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Benjamin Kearns, Katy Cooper, Martin Orr, Munira Essat, Jean Hamilton, Anna Cantrell School of Health and Related Research (SCHARR), the University of Sheffield, Sheffield, UKCorrespondence: Benjamin Kearns, SCHARR, the University of Sheffield, Regent Court, 30 Regent Street, Sheffield, S1 4DA, UK, Tel +44 114 222 6380, Email b.kearns@sheffield.ac.ukPurpose: There is variation in the safety profile of antidepressants. Rates of adverse events along with the costs of treating them can be an important factor influencing the choice of depression treatment. This study sought to estimate the comparative safety of commonly prescribed antidepressants, and how the costs of treating these varied across European countries.Methods: A systematic literature review was conducted (in Medline, Embase, PsycINFO and CENTRAL) to identify placebo-controlled trials reporting rates of at least one type of sexual dysfunction, weight change, insomnia, anxiety, and anhedonia. Eight antidepressants were considered: duloxetine, escitalopram, fluoxetine, paroxetine, sertraline, trazodone, venlafaxine, and vortioxetine. This evidence was synthesised via Bayesian random effects network meta-analyses to provide comparative estimates of safety. A systematic search identified country-specific costs of managing depression and adverse events of antidepressants. Evidence on costs and safety was combined in an economic model to provide country-specific costs for Bulgaria, the Czech Republic, Greece, Hungary, Italy, Romania, Slovakia, Portugal, and Poland.Results: Trazodone had the lowest rates of both insomnia (odds ratio 0.66, 95% credible interval 0.31 to 1.38) and anxiety (0.13, < 0.01 to 1.80). All antidepressants were associated with increased rates of sexual dysfunction relative to placebo. Weight change was largest for fluoxetine (kg change − 1.01, − 1.40 to − 0.60) and sertraline (− 1.00, − 1.36 to − 0.65), although heterogeneity was extreme for this outcome. No evidence was identified for anhedonia. Total costs were lowest for trazodone in all nine of the countries evaluated. This was primarily due to reduced rates of treatment discontinuation.Conclusion: Trazodone generally had the best safety profile of the antidepressants evaluated. This led to healthcare costs being lowest for trazodone in all nine European countries, emphasising the importance of considering rates of adverse events when choosing a pharmacological treatment to treat symptoms of depression.Keywords: cost analysis, side-effects, Europe, treatment discontinuation

Herpes simplex virus encephalitis (HSE) is the most common cause of sporadic viral encephalitis, and despite targeted antiviral therapy, outcomes remain poor. Although the innate immune system is critical for restricting herpes simplex virus type I (HSV-1) in the brain, there is evidence that prolonged neuroinflammation contributes to HSE pathogenesis. In this study, we investigated the contribution of inflammasomes to disease pathogenesis in a murine model of HSE. Inflammasomes are signaling platforms that activate the pro-inflammatory cytokines interleukin-1β (IL-1β) and IL-18. We found that mice deficient in the inflammasome adaptor protein, apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC), had significantly improved survival and lower levels of IL-1β and IL-18 in the brain. Importantly, this difference in survival was independent of viral replication in the central nervous system (CNS). We found that microglia, the resident macrophages of the CNS, are the primary mediators of the ASC-dependent inflammasome response during infection. Using in vitro glial infections and a murine HSE model, we demonstrate that inflammasome activation contributes to the expression of chemokine (C-C motif) ligand 6 (CCL6), a leukocyte chemoattractant. The lower concentration of CCL6 in the brains of ASC-/- mice correlated with lower numbers of infiltrating macrophages during infection. Together, these data suggest that inflammasomes contribute to pathogenic inflammation in HSE and provide a mechanistic link between glial inflammasome activation and leukocyte infiltration. The contribution of inflammasomes to survival was independent of viral replication in our study, suggesting a promising new target in combating harmful inflammation in HSE.

Purpose: As drug‐related epidemics have expanded from cities to rural areas, syringe service programs (SSPs) and other harm reduction programs have been slow to follow. The recent implementation of SSPs in rural areas demands attention to program fidelity based on core components of SSP success. Methods: Semistructured interviews conducted with clients and staff at 5 SSPs in 5 counties within 2 Central Appalachian health districts. Interviews covered fidelity of SSP implementation to 6 core components: (1) meet needs for harm reduction supplies; (2) education and counseling for sexual, injection, and overdose risks; (3) cooperation between SSPs and local law enforcement; (4) provide other health and social services; (5) ensure low threshold access to services; and (6) promote dignity, the impact of poor fidelity on vulnerability to drug‐related harms, and the risk environment's influence on program fidelity. We applied thematic methods to analyze the data. Findings: Rural SSPs were mostly faithful to the 6 core components. Deviations from core components can be attributed to certain characteristics of the local rural risk environment outlined in the risk environment model, including geographic remoteness, lack of resources and underdeveloped infrastructure, and stigma against people who inject drugs (PWID) Conclusions: As drug‐related epidemics continue to expand outside cities, scaling up SSPs to serve rural PWID is essential. Future research should explore whether the risk environment features identified also influence SSP fidelity in other rural areas and develop and test strategies to strengthen core components in these vulnerable areas. [ABSTRACT FROM AUTHOR]

When post-traumatic stress disorder (PTSD) co-occurs with obsessive compulsive disorder (OCD), symptoms of the former can interfere with evidence-based treatment of the latter. As a result, exposure-based treatments are recommended for both OCD and PTSD, potentially facilitating a concurrent treatment approach. This case study describes the application of concurrent cognitive behaviour therapy (CBT including exposure and response prevention; ERP) for OCD and narrative exposure therapy to treat a patient whose PTSD symptoms of intrusive images of memories and hyperarousal were interfering with standard CBT (including ERP) treatment for OCD. Following this concurrent approach, the patient's symptoms of OCD reduced to non-clinical levels and showed reliable improvement in PTSD symptoms. Whilst further methodologically robust research is required, this case study highlights that this approach may be beneficial to the treatment of OCD where PTSD symptoms are impacting on treatment. Key learning aims: (1) To explore the literature considering explanations of the co-occurrence of OCD and PTSD symptomology. (2) To consider how symptoms of two mental health conditions can maintain one another and attenuate the effectiveness of evidence-based treatment for the other mental health condition. (3) Consider the use of concurrent therapeutic approaches to treat co-occurring mental health conditions. [ABSTRACT FROM AUTHOR]

Herpes simplex virus (HSV) infection of the neonatal brain causes severe encephalitis and permanent neurologic deficits. However, infants infected with HSV at the time of birth follow varied clinical courses, with approximately half of infants experiencing only external infection of the skin rather than invasive neurologic disease. Understanding the cause of these divergent outcomes is essential to developing neuroprotective strategies. To directly assess the contribution of viral variation to neurovirulence, independent of human host factors, we evaluated clinical HSV isolates from neonates with different neurologic outcomes in neurologically relevant in vitro and in vivo models. We found that isolates taken from neonates with encephalitis are more neurovirulent in human neuronal culture and mouse models of HSV encephalitis, as compared to isolates collected from neonates with skin-limited disease. These findings suggest that inherent characteristics of the infecting HSV strain contribute to disease outcome following neonatal infection. [ABSTRACT FROM AUTHOR]