Multisite 11-year experience of less-intensive vs intensive therapies in acute myeloid leukemia.

Less-intensive induction therapies are increasingly used in older patients with acute myeloid leukemia (AML). Using an AML composite model (AML-CM) assigning higher scores to older age, increased comorbidity burdens, and adverse cytogenetic risks, we defined 3 distinct prognostic groups and compared outcomes after less-intensive vs intensive induction therapies in a multicenter retrospective cohort (n = 1292) treated at 6 institutions from 2008 to 2012 and a prospective cohort (n = 695) treated at 13 institutions from 2013 to 2017. Prospective study included impacts of Karnofsky performance status (KPS), quality of life (QOL), and physician perception of cure. In the retrospective cohort, recipients of less-intensive therapies were older and had more comorbidities, more adverse cytogenetics, and worse KPS. Less-intensive therapies were associated with higher risks of mortality in AML-CM scores of 4 to 6, 7 to 9, and ≥10. Results were independent of allogeneic transplantation and similar in those age 70 to 79 years. In the prospective cohort, the 2 groups were similar in baseline QOL, geriatric assessment, and patient outcome preferences. Higher mortality risks were seen after less-intensive therapies. However, in models adjusted for age, physician-assigned KPS, and chance of cure, mortality risks and QOL were similar. Less-intensive therapy recipients had shorter length of hospitalization (LOH). Our study questions the survival and QOL benefits (except LOH) of less-intensive therapies in patients with AML, including those age 70 to 79 years or with high comorbidity burdens. A randomized trial in older/medically infirm patients is required to better assess the value of less-intensive and intensive therapies or their combination. This trial was registered at www.clinicaltrials.gov as #NCT01929408.

Acute glucagon-like peptide-1 receptor agonist liraglutide prevents cue-, stress-, and drug-induced heroin-seeking in rats.

Substance use disorder is challenging to treat due to its relapsing nature. In the last decade, opioid use disorder has been a threat to public health, being declared an epidemic by the Centers for Disease Control and Prevention. This is a tragic situation, considering there currently are only three effective, yet not ideal, treatments to prevent relapse to opioids. Recent research has shown that hormones that modulate hunger and satiety also can modulate motivated behavior for drugs of abuse. For example, the short-acting analog of glucagon-like peptide-1 (GLP-1), an incretin hormone that regulates homeostatic feeding, has been shown to reduce responding for rewarding stimuli such as food, cocaine, heroin, and nicotine when administered over several days or weeks. This may serve as an effective adjuvant during treatment; however, whether it would be effective when used acutely to bridge a patient between cessation of use and onset of medication for the treatment of an opioid addiction is unknown. Here, we tested the acute effects of the longer acting GLP-1 analog, liraglutide, on heroin-seeking. In rats with heroin self-administration experience, we found that subcutaneous administration of an acute dose of 0.3-mg/kg liraglutide was effective in preventing drug-seeking after exposure to three major precipitators: drug-associated cues, stress (yohimbine-induced), and the drug itself. Finally, we confirmed that the reduction in drug-seeking is not due to a locomotor impairment, as liraglutide did not significantly alter performance in a rotarod test. As such, acute use of GLP-1 analogs may serve as a new and effective nonopioid bridge to treatment.

Glucagon-like peptide-1 receptor agonist, liraglutide, reduces heroin self-administration and drug-induced reinstatement of heroin-seeking behaviour in rats.

Drug addiction is a chronic brain disease characterized by the uncontrolled use of a substance. Due to its relapsing nature, addiction is difficult to treat, as individuals can relapse following even long periods of abstinence and, it is during this time, that they are most vulnerable to overdose. In America, opioid overdose has been increasing for decades, making finding new treatments to help patients remain abstinent and prevent overdose deaths imperative. Recently, glucagon-like peptide-1 (GLP-1) receptor agonists have shown promise in reducing motivated behaviours for drugs of abuse. In this study, we test the effectiveness of the GLP-1 analogue, liraglutide (LIR), in reducing heroin addiction-like behaviour, and the potential side effects associated with the treatment. We show that daily treatment with LIR (0.1 mg/kg sc) increases the latency to take heroin, reduces heroin self-administration, prevents escalation of heroin self-administration and reduces drug-induced reinstatement of heroin-seeking behaviour in rats. A 1-h pretreatment time, however, was too short to reduce cue-induced seeking in our study. Moreover, we showed that, while LIR (0.1, 0.3, 0.6 and 1.0 mg/kg sc) supported conditioned taste avoidance of a LIR-paired saccharin cue, it did not elicit intake of the antiemetic kaolin in heroin-naïve or heroin-experienced rats. Further, 0.1 mg/kg LIR did not produce great disruptions in food intake or body weight. Overall, the data show that LIR is effective in reducing heroin taking and heroin seeking at doses that do not cause malaise and have a modest effect on food intake and body weight gain.

The relationship between police contacts for drug use-related crime and future arrests, incarceration, and overdoses: a retrospective observational study highlighting the need to break the vicious cycle.

BACKGROUND: Individuals with substance use disorder often encounter law enforcement due to drug use-related criminal activity. Traditional policing approaches may not be effective for reducing recidivism and improving outcomes in this population. Here, we describe the impact of traditional policing approach to drug use-related crime on future recidivism, incarceration, and overdoses. METHODS: Using a local Police Department (PD) database, we identified individuals with a police contact with probable cause to arrest for a drug use-related crime ("index contact"), including for an opioid-related overdose, between September 1, 2015, and August 31, 2016 (Group 1, N = 52). Data on police contacts, arrests, and incarceration 12 months before and after the index contact were extracted and compared using Fisher's exact or Wilcoxon signed-rank tests. County-level data on fatal overdoses and estimates of time spent by PD officers in index contact-related responses were also collected. To determine whether crime-related outcomes changed over time, we identified a second group (Group 2, N = 263) whose index contact occurred between September 1, 2017, and August 31, 2020, and extracted data on police contacts, arrests, and incarceration during the 12 months prior to their index contact. Pre-index contact data between Groups 1 and 2 were compared with Fisher's exact or Mann-Whitney U tests. RESULTS: Comparison of data during 12 months before and 12 months after the index contact showed Group 1 increased their total number of overdose-related police contacts (6 versus 18; p = 0.024), incarceration rate (51.9% versus 84.6%; p = 0.001), and average incarceration duration per person (16.2 [SD = 38.6] to 50 days [SD = 72]; p < 0.001). In the six years following the index contact, 9.6% sustained a fatal opioid-related overdose. For Group 1, an average of 4.7 officers were involved, devoting an average total of 7.2 h per index contact. Comparison of pre-index contact data between Groups 1 and 2 showed similar rates of overdose-related police contacts and arrests. CONCLUSIONS: The results indicated that the traditional policing approach to drug use-related crime did not reduce arrests or incarceration and was associated with a risk of future overdose fatalities. Alternative law enforcement-led strategies, e.g., pre-arrest diversion-to-treatment programs, are urgently needed.

Mercury exposure, serum antinuclear antibodies, and serum cytokine levels in the Long Island Study of Seafood Consumption: A cross-sectional study in NY, USA.

Mercury (Hg) is a well-known neurotoxin, and has been more recently studied specifically as an immunotoxin. In experimental and a few epidemiologic studies, Hg has been associated with distinct cytokine profiles and antinuclear antibody (ANA) positivity, though patterns at lower levels of exposure, typical of seafood consumers with a western diet, are not well characterized. Seafood consumers (n=287) recruited on Long Island, NY completed food frequency and health questionnaires and provided blood for analysis of Hg, poly-unsaturated fatty acids (omega-3 and omega-6 fatty acids), selenium (Se), ANA, and several cytokines (IL-1ß, IL-4, IL-10, TNF-α, IL-17, IFN-γ, and IL-1ra). Logistic and linear regression analyses were conducted to evaluate associations between serum Hg and cytokines and ANA. Adjusted models accounted for gender, age, ethnicity, income, education, smoking, BMI, selenium, omega-3 fatty acids, omega-6 fatty acids, omega-6/omega-3 ratio, and fish intake. Sex-stratified models were also generated with the expectation that immune profiles would differ between women and men. Median blood Hg was 4.58µg/L with 90th %ile =19.8µg/L. Nine individuals displayed ANA positivity at serum titers above 1:80; many of the cytokines were below detection limits, and the ability to detect was used in the logistic regression analyses. In linear and logistic regression analyses, Hg was not significantly associated with any of the seven investigated cytokines or with ANA-positivity. Therefore, Hg was not associated with altered immune profiles in this population of seafood consumers.

Low-dose mercury heightens early innate response to coxsackievirus infection in female mice.

OBJECTIVE: Mercury is a ubiquitous environmental contaminant with toxic outcomes over a range of exposures. In this study, we investigated the effects of mercury exposure on early immune responses to coxsackievirus B3 (CVB3) infection in a murine model of autoimmune heart disease. MATERIALS AND METHODS: Female BALB/c mice, susceptible to CVB3-induced autoimmune myocarditis, were treated with mercuric chloride (200 µg/kg body weight every other day for 2 weeks) prior to infection with CVB3. Six hours post-infection, immune cells were isolated from the spleen and peritoneum for flow cytometry, gene expression, and cytokine profiling. Thirty-five days post-infection, hearts were collected for histological examination of immune cell infiltration. RESULTS: As for male mice, mercury exposure significantly increased autoimmune myocarditis and immune infiltration into the heart. During the innate response 6 h post-infection, mercury increased expression of co-stimulatory molecules and innate immune receptors on peritoneal macrophages. At the same time point, the alternatively activated macrophage gene, arginase, was increased while the classically activated macrophage gene, inducible nitric oxide synthase, was unaffected. Expression of activation markers were decreased on peritoneal B cells with mercury exposure while T cells were unaffected. Mercury increased production of pro-inflammatory mediators in the spleen. Macrophage-recruiting chemokines and activating cytokines, such as CCL2, CCL4, and IL-6, were increased with mercury following CVB3 infection. CONCLUSIONS: Thus, mercury treatment exacerbates autoimmune myocarditis in female mice and alters early innate signaling on peritoneal macrophages. Mercury also modulates the cytokine profile in the spleen toward a macrophage-activating milieu, and upregulates alternatively activated macrophage genes, providing evidence that mercury exposure promotes inflammation in the context of infection.

Novel biomarkers of mercury-induced autoimmune dysfunction: a cross-sectional study in Amazonian Brazil.

Mercury is a ubiquitous environmental contaminant, causing both neurotoxicity and immunotoxicity. Given its ability to amalgamate gold, mercury is frequently used in small-scale artisanal gold mining. We have previously reported that elevated serum titers of antinuclear autoantibodies (ANA) are associated with mercury exposures of miners in gold mining. The goal of this project was to identify novel serum biomarkers of mercury-induced immunotoxicity and autoimmune dysregulation. We conducted an analysis of serum samples from a cross-sectional epidemiological study on miners working in Amazonian Brazil. In proteomic screening analyses, samples were stratified based on mercury concentrations and ANA titer and a subset of serum samples (N=12) were profiled using Immune Response Biomarker Profiling ProtoArray protein microarray for elevated autoantibodies. Of the up-regulated autoantibodies in the mercury-exposed cohort, potential target autoantibodies were selected based on relevance to pro-inflammatory and macrophage activation pathways. ELISAs were developed to test the entire sample cohort (N=371) for serum titers to the highest of these autoantibodies (anti-glutathione S-transferase alpha, GSTA1) identified in the high mercury/high ANA group. We found positive associations between elevated mercury exposure and up-regulated serum titers of 3760 autoantibodies as identified by ProtoArray. Autoantibodies identified as potential novel biomarkers of mercury-induced immunotoxicity include antibodies to the following proteins: GSTA1, tumor necrosis factor ligand superfamily member 13, linker for activation of T cells, signal peptide peptidase like 2B, stimulated by retinoic acid 13, and interferon induced transmembrane protein. ELISA analyses confirmed that mercury-exposed gold miners had significantly higher serum titers of anti-GSTA1 autoantibody [unadjusted odds ratio=89.6; 95% confidence interval: 27.2, 294.6] compared to emerald miners (referent population). Mercury exposure was associated with increased titers of several autoantibodies in serum including anti-GSTA1. These proteins play a wide variety of roles, including as antioxidants, in the regulation of pro- and anti-inflammatory cytokines, as well as danger and oxidative stress signaling. Dysregulation of these proteins and pathways is believed to play a role in autoimmune diseases such as rheumatoid arthritis, Sjögren׳s syndrome, and multiple sclerosis. Taken together, these results suggest that mercury exposure can induce complex autoimmune dysfunction and the immunotoxic effects of this dysfunction may be measured by serum titers to autoantibodies such as anti-GSTA1.

Treatment Utilization Pattern of Preschool Children With Attention-Deficit/Hyperactivity Disorder.

OBJECTIVE: The aim of this study was to identify patterns of ADHD care, including factors that guide selection and sequencing of treatments in a large nationwide sample of preschool-aged youth over the past 6 years. METHOD: A retrospective cohort study utilizing a large electronic health record (TriNetX) of nearly 24,000 children ages 3 to 6 diagnosed with ADHD. RESULTS: One in three preschoolers with ADHD were prescribed psychotropic medication, most commonly methylphenidate and guanfacine. One in 10 had at least one psychotherapy billing code during the entire assessment with most youth starting medication before psychotherapy. Rates of most treatments, including polypharmacy, increased with comorbid psychiatric disorders or sleep problems and over the course of the coronavirus pandemic. CONCLUSION: Rates of treatment have increased over time but are still largely inconsistent with published care guidelines that advise therapy before medication. Clinicians appear to prioritize psychiatric comorbidity and sleep problems when selecting treatments.

Cannabidiol-Derived Cannabinoids: The Unregulated Designer Drug Market Following the 2018 Farm Bill.

Background: In this review, we summarize current scientific knowledge on psychoactive cannabinoids synthesized from cannabidiol (CBD) and sold in the semi-legal market established in response to the passage of the US Agriculture Improvement Act of 2018, commonly known as the 2018 Farm Bill. The discussion focuses on recent developments that suggest this unregulated market may be fertile ground for a potential health crisis. Summary: Current research into CBD-derived cannabinoids is mainly limited to Δ8-tetrahydrocannabinol (Δ8-THC) products, with some recent publications beginning to explore O-acetyl-THC, a term describing the acetate ester of Δ8-THC or Δ9-THC, and its potential pulmonary toxicity. We advance the discussion on the CBD-derived cannabinoid market, shedding light on the introduction and associated dangers of novel cannabinoids, likely produced via fully synthetic routes using sidechain variants of CBD, with purportedly greater agonist activity at the human cannabinoid receptor 1 (as a source of euphorigenic activity) than Δ9-THC. We discuss the expanded incorporation of the acetate ester motif into other THC analogues. We also discuss the lack of regulatory oversight for the production of CBD-derived cannabinoids and the unlabeled presence of under-researched cannabinoids formed as reaction side products in the CBD-derived cannabinoid products being sold. Accordingly, we suggest approaches to monitoring the CBD-derived cannabinoid market and investigating the pharmacology of the cannabinoids being consumed. Finally, important epidemiological findings are discussed and future directions for research are suggested to call investigators to this critically understudied field. Key Messages: The CBD-derived cannabinoid market is growing internationally, and the market has diversified to include potent synthetic cannabinoids. The products sold on this unregulated market are under-researched despite growing availability and consumer interest. Ernest investigation of the pharmacology of these novel cannabinoids and the contents of CBD-derived cannabinoid products is critical for monitoring this potential source of another vaping-related epidemic.

Offering recovery rather than punishment: Implementation of a law enforcement-led pre-arrest diversion-to-treatment program for adults with substance use disorders.

BACKGROUND: The opioid epidemic has strained the US criminal justice system. Law enforcement frequently encounters persons with substance use disorder (SUD). Law enforcement-led, pre-arrest diversion programs linking individuals with SUD to addiction treatment instead of arrest and prosecution has the potential to reduce crime, overdoses, and other community harms. We implemented a pre-arrest diversion-to-treatment program-the Madison Addiction Recovery Initiative (MARI)-from September 2017 to August 2020, and describe the key components of MARI's effective implementation. METHODS: Adults who committed an eligible, drug use-related crime were offered a 6-month MARI participation with referral to treatment in lieu of arrest; criminal charges for that crime were "voided" upon the successful MARI completion. Formative evaluation, with stakeholder feedback and team meeting minutes, assessed key factors influencing implementation. Process evaluation consisted of tracking participant referrals, enrollment, and engagement. Police officers, MARI participants, and treatment center staff members were surveyed about program experiences and attitudes. The study used descriptive statistics to describe quantitative survey responses; thematic qualitative analysis identified major themes in qualitative responses. RESULTS: Of 263 participants, 160 initiated program engagement, with 100 successfully completing MARI. Interim evaluations and community partner feedback informed program protocol adjustments to increase participant enrollment, retention and diversity, streamline the referral processes, and transition to telehealth during the COVID-19 pandemic. CONCLUSION: Rigorous evaluation and community partner feedback are essential components of effective implementation and sustainability of a law enforcement-led pre-arrest diversion-to-treatment program, which has the potential to both reduce crime and overdose, and change the lives of people with SUD.

Law enforcement-led, pre-arrest diversion-to-treatment may reduce crime recidivism, incarceration, and overdose deaths: Program evaluation outcomes.

INTRODUCTION: Substance use disorder (SUD), overdose, and drug use-related crime continue to increase in the U.S. Pre-arrest diversion-to-treatment programs may decrease crime recidivism and overdose deaths. We assessed the impact of a community-wide diversion-to-treatment initiative on crime, incarceration, and overdose. METHODS: This article reports on the prospective evaluation of a law enforcement-led, pre-arrest diversion-to-treatment program on crime, incarceration, and overdose deaths compared between participants who did not engage (non-engaged; n = 103), engaged but did not complete (non-completers; n = 60) and completed (completers; n = 100) the program. Participants included 263 adults apprehended by police officers for low-level, drug use-related crimes between September 1, 2017 and August 31, 2020. The program offered eligible persons participation in a six-month program consisting of a clinical assessment, referral to addiction treatment services based on each individual's needs, connection to recovery peer support, and treatment engagement monitoring. Completers had their initial criminal charges 'voided,' while non-engaged and non-Completer participants had their original charges filed with local prosecutors. The project collected participant-level data on arrests and incarceration within 12 months before and 12 months after program enrollment and data on fatal overdose within 12 months after program enrollment. Logistic regression predicted outcomes using baseline demographics (sex, age, race, housing status) and pre-index crime arrest and incarceration indices as covariates. RESULTS: After accounting for baseline demographics and pre-enrollment arrest/incarceration history, logistic regression models found that the non-engaged and the non-Completer groups were more likely than completers to be arrested (odds ratios [ORs]: 3.9 [95 % CI, 2.0-7.7] and 3.6 [95 % CI, 1.7-7.5], respectively) and incarcerated (ORs: 10.3 [95 % CI, 5.0-20.8] and 21.0 [95 % CI, 7.9-55.7], respectively) during the 12-month follow-up. Rates of overdose deaths during the 12-month follow-up were greatest in non-engaged (6/103, 5.8 %) and non-Completer (2/60, 3.3 %) groups; completers had the lowest rate (2/100, 2.0 %), with all deaths occurring after completion of the six-month treatment/monitoring program. CONCLUSIONS: Collaboration between law enforcement, clinicians, researchers, and the broader community to divert adults who commit a low-level, drug use-related crime from criminal prosecution to addiction treatment may effectively reduce crime recidivism, incarceration, and overdose deaths.

Ecological momentary assessment and cue-elicited drug craving as primary endpoints: study protocol for a randomized, double-blind, placebo-controlled clinical trial testing the efficacy of a GLP-1 receptor agonist in opioid use disorder.

BACKGROUND: Despite continuing advancements in treatments for opioid use disorder (OUD), continued high rates of relapse indicate the need for more effective approaches, including novel pharmacological interventions. Glucagon-like peptide 1 receptor agonists (GLP-1RA) provide a promising avenue as a non-opioid medication for the treatment of OUD. Whereas GLP-1RAs have shown promise as a treatment for alcohol and nicotine use disorders, to date, no controlled clinical trials have been conducted to determine if a GLP-1RA can reduce craving in individuals with OUD. The purpose of the current protocol was to evaluate the potential for a GLP-1RA, liraglutide, to safely and effectively reduce craving in an OUD population in residential treatment. METHOD: This preliminary study was a randomized, double-blinded, placebo-controlled clinical trial designed to test the safety and efficacy of the GLP-1RA, liraglutide, in 40 participants in residential treatment for OUD. Along with taking a range of safety measures, efficacy for cue-induced craving was evaluated prior to (Day 1) and following (Day 19) treatment using a Visual Analogue Scale (VAS) in response to a cue reactivity task during functional near-infrared spectroscopy (fNIRS) and for craving. Efficacy of treatment for ambient craving was assessed using Ecological Momentary Assessment (EMA) prior to (Study Day 1), across (Study Days 2-19), and following (Study Days 20-21) residential treatment. DISCUSSION: This manuscript describes a protocol to collect clinical data on the safety and efficacy of a GLP-1RA, liraglutide, during residential treatment of persons with OUD, laying the groundwork for further evaluation in a larger, outpatient OUD population. Improved understanding of innovative, non-opioid based treatments for OUD will have the potential to inform community-based interventions and health policy, assist physicians and health care professionals in the treatment of persons with OUD, and to support individuals with OUD in their effort to live a healthy life. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04199728. Registered 16 December 2019, https://clinicaltrials.gov/study/NCT04199728?term=NCT04199728 . PROTOCOL VERSION: 10 May 2023.

Potential problems and solutions of opioid-based treatment in neonatal opioid withdrawal syndrome (NOWS): a scoping review protocol.

INTRODUCTION: Rates of neonatal opioid withdrawal syndrome (NOWS) have paralleled the rise of opioid use during pregnancy. While short-term phenotypic symptoms of NOWS are well defined, molecular implications and long-term effects are not well understood. Preferred and first-line of treatment for NOWS includes non-pharmacological interventions; however, more than half of the NOWS neonates will need pharmacologics, with opioids as the primary pharmacological treatment. While effective at reducing symptoms, treating NOWS with opioids is paradoxical given that molecular and long-term developmental consequences with such exposure are unknown. There is a pressing need for a synthesis of current and potential/ novel treatment options for NOWS. METHODS AND ANALYSIS: Following a published framework, a scoping review will be conducted to evaluate NOWS treatment, including established treatment methods and novel methods that may warrant future research and consideration. Using broad search terms, as well as Medical Subject Headings terms, a comprehensive search of PubMed, Cochrane Library, Google Scholar, CINAHL, Web of Science and Scopus, as well as references of selected literature, will take place, followed by a screening procedure to identify included and excluded articles. Included studies must address NOWS treatment, or opioid withdrawal treatment of any age group, that may or may not have been tested in preclinical or clinical models. Results will summarise the current pharmacological and non-pharmacological treatment methods for NOWS, as well as potential novel treatments with a specific interest in non-opioid pharmacological interventions. ETHICS AND DISSEMINATION: This scoping review aims to broadly search preclinical and clinical literature as it relates to treatment of NOWS, including potential novel treatments with a specific interest in non-opioid pharmacological interventions. Given that this study does not directly involve human subjects or animal subjects research, Institutional Review Board (IRB) or Institutional Animal Care and Use Committee (IACUC) approval is not required. Results of this scoping review will be disseminated at conferences and submitted for publication in a peer-reviewed journal.

Micro-doppler radar to evaluate risk for musculoskeletal injury: Protocol for a case-control study with gold standard comparison.

BACKGROUND: Beyond causing significant morbidity and cost, musculoskeletal injuries (MSKI) are among the most common reasons for primary care visits. A validated injury risk assessment tool for MSKI is conspicuously absent from current care. While motion capture (MC) systems are the current gold standard for assessing human motion, their disadvantages include large size, non-portability, high cost, and limited spatial resolution. As an alternative we introduce the Micro Doppler Radar (MDR); in contrast with MC, it is small, portable, inexpensive, and has superior spatial resolution capabilities. While Phase 1 testing has confirmed that MDR can identify individuals at high risk for MSKI, Phase 2 testing is still needed. Our aims are to 1) Use MDR technology and MC to identify individuals at high-risk for MSKI 2) Evaluate whether MDR has diagnostic accuracy superior to MC 3) Develop MDR algorithms that enhance accuracy and enable automation. METHODS AND FINDINGS: A case control study will compare the movement patterns of 125 ACL reconstruction patients to 125 healthy controls. This study was reviewed and approved by the Pennsylvania State University Human Research Protection Program (HRPP) on May 18, 2022, and the IRB approval number is STUDY00020118. The ACL group is used as a model for a "high risk" population as up to 24% will have a repeat surgery within 2 years. An 8-camera Motion Analysis MC system with Cortex 8 software to collect MC data. Components for the radar technology will be purchased, assembled, and packaged. A micro-doppler signature projection algorithm will determine correct classification of ACL versus healthy control. Our previously tested algorithm for processing the MDR data will be used to identify the two groups. Discrimination, sensitivity and specificity will be calculated to compare the accuracy of MDR to MC in identifying the two groups. CONCLUSIONS: We describe the rationale and methodology of a case-control study using novel MDR technology to detect individuals at high-risk for MSKI. We expect this novel approach to exhibit superior accuracy than the current gold standard. Future translational studies will determine utility in the context of clinical primary care.

Mechanisms of environmental influence on human autoimmunity: a National Institute of Environmental Health Sciences expert panel workshop.

The mechanisms leading to autoimmune diseases remain largely unknown despite numerous lines of experimental inquiry and epidemiological evidence. The growing number of genome-wide association studies and the largely incomplete concordance for autoimmune diseases in monozygotic twins support the role of the environment (including infectious agents and chemicals) in the breakdown of tolerance leading to autoimmunity via numerous mechanisms. The present article reviews the major theories on the mechanisms of the environmental influence on autoimmunity by addressing the different degrees of confidence that characterize our knowledge. The theories discussed herein include (i) the role of innate immunity mediated by toll-like receptors in triggering the autoimmune adaptive response characterizing the observed pathology; (ii) changes in spleen marginal zone B cells in autoantibody production with particular focus on the B10 subpopulation; (iii) Th17 cell differentiation and T regulatory cells in the aryl hydrocarbon receptor model; (iv) self antigen changes induced by chemical and infectious agents which could break tolerance by post-translational modifications and molecular mimicry; and finally (v) epigenetic changes, particularly DNA methylation, that are induced by environmental stimuli and may contribute to autoimmunity initiation. We are convinced that these working hypotheses, in most cases supported by solid evidence, should be viewed in parallel with animal models and epidemiological observations to provide a comprehensive picture of the environmental causes of autoimmune diseases.

Attachment Style and Burn Pain.

Pain management is a challenge when treating patients with burn injuries. Understanding the behavioral and interpersonal aspects of the experience of burn pain may aid in its management. Attachment style-which influences how an individual relates to other people-is one aspect that may affect the experience of burn pain. Past research has shown a relationship between an individual's attachment style and certain types of pain and disorders. The study builds upon that past work to investigate specifically how attachment style affects the experience of acute burn pain. Participants were at least 18 years old and admitted to an American Burn Association verified burn center with burns encompassing 30% or less TBSA. Participants completed demographic questionnaires and a standardized measure of adult attachment style. Data regarding use of analgesics, daily pain scores, and burn-related information were collected through medical chart review. Participants who reported a secure attachment style required less pain medication and reported less pain compared with participants who reported an insecure attachment style. There was no difference in burn-related variables between participants with secure and insecure attachment styles, suggesting that these differences were not due to burn-related factors. Attachment, therefore, may play a role in an individual's perception of acute burn pain, which impacts analgesic requirements needed to manage the pain. These results have potential implications for the use of psychosocial interventions to reduce the experience of pain and the amount of pain medication needed to manage acute burn pain.

Dose titration with the glucagon-like peptide-1 agonist, liraglutide, reduces cue- and drug-induced heroin seeking in high drug-taking rats.

Opioid use disorder (OUD), like other substance use disorders (SUDs), is widely understood to be a disorder of persistent relapse. Despite the use of three FDA-approved medications for OUD, typically in conjunction with behavioral treatments, relapse rates remain unacceptably high. Whereas medication assisted therapy (MAT) reduces the risk of opioid overdose mortality, the benefits of MAT are negated when people discontinue the medications. Currently approved medications present barriers to efficient use, including daily visits to a treatment center or work restrictions. With spiking increases in opioid relapse and death, it is imperative to identify new treatments that can reduce the risk of relapse. Recent evidence suggests that glucagon-like peptide-1 receptor agonists (GLP-1RAs), currently FDA-approved to treat obesity and type two diabetes, may be promising candidates to reduce relapse. GLP-1RAs have been shown to reduce relapse in rats, whether elicited by cues, drug, and/or stress. However, GLP-1RAs also can cause gastrointestinal malaise, and therefore, in humans, the medication typically is titrated up to full dose when initiating treatment. Here, we used a rodent model to test whether cue- and drug-induced heroin seeking can be reduced by the GLP-1RA, liraglutide, when the dose is titrated across the abstinence period and prior to test. The results show this titration regimen is effective in reducing both cue-induced heroin seeking and drug-induced reinstatement of heroin seeking, particularly in rats with a history of high drug-taking. Importantly, this treatment regimen had no effect on either circulating glucose or insulin. GLP-1RAs, then, appear strong candidates for the non-opioid prevention of relapse to opioids.

Fetal and maternal immune responses to methylmercury exposure: a cross-sectional study.

Methylmercury (MeHg) is a ubiquitous environmental contaminant with known neurodevelopmental effects. In humans, prenatal exposures primarily occur through maternal consumption of contaminated fish. In this study, we evaluated the association between prenatal exposure to MeHg and titers of total immunoglobulins (Ig) and specific autoantibodies in both mothers and fetuses by analyzing maternal and cord blood serum samples. We examined multiple immunoglobulin isotypes to determine if these biomarkers could inform as to fetal or maternal responses since IgG but not IgM can cross the placenta. Finally, we evaluated serum cytokine levels to further characterize the immune response to mercury exposure. The study was conducted using a subset of serum samples (N=61 pairs) collected from individuals enrolled in a population surveillance of MeHg exposures in the Brazilian Amazon during 2000/2001. Serum titers of antinuclear and antinucleolar autoantibodies were measured by indirect immunofluorescence. Serum immunoglobulins were measured by enzyme-linked immunosorbent assay (ELISA) and BioPlex multiplex assay. Serum cytokines were measured by BioPlex multiplex assay. In this population, the geometric mean mercury level was within the 95th percentile for US populations of women of childbearing age but the upper level of the range was significantly higher. Fetal blood mercury levels were higher (1.35 times) than those in their mothers, but highly correlated (correlation coefficient [r]=0.71; 95% CI: 0.54, 0.89). Total IgG (r=0.40; 95% CI: 0.19, 0.62) and antinuclear autoantibody (odds ratio [OR]=1.05; 95% CI: 1.02, 1.08) levels in paired maternal and fetal samples were also associated; in contrast, other immunoglobulin (IgM, IgE, and IgA) levels were not associated between pairs. Total IgG levels were significantly correlated with both maternal (r=0.60; 95% CI: 0.25, 0.96) and cord blood mercury levels (r=0.61; 95% CI: 0.25, 0.97), but individual isotypes were not. Serum cytokines, interleukin-1ß (r=0.37; 95% CI: 0.01, 0.73), interleukin-6 (r=0.34; 95% CI: 0.03, 0.65), and tumor necrosis factor-α (r=0.24; 95% CI: 0.015, 0.47), were positively correlated between maternal and fetal samples. Antinuclear and antinucleolar autoantibody titer and serum cytokine levels, in either maternal or cord blood, were not significantly associated with either maternal or cord blood mercury levels. These data provide further evidence that there are likely IgG biomarkers of mercury-induced immunotoxicity in this population since IgG levels were elevated with increased, and associated with, mercury exposure. However, unlike previous data from adult males and non-pregnant females, we found no evidence that antinuclear and antinucleolar autoantibody titer is a reliable biomarker of mercury immunotoxicity in this population.

Vagotomy increases alcohol intake in female rats in diet dependent manner: Implications for increased alcohol use disorder after roux-en-y gastric bypass surgery.

A variety of weight loss surgeries have been developed to fight the obesity epidemic, with Roux-en-Y gastric bypass (RYGB) being one of the most effective and popular procedures. However, the underlying mechanisms behind its efficacy are still not well understood. Furthermore, growing clinical evidence suggests that RYGB may result in increased risk for development of alcohol use disorder (AUD). The vagus nerve is a potentially critical contributor to increased risk of AUD following RYGB due to the potential for significant damage to the vagus during surgery, which has been confirmed in rodent studies. Studies aiming at the mechanisms underlying development of alcohol or substance use disorders following the surgery have exclusively used male rats, despite the majority of RYGB patients being female. Thus, the current study had two objectives: 1) to investigate the effect of RYGB on ethanol (EtOH) intake in female rats using a protocol previously established in male rats, and 2) to test the effect of vagal damage and high fat diet (HFD) on EtOH intake in female rats. In the first study, 22 female rats were maintained on HFD for four weeks and then split into two surgical groups, RYGB (n = 10) and Sham (n = 12). All rats then underwent a two-bottle choice test of increasing EtOH concentrations: 2%, 4%, 6%, 8%. Rats were then forced to abstain from EtOH for two weeks, after which access to 8% EtOH was reinstated. The RYGB female rats significantly increased their intake for low concentrations of EtOH (2% and 4%) and during the reinstatement period for 8%. These results mirror those seen in male rats, and thus, confirms RYGB in female rats as an equally viable model to males. In the second study, 40 female rats were separated into four groups: HFD/Sham, HFD/Vagotomy, normal diet (ND)/Sham, and ND/Vagotomy. All rats then were subjected to the same two-bottle choice test protocol as in the previous study. Rats in the vagotomy condition had significantly greater preference for 2% and 4% EtOH compared with Sham-operated controls. EtOH intake, either in ml or adjusted for body weight, was greater in rats maintained on ND compared with rats maintained on HFD. These data suggest that vagal damage may, at least in part, contribute to increased preference for EtOH. Furthermore, this increase in EtOH preference is counter to the blunting effect of HFD. In conclusion, the data presented here suggest a role for vagal damage in risk of AUD after weight loss surgery.