"Because of this rotation, this is what I want to do": Implementation and evaluation of a telehealth opioid use disorder clinical placement for nurse practitioner students.

ABSTRACT: The lack of clinicians comfortable prescribing buprenorphine is a barrier to access for people with opioid use disorder (OUD). Accordingly, a telehealth OUD treatment clinic, Ophelia, launched a clinical training program for nurse practitioner (NP) students. The goal of this study was to assess a telehealth-based model of OUD clinical training. To evaluate the program, we (1) identified students' knowledge related to providing OUD care to patients before and after their clinical rotation with Ophelia and (2) characterized students' attitudes about providing OUD care following their clinical rotation with Ophelia. Online pre- and postsurveys were conducted with 57 and 29 students, respectively, and semistructured interviews were conducted with 19 students who completed clinical rotations with Ophelia. We used quantitative descriptive analysis to compare presurvey and postsurvey results and conducted thematic analysis to analyze qualitative interview data. We identified three themes from the interviews: the continuum of learning opportunities, the comfort providing OUD treatment following participants' clinical rotation, and the relevance of a substance use disorder clinical rotation for all NP students. The survey also supported these findings. Of note, there were descriptive differences between presurvey and postsurvey responses related to an increase in knowledge, preparedness, and acquisition of skills to treat OUD. Using a telehealth clinical rotation for NP students to learn about OUD treatment may represent an important step in increasing the number of clinicians who can prescribe buprenorphine. These findings can inform interventions and policies that target clinician training barriers.

Rare disease variant curation from literature: assessing gaps with creatine transport deficiency in focus.

BACKGROUND: Approximately 4-8% of the world suffers from a rare disease. Rare diseases are often difficult to diagnose, and many do not have approved therapies. Genetic sequencing has the potential to shorten the current diagnostic process, increase mechanistic understanding, and facilitate research on therapeutic approaches but is limited by the difficulty of novel variant pathogenicity interpretation and the communication of known causative variants. It is unknown how many published rare disease variants are currently accessible in the public domain. RESULTS: This study investigated the translation of knowledge of variants reported in published manuscripts to publicly accessible variant databases. Variants, symptoms, biochemical assay results, and protein function from literature on the SLC6A8 gene associated with X-linked Creatine Transporter Deficiency (CTD) were curated and reported as a highly annotated dataset of variants with clinical context and functional details. Variants were harmonized, their availability in existing variant databases was analyzed and pathogenicity assignments were compared with impact algorithm predictions. 24% of the pathogenic variants found in PubMed articles were not captured in any database used in this analysis while only 65% of the published variants received an accurate pathogenicity prediction from at least one impact prediction algorithm. CONCLUSIONS: Despite being published in the literature, pathogenicity data on patient variants may remain inaccessible for genetic diagnosis, therapeutic target identification, mechanistic understanding, or hypothesis generation. Clinical and functional details presented in the literature are important to make pathogenicity assessments. Impact predictions remain imperfect but are improving, especially for single nucleotide exonic variants, however such predictions are less accurate or unavailable for intronic and multi-nucleotide variants. Developing text mining workflows that use natural language processing for identifying diseases, genes and variants, along with impact prediction algorithms and integrating with details on clinical phenotypes and functional assessments might be a promising approach to scale literature mining of variants and assigning correct pathogenicity. The curated variants list created by this effort includes context details to improve any such efforts on variant curation for rare diseases.

Clinical Trials in Pancreatitis: Opportunities and Challenges in the Design and Conduct of Patient-Focused Clinical Trials in Recurrent Acute and Chronic Pancreatitis: Summary of a National Institute of Diabetes and Digestive and Kidney Diseases Workshop.

ABSTRACT: Recurrent acute pancreatitis and chronic pancreatitis represent high morbidity diseases, which are frequently associated with chronic abdominal pain, pancreatic insufficiencies, and reduced quality of life. Currently, there are no therapies to reverse or delay disease progression, and clinical trials are needed to investigate potential interventions that would address this important gap. This conference report provides details regarding information shared during a National Institute of Diabetes and Digestive and Kidney Diseases-sponsored workshop on Clinical Trials in Pancreatitis that sought to clearly delineate the current gaps and opportunities related to the design and conduct of patient-focused trials in recurrent acute pancreatitis and chronic pancreatitis. Key stakeholders including representatives from patient advocacy organizations, physician investigators (including clinical trialists), the US Food and Drug Administration, and the National Institutes of Health convened to discuss challenges and opportunities with particular emphasis on lessons learned from trials in participants with other painful conditions, as well as the value of incorporating the patient perspective throughout all stages of trials.

Developing Drugs for Prevention of Chemotherapy-Induced Nausea and Vomiting: Draft Guidance from the FDA.

The administration of preventative therapy for chemotherapy-induced nausea and vomiting (CINV) is an essential component of the treatment plan for many patients with cancer. In May 2021, the FDA issued a draft guidance for industry to facilitate the clinical development of drugs for the prevention of CINV in adults. FDA guidance has a vital role in the regulatory dialogue between the Agency and external stakeholders. Sharing the FDA's current recommended approach can expedite drug development and ultimately the availability of safe and effective therapies to patients in need. In addition, guidance documents may be leveraged to facilitate communication between regulatory agencies, the academic community, patient advocacy groups, and the pharmaceutical industry. The draft guidance for industry Chemotherapy-Induced Nausea and Vomiting: Developing Drugs for Prevention (May 2021) outlines the FDA's current recommendations regarding clinical development programs for drugs for the prevention of CINV and the required attributes of patients for enrollment, aspects of trial design, and efficacy assessments. This article provides an overview of the recommendations contained in the draft guidance.

Review article: the evolution of endpoint assessments for chemotherapy-induced nausea and vomiting and post-operative nausea and vomiting-a perspective from the US Food and Drug Administration.

BACKGROUND: Nausea and vomiting can result in decreased compliance with oncologic therapies for patients with chemotherapy-induced nausea and vomiting (CINV); and increase complications and recovery time for patients with post-operative nausea and vomiting (PONV). CINV refers to nausea and vomiting after antineoplastic therapy administration and PONV is nausea and/or vomiting that occurs in the post-anaesthesia care unit or during the 24 hours following surgery. AIM: To analyse the evolution of endpoint assessments utilised in clinical trials to support FDA approval of CINV and PONV therapeutics. METHODS: A review supported by the US FDA analysed 31 approved New Drug Applications, respective clinical trial protocols and product labelling for CINV or PONV therapeutics with an emphasis on primary endpoint selection. RESULTS: Analysis revealed primary endpoints have become more refined and now often include the assessment of both vomiting and rescue medication use (ie, Complete Response). Additionally, the visual analogue scale was recognised as the most prevalent instrument to assess nausea as 58% of reviewed applications included this assessment. An imbalance between available therapies for adults and paediatric patients was also identified as only 39% of the reviewed approved products were indicated for paediatric use. CONCLUSION: The goal of this research was to inform and identify future opportunities for enhanced clinical trial design. Nausea assessment was identified as an opportunity for continued research and development due to the large heterogeneity of instruments used. Furthermore, there is a need for the development of safe and efficacious antiemetic treatments for paediatric patients.

Cannabinoid receptor subtype influence on neuritogenesis in human SH-SY5Y cells.

Human SH-SY5Y neuroblastoma cells stably expressing exogenous CB1 (CB1XS) or CB2 (CB2XS) receptors were developed to investigate endocannabinoid signaling in the extension of neuronal projections. Expression of cannabinoid receptors did not alter proliferation rate, viability, or apoptosis relative to parental SH-SY5Y. Transcripts for endogenous cannabinoid system enzymes (diacylglycerol lipase, monoacylglycerol lipase, α/ß-hydrolase domain containing proteins 6 and 12, N-acyl phosphatidylethanolamine-phospholipase D, and fatty acid amide hydrolase) were not altered by CB1 or CB2 expression. Endocannabinoid ligands 2-arachidonoylglycerol (2-AG) and anandamide were quantitated in SH-SY5Y cells, and diacylglycerol lipase inhibitor tetrahydrolipstatin decreased 2-AG abundance by 90% but did not alter anandamide abundance. M3 muscarinic agonist oxotremorine M, and inhibitors of monoacylglycerol lipase and α/ß hydrolase domain containing proteins 6 &12 increased 2-AG abundance. CB1 receptor expression increased lengths of short (<30 µm) and long (>30 µm) projections, and this effect was significantly reduced by tetrahydrolipstatin, indicative of stimulation by endogenously produced 2-AG. Pertussis toxin, Gßγ inhibitor gallein, and ß-arrestin inhibitor barbadin did not significantly alter long projection length in CB1XS, but significantly reduced short projections, with gallein having the greatest inhibition. The rho kinase inhibitor Y27632 increased CB1 receptor-mediated long projection extension, indicative of actin cytoskeleton involvement. CB1 receptor expression increased GAP43 and ST8SIA2 mRNA and decreased ITGA1 mRNA, whereas CB2 receptor expression increased NCAM and SYT mRNA. We propose that basal endogenous production of 2-AG provides autocrine stimulation of CB1 receptor signaling through Gi/o, Gßγ, and ß-arrestin mechanisms to promote neuritogenesis, and rho kinase influences process extension.

Cannabinoid receptor interacting protein suppresses agonist-driven CB1 receptor internalization and regulates receptor replenishment in an agonist-biased manner.

Cannabinoid receptor interacting protein 1a (CRIP1a) is a CB1 receptor (CB1 R) distal C-terminus-associated protein that modulates CB1 R signaling via G proteins, and CB1 R down-regulation but not desensitization (Blume et al. [2015] Cell Signal., 27, 716-726; Smith et al. [2015] Mol. Pharmacol., 87, 747-765). In this study, we determined the involvement of CRIP1a in CB1 R plasma membrane trafficking. To follow the effects of agonists and antagonists on cell surface CB1 Rs, we utilized the genetically homogeneous cloned neuronal cell line N18TG2, which endogenously expresses both CB1 R and CRIP1a, and exhibits a well-characterized endocannabinoid signaling system. We developed stable CRIP1a-over-expressing and CRIP1a-siRNA-silenced knockdown clones to investigate gene dose effects of CRIP1a on CB1 R plasma membrane expression. Results indicate that CP55940 or WIN55212-2 (10 nM, 5 min) reduced cell surface CB1 R by a dynamin- and clathrin-dependent process, and this was attenuated by CRIP1a over-expression. CP55940-mediated cell surface CB1 R loss was followed by a cycloheximide-sensitive recovery of surface receptors (30-120 min), suggesting the requirement for new protein synthesis. In contrast, WIN55212-2-mediated cell surface CB1 Rs recovered only in CRIP1a knockdown cells. Changes in CRIP1a expression levels did not affect a transient rimonabant (10 nM)-mediated increase in cell surface CB1 Rs, which is postulated to be as a result of rimonabant effects on 'non-agonist-driven' internalization. These studies demonstrate a novel role for CRIP1a in agonist-driven CB1 R cell surface regulation postulated to occur by two mechanisms: 1) attenuating internalization that is agonist-mediated, but not that in the absence of exogenous agonists, and 2) biased agonist-dependent trafficking of de novo synthesized receptor to the cell surface.

Procollagen C-endopeptidase Enhancer Protein 2 (PCPE2) Reduces Atherosclerosis in Mice by Enhancing Scavenger Receptor Class B1 (SR-BI)-mediated High-density Lipoprotein (HDL)-Cholesteryl Ester Uptake.

Studies in human populations have shown a significant correlation between procollagen C-endopeptidase enhancer protein 2 (PCPE2) single nucleotide polymorphisms and plasma HDL cholesterol concentrations. PCPE2, a 52-kDa glycoprotein located in the extracellular matrix, enhances the cleavage of C-terminal procollagen by bone morphogenetic protein 1 (BMP1). Our studies here focused on investigating the basis for the elevated concentration of enlarged plasma HDL in PCPE2-deficient mice to determine whether they protected against diet-induced atherosclerosis. PCPE2-deficient mice were crossed with LDL receptor-deficient mice to obtain LDLr(-/-), PCPE2(-/-) mice, which had elevated HDL levels compared with LDLr(-/-) mice with similar LDL concentrations. We found that LDLr(-/-), PCPE2(-/-) mice had significantly more neutral lipid and CD68+ infiltration in the aortic root than LDLr(-/-) mice. Surprisingly, in light of their elevated HDL levels, the extent of aortic lipid deposition in LDLr(-/-), PCPE2(-/-) mice was similar to that reported for LDLr(-/-), apoA-I(-/-) mice, which lack any apoA-I/HDL. Furthermore, LDLr(-/-), PCPE2(-/-) mice had reduced HDL apoA-I fractional clearance and macrophage to fecal reverse cholesterol transport rates compared with LDLr(-/-) mice, despite a 2-fold increase in liver SR-BI expression. PCPE2 was shown to enhance SR-BI function by increasing the rate of HDL-associated cholesteryl ester uptake, possibly by optimizing SR-BI localization and/or conformation. We conclude that PCPE2 is atheroprotective and an important component of the reverse cholesterol transport HDL system.