Developing an international concept-based curriculum for pharmacology education: The promise of core concepts and concept inventories.

Over recent years, studies have shown that science and health profession graduates demonstrate gaps in their fundamental pharmacology knowledge and ability to apply pharmacology concepts in practice. This article reviews the current challenges faced by pharmacology educators, including the exponential growth in discipline knowledge and competition for curricular time. We then argue that pharmacology education should focus on essential concepts that enable students to develop beyond 'know' towards 'know how to'. A concept-based approach will help educators prioritize and benchmark their pharmacology curriculum, facilitate integration of pharmacology with other disciplines in the curriculum, create alignment between universities and improve application of pharmacology knowledge to professional contexts such as safe prescribing practices. To achieve this, core concepts first need to be identified and unpacked, and methods for teaching and assessment using concept inventories developed. The International Society for Basic and Clinical Pharmacology Education Section (IUPHAR-Ed) Core Concepts of Pharmacology (CCP) initiative involves over 300 educators from the global pharmacology community. CCP has identified and defined the core concepts of pharmacology, together with key underpinning sub-concepts. To realize these benefits, pharmacology educators must develop methods to teach and assess core concepts. Work to develop concept inventories is ongoing, including identifying student misconceptions of the core concepts and creating a bank of multiple-choice questions to assess student understanding. Future work aims to develop and validate materials and methods to help educators embed core concepts within curricula. Potential strategies that educators can use to overcome factors that inhibit adoption of core concepts are presented.

The Role of Harassment in the Mental Well-being of Local Public Health Professionals and Its Relationship With an Intent to Leave Their Organization During the COVID-19 Pandemic.

Since the onset of the COVID-19 pandemic, news and nationwide survey efforts have reported harassment and bullying among local health officials, departments, and personnel, concurrent to a shortage of public health staff in the United States. We examined a nationally representative sample of local public health professionals (LPHPs) from the 2021 Public Health Workforce Interests and Needs Survey (PH WINS) data set to explore reported experiences with harassment, threats, and bullying; self-rated mental and emotional well-being; and intent to leave an organization. Results indicated that experience of harassment was negatively associated with ratings of mental and emotional health and positively associated with an intent to leave an organization. We discuss implications and recommendations to mitigate these risks for the nation's local public health workforce.

A new model for regulation of sphingosine kinase 1 translocation to the plasma membrane in breast cancer cells.

The translocation of sphingosine kinase 1 (SK1) to the plasma membrane (PM) is crucial in promoting oncogenesis. We have previously proposed that SK1 exists as both a monomer and dimer in equilibrium, although it is unclear whether these species translocate to the PM via the same or different mechanisms. We therefore investigated the structural determinants involved to better understand how translocation might potentially be targeted for therapeutic intervention. We report here that monomeric WT mouse SK1 (GFP-mSK1) translocates to the PM of MCF-7L cells stimulated with carbachol or phorbol 12-myristate 13-acetate, whereas the dimer translocates to the PM in response to sphingosine-1-phosphate; thus, the equilibrium between the monomer and dimer is sensitive to cellular stimulus. In addition, carbachol and phorbol 12-myristate 13-acetate induced translocation of monomeric GFP-mSK1 to lamellipodia, whereas sphingosine-1-phosphate induced translocation of dimeric GFP-mSK1 to filopodia, suggesting that SK1 regulates different cell biological processes dependent on dimerization. GFP-mSK1 mutants designed to modulate dimerization confirmed this difference in localization. Regulation by the C-terminal tail of SK1 was investigated using GFP-mSK1 truncations. Removal of the last five amino acids (PPEEP) prevented translocation of the enzyme to the PM, whereas removal of the last ten amino acids restored translocation. This suggests that the penultimate five amino acids (SRRGP) function as a translocation brake, which can be released by sequestration of the PPEEP sequence. We propose that these determinants alter the arrangement of N-terminal and C-terminal domains in SK1, leading to unique surfaces that promote differential translocation to the PM.

The development of proteinase-activated receptor-2 modulators and the challenges involved.

Protease-activated receptor-2 (PAR2) has been extensively studied since its discovery in the mid-1990. Despite the advances in understanding PAR2 pharmacology, it has taken almost 25 years for the first inhibitor to reach clinical trials, and so far, no PAR2 antagonist has been approved for human use. Research has employed classical approaches to develop a wide array of PAR2 agonists and antagonists, consisting of peptides, peptoids and antibodies to name a few, with a surge in patent applications over this period. Recent breakthroughs in PAR2 structure determination has provided a unique insight into proposed PAR2 ligand binding sites. Publication of the first crystal structures of PAR2 resolved in complex with two novel non-peptide small molecule antagonists (AZ8838 and AZ3451) revealed two distinct binding pockets, originally presumed to be allosteric sites, with a PAR2 antibody (Fab3949) used to block tethered ligand engagement with the peptide-binding domain of the receptor. Further studies have proposed orthosteric site occupancy for AZ8838 as a competitive antagonist. One company has taken the first PAR2 antibody (MEDI0618) into phase I clinical trial (NCT04198558). While this first-in-human trial is at the early stages of the assessment of safety, other research into the structural characterisation of PAR2 is still ongoing in an attempt to identify new ways to target receptor activity. This review will focus on the development of novel PAR2 modulators developed to date, with an emphasis placed upon the advances made in the pharmacological targeting of PAR2 activity as a strategy to limit chronic inflammatory disease.

Military veteran engagement with mental health and well-being services: a qualitative study of the role of the peer support worker.

Background: Many UK military veterans experiencing mental health and well-being difficulties do not engage with support services to get the help they need. Some mental health clinics employ Peer Support Workers (PSWs) to help veteran patients engage, however it is not known how the role influences UK veteran engagement.Aims: To gain insight into the role of peer support in UK veteran engagement with mental health and well-being services.Method: A qualitative study based on 18 semi-structured interviews with veterans, PSWs and mental health clinicians at a specialist veteran mental health and well-being clinic in Scotland.Results: Four themes of the PSW role as positive first impression, understanding professional friend, helpful and supportive connector, and an open door were identified across all participants. The PSWs' military connection, social and well-being support and role in providing veterans with an easily accessible route to dis-engage and re-engage with the service over multiple engagement attempts were particularly crucial.Conclusions: The Peer Support role enhanced veteran engagement in the majority of instances. Study findings mirrored existing peer support literature, provided new evidence in relation to engaging UK veterans, and made recommendations for future veteran research and service provision.

Nosocomial Outbreak of Extensively Drug-Resistant Acinetobacter baumannii Isolates Containing blaOXA-237 Carried on a Plasmid.

Carbapenem antibiotics are among the mainstays for treating infections caused by Acinetobacter baumannii, especially in the Northwest United States, where carbapenem-resistant A. baumannii remains relatively rare. However, between June 2012 and October 2014, an outbreak of carbapenem-resistant A. baumannii occurred in 16 patients from five health care facilities in the state of Oregon. All isolates were defined as extensively drug resistant. Multilocus sequence typing revealed that the isolates belonged to sequence type 2 (international clone 2 [IC2]) and were >95% similar as determined by repetitive-sequence-based PCR analysis. Multiplex PCR revealed the presence of a blaOXA carbapenemase gene, later identified as blaOXA-237 Whole-genome sequencing of all isolates revealed a well-supported separate branch within a global A. baumannii phylogeny. Pacific Biosciences (PacBio) SMRT sequencing was also performed on one isolate to gain insight into the genetic location of the carbapenem resistance gene. We discovered that blaOXA-237, flanked on either side by ISAba1 elements in opposite orientations, was carried on a 15,198-bp plasmid designated pORAB01-3 and was present in all 16 isolates. The plasmid also contained genes encoding a TonB-dependent receptor, septicolysin, a type IV secretory pathway (VirD4 component, TraG/TraD family) ATPase, an integrase, a RepB family plasmid DNA replication initiator protein, an alpha/beta hydrolase, and a BrnT/BrnA type II toxin-antitoxin system. This is the first reported outbreak in the northwestern United States associated with this carbapenemase. Particularly worrisome is that blaOXA-237 was carried on a plasmid and found in the most prominent worldwide clonal group IC2, potentially giving pORAB01-3 great capacity for future widespread dissemination.

Protease-Activated Receptor 4 Variant p.Tyr157Cys Reduces Platelet Functional Responses and Alters Receptor Trafficking.

OBJECTIVE: Protease-activated receptor 4 (PAR4) is a key regulator of platelet reactivity and is encoded by F2RL3, which has abundant rare missense variants. We aimed to provide proof of principle that rare F2LR3 variants potentially affect platelet reactivity and responsiveness to PAR1 antagonist drugs and to explore underlying molecular mechanisms. APPROACH AND RESULTS: We identified 6 rare F2RL3 missense variants in 236 cardiac patients, of which the variant causing a tyrosine 157 to cysteine substitution (Y157C) was predicted computationally to have the greatest effect on PAR4 structure. Y157C platelets from 3 cases showed reduced responses to PAR4-activating peptide and to α-thrombin compared with controls, but no reduction in responses to PAR1-activating peptide. Pretreatment with the PAR1 antagonist vorapaxar caused lower residual α-thrombin responses in Y157C platelets than in controls, indicating greater platelet inhibition. HEK293 cells transfected with a PAR4 Y157C expression construct had reduced PAR4 functional responses, unchanged total PAR4 expression but reduced surface expression. PAR4 Y157C was partially retained in the endoplasmic reticulum and displayed an expression pattern consistent with defective N-glycosylation. Mutagenesis of Y322, which is the putative hydrogen bond partner of Y157, also reduced PAR4 surface expression in HEK293 cells. CONCLUSIONS: Reduced PAR4 responses associated with Y157C result from aberrant anterograde surface receptor trafficking, in part, because of disrupted intramolecular hydrogen bonding. Characterization of PAR4 Y157C establishes that rare F2RL3 variants have the potential to markedly alter platelet PAR4 reactivity particularly after exposure to therapeutic PAR1 antagonists.

Proteinase-activated receptors (PARs) as targets for antiplatelet therapy.

Since the identification of the proteinase-activated receptor (PAR) family as mediators of serine protease activity in the 1990s, there has been tremendous progress in the elucidation of their pathophysiological roles. The development of drugs that target PARs has been the focus of many laboratories for the potential treatment of thrombosis, cancer and other inflammatory diseases. Understanding the mechanisms of PAR activation and G protein signalling pathways evoked in response to the growing list of endogenous proteases has yielded great insight into receptor regulation at the molecular level. This has led to the development of new selective modulators of PAR activity, particularly PAR1. The mixed success of targeting PARs has been best exemplified in the context of inhibiting PAR1 as a new antiplatelet therapy. The development of the competitive PAR1 antagonist, vorapaxar (Zontivity), has clearly shown the value in targeting PAR1 in acute coronary syndrome (ACS); however the severity of associated bleeding with this drug has limited its use in the clinic. Due to the efficacy of thrombin acting via PAR1, strategies to selectively inhibit specific PAR1-mediated G protein signalling pathways or to target the second thrombin platelet receptor, PAR4, are being devised. The rationale behind these alternative approaches is to bias downstream thrombin activity via PARs to allow for inhibition of pro-thrombotic pathways but maintain other pathways that may preserve haemostatic balance and improve bleeding profiles for widespread clinical use. This review summarizes the structural determinants that regulate PARs and the modulators of PAR activity developed to date.

Predictors of quality of life in head and neck cancer survivors up to 5 years after end of treatment: a cross-sectional survey.

PURPOSE: This study aimed to assess quality of life (QoL) in head and neck cancer (HNC) survivors and determine factors predictive of poor QoL in the first 5 years after the end of treatment. METHODS: A cross-sectional survey, including the Quality of Life in Adult Cancer Survivors (QLACS) measure, was sent to HNC survivors in three Scottish health regions, with responses linked to routinely collected clinical data. Independent sample t tests, ANOVAs, Pearson correlations and multiple hierarchical regressions were used to explore associations between and to determine the contribution made by demographic, lifestyle and clinical factors to predicting 'generic' and 'cancer-specific' quality of life. RESULTS: Two hundred eighty patients (65 %) returned questionnaires. After adjustment, multivariate analysis showed that younger age, lower socio-economic status, unemployment and self-reported comorbidity independently contributed to poorer generic and cancer-specific quality of life. In addition to these factors, having had a feeding tube or a diagnosis of oral cavity cancer were independently predictive of poorer cancer-specific quality of life. CONCLUSIONS: Socio-economic factors and comorbidity are important predictors of QoL in HNC survivors. These factors and the detrimental long-term effects of feeding tubes need further attention in research and practice.

Intensive versus conventional glycaemic control for treating diabetic foot ulcers.

BACKGROUND: The estimated likelihood of lower limb amputation is 10 to 30 times higher amongst people with diabetes compared to those without diabetes. Of all non-traumatic amputations in people with diabetes, 85% are preceded by a foot ulcer. Foot ulceration associated with diabetes (diabetic foot ulcers) is caused by the interplay of several factors, most notably diabetic peripheral neuropathy (DPN), peripheral arterial disease (PAD) and changes in foot structure. These factors have been linked to chronic hyperglycaemia (high levels of glucose in the blood) and the altered metabolic state of diabetes. Control of hyperglycaemia may be important in the healing of ulcers. OBJECTIVES: To assess the effects of intensive glycaemic control compared to conventional control on the outcome of foot ulcers in people with type 1 and type 2 diabetes. SEARCH METHODS: In December 2015 we searched: The Cochrane Wounds Specialised Register; The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library); Ovid MEDLINE; Ovid MEDLINE (In-Process & Other Non-Indexed Citations); Ovid EMBASE; EBSCO CINAHL; Elsevier SCOPUS; ISI Web of Knowledge Web of Science; BioMed Central and LILACS. We also searched clinical trial databases, pharmaceutical trial databases and current international and national clinical guidelines on diabetes foot management for relevant published, non-published, ongoing and terminated clinical trials. There were no restrictions based on language or date of publication or study setting. SELECTION CRITERIA: Published, unpublished and ongoing randomised controlled trials (RCTs) were considered for inclusion where they investigated the effects of intensive glycaemic control on the outcome of active foot ulcers in people with diabetes. Non randomised and quasi-randomised trials were excluded. In order to be included the trial had to have: 1) attempted to maintain or control blood glucose levels and measured changes in markers of glycaemic control (HbA1c or fasting, random, mean, home capillary or urine glucose), and 2) documented the effect of these interventions on active foot ulcer outcomes. Glycaemic interventions included subcutaneous insulin administration, continuous insulin infusion, oral anti-diabetes agents, lifestyle interventions or a combination of these interventions. The definition of the interventional (intensive) group was that it should have a lower glycaemic target than the comparison (conventional) group. DATA COLLECTION AND ANALYSIS: All review authors independently evaluated the papers identified by the search strategy against the inclusion criteria. Two review authors then independently reviewed all potential full-text articles and trials registry results for inclusion. MAIN RESULTS: We only identified one trial that met the inclusion criteria but this trial did not have any results so we could not perform the planned subgroup and sensitivity analyses in the absence of data. Two ongoing trials were identified which may provide data for analyses in a later version of this review. The completion date of these trials is currently unknown. AUTHORS' CONCLUSIONS: The current review failed to find any completed randomised clinical trials with results. Therefore we are unable to conclude whether intensive glycaemic control when compared to conventional glycaemic control has a positive or detrimental effect on the treatment of foot ulcers in people with diabetes. Previous evidence has however highlighted a reduction in risk of limb amputation (from various causes) in people with type 2 diabetes with intensive glycaemic control. Whether this applies to people with foot ulcers in particular is unknown. The exact role that intensive glycaemic control has in treating foot ulcers in multidisciplinary care (alongside other interventions targeted at treating foot ulcers) requires further investigation.

Differential endosomal sorting of a novel P2Y12 purinoreceptor mutant.

P2Y12 receptor internalization and recycling play an essential role in ADP-induced platelet activation. Recently, we identified a patient with a mild bleeding disorder carrying a heterozygous mutation of P2Y12 (P341A) whose P2Y12 receptor recycling was significantly compromised. Using human cell line models, we identified key proteins regulating wild-type (WT) P2Y12 recycling and investigated P2Y12 -P341A receptor traffic. Treatment with ADP resulted in delayed Rab5-dependent internalization of P341A when compared with WT P2Y12 . While WT P2Y12 rapidly recycled back to the membrane via Rab4 and Rab11 recycling pathways, limited P341A recycling was observed, which relied upon Rab11 activity. Although minimal receptor degradation was evident, P341A was localized in Rab7-positive endosomes with considerable agonist-dependent accumulation in the trans-Golgi network (TGN). Rab7 activity is known to facilitate recruitment of retromer complex proteins to endosomes to transport cargo to the TGN. Here, we identified that P341A colocalized with Vps26; depletion of which blocked limited recycling and promoted receptor degradation. This study has identified key points of divergence in the endocytic traffic of P341A versus WT-P2Y12 . Given that these pathways are retained in human platelets, this research helps define the molecular mechanisms regulating P2Y12 receptor traffic and explain the compromised receptor function in the platelets of the P2Y12 -P341A-expressing patient.

Lower limb biomechanical characteristics of patients with neuropathic diabetic foot ulcers: the diabetes foot ulcer study protocol.

BACKGROUND: Foot ulceration is the main precursor to lower limb amputation in patients with type 2 diabetes worldwide. Biomechanical factors have been implicated in the development of foot ulceration; however the association of these factors to ulcer healing remains less clear. It may be hypothesised that abnormalities in temporal spatial parameters (stride to stride measurements), kinematics (joint movements), kinetics (forces on the lower limb) and plantar pressures (pressure placed on the foot during walking) contribute to foot ulcer healing. The primary aim of this study is to establish the biomechanical characteristics (temporal spatial parameters, kinematics, kinetics and plantar pressures) of patients with plantar neuropathic foot ulcers compared to controls without a history of foot ulcers. The secondary aim is to assess the same biomechanical characteristics in patients with foot ulcers and controls over-time to assess whether these characteristics remain the same or change throughout ulcer healing. METHODS/DESIGN: The design is a case-control study nested in a six-month longitudinal study. Cases will be participants with active plantar neuropathic foot ulcers (DFU group). Controls will consist of patients with type 2 diabetes (DMC group) and healthy participants (HC group) with no history of foot ulceration. Standardised gait and plantar pressure protocols will be used to collect biomechanical data at baseline, three and six months. Descriptive variables and primary and secondary outcome variables will be compared between the three groups at baseline and follow-up. DISCUSSION: It is anticipated that the findings from this longitudinal study will provide important information regarding the biomechanical characteristic of type 2 diabetes patients with neuropathic foot ulcers. We hypothesise that people with foot ulcers will demonstrate a significantly compromised gait pattern (reduced temporal spatial parameters, kinematics and kinetics) at base line and then throughout the follow-up period compared to controls. The study may provide evidence for the design of gait-retraining, neuro-muscular conditioning and other approaches to off-load the limbs of those with foot ulcers in order to reduce the mechanical loading on the foot during gait and promote ulcer healing.

Epidemiology of Carbapenem-Resistant Enterobacteriaceae in 7 US Communities, 2012-2013.

IMPORTANCE: Carbapenem-resistant Enterobacteriaceae (CRE) are increasingly reported worldwide as a cause of infections with high-mortality rates. Assessment of the US epidemiology of CRE is needed to inform national prevention efforts. OBJECTIVE: To determine the population-based CRE incidence and describe the characteristics and resistance mechanism associated with isolates from 7 US geographical areas. DESIGN, SETTING, AND PARTICIPANTS: Population- and laboratory-based active surveillance of CRE conducted among individuals living in 1 of 7 US metropolitan areas in Colorado, Georgia, Maryland, Minnesota, New Mexico, New York, and Oregon. Cases of CRE were defined as carbapenem-nonsusceptible (excluding ertapenem) and extended-spectrum cephalosporin-resistant Escherichia coli, Enterobacter aerogenes, Enterobacter cloacae complex, Klebsiella pneumoniae, or Klebsiella oxytoca that were recovered from sterile-site or urine cultures during 2012-2013. Case records were reviewed and molecular typing for common carbapenemases was performed. EXPOSURES: Demographics, comorbidities, health care exposures, and culture source and location. MAIN OUTCOMES AND MEASURES: Population-based CRE incidence, site-specific standardized incidence ratios (adjusted for age and race), and clinical and microbiological characteristics. RESULTS: Among 599 CRE cases in 481 individuals, 520 (86.8%; 95% CI, 84.1%-89.5%) were isolated from urine and 68 (11.4%; 95% CI, 8.8%-13.9%) from blood. The median age was 66 years (95% CI, 62.1-65.4 years) and 284 (59.0%; 95% CI, 54.6%-63.5%) were female. The overall annual CRE incidence rate per 100<000 population was 2.93 (95% CI, 2.65-3.23). The CRE standardized incidence ratio was significantly higher than predicted for the sites in Georgia (1.65 [95% CI, 1.20-2.25]; P < .001), Maryland (1.44 [95% CI, 1.06-1.96]; P = .001), and New York (1.42 [95% CI, 1.05-1.92]; P = .048), and significantly lower than predicted for the sites in Colorado (0.53 [95% CI, 0.39-0.71]; P < .001), New Mexico (0.41 [95% CI, 0.30-0.55]; P = .01), and Oregon (0.28 [95% CI, 0.21-0.38]; P < .001). Most cases occurred in individuals with prior hospitalizations (399/531 [75.1%; 95% CI, 71.4%-78.8%]) or indwelling devices (382/525 [72.8%; 95% CI, 68.9%-76.6%]); 180 of 322 (55.9%; 95% CI, 50.0%-60.8%) admitted cases resulted in a discharge to a long-term care setting. Death occurred in 51 (9.0%; 95% CI, 6.6%-11.4%) cases, including in 25 of 91 cases (27.5%; 95% CI, 18.1%-36.8%) with CRE isolated from normally sterile sites. Of 188 isolates tested, 90 (47.9%; 95% CI, 40.6%-55.1%) produced a carbapenemase. CONCLUSIONS AND RELEVANCE: In this population- and laboratory-based active surveillance system in 7 states, the incidence of CRE was 2.93 per 100<000 population. Most CRE cases were isolated from a urine source, and were associated with high prevalence of prior hospitalizations or indwelling devices, and discharge to long-term care settings.

Visceral adiposity is not associated with abdominal aortic aneurysm presence and growth.

Previous studies in rodent models and patients suggest that visceral adipose could play a direct role in the development and progression of abdominal aortic aneurysm (AAA). This study aimed to assess the association of visceral adiposity with AAA presence and growth. This study was a case-control investigation of patients that did (n=196) and did not (n=181) have an AAA who presented to The Townsville Hospital vascular clinic between 2003 and 2012. Cases were patients with AAA (infra-renal aortic diameter >30 mm) and controls were patients with intermittent claudication but no AAA (infra-renal aortic diameter <30 mm). All patients underwent computed tomography angiography (CTA). The visceral to total abdominal adipose volume ratio was estimated from CTAs by assessing total and visceral adipose deposits using an imaging software program. Measurements were assessed for reproducibility by repeat assessments on 15 patients. AAA risk factors were recorded at entry. Forty-five cases underwent two CTAs more than 6 months apart to assess AAA expansion. The association of visceral adiposity with AAA presence and growth was examined using logistic regression. Visceral adipose assessment by CTA was highly reproducible (mean coefficient of variation 1.0%). AAA was positively associated with older age and negatively associated with diabetes. The visceral to total abdominal adipose volume ratio was not significantly associated with AAA after adjustment for other risk factors. Patients with a visceral to total abdominal adipose volume ratio in quartile four had a 1.63-fold increased risk of AAA but with wide confidence intervals (95% CI 0.71-3.70; p=0.248). Visceral adiposity was not associated with AAA growth. In conclusion, this study suggests that visceral adiposity is not specifically associated with AAA presence or growth although larger studies are required to confirm these findings.

Local public health under threat: Harassment faced by local health department leaders during the COVID-19 pandemic.

Background: Prior to the COVID-19 pandemic, local health departments (LHDs) faced several challenges including underfunding and understaffing. COVID-19 exacerbated these challenges and introduced new ones, including harassment of the agency, staff, and leadership. The objective of this study was to qualitatively understand the experiences and impact of harassment faced by LHDs during the pandemic and provide recommendations to prevent future harassment. Study design: A qualitative study was conducted utilizing focus groups for data collection. Methods: LHDs were sampled from the 2022 National Profile of Local Health Departments (Profile) study to ensure diversity in LHD size. Four virtual focus groups were conducted in Fall 2022 with a total of 16 LHD leaders surveyed in Profile, who were still in their positions. Focus group transcripts were then coded by two independent coders and analyzed using thematic analysis. Findings: Four common domains arose from the data: aggravating factors of harassment, content and formats of harassment, protective factors, and effects on individuals and on the workforce. Conclusion: Findings suggest that harassment was pervasive with many forms and impacts on the LHD leaders and workforce overall. Recommendations are proposed for the local as well as federal partners because the public health system is threatened without immediate, substantial, and coordinated solutions to address harassment and offer protection.

Defining and unpacking the core concepts of pharmacology: A global initiative.

BACKGROUND AND PURPOSE: Development of core concepts in disciplines such as biochemistry, microbiology and physiology have transformed teaching. They provide the foundation for the development of teaching resources for global educators, as well as valid and reliable approaches to assessment. An international research consensus recently identified 25 core concepts of pharmacology. The current study aimed to define and unpack these concepts. EXPERIMENTAL APPROACH: A two-phase, iterative approach, involving 60 international pharmacology education experts, was used. The first phase involved drafting definitions for core concepts and identifying key sub-concepts via a series of online meetings and asynchronous work. These were refined in the second phase, through a 2-day hybrid workshop followed by a further series of online meetings and asynchronous work. KEY RESULTS: The project produced consensus definitions for a final list of 24 core concepts and 103 sub-concepts of pharmacology. The iterative, discursive methodology resulted in modification of concepts from the original study, including change of 'drug-receptor interaction' to 'drug-target interaction' and the change of the core concept 'agonists and antagonists' to sub-concepts of drug-target interaction. CONCLUSIONS AND IMPLICATIONS: Definitions and sub-concepts of 24 core concepts provide an evidence-based foundation for pharmacology curricula development and evaluation. The next steps for this project include the development of a concept inventory to assess acquisition of concepts, as well as the development of case studies and educational resources to support teaching by the global pharmacology community, and student learning of the most critical and fundamental concepts of the discipline.

Ethanol reversal of cellular tolerance to morphine in rat locus coeruleus neurons.

Consumption of ethanol is a considerable risk factor for death in heroin overdose. We sought to determine whether a mildly intoxicating concentration of ethanol could alter morphine tolerance at the cellular level. In rat locus coeruleus (LC) neurons, tolerance to morphine was reversed by acute exposure of the brain slice to ethanol (20 mM). Tolerance to the opioid peptide [d-Ala(2),N-MePhe(4),Gly-ol]-enkephalin was not reversed by ethanol. Previous studies in LC neurons have revealed a role for protein kinase C (PKC)α in µ-opioid receptor (MOPr) desensitization by morphine and in the induction and maintenance of morphine tolerance, but we have been unable to demonstrate that 20 mM ethanol produces significant inhibition of PKCα. The ability of ethanol to reverse cellular tolerance to morphine in LC neurons was absent in the presence of the phosphatase inhibitor okadaic acid, indicating that dephosphorylation is involved. In human embryonic kidney 293 cells expressing the MOPr, ethanol reduced the level of MOPr phosphorylation induced by morphine. Ethanol reversal of tolerance did not appear to result from a direct effect on MOPr since acute exposure to ethanol (20 mM) did not modify the affinity of binding of morphine to the MOPr or the efficacy of morphine for G-protein activation as measured by guanosine 5'-O-(3-[(35)S]thio)triphosphate binding. Similarly, ethanol did not affect MOPr trafficking. We conclude that acute exposure to ethanol enhances the effects of morphine by reversing the processes underlying morphine cellular tolerance.