Discoidin domain receptor regulates ensheathment, survival and caliber of peripheral axons.

Most invertebrate axons and small-caliber axons in mammalian peripheral nerves are unmyelinated but still ensheathed by glia. Here, we use Drosophila wrapping glia to study the development and function of non-myelinating axon ensheathment, which is poorly understood. Selective ablation of these glia from peripheral nerves severely impaired larval locomotor behavior. In an in vivo RNA interference screen to identify glial genes required for axon ensheathment, we identified the conserved receptor tyrosine kinase Discoidin domain receptor (Ddr). In larval peripheral nerves, loss of Ddr resulted in severely reduced ensheathment of axons and reduced axon caliber, and we found a strong dominant genetic interaction between Ddr and the type XV/XVIII collagen Multiplexin (Mp), suggesting that Ddr functions as a collagen receptor to drive axon wrapping. In adult nerves, loss of Ddr decreased long-term survival of sensory neurons and significantly reduced axon caliber without overtly affecting ensheathment. Our data establish essential roles for non-myelinating glia in nerve development, maintenance and function, and identify Ddr as a key regulator of axon-glia interactions during ensheathment and establishment of axon caliber.

The secreted neurotrophin Spätzle 3 promotes glial morphogenesis and supports neuronal survival and function.

Most glial functions depend on establishing intimate morphological relationships with neurons. Significant progress has been made in understanding neuron-glia signaling at synaptic and axonal contacts, but how glia support neuronal cell bodies is unclear. Here we explored the growth and functions of Drosophila cortex glia (which associate almost exclusively with neuronal cell bodies) to understand glia-soma interactions. We show that cortex glia tile with one another and with astrocytes to establish unique central nervous system (CNS) spatial domains that actively restrict glial growth, and selective ablation of cortex glia causes animal lethality. In an RNAi-based screen, we identified αSNAP (soluble NSF [N-ethylmalemeide-sensitive factor] attachment protein α) and several components of vesicle fusion and recycling machinery as essential for the maintenance of cortex glial morphology and continued contact with neurons. Interestingly, loss of the secreted neurotrophin Spätzle 3 (Spz3) phenocopied αSNAP phenotypes, which included loss of glial ensheathment of neuron cell bodies, increased neuronal cell death, and defects in animal behavior. Rescue experiments suggest that Spz3 can exert these effects only over very short distances. This work identifies essential roles for glial ensheathment of neuronal cell bodies in CNS homeostasis as well as Spz3 as a novel signaling factor required for maintenance of cortex glial morphology and neuron-glia contact.

TSG101 negatively regulates mitochondrial biogenesis in axons.

There is a tight association between mitochondrial dysfunction and neurodegenerative diseases and axons that are particularly vulnerable to degeneration, but how mitochondria are maintained in axons to support their physiology remains poorly defined. In an in vivo forward genetic screen for mutants altering axonal mitochondria, we identified tsg101 Neurons mutant for tsg101 exhibited an increase in mitochondrial number and decrease in mitochondrial size. TSG101 is best known as a component of the endosomal sorting complexes required for transport (ESCRT) complexes; however, loss of most other ESCRT components did not affect mitochondrial numbers or size, suggesting TSG101 regulates mitochondrial biology in a noncanonical, ESCRT-independent manner. The TSG101-mutant phenotype was not caused by lack of mitophagy, and we found that autophagy blockade was detrimental only to the mitochondria in the cell bodies, arguing mitophagy and autophagy are dispensable for the regulation of mitochondria number in axons. Interestingly, TSG101 mitochondrial phenotypes were instead caused by activation of PGC-1ɑ/Nrf2-dependent mitochondrial biogenesis, which was mTOR independent and TFEB dependent and required the mitochondrial fission-fusion machinery. Our work identifies a role for TSG101 in inhibiting mitochondrial biogenesis, which is essential for the maintenance of mitochondrial numbers and sizes, in the axonal compartment.

Ixekizumab: A Review of Its Use for the Management of Moderate to Severe Plaque Psoriasis.

OBJECTIVE: To review the efficacy, safety, and place in therapy of ixekizumab for the treatment of moderate to severe plaque psoriasis. DATA SOURCES: PubMed (1966 to July 2018) and clinicaltrials.gov were searched using the terms ixekizumab, LY2439821, interleukin-17, and psoriasis. STUDY SELECTION AND DATA EXTRACTION: Human studies published in peer-reviewed medical journals in English were used. DATA SYNTHESIS: The efficacy and safety of ixekizumab has been primarily reported by 4 phase III trials (UNCOVER-1, UNCOVER-2, UNCOVER-3, and UNCOVER-J) and multiple post hoc analyses. The average proportions of patients achieving a 75%, 90%, and 100% reduction in their Psoriasis Area and Severity Index (PASI) were 89%, 70%, and 38%, respectively, after 12 weeks of therapy. PASI75 was maintained for up to 3 years in 80.5% of participants. Ixekizumab was statistically significantly more effective than ustekinumab, with 76.5%, compared with 59%, of patients achieving PASI90 in 52 weeks. The most common adverse events include nasopharyngitis (14.1%), upper respiratory tract infections (7.9%), and injection-site reactions (6.8%), which are similar to that for other biological agents. The risk of inflammatory bowel disease may be increased with ixekizumab. Relevance to Patient Care and Clinical Practice: This review summarizes and evaluates clinical data regarding the efficacy and safety of ixekizumab and discusses relevant differences compared with other biological agents used for the management of chronic plaque psoriasis. CONCLUSIONS: Ixekizumab is a highly efficacious and well-tolerated treatment option for patients with moderate to severe plaque psoriasis.

PI3K signaling and Stat92E converge to modulate glial responsiveness to axonal injury.

Glial cells are exquisitely sensitive to neuronal injury but mechanisms by which glia establish competence to respond to injury, continuously gauge neuronal health, and rapidly activate reactive responses remain poorly defined. Here, we show glial PI3K signaling in the uninjured brain regulates baseline levels of Draper, a receptor essential for Drosophila glia to sense and respond to axonal injury. After injury, Draper levels are up-regulated through a Stat92E-modulated, injury-responsive enhancer element within the draper gene. Surprisingly, canonical JAK/STAT signaling does not regulate draper expression. Rather, we find injury-induced draper activation is downstream of the Draper/Src42a/Shark/Rac1 engulfment signaling pathway. Thus, PI3K signaling and Stat92E are critical in vivo regulators of glial responsiveness to axonal injury. We provide evidence for a positive auto-regulatory mechanism whereby signaling through the injury-responsive Draper receptor leads to Stat92E-dependent, transcriptional activation of the draper gene. We propose that Drosophila glia use this auto-regulatory loop as a mechanism to adjust their reactive state following injury.

Glial wingless/Wnt regulates glutamate receptor clustering and synaptic physiology at the Drosophila neuromuscular junction.

Glial cells are emerging as important regulators of synapse formation, maturation, and plasticity through the release of secreted signaling molecules. Here we use chromatin immunoprecipitation along with Drosophila genomic tiling arrays to define potential targets of the glial transcription factor Reversed polarity (Repo). Unexpectedly, we identified wingless (wg), a secreted morphogen that regulates synaptic growth at the Drosophila larval neuromuscular junction (NMJ), as a potential Repo target gene. We demonstrate that Repo regulates wg expression in vivo and that local glial cells secrete Wg at the NMJ to regulate glutamate receptor clustering and synaptic function. This work identifies Wg as a novel in vivo glial-secreted factor that specifically modulates assembly of the postsynaptic signaling machinery at the Drosophila NMJ.

Memantine for the prevention of primary headache disorders.

OBJECTIVE: To describe the current data evaluating the efficacy and safety of memantine for the prevention of primary headache disorders. DATA SOURCES: A literature search using MEDLINE (1966-July 2014) and EMBASE (1973-July 2014) was conducted using the search terms memantine, headache, migraine, glutamate, and NMDA. References of identified articles were reviewed for additional, relevant citations. STUDY SELECTION AND DATA EXTRACTION: All English-language articles dealing with the use of memantine for prevention of primary headache disorders were included. DATA SYNTHESIS: Data from several retrospective reports and 2 prospective clinical trials suggest that memantine may be a useful treatment option for the prevention of primary headache disorders. The majority of available literature focuses specifically on chronic migraine prevention in refractory patients who had failed multiple previous prophylactic therapies. In these patients, 10 to 20 mg of memantine daily reduced the frequency and intensity of migraine headaches and was generally well tolerated, with few adverse events. Data regarding the efficacy of memantine for other primary headache disorders such as chronic tension type and cluster headaches are limited. CONCLUSION: Although further studies evaluating the efficacy of memantine for prevention of primary headache disorders are warranted, memantine may be a reasonable option, used either as monotherapy or adjunctive therapy, in the refractory chronic migraine prophylaxis setting.

Draper-dependent glial phagocytic activity is mediated by Src and Syk family kinase signalling.

The cellular machinery promoting phagocytosis of corpses of apoptotic cells is well conserved from worms to mammals. An important component is the Caenorhabditis elegans engulfment receptor CED-1 (ref. 1) and its Drosophila orthologue, Draper. The CED-1/Draper signalling pathway is also essential for the phagocytosis of other types of 'modified self' including necrotic cells, developmentally pruned axons and dendrites, and axons undergoing Wallerian degeneration. Here we show that Drosophila Shark, a non-receptor tyrosine kinase similar to mammalian Syk and Zap-70, binds Draper through an immunoreceptor tyrosine-based activation motif (ITAM) in the Draper intracellular domain. We show that Shark activity is essential for Draper-mediated signalling events in vivo, including the recruitment of glial membranes to severed axons and the phagocytosis of axonal debris and neuronal cell corpses by glia. We also show that the Src family kinase (SFK) Src42A can markedly increase Draper phosphorylation and is essential for glial phagocytic activity. We propose that ligand-dependent Draper receptor activation initiates the Src42A-dependent tyrosine phosphorylation of Draper, the association of Shark and the activation of the Draper pathway. These Draper-Src42A-Shark interactions are strikingly similar to mammalian immunoreceptor-SFK-Syk signalling events in mammalian myeloid and lymphoid cells. Thus, Draper seems to be an ancient immunoreceptor with an extracellular domain tuned to modified self, and an intracellular domain promoting phagocytosis through an ITAM-domain-SFK-Syk-mediated signalling cascade.

Graduating student pharmacists' perspectives on e-professionalism and social media: qualitative findings.

OBJECTIVE To characterize students' views and opinions of professionalism on popular social media sites and compare responses about social media behavior among students in different groups. DESIGN Cross-sectional survey. SETTING Four colleges of pharmacy in midwestern United States. PARTICIPANTS 516 graduating student pharmacists. INTERVENTIONS Online survey with open-ended questions. MAIN OUTCOME MEASURES Qualitative analysis of responses and themes. RESULTS A total of 212 student pharmacists completed surveys (41% response rate). Mean (± SD) age was 25.2 ± 4.6 years, and 72% of respondents were women. Major overarching themes identified in the qualitative analysis were separation of personal and professional lives, how accountability for actions should vary by severity, and the extent of representation of the students' character on social media. CONCLUSION Identified themes provided important insights into the ways in which student pharmacists view social media and use this widely accessible means of personal communication.

Pharmacist perception and use of UpToDate®.

A cross-sectional survey of a convenience sample of 1,199 pharmacists was conducted to describe pharmacists' use and perception of UpToDate®. Of 472 (39%) respondents, 217 (46%) reported using UpToDate. Most respondents who used or had heard of UpToDate indicated willingness to change a treatment plan based on UpToDate recommendations (77%). Many believed that UpToDate is updated weekly (31%) or monthly (49%) and that all articles undergo external peer review (51%). In conclusion, the majority of respondents reported that they would adjust drug therapy based on UpToDate recommendations; however, many pharmacists may hold misconceptions regarding the updating and peer-review processes.

Developmental and age-related synapse elimination is mediated by glial Croquemort.

Neurons and glia work together to dynamically regulate neural circuit assembly and maintenance. In this study, we show Drosophila exhibit large-scale synapse formation and elimination as part of normal CNS circuit maturation, and that glia use conserved molecules to regulate these processes. Using a high throughput ELISA-based in vivo screening assay, we identify new glial genes that regulate synapse numbers in Drosophila in vivo, including the scavenger receptor ortholog Croquemort (Crq). Crq acts as an essential regulator of glial-dependent synapse elimination during development, with glial Crq loss leading to excess CNS synapses and progressive seizure susceptibility in adults. Loss of Crq in glia also prevents age-related synaptic loss in the adult brain. This work provides new insights into the cellular and molecular mechanisms that underlie synapse development and maintenance across the lifespan, and identifies glial Crq as a key regulator of these processes.

Scholarship of Drug Information and Library Sciences Instruction in North American Pharmacy Education: A Systematic Review of English-Language Research.

OBJECTIVES: This study aimed to characterize the scholarship of teaching and learning specific to drug information and library sciences (DILS) in pharmacy education and provide a comprehensive, evidence-based resource for faculty, detailing published practices for content delivery and scholarly research gaps. FINDINGS: Systematic searches of PubMed, Embase, International Pharmaceutical Abstracts, Educational Resources Information Center, Scopus, Library Literature & Information Science Full Text, and Library, Information Science & Technology Abstracts were conducted from January 1997 through early February 2022. Included studies were published in English, involved DILS content, were specific to pharmacy education, were original research, and were conducted in North America. The review excluded abstract-only records and studies that did not include learners (ie, pharmacy students and residents) as participants. Duplicate records were removed. After screening and review, 166 articles met the eligibility criteria, 60% of which (n = 100/166) were published in the last 10 years. Most studies focused on literature evaluation (45/166, 27%), fundamentals of drug information (43/166, 25%), evidence-based medicine (21/166, 13%), and resource utilization (21/166, 13%). Studied learners were mainly pharmacy students (77%), and 82% of research included authors who were pharmacists, whereas 14% included librarians. Assessment techniques used primarily focused on student perception (61/166, 37%), followed by summative assessment (46/166, 28%), other (25/166, 15%), and formative assessment (18/166, 11%). SUMMARY: This article presents a systematically identified collection of North American literature examining the education in DILS of pharmacy learners. Areas for continued research of DILS content include evaluating underrepresented educational domains (ie, systematic approach, response development and provision, literature searching, study design), using librarians more in scholarship of teaching and learning research, and using formative and summative assessments as outcomes.

Astrocyte growth is driven by the Tre1/S1pr1 phospholipid-binding G protein-coupled receptor.

Astrocytes play crucial roles in regulating neural circuit function by forming a dense network of synapse-associated membrane specializations, but signaling pathways regulating astrocyte morphogenesis remain poorly defined. Here, we show the Drosophila lipid-binding G protein-coupled receptor (GPCR) Tre1 is required for astrocytes to establish their intricate morphology in vivo. The lipid phosphate phosphatases Wunen/Wunen2 also regulate astrocyte morphology and, via Tre1, mediate astrocyte-astrocyte competition for growth-promoting lipids. Loss of s1pr1, the functional analog of Tre1 in zebrafish, disrupts astrocyte process elaboration, and live imaging and pharmacology demonstrate that S1pr1 balances proper astrocyte process extension/retraction dynamics during growth. Loss of Tre1 in flies or S1pr1 in zebrafish results in defects in simple assays of motor behavior. Tre1 and S1pr1 are thus potent evolutionarily conserved regulators of the elaboration of astrocyte morphological complexity and, ultimately, astrocyte control of behavior.

Glial TGFß activity promotes neuron survival in peripheral nerves.

Maintaining long, energetically demanding axons throughout the life of an animal is a major challenge for the nervous system. Specialized glia ensheathe axons and support their function and integrity throughout life, but glial support mechanisms remain poorly defined. Here, we identified a collection of secreted and transmembrane molecules required in glia for long-term axon survival in vivo. We showed that the majority of components of the TGFß superfamily are required in glia for sensory neuron maintenance but not glial ensheathment of axons. In the absence of glial TGFß signaling, neurons undergo age-dependent degeneration that can be rescued either by genetic blockade of Wallerian degeneration or caspase-dependent death. Blockade of glial TGFß signaling results in increased ATP in glia that can be mimicked by enhancing glial mitochondrial biogenesis or suppressing glial monocarboxylate transporter function. We propose that glial TGFß signaling supports axon survival and suppresses neurodegeneration through promoting glial metabolic support of neurons.

Concomitant use of ipratropium and tiotropium in chronic obstructive pulmonary disease.

OBJECTIVE: To describe the current data evaluating the efficacy and safety of ipratropium used in combination with tiotropium in patients with chronic obstructive pulmonary disease. DATA SOURCES: A literature search using MEDLINE (1966-August 2012) and EMBASE (1973-August 2012) was conducted using the search terms ipratropium, tiotropium, combination drug therapy, and chronic obstructive pulmonary disease. References of identified articles were reviewed for additional relevant citations. STUDY SELECTION AND DATA EXTRACTION: All English-language articles regarding the concomitant use of ipratropium and tiotropium were reviewed. DATA SYNTHESIS: Two prospective randomized controlled trials have demonstrated increases in bronchodilation with ipratropium when added to maintenance tiotropium therapy, suggesting potential benefits during short-term, combined use. One study reported significantly higher peak forced expiratory volume in 1 second (FEV(1)) responses with both ipratropium (230 mL) and fenoterol (315 mL) compared to placebo (178 mL) when added to maintenance tiotropium. The peak response with fenoterol was significantly higher than with ipratropium (FEV(1) difference = 84 mL). Another study reported a mean difference in FEV(1) of 81 mL (95% CI 27 to 136) with albuterol versus placebo and a mean difference in FEV(1) of 68 mL (95% CI 3 to 132) with ipratropium versus placebo. The difference between albuterol and ipratropium when added to maintenance tiotropium was not significant. One large observational study reported a significantly higher risk of acute urinary retention in individuals receiving combination therapy with a short- and long-acting anticholinergic agent compared to those receiving monotherapy (OR 1.84; 95% CI 1.25 to 2.71). Individuals at highest risk were men and those with evidence of benign prostatic hypertrophy. CONCLUSIONS: While ipratropium may provide spirometric improvements in lung function for patients receiving tiotropium maintenance therapy, the clinical significance of these improvements has not been documented and the risk of anticholinergic adverse effects is increased with combination therapy. Further studies evaluating the safety and efficacy of concomitant ipratropium and tiotropium are warranted before combination use can be recommended for select patients.

Factors associated with reported preventable adverse drug events: a retrospective, case-control study.

BACKGROUND: It has been reported that error occurs at some point during the medication use process in approximately 6% of medication doses administered in the inpatient setting. An estimated 1-10% of medication errors lead to patient harm; however, factors affecting the risk of harm from a medication error are undefined in the literature. OBJECTIVE: To identify independent factors affecting the risk of reported preventable adverse drug events (ADEs) (ie, medication errors contributing to patient harm) compared to medication errors that did not contribute to patient harm in a diverse patient population. METHODS: This was a retrospective, case-control study conducted at 3 hospitals within a large health system. Medication error reports from July 1, 2009, through June 30, 2010, were assessed. All reported medication errors determined to have contributed to patient harm were matched 1:1 with a medication error that did not contribute to harm. Data collected through review of the incident report and medical record included patient, provider, medication, and other related factors. Multivariable logistic regression was used to determine the relationship of potential factors to patient harm. RESULTS: Of 4321 medication errors reported at study sites, 182 (4%) contributed to patient harm. Factors associated with increased independent risk of harm were 30-day readmission, time of day 0300-0659, and Institute for Safe Medication Practices (ISMP) high-alert medications. Factors associated with decreased independent risk of harm were multiple medication errors, occurrence during February or April, dispensing errors, and pharmacist review of medication order. CONCLUSIONS: Health systems should develop programs to promote safe, conscientious use of ISMP high-alert medications, promote pharmacist review, control the use of cabinet overrides, and direct provider attention toward recently admitted patients. Efforts should be made to determine factors associated with risk of harm at local levels.

Solriamfetol for the Management of Excessive Daytime Sleepiness.

OBJECTIVE: To review efficacy, safety, and place in therapy of solriamfetol for management of excessive daytime sleepiness (EDS) in patients with narcolepsy and obstructive sleep apnea (OSA). METHODS: PubMed (1966 to January 2021) was searched using the terms solriamfetol, JZP-110, ADX-N05 and Sunosi. Human studies published in peer-reviewed medical journals in English language were reviewed. RESULTS: The efficacy and safety of solriamfetol has been reported in 2 phase II trials and 4 phase III trials (TONES 2, TONES 3, TONES 4, and TONES 5). Statistically significant improvements in the maintenance of wakefulness test were reported with solriamfetol 150 mg and 300 mg vs placebo in participants with narcolepsy (7.65- to 10.14-minute difference from placebo). In subjects with OSA, statistically significant improvements in maintenance of wakefulness test difference from placebo were also observed in those taking solriamfetol 75 mg, 150 mg, or 300 mg vs placebo (4.5- to 12.8-minute difference from placebo). Statistically significant reductions in Epworth Sleepiness Scale scores were also reported in phase III trials in subjects with narcolepsy or OSA taking solriamfetol vs placebo (ranging from - 4.7 to - 1.9 difference from placebo). Common adverse events in reported in phase III trials were headache, nausea, decreased appetite, anxiety, dry mouth, and diarrhea. Solriamfetol appears to have a reduced risk for drug interactions and fewer adverse effects compared to other agents available for management of EDS in patients with narcolepsy and OSA. CONCLUSIONS: Solriamfetol is an effective option for management of EDS in patients with narcolepsy and OSA.

Nitroglycerin ointment for the prevention of postmenopausal osteoporosis.

OBJECTIVE: To determine whether clinical trial data support the use of nitroglycerin for prevention of postmenopausal osteoporosis. DATA SOURCES: A literature search using MEDLINE (1966-September 2011) and EMBASE (1973-September 2011) was conducted using the search terms nitroglycerin, bone mineral density, fracture, and osteoporosis. References of identified articles were reviewed for additional citations. STUDY SELECTION AND DATA EXTRACTION: All English-language articles related to the use of nitroglycerin ointment in postmenopausal women were reviewed. DATA SYNTHESIS: Four observational studies reported significant improvements in bone mineral density of postmenopausal women with the use of nitrates. One pilot study and 2 prospective, randomized, placebo-controlled clinical trials reported conflicting results regarding the efficacy of nitroglycerin ointment. CONCLUSIONS: Clinical data do not support use of nitroglycerin for this indication; its potential is limited at this time by inconclusive efficacy and a high incidence of headache. Further well-designed clinical trials demonstrating efficacy and safety of nitroglycerin ointment for prevention of postmenopausal osteoporosis are needed before this medication can be recommended for routine use.

Implementation of a Teaching Electronic Medical Record within Didactic Instruction Using a Drug Information Question Assignment.

BACKGROUND: Pharmacy graduates are expected to be practice-ready to deliver quality patient care, which includes having comprehensive knowledge of health informatics and electronic medical records (EMRs). The purpose of this study was to (1) incorporate an EMR within a pharmacy student assignment, and (2) assess student perceptions of use of the EMR. METHODS: Student pharmacists received a patient-specific drug-related question and were required to use an EMR to provide an accurate response. Following completion of the assignment, students were invited to complete a retrospective, pre-post survey instrument to collect their perceptions. RESULTS: Only 28.8% of respondents reported prior experience using an EMR. Student perceptions about use of an EMR within the didactic setting significantly improved from before to after the assignment. Differences were found in respondents who agreed that didactic use of an EMR increased their confidence in obtaining information from an EMR (20.5% to 82.8%) and improved their knowledge of EMR systems (61.4% to 89.3%). CONCLUSIONS: Implementation of an EMR within didactic instruction may serve as the first exposure to health informatics for students and positively impacts student perceptions of these tools prior to entry into pharmacy practice.