Physical activity is important for cardiovascular health and cardiorespiratory fitness in patients with psoriasis.

BACKGROUND: Patients with psoriasis have a level of physical activity below that recommended for cardiovascular health, which is significantly limited by disease severity and other psoriasis-specific barriers. We hypothesized that physical activity is important for cardiovascular health in patients with psoriasis and that its objective measurement could have clinical utility. AIM: To explore whether physical activity influences the risk of cardiovascular disease (CVD) in patients with psoriasis. METHODS: In total, 242 patients with chronic plaque psoriasis were recruited. History, examination and physical activity were assessed and arteriography, the noninvasive measurement of arterial function, was performed for each participant. RESULTS: We observed a significant relationship between volume of physical activity and the likelihood of future CVD as measured by pulse wave velocity (PWV; P < 0.02). We identified a significant relationship between the diastolic reflection area (DRA) and health-promoting levels of physical activity (P < 0.001), in addition to a significant correlation between DRA and the likelihood of future CVD (P < 0.001). The DRA is a complex, dimensionless variable that describes the intensity of diastolic wave reflection and the duration of diastole, which are key determinants of the blood supply to the left ventricle. Our data suggest that DRA may represent a surrogate marker for cardiorespiratory fitness. CONCLUSION: Our study describes a significant relationship between exercise, cardiorespiratory fitness and PWV, a preclinical indicator of future CVD risk, in patients with psoriasis. The DRA offers a noninvasive, objective measurement of exercise adherence, which could have clinical utility in the future.

Research priorities and identification of a health-service delivery model for psoriasis from the UK Psoriasis Priority Setting Partnership.

BACKGROUND: Psoriasis impacts the health and psychosocial functioning of patients, conferring a significant economic burden on healthcare systems. There remain unmet needs in psoriasis care, which if addressed by research, could improve clinical outcomes. AIM: To research priorities and identify a health service delivery model from the UK Psoriasis Priority Setting Partnership (PsPSP). METHODS: Between July 2017 and November 2018, we invited people with lived experience of psoriasis and healthcare professionals to (i) identify unmet needs, and (ii) prioritize the order in which these should be addressed by research. We collaborated with the Psoriasis Association and used methodology established by the James Lind Alliance, which pioneers the joint setting of research priorities by patients and clinicians worldwide. RESULTS: In our initial harvesting survey (Survey 1), 2133 questions were submitted by 805 individuals. Submissions that had not been answered by research (true uncertainties) were supplemented with evidence gaps from systematic reviews/guidelines published in the previous 5 years and refined to produce 55 indicative questions. Voting in Survey 2, by 1154 individuals, enabled a shortlist of questions, which were prioritized during the final workshop to produce a top 20 list of research questions. Submissions on health service delivery (5.8% of the total submissions), which were analysed separately, described a blueprint for psoriasis care. CONCLUSIONS: The PsPSP will inform the translational research agenda, ensuring that future research is relevant for the needs of people with psoriasis and those who manage the disease. Submissions on health service delivery describe a model of holistic, patient-focused care providing high-quality, effective management for patients with psoriasis.

Organic osmolytes increase expression of specific tight junction proteins in skin and alter barrier function in keratinocytes.

BACKGROUND: The epidermal barrier is important for water conservation, failure of which is evident in dry-skin conditions. Barrier function is fulfilled by the stratum corneum, tight junctions (TJs, which control extracellular water) and keratinocyte mechanisms, such as organic osmolyte transport, which regulate intracellular water homeostasis. Organic osmolyte transport by keratinocytes is largely unexplored and nothing is known regarding how cellular and extracellular mechanisms of water conservation may interact. OBJECTIVES: We aimed to characterize osmolyte transporters in skin and keratinocytes, and, using transporter inhibitors, to investigate whether osmolytes can modify TJs. Such modification would suggest a possible link between intracellular and extracellular mechanisms of water regulation in skin. METHODS: Immunostaining and quantitative polymerase chain reaction of organic osmolyte-treated organ-cultured skin were used to identify changes to organic osmolyte transporters, and TJ protein and gene expression. TJ functional assays were performed on organic osmolyte-treated primary human keratinocytes in culture. RESULTS: Immunostaining demonstrated the expression of transporters for betaine, taurine and myo-inositol in transporter-specific patterns. Treatment of human skin with either betaine or taurine increased the expression of claudin-1, claudin-4 and occludin. Osmolyte transporter inhibition abolished this response. Betaine and taurine increased TJ function in primary human keratinocytes in vitro. CONCLUSIONS: Treatment of skin with organic osmolytes modulates TJ structure and function, which could contribute to the epidermal barrier. This emphasizes a role for organic osmolytes beyond the maintenance of intracellular osmolarity. This could be harnessed to enhance topical therapies for diseases characterized by skin barrier dysfunction.

Next steps in dermatology training: choosing to enter higher speciality training and the transition from trainee to consultant dermatologist.

BACKGROUND: Junior doctors are required to make career decisions at an early stage in their postgraduate training. Trainees also feel inadequately prepared for the transition to consultant roles. AIM: To explore the key factors influencing the choice of dermatology as a postgraduate medical career and to identify the training needs required for transition from trainee to consultant. METHODS: An online questionnaire was designed to identify (i) why trainees chose a postgraduate medical career in dermatology, and (ii) the training required for transition from trainee to consultant. RESULTS: In total, 46 responses were received from trainees in their first to final years (ST3-6), of whom 89% had undertaken an undergraduate dermatology placement, with a median duration of 2 weeks. Dermatology was considered as a career during medical school by 61% of trainees, and 41% confirmed their decision to pursue a career in dermatology during foundation training. The most influential factors involved in speciality selection were first, enjoyment of the work, second, postgraduate experience and equal third, the variety of the speciality and the regularity of working hours (P < 0.05). Mentoring was pivotal to career decision-making. Significant numbers of trainees expressed a need for training in medical leadership, such as running an outpatient clinic and supervising clinical multidisciplinary teams. Although larger numbers of trainees had training in management of dermatology services, such as service improvement (52%) and local governance/National Health Service structures (43%), significant numbers of trainees had no training in writing job plans (89%) or business plans (85%). Training was significantly deficient for personal management and self-awareness. CONCLUSION: Our study highlights important considerations in career decision-making for trainees. Training in medical leadership, management and self-awareness could be enhanced to ensure that trainees feel adequately equipped for consultant roles.

What are the barriers to physical activity in patients with chronic plaque psoriasis?

BACKGROUND: Psoriasis is associated with an increased risk of cardiovascular disease. Despite recommendation that exercise is important for cardiorespiratory fitness, patients with psoriasis avoid participation in physical activities for reasons that are, as yet, unclear. OBJECTIVES: This study investigated the relationship between psoriasis-specific experiences and self-reported patterns of exercise, hypothesizing that individuals with psoriasis are less likely to engage in physical activity for reasons that are related to their psoriasis. METHODS: In total 404 patients with chronic plaque psoriasis were recruited. History, examination and physical activity were assessed for each participant. RESULTS: Overall, 52·8% (n = 188) of patients with psoriasis aged 18-65 years and 66% (n = 37) of those aged > 65 years engaged in less than the recommended amount of physical activity for cardiorespiratory fitness. As the severity and psychosocial impact of psoriasis increased, the participation in exercise (of all intensities) decreased. There was a significant negative correlation between Psoriasis Area and Severity Index and total activity in women aged 18-65 years (r = -0·19, 95% confidence interval -0·36 to 0; P = 0·04) and a significant negative correlation between physical activity and Dermatology Life Quality Index (DLQI) in all participants (r = -0·11, 95% confidence interval -0·21 to 0; P = 0·04). Individual components of the DLQI identified barriers to physical activity including skin sensitivity and reluctance to participate in leisure activities. CONCLUSIONS: Psoriasis-specific factors - severity, skin sensitivity, clothing choice, participation in social/leisure activities, and treatments - contribute to exercise avoidance and may augment the increased risk of cardiovascular disease in patients with psoriasis.

Genetic interaction between placental growth factor and vascular endothelial growth factor A in psoriasis.

BACKGROUND: Expression of vascular endothelial growth factor A (VEGFA) is increased in chronic inflammatory skin diseases, including psoriasis, and loci for two VEGFA single nucleotide polymorphisms are associated with early-onset psoriasis (presenting before the age of 40 years). Studies have suggested that expression of placenta growth factor (PGF) is also upregulated in cutaneous inflammation and that VEGFA-mediated angiogenesis may be dependent on the simultaneous presence of PGF within the skin. AIM: To elucidate the biological importance of PGF in psoriasis. METHODS: We investigated whether two commonly occurring PGF polymorphisms were associated with early-onset psoriasis and the genetic interaction between VEGFA and PGF in psoriasis. RESULTS: We observed a significant (P = 0.04) association between rs2268614 TT and rs2268615 AA genotypes of PGF and early-onset psoriasis. In addition, genetic complement, comprising the PGF rs2268615 AA genotype and the VEGFA -460 (rs833061) T allele, was significantly associated with the development of early-onset psoriasis (P < 0.03). We identified that the VEGFA genotype influences PGF expression (P = 0.001) and that mean plasma levels of PGF are lower in patients with severe psoriasis compared with those with mild-moderate disease (P = 0.04). CONCLUSION: Our observed genetic interaction between PGF and VEGFA appears relevant to psoriasis, a disease with an angiogenic basis, and may influence development of an antiangiogenic approach to treatment.

Tropical seabirds sample broadscale patterns of marine contaminants.

Contaminants in the marine environment are widespread, but ship-based sampling routines are much narrower. We evaluated the utility of seabirds, highly-mobile marine predators, as broad samplers of contaminants throughout three tropical ocean regions. Our aim was to fill a knowledge gap in the distributions of, and processes that contribute to, tropical marine contaminants; and explore how species-specific foraging ecologies could inform or bias our understanding of contaminant distributions. Mercury and persistent organic pollutant (POPs) concentrations were measured in adults of five seabird species from four colonies in the central Pacific (Laysan and Tern Islands, Hawaii; Palmyra Atoll) and the eastern Caribbean (Barbuda). Blood-based total mercury (THg) and 89 POPs were measured in two seabird families: surface-foraging frigatebirds (Fregata spp.) and plunge-diving boobies (Sula spp.). Overall, largescale contaminant differences between colonies were more informative of contaminant distributions than inter-specific foraging ecology. Model selection results indicated that proximity to human populations was the best predictor of THg and POPs. Regional differences in contaminants were distinct: Barbudan Magnificent Frigatebirds had more compounds (n=52/89 POP detected) and higher concentrations (geometric mean THg=0.97µgg-1; mean ΣPOP53=26.6ngmL-1) than the remote colonies (34-42/89 POP detected; range of THg geometric means=0.33-0.93µgg-1; range of mean ΣPOP53:7.3-17.0ngmL-1) and had the most recently-synthesized POPs. Moderate differences in foraging ecologies were somewhat informative of inter-specific differences in contaminant types and concentrations between nearshore and offshore foragers. Across species, contaminant concentrations were higher in frigatebirds (THg=0.87µgg-1; ΣPOP53=17.5ngmL-1) compared to boobies (THg=0.48µgg-1; ΣPOP53=9.8). Ocean currents and contaminants' physiochemical properties provided additional insight into the scales of spatial and temporal contaminant exposure. Seabirds are excellent, broad samplers with which we can understand contaminant distributions in the marine environment. This is especially important for tropical remote regions that are under-sampled.

Ecological and Evolutionary Consequences of Parasite Avoidance.

Predators often cause prey to adopt defensive strategies that reduce predation risk. The 'ecology of fear' examines these trait changes and their consequences. Similarly, parasites can cause hosts to adopt defensive strategies that reduce infection risk. However the ecological and evolutionary consequences of these behaviors (the 'ecology of disgust') are seldom considered. Here we identify direct and indirect effects of parasite avoidance on hosts and parasites, and examine differences between predators and parasites in terms of cost, detectability, and aggregation. We suggest that the nonconsumptive effects of parasites might overshadow their consumptive effects, as has been shown for predators. We emphasize the value of uniting predator-prey and parasite-host theory under a general consumer-resource framework.

Biosimilars for psoriasis: worldwide overview of regulatory guidelines, uptake and implications for dermatology clinical practice.

The introduction of biological drugs for the treatment of patients with psoriasis has revolutionized treatment paradigms and enabled numerous patients to achieve disease control with an acceptable safety profile. However, the high cost of biologics limits access to these medications for the majority of patients worldwide. In recent years, the introduction of biosimilars for inflammatory diseases has become a fast evolving field. The future use of biosimilars offers the potential for decreased cost and increased access to biologics for patients with psoriasis. For approval of biosimilars, different regulatory agencies use highly variable methods for definition, production, approval, marketing and postmarketing surveillance. Due to potential interchangeability between biologics and biosimilars, traceability and pharmacovigilance are required to collect accurate data about adverse events in patients with psoriasis; spontaneous reporting, registries and use of 'big data' should facilitate this process on a global basis. The current article describes biosimilar regulatory guidelines and examples of biosimilar uptake in clinical practice in several countries around the world. As it is apparent that biological therapy treatment decisions may become more physician independent, the International Psoriasis Council recommends that dermatologists should take an active role in the development of biosimilar prescribing policies with their respective healthcare settings and government agencies.

The Structure of Mammalian Prions and Their Aggregates.

Prion diseases, such as Creutzfeldt-Jakob disease in humans, bovine spongiform encephalopathy in cattle, chronic wasting disease in cervids (i.e., deer, elk, moose, and reindeer), and sheep scrapie, are caused by the misfolding of the cellular prion protein (PrPC) into a disease-causing conformer (PrPSc). PrPC is a normal, GPI-anchored protein that is expressed on the surface of neurons and other cell types. The structure of PrPC is well understood, based on studies of recombinant PrP, which closely mimics the structure of native PrPC. In contrast, PrPSc is prone to aggregate into a variety of quaternary structures, such as oligomers, amorphous aggregates, and amyloid fibrils. The propensity of PrPSc to assemble into these diverse forms of aggregates is also responsible for our limited knowledge about its structure. Then again, the repeating nature of certain regular PrPSc aggregates has allowed (lower resolution) insights into the structure of the infectious conformer, establishing a four-rung ß-solenoid structure as a key element of its architecture.

Primary care-based screening for cardiovascular risk factors in patients with psoriasis.

BACKGROUND: Studies assessing cardiovascular disease (CVD) risk factors in patients with psoriasis have been limited by selection bias, inappropriate controls or a reliance on data collected for clinical reasons. OBJECTIVES: To investigate whether screening for CVD risk factors in patients with psoriasis in primary care augments the known prevalence of CVD risk factors in a cross-sectional study. METHODS: Patients listed as having psoriasis in primary care were recruited, screened and risk assessed by QRISK2. RESULTS: In total, 287 patients attended (mean age 53 years, 57% women, 94% white British, 22% severe disease, 33% self-reported psoriatic arthritis). The proportion with known and screen-detected (previously unknown) risk factors was as follows: hypertension 35% known and 13% screen-detected; hypercholesterolaemia 32% and 37%; diabetes 6·6% and 3·1% and chronic kidney disease 1·1% and 4·5%. At least one screen-detected risk factor was found in 48% and two or more risk factors were found in 21% of patients. One in three patients (37%) not previously known to be at high risk were found to have a high (> 10%) 10-year CVD risk. Among the participants receiving treatment for known CVD risk factors, nearly half had suboptimal levels for blood pressure (46%) and cholesterol (46%). CONCLUSIONS: Cardiovascular risk factor screening of primary care-based adults with psoriasis identified a high proportion of patients (i) at high CVD risk, (ii) with screen-detected risk factors and (iii) with suboptimally managed known risk factors. These findings need to be considered alongside reports that detected limited responses of clinicians to identified risk factors before universal CVD screening can be recommended.

Novel investigational vascular endothelial growth factor (VEGF) receptor antagonists for psoriasis.

INTRODUCTION: Affecting 1 million people in the UK, psoriasis is a commonly diagnosed inflammatory disease arising from autoimmune processes that are triggered by environmental factors in genetically susceptible individuals. The pathophysiology of psoriasis has been widely studied and there is evidence that angiogenesis is a key component. AREAS COVERED: In this review the role of vascular endothelial growth factor-A (VEGF), as a key angiogenic mediator in psoriasis pathogenesis is discussed. VEGF is found in higher levels in plaques, normal skin and plasma of patients with psoriasis. The level of VEGF also fluctuates in accordance with disease activity and in response to conventional treatments. There are several VEGF inhibitors currently licenced for use; primarily in the fields of oncology and there are case reports of patients being treated with these therapies for metastatic cancer who have demonstrated significant improvement in their psoriasis. VEGF inhibitory agents have suggested promising utility for the treatment of psoriasis following animal studies. EXPERT OPINION: VEGF may represent a novel treatment target in psoriasis. However, VEGF inhibitors can cause significant side effects such as hypertension and left ventricular dysfunction. The risks of treatment must be carefully evaluated before VEGF inhibitors are trialled or advocated for psoriasis.

Investigational VEGF antagonists for psoriasis.

INTRODUCTION: Vascular endothelial growth factor (VEGF) mediates angiogenesis consequent to binding to VEGF receptors (VEGFRs) and is upregulated in patients with psoriasis. VEGF is also upregulated in other diseases characterised by angiogenesis including proliferative retinopathy and cancer. Several VEGF antagonists have been approved for the treatment of these conditions and may also have the potential to treat psoriasis. AREAS COVERED: A PubMed literature search was performed to identify preclinical and clinical research regarding investigational VEGF antagonists for the treatment of psoriasis. Various agents have been reviewed including monoclonal antibodies against VEGF and VEGFRs, decoy anti-VEGF receptors and tyrosine kinase inhibitors that block the effects of VEGF/VEGFR binding. EXPERT OPINION: Several investigational drugs have demonstrated potential to treat psoriasis. Clinical observations of psoriasis remission following administration of bevacizumab, sunitinib and sorafenib in cancer patients are encouraging. Of particular interest is a novel anti-VEGF/anti-TNF-α decoy receptor (Valpha), whose dual action could be beneficial given the numerous pathogenetic pathways in psoriasis. A topical tyrosine kinase inhibitor also has potential given the cost and safety advantages conferred by this mode of administration. More research is warranted both in the prototypical drugs and in those already marketed for other indications.

Polymorphisms in the PTPN22 region are associated with psoriasis of early onset.

BACKGROUND: Psoriasis, a chronic inflammatory skin disease, affects approximately 2% of the population worldwide. Although the aetiology of psoriasis is poorly understood, patients with disease of early onset (Type I, age of onset