Dermatologist and Patient Preferences in Choosing Treatments for Moderate to Severe Psoriasis

INTRODUCTION: The objective of the study was to determine the relative importance (RI) of treatment attributes psoriasis patients and physicians consider when choosing between biologic therapies based on psoriasis severity. METHODS: A discrete choice experiment (DCE) weighting preference for eight sets of hypothetical treatments for moderate or severe psoriasis was conducted. DCE hypothetical treatments were defined and varied on combinations of efficacy, safety, and dosing attributes [frequency/setting/route of administration (ROA)]. RESULTS: When assuming moderate psoriasis in the patient DCE, ROA (RI 29%) and efficacy (RI 27%) drive treatment choices. When assuming severe disease in the DCE, patients preferred treatments with higher efficacy (RI 36%); ROA was relatively less important (RI 15%). From the physician perspective, ROA (RI 32%) and efficacy (RI 26%) were most important for moderate psoriasis patients. In the physician model for severe psoriasis, efficacy (RI 42%) was the predominant driver followed by ROA (RI 22%). Regardless of severity, probability of loss of response within 1 year was the least important factor. CONCLUSIONS: The severity of disease is a critical element in psoriasis treatment selection. There are high levels of alignment between physician- and patient-derived preferences in biologic treatment choice selection for psoriasis. FUNDING: Janssen Pharmaceuticals

Novel mutations in TARDBP (TDP-43) in patients with familial amyotrophic lateral sclerosis.

The TAR DNA-binding protein 43 (TDP-43) has been identified as the major disease protein in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin inclusions (FTLD-U), defining a novel class of neurodegenerative conditions: the TDP-43 proteinopathies. The first pathogenic mutations in the gene encoding TDP-43 (TARDBP) were recently reported in familial and sporadic ALS patients, supporting a direct role for TDP-43 in neurodegeneration. In this study, we report the identification and functional analyses of two novel and one known mutation in TARDBP that we identified as a result of extensive mutation analyses in a cohort of 296 patients with variable neurodegenerative diseases associated with TDP-43 histopathology. Three different heterozygous missense mutations in exon 6 of TARDBP (p.M337V, p.N345K, and p.I383V) were identified in the analysis of 92 familial ALS patients (3.3%), while no mutations were detected in 24 patients with sporadic ALS or 180 patients with other TDP-43-positive neurodegenerative diseases. The presence of p.M337V, p.N345K, and p.I383V was excluded in 825 controls and 652 additional sporadic ALS patients. All three mutations affect highly conserved amino acid residues in the C-terminal part of TDP-43 known to be involved in protein-protein interactions. Biochemical analysis of TDP-43 in ALS patient cell lines revealed a substantial increase in caspase cleaved fragments, including the approximately 25 kDa fragment, compared to control cell lines. Our findings support TARDBP mutations as a cause of ALS. Based on the specific C-terminal location of the mutations and the accumulation of a smaller C-terminal fragment, we speculate that TARDBP mutations may cause a toxic gain of function through novel protein interactions or intracellular accumulation of TDP-43 fragments leading to apoptosis

Smoking cessation programmes for women living in disadvantaged communities, “We Can Quit 2”: A systematic review protocol [version 3]

Tobacco use is the leading cause of preventable death in Ireland with almost 6,000 smokers dying each year from smoking-related diseases. Amongst younger Irish women, smoking rates are considerably higher in those from socially disadvantaged areas compared to women from affluent areas. Women from poorer areas also experience higher rates of lung cancer. To our knowledge, there are no peer reviewed published systematic reviews on the effectiveness of interventions tailored to reduce smoking rates in women from disadvantaged areas. This systematic review protocol will aim to examine the effectiveness of such interventions and to describe trial processes such as recruitment, follow-up and dropout prevention strategies, as well as barriers and enablers of successful implementation. A systematic review will be conducted of peer-reviewed randomised controlled trials and associated process evaluations of smoking cessation interventions designed for women living in socially disadvantaged areas. If the search returns, less than five studies are review criteria will expand to include quasi-experimental studies. A number of databases of scholarly literature will be searched from inception using a detailed search strategy. Two independent reviewers will screen titles, abstracts and full-text articles to identify relevant studies using a pre-defined checklist based on PICOS. In the case of disagreement, a third reviewer will be consulted. The quality of included studies will be assessed using the ‘Grading of Recommendations Assessment, Development and Evaluation’ (GRADE) criteria. Quantitative data will be extracted and, if comparable, will be assessed using meta-analysis. A narrative meta-synthesis of qualitative data will be conducted. This review aims to synthesise information from relevant studies on smoking cessation interventions tailored for women from socially disadvantaged areas. The evidence obtained from studies and presented in this review will help guide future research in this area

Novel mutations support a role for Profilin 1 in the pathogenesis of ALS

AbstractMutations in the gene encoding profilin 1 (PFN1) have recently been shown to cause amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder. We sequenced the PFN1 gene in a cohort of ALS patients (n = 485) and detected 2 novel variants (A20T and Q139L), as well as 4 cases with the previously identified E117G rare variant (∼ 1.2%). A case-control meta-analysis of all published E117G ALS+/− frontotemporal dementia cases including those identified in this report was significant p = 0.001, odds ratio = 3.26 (95% confidence interval, 1.6–6.7), demonstrating this variant to be a susceptibility allele. Postmortem tissue from available patients displayed classic TAR DNA-binding protein 43 pathology. In both transient transfections and in fibroblasts from a patient with the A20T change, we showed that this novel PFN1 mutation causes protein aggregation and the formation of insoluble high molecular weight species which is a hallmark of ALS pathology. Our findings show that PFN1 is a rare cause of ALS and adds further weight to the underlying genetic heterogeneity of this disease

The effectiveness of smoking cessation interventions for socio-economically disadvantaged women: A systematic review and meta-analysis

IntroductionThis systematic review and meta-analysis assessed the effectiveness of smoking cessation interventions among women smokers in low socio-economic status (SES) groups or women living in disadvantaged areas who are historically underserved by smoking cessation services.MethodsA systematic literature search was conducted using MEDLINE (OVID), EMBASE, Cochrane, CINAHL, PsychINFO and Web of Science databases. Eligibility criteria included randomised controlled trials of any smoking cessation intervention among women in low SES groups or living in socio-economically disadvantaged areas. A random effects meta-analysis assessed effectiveness of interventions on smoking cessation. Risk of bias was assessed with the Cochrane Risk of Bias tool. The GRADE approach established certainty of evidence.ResultsA total of 396 studies were screened for eligibility and 11 (6153 female participants) were included. Seven studies targeted women-only. 5/11 tested a form of face-to-face support. A pooled effect size was estimated in 10/11 studies. At end of treatment, two-thirds more low SES women who received a smoking cessation intervention were more likely to stop smoking than women in control groups (risk ratio (RR) 1.68, 95% CI 1.36–2.08, I2= 34%). The effect was reduced but remained significant when longest available follow-up periods were pooled (RR 1.23, 95% CI 1.04–1.48, I2 = 0%). There was moderate-to-high risk of bias in most studies. Certainty of evidence was low.ConclusionsBehavioural and behavioural + pharmacotherapy interventions for smoking cessation targeting women in low SES groups or women living in areas of disadvantage were effective in the short term. However, longer follow-up periods indicated reduced effectiveness. Future studies to explore ways to prevent smoking relapse in this population are needed.Systematic review registrationPROSPERO: CRD4201913016

An Application of PRECIS-2 to Evaluate Trial Design in a Pilot Cluster Randomised Controlled Trial of a Community-based Smoking Cessation Intervention for Women Living in Disadvantaged Areas of Ireland

Background“We Can Quit2” (WCQ2) was a pilot cluster randomised controlled trial with an embedded process evaluation assessing the feasibility and acceptability of ‘We Can Quit’ (WCQ), a peer-delivered community-based stop-smoking programme for women in disadvantaged communities. The control group comprised ‘enhanced usual care’ offered by the Irish Health Service Executive (HSE). The PRagmatic Explanatory Continuum Indicator Summary (PRECIS-2) is a tool to assess whether a trial design is more explanatory (working under ideal conditions) or pragmatic (working under ‘real world’ conditions). The aim of this paper was to retrospectively evaluate the WCQ2 pilot trial using PRECIS-2 to inform the decision-making process on progression to a future definitive trial (DT).MethodsThe WCQ2 trial protocol and HSE standard stop-smoking service were described across the nine PRECIS-2 domains: Eligibility, Recruitment, Setting, Organisation, Flexibility-Delivery, Flexibility-Adherence, Follow-up, Primary Outcome. Team members scored the domains as pragmatic or explanatory for each arm in a half-day workshop.ResultsSeven team members (practitioners and researchers) assessed the overall trial design as more explanatory than pragmatic. Important differences emerged between the two arms. WCQ targeted adult women from disadvantaged communities whereas HSE run a limited enhanced service for all quitters. Recruitment to trial was challenging, intense efforts were needed as the trial proceeded. WCQ was delivered in a non-clinical community setting, HSE services in a clinical setting. WCQ organisation was co-designed with community partners and comprises peer-to-peer group support delivered by trained lay community facilitators, whereas HSE one-to-one support is delivered by Smoking Cessation Officers with a clinical background. Only WCQ allowed flexibility in delivery and adherence. Follow-up was more intensive in WCQ. Greater efforts to improve participant retention will be required in a future DT.ConclusionsPRECIS-2 allowed the reflection of practitioners and researchers on similarities and differences between intervention and control arms. Results will inform the decision on progression to an effectiveness DT, which will require more a pragmatic and less explanatory design. This novel use of PRECIS-2 to retrospectively evaluate a complex community-based pilot trial in advance of a full DT will also support learning for those undertaking hybrid trials of implementation and effectiveness.Trial registration: This trial is registered with the ISRCTN registry (No. 74721694), available at https://doi.org/10.1186/ISRCTN7472169

Ancient homology underlies adaptive mimetic diversity across butterflies

Convergent evolution provides a rare, natural experiment with which to test the predictability of adaptation at the molecular level. Little is known about the molecular basis of convergence over macro-evolutionary timescales. Here we use a combination of positional cloning, population genomic resequencing, association mapping and developmental data to demonstrate that positionally orthologous nucleotide variants in the upstream region of the same gene, WntA, are responsible for parallel mimetic variation in two butterfly lineages that diverged >65 million years ago. Furthermore, characterization of spatial patterns of WntA expression during development suggests that alternative regulatory mechanisms underlie wing pattern variation in each system. Taken together, our results reveal a strikingly predictable molecular basis for phenotypic convergence over deep evolutionary time.We thank the governments of Ecuador, Costa Rica and the United States for permission to collect butterflies. In addition, we thank Larry Gilbert, Durrell Kapan, Ryan Hill, Kenny Kronforst and Nicholas Crawford for their assistance in collecting butterflies. The funding was provided by National Science Foundation awards to S. P. M., M. R. K. and R.D.R. (National Science Foundation

RNA-interference in rice against Rice tungro bacilliform virus results in its decreased accumulation in inoculated rice plants

Rice tungro is a viral disease seriously affecting rice production in South and Southeast Asia. Tungro is caused by the simultaneous infection in rice of Rice tungro bacilliform virus (RTBV), a double-stranded DNA virus and Rice tungro spherical virus (RTSV), a single-stranded RNA virus. To apply the concept of RNA-interference (RNAi) for the control of RTBV infection, transgenic rice plants expressing DNA encoding ORF IV of RTBV, both in sense as well as in anti-sense orientation, resulting in the formation of double-stranded (ds) RNA, were raised. RNA blot analysis of two representative lines indicated specific degradation of the transgene transcripts and the accumulation of small molecular weight RNA, a hallmark for RNA-interference. In the two transgenic lines expressing ds-RNA, different resistance responses were observed against RTBV. In one of the above lines (RTBV-O-Ds1), there was an initial rapid buildup of RTBV levels following inoculation, comparable to that of untransformed controls, followed by a sharp reduction, resulting in approximately 50-fold lower viral titers, whereas the untransformed controls maintained high levels of the virus till 40 days post-inoculation (dpi). In RTBV-O-Ds2, RTBV DNA levels gradually rose from an initial low to almost 60% levels of the control by 40 dpi. Line RTBV-O-Ds1 showed symptoms of tungro similar to the untransformed control lines, whereas line RTBV-O-Ds2 showed extremely mild symptoms