A comprehensive measure of Golgi sphingolipid flux using NBD C6-ceramide: evaluation of sphingolipid inhibitors.

Measurements of sphingolipid metabolism are most accurately performed by LC-MS. However, this technique is expensive, not widely accessible, and without the use of specific probes, it does not provide insight into metabolic flux through the pathway. Employing the fluorescent ceramide analogue NBD-C6-ceramide as a tracer in intact cells, we developed a comprehensive HPLC-based method that simultaneously measures the main nodes of ceramide metabolism in the Golgi. Hence, by quantifying the conversion of NBD-C6-ceramide to NBD-C6-sphingomyelin, NBD-C6-hexosylceramides, and NBD-C6-ceramide-1-phosphate (NBD-C1P), the activities of Golgi resident enzymes sphingomyelin synthase 1, glucosylceramide synthase, and ceramide kinase (CERK) could be measured simultaneously. Importantly, the detection of NBD-C1P allowed us to quantify CERK activity in cells, a usually difficult task. By applying this method, we evaluated the specificity of commonly used sphingolipid inhibitors and discovered that 1-phenyl-2-decanoylamino-3-morpholino-1-propanol, which targets glucosylceramide synthase, and fenretinide (4HPR), an inhibitor for dihydroceramide desaturase, also suppress CERK activity. This study demonstrates the benefit of an expanded analysis of ceramide metabolism in the Golgi, and it provides a qualitative and easy-to-implement method.

Changes in opioid prescribing and prescription drug monitoring program utilization following electronic health record integration-Massachusetts, 2018.

OBJECTIVE: In this study, we explored key prescription drug monitoring program-related outcomes among clinicians from a broad cohort of Massachusetts healthcare facilities following prescription drug monitoring program (PDMP) and electronic health record (EHR) data integration. METHODS: Outcomes included seven-day rolling averages of opioids prescribed, morphine milligram equivalents (MMEs) prescribed, and PDMP queries. We employed a longitudinal study design to analyze PDMP data over a 15-month study period which allowed for six and a half months of pre- and post-integration observations surrounding a two-month integration period. We used longitudinal mixed effects models to examine the effect of EHR integration on each of the key outcomes. RESULTS: Following EHR integration, PDMP queries increased both through the web-based portal and in total (0.037, [95% CI = 0.017, 0.057] and 0.056, [95% CI = 0.035, 0.077]). Both measures of clinician opioid prescribing declined throughout the study period; however, no significant effect following EHR integration was observed. These results were consistent when our analysis was applied to a subset consisting only of continuous PDMP users. CONCLUSIONS: Our results support EHR integration contributing to PDMP utilization by clinicians but do not support changes in opioid prescribing behavior.

Impact of Recreational Cannabis Legalization on Opioid Prescribing and Opioid-Related Hospital Visits in Colorado: an Observational Study.

BACKGROUND: Cannabis may be a substitute for opioids but previous studies have found conflicting results when using data from more recent years. Most studies have examined the relationship using state-level data, missing important sub-state variation in cannabis access. OBJECTIVE: To examine cannabis legalization on opioid use at the county level, using Colorado as a case study. Colorado allowed recreational cannabis stores in January 2014. Local communities could decide whether to allow dispensaries, creating variation in the level of exposure to cannabis outlets. DESIGN: Observational, quasi-experimental design exploiting county-level variation in allowance of recreational dispensaries. SUBJECTS: Colorado residents MEASURES: We use licensing information from the Colorado Department of Revenue to measure county-level exposure to cannabis outlets. We use the state's Prescription Drug Monitoring Program (2013-2018) to construct opioid-prescribing measures of number of 30-day fills and total morphine equivalents, both per county resident per quarter. We construct outcomes of opioid-related inpatient visits (2011-2018) and emergency department visits (2013-2018) with Colorado Hospital Association data. We use linear models in a differences-in-differences framework that accounts for the varying exposure to medical and recreational cannabis over time. There are 2048 county-quarter observations used in the analysis. RESULTS: We find mixed evidence of cannabis exposure on opioid-related outcomes at the county level. We find increasing exposure to recreational cannabis is associated with a statistically significant decrease in number of 30-day fills (coefficient: -117.6, p-value<0.01) and inpatient visits (coefficient: -0.8, p-value: 0.03), but not total MME nor ED visits. Counties with no medical exposure prior to recreational legalization experience greater reductions in the number of 30-day fills and MME than counties with prior medical exposure (p=0.02 for both). CONCLUSIONS: Our mixed findings suggest that further increases in cannabis beyond medical access may not always reduce opioid prescribing or opioid-related hospital visits at a population level.

Salvianolic acid B suppresses hepatic fibrosis by inhibiting ceramide glucosyltransferase in hepatic stellate cells.

UDP-glucose ceramide glucosyltransferase (UGCG) is the first key enzyme in glycosphingolipid (GSL) metabolism that produces glucosylceramide (GlcCer). Increased UGCG synthesis is associated with cell proliferation, invasion and multidrug resistance in human cancers. In this study we investigated the role of UGCG in the pathogenesis of hepatic fibrosis. We first found that UGCG was over-expressed in fibrotic livers and activated hepatic stellate cells (HSCs). In human HSC-LX2 cells, inhibition of UGCG with PDMP or knockdown of UGCG suppressed the expression of the biomarkers of HSC activation (α-SMA and collagen I). Furthermore, pretreatment with PDMP (40 µM) impaired lysosomal homeostasis and blocked the process of autophagy, leading to activation of retinoic acid signaling pathway and accumulation of lipid droplets. After exploring the structure and key catalytic residues of UGCG in the activation of HSCs, we conducted virtual screening, molecular interaction and molecular docking experiments, and demonstrated salvianolic acid B (SAB) from the traditional Chinese medicine Salvia miltiorrhiza as an UGCG inhibitor with an IC50 value of 159 µM. In CCl4-induced mouse liver fibrosis, intraperitoneal administration of SAB (30 mg · kg-1 · d-1, for 4 weeks) significantly alleviated hepatic fibrogenesis by inhibiting the activation of HSCs and collagen deposition. In addition, SAB displayed better anti-inflammatory effects in CCl4-induced liver fibrosis. These results suggest that UGCG may represent a therapeutic target for liver fibrosis; SAB could act as an inhibitor of UGCG, which is expected to be a candidate drug for the treatment of liver fibrosis.

The prescription drug monitoring program in a multifactorial approach to the opioid crisis: PDMP data, Pennsylvania, 2016-2020.

BACKGROUND: Prescription opioids remain an important contributor to the United States opioid crisis and to the development of opioid use disorder for opioid-naïve individuals. Recent legislative actions, such as the implementation of state prescription drug monitoring programs (PDMPs), aim to reduce opioid morbidity and mortality through enhanced tracking and reporting of prescription data. The primary objective of our study was to describe the opioid prescribing trends in the state of Pennsylvania (PA) as recorded by the PA PDMP following legislative changes in reporting guidelines, and discuss the PDMP's role in a multifactorial approach to opioid harm reduction. METHODS: State-level opioid prescription data summaries recorded by the PA PDMP for each calendar quarter from August 2016 through March 2020 were collected from the PA Department of Health. Data for oxycodone, hydrocodone, and morphine were analyzed by quarter for total prescription numbers and refills. Prescription lengths, pill quantities, and average morphine milliequivalents (MMEs) were analyzed by quarter for all 14 opioid prescription variants recorded by the PA PDMP. Linear regression was conducted for each group of variables to identify significant differences in prescribing trends. RESULTS: For total prescriptions dispensed, the number of oxycodone, hydrocodone, and morphine prescriptions decreased by 34.4, 44.6, and 22.3% respectively (p < 0.0001). Refills fluctuated less consistently with general peaks in Q3 of 2017 and Q3 of 2018 (p = 0.2878). The rate of prescribing for all opioid prescription lengths decreased, ranging in frequency from 22 to 30 days (47.5% of prescriptions) to 31+ days of opioids (0.8% of prescriptions) (p < 0.0001). Similarly, decreased prescribing was observed for all prescription amounts, ranging in frequency from 22 to 60 pills (36.6% of prescriptions) to 60-90 pills (14.2% of prescriptions) (p < 0.0001). Overall, the average MME per opioid prescription decreased by 18.9%. CONCLUSIONS: Per the PA PDMP database, opioid prescribing has decreased significantly in PA from 2016 to 2020. The PDMP database is an important tool for tracking opioid prescribing trends in PA, and PDMPs structured similarly in other states may enhance our ability to understand and influence the trajectory of the U.S. opioid crisis. Further research is needed to determine optimal PDMP policies and practices nationwide.

Perspectives of opioid prescribers in overdose hotspots and coldspots, Massachusetts, 2019.

BACKGROUND: Prescription opioids (POs) have had a devastating effect on people and public health systems in the U.S. Due to the urgency and complexity of the opioid crisis, there is a need to expand qualitative research on the medical community's perspectives on opioid prescribing practices and the role that prescription drug monitoring programs (PDMPs) have played in mitigating this crisis. METHODS: We conducted qualitative interviews with clinicians (n = 23) across specialties and a range of overdose hotspot and coldspot locations in Massachusetts during 2019. We aimed to capture their perspectives on the opioid crisis, changes in clinical practice, and experiences with opioid prescribing and PDMPs. RESULTS: Respondents consistently recognized the role clinicians played in the opioid crisis and reported reductions in their opioid prescribing, which were motivated by the crisis itself. The limitations of opioids in pain management were frequently discussed. While clinicians appreciated having greater awareness of their opioid prescribing and increased access to patient prescription histories, they also expressed concerns about surveillance of their prescribing and other unintended consequences. We observed that clinicians in opioid prescribing hotspots had more detailed and specific reflections on their experiences with the Massachusetts PDMP, MassPAT. CONCLUSION: Clinician perceptions of the severity of the opioid crisis in Massachusetts and thoughts on their role as prescribers were consistent across specialty, prescribing level, and practice location. Many clinicians in our sample cited use of the PDMP as an influence on their prescribing. Those practicing in opioid overdose hotspots had the most nuanced reflections about the system.

Automated opioid risk scores: a case for machine learning-induced epistemic injustice in healthcare.

Artificial intelligence-based (AI) technologies such as machine learning (ML) systems are playing an increasingly relevant role in medicine and healthcare, bringing about novel ethical and epistemological issues that need to be timely addressed. Even though ethical questions connected to epistemic concerns have been at the center of the debate, it is going unnoticed how epistemic forms of injustice can be ML-induced, specifically in healthcare. I analyze the shortcomings of an ML system currently deployed in the USA to predict patients' likelihood of opioid addiction and misuse (PDMP algorithmic platforms). Drawing on this analysis, I aim to show that the wrong inflicted on epistemic agents involved in and affected by these systems' decision-making processes can be captured through the lenses of Miranda Fricker's account of hermeneutical injustice. I further argue that ML-induced hermeneutical injustice is particularly harmful due to what I define as an automated hermeneutical appropriation from the side of the ML system. The latter occurs if the ML system establishes meanings and shared hermeneutical resources without allowing for human oversight, impairing understanding and communication practices among stakeholders involved in medical decision-making. Furthermore and very much crucially, an automated hermeneutical appropriation can be recognized if physicians are strongly limited in their possibilities to safeguard patients from ML-induced hermeneutical injustice. Overall, my paper should expand the analysis of ethical issues raised by ML systems that are to be considered epistemic in nature, thus contributing to bridging the gap between these two dimensions in the ongoing debate.

Anti-inflammatory role of GM1 and other gangliosides on microglia.

BACKGROUND: Gangliosides are glycosphingolipids highly enriched in the brain, with important roles in cell signaling, cell-to-cell communication, and immunomodulation. Genetic defects in the ganglioside biosynthetic pathway result in severe neurodegenerative diseases, while a partial decrease in the levels of specific gangliosides was reported in Parkinson's disease and Huntington's disease. In models of both diseases and other conditions, administration of GM1-one of the most abundant gangliosides in the brain-provides neuroprotection. Most studies have focused on the direct neuroprotective effects of gangliosides on neurons, but their role in other brain cells, in particular microglia, is not known. In this study we investigated the effects of exogenous ganglioside administration and modulation of endogenous ganglioside levels on the response of microglia to inflammatory stimuli, which often contributes to initiation or exacerbation of neurodegeneration. METHODS: In vitro studies were performed using BV2 cells, mouse, rat, and human primary microglia cultures. Modulation of microglial ganglioside levels was achieved by administration of exogenous gangliosides, or by treatment with GENZ-123346 and L-t-PDMP, an inhibitor and an activator of glycolipid biosynthesis, respectively. Response of microglia to inflammatory stimuli (LPS, IL-1ß, phagocytosis of latex beads) was measured by analysis of gene expression and/or secretion of pro-inflammatory cytokines. The effects of GM1 administration on microglia activation were also assessed in vivo in C57Bl/6 mice, following intraperitoneal injection of LPS. RESULTS: GM1 decreased inflammatory microglia responses in vitro and in vivo, even when administered after microglia activation. These anti-inflammatory effects depended on the presence of the sialic acid residue in the GM1 glycan headgroup and the presence of a lipid tail. Other gangliosides shared similar anti-inflammatory effects in in vitro models, including GD3, GD1a, GD1b, and GT1b. Conversely, GM3 and GQ1b displayed pro-inflammatory activity. The anti-inflammatory effects of GM1 and other gangliosides were partially reproduced by increasing endogenous ganglioside levels with L-t-PDMP, whereas inhibition of glycolipid biosynthesis exacerbated microglial activation in response to LPS stimulation. CONCLUSIONS: Our data suggest that gangliosides are important modulators of microglia inflammatory responses and reveal that administration of GM1 and other complex gangliosides exerts anti-inflammatory effects on microglia that could be exploited therapeutically.

Metabolic Depletion of Sphingolipids Does Not Alter Cell Cycle Progression in Chinese Hamster Ovary Cells.

The cell cycle is a sequential multi-step process essential for growth and proliferation of cells comprising multicellular organisms. Although a number of proteins are known to modulate the cell cycle, the role of lipids in regulation of cell cycle is still emerging. In our previous work, we monitored the role of cholesterol in cell cycle progression in CHO-K1 cells. Since sphingolipids enjoy a functionally synergistic relationship with membrane cholesterol, in this work, we explored whether sphingolipids could modulate the eukaryotic cell cycle using CHO-K1 cells. Sphingolipids are essential components of eukaryotic cell membranes and are involved in a number of important cellular functions. To comprehensively monitor the role of sphingolipids on cell cycle progression, we carried out metabolic depletion of sphingolipids in CHO-K1 cells using inhibitors (fumonisin B1, myriocin, and PDMP) that block specific steps of the sphingolipid biosynthetic pathway and examined their effect on individual cell cycle phases. Our results show that metabolic inhibitors led to significant reduction in specific sphingolipids, yet such inhibition in sphingolipid biosynthesis did not show any effect on cell cycle progression in CHO-K1 cells. We speculate that any role of sphingolipids on cell cycle progression could be context and cell-type dependent, and cancer cells could be a better choice for monitoring such regulation, since sphingolipids are differentially modulated in these cells.

Gangliosides in T cell development and function of mice.

The molecular diversity of glycosphingolipids (GSLs) that arouse during the course of evolution clearly plays an essential role in maintenance of biological homeostasis. Why is such a wide variety of GSLs necessary, and what gave rise to the expression mechanisms that are selective and specific to individual cells, tissues, or organs? What is the biological significance of these mechanisms? The same questions apply to GSLs involved in T cell development and activation. Primary CD4+ T cells and CD8+ T cells preferentially express differing ganglioside series: a-series and o-series, respectively. Conversely, a-series and o-series ganglioside deficiency results respectively in CD4+ and CD8+ T cell dysfunction. Dynamic changes in ganglioside expression occur during T cell development in thymus. Ganglioside GM3 synthase deficiency, which results in lack of a-series gangliosides, ameliorated CD4+ T cell-mediated airway hypersensitivity in a mouse model of allergic asthma. In this review, we summarize findings from these and many studies to illustrate the key roles of gangliosides in T cell differentiation and function.

Accuracy and validity of reported opioid prescription days' supply.

PURPOSE: The primary objective of this study was to estimate the percentage of opioid analgesic (OA) prescriptions dispensed by Kentucky independent pharmacies with correctly entered days' supply in the state prescription drug monitoring program (PDMP) system in 2019. METHODS: Using a two-stage cluster design, pharmacies were sampled with probabilities proportional to the volume of dispensed OAs; 100 random OA prescriptions were sampled from PDMP records submitted by each pharmacy. Following recruitment, demographic information and hard-copy prescription data for sampled records were abstracted on-site. Days' supply was independently calculated by two pharmacists using a standard formula with disagreements adjudicated blindly by a third pharmacist. Adjudicated days' supply was compared with that submitted to the PDMP and classified as accurate/inaccurate. Descriptive statistics were used to characterize the sample and a multivariable logistic regression model was used to assess the relationship between accuracy and prescription/practice-related factors. RESULTS: A total of 1281 OA prescriptions were reviewed at 13 participating pharmacies. Accuracy of reported OA days' supply was 89.85%, (95% CI: 86.90, 92.80). Factors associated with accuracy were presence of special instructions from the prescriber (OR 3.13 [95% CI: 1.43, 6.82]), presence of 'as-needed' directions (OR 0.29 [95% CI: 0.18, 0.47]), and billing to a third-party payer (OR 1.43 [95% CI: 1.01, 2.02]). CONCLUSIONS: Accuracy of OA days' supply reported to the state PDMP was found to be moderately high. Certain prescription-related factors influence accuracy and should be accounted for in future studies. Patterns, including opioid 'split-billing' were identified and may impact validity of PDMP and administrative claims studies.

Fewer Opioids but More Benzodiazepines? Prescription Trends by Specialty in Response to the Implementation of Michigan's Opioid Laws.

OBJECTIVES: To characterize the effects of Michigan's controlled substance legislation on acute care prescriber behavior by specialty, in a single hospital system. DESIGN: A retrospective study of opioid and benzodiazepine prescription records from a hospital electronic medical record system between August 1, 2016, and March 31, 2019, in Detroit, Michigan. SETTING: Discharges from inpatient and emergency department visits. INTERVENTION: Evaluating the impact of implementation of state controlled substance legislation, comparing prescriptions by physicians before, upon, and after June 1, 2018, using regression discontinuity analysis. METHODS: Total daily prescriptions of opioids and total daily prescriptions of benzodiazepine by physicians in the hospital system. Prescriptions were converted to morphine and lorazepam equivalents for comparability. RESULTS: We find 38.5% (95% confidence interval [CI] : 74.1% - 2.9%) decrease of prescription in milligrams of opioid equivalents attributable to implementation of legislation. The main catalyst of the decrease was emergency medicine which experienced 63.9% (95% CI: 109.7%-18.0%) decrease in milligrams of opioid equivalent prescriptions, while surgery increased prescriptions. Though we do not find any statistically significant changes in prescriptions of milligram equivalent of benzodiazepines, we estimate 43.1% (95% CI: 82.6%-3.7%) decrease in count of these prescriptions, implying a significant increase in average dosage of prescriptions. CONCLUSIONS: The introduction of new regulatory requirements for the prescription of controlled substances led to a general decrease in morphine equivalent milligrams prescribed in most specialties, though it may have increased the dosage of benzodiazepine prescriptions. The change in prescription behavior could be motivated by regulatory hassle or by change in attitude towards opioid prescriptions and increased recognition of opioid use disorder.

Penicillium chrysogenum polypeptide extract protects tobacco plants from tobacco mosaic virus infection through modulation of ABA biosynthesis and callose priming.

The polypeptide extract of the dry mycelium of Penicillium chrysogenum (PDMP) can protect tobacco plants from tobacco mosaic virus (TMV), although the mechanism underlying PDMP-mediated TMV resistance remains unknown. In our study, we analysed a potential mechanism via RNA sequencing (RNA-seq) and found that the abscisic acid (ABA) biosynthetic pathway and ß-1,3-glucanase, a callose-degrading enzyme, might play an important role in PDMP-induced priming of resistance to TMV. To test our hypothesis, we successfully generated a Nicotiana benthamiana ABA biosynthesis mutant and evaluated the role of the ABA pathway in PDMP-induced callose deposition during resistance to TMV infection. Our results suggested that PDMP can induce callose priming to defend against TMV movement. PDMP inhibited TMV movement by increasing callose deposition around plasmodesmata, but this phenomenon did not occur in the ABA biosynthesis mutant; moreover, these effects of PDMP on callose deposition could be rescued by treatment with exogenous ABA. Our results suggested that callose deposition around plasmodesmata in wild-type plants is mainly responsible for the restriction of TMV movement during the PDMP-induced defensive response to TMV infection, and that ABA biosynthesis apparently plays a crucial role in PDMP-induced callose priming for enhancing defence against TMV.

Glucosylceramide synthase regulates adipo-osteogenic differentiation through synergistic activation of PPARγ with GlcCer.

Dysregulation of the adipo-osteogenic differentiation balance of mesenchymal stem cells (MSCs), which are common progenitor cells of adipocytes and osteoblasts, has been associated with many pathophysiologic diseases, such as obesity, osteopenia, and osteoporosis. Growing evidence suggests that lipid metabolism is crucial for maintaining stem cell homeostasis and cell differentiation; however, the detailed underlying mechanisms are largely unknown. Here, we demonstrate that glucosylceramide (GlcCer) and its synthase, glucosylceramide synthase (GCS), are key determinants of MSC differentiation into adipocytes or osteoblasts. GCS expression was increased during adipogenesis and decreased during osteogenesis. Targeting GCS using RNA interference or a chemical inhibitor enhanced osteogenesis and inhibited adipogenesis by controlling the transcriptional activity of peroxisome proliferator-activated receptor γ (PPARγ). Treatment with GlcCer sufficiently rescued adipogenesis and inhibited osteogenesis in GCS knockdown MSCs. Mechanistically, GlcCer interacted directly with PPARγ through A/B domain and synergistically enhanced rosiglitazone-induced PPARγ activation without changing PPARγ expression, thereby treatment with exogenous GlcCer increased adipogenesis and inhibited osteogenesis. Animal studies demonstrated that inhibiting GCS reduced adipocyte formation in white adipose tissues under normal chow diet and high-fat diet feeding and accelerated bone repair in a calvarial defect model. Taken together, our findings identify a novel lipid metabolic regulator for the control of MSC differentiation and may have important therapeutic implications.

Assessment of gabapentin misuse using prescription drug monitoring program data.

Background: Gabapentin is an anticonvulsant medication with potential misuse reported in case reports and population studies, highlighting the need to reexamine its abuse liability. The purpose of this study was to describe gabapentin dispensing patterns and assess potential misuse. Methods: We used data from Ohio's Prescription Drug Monitoring Program (PDMP) from December 1, 2016 to March 31, 2017 and restricted the population to adults who filled at least one gabapentin prescription (N = 379,372). Gabapentin dispensing patterns are described and multiple strategies were used to assess potential misuse, including Lorenz-1 curve analysis. Supratherapeutic dosing, number of prescribers and number of pharmacies used were compared for individuals who were co-dispensed medications for opioid use disorder (MOUD) and those who were not. Results: More than one million gabapentin prescriptions were dispensed during the 4-month period, with a mean dose of 1103.8 mg. While few individuals received supratherapeutic dosing, exceptionally high doses were observed. Half of the individuals (50.9%) were co-dispensed gabapentin and opioids. The Lorenz-1 value for gabapentin (5.5%) did not exceed the threshold for misuse potential. Individuals co-dispensed MOUD were more likely to have supratherapeutic dosing; however, they had a lower Lorenz-1 value compared to individuals not co-dispensed MOUD. Conclusions: Among Ohio residents dispensed gabapentin, there was no evidence of misuse using PDMP data based on the Lorenz-1 value, yet supratherapeutic dosing of gabapentin was observed and was associated with OUD. New strategies may be needed to identify the non-medical use of gabapentin.

Impact of prescription drug monitoring program mandate on postoperative opioid prescriptions in children.

PURPOSE: Prescription drug monitoring programs (PDMPs) have been established to combat the opioid epidemic, but there is no data on their efficacy in children. We hypothesized that a statewide PDMP mandate would be associated with fewer opioid prescriptions in pediatric surgical patients. METHODS: Patients < 18 undergoing inguinal hernia repair, orchiopexy, orchiectomy, appendectomy, or cholecystectomy at a tertiary children's hospital were included. The primary outcome, discharge opioid prescription, was compared for 10 months pre-PDMP (n = 158) to 10 months post-PDMP (n = 228). Interrupted time series analysis was performed to determine the effect of the PDMP on opioid prescribing. RESULTS: Over the 20-month study period, there was an overall decrease in the rate of opioid prescriptions per month (- 3.6% change, p < 0.001). On interrupted time series analysis, PDMP implementation was not associated with a significant decrease in the monthly rate of opioid prescriptions (1.27% change post-PDMP, p = 0.4). However, PDMP implementation was associated with a reduction in opioid prescriptions of greater than 5 days' supply (- 2.7% per month, p = 0.03). CONCLUSION: Opioid prescriptions declined in pediatric surgical patients over the study time period. State-wide PDMP implementation was associated with a reduction in postoperative opioid prescriptions of more than 5 days' duration.

The ceramide analogue N-(1-hydroxy-3-morpholino-1-phenylpropan-2-yl)decanamide induces large lipid droplet accumulation and highlights the effect of LAMP-2 deficiency on lipid droplet degradation.

Excess accumulation of intracellular lipids leads to various diseases. Lipid droplets (LDs) are ubiquitous cellular organelles for lipid storage. LDs are hydrolyzed via cytosolic lipases (lipolysis) and also degraded in lysosomes through autophagy; namely, lipophagy. A recent study has shown the size-dependent selection of LDs by the two major catabolic pathways (lipolysis and lipophagy), and thus experimental systems that can manipulate the size of LDs are now needed. The ceramide analogue N-(1-hydroxy-3-morpholino-1-phenylpropan-2-yl)decanamide (PDMP) affects the structures and functions of lysosomes/late endosomes and the endoplasmic reticulum (ER), and alters cholesterol homeostasis. We previously reported that PDMP induces autophagy via the inhibition of mTORC1. In the present study, we found that PDMP induced the accumulation of LDs, especially that of large LDs, in mouse fibroblast (L cells). Surprisingly, the LD accumulation was relieved by PDMP in L cells deficient in lysosome-associated membrane protein-2 (LAMP-2), which is reportedly important for lipophagy. An electron microscopy analysis demonstrated that the LAMP-2 deficiency caused enlarged autophagosomes/autolysosomes in L cells, which may promote the sequestration and degradation of the PDMP-dependent large LDs. Accordingly, PDMP will be useful to explore the mechanism of LD degradation, by inducing large LDs.

Plasma supply in the United States.

This descriptive article summarizes the current state of source plasma collection in the United States. It follows the trend of collections over the past several years, ending at 2019, and also includes the number of source plasma collection centers. Usage and distribution of the plasma is also discussed, along with a brief summary of donor compensation policies in the United States.

Physician Responses to Enhanced Prescription Drug Monitoring Program Profiles.

OBJECTIVE: Many states have begun implementing enhancements to PDMP patient profiles such as summaries or graphics to highlight issues of concern and enhance comprehension. The purpose of this study was to examine how physicians respond to sample enhanced PDMP profiles based on patient vignettes. DESIGN: Brief semistructured interviews with physicians. SETTING: Three national medical conferences for targeted specialties. SUBJECTS: Ninety-three physicians practicing in primary care, emergency medicine, or pain management. METHODS: We presented participants with one of three patient vignettes with corresponding standard and enhanced PDMP profiles and conducted brief interviews. RESULTS: Findings indicated that enhanced profiles could increase ease of comprehension, reduce time burden, and aid in communicating with patients about opioid risks. Physicians also expressed concern about liability for prescribing when the enhanced profile indicates risk and cautioned against any implication that risk warnings should override clinical judgment based on the patient's complete medical history or presenting condition. Physicians emphasized the need for transparency of measures and evidence of validation of risk scores. We found little indication that enhanced profiles would change opioid prescribing decisions, though decisions varied by physician. CONCLUSIONS: Our study underscores the importance of involving prescribers in developing and testing PDMP profile enhancements, as well as providing guidance in the interpretation and clinical use of enhanced profiles. Reduced time burden is an important benefit to consider as the number of states mandating PDMP use increases.

Prescription Drug Histories among Drug Overdose Decedents in Delaware.

Background: The US opioid epidemic largely featured deaths from prescribed medications during Wave 1 (1990-2010), but its progression since then has resulted more so from deaths to illegal opioids-such as heroin (Wave 2 - 2010-2013) and fentanyl (Wave 3 - 2013-present). As deaths to illegally manufactured fentanyl have increased, attention to the role of prescribed opioids may be waning. However, the shifting nature of today's opioid epidemic demands we monitor how both legal and illegal drugs are involved in overdose deaths. Objectives: The purpose of our study is to investigate the prescription drug (Rx) records of overdose death decedents to illuminate the continued role of prescribed medications in Wave 3 deaths. Methods: We matched drug overdose death data and prescription drug monitoring data to investigate the prescription drug records (i.e. types of opioids and other medications) of Delaware, USA, decedents who died from a drug overdose death between January 1, 2013, and March 31, 2015 (27 months). Results: Fentanyl decedents differed significantly from other decedents in prescribed medications, including the amount and proximity of opioid and Rx fentanyl prescriptions before death. These relationships held while controlling for demographic characteristics and contributing health conditions. Conclusions: Our findings show a continued presence of Rx opioids in overdose deaths and that those dying from fentanyl had different Rx records than those who died from other drugs. Continued monitoring of Rx drugs, improved toxicology testing and greater data access for more research should follow to inform effective interventions.