Exploring the Content Validity of the Unified Wilson Disease Rating Scale: Insights from Qualitative Research.

INTRODUCTION: Wilson disease (WD) is a rare metabolic disorder of impaired copper transport manifesting in hepatic, neurological, and psychiatric symptoms. To evaluate the clinical symptoms of WD in clinical trials, a group of clinicians created the Unified Wilson Disease Rating Scale (UWDRS). Content validity of this scale has not been established. The aim of this study was to evaluate the content validity of the UWDRS Part II from the patient perspective. METHODS: This study utilized multiple qualitative research methods including concept elicitation interviews, concept/instrument mapping, and cognitive debriefing interviews. RESULTS: Concept elicitation interviews with a sample of patients with WD and one or more neurological signs/symptoms identified several signs, symptoms, and impacts related to neurological dysfunction, strengthening our understanding of the importance of the neurological aspects of the WD patient experience. Mapping neurological concepts to Part II and III items of the UWDRS showed complete coverage of all salient neurological concepts and near complete coverage of all neurological concepts reported by patients in concept elicitation interviews. Item debriefing of Part II of the UWDRS revealed that patients generally found the items clear and personally relevant to their experience with WD. CONCLUSION: Overall, the findings from this study provide evidence for the content validity of the UWDRS Part II and supportive evidence for the content validity of Part III. The UWDRS should be used in conjunction with additional clinical outcomes assessments, specifically those evaluating the hepatic and psychiatric signs/symptoms of WD, to provide a comprehensive evaluation of the WD patient experience.

The patient experience of Wilson disease: a conceptual model based on qualitative research.

BACKGROUND: Wilson disease (WD) is a rare disease wherein copper accumulates in tissues, leading to hepatic degeneration, neurological impairments, and psychiatric symptoms. This study aimed to characterize the patient experience of WD and develop a conceptual model containing key symptoms and impacts of the disease. RESULTS: A targeted literature review was conducted to develop a preliminary conceptual model of WD that was subsequently refined through one-on-one interviews with 3 WD clinicians and finalized following concept elicitation interviews with 11 patients and 1 caregiver. The literature review returned 30 articles, from which 45 concepts (35 signs/symptoms and 10 impacts) were selected for inclusion in the preliminary conceptual model. After interviews with clinicians, the model was expanded to include 45 signs/symptoms and 14 impacts. The final comprehensive conceptual model developed after interviews with patients included 54 symptoms in total (n = 22 hepatic, n = 19 neurological, n = 13 psychiatric), and 21 impacts. Across symptoms, patients reported a high level of bother, with approximately 49% of symptoms reported by patients having an average peak bother rating of ≥ 7 out of 10 (10 = most bothersome). Patient interviews identified 2 subgroups of patients: those who experience neurological, psychiatric, and hepatic symptoms and those who experience mostly hepatic and some psychiatric symptoms, but no neurological symptoms. CONCLUSIONS: This research underscores the substantial multisystemic symptoms and impacts that patients with WD describe as highly bothersome in their lives. Hepatic symptoms emerged as especially common and important to patients with WD, possibly beyond what is commonly understood in research and clinical practice. Further, the description of 2 distinct patient groups may help to inform patient management and support more targeted drug development processes.

Influence of titration of antiseizure medications on treatment selection: Results of an online survey with clinicians in the United States.

INTRODUCTION: Most antiseizure medications (ASM) need to be titrated before the optimal dose is achieved. Titration can last several weeks to months. We assessed the impact titration schedules have on ASM treatment-related decisions in the United States (US). METHODS: An online survey was conducted with different healthcare providers (HCPs) in the US involved in the treatment and management of patients with epilepsy. The survey contained three sections: the first section with screening questions; the second on key factors that influence a HCP's decision-making when selecting treatments for different types of seizures and different treatment lines; and the third on the HCP's knowledge and perceptions regarding ASM titration for the treatment of patients with epilepsy. RESULTS: One-hundred and fifty HCPs (63% neurologists) completed the survey. Most HCPs considered titration schedule to be important, with only 1-3% of HCPs, depending on type of seizure, considering the titration schedule to be "not important at all" when prescribing therapy. Healthcare providers' acceptance of titration increased with shorter durations (≥50% accepted titration periods of ≤2 weeks), and lower number of tablets/capsules per dose (≥50% accepted ≤3 tablets/capsules per dose), doses (≥50% accepted ≤2 doses/day), and steps (≥50% accepted ≤3 steps/dose change). Most HCPs (68-91% depending on type of seizure) considered a titration duration of 6 or more weeks only somewhat acceptable or somewhat or highly unacceptable. Almost all HCPs selected "somewhat familiar", "familiar", or "very familiar" as the attribute that best defines their knowledge level of titration, with only 4% selecting "a little familiar". While 87% of HCPs agreed or strongly agreed that they could easily understand titration schedules, only 27% of them agreed or strongly agreed that patients could easily understand titration schedules and 58% of HCPs considered that adhering to the titration schedule was difficult for patients. Most HCPs agreed or strongly agreed that a complex or long titration schedule renders it difficult to achieve their treatment objectives. CONCLUSIONS: Healthcare providers take into account the duration and complexity of the titration period in their ASM prescribing decision-making and prefer shorter and simpler titration schedules, particularly for patients who are experiencing convulsive seizures and starting monotherapy. There was a clear difference between the HCP's belief in their own ability to understand a titration schedule, and their belief that the patient would be able to follow the titration schedule appropriately.

Identification of multiple transcripts for antioxidant protein 2 (Aop2): differential regulation by oxidative stress and growth factors.

Antioxidant protein 2 is a unique member of the thiol-specific antioxidant family of proteins known to reduce reactive oxygen species in the presence of thiol-containing electron donors. It is also a candidate atherosclerosis susceptibility gene in mice. In the present study, we sought to characterize the transcripts of this gene, and determine which, if any, are regulated by conditions associated with oxidative stress. We have identified multiple Aop2 transcripts by Northern blot, each exhibiting a unique tissue distribution. These include the previously reported 1.47 kb major transcript, two alternative Aop2 transcripts found exclusively in liver, and a testis-specific transcript believed to be the highly related intronless gene Aop2-rs1. Treatment of a murine hepatocyte cell line with glucose oxidase led to the specific and transient induction of the 1.47 kb transcript, while the 3.1 kb transcript was regulated by serum deprivation and re-stimulation with either keratinocyte growth factor or serum in a time-dependent manner. Since these ROS-inducing stimuli involve different mechanisms of action and cellular responses, our data suggest that alternative Aop2 transcripts may play distinct roles in different oxidative stress responses, and possibly in atherosclerosis.