Managing Grief for Pharmacy Leaders.

Grief is everywhere and affects individuals and teams in many different ways. The negative effects may not only be felt by the individual, but they can disrupt a team or an entire organization. While grief is common, understanding how to interact with others who are grieving is not. As leaders within healthcare institutions, pharmacists encounter many individuals and teams that are experiencing grief. The sources of grief can arise from pharmacy team members, other healthcare providers, patients, or our own personal experiences. This literature review introduces grief, where it comes from, and how it is emotionally and physically expressed in individuals. It discusses grief's disruptive nature and how to effectively communicate with those grieving to limit disturbances to individual, team, and organizational performance. Understanding what grief is, how it manifests in individuals and teams, and how to navigate a grieving workplace are vital skills for pharmacy leaders and will enable a more productive workplace.

A Comparison of Inventory Management Models in Automated Dispensing Cabinets at a Large Academic Medical Center.

Purpose: To compare and evaluate 2 methods of inventory management in automated dispensing cabinets (ADCs). Methods: Ten profiled ADCs had 2 inventory management models implemented over 2 months. Implementation of the models on each ADC involved adjustment of par levels (desired accessible quantities of medication) and removal of medications not used in the past 90 days or more. The par levels of 5 ADCs were adjusted using a formula developed based on the economic order quantity model. The par levels of the other 5 ADCs were adjusted using a formula based on historical average daily usage. The study endpoints include stock out rate, vend:fill ratio, quantity of expired medications, and inventory carrying cost. Results: The total of number of medications stocked in the 10 ADCs was reduced from 3035 in a 2-month pre-implementation period to 2932 in a 2-month post-implementation period yielding a reduction of inventory carrying cost by $11 011. The mean stock out rate in both study groups increased and vend:fill ratio decreased after implementation. The quantity of expired medications increased in the modified economic order quantity formula inventory management model and decreased in the average daily usage inventory management model. Conclusion: The implementation of 2 inventory management models on ADCs had a negative impact on stock out rate and vend:fill ratio, a mixed impact on quantity of expired medications, and a positive impact on inventory carrying cost reduction.

Polyethylene Glycol-Mediated Axonal Fusion Promotes Early Sensory Recovery After Digital Nerve Injury: A Randomized Clinical Trial.

BACKGROUND: Peripheral nerve repair is limited by Wallerian degeneration coupled with the slow and inconsistent rates of nerve regrowth. In more proximal injuries, delayed nerve regeneration can cause debilitating muscle atrophy. Topical application of polyethylene glycol (PEG) during neurorrhaphy facilitates the fusion of severed axonal membranes, immediately restoring action potentials across the coaptation site. In preclinical animal models, PEG-fusion resulted in remarkable early functional recovery. METHODS: This is the first randomized clinical trial comparing functional outcomes between PEG-fusion and standard neurorrhaphy. Participants with digital nerve transections were followed up at 2 weeks, 1 month, and 3 months postoperatively. The primary outcome was assessed using the Medical Research Council Classification (MRCC) rating for sensory recovery at each timepoint. Semmes-Weinstein monofilaments and static two-point discrimination determined MRCC ratings. Postoperative quality of life was measured using the Michigan Hand Questionnaire (MHQ). RESULTS: Forty-eight transected digital nerves (25 control, 23 PEG) across twenty-two patients were analyzed. PEG-fused nerves demonstrated significantly higher MRCC scores at 2 weeks (OR 16.95, 95% CI: 1.79 - 160.38, p = 0.008) and 1 month (OR 13.40, 95% CI: 1.64 - 109.77, p = 0.009). Participants in the PEG cohort also had significantly higher average MHQ scores at 2 weeks (Hodge's g 1.28, 95% CI: 0.23 - 2.30, p = 0.0163) and 1 month (Hodge's g 1.02, 95% CI: 0.04 - 1.99, p = 0.049). No participants had adverse events related to the study drug. CONCLUSION: PEG-fusion promotes early sensory recovery and improved patient well-being following peripheral nerve repair of digital nerves.

Analyzing Gene Expression After Administration of Low-Intensity Therapeutic Ultrasound in Human Islet Cells.

OBJECTIVES: Diabetes mellitus is a complex heterogenous metabolic disease that significantly affects the world population. Although many treatments exist, including medications such as metformin, sulfonylureas, and glucagon-like peptide-1 (GLP) receptor agonist, there is growing interest in finding alternative methods to noninvasively treat this disease. It has been previously shown that low-intensity ultrasound stimulation of pancreatic ß-cells in mice can elicit insulin secretion as a potential treatment for this disease. This is desirable as therapeutic ultrasound has the ability to induce bioeffects while selectively focusing deep within tissues, allowing for modulation of hormone secretion in the pancreas to mitigate insufficient levels of insulin. METHODS: Exactly 800 kHz ultrasound with intensity 0.5 W/cm2 was administered 5 minutes continuously, that is, 100% duty cycle, to donor pancreatic human islets, followed by 1 hour incubation and RT-qPCR to assess the effect of ultrasound stimulation on gene expression. The genes were insulin (INS), glucagon (Glu), amylin (Amy), and binding immunoglobulin protein (BiP). Nine donor pancreatic human islets were used to assess insulin and glucagon secretion, while eight samples were used for amylin and BiP. Fold change (FC) was calculated to analyze the effect of ultrasound stimulation on the gene expression of the donor islet cells. High-glucose and thapsigargin-treated islets were utilized as positive controls. Cell viability testing was done using a Trypan Blue Exclusion Test. RESULTS: Ultrasound stimulation did not cause a statistically significant upregulation in any of the tested genes (INS FC = 1.15, P-value = .5692; Glu FC = 1.60, P-value = .2231; Amy FC, P-value = .2863; BiP FC = 2.68, P-value = .3907). CONCLUSIONS: The results of this study show that the proposed ultrasound treatment parameters do not appear to significantly affect gene expression of any gene tested.

Unveiling the Complex World of Extracellular Vesicles: Novel Characterization Techniques and Manufacturing Considerations.

Extracellular vesicles (EVs) function as potent mediators of intercellular communication for many in vivo processes, contributing to both health and disease related conditions. Given their biological origins and diverse functionality from correspondingly unique "cargo" compositions, both endogenous and modified EVs are garnering attention as promising therapeutic modalities and vehicles for targeted therapeutic delivery applications. Their diversity in composition, however, has revealed a significant need for more comprehensive analytical-based characterization methods, and manufacturing processes that are consistent and scalable. In this review, we explore the dynamic landscape of EV research and development efforts, ranging from novel isolation approaches, to their analytical assessment through novel characterization techniques, and to their production by industrial-scale manufacturing process considerations. Expanding the horizon of these topics to EVs for in-human applications, we underscore the need for stringent development and adherence to Good Manufacturing Practice (GMP) guidelines. Wherein, the intricate interplay of raw materials, production in bioreactors, and isolation practices, along with analytical assessments compliant with the Minimal Information for Studies of Extracellular Vesicles (MISEV) guidelines, in conjunction with reference standard materials, collectively pave the way for standardized and consistent GMP production processes.

DNA transfer between two different species mediated by heterologous cell fusion in Clostridium coculture.

Prokaryotic evolution is driven by random mutations and horizontal gene transfer (HGT). HGT occurs via transformation, transduction, or conjugation. We have previously shown that in syntrophic cocultures of Clostridium acetobutylicum and Clostridium ljungdahlii, heterologous cell fusion leads to a large-scale exchange of proteins and RNA between the two organisms. Here, we present evidence that heterologous cell fusion facilitates the exchange of DNA between the two organisms. Using selective subculturing, we isolated C. acetobutylicum cells which acquired and integrated into their genome portions of plasmid DNA from a plasmid-carrying C. ljungdahlii strain. Limiting-dilution plating and DNA methylation data based on PacBio Single-Molecule Real Time (SMRT) sequencing support the existence of hybrid C. acetobutylicum/C. ljungdahlii cells. These findings expand our understanding of multi-species microbiomes, their survival strategies, and evolution.IMPORTANCEInvestigations of natural multispecies microbiomes and synthetic microbial cocultures are attracting renewed interest for their potential application in biotechnology, ecology, and medical fields. Previously, we have shown the syntrophic coculture of C. acetobutylicum and C. ljungdahlii undergoes heterologous cell-to-cell fusion, which facilitates the exchange of cytoplasmic protein and RNA between the two organisms. We now show that heterologous cell fusion between the two Clostridium organisms can facilitate the exchange of DNA. By applying selective pressures to this coculture system, we isolated clones of wild-type C. acetobutylicum which acquired the erythromycin resistance (erm) gene from the C. ljungdahlii strain carrying a plasmid with the erm gene. Single-molecule real-time sequencing revealed that the erm gene was integrated into the genome in a mosaic fashion. Our data also support the persistence of hybrid C. acetobutylicum/C. ljungdahlii cells displaying hybrid DNA-methylation patterns.

Clinical presentation of Warburg effect in aggressive lymphoma: a case report.

BACKGROUND: The Warburg effect is a rare condition in tumor biology, illustrated by significant lactate production in the presence of oxygen. The Warburg effect is associated with very poor prognosis in patients with malignancy. CASE PRESENTATION: We report a 76-year-old Caucasian woman with double-expressor diffuse large B cell lymphoma who presented with severe lactic acidosis and extreme hypoglycemia with normal mentation. Her lactic acidosis was initially controlled with a bicarbonate infusion, and the patient was started promptly on steroids, followed by chemotherapy, but her clinical course was complicated by tumor lysis syndrome, acute renal failure requiring hemodialysis, and progressive liver failure. She manifested a temporary clinical response to chemotherapy but eventually died of complications. CONCLUSIONS: This case demonstrates the importance of prompt recognition of the Warburg effect, aggressive supportive measures, and early initiation of chemotherapy. Future studies are needed to characterize the role of hemodialysis in this setting.

A Data-Driven Approach to Evaluate Barcode-Assisted Medication Preparation Alerts at a Large Academic Medical Center.

BACKGROUND: The purpose of this study was to develop a data-driven process to analyze barcode-assisted medication preparation alert data with a goal of minimizing inaccurate alerts. METHODS: Medication preparation data for the prior three-month period was obtained from an electronic health record system. A dashboard was developed to identify recurrent, high-volume alerts and associated medication records. A randomization tool was used to obtain a prespecified proportion of the alerts to review for appropriateness. Alert root causes were identified by chart review. Depending on the alert's cause(s), targeted informatics build changes, workflow and purchasing changes, and/or staff education were implemented. The rate of alerts was measured postintervention for select drugs. RESULTS: The institution averaged 31,000 medication preparation alerts per month. The "barcode not recognized" alert (13,000) was the highest volume over the study period. Eighty-five medication records were identified as contributing to a high volume of alerts (5,200/31,000), representing 49 unique drugs. Of the 85 medication records triggering alerts, 36 required staff education, 22 required informatics build changes, and 8 required workflow changes. Targeted interventions for 2 medications, resulted in reducing the rate of the "barcode not recognized" alert from 26.6% to 1.3% for polyethylene glycol and from 48.7% to 0% for cyproheptadine. CONCLUSION: This quality improvement project highlighted opportunities to improve medication purchasing, storage, and preparation through development of a standard process to evaluate barcode-assisted medication preparation alert data. A data-driven approach can help identify and minimize inaccurate alerts ("noise") and promote medication safety.

Analysis of the AUA Guidelines: Strength of Evidence Correlates With Recommendation Levels.

INTRODUCTION: As part of its mission to provide the highest standards of clinical care, the AUA publishes guidelines on numerous urological topics. We sought to evaluate the caliber of evidence used establish the currently available AUA guidelines. METHODS: All available AUA guideline statements in 2021 were reviewed for their level of evidence and recommendation strength. Statistical analysis was performed to identify differences between oncological and nononcologic topics, and statements pertinent to diagnosis, treatment, and follow-up. A multivariate analysis was utilized to identify factors associated with strong recommendations. RESULTS: A total of 939 statements across 29 guidelines were analyzed; 39 (4.2%) were backed by Grade A evidence, 188 (20%) Grade B, 297 (31.6%) Grade C, 185 (19.7%) Clinical Principle, and 230 (24.5%) Expert Opinion. There was a significant association of oncology guidelines (6% vs 3%, P = .021) with more grade A evidence and less Grade C Evidence (24% vs 35%, P = .002). Statements pertaining to diagnosis and evaluation were more likely backed by Clinical Principle (31% vs 14% vs 15%, P < .01), treatment statements backed by B (26% vs 13% vs 11%, P < .01) and C (35% vs 30% vs 17%, P < .01) grade evidence, and follow-up statements backed by Expert Opinion (53% vs 23% vs 24%, P < .01). On multivariate analysis, strong recommendations were more likely supported by high-grade evidence (OR = 12, P < .01). CONCLUSIONS: The majority of evidence for the AUA guidelines is not high grade. Additional high-quality urological studies are needed to improve evidence based urological care.

Formulary & benefit and real-time pharmacy Benefit: Electronic standards delivering value to prescribers and pharmacists.

The use of standard transactions in the electronic sharing of prescription-related information among payers, prescribers and pharmacists aids in the delivery of effective, safe, and affordable medication therapy to patients. Integral to electronic medication management (eMM) in this environment is the availability of data to aid in the determination of the most appropriate medication for a patient considering benefits coverage restrictions, therapeutic effectiveness, and cost. Key elements of this formulary decision support are the National Council for Prescription Drug Programs Formulary & Benefit (F&B) standard and the related Real-time Pharmacy Benefit (RTPB) standard. In this article, we review the foundational role of F&B in the electronic prescribing of medications, the value it delivers to prescribers, and dispensing pharmacists. The combination of F&B and RTPB to enhance the quality of information available in eMM is also discussed with evidence presented on how these standards help to minimize manual tasks and rework in the pharmacy, optimize time to therapy, lower patient out-of-pocket costs, and result in the dispensing of prescriptions less likely to be abandoned. We conclude with a view of the future of F&B to support new eMM requirements.

Gender and Ethnic Diversity in Plastic Surgery: Temporal Trends among Speakers at National and Regional Plastic Surgery Conferences.

BACKGROUND: Scientific leadership among women and underrepresented minorities is lacking in plastic surgery. It is unknown whether the underrepresentation of women and ethnic minorities extends into academic conferences. The authors evaluated the temporal trends of female and ethnic minority representation at plastic surgery conferences in the United States. METHODS: A retrospective analysis of all presentations from seven national and regional plastic surgery meetings between 2014 and 2018 was conducted. Gender, ethnicity, and academic rank of the first authors were determined by analyzing pronouns, institutional biographies, and accompanying images identified in online searches. RESULTS: A total of 4180 abstracts were presented by 3452 first authors. The majority of first authors were of European descent (53%), male (65%), and most commonly a resident physician (42%). Women were found to have a greater representation at plastic surgery conferences than in the plastic surgery workforce (34% versus 17%; P < 0.0001). Similarly, relative to American Association of Medical Colleges demographics, individuals of Asian descent were overrepresented as first authors (27% versus 12%; P < 0.0001), whereas first authors of European descent were less prevalent (53% versus 64%; P < 0.0001). When compared with national plastic surgery conferences, regional conferences had a greater proportion of first authors of European descent (51% versus 58%; P < 0.0001) but a lower proportion of first authors of East Asian descent (21% versus 16%; P = 0.0001). Ethnic representation remained persistently low, with first authors of South Asian descent decreasingly represented [from 2014 (10%) to 2018 (6%); P = 0.0062]. CONCLUSIONS: Collectively, we present multilevel data that show a promising trend of increased female representation at national meetings. However, there appears to be a decline in ethnic diversity.

Correlation consistent auxiliary basis sets in density fitting Hartree-Fock: The atoms sodium through argon revisited.

We present a series of auxiliary basis sets, for the elements Na to Ar, for use in density-fitted Hartree-Fock calculations with the correlation consistent cc-pV(n + d)Z orbital basis sets. Benchmarking on total molecular energies, reaction energies and the spectroscopic constants of the SO molecule demonstrate that the new sets address the deficiencies of using existing auxiliary sets in combination with these orbital basis sets. We also report auxiliary basis sets for Na and Mg matched to cc-pVnZ, along with recommendations for pairing auxiliary basis sets to the cc-pVnZ-F12 basis sets for Hartree-Fock calculations.

Patient-Reported Lower Extremity Outcomes Following Fibula or Medial Femoral Condyle Free Flaps for Upper Extremity Defects.

BACKGROUND: Free fibula flap (FFF) and medial femoral condyle (MFC) flap are commonly used for upper extremity osseous reconstruction, yet donor-site morbidity has never been systematically compared. METHODS: Patients who underwent an FFF or MFC for upper extremity extra-carpal osseous reconstruction at 3 academic hand centers were retrospectively identified. Only patients who underwent reconstruction for a defect in which either flap type is routinely used or has been described in the literature were deemed eligible. Patients who agreed to participate were asked to complete the Lower Extremity Functional Scale (LEFS) and Lower Limb Core Scale (LLCS). The reported population norm median score of LEFS is 77 points. The LLCS population norm mean score is 90.52 points. RESULTS: Twenty-one patients (10 MFC, 11 FFF) were enrolled. The median LEFS score for patients after MFC was 76 (interquartile range [IQR], 49-80) points and 75 (IQR, 56-79) points after FFF. The median LLCS score for patients after MFC was 96.4 (IQR, 87.9-100) points and 100 (IQR, 91-100) points after FFF. Median LEFS scores were slightly below the population norm, whereas median LLCS scores were above the norm for both FFF and MFC. All patients stated they would have the surgery again and that any dysfunction or pain in the leg was justified by the benefit in the arm. CONCLUSIONS: When considering whether to use an MFC or FFF for upper extremity reconstruction, both flap types appear to result in modest and comparable donor-site morbidity.

Venetoclax: A Novel Therapeutic Agent for CLL with CNS Involvement.

Chronic lymphocytic leukemia (CLL) involves the proliferation of a clonal population of B cells within the bone marrow that classically spreads to the blood and lymphatic system. Central nervous system (CNS) manifestations of CLL occur rarely, and no gold standard treatment regimen has been designated to date. We report a case of CLL with CNS involvement in a 68-year-old woman who presented with a severe headache 4 years after initial diagnosis. She was started on ibrutinib, which failed to clear her CSF of malignancy. Venetoclax was then added, and this was successful in clearing her CSF. For its CNS penetration and efficacy in achieving CSF remission of CLL, we propose that venetoclax be considered as a treatment option for CLL meningitis.

Exosome Processing and Characterization Approaches for Research and Technology Development.

Exosomes are extracellular vesicles that share components of their parent cells and are attractive in biotechnology and biomedical research as potential disease biomarkers as well as therapeutic agents. Crucial to realizing this potential is the ability to manufacture high-quality exosomes; however, unlike biologics such as proteins, exosomes lack standardized Good Manufacturing Practices for their processing and characterization. Furthermore, there is a lack of well-characterized reference exosome materials to aid in selection of methods for exosome isolation, purification, and analysis. This review informs exosome research and technology development by comparing exosome processing and characterization methods and recommending exosome workflows. This review also provides a detailed introduction to exosomes, including their physical and chemical properties, roles in normal biological processes and in disease progression, and summarizes some of the on-going clinical trials.

Ablation of typical atrial flutter using mini electrode measurements for maximum voltage-guided ablation: A randomized, controlled trial.

BACKGROUND: Novel ablation catheters with mini electrode (ME) sensing have become available but their utility is unclear. We investigated whether ablation of the cavotricuspid isthmus (CTI) for atrial flutter (AFL) would be improved using ME signals. METHODS: Sixty-one patients (76% male, 63 ± 10 years) with CTI-dependent AFL underwent ablation using a maximum voltage-guided approach, randomized to either standard 8 mm non-irrigated catheter with bipolar signals or IntellaTip MiFi catheter using ME signals alone. RESULTS: Acute bidirectional block was achieved in 97%. Mean follow-up was 16.7 ± 10 months. The median number of ablation lesions was 13 in both groups (range 3-62 vs. 1-43, p = .85). No significant differences were observed in AFL recurrences (17% vs. 11%, p = .7), median procedure durations (97 min [interquartile range (IQR), 71-121] vs. 87 min [IQR, 72-107], p = .55) or fluoroscopy times (31 min [IQR, 21-52] vs. 38 min [IQR, 25-70], p = .56). Amplitudes of ME signals were on average 160% greater than blinded bipolar signals. In 23.7% of lesions where bipolar signals were difficult to interpret, 13.6% showed a clear ME signal. CONCLUSIONS: There was no difference in the effectiveness of CTI ablation guided by ME signals, compared with using bipolar signals from a standard 8 mm ablation catheter. While ME signal amplitudes were larger and sometimes present when the bipolar signal was unclear, this did not improve procedural characteristics or outcomes. The results suggest future research should focus on lesion integrity rather than signal sensing.

Best Practices for Aggregate Quantitation of Antibody Therapeutics by Sedimentation Velocity Analytical Ultracentrifugation.

Analytical ultracentrifugation (AUC) is a critical analytical tool supporting the development and manufacture of protein therapeutics. AUC is routinely used as an assay orthogonal to size exclusion chromatography for aggregate quantitation. This article distills the experimental and analysis procedures used by the authors for sedimentation velocity AUC into a series of best-practices considerations. The goal of this distillation is to help harmonize aggregate quantitation approaches across the biopharmaceutical industry. We review key considerations for sample and instrument suitability, experimental design, and data analysis best practices and conversely, highlight potential pitfalls to accurate aggregate analysis. Our goal is to provide experienced users benchmarks against which they can standardize their analyses and to provide guidance for new AUC analysts that will aid them to become proficient in this fundamental technique.

Synovial Fluid Cytokines, Chemokines and MMP Levels in Osteoarthritis Patients with Knee Pain Display a Profile Similar to Many Rheumatoid Arthritis Patients.

BACKGROUND: There are currently no effective disease-modifying drugs to prevent cartilage loss in osteoarthritis and synovial fluid is a potentially valuable source of biomarkers to understand the pathogenesis of different types of arthritis and identify drug responsiveness. The aim of this study was to compare the differences between SF cytokines and other proteins in patients with OA (n = 21) to those with RA (n = 27) and normal knees (n = 3). METHODS: SF was obtained using ultrasound (US) guidance and an external pneumatic compression device. RA patients were categorized as active (n = 20) or controlled (n = 7) based upon SF white blood cell counts (> or <300 cells/mm3). Samples were cryopreserved and analyzed by multiplex fluorescent bead assays (Luminex). Between-group differences of 16 separate biomarker proteins were identified using ANOVA on log10-transformed concentrations with p values adjusted for multiple testing. RESULTS: Only six biomarkers were significantly higher in SF from active RA compared to OA-TNF-α, IL-1-ß IL-7, MMP-1, MMP-2, and MMP-3. Only MMP-8 levels in RA patients correlated with SF WBC counts (p < 0.0001). Among OA patients, simultaneous SF IL-4, IL-6, IL-8, and IL-15 levels were higher than serum levels, whereas MMP-8, MMP-9, and IL-18 levels were higher in serum (p < 0.05). CONCLUSION: These results support the growing evidence that OA patients have a pro-inflammatory/catabolic SF environment. SF biomarker analysis using multiplex testing and US guidance may distinguish OA phenotypes and identify treatment options based upon targeted inflammatory pathways similar to patients with RA.

Laser-induced transient magnons in Sr3Ir2O7 throughout the Brillouin zone.

Although ultrafast manipulation of magnetism holds great promise for new physical phenomena and applications, targeting specific states is held back by our limited understanding of how magnetic correlations evolve on ultrafast timescales. Using ultrafast resonant inelastic X-ray scattering we demonstrate that femtosecond laser pulses can excite transient magnons at large wavevectors in gapped antiferromagnets and that they persist for several picoseconds, which is opposite to what is observed in nearly gapless magnets. Our work suggests that materials with isotropic magnetic interactions are preferred to achieve rapid manipulation of magnetism.