recommendations for third add-on agents to metformin plus a sulfonylurea. This study compared the effectiveness and safety of dipeptidyl peptidase-4 inhibitors (DPP4is) to thiazolidinedione (TZD) or insulin as a third add-on agent to metformin plus a sulfonylurea in an integrated health care setting. METHODS: This retrospective database cohort study included adults with type 2 diabetes not at goal hemoglobin A1C (HbA1C) who initiated DPP4i, TZD, or insulin as a third add-on agent to metformin plus a sulfonylurea from January 2006 to June 2016. Primary outcomes were the proportion of patients who achieved goal HbA1C after starting the third add-on agent and change in HbA1C. Subgroup analysis was performed for patients with baseline HbA1C greater than 9%. RESULTS: In this study, 2080 patients started on a DPP4i were matched to 8320 patients started on TZD and to 8320 patients taking insulin. A significantly higher percentage of patients taking TZD reached goal HbA1C (31.0% versus 23.6%; p < 0.05) and had a significantly larger HbA1C reduction (-0.94% ± 1.34% versus -0.79% ± 1.23%; p < 0.01) compared to patients taking a DPP4i. No difference in the percentage of patients meeting goal HbA1C nor in change in HbA1C was demonstrated between insulin versus DPP4i regimens. For patients with baseline HbA1C greater than 9%, insulin or TZD resulted in a significantly higher proportion of patients achieving goal HbA1C compared to DPP4i (17.3% and 19.0% versus 12.4%, respectively; p < 0.01). CONCLUSION: TZD was more effective than DPP4i but DPP4i was as effective as insulin as a third add-on agent in the overall study population. Insulin was more effective than DPP4i only in the subgroup analysis of patients with baseline HbA1C greater than 9%.

Evaluation of a Pharmacist-Managed Antidiabetic Deprescribing Program in an Integrated Health Care System.

BACKGROUND: In the elderly, use of medications may increase the propensity for adverse drug events due to alterations in pharmacokinetic and pharmacodynamic profiles from normal aging processes. Deprescribing is the planned and supervised process of dose reduction or discontinuation of medications that may lead to harm or are no longer beneficial. While there are studies detailing strategies to deprescribe medications such as benzodiazepines and antipsychotics in nursing homes or for patients with dementia, there is a lack of guidance to safely deprescribe chronic medications, such as antidiabetics, for older patients in the community setting. OBJECTIVE: To evaluate the risk of hypoglycemia and other outcomes of pharmacist-managed deprescribing on selected antidiabetic medications under the guidance of a standardized program compared with usual care within an integrated health care system. METHODS: This was a retrospective propensity score-matched cohort study. The pharmacist-managed deprescribing group included patients who were enrolled in the deprescribing program between July 1, 2016, and June 30, 2017. The usual care group included eligible patients who did not receive the deprescribing intervention and were matched to the deprescribing group using propensity score matching (PSM). Baseline demographics and clinical variables were used for matching. Patients were followed for 6 months or the end of membership or death, whichever occurred first. Primary outcome was the risk of hypoglycemia. Secondary outcomes included risk of hyperglycemia, proportion of patients at goal (A1c), change in A1c, change in monthly antidiabetic drug cost, and all-cause mortality. Outcomes were analyzed using descriptive statistics and multivariant regression or Cox proportional hazard models when appropriate. RESULTS: After PSM, 685 patients in the deprescribing group and 2,055 patients in the usual care group were similar in age, gender, weight, and comorbidity burden (mean [SD] age 82.4 [5.4] years, 48% female, mean [SD] weight 81.7 [19.2] kg, mean [SD] Charlson Comorbidity Index score 3.2 [1.6]). Compared with the usual care group, the deprescribing group had a lower risk of hypoglycemia (1.5% vs. 3.1%, P < 0.02; adjusted odds ratio 0.42, P < 0.01). As for the secondary outcomes, the deprescribing group had a greater change (SD) in A1c (0.3 [0.6] vs. 0.2 [0.7] P < 0.01) and lower all-cause mortality (2.3% vs 5.6%, P < 0.01; adjusted hazard ratio 0.35, P < 0.01). There were no differences observed in the risk of hyperglycemia, proportion of patients at goal A1c < 7%, and change in monthly antidiabetic drug costs between the 2 groups. CONCLUSIONS: There are currently no studies to our knowledge that evaluate the outcomes of a pharmacist-managed deprescribing program targeting antidiabetic medications. The results of our study showed that deprescribing of selected antidiabetics reduced the risk of hypoglycemia and may have mortality benefit in elderly patients with well-controlled type 2 diabetes, who are taking medications that can cause hypoglycemia. Further and longer studies are needed to validate these benefits. DISCLOSURES: No outside funding was provided to support this research study. The authors of this study have no actual or potential conflicts of interest to report. Parts of this study were presented in a nonreviewed resident poster at the Academy of Managed Care Pharmacy Managed Care and Specialty Pharmacy Annual Meeting; April 23-26, 2018; Boston, MA.

Antioxidant vitamin E protects embryos of Xenopus tropicalis against lambda-cyhalothrin induced embryotoxicity.

Pesticides are capable of increasing risks to the early development of nontarget organisms through oxidative stress. The supplementation of antioxidants could help to modulate the toxic effects of pesticides, but much remains to be understood in the interactions between pesticides and antioxidants in amphibians. In the present study, the embryotoxicity of a widely used pyrethroid, lambda-cyhalothrin (LCT), and the potential effect of α-tocopherol (TOC) on embryos of Xenopus tropicalis were evaluated. Exposure to LCT did not affect the hatch rate, survival, or body length of the embryos. However, environmentally relevant concentrations of LCT could induce significant malformations on the larvae. Exposure to LCT led to a concentration-dependent induction of oxidative stress and cytotoxicity that subsequently resulted in embryotoxicity. During the early developmental stages, vitamin E could work as a powerful protective antioxidant. The LCT-induced overproduction of reactive oxygen species and increased enzymatic activities were fully inhibited by treatment with 1 µg/L TOC. However, only supplementation with 100 µg/L TOC provided partial protection against the morphological changes caused by LCT. The results from the present study suggest that antioxidant vitamin E possesses protective potential against pyrethroid-induced embryotoxicity in amphibian embryos through the prevention of oxidative stress.

Evaluation of Outcomes After Initiating Triple Antidiabetic Therapy with a GLP-1 RA in an Integrated Health Care System.

BACKGROUND: Type 2 diabetes (T2D) is characterized by chronic hyper-glycemia and can lead to life-threatening complications if not treated. A stepwise and patient-centered approach is recommended when managing patients with T2D. Metformin is the preferred first-line agent, while sulfonylureas (SU) are often chosen as second-line agents. If a patient's hemoglobin A1c (A1c) goal is not achieved despite 3 months of treatment with dual therapy, then triple therapy is recommended. However, due to the lack of head-to-head trials for different triple antidiabetic regimens, the recommendations are unclear for selection of an optimal third-line agent. OBJECTIVE: To evaluate the comparative effectiveness of a glucagon-like peptide-1 receptor agonist (GLP-1 RA) compared with a thiazolidinedione (TZD) or insulin as a third-line add-on therapy in patients who have not achieved A1c goals while receiving metformin and SU dual therapy in the real-world setting within an integrated health care system. METHODS: This is a retrospective cohort study of adult patients with T2D who were not at goal A1c while on dual therapy with metformin and an SU and initiated triple antidiabetic therapy. The primary outcome was the proportion of patients who achieved goal A1c within 3-7 months after starting triple therapy with a GLP-1 RA compared with a TZD or insulin. Goal A1c was defined as an A1c of < 7% for patients aged less than 65 years and A1c of < 8% for patients aged 65 years or older. Secondary outcomes included mean change in A1c, mean change in weight, and the proportion of patients with an emergent health care encounter due to a hypoglycemic event. Propensity score matching was used to select comparison groups from the insulin and TZD groups with similar baseline characteristics to the GLP-1 RA group in a 4:1 ratio. RESULTS: 274 patients initiated a GLP-1 RA in addition to dual therapy with metformin and an SU. A propensity matched group of 1,096 patients who initiated insulin and 1,096 patients who initiated a TZD were selected as the control groups. Addition of a GLP-1 RA resulted in a significantly lower proportion of patients achieving goal A1c (23.0%) compared with the addition of a TZD (30.8%, P = 0.011). There was no significant difference with the addition of a GLP-1 RA when compared with insulin (24.1%, P = 0.704). CONCLUSIONS: This study reflects data from real-world practice in a large integrated health care system. Significantly less patients achieved goal A1c with the addition of a GLP-1 RA as a third-line add-on option to dual therapy with metformin and an SU compared with the addition of a TZD. Providers and patients should carefully weigh the risks and benefits of different antidiabetic agents when choosing triple therapy regimens. DISCLOSURES: No outside funding supported this study. The authors have nothing to disclose. Part of this study was presented as a nonreviewed resident poster at the Academy of Managed Care & Specialty Pharmacy Annual Meeting 2017 in Denver, CO, on March 27-29, 2017.

Identification of autotoxic compounds from Atractylodes macrocephala Koidz and preliminary investigations of their influences on immune system.

Atractylodes macrocephala Koidz (A. macrocephala) is a traditional Chinese medicine that has been widely used in China, Japan, and Korea due to its health benefits. Autotoxicity, as one of the major problems hindering continuous cultivation of A. macrocephala, has been reported to inhibit plant growth by various means. However, the impact of autotoxicity on the plant immune system is rarely reported. In this study, 2, 4-Ditertbutyl phenol (2,4-DP), an autotoxic compound, isolated from root exudates and rhizosphere soil of A. macrocephala was identified by gas chromatography-mass spectrometry (GC-MS). The results of germination trials showed that 2,4-DP had a significant inhibitory effect on seed germination. In addition, in non-inoculated seedlings, three concentrations of 2,4-DP (0.1, 1 and 10 mmol/L) affected indicators of systemic acquired resistance (SAR): accumulation of salicylic acid (SA), activities of protective enzymes, atractylenolides contents, and increased the disease index (DI). In inoculated seedlings, 2,4-DP decreased indicators of SAR and increased the DIs at low and high concentrations but increased indicators of SAR and decreased the DI at a moderate concentration. These results suggest that 2,4-DP has an inhibitory effect on the plant immune system, but it can induce the SAR at a certain concentration by controlling the pathogenic fungi.

Trends in bisphosphonate initiation within an integrated healthcare delivery system.

In the setting of changing temporal trends in the management of osteoporosis, we examined how select characteristics of new oral bisphosphonate (BP) initiators changed over time among 94,073 women within a large, integrated healthcare organization during the period 2004 to 2012. In the earlier era (2004-2007), approximately half of women younger than 65 years initiating BP therapy (47%-54%) had osteoporosis by bone mineral density (BMD) criteria, but this proportion increased sharply in the later era (2008-2012), with 55% to 81% having osteoporosis. This trend was not evident in older women (≥65 years). The proportion of younger women with prior fracture increased from 15% in 2008 to 32% in 2012, after remaining relatively stable (10%-15%) during the earlier era. Again, this trend was not observed among older women. Thus, among women younger than 65 years, we observed a marked temporal shift in initiation of BP treatment toward women at high risk (including those with prior fracture and those with osteoporosis by BMD testing) and away from those at lower risk (such as those with osteopenia and/or no prior fracture).