Exploring how hospitalization can alter hepatitis c virus treatment prioritization and trajectories in people who use drugs: A qualitative analysis.

Background: People who use drugs (PWUD) have high rates of hepatitis C virus (HCV) infection. Hospitalization can be a time for PWUD to engage in addiction treatment, but little is known about how hospitalization shapes HCV treatment readiness. We aimed to describe how hospitalization and addiction medicine consult service (AMCS) can alter HCV prioritization of inpatient PWUD with HCV. Methods: We conducted a qualitative study consisting of semi-structured interviews (n = 27) of hospitalized adults with addiction and HCV infection seen by an AMCS at a single, urban, academic center. Interviews were audio-recorded, transcribed, and coded iteratively at the semantic level, and analyzed for themes. Results: Of the 27 participants, most identified as Caucasian (85%), male gender (67%), and they primarily used opioids (78%); approximately half (48%) reported HCV diagnosis over 5 years ago. We identified three main themes around hospitalization altering the prioritizations and HCV treatment preferences for PWUD: (1) HCV treatment non-engaged (2) HCV treatment urgency, and (3) HCV treatment in the future. Those wanting to treat HCV-whether urgently or in the future-shared the overlapping theme of hospitalization as a reachable moment for their addiction and HCV. These participants recognized the long-term benefits of addressing HCV and connected their hospitalization to substance use. Conclusion: In our study, PWUD with HCV expressed varying and competing priorities and life circumstances contributing to three main HCV treatment trajectories. Our results suggest ways hospitalization can serve as an HCV touchpoint for PWUD, especially in the context of addressing substance use, and could be used when designing and implementing targeted interventions to improve the HCV care continuum for PWUD.

Prenatal deletion of the RNA-binding protein HuD disrupts postnatal cortical circuit maturation and behavior.

The proper functions of cortical circuits are dependent upon both appropriate neuronal subtype specification and their maturation to receive appropriate signaling. These events establish a balanced circuit that is important for learning, memory, emotion, and complex motor behaviors. Recent research points to mRNA metabolism as a key regulator of this development and maturation process. Hu antigen D (HuD), an RNA-binding protein, has been implicated in the establishment of neuronal identity and neurite outgrowth in vitro. Therefore, we investigated the role of HuD loss of function on neuron specification and dendritogenesis in vivo using a mouse model. We found that loss of HuD early in development results in a defective early dendritic overgrowth phase and pervasive deficits in neuron specification in the lower neocortical layers and defects in dendritogenesis in the CA3 region of the hippocampus. Subsequent behavioral analysis revealed a deficit in performance of a hippocampus-dependent task: the Morris water maze. Further, HuD knock-out (KO) mice exhibited lower levels of anxiety than their wild-type counterparts and were overall less active. Last, we found that HuD KO mice are more susceptible to auditory-induced seizures, often resulting in death. Our findings suggest that HuD is necessary for the establishment of neocortical and hippocampal circuitry and is critical for their function.

Utilising an access to care integrated framework to explore the perceptions of hepatitis C treatment of hospital-based interventions among people who use drugs.

BACKGROUND: Gaps remain in the hepatitis C virus (HCV) care cascade for people who use drugs (PWUD). Acute medical or surgical illnesses requiring hospitalisation are an opportunity to address addiction, but how inpatient strategies could affect HCV care accessibility for PWUD remains unknown. We explored patient perspectives of hospital-based interventions using an integrated framework of access to HCV care. METHODS: We conducted a qualitative study of hospitalised adults (n=27) with HCV and addiction admitted to an urban academic medical centre in the United States between June and November 2019. Individual interviews were audio-recorded, transcribed, and dual-coded. We analysed data with coding specific for hospital-based interventions including screening, conducting HCV-related laboratory work-up, starting treatment, connecting with peers, and coordinating outpatient care. We analysed coded data at the semantic level for emergent themes using a framework approach based off an integrated framework of access to HCV care. RESULTS: The majority of participants primarily used opioids (78%), were white (85%) and men (67%). Participants frequently reported HCV screening during previous hospitalisation with rare inpatient connection to HCV-related services. Participants expressed willingness to discuss HCV treatment candidacy during hospitalisation; however, lack of inpatient conversations led to perception that "nothing could be done" during admission. Participants expressed interest in completing inpatient HCV work-up to "get the ball rollin'" - consolidating care would enhance outpatient service permeability by reducing barriers. Others resisted HCV care coordination, preferring to focus on "immediate" issues including health conditions and addiction treatment. Participants also expressed openness to engaging with peers about HCV, noting shared drug use experience as critical to a peer relationship when discussing HCV. CONCLUSION: Hospitalised PWUD have varied priorities, necessitating adaptable interventions for addressing HCV. Hospitalisation can be an opportunity to address HCV access to care including identification of treatment eligibility, consolidation of care, and facilitation of HCV-related referrals.

"Sobriety equals getting rid of hepatitis C": A qualitative study exploring the interplay of substance use disorder and hepatitis C among hospitalized adults.

BACKGROUND: People who use drugs (PWUD) commonly experience complex illness, psychosocial stressors, housing insecurity, and stigma, which may play key roles in their struggles with addiction. In a study of hospitalized PWUD with hepatitis C virus infection (HCV), participants described treating HCV as "part of recovery." These findings led us to explore how hospitalization and acute illness altered patients' perceptions of substance use disorder (SUD) and HCV. METHODS: Researchers audio recorded in-depth semi-structured individual interviews of 27 hospitalized adults with SUD and HCV seen by an addiction consult service (ACS) at an urban academic medical center between June and November 2019. Research staff transcribed interviews and dual coded them deductively and inductively at the semantic level. Researchers used a matrix visualization to discern relationships among codes and conducted a thematic analysis. RESULTS: Many participants believed addictions treatment should precede an HCV cure for varying reasons. Some wanted to avoid reinfection; others believed "getting clean" afforded the mental clarity to address health issues, including HCV. Patients newly engaged in SUD treatment described HCV treatment as a "step towards recovery" and could serve as motivation to continue SUD treatment. Participants believed HCV cure could facilitate sobriety by "mentally putting drugs in the past" and was a future-oriented action toward "better health." Many participants described the compounded stigma of having HCV infection and SUD by multiple groups, including friends/family who do not use drugs, other drug users, and health care workers. CONCLUSION: Hospitalized adults with SUD and HCV believed addictions engagement should precede HCV treatment and HCV cure could play an important role in their "recovery" journey. Discussing HCV treatment during hospitalization may be an opportunity to support engagement in SUD treatment and targets an untreated patient population critical for achieving HCV elimination.

Working memory, cortical dopamine tone, and frontoparietal brain recruitment in post-traumatic stress disorder: a randomized controlled trial.

Post-traumatic stress disorder (PTSD) leads to impairments in both cognitive and affective functioning. Animal work suggests that chronic stress reduces dopamine tone, and both animal and human studies argue that changes in dopamine tone influence working memory, a core executive function. These findings give rise to the hypothesis that increasing cortical dopamine tone in individuals with greater PTSD symptomatology should improve working memory performance. In this pharmacological functional magnetic resonance imaging (fMRI) study, 30 US military veterans exhibiting a range of PTSD severity completed an emotional working memory task. Each subject received both placebo and the catechol-O-methyl transferase inhibitor tolcapone, which increases cortical dopamine tone, in randomized, double-blind, counterbalanced fashion. Mnemonic discriminability (calculated with d', an index of the detectability of working memory signals) and response bias were evaluated in the context of task-related brain activations. Subjects with more severe PTSD showed both greater tolcapone-mediated improvements in d' and larger tolcapone-mediated reductions in liberally-biased responding for fearful stimuli. FMRI revealed that tolcapone augmented activity within bilateral frontoparietal control regions during the decision phase of the task. Specifically, tolcapone increased cortical responses to fearful relative to neutral stimuli in higher severity PTSD subjects, and reduced cortical responses to fearful stimuli for lower severity PTSD subjects. Moreover, tolcapone modulated prefrontal connectivity with areas overlapping the default mode network. These findings suggest that enhancing cortical dopamine tone may represent an approach to remediating cognitive and affective dysfunction in individuals with more severe PTSD symptoms.

The catechol-O-methyltransferase inhibitor tolcapone modulates alcohol consumption and impulsive choice in alcohol use disorder.

RATIONALE: Individuals suffering from alcohol use disorder (AUD) demonstrate difficulty with decision-making and impulsivity that may be associated with impaired frontal cortical function. Therapeutics that enhance frontal dopamine tone could decrease impulsivity and in turn reduce alcohol consumption in individuals with AUD. OBJECTIVES: To determine if the catechol-O-methyltransferase (COMT) inhibitor tolcapone can attenuate alcohol consumption in individuals with AUD and whether this attenuation correlates with tolcapone-induced changes in laboratory-based decision-making tasks. METHODS: We used daily self-report and a novel group laboratory bar task to assess the effects of randomized double-blind crossover administration of tolcapone (100 mg TID for 5 days) on alcohol consumption and laboratory tasks assessing impulsivity in 55 non-treatment-seeking subjects with AUD. RESULTS: Tolcapone significantly reduced self-reported alcohol consumption (t (54) = 2.05, p = 0.045). The effects of tolcapone on drinking significantly correlated with changes in impulsive decision-making, such that subjects with the greatest decrease in impulsive choice on tolcapone also reported the greatest decrease in alcohol consumption (r (45) = 0.40, p = 0.0053). We did not see effects of tolcapone on laboratory bar consumption. Adverse event (AE) reporting was low, with no significant difference in frequency or severity of AEs on tolcapone versus placebo. CONCLUSIONS: These data demonstrate that COMT inhibitors such as tolcapone may be useful therapeutics for AUD. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02740582.