Author Correction: Oleoylethanolamide treatment reduces neurobehavioral deficits and brain pathology in a mouse model of Gulf War Illness

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A permethrin metabolite is associated with adaptive immune responses in Gulf War Illness

Gulf War Illness (GWI), affecting 30% of veterans from the 1991 Gulf War (GW), is a multi-symptom illness with features similar to those of patients with autoimmune diseases. The objective of the current work is to determine if exposure to GW-related pesticides, such as permethrin (PER), activates peripheral and central nervous system (CNS) adaptive immune responses. In the current study, we focused on a PER metabolite, 3-phenoxybenzoic acid (3-PBA), as this is a common metabolite previously shown to form adducts with endogenous proteins. We observed the presence of 3-PBA and 3-PBA modified lysine of protein peptides in the brain, blood and liver of pyridostigmine bromide (PB) and  PER (PB+PER) exposed mice at acute and chronic post-exposure timepoints. We tested whether 3-PBA-haptenated albumin (3-PBA-albumin) can activate immune cells since it is known that chemically haptenated proteins can stimulate immune responses. We detected autoantibodies against 3-PBA-albumin in plasma from PB + PER exposed mice and veterans with GWI at chronic post-exposure timepoints. We also observed that in vitro treatment of blood with 3-PBA-albumin resulted in the activation of B- and T-helper lymphocytes and that these immune cells were also increased in blood of PB + PER exposed mice and veterans with GWI. These immune changes corresponded with elevated levels of infiltrating monocytes in the brain and blood of PB + PER exposed mice which coincided with alterations in the markers of blood-brain barrier disruption, brain macrophages and neuroinflammation. These studies suggest that pesticide exposure associated with GWI may have resulted in the activation of the peripheral and CNS adaptive immune responses, possibly contributing to an autoimmune-type phenotype in veterans with GWI

The multimodal Munich Clinical Deep Phenotyping study to bridge the translational gap in severe mental illness treatment research

Introduction: Treatment of severe mental illness (SMI) symptoms, especially negative symptoms and cognitive dysfunction in schizophrenia, remains a major unmet need. There is good evidence that SMIs have a strong genetic background and are characterized by multiple biological alterations, including disturbed brain circuits and connectivity, dysregulated neuronal excitation-inhibition, disturbed dopaminergic and glutamatergic pathways, and partially dysregulated inflammatory processes. The ways in which the dysregulated signaling pathways are interconnected remains largely unknown, in part because well-characterized clinical studies on comprehensive biomaterial are lacking. Furthermore, the development of drugs to treat SMIs such as schizophrenia is limited by the use of operationalized symptom-based clusters for diagnosis. Methods: In line with the Research Domain Criteria initiative, the Clinical Deep Phenotyping (CDP) study is using a multimodal approach to reveal the neurobiological underpinnings of clinically relevant schizophrenia subgroups by performing broad transdiagnostic clinical characterization with standardized neurocognitive assessments, multimodal neuroimaging, electrophysiological assessments, retinal investigations, and omics-based analyzes of blood and cerebrospinal fluid. Moreover, to bridge the translational gap in biological psychiatry the study includes in vitro investigations on human-induced pluripotent stem cells, which are available from a subset of participants. Results: Here, we report on the feasibility of this multimodal approach, which has been successfully initiated in the first participants in the CDP cohort; to date, the cohort comprises over 194 individuals with SMI and 187 age and gender matched healthy controls. In addition, we describe the applied research modalities and study objectives. Discussion: The identification of cross-diagnostic and diagnosis-specific biotype-informed subgroups of patients and the translational dissection of those subgroups may help to pave the way toward precision medicine with artificial intelligence-supported tailored interventions and treatment. This aim is particularly important in psychiatry, a field where innovation is urgently needed because specific symptom domains, such as negative symptoms and cognitive dysfunction, and treatment-resistant symptoms in general are still difficult to treat

Modernizing Withdrawal Management Services

Alcohol, opioid, and stimulant withdrawal syndromes are serious clinical presentations, some of which can be life-threatening if untreated. Patients presenting with withdrawal syndromes offer an important opportunity for healthcare providers to ally in deciding the most appropriate treatment setting, safely treating withdrawal symptoms, preventing potentially severe medical complications, and facilitating a transition to longer-term low-barrier substance use care including, where available, psychosocial interventions, evidence-based pharmacotherapies, and referrals for other community-based or specialist-led services. Given that substance use disorders are chronic biopsychosocial disorders commonly characterized by periods of relapse and remission, patients presenting in substance withdrawal deserve a long term and holistic approach to management that cannot be simply achieved in short-term withdrawal management siloed and separate from a continuum of care. This narrative review of withdrawal management literature describes recent advances in clinical care for patients in withdrawal from alcohol, opioids, and stimulants.Medicine, Faculty ofNon UBCAnesthesiology, Pharmacology and Therapeutics, Department ofFamily Practice, Department ofMedicine, Department ofReviewedFacultyResearcherUndergraduat

Targeting sirtuin activity with nicotinamide riboside reduces neuroinflammation in a GWI mouse model

Gulf War Illness (GWI) affects 30% of veterans from the 1991 Gulf War (GW), who suffer from symptoms that reflect ongoing mitochondria dysfunction. Brain mitochondria bioenergetics dysfunction in GWI animal models corresponds with astroglia activation and neuroinflammation. In a pilot study of GW veterans (n = 43), we observed that blood nicotinamide adenine dinucleotide (NAD) and sirtuin 1 (Sirt1) protein levels were decreased in the blood of veterans with GWI compared to healthy GW veterans. Since nicotinamide riboside (NR)-mediated targeting of Sirt1 is shown to improve mitochondria function, we tested whether NR can restore brain bioenergetics and reduce neuroinflammation in a GWI mouse model. We administered a mouse diet supplemented with NR at 100μg/kg daily for 2-months to GWI and control mice (n = 27). During treatment, mice were assessed for fatigue-type behavior using the Forced Swim Test (FST), followed by euthanasia for biochemistry and immunohistochemistry analyses. Fatigue-type behavior was elevated in GWI mice compared to control mice and lower in GWI mice treated with NR compared to untreated GWI mice. Levels of plasma NAD and brain Sirt1 were low in untreated GWI mice, while GWI mice treated with NR had higher levels, similar to those of control mice. Deacetylation of the nuclear-factor κB (NFκB) p65 subunit and peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α) was an increase in the brains of NR-treated GWI mice. This corresponded with a decrease in pro-inflammatory cytokines and lipid peroxidation and an increase in markers of mitochondrial bioenergetics in the brains of GWI mice. These findings suggest that targeting NR mediated Sirt1 activation restores brain bioenergetics and reduces inflammation in GWI mice. Further evaluation of NR in GWI is warranted to determine its potential efficacy in treating GWI

Characteristics and incidence of opioid analgesic initiations to opioid naïve patients in a Canadian primary care setting

Objective: To examine characteristics and incidence of opioid analgesic initiations to opioid naïve patients in a Canadian primary care setting. Methods: This is a population-based cross-sectional study, outlining an analysis of health administrative data recorded in a centralized medication monitoring database (PharmaNet) covering 96% of population in British Columbia (BC), Canada. From the PharmaNet database, 5,657 doctors (87% of all practicing family physicians) were selected on the bases of (1) having been currently treating patients (defined as having written at least 25 prescriptions, for any drug, in preceding 12 months); and (2) having prescribed at least one opioid during study period. The primary outcome measure is incidence of new starts for opioid analgesics in opioid naïve people, stratified by several important prescriber and regional characteristics (e.g., graduation year, geographical location). Results: Between December 1 st , 2018 and November 30th , 2019, there were 139,145 opioid initiations to opioid naïve patients. The mean monthly initiation rate was 2.05 prescriptions per physician. Most initiations were in Lower Mainland regions of BC, also where the population is most concentrated (46,456, 33% in the Fraser region), by prescribers who graduated between 1986-1995 (39,601, 28%), and had less than 10 patient visits per day (72,506, 52%). Conclusions: From data presented in this study, it appears that the rate of opioid analgesic initiations in primary care remains unchanged. Individualized prescribing interventions targeted at physicians are urgently needed considering the current opioid epidemic and known links with opioid analgesics that raise concerns about the potential to cause harm.Medicine, Faculty ofNon UBCAnesthesiology, Pharmacology and Therapeutics, Department ofFamily Practice, Department ofMedicine, Department ofReviewedFacultyGraduat

Individualized prescribing portraits to reduce inappropriate initiation of opioid analgesics to opioid naïve patients in primary care : Protocol for a randomized controlled trial

Background: Opioid analgesics are frequently initiated for chronic and acute pain despite weak evidence of benefit, although prescribing rates of some analgesics decreased in the context of the epidemic. In some populations, up to a quarter of opioid naïve persons prescribed opioids for noncancer pain develop prescription opioid use disorder (OUD). Audit and feedback interventions rely on constructive use of routinely collected data to align professional behaviours and clinical practice with best evidence. These interventions have been shown to help reduce inappropriate initiation. However, effectiveness and acceptability of individualized “portraits” of physicians’ prescribing patterns, to reduce inappropriate initiation of opioid analgesics to opioid naïve persons, have not been evaluated. Methods: REDONNA is a mixed-methods randomized study testing the effectiveness of individualized prescribing Portraits to reduce inappropriate initiation of opioid analgesics. This intervention to improve safety of opioid prescribing in primary care in British Columbia (BC), Canada involves mailing individual prescribing portraits to an ‘early group’ of 2604 family physicians, followed in six months by a mailing to 2553 family physicians in the ‘delayed group’. Primary outcome is number of new opioid prescriptions initiated in opioid naïve people, measured using administrative data from a centralized medication monitoring database covering all prescription opioids dispensed from BC community pharmacies. Secondary endpoints will compare prescribing impact between the two groups. A qualitative sub-study will examine feasibility among a purposive sample of physicians and patients. Discussion: This trial provides important evidence on the intervention’s potential to steer policy and practice on inappropriate opioid analgesics initiation.Medicine, Faculty ofNon UBCAnesthesiology, Pharmacology and Therapeutics, Department ofFamily Practice, Department ofMedicine, Department ofReviewedFacultyResearche

A permethrin metabolite is associated with adaptive immune responses in Gulf War Illness

Gulf War Illness (GWI), affecting 30% of veterans from the 1991 Gulf War (GW), is a multi-symptom illness with features similar to those of patients with autoimmune diseases. The objective of the current work is to determine if exposure to GW-related pesticides, such as permethrin (PER), activates peripheral and central nervous system (CNS) adaptive immune responses. In the current study, we focused on a PER metabolite, 3-phenoxybenzoic acid (3-PBA), as this is a common metabolite previously shown to form adducts with endogenous proteins. We observed the presence of 3-PBA and 3-PBA modified lysine of protein peptides in the brain, blood and liver of pyridostigmine bromide (PB) and  PER (PB+PER) exposed mice at acute and chronic post-exposure timepoints. We tested whether 3-PBA-haptenated albumin (3-PBA-albumin) can activate immune cells since it is known that chemically haptenated proteins can stimulate immune responses. We detected autoantibodies against 3-PBA-albumin in plasma from PB + PER exposed mice and veterans with GWI at chronic post-exposure timepoints. We also observed that in vitro treatment of blood with 3-PBA-albumin resulted in the activation of B- and T-helper lymphocytes and that these immune cells were also increased in blood of PB + PER exposed mice and veterans with GWI. These immune changes corresponded with elevated levels of infiltrating monocytes in the brain and blood of PB + PER exposed mice which coincided with alterations in the markers of blood-brain barrier disruption, brain macrophages and neuroinflammation. These studies suggest that pesticide exposure associated with GWI may have resulted in the activation of the peripheral and CNS adaptive immune responses, possibly contributing to an autoimmune-type phenotype in veterans with GWI