Cutaneous Manifestations in Patients with Dermatomyositis, Are They Only Skin Deep?

Background: Dermatomyositis (DM) is a rare and severely debilitating autoimmune disease that can affect children and adults; however, there is little understanding of the patient-reported experience and uncertainty around validated clinical outcomes assessments (COAs) that could measure changes in the condition during clinical trials of new treatments.

Objectives: The aim of this study was to understand the patient experience of DM, with a focus on its cutaneous manifestations, to describe the patient experience and determine the suitability of existing COA measures.

Methods: Adult (≥ 18 years) patients (N = 28) with severe active cutaneous manifestations of DM were interviewed.

Patient Experience of Hepatocellular Carcinoma and Their Treatment Goals: An International Qualitative Study and Patient Journey Map.

Introduction: Understanding the patient journey of hepatocellular carcinoma (HCC) may inform future clinical decision-making and enhance the patient experience. The objectives of this study were to explore the patient experience of HCC in relation to treatment options, treatment decision-making and treatment goals throughout the disease journey. This study also aimed to determine the symptoms and impacts of HCC across early, intermediate and advanced HCC.

Development of the Cutaneous Dermatomyositis Investigator Global Assessment (CDM-IGA): A De Novo IGA of Cutaneous Manifestations of Dermatomyositis.

Introduction: Dermatomyositis (DM) is a rare systemic autoimmune disease characterized by a distinctive debilitating skin rash and skeletal muscle weakness. It is unclear if existing clinical outcome assessment (COA) measures include the concepts of priority to patients and those necessary to fully capture improvements in the active cutaneous manifestations of DM. This study aimed to develop the Cutaneous Dermatomyositis Investigator Global Assessment (CDM-IGA), a de novo IGA, for use in clinical trials of adult DM.

Understanding alcohol use and changes in drinking habits among people with a severe mental illness: a qualitative framework analysis study.

Introduction: Individuals with a severe mental illness (SMI) are more likely to drink at harmful levels or abstain. While it is known that drinking patterns change over time, the reasons for this among those with a SMI are unclear. This study aimed to (i) explore the experiences with alcohol, particularly in relation to mental health symptoms, and (ii) how drinking patterns have changed over time, among individuals who have a SMI diagnosis, who either currently drink alcohol or no longer drink.

Are commonly used lab-based measures of food value and choice predictive of self-reported real-world snacking? An ecological momentary assessment study.

Objectives: While the assessment of actual food intake is essential in the evaluation of behaviour change interventions for weight-loss, it may not always be feasible to collect this information within traditional experimental paradigms. For this reason, measures of food preference (such as measures of food value and choice) are often used as more accessible alternatives. However, the predictive validity of these measures (in relation to subsequent food consumption) has not yet been studied.

A scoping review of outdoor food marketing: exposure, power and impacts on eating behaviour and health.

Background: There is convincing evidence that unhealthy food marketing is extensive on television and in digital media, uses powerful persuasive techniques, and impacts dietary choices and consumption, particularly in children. It is less clear whether this is also the case for outdoor food marketing. This review (i) identifies common criteria used to define outdoor food marketing, (ii) summarises research methodologies used, (iii) identifies available evidence on the exposure, power (i.

Use of motivational interviewing in behavioural interventions among adults with obesity: A systematic review and meta-analysis.

This review aimed to identify whether motivational interviewing (MI) (a counselling approach for supporting behaviour change [BC]) helps to reduce bodyweight and BMI in an adult obesity context. This included evaluating effectiveness of MI interventions within this population and reporting the methodology used, including theoretical underpinnings and identification of BC and MI techniques. Eight databases were searched using controlled vocabulary.

Identification of Behavior Change Techniques From Successful Web-Based Interventions Targeting Alcohol Consumption, Binge Eating, and Gambling: Systematic Review.

Background: Web-based interventions are thought to overcome barriers to treatment, such as accessibility and geographical location, which can undermine the effectiveness of traditional face-to-face interventions. Owing to these features, researchers are increasingly testing the efficacy of web-based interventions as ways to reduce alcohol misuse, binge eating, and gambling. However, many web-based interventions have poorly defined mechanisms of action; therefore, it is often uncertain how they propose to bring about behavior change.

Welcome to volume 9 of Therapeutic Delivery.

Happy New Year to all of our readers! Welcome to volume 9 of Therapeutic Delivery. We would like to take the opportunity to look back over 2017, which was another excellent year for us. We thank all our readers, reviewers, authors and Editorial Board members for their continued support and very much look forward to working with all our contributors again in 2018.

Hydroxyvitamin D assays: An historical perspective from DEQAS.

Recent years have seen a substantial increase in demand for 25-hydroxyvitamin D (25-OHD) assays. DEQAS (the Vitamin D External Quality Assessment Scheme) has been monitoring the performance of these assays since 1989. The first DEQAS distribution was in June 1989 and results were submitted by 13 laboratories in the UK, two of which used HPLC/UV; the rest used ligand binding assays with a tritium tracer.

Quality assessment of vitamin D metabolite assays used by clinical and research laboratories.

The Vitamin D External Quality Assessment Scheme (DEQAS) was launched in 1989 and monitors the performance of 25-hydroxyvitamin D (25-OHD) and 1,25- dihydroxyvitamin D (1,25(OH)D) assays. In April 2015 a pilot scheme for 24,25-dihydroxyvitamin D (24,25(OH)D) was introduced. The 25-OHD scheme is accuracy - based with target values assigned by the NIST Reference Measurement Procedure (RMP) for 25-OHD and 25-OHD.

Studies on the analysis of 25-hydroxyvitamin D(3) by isotope-dilution liquid chromatography-tandem mass spectrometry using enzyme-assisted derivatisation.

The total serum concentration of 25-hydroxyvitamins D (25-hydroxyvitamin D3 and 25-hydroxyvitamin D2) is currently used as an indicator of vitamins D status. Vitamins D insufficiency is claimed to be associated with multiple diseases, thus accurate and precise reference methods for the quantification of 25-hydroxyvitamins D are needed. Here we present a novel enzyme-assisted derivatisation method for the analysis of vitamins D metabolites in adult serum utilising 25-[26,26,26,27,27,27-(2)H6]hydroxyvitamin D3 as the internal standard.

Proficiency testing of 25-hydroxyvitamin D (25-OHD) assays.

The Vitamin D External Quality Assessment Scheme (DEQAS) has been monitoring 25-OHD assay performance since 1989. The scheme has expanded rapidly in recent years and has 670 participants in 35 countries (July 2009). Five samples of human serum are distributed quarterly and the results analyzed to give an All-Laboratory Trimmed Mean (ALTM) and SD.

Contemporary diagnosis and treatment of vitamin D-related disorders.

Plasma 25(OH)D has emerged as a valuable biomarker for the many varied health-related effects of vitamin D in the clinic mainly because of the recognition of the importance of the enzyme, CYP27B1, or the 25(OH)D-alpha-hydroxylase in the extrarenal, target cell production of calcitriol. This review briefly assesses current methodology for plasma 25(OH)D assay focusing mainly on currrent controversies surrounding the definition of the normal range and performance characteristics of the assay, separate measurement of both 25(OH)D(2) and 25(OH)D(3), and quality assurance tesing of laboratories offering the test. Clinicians have two main types of 25(OH)D assay based on either high-performance liquid chromatography with UV or mass detection or higher throughput kits based on protein (competitive protein binding assay or radioimmunoassay) binding.

Measurement of Vitamin D metabolites: an international perspective on methodology and clinical interpretation.

The International Quality Assessment Scheme for Vitamin D metabolites (DEQAS) was introduced in 1989. Initially, the aim was to improve the reliability of 25-hydroxyvitamin D (25-OHD) assays but the scheme was extended in 1997 to include 1,25-dihydroxyvitamin D (1,25(OH)(2)D). DEQAS has 95 members in 18 countries (January 2003).

Insights into Vitamin D metabolism using cyp24 over-expression and knockout systems in conjunction with liquid chromatography/mass spectrometry (LC/MS).

The development of novel gene expression systems for cytochrome P450s (CYPs) together with a revolution in analytical mass spectrometry with the emergence of liquid chromatography/mass spectrometry (LC/MS) has opened the door to answering some long-standing questions in Vitamin D metabolism. Our studies focused on: (1) elucidating the role of CYP24 in 25-OH-D3 and 1alpha,25-(OH)2D3 metabolism; (2) exploring how DBP influences this process; (3) measuring 25-OH-D3 metabolism in CYP24-knockout (CYP24-XO) cells and; (4) comparing 1alpha-OH-D2 metabolism in the CYP24-XO mouse in vivo and in vitro. Methodology employed CYP24 over-expression and knockout systems in conjunction with state-of-the-art analytical LC/MS, diode array, and radioisotopic detection methods.

Effects of 'non-calcaemic' vitamin D analogues on 24-hydroxylase expression in MG-63 osteoblast-like cells.

Background: New 'non-calcaemic' analogues of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) are entering the clinical arena and some of them have been shown to have differential effects in bone. This may have a bearing on the evolution of bone lesions in uraemic patients receiving vitamin D therapies. A potential mechanism for differential effects of analogues lies in their target cell inactivation.

Use of vitamin D(4) analogs to investigate differences in hepatic and target cell metabolism of vitamins D(2) and D(3).

In this study, we used molecules with either of the structural differences in the side chains of vitamin D(2) and vitamin D(3) to investigate which feature is responsible for the significant differences in their respective metabolism, pharmacokinetics and toxicity. We used two cell model systems-HepG2 and HPK1A-ras-to study hepatic and target cell metabolism, respectively. Studies with HepG2 revealed that the pattern of 24- and 26-hydroxylation of the side chain reported for 1alpha-hydroxyvitamin D(2) (1alpha-OH-D(2)) but not for 1alpha-OH-D(3) is also observed in both 1alpha-OH-D(4) and Delta(22)-1alpha-OH-D(3) metabolism.

In vitro metabolism of 19-nor-1alpha, 25-(OH)2D2 in cultured cell lines: inducible synthesis of lipid- and water-soluble metabolites.

The active vitamin D analog, 19-nor-1alpha,25-dihydroxyvitamin D2 (19-nor-1alpha,25-(OH)2D2), has a similar structure to the natural vitamin D hormone, 1a,25-dihydroxyvitamin D3 (1alpha,25-(OH)2D3), but lacks the C10-19 methylene group and possesses an ergosterol/ vitamin D2 rather than a cholesterol/vitamin D3 side chain. We have used this analog to investigate whether any of these structural features has any effect upon the type and rate of in vitro metabolism observed. Using a vitamin D-target cell, the human keratinocyte, HPK1A-ras, we observed formation of a number of metabolites, three of which were purified by extensive HPLC and conclusively identified by a combination of GC-MS and chemical derivatization as 19-nor-1alpha,24,25-(OH) 3D2, 19-nor-1alpha,24,25,26-(OH) 4D2, and 19-nor-1alpha,24,25,28-(OH)4,D2.

Metabolism of a 20-methyl substituted series of vitamin D analogs by cultured human cells: apparent reduction of 23-hydroxylation of the side chain by the 20-methyl group.

We describe here for the first time the effect of introducing a 20-methyl group on the side-chain metabolism of the vitamin D molecule. Using a series of 20-methyl-derivatives of 1alpha,25-(OH)2D3 incubated with two different cultured human cell lines, HPK1A-ras and HepG2, previously shown to metabolize vitamin D compounds, we obtained a series of metabolic products that were identified by comparison to chemically synthesized standards on HPLC and GC-MS. 24-Hydroxylated-, 24-oxo-hydroxylated-, and 24-oxo-23-hydroxylated products of 20-methyl-1alpha,25-(OH)2D3 were observed, but the efficiency of 23-hydroxylation was low as compared with that of the natural hormone and, in contrast to 1alpha,25-(OH)2D3, no truncated 23-alcohol was formed from the 20-methyl analog.

Potent suppression of the parathyroid glands by hydroxylated metabolites of dihydrotachysterol(2).

Background: Dihydrotachysterol(2), a licensed pharmaceutical, is hydroxylated to 25-hydroxydihydrotachysterol(2) (25(OH)DHT(2)) and 1 alpha,25-dihydroxydihydrotachysterol(2) (1 alpha,25(OH)(2)DHT(2)) in man. We have compared the biological activity of these metabolites with calcitriol and the 'non-calcaemic' analogue, 22-oxacalcitriol (OCT) in bovine parathyroid cell cultures and in rats.

Methods: The effect of each sterol on parathyroid hormone (PTH) secreted by primary bovine parathyroid cells was measured.

Characterization of 3-epi-1alpha,25-dihydroxyvitamin D3 involved in 1alpha,25-dihydroxyvitamin D3 metabolic pathway in cultured cell lines.

Using six different cultured cell models representing osteoblast, intestine, kidney and keratinocyte, we have demonstrated that 1alpha,25-dihydroxyvitamin D3 (1alpha,25(OH)2D3) is metabolized into 3-epi-1alpha,25(OH)2D3 in vitamin D-target cells. Although differences existed in the amount of 3-epi-1alpha,25(OH)2D3 formed with different cell types, it was apparent that 1alpha,25(OH)2D3 was subjected to metabolism both through the C24-oxidation and 3-epimerization pathways. Time course and dose response studies showed that the production of 3-epi-1alpha,25(OH)2D3 was enzymatic.

Contribution of several metabolites of the vitamin D analog 20-epi-22-oxa-24a,26a,27a-tri-homo-1,25-(OH)(2) vitamin D(3) (KH 1060) to the overall biological activity of KH1060 by a shared mechanism of action.

The synthetic 1,25-dihydroxyvitamin D(3) (1,25-(OH)(2)D(3)) analog 20-epi-22-oxa-24a,26a,27a-tri-homo-1,25-(OH)(2)vitamin D(3) (KH1060) is considerably more potent than its cognate hormone. The mechanism of action of KH1060 includes interaction with the vitamin D receptor (VDR). We previously showed that KH1060 increases VDR stability in ROS 17/2.