In vivo, Pikfyve generates PI(3,5)P2, which serves as both a signaling lipid and the major precursor for PI5P.

Mutations that cause defects in levels of the signaling lipid phosphatidylinositol 3,5-bisphosphate [PI(3,5)P(2)] lead to profound neurodegeneration in mice. Moreover, mutations in human FIG4 predicted to lower PI(3,5)P(2) levels underlie Charcot-Marie-Tooth type 4J neuropathy and are present in selected cases of amyotrophic lateral sclerosis. In yeast and mammals, PI(3,5)P(2) is generated by a protein complex that includes the lipid kinase Fab1/Pikfyve, the scaffolding protein Vac14, and the lipid phosphatase Fig4. Fibroblasts cultured from Vac14(-/-) and Fig4(-/-) mouse mutants have a 50% reduction in the levels of PI(3,5)P(2), suggesting that there may be PIKfyve-independent pathways that generate this lipid. Here, we characterize a Pikfyve gene-trap mouse (Pikfyve(ß-geo/ß-geo)), a hypomorph with ~10% of the normal level of Pikfyve protein. shRNA silencing of the residual Pikfyve transcript in fibroblasts demonstrated that Pikfyve is required to generate all of the PI(3,5)P(2) pool. Surprisingly, Pikfyve also is responsible for nearly all of the phosphatidylinositol-5-phosphate (PI5P) pool. We show that PI5P is generated directly from PI(3,5)P(2), likely via 3'-phosphatase activity. Analysis of tissues from the Pikfyve(ß-geo/ß-geo) mouse mutants reveals that Pikfyve is critical in neural tissues, heart, lung, kidney, thymus, and spleen. Thus, PI(3,5)P(2) and PI5P have major roles in multiple organs. Understanding the regulation of these lipids may provide insights into therapies for multiple diseases.

Prevalence and impact of antipsychotic discontinuation among commercially-insured patients with bipolar disorder.

BACKGROUND: Antipsychotic discontinuation is common among patients with bipolar disorder, especially when psychotic symptoms are remitted. This analysis describes the prevalence, predictors, and economic impact of antipsychotic discontinuation among patients with bipolar disorder. METHODS: A retrospective, observational study was conducted using administrative claims data in the IBM MarketScan Commercial Database. Patients with ≥1 claim with a diagnosis for bipolar disorder (manic or mixed) and newly-initiating antipsychotic therapy between 1 January 2011 and 30 June 2016 were included. Baseline characteristics were assessed in the 12 months prior to the initiation. Outcomes were assessed during a 24-month follow-up. Discontinuation of antipsychotic therapy was utilized as a predictor of healthcare costs in models adjusted for baseline characteristics. Using limited set of variables in the claims database, predictors of discontinuation were also assessed. RESULTS: A total of 18,259 commercially-insured patients were identified as initiators of antipsychotics. Common comorbidities among the cohorts included major depressive disorder and dyslipidemia. Discontinuation was very common among these patients (85%). Major depressive disorder, drug abuse, and other substance abuse/dependency were predictive of discontinuation. Controlling for differences in baseline characteristics, discontinuation was associated with 33% higher inpatient and emergency visit costs (p <.001) among those using these services, and 24% higher total healthcare costs (p <.001) for the overall cohort. CONCLUSIONS: Most patients with bipolar mania or mixed states discontinue antipsychotic treatment in less than 2 years. Antipsychotic discontinuation contributes to excess healthcare costs. Future research focusing on the reasons for discontinuation and tailoring disease management based on comorbidities may inform adherence improvement initiatives.

Age-appropriate compliance and completion of up to five doses of pertussis vaccine in US children.

Background: In the United States (US), diphtheria, tetanus, and acellular pertussis (DTaP) vaccination is recommended at 2, 4, and 6 months (doses 1-3), 15-18 months (dose 4), and 4-6 years (dose 5). The objective of this study (GSK study identifier: HO-14-14383) was to examine DTaP completion and compliance rates among commercially insured and Medicaid-enrolled children. Secondarily, the study aimed at identifying predictors of compliance/completion. Methods: Truven Health MarketScan Commercial and Multi-State Medicaid databases (2005-2013) were analyzed separately. Children born during 2005-2011 with ≥ 2 years continuous enrollment from birth provided data for doses 1-4; those with continuous enrollment from birth to their seventh birthday provided dose 5 data. Series compliance (each recommended dose by 3, 5, and 7 months; 19 months; seventh birthday) and completion (3 doses by 8 months; 4 by 24 months; 5 by seventh birthday) were calculated. Predictors of compliance/completion were identified using multivariable logistic regression. Results: A total of 367,493 commercially insured and 766,153 Medicaid-enrolled children were followed for ≥ 2 years; and 23,574 and 41,284, respectively, for ≥ 7 years. Series compliance to doses 1-3, 1-4, and 1-5 were 67.2%, 55.3%, 47.5% (commercial) and 37.4%, 27.3%, 14.4% (Medicaid), respectively. Predictors of better compliance/completion included: later birth year (commercial/Medicaid) and higher household income (commercial); predictors of worse compliance/completion included: Northeast residence (commercial), birth hospitalization ≥ 14 days (commercial/Medicaid), and Black race/ethnicity (Medicaid). Conclusions: DTaP series compliance/completion improved over time, but appear to be suboptimal. As this could increase pertussis risk, greater awareness of the importance of timely vaccination completion is needed. GSK study identifier: HO-14-14383.

Treatment Patterns and Associated Health Care Costs Before and After Treatment Initiation Among Pulmonary Arterial Hypertension Patients in the United States.

BACKGROUND: Despite multiple treatment options, the prognosis of pulmonary arterial hypertension (PAH) remains poor. PAH patients experience a high economic burden due to comorbidities, hospitalizations, and medication costs. Although combination therapy has been shown to reduce hospitalizations, the relationship between treatment, health care utilization, and costs remains unclear. OBJECTIVE: To provide a characterization of health care utilization and costs in real-world settings by comparing periods before and after initiating PAH-specific treatment. METHODS: This retrospective study identified PAH patients in the Truven Health MarketScan Commercial and Medicare Supplemental Databases between 2010 and 2014 who initiated treatment with endothelin receptor antagonists (ERAs), phosphodiesterase-5 inhibitors (PDE-5Is), or soluble guanylate cyclase (sGC) stimulators. The index date was the date of the first PAH pharmacy claim. We included patients with ≥ 2 medical claims with diagnoses for PAH (ICD-9-CM: 416.0, 416.8) or PAH-related conditions and continuous enrollment in medical and pharmacy benefits for the 6 months before and after the index date. Treatment patterns were assessed at the drug class level (ERAs, PDE-5Is, sGC stimulators, and prostacyclins) from outpatient pharmacy claims during the 6-month post-index period. All-cause and PAH-related utilization and costs were measured. McNemar's and paired t-tests were used to compare patients' health care resource utilization and costs in the 6-month pre- and posttreatment periods. RESULTS: A total of 3,908 patients met the selection criteria. The study sample was 63% female with a mean age of 63 ± 15 years. Only 5% of patients began initial combination therapy for PAH, defined as claims for ≥ 2 medication classes within the first 30 days of treatment. Treatment interruption (≥ 30-day gap in days supply) of any PAH-specific medication was observed in 38% of patients. Compared with the 6-month pre-index period, the proportion of patients in the 6-month post-index period with any inpatient admission decreased, 42% versus 30% (P < 0.001). In addition, PAH-related inpatient admissions decreased in the 6-month post-index period from 7% to 3% (P < 0.001). After treatment initiation, patients' nonpharmacy medical costs decreased from $48,200 (SD = $117,686) to $33,962 (SD = $90,294; P < 0.001), mainly attributable to reduced inpatient costs. However, total average medical costs including pharmacy costs remained comparable after treatment initiation (pre-index period = $51,455 vs. post-index period = $53,923; P = 0.213). CONCLUSIONS: This study found that while patients' PAH-related pharmacy costs increased after treatment initiation, the increase was offset by reduced inpatient utilization; therefore, total health care costs remained constant. While the majority of patients in this study were treated with monotherapy, the recently completed AMBITION study indicated that initial combination therapy with ambrisentan plus tadalafil reduced PAH-related hospitalizations compared with initial monotherapy with either of these agents. Future cost analyses of patients treated with combination therapy will be required to determine the economic effect of initial combination therapy. DISCLOSURES: This study was sponsored and funded by Gilead Sciences. Ozbay is an employee of Gilead Sciences. At the time that this project and manuscript were developed, Lazarus was an employee of Gilead Sciences and may own stock/stock options. Riehle, Montejano, and Lenhart are employees of Truven Health Analytics, an IBM company, which received funding from Gilead Sciences to conduct this study. Burger and White do research with, and are paid consultants for, Gilead Sciences; they do not own equity and received no personal compensation for the work here. Burger also reports consultancy and advisory board work for Actelion Pharmaceuticals and grants from Gilead Sciences, Actelion Pharmaceuticals, Bayer, and United Therapeutics.

Real-world Direct Health Care Costs for Metastatic Colorectal Cancer Patients Treated With Cetuximab or Bevacizumab-containing Regimens in First-line or First-line Through Second-line Therapy.

BACKGROUND: The present study examined real-world direct health care costs for metastatic colorectal cancer (mCRC) patients initiating first-line (1L) bevacizumab (BEV)- or cetuximab (CET)-containing regimen in 1L or 1L-through-second-line (1L-2L) therapy. PATIENTS AND METHODS: Using a large US insurance claims database, patients with mCRC initiating 1L BEV- or 1L CET-containing regimen from January 1, 2008 to September 30, 2014 were identified. The per-patient per-month (PPPM) all-cause health care costs (2014 US dollars) were measured during 1L therapy and, for patients continuing to a 2L biologic-containing regimen, 1L-2L therapy. Multivariable regression analyses were used to compare PPPM total health care costs between patients initiating a 1L BEV- versus 1L CET-containing regimen. RESULTS: A total of 6095 patients initiating a 1L BEV- and 453 initiating a 1L CET-containing regimen were evaluated for 1L costs; 2218 patients initiating a 1L BEV- and 134 initiating a 1L CET-containing regimen were evaluated for 1L-2L costs. In 1L therapy, 1L CET had adjusted PPPM costs that were $3135 (95% confidence interval [CI], $1174-$5040; P < .001) greater on average than 1L BEV. In 1L-2L therapy, 1L BEV-2L CET had adjusted PPPM costs that were $1402 (95% CI, $1365-$1442; P = .010) greater than those for 1L BEV-2L BEV, and 1L CET-2L BEV had adjusted PPPM costs that were $4279 (95% CI, $4167-$4400; P = .001) greater on average than those for 1L BEV-2L BEV. The adjusted PPPM cost differences for 1L BEV-2L other biologic or 1L CET-2L other biologic agent were numerically greater but statistically insignificant. CONCLUSION: PPPM total health care costs for 1L and 2L therapy tended to be greater for patients treated with 1L CET-containing regimens than for 1L BEV-containing regimens. Also, continuing treatment with BEV-containing regimens 1L-2L was less costly than switching between BEV and CET. The cost differences between BEV and CET hold important implications for treatment decisions of mCRC patients in real-world clinical practice.

Association Between Hospitalization for Heart Failure and Dipeptidyl Peptidase 4 Inhibitors in Patients With Type 2 Diabetes: An Observational Study.

OBJECTIVE: To examine, among patients with type 2 diabetes, the association between hospitalization for heart failure (hHF) and treatment with dipeptidyl peptidase 4 inhibitors (DPP-4is) versus sulfonylureas (SUs), and treatment with saxagliptin versus sitagliptin. RESEARCH DESIGN AND METHODS: This was a retrospective, observational study using a U.S. insurance claims database. Patients initiated treatment between 1 August 2010 and 30 August 2013, and had no use of the comparator treatments in the prior 12 months (baseline). Each comparison consisted of patients matched 1:1 on a propensity score. Time to each outcome was compared between matched groups using Cox models. Analyses were stratified by the presence of baseline cardiovascular disease (CVD). Secondary analyses examined associations between comparator treatments and other selected cardiovascular events. RESULTS: After matching, the study included 218,556 patients in comparisons of DPP-4i and SU, and 112,888 in comparisons of saxagliptin and sitagliptin. The hazard ratios (HRs) of hHF were as follows: DPP-4i versus SU (reference): HR 0.95 (95% CI 0.78-1.15), P = 0.580 for patients with baseline CVD; HR 0.59 (95% CI 0.38-0.89), P = 0.013 for patients without baseline CVD; saxagliptin versus sitagliptin (reference): HR 0.95 (95% CI 0.70-1.28), P = 0.712 for patients with baseline CVD; HR 0.99 (95% CI 0.56-1.75), P = 0.972 for patients without baseline CVD. Comparisons of the individual secondary and composite cardiovascular outcomes followed a similar pattern. CONCLUSIONS: In patients with type 2 diabetes, there was no association between hHF, or other selected cardiovascular outcomes, and treatment with a DPP-4i relative to SU or treatment with saxagliptin relative to sitagliptin.

Costs and Work Loss Burden of Diagnosed Opioid Abuse Among Employees on Workers Compensation or Short-term Disability.

OBJECTIVE: To compare 12-month healthcare costs between employees with versus without diagnosed opioid abuse within 12 months after an injury-related workers' compensation (WC) or short-term disability (STD) claim. METHODS: Retrospective study using 2003 to 2014 US insurance claims linked to administrative data on WC/STD claims. Multivariable models compared healthcare costs between employees with versus without diagnosed opioid abuse. RESULTS: Study included 107,975 opioid-treated employees with an injury-related WC or STD claim. Mean number of opioid prescription fills and adjusted total healthcare costs were substantially greater in employees with diagnosed opioid abuse versus without (WC: 13.4 vs. 4.5, P < 0.001; $18,073 vs. $8470, P < 0.001; STD: 13.7 vs. 4.5, P < 0.001; $25,693 vs. $14,939, P < 0.001). CONCLUSION: Opioids are commonly prescribed to employees with injury-related WC/STD claims. Employers may benefit from proactively addressing the issue of opioid abuse in these populations.

SLC2A9 Genotype Is Associated with SLC2A9 Gene Expression and Urinary Uric Acid Concentration.

OBJECTIVES: SLC2A9 gene variants have been associated with urinary uric acid (UA) concentration, but little is known about the functional mechanism linking these gene variants with UA. SLC2A9 encodes a UA transporter present in the proximal tubule of the kidney, and gene expression levels of SLC2A9 and other genes in the uricosuric pathway (ABCG2, SLC17A1, SLC17A3, and SLC22A12) could potentially mediate the relationship between SLC2A9 gene variants and urinary UA excretion. METHODS: The association between urinary UA concentrations and single nucleotide polymorphisms (SNPs) within the SLC2A9 gene region, expression levels of genes in the uricosuric pathway, and dietary protein intake were analyzed for a sample of non-Hispanic white participants from the Genetic Epidemiology Network of Arteriopathy (GENOA) cohort. The SLC2A9 SNP most significantly associated with urinary UA concentration was then tested for associations with gene expression levels from uric acid absorption/secretion associated genes. Models including interactions between dietary protein (total, animal, and vegetable) and genetic factors were also assessed. RESULTS: The most significant SLC2A9 SNP associated with urinary UA (rs12509955, corrected p = 0.001) was also associated with SLC2A9 gene expression levels (corrected p = 0.0084); however, SLC2A9 gene expression levels were not significantly associated with urinary UA concentrations (p = 0.509). The interactions between rs12509955 and total dietary protein, and SLC2A9 gene-level gene expression and dietary vegetable protein on the outcome of urinary UA were marginally significant (p = 0.11 and p = 0.07, respectively). Gene expression level of one SLC2A9 transcript had a significant interaction with dietary animal protein (SLC2A9-001 ENST00000506583, p = 0.01) and a marginally significant interaction with total dietary protein (p = 0.07) on urinary UA. CONCLUSION: Our results illustrate that SNPs in the SLC2A9 gene influence SLC2A9 gene expression as well as urinary UA excretion. Evidence is also suggestive that gene-by-diet interactions may disproportionately increase urinary UA in genetically susceptible individuals that consume higher amounts of protein.