Evaluation of a novel therapeutic education programme for people with alcohol use disorder in France: a mixed-methods intervention study protocol (ETHER).

BACKGROUND: ETHER ("Education THEérapeutique pour la Réduction des dommages en alcoologie" or Therapeutic education for alcohol-related harm reduction) is a multicentre community-based mixed-methods study, which aims to evaluate the effectiveness of the innovative therapeutic patient education (TPE) programme 'Choizitaconso' in a sample of French people with alcohol use disorder (people with AUD). Choizitaconso teaches people with AUD psychosocial skills to help them (re)establish controlled drinking and reduce alcohol-related harms. Recruitment started in October 2019. We present here the protocol of the ETHER study. METHODS: ETHER's quantitative component involves a 6-month controlled intervention study which evaluates Choizitaconso's effectiveness by comparing 30 people with AUD following the programme with a control group of 60 people with AUD not enrolled in it, using a questionnaire co-constructed by the research team and members of the people with AUD community. Thirty-four alcohol-related harms are assessed and summed to provide an individual measure of the 'harm burden' from consuming alcohol (primary outcome). Secondary outcomes are anticipated and internalized stigma, alcohol consumption measures, craving for alcohol, coping strategies, health-related quality of life, self-confidence to control or abstain from drinking, treatment self-regulation, anxiety and depressive symptoms, alcohol-related neuropsychological impairments, and capabilities (a measure of wellbeing in adults). Data will be collected in face-to-face and phone-based interviews at enrolment and 6 months later. Linear regression models will be used to assess the impact of the TPE programme on changes in the primary and secondary outcomes, while adjusting for other correlates and confounders. The study's qualitative component comprises semi-structured interviews with 16 people with AUD who have already completed the TPE programme at least 6 months before the interview. Qualitative interviews will be analysed using thematic analysis. RESULTS AND CONCLUSIONS: ETHER is the first evaluation study of an innovative TPE programme specifically designed to reduce alcohol-related harms and reach controlled drinking in France. The involvement of the people with AUD community in selecting which experienced and perceived alcohol-related harms to measure ensures that ETHER will provide healthcare staff and researchers with a relevant set of harm reduction criteria for use in future research. Finally, ETHER will provide scientific justification for implementing novel alcohol-related harm reduction approaches and champion controlled drinking as a therapeutic goal. Trial registration ClinicalTrials.gov, NCT03954054. Registered 17 May 2019-Prospectively registered, https://clinicaltrials.gov/ct2/show/NCT03954054?cond=alcohol&cntry=FR&city=Marseille&draw=1&rank=1 .

Prion replication occurs in endogenous adult neural stem cells and alters their neuronal fate: involvement of endogenous neural stem cells in prion diseases.

Prion diseases are irreversible progressive neurodegenerative diseases, leading to severe incapacity and death. They are characterized in the brain by prion amyloid deposits, vacuolisation, astrocytosis, neuronal degeneration, and by cognitive, behavioural and physical impairments. There is no treatment for these disorders and stem cell therapy therefore represents an interesting new approach. Gains could not only result from the cell transplantation, but also from the stimulation of endogenous neural stem cells (NSC) or by the combination of both approaches. However, the development of such strategies requires a detailed knowledge of the pathology, particularly concerning the status of the adult neurogenesis and endogenous NSC during the development of the disease. During the past decade, several studies have consistently shown that NSC reside in the adult mammalian central nervous system (CNS) and that adult neurogenesis occurs throughout the adulthood in the subventricular zone of the lateral ventricle or the Dentate Gyrus of the hippocampus. Adult NSC are believed to constitute a reservoir for neuronal replacement during normal cell turnover or after brain injury. However, the activation of this system does not fully compensate the neuronal loss that occurs during neurodegenerative diseases and could even contribute to the disease progression. We investigated here the status of these cells during the development of prion disorders. We were able to show that NSC accumulate and replicate prions. Importantly, this resulted in the alteration of their neuronal fate which then represents a new pathologic event that might underlie the rapid progression of the disease.

A novel community-based therapeutic education program for reducing alcohol-related harms and stigma in people with alcohol use disorders: A quasi-experimental study (ETHER study).

INTRODUCTION: Alcohol use disorder (AUD) is associated with a significant disease burden in France, where alcohol use is deeply rooted in culture. However, the treatment gap is large because of several barriers, including stigmatisation and drinkers' apprehension about total abstinence. However, standardised and evidence-based interventions based on controlled-drinking for people with AUD are lacking. We aimed to assess the effectiveness of a novel community-based French therapeutic patient education (TPE) program for people with AUD named Choizitaconso. METHODS: A before-after non-randomised quasi-experimental study, named ETHER, was designed and implemented with people living with AUD, over a period of 6 months. The primary outcome was percentage change in the number of alcohol-related harms experienced. Secondary outcomes were percentage changes in psycho-social patient-reported and community-validated outcomes. Participants in the intervention group (n = 34) benefited from the 10-week TPE program Choizitaconso, while the comparison group (n = 58) received standard care. The Kruskall-Wallis and chi-squared or Fisher's exact tests were used to compare before-after changes in variables in both groups. Linear regression models were used to test for the effect of study group on each outcome and to test for the effect of alcohol consumption as a confounder. RESULTS: At 6 months, all outcomes but one either remained stable or numerically improved in both groups. Internalised stigma significantly improved in the intervention group (p = 0.026) but not in the comparison group (p = 0.207), with a significant group effect (p = 0.014). DISCUSSION AND CONCLUSIONS: This study demonstrates the effectiveness of the Choizitaconso TPE program on community-validated outcomes, especially internalised stigma.

A Community-Based Therapeutic Education Programme for People with Alcohol Use Disorder in France: A Qualitative Study (ETHER).

Therapeutic patient education (TPE) aims to help people with chronic disease strengthen their empowerment and psychosocial skills to better manage their condition. Although TPE has great potential for addiction medicine, studies on its benefits for reducing alcohol-related harms and increasing empowerment are sparse. We conducted a qualitative study of people with alcohol use disorder (AUD) who participated in the community-based TPE programme Choizitaconso to assess their perceptions and experiences of it. Semi-structured interviews were conducted with 16 participants who had completed the TPE programme at least six months previously. The interviews were transcribed and analysed using a sequential thematic analysis. We identified four general themes: (1) the context of participation: the TPE programme could be a strategy to facilitate engagement in AUD care; (2) representations and experiences: the programme helped to "normalize" participants' relationship with alcohol use by increasing empowerment; (3) TPE strengths: improved knowledge about alcohol use, self-image, weight loss, self-stigma reduction; (4) TPE limitations: difficulty putting learning into practice after the programme ended. The Choizitaconso programme met participants' health and psychosocial expectations, strengthening their empowerment and reducing self-stigma, thereby facilitating engagement in AUD care.

HEPES inhibits the conversion of prion protein in cell culture.

HEPES is a well-known buffering reagent used in cell-culture medium. Interestingly, this compound is also responsible for significant modifications of biological parameters such as uptake of organic molecules, alteration of oxidative stress mechanisms or inhibition of ion channels. While using cell-culture medium supplemented with HEPES on prion-infected cells, it was noticed that there was a significant concentration-dependent inhibition of accumulation of the abnormal isoform of the prion protein (PrP(Sc)). This effect was present only in live cells and was thought to be related to modification of the PrP environment or biology. These results could modify the interpretation of cell-culture assays of prion therapeutic agents, as well as of previous cell biology results obtained in the field using HEPES buffers. This inhibitory effect of HEPES could also be exploited to prevent contamination or propagation of prions in cell culture.

Building Successful Models in Primary Care to Improve the Management of Adult Patients with Obesity.

Although several obesity clinical practice guidelines are available and relevant for primary care, a practical and effective medical model for treating obesity is necessary. The aim of this study was to develop and implement a holistic population health-based framework with components to support primary care-based obesity management in US health care organizations. The Obesity Care Model Collaborative (OCMC) was conducted with guidance and expertise of an advisory committee, which selected participating health care organizations based on prespecified criteria. A committee comprising obesity and quality improvement specialists and representatives from each organization developed and refined the obesity care framework for testing and implementing guideline-based practical interventions targeting obesity. These interventions were tracked over time, from an established baseline to 18 months post implementation. Ten geographically diverse organizations, treating patients with diverse demographics, insurance coverage, and health status, participated in the collaborative. The key interventions identified for managing obesity in primary care were applicable across the 4 OCMC framework domains: community, health care organization, care team, and patient/family. Care model components were developed within each domain to guide the primary care of obesity based on each organization's structure, resources, and culture. Key interventions included development of quality monitoring systems, training of leadership and staff, identifying clinical champions, patient education, electronic health record best practice alerts, and establishment of community partnerships, including the identification of external resources. This article describes the interventions developed based on the framework, with a focus on implementation of the model and lessons learned.

Impact of a Learning Collaborative Approach on Influenza and Pneumococcal Immunization Rates in US Adults: A Mixed Methods Approach.

The objective of this research was to test the impact of a learning collaborative model (intervention) on adult vaccination rates for influenza and pneumococcal disease. A mixed methods approach was used to identify changes in adult vaccination rates over time and organizational factors contributing to successful programs. Provider-level propensity scores were used to match intervention to non-intervention providers to control for inherent selection bias of participating organizations. Comparative analyses were conducted between intervention and non-intervention sites on vaccination rates, using a difference-in-differences approach. Qualitative data (eg, semi-structured interviews) were analyzed using a constant comparison approach to identify themes related to successful strategies. From 2014-2016, intervention providers demonstrated greater improvement than their matched providers in pneumococcal vaccinations (PV) for patients aged 65 years and older (treatment effect: 4.3%, P < 0.05) and PV for high-risk patients (eg, with immunocompromising conditions) aged 19-64 years (2.7%, P < 0.001). Significant effects were also observed for PV for at-risk patients (eg, with diabetes) aged 19-64 years (1.7%, P < 0.05). Individual health systems demonstrated even greater improvements (eg, greater increase in PV rates for patients aged 65 years and older), with treatment effects as high as 20.4% (P < 0.05). A learning collaborative approach was demonstrated to be an effective approach to improve adult vaccination rates among participating integrated delivery systems and medical groups. Factors associated with success included organization type (ie, integrated delivery systems) and systems characterized by a positive learning climate and collaborative culture.

An Adult Immunization Best Practices Learning Collaborative: Impact, Scale Up, and Spread.

The research objective was to rapidly scale up and spread a proven learning collaborative approach (intervention) for adult vaccination rates for influenza and pneumococcal disease from 7 to 39 US health care organizations and to examine improvement in adult immunization rates after scale-up. Comparative analyses were conducted between intervention and nonintervention propensity score-matched providers on vaccination rates using a difference-in-differences approach. Qualitative data, collected during site visits and in-person and virtual meetings, were used to enhance understanding of quantitative results. In 2017-2018, an analysis of a subset of sites (n = 9) from 2 intervention cohorts (∼20 sites each) demonstrated greater improvement than their matched providers in pneumococcal vaccinations (PV) for patients ages ≥65 years (treatment effect range: 1.4%-3.7%, P < 0.01) and PV for high-risk patients (eg, with immunocompromising conditions) aged 19-64 years (0.8%-1.6%, P < 0.01). Significant effects were observed in one of the study cohorts for PV for at-risk patients (eg, with diabetes) aged 19-64 years (1.7%, P < 0.01), and influenza vaccination rates (2.4%, P < 0.001). Individual health systems demonstrated even greater improvements across all 4 vaccinations: 9.5% influenza; 8.7% PV ages ≥65 years; 11.8% PV high-risk; 16.3% PV at-risk (all P < 0.01). Results demonstrated that a 7-site pilot could be successfully scaled to 39 additional sites, with similar improvements in vaccination rates. Between 2014 and 2018, vaccination improvements among all 46 groups (7 pilot, 39 in subsequent cohorts) resulted in an estimated 5.5 million adult vaccinations administered or documented in 27 states.

Access to care for people with alcohol use disorder in France: a mixed-method cross-sectional study protocol (ASIA).

INTRODUCTION: Alcohol use disorder (AUD) is a major public health concern worldwide. In France, only 10% of people with AUD (PWAUD) receive medical care. General practitioners (GP) are one of the main entry points for AUD care. The present ongoing study, entitled ASIA (Access to Care and Indifference toward Alcohol, Accès aux Soins et Indifference à l'Alcool in French), aims to improve knowledge about factors associated with access to care for AUD by exploring related GP and PWAUD practices, experiences and perceptions. METHODS AND ANALYSIS: The ASIA project is an ongoing cross-sectional multisite study based on a complementary mixed-method approach (quantitative and qualitative) using a convergent parallel design. The double-perspective design of the study will enable us to collect and compare data regarding both PWAUD and GP points of view. For the PWAUD quantitative study, 260 PWAUD will be interviewed using a telephone-based questionnaire. For the qualitative study, 36 PWAUD have already been interviewed. The GP quantitative study will include 100 GP in a 15 min survey. Fifteen GP have already participated in semistructured interviews for the qualitative study. Logistic regression will be used to identify predictors for access to care. With respect to data analyses, qualitative interviews will be analysed using semantic analysis while quantitative logistic regression will be used for quantitative interviews. ETHICS AND DISSEMINATION: This study was approved by the CNIL (French National Commission on Informatics and Liberties) (approval reference number: C16-10, date of approval: 17 July 2017), the CCTIRS (Advisory Committee on Information Processing in Material Research in the Field of Health) and the CEEI (Evaluation and Ethics Committee) (approval reference number: 16-312, date of approval: 8 July 2016) of INSERM (French National Institute of Health and Medical Research). Results from ASIA will be disseminated in peer-reviewed publications, conference presentations, reports and in a PhD thesis.

Systemic delivery of siRNA down regulates brain prion protein and ameliorates neuropathology in prion disorder.

One of the main challenges for neurodegenerative disorders that are principally incurable is the development of new therapeutic strategies, which raises important medical, scientific and societal issues. Creutzfeldt-Jakob diseases are rare neurodegenerative fatal disorders which today remain incurable. The objective of this study was to evaluate the efficacy of the down-regulation of the prion protein (PrP) expression using siRNA delivered by, a water-in-oil microemulsion, as a therapeutic candidate in a preclinical study. After 12 days rectal mucosa administration of Aonys/PrP-siRNA in mice, we observed a decrease of about 28% of the brain PrP(C) level. The effect of Aonys/PrP-siRNA was then evaluated on prion infected mice. Several mice presented a delay in the incubation and survival time compared to the control groups and a significant impact was observed on astrocyte reaction and neuronal survival in the PrP-siRNA treated groups. These results suggest that a new therapeutic scheme based an innovative delivery system of PrP-siRNA can be envisioned in prion disorders.

Proteomic consequences of expression and pathological conversion of the prion protein in inducible neuroblastoma N2a cells.

Neurodegenerative diseases are often associated with misfolding and deposition of specific proteins in the nervous system. The prion protein, which is associated with transmissible spongiform encephalopathies (TSEs), is one of them. The normal function of the cellular form of the prion protein (PrP(C)) is mediated through specific signal transduction pathways and is linked to resistance to oxidative stress, neuronal outgrowth and cell survival. In TSEs, PrP(C) is converted into an abnormally folded isoform, called PrP(Sc), that may impair the normal function of the protein and/or generate toxic aggregates. To investigate these molecular events we performed a two-dimensional gel electrophoresis comparison of neuroblastoma N2a cells expressing different amounts of PrP(C) and eventually infected with the 22L prion strain. Mass spectrometry and peptide mass fingerprint analysis identified a series of proteins with modified expression. They included the chaperones Grp78/BiP, protein disulfide-isomerase A6, Grp75 and Hsp60 which had an opposite expression upon PrPC expression and PrP(Sc) production. The detection of these proteins was coherent with the idea that protein misfolding plays an important role in TSEs. Other proteins, such as calreticulin, tubulin, vimentin or the laminin receptor had their expression modified in infected cells, which was reminiscent of previous results. Altogether our data provide molecular information linking PrP expression and misfolding, which could be the basis of further therapeutic and pathophysiological research in this field.

Genetic heterogeneity versus molecular analysis of prion susceptibility in neuroblasma N2a sublines.

The neuroblastoma-derived cell line N2a is permissive to certain prion strains but resistant sublines unable to accumulate the pathological proteinase-K resistant form of the prion protein can be isolated. We compared for gene expression and phenotypes different N2a sublines that were susceptible or resistant to the 22L prion strain. Karyotypes and comparative genomic hybridization arrays revealed chromosomal imbalances but did not demonstrate a characteristic profile of genomic alterations linked to prion susceptibility. Likewise, we showed that this phenotype was not dependent on the binding of PrPres, the expression of the prion protein gene, or on its primary sequence. We completed this analysis by looking using real-time quantitative PCR at the expression of a set of genes encoding proteins linked to prion biology. None of the candidates could account by itself for the infection phenotype, nevertheless sublines had distinct transcriptional profiles. Taken together, our results do not support a role for specific genomic abnormalities and possible candidate proteins in N2a prion susceptibility. They also reveal genetic heterogeneity among the sublines and serve as a guidance for further investigation into the molecular mechanisms of prion infection.

The truncated 23-230 form of the prion protein localizes to the nuclei of inducible cell lines independently of its nuclear localization signals and is not cytotoxic.

The mechanisms of prion-induced neurological dysfunction observed in prion diseases are poorly understood. Transgenic mice expressing a truncated form of the prion protein (23-230 PrP) acquire cerebellar degeneration (Ma and Lindquist, Science, 2002). To decipher the mechanisms of neurodegeneration induced by 23-230 PrP, we established inducible cell lines expressing this truncated form of PrP. We found that 23-230 PrP, expected to be cytosolic, accumulated mostly in the nucleus of the cells and was not cytotoxic. Nuclear localization of this mutant form of PrP is independent of its predicted nuclear localization signals. In contrast to what we previously described for PrPSc, nuclear accumulation of 23-230 PrP does not require a functional microtubule network. We observed that 23-230 PrP interacts with chromatin in vivo, as already described for recombinant PrP and for PrPSc. Our data demonstrate that the 23-230 PrP model does not reflect the situation of a cytosolic PrP but could represent a very useful tool to understand the consequences of the accumulation of the prion protein in the nucleus.

Neural stem cell model for prion propagation.

The study of prion transmission and targeting is a major scientific issue with important consequences for public health. Only a few cell culture systems that are able to convert the cellular isoform of the prion protein into the pathologic scrapie isoform of the prion protein (PrP(Sc)) have been described. We hypothesized that central nervous system neural stem cells (NSCs) could be the basis of a new cell culture model permissive to prion infection. Here, we report that monolayers of differentiated fetal NSCs and adult multipotent progenitor cells isolated from mice were able to propagate prions. We also demonstrated the large influence of neural cell fate on the production of PrP(Sc), allowing the molecular study of prion neuronal targeting in relation with strain differences. This new stem cell-based model, which is applicable to different species and to transgenic mice, will allow thoughtful investigations of the molecular basis of prion diseases, and will open new avenues for diagnostic and therapeutic research.