An explanatory sequential mixed-methods design to establish thresholds of within-individual meaningful change on a sleep disturbance numerical rating scale score in atopic dermatitis.

PURPOSE: Establishing a meaningful within-individual change (MWIC) threshold is a key aspect for interpreting scores used as endpoints for evaluating treatment benefit. A new patient-reported outcome (PRO), a sleep disturbance numerical rating scale (SD NRS), was developed in adults and adolescents with moderate-to-severe atopic dermatitis (AD). This research aims to establish a MWIC threshold of the SD NRS score in the context of a drug development program. METHODS: An explanatory sequential mixed-methods design was used to address the research objective. This mixed-methods design used phase IIb data and a stand-alone qualitative study. Quantitative anchor-based and distribution-based approaches supported by qualitative-based approaches were conducted, and results were triangulated to determine preliminary MWIC thresholds of the SD NRS score. RESULTS: Triangulation of results from both quantitative and qualitative approaches suggested that a 2- to 6-point decrease in the SD NRS score change constitutes a preliminary range of MWIC threshold estimates. CONCLUSION: This research determined MWIC threshold estimates for the SD NRS score in both adolescents and adults with moderate-to-severe AD using an explanatory sequential mixed-methods design. This mixed-methods design provides interesting insights for establishing MWIC thresholds of a PRO score in the context of a drug development program.

Application of the RE-AIM framework to evaluate the implementation of telehealth pulmonary rehabilitation in a randomized controlled trial among African-American and Hispanic patients with advanced stage Chronic Obstructive Pulmonary Disease.

BACKGROUND: Pulmonary rehabilitation (PR) decreases rehospitalization for people with COPD. However, less than 2% receive PR, partly due to lack of referral and sparsity of PR facilities. This disparity is particularly pronounced in African American and Hispanic persons with COPD. Telehealth-provided PR could increase access and improve health outcomes. METHODS: We applied the RE-AIM framework in a post-hoc analysis of our mixed methods RCT comparing referral to Telehealth-delivered PR (TelePR) versus standard PR (SPR) for African American and Hispanic COPD patients hospitalized for COPD exacerbation. Both arms received a referral to PR for 8 weeks, social worker follow-up, and surveys administered at baseline, 8 weeks, 6, and 12 months. PR sessions were conducted twice a week for 90 min each (16 sessions total). Quantitative data were analyzed using 2-sample t tests or nonparametric Wilcoxon tests for continuous data and χ2/Fisher exact tests for categorical data. Logistic regression-estimated odds ratios (ORs) were used for the intention-to-treat primary outcome. Qualitative interviews were conducted at the end of the study to assess adherence and satisfaction and were analyzed using inductive and deductive methods. The goal was to understand Reach (whether the target population was able to be enrolled), Effectiveness (primary outcome was a composite of 6-month COPD rehospitalization and death), Adoption (proportion of people willing to initiate the program), Implementation (whether the program was able to be executed as intended, and Maintenance (whether the program was continued). RESULTS: Two hundred nine people enrolled out of a 276-recruitment goal. Only 85 completed at least one PR session 57/111 (51%) TelePR; 28/98 (28%) SPR. Referral to TelePR compared to SPR did not decrease the composite outcome of 6-month COPD-readmission rate/death (OR1.35;95%CI 0.69,2.66). There was significant reduction in fatigue (PROMIS® scale) from baseline to 8-weeks in TelePR compared to SPR (MD-1.34; ± SD4.22; p = 0.02). Participants who received TelePR experienced improvements from baseline in several outcomes (ie, before and after 8 weeks of PR) in the following: COPD symptoms, knowledge about COPD management, fatigue, and functional capacity. Among the patients who had 1 initial visit, adherence rates were similar (TelePR arm, 59% of sessions; SPR arm, 63%). No intervention-related adverse events occurred. Barriers to PR adoption included difficulty or reluctance to complete medical clearances and beliefs about PR efficacy. Notably, only 9 participants sustained exercise after program completion. Maintenance of the program was not possible due to low insurance reimbursement and sparsity of Respiratory Therapists. CONCLUSIONS: TelePR can reach COPD patients with health disparities and can be successfully implemented. The small sample size and large confidence intervals prevent conclusion about the relative effectiveness of participating in TelePR compared to SPR. However, improved outcomes were seen for those in TelePR as well as in SPR. Increasing adoption of PR and TelePR requires consideration of comorbidity burden, and perception of PR utility, and must facilitate medical clearances. Given the sparsity of SPR locations, TelePR can overcome at least the barrier of access. However, given the challenges to the uptake and completion of PR - many of the additional barriers in PR (both in TelePR and SPR) need to be addressed. Awareness of these real-world challenges will not only inform implementation of TelePR for clinicians seeking to adopt this platform but will also inform study designers and reviewers regarding the feasibility of approaches to patient recruitment and retention.

Socioeconomic gradients in cancer incidence by race and ethnicity in California, 2008-2012: the influence of tobacco use or screening detectable cancers.

PURPOSE: There are clearly documented inequalities in cancer incidence by socioeconomic position, but it is unclear whether this is due primarily to differences in tobacco exposure and screening practices or to other factors. METHODS: Our study included 741,373 incident cases of invasive cancer from 2008 to 2012 in California. We calculated age-standardized incidence rates across twelve categories of census tract poverty as a measure of socioeconomic position (SEP) for (1) all cancer sites combined, (2) sites not strongly related to tobacco use, (3) sites not related to screening, and (4) sites not related to tobacco use or screening. RESULTS: There was higher cancer incidence among those living in areas with higher levels of poverty for sites not strongly related to tobacco use or screening, among Whites, Blacks, and Asians, but not among Latinos. Among Whites there was no relationship with census tract poverty at lower levels of poverty-the relationship with cancer incidence was primarily among those in higher poverty. For Blacks and Asians, there is a more linear relationship with cancer incidence across levels of poverty. CONCLUSIONS: SEP gradients in cancer incidence remain after exclusion of cancer sites strongly related to tobacco use and screening. Our findings demonstrate a need for research on other environmental and social causes of cancer where exposures are differentially distributed by SEP.

Contribution of clinical and socioeconomic factors to differences in breast cancer subtype and mortality between Hispanic and non-Hispanic white women.

PURPOSE: To assess tumor subtype distribution and the relative contribution of clinical and sociodemographic factors on breast cancer survival between Hispanic and non-Hispanic whites (NHWs). METHODS: We analyzed data from the California Cancer Registry, which included 29,626 Hispanic and 99,862 NHW female invasive breast cancer cases diagnosed from 2004 to 2014. Logistic regression was used to assess ethnic differences in tumor subtype, and Cox proportional hazard modeling to assess differences in breast cancer survival. RESULTS: Hispanics compared to NHWs had higher odds of having triple-negative (OR = 1.29; 95% CI 1.23-1.35) and HER2-overexpressing tumors (OR = 1.19; 95% CI 1.14-1.25 [HR-] and OR = 1.39; 95% CI 1.31-1.48 [HR+]). In adjusted models, Hispanic women had a higher risk of breast cancer mortality than NHW women (mortality rate ratio [MRR] = 1.24; 95% CI 1.19-1.28). Clinical factors accounted for most of the mortality difference (MRR = 1.05; 95% CI 1.01-1.09); however, neighborhood socioeconomic status (SES) and health insurance together accounted for all of the mortality difference (MRR = 1.01; 95% CI 0.97-1.05). CONCLUSIONS: Addressing SES disparities, including increasing access to health care, may be critical to overcoming poorer breast cancer outcomes in Hispanics.

Trends in early-stage hepatocellular carcinoma, California 1988-2010.

PURPOSE: California Cancer Registry data were used to explore the impact of hepatocellular carcinoma (HCC) surveillance on patient outcomes. The purpose of this analysis was to determine the trend in diagnosis of early-stage HCC in California from 1988 to 2010. METHODS: Patients 20+ years old, diagnosed with early HCC during 1988-2010 in California, were included. Stratified proportions of early HCC were evaluated to estimate any trends and significant disparities. The primary endpoint was the average annual percent change (AAPC) of the proportion of early-stage HCC; 2- and 5-year survival trends were calculated for age, sex, race, SES, and stage. RESULTS: A total of 13,855 patients were diagnosed with early HCC. The proportion of patients diagnosed early increased from 19.2 to 49.2 % between 1988 and 2010, at an AAPC of 4.3 %. The proportion of cases diagnosed with early HCC increased in all demographic groups. Both the 2- and 5-year cause-specific survival analyses showed that survival among HCC patients has been increasing since 1988. CONCLUSION: The proportion of HCC cases diagnosed early, and the 2- and 5-year survival trends of all HCC patients have increased in California since 1988. It is not entirely clear whether better diagnostic imaging or better surveillance has led to these findings and whether earlier diagnosis has led to improved patient survival. This increase in survival among patients with HCC may be correlated with the innovation of new treatments and most importantly that patients are being diagnosed earlier to receive such treatments.

Validation of the Onset of Effect Questionnaire in Participants With Chronic Obstructive Pulmonary Disease.

Background: Patient perception of medication onset of effect is important for adherence. Although the Onset of Effect Questionnaire (OEQ) has been validated in patients with asthma, it has not been evaluated in patients with chronic obstructive pulmonary disease (COPD). This study evaluated the COPD-OEQ in patients with COPD. Methods: Two analyses (qualitative and quantitative) were conducted to assess the content validity and psychometric properties of the COPD-OEQ in participants with COPD. In the qualitative analysis, interviews assessed content validity by concept elicitation (CE) and cognitive interviewing (CI). CE included questions to understand patient experience related to onset of medication effect. CI included completion of the COPD-OEQ and assessment of the COPD-OEQ items, response options, and instructions. During the 2-week quantitative analysis, 2 versions of the COPD-OEQ (Weekly and Daily) were administered to assess test-retest reliability, construct validity, and known-groups validity. Results: The qualitative analysis demonstrated that 3 of the 5 COPD-OEQ items were relevant and understood as intended. Qualitative findings demonstrated inconsistent evidence that the COPD-OEQ Weekly and Daily were reliable and valid measures in participants with COPD. Test-retest reliability was observed for the COPD-OEQ Weekly and Daily; however, construct validitywas weak and demonstrated inconsistent correlations among COPD-OEQ items. Overall, known-groups validity was not demonstrated. Conclusion: The weak evidence from the quantitative analysis of the COPD-OEQ Weekly and Daily tools does not support use of the OEQ in general COPD. The study supports the content validity for the assessment of perceived onset of effect in patients with COPD.

Validation of the Peak Pruritus Numerical Rating Scale as a Patient-Reported Outcome Measure in Prurigo Nodularis.

INTRODUCTION: Validated patient report tools for quantifying patient experiences of itch in prurigo nodularis (PN) are limited. This study aimed to evaluate the validity of the 11-point peak pruritus numerical rating scale (PP NRS) as a single-item patient-reported outcome (PRO) measure for assessing itch severity in PN. METHODS: Content validity of the PP NRS was evaluated through qualitative interviews with adults with PN. The PP NRS was then psychometrically evaluated using data from a placebo-controlled trial of nemolizumab in adults with PN, during which patients completed the PP NRS daily. Meaningful within-patient change was estimated from the qualitative interviews and by anchor- and distribution-based analyses of trial data. RESULTS: The interview participants (N = 21) all understood the PP NRS and reported itch as their worst symptom overall. The PP NRS showed good test-retest reliability and demonstrated convergent validity and known-groups validity. PP NRS scores improved more in patients classified as "improved" on other clinical outcome measures than in those classified as "worsened/unchanged". Triangulation of the different estimates identified a 2- to 5-point decrease in PP NRS score as a meaningful within-patient change threshold. CONCLUSION: The PP NRS is a content-valid and reliable PRO measure for quantifying itch severity in adults with PN in clinical trials. TRIAL REGISTRATION NUMBER: NCT03181503.

Prurigo nodularis is a skin disease where the skin becomes inflamed and very itchy. Itching and scratching can ruin the lives of people with prurigo nodularis. For doctors to know how well treatments for prurigo nodularis are working, they need to be able measure how bad their patients' itching is. Here we tested whether a tool called the peak pruritus numeric rating scale (PP NRS) can be used to reliably measure itching in patients with prurigo nodularis. The PP NRS asks patients to rate their itch "at the worst moment during the previous 24 h" on a scale from 0 ("no itch") to 10 ("worst itch imaginable"). We interviewed 21 patients with prurigo nodularis. Overall, itch was their worst symptom. They were able to use the PP NRS with few or no problems. To further explore whether the PP NRS can be used by patients with prurigo nodularis, we also obtained data from a clinical study. In this clinical study, patients with prurigo nodularis received a drug that might one day be used to treat their disease. They completed the PP NRS daily during the time they received the drug. When we analyzed the data from the clinical study, we found that the PP NRS has the properties a tool like this needs to be useful. We also concluded that a decrease of 2­5 points on the PP NRS scale would be a meaningful improvement in itching for patients with prurigo nodularis.

The Sleep Disturbance Numerical Rating Scale: Content Validity, Psychometric Validation, and Meaningful Within-Patient Change in Prurigo Nodularis.

INTRODUCTION: Sleep is often disturbed in patients with prurigo nodularis (PN). To address the lack of validated patient-reported outcome (PRO) measures for quantifying sleep disturbance in PN, we evaluated the Sleep Disturbance Numerical Rating Scale (SD NRS) as a single-item PRO measure for quantifying sleep disturbance in PN. METHODS: Adults with PN participated in qualitative interviews, which included concept elicitation and cognitive debriefing of the SD NRS. The SD NRS was evaluated psychometrically using data from a phase 2 randomized trial in adults with PN (NCT03181503). Other PRO assessments included the Average Pruritus (AP) NRS, AP Verbal Rating Scale (VRS), peak pruritus (PP) NRS, PP VRS, and Dermatology Life Quality Index (DLQI). Reliability, validity, and responsiveness of the SD NRS were evaluated, and meaningful within-patient change was estimated from qualitative interview responses and quantitative trial data. RESULTS: All interview participants (N = 21) experienced sleep disturbance and most (95%) understood the SD NRS as intended. The SD NRS demonstrated test-retest reliability based on intra-class correlation coefficients for itch-stable participants of 0.87 for the AP VRS and 0.76 for the PP VRS. At baseline, Spearman's rank-order correlation coefficients were moderate to strong (0.3-0.8) between the SD NRS and the AP NRS, AP VRS, PP NRS, PP VRS, and DLQI. Known-groups validity was demonstrated by higher (worse) SD NRS scores in participants with worse scores on the AP NRS, AP VRS, PP VRS, and DLQI. Improvements in SD NRS scores were greater in participants classified as "improved" versus "worsened/unchanged" on the anchor PROs. A 2- to 4-point decrease on the 11-point SD NRS scale was identified as a meaningful within-patient change. CONCLUSION: The SD NRS is a well-defined, reliable, and valid PRO measure that can be used in daily practice and clinical trials to capture sleep disturbance in adults with PN.

Patients with the skin disease prurigo nodularis often sleep badly because their skin is very itchy in the evening and at night. In assessing the effectiveness of new treatments for prurigo nodularis, it is useful to know whether patients sleep better when taking them. Here, we tested whether the "Sleep Disturbance Numerical Rating Scale" (SD NRS), a tool for measuring sleep, can be used by patients with prurigo nodularis. The SD NRS asks patients to score their sleep loss during the previous night on a scale of 0 ("no sleep loss") to 10 ("I did not sleep at all"). When we interviewed 21 patients with prurigo nodularis, 19 of them had problems falling asleep and 18 of them woke up every night. Most of the patients found the SD NRS easy to use. To further explore whether the SD NRS is suitable for patients with prurigo nodularis, we also analyzed data from a European clinical study in which patients with prurigo nodularis received nemolizumab, a new treatment being developed for the disease. Patients completed the SD NRS each morning during the clinical study. We found that the SD NRS has the necessary properties to be useful for assessing sleep on a daily basis. We also determined that a 2- to 4-point decrease on the SD NRS scale would represent a meaningful improvement in sleep for patients with prurigo nodularis. We conclude that the SD NRS is a useful tool for assessing sleep in prurigo nodularis patients participating in clinical studies.

Patient Perspectives on Living With Severe Prurigo Nodularis.

Importance: Because of a paucity of qualitative research on prurigo nodularis (PN), the symptoms and impacts of PN that are most important to patients are poorly understood. Objective: To explore patients' perspectives on their PN symptoms and to understand the impacts of the condition. Design, Setting, and Participants: One-on-one qualitative telephone interviews were held with English-speaking US adults aged 18 years or older with a confirmed diagnosis of PN, severe pruritus, and moderate to severe sleep disturbance. Participants were recruited via patient associations, patient panels, and social media posts. Interviews took place between September 10, 2020, and March 16, 2021. Main Outcomes and Measures: The main symptoms of PN and their impacts on quality of life were identified by content analysis of deidentified interview transcripts. Results: A total of 21 adults with PN (mean [SD] age, 53.1 [11.8] years; 15 [71%] female; 2 African American or Black patients [10%], 1 Asian patient [5%], and 18 White patients [86%]; of these, 1 patient [ 5%] had Hispanic or Latino ethnicity) participated in the interviews. All participants reported itch, pain associated with PN, bleeding or scabbing, and dry skin. Other frequently reported symptoms included lumps or bumps (95%), having a crust on the skin (95%), burning (90%), stinging (90%), lesions or sores (86%), skin discoloration (86%), and raw skin (81%). Of the 17 participants who indicated what their worst symptoms were, 15 (88%) identified itching as the worst or 1 of the worst symptoms. The most frequently reported impacts of PN for quality of life were changes in sleep (100%), daily life (100%), feelings or mood (95%), relationships (95%), social life (81%), and work or school (71%). Overall, the worst impact of PN was its association with impaired feelings or mood. Conclusions and Relevance: This qualitative study suggests the importance of itching, sleep disturbance, and other symptoms and impacts of PN. This information can be used to guide end point selection in clinical trials and to inform patient-centric decision-making in clinical practice.

Consistently High Agreement Between Independent Raters of Niemann-Pick Type C1 Clinical Severity Scale in Phase 2/3 Trial.

BACKGROUND: Niemann-Pick disease, type C1 (NPC1) is a rare neurodegenerative genetic disorder characterized by impaired intracellular transport of cholesterol and other lipids. The Niemann-Pick Disease, type C1 Severity Scale (NPC-SS) was developed to quantify neurological progression of NPC; it is used to monitor the natural history of disease progression and assess response to treatment. The objective of the study was to examine the interrater reliability of the NPC-SS in a phase 2/3 trial. METHODS: Study data were from a multicenter, prospective, randomized, double-blind trial of adrabetadex in 56 subjects with NPC1. Clinical data recorded at each study site were distributed to two independent blinded central raters to generate a severity score. A composite four-item score was utilized as the primary clinical study end point, whereas a five-item focused score has been utilized in other NPC1 trials. Interrater reliability was assessed using two-way mixed models for instrument stability, Cohen kappa, weighted kappa, and percent agreement for the four- and five-item scores. RESULTS: The frequency distribution and mean (S.D.) of the NPC-SS domain assessments by the raters were almost identical. Evaluation at the patient visit level showed wide variability between visits; however, weighted kappa calculation provided a lower variability between visits. The average kappa coefficients ranged between 0.69 and 0.89, indicating good to very good agreement between raters. CONCLUSIONS: These results support the NPC-SS, including derived four- and five-item composite scores, as reliable measures for use in a clinical trial setting.

Changing Incidence of Metastatic Prostate Cancer by Race and Age, 1988-2015.

BACKGROUND: Screening for prostate cancer (PCa) has dramatically declined in the United States (US) since the United States Preventive Services Task Force recommended against routine prostate-specific antigen (PSA)-based PCa screening in all men in 2012. This led to dramatic reductions in the diagnosis of localized disease across all clinical risk groups. OBJECTIVE: In light of decreased PSA screening for men in the US, we sought to study trends in newly diagnosed metastatic PCa incidence and how this may vary by race and age. DESIGN, SETTING, AND PARTICIPANTS: We analyzed new PCa incidence by stage at diagnosis between 1988 and 2015 within the Cancer Registry of Greater California. We further stratified the patients by age and four major race/ethnicity groups (Hispanic, non-Hispanic white [NHW], non-Hispanic black [NHB], and non-Hispanic Asian/Pacific Islander [API]). Incidence rates were calculated and compared per 100000 and age-adjusted to the 2000 US standard population. OUTCOME MEASUREMENT AND STATISTICAL ANALYSIS: The primary outcome was incidence of metastatic PCa at the time of cancer diagnosis. Joinpoint regression program was used to detect changes in incidence and to calculate the average percent change (APC) over time. All data were analyzed using SEER*Stat version 8.1.15 and Joinpoint Regression Program version 4.1.0, and a two-sided p value of <0.05 was considered statistically significant. RESULTS AND LIMITATIONS: Adjusted rates of metastatic PCa incidence for NHW men significantly increased by 4.3% since 2010, while remaining down (NHB, Hispanic) or level (API) for other racial groups. Stratified by age, incidence of metastatic disease for all races has increased significantly for men aged 64-75 yr since 2008 with an APC of 2.8% while remaining level for other age groups. The limitations of our study include retrospective design and no data on extent of PSA screening in the study cohort. CONCLUSIONS: Incidence rates of newly diagnosed metastatic PCa have significantly increased for NHW men and men aged 65-74 yr. PATIENT SUMMARY: Prostate-specific antigen screening has declined in the Unites States with a subsequent sharp drop in the incidence of screen-detected localized prostate cancer. The incidence of men presenting with metastatic disease seems to be rising recently, and men should continue to discuss the benefits of PSA screening with their primary care doctor.

The complete mitochondrial genome of Xiphister atropurpureus (Perciformes: Stichaeidae).

Analysis of the marine black prickleback Xiphister atropurpureus Kittlitz using 76 bp paired-end Illumina sequences resulted in the assembly of its complete mitogenome. The mitogenome is 16,518 bp in length and contains an origin of light strand replication (OL), control region, 22 tRNA, 2 rRNA, and 13 protein-coding genes. Content and organization of the X. atropurpureus mitogenome is consistent with other teleost. Phylogenetic analysis of X. atropurpureus resolves it in a clade with another member of the Stichaeidae, Chirolophis japonicus Herzenstein.

Age, period, and cohort effects in adult lifetime asthma prevalence in California: an application of hierarchical age-period-cohort analysis.

PURPOSE: Using 27 years of survey data, the contributions of age, period, and cohort effects on the increase in adult lifetime asthma prevalence in California were examined. METHODS: Lifetime asthma diagnosis for adults was assessed in 1984-1992 and 1995-2011 through the California Behavioral Risk Factor Surveillance System, an annual, cross-sectional, population-based survey (n = 144,100). Using date of survey and date of birth, we classified 18,305 adult respondents with lifetime asthma into 7 age groups, 6 periods, and 17 cohorts. Using hierarchical, cross-classified random effects models, birth cohort, period, and age patterns in adult lifetime asthma prevalence were analyzed. RESULTS: After adjusting for sex, ethnicity, education, and smoking, age effects peak in young adulthood, flatten from 40 to 60 years old, and then decrease in older adulthood. A significant positive trend in asthma prevalence was observed in the two earliest survey periods (1984-1993; P value < .0001). Survey period trends appear to flatten beginning in 2004. Although the overall birth cohort effect was statistically significant, the magnitude of the effect for each birth cohort category was small (P value = .0005). CONCLUSIONS: We observed that strong age and period effects have been driving the increase in lifetime asthma prevalence in California over the past 3 decades.

COST SAVINGS AND PALLIATIVE CARE REFERRALS FROM THE EMERGENCY DEPARTMENT.

Early palliative care consultation ha the potential to provide comfort to patients and families, and decrease costs and length of stay.