Assessment of health state utilities associated with adult and pediatric acid sphingomyelinase deficiency (ASMD).

INTRODUCTION: Acid sphingomyelinase deficiency (ASMD) type B is a rare genetic disorder leading to enlargement of the spleen and liver, pulmonary dysfunction, and other symptoms. Cost-utility analyses are often conducted to quantify the value of new treatments, and these analyses require health state utilities. Therefore, the purpose of this study was to estimate utilities associated with varying levels of severity of adult and pediatric ASMD type B. METHODS: Seven adult and seven child health state vignettes describing ASMD were developed based on published literature, clinical trial results, and interviews with clinicians, patients with ASMD, and parents of children with ASMD. The health states were valued in time trade-off interviews with adult general population respondents in the UK. RESULTS: Interviews were completed with 202 participants (50.0% female; mean age = 41.3 years). The health state representing ASMD without impairment had the highest mean utility for both the adult and child health states (0.92/0.94), and severe ASMD had the lowest mean utility (0.33/0.45). Every child health state had a significantly greater utility than the corresponding adult health state. Differences between adult/child paired states ranged from 0.02 to 0.13. Subgroup analyses explored the impact of parenting status on valuation of child health states. DISCUSSION: Greater severity of ASMD was associated with lower mean utility. Results have implications for valuation of pediatric health states. The resulting utilities may be useful in cost-utility modeling estimating the value of treatment for ASMD.

Health state utilities associated with weight loss: preferences of people with type 2 diabetes and obesity in Japan.

AIMS: Health state utilities associated with weight change are needed for cost-utility analyses (CUAs) examining the value of treatments for type 2 diabetes and obesity. Previous studies have estimated the utility benefits associated with various amounts of weight reduction in the US and Europe, but preferences for weight change in Asian cultures may differ from these published values. The purpose of this study was to estimate utilities associated with reductions in body weight based on preferences of individuals with type 2 diabetes and obesity in Japan. METHODS: Health state vignettes represented type 2 diabetes with respondents' own current weight and weight reductions of 2.5%, 5%, 7.5%, 10%, 12.5%, 15%, and 20%. Utilities were elicited in time trade-off interviews with a sample of respondents in Japan with type 2 diabetes and body mass index (BMI) ≥25 kg/m2 (the cutoff for obesity in Japan). RESULTS: Analyses were conducted with data from 138 respondents (84.8% male; mean age = 58.0 years; mean BMI = 29.4 kg/m2) from all eight regions of Japan. Utility gains gradually increased with rising percentage of weight reductions ranging from 2.5% to 15%. Weight reductions of 2.5% to 15% resulted in utility increases of 0.013 to 0.048. The health state representing a 20% weight reduction yielded a wide range of preferences (mean utility increase of 0.044). Equations are recommended for estimating utility change based on any percentage of weight reduction (up to 20%) in Japanese people with type 2 diabetes and obesity. LIMITATIONS: This study was conducted in a sample with limited representation of patients with BMI >35 kg/m2 (n = 13) and relatively few women (n = 21). CONCLUSION: Results may be used to provide inputs for CUAs examining the value of treatments that are associated with weight loss in patients with type 2 diabetes and obesity in Japan.

Capturing the Range of Disease Involvement in Localized Scleroderma: The Localized Scleroderma Total Severity Scale.

OBJECTIVE: Juvenile localized scleroderma (jLS) is a chronic autoimmune disease commonly associated with poor outcomes, including contractures, hemiatrophy, uveitis, and seizures. Despite improvements in treatment, >25% of patients with jLS have functional impairment. To improve patient evaluation, our workgroup developed the Localized scleroderma Total Severity Scale (LoTSS), an overall disease severity measure. METHODS: LoTSS was developed as a weighted measure by a consensus process involving literature review, surveys, case vignettes, and multicriteria decision analysis. Feasibility was assessed in larger Childhood Arthritis and Rheumatology Research Alliance groups. Construct validity with physician assessment and inter-rater reliability was assessed using case vignettes. Additional evaluation was performed in a prospective patient cohort initiating treatment. RESULTS: LoTSS severity items were organized into modules that reflect jLS disease patterns, with modules for skin, extracutaneous, and craniofacial manifestations. Construct validity of LoTSS was supported by a strong positive correlation with the Physician Global Assessment (PGA) of severity and damage and weak positive correlation with PGA-Activity, as expected. LoTSS was responsive, with a small effect size identified. Moderate-to-excellent inter-rater reliability was demonstrated. LoTSS was able to discriminate between patient subsets, with higher scores identified in those with greater disease burden and functional limitation. CONCLUSION: We developed a new LS measure for assessing cutaneous and extracutaneous severity and have shown it to be reliable, valid, and responsive. LoTSS is the first measure that assesses and scores all the major extracutaneous manifestations in LS. Our findings suggest LoTSS could aid assessment and management of patients and facilitate outcome evaluation in treatment studies.

Engineering Synthetic Electron Transfer Chains from Metallopeptide Membranes.

The energetic and geometric features enabling redox chemistry across the copper cupredoxin fold contain key components of electron transfer chains (ETC), which have been extended here by templating the cross-ß bilayer assembly of a synthetic nonapeptide, HHQALVFFA-NH2 (K16A), with copper ions. Similar to ETC cupredoxin plastocyanin, these assemblies contain copper sites with blue-shifted (λmax 573 nm) electronic transitions and strongly oxidizing reduction potentials. Electron spin echo envelope modulation and X-ray absorption spectroscopies define square planar Cu(II) sites containing a single His ligand. Restrained molecular dynamics of the cross-ß peptide bilayer architecture support metal ion coordination stabilizing the leaflet interface and indicate that the relatively high reduction potential is not simply the result of distorted coordination geometry (entasis). Cyclic voltammetry (CV) supports a charge-hopping mechanism across multiple copper centers placed 10-12 Å apart within the assembled peptide leaflet interface. This metal-templated scaffold accordingly captures the electron shuttle and cupredoxin functionality in a peptide membrane-localized electron transport chain.

Development of a patient-reported outcome (PRO) measure to assess patient perceptions of simplicity and complexity of treatment for type 2 diabetes.

INTRODUCTION: Treatments for type 2 diabetes vary widely in their complexity. The simplicity or complexity of a treatment regimen may have an impact on patient preference, treatment adherence, and health outcomes. The purpose of this qualitative study was to develop two draft patient-reported outcome instruments focusing on patients' experience with simplicity and complexity of treatment for type 2 diabetes. METHODS: The instruments were developed in a series of steps: gather information to support development of a concept elicitation interview guide (literature review and expert interviews), concept elicitation interviews with patients (N = 30), cognitive interviews with patients (N = 20), and a translatability assessment. RESULTS: In concept elicitation interviews, patients with type 2 diabetes reported a range of treatment attributes that influence their perceptions of treatment simplicity and complexity, such as injection devices, medication preparation, dose timing, dose frequency, ease of taking the correct dose, flexibility of dose schedule, remembering to take medication, and food requirements. Two draft questionnaires were developed based on the literature review, expert interviews, and concept elicitation interviews with patients. Revisions were made to these draft instruments based on qualitative interviews with patients and translatability assessment. DISCUSSION: The qualitative research conducted in this study supports the content validity of two newly developed instruments, the Simplicity of Diabetes Treatment Questionnaire (Sim-Q) and the Simplicity of Diabetes Treatment Questionnaire-Comparison (Sim-Q-Comp), designed to assess the simplicity and complexity of diabetes treatment from the patient's perspective.

Treatments for type 2 diabetes vary widely in their complexity, and previous research suggests that simpler treatments may have benefits for patients, such as better medication adherence and improved glycemic control. Despite the benefits of treatment simplicity, there are limited options for assessing simplicity of treatment from the patient perspective. This study was designed to develop two patient-reported outcome measures that assess simplicity and complexity of treatment for type 2 diabetes. Thirty patients with type 2 diabetes reported a range of treatment attributes that influence their perceptions of treatment simplicity and complexity. These attributes included injection devices, medication preparation, dose timing, dose frequency, ease of taking the correct dose, flexibility of dose schedule, and food requirements. Two questionnaires were developed based on literature review, expert interviews, and patient interviews (one questionnaire for rating a single treatment, and another questionnaire for comparing two treatments). Revisions were made to the draft instruments based on feedback from 20 additional participants and a translatability assessment. The resulting instruments are called the Simplicity of Diabetes Treatment Questionnaire (Sim-Q) and Simplicity of Diabetes Treatment Questionnaire-Comparison (Sim-Q-Comp). Future research with more patients is needed to further examine the psychometric properties of the questionnaires.

An unconventional mechanism of IL-1ß secretion that requires Type I IFN in lupus monocytes.

Systemic Lupus Erythematosus (SLE) is characterized by autoreactive B cell activation, upregulation of Type I Interferon (IFN) and widespread inflammation. Mitochondrial nucleic acids (NAs) are increasingly recognized as triggers of IFN 1 . Thus, defective removal of mitochondria from mature red blood cells (Mito + RBCs), a feature of SLE, contributes to IFN production by myeloid cells 2 . Here we identify blood monocytes (Mo) that have internalized RBCs and co-express IFN-stimulated genes (ISGs) and interleukin-1ß (IL-1ß) in SLE patients with active disease. We show that ISG expression requires the interaction between Mito + RBC-derived mitochondrial DNA (mtDNA) and cGAS, while IL-1ß production entails Mito + RBC-derived mitochondrial RNA (mtRNA) triggering of RIG-I-like receptors (RLRs). This leads to the cytosolic release of Mo-derived mtDNA that activates the NLRP3 inflammasome. Importantly, IL-1ß release depends on the IFN-inducible myxovirus resistant protein 1 (MxA), which enables the translocation of this cytokine into a trans-Golgi network (TGN)-mediated unconventional secretory pathway. Our study highlights a novel and synergistic pathway involving IFN and the NLRP3 inflammasome in SLE.

Looking beyond workforce parity: addressing gender inequity in pathology.

While women pathologists have made up over one-third of pathologists in the Australian workforce for over 15 years and at least 50% since 2019, they are under-represented in senior leadership roles, scientific publications, grant recipients, editorial boards, key presentations, and professional awards. This is not unique to pathology and is seen in the broader medical and academic community. Barriers to gender equity and equality in pathology, medicine and academia include gender stereotypes, gender-based discrimination, structural and organisational barriers as well as broader social and cultural barriers. A diverse leadership reflective of the whole professional body and the broader community is important for optimal health outcomes. It is the responsibility and moral duty of individuals and organisations to address any gender disparities, inequities, and inequalities by monitoring, identifying, and acting on gender biases and systemic barriers that hinder appropriate levels of representation by women.

Impact of Sex on Cardiovascular Adaptations to Exercise: JACC Review Topic of the Week.

Routine exercise leads to cardiovascular adaptations that differ based on sex. Use of cardiac testing to screen athletes has driven research to define how these sex-based adaptations manifest on the electrocardiogram and cardiac imaging. Importantly, sex-based differences in cardiovascular structure and outcomes in athletes often parallel findings in the general population, underscoring the importance of understanding their mechanisms. Substantial gaps exist in the understanding of why cardiovascular adaptations and outcomes related to exercise differ by sex because of underrepresentation of female participants in research. As female sports participation rates have increased dramatically over several decades, it also remains unknown if differences observed in older athletes reflect biological mechanisms vs less lifetime access to sports in females. In this review, we will assess the effect of sex on cardiovascular adaptations and outcomes related to exercise, identify the impact of sex hormones on exercise performance, and highlight key areas for future research.

Development of a Patient-Reported Outcome (PRO) Measure to Assess Emotional Impact of Treatment for Type 2 Diabetes.

INTRODUCTION: Patients receiving treatment for type 2 diabetes (T2D) may experience an emotional impact associated with treatment-related changes. A patient-reported outcome (PRO) measure assessing both positive and negative emotional impact of medication treatment for T2D is needed to better understand the patient experience of treatment. The purpose of this qualitative study was to explore the emotional impact of treatment for T2D and support the development of a questionnaire to assess the emotional impact of treatment for T2D. METHODS: Exit interviews were conducted with patients with T2D participating in the SURPASS-2 and SURPASS-3 trials for tirzepatide. The exit interviews included a concept elicitation section focusing on the emotional impact of their study treatment. Results were used to develop two questionnaires that were evaluated in cognitive interviews with patients with T2D. RESULTS: The concept elicitation interviews included 28 patients (mean age 57.6 years; 64.3% female). Most patients reported positive changes in emotions associated with tirzepatide, including increased confidence (n = 23; 82.1%), hope (n = 23; 82.1%), self-esteem (n = 23; 82.1%), relief (n = 22; 78.6%), optimism (n = 21; 75.0%), sense of control (n = 21; 75.0%), happiness (n = 15; 53.6%), and motivation (n = 15; 53.6%), as well as reduced worry/anxiety (n = 19; 67.9%). Negative emotional impact was less commonly reported but included frustration (n = 2; 7.1%), worry/anxiety (n = 1; 3.6%), fear (n = 1; 3.6%), and feeling depressed (n = 1; 3.6%). Two new PROs, the Emotional Impact of Diabetes Treatment Questionnaires (EIDTQ, status and comparison versions), were developed based on these finding. The status version assesses the emotional impact of current treatment, while the comparison version allows for comparison of the current treatment to a previous treatment. The questionnaires were refined on the basis of cognitive interviews with 20 additional patients (mean age 58.3 years; 60.0% female), and results suggest that the final instruments were clear, comprehensible, and relevant to patients. CONCLUSION: The EIDTQ-Status and Comparison measures can be used as a supplement to clinical outcomes, such as hemoglobin A1c (HbA1c) and body weight, to provide a broader picture of the patient's emotional experience with medication treatment for T2D.

Medical treatment can have broad effects beyond symptom improvement, including an emotional impact. Emotional impact is subjective and therefore can only be assessed from the patient perspective. However, there is no previously published patient-reported outcome measure assessing both positive and negative emotional impact of medication treatment for type 2 diabetes. Thus, the purpose of this study was to conduct qualitative research to support the development of two new patient-reported outcome measures designed to assess the emotional impact of type 2 diabetes. Overall, the results add to previous research indicating that treatment for type 2 diabetes can have an emotional impact. The newly developed Emotional Impact of Diabetes Treatment Questionnaires were designed to assess this emotional impact, and current qualitative results support the content validity of these instruments in patients with type 2 diabetes. These instruments can be used as a supplement to clinical outcomes, such as HbA1c and body weight, to provide a broader picture of the patient's experience with medication treatment for type 2 diabetes.

Barriers to care in juvenile localized and systemic scleroderma: an exploratory survey study of caregivers' perspectives.

BACKGROUND: Juvenile localized scleroderma (LS) and systemic sclerosis (SSc) are rare pediatric conditions often associated with severe morbidities. Delays in diagnosis are common, increasing the risk for permanent damage and worse outcomes. This study explored caregiver perspectives on barriers they encountered while navigating diagnosis and care for their child's scleroderma. METHODS: In this cross-sectional study, caregivers of juvenile LS or SSc patients were recruited from a virtual family scleroderma educational conference and a juvenile scleroderma online interest group. The survey queried respondents about their child's condition and factors affecting diagnosis and treatment. RESULTS: The response rate was 61% (73/120), with 38 parents of LS patients and 31 parents of SSc patients. Most patients were female (80%) and over half were non-Hispanic white (55%). Most families had at least one person with a college education or higher (87%), traveled ≤ 2 h to see their rheumatologist (83%), and had private insurance (75%). Almost half had an annual household income ≥ $100,000 (46%). Families identified the following factors as barriers to care: lack of knowledge about scleroderma in the medical community, finding reliable information about pediatric scleroderma, long wait times/distances for a rheumatology/specialist appointment, balance of school/work and child's healthcare needs, medication side effects, and identifying effective medications. The barrier most identified as a major problem was the lack of knowledge about juvenile scleroderma in the medical community. Public insurance, household income less than $100,000, and Hispanic ethnicity were associated with specific barriers to care. Lower socioeconomic status was associated with longer travel times to see the rheumatologist/specialist. Diagnosis and systemic treatment initiation occurred at greater than one year from initial presentation for approximately 28% and 36% of patients, respectively. Families of LS patients were commonly given erroneous information about the disease, including on the need and importance of treating active disease with systemic immunosuppressants in patients with deep tissue or rapidly progressive disease. CONCLUSION: Caregivers of children with LS or SSc reported numerous common barriers to the diagnosis, treatment, and ongoing care of juvenile scleroderma. The major problem highlighted was the lack of knowledge of scleroderma within the general medical community. Given that most of the caregiver respondents to the survey had relatively high socioeconomic status, additional studies are needed to reach a broader audience, including caregivers with limited English proficiency, geographical limitations, and financial constraints, to determine if the identified problems are generalizable. Identifying key care barriers will help direct efforts to address needs, reduce disparities in care, and improve patient outcomes.

Association of Juvenile Dermatomyositis Disease Activity With the Expansion of Blood Memory B and T Cell Subsets Lacking Follicular Markers.

OBJECTIVE: This study was undertaken to identify blood markers of juvenile dermatomyositis (DM) disease activity (DA), which are needed to improve disease management. METHODS: The study comprised a total of 123 juvenile DM patients and 53 healthy controls. Results of laboratory tests (aldolase, creatinine kinase, lactate dehydrogenase [LDH], aspartate aminotransferase) and clinical measures of DA in patients with juvenile DM, including the Manual Muscle Testing in 8 muscles (MMT-8), Childhood Myositis Assessment Scale (CMAS), and disease activity scores (DAS) (total DAS for juvenile DM, the muscle DAS, and the skin DAS), were recorded when available. Surface phenotype of peripheral blood mononuclear cells was assessed using flow cytometry. Whole blood transcriptional profiles were studied using either RNA-sequencing or microarrays. Differential gene expression was determined using DESeq and compared by pathway and gene ontology analyses. RESULTS: Conventional memory (CD27+IgD-) B cells expressing low CXCR5 levels (CXCR5low/- CM B cells) were significantly increased in frequency and absolute numbers in 2 independent cohorts of juvenile DM patients compared with healthy controls. The frequency of CD4+ Th2 memory cells (CD45RA-CXCR5-CCR6-CXCR3-) was also increased in juvenile DM, especially in patients who were within <1 year from diagnosis. The frequency of CXCR5low/- CM B cells correlated with serum aldolase levels and with a blood interferon-stimulated gene transcriptional signature. Furthermore, both the frequency and absolute numbers of CXCR5low/- CM B cells correlated with clinical and laboratory measures of muscle DA (MMT-8, CMAS, aldolase, and LDH). CONCLUSION: These findings suggest that both CM B cells lacking the CXCR5 follicular marker and CXCR5- Th2 cells represent potential biomarkers of DA in juvenile DM and may contribute to its pathogenesis.

Qualitative interviews to evaluate content validity of the ACTIV-2 COVID-19 Symptom Diary (ACSD).

BACKGROUND: Patient-reported outcome measures are needed to assess the impact of treatments for COVID-19 on symptoms. The ACTIV-2 COVID-19 Symptom Diary (ACSD) is being used in the ongoing Accelerating COVID-19 Therapeutic Interventions and Vaccines-2 (ACTIV-2) platform clinical trial. The purpose of the current study was to conduct qualitative interviews to assess content validity of the ACSD. METHODS: Interviews were conducted with adults who had tested positive for SARS-CoV-2. The ACSD begins with global items, followed by a symptom checklist. Each interview began with concept elicitation focusing on participant experiences with COVID-19. Then, participants completed the ACSD, and cognitive interviews were conducted to evaluate the questionnaire. Interviews were recorded, transcribed, and coded following a qualitative content analysis. For the qualitative analysis, a coding dictionary was developed with a list of all potential codes and instructions for how the codes should be applied and combined. RESULTS: Interviews were conducted with 30 participants (mean age = 39 years; 57% female; 17% Latinx; 17% Black/African American; 40% meeting at least one criterion for classification as high risk of progression to severe COVID-19). Commonly reported symptoms included fatigue (reported by 100% of the sample), body pain/muscle pain/aches (87%), headaches (87%), cough (83%), loss of smell (73%), shortness of breath/difficulty breathing (70%), and chills (70%). The 13 symptoms most commonly reported in this study are included in the ACSD. After completing the ACSD, participants consistently reported that it was clear and easy to complete, and all items were generally interpreted as intended. Based on participants' input, the ACSD was edited slightly after the first 13 interviews, and the revised version was used for the final 17 interviews. Two additional items assessing "brain fog" and dizziness were recommended for addition to the ACSD in future research. CONCLUSIONS: This qualitative study supports the content validity of the ACSD for assessment of COVID-19 symptoms. Quantitative research with larger samples will be needed to examine the questionnaire's measurement properties.

This study focused on the ACTIV-2 COVID-19 Symptom Diary (ACSD), a questionnaire that assesses symptom severity of COVID-19. The ACSD begins with global items assessing overall symptom severity, followed by a symptom checklist focusing on individual symptoms. Interviews were conducted with 30 adults who had tested positive for COVID-19. The patients reported their experiences with COVID-19, completed the ACSD, and provided their opinions about the ACSD. Based on input from these patients, the ACSD appears to be clear and easy to complete, and it includes the most common and important symptoms of COVID-19. The ACSD was edited for clarity, and "brain fog" and dizziness were recommended additions for future research. This study suggests that the ACSD is a useful questionnaire for assessment of COVID-19 symptoms in clinical studies. Studies like this are important for ensuring that symptoms are measured appropriately and accurately in clinical trials. Future research with larger samples will be needed to further examine the questionnaire.

Exit Interviews Examining the Patient Experience in Clinical Trials of Tirzepatide for Treatment of Type 2 Diabetes.

INTRODUCTION: Qualitative exit interviews can supplement clinical trial results by providing a rich and detailed picture of the patient's experience, while highlighting the treatment benefits that are meaningful to patients. Exit interviews can be particularly useful for providing insight into newer medications when less is known about the patient's subjective experience of treatment. Tirzepatide is a novel dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist for type 2 diabetes mellitus. The purpose of this study was to conduct exit interviews with patients following participation in two trials to better understand the impact of tirzepatide from the patients' point of view. METHODS: Telephone interviews were conducted with patients with type 2 diabetes treated with tirzepatide soon after completing one of two trials (SURPASS-2, SURPASS-3). Interviews, conducted according to a semi-structured interview guide, were recorded, transcribed, and analyzed following a content analysis approach using ATLAS.ti. RESULTS: A total of 28 patients (64% female; mean age 57.6 years) completed interviews. All participants (100%) reported at least one treatment benefit. Patients provided descriptions of treatment benefits, including improved glycemic control (reported by 96% of the sample), weight loss (93%), decreased appetite (79%), and increased energy (79%), as indicated by qualitative coding. All participants said these treatment-related changes mattered to them. Patients described improvements in quality of life and daily activities associated with these treatment benefits. Despite adverse events reported by some patients (most commonly nausea, reported by 13 patients), all 28 said they would recommend tirzepatide to others, and 27 said they would be willing to continue treatment. Examples of representative quotations are presented for descriptions of treatment benefits, quality-of-life impact, and adverse events. DISCUSSION: The current results indicate that treatment benefits observed in clinical trials of tirzepatide are important to patients. As demonstrated in quotations from patients, the most enthusiastic descriptions of treatment outcomes focused on the weight loss associated with tirzepatide. The study also highlights the usefulness of exit interviews, which can supplement quantitative trial data by showing how these benefits have a meaningful impact on patients' quality of life.

Health state utilities associated with weight loss in type 2 diabetes and obesity.

INTRODUCTION: Health state utilities associated with weight change are needed as inputs for cost-utility analyses (CUAs) examining the value of treatments for obesity and type 2 diabetes (T2D). Although some pharmaceutical treatments currently in development are associated with substantial weight loss, little is known about the utility impact of weight decreases greater than 10%. The purpose of this study was to estimate utilities associated with body weight decreases up to 20% based on preferences of individuals with obesity, with and without T2D. METHODS: Health state vignettes were developed to represent respondents' own current weight and weight decreases of 2.5, 5, 10, 15, and 20%. Health state utilities were elicited in time trade-off interviews in two UK locations (Edinburgh and London) with a sample of participants with obesity, with and without T2D. Mean utility increases associated with each amount of weight decrease were calculated. Regression analyses were performed to derive a method for estimating utility change associated with weight decreases. RESULTS: Analyses were conducted with data from 405 individuals with obesity (202 with T2D, 203 without T2D). Utility increases associated with various levels of weight decrease ranged from 0.011 to 0.060 in the subgroup with T2D and 0.015 to 0.077 in the subgroup without T2D. All regression models found that the percentage of weight decrease was a highly significant predictor of change in utility (p < .0001). The relationship between weight change and utility change did not appear to be linear. Equations are recommended for estimating utility change based on the natural logarithm of percentage of weight decrease. DISCUSSION: Results of this study may be used to provide inputs for CUAs examining and comparing the value of treatments that are associated with substantial amounts of weight loss in patients with obesity, with or without T2D.

Erythroid mitochondrial retention triggers myeloid-dependent type I interferon in human SLE.

Emerging evidence supports that mitochondrial dysfunction contributes to systemic lupus erythematosus (SLE) pathogenesis. Here we show that programmed mitochondrial removal, a hallmark of mammalian erythropoiesis, is defective in SLE. Specifically, we demonstrate that during human erythroid cell maturation, a hypoxia-inducible factor (HIF)-mediated metabolic switch is responsible for the activation of the ubiquitin-proteasome system (UPS), which precedes and is necessary for the autophagic removal of mitochondria. A defect in this pathway leads to accumulation of red blood cells (RBCs) carrying mitochondria (Mito+ RBCs) in SLE patients and in correlation with disease activity. Antibody-mediated internalization of Mito+ RBCs induces type I interferon (IFN) production through activation of cGAS in macrophages. Accordingly, SLE patients carrying both Mito+ RBCs and opsonizing antibodies display the highest levels of blood IFN-stimulated gene (ISG) signatures, a distinctive feature of SLE.

Vignette-Based Utilities: Usefulness, Limitations, and Methodological Recommendations.

Health technology assessment agencies often prefer that utilities used to calculate quality-adjusted life years in cost-utility analyses (CUAs) are derived using standardized methods, such as generic preference-based measures completed by patients in clinical trials. However, there are situations when no standardized approach is feasible or appropriate for a specific medical condition or treatment that must be represented in a CUA. When this occurs, vignette-based methods are often used to estimate utilities. A vignette (sometimes called a "scenario," "health state description," "health state vignette," or "health state") is a description of a health state that is valued in a preference elicitation task to obtain a utility estimate. This method is sometimes the only feasible way to estimate utilities representing a concept that is important for a CUA. Consequently, vignette-based studies continue to be conducted and published, with the resulting utilities used in economic models to inform decision making about healthcare resource allocation. Despite the potential impact of vignette-based utilities on medical decision making, there is no published guidance or review of this methodology. This article provides recommendations for researchers, health technology assessment reviewers, and policymakers who may be deciding whether to use vignette-based methods, designing a vignette study, using vignette-based utilities in a CUA, or evaluating a CUA that includes vignette-based utilities. Recommendations are provided on: (A) when to use vignette-based utilities, (B) methods for developing vignettes, (C) valuing vignettes, (D) use of vignette-based utilities in models, and (E) limitations of vignette methods.

Health state utilities associated with treatment process for oral and injectable GLP-1 receptor agonists for type 2 diabetes.

PURPOSE: Previous research suggests that treatment process can have an influence on patient preference and health state utilities. This study examined preferences and estimated utilities for treatment processes of two daily oral treatment regimens and two weekly injectable regimens for treatment of type 2 diabetes (T2D). METHODS: Participants with T2D in the UK reported preferences and valued four health state vignettes in time trade-off utility interviews. The vignettes had identical descriptions of T2D but differed in treatment process: (1) daily simple oral treatment (tablets without administration requirements), (2) daily oral semaglutide (with administration requirements per product label), (3) weekly dulaglutide injection, (4) weekly semaglutide injection. RESULTS: Interviews were completed by 201 participants (52.7% male; mean age = 58.7). Preferences between treatment processes varied widely. Mean utilities were 0.890 for simple oral, 0.880 for oral semaglutide, 0.878 for dulaglutide injection, and 0.859 for semaglutide injection (with higher scores indicating greater preference). All pairwise comparisons found statistically significant differences between utilities (p < 0.01), except the comparison between oral semaglutide and the dulaglutide injection (p = 0.49). CONCLUSIONS: Results suggest that routes of administration cannot be compared using only the simplest descriptions (e.g., oral versus injectable). Dose frequency and specific details of the treatment process administration had an impact on patient preference and health state utilities. The utilities estimated in this study may be useful in cost-utility models comparing these treatments for T2D. Results also suggest that it may be helpful to consider patient preferences for treatment process when selecting medications for patients in clinical settings.

Extracutaneous involvement is common and associated with prolonged disease activity and greater impact in juvenile localized scleroderma.

OBJECTIVE: The aim of this study was to evaluate factors associated with extracutaneous involvement (ECI) in juvenile localized scleroderma (jLS). METHODS: A prospective, multicentre, 6-month observational study was performed. The data collected included disease features, global assessments, and subject symptoms. Bivariate and linear multilevel regression analyses were performed. RESULTS: A total of 86 jLS subjects (80% female, 80% Caucasian), median age of disease onset 7.7 years, were evaluated. Most had linear scleroderma or mixed morphea. Of the 86 subjects, 49 (57%) had 125 extracutaneous problems {median 2 [interquartile range (IQR) 1, 3] per subject} from nine organ systems. Most of these subjects had multiple musculoskeletal problems. ECI was associated with more extensive cutaneous involvement, higher number of symptoms, family history of autoimmunity, and ANA and RF positivity. Subjects with ECI had higher scores for physician global assessment of damage (PGA-D), and parental global assessment of disease impact, but not baseline physician global assessment of disease activity (PGA-A). Although subjects with ECI received more MTX and glucocorticoid treatment, they had a slower reduction in PGA-A scores and symptoms over time, suggesting a poorer response to treatment. In logistic regression modelling, female sex had the largest effect on parental impact scores. CONCLUSION: ECI occurred in the majority of subjects with jLS, and was associated with more medication use, longer treatment duration, higher PGA-D scores, and higher parental assessment of disease impact. Our findings suggest that jLS subjects with ECI have greater overall disease burden, both cutaneous and extracutaneous, and poorer response to treatment. More study of the treatment needs of this population is warranted.

Advances in the World of Bacterial Microcompartments.

Bacterial microcompartments (MCPs) are extremely large (100-400 nm) and diverse proteinaceous organelles that compartmentalize multistep metabolic pathways, increasing their efficiency and sequestering toxic and/or volatile intermediates. This review highlights recent studies that have expanded our understanding of the diversity, structure, function, and potential biotechnological uses of MCPs. Several new types of MCPs have been identified and characterized revealing new functions and potential new associations with human disease. Recent structural studies of MCP proteins and recombinant MCP shells have provided new insights into MCP assembly and mechanisms and raised new questions about MCP structure. We also discuss recent work on biotechnology applications that use MCP principles to develop nanobioreactors, nanocontainers, and molecular scaffolds.

A Scoring Algorithm for Deriving Utility Values from the Neuro-QoL for Patients with Multiple Sclerosis.

INTRODUCTION: The Neuro-QoL is a standardized approach to assessing health-related quality of life in people with neurological conditions, including multiple sclerosis (MS). Item banks were developed with item response theory (IRT) methodology so items are calibrated along a continuum of each construct. The purpose of this study was to develop a preference-based scoring algorithm for the Neuro-QoL to derive utilities that could be used in economic modeling. METHODS: With input from neurologists, 6 Neuro-QoL domains were selected based on relevance to MS and used to define health states for a utility elicitation study in the United Kingdom. General population participants and individuals with MS valued the health states and completed questionnaires (including Neuro-QoL short forms). The Neuro-QoL Utility Scoring System (NQU) was derived based on multi-attribute utility theory using data from the general population sample. Single-attribute disutility functions for 6 Neuro-QoL domains were estimated using isotonic regression with linear interpolation and then combined with a multiplicative model. NQU validity was assessed using MS participant data. RESULTS: Interviews were completed with 203 general population participants (50.2% female; mean age = 45.0 years) and 62 participants with MS (62.9% female; mean age = 46.1 years). Mean (SD) NQU scores were 0.94 (0.06) and 0.82 (0.13) for the general population and MS samples, respectively. The NQU demonstrated known-groups validity by differentiating among subgroups categorized based on level of disability. The NQU demonstrated convergent validity via correlations with generic measures (0.66 and 0.63 with EQ-5D-5L and Health Utilities Index Mark 3, respectively; both P < 0.001). DISCUSSION: With the NQU, utilities can be derived from any MS treatment group, subgroup, or patient sample who completes items from 6 Neuro-QoL domains. Because the Neuro-QoL is frequently used with MS patients, the NQU greatly expands the options for quantifying outcomes in cost-utility analyses conducted to inform allocation of resources for MS treatment.