Community-Based Cluster-Randomized Trial to Reduce Opioid Overdose Deaths.

BACKGROUND: Evidence-based practices for reducing opioid-related overdose deaths include overdose education and naloxone distribution, the use of medications for the treatment of opioid use disorder, and prescription opioid safety. Data are needed on the effectiveness of a community-engaged intervention to reduce opioid-related overdose deaths through enhanced uptake of these practices. METHODS: In this community-level, cluster-randomized trial, we randomly assigned 67 communities in Kentucky, Massachusetts, New York, and Ohio to receive the intervention (34 communities) or a wait-list control (33 communities), stratified according to state. The trial was conducted within the context of both the coronavirus disease 2019 (Covid-19) pandemic and a national surge in the number of fentanyl-related overdose deaths. The trial groups were balanced within states according to urban or rural classification, previous overdose rate, and community population. The primary outcome was the number of opioid-related overdose deaths among community adults. RESULTS: During the comparison period from July 2021 through June 2022, the population-averaged rates of opioid-related overdose deaths were similar in the intervention group and the control group (47.2 deaths per 100,000 population vs. 51.7 per 100,000 population), for an adjusted rate ratio of 0.91 (95% confidence interval, 0.76 to 1.09; P = 0.30). The effect of the intervention on the rate of opioid-related overdose deaths did not differ appreciably according to state, urban or rural category, age, sex, or race or ethnic group. Intervention communities implemented 615 evidence-based practice strategies from the 806 strategies selected by communities (254 involving overdose education and naloxone distribution, 256 involving the use of medications for opioid use disorder, and 105 involving prescription opioid safety). Of these evidence-based practice strategies, only 235 (38%) had been initiated by the start of the comparison year. CONCLUSIONS: In this 12-month multimodal intervention trial involving community coalitions in the deployment of evidence-based practices to reduce opioid overdose deaths, death rates were similar in the intervention group and the control group in the context of the Covid-19 pandemic and the fentanyl-related overdose epidemic. (Funded by the National Institutes of Health; HCS ClinicalTrials.gov number, NCT04111939.).

Phenotype onset in Huntington's disease knock-in mice is correlated with the incomplete splicing of the mutant huntingtin gene.

Huntington's disease (HD) is a progressive neurodegenerative disorder caused by an expanded CAG repeat within the huntingtin (HTT) gene. The Q140 and HdhQ150 knock-in HD mouse models were generated such that HdhQ150 mice have an expanded CAG repeat inserted into the mouse Htt gene, whereas in the Q140s, mouse exon 1 Htt was replaced with a mutated version of human exon 1. By standardizing mouse strain background, breeding to homozygosity and employing sensitive behavioral tests, we demonstrate that the onset of behavioral phenotypes occurs earlier in the Q140 than the HdhQ150 knock-in mouse models and that huntingtin (HTT) aggregation appears earlier in the striata of Q140 mice. We have previously found that the incomplete splicing of mutant HTT from exon 1 to exon 2 results in the production of a small polyadenylated transcript that encodes the highly pathogenic mutant HTT exon 1 protein. In this report, we have identified a functional consequence of the sequence differences between these two models at the RNA level, in that the level of incomplete splicing, and of the mutant exon 1 HTT protein, are greater in the brains of Q140 mice. While differences in the human and mouse exon 1 HTT proteins (e.g., proline rich sequences) could also contribute to the phenotypic differences, our data indicate that the incomplete splicing of HTT and approaches to lower the levels of the exon 1 HTT transcript should be pursued as therapeutic targets.

Chronic nicotine improves cognitive and social impairment in mice overexpressing wild type α-synuclein.

In addition to dopaminergic and motor deficits, patients with Parkinson's disease (PD) suffer from non-motor symptoms, including early cognitive and social impairment, that do not respond well to dopaminergic therapy. Cholinergic deficits may contribute to these problems, but cholinesterase inhibitors have limited efficacy. Mice over-expressing α-synuclein, a protein critically associated with PD, show deficits in cognitive and social interaction tests, as well as a decrease in cortical acetylcholine. We have evaluated the effects of chronic administration of nicotine in mice over-expressing wild type human α-synuclein under the Thy1-promoter (Thy1-aSyn mice). Nicotine was administered subcutaneously by osmotic minipump for 6 months from 2 to 8 months of age at 0.4 mg/kg/h and 2.0 mg/kg/h. The higher dose was toxic in the Thy1-aSyn mice, but the low dose was well tolerated and both doses ameliorated cognitive impairment in Y-maze performance after 5 months of treatment. In a separate cohort of Thy1-aSyn mice, nicotine was administered at the lower dose for one month beginning at 5 months of age. This treatment partially eliminated the cognitive deficit in novel object recognition and social impairment. In contrast, chronic nicotine did not improve motor deficits after 2, 4 or 6 months of treatment, nor modified α-synuclein aggregation, tyrosine hydroxylase immunostaining, synaptic and dendritic markers, or microglial activation in Thy1-aSyn mice. These results suggest that cognitive and social impairment in synucleinopathies like PD may result from deficits in cholinergic neurotransmission and may benefit from chronic administration of nicotinic agonists.

Chronic administration of cholesterol oximes in mice increases transcription of cytoprotective genes and improves transcriptome alterations induced by alpha-synuclein overexpression in nigrostriatal dopaminergic neurons.

Cholesterol-oximes TRO19622 and TRO40303 target outer mitochondrial membrane proteins and have beneficial effects in preclinical models of neurodegenerative diseases leading to their advancement to clinical trials. Dopaminergic neurons degenerate in Parkinson's disease (PD) and are prone to oxidative stress and mitochondrial dysfunction. In order to provide insights into the neuroprotective potential of TRO19622 and TRO40303 for dopaminergic neurons in vivo, we assessed their effects on gene expression in laser captured nigrostriatal dopaminergic neurons of wildtype mice and of mice that over-express alpha-synuclein, a protein involved in both familial and sporadic forms of PD (Thy1-aSyn mice). Young mice were fed the drugs in food pellets or a control diet from 1 to 4months of age, approximately 10months before the appearance of striatal dopamine loss in this model. Unbiased weighted gene co-expression network analysis (WGCNA) of transcriptional changes revealed effects of cholesterol oximes on transcripts related to mitochondria, cytoprotection and anti-oxidant response in wild-type and transgenic mice, including increased transcription of stress defense (e.g. Prdx1, Prdx2, Glrx2, Hspa9, Pink1, Drp1, Trak1) and dopamine-related (Th, Ddc, Gch1, Dat, Vmat2, Drd2, Chnr6a) genes. Even at this young age transgenic mice showed alterations in transcripts implicated in mitochondrial function and oxidative stress (e.g. Bcl-2, Bax, Casp3, Nos2), and both drugs normalized about 20% of these alterations. Young Thy1-aSyn mice exhibit motor deficits that differ from parkinsonism and are established before the onset of treatment; these deficits were not improved by cholesterol oximes. However, high doses of TRO40303 improved olfaction and produced the same effects as dopamine agonists on a challenging beam test, specifically an increase in footslips, an observation congruent with its effects on transcripts involved in dopamine synthesis. High doses of TRO19622 increased alpha-synuclein aggregates in the substantia nigra; this effect, not seen with TRO40303 was inconsistent and may represent a protective mechanism as in other neurodegenerative diseases. Overall, the results suggest that cholesterol oximes, while not improving early effects of alpha-synuclein overexpression on motor behavior or pathology, may ameliorate the function and resilience of dopaminergic neurons in vivo and support further studies of neuroprotection in models with dopaminergic cell loss.

Application of Point-of-care Ultrasound for Screening Climbers at High Altitude for Pulmonary B-lines.

INTRODUCTION: High-altitude pulmonary edema (HAPE) occurs as a result of rapid ascent to altitude faster than the acclimatization processes of the body. Symptoms can begin at an elevation of 2,500 meters above sea level. Our objective in this study was to determine the prevalence and trend of developing B-lines at 2,745 meters above sea level among healthy visitors over four consecutive days. METHODS: We performed a prospective case series on healthy volunteers at Mammoth Mountain, CA, USA. Subjects underwent pulmonary ultrasound for B-lines over four consecutive days. RESULTS: We enrolled 21 male and 21 female participants. There was an increase in the sum of B-lines at both lung bases from day 1 to day 3, with a subsequent decrease from day 3 to day 4(P<0.001). By the third day at altitude, B-lines were detectable at base of lungs of all participants. Similarly, B-lines increased at apex of lungs from day 1 to day 3 and decreased on day 4 (P=0.004). CONCLUSION: By the third day at 2,745 meters altitude, B-lines were detectable in the bases of both lungs of all healthy participants in our study. We assume that increasing the number of B-lines could be considered an early sign of HAPE. Point-of-care ultrasound could be used to detect and monitor B-lines at altitude to facilitate early detection of HAPE, regardless of pre-existing risk factors.

Accreditation Council for Graduate Medical Education Milestones for Emergency Medicine Residency Training Incorporated into First- and Second-Year Medical Student Elective.

INTRODUCTION: As part of its Next Accreditation System, the Accreditation Council for Graduate Medical Education and the American Board of Emergency Medicine describe 6 competencies containing 23 sub-competencies graded by milestones ranging from level 1 (expected of an incoming intern) to level 5 (demonstrates abilities of an attending) that are used to track resident training progression. To the best of our knowledge, there have been no studies introducing a milestones-based curriculum to medical students prior to their introduction to the wards, so we sought to determine the effects that a pre-clinical Emergency Medicine Interest Group (EMIG) Milestones Elective would have on preparing the students interested in Emergency Medicine (EM) as a specialty to meet the level 1 milestones prior to their intern year. METHODS: The elective hosted 15 events throughout the academic year, and pre- and post-curriculum surveys were administered. Thirteen first- and second-year medical students at our institution who completed the elective self-reported their perception of preparedness for each level 1 milestone in the 19 sub-competencies. A repeated measures design was used through identical pre- and post-curriculum surveys to determine any changes in self-reported preparedness for meeting level 1 milestones after completing the elective using Wilcoxon Signed Ranks Test. RESULTS: There was a significant increase in the median scoring from 1 to 2 (p=0.027) in overall self-reported preparedness for meeting the level 1 milestones included in the elective, as well as significant increases in subcategories across competencies 1-4 outlined by the ACGME. There was no significant increase in preparedness for professionalism or interpersonal communication competencies. There was no significant increase in interest in EM as a result of the elective. CONCLUSION: Implementing a milestones-based curriculum during the pre-clinical years shows improved self-reported preparedness of students interested in pursuing EM for meeting level 1 milestones prior to residency. Additionally, a specialty-based elective such as this one offered through EMIG may further increase interest in the field during pre-clinical years.

Improving feedback by using first-person video during the emergency medicine clerkship.

PURPOSE: Providing feedback to students in the emergency department during their emergency medicine clerkship can be challenging due to time constraints, the logistics of direct observation, and limitations of privacy. The authors aimed to evaluate the effectiveness of first-person video, captured via Google Glass™, to enhance feedback quality in medical student education. MATERIAL AND METHODS: As a clerkship requirement, students asked patients and attending physicians to wear the Google Glass™ device to record patient encounters and patient presentations, respectively. Afterwards, students reviewed the recordings with faculty, who provided formative and summative feedback, during a private, one-on-one session. We introduced the intervention to 45, fourth-year medical students who completed their mandatory emergency medicine clerkships at a United States medical school during the 2015-2016 academic year. RESULTS: Students assessed their performances before and after the review sessions using standardized medical school evaluation forms. We compared students' self-assessment scores to faculty assessment scores in 14 categories using descriptive statistics and symmetric tests. The overall mean scores, for each of the 14 categories, ranged between 3 and 4 (out of 5) for the self-assessment forms. When evaluating the propensity of self-assessment scores toward the faculty assessment scores, we found no significant changes in all 14 categories. Although not statistically significant, one fifth of students changed perspectives of their clinical skills (history taking, performing physical exams, presenting cases, and developing differential diagnoses and plans) toward faculty assessments after reviewing the video recordings. CONCLUSION: First-person video recording still initiated the feedback process, allocated specific time and space for feedback, and possibly substituted for the direct observation procedure. Additional studies, with different outcomes and larger sample sizes, are needed to understand the effectiveness of first-person video in improving feedback quality.

A Molecular Tweezer Ameliorates Motor Deficits in Mice Overexpressing α-Synuclein.

Aberrant accumulation and self-assembly of α-synuclein are tightly linked to several neurodegenerative diseases called synucleinopathies, including idiopathic Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. Deposition of fibrillar α-synuclein as insoluble inclusions in affected brain cells is a pathological hallmark of synucleinopathies. However, water-soluble α-synuclein oligomers may be the actual culprits causing neuronal dysfunction and degeneration in synucleinopathies. Accordingly, therapeutic approaches targeting the toxic α-synuclein assemblies are attractive for these incurable disorders. The "molecular tweezer" CLR01 selectively remodels abnormal protein self-assembly through reversible binding to Lys residues. Here, we treated young male mice overexpressing human wild-type α-synuclein under control of the Thy-1 promoter (Thy1-aSyn mice) with CLR01 and examined motor behavior and α-synuclein in the brain. Intracerebroventricular administration of CLR01 for 28 days to the mice improved motor dysfunction in the challenging beam test and caused a significant decrease of buffer-soluble α-synuclein in the striatum. Proteinase-K-resistant, insoluble α-synuclein deposits remained unchanged in the substantia nigra, whereas levels of diffuse cytoplasmic α-synuclein in dopaminergic neurons increased in mice receiving CLR01 compared with vehicle. More moderate improvement of motor deficits was also achieved by subcutaneous administration of CLR01, in 2/5 trials of the challenging beam test and in the pole test, which requires balance and coordination. The data support further development of molecular tweezers as therapeutic agents for synucleinopathies.