Changes in real-world dispensing of ADHD stimulants in youth from 2019 to 2021 in California.

Introduction: Attention-deficit/hyperactivity disorder (ADHD) is one of the most common pediatric neurobehavioral disorders in the U.S. Stimulants, classified as controlled substances, are commonly used for ADHD management. We conducted an analysis of real-world stimulants dispensing data to evaluate the pandemic's impact on young patients (≤ 26 years) in California. Methods: Annual prevalence of patients on stimulants per capita across various California counties from 2019 and 2021 were analyzed and further compared across different years, sexes, and age groups. New patients initiating simulants therapy were also examined. A case study was conducted to determine the impact of socioeconomic status on patient prevalence within different quintiles in Los Angeles County using patient zip codes. Logistic regression analysis using R Project was employed to determine demographic factors associated with concurrent use of stimulants with other controlled substances. Results: There was a notable reduction in prevalence of patients ≤26 years old on stimulants during and after the pandemic per 100,000 people (777 in 2019; 743 in 2020; 751 in 2021). These decreases were more evident among the elementary and adolescent age groups. The most prevalent age group on stimulants were adolescents (12-17 years) irrespective of the pandemic. A significant rise in the number of female patients using stimulants was observed, increasing from 107,957 (35.2%) in 2019 to 121,241 (41.1%) in 2021. New patients initiating stimulants rose from 102,754 in 2020 to 106,660 in 2021, with 33.2% being young adults. In Los Angeles County, there was an increasing trend in patient prevalence from Q1 to Q5 income quintiles among patients ≥6 years. Consistently each year, the highest average income quintile exhibited the highest per capita prevalence. Age was associated with higher risk of concurrent use of benzodiazepines (OR, 1.198 [95% CI, 1.195-1.201], p < 0.0001) and opioids (OR, 1.132 [95% CI, 1.130-1.134], p < 0.0001) with stimulants. Discussion: Our study provides real-world information on dispensing of ADHD stimulants in California youth from 2019 to 2021. The results underscore the importance of optimizing evidence-based ADHD management in pediatric patients and young adults to mitigate disparities in the use of stimulants.

Real-World Dispensing of Buprenorphine in California during Prepandemic and Pandemic Periods.

INTRODUCTION: The opioid overdose crisis in the United States has become a significant national emergency. Buprenorphine, a primary medication for individuals coping with opioid use disorder (OUD), presents promising pharmacokinetic properties for use in primary care settings, and is often delivered as a take-home therapy. The COVID-19 pandemic exacerbated the scarcity of access to buprenorphine, leading to dire consequences for those with OUD. Most existing studies, primarily focused on the immediate aftermath of the COVID-19 outbreak, highlight the challenges in accessing medications for opioid use disorder (MOUDs), particularly buprenorphine. However, these studies only cover a relatively short timeframe. METHODS: To bridge this research gap, in our study, we utilized 33 months of California's prescription drug monitoring program (PDMP) data to provide insights into real-world buprenorphine dispensing trends since the onset of the pandemic from 2018 to 2021, focusing on outcomes such as patient counts, prescription volumes, prescriber involvement, days' supply, and dosage. Statistical analysis employed interrupted time series analysis to measure changes in trends before and during the pandemic. RESULTS: We found no significant impact on patient counts or prescription volumes during the pandemic, although it impeded the upward trajectory of prescriber numbers that was evident prior to the onset of the pandemic. An immediate increase in days' supply per prescription was observed post-pandemic. CONCLUSION: Our findings differ in comparison to previous data regarding the raw monthly count of patients and prescriptions. The analysis encompassed uninsured patients, offering a comprehensive perspective on buprenorphine prescribing in California. Our study's insights contribute to understanding the impact of COVID-19 on buprenorphine access, emphasizing the need for policy adjustments.

Effects of Transition from Closed-Book to Open-Book Assessment on Students' Scores in a Pharmacokinetics Course.

Closed-book summative assessment of student learning, common in pharmacy education, is challenging to administer in a remote setting due to the need for costly and intrusive monitoring technology. Therefore, open-book assessments without monitoring have been considered an alternative in remote settings. The present study investigated the effects of the transition from in-person closed-book to remote open-book format on the students' scores in different assessment categories in a Pharmacokinetics course. The students' performances in the transition cohort (Transition, n = 96) during the in-person and remote periods were compared with those of an in-person cohort (Control, n = 85) during the same periods. Assessments included take-home assignments, daily quizzes, and progress/final examinations. Whereas the take-home assignments were open-book for cohorts and periods, the quizzes and examinations were open-book only for the Transition cohort during the remote period. Only the quiz/examination questions that were identical for both cohorts were included in the analysis. Statistical analysis by a linear, mixed-effects model indicated that the transition did not have any significant impact on the scores of students in the assignments, which were open-book for both cohorts and both periods. However, there were significant increases in the Transition cohort's scores (mean ± SE) during the remote open-book period in both quizzes (+8.4 ± 1.9%) and examination (+6.8 ± 1.5%) questions, compared with the Control cohort who had in-person closed-book assessments. These differences amounted to Cohen's d-effect sizes of 0.61 and 0.59 for the quiz and examination questions, respectively. It is concluded that when the questions are similar, the students' scores in pharmacokinetic assessments are higher (medium effect size) in a remote open-book format compared with the in-person closed-book format.

Comparison of Virtual Simulations with Peers versus Actors as Standardized Patients on Virtual OSCE Scores.

OBJECTIVE: This study's primary aim is to assess the use of different types of standardized patients (SPs) during formative simulation activities on summative objective structured clinical exams (OSCE) in a PharmD curriculum. METHODS: Randomized-controlled study with first-year pharmacy students in a Pharmacist Patient Care Lab (PCL) course. Students were randomized into groups with either hired actors or their peers as SPs for virtual simulation activities. All students then completed a virtual teaching OSCE (TOSCE) and virtual OSCE. A mixed effects analysis was done to compare TOSCE and OSCE scores between the two groups. RESULTS: There were no significant differences between the two groups in their TOSCE or OSCE scores for the analytical and global rubrics. CONCLUSION: This study demonstrates that peers may be as effective as having hired actors as SPs in preparing students for virtual skills exams.

Factors Affecting Initiation and Retention of Medication-Assisted Recovery (MAR) within a Pilot Pharmacist-Involved Practice Model at a Federally Qualified Healthcare Center (FQHC) during the COVID-19 Pandemic.

BACKGROUND: During the COVID-19 pandemic, opioid-related overdose deaths increased. Although Medication-Assisted Treatment or Recovery (MAT or MAR) is available, initiation and retention rates vary. The goal of this study was to evaluate clinical, demographic, and Social Determinant of Health factors affecting MAR initiation, on-time initiation of medications, and successful retention in the program. The secondary goal was to evaluate the impact of a novel interprofessional practice model incorporating pharmacists. METHODS: A retrospective analysis was conducted using electronic health record data from a pilot MAR Program initiated within a California Federally Qualified Healthcare Center. RESULTS: From September 2019 to August 2020, 48 patients enrolled into the program. On-time initiation of medications occurred in 68% of patients and average program retention was 96.4 ± 95.8 days. Patients currently using opioids (p = 0.005) and those receiving supportive medications (p = 0.049) had lower odds of on-time MAR initiation. There were no statistically significant factors associated with successful retention in the program. The number of visits with members of the interprofessional team did not significantly affect on-time initiation or successful retention. CONCLUSIONS: Current opioid use and receipt of supportive medications were associated with lower on-time medication initiation. Further studies are warranted to explore additional factors which may affect initiation and retention.

The effect of interprofessional simulations on pharmacy and physician assistant students' learning of advanced cardiac life support concepts.

BACKGROUND: The Interprofessional Education Collaborative (IPEC) defined core competencies for IPE in 2011, and use of simulation in interprofessional education (IPE) continues to be developed in prelicensure health education programs. INTERPROFESSIONAL EDUCATION ACTIVITY: In this prospective, observational study, interprofessional student teams addressed reversible causes of cardiac arrest in weekly simulations during an Emergency Medicine course. Each simulation was followed by sequential team debriefs, first regarding the IPEC core competencies of interprofessional communication, teamwork, and roles and responsibilities, and second regarding the patient-related content of the case. DISCUSSION: Twenty-eight pharmacy students and 60 physician assistant students completed the course. A didactic knowledge exam was administered before, immediately after, and 150 days after the course. Both disciplines' exam scores significantly increased from baseline to the end of the course and from baseline to the 150-day follow-up. Students also completed the validated Interprofessional Perceptions Survey before and after the course. Both disciplines demonstrated significant increases in Team Value, Efficiency and Interprofessional Accommodation components. IMPLICATIONS: Participation in this simulation-based course resulted in 150-day retention of advanced cardiovascular life support knowledge and improved interprofessional perceptions in both pharmacy and physician assistant students.

Predicting survival of NSCLC patients treated with immune checkpoint inhibitors: Impact and timing of immune-related adverse events and prior tyrosine kinase inhibitor therapy.

Introduction: Immune checkpoint inhibitors (ICIs) produce a broad spectrum of immune-related adverse events (irAEs) affecting various organ systems. While ICIs are established as a therapeutic option in non-small cell lung cancer (NSCLC) treatment, most patients receiving ICI relapse. Additionally, the role of ICIs on survival in patients receiving prior targeted tyrosine kinase inhibitor (TKI) therapy has not been well-defined. Objective: To investigate the impact of irAEs, the relative time of occurrence, and prior TKI therapy to predict clinical outcomes in NSCLC patients treated with ICIs. Methods: A single center retrospective cohort study identified 354 adult patients with NSCLC receiving ICI therapy between 2014 and 2018. Survival analysis utilized overall survival (OS) and real-world progression free survival (rwPFS) outcomes. Model performance matrices for predicting 1-year OS and 6-month rwPFS using linear regression baseline, optimal, and machine learning modeling approaches. Results: Patients experiencing an irAE were found to have a significantly longer OS and rwPFS compared to patients who did not (median OS 25.1 vs. 11.1 months; hazard ratio [HR] 0.51, confidence interval [CI] 0.39- 0.68, P-value <0.001, median rwPFS 5.7 months vs. 2.3; HR 0.52, CI 0.41- 0.66, P-value <0.001, respectively). Patients who received TKI therapy before initiation of ICI experienced significantly shorter OS than patients without prior TKI therapy (median OS 7.6 months vs. 18.5 months; P-value < 0.01). After adjusting for other variables, irAEs and prior TKI therapy significantly impacted OS and rwPFS. Lastly, the performances of models implementing logistic regression and machine learning approaches were comparable in predicting 1-year OS and 6-month rwPFS. Conclusion: The occurrence of irAEs, the timing of the events, and prior TKI therapy were significant predictors of survival in NSCLC patients on ICI therapy. Therefore, our study supports future prospective studies to investigate the impact of irAEs, and sequence of therapy on the survival of NSCLC patients taking ICIs.

Clinical application and feasibility of utilizing the PEDI-CAT to assess activity and participation among children receiving physical therapy incorporating hippotherapy.

BACKGROUND: Hippotherapy (HPOT) is a physical therapy (PT) treatment tool using equine movement to improve mobility for children with movement impairments. Although research suggests HPOT improves body structure and function, there is limited evidence regarding its impact on activity and participation outcomes in a clinical setting. The Pediatric Evaluation of Disability Inventory Computer Adaptive Test (PEDI-CAT) may be useful in HPOT settings to highlight changes in activity and participation. PURPOSE: 1) Evaluate the PEDI-CAT's sensitivity to changes in activity and participation among children receiving PT using HPOT; 2) determine feasibility of administering the PEDI-CAT in a HPOT setting; and 3) examine how PEDI-CAT scores influence clinical decision-making. METHODS: Participants (N = 34) were children who attended weekly PT using HPOT for 6 months. The PEDI-CAT was completed for all participants by a parent or caregiver at initial treatment (T1) and 6 months later (T2). A linear mixed effects model was used to evaluate changes in scores over time. Team meetings occurred monthly to discuss how PEDI-CAT scores impacted treatment. RESULTS: There were significant improvements across 3 PEDI-CAT domains between T1 and T2 for all children with small effect sizes and nonsignificant changes noted within two diagnostic subgroups with small-to-medium effect sizes. The PEDI-CAT was completed by all participants without interrupting treatment flow. PEDI-CAT score reports enriched therapist-client conversations increasing shared decision-making. CONCLUSION: PTs who treat children using HPOT may feasibly use the PEDI-CAT to assess changes in activity level outcomes and to assist clinical decision-making.

Design, implementation, and evaluation of a pharmacist-led outpatient benzodiazepine-tapering clinic.

BACKGROUND: Benzodiazepines are commonly used among older adults, despite well-known risks. Clinical pharmacists can lead tapering efforts, leveraging their clinical expertise and relieving time-pressured primary care providers. OBJECTIVES: The objective of this study is to describe the design, implementation, and evaluation of an outpatient pharmacist-led benzodiazepine-tapering clinic. PRACTICE DESCRIPTION: The clinic is based within a community medical group associated with a large academic health system in Los Angeles, California. PRACTICE INNOVATION: The clinic is staffed by clinical pharmacists and supervised by a psychiatrist. The initial visit consists of patient education, design of patient-driven tapering schedule, and medical history review. Follow-up phone/video visits are used to monitor withdrawal symptoms and provide support. EVALUATION METHODS: We used chart review to assess tapering status among those enrolled in the tapering clinic versus those who did not enroll. We compared outcomes across the 2 groups using bivariate statistics. RESULTS: From March 2017 to May 2019, 176 patients were referred to the clinic; 17 were deemed ineligible. Of the 159 patients contacted, 62 patients enrolled in the clinic; 97 patients did not enroll. Among patients in the clinic, 13 (27%) of patients were tapered down, 29 (60%) completely tapered off, 6 (13%) were unable to taper, and 14 (23%) were in the process of tapering. In contrast, among patients who did not enroll, 3 (4%) of patients were tapered down, 15 (20%) completely tapered off, 57 (76%) were unable to taper, and 22 (22%) were in the process of tapering. Ninety percent of patients had at least some benzodiazepine tapering when enrolled in the clinic compared to 41% among not enrolled in the clinic (P<0.001). CONCLUSION: A pharmacist-led benzodiazepine-tapering clinic can be an effective way to engage patients motivated to taper down. Lessons learned include the importance of ensuring referring providers adequately counsel patients prior to referral.

Effects of GLP-1 receptor agonists on cardiovascular outcomes in patients with type 2 diabetes and chronic kidney disease: A systematic review and meta-analysis.

AIM: To evaluate the cardiovascular outcomes of glucagon-like peptide-1 receptor agonists (GLP1-RA) in patients with type 2 diabetes (T2DM) and chronic kidney disease (CKD). MATERIALS AND METHODS: We searched PubMed, Ovid MEDLINE, CINAHL, and Web of Science databases for randomized controlled trials reporting event rates for a composite cardiovascular outcome of cardiovascular death, myocardial infarction, and stroke in patients with T2DM and CKD receiving GLP1-RA or placebo. Studies were restricted to those reporting specific event rates for patients with CKD separately from the overall population. We conducted a meta-analysis using a random-effects model. This meta-analysis was registered on PROSPERO (CRD42022320157). RESULTS: A total of four studies comprising 7130 patients was included in our analysis. Four different GLP1-RA were assessed in a population with CKD defined as estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2 . Treatment with GLP1-RA was not associated with a significant reduction in the composite cardiovascular end point of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke (odds ratio (OR) 0.80; 95% confidence interval (CI), 0.59-1.07; p = 0.13) among patients with T2DM and CKD. Individual components of the composite cardiovascular end point were assessed in two trials and did not show evidence of an effect of GLP1-RA in reducing cardiovascular end points. CONCLUSIONS: Pooled analysis of clinical trials reporting separate cardiovascular events rates in patients with T2DM and CKD did not find GLP1-RA to be associated with a reduction in composite cardiovascular event rates. Select GLP1-RA may offer cardiovascular event reduction in patients with T2DM and CKD, but this does not appear to be a class effect. Use of GLP1-RA with demonstrated cardiovascular benefits should be preferred in patients with CKD and T2DM to further reduce cardiovascular risk.

A Nonrestrictive Approach to Fluoroquinolone Stewardship at Two Community Hospitals.

Background: Fluoroquinolones are one of the most prescribed antimicrobials in the United States and have been increasingly used in inpatient and outpatient settings to treat various infectious diseases syndromes. Due to the unwanted collateral effects on antibiotic resistance, poor susceptibility rates among Gram-negative pathogens, and adverse effects, fluoroquinolones are often targeted by hospital antimicrobial stewardship programs to prevent overutilization. This study describes the association of nonrestrictive antimicrobial stewardship interventions at 2 nonacademic community hospitals on levofloxacin utilization, prescribing patterns on alternative antibiotics, and Pseudomonas aeruginosa nonsusceptibility rates to levofloxacin. Methods: Nonrestrictive antimicrobial stewardship interventions included monitoring and reporting of fluoroquinolone susceptibility trends to physician groups, performing medication use evaluations of levofloxacin accompanied with prescriber detailing, daily prospective audit and feedback, implementation of beta-lactam-based institutional guidelines for empiric therapy in various infectious disease syndromes, review and adjustment of electronic medical record order sets containing fluoroquinolones, and intensive prescriber education. No preauthorization of levofloxacin was used during this study period. Antibiotic utilization data were collected for the time periods of August 2015 through January 2021. Correlation between levofloxacin and other broad-spectrum antibiotc use was investigated as well as the impact on Pseudomonas aeruginosa levofloxacin nonsusceptibility rates. Results: Both hospitals showed an overall downward trend in the prescribing of levofloxacin during the time period of August 2015 to January 2021. There was a significant negative correlation between monthly ceftriaxone and levofloxacin days of therapy for both hospitals (P < .0001). There was a positive correlation between levofloxacin days of therapy and P aeruginosa nonsusceptibility (P < .02 at both hospitals). Conclusions: Our results demonstrate that a nonrestrictive approach to fluoroquinolone stewardship interventions had a significant impact on reducing levofloxacin utilization, increasing ceftriaxone utilization, and improving P aeruginosa levofloxacin susceptibility.

Evaluation of step-down oral antibiotic therapy for uncomplicated streptococcal bloodstream infections on clinical outcomes.

BACKGROUND: Despite the severity and frequency of streptococcal bloodstream infections (BSIs), the effectiveness of oral definitive therapy remains unknown. The objective of this study was to evaluate the clinical outcomes of step-down oral antibiotics for the treatment of uncomplicated streptococcal BSIs. METHODS: In this retrospective cohort study, adult patients admitted with uncomplicated streptococcal BSI between June 2015 and June 2017 were included. Patients were excluded if they received <48 h of antibiotic therapy; therapy was started >48 h after first positive culture; had complicated infections of endocarditis, bone and joint infections, or central nervous system infections; Pitt bacteremia score (PBS) ⩾ 4; or failed to respond to effective therapy necessitating continued intravenous (IV) therapy. Patients were grouped by receipt of step-down oral antibiotic therapy (PO group) versus continued IV therapy (IV group). Outcomes included hospital length of stay (LOS), 30-day recurrence of BSI, 30-day readmission, 30-day all-cause mortality, and catheter-related or drug-related adverse events (AEs). RESULTS: Of 244 patients included, 40% received step-down oral therapy (n = 98). Overall, the most common source of BSI was pneumonia (22%), followed by skin and soft tissue infections (SSTI) (18%). Severity of illness measured by intensive care unit (ICU) admission and PBS was similar. The IV group had significantly longer LOS [median 10 (interquartile range [IQR] = 5-21) versus 5 (4-6) days, p < 0.01] compared with the PO group. BSI recurrence, readmission, all-cause mortality within 30 days, and AEs were similar between the groups (p = ns). CONCLUSION: In uncomplicated streptococcal BSI, patients treated with step-down oral antibiotic therapy had significantly shorter LOS compared with continued IV therapy without compromise of clinical outcomes.

Gaps in Patient Education on Safe Handling and Disposal of Oral Chemotherapy Drugs: A Pilot Prospective Cohort Survey Study.

Background: Oral anticancer chemotherapy (OC) has been misperceived as being safer than intravenous chemotherapy, leading to its increased risk of improper handling and disposal. This survey study assessed the knowledge, practices and attitudes of pharmacists and patients regarding OC handling and disposal, gaps in knowledge and barriers to patient education. Methods: Surveys were developed based on literature review and pilot study validation results. Patients completed a 33-item paper or electronic survey whereas pharmacists completed a 38-item electronic survey. Descriptive statistics and Fisher's exact test computed using the R Project were used for analyses. Results: Pharmacist group (16/25, 62.5%) and patient group (14/29, 48.3%) believed that the oral route is safer than IV. Average overall correct response rates for pharmacist and patient groups were 78.3% and 61.9%, respectively. Significant gaps in knowledge between groups were observed in three sections (p < 0.05). Common barriers to providing patient education were insufficient training (70.8%) and insufficient time (50%). Conclusion: Pharmacist and patient knowledge, awareness and practices of OC safe handling and disposal are suboptimal. Areas of knowledge gaps and barriers to patient education were identified. Enhanced supports are needed to empower pharmacists to assume an active role in patient education on safe handling and disposal of OC.

Clinical Implications of Combinatorial Pharmacogenomic Tests Based on Cytochrome P450 Variant Selection.

Despite the potential to improve patient outcomes, the application of pharmacogenomics (PGx) is yet to be routine. A growing number of PGx implementers are leaning toward using combinatorial PGx (CPGx) tests (i.e., multigene tests) that are reusable over patients' lifetimes. However, selecting a single best available CPGx test is challenging owing to many patient- and population-specific factors, including variant frequency differences across ethnic groups. The primary objective of this study was to evaluate the detection rate of currently available CPGx tests based on the cytochrome P450 (CYP) gene variants they target. The detection rate was defined as the percentage of a given population with an "altered metabolizer" genotype predicted phenotype, where a CPGx test targeted both gene variants a prospective diplotypes. A potential genotype predicted phenotype was considered an altered metabolizer when it resulted in medication therapy modification based on Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines. Targeted variant CPGx tests found in the Genetic Testing Registry (GTR), gene selection information, and diplotype frequency data from the Pharmacogenomics Knowledge Base (PharmGKB) were used to determine the detection rate of each CPGx test. Our results indicated that the detection rate of CPGx tests covering CYP2C19, CYP2C9, CYP2D6, and CYP2B6 show significant variation across ethnic groups. Specifically, the Sub-Saharan Africans have 63.9% and 77.9% average detection rates for CYP2B6 and CYP2C19 assays analyzed, respectively. In addition, East Asians (EAs) have an average detection rate of 55.1% for CYP2C9 assays. Therefore, the patient's ethnic background should be carefully considered in selecting CPGx tests.

Design and application of hybrid cyclic-linear peptide-doxorubicin conjugates as a strategy to overcome doxorubicin resistance and toxicity.

Doxorubicin (Dox) is used for breast cancer, leukemia, and lymphoma treatment as an effective chemotherapeutic agent. However, Dox use is restricted due to inherent and acquired resistance and an 8-fold increase in the risk of potentially fatal cardiotoxicity. Hybrid cyclic-linear peptide [R5K]W7A and linear peptide R5KW7A were conjugated with Dox through a glutarate linker to afford [R5K]W7A-Dox and R5KW7A-Dox conjugates to generate Dox derivatives. Alternatively, [R5K]W7C was conjugated with Dox via a disulfide linker to generate [R5K]W7C-S-S-Dox conjugate, where S-S is a disulfide bond. Comparative antiproliferative assays between conjugates [R5K]W7A-Dox, [R5K]W7C-S-S-Dox, linear R5KW7A-Dox, the corresponding physical mixtures of the peptides, and Dox were performed in normal and cancer cells. [R5K]W7A-Dox conjugate was 2-fold more efficient than R5KW7A-Dox, and [R5K]W7C-S-S-Dox conjugates in inhibiting the cell proliferation of human leukemia cells (CCRF-CEM). Therefore, hybrid cyclic-linear [R5K]W7A-Dox conjugate was selected for further studies and inhibited the cell viability of CCRF-CEM (84%), ovarian adenocarcinoma (SK-OV-3, 39%), and gastric carcinoma (AGS, 73%) at a concentration of 5 µM after 72 h of incubation, which was comparable to Dox (5 µM) efficacy (CCRF-CEM (85%), SK-OV-3 (33%), and AGS (87%)). While [R5K]W7A-Dox had a significant effect on the viability of cancer cells, it exhibited minimal cytotoxicity to normal kidney (LLC-PK1, 5-7%) and heart cells (H9C2, <9%) at concentrations of 5-10 µM (compared to free Dox at 5 µM that reduced the viability of kidney and heart cells by 85% and 44%, respectively). The fluorescence microscopy images were consistent with the cytotoxicity studies, indicating minimal uptake of the cyclic-linear [R5K]W7A-Dox (5 µM) in H9C2 cells. In comparison, Dox (5 µM) showed significant uptake, reduced cell viability, and changed the morphology of the cells after 24 h. [R5K]W7A-Dox showed 16-fold and 9.5-fold higher activity against Dox-resistant cells MDA231R and MES-SA/MX2 (lethal dose for 50% cell death or LC50 of 2.3 and 4.3 µM, respectively) compared to free Dox (LC50 of 36-41 µM, respectively). These data, along with the results obtained from the cell viability tests, indicate comparable efficiency of [R5K]W7A-Dox to free Dox in leukemia, ovarian, and gastric cancer cells, significantly reduced toxicity in normal kidney LLC-PK1 and heart H9C2 cells, and significantly higher efficiency in Dox-resistant cells. A number of endocytosis inhibitors did not affect the cellular uptake of [R5K]W7A-Dox.

Ciliary extracellular vesicles are distinct from the cytosolic extracellular vesicles.

Extracellular vesicles (EVs) are cell-derived membrane vesicles that are released into the extracellular space. EVs encapsulate key proteins and mediate intercellular signalling pathways. Recently, primary cilia have been shown to release EVs under fluid-shear flow, but many proteins encapsulated in these vesicles have never been identified. Primary cilia are ubiquitous mechanosensory organelles that protrude from the apical surface of almost all human cells. Primary cilia also serve as compartments for signalling pathways, and their defects have been associated with a wide range of human genetic diseases called ciliopathies. To better understand the mechanism of ciliopathies, it is imperative to know the distinctive protein profiles of the differently sourced EVs (cilia vs cytosol). Here, we isolated EVs from ciliated wild-type (WT) and non-ciliated IFT88 knockout (KO) mouse endothelial cells using fluid-shear flow followed by a conventional method of EV isolation. EVs isolated from WT and KO exhibited distinctive sizes. Differences in EV protein contents were studied using liquid chromatography with tandem mass spectrometry (LC-MS-MS) and proteomic comparative analysis, which allowed us to classify proteins between ciliary EVs and cytosolic EVs derived from WT and KO, respectively. A total of 79 proteins were exclusively expressed in WT EVs, 145 solely in KO EVs, and 524 in both EVs. Our bioinformatics analyses revealed 29% distinct protein classes and 75% distinct signalling pathways between WT and KO EVs. Based on our statistical analyses and in vitro studies, we identified NADPH-cytochrome P450 reductase (POR), and CD166 antigen (CD166) as potential biomarkers for ciliary and cytosolic EVs, respectively. Our protein-protein interaction network analysis revealed that POR, but not CD166, interacted with either established or strong ciliopathy gene candidates. This report shows the unique differences between EVs secreted from cilia and the cytosol. These results will be important in advancing our understanding of human genetic diseases.

Evaluating risk factors for acute graft versus host disease in pediatric hematopoietic stem cell transplant patients receiving tacrolimus.

To identify the clinical and pharmacological risk factors associated with tacrolimus pharmacodynamics for acute graft-versus-host disease (aGVHD) in pediatric patients receiving allogeneic hematopoietic stem cell transplantation (HSCT) from a matched related donor. A retrospective cohort single center chart review study was conducted with pediatric patients who received tacrolimus prophylaxis after allogeneic HSCT between January 1, 2017, and December 31, 2019. Potential risk factors were tested separately between aGVHD and non-aGVHD cohorts and were further analyzed in a logistic regression model with backward elimination and a partial least squares discriminant analysis. Thirty-three patient cases were included in our study and 52% (17/33) developed aGVHD while on tacrolimus prophylaxis. When tested independently, donor age and sibling versus parent donor/recipient relation were shown to be statistically significant between aGVHD and non-aGVHD patients (p < 0.005). Pharmacological factors associated with tacrolimus treatment failed to demonstrate a significant impact on patient's risk of aGVHD. Using a best fit logistic regression model that tested all the variables together, donor age was the only significant variable predicting patient's risk of aGVHD (p < 0.01). Donor relationship and donor age were unable to be evaluated separately and are therefore confounding variables. Among pediatric patients receiving allogeneic HSCT, aGVHD risk is significantly decreased by either sibling donor and/or younger donors. Although no conclusions were drawn on the effect of tacrolimus therapy (p = 0.08), results warrant additional research with a larger sample size to evaluate the accuracy of monitoring tacrolimus serum trough levels.

Risk Factors Associated With Low Back Pain in Golfers: A Systematic Review and Meta-analysis.

CONTEXT:: Low back pain is common in golfers. The risk factors for golf-related low back pain are unclear but may include individual demographic, anthropometric, and practice factors as well as movement characteristics of the golf swing. OBJECTIVE:: The aims of this systematic review were to summarize and synthesize evidence for factors associated with low back pain in recreational and professional golfers. DATA SOURCES:: A systematic literature search was conducted using the PubMed, CINAHL, and SPORTDiscus electronic databases through September 2017. STUDY SELECTION:: Studies were included if they quantified demographic, anthropometric, biomechanical, or practice variables in individuals with and without golf-related low back pain. STUDY DESIGN:: Systematic review and meta-analysis. LEVEL OF EVIDENCE:: Level 3. DATA EXTRACTION:: Studies were independently reviewed for inclusion by 2 authors, and the following data were extracted: characterization of low back pain, participant demographics, anthropometrics, biomechanics, strength/flexibility, and practice characteristics. The methodological quality of studies was appraised by 3 authors using a previously published checklist. Where possible, individual and pooled effect sizes of select variables of interest were calculated for differences between golfers with and without pain. RESULTS:: The search retrieved 73 articles, 19 of which met the inclusion criteria (12 case-control studies, 5 cross-sectional studies, and 2 prospective longitudinal studies). Methodological quality scores ranged from 12.5% to 100.0%. Pooled analyses demonstrated a significant association between increased age and body mass and golf-related low back pain in cross-sectional/case-control studies. Prospective data indicated that previous history of back pain predicts future episodes of pain. CONCLUSION:: Individual demographic and anthropometric characteristics may be associated with low back pain, but this does not support a relationship between swing characteristics and the development of golf-related pain. Additional high-quality prospective studies are needed to clarify risk factors for back pain in golfers.

Effects of a Multicourse, Composite Examination Method on the Performance of PharmD Students in a Basic Pharmacokinetics Course.

Objective. To investigate the effects of multicourse, composite examinations on student performance in a pharmacokinetics course. Methods. A linear, mixed-effects model was used to analyze student performance in identical daily quiz and examination questions in a pharmacokinetics course at two pharmacy schools. The same instructor taught the entire course at both institutions. The only difference between the two courses was the method of administration of examinations between the two school cohorts. Results. Students' scores on identical daily quizzes that were administered similarly to students in both schools were the same. However, student grades on multicourse examinations were significantly lower than those administered as individual course examinations in the other school group. The effect size was 1.15, indicating a large difference between the two cohorts in terms of their examination scores. The mixed-effects model revealed a negligible difference (0.622%) between the two student cohorts in terms of their academic abilities but showed a substantial effect (9.40%) for the examination format in favor of single course assessment. Conclusion. When compared to traditional, individual course examination, multicourse, composite examinations may significantly lower student grades in a pharmacokinetics course.