Patient experiences with oily skin: The qualitative development of content for two new patient reported outcome questionnaires

<p>Abstract</p> <p>Objective</p> <p>To develop the content for two new patient reported outcome (PRO) measures to: a) assess the severity of symptoms; and b) the impact of facial skin oiliness on emotional wellbeing using qualitative data from face to face, and internet focus groups in Germany and the US.</p> <p>Methods</p> <p>Using input from initial treatment satisfaction focus groups (n = 42), a review of relevant literature and expert clinicians (n = 3), a discussion guide was developed to guide qualitative inquiry using Internet focus groups (IFGs). IFGs were conducted with German (n = 26) and US (n = 28) sufferers of oily skin. Questionnaire items were generated using coded transcript data from the focus groups. Cognitive debriefing was conducted online with 42 participants and face to face with an additional five participants to assess the comprehension of the items.</p> <p>Results</p> <p>There were equal numbers of male and female participants; mean age was 35.4 (SD 9.3) years. On average, participants had had oily skin for 15.2 years, and 74% (n = 40) reported having mild-moderate acne. Participants reported using visual, tactile and sensory (feel without touching their face) methods to evaluate the severity of facial oiliness. Oily facial skin had both an emotional and social impact, and was associated with feelings of unattractiveness, self-consciousness, embarrassment, irritation and frustration. Items were generated for a measure of oily skin severity (Oily Skin Self-Assessment Scale) and a measure of the impact of oily skin on emotional well-being (Oily Skin Impact Scale). Cognitive debriefing resulted in minor changes to the draft items and confirmed their face and content validity.</p> <p>Conclusion</p> <p>The research provides insight into the experience of having oily skin and illustrates significant difficulties associated with the condition. Item content was developed for early versions of two PRO measures of the symptoms and emotional impact of oily facial skin. The psychometric validation of these measures reported elsewhere.</p

Oxytocin, a Novel Treatment for Methamphetamine Use Disorder

The treatment of substance abuse with oxytocin is a novel approach to a challenging public health issue that continues to contribute to a growing economic cost for societies worldwide. Methamphetamine addiction is one of the leading causes of mortality worldwide, and despite advances in understanding the neurobiology of methamphetamine addiction, treatment options are limited. There are no medications that the Food and Drug Administration currently approves for stimulant use disorder. Off-label use of therapies for stimulant misuse include antidepressants, anxiolytics, and milder stimulants as replacement agents. Due to the shortcomings of these attempts to treat a complicated psychiatric disorder, recent attention to oxytocin therapy (OT) has gained momentum in clinical studies as a possible therapy in the context of social stress, social anxiety, social cognition, and psychosis. Oxytocin produces enhanced connectivity between cortical regions. The results from studies in rodents with OT suggest that central neuromodulation of oxytocin may be beneficial across transition states of stimulant dependence and may alleviate intense withdrawal symptoms. Studies of oxytocin in the context of other drugs of abuse, including cocaine, cannabis, and alcohol, also support the potential of oxytocin to treat stimulant use disorder, methamphetamine type. Methamphetamine abuse continues to be a significant cause of distress and dysfunction throughout the world. The effects of oxytocin on methamphetamine use outlined in this review should act as a catalyst for further investigation into the efficacy of treating stimulant use disorder, methamphetamine type with oxytocin in humans. More human-based research should initiate studies involving the long-term efficacy, side effects, and patient selection

A phase I pharmacokinetic and pharmacodynamic study of the oral mitogen-activated protein kinase kinase (MEK) inhibitor, WX-554, in patients with advanced solid tumours

Purpose: We performed a multi-centre phase I study to assess the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of the orally available small molecule mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor, WX-554, and to determine the optimal biological dose for subsequent trials. Experimental design: Patients with treatment-refractory, advanced solid tumours, with adequate performance status and organ function were recruited to a dose-escalation study in a standard 3 + 3 design. The starting dose was 25 mg orally once weekly with toxicity, PK and PD guided dose-escalation with potential to explore alternative schedules. Results: Forty-one patients with advanced solid tumours refractory to standard therapies and with adequate organ function were recruited in eight cohorts up to doses of 150 mg once weekly and 75 mg twice weekly. No dose-limiting toxicities were observed during the study, and a maximum tolerated dose (MTD) was not established. The highest dose cohorts demonstrated sustained inhibition of extracellular signal-regulated kinase (ERK) phosphorylation in peripheral blood mononuclear cells following ex-vivo phorbol 12-myristate 13-acetate stimulation. There was a decrease of 70 ± 26% in mean phosphorylated (p)ERK in C1 day 8 tumour biopsies when compared with pre-treatment tumour levels in the 75 mg twice a week cohort. Prolonged stable disease (&gt;6 months) was seen in two patients, one with cervical cancer and one with ampullary carcinoma. Conclusions: WX-554 was well tolerated, and an optimal biological dose was established for further investigation in either a once or twice weekly regimens. The recommended phase 2 dose is 75 mg twice weekly

Trials and tribulations of recruiting 2,000 older women onto a clinical trial investigating falls and fractures : vital D study

Background Randomised, placebo-controlled trials are needed to provide evidence demonstrating safe, effective interventions that reduce falls and fractures in the elderly. The quality of a clinical trial is dependent on successful recruitment of the target participant group. This paper documents the successes and failures of recruiting over 2,000 women aged at least 70 years and at higher risk of falls or fractures onto a placebo-controlled trial of six years duration. The characteristics of study participants at baseline are also described for this study.Methods The Vital D Study recruited older women identified at high risk of fracture through the use of an eligibility algorithm, adapted from identified risk factors for hip fracture. Participants were randomised to orally receive either 500,000 IU vitamin D3 (cholecalciferol) or placebo every autumn for five consecutive years. A variety of recruitment strategies were employed to attract potential participants.Results Of the 2,317 participants randomised onto the study, 74% (n = 1716/2317) were consented onto the study in the last five months of recruiting. This was largely due to the success of a targeted mail-out. Prior to this only 541 women were consented in the 18 months of recruiting. A total of 70% of all participants were recruited as a result of targeted mail-out. The response rate from the letters increased from 2 to 7% following revision of the material by a public relations company. Participant demographic or risk factor profile did not differ between those recruited by targeted mail-outs compared with other methods.Conclusion The most successful recruitment strategy was the targeted mail-out and the response rate was no higher in the local region where the study had extensive exposure through other recruiting strategies. The strategies that were labour-intensive and did not result in successful recruitment include the activities directed towards the GP medical centres. Comprehensive recruitment programs employ overlapping strategies simultaneously with ongoing assessment of recruitment rates. In our experience, and others direct mail-outs work best although rights to privacy must be respected. <br /

Using non-invasive biomarkers to identify hepatic fibrosis in people with type 2 diabetes mellitus: the Edinburgh type 2 diabetes study

BACKGROUND & AIMS: It is difficult to determine the different stages of non-alcoholic fatty liver disease without the use of invasive liver biopsy. In this study we investigated five non-invasive biomarkers used previously to detect hepatic fibrosis and determined the level of agreement between them in order to inform future research. METHODS: In the Edinburgh Type 2 Diabetes Study, a population-based cohort aged 60-74 years with type 2 diabetes, 831 participants underwent ultrasound assessment for fatty liver and had serum aspartate aminotransferase to alanine aminotransferase ratio (AST/ALT), aspartate to platelet ratio index (APRI), European Liver Fibrosis panel (ELF), Fibrosis-4 Score (FIB4) and liver stiffness measurement (LSM) measured. RESULTS: Literature based cut-offs yielded marked differences in the proportions of the cohort with probable liver fibrosis in the full cohort. Agreement between the top 5% of the distribution for each biomarker pair was poor. APRI and FIB4 had the best positive agreement at 76.4%, but agreement for all of the other serum biomarker pairs was between 18% and 34%. Agreement with LSM was poor (9-16%). CONCLUSIONS: We found poor correlation between the five biomarkers of liver fibrosis studied. Using the top 5% of each biomarker resulted in good agreement on the absence of advanced liver disease but poor agreement on the presence of advanced disease. Further work is required to validate these markers against liver biopsy and to determine their predictive value for clinical liver-related endpoints, in a range of different low and high risk population groups

Comparing genotyping algorithms for Illumina's Infinium whole-genome SNP BeadChips

The Brassica napus 60K Illumina Infinium™ SNP array has had huge international uptake in the rapeseed community due to the revolutionary speed of acquisition and ease of analysis of this high-throughput genotyping data, particularly when coupled with the newly available reference genome sequence. However, further utilization of this valuable resource can be optimized by better understanding the promises and pitfalls of SNP arrays. We outline how best to analyze Brassica SNP marker array data for diverse applications, including linkage and association mapping, genetic diversity and genomic introgression studies. We present data on which SNPs are locus-specific in winter, semi-winter and spring B. napus germplasm pools, rather than amplifying both an A-genome and a C-genome locus or multiple loci. Common issues that arise when analyzing array data will be discussed, particularly those unique to SNP markers and how to deal with these for practical applications in Brassica breeding applications

An international effort towards developing standards for best practices in analysis, interpretation and reporting of clinical genome sequencing results in the CLARITY Challenge

There is tremendous potential for genome sequencing to improve clinical diagnosis and care once it becomes routinely accessible, but this will require formalizing research methods into clinical best practices in the areas of sequence data generation, analysis, interpretation and reporting. The CLARITY Challenge was designed to spur convergence in methods for diagnosing genetic disease starting from clinical case history and genome sequencing data. DNA samples were obtained from three families with heritable genetic disorders and genomic sequence data were donated by sequencing platform vendors. The challenge was to analyze and interpret these data with the goals of identifying disease-causing variants and reporting the findings in a clinically useful format. Participating contestant groups were solicited broadly, and an independent panel of judges evaluated their performance. RESULTS: A total of 30 international groups were engaged. The entries reveal a general convergence of practices on most elements of the analysis and interpretation process. However, even given this commonality of approach, only two groups identified the consensus candidate variants in all disease cases, demonstrating a need for consistent fine-tuning of the generally accepted methods. There was greater diversity of the final clinical report content and in the patient consenting process, demonstrating that these areas require additional exploration and standardization. CONCLUSIONS: The CLARITY Challenge provides a comprehensive assessment of current practices for using genome sequencing to diagnose and report genetic diseases. There is remarkable convergence in bioinformatic techniques, but medical interpretation and reporting are areas that require further development by many groups

Abdominal aortic aneurysm is associated with a variant in low-density lipoprotein receptor-related protein 1

Abdominal aortic aneurysm (AAA) is a common cause of morbidity and mortality and has a significant heritability. We carried out a genome-wide association discovery study of 1866 patients with AAA and 5435 controls and replication of promising signals (lead SNP with a p value &lt; 1 × 10-5) in 2871 additional cases and 32,687 controls and performed further follow-up in 1491 AAA and 11,060 controls. In the discovery study, nine loci demonstrated association with AAA (p &lt; 1 × 10-5). In the replication sample, the lead SNP at one of these loci, rs1466535, located within intron 1 of low-density-lipoprotein receptor-related protein 1 (LRP1) demonstrated significant association (p = 0.0042). We confirmed the association of rs1466535 and AAA in our follow-up study (p = 0.035). In a combined analysis (6228 AAA and 49182 controls), rs1466535 had a consistent effect size and direction in all sample sets (combined p = 4.52 × 10-10, odds ratio 1.15 [1.10-1.21]). No associations were seen for either rs1466535 or the 12q13.3 locus in independent association studies of coronary artery disease, blood pressure, diabetes, or hyperlipidaemia, suggesting that this locus is specific to AAA. Gene-expression studies demonstrated a trend toward increased LRP1 expression for the rs1466535 CC genotype in arterial tissues; there was a significant (p = 0.029) 1.19-fold (1.04-1.36) increase in LRP1 expression in CC homozygotes compared to TT homozygotes in aortic adventitia. Functional studies demonstrated that rs1466535 might alter a SREBP-1 binding site and influence enhancer activity at the locus. In conclusion, this study has identified a biologically plausible genetic variant associated specifically with AAA, and we suggest that this variant has a possible functional role in LRP1 expression

Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial

Background Non-alcoholic steatohepatitis (NASH) is a common type of chronic liver disease that can lead to cirrhosis. Obeticholic acid, a farnesoid X receptor agonist, has been shown to improve the histological features of NASH. Here we report results from a planned interim analysis of an ongoing, phase 3 study of obeticholic acid for NASH. Methods In this multicentre, randomised, double-blind, placebo-controlled study, adult patients with definite NASH,non-alcoholic fatty liver disease (NAFLD) activity score of at least 4, and fibrosis stages F2–F3, or F1 with at least oneaccompanying comorbidity, were randomly assigned using an interactive web response system in a 1:1:1 ratio to receive oral placebo, obeticholic acid 10 mg, or obeticholic acid 25 mg daily. Patients were excluded if cirrhosis, other chronic liver disease, elevated alcohol consumption, or confounding conditions were present. The primary endpointsfor the month-18 interim analysis were fibrosis improvement (≥1 stage) with no worsening of NASH, or NASH resolution with no worsening of fibrosis, with the study considered successful if either primary endpoint was met. Primary analyses were done by intention to treat, in patients with fibrosis stage F2–F3 who received at least one dose of treatment and reached, or would have reached, the month 18 visit by the prespecified interim analysis cutoff date. The study also evaluated other histological and biochemical markers of NASH and fibrosis, and safety. This study is ongoing, and registered with ClinicalTrials.gov, NCT02548351, and EudraCT, 20150-025601-6. Findings Between Dec 9, 2015, and Oct 26, 2018, 1968 patients with stage F1–F3 fibrosis were enrolled and received at least one dose of study treatment; 931 patients with stage F2–F3 fibrosis were included in the primary analysis (311 in the placebo group, 312 in the obeticholic acid 10 mg group, and 308 in the obeticholic acid 25 mg group). The fibrosis improvement endpoint was achieved by 37 (12%) patients in the placebo group, 55 (18%) in the obeticholic acid 10 mg group (p=0·045), and 71 (23%) in the obeticholic acid 25 mg group (p=0·0002). The NASH resolution endpoint was not met (25 [8%] patients in the placebo group, 35 [11%] in the obeticholic acid 10 mg group [p=0·18], and 36 [12%] in the obeticholic acid 25 mg group [p=0·13]). In the safety population (1968 patients with fibrosis stages F1–F3), the most common adverse event was pruritus (123 [19%] in the placebo group, 183 [28%] in the obeticholic acid 10 mg group, and 336 [51%] in the obeticholic acid 25 mg group); incidence was generally mild to moderate in severity. The overall safety profile was similar to that in previous studies, and incidence of serious adverse events was similar across treatment groups (75 [11%] patients in the placebo group, 72 [11%] in the obeticholic acid 10 mg group, and 93 [14%] in the obeticholic acid 25 mg group). Interpretation Obeticholic acid 25 mg significantly improved fibrosis and key components of NASH disease activity among patients with NASH. The results from this planned interim analysis show clinically significant histological improvement that is reasonably likely to predict clinical benefit. This study is ongoing to assess clinical outcomes

How to specify healthcare process improvements collaboratively using rapid, remote consensus-building: a framework and a case study of its application

Abstract: Background: Practical methods for facilitating process improvement are needed to support high quality, safe care. How best to specify (identify and define) process improvements – the changes that need to be made in a healthcare process – remains a key question. Methods for doing so collaboratively, rapidly and remotely offer much potential, but are under-developed. We propose an approach for engaging diverse stakeholders remotely in a consensus-building exercise to help specify improvements in a healthcare process, and we illustrate the approach in a case study. Methods: Organised in a five-step framework, our proposed approach is informed by a participatory ethos, crowdsourcing and consensus-building methods: (1) define scope and objective of the process improvement; (2) produce a draft or prototype of the proposed process improvement specification; (3) identify participant recruitment strategy; (4) design and conduct a remote consensus-building exercise; (5) produce a final specification of the process improvement in light of learning from the exercise. We tested the approach in a case study that sought to specify process improvements for the management of obstetric emergencies during the COVID-19 pandemic. We used a brief video showing a process for managing a post-partum haemorrhage in women with COVID-19 to elicit recommendations on how the process could be improved. Two Delphi rounds were then conducted to reach consensus. Results: We gathered views from 105 participants, with a background in maternity care (n = 36), infection prevention and control (n = 17), or human factors (n = 52). The participants initially generated 818 recommendations for how to improve the process illustrated in the video, which we synthesised into a set of 22 recommendations. The consensus-building exercise yielded a final set of 16 recommendations. These were used to inform the specification of process improvements for managing the obstetric emergency and develop supporting resources, including an updated video. Conclusions: The proposed methodological approach enabled the expertise and ingenuity of diverse stakeholders to be captured and mobilised to specify process improvements in an area of pressing service need. This approach has the potential to address current challenges in process improvement, but will require further evaluation