Burden of selected chronic non-communicable diseases in a primary healthcare setting in Nuuk, Greenland, compared to a Danish suburb.

INTRODUCTION: Noncommunicable diseases (NCDs) constitute a massive global burden and are the leading cause of death and disability worldwide. In Greenland, the prevalence of NCDs has historically been low. However, during the past approximately 70 years, life circumstances have changed dramatically resulting in increased life expectancy. Today, the proportion of inhabitants in Greenland ≥65 years has nearly tripled since the 1980s, and the prevalence of obesity and diabetes has increased rapidly within the past decades. The aim of this study was to describe the burden of selected NCDs in a primary care setting in Nuuk and compare it to a modern westernized suburban general practice in Denmark. METHODS: The study was performed as a cross sectional register-based study using data extracted from the electronic medical records (EMR) based on diagnosis codes from inhabitants living in Nuuk, Greenland, and a suburb in Denmark. Estimates of prevalence were age-standardized to the WHO world standard population. RESULTS: In both Nuuk and the Danish suburb, the highest prevalence was observed for hypertension (13.2% for both populations), followed by asthma (4.4 and 9.5%, respectively) and diabetes (4.3 and 2.9%, respectively). The age-standardized prevalences of diabetes, COPD, atrial fibrillation, and heart failure, were significantly higher in Nuuk, while seven NCDs including asthma, ischemic heart disease, arthritis urica, psoriasis, hyperthyreosis, hypothyreosis and osteoporosis were significantly higher in the Danish suburb. CONCLUSION: In contrast to the disease pattern observed in Greenland in the last century, the prevalence of diagnosed NCDs in Nuuk is no longer rare. Thus, the overall prevalence of NCDs in the population of Nuuk is now comparable to or even higher than in the suburb in Denmark. This calls for increased focus on all NCDs in the primary healthcare system in Greenland and adaption of the primary healthcare services to a changed disease spectrum.

Psychoplastogenic DYRK1A Inhibitors with Therapeutic Effects Relevant to Alzheimer's Disease.

Tauopathy, neuronal atrophy, and psychological impairments are hallmarks of neurodegenerative diseases, such as Alzheimer's disease, that currently lack efficacious clinical treatments capable of rectifying these issues. To address these unmet needs, we used rational drug design to combine the pharmacophores of DYRK1A inhibitors and isoDMTs to develop psychoplastogenic DYRK1A inhibitors. Using this approach, we discovered a nonhallucinogenic compound capable of promoting cortical neuron growth and suppressing tau hyperphosphorylation while also having the potential to mitigate the biological and psychological symptoms of dementia. Together, our results suggest that hybridization of the DYRK1A and psychoplastogen pharmacophores represents a promising strategy for identifying compounds that might address the cognitive as well as the behavioral and psychological symptoms of dementia.

Age-dependent dysregulation of locus coeruleus firing in a transgenic rat model of Alzheimer's disease.

Hyperphosphorylated tau in the locus coeruleus (LC) is ubiquitous in prodromal Alzheimer's disease (AD), and LC neurons degenerate as AD progresses. Hyperphosphorylated tau alters firing rates in other brain regions, but its effects on LC neurons are unknown. We assessed single unit LC activity in anesthetized wild-type (WT) and TgF344-AD rats at 6 months, which represents a prodromal stage when LC neurons are the only cells containing hyperphosphorylated tau in TgF344-AD animals, and at 15 months when amyloid-ß (Aß) and tau pathology are both abundant in the forebrain. At baseline, LC neurons from TgF344-AD rats were hypoactive at both ages compared to WT littermates but showed elevated spontaneous bursting properties. Differences in footshock-evoked LC firing depended on age, with 6-month TgF344-AD rats demonstrating aspects of hyperactivity, and 15-month transgenic rats showing hypoactivity. Early LC hyperactivity is consistent with appearance of prodromal neuropsychiatric symptoms and is followed by LC hypoactivity which contributes to cognitive impairment. These results support further investigation into disease stage-dependent noradrenergic interventions for AD.

Clinical Trial Design Challenges and Opportunities for Emerging Treatments for Opioid Use Disorder: A Review.

Importance: Novel treatments for opioid use disorder (OUD) are needed to address both the ongoing opioid epidemic and long-standing barriers to existing OUD treatments that target the endogenous µ-opioid receptor (MOR) system. The goal of this review is to highlight unique clinical trial design considerations for the study of emerging treatments for OUD that address targets beyond the MOR system. In November 2019, the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership with the US Food and Drug Administration sponsored a meeting to discuss the current evidence regarding potential treatments for OUD, including cannabinoids, psychedelics, sedative-hypnotics, and immunotherapeutics, such as vaccines. Observations: Consensus recommendations are presented regarding the most critical elements of trial design for the evaluation of novel OUD treatments, such as: (1) stage of treatment that will be targeted (eg, seeking treatment, early abstinence/detoxification, long-term recovery); (2) role of treatment (adjunctive with or independent of existing OUD treatments); (3) primary outcomes informed by patient preferences that assess opioid use (including changes in patterns of use), treatment retention, and/or global functioning and quality of life; and (4) adverse events, including the potential for opioid-related relapse or overdose, especially if the patient is not simultaneously taking maintenance MOR agonist or antagonist medications. Conclusions and Relevance: Applying the recommendations provided here as well as considering input from people with lived experience in the design phase will accelerate the development, translation, and uptake of effective and safe therapeutics for individuals struggling with OUD.

Work environment, occupational diseases and accidents among seafood industry workers in Greenland.

INTRODUCTION: The seafood industry is the largest industry in Greenland. Work-related diseases and accidents appear to constitute health risks in this sector. The aim was to describe the prevalence of work-related diseases and accidents among workers in the seafood industry in Greenland. METHODS: Data from 311 workers included a questionnaire, lung function measurements, skin prick tests, blood samples, clinical examinations, personal inhalable dust samples and stationary dust measurements. Accident risk was evaluated by work site observations and safety walks. Statistical analyses included mean values and percentage distribution. RESULTS: Exposure levels were highest in shrimp production; 16.1% were sensitised to snow crab, 10.1% to shrimp and 0.3% to fish; 5.2% had probable occupational asthma. Regarding accidents, the annual incidence rate per 100 workers was 10.3%. CONCLUSIONS: Workers in the seafood industry in Greenland have a high prevalence of sensitisation to work-related allergens and occupational asthma closely related to high exposures to shrimp and snow crab allergens. The rate of severe workplace injuries was high. Preventive measures are required. FUNDING: The Health Science Research Council; The Work Environment Council of Greenland; The Greenlandic Workers' Union; Greenland Business Association; Royal Greenland; Polar Seafood; The BANK of Greenland; The Danish Working Environment Research Fund. TRIAL REGISTRATION: The Scientific Ethical Committee for Greenland (2015-11317); The Danish Data Protection Agency, the Central Denmark Region (2012-58-006).

Safety interventions for the prevention of accidents at work: A systematic review.

Background: Limited knowledge regarding the relative effectiveness of workplace accident prevention approaches creates barriers to informed decision-making by policy makers, public health practitioners, workplace, and worker advocates. Objectives: The objective of this review was to assess the effectiveness of broad categories of safety interventions in preventing accidents at work. The review aims to compare effects of safety interventions to no intervention, usual activities, or alternative intervention, and if possible, to examine which constituent components of safety intervention programs contribute more strongly to preventing accidents at work in a given setting or context. Date Sources: Studies were identified through electronic bibliographic searches, government policy databanks, and Internet search engines. The last search was carried out on July 9, 2015. Gray literature were identified by searching OSH ROM and Google. No language or date restrictions were applied. Searches done between February and July of 2015 included PubMed (1966), Embase (1980), CINAHL (1981), OSH ROM (NIOSHTIC 1977, HSELINE 1977, CIS-DOC 1974), PsycINFO (1806), EconLit (1969), Web of Science (1969), and ProQuest (1861); dates represent initial availability of each database. Websites of pertinent institutions (NIOSH, Perosh) were also searched. Study Eligibility Criteria Participants and Interventions: Included studies had to focus on accidents at work, include an evaluation of a safety intervention, and have used injuries at work, or a relevant proxy, as an outcome measure. Experimental, quasi-experimental, and observational study designs were utilized, including randomized controlled trials (RCTs), controlled before and after (CBA) studies, and observational designs using serial measures (interrupted time series, retrospective cohort designs, and before and after studies using multiple measures). Interventions were classified by approach at the individual or group level, and broad categories based on the prevention approach including modification of: Attitudes (through information and persuasive campaign messaging).Behaviors (through training, incentives, goal setting, feedback/coaching).Physiological condition (by physical training).Climate/norms/culture (by coaching, feedback, modification of safety management/leadership).Structural conditions (including physical environment, engineering, legislation and enforcement, sectorial-level norms). When combined approaches were used, interventions were termed "multifaceted," and when an approach(es) is applied to more than one organizational level (e.g., individual, group, and/or organization), it is termed "across levels." Study Appraisal and Synthesis Methods: Narrative report review captured industry (NACE), work setting, participant characteristics, theoretical basis for approach, intervention fidelity, research design, risk of bias, contextual detail, outcomes measures and results. Additional items were extracted for studies with serial measures including approaches to improve internal validity, assessments of reasonable statistical approaches (Effective Practice of Organization of Care [EPOC] criteria) and overall inference. Random-effects inverse variance weighted meta-analytic methods were used to synthesize odds ratios, rate ratios, or standardized mean differences for the outcomes for RCT and CBA studies with low or moderate levels of heterogeneity. For studies with greater heterogeneity and those using serial measures, we relied on narrative analyses to synthesize findings. Results: In total 100 original studies were included for synthesis analysis, including 16 RCT study designs, 30 CBA study designs, and 54 studies using serial measures (ITS study designs). These studies represented 120 cases of safety interventions. The number of participants included 31,971,908 individuals in 59 safety interventions, 417,693 groups/firms in 35 safety interventions, and 15,505 injuries in 17 safety interventions. Out of the 59 safety interventions, two were evaluating national prevention measures, which alone accounted for 31,667,110 individuals. The remaining nine safety interventions used other types of measures, such as safety exposure, safety observations, gloves or claim rates. Strong evidence supports greater effects being achieved with safety interventions directed toward the group or organization level rather than individual behavior change. Engineering controls are more effective at reducing injuries than other approaches, particularly when engineered changes can be introduced without requiring "decision-to-use" by workplaces. Multifaceted approaches combining intervention elements on the organizational level, or across levels, provided moderate to strong effects, in particular when engineering controls were included. Interventions based on firm epidemiologic evidence of causality and a strong conceptual approach were more effective. Effects that are more modest were observed (in short follow-up) for safety climate interventions, using techniques such as feedback or leadership training to improve safety communication. There was limited evidence for a strong effect at medium-term with more intense counseling approaches. Evidence supports regulation/legislation as contributing to the prevention of accidents at work, but with lower effect sizes. Enforcement appears to work more consistently, but with smaller effects. In general, the results were consistent with previous systematic reviews of specific types of safety interventions, although the effectiveness of economic incentives to prevent accidents at work was not consistent with our results, and effectiveness of physiological safety intervention was only consistent to some extent. Limitations: Acute musculoskeletal injuries and injuries from more long-time workplace exposures were not always clearly distinguished in research reports. In some studies acute and chronic exposures were mixed, resulting in inevitable misclassification. Of note, the classification of these events also remains problematic in clinical medicine. It was not possible to conduct meta-analyses on all types of interventions (due to variability in approach, context, and participants). The findings presented for most intervention types are from limited sources, and assessment of publication bias was not possible. These issues are not surprising, given the breadth of the field of occupational safety. To incorporate studies using serial measures, which provide the only source of information for some safety interventions such as legislation, we took a systematic, grounded approach to their review. Rather than requiring more stringent, specific criteria for inclusion of ITS studies, we chose to assess how investigators justified their approach to design and analyses, based on the context in which they were working. We sought to identify measures taken to improve external validity of studies, reasonable statistical inference, as well as an overall appropriate inferential process. We found the process useful and enlightening. Given the new approach, we may have failed to extract points others may find relevant. Similarly, to facilitate the broad nature of this review, we used a novel categorization of safety interventions, which is likely to evolve with additional use. The broad scope of this review and the time and resources available did not allow for contacting authors of original papers or seeking translation of non-English manuscripts, resulting in a few cases where we did not have sufficient information that may have been possible to obtain from the authors. Conclusions and Implications of Key Findings: Our synthesis of the relative effectiveness of workplace safety interventions is in accordance with the Public Health Hierarchy of Hazard Control. Specifically, more effective interventions eliminate risk at the source of the hazard through engineering solutions or the separation of workers from hazards; effects were greater when these control measures worked independently of worker "decision-to-use" at the worksite. Interventions based on firm epidemiological evidence of causality and clear theoretical bases for the intervention approach were more effective in preventing injuries. Less effective behavioral approaches were often directed at the prevention of all workplace injuries through a common pathway, such as introducing safety training, without explicitly addressing specific hazards. We caution that this does not mean that training does not play an essential function in worker safety, but rather that it is not effective in the absence of other efforts. Due to the potential to reach large groups of workers through regulation and enforcement, these interventions with relatively modest effects, could have large population-based effects.

Causes of irritant contact dermatitis after occupational skin exposure: a systematic review.

PURPOSE: Irritant contact dermatitis (ICD) is a major cause of occupational disease. The aim was to review the relation between exposure to occupational irritants and ICD and the prognosis of ICD. METHODS: Through a systematic search, 1516 titles were identified, and 48 studies were included in the systematic review. RESULTS: We found that the evidence for an association between ICD and occupational irritants was strong for wet work, moderate for detergents and non-alcoholic disinfectants, and strong for a combination. The highest quality studies provided limited evidence for an association with use of occlusive gloves without other exposures and moderate evidence with simultaneous exposure to other wet work irritants. The evidence for an association between minor ICD and exposure to metalworking fluids was moderate. Regarding mechanical exposures, the literature was scarce and the evidence limited. We found that the prognosis for complete healing of ICD is poor, but improves after decrease of exposure through change of occupation or work tasks. There was no substantial evidence for an influence of gender, age, or household exposures. Inclusion of atopic dermatitis in the analysis did not alter the risk of ICD. Studies were at risk of bias, mainly due to selection and misclassification of exposure and outcome. This may have attenuated the results. CONCLUSION: This review reports strong evidence for an association between ICD and a combination of exposure to wet work and non-alcoholic disinfectants, moderate for metalworking fluids, limited for mechanical and glove exposure, and a strong evidence for a poor prognosis of ICD.

Rhino Conjunctivitis and Asthma Among Seafood Processing Workers in Greenland. A Cross-Sectional Study.

Introduction: The fishing- and the seafood processing industries are the largest industrial sectors in Greenland. Despite this, only a few cases of occupational diseases in this industry have been reported to the Danish Labor Market Insurance. Occupational asthma and allergy are well-known occupational diseases in the seafood processing industry worldwide and underreporting of occupational diseases in Greenland is suspected. Objective: The aim of the current study was to examine the associations between job exposures and occupational asthma and rhino conjunctivitis in workers in the Greenlandic seafood processing industry and to compare the prevalence of sensitization by type and degree of exposure to snow crab, shrimp, fish, and the fish parasite, Anisakis simplex. Methods: Data from 382 Greenlandic seafood processing workers were collected during 2016-2018. Data included questionnaire answers, lung function measurements, skin prick tests, and blood samples with ImmunoCAP. For all analyses, p < 0.05 was considered the level of significance. Results: 5.5% of the workers had occupational asthma and 4.6% had occupational rhino conjunctivitis. A large proportion of the workers were sensitized to allergens specific to the workplace; 18.1% to snow crab, 13.6% to shrimp, 1.4% to fish, and 32.6% to the fish parasite, A. simplex. We found a dose-response relationship between the risk of being sensitized to snow crab and A. simplex and years of exposure to the allergens in the seafood processing industry. Conclusion: This study showed that a considerable proportion of workers in the Greenlandic seafood processing industry had occupational asthma and rhino conjunctivitis. Additionally, the study showed high sensitization levels toward snow crab, shrimp, and the fish parasite, A. simplex. This supports the hypothesis of a considerable degree of underreporting of occupational allergic airway disease in the Greenlandic seafood processing industry. Prospectively, it is important to inform workers, leaders, and health care professionals of the health problems and the law on worker's compensation, and to initiate preventive actions at factory and trawler level.

The Opioid Crisis and the Future of Addiction and Pain Therapeutics.

Opioid misuse and addiction are a public health crisis resulting in debilitation, deaths, and significant social and economic impact. Curbing this crisis requires collaboration among academic, government, and industrial partners toward the development of effective nonaddictive pain medications, interventions for opioid overdose, and addiction treatments. A 2-day meeting, The Opioid Crisis and the Future of Addiction and Pain Therapeutics: Opportunities, Tools, and Technologies Symposium, was held at the National Institutes of Health (NIH) to address these concerns and to chart a collaborative path forward. The meeting was supported by the NIH Helping to End Addiction Long-TermSM (HEAL) Initiative, an aggressive, trans-agency effort to speed scientific solutions to stem the national opioid crisis. The event was unique in bringing together two research disciplines, addiction and pain, in order to create a forum for crosscommunication and collaboration. The output from the symposium will be considered by the HEAL Initiative; this article summarizes the scientific presentations and key takeaways. Improved understanding of the etiology of acute and chronic pain will enable the discovery of novel targets and regulatable pain circuits for safe and effective therapeutics, as well as relevant biomarkers to ensure adequate testing in clinical trials. Applications of improved technologies including reagents, assays, model systems, and validated probe compounds will likely increase the delivery of testable hypotheses and therapeutics to enable better health outcomes for patients. The symposium goals were achieved by increasing interdisciplinary collaboration to accelerate solutions for this pressing public health challenge and provide a framework for focused efforts within the research community. SIGNIFICANCE STATEMENT: This article summarizes key messages and discussions resulting from a 2-day symposium focused on challenges and opportunities in developing addiction- and pain-related medications. Speakers and attendees came from 40 states in the United States and 15 countries, bringing perspectives from academia, industry, government, and healthcare by researchers, clinicians, regulatory experts, and patient advocates.

Evaluation of 5-HT7 receptor antagonism for the treatment of anxiety, depression, and schizophrenia through the use of receptor-deficient mice.

The 5-HT7 receptor is the most recently identified receptor subtype within a family of 5-HT receptors activated by the neurotransmitter serotonin. There has been significant interest in investigating the potential role of this receptor in psychiatric disorders including depression, anxiety, and schizophrenia. Behaviors of 5-HT7 +/+ (wild-type or WT) and 5-HT7 -/- (receptor knockout or KO) mice were compared across 10 different assays (7 for anxiety, 1 for depression, 2 for psychosis) to identify differences that could indicate clinical potential for 5-HT7 receptor antagonism. Evaluation of KO vs. WT mice demonstrated significant differences between the genotypes in the fear conditioning, shock-probe burying, novelty-suppressed feeding, punishment memory, forced swim test, and d-amphetamine hyperactivity assays. There was not consistency in either the direction of behavioral effects across genotypes or across assays. Thus, data from these behavioral assays did not uniformly support the idea that 5-HT7 receptors constitute an important drug target for these psychiatric disorders. The present findings are generally congruent with the mixed results in the literature on the behaviors of 5-HT7 -/-mice and with the data on effects of 5-HT7 receptor antagonists in rodent models that detect activity of anxiolytic, antidepressant, and antipsychotic effects.

Collaboration and patient safety at an emergency department - a qualitative case study.

Purpose The purpose of this paper is to examine how conflicts about collaboration between staff at different departments arose during the establishment of a new emergency department and how these conflicts affected the daily work and ultimately patient safety at the emergency department. Design/methodology/approach This qualitative single case study draws on qualitative semi-structured interviews and participant observation. The theoretical concepts "availability" and "receptiveness" as antecedents for collaboration will be applied in the analysis. Findings Close collaboration between departments was an essential precondition for the functioning of the new emergency department. The study shows how a lack of antecedents for collaboration affected the working relation and communication between employees and departments, which spurred negative feelings and reproduced conflicts. This situation was seen as a potential threat for the safety of the emergency patients. Research limitations/implications This study presents a single case study, at a specific point in time, and should be used as an illustrative example of how contextual and situational factors affect the working environment and through that patient safety. Originality/value Few studies provide an in-depth investigation of what actually takes place when collaboration between professional groups goes wrong and escalates, and how problems in collaboration may affect patient safety.

Costs associated with adverse events among acute patients.

BACKGROUND: The aim of this study was to analyse the additional treatment costs of acute patients admitted to a Danish hospital who suffered an adverse event (AE) during in-hospital treatment. METHODS: A matched case-control design was utilised. Using a combination of trigger words and patient record reviews 91 patients exposed to AEs were identified. Controls were identified among patients admitted to the same department during the same 20-month period. The matching was based on age, gender, and main diagnosis. Cost data was extracted from the Danish National Cost Database for four different periods after beginning of the admission. RESULTS: Patients exposed to an AE were associated with higher mean cost of EUR 9505 during their index admission (p = 0.014). For the period of 6 months from the beginning of the admission minus the admission itself they were associated with higher mean cost of EUR 4968 (p = 0.016). For the period from the 7th month until the end of the 12th month there was no statistically significant difference (p = 0.104). For the total period of 12 month, patients exposed to an AE were associated with statistically significant higher mean cost of EUR 13,930 (p = 0.001). CONCLUSIONS: AEs are associated with significant hospital costs. Our findings suggest that a follow-up period of 6 months is necessary when investigating the costs associated with AEs among acute patients. Further research of specific types of AEs and the costs of preventing these types of AEs would improve the understanding of the relationship between adverse events and costs.

Phosphodiesterase-1b (Pde1b) knockout mice are resistant to forced swim and tail suspension induced immobility and show upregulation of Pde10a.

RATIONALE: Major depressive disorder is a leading cause of suicide and disability. Despite this, current antidepressants provide insufficient efficacy in more than 60% of patients. Most current antidepressants are presynaptic reuptake inhibitors; postsynaptic signal regulation has not received as much attention as potential treatment targets. OBJECTIVES: We examined the effects of disruption of the postsynaptic cyclic nucleotide hydrolyzing enzyme, phosphodiesterase (PDE) 1b, on depressive-like behavior and the effects on PDE1B protein in wild-type (WT) mice following stress. METHODS: Littermate knockout (KO) and WT mice were tested in locomotor activity, tail suspension (TST), and forced swim tests (FST). FST was also used to compare the effects of two antidepressants, fluoxetine and bupropion, in KO versus WT mice. Messenger RNA (mRNA) expression changes were also determined. WT mice underwent acute or chronic stress and markers of stress and PDE1B expression were examined. RESULTS: Pde1b KO mice exhibited decreased TST and FST immobility. When treated with antidepressants, both WT and KO mice showed decreased FST immobility and the effect was additive in KO mice. Mice lacking Pde1b had increased striatal Pde10a mRNA expression. In WT mice, acute and chronic stress upregulated PDE1B expression while PDE10A expression was downregulated after chronic but not acute stress. CONCLUSIONS: PDE1B is a potential therapeutic target for depression treatment because of the antidepressant-like phenotype seen in Pde1b KO mice.

Work injuries among migrant workers in Denmark.

OBJECTIVES: Work migration into Denmark has increased during the recent decades, especially after the enlargement of the European Union (EU) in 2004. Whether or not migrant workers experience more work injuries than the native workforce has been debated and results are conflicting, most likely due to methodological difficulties and cultural disparities. We set out to meet these challenges using population-based work injury registers, targeting a specific and representative region in Denmark. METHODS: This population-based study used data on work injuries from an emergency department (ED) and reported injuries from the ED's catchment area to the Danish Working Environment Authority during 11 years. We calculated incidences of work injury for groups of migrant workers compared with native Danes and adjusted incidence rate ratios based on information on the complete working population. RESULTS: The incidences of work injuries among migrant workers from the new EU countries and from the rest of the world were higher compared with Danish workers and workers from the old EU countries and other Western countries. Especially migrants older than 30 years and in low-risk industries were at higher risk. Workers who had migrated recently were at even higher risk. CONCLUSIONS: We found increased risk of work injuries among migrant workers. Studying migrants in registers is a methodological challenge as some migrants are not registered, for legal or illegal reasons; thus, only a selected group is studied, but this may most likely underestimate the risk.

Forebrain-selective AMPA-receptor antagonism guided by TARP γ-8 as an antiepileptic mechanism.

Pharmacological manipulation of specific neural circuits to optimize therapeutic index is an unrealized goal in neurology and psychiatry. AMPA receptors are important for excitatory synaptic transmission, and their antagonists are antiepileptic. Although efficacious, AMPA-receptor antagonists, including perampanel (Fycompa), the only approved antagonist for epilepsy, induce dizziness and motor impairment. We hypothesized that blockade of forebrain AMPA receptors without blocking cerebellar AMPA receptors would be antiepileptic and devoid of motor impairment. Taking advantage of an AMPA receptor auxiliary protein, TARP γ-8, which is selectively expressed in the forebrain and modulates the pharmacological properties of AMPA receptors, we discovered that LY3130481 selectively antagonized recombinant and native AMPA receptors containing γ-8, but not γ-2 (cerebellum) or other TARP members. Two amino acid residues unique to γ-8 determined this selectivity. We also observed antagonism of AMPA receptors expressed in hippocampal, but not cerebellar, tissue from an patient with epilepsy. Corresponding to this selective activity, LY3130481 prevented multiple seizure types in rats and mice and without motor side effects. These findings demonstrate the first rationally discovered molecule targeting specific neural circuitries for therapeutic advantage.

Learning and feedback from the Danish patient safety incident reporting system can be improved.

INTRODUCTION: The perceived usefulness of incident reporting systems is an important motivational factor for reporting. The usefulness may be facilitated by well-established feedback mechanisms and by learning processes. The aim of this study was to investigate how feedback mechanisms and learning processes were implemented at four Danish hospital units all located in one of the five Danish regions. METHODS: Based on the concepts of feedback and learning from incident processes, a questionnaire was developed and distributed to 335 patient safety representatives from 200 departments at four Danish hospital units in one of the five Danish regions. RESULTS: The study showed that external reporters were rarely contacted for dialogue, grouped front-line staff were sparsely involved in the learning process, few evaluated the effectiveness of implemented interventions and personal factors were frequently perceived as a primary contributory factor to these incidents. In contrast, the patient safety representatives perceived their competencies as sufficient for the job, internal reporters were often contacted for dialogue, evaluation was widely used and management supported the work with incident reports. CONCLUSIONS: The results of the study identified several shortcomings in the implementation of learning processes and feedback mechanisms. The apparent existence of a person-focused approach stands out as an element of notice. The insufficient implementation we observed indicates that there is room for improvement in the efforts made to maximise learning from incidents in the investigated population. FUNDING: not relevant. TRIAL REGISTRATION: not relevant.

Psychological Stress Activates the Inflammasome via Release of Adenosine Triphosphate and Stimulation of the Purinergic Type 2X7 Receptor.

BACKGROUND: The mechanisms underlying stress-induced inflammation that contribute to major depressive disorder are unknown. We examine the role of the adenosine triphosphate (ATP)/purinergic type 2X7 receptor (P2X7R) pathway and the NLRP3 (nucleotide-binding, leucine-rich repeat, pyrin domain containing 3) inflammasome in interleukin (IL)-1ß and depressive behavioral responses to stress. METHODS: The influence of acute restraint stress on extracellular ATP, glutamate, IL-1ß, and tumor necrosis factor alpha in hippocampus was determined by microdialysis, and the influence of acute restraint stress on the NLRP3 inflammasome was determined by western blot analysis. The influence of P2X7R antagonist administration on IL-1ß and tumor necrosis factor alpha and on anxiety and depressive behaviors was determined in the chronic unpredictable stress rodent model. The role of the NLRP3 inflammasome was determined by analysis of Nlrp3 null mice. RESULTS: Acute restraint stress rapidly increased extracellular ATP, an endogenous agonist of P2X7R; the inflammatory cytokine IL-1ß; and the active form of the NLRP3 inflammasome in the hippocampus. Administration of a P2X7R antagonist completely blocked the release of IL-1ß and tumor necrosis factor alpha, another stress-induced cytokine, and activated NLRP3. Moreover, P2X7R antagonist administration reversed the anhedonic and anxiety behaviors caused by chronic unpredictable stress exposure, and deletion of the Nlrp3 gene rendered mice resistant to development of depressive behaviors caused by chronic unpredictable stress. CONCLUSIONS: These findings demonstrate that psychological "stress" is sensed by the innate immune system in the brain via the ATP/P2X7R-NLRP3 inflammasome cascade, and they identify novel therapeutic targets for the treatment of stress-related mood disorders and comorbid illnesses.