Separating the contributions of SLC26A9 and CFTR to anion secretion in primary human bronchial epithelia.

Aberrant anion secretion across the bronchial epithelium is associated with airway disease, most notably in cystic fibrosis. Although the cystic fibrosis transmembrane conductance regulator (CFTR) is recognized as the primary source of airway anion secretion, alternative anion transport mechanisms play a contributing role. An alternative anion transporter of growing interest is SLC26A9, a constitutively active chloride channel that has been shown to interact with CFTR and may also contribute to bicarbonate secretion. Interest in SLC26A9 has been fueled by genome-wide association studies that suggest it is a significant modifier of CF disease severity. Despite this growing evidence that SLC26A9 plays an important role in the airway, its presence and function in bronchial epithelia remain poorly understood, in part, because its activity is difficult to separate from the activity of CFTR. Here, we present results using primary human bronchial epithelia (HBE) from multiple patient sources to confirm that SLC26A9 mRNA is present in HBE and that its constitutive channel activity is unaffected by knockdown of CFTR. Furthermore, SLC26A9 and CFTR show differential responses to common inhibitors of anion secretion. Finally, we assess the impact of bicarbonate on the activity of SLC26A9 and CFTR. These results confirm that SLC26A9 is the primary source of constitutive anion secretion across HBE, and should inform future studies focused on activation of SLC26A9 as an alternative anion channel in CF. These results should provide a strong foundation to investigate how single-nucleotide polymorphisms in SLC26A9 modulate airway disease.

Comparative effectiveness of first-line tumour necrosis factor inhibitor versus non-tumour necrosis factor inhibitor biologics and targeted synthetic agents in patients with rheumatoid arthritis: results from a large US registry study.

OBJECTIVES: This study evaluated the comparative effectiveness of a tumour necrosis factor inhibitor (TNFi) versus a non-TNFi (biological disease-modifying antirheumatic drugs (bDMARDs) and targeted synthetic DMARDs (tsDMARDs)) as the first-line treatment following conventional synthetic DMARDs, as well as potential modifiers of response, observed in US clinical practice. METHODS: Data were from a large US healthcare registry (Consortium of Rheumatology Researchers of North America Rheumatoid Arthritis Registry). The analysis included patients (aged ≥18 years) with a documented diagnosis of rheumatoid arthritis (RA), a valid baseline Clinical Disease Activity Index (CDAI) score of >2.8 and no prior bDMARD or tsDMARD use. Outcomes were captured at 1-year postinitiation of a TNFi (adalimumab, etanercept, certolizumab pegol, golimumab or infliximab) or a non-TNFi (abatacept, tocilizumab, rituximab, anakinra or tofacitinib) and included CDAI, 28-Joint Modified Disease Activity Score, patient-reported outcomes (including the Health Assessment Questionnaire Disability Index, EuroQol-5 Dimension score, sleep, anxiety, morning stiffness and fatigue) and rates of anaemia. Groups were propensity score-matched at baseline to account for potential confounding. RESULTS: There were no statistically significant differences observed between the TNFi and non-TNFi treatment groups for outcomes assessed, except the incidence rate ratio for anaemia, which slightly favoured the TNFi group (19.04 per 100 person-years) versus the non-TNFi group (24.01 per 100 person-years, p=0.03). No potential effect modifiers were found to be statistically significant. CONCLUSIONS: The findings of no significant differences in outcomes between first-line TNF versus first-line non-TNF groups support RA guidelines, which recommend individualised care based on clinical judgement and consideration of patient preferences.

Patient-reported barriers to statin adherence: Excerpts from a motivational interviewing intervention in older adults.

OBJECTIVE: Despite a known benefit in the reduction of cardiovascular risk, adherence to statins remains suboptimal. A qualitative analysis was conducted within an intervention that identified trajectories of statin adherence in patients and used motivational interviewing (MoI) to improve adherence. The objective of this qualitative study was to evaluate transcripts of an MoI telephonic intervention to identify potential, past, and current barriers to statin adherence and barriers specific to distinct adherence trajectories. METHODS: The MoI intervention was customized by past 1-year adherence trajectories (rapid discontinuation, gradual decline, and gaps in adherence). Two authors independently extracted and documented barriers from phone transcripts. Themes were derived from literature a priori and by cataloging recurring themes from the transcripts. RESULTS: The transcripts of calls made to 157 patients were reviewed of which 25.2% did not communicate a specific adherence barrier despite falling into a low-adherence trajectory when examining refill data. The most commonly reported barriers to statin adherence included adverse effects (40.1%), forgetfulness (30.0%), and lack of skills or knowledge pertaining to statins (25%). More patients in the rapid discontinuation group perceived medication as unnecessary, whereas more patients in the gaps in adherence group reported a communication barrier with their health care provider. Several barriers among patients who fell into low-adherence trajectories were reported. Some patients did not report any barriers, which may have indicated denial. MoI phone calls were useful in providing knowledge, clarifying medication regimens, and reinforcing the need to take statins. CONCLUSION: This study identified patient-reported barriers to statin adherence elicited during an MoI telephonic intervention conducted by student pharmacists. There were differences in barriers reported by patients from each trajectory, which emphasize the need for additional tailored interventions to improve patient adherence.

Evaluating trajectories of statin adherence after a motivational interviewing intervention.

OBJECTIVE: The objective of the current study was to compare postintervention adherence trajectories with preintervention trajectories for those receiving a telephonic motivational interviewing (MoI) intervention to determine predictors associated with each distinct postintervention trajectory and any association between pre- and postintervention trajectories. DESIGN: Retrospective study design using group-based trajectory modeling. SETTINGS AND PARTICIPANTS: A telephonic MoI intervention was conducted by trained student pharmacists to improve statin adherence in a Medicare Advantage plan. Four preintervention adherence trajectories were previously identified: rapid decline (RD), gradual decline (GD), gaps in adherence (GA), and adherent and were used to customize the MoI intervention. Patients from the 3 nonadherent preintervention trajectories were randomized to control or intervention groups and were followed for 6 months from the date of MoI intervention. OUTCOME MEASURES: Group-based trajectory modeling was performed to identify 3 relevant postintervention trajectories. Descriptive statistics were used to assess differences in pre- and postintervention adherence trajectories. Multinomial logistic regression was conducted to determine predictors associated with each identified postintervention trajectory. RESULTS: There were 152 intervention patients and 304 randomly selected controls. The prominent postintervention trajectories that were identified differed from the preintervention trajectories and were (1) GD (17.2%), (2) adherent (61.9%), and (3) discontinuation (20.9%). Among the intervention group, more patients in the GA preintervention trajectory (58.65%) moved to the adherent trajectory postintervention than those in the RD and GD preintervention trajectories. Furthermore, the predictors associated with the postintervention trajectories included MoI intervention, prescriber specialty, presence of diabetes, presence of congestive heart failure, Centers for Medicare & Medicaid Services risk score, and preintervention trajectories. CONCLUSION: The postintervention adherence trajectory patterns differed from the preintervention trajectory patterns with many patients moving into an adherent trajectory especially among those receiving the intervention.

Cesarean Section in a Group 1 Pulmonary Hypertension Parturient Patient: A Case Report.

Severe pulmonary hypertension (PH) during pregnancy poses considerable challenges due to the physiological changes and increased cardiovascular demands. Close multidisciplinary management is essential throughout the peripartum period. The critical steps taken to provide anesthesia safely and successfully for a planned cesarian section are outlined, with special care for communication between the cardiothoracic surgery and obstetric team. A 31-year-old G3P1112 (three pregnancies, one term delivery, one pre-term delivery, one abortion, with two living children) patient with a history of systemic lupus erythematosus complicated by Group 1 PH presented to the operating room for a planned 34-week cesarean section. Pulmonary artery systolic pressure (PASP) was noted to be 68 mmHg at this time. Intravenous (IV) treprostinil at 8 ng/kg/min through a tunneled right subclavian line was initiated in her third trimester, and a day before her cesarean section, she was admitted for a lumbar epidural catheter placement. In the operating room, IV treprostinil was continued and a high-flow nasal cannula with inhaled nitric oxide at 20 ppm was initiated. A right internal jugular vein pulmonary artery catheter was placed for close monitoring of her pulmonary artery pressures, with a PASP reading of 64 mmHg at the start of the case. Femoral arterial and venous access was placed by the cardiothoracic surgery team for cardiopulmonary bypass standby. Intra-operative surgical analgesia was achieved by epidural lidocaine. A cesarean section was performed and was uncomplicated despite her post-delivery autotransfusion, where her PASP went as high as 89 mmHg. Uterine atony was managed with an oxytocin infusion. Epidural morphine was administered through the epidural catheter for post-operative analgesia. In the post-operative recovery room, her PASP was back down to baseline at 62 mmHg. The patient proceeded to have an uneventful postpartum hospital stay and was discharged home without any complications. While severe PH poses a challenge in the care of a parturient patient, safe and successful management may be achieved as outlined in this case report.

Adherence and persistence in patients with rheumatoid arthritis at an integrated health system specialty pharmacy.

BACKGROUND: Disease-modifying anti-rheumatic drugs (DMARDs) improve symptoms and delay progression of rheumatoid arthritis (RA), but adherence is often sub-optimal and many patients change medication (either "switching" to a medication with a different mechanism of action or "cycling" to a medication with the same mechanism of action) during the first year of therapy. Some integrated health-system specialty pharmacies embed pharmacists in clinics to help patients access and adhere to specialty medication. OBJECTIVE: This study assessed DMARD switching, cycling, adherence, and persistence at an outpatient rheumatology clinic with an integrated health-system specialty pharmacy. METHODS: We conducted a retrospective cohort study of adults with RA, naïve to biologic or targeted synthetic DMARDs, who filled ≥ 2 biologic or targeted synthetic DMARD prescriptions within 12 months. Adherence was measured using proportion of days covered (PDC); persistence was computed at 12 months. Univariate analyses compared adherence and persistence between patients with and without a medication change. Ordinal logistic regression examined whether PDC was associated with patient age, gender, race, insurance type, and medication change. RESULTS: We included 772 patients: 79% female/21% male, 89% White/11% non-White, median age 56 years (interquartile range = 48-63). Most patients (84%) did not change medication during the study period, 5% cycled medication one or more times (but did not switch), 9% switched medication one or more times (but did not cycle), and 2% of patients both switched and cycled during the study period. Median PDC of the sample was 0.94 and 73% of patients were persistent. Patients with a medication change had lower PDC than those without (0.89 vs 0.95, P = 0.004), but rate of persistence did not significantly differ between groups (77 vs 72%, P = 0.300). Odds of higher PDC was more likely for men (Odds ratio [OR] = 1.82, 95% confidence interval [CI]: 1.34-2.48, P < 0.001) and less likely for patients who changed medication (OR = 0.65, CI: 0.47-0.91, P = 0.011); age, race, and insurance type were not significant. CONCLUSIONS: Patients with RA demonstrated high medication adherence and persistence, and low rates of switching and cycling. Findings support evidence that integrated health-system specialty pharmacies with clinical pharmacists embedded in outpatient clinics help patients overcome barriers to medication adherence to persist on therapy. DISCLOSURES: This study was funded by Sanofi, Inc. James and J. Choi were employed by Sanofi, Inc., at the time of this study. Peter, Zuckerman, DeClercq, L. Choi, and Tanner, received research funding from Sanofi, Inc., for work on this study. Tanner has also received advisory board/speaker bureau fees from Pfizer, Regeneron, and Sanofi-Aventis. This study was presented as a poster at AMCP Nexus in October 2019 at National Harbor, MD.

Biologic Disease-Modifying Antirheumatic Drug Prescription Patterns for Rheumatoid Arthritis Among United States Physicians.

INTRODUCTION: Some patients with rheumatoid arthritis (RA) using tumor necrosis factor inhibitors (TNFi) experience inefficacy or lack of tolerability and hence switch to another TNFi (cycling) or to a therapy with another mode of action (switching). This study examined patient characteristics, prescribing patterns and treatment practice for RA in the United States. METHODS: Data were from the Adelphi Disease Specific Programme (Q2-Q3 2016). Rheumatologists completed a survey and patient record forms for adult patients with RA who had received ≥ 1 targeted therapy. Patients were grouped by class of first-used targeted therapy, and monotherapy vs. combination therapy. TNFi patients who received ≥ 1 targeted therapy were classified as cyclers or switchers. Univariate analyses compared patient characteristics and physician factors across the analysis groups. RESULTS: Overall, 631 patients received ≥ 1 targeted therapy; 535 were prescribed a TNFi as first targeted therapy, 53 a nonTNFi biologic disease-modifying antirheumatic drug (bDMARD), and 43 tofacitinib. Of 577 patients with known conventional synthetic (cs) DMARD status, 18.7% were prescribed monotherapy and 81.3% combination therapy. Combination therapy patients received significantly more concomitant medications prior to initiation of first targeted therapy than monotherapy patients (P < 0.05). The top reason for physicians to prescribe first use targeted therapy was strong overall efficacy (79.9%). Of 163 patients who progressed to second targeted therapy, 60.7% were cyclers. A lower proportion of cyclers persisted on their first use targeted therapy versus switchers (P = 0.03). The main reason physicians gave for switching patients at this stage was worsening condition (46.6%). CONCLUSIONS: Most patients were prescribed a TNFi as their first targeted therapy; over half then cycled to another TNFi. This suggests other factors may influence second use targeted treatment choice and highlights the need for greater understanding of outcomes associated with subsequent treatment choices and potential benefits of switching.

Examination of physicians' adherence to the 2013 ACC/AHA statin/cholesterol guidelines using a framework of awareness to adherence: A cross-sectional study.

BACKGROUND: Currently, limited data exists regarding primary care physicians' awareness and implementation of the 2013 cholesterol guidelines. OBJECTIVES: To evaluate primary care physicians' adherence to the 2013 ACC/AHA cholesterol management guidelines using the framework of the awareness-to-adherence model. METHODS: The study was a cross-sectional pre-post survey design based on the constructs of the awareness-to-adherence model to capture physicians' awareness of, agreement with, adoption of, and adherence to the 2013 ACC/AHA guidelines for cholesterol treatment and statin and cholesterol management software applications. Physicians with a Medicare Advantage organization in Texas were surveyed before and after educational interventions. RESULTS: A total of 170 responses were considered usable (post-survey). A significant difference was observed when physicians were divided into 2 groups (any intervention vs no intervention) (P = .027). Physicians with a higher level of agreement were 4.8 times more likely to be adherent to the guidelines (P = .011), compared with those with a lower level of agreement. Also, physicians practicing in the Rio Grande Valley area were 4.7 times more likely to be adherent to the guidelines (P = .001) compared with those from the Greater Houston area. CONCLUSION: A high level of awareness, but a lower level of adherence to the guidelines was reported among responding physicians. The awareness-to-adherence model was useful in examining physicians' level of adherence to the cholesterol guidelines and the utilization of statin and cholesterol management cellular apps and online websites. Future studies are required to examine physicians' adoption and adherence of new guidelines.

Real-World Dose Modification Patterns of Subcutaneous Tocilizumab Among Patients with Rheumatoid Arthritis.

BACKGROUND: The treatment of rheumatoid arthritis is based on the use of disease-modifying antirheumatic drugs (DMARDs). Tocilizumab can be used as monotherapy or in combination with conventional synthetic DMARDs for the treatment of moderate-to-severe active rheumatoid arthritis. Subcutaneous (SC) and intravenous forms of the drug are available, but the SC form is more widely used. OBJECTIVE: To understand the real-world dose modification patterns of SC tocilizumab in the treatment of patients with rheumatoid arthritis in the United States. METHODS: Data were obtained from the Truven (now IBM) MarketScan and Optum Clinformatics databases. Patients were included if they had ≥1 pharmacy claims for SC tocilizumab and met other inclusion criteria. The mean, standard deviation, and median values were reported for the continuous variables, and frequency was reported for the categorical variables. Kaplan-Meier analysis was used to analyze the time to first dose modification. Logistic regression modeling was used to identify predictors of the likelihood of dose modification. RESULTS: The study included 1266 patients in the Truven database and 512 patients in the Optum database who had commercial or Medicare Advantage or supplemental insurance. Of the patients who started treatment with biweekly SC tocilizumab (48% each in the Truven and Optum databases), 37% in Truven and 40% in Optum had dose escalation to a weekly dose. Of those who started weekly SC tocilizumab (43% in the Truven and 49% in the Optum databases), 3% (Truven) and 4% (Optum) had dose reduction. The remaining patients started alternative SC tocilizumab doses. Overall, 60% and 68% of patients in the Truven and Optum cohorts, respectively, initiated or escalated to the higher weekly dose of tocilizumab; the mean time to dose escalation was 126 days and 112 days, respectively. In the Truven cohort, corticosteroid use, age, and anemia were the main predictors for dose escalation. In the Optum cohort, female patients had increased odds of dose escalation compared with male patients. CONCLUSION: The dosing trends observed in this study show that physicians have taken advantage of the option to increase SC tocilizumab dosing, but only a few providers chose to reduce the dose. This trend in dose modification may increase the costs related to SC tocilizumab therapy.

Enhancing Statin Adherence Using a Motivational Interviewing Intervention and Past Adherence Trajectories in Patients with Suboptimal Adherence.

BACKGROUND: Statins have been shown to be effective in reducing the occurrence of cardiovascular (CV) events and are widely prescribed for the risk reduction of CV diseases and recurrent CV events. However, poor adherence prevents some patients from receiving the maximum benefit of the therapy. Motivational interviewing (MoI) is a patient-centered collaborative approach that can be used to improve medication adherence. Group-based trajectory modeling depicts patterns of adherence over time and may help tailor the MoI intervention to further enhance adherence. OBJECTIVE: To assess the effect of a phone-based MoI intervention tailored by patients' past adherence trajectory in improving adherence to statins among patients in a Medicare Advantage prescription drug plan (MAPD). METHODS: Patients continuously enrolled in an MAPD from 2013 to 2017 with a statin prescription between January and June 2015 to allow 2 years of pre-index period and 1 year of follow-up were included in the study. Adherence to statins was measured monthly during the 1-year follow-up as proportion of days covered (PDC) and incorporated into a group-based trajectory model to provide 4 distinct patterns of adherence: adherent, rapid decline, gradual decline, and gaps in adherence. Patients in the 3 nonadherent groups were randomized to either control or intervention. The intervention was an initial counseling call and up to 2 monthly follow-up calls by pharmacy students trained in MoI, providing education consistent with a previously identified pattern of use. Refill data at 6 months post-intervention were evaluated to examine the intervention's effect on PDC, as continuous and dichotomized as PDC ≥ 0.8, as well as discontinuation. Multivariable regression adjusted for baseline demographics, clinical characteristics, and past adherence trajectory. RESULTS: There were 152 patients included in the analysis who received MoI phone calls and 304 randomly selected controls. Mean PDC for the intervention group (0.67 ± 0.3) was significantly higher than the control (0.55 ± 0.4; P < 0.001). The intervention group was also less likely to discontinue (OR = 0.38; 95% CI = 0.19-0.76) and more likely to be adherent in the linear regression model (ß = 12.4; P < 0.001) as well as in the logistic regression model (OR = 1.87; 95% CI = 1.18-2.95). Previous adherence trajectories were significantly associated with adherence in the follow-up. CONCLUSIONS: Patients who received the MoI intervention were more likely to be adherent and less likely to discontinue the statin in the 6 months follow-up compared with controls. Future research can identify other approaches to tailor interventions and expand the intervention to other languages. This intervention may also prove valuable to improve adherence to other medications for chronic and asymptomatic diseases. DISCLOSURES: This study was funded by Regeneron Pharmaceuticals, which provided critical input during study design, implementation, and manuscript preparation. Abughosh reports grants from Sanofi, BMS/Pfizer, and Valeant Pharmaceuticals, unrelated to this study. Vadhariya reports a past internship at Regeneron Pharmaceuticals, unrelated to this study. Esse, Serna, and Gallardo are employees of CareAllies, a Cigna subsidiary. Boklage is an employee of Regeneron Pharmaceuticals. Choi was an employee of Sanofi during this study. Johnson, Essien, Fleming, and Holstad have nothing to disclose. A poster based on this study was presented at AMCP Nexus 2018; October 22-25, 2018; Orlando, FL.

Group-Based Trajectory Models to Identify Sociodemographic and Clinical Predictors of Adherence Patterns to Statin Therapy Among Older Adults.

BACKGROUND: The benefits of statins in the prevention of primary and secondary atherosclerotic cardiovascular (CV) disease events have been well documented. Suboptimal adherence is a persistent problem associated with increased CV events and increased healthcare utilization. Proportion of days covered (PDC) is widely used to measure medication adherence, and provides a single value that does not adequately depict different adherence behavior patterns. Group-based trajectory modeling has been used to identify adherence patterns (or trajectories) over time. The identification of characteristics unique to each pattern can help in the early identification of patients who are likely to be poor adherents and can inform the development of interventions. OBJECTIVES: To identify distinct trajectories of statin adherence in patients enrolled in a Medicare Advantage plan and the sociodemographic and clinical predictors associated with each trajectory. METHODS: Patients were included in the study if they were continuously enrolled in a Medicare Advantage plan between 2013 and 2016 and had a statin prescription between January 2015 and June 2015. We observed each patient for 360 days and computed the monthly PDC. The monthly PDC was incorporated into a group-based trajectory model to provide distinct patterns of adherence. Using group-based trajectory modeling, the patients were categorized into groups based on their adherence patterns. Multinomial logistic regression was performed to identify the sociodemographic and clinical factors associated with each group. RESULTS: A total of 7850 patients were included in the analysis and were categorized into 4 distinct groups based on statin adherence-rapid discontinuation (7.8%), gradual decline (16.8%), gaps in adherence (17.2%), and high or nearly perfect adherence (58.2%). Significant predictors of being placed into one or more of the low-adherence trajectories compared with the high-adherence trajectory included sex, age, low-income subsidy, language, Charlson Comorbidity Index score, statin intensity, and 90-day refills. CONCLUSIONS: The predictors identified in this study provide valuable insight into patient characteristics that increase the risk for statin nonadherence, which has the potential to inform targeted interventions. Identifying patient trajectories can inform the future development of protocols to individualize appropriate interventions for these patients.

A prospective study on the implications of a base deficit during fluid resuscitation.

An excessive base deficit (BD) and elevated serum lactate are increasingly recognized as important markers of a malperfusion state during the resuscitation of thermally injured patients. In a previous retrospective study, we found that patients with a BD less than -6 mmol/l during fluid resuscitation developed more severe systemic inflammatory response syndrome (SIRS), more frequent acute respiratory distress syndrome (ARDS), and more severe multiple organ dysfunction syndrome (MODS). The object of this study was to reexamine prospectively the relationship between the BD during fluid resuscitation and the subsequent development of SIRS, ARDS, and MODS by undertaking a prospective observational study of a cohort of consecutive burn patients. Analysis was completed on 38 patients with a mean age of 39 +/- 17 years and a mean %TBSA burn of 36 +/- 15%. The mean BD in the first 24 hours was less than -6 mmol/l in five patients (BD24 < -6 group), and was greater than -6 mmol/L in 33 patients (BD24 > -6 group). Patients in both groups were resuscitated to nearly identical endpoints of urinary output (1.2 ml/kg/hr in the BD24 < -6 group vs 1.3 ml/kg/hr in the BD24 > -6 group). Patients in the BD24 < -6 group had a trend toward a greater number of SIRS signs on the first postburn day, had a significantly higher incidence of ARDS (P =.02), and had significantly more severe MODS (P <.001) than patients in the BD24 > -6 group. The results concur with those of our previous retrospective study. Despite resuscitation to an acceptable urinary output, some burn patients develop a more extreme BD and go on to experience more severe organ dysfunction than do patients who do not generate a BD. The effect of specific correction of the BD during fluid resuscitation is not known at this time.