Spatial visualization of A-to-I Editing in cells using Endonuclease V Immunostaining Assay (EndoVIA).

Adenosine-to-Inosine (A-to-I) editing is one of the most widespread post-transcriptional RNA modifications and is catalyzed by adenosine deaminases acting on RNA (ADARs). Varying across tissue types, A-to-I editing is essential for numerous biological functions and dysregulation leads to autoimmune and neurological disorders, as well as cancer. Recent evidence has also revealed a link between RNA localization and A-to-I editing, yet understanding of the mechanisms underlying this relationship and its biological impact remains limited. Current methods rely primarily on in vitro characterization of extracted RNA that ultimately erases subcellular localization and cell-to-cell heterogeneity. To address these challenges, we have repurposed Endonuclease V (EndoV), a magnesium dependent ribonuclease that cleaves inosine bases in edited RNA, to selectively bind and detect A-to-I edited RNA in cells. The work herein introduces Endonuclease V Immunostaining Assay (EndoVIA), a workflow that provides spatial visualization of edited transcripts, enables rapid quantification of overall inosine abundance, and maps the landscape of A-to-I editing within the transcriptome at the nanoscopic level.

Untangling Macropore Formation and Current Facilitation in P2X7.

Macropore formation and current facilitation are intriguing phenomena associated with ATP-gated P2X7 receptors (P2X7). Macropores are large pores formed in the cell membrane that allow the passage of large molecules. The precise mechanisms underlying macropore formation remain poorly understood, but recent evidence suggests two alternative pathways: a direct entry through the P2X7 pore itself, and an indirect pathway triggered by P2X7 activation involving additional proteins, such as TMEM16F channel/scramblase. On the other hand, current facilitation refers to the progressive increase in current amplitude and activation kinetics observed with prolonged or repetitive exposure to ATP. Various mechanisms, including the activation of chloride channels and intrinsic properties of P2X7, have been proposed to explain this phenomenon. In this comprehensive review, we present an in-depth overview of P2X7 current facilitation and macropore formation, highlighting new findings and proposing mechanistic models that may offer fresh insights into these untangled processes.

Dyspnea-induced Limitation (DYSLIM), a new self-administered concise questionnaire to evaluate dyspnea-related activity limitation in chronic respiratory diseases.

BACKGROUND AND AIM: Few questionnaires are available for routine assessment of dyspnea. The study aimed to design a self-administered questionnaire assessing the impact of chronic dyspnea on daily activities, named DYSLIM (Dyspnea-induced Limitation). METHODS: The development followed 4 steps: 1: selection of relevant activities and related questions (focus groups); 2: clinical study: internal and concurrent validity vs. modified Medical Research Council (mMRC), Baseline Dyspnea Index (BDI) and Saint George Respiratory Questionnaire (SGRQ); 3: item reduction; 4: responsiveness. Eighteen activities (from eating to climbing stairs) were considered with 5 modalities for each: doing the task slowly, taking breaks, seeking assistance, changing habits, and activity avoidance. Each modality was graded from 5 (never) to 1 (very often). Validation study included 194 patients: COPD (FEV1 ≥ 50% pred: n = 40; FEV1 < 50% pred: n = 65); cystic fibrosis (n = 30), interstitial lung disease (n = 30), pulmonary hypertension (n = 29). Responsiveness was evaluated by post-pulmonary rehabilitation data in 52 COPD patients. RESULTS: Acceptability was high and short term (7 days) reproducibility was satisfactory (Kappa mostly above 0.7). Concurrent validity was high vs. mMRC (Spearman correlation coefficient, r = 0.71), BDI (r = - 0.75) and SGRQ (r = - 0.79). The reduced questionnaire with 8 activities (from cleaning to climbing stairs) and 3 modalities (slowly, seeking help, changing habits) showed a comparable validity and was chosen as the final short version. Effect size of rehabilitation was good for both the full (0.57) and short (0.51) versions. A significant correlation was also found between changes of SGRQ and DYSLIM post rehabilitation: r = - 0.68 and r = - 0.60 for full and reduced questionnaires, respectively. CONCLUSION: The DYSLIM questionnaire appears promising for the evaluation of dyspnea-induced limitations in chronic respiratory diseases and seems suitable for use in various contexts.

Keratoconus and the Impact of Treatment on Patients' Quality of Life: A Qualitative Study.

INTRODUCTION: Keratoconus has a significant impact on patients' quality of life (QoL), from diagnosis to the advanced stages of the disease. The aim of this research was to identify domains of QoL affected by this disease and its treatment. METHODS: Phone interviews were conducted using a semi-structured interview guide, with patients with keratoconus stratified according to their current treatment. A board of keratoconus experts helped identify the guide's main themes. RESULTS: Thirty-five patients (rigid contact lenses, n = 9; cross-linking, n = 9; corneal ring implants, n = 8; and corneal transplantation, n = 9) were interviewed by qualitative researchers. Phone interviews revealed several QoL domains affected by the disease and its treatments: "psychological", "social life", "professional life", "financial costs" and "student life". All domains were impacted, independently of the treatment history. Few differences were found between treatment regimens and keratoconus stages. Qualitative analysis enabled the development of a conceptual framework based on Wilson and Cleary's model for patient outcomes common to all patients. This conceptual model describes the relationship between patients' characteristics, their symptoms, their environment, their functional visual impairment and the impact on their QoL. CONCLUSIONS: These qualitative findings supported the generation of a questionnaire to evaluate the impact of keratoconus and its treatment on patients' QoL. Cognitive debriefings confirmed its content validity. The questionnaire is applicable for all stages of keratoconus and treatments and may help tracking change over time in regular clinical settings. Psychometric validation is yet to be performed before its use in research and clinical practices.

Tracking the Message: Applying Single Molecule Localization Microscopy to Cellular RNA Imaging.

RNA function is increasingly appreciated to be more complex than merely communicating between DNA sequence and protein structure. RNA localization has emerged as a key contributor to the intricate roles RNA plays in the cell, and the link between dysregulated spatiotemporal localization and disease warrants an exploration beyond sequence and structure. However, the tools needed to visualize RNA with precise resolution are lacking in comparison to methods available for studying proteins. In the past decade, many techniques have been developed for imaging RNA, and in parallel super resolution and single-molecule techniques have enabled imaging of single molecules in cells. Of these methods, single molecule localization microscopy (SMLM) has shown significant promise for probing RNA localization. In this review, we highlight current approaches that allow super resolution imaging of specific RNA transcripts and summarize challenges and future opportunities for developing innovative RNA labeling methods that leverage the power of SMLM.

Optical control of PIEZO1 channels.

PIEZO proteins are unusually large, mechanically-activated trimeric ion channels. The central pore features structural similarities with the pore of other trimeric ion channels, including purinergic P2X receptors, for which optical control of channel gating has been previously achieved with photoswitchable azobenzenes. Extension of these chemical optogenetics methods to mechanically-activated ion channels would provide tools for specific manipulation of pore activity alternative to non-specific mechanical stimulations. Here we report a light-gated mouse PIEZO1 channel, in which an azobenzene-based photoswitch covalently tethered to an engineered cysteine, Y2464C, localized at the extracellular apex of the transmembrane helix 38, rapidly triggers channel gating upon 365-nm-light irradiation. We provide evidence that this light-gated channel recapitulates mechanically-activated PIEZO1 functional properties, and show that light-induced molecular motions are similar to those evoked mechanically. These results push the limits of azobenzene-based methods to unusually large ion channels and provide a simple stimulation means to specifically interrogate PIEZO1 function.

Perceived Unmet Needs in Patients Living With Advanced Bladder Cancer and Their Caregivers: Infodemiology Study Using Data From Social Media in the United States.

BACKGROUND: Locally advanced or metastatic bladder cancer (BC), which is generally termed advanced BC (aBC), has a very poor prognosis, and in addition to its physical symptoms, it is associated with emotional and social challenges. However, few studies have assessed the unmet needs and burden of aBC from patient and caregiver perspectives. Infodemiology, that is, epidemiology based on internet health-related content, can help obtain more insights on patients' and caregivers' experiences with aBC. OBJECTIVE: The study aimed to identify the main discussion themes and the unmet needs of patients with aBC and their caregivers through a mixed methods analysis of social media posts. METHODS: Social media posts were collected between January 2015 and April 2021 from US geolocalized sites using specific keywords for aBC. Automatic natural language processing (regular expressions and machine learning) methods were used to filter out irrelevant content and identify verbatim posts from patients and caregivers. The verbatim posts were analyzed to identify main discussion themes using biterm topic modeling. Difficulties or unmet needs were further explored using qualitative research methods by 2 independent annotators until saturation of concepts. RESULTS: A total of 688 posts from 262 patients and 1214 posts from 679 caregivers discussing aBC were identified. Analysis of 340 randomly selected patient posts and 423 randomly selected caregiver posts uncovered 33 unique unmet need categories among patients and 36 among caregivers. The main unmet patient needs were related to challenges regarding adverse events (AEs; 28/95, 29%) and the psychological impact of aBC (20/95, 21%). Other patient unmet needs identified were prognosis or diagnosis errors (9/95, 9%) and the need for better management of aBC symptoms (9/95, 9%). The main unmet caregiver needs were related to the psychological impacts of aBC (46/177, 26.0%), the need for support groups and to share experiences between peers (28/177, 15.8%), and the fear and management of patient AEs (22/177, 12.4%). CONCLUSIONS: The combination of manual and automatic methods allowed the extraction and analysis of several hundreds of social media posts from patients with aBC and their caregivers. The results highlighted the emotional burden of cancer for both patients and caregivers. Additional studies on patients with aBC and their caregivers are required to quantitatively explore the impact of this disease on quality of life.

Development of the SPUR tool: a profiling instrument for patient treatment behavior.

BACKGROUND: Long-term treatment adherence is a worldwide concern, with nonadherence resulting from a complex interplay of behaviors and health beliefs. Determining an individual's risk of nonadherence and identifying the drivers of that risk are crucial for the development of successful interventions for improving adherence. Here, we describe the development of a new tool assessing a comprehensive set of characteristics predictive of patients' treatment adherence based on the Social, Psychological, Usage and Rational (SPUR) adherence framework. Concepts from existing self-reporting tools of adherence-related behaviors were identified following a targeted MEDLINE literature review and a subset of these concepts were then selected for inclusion in the new tool. SPUR tool items, simultaneously generated in US English and in French, were tested iteratively through two rounds of cognitive interviews with US and French patients taking long-term treatments for chronic diseases. The pilot SPUR tool, resulting from the qualitative analysis of patients' responses, was then adapted to other cultural settings (China and the UK) and subjected to further rounds of cognitive testing. RESULTS: The literature review identified 27 relevant instruments, from which 49 concepts were included in the SPUR tool (Social: 6, Psychological: 13, Usage: 11, Rational: 19). Feedback from US and French patients suffering from diabetes, multiple sclerosis, or breast cancer (n = 14 for the first round; n = 16 for the second round) indicated that the SPUR tool was well accepted and consistently understood. Minor modifications were implemented, resulting in the retention of 45 items (Social: 5, Psychological: 14, Usage: 10, Rational: 16). Results from the cognitive interviews conducted in China (15 patients per round suffering from diabetes, breast cancer or chronic obstructive pulmonary disease) and the UK (15 patients suffering from diabetes) confirmed the validity of the tool content, with no notable differences being identified across countries or chronic conditions. CONCLUSION: Our qualitative analyses indicated that the pilot SPUR tool is a promising model that may help clinicians and health systems to predict patient treatment behavior. Further steps using quantitative methods are needed to confirm its predictive validity and other psychometric properties.

Finalization and Validation of Questionnaire and Algorithm of SPUR, a New Adherence Profiling Tool.

Purpose: The SPUR (Social, Psychological, Usage and Rational) Adherence Profiling Tool is a recently developed adaptive instrument for assessing key patient-level drivers for non-adherence. This study describes the SPUR questionnaire's finalization and psychometric evaluation. Patients and Methods: Data were collected through an online survey among patients with type 2 diabetes included by general practitioners and diabetologists in France. The survey included four questionnaires, SPUR and three validated adherence measures: BMQ, MARS and ACCEPT. Item-level analysis and a partial credit model (PCM) were performed to refine the response option coding of SPUR items. The final item selection of SPUR was defined using a PCM and a principal component analysis (PCA). Construct validity, concurrent validity and known-groups validity were assessed on the final SPUR questionnaire. Results: A total of 245 patients (55% men, mean age of 63 years) completed the survey remotely and were included in this analysis. Refining response option coding allowed a better discrimination of patients on the latent trait. After item selection, a short, an intermediate, and a long form composed the final SPUR questionnaire. The short form will be used to screen patients for risk and then the other forms will allow the collection of further information to refine the risk assessment and decide the best levers for action. Results obtained were supportive of the construct validity of the forms. Their concurrent validity was demonstrated: moderate to high significant correlations were obtained with BMQ, MARS and ACCEPT scores. Their known-groups validity were shown with a logical pattern of higher scores obtained for patients considered non-adherent and significant differences between the scores obtained for patients considered adherent versus non-adherent. Conclusion: SPUR is a valid tool to evaluate the risk of non-adherence of patients, allowing effective intervention by providing insights into the respective individual reasons for lack of adherence.

Attitudes & behaviors toward the management of tobacco smoking patients: qualitative study with French primary care physicians.

BACKGROUND: Smoking cessation is a major public health issue. In France, primary care physicians (PCP) are the first contact points for tobacco management. The objective of this study was to understand how PCPs are involved in the management of smoking cessation: ownership, commitment, barriers. METHODS: A qualitative study was conducted using group and individual semi-structured techniques with PCPs. A thematic analysis of verbatim transcripts was performed to identify concepts and sub-concepts of interest. Saturation was evaluated retrospectively to ensure adequate sample size. RESULTS: A sample of 35 PCPs were interviewed, 31 in four focus groups and four in individual interviews. PCPs discussed their roles in the management of tobacco smoking cessation, including the different strategies they are using (e.g., Minimal Intervention Strategy, Motivational Interviewing), the multiple barriers encountered (e.g., lack of time, patients' resistance to medical advice), the support resources and the treatment and intervention they prescribed (e.g. nicotine replacement therapy, supporting therapist). CONCLUSIONS: This study provides a better understanding of the beliefs, attitudes, and behaviors of PCPs in managing smoking cessation. Guiding and encouraging patients toward smoking cessation remains a major objective of PCPs. While PCPs reported that progress has been made in recent years in terms of tools, technology and general awareness, they still face major barriers, some of which could be overcome by appropriate training.

Understanding disease symptoms and impacts and producing qualitatively-derived severity stages for MPS IIIA: a mixed methods approach.

BACKGROUND: MPS IIIA is a rare, degenerative pediatric genetic disease characterized by symptoms impacting cognition, mobility and behavior; the mean age of death is around 15 years of age. Currently, there are no approved therapies for MPS IIIA. METHODS: A two-year, multi-center, prospective, descriptive cohort study was conducted to document the natural history course of MPS IIIA. In the context of this study, semi-structured interviews were performed with parents of children at study entry and one year later. Interview transcripts were analyzed using thematic analysis methods to identity concepts of interest to children and parents, identify what factors impacted parents' burden the most, and develop qualitatively-derived disease severity stages. Children were sorted into these stages according to the symptoms their parents described at the entry interview. This sorting was compared quantitatively to the sorting of children at baseline according to the child's calendar age and their BSID development quotient (DQ). RESULTS: 22 parents in France, Germany, the Netherlands and the UK were interviewed. Children ranged in age from 28 to 105 months (mean 61.4 months). The conceptual models for children's symptoms and impacts and parents' impacts provided a detailed and comprehensive picture of what it is like for children of various ages and their parents to live with MPS IIIA. Four factors were identified as mediating the burden perceived by parents: state support, family support, time since diagnosis, and parent coping strategy. Four disease stages were developed, accounting for both the presence and the severity of MPS IIIA symptoms. The comparison of children's sorting into these stages with the BSID DQ and the child's calendar age showed strong statistical associations. CONCLUSIONS: The findings of this qualitative research embedded in a natural history study add to the current understanding of MPS IIIA as a complex disease that impacts every aspect of the lives of children and their families. This study demonstrates the unique potential of mixed methods research in rare diseases to address some of the current limitations of more traditional quantitative approaches by providing an individualized, detailed understanding of the patient experience.

The SPUR adherence profiling tool: preliminary results of algorithm development.

OBJECTIVE: The SPUR (Social, Psychological, Usage, and Rational) Adherence Profiling Tool is a recently developed adaptive instrument for measuring key patient-level risk factors for adherence problems. This study describes the SPUR questionnaire's psychometric refinement and evaluation. METHODS: Data were collected through an online survey among individuals with type 2 diabetes in the United States. 501 participants completed multiple questionnaires, including SPUR and several validated adherence measures. A Partial Credit Model (PCM) analysis was performed to evaluate the structure of the SPUR tool and verify the assumption of a single underlying latent variable reflecting adherence. Partial least-squares discriminant analyses (PLS-DA) were conducted to identify which hierarchically-defined items within each dimension needed to be answered by a given patient. Lastly, correlations were calculated between the latent trait of SPUR adherence and other patient-reported adherence measures. RESULTS: Of the 45 candidate SPUR items, 39 proved to fit well to the PCM confirming that SPUR responses reflected one underlying latent trait hypothesized as non-adherence. Correlations between the latent trait of the SPUR tool and other adherence measures were positive, statistically significant, and ranged from 0.32 to 0.48 (p-values < .0001). The person-item map showed that the items reflected well the range of adherence behaviors from perfect adherence to high levels of non-adherence. The PLS-DA results confirmed the relevance of using four meta-items as filters to open or close subsequent items from their corresponding SPUR dimensions. CONCLUSIONS: The SPUR tool represents a promising new adaptive instrument for measuring adherence accurately and efficiently using the digital behavioral diagnostic tool.

Development and validation of the Methotrexate Experience Questionnaire, a new methotrexate oral treatment adherence tool in rheumatoid arthritis.

OBJECTIVE: Despite the development of new biologic therapies, methotrexate (MTX) remains the preferred initial disease-modifying anti-rheumatic drug to treat rheumatoid arthritis (RA). Adherence to disease-modifying anti-rheumatic drugs is suspected to be highly variable potentially leading to reduced treatment effectiveness. This work aimed to develop and validate the Methotrexate Experience Questionnaire (MEQ), a tool to identify and characterize non-adherence to oral MTX. METHODS: MEQ development included a literature review and qualitative interviews with RA patients and physicians in the United States. A retrospective, cross-sectional study using data from Optimum Patient Care Research Database, a large primary care database of electronic medical records in the United Kingdom, was conducted to finalize the MEQ and evaluate its psychometric properties. RESULTS: Three hundred seven e-consented subjects (66% women, mean age of 65 years) completed the MEQ remotely, and were included in this analysis. Item-convergent and divergent validity were generally supportive of the construct validity of the MEQ and Cronbach's alpha of 0.87 supported its reliability. The MEQ Total score presented statistically significant correlations of small to medium size with all selected concurrent scales, as expected; the highest correlation was obtained between the general acceptance score of ACCEPT and the MEQ Total score (0.55, p < 0.001). Known-groups validity was demonstrated as a logical pattern of higher MEQ scores was obtained for patients considered adherent with both the 6- and 12-month Proportion of Days Covered (mean MEQ total score 82.7 for 12-month PDC ≥ 80% against 76.3 for 12-month PDC < 80%, p< 0.0001). Additionally, a pattern of lower MEQ scores was obtained for patients with more severe disease assessed with Routine Assessment of Patient Index Data 3. CONCLUSION: The 24-item MEQ is a reliable and valid instrument to assess the adherence of RA patients taking MTX, potentially improving over historical refill rate metrics by providing insights into the individual reasons for lack of adherence. This information should facilitate clinician-patient discussions and help inform treatment decisions.

To what degree are orphan drugs patient-centered? A review of the current state of clinical research in rare diseases.

BACKGROUND: Over the past 30 years, the healthcare industry has increasingly turned its attention to rare diseases. Regulators have emphasized the need for clinical research in this area to be patient-centered. However, there is a lack of evidence concerning whether this need is actually met. In this paper, we aim to address this gap. METHODS: First, we describe the state of patient-centricity in clinical research in rare diseases based on a targeted literature review. Second, we discuss recommendations from scientific bodies on patient-reported outcome (PRO) measures in rare diseases. Third, we analyze data collected from EMA's and FDA's websites concerning rare disease labeling claims and data from Clinicaltrials.gov concerning the use of PRO measures in rare disease pivotal trials. Fourth, we perform an exhaustive literature review on the use of PRO measures in the pharmaceutical industry, including all phases of clinical research, observational/registry studies, and instrument development and validation. RESULTS: There is limited information on rare disease patient engagement in study design, recruitment, and retention. None of the initiatives describing methods for developing PRO measures in rare diseases provide the clear guidance clinical researchers need. Only 17.4% of orphan drug labels contain a PRO measure. Less than half of pivotal trials in orphan drugs have a PRO measure as a primary or a secondary endpoint. Although the number of publications about PRO measures in rare diseases has risen in the past fifteen years, our results indicate that substantial improvements are needed to achieve patient-centricity. CONCLUSIONS: The nature and extent of patient engagement in rare disease research is under-documented. The current paradigm for developing and using PRO measures in clinical research is failing to meet the needs of rare disease patients. Not only are PROs rarely used as high-level endpoints in clinical trials or taken into account in labeling claims, they are also under-researched overall - there are too few measures for the multitude of rare diseases. We call for a clear guidance on patient engagement and suggest a realistic approach to the adaptation of PRO strategy to the specific context of clinical research in rare diseases.

Living with type I Usher syndrome: insights from patients and their parents.

BACKGROUND: Type 1 Usher syndrome (USH1) is a rare disease and major cause of genetic deaf-blindness. Deafness is present from birth while retinitis pigmentosa (RP) which typically presents during childhood is progressive leading to blindness. The aim of this research was to develop a disease model describing USH1 symptoms and their impact on patients' lives. MATERIALS AND METHODS: Qualitative interviews were conducted with patients (pediatric and adult) and parents of children and adolescents with USH1. Interviewed subjects were enrolled through ophthalmologists from specialized eye centers in the USA and in France. Trained interviewers used semi-structured techniques to elicit concepts relevant to patients and their parents. Thematic analysis of interview transcripts led to the identification of concepts which were organized to generate a disease model. RESULTS: A total of 18 patients (7 in the US; 11 in France)- 9 adults, 4 adolescents, and 5 children- and 9 mothers were interviewed. The most cited ocular symptoms were difficulty seeing at night and loss of peripheral vision. Interviewees reported limitations on Physical (e.g. difficulty moving), Mental (e.g. fear about falling), Social (e.g. difficulty discussing disease with others) and Role (e.g. difficulties at school/work) functioning. These impacts were, when possible, mitigated by coping strategies and support (e.g. using electronic devices, having a positive/proactive attitude). CONCLUSIONS: This research provides an overview of symptoms experienced by patients with USH1 and highlights the dramatic impact these have on patients' lives, allowing the identification of concepts of importance when evaluating therapeutic treatments in development for RP.

Diazaquinomycin Biosynthetic Gene Clusters from Marine and Freshwater Actinomycetes.

Tuberculosis is an infectious disease of global concern. Members of the diazaquinomycin (DAQ) class of natural products have shown potent and selective activity against drug-resistant Mycobacterium tuberculosis. However, poor solubility has prevented further development of this compound class. Understanding DAQ biosynthesis may provide a viable route for the generation of derivatives with improved properties. We have sequenced the genomes of two actinomycete bacteria that produce distinct DAQ derivatives. While software tools for automated biosynthetic gene cluster (BGC) prediction failed to detect DAQ BGCs, comparative genomics using MAUVE alignment led to the identification of putative BGCs in the marine Streptomyces sp. F001 and in the freshwater Micromonospora sp. B006. Deletion of the identified daq BGC in strain B006 using CRISPR-Cas9 genome editing abolished DAQ production, providing experimental evidence for BGC assignment. A complete model for DAQ biosynthesis is proposed based on the genes identified. Insufficient knowledge of natural product biosynthesis is one of the major challenges of productive genome mining approaches. The results reported here fill a gap in knowledge regarding the genetic basis for the biosynthesis of DAQ antibiotics. Moreover, identification of the daq BGC shall enable future generations of improved derivatives using biosynthetic methods.

Illustration of patient-reported outcome challenges and solutions in rare diseases: a systematic review in Cushing's syndrome.

Rare diseases are often not fully understood and efforts put in investigating it from patient perspective are usually met with challenges. We performed a systematic literature review (SLR) for the last 20 years in Cushing's Syndrome (CS) to illustrate Patient-Reported Outcome (PRO) challenges, and show what solutions were found.PROs and other Clinical Outcome Assessment (COA) used with CS patients were reviewed in 36 studies. Two CS-specific Health Related Quality of Life (HRQL) measures were identified (i.e., CushingQoL, Tuebingen CD-25), as well as depression and neurocognitive measures. For CS-specific HRQL measures, the CushingQoL was the most widely used measure due in part to being the first CS-specific HRQL measure developed. With algorithms mapping the CushingQoL to both the SF-6D and EQ-5D, the CushingQoL could be used to facilitate economic modelling studies in the absence of a generic HRQL measure. While the CushingQoL offers only the global scale and two subscales compared to the six subscales of the Tuebingen CD-25, there is not yet adequate statistical validation data available for the Tuebingen CD-25 to suggest it can withstand the scrutiny of review by multiple stakeholders. Results of this review indicate that the inclusion of a measure of depressive symptoms, such as the BDI-II or similar measure, would be reasonable to include given the high level of comorbidity of depression among CS patients. A brief neurocognitive performance outcome, such as Trail Making tasks A and D or Digit Symbol, could help inform the interpretation of HRQL results. Neurocognitive differences may be an unassessed mediator of HRQL outcomes, partly accounting for the persistence of depressive symptoms and HRQL deficits despite treatment. Results suggest that HRQL improvements are possible within this population. These results are limited by small sample sizes and pre/post study design.CS showcases the difficulties encountered in measuring PROs in rare diseases. A solution for this specific case was developed in the form of dedicated PRO instruments, the CushingQOL and the Tuebingen-25. However, some aspects of CS may not be fully answered or not yet validated (e.g., depressive and cognitive symptoms). Further research needs to be done to address them.

The multidimensional nature of dyspnoea in amyotrophic lateral sclerosis patients with chronic respiratory failure: Air hunger, anxiety and fear.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder leading to chronic respiratory failure. Few studies have investigated ALS-related dyspnoea, and none have characterised the emotional distress it inflicts. We hypothesised that ALS-related dyspnoea has a strong affective component that relates to quality of life. METHODS: This prospective, observational study was conducted in 41 ALS patients >18 with chronic respiratory failure and an indication for noninvasive ventilation (NIV). Dyspnoea was assessed using the Multidimensional Dyspnea Profile (MDP) at baseline and 1 month after NIV initiation. Correlations between scores evaluating the sensory and affective dimensions of dyspnoea and other patient-reported outcomes and pulmonary function tests were analysed. RESULTS: Dyspnoea was described as intense (median [IQR] score on a 0-10 scale: 6.5 [4.0-7.5]). The sensory dimension of dyspnoea was polymorphic, but «air hunger¼ was the most common (48.8%) and the most intense (6 [4-8]) sensory descriptor. In the affective domain, most patients rated «anxious¼ (85.4%) and «afraid¼ (60.9%) above 0. The MDP affective dimension correlated significantly with other patient-reported outcomes, with the strongest correlation being between MDP «anxious¼ and the anxiety component of the Hospital Anxiety Depression Scale (Pearson's R = 0.70). One month after initiation of NIV, dyspnoea during unassisted breathing was described in virtually the same terms, particularly the affective dimension. DISCUSSION: ALS-related dyspnoea is intense and fear-provoking, persists during unassisted breathing between NIV sessions, and significantly impacts health-related quality of life. This study highlights the need for increased awareness of and research into ALS-related dyspnoea.

Comparative effectiveness of avelumab versus chemotherapy in Merkel cell carcinoma: innovative use of patient insights.

AIM: To assess patient experience with chemotherapy and avelumab in metastatic Merkel cell carcinoma (mMCC). METHODS: In the JAVELIN Merkel 200 trial, chemotherapy-refractory mMCC patients could participate in optional qualitative interviews at baseline documenting recollection of previous chemotherapy experience, and at weeks 13/25 documenting current experience with avelumab. Functional Assessment of Cancer Therapy subscale for melanoma questionnaire (FACT-M) was administered in parallel. RESULTS: In our sample, chemotherapy was associated with an unpleasant experience. On selected FACT-M items addressing chemotherapy-impacted concepts, most patients receiving avelumab were improved or stable; few worsened. In addition, a few patients spontaneously reported experiencing less toxicity with avelumab than experienced during previous chemotherapy. CONCLUSION: This approach merging qualitative and quantitative data suggests that mMCC patients report a better experience with avelumab than with chemotherapy.

Assessing patients' acceptance of their medication to reveal unmet needs: results from a large multi-diseases study using a patient online community.

BACKGROUND: Patients with chronic conditions are required to take long-term treatments for their disease itself or to prevent any potential health risks. Measuring patient acceptance of their medication should help to better understand and predict patients' behavior toward treatment. This study aimed to describe the level of patient acceptance toward various long-term treatments in real life using an online patient community. METHODS: This was an observational, cross-sectional study conducted through the French Carenity platform. All Carenity patient members were invited to complete an online questionnaire including the 25-item ACCEptance by the Patients of their Treatment (ACCEPT©) questionnaire. ACCEPT© measures patient acceptance toward their medication and includes one general acceptance dimension (Acceptance/General) and six treatment-attribute specific dimensions (scores 0-100; lowest to highest acceptance): Acceptance/Medication Inconvenience, Acceptance/Long-term Treatment, Acceptance/Regimen Constraints, Acceptance/Side effects, Acceptance/Effectiveness, and Acceptance/Numerous Medications. Patients included in the analysis were treated adults experiencing any chronic diseases and who responded to at least one ACCEPT© item. RESULTS: Among the 4193 patients included in the analysis, more than 270 chronic diseases were represented, amidst which 19 included more than 30 patients. Mean ACCEPT© Acceptance/General score for those 19 diseases were 61.2 (SD = 31.9) for type 1 diabetes, 59.8 (SD = 32.3) for asthma, 56.3 (SD = 34.3) for hypertension, 52.0 (SD = 32.2) for chronic obstructive pulmonary disease, 51.7 (SD = 27.0) for epilepsy, 50.1 (SD = 33.1) for bipolar disorder, 49.9 (SD = 33.1) for type 2 diabetes, 48.6 (SD = 31.6) for multiple sclerosis, 46.1 (SD = 34.5) for Crohn's disease/ulcerative colitis, 44.3 (SD = 31.5) for depression, 42.8 (SD = 31.5) for lupus, 42.3 (SD = 33.0) for arthrosis, 41.8 (SD = 32.6) for Parkinson's disease, 40.5 (SD = 32.2) for rheumatoid arthritis, 38.6 (SD = 31.7) for breast cancer, 36.4 (SD = 36.4) for myocardial infarction, 35.8 (SD = 32.0) for ankylosing spondylitis, 34.1 (SD = 32.3) for psoriasis, and 33.7 (SD = 31.7) for fibromyalgia. CONCLUSIONS: This first of its kind study enabled ACCEPT© data to be collected in real life for a variety of chronic diseases. These data may help in evaluating and interpreting levels of acceptance in future studies and provide valuable insights about patient priorities and current unmet needs.