Outcome Measure In Clinical Trials Research Articles

A cross-sectional study on the application of patient-reported outcome measurements in clinical trials of traditional Chinese medicine in mainland China.

Objectives: Patient-reported outcomes (PROs) provide a global perspective of patient health status which plays an enormous role in evaluating clinical efficacy. However, the application of PROs in traditional Chinese medicine (TCM) was still insufficiently studied in mainland China. Methods: This cross-sectional study was performed based on interventional clinical trials of TCM that were conducted in mainland China from 1 January 2010, to 15 July 2022. Data was retrieved from the ClinicalTrials.gov and Chinese Clinical Trial Registry. We included interventional clinical trials of TCM for which the country of the primary sponsors or recruitment settings in mainland China. For each included trial, data including clinical trial phases, study settings, participant's age, sex, diseases, and the patient-reported outcome measures (PROMs) were extracted. Trials were categorized into four categories according to 1) listed PROs as primary endpoints, 2) listed PROs as secondary endpoints, 3) listed PROs as coprimary outcomes (both primary and secondary endpoints), and 4) did not mention any PROMs. Results: Among a total of 3,797 trials, 680 (17.9%) trials listed PROs as primary endpoints, 692 (18.2%) trials listed PROs as secondary endpoints, and 760 (20.0%) trials listed PROs as coprimary endpoints. Among 675,787 participants included in the registered trials, 448,359 (66.3%) patients' data were scientifically collected by PRO instruments. Neurological diseases (11.8%), musculoskeletal symptoms (11.5%), mental health conditions (9.1%) were the most common conditions evaluated by PROMs. Disease-specific symptoms related concepts were used most frequently (51.3%), followed by health-related quality of life concepts. Visual analog scale, 36-item Short-Form Health Questionnaire, and TCM symptom score were the most common PROMs in these trials. Conclusion: In this cross-sectional study, the use of PROs increased in the past decades according to clinical trials of TCM conducted in mainland China. Considering that the application of PROs in clinical trials of TCM has some existing issues including uneven distribution and lack of normalized PROs of TCM, further study should be focused on the standardization and normalization of TCM-specific scales.

Interobserver Agreement on Intracranial Hemorrhage on Magnetic Resonance Imaging in Patients With Ischemic Stroke.

The Heidelberg Bleeding Classification, developed for computed tomography, is also frequently used to classify intracranial hemorrhage (ICH) on magnetic resonance imaging. Additionally, the presence of any ICH is frequently used as (safety) outcome measure in clinical stroke trials that evaluate acute interventions. We assessed the interobserver agreement on the presence of any ICH and the type of ICH according to the Heidelberg Bleeding Classification on magnetic resonance imaging in patients treated with reperfusion therapy. We used 300 magnetic resonance imaging scans including susceptibility-weighted imaging or T2*-weighted gradient echo imaging of ischemic stroke patients within 1 week after reperfusion therapy. Six observers, blinded to clinical characteristics except for suspected location of the infarction, independently rated ICH according to the Heidelberg Bleeding Classification in random pairs. Percent agreement and Cohen's kappa (κ) were estimated for the presence of any ICH (yes/no), and for agreement on the Heidelberg Bleeding Classification class 1 and 2. For the Heidelberg Bleeding Classification class 1 and 2, weighted κ was estimated to take the degree of disagreement into account. In 297 of 300 scans, the quality of scans was sufficient to score ICH. Observers agreed on the presence or absence of any ICH in 264 of 297 scans (88.9%; κ 0.78 [95% CI, 0.71-0.85]). There was agreement on the Heidelberg Bleeding Classification class 1 and 2 and no ICH in class 1 and 2 in 226 of 297 scans (76.1%; κ 0.63 [95% CI, 0.56-0.69]; weighted κ 0.90 [95% CI, 0.87-0.93]). The presence of any ICH can be reliably scored on magnetic resonance imaging and can, therefore, be used as (safety) outcome measure in clinical stroke trials that evaluate acute interventions. Agreement of ICH types according to the Heidelberg Bleeding Classification is substantial and disagreements are small.

Priority acute and preventive migraine treatment benefits: Results of the Migraine Clinical Outcome Assessment System (MiCOAS) qualitative study of people living with migraine.

There is renewed emphasis on including patients in determining, defining, and prioritizing outcomes for migraine treatment. To obtain insights directly from people living with migraine on their priorities for treatment. A total of 40 qualitative interviews were conducted as part of the Migraine Clinical Outcome Assessment System project, a United States Food and Drug Administration grant-funded program to develop a core set of patient-centered outcome measures for migraine clinical trials. Interviews included a structured exercise in which participants rank-ordered pre-defined lists of potential benefits for acute and preventive migraine therapy. The 40 study participants who reported being diagnosed with migraine by a clinician ranked the benefits and explained their rationale. Study participants consistently ranked either pain relief or absence of pain as their top priority for acute treatment. Relief/absence of other migraine symptoms and improved functioning were also prioritized. For preventive treatment, participants prioritized reductions in migraine frequency, symptom severity, and attack duration. Few differences were found between participants with episodic migraine and those with chronic migraine. However, participants with chronic migraine ranked "increased predictability of attacks" much higher than those with episodic migraine. Participants' rankings were influenced by prior expectations and experiences of migraine treatments, which caused many participants to deprioritize desired benefits as unrealistic. Participants also identified several additional priorities, including limited side-effects and reliable treatment efficacy in both acute and preventive treatments. The results showed the participants prioritized treatment benefits aligned with existing core clinical outcomes used in migraine research, but also valued benefits that are not typically assessed, such as predictability. Participants also deprioritized important benefits when they believed treatment was unlikely to deliver those outcomes.

Objective measurement of oral function in adults with spinal muscular atrophy

BackgroundImpairment of bulbar function in adult individuals with spinal muscular atrophy (SMA) usually is not assessed by established motor scores. Measurements of oral function including quantitative muscle and endurance tests are able to detect subtle changes. The aim of this study was to systematically evaluate the measurement of maximum bite force and endurance, maximum tongue pressure and endurance, as well as maximum mouth opening in adult individuals with SMA types 2 and 3. MethodsData from oral function tests in 43 individuals were analyzed. Differences in oral function between individuals with different SMA types and numbers of SMN2 copies were tested. Spearman´s rho correlations among oral function measures themselves as well as with established clinical outcome scales were analyzed.ResultsThe absolute maximum measures of oral function (maximum bite force, maximum tongue pressure, maximum mouth opening) were able to discriminate between individuals with different SMA types, individuals with a different number of SMN2 copies and with different walking abilities. The pairwise correlations of the absolute maximum measures of oral function were fair to moderate in size; the same was true for their correlations with the established motor scores. All correlations assessing endurance measures of oral function were weaker and statistically insignificant.ConclusionsAmong the oral function tests maximum tongue pressure and maximum mouth opening are particulary promising as clinical and sensitive outcome measures for clinical trials. Oral function tests may supplement existing motor scores, in particular concerning specific questions about bulbar function or in severely affected non-ambulatory individuals where mild (treatment-related) changes would otherwise remain undetected.Trial registration DRKS, DRKS00015842. Registered 30 July 2019, https://drks.de/search/de/trial/DRKS00015842

Editorial: Core outcome sets and measures for clinical trials in implant dentistry

Journal of Clinical PeriodontologyVolume 50, Issue S25 p. 4-4 INVITED EDITORIAL Editorial: Core outcome sets and measures for clinical trials in implant dentistry Lisa Heitz-Mayfield, Corresponding Author Lisa Heitz-Mayfield [email protected] orcid.org/0000-0001-5755-8265 International Research Collaborative, Oral Health and Equity, School of Human Anatomy and Biology, The University of Western Australia, Crawley, WA, Australia Discipline of Periodontics, School of Dentistry, Faculty of Medicine and Health, The university of Sydney, Sydney, NSW, Australia Correspondence Panos N. Papapanou, Division of Periodontics, Section of Oral, Diagnostic and Rehabilitation Sciences, College of Dental Medicine, Columbia University, 630 W 168th Street, PH-7E-110, New York, NY 10032, USA. Email: [email protected] Lisa Heitz-Mayfield, International Research Collaborative, Oral Health and Equity, School of Human Anatomy and Biology, The University of Western Australia, Crawley, WA, Australia. Email: [email protected]Search for more papers by this authorPanos N. Papapanou, Corresponding Author Panos N. Papapanou [email protected] orcid.org/0000-0002-6538-3618 Division of Periodontics, Section of Oral, Diagnostic and Rehabilitation Sciences, College of Dental Medicine, Columbia University, New York, NY, USA Correspondence Panos N. Papapanou, Division of Periodontics, Section of Oral, Diagnostic and Rehabilitation Sciences, College of Dental Medicine, Columbia University, 630 W 168th Street, PH-7E-110, New York, NY 10032, USA. Email: [email protected] Lisa Heitz-Mayfield, International Research Collaborative, Oral Health and Equity, School of Human Anatomy and Biology, The University of Western Australia, Crawley, WA, Australia. Email: [email protected]Search for more papers by this author Lisa Heitz-Mayfield, Corresponding Author Lisa Heitz-Mayfield [email protected] orcid.org/0000-0001-5755-8265 International Research Collaborative, Oral Health and Equity, School of Human Anatomy and Biology, The University of Western Australia, Crawley, WA, Australia Discipline of Periodontics, School of Dentistry, Faculty of Medicine and Health, The university of Sydney, Sydney, NSW, Australia Correspondence Panos N. Papapanou, Division of Periodontics, Section of Oral, Diagnostic and Rehabilitation Sciences, College of Dental Medicine, Columbia University, 630 W 168th Street, PH-7E-110, New York, NY 10032, USA. Email: [email protected] Lisa Heitz-Mayfield, International Research Collaborative, Oral Health and Equity, School of Human Anatomy and Biology, The University of Western Australia, Crawley, WA, Australia. Email: [email protected]Search for more papers by this authorPanos N. Papapanou, Corresponding Author Panos N. Papapanou [email protected] orcid.org/0000-0002-6538-3618 Division of Periodontics, Section of Oral, Diagnostic and Rehabilitation Sciences, College of Dental Medicine, Columbia University, New York, NY, USA Correspondence Panos N. Papapanou, Division of Periodontics, Section of Oral, Diagnostic and Rehabilitation Sciences, College of Dental Medicine, Columbia University, 630 W 168th Street, PH-7E-110, New York, NY 10032, USA. Email: [email protected] Lisa Heitz-Mayfield, International Research Collaborative, Oral Health and Equity, School of Human Anatomy and Biology, The University of Western Australia, Crawley, WA, Australia. Email: [email protected]Search for more papers by this author First published: 26 May 2023 https://doi.org/10.1111/jcpe.13810 This manuscript was simultaneously and jointly published in the Journal of Clinical Periodontology and Clinical Oral Implants Research Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL No abstract is available for this article. Volume50, IssueS25Supplement: The Implant Dentistry Core Outcome Set and Measurement (ID‐COSM) International Consensus ReportMay 2023Pages 4-4 RelatedInformation

Editorial: Core outcome sets and measures for clinical trials in implant dentistry

Clinical Oral Implants ResearchVolume 34, Issue S25 p. 3-3 INVITED EDITORIAL Editorial: Core outcome sets and measures for clinical trials in implant dentistry Lisa Heitz-Mayfield, Corresponding Author Lisa Heitz-Mayfield [email protected] orcid.org/0000-0001-5755-8265 International Research Collaborative, Oral Health and Equity, School of Human Anatomy and Biology, The University of Western Australia, Crawley, WA, Australia Discipline of Periodontics, School of Dentistry, Faculty of Medicine and Health, The university of Sydney, Sydney, NSW, Australia Correspondence Panos N. Papapanou, Division of Periodontics, Section of Oral, Diagnostic and Rehabilitation Sciences, College of Dental Medicine, Columbia University, 630 W 168th Street, PH-7E-110, New York, NY 10032, USA. Email: [email protected] Lisa Heitz-Mayfield, International Research Collaborative, Oral Health and Equity, School of Human Anatomy and Biology, The University of Western Australia, Crawley, WA, Australia. Email: [email protected]Search for more papers by this authorPanos N. Papapanou, Corresponding Author Panos N. Papapanou [email protected] orcid.org/0000-0002-6538-3618 Division of Periodontics, Section of Oral, Diagnostic and Rehabilitation Sciences, College of Dental Medicine, Columbia University, New York, NY, USA Correspondence Panos N. Papapanou, Division of Periodontics, Section of Oral, Diagnostic and Rehabilitation Sciences, College of Dental Medicine, Columbia University, 630 W 168th Street, PH-7E-110, New York, NY 10032, USA. Email: [email protected] Lisa Heitz-Mayfield, International Research Collaborative, Oral Health and Equity, School of Human Anatomy and Biology, The University of Western Australia, Crawley, WA, Australia. Email: [email protected]Search for more papers by this author Lisa Heitz-Mayfield, Corresponding Author Lisa Heitz-Mayfield [email protected] orcid.org/0000-0001-5755-8265 International Research Collaborative, Oral Health and Equity, School of Human Anatomy and Biology, The University of Western Australia, Crawley, WA, Australia Discipline of Periodontics, School of Dentistry, Faculty of Medicine and Health, The university of Sydney, Sydney, NSW, Australia Correspondence Panos N. Papapanou, Division of Periodontics, Section of Oral, Diagnostic and Rehabilitation Sciences, College of Dental Medicine, Columbia University, 630 W 168th Street, PH-7E-110, New York, NY 10032, USA. Email: [email protected] Lisa Heitz-Mayfield, International Research Collaborative, Oral Health and Equity, School of Human Anatomy and Biology, The University of Western Australia, Crawley, WA, Australia. Email: [email protected]Search for more papers by this authorPanos N. Papapanou, Corresponding Author Panos N. Papapanou [email protected] orcid.org/0000-0002-6538-3618 Division of Periodontics, Section of Oral, Diagnostic and Rehabilitation Sciences, College of Dental Medicine, Columbia University, New York, NY, USA Correspondence Panos N. Papapanou, Division of Periodontics, Section of Oral, Diagnostic and Rehabilitation Sciences, College of Dental Medicine, Columbia University, 630 W 168th Street, PH-7E-110, New York, NY 10032, USA. Email: [email protected] Lisa Heitz-Mayfield, International Research Collaborative, Oral Health and Equity, School of Human Anatomy and Biology, The University of Western Australia, Crawley, WA, Australia. Email: [email protected]Search for more papers by this author First published: 26 May 2023 https://doi.org/10.1111/clr.14075 This manuscript was simultaneously and jointly published in the Journal of Clinical Periodontology and Clinical Oral Implants Research Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL No abstract is available for this article. Volume34, IssueS25Special Issue: The Implant Dentistry Core Outcome Set and Measurement (ID‐COSM) International Consensus ReportMay 2023Pages 3-3 RelatedInformation

Current Understanding of Verbal Fluency in Alzheimer's Disease: Evidence to Date.

Since their development, verbal fluency tests (VFTs) have been used extensively throughout research and in clinical settings to assess a variety of cognitive functions in diverse populations. In Alzheimer's disease (AD), these tasks have proven particularly valuable in identifying the earliest forms of cognitive decline in semantic processing and have been shown to relate specifically to brain regions associated with the initial stages of pathological change. In recent years, researchers have developed more nuanced techniques to evaluate verbal fluency performance, extracting a wide range of cognitive metrics from these simple neuropsychological tests. Such novel techniques allow for a more detailed exploration of the cognitive processes underlying successful task performance beyond the raw test score. The versatility of VFTs and the richness of data they may provide, in light of their low cost and speed of administration, therefore, highlight their potential value both in future research as outcome measures for clinical trials and in a clinical setting as a screening measure for early detection of neurodegenerative diseases.

A Pilot Study of Lung Clearance Index as a Useful Outcome Marker in the Follow-Up of Pediatric Patients with Non-Cystic Fibrosis Bronchiectasis?

The forced expiratory volume in one second (FEV1) is regularly used for the follow-up of patients with non-cystic fibrosis bronchiectasis (nCF-BE). The lung clearance index (LCI), measured by the multiple breath washout test, has been recently proposed as a lung function measure and a potential tool more sensitive than the FEV1 measured by spirometry in assessing airway changes seen on imaging. While several data have been endorsed as a useful endpoint in clinical trials of patients with early or mild CF lung disease and as the main outcome measure in clinical trials with CFTR modulators in children and adolescents with CF, few data are available in the context of non-CF bronchiectasis. The aim of this pilot study was to compare the LCI with the FEV1 as well as the forced vital capacity (FVC), the forced expiratory flow at 25-75% of the FVC (FEF 25-75%), and chest imaging based on the modified Reiff score in patients with primary ciliary dyskinesia (PCD) and non-CF, non-PCD bronchiectasis (PCD-BE and nCFnPCD-BE). Additionally, we compared each test's duration and the preferred technique. Twenty children were included; nine had PCD-BE and eleven had nCFnPCD-BE. The median age was twelve years (ages ranging between five and eighteen years). The median LCI was seven while the median z-scores of the FEV1, FVC, and FEF 25-75% were -0.6, 0, and -0.9, respectively. No significant associations or correlations were observed between LCI, spirometric parameters, or the modified Reiff score. However, nearly half of the population (n = 9) had an abnormal LCI, while only 10% had an abnormal FEV1. A total of 75% of children preferred MBW, despite it lasting five times longer than spirometry. In this paper, the authors suggest that LCI might be useful in a cohort of pediatric patients with PCD-BE and nCFnPCD-BE for detecting early lung function changes during their follow-up. Additionally, MBW seems to be preferred by patients. These data may encourage further studies on this topic.

Determining minimal clinically important differences in the North Star Ambulatory Assessment (NSAA) for patients with Duchenne muscular dystrophy.

The North Star ambulatory assessment (NSAA) is a functional motor outcome measure in Duchenne muscular dystrophy (DMD), widely used in clinical trials and natural history studies, as well as in clinical practice. However, little has been reported on the minimal clinically important difference (MCID) of the NSAA. The lack of established MCID estimates for NSAA presents challenges in interpreting the significance of the results of this outcome measure in clinical trials, natural history studies and clinical practice. Combining statistical approaches and patient perspectives, this study estimated MCID for NSAA using distribution-based estimates of 1/3 standard deviation (SD) and standard error of measurement (SEM), an anchor-based approach, with six-minute walk distance (6MWD) as the anchor, and evaluation of patient and parent perception using participant-tailored questionnaires. The MCID for NSAA in boys with DMD aged 7 to 10 years based on 1/3 SD ranged from 2.3-2.9 points, and that on SEM ranged from 2.9-3.5 points. Anchored on the 6MWD, the MCID for NSAA was estimated as 3.5 points. When the impact on functional abilities was considered using participant response questionnaires, patients and parent perceived a complete loss of function in a single item or deterioration of function in one to two items of the assessment as an important change. Our study examines MCID estimates for total NSAA scores using multiple approaches, including the impact of patient and parent perspective on within scale changes in items based on complete loss of function and deterioration of function, and provides new insight on evaluation of differences in these widely used outcome measure in DMD.

The Challenges of MRI in Clinical Practice (P11-3.008)

The Challenges of MRI in Clinical Practice (P11-3.008)

P160 Pilot study to determine whether skin blood flow, oxygenation and skin colour are related in patients with systemic sclerosis

Abstract Background/Aims Improved treatments are needed for Raynaud’s phenomenon. Clinical trials can be difficult since it is challenging to measure Raynaud’s ‘attacks’ outside the laboratory. Ambulatory monitoring would allow testing of new treatments in the patients’ home environment where they usually experience attacks, thus allowing a much more realistic assessment of efficacy. Smartphone technology advancements mean that ambulatory monitoring of, and capture of biomarkers from, patients is now possible and could facilitate clinical trials. The aim of this study was to establish whether smartphone monitoring of skin temperature, an indirect measure of blood flow, and changes in skin colour as compared to laboratory measures of oxygenation could inform outcome measures in future clinical trials. Methods Following acclimatisation in a temperature-controlled room, participants underwent finger occlusion in order to simulate a decrease in perfusion and oxygenation. Simultaneous images were taken of the whole hand at baseline, during occlusion, at release and at 1 and 5 minute(s) post-release. Images of skin temperature (henceforth referred to as blood flow) and skin colour were taken with smartphone thermography (FLIRone) and camera respectively. Oxygenation was measured with multispectral imaging. Blood flow, colour and oxygenation data were extracted from images using automated bespoke software that identified the boundary of the hand and selected regions of interest. Colour data was split into red, green and blue channels. Data were plotted over time at each time point. Results Thirty patients with systemic sclerosis (SSc, median 62 interquartile range [57-69] years of age, 26[87%] female, duration of Raynaud’s phenomenon 20[10-32] years, duration of SSc 17[6-25] years, 6[20%] smokers) and 25 healthy controls (53[40-56] years of age, 23[92%] female, 0[0%] smokers) were recruited into the study. The measures of blood flow, colour (red channel) and oxygenation followed similar trajectories over time for both patients and controls (decreasing during occlusion and increasing post occlusion). Oxygenation data was significantly different between patients and controls for baseline to occlusion (-0.24[-0.30 - -0.14] vs. -0.34[-0.46 - -0.26] arb units, p = 0.004) and occlusion to release (0.42[0.12-0.53] vs. 0.74[0.64-0.82] arb units, p < 0.0001). Grouping all data together (at occlusion to release), correlations were identified between colour (red channel) and blood flow r=-0.36 p = 0.003; colour (red channel) and oxygenation r = 0.31 p = 0.003 and between oxygenation and blood flow r=-0.38 p = 0.003. Conclusion Blood flow, skin colour and oxygenation in both patients with SSc and healthy controls follow similar distributions with time under occlusion and release. Blood flow, skin colour and oxygenation are related suggesting that measuring skin colour (redness) may be an alternative way to assess perfusion and oxygenation. Further larger studies are now required to validate this. Smartphone measures of outcomes offer promise for the future of ambulatory monitoring for clinical trials of Raynaud’s phenomenon. Disclosure G. Dinsdale: None. C. Heal: None. J. Manning: None. S. Wilkinson: None. J. Wilkinson: None. M. Dickinson: None. A. Herrick: None. A. Murray: None.

Measuring cough: what really matters?

The clinical and research discipline of cough has grown substantially over the last two decades as methods to measure cough have developed and evolved. Cough can be thought of both as a symptom and an objectively observable pathophysiological phenomenon, two aspects whose interrelationship is complicated. The following review explores the varied methods to measuring cough, both subjective, patient-reported measures and objective approaches. Specifically, symptom scores, questionnaires of cough-related quality of life, and associated mental health impacts of chronic cough are addressed, as are developments in measuring cough frequency, cough intensity, cough reflex sensitivity, and cough suppressibility. Measuring patient reported cough-severity with a simple visual analogue scale increasingly appears to be justified, but has limitations. The Leicester Cough Questionnaire has been widely used for twenty years, within varied settings and diseases, in research and routine clinical practice, and captures cough-related quality of life. Objective cough frequency has become the primary outcome measure for clinical trials of antitussives, and technology is now enabling the wider application of cough counting. Inhaled tussive challenge testing still has a role, including in the assessment of cough hypersensitivity, and in the identification of failure to supress cough. Ultimately, many measures have a contributory and complementary role, with differing merits in quantifying the multiple facets of cough, the complexity of which is being increasingly recognised.

METHODS TO DERIVE A MODIFIED MAYO SCORE FROM ELECTRONIC HEALTH RECORDS DATA

The modified Mayo Score (MMS), which consists of stool frequency, rectal bleeding, and endoscopic subscores, is the most commonly used method for measuring disease activity in Ulcerative Colitis (UC) patients. It is a standard outcome measure in clinical trials, and is recommended as a clinical trial endpoint by the US Food and Drug Administration. Each component has a score from 0-3; the total MMS ranges from 0 to 9. MMS is infrequently recorded in routine care, in part because it requires an endoscopic assessment. Real world data, including electronic health record (EHR) databases, are useful for studying longitudinal disease and treatment outcomes, but most EHR databases do not include Mayo scores. Building off the methods described by Rudrapatna et al., 2021, we calculated a derived MMS using data elements available in EHRs.

METHODS TO DERIVE A CROHN’S DISEASE ACTIVITY INDEX FROM ELECTRONIC HEALTH RECORDS DATA

The Crohn’s Disease Activity Index (CDAI) is currently the gold-standard for measuring disease activity in Crohn’s disease (CD) patients. It is the most commonly used outcome measure in clinical trials, however, due to the burden of completion, it is infrequently used in routine care. Real world data, including electronic health records (EHR), are useful for studying longitudinal disease and treatment outcomes in the real world, but most EHR databases do not include CDAI. Building off the methods presented by Rudrapatna et al. 2021, we calculated a derived CDAI using data elements available in EHRs.

Utility of the visual system to monitor neurodegeneration in multiple sclerosis.

Neurodegeneration occurs early in the multiple sclerosis (MS) disease course and is an important driver of permanent disability. Current immunomodulatory therapies do not directly target neuronal health; thus, there is a critical need to develop neuroprotective strategies in MS. Outcome measures in clinical trials primarily evaluate disease activity and clinical disability scores rather than measures of neurodegeneration. The visual system provides a noninvasive correlate of brain atrophy and neuronal function through structural and functional exams. Furthermore, optic nerve axons and their respective neuronal cell bodies in the retina, in addition to their synaptic input to the thalamus, provide a distinct anatomy to investigate neurodegenerative processes. This review discusses the utility of the visual system as an early output measure of neurodegeneration in MS as well as an important platform to evaluate neuroprotective strategies in preclinical models.

Change in Cone Structure Over 24 Months in USH2A-Related Retinal Degeneration

To describe cone structure changes using adaptive optics scanning laser ophthalmoscopy (AOSLO) in the Rate of Progression of USH2A-related Retinal Degeneration (RUSH2A) study. Multicenter, longitudinal natural history study. AOSLO images were acquired at 4 centers, twice at baseline and annually for 24 months in this natural history study. For each eye, at least 10 regions of interest (ROIs) with ≥50 contiguous cones were analyzed by masked, independent graders. Cone spacing Z-scores, standard deviations from the normal mean at the measured location, were compared between graders and tests at baseline. The association of cone spacing with clinical characteristics was assessed using linear mixed effects regression models weighted by image quality score. Annual rates of change were calculated based on differences between visits. Fourteen eyes of 14 participants were imaged, with 192 ROIs selected at baseline. There was variability among graders, which was greater in images with lower image quality score (P < .001). Cone spacing was significantly correlated with eccentricity, quality score, and disease duration (P < .02). On average, the cone spacing Z-score increased 0.14 annually (about 9%, P < .001). We observed no significant differences in rate of change between disease type (Usher syndrome or retinitis pigmentosa), imaging site, or grader. Using current methods, the analysis of quantitative measures of cone structure showed some challenges, yet showed promise that AOSLO images can be used to characterize progressive change over 24 months. Additional multicenter studies using AOSLO are needed to advance cone mosaic metrics as sensitive outcome measures for clinical trials. NOTE: Publication of this article is sponsored by the American Ophthalmological Society.

Reliability of spinal cord measures based on synthetic T1-weighted MRI derived from multiparametric mapping (MPM)

Short MRI acquisition time, high signal-to-noise ratio, and high reliability are crucial for image quality when scanning healthy volunteers and patients. Cross-sectional cervical cord area (CSA) has been suggested as a marker of neurodegeneration and potential outcome measure in clinical trials and is conventionally measured on T1-weigthed 3D Magnetization Prepared Rapid Acquisition Gradient-Echo (MPRAGE) images. This study aims to reduce the acquisition time for the comprehensive assessment of the spinal cord, which is typically based on MPRAGE for morphometry and multi-parameter mapping (MPM) for microstructure. The MPRAGE is replaced by a synthetic T1-w MRI (synT1-w) estimated from the MPM, in order to measure CSA. SynT1-w images were reconstructed using the MPRAGE signal equation based on quantitative maps of proton density (PD), longitudinal (R1) and effective transverse (R2*) relaxation rates. The reliability of CSA measurements from synT1-w images was determined within a multi-center test-retest study format and validated against acquired MPRAGE scans by assessing the agreement between both methods. The response to pathological changes was tested by longitudinally measuring spinal cord atrophy following spinal cord injury (SCI) for synT1-w and MPRAGE using linear mixed effect models. CSA measurements based on the synT1-w MRI showed high intra-site (Coefficient of variation [CoV]: 1.43% to 2.71%) and inter-site repeatability (CoV: 2.90% to 5.76%), and only a minor deviation of -1.65 mm2 compared to MPRAGE. Crucially, by assessing atrophy rates and by comparing SCI patients with healthy controls longitudinally, differences between synT1-w and MPRAGE were negligible. These results demonstrate that reliable estimates of CSA can be obtained from synT1-w images, thereby reducing scan time significantly.

ADNP Syndrome: A Qualitative Assessment of Symptoms, Therapies, and Challenges

ADNP syndrome is a neurodevelopmental disorder characterized by autism spectrum disorder (ASD), intellectual disability, sensory reactivity symptoms, facial dysmorphisms, and a wide variety of other physical and behavioral health manifestations. Research on ADNP syndrome has been limited, and there are currently no validated tools for assessing clinical outcomes in ADNP syndrome specifically. The goal of this qualitative study was to ascertain the symptoms of ADNP syndrome based on caregiver interviews, with the primary aim of identifying areas for clinical improvement that may inform the development of outcome measures specific to ADNP syndrome. Data collection consisted of loosely structured interviews with 10 caregivers of children with ADNP syndrome, representing 6 males and 4 females of ages 4 to 17 (M = 10.1; SD = 4.2). Interviews were conducted via phone between November 2020 and April 2021. The analysis of coded interview data identified three overarching themes: symptoms, therapies, and challenges. Each theme encompasses several distinct codes, which were individually addressed. Our results could ultimately be useful in educating clinicians about ADNP syndrome, selecting or designing refined outcome measures for clinical trials, and informing efforts to increase support for caregivers.

Development of a Novel Electrochemiluminescence ELISA for Quantification of α-Synuclein Phosphorylated at Ser129 in Biological Samples.

Synucleinopathies are a group of neurodegenerative diseases including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). These diseases are characterized by the aggregation and deposition of α-synuclein (α-syn) in Lewy bodies (LBs) in PD and DLB or as glial cytoplasmic inclusions in MSA. In healthy brains, only ∼4% of α-syn is phosphorylated at Ser129 (pS129-α-syn), whereas >90% pS129-α-syn may be found in LBs, suggesting that pS129-α-syn could be a useful biomarker for synucleinopathies. However, a widely available, robust, sensitive, and reproducible method for measuring pS129-α-syn in biological fluids is currently missing. We used Meso Scale Discovery (MSD)'s electrochemiluminescence platform to create a new assay for sensitive detection of pS129-α-syn. We evaluated several combinations of capture and detection antibodies and used semisynthetic pS129-α-syn as a standard for the assay at a concentration range from 0.5 to 6.6 × 104 pg/mL. Using the antibody EP1536Y for capture and an anti-human α-syn antibody (MSD) for detection was the best combination in terms of assay sensitivity, specificity, and reproducibility. We tested the utility of the assay for the detection and quantification of pS129-α-syn in human cerebrospinal fluid, serum, plasma, saliva, and CNS-originating small extracellular vesicles, as well as in mouse brain lysates. Our data suggest that the assay can become a widely used method for detecting pS129-α-syn in biomedical studies including when only a limited volume of sample is available and high sensitivity is required, offering new opportunities for diagnostic biomarkers, monitoring disease progression, and quantifying outcome measures in clinical trials.

Adaptation and validation of the Bulgarian version of the Systemic Lupus Erythematosus Quality of Life Questionnaire (L-QoL).

Systemic lupus erythematosus (SLE) is a heterogeneous disease with multiple clinical manifestations, which causes a significant deterioration in the quality of life (QoL). The Systemic Lupus Erythematosus Quality of Life Questionnaire (L-QoL) is a lupus-specific measure used to determine the burden of the disease and it applies the need-based model of QoL. Our aim was to produce the first successfully validated foreign language version of the questionnaire. The development of the Bulgarian version involved three stages: translation, field testing and psychometric evaluation. Translation was conducted by an expert linguist working with a developer of the original L-QoL, followed by interviews with monolingual lay individuals. Face and content validity of the translation were assessed by cognitive debriefing interviews with Bulgarian SLE patients. Finally, the L-QoL was validated by administering the questionnaire to a random sample of SLE patients on two occasions, 2 weeks apart to evaluate its reliability and validity. In the validation survey, the new Bulgarian version demonstrated high internal consistency (the Cronbach's alpha coefficient was 0.92), and test-retest reliability (0.97). Additionally, scores on the L-QoL were correlated with those on the SF-36 sections to determine convergent validity and the strongest correlation was observed between L-QoL scores and the social functioning section of the SF-36. Known group validity was established by testing the ability of the Bulgarian L-QoL to distinguish between subgroups of patients from the study pool. The demonstrated excellent psychometric properties ensure that the Bulgarian L-QoL accurately captures the impact of SLE on the quality of life. Key points • The Bulgarian version of the L-QoL is a valid and reliable measure of QoL in lupus patients. • The Bulgarian version of the L-QoL can be used as an outcome measure in research, clinical trials and routine clinical practice.