Definitions and assessments of recovery from gambling disorder: A scoping review.

Background and aims: While the concept of recovery is receiving increasing attention in the context of gambling disorder (GD), no consensus has yet been reached regarding its definition. This scoping review aims to map the literature on GD recovery, identify gaps, and provide insights for a more holistic and patient-centred perspective. Methods: A systematic search of three databases was conducted (PubMed, PsycINFO, and ScienceDirect). Based on the method by which the results of these studies were produced, the studies included were sorted into four categories (quantitative, instrument validation, qualitative, and mixed studies) and subsequently examined using conceptual analysis. Results: One hundred thirteen articles were included in this research after the screening process. In the quantitative and instrument validation studies, recovery was defined or operationalized in terms of abstinence, the absence of a GD diagnosis, or mild GD severity, or by reference to treatment outcomes or controlled gambling. A meta-synthesis of the results of the qualitative studies revealed four core features of recovery (insight, empowerment and commitment, wellbeing enhancement, and reconsideration of the issue of relapse). Discussion: Discrepancies in definitions, outcomes, and variables used were evident across studies. Additionally, the quantitative and standardized approaches employed in most studies exhibited severe limitations with regard to defining recovery from the subjective and multidimensional perspectives of people recovering from GD. Conclusions: This lack of definitional clarity emphasizes the necessity for further qualitative research. This research should encompass multiple stakeholder perspectives to develop a working definition promoting recovery from a holistic, patient-centred, and tailored approach.

Translation, validity and reliability of the pain attitudes and beliefs scale for physiotherapists in French.

BACKGROUND: The Pain Attitudes and Beliefs Scale for Physiotherapists (PABS-PT) questionnaire evaluates manual therapists' biomedical and biopsychosocial beliefs regarding the management of chronic low back pain. Its usage in clinical settings is an important step in the implementation of national guidelines and policies to improve patient management. OBJECTIVES: The objective of this study was to translate the PABS-PT questionnaire into French, to adapt it culturally, and to conduct a psychometric analysis. DESIGN: Qualitative and cross-sectional study. METHOD: The translation process followed published guidelines with cross-cultural validation by an expert committee. We followed a forward and backward translation procedure and an expert committee, including the original author of the questionnaire and a linguistics expert ensuring good cultural adaptation, issued a finalised version. Psychometric analysis of the French version of the questionnaire was conducted among 390 French manual therapists in two phases. The first phase evaluated structural validity as well as external validity compared with the TSK and BBQ questionnaires. Then, reliability and scalability were analysed. The second phase evaluated test-retest reproducibility by sending the same questionnaire 3 months later. RESULTS: The validity study revealed three subscales: the classic biomedical subscale and two subscales for biopsychosocial beliefs (aetiology of pain and physical activity). With 21 items in total for the PABS-PT-FR, the structural validity scores were good (BM: alpha = 0.82, H = 0.38; Physical Activity: alpha = 0.62, H = 0.32; Aetiology of Pain: alpha = 0.55, H = 0.29). CONCLUSIONS: This study provides a validated tool to assess French physiotherapists' and, more generally, healthcare providers' beliefs about chronic low back pain, with a new insight into the BPS subscale internal construct.

Equating and linking Patient-Reported Outcomes Measurement Information System 29-item questionnaire and 36-item Short-Form Health Survey domains using Rasch modeling.

OBJECTIVES: To develop a simple, practical methodology to equate or link equivalent domains of the 36-item Short-Form Health Survey (SF-36) and the Patient-Reported Outcomes Measurement Information System 29-item questionnaire (PROMIS-29) using the Rasch framework. STUDY DESIGN AND SETTING: In April 2016, the PROMIS-29 and SF-36 were completed by 1501 individuals selected to be representative of the French population. For each domain common to the two questionnaires, a Partial Credit Model was fitted to the items related to that dimension in the two questionnaires. These items were then calibrated on the same metric, which enabled the scores from one questionnaire to be associated with the scores from the other. RESULTS: Six of the seven PROMIS-29 scales and five of the six SF-36 subscales (physical, pain, social, vitality, depression and anxiety domains) were equated or linked. Correspondence tables between scores, with a 95% confidence interval, were established for each domain. A freely available Stata macro program was developed to automatize the equating or linking process. CONCLUSION: These results should facilitate comparisons across studies using the SF-36 and the PROMIS-29 in France. The equating or linking process developed is simple to implement and can be used in other countries and for other instruments.

Efficacy and comparison of corticosteroids only and corticosteroids with plasmapheresis or intravenous immunoglobulin for the treatment of optic neuritis in demyelinating disease: A systematic review and network meta-analysis.

PURPOSE: To compare the efficacy of treatment of optic neuritis (ON) with corticosteroids (CTC) alone, CTC+plasmapheresis (PLP), and CTC+intravenous immunoglobulin (IVIG). DESIGN: After an episode of ON, although visual recovery is usually good, some patients may have significant visual sequelae. While the efficacy of first-line CTC is now indisputable, there is no consensus on the nature of second-line treatment. To date, no systematic review has compared the efficacy of treatment of ON with CTC alone, CTC+plasmapheresis (PLP), and CTC+intravenous immunoglobulin (IVIG). A meta-analysis is needed to compare the efficacy of PLP and IVIG in steroid-resistant ON. METHODS: This systematic review included all studies comparing at least two of the three treatments for steroid-resistant ON (CTC alone, CTC+PLP, and CTC+IVIG). From all articles published on PubMed between January 2000 and June 2022, two independent ophthalmologists selected studies of interest using the PRISMA method. Methodology, patient characteristics, and outcomes were identified. A network metaanalysis was then performed to compare the efficacy of the three treatments. RESULTS: Six comparative studies were included, representing 209 patients. The percentage of significant visual recovery after CTC alone, CTC+PLP, and CTC+IVIG in the acute treatment of steroid-resistant ON was 30 %, 45 %, and 77 %, respectively. Comparison of CTC+IVIG vs CTC alone, CTC+PLP vs CTC only, and CTC+PLP vs CTC+IVIG yielded odds ratios of 12.81, 2.47, and 0.19 respectively. CONCLUSION: Treatment of steroid-resistant ON with CTC+PLP or CTC+IVIG is more effective than treatment with CTC alone. Although no study has directly compared the two treatments, IVIG may be more effective than PLP.

Parkinson's Disease, Impulsive-Compulsive Behaviors, and Health-Related Quality of Life.

OBJECTIVE: A large body of literature has examined the links between the use of dopamine replacement therapy (DRT) in Parkinson's disease (PD) and the development of "impulsive-compulsive behaviors (ICBs)." Little is known regarding the link between the development of ICBs and health-related quality of life (HRQOL). We aimed to explore the factors that are associated with poorer HRQOL, especially in relation to DRT-induced ICBs, in a sample of PD patients. METHODS: This PARKADD (PARK: PARKinson's disease; ADD: behavioral ADDictions) study was a prospective case‒control study initially designed to assess the factors associated with ICBs in PD patients. A prospective clinical follow-up was added, aiming to capture the long-term evolution of HRQOL in relation to ICBs occurring or worsening after the beginning of PD. We focused on sociodemographic and PD characteristics and the history or presence of ICBs. HRQOL was measured using the Parkinson's Disease Questionnaire-8. A multivariate linear regression was performed to identify factors related to poorer HRQOL. RESULTS: A total of 169 patients were eligible for the follow-up study. The presence of an ICB, a higher levodopa equivalent daily dose (LEDD) and a longer PD duration were significantly associated with poorer HRQOL, with an interaction between LEDD and PD duration. CONCLUSION: The presence of an ICB was related to poorer HRQOL and should be considered a crucial factor for the management of PD patients. Several studies were recently published that provide guidelines for the management of these patients, with recommendations based on two key principles: prevention and specific treatment.

Identification of sources of DIF using covariates in patient-reported outcome measures: a simulation study comparing two approaches based on Rasch family models.

When analyzing patient-reported outcome (PRO) data, sources of differential item functioning (DIF) can be multiple and there may be more than one covariate of interest. Hence, it could be of great interest to disentangle their effects. Yet, in the literature on PRO measures, there are many studies where DIF detection is applied separately and independently for each covariate under examination. With such an approach, the covariates under investigation are not introduced together in the analysis, preventing from simultaneously studying their potential DIF effects on the questionnaire items. One issue, among others, is that it may lead to the detection of false-positive effects when covariates are correlated. To overcome this issue, we developed two new algorithms (namely ROSALI-DIF FORWARD and ROSALI-DIF BACKWARD). Our aim was to obtain an iterative item-by-item DIF detection method based on Rasch family models that enable to adjust group comparisons for DIF in presence of two binary covariates. Both algorithms were evaluated through a simulation study under various conditions aiming to be representative of health research contexts. The performance of the algorithms was assessed using: (i) the rates of false and correct detection of DIF, (ii) the DIF size and form recovery, and (iii) the bias in the latent variable level estimation. We compared the performance of the ROSALI-DIF algorithms to the one of another approach based on likelihood penalization. For both algorithms, the rate of false detection of DIF was close to 5%. The DIF size and form influenced the rates of correct detection of DIF. Rates of correct detection was higher with increasing DIF size. Besides, the algorithm fairly identified homogeneous differences in the item threshold parameters, but had more difficulties identifying non-homogeneous differences. Over all, the ROSALI-DIF algorithms performed better than the penalized likelihood approach. Integrating several covariates during the DIF detection process may allow a better assessment and understanding of DIF. This study provides valuable insights regarding the performance of different approaches that could be undertaken to fulfill this aim.

Taste and smell alterations affect nutritional status in children under chemotherapy.

AIM: This study aimed to evaluate the incidence of self-reported taste and smell alterations (TSA) in cancer paediatric patients and evaluate the impact of TSA on nutritional status in this population. We also developed and validated a composite score to detect TSA in children undergoing chemotherapy. METHODS: Paediatric patients who were undergoing chemotherapy in a paediatric oncology unit were included. TSA were assessed from the Gustonco questionnaire from which a composite score was developed and internally validated, eating behaviour was assessed using Child Eating Behaviour Questionnaire, and major weight loss was defined from nutritional status. All data were calculated at 1, 3 and 6 months after chemotherapy start. Associations between nutritional status and scores were studied by using logistic models. RESULTS: Among 49 patients included, TSA occurred in 71.7% of patients at 1 month after chemotherapy start and persisted at 3 and 6 months. TSA led to altered appetite since 1 month after chemotherapy start. The occurrence of a major weight loss at 6 months seemed to be associated with a high Gustonco score. CONCLUSION: Taste and smell alterations often occurred in paediatric cancer patients after chemotherapy start and seemed to be associated with impaired nutrition at 6 months after chemotherapy.

French translation and validation of the cross-cultural adaptation of the MSTS functional assessment questionnaire completed after tumor surgery.

INTRODUCTION: Malignant tumors of the extremities are uncommon. Their surgical treatment, whether conservative or not, may cause sequelae. Functional assessment of patients is essential for research purposes, but also follow-ups and adaptation of treatments. The Musculoskeletal Tumor Society Rating Scale (MSTS) is a disease-specific functional scoring system often used in English literature. Currently, no studies have been published on a valid French translation of the MSTS, whether for the lower or upper extremities. We, therefore, conducted a prospective study to answer the following questions: (1) Are the proposed adapted French versions of the MSTS valid? (2) Do the psychometric properties of the two versions obtained make their use relevant? MATERIALS AND METHODS: The translation and cross-cultural adaptation were carried out following the recommendations of Beaton and Guillemin to obtain two versions: one for patients who had undergone upper extremity surgery (MSTS-UE) and one for those who had undergone lower extremity surgery (MSTS-LE). A prospective multicenter cohort study was then carried out to analyze the psychometric properties of these two versions. RESULTS: A total of 250 patients from 3 referral centers were enrolled in this study. A confirmatory factor analysis (CFA) demonstrated that the two French versions of the MSTS (MSTS-LE and MSTS-UE) were a good fit with a root mean square error of approximation (RMSEA)<0.08 and a comparative fit index (CFI)>0.90. The psychometric properties of the two versions were validated with internal consistency (Cronbach alpha>0.7), convergent validity of each item with its score (> 0.4), and sufficient criterion validity (Pearson correlation coefficient>0.4). The discriminant validity analysis showed that there was a significant correlation between each version and the performance status (PS) (p<0.05). CONCLUSION: This study produced a French version of the MSTS scoring system and validated the psychometric properties of the two versions obtained (MSTS-UE and MSTS-LE). Therefore, the French MSTS scoring system is a valid measurement that can be used in international studies. LEVEL OF EVIDENCE: I.

Intravenous acetaminophen with morphine versus intravenous morphine alone for acute pain in the emergency room: protocol for a multicenter, randomized, placebo-controlled, double-blinded study (ADAMOPA).

BACKGROUND: In emergency medicine, pain is a frequent reason for consultation. However, there is a great variation in its management which is often insufficient. The use intravenous morphine alone or multimodal analgesia with paracetamol is recommended for severe pain. But robust data are lacking to justify the association of paracetamol with morphine versus morphine alone for pain management in the emergency room (ER). The aim of our study is therefore to assess if in patients with acute pain of moderate to severe intensity with a numerical verbal scale (NVS) ≥5 in the ER, the intravenous administration of morphine alone is not inferior to the administration of intravenous morphine combined with paracetamol at 30 min from the first administration of the study drug. METHODS: ADAMOPA is a prospective, non-inferiority, multicenter, placebo-controlled, parallel-group, randomized (1:1), double-blind trial. Subjects will be enrolled in the ER if they experience moderate to severe, acute, non-traumatic, and traumatic pain, defined as an NVS ≥5. The primary endpoint will be the between-group difference in mean change in NVS pain scores among patients receiving the combination of intravenous morphine plus paracetamol or intravenous morphine given alone, measured from the time before administration of the study medication to 30 min later. DISCUSSION: This trial will determine the clinical utility of the association of paracetamol with morphine for pain management in the emergency room. The ADAMOPA trial will be conducted in accordance with the International Council on Harmonization Good Clinical Practices. TRIAL REGISTRATION: EudraCT number: 2019-002149-39. CLINICALTRIALS: gov identifier: NCT04148495. Date of trial registration: November 1, 2019.

Posttraumatic growth inventory: challenges with its validation among French cancer patients.

BACKGROUND: The Posttraumatic growth inventory (PTGI) aims to assess the positive psychological changes that individuals can perceive after a traumatic life event such as a cancer diagnosis. Several French translations of the PTGI have been proposed, but comprehensive data on their psychometric properties are lacking. This study aimed to provide a more complete assessment of the psychometric properties of one of the most used PTGI translations in early-stage breast cancer and melanoma patients. METHODS: A sample of 379 patients completed the PTGI two years after their cancer diagnosis. A confirmatory analysis was first performed to determine whether the initial five-factor structure of the PTGI was adequate for this French version. As issues were identified in the translation and in the questionnaire structure, we performed an exploratory analysis to determine the most suitable structure for this questionnaire. Validity and reliability of the evidenced structured were then assessed. RESULTS: The exploratory analysis evidenced a four-factor structure close to the initial structure: four of the five initial domains were recovered, and items from the unrecovered domain were split into the other domains. This new structure showed good internal consistency and acceptable validity. CONCLUSIONS: This study highlights that the process of translation and cross-cultural validation of questionnaires is crucial to obtain valid and reliable psychometric instruments. We advise French psycho-oncology researchers and psychotherapists to (i) use the revised translation of Lelorain et al. (2010) proposed in this manuscript and (ii) use the four scores newly evidenced with a grouping of two response categories.

Development and validation of a prediction model for online gambling problems based on players' account data.

Background and aims: Gambling disorder is characterized by problematic gambling behavior that causes significant problems and distress. This study aimed to develop and validate a predictive model for screening online problem gamblers based on players' account data. Methods: Two random samples of French online gamblers in skill-based (poker, horse race betting and sports betting, n = 8,172) and pure chance games (scratch games and lotteries, n = 5,404) answered an online survey and gambling tracking data were retrospectively collected for the participants. The survey included age and gender, gambling habits, and the Problem Gambling Severity Index (PGSI). We used machine learning algorithms to predict the PGSI categories with gambling tracking data. We internally validated the prediction models in a leave-out sample. Results: When predicting gambling problems binary based on each PGSI threshold (1 for low-risk gambling, 5 for moderate-risk gambling and 8 for problem gambling), the predictive performances were good for the model for skill-based games (AUROCs from 0.72 to 0.82), but moderate for the model for pure chance games (AUROCs from 0.63 to 0.76, with wide confidence intervals) due to the lower frequency of problem gambling in this sample. When predicting the four PGSI categories altogether, performances were good for identifying extreme categories (non-problem and problem gamblers) but poorer for intermediate categories (low-risk and moderate-risk gamblers), whatever the type of game. Conclusions: We developed an algorithm for screening online problem gamblers, excluding online casino gamblers, that could enable the setting of prevention measures for the most vulnerable gamblers.

Parkinson's disease and iatrogenic impulsive-compulsive behaviors: A case/non-case study to build a complete model of individual vulnerability.

Background and aims: Parkinson's disease (PD) is one of the most prevalent neurodegenerative diseases. First-line medications consist of drugs that act by counteracting dopamine deficiency in the basal ganglia. Unfortunately, iatrogenic impulsive-compulsive behaviors (ICBs) can occur in up to 20% of PD patients over the course of their illness. ICBs must be considered multifactorial disorders that reflect the interactions of the medication with an individual's vulnerability and the underlying neurobiology of PD. We aimed to explore the predictive genetic, psychopathological and neurological factors involved in the development of ICBs in PD patients by building a complete model of individual vulnerability. Methods: The PARKADD study was a case/non-case study. A total of 225 patients were enrolled ("ICB" group, N = 75; "no ICB" group, N = 150), and 163 agreed to provide saliva samples for genetic analysis. Sociodemographic, neurological and psychiatric characteristics were assessed, and genotyping for the characterization of polymorphisms related to dopaminergic and opioid systems was performed. Results: Factors associated with "ICBs" were younger age of PD onset, personal history of ICB prior to PD onset and higher scores on the urgency and sensation seeking facets of impulsivity. No gene variant was significantly associated, but the association with the opioid receptor mu 1 (OPRM1) rs1799971 polymorphism was close to significance. Discussion and conclusions: The influence of gene-environment interactions probably exists, and additional studies are needed to decipher the possible role of the opioid system in the development of ICBs in PD patients.

Evaluating the impact of calibration of patient-reported outcomes measures on results from randomized clinical trials: a simulation study based on Rasch measurement theory.

BACKGROUND: Meaningfully interpreting patient-reported outcomes (PRO) results from randomized clinical trials requires that the PRO scores obtained in the trial have the same meaning across patients and previous applications of the PRO instrument. Calibration of PRO instruments warrants this property. In the Rasch measurement theory (RMT) framework, calibration is performed by fixing the item parameter estimates when measuring the targeted concept for each individual of the trial. The item parameter estimates used for this purpose are typically obtained from a previous "calibration" study. But imposing this constraint on item parameters, instead of freely estimating them directly in the specific sample of the trial, may hamper the ability to detect a treatment effect. The objective of this simulation study was to explore the potential negative impact of calibration of PRO instruments that were developed using RMT on the comparison of results between treatment groups, using different analysis methods. METHODS: PRO results were simulated following a polytomous Rasch model, for a calibration and a trial sample. Scenarios included varying sample sizes, with instrument of varying number of items and modalities, and varying item parameters distributions. Different treatment effect sizes and distributions of the two patient samples were also explored. Cross-sectional comparison of treatment groups was performed using different methods based on a random effect Rasch model. Calibrated and non-calibrated approaches were compared based on type-I error, power, bias, and variance of the estimates for the difference between groups. RESULTS: There was no impact of the calibration approach on type-I error, power, bias, and dispersion of the estimates. Among other findings, mistargeting between the PRO instrument and patients from the trial sample (regarding the level of measured concept) resulted in a lower power and higher position bias than appropriate targeting. CONCLUSIONS: Calibration does not compromise the ability to accurately assess a treatment effect using a PRO instrument developed within the RMT paradigm in randomized clinical trials. Thus, given its essential role in producing interpretable results, calibration should always be performed when using a PRO instrument developed using RMT as an endpoint in a randomized clinical trial.

Exploring the Personal Recovery Construct in Bipolar Disorders: Definition, Usage and Measurement. A Systematic Review.

Personal recovery from psychiatric disorders is a journey toward a satisfying and hopeful life despite the possible persistence of symptoms. This concept has gained interest and become an increasingly important goal in mental health care programmes. Personal Recovery is well described in the context of severe mental illnesses in general, but little is known about this journey in bipolar disorders and the factors underlying it. A systematic review was conducted according to the PRISMA recommendations, focusing on studies exploring personal recovery in bipolar disorder specifically. The latter have integrated a comprehensive approach to the concept, the existing means of measurement or have explored the levers of recovery in care. Twenty-four articles were selected, including seven qualitative, 12 observational, and five interventional studies. The Bipolar Recovery Questionnaire was the only scale developed de novo from qualitative work with bipolar people. Personal recovery did not correlate very closely with symptomatology. Some elements of personal recovery in bipolar disorder were similar to those in other severe mental illnesses: meaning in life, self-determination, hope, and low self-stigma. Specific levers differed: mental relationships with mood swings, including acceptance and decrease in hypervigilance, and openness to others, including trust and closeness. The studies highlighted the role of caregiver posture and the quality of communication within care, as well as the knowledge gained from peers. The choice to exclude articles not focused on bipolar disorder resulted in the provision of very specific information, and the small number of articles to date may limit the scope of the evidence. New components of personal recovery in bipolar disorder emerged from this review; these components could be taken into account in the construction of care tools, as well as in the caregiving posture. Strengthening skills of openness to others could also be a central target of recovery-focused care.

How do people who use drugs receiving Opioid Medication Therapy perceive their treatment ? A multicentre study.

BACKGROUND: The resurgence of heroin use and the misuse of pharmaceutical opioids are some of the reasons for a worldwide increase in opioid dependence. Opioid Medication Therapies (OMT) have amply demonstrated their efficacy. From a medical point of view, the main objectives of OMT concern medical and social outcomes, centred on risk reduction and the cessation of opioid use. But patient points of view can differ and few studies have explored opioid-dependent patient viewpoints on their OMT. This variable seems important to consider in a patient-centred approach. The aim of our study was to explore points of view of people who use drugs (PWUD) treated with OMT, in a large multicentre sample. METHOD: A cross-sectional multicentre study explored the points of view of PWUD with Opioid Use Disorder following OMT. Data regarding the patients' points of view were collected using a self-administered questionnaire developed by the scientific committee of the study. A descriptive analysis and an exploratory factor analysis were performed to explore the structure of items exploring patient viewpoints. RESULTS: 263 opioid dependent PWUD were included, a majority were men consuming heroin prior to being prescribed OMT. 68% were on methadone, 32% were on buprenorphine. Most PWUD identified a positive impact on their lives, with 92.8% agreeing or strongly agreeing that OMT had changed a lot of things in their lives. The exploratory factor analysis identified three factors: (F1) items related to points of views concerning the objectives and efficacy of OMT; (F2) items related to the legitimacy of OMT as a treatment compared to a drug, (F3) items related to experiences and relationships with OMT. CONCLUSION: Patient viewpoints on efficacy were correlated with the pharmacological benefits of OMT and with the associated psychosocial measures. The implications of OMT in relationships, such as the feeling of being judged, concerned a majority. Points of view were ambivalent concerning the role of OMT as a treatment or as a drug. Involving patient points of view in therapeutic strategies decisions could help enhance positive views among PWUD on OMT and help PWUD towards their recovery. TRIAL REGISTRATION: OPAL study was registered: (NCT01847729).

Evaluation of the Post-COVID-19 Functional Status (PCFS) Scale in a cohort of patients recovering from hypoxemic SARS-CoV-2 pneumonia.

INTRODUCTION: COVID-19 sequelae are numerous and multisystemic, and how to evaluate those symptomatic patients is a timely issue. Klok et al proposed the Post-COVID-19 Functional Status (PCFS) Scale as an easy tool to evaluate limitations related to persistent symptoms. Our aim was to analyse PCFS Scale ability to detect functional limitations and its correlation with quality of life in a cohort of patients, 2-9 months after hospitalisation for COVID-19 hypoxemic pneumonia. METHODS: PCFS Scale was evaluated in 121 patients together with quality of life and dyspnoea questionnaires, pulmonary function tests and CT scans. RESULTS: We observed a high correlation with multiple questionnaires (Short Form-36, Hospital Anxiety and Depression Scale, modified Medical Research Council, end Borg Six-Minute Walk Test), making the PCFS Scale a quick and global tool to evaluate functional limitations related to various persistent symptoms following COVID-19 pneumonia. DISCUSSION: The PCFS Scale seems to be a suitable instrument to screen for patients who will require careful follow-up after COVID-19 hypoxemic pneumonia even in the absence of pulmonary sequelae.

Toward a rigorous assessment of the statistical performances of methods to estimate the Minimal Important Difference of Patient-Reported Outcomes: A protocol for a large-scale simulation study.

Interpreting observed changes over time in Patient-Reported Outcomes (PRO) measures is still considered a challenge. Indeed, concluding an observed change at group level is statistically significant does not necessarily equate this change is meaningful from the perspective of the patient. To help interpret within and/or between group changes in the measure over time, the estimation of the Minimal Important Difference (MID) of the instrument - the smallest value that patients consider as a perceived change - is useful. In the last 30 years, a plethora of methods and estimators have been proposed to derive this MID value using clinical data from sample of patients. MIDs for hundreds of PROs have been estimated, with frequently a substantial variability in the results depending on the method used. Nonetheless, a rigorous assessment of the statistical performances of numerous proposed methods for estimating MIDs by experimental design such as Monte-Carlo study has never been performed. The purpose of this paper is to thoroughly depict a protocol for a large-scale simulation study designed to investigate the statistical performances, especially bias against a true populational value, of the common proposed estimators for MID. This paper depicts how investigated methods and estimators were retained after the conduct of a systematic review, the design of a conceptual model that formally defines what is the true populational MID value and the translation of the conceptual model into a model allowing the simulation of responses of items to a hypothetical PRO at two times of measurement along with the response to a Patient Global Rating of Change at the second time under the constraint of a known true MID value. A statistical analysis plan is depicted in order to conclude if working hypotheses on what could be appropriate MID estimators will be verified. Strengths, assumptions, and limits of the simulation model are exposed. Finally, we show how this protocol could be the basis for fostering future methodological research on the issue of interpreting changes in PRO measures.

Impact of TR34/L98H, TR46/Y121F/T289A and TR53 Alterations in Azole-Resistant Aspergillus fumigatus on Sterol Composition and Modifications after In Vitro Exposure to Itraconazole and Voriconazole.

BACKGROUND: Sterols are the main components of fungal membranes. Inhibiting their biosynthesis is the mode of action of azole antifungal drugs that are widely used to treat fungal disease including aspergillosis. Azole resistance has emerged as a matter of concern but little is known about sterols biosynthesis in azole resistant Aspergillus fumigatus. METHODS: We explored the sterol composition of 12 A. fumigatus isolates, including nine azole resistant isolates with TR34/L98H, TR46/Y121F/T289A or TR53 alterations in the cyp51A gene and its promoter conferring azole resistance. Modifications in sterol composition were also investigated after exposure to two azole drugs, itraconazole and voriconazole. RESULTS: Overall, under basal conditions, sterol compositions were qualitatively equivalent, whatever the alterations in the target of azole drugs with ergosterol as the main sterol detected. Azole exposure reduced ergosterol composition and the qualitative composition of sterols was similar in both susceptible and resistant isolates. Interestingly TR53 strains behaved differently than other strains. CONCLUSIONS: Elucidating sterol composition in azole-susceptible and resistant isolates is of interest for a better understanding of the mechanism of action of these drugs and the mechanism of resistance of fungi.

Feasibility of Combining Transcranial Direct Current Stimulation and Active Fully Embodied Virtual Reality for Visual Height Intolerance: A Double-Blind Randomized Controlled Study.

BACKGROUND: Transcranial Direct Current Stimulation (tDCS) and Virtual Reality Exposure Therapy (VRET) are individually increasingly used in psychiatric research. OBJECTIVE/HYPOTHESIS: Our study aimed to investigate the feasibility of combining tDCS and wireless 360° full immersive active and embodied VRET to reduce height-induced anxiety. METHODS: We carried out a pilot randomized, double-blind, controlled study associating VRET (two 20 min sessions with a 48 h interval, during which, participants had to cross a plank at rising heights in a building in construction) with online tDCS (targeting the ventromedial prefrontal cortex) in 28 participants. The primary outcomes were the sense of presence level and the tolerability. The secondary outcomes were the anxiety level (Subjective Unit of Discomfort) and the salivary cortisol concentration. RESULTS: We confirmed the feasibility of the association between tDCS and fully embodied VRET associated with a good sense of presence without noticeable adverse effects. In both groups, a significant reduction in the fear of height was observed after two sessions, with only a small effect size of add-on tDCS (0.1) according to the SUD. The variations of cortisol concentration differed in the tDCS and sham groups. CONCLUSION: Our study confirmed the feasibility of the association between wireless online tDCS and active, fully embodied VRET. The optimal tDCS paradigm remains to be determined in this context to increase effect size and then adequately power future clinical studies assessing synergies between both techniques.