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BACKGROUND: Drug overdose is a leading cause of death and opioid-related deaths increased by more than 300% from 2010 to 2020 in New York State. Experts holding a range of senior leadership positions from across New York State were asked to identify the greatest challenges in substance misuse prevention, harm reduction, and treatment continuum of care. Expert input was used to shape funding priorities. METHOD: Individual semi-structured interviews of sixteen experts were conducted in April and May 2023. Experts included academics, medical directors, leaders of substance misuse service agencies, administrators of a state agency, a county mental health commissioner, the president of a pharmacy chain, and a senior vice president of an addiction-related national non-profit. Zoom interviews were conducted individually by an experienced qualitative interviewer and were recorded, transcribed, and coded for content. An initial report, with the results of the interviews organized by thematic content, was reviewed by the research team and emailed to the expert interviewees for feedback. RESULTS: The research team identified five major themes: 1. Siloed and fragmented care delivery systems; 2. Need for a skilled workforce; 3. Attitudes towards addiction (stigma); 4. Limitations in treatment access; and 5. Social and drug related environmental factors. Most experts identified challenges in each major theme; over three-quarters identified issues related to siloed and fragmented systems and the need for a skilled workforce. Each expert mentioned more than one theme, three experts mentioned all five themes and six experts mentioned four themes. CONCLUSIONS: Research, educational, and programmatic agendas should focus on identified topics as a means of improving the lives of patients at risk for or suffering from substance use-related disorders. The results of this project informed funding of pilot interventions designed to address the identified care challenges.

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INTRODUCTION: Telemedicine is a feasible alternative to in-person evaluations for people with opioid use disorder (OUD). The literature on medications for opioid use disorder (MOUD) telemedicine has focused on ongoing OUD treatment. Emergency department (ED) visits are an opportunity to initiate MOUD; however, little is known regarding the outcomes of patients following telemedicine referrals for MOUD from emergency settings. The current study describes rates of initial outpatient clinic appointment attendance and 30-day retention in care among patients referred by telemedicine compared to ED referrals. METHODS: This paper reports a retrospective review of data for patients referred from EDs or telemedicine through the Medication for Addiction Treatment and Electronic Referrals (MATTERS) Network. The MATTERS online platform collects data on patient demographic information (e.g., age, gender, race/ethnicity, and insurance type), reason for visit, prior medical and mental health history, prior OUD treatment history, and past 30-day substance use behaviors. Analyses compared initial visit attendance and 30-day retention among the patients for whom follow-up data were received from clinics by demographic and initial treatment factors. RESULTS: Between October 2020 and September 2022, the MATTERS Network made 1349 referrals; 39.7 % originated from an ED and 47.8 % originated from telemedicine. For patients with available data, those referred from telemedicine were 1.64 times more likely to attend their initial clinic appointment and 2.59 times more likely be engaged in treatment at 30 days compared to those referred from an ED. More than two-thirds of patients referred from the emergency telemedicine environment followed up at their first clinic visit and more than half of these patients were still retained in treatment 30 days after referral. CONCLUSIONS: The rates of initial clinic visit and 30-day retention when referred following a telemedicine evaluation are encouraging. Further development of telemedicine programs that offer evaluations, access to medications, and referrals to treatment should be considered.

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Purpose: This study compares substance use, treatment histories, and sociodemographic characteristics of patients presenting to an emergency department (ED) following a heroin overdose or seeking detoxification services for heroin and examines risk factors for a subsequent return to the ED for a substance-related problem. Methods: A convenience sample of patients presenting for an overdose or detoxification at an urban teaching ED was recruited for this study. During their ED visit, patients were interviewed regarding demographics, substance use experiences, and treatment history. Subsequently, a review of patient records for past and subsequent ED use was performed. Results: Patients requesting detox and those with an overdose were similar in terms of prior treatment. Both groups had similar extensive polysubstance histories. As a group, however, patients presenting for detox were more likely to report use of each of three substances (benzodiazepines, opioid pain medications, and heroin) more than three times per week, compared to those presenting for overdose. Detox patients had higher scores on the 3-item Alcohol Use Disorder Identification Test-C and the drug problems scale compared to overdose patients. Overall, 28% of the patients returned to the ED within 90 days for a drug-related issue, including 8% that returned for an overdose. Factors predictive of a return ED visit included ED visits for substance use in the previous year and recent frequent heroin use. Conclusion: Patients requesting detox were similar in most domains to those presenting following an overdose. Notably, overdose patients were less likely to use heroin more than three times per week compared to detox patients. Both groups were equally likely to return for an SUD reason within 3-months, however for both groups, previous ED visits and recent frequent heroin use predicted a return visit.

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A 44-year-old male with a history of deep venous thrombosis (DVT) and pulmonary embolism (PE) with the inferior vena cava (IVC) filter in place and peripheral vascular disease (PVD) status post lower extremity vascular stenting presented from a COVID-19 rehabilitation center with bilateral phlegmasia cerulea dolens and no palpable popliteal or dorsalis pedis pulses, at risk for venous gangrene and loss of limbs. The patient was anticoagulated and taken emergently to the operating room for vascular surgery where thrombolysis with alteplase and mechanical thrombectomy were performed. Bilateral thrombolysis infusion catheters were placed for two days. The patient had a return of arterial signals in the feet and decreasing clot burden. The patient is expected to make a full recovery.

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Gi/o-coupled somatostatin or α2-adrenergic receptor activation stimulated ß-cell NKA activity, resulting in islet Ca2+ fluctuations. Furthermore, intra-islet paracrine activation of ß-cell Gi/o-GPCRs and NKAs by δ-cell somatostatin secretion slowed Ca2+ oscillations, which decreased insulin secretion. ß-cell membrane potential hyperpolarization resulting from Gi/o-GPCR activation was dependent on NKA phosphorylation by Src tyrosine kinases. Whereas, ß-cell NKA function was inhibited by cAMP-dependent PKA activity. These data reveal that NKA-mediated ß-cell membrane potential hyperpolarization is the primary and conserved mechanism for Gi/o-GPCR control of electrical excitability, Ca2+ handling, and insulin secretion.

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INTRODUCTION: Medications for opioid use disorder (MOUD), including buprenorphine, represent an evidence-based treatment that supports long-term recovery and reduces risk of overdose death. Patients in crisis from opioid use disorder (OUD) often seek care from emergency departments (ED). The New York Medication for Addiction Treatment and Electronic Referrals (MATTERS) network is designed to support ED-initiated buprenorphine and urgent referrals to long-term care for patients suffering from OUD. METHODS: Using the PRECEDE-PROCEED implementation science framework, we provide an overview of the creation of the MATTERS network in Western New York. We also include an explanation of how the network was designed and launched as a response to the opioid epidemic. Finally, we analyzed the program's outputs and outcomes, thus far, as it continues to grow across the state. RESULTS: The New York MATTERS network was created and implemented in 2019 with a single hospital referring patients with OUD to three local clinics. In the social assessment and situational analysis phase, we describe the opioid epidemic and available resources in the region at the outset of the program. In the epidemiological assessment phase, we quantify the epidemic on the state and regional levels. In the educational and ecological assessment, we review local ED practices and resources. In the administrative and policy assessment and intervention alignment phase, the program's unique framework is reviewed. In the piloting phase, we describe the initial deployment of New York MATTERS. Finally, in the process evaluation phase, we depict the early lessons we learned. By the beginning of 2021, the New York MATTERS network included 35 hospitals that refer to 47 clinics throughout New York State. CONCLUSION: The New York MATTERS network provides a structured approach to reduce barriers to ED-initiated buprenorphine and urgent referral to long-term care. An implementation framework provides a structured means of evaluating this best practice model.

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AIM: To determine whether hyperpolarization-activated cyclic nucleotide-gated (HCN) channels impact glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) modulation of islet Ca2+ handling and insulin secretion. METHODS: The impact of liraglutide (GLP-1 analogue) on islet Ca2+ handling, HCN currents and insulin secretion was monitored with fluorescence microscopy, electrophysiology and enzyme immunoassays, respectively. Furthermore, liraglutide-mediated ß-to-δ-cell cross-communication was assessed following selective ablation of either mouse islet δ or ß cells. RESULTS: Liraglutide increased ß-cell Ca2+ oscillation frequency in mouse and human islets under stimulatory glucose conditions. This was dependent in part on liraglutide activation of HCN channels, which also enhanced insulin secretion. Similarly, liraglutide activation of HCN channels also increased ß-cell Ca2+ oscillation frequency in islets from rodents exposed to a diabetogenic diet. Interestingly, liraglutide accelerated Ca2+ oscillations in a majority of islet δ cells, which showed synchronized Ca2+ oscillations equivalent to ß cells; therefore, we assessed if either cell type was driving this liraglutide-mediated islet Ca2+ response. Although δ-cell loss did not impact liraglutide-mediated increase in ß-cell Ca2+ oscillation frequency, ß-cell ablation attenuated liraglutide-facilitated acceleration of δ-cell Ca2+ oscillations. CONCLUSION: The data presented here show that liraglutide-induced stimulation of islet HCN channels augments Ca2+ oscillation frequency. As insulin secretion oscillates with ß-cell Ca2+ , these findings have important implications for pulsatile insulin secretion that is probably enhanced by liraglutide activation of HCN channels and therapeutics that target GLP-1Rs for treating diabetes. Furthermore, these studies suggest that liraglutide as well as GLP-1-based therapies enhance δ-cell Ca2+ oscillation frequency and somatostatin secretion kinetics in a ß-cell-dependent manner.

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BACKGROUND: Scientists have amassed a wealth of microbiome datasets, making it possible to study microbes in biotic and abiotic systems on a population or planetary scale; however, this potential has not been fully realized given that the tools, datasets, and computation are available in diverse repositories and locations. To address this challenge, we developed iMicrobe.us, a community-driven microbiome data marketplace and tool exchange for users to integrate their own data and tools with those from the broader community. FINDINGS: The iMicrobe platform brings together analysis tools and microbiome datasets by leveraging National Science Foundation-supported cyberinfrastructure and computing resources from CyVerse, Agave, and XSEDE. The primary purpose of iMicrobe is to provide users with a freely available, web-based platform to (1) maintain and share project data, metadata, and analysis products, (2) search for related public datasets, and (3) use and publish bioinformatics tools that run on highly scalable computing resources. Analysis tools are implemented in containers that encapsulate complex software dependencies and run on freely available XSEDE resources via the Agave API, which can retrieve datasets from the CyVerse Data Store or any web-accessible location (e.g., FTP, HTTP). CONCLUSIONS: iMicrobe promotes data integration, sharing, and community-driven tool development by making open source data and tools accessible to the research community in a web-based platform.

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BACKGROUND: Greater than half of Emergency Medical Services (EMS) shift workers report fatigue at work and most work long duration shifts. We sought to compare the alertness level of EMS shift workers by shift duration. METHODS: We used a multi-site, 14-day prospective observational cohort study design of EMS clinician shift workers at four air-medical EMS organizations. The primary outcome was behavioral alertness as measured by psychomotor vigilance tests (PVT) at the start and end of shifts. We stratified shifts by duration (< 24 h and 24 h), night versus day, and examined the impact of intra-shift napping on PVT performance. RESULTS: One hundred and twelve individuals participated. The distribution of shifts <24 h and 24 h with complete data were 54% and 46%, respectively. We detected no differences in PVT performance measures stratified by shift duration (P > 0.05). Performance for selected PVT measures (lapses and false starts) was worse on night shifts compared to day shifts (P < 0.05). Performance also worsened with decreasing time between waking from a nap and the end of shift PVT assessment. CONCLUSIONS: Deficits in performance in the air-medical setting may be greatest during night shifts and proximal to waking from an intra-shift nap. Future research should examine alertness and performance throughout air-medical shifts, as well as investigate the timing and duration of intra-shift naps on outcomes.

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Objective: The aims of this study were: 1) to determine the short-term impact of the SleepTrackTXT2 intervention on air-medical clinician fatigue during work shifts and 2) determine the longer-term impact on sleep quality over 120 days. Methods: We used a multi-site randomized controlled trial study design with a targeted enrollment of 100 (ClinicalTrials.gov NCT02783027). The intervention was behavioral (non-pharmacological) and participation was scheduled for 120 days. Participation was voluntary. All consented participants answered baseline as well as follow-up surveys. All participants answered text message queries, which assessed self-rated fatigue, sleepiness, concentration, recovery, and hours of sleep. Intervention participants received additional text messages with recommendations for behaviors that can mitigate fatigue. Intervention participants received weekly text messages that promoted sleep. Our analysis was guided by the intent-to-treat principle. For the long-term outcome of interest (sleep quality at 120 days), we used a two-sample t-test on the change in sleep quality to determine the intervention effect. Results: Eighty-three individuals were randomized and 2,828 shifts documented (median shifts per participant =37, IQR 23-49). Seventy-one percent of individuals randomized (n = 59) participated up to the 120-day study period and 52% (n = 43) completed the follow-up survey. Of the 69,530 text messages distributed, participants responded to 61,571 (88.6%). Mean sleep quality at 120 days did not differ from baseline for intervention (p > 0.05) or control group participants (p > 0.05), and did not differ between groups (p > 0.05). There was no change from baseline to 120 days in the proportion with poor sleep quality in either group. Intra-shift fatigue increased (worsened) over the course of 12-hour shifts for participants in both study arms. Fatigue at the end of 12-hour shifts was higher among control group participants than participants in the intervention group (p < 0.05). Pre-shift hours of sleep were often less than 7 hours and did not differ between the groups over time. Conclusions: The SleepTrackTXT2 behavioral intervention showed a positive short-term impact on self-rated fatigue during 12-hour shifts, but did not impact longer duration shifts or have a longer-term impact on sleep quality among air-medical EMS clinicians.

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MicroRNA-29 (miR-29) negatively regulates fibrosis and is downregulated in multiple fibrotic organs and tissues, including in the skin. miR-29 mimics prevent pulmonary fibrosis in mouse models but have not previously been tested in the skin. This study aimed to identify pharmacodynamic biomarkers of miR-29 in mouse skin, to translate those biomarkers across multiple species, and to assess the pharmacodynamic activity of a miR-29b mimic (remlarsen) in a clinical trial. miR-29 biomarkers were selected based on gene function and mRNA expression using quantitative reverse transcriptase polymerase chain reaction. Those biomarkers comprised multiple collagens and other miR-29 direct and indirect targets and were conserved across species; remlarsen regulated their expression in mouse, rat, and rabbit skin wounds and in human skin fibroblasts in culture, while a miR-29 inhibitor reciprocally regulated their expression. Biomarker expression translated to clinical proof-of-mechanism; in a double-blinded, placebo-randomized, within-subject controlled clinical trial of single and multiple ascending doses of remlarsen in normal healthy volunteers, remlarsen repressed collagen expression and the development of fibroplasia in incisional skin wounds. These results suggest that remlarsen may be an effective therapeutic to prevent formation of a fibrotic scar (hypertrophic scar or keloid) or to prevent cutaneous fibrosis, such as scleroderma.

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miR-155, a microRNA associated with poor prognosis in lymphoma and leukaemia, has been implicated in the progression of mycosis fungoides (MF), the most common form of cutaneous T-cell lymphoma (CTCL). In this study, we developed and tested cobomarsen (MRG-106), a locked nucleic acid-modified oligonucleotide inhibitor of miR-155. In MF and human lymphotropic virus type 1 (HTLV-1+) CTCL cell lines in vitro, inhibition of miR-155 with cobomarsen de-repressed direct miR-155 targets, decreased expression of multiple gene pathways associated with cell survival, reduced survival signalling, decreased cell proliferation and activated apoptosis. We identified a set of genes that are significantly regulated by cobomarsen, including direct and downstream targets of miR-155. Using clinical biopsies from MF patients, we demonstrated that expression of these pharmacodynamic biomarkers is dysregulated in MF and associated with miR-155 expression level and MF lesion severity. Further, we demonstrated that miR-155 simultaneously regulates multiple parallel survival pathways (including JAK/STAT, MAPK/ERK and PI3K/AKT) previously associated with the pathogenesis of MF, and that these survival pathways are inhibited by cobomarsen in vitro. A first-in-human phase 1 clinical trial of cobomarsen in patients with CTCL is currently underway, in which the panel of proposed biomarkers will be leveraged to assess pharmacodynamic response to cobomarsen therapy.

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Recent studies have uncovered a strong effect of host genetic variation on the composition of host-associated microbiota. Here, we present HOMINID, a computational approach based on Lasso linear regression, that given host genetic variation and microbiome taxonomic composition data, identifies host single nucleotide polymorphisms (SNPs) that are correlated with microbial taxa abundances. Using simulated data, we show that HOMINID has accuracy in identifying associated SNPs and performs better compared with existing methods. We also show that HOMINID can accurately identify the microbial taxa that are correlated with associated SNPs. Lastly, by using HOMINID on real data of human genetic variation and microbiome composition, we identified 13 human SNPs in which genetic variation is correlated with microbiome taxonomic composition across body sites. In conclusion, HOMINID is a powerful method to detect host genetic variants linked to microbiome composition and can facilitate discovery of mechanisms controlling host-microbiome interactions.

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BACKGROUND: Most air medical Emergency Medical Services (EMS) clinicians work extended duration shifts, and more than 50% report inadequate sleep, poor sleep quality, and/or poor recovery between shifts. The SleepTrackTXT pilot trial (ClinicalTrials.gov, NCT02063737) showed that use of mobile phone text messages could impact EMS clinician self-reported fatigue and sleepiness during long duration shifts. The purpose of the SleepTrackTXT2 trial is to leverage lessons learned from the first SleepTrackTXT study and test an enhanced intervention targeting air medical EMS clinicians. METHODS/DESIGN: We will conduct a multi-site randomized trial with a sample of adult EMS clinicians recruited from four air medical EMS systems located in the midwest, northeastern, and southern USA. Participants will be allocated to one of two possible arms for a 4-month (120-day) study period. The intervention arm will involve text-message assessments of sleepiness, fatigue, and difficulty concentrating at the beginning, every 4 hours during, and at the end of scheduled shifts. Participants reporting high levels of sleepiness, fatigue, or difficulty with concentration will receive one of nine randomly selected intervention messages to promote behavior change during shift work to improve alertness. Intervention participants will receive a text-message report on Friday of each week that shows their sleep debt over the previous 7 days followed by a text message to promote paying back sleep debt recovery when feasible. Participants in the control group receive text messages that only include assessments. Both arms will receive text-message assessments of perceived recovery since last shift, sleepiness, fatigue, or difficulty with concentration at noon (1200 hours) on days between scheduled shifts (off-duty days). We have two aims for this study: (1) to determine the short-term impact of the enhanced SleepTrackTXT2 intervention on air medical clinician fatigue reported in real time during and at the end of shift work, and (2) to determine the long-term impact of the SleepTrackTXT2 intervention on sleep quality and sleep health indicators including hours of sleep and recovery between shift work. DISCUSSION: The SleepTrackTXT2 trial may provide evidence of real-world effectiveness that would support widespread expansion of fatigue mitigation interventions in emergency care clinician shift workers. The trial may specifically support use of real-time assessments and interventions delivered via mobile technology such as text messaging. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02783027 . Registered on 23 May 2016.

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MicroRNAs (miRNAs) are important regulators of biology and disease. Recent animal efficacy studies validate the therapeutic benefit of miRNA modulation and underscore the therapeutic value of miRNA-targeting oligonucleotides. However, whether disease conditions (stress) influence the pharmacological effects of an anti-miR is currently unknown. To study the effect of disease on target regulation after anti-miR treatment, we injected animals with anti-miR-208a, a synthetic oligonucleotide that inhibits the cardiomyocyte-specific miR-208a. Our data indicate that the presence of stress increases the number of regulated miR-208a targets, and that higher stress levels correlate with stronger target derepression. Additionally, the type of stress also influences which targets are regulated upon miR-208a inhibition. Studies in a large animal model indicate a similar stress-dependent anti-miR effect. Subsequent in vitro studies suggest that the influence of stress on anti-miR efficacy depends at least in part on increased cellular anti-miR uptake. These data indicate that the pharmacological effect of anti-miRs is stronger under disease conditions, and that both the type and severity of disease determine the therapeutic outcome. These facts will be important for assessing the therapeutic dose and predicting the therapeutic outcome when applying anti-miRs in a clinical setting.

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The human gut microbiota is impacted by host nutrition and health status and therefore represents a potentially adaptive phenotype influenced by metabolic and immune constraints. Previous studies contrasting rural populations in developing countries to urban industrialized ones have shown that industrialization is strongly correlated with patterns in human gut microbiota; however, we know little about the relative contribution of factors such as climate, diet, medicine, hygiene practices, host genetics, and parasitism. Here, we focus on fine-scale comparisons of African rural populations in order to (i) contrast the gut microbiota of populations inhabiting similar environments but having different traditional subsistence modes and either shared or distinct genetic ancestry, and (ii) examine the relationship between gut parasites and bacterial communities. Characterizing the fecal microbiota of Pygmy hunter-gatherers as well as Bantu individuals from both farming and fishing populations in Southwest Cameroon, we found that the gut parasite Entamoeba is significantly correlated with microbiome composition and diversity. We show that across populations, colonization by this protozoa can be predicted with 79% accuracy based on the composition of an individual's gut microbiota, and that several of the taxa most important for distinguishing Entamoeba absence or presence are signature taxa for autoimmune disorders. We also found gut communities to vary significantly with subsistence mode, notably with some taxa previously shown to be enriched in other hunter-gatherers groups (in Tanzania and Peru) also discriminating hunter-gatherers from neighboring farming or fishing populations in Cameroon.

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