Complex interplay between RAS GTPases and RASSF effectors regulates subcellular localization of YAP.

RAS GTPases bind effectors to convert upstream cues to changes in cellular function. Effectors of classical H/K/NRAS are defined by RBD/RA domains which recognize the GTP-bound conformation of these GTPases, yet the specificity of RBD/RAs for over 160 RAS superfamily proteins remains poorly explored. We have systematically mapped interactions between BRAF and four RASSF effectors, the largest family of RA-containing proteins, with all RAS, RHO and ARF small GTPases. 39 validated complexes reveal plasticity in RASSF binding, while BRAF demonstrates tight specificity for classical H/K/NRAS. Complex between RASSF5 and diverse RAS GTPases at the plasma membrane can activate Hippo signalling and sequester YAP in the cytosol. RASSF8 undergoes liquid-liquid phase separation and resides in YAP-associated membraneless condensates, which also engage several RAS and RHO GTPases. The poorly studied RASSF3 has been identified as a first potential effector of mitochondrial MIRO proteins, and its co-expression with these GTPases impacts mitochondria and peroxisome distribution. These data reveal the complex nature of GTPase-effector interactions and show their systematic elucidation can reveal completely novel and biologically relevant cellular processes.

Biallelic variants in TRAPPC10 cause a microcephalic TRAPPopathy disorder in humans and mice.

The highly evolutionarily conserved transport protein particle (TRAPP) complexes (TRAPP II and III) perform fundamental roles in subcellular trafficking pathways. Here we identified biallelic variants in TRAPPC10, a component of the TRAPP II complex, in individuals with a severe microcephalic neurodevelopmental disorder. Molecular studies revealed a weakened interaction between mutant TRAPPC10 and its putative adaptor protein TRAPPC2L. Studies of patient lymphoblastoid cells revealed an absence of TRAPPC10 alongside a concomitant absence of TRAPPC9, another key TRAPP II complex component associated with a clinically overlapping neurodevelopmental disorder. The TRAPPC9/10 reduction phenotype was recapitulated in TRAPPC10-/- knockout cells, which also displayed a membrane trafficking defect. Notably, both the reduction in TRAPPC9 levels and the trafficking defect in these cells could be rescued by wild type but not mutant TRAPPC10 gene constructs. Moreover, studies of Trappc10-/- knockout mice revealed neuroanatomical brain defects and microcephaly, paralleling findings seen in the human condition as well as in a Trappc9-/- mouse model. Together these studies confirm autosomal recessive TRAPPC10 variants as a cause of human disease and define TRAPP-mediated pathomolecular outcomes of importance to TRAPPC9 and TRAPPC10 mediated neurodevelopmental disorders in humans and mice.

Updates to a pharmacy-technician driven centralized medication refill service in a large community health system.

sIn 2020 we published a description of the newly implemented centralized medication refill service (CRS) led by pharmacy technicians in our large community health system. Since that time, the CRS has been refined, updated, and expanded. We have also received many inquiries with common questions about the process from those who seek to implement a similar process. The purpose of this commentary is to 1) provide updates to the process in the five years since its implementation, and 2) provide additional insights on specific topics from inquiries to the organization.

Tuning Minimum-Norm regularization parameters for optimal MEG connectivity estimation.

The accurate characterization of cortical functional connectivity from Magnetoencephalography (MEG) data remains a challenging problem due to the subjective nature of the analysis, which requires several decisions at each step of the analysis pipeline, such as the choice of a source estimation algorithm, a connectivity metric and a cortical parcellation, to name but a few. Recent studies have emphasized the importance of selecting the regularization parameter in minimum norm estimates with caution, as variations in its value can result in significant differences in connectivity estimates. In particular, the amount of regularization that is optimal for MEG source estimation can actually be suboptimal for coherence-based MEG connectivity analysis. In this study, we expand upon previous work by examining a broader range of commonly used connectivity metrics, including the imaginary part of coherence, corrected imaginary part of Phase Locking Value, and weighted Phase Lag Index, within a larger and more realistic simulation scenario. Our results show that the best estimate of connectivity is achieved using a regularization parameter that is 1 or 2 orders of magnitude smaller than the one that yields the best source estimation. This remarkable difference may imply that previous work assessing source-space connectivity using minimum-norm may have benefited from using less regularization, as this may have helped reduce false positives. Importantly, we provide the code for MEG data simulation and analysis, offering the research community a valuable open source tool for informed selections of the regularization parameter when using minimum-norm for source space connectivity analyses.

Trends in utilization, reimbursement, and price for DOACs and warfarin in the US Medicaid population from 2000 to 2020.

The use of direct oral anticoagulants (DOACs) is widely increasing in the United States (US). Warfarin has been the conventional anticoagulant used in the past few decades, but it has been gradually replaced by DOACs. The objective of the study was to analyze trends in utilization, reimbursement, and price for those anticoagulants in the US Medicaid population. Retrospective data analysis was conducted using the National Summary Files for the Medicaid State Drug Utilization Data. Study drugs included dabigatran, rivaroxaban, apixaban, edoxaban and warfarin. The study assessed secular trends of utilization, reimbursement, and per-prescription price. The data was collected from the first quarter of 2000 through to the second quarter of 2020 restricted for outpatient prescriptions only. During the 21-year study period, a substantial rise in total expenditures on warfarin and DOACs was observed from $144 million in 2000 to $694 million in 2020. Moreover, the utilization of DOACs has increased significantly since the first approval of Xarelto in 2010 from 1079 in 2011 to 1.5 million in 2019. The per-prescription price of DOACs increased from an average of $200 in 2011 to $407 in 2020. Conversely, the total number of prescriptions of Warfarin and branded Coumadin decreased from 2.4 million to 1.4 million and from 3.9 million to less than a million, respectively. The present study demonstrated a change in the trends of US expenditure and utilization for warfarin and DOACs with DOACs representing the majority of market share of both spending per prescription and reimbursement.

TAOK3 limits age-associated inflammation by negatively modulating macrophage differentiation and their production of TNFα.

BACKGROUND: Human aging is characterized by a state of chronic inflammation, termed inflammaging, for which the causes are incompletely understood. It is known, however, that macrophages play a driving role in establishing inflammaging by promoting pro-inflammatory rather than anti-inflammatory responses. Numerous genetic and environmental risk factors have been implicated with inflammaging, most of which are directly linked to pro-inflammatory mediators IL-6, IL1Ra, and TNFα. Genes involved in the signaling and production of those molecules have also been highlighted as essential contributors. TAOK3 is a serine/threonine kinase of the STE-20 kinase family that has been associated with an increased risk of developing auto-immune conditions in several genome-wide association studies (GWAS). Yet, the functional role of TAOK3 in inflammation has remained unexplored. RESULTS: We found that mice deficient in the serine/Threonine kinase Taok3 developed severe inflammatory disorders with age, which was more pronounced in female animals. Further analyses revealed a drastic shift from lymphoid to myeloid cells in the spleens of those aged mice. This shift was accompanied by hematopoietic progenitor cells skewing in Taok3-/- mice that favored myeloid lineage commitment. Finally, we identified that the kinase activity of the enzyme plays a vital role in limiting the establishment of proinflammatory responses in macrophages. CONCLUSIONS: Essentially, Taok3 deficiency promotes the accumulation of monocytes in the periphery and their adoption of a pro-inflammatory phenotype. These findings illustrate the role of Taok3 in age-related inflammation and highlight the importance of genetic risk factors in this condition.

Pharmacists' facilitators and barriers to implementing and billing for patient care services: Interviews from the Ohio Medicaid Project.

BACKGROUND: In the past several decades, a growing body of literature is recognizing the benefits of pharmacist-led health care services in improving clinical and economic outcomes. Despite this evidence, pharmacists are not recognized on a federal level as health care providers in the United States. Ohio Medicaid managed care plans began partnering with local pharmacies in 2020 to launch initial programs for implementing pharmacist-provided clinical services. OBJECTIVES: This study aimed to identify barriers and facilitators to implementing and billing for pharmacist-provided services in Ohio Medicaid managed care plan programs. METHODS: This qualitative study interviewed pharmacists involved in the initial programs using a semistructured interview based on the Consolidated Framework for Implementation Research (CFIR). Interview transcripts were coded for thematic analysis. Identified themes were mapped to the CFIR domains. RESULTS: Four Medicaid payors partnered with 12 pharmacy organizations, representing 16 unique sites of care. Interviews were conducted with 11 participants. The thematic analysis found data fit within the 5 domains with 32 total themes. Pharmacists described the implementation process of their services. The primary themes for improvement of implementation process were system integration, payor rule clarity, and patient eligibility and access. The 3 themes that emerged as key facilitators were communication between payors and pharmacists, communication between pharmacist and care teams, and the perceived value of the service. CONCLUSIONS: Payors and pharmacists can work collaboratively to improve patient care opportunities by increasing access with sustainable reimbursement, clear guidelines, and open communication. Continued improvement is needed in system integration, payor rule clarity, and patient eligibility and access.

The effect of polypharmacy on quality of life in adult patients with nonalcoholic fatty liver disease in the United States.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a significant epidemiological problem with rising prevalence. Due to limited literature, the objective of this study is to examine the association between polypharmacy and health-related quality of life (QoL) in NAFLD adult patients. METHODS: A retrospective observational study design was conducted to analyze health data collected by Steatohepatitis Clinical Research Network (NASH CRN). Patients were classified as receiving a polypharmacy therapy with five or more medications in their first screening visit. QoL was measured using the Short Form 36 (SF-36) instrument. Each patient self-reported the SF-36 form during the screening visit was compared between polypharmacy and non-polypharmacy groups using Wilcoxon Rank Sum test. Multivariable generalized linear models and multinomial logistic regression were performed to examine each predictor and its effect on QoL. RESULTS: Data included 1067 NAFLD adult patients; 834 patients used polypharmacy. The mean age was 48.64 years, and most patients were female (62%). Comparing NAFLD patients without steatohepatitis, borderline NASH, and definite NASH, the non-polypharmacy group had a significantly higher QoL than the polypharmacy group in Physical Component Summary (PCS) (86.25 vs 66.88, 85 vs 67.5, and 79.375 vs 63.12, respectively, all p < 0.01) and Mental Component Summary (MCS) (83.5 vs 73.38, 78.75 vs 67.62, and 78.75 vs 70.65, respectively, all p < 0.01). DISCUSSION AND CONCLUSION: Adults with NAFLD and polypharmacy have lower QoL than adults with NAFLD and non-polypharmacy. Number of medications had a significant negative impact on PCS, MCS, and all SF-36 domains except mental health, role physical limitation and role emotional limitation domains. Other factors that affect QoL negatively in NAFLD adult patients are female gender, obesity, diabetes, depression, and unemployment. Higher income had favorable effect on QoL.

Comparative effectiveness and persistence of TNFi and non-TNFi in juvenile idiopathic arthritis: a large paediatric rheumatology centre in the USA.

OBJECTIVE: To evaluate the persistence and effectiveness of TNF inhibitors (TNFi) vs non-TNFi among newly diagnosed JIA patients after initiation of biologic DMARD (bDMARD). METHODS: Using longitudinal patient-level data extracted from electronic medical records in a large Midwestern paediatric hospital from 2009 to 2018, we identified JIA patients initiating TNFi and non-TNFi treatment. Treatment effectiveness was assessed based on disease activity. Inverse probability of treatment weighting of propensity score was used to estimate the treatment effectiveness and Kaplan-Meier analyses were conducted to assess persistence. RESULTS: Of 667 JIA patients, most (92.0%) were prescribed one of the class of TNFi as their initial biologic treatment. Etanercept was the most frequently prescribed (67.1%) treatment, followed by adalimumab (27.5%). Only around 5% of patients were prescribed off-label bDMARDs as their first-course treatment; however, >20% were prescribed off-label biologics as their second-course therapy. Some 7.2% of patients received four or more bDMARDs. The median persistence of the first-course bDMARD is 320 days, with TNFi being significantly longer than the non-TNFi (395 vs 320 days, P = 0.010). The clinical Juvenile Disease Activity Score (cJADAS) reduction of TNFi users (6.6, 95% CI 5.7, 7.5) was significant greater compared with non-TNFi users (3.0, 95% CI 1.5, 4.6, P < 0.0001) at 6-month follow-up visit. CONCLUSION: Persistence was significantly longer among patients initiating TNFi as their first biologic therapy than those receiving non-TNFi. Patients receiving TNF therapy had significant greater reduction of cJADAS at the 6-month follow-up visit compared with patients in the non-TNF cohort.

Drug Expenditure, Price, and Utilization in the U.S. Medicaid: A Trend Analysis for SSRI and SNRI Antidepressants from 1991 to 2018.

BACKGROUND: SSRIs and SNRIs are antidepressants that have largely substituted old antidepressants like Monoamine Oxidase Inhibitors (MAOIs) and Tricyclic Antidepressants (TCAs). They have been widely used since 1987 when the FDA approved the first SSRI Fluoxetine and the first SNRI Venlafaxine in 1993. Since then, several new SSRIs and SNRIs have been approved and entered the market. Utilization, pricing, and spending trends of SSRIs and SNRIs have not been analyzed yet in Medicaid. AIM: To assess the trends of drug expenditure, utilization, and price of SSRI and SNRI antidepressants in the US Medicaid program, and to highlight the market share of SSRIs and SNRIs and the effect of generic drug entry on Medicaid drug expenditure. METHODS: A retrospective descriptive data analysis was conducted for this study. National pharmacy summary data for study brand and generic drugs were retrieved from the Medicaid State Outpatient Drug Utilization Data. These data were collected by the US Centers for Medicare and Medicaid Services (CMS). The study period was between 1991 and 2018. Study drugs include 12 different SSRI and SNRI brands and their generics available in the market, such as citalopram, escitalopram, paroxetine, fluoxetine, sertraline, venlafaxine, desvenlafaxine, duloxetine, and levomilnacipran. Data were analyzed annually and categorized by total prescriptions (utilization), total reimbursement (spending), and cost per prescription as the proxy of the price for each drug. RESULTS: From 1991 to 2018, total prescriptions of SSRI and SNRI drugs rose by 3001%. Total Medicaid spending on SSRIs and SNRIs increased from USD 64.5 million to USD 2 billion in 2004, then decreased steadily until it reached USD 755 million in 2018. The SSRIs average utilization market share was 87% compared to 13% of the SNRIs utilization market share. About 72% of total Medicaid spending on the two groups goes to SSRIs, while the remaining 28% goes to SNRIs. Brand SSRIs and SNRIs prices increased over time. On the contrary, generic drugs prices steadily decreased over time. DISCUSSION: An increase in utilization and spending for both SSRI and SNRI drugs was observed. After each generic drug entered the market, utilization shifted from the brand name to the respective generic due to their lower price. These generic substitutions demonstrate a meaningful cost-containment policy for Medicaid programs. IMPLICATIONS FOR HEALTH POLICIES: Our findings show the overall view of Medicaid expenditure on one of the most commonly prescribed drug classes in the US. They also provide an important insight toward the antidepressant market and the importance of monitoring different drugs and their alternatives.

Continuous quality improvement regulations for community pharmacy practice in the United States.

OBJECTIVES: In the United States, medication errors are considered to be the cause of 7000 deaths annually. Continuous quality improvement (CQI) is a management process that focuses on continually and systematically evaluating the organization's work process. In community pharmacy, CQI leads to enhanced patient safety through a reduction in medication errors and quality-related events (QREs). There is limited information about the variations in CQI regulations required by State Boards of Pharmacy (SBPs) for community pharmacy across the country. The objective of this study is to comprehensively describe CQI regulations required by SBPs for community pharmacy practice in the United States. METHODS: This was a cross-sectional study. Information regarding SBPs community pharmacy CQI regulations was collected electronically by surveying a representative of each SBP. In addition, a review of State Pharmacy Laws published online complemented the survey data. The percentage of states with CQI regulations for community pharmacy was estimated. RESULTS: Of the 50 Boards, 16 require pharmacies to maintain CQI programs to monitor and prevent QREs in community pharmacy. The most common elements of CQI programs include the management of known, alleged, and suspected medication errors that reach the patient (73%) and regular reviews of the pharmacy's aggregate data of medication errors or incidents (73%). The North Dakota SBP regulation is the most comprehensive, followed by that of Iowa, Maryland, Massachusetts, and Montana. CONCLUSION: There is wide variation among SBP CQI regulations for community pharmacy practice. Standardization of CQI programs across Boards, including a national database for reporting medication errors and QREs would enhance patient safety.

Healthcare services expenditures among prostate cancer patients with and without mood disorders in the United States: A propensity score-matched cross-sectional study.

OBJECTIVES: To compare the averages of healthcare services utilization and of expenditures for men with prostate cancer with and without diagnoses of mood disorders applying propensity score matching (PSM), and to identify the potential predictors associated with increased healthcare expenditures. DESIGN: Cross-sectional study. SAMPLE AND METHODS: A total of 308,602 weighted patients with prostate cancer were identified after applying PSM. The datasets for men with prostate cancer were extracted from the Medical Expenditure Panel Survey (MEPS) from 2010 to 2015. For cohort formation, 1:1 PSM was applied. Healthcare utilization and expenditures analyzed included emergency room visits, length of stay for hospital inpatients, outpatient visits, office-based visits, and prescriptions. Generalized linear model with gamma distribution and log link was used to determine which covariates are associated with the increase in healthcare expenditures for each healthcare service. FINDINGS: The mean expenditures for emergency room visits between men with prostate cancer and mood disorders was $3,092.34, and it was $1,330.64 for patients without mood disorders (p = 0.038). The weighted total expenditures for emergency room visits in prostate cancer patients with mood disorders is 57% higher (p = 0.0109). Moreover, the weighted total expenditures for outpatient visits in prostate cancer patients with mood disorders is 93% higher (p = 0.0001). The potential predictor in total healthcare expenditures is perceived health status (fair/poor) (p = 0.0066). CONCLUSIONS AND IMPLICATIONS FOR PSYCHOSOCIAL PROVIDERS OR POLICY: Individuals with a diagnosis of mood disorders were found to have higher average healthcare expenditures in emergency room visits than those without mood disorders. Therefore, the implications of this study are to inform the patient care team that the assessment and management of mood disorders is a priority. Moreover, screening of mood- disorder symptoms should occur early to optimize care. Finally, policymakers should provide accessible care to minimize emergency room visits.

A survey of Alberta pharmacists' attitudes, comfort and perceived barriers to a community-based naloxone program.

BACKGROUND: Community pharmacists play an important role in the wellness of patients, families and friends affected by prescription and illicit opioid drugs. They are key partners of the Community Based Naloxone (CBN) Program in Alberta and similar programs across other Canadian jurisdictions. This publicly funded program is an evidence-based response to the opioid overdose crisis, facilitating access to and distribution of naloxone kits through pharmacies. The study aimed to describe Alberta community pharmacists' practices, training, comfort levels and views in dispensing naloxone kits through the CBN program and detail potential perceived barriers to program participation. METHODS: The study was conducted as a cross-sectional online survey of Alberta pharmacists. Data collected from the survey were descriptive and evaluated using Microsoft Excel. Fisher exact tests were used to study the associations in responses among several demographic characteristics and related to dispensing practices, pharmacists' beliefs and perceived barriers. RESULTS: A total of 255 responses were included in the final analysis, with 89.8% of pharmacists replying "yes" to CBN program participation. Pharmacists on average were "comfortable" dispensing naloxone to patients for varying indications, with 85% reporting always providing education when dispensing naloxone to an individual for the first time. About 41% of pharmacists reported no barriers to the program, with the most common perceived barriers being lack of time (29%), demand (20%) and funding (19%). CONCLUSION: Most community pharmacists who responded to the survey participate in the CBN program in Alberta. They held positive beliefs about their role in screening patients for the risk of opioid overdose and are confident in their abilities to recommend and educate on naloxone kits. Proactive screening appeared lower, however, and dispensing kits were potentially variable. Addressing factors such as time, funding for services and demand may help further pharmacist uptake and success of the program. Can Pharm J (Ott) 2021;154:xx-xx.

Development and validation of coding algorithms to identify patients with incident lung cancer in United States healthcare claims data.

PURPOSE: Our aim was to develop and validate a practical US healthcare claims algorithm for identifying incident lung cancer that improves on positive predictive value (PPV) and sensitivity observed in past studies. METHODS: Patients newly diagnosed with lung cancer in Surveillance, Epidemiology, and End Results (SEER) (gold standard) were linked with Medicare claims. A 5% Medicare "other cancer" sample and noncancer sample served as controls. A split-sample validation approach was used. Rules-based, regression, and machine learning models for developing algorithms were explored. Algorithms were developed in the model building subset. Rules-based algorithms and those with the highest F scores were evaluated in the validation subset. F scores were compared for 1000 bootstrap samples. Misclassification was evaluated by calculating the odds of selection by the algorithm among true positives and true negatives. RESULTS: A practical single-score algorithm derived from a logistic regression model had sensitivity = 78.22% and PPV = 78.50% (F score: 78.36). The algorithm was most likely to misclassify older patients (ages ≥80 years) or with missing data in the SEER registry, shorter follow-up time in Medicare (<3 months), insurance through Veterans Affairs, >1 cancer in SEER, or certain Charlson comorbidities (dementia, chronic pulmonary disease, liver disease, or myocardial infarction). CONCLUSION: In this dataset, a practical point-based algorithm for identifying incident lung cancer demonstrated significant and substantial improvement (7.9% and 23.9% absolute improvement in sensitivity and PPV, respectively) compared with a current standard.

Impact of an adherence intervention program on patient adherence and star ratings measures in a large community pharmacy chain.

OBJECTIVE: This study aimed to determine the impact of an adherence intervention program on medication adherence rates and performance on the Centers for Medicare and Medicaid Services star ratings measures. SETTING: The study was conducted in a large community pharmacy chain comprising more than 2200 pharmacies and 7000 pharmacists across 36 states. PRACTICE DESCRIPTION: Pharmacists conducted adherence interventions with patients with a proportion of days covered (PDC) of less than 80% for hypertension, cholesterol, and diabetes star ratings medications. PRACTICE INNOVATION: A longitudinal, pharmacist-led adherence intervention program with automated follow-up interventions was implemented between June 2017 and December 2017. EVALUATION: The percentage of patients with a PDC of greater than or equal to 80% and performance on CMS star ratings measures were evaluated for Medicare Part D Prescription Drug Plan (PDP) and Medicare Advantage Prescription Drug (MAPD) Plan populations in 2017 compared with that of 2015 and 2016. Patient-level PDC change, pharmacist intervention completion, and pharmacist recommendation of additional pharmacy services were also measured. RESULTS: A total of 241,261 interventions were generated in the electronic dispensing systems. Pharmacists enrolled 60,232 patients and completed 75.4% of follow-up interventions, with an average of 1.3 follow-ups per patient. For the Medicare PDP population, improvement in the percentage of adherent patients ranged from 1.1% to 1.2% and 0.9% to 1.8% for 2015-2016 and 2016-2017, respectively, whereas improvement ranged from 2.1% to 2.5% and 2.0% to 3.0% for 2015-2016 and 2016-2017, respectively, for the MAPD Plan population. In 2016 and 2017, performance on cholesterol and diabetes measures achieved the 4-star cut point, and the hypertension measure achieved the 5-star cut point. CONCLUSION: This study demonstrated the successful implementation and pharmacist participation in an adherence intervention program in a large community pharmacy chain. Compared with the previous year, medication adherence improved for patients attributed to hypertension, cholesterol, and diabetes measures, and performance on CMS star rating measures was maintained, despite an increase in cut points.

Implementation of a protocol-driven pharmacy technician refill process at a large physician network.

OBJECTIVES: To describe the implementation of a centrally located certified pharmacy technician (CPhT) team to streamline the process of approving medication refills for chronic disease state management within a multisite physician network. SETTING: Primary care (PC) offices within a large physician network. PRACTICE DESCRIPTION: Incoming medication refill requests from patients and community pharmacies were typically received at each PC office and processed by medical assistants, nurses, or providers. PRACTICE INNOVATIONS: A centralized team of CPhTs managed medication refill requests for 9 PC offices. Standardized protocols for 14 drug classes were built into the electronic medical record (EMR) system. Incoming medication refills were shifted from PC offices to the centrally located CPhT team. EVALUATION: The implementation process was assessed through pharmacists' random audits and feedback from providers, office staff, and patients. Refill reports from January 2020 through March 2020 were obtained. Refill requests' characteristics were summarized and evaluated to determine the volume of refill requests, approved or denied requests, and requests requiring further PC staff analysis. RESULTS: Changes to the protocol process and EMR documentation included modifying or removing laboratory test value parameters, adjusting "grace period" refill quantity on the basis of the scheduled office visit date, and expanding the CPhT role to include communicating with patients and pharmacies regarding denied refills. Data showed that the CPhT team processed 81.7% of all refill requests. This averaged 215 requests per CPhT per day. Of the refill requests approved, 22.5% passed the protocol for the maximum quantity and refills permitted, and 17.3% were granted grace supplies until office visit protocol criteria were met. CONCLUSION: A CPhT team processed 81% of the medication refill requests for 9 PC offices with institution-approved EMR protocols and ambulatory pharmacist supervision. There were many barriers identified and addressed, but through continuous evaluation the workflow and protocol continue to improve.

Appointment-based models: A comparison of three model designs in a large chain community pharmacy setting.

OBJECTIVES: To compare the effects of 3 different appointment-based model (ABM) designs on medication adherence and medication use outcomes controlling for patient and pharmacy characteristics. METHODS: This study was a retrospective cohort analysis in a large grocery store chain from January 1, 2012, to October 31, 2015. A total of 500 comparison and 613 intervention patients in 3 different model designs were analyzed. The outcome measures were proportion of days covered for selected medication classes, number of fills, administered vaccinations, number of trips, statin use in persons with diabetes, use of high-risk medications in older adults, and medication therapy for persons with asthma. RESULTS: After adjusting for relevant covariates, the authors found that all of the ABM designs significantly increased the number of fills after enrollment. Model designs 1 and 3 also significantly reduced the number of trips after enrollment: 4.5 fewer trips (95% CI -5.3 to -3.8; P < 0.05) for model 1 and 1.9 fewer trips (95% CI -3 to -0.9; P < 0.05) for model 3. Models 1 and 3 increased the percentage of patients considered to be adherent for diabetes medications and increased the number of vaccinations patients received. Models 1 and 2 significantly increased the percentage of patients considered to be adherent for statins. No model design was significantly associated with statin use in diabetes, high-risk medication use in older adults, nor percentage of patients considered to be adherent for the hypertension measure. CONCLUSION: All of the ABM designs were effective at increasing the number of fills after enrollment. This paralleled an increase in percentage of patients considered to be adherent to diabetes and statin therapies after enrollment. Models that included face-to-face delivery of the appointment and telephonic synchronization, or face-to-face delivery for all components, increased the number of vaccinations that patients received after enrollment and significantly reduced the number of trips a patient made to the pharmacy.

The impact of MEG source reconstruction method on source-space connectivity estimation: A comparison between minimum-norm solution and beamforming.

Despite numerous important contributions, the investigation of brain connectivity with magnetoencephalography (MEG) still faces multiple challenges. One critical aspect of source-level connectivity, largely overlooked in the literature, is the putative effect of the choice of the inverse method on the subsequent cortico-cortical coupling analysis. We set out to investigate the impact of three inverse methods on source coherence detection using simulated MEG data. To this end, thousands of randomly located pairs of sources were created. Several parameters were manipulated, including inter- and intra-source correlation strength, source size and spatial configuration. The simulated pairs of sources were then used to generate sensor-level MEG measurements at varying signal-to-noise ratios (SNR). Next, the source level power and coherence maps were calculated using three methods (a) L2-Minimum-Norm Estimate (MNE), (b) Linearly Constrained Minimum Variance (LCMV) beamforming, and (c) Dynamic Imaging of Coherent Sources (DICS) beamforming. The performances of the methods were evaluated using Receiver Operating Characteristic (ROC) curves. The results indicate that beamformers perform better than MNE for coherence reconstructions if the interacting cortical sources consist of point-like sources. On the other hand, MNE provides better connectivity estimation than beamformers, if the interacting sources are simulated as extended cortical patches, where each patch consists of dipoles with identical time series (high intra-patch coherence). However, the performance of the beamformers for interacting patches improves substantially if each patch of active cortex is simulated with only partly coherent time series (partial intra-patch coherence). These results demonstrate that the choice of the inverse method impacts the results of MEG source-space coherence analysis, and that the optimal choice of the inverse solution depends on the spatial and synchronization profile of the interacting cortical sources. The insights revealed here can guide method selection and help improve data interpretation regarding MEG connectivity estimation.

Patient perceptions of a pharmacy star rating model.

OBJECTIVES: To identify patients' understanding of what constitutes a "quality pharmacy" and to obtain their feedback regarding the development and use of the pharmacy star rating model, a pharmacy-specific aggregate performance score based on the Centers for Medicare and Medicaid Services' Medicare Star Rating. DESIGN: Prospective cross-sectional study. SETTING AND PARTICIPANTS: Focus groups were conducted in Arizona, California, Mississippi, Maryland, and the District of Columbia, and one-on-one interviews were conducted in Indiana. Eligible patients were required to routinely use a community pharmacy. MAIN OUTCOME MEASURES: Consumer insights on their experiences with their pharmacies and their input on the pharmacy star rating model were attained. Key themes from the focus groups and interviews were obtained through the use of qualitative data analyses. RESULTS: Forty-nine subjects from 5 states and DC participated in 6 focus groups and 4 one-on-one interviews. Eighty-eight percent of participants reported currently taking at least 1 medication, and 87% reported having at least 1 health condition. The 7 themes identified during qualitative analysis included patient care, relational factors for choosing a pharmacy, physical factors for choosing a pharmacy, factors related to use of the pharmacy star rating model, reliability of the pharmacy star rating model, trust in pharmacists, and measures of pharmacy quality. Most participants agreed that the ratings would be useful and could aid in selecting a pharmacy, especially if they were moving to a new place or if they were dissatisfied with their current pharmacy. CONCLUSION: Pharmacy quality measures are new to patients. Therefore, training and education will need to be provided to patients, as pharmacies begin to offer additional clinical services, such as medication therapy management and diabetes education. The use of the pharmacy star rating model was dependent on the participants' situation when choosing a pharmacy.

The roles of type 2 diabetes and obesity in disease activity and progression of non-alcoholic fatty liver disease/non-alcoholic steatohepatitis.

OBJECTIVE: We examined the roles of type 2 diabetes (T2D) and obesity in disease activity and fibrosis progression/regression in patients with non-alcoholic fatty liver disease/non-alcoholic steatohepatitis (NAFLD/NASH). METHODS: This multi-center, retrospective study included patients with suspected or histologically proven NAFLD/NASH from the NASH Clinical Research Network. Outcomes included disease activity and rate of fibrosis, assessed using liver-biopsy driven measures (NAFLD activity score [NAS] and fibrosis score [FS]). Logistic regression and doubly robu estimation of causal effects tested relationships among T2D, obesity, and NAFLD/NASH. RESULTS: The analytical sample included 870 adult patients with baseline biopsy data and 157 patients with multiple biopsy data. Patients with NAFLD/NASH and T2D had significantly higher baseline average NAS (4.52 vs. 4.13; p = 0.009) and FS (2.17 vs. 1.56; p < 0.0001); those with T2D had a significantly greater reduction in average NAS over time (-0.77/year vs. -0.17/year; p = 0.0008). Change in FS over time did not differ significantly by T2D status (-0.23/year vs. -0.04/year; p = 0.34). Baseline NAS, baseline FS, and change in average NAS over time did not differ significantly by obesity status (4.17 vs. 4.47; p = 0.16; 1.73 vs.1.92; p = 0.31; -0.40/year vs. -0.59/year; p = 0.62, respectively). Patients with obesity had a slight increase in FS but those without obesity had a reduction in average FS over time (0.07/year vs. -0.27/year; p = 0.008). CONCLUSIONS: Patients with NAFLD/NASH and T2D had greater baseline disease activity versus those without T2D, but there was greater regression of disease activity over time among those with T2D. Patients with NAFLD/NASH and obesity had worsening of fibrosis versus those without obesity. NCT00063622.