Harm reduction in undergraduate and graduate medical education: a systematic scoping review.

BACKGROUND: Substance use increasingly contributes to early morbidity and mortality, which necessitates greater preparation of the healthcare workforce to mitigate its harm. The purpose of this systematic scoping review is to: 1) review published curricula on harm reduction for substance use implemented by undergraduate (UME) and graduate medical education (GME) in the United States and Canada, 2) develop a framework to describe a comprehensive approach to harm reduction medical education, and 3) propose additional content topics for future consideration. METHODS: PubMed, Scopus, ERIC: Education Resources Information Center (Ovid), and MedEdPORTAL were searched. Studies included any English language curricula about harm reduction within UME or GME in the United States or Canada from 1993 until Nov 22, 2021. Two authors independently reviewed and screened records for data extraction. Data were analyzed on trainee population, curricula objectives, format, content, and evaluation. RESULTS: Twenty-three articles describing 19 distinct educational programs across the United States were included in the final sample, most of which created their own curricula (n = 17). Data on educational content were categorized by content and approach. Most programs (85%) focused on introductory substance use knowledge and skills without an understanding of harm reduction principles. Based on our synthesis of the educational content in these curricula, we iteratively developed a Harm Reduction Educational Spectrum (HRES) framework to describe curricula and identified 17 discrete content topics grouped into 6 themes based on their reliance on harm reduction principles. CONCLUSIONS: Harm reduction is under-represented in published medical curricula. Because the drug supply market changes rapidly, the content of medical curricula may be quickly outmoded thus curricula that include foundational knowledge of harm reduction principles may be more enduring. Students should be grounded in harm reduction principles to develop the advanced skills necessary to reduce the physical harm associated with drugs while still simultaneously recognizing the possibility of patients' ongoing substance use. We present the Harm Reduction Educational Spectrum as a new framework to guide future healthcare workforce development and to ultimately provide the highest-quality care for patients who use drugs.

Reducing Hospital Readmissions of Older Adults Pursuing Postacute Care at Skilled Nursing Facilities: A Scoping Review.

IMPORTANCE: Unplanned hospital readmissions can profoundly affect older adults' quality of life and the financial status of skilled nursing facilities (SNFs). Although many clinical practices focus on reforming these issues, occupational therapy's involvement remains unclear. OBJECTIVE: To explore clinical practices aimed at reducing hospital readmissions of older adults pursuing postacute care (PAC) at SNFs and describe how they align with occupational therapy's scope of practice. DATA SOURCES: We searched CINAHL, Scopus, PubMed, and OTseeker for articles published from January 2011 to February 2020. Study Selection and Data Collection: We conducted a scoping review of peer-reviewed articles with functional outcomes of clinical practices reducing unplanned hospital readmissions of patients older than age 65 yr pursuing PAC services in SNFs. Trained reviewers completed the title and abstract screens, full-text reviews, and data extraction. FINDINGS: Thirteen articles were included and focused on five areas: risk and medical disease management and follow-up, hospital-to-SNF transition, enhanced communication and care, function, and nutrition. Early coordination of care and early identification of patients' needs and risk of readmission were common features. All clinical practices aligned with occupational therapy domains and processes, but only 1 study specified occupational therapy as part of the research team. CONCLUSIONS AND RELEVANCE: Comprehensive, multipronged clinical practices encompassing care coordination and early identification and management of acute conditions are critical in reducing preventable readmissions among older adults pursuing PAC services in SNFs. Further research is needed to support occupational therapy's value in preventing hospital readmissions of older adults in this setting. What This Article Adds: This scoping review maps the presence of occupational therapy's domains and processes in the clinical practices that reduce hospital readmissions of older adults pursuing PAC services in SNFs. Findings provide occupational therapy practitioners with opportunities to assume roles beyond direct patient care, research, advocate, and publish more, thereby increasing their presence and adding value to occupational therapy interventions that reduce hospital readmissions.

Increased novelty-induced locomotion, sensitivity to amphetamine, and extracellular dopamine in striatum of Zdhhc15-deficient mice.

Novelty-seeking behaviors and impulsivity are personality traits associated with several psychiatric illnesses including attention deficits hyperactivity disorders. The underlying neural mechanisms remain poorly understood. We produced and characterized a line of knockout mice for zdhhc15, which encodes a neural palmitoyltransferase. Genetic defects of zdhhc15 were implicated in intellectual disability and behavioral anomalies in humans. Zdhhc15-KO mice showed normal spatial learning and working memory but exhibited a significant increase in novelty-induced locomotion in open field. Striatal dopamine content was reduced but extracellular dopamine levels were increased during the habituation phase to a novel environment. Administration of amphetamine and methylphenidate resulted in a significant increase in locomotion and extracellular dopamine levels in the ventral striatum of mutant mice compared to controls. Number and projections of dopaminergic neurons in the nigrostriatal and mesolimbic pathways were normal. No significant change in the basal palmitoylation of known ZDHHC15 substrates including DAT was detected in striatum of zdhhc15 KO mice using an acyl-biotin exchange assay. These results support that a transient, reversible, and novelty-induced elevation of extracellular dopamine in ventral striatum contributes to novelty-seeking behaviors in rodents and implicate ZDHHC15-mediated palmitoylation as a novel regulatory mechanism of dopamine in the striatum.

Mice lacking GRIP1/2 show increased social interactions and enhanced phosphorylation at GluA2-S880.

Glutamate receptor interacting proteins 1 and 2 (GRIP1/2) play an important role in regulating synaptic trafficking of AMPA receptor 2/3 (GluA2/3) and synaptic strength. Gain-of-function GRIP1 mutations are implicated in social behavioral deficits in autism. To study mechanisms of Grip1/2-mediated AMPA signaling in the regulation of social behaviors, we performed social behavioral testing on neuron-specific Grip1/2-double knockout (DKO) and wild type (WT) mice that are matched for age, sex, and strain background. We determined the expression profile of key signaling proteins in AMPAR, mGluR, mTOR, and GABA pathways in frontal cortex, striatum, and cerebellum of DKO mice. Compared to WT mice, DKO mice show increased sociability in a modified three-chamber social behavioral test [mean±sem for interaction time in seconds; WT: 44.0±5.0; n=10; DKO: 81.0±9.0; n=9; two factor repeated measures ANOVA: F(1,37)=14.45; p<0.01 and planned t-test; p<0.01] and in a dyadic male-male social interaction test (mean±sem for total time in seconds: sniffing, WT-WT, 18.9±1.1; WT-DKO, 42.5±2.1; t-test: p<0.001; following, WT-WT, 7.7±0.72; WT-DKO,14.4±1.8; t-test: p<0.001). Immunoblot studies identified an increase in phosphorylation at GluA2-Serine 880 (GluA2-pS880) in frontal cortex (mean±sem; WT: 0.69±0.06, n=5; DKO: 0.96±0.06, n=6; t-test; p<0.05) and reduced GABAß3 expression in striatum (mean±sem; WT: 1.16±0.04, n=4; DKO: 0.95±0.06, n=4; t-test; p<0.05) in DKO mice. GluA2-S880 phosphorylation is known to regulate GluA2synaptic recycling, AMPA signaling strength and plasticity. GABAß3 has been implicated in the etiology and pathogenesis in autism. These data support an important role of Grip1/2-mediated AMPA signaling in regulating social behaviors and disturbance of glutamate- and GABA-signaling in specialized brain regions in autism-related social behavioral deficits.

Assessing clinical researchers' information needs to create responsive portals and tools: my Research Assistant (MyRA) at the University of Utah: a case study.

QUESTION: How can health sciences librarians and biomedical informaticians offer relevant support to Clinical and Translational Science Award (CTSA) personnel? SETTING: The Spencer S. Eccles Health Sciences Library and the associate vice president for information technology for the health sciences office at the University of Utah conducted a needs assessment. METHODS: Faculty and staff from these two units, with the services of a consultant and other CTSA partners, employed a survey, focus groups, interviews, and committee discussions. An information portal was created to meet identified needs. RESULTS: A directive white paper was created. The process employed to plan a virtual and physical collaborative, collegial space for clinical researchers at the university and its three inter-institutional CTSA partners is described. CONCLUSION: The university's model can assist other librarians and informaticians with how to become part of a CTSA-focused infrastructure for clinical and translational research and serve researchers in general.

GluA3-deficiency in mice is associated with increased social and aggressive behavior and elevated dopamine in striatum.

Glutamate signaling has been implicated in the regulation of social behavior. AMPA-glutamate receptors are assembled from four subunits (GluA1-4) of mainly GluA1/2 and GluA2/3 tetramers that form ion channels of distinct functional properties. Mice lacking GluA1 showed a reduced anxiety and male aggression. To understand the role of GluA3 in modulating social behavior, we investigated GluA3-deficient mice (Gria3-/Y) on C57BL/6J background. Compared to wild type (WT) littermates (n=14), Gria3-/Y mice (n=13) showed an increase in isolation-induced male aggression (p=0.011) in home cage resident-intruder test; an increase in sociability (p=0.01), and increase in male-male social interactions in neutral arena (p=0.005); an increase in peripheral activities in open field test (p=0.037) with normal anxiety levels in elevated plus maze and light-dark box; and minor deficits in motor and balance function in accelerating rotarod test (p=0.016) with normal grip strength. Gria3-/Y mice showed no significant deficit in spatial memory function in Morris-water maze and Y-maze tests, and normal levels of testosterone. Increased dopamine concentrations in stratum (p=0.034) and reduced serotonin turnover in olfactory bulb (p=0.002) were documented in Gria3-/Y mice. These results support a role of GluA3 in the modulation of social behavior through brain dopamine and/or serotonin signaling and different AMPA receptor subunits affect social behavior through distinct mechanisms.

Effective detection of rare variants in pooled DNA samples using Cross-pool tailcurve analysis.

Sequencing targeted DNA regions in large samples is necessary to discover the full spectrum of rare variants. We report an effective Illumina sequencing strategy utilizing pooled samples with novel quality (Srfim) and filtering (SERVIC4E) algorithms. We sequenced 24 exons in two cohorts of 480 samples each, identifying 47 coding variants, including 30 present once per cohort. Validation by Sanger sequencing revealed an excellent combination of sensitivity and specificity for variant detection in pooled samples of both cohorts as compared to publicly available algorithms.

Gain-of-function glutamate receptor interacting protein 1 variants alter GluA2 recycling and surface distribution in patients with autism.

Glutamate receptor interacting protein 1 (GRIP1) is a neuronal scaffolding protein that interacts directly with the C termini of glutamate receptors 2/3 (GluA2/3) via its PDZ domains 4 to 6 (PDZ4-6). We found an association (P<0.05) of a SNP within the PDZ4-6 genomic region with autism by genotyping autistic patients (n=480) and matched controls (n=480). Parallel sequencing identified five rare missense variants within or near PDZ4-6 only in the autism cohort, resulting in a higher cumulative mutation load (P=0.032). Two variants correlated with a more severe deficit in reciprocal social interaction in affected sibling pairs from proband families. These variants were associated with altered interactions with GluA2/3 and faster recycling and increased surface distribution of GluA2 in neurons, suggesting gain-of-function because GRIP1/2 deficiency showed opposite phenotypes. Grip1/2 knockout mice exhibited increased sociability and impaired prepulse inhibition. These results support a role for GRIP in social behavior and implicate GRIP1 variants in modulating autistic phenotype.

Genetic and functional studies of a missense variant in a glutamate transporter, SLC1A3, in Tourette syndrome.

OBJECTIVE: Abnormalities in neurotransmission within the cortico-striatal-thalamo-cortical circuitry are implicated in the pathogenesis of Tourette syndrome. Glutamate is a major excitatory neurotransmitter and an important member in the cortico-striatal-thalamo-cortical circuitry. To explore the role of glutamatergic neurotransmission in genetic susceptibility of Tourette syndrome, we carried out the genetic and functional characterization of sequence variants in SLC1A3 gene, which encodes the main glutamate transporter in astrocytes in individuals with well-characterized Tourette syndrome (n=256) and normal controls (n=224). METHODS: Exon-containing regions of SLC1A3 gene were screened using capillary electrophoresis-single strand conformation polymorphism followed by direct sequencing. Sequence variants were genotyped by restriction enzyme digestion and studied using glutamate uptake assay and membrane protein pull-down for transporter function. RESULTS: A missense variant involving a highly conserved residue, E219D, was identified in 11 heterozygous individuals with Tourette syndrome and four in the controls. The allele frequency for E219D was 2.4 folds higher in the Tourette syndrome (0.022) compared with the control cohort (0.009) although the difference did not reach statistical significance in the current cohorts (P=0.09). A H-glutamate-uptake assay showed that E219D conveys a significant increase (1.66 fold) in the SLC1A3-mediated glutamate uptake in HEK293 cells. A biotin-mediated membrane pull-down analysis showed a similar increase (1.5 fold) of mutant SLC1A3 protein in the membrane fraction of transfected HEK293 cells compared with that in the wild type controls. CONCLUSION: These results indicate that E219D is a functional SLC1A3 variant that is presented in a small number of individuals with Tourette syndrome. Further studies on possible changes in glutamate transport in the pathogenesis of Tourette syndrome are warranted.