Using Real-World Data to Guide Ustekinumab Dosing Strategies for Psoriasis: A Prospective Pharmacokinetic-Pharmacodynamic Study.

Variation in response to biologic therapy for inflammatory diseases, such as psoriasis, is partly driven by variation in drug exposure. Real-world psoriasis data were used to develop a pharmacokinetic/pharmacodynamic (PK/PD) model for the first-line therapeutic antibody ustekinumab. The impact of differing dosing strategies on response was explored. Data were collected from a UK prospective multicenter observational cohort (491 patients on ustekinumab monotherapy, drug levels, and anti-drug antibody measurements on 797 serum samples, 1,590 measurements of Psoriasis Area Severity Index (PASI)). Ustekinumab PKs were described with a linear one-compartment model. A maximum effect (Emax ) model inhibited progression of psoriatic skin lesions in the turnover PD mechanism describing PASI evolution while on treatment. A mixture model on half-maximal effective concentration identified a potential nonresponder group, with simulations suggesting that, in future, the model could be incorporated into a Bayesian therapeutic drug monitoring "dashboard" to individualize dosing and improve treatment outcomes

Development and validation of a multivariable risk prediction model for serious infection in patients with psoriasis receiving systemic therapy

BACKGROUND: Patients with psoriasis are often concerned about the risk of serious infection associated with systemic psoriasis treatments. OBJECTIVES: To develop and externally validate a prediction model for serious infection in patients with psoriasis within 1 year of starting systemic therapies. METHODS: The risk prediction model was developed using the British Association of Dermatologists Biologic Interventions Register (BADBIR), and the German Psoriasis Registry PsoBest was used as the validation dataset. Model discrimination and calibration were assessed internally and externally using the C-statistic, the calibration slope and the calibration in the large. RESULTS: Overall 175 (1·7%) out of 10 033 participants from BADBIR and 41 (1·7%) out of 2423 participants from PsoBest developed a serious infection within 1 year of therapy initiation. Selected predictors in a multiple logistic regression model included nine baseline covariates, and starting infliximab was the strongest predictor. Evaluation of model performance showed a bootstrap optimism-corrected C-statistic of 0·64 [95% confidence interval (CI) 0·60-0·69], calibration in the large of 0·02 (95% CI -0·14 to 0·17) and a calibration slope of 0·88 (95% CI 0·70-1·07), while external validation performance was poor, with C-statistic 0·52 (95% CI 0·42-0·62), calibration in the large 0·06 (95% CI -0·25 to 0·37) and calibration slope 0·36 (95% CI -0·24 to 0·97). CONCLUSIONS: We present the first results of the development of a multivariable prediction model. This model may help patients and dermatologists in the U.K. and the Republic of Ireland to identify modifiable risk factors and inform therapy choice in a shared decision-making process

Complete Genome Sequences of Chop, DelRio, and GrandSlam, Three Gordonia Phages Isolated from Soil in Central Arkansas

Chop, DelRio, and GrandSlam are phage with a Siphoviridae morphotype isolated from soil in Arkansas using the host Gordonia terrae 3612. All three are temperate, and their genomes share at least 96% nucleotide identity. These phage are assigned to cluster DI based on gene content similarity to other sequenced actinobacteriophage

Collaborative design of accessible information with people with aphasia

Background: People with aphasia report preferences for specially formatted health information materials, but there is little evidence that modified materials result in improved comprehension. Potential explanations for this include language included not taking account of aphasic processing difficulties, topics unrelated to aphasia, lack of clarity regarding the use of images, and the lack of end-user involvement in the design. Additionally, no definitive criteria for production of accessible information have been identified. Aims: The first aim of this study was to collaborate with people with aphasia in an iterative design process to develop and finalise accessible information materials. The second aim was to identify definitive criteria for use in the future production of information materials for people with aphasia. Methods and procedure: Prototype materials were developed for the study, were based on criteria identified from the existing research into aphasia-accessible information, and on the evidence base concerning language processing in aphasia. Fourteen people with aphasia took part in two rounds of consensus group meetings and viewed information about aphasia presented within the prototype materials. Consensus points were identified within the groups through discussion and through ratings using Likert scales. The set of consensus points and ratings were adapted into criteria for graphic designers to incorporate into subsequent designs of the materials, in order to generate a final version, and related criteria. Outcomes and results: The group discussions and the ratings of materials led to the identification of an agreed layout within which to present information, and specific criteria for the following: information consisting of one proposition expressed via everyday words and canonical syntactic forms; one or two images relating directly to keywords; sans serif typography with keyword emphasis. Individual preferences with regard to image types were identified. Novel criteria were identified in the study, relating to layout, language, images and typography. These were added to the original set of criteria to form definitive criteria for use in the development of accessible aphasia materials. Conclusions: This study successfully involved people with aphasia in the design process to produce novel materials, and related design criteria. The resulting materials and criteria differ from those previously proposed, by reflecting directly people with aphasia’s views and preferences, and by incorporating language and images suitable for people with aphasia, based on the existing research evidence and the outcomes of this study. The materials and criteria have the potential to improve people with aphasia’s understanding of health information

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Exploring adults’ experiences of sedentary behaviour and participation in nonworkplace interventions designed to reduce sedentary behaviour: a thematic synthesis of qualitative studies

Background: Sedentary behaviour is any waking behaviour characterised by an energy expenditure of ≤1.5 metabolic equivalent of task while in a sitting or reclining posture. Prolonged bouts of sedentary behaviour have been associated with negative health outcomes in all age groups. We examined qualitative research investigating perceptions and experiences of sedentary behaviour and of participation in non-workplace interventions designed to reduce sedentary behaviour in adult populations. Method: A systematic search of seven databases (MEDLINE, AMED, Cochrane, PsychINFO, SPORTDiscus, CINAHL and Web of Science) was conducted in September 2017. Studies were assessed for methodological quality and a thematic synthesis was conducted. Prospero database ID: CRD42017083436. Results: Thirty individual studies capturing the experiences of 918 individuals were included. Eleven studies examined experiences and/or perceptions of sedentary behaviour in older adults (typically ≥60 years); ten studies focused on sedentary behaviour in people experiencing a clinical condition, four explored influences on sedentary behaviour in adults living in socio-economically disadvantaged communities, two examined university students’ experiences of sedentary behaviour, two on those of working-age adults, and one focused on cultural influences on sedentary behaviour. Three analytical themes were identified: 1) the impact of different life stages on sedentary behaviour 2) lifestyle factors influencing sedentary behaviour and 3) barriers and facilitators to changing sedentary behaviour. Conclusions: Sedentary behaviour is multifaceted and influenced by a complex interaction between individual, environmental and socio-cultural factors. Micro and macro pressures are experienced at different life stages and in the context of illness; these shape individuals’ beliefs and behaviour related to sedentariness. Knowledge of sedentary behaviour and the associated health consequences appears limited in adult populations, therefore there is a need for provision of accessible information about ways in which sedentary behaviour reduction can be integrated in people’s daily lives. Interventions targeting a reduction in sedentary behaviour need to consider the multiple influences on sedentariness when designing and implementing interventions

Clinical outcomes and response to treatment of patients receiving topical treatments for pyoderma gangrenosum: a prospective cohort study

Background: pyoderma gangrenosum (PG) is an uncommon dermatosis with a limited evidence base for treatment. Objective: to estimate the effectiveness of topical therapies in the treatment of PG. Methods: prospective cohort study of UK secondary care patients with a clinical diagnosis of PG suitable for topical treatment (recruited July 2009 to June 2012). Participants received topical therapy following normal clinical practice (mainly Class I-III topical corticosteroids, tacrolimus 0.03% or 0.1%). Primary outcome: speed of healing at 6 weeks. Secondary outcomes: proportion healed by 6 months; time to healing; global assessment; inflammation; pain; quality-of-life; treatment failure and recurrence. Results: Sixty-six patients (22 to 85 years) were enrolled. Clobetasol propionate 0.05% was the most commonly prescribed therapy. Overall, 28/66 (43.8%) of ulcers healed by 6 months. Median time-to-healing was 145 days (95% CI: 96 days, ∞). Initial ulcer size was a significant predictor of time-to-healing (hazard ratio 0.94 (0.88;80 1.00); p = 0.043). Four patients (15%) had a recurrence. Limitations: No randomised comparator Conclusion: Topical therapy is potentially an effective first-line treatment for PG that avoids possible side effects associated with systemic therapy. It remains unclear whether more severe disease will respond adequately to topical therapy alone

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Velocity-space sensitivity of the time-of-flight neutron spectrometer at JET

The velocity-space sensitivities of fast-ion diagnostics are often described by so-called weight functions. Recently, we formulated weight functions showing the velocity-space sensitivity of the often dominant beam-target part of neutron energy spectra. These weight functions for neutron emission spectrometry (NES) are independent of the particular NES diagnostic. Here we apply these NES weight functions to the time-of-flight spectrometer TOFOR at JET. By taking the instrumental response function of TOFOR into account, we calculate time-of-flight NES weight functions that enable us to directly determine the velocity-space sensitivity of a given part of a measured time-of-flight spectrum from TOFOR