Conversation on Paul Oslington's Deus Economicus

Tony Kelly and Neil Ormerod respond to Paul Oslingtons Deus Economicus proposal. Finally, Paul Oslington responds to his respondents

Topical tacrolimus 0.1% ointment for treatment of cutaneous Crohn's Disease

Peer reviewedPublisher PD

An observational prospective study of topical acidified nitrite for killing methicillin-resistant Staphylococcus aureus (MRSA) in contaminated wounds

Background Endogenous nitric oxide (NO) kills bacteria and other organisms as part of the innate immune response. When nitrite is exposed to low pH, NO is generated and has been used as an NO delivery system to treat skin infections. We demonstrated eradication of MRSA carriage from wounds using a topical formulation of citric acid (4.5%) and sodium nitrite (3%) creams co-applied for 5 days to 15 wounds in an observational prospective pilot study of 8 patients. Findings Following treatment with topical citric acid and sodium nitrite, 9 of 15 wounds (60%) and 3 of 8 patients (37%) were cleared of infection. MRSA isolates from these patients were all sensitive to acidified nitrite in vitro compared to methicillin-sensitive S. aureus and a reference strain of MRSA. Conclusions Nitric oxide and acidified nitrite offer a novel therapy for control of MRSA in wounds. Wounds that were not cleared of infection may have been re-contaminated or the bioavailability of acidified nitrite impaired by local factors in the tissue

Polystyrene microplastics decrease accumulation of essential fatty acids in common freshwater algae

Despite growing concern about the occurrence of microplastics in aquatic ecosystems there is only rudimentary understanding of the pathways through which any adverse effects might occur. Here, we assess the effects of polystyrene microplastics (PS-MPs; <70 μm) on a common and widespread algal species, Chlorella sorokiniana. We used laboratory exposure to test the hypothesis that the lipids and fatty acids (FAs) are important molecules in the response reactions of algae to this pollutant. Cultivation with PS-MPs systematically reduced the concentration of essential linoleic acid (ALA, C18:3n-3) in C. sorokiniana, concomitantly increasing oleic acid (C18:1n-9). Among the storage triacylglycerols, palmitoleic and oleic acids increased at the expenses of two essential fatty acids, linoleic (LIN, C18:2n-6) and ALA, while PS-MPs had even more pronounced effects on the fatty acid and hydrocarbon composition of waxes and steryl esters. The FA composition of two major chloroplast galactolipids, monogalactosyldiacylglycerol (MGDG) and digalactosyldiacylglycerol (DGDG), were affected implying changes in the conformational structure of photosynthetic complexes in ways that can impair the photosynthesis. These data reveal how exposure to polystyrene microplastics can modify the concentrations of lipid molecules that are important intrinsically in cell membranes, and hence the lipid bilayers that could form an important barrier between algal cellular compartments and plastics in the aquatic environment. Changes in lipid synthesis and fatty acid composition in algae could also have repercussions for food quality, growth and stressor resistance in primary consumers. We advocate further studies of microplastics effects on the lipid composition of primary producers, and of their potential propagation through aquatic food webs

Comparison of the two most commonly used treatments for pyoderma gangrenosum: results of the STOP GAP randomised controlled trial

Objective To determine whether ciclosporin is superior to prednisolone for the treatment of pyoderma gangrenosum, a painful, ulcerating skin disease with a poor evidence base for management. Design Multicentre, parallel group, observer blind, randomised controlled trial. Setting 39 UK hospitals, recruiting from June 2009 to November 2012. Participants 121 patients (73 women, mean age 54 years) with clinician diagnosed pyoderma gangrenosum. Clinical diagnosis was revised in nine participants after randomisation, leaving 112 participants in the analysis set (59 ciclosporin; 53 rednisolone). Intervention Oral prednisolone 0.75 mg/kg/day compared with ciclosporin 4 mg/kg/day, to a maximum dose of 75 and 400 mg/day, respectively. Main outcome measures The primary outcome was speed of healing over six weeks, captured using digital images and assessed by blinded investigators. Secondary outcomes were time to healing, global treatment response, resolution of inflammation, self reported pain, quality of life, number of treatment failures, adverse reactions, and time to recurrence. Outcomes were assessed at baseline and six weeks and when the ulcer had healed (to a maximum of six months). Results Of the 112 participants, 108 had complete primary outcome data at baseline and six weeks (57 ciclosporin; 51 rednisolone). Groups were balanced at baseline. The mean (SD) speed of healing at six weeks was −0.21 (1.00) cm2/day in the ciclosporin group compared with −0.14 (0.42) cm2/day in the prednisolone group. The adjusted mean difference showed no between group difference (0.003 cm2/day, 95% confidence interval −0.20 to 0.21; P=0.97). By six months, ulcers had healed in 28/59 (47%) participants in the ciclosporin group compared with 25/53 (47%) in the prednisolone group. In those with healed ulcers, eight (30%) receiving ciclosporin and seven (28%) receiving prednisolone had a recurrence. Adverse reactions were similar for the two groups (68% ciclosporin and 66% prednisolone), but serious adverse reactions, especially infections, were more common in the prednisolone group. Conclusion Prednisolone and ciclosporin did not differ across a range of objective and patient reported outcomes. Treatment decisions for individual patients may be guided by the different side effect profiles of the two drugs and patient preference. Trial registration Current Controlled Trials ISRCTN35898459

Differential Drug Survival of Biologic Therapies for the Treatment of Psoriasis: A Prospective Observational Cohort Study from the British Association of Dermatologists Biologic Interventions Register (BADBIR)

Drug survival reflects a drug’s effectiveness, safety, and tolerability. We assessed the drug survival of biologics used to treat psoriasis in a prospective national pharmacovigilance cohort (British Association of Dermatologists Biologic Interventions Register (BADBIR)). The survival rates of the first course of biologics for 3,523 biologic-naive patients with chronic plaque psoriasis were compared using survival analysis techniques and predictors of discontinuation analyzed using a multivariate Cox proportional hazards model. Data for patients on adalimumab (n=1,879), etanercept (n=1,098), infliximab (n=96), and ustekinumab (n=450) were available. The overall survival rate in the first year was 77%, falling to 53% in the third year. Multivariate analysis showed that female gender (hazard ratio (HR) 1.22; 95% confidence interval (CI): 1.09–1.37), being a current smoker (HR 1.19; 95% CI: 1.03–1.38), and a higher baseline dermatology life quality index (HR 1.01; 95% CI: 1.00–1.02) were predictors of discontinuation. Presence of psoriatic arthritis (HR 0.82; 95% CI: 0.71–0.96) was a predictor for drug survival. As compared with adalimumab, patients on etanercept (HR 1.63; 95% CI: 1.45–1.84) or infliximab (HR 1.56; 95% CI: 1.16–2.09) were more likely to discontinue therapy, whereas patients on ustekinumab were more likely to persist (HR 0.48; 95% CI: 0.37–0.62). After accounting for relevant covariates, ustekinumab had the highest first-course drug survival. The results of this study will aid clinical decision making when choosing biologic therapy for psoriasis patients

TGFb2 induces the soluble isoform of CTLA-4 – implications for CTLA-4 based checkpoint inhibitor antibodies in malignant melanoma

FUNDING This work was funded by the Chief Scientist’s office, Scotland grant no. ETM/280. Acknowledgments Microscopy was performed in the Microscopy and Histology Core Facility at the University of Aberdeen. Flow cytometry was performed in the Iain Fraser Cytometry Centre. We are very grateful to our lab manager Ms. Gill Moir for her assistance with this work and also to the many BSc/MSc project students who worked on this project. We are extremely grateful for all of the volunteer melanoma patient donors and healthy donors that supported this work. FA-F received an Elphinstone PhD scholarship funded by the School of Medicine, Medical Sciences & Nutrition at the University of Aberdeen.Peer reviewedPublisher PD

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

Is speed of healing a good predictor of eventual healing of pyoderma gangrenosum?

Background: Pyoderma gangrenosum is a rare inflammatory skin condition. The STOPGAP studies compared treatments for pyoderma gangrenosum using a primary outcome of healing speed at 6 weeks. Objective: Using data from both studies we assessed the predictive value of three early predictors for healing at 6 months - speed of healing, Investigator Global Assessment and resolution of inflammation, recorded at 2 and 6 weeks. Methods: Logistic regression models were applied and the effectiveness of the three measures was assessed through estimating the positive (PPV) and negative predictive values (NPV) and the area under the receiver operating characteristic curve (AUC). Results: The PPV and NPV at 6 weeks were 63.5% (95% CI:52.4%, 73.7%) and 74.6% (95% CI:62.5%, 84.5%) respectively for speed of healing; 80% (95% CI:68.7%, 88.6%) and 74.2% (95% CI:64.1%, 2.7%) for IGA; and 72.1% (95% CI:59.9%, 82.3%) and 68.1% (95% CI:57.7%, 77.3%) for resolution of inflammation. Investigator Global Assessment had the best combined PPV, NPV and AUC at 2 and 6 weeks. Limitations: We were limited by data available from the STOP GAP trial and cohort study. Conclusion: Speed of healing, Investigator Global Assessment and resolution of inflammation were all shown to be good predictors of eventual healing