Higher Dietary Vitamin K Intake is Associated with Better Physical Function and Lower Long-Term Injurious Falls Risk in Community-Dwelling Older Women.

BACKGROUND: In recent years, a potential beneficial role of Vitamin K in neuromuscular function has been recognised. However, the optimal dietary intake of Vitamin K to support muscle function in the context of falls prevention remains unknown. OBJECTIVE: To examine the relationship of dietary Vitamin K1 and K2 with muscle function and long-term injurious fall-related hospitalisations in older women. DESIGN: Cohort study. PARTICIPANTS: 1347 community-dwelling older Australian women ≥70 years. MEASUREMENTS: A new Australian Vitamin K nutrient database, supplemented with published data, was used to calculate Vitamin K1 and K2 intake from a validated food frequency questionnaire at baseline (1998). Muscle function (grip strength and timed-up-and-go; TUG) as well plasma Vitamin D status (25OHD) were also assessed at baseline. Fall-related hospitalisations over 14.5 years were obtained from linked health records. Multivariable-adjusted logistic regression and Cox-proportional hazard models were used to analyse the data. RESULTS: Over 14.5 years of follow-up (14,774 person-years), 535 (39.7%) women experienced a fall-related hospitalisation. Compared to women with the lowest Vitamin K1 intake (Quartile 1, median 49 µg/d), those with the highest intake (Quartile 4, median 120 µg/d) had 29% lower odds (OR 0.71 95%CI 0.52-0.97) for slow TUG performance (>10.2 s), and 26% lower relative hazards of a fall-related hospitalisation (HR 0.74 95%CI 0.59-0.93) after multivariable adjustment. These associations were non-linear and plateaued at moderate intakes of ~70-100 µg/d. There was no relation to grip strength. Vitamin K2 intakes were not associated with muscle function or falls. CONCLUSION: A higher habitual Vitamin K1 intake was associated with better physical function and lower long-term injurious falls risk in community-dwelling older women. In the context of musculoskeletal health, Vitamin K1 found abundantly in green leafy vegetables should be promoted.

Rooibos (Aspalathus linearis) alters secretome trace amine profile of probiotic and commensal microbes in vitro.

ETHNOPHARMACOLOGY RELEVANCE: Aspalathus linearis (Burm.f.) R. Dahlgren (rooibos) tea is anecdotally renowned for its calming effect in the context of gastrointestinal discomfort, but little scientific support is available to elucidate potential mechanisms of action. Enhancement of dietary polyphenol content to improve gut health via prebiotic-like modulation of the gut microbiota has gained significant research interest. Given the known high polyphenol content of rooibos, rooibos tea may potentially exert a prebiotic effect in the gut to facilitate an improvement in chronic inflammatory gastrointestinal conditions. AIM OF THE STUDY: This study aimed to determine the prebiotic or health-modulating potential of rooibos tea in terms of its effect on gut microbial growth and secretome trace amine composition, as well as to determine how differential rooibos processing alters this activity. METHODS: Three rooibos preparations (green and fermented leave aqueous extracts, as well as a green leaf ethanol extract) were compared in terms of their phenolic composition (qTOF-LC/MS). Moreover, the effect of rooibos exposure on growth and secretome trace amine levels of probiotic and commensal microbes were assessed (LC/MS). In addition, given the known female bias prevalent for many gastrointestinal disorders, experiments were conducted in the absence and presence of estradiol. RESULTS: Polyphenolic composition of rooibos was drastically reduced by fermentation. Aqueous extracts of both green and fermented rooibos improved microbial growth, although fermented rooibos had the most pronounced effect (p < 0.01). In terms of secretome trace amine profile, both aqueous extracts of rooibos seemed to facilitate increased putrescine secretion (p < 0.0001) and decreased tryptamine production (p < 0.0001). Estradiol seemed to suppress trace amine secretion by bacteria (Lactobacillus plantarum, Lactobacillus reuteri and Enterococcus mundtii) but increased it in yeast (Saccharomyces boulardii). CONCLUSION: Rooibos altered gut probiotic and commensal microbial growth and secretome trace amine profiles in vitro, suggesting it has potential to modulate gut microbial composition and functionality as a prebiotic. Current data suggest that these effects are highly dependent on raw material processing. Finally, rooibos may be able to prevent estradiol-associated alterations in trace amine profile, which may have important implications for patient management in female-predominant gastrointestinal disorders.

Drivers of ecological assembly in the hindgut of Atlantic Cod fed a macroalgal supplemented diet.

It is difficult to disentangle the many variables (e.g. internal or external cues and random events) that shape the microbiota in the gastrointestinal tract of any living species. Ecological assembly processes applied to microbial communities can elucidate these drivers. In our study, farmed Atlantic cod (Gadus morhua) were fed a diet of 10% macroalgae supplement (Ulva rigida [ULVA] or Ascophyllum nodosum [ASCO] or a non-supplemented control diet [CTRL]) over 12 weeks. We determined the influence of ecological assembly processes using a suite of null-modelling tools. We observed dissimilarity in the abundance of common OTUs over time, which was driven by deterministic assembly. The CTRL samples showed selection as a critical assembly process. While dispersal limitation was a driver of the gut microbiome for fish fed the macroalgae supplemented diet at Week 12 (i.e., ASCO and ULVA). Fish from the ASCO grouping diverged into ASCO_N (normal) and ASCO_LG (lower growth), where ASCO_LG individuals found the diet unpalatable. The recruitment of new taxa overtime was altered in the ASCO_LG fish, with the gut microbiome showing phylogenetic underdispersion (nepotistic species recruitment). Finally, the gut microbiome (CTRL and ULVA) showed increasing robustness to taxonomic disturbance over time and lower functional redundancy. This study advances our understanding of the ecological assembly and succession in the hindgut of juvenile Atlantic cod across dietary treatments. Understanding the processes driving ecological assembly in the gut microbiome, in fish research specifically, could allow us to manipulate the microbiome for improved health or resilience to disease for improved aquaculture welfare and production.

Defining trajectories of response in patients with psoriasis treated with biologic therapies.

BACKGROUND: The effectiveness and cost-effectiveness of biologic therapies for psoriasis are significantly compromised by variable treatment responses. Thus, more precise management of psoriasis is needed. OBJECTIVES: To identify subgroups of patients with psoriasis treated with biologic therapies, based on changes in their disease activity over time, that may better inform patient management. METHODS: We applied latent class mixed modelling to identify trajectory-based patient subgroups from longitudinal, routine clinical data on disease severity, as measured by the Psoriasis Area and Severity Index (PASI), from 3546 patients in the British Association of Dermatologists Biologics and Immunomodulators Register, as well as in an independent cohort of 2889 patients pooled across four clinical trials. RESULTS: We discovered four discrete classes of global response trajectories, each characterized in terms of time to response, size of effect and relapse. Each class was associated with differing clinical characteristics, e.g. body mass index, baseline PASI and prevalence of different manifestations. The results were verified in a second cohort of clinical trial participants, where similar trajectories following the initiation of biologic therapy were identified. Further, we found differential associations of the genetic marker HLA-C*06:02 between our registry-identified trajectories. CONCLUSIONS: These subgroups, defined by change in disease over time, may be indicative of distinct endotypes driven by different biological mechanisms and may help inform the management of patients with psoriasis. Future work will aim to further delineate these mechanisms by extensively characterizing the subgroups with additional molecular and pharmacological data.

The use of extensively hydrolysed and amino acid feeds beyond cow's milk allergy: a national survey.

BACKGROUND: Extensively hydrolysed formulas (EHFs) and amino acid formulas (AAFs) with proven hypoallergenicity are used for children suffering from cow's milk allergy, when breast milk is not available. However, these feeds are often used in other medical conditions where tolerance and absorption of whole protein is affected, frequently without assessment of efficacy. This practice survey assessed the use of these feeds in paediatric conditions other than cow's milk allergy; aiming to describe the population, growth parameters and micronutrient status. METHODS: Four National Health Service tertiary paediatric centres participated in this practice survey. Inclusion: children between 0 and 18 years, consuming >25% of their estimated energy requirements of an EHF/AAF for any condition other than allergic disease. Anonymised data were collected: (i) descriptive information; (ii) indications; (iii) type and route of feeding; (iv) growth status and nutritional deficiencies; and (v) medication and vitamin and mineral supplementation. RESULTS: One hundred-and-ninety-one children were included with a median age of 19 months (interquartile range 4-63]. Seventeen percent (33/191) were on AAFs and 83% (158/191) were on EHFs. The feeds were commonly used in cancer for 26% and in critical illness for 31%. The majority (73%) of children had enteral feeds via a nasogastric tube. Nutritional biomarkers were performed in 29% of children and 83% were on a vitamin or mineral supplement. CONCLUSIONS: This practice survey found that EHFs and AAFs were used in a variety of medical conditions. Indications for feed choice varied, and evidence-based research supporting the use was scarce. Awaiting further research, children on these types of feeds should have regular nutritional monitoring.

Immunogenicity of biologic therapies in psoriasis: Myths, facts and a suggested approach.

With biologic drugs dominating the therapeutic space for severe immune-mediated inflammatory disease, it is critical for clinicians to be familiar with the concept of drug immunogenicity, with the potential for our patients to develop antidrug antibodies (ADA) of clinical relevance. Whilst there are clear differences between different therapeutic biologics in terms of reported ADA rates, there is no accepted dermatology guideline or grouping of drugs by risk of clinically relevant ADA, nor a consensus on approach to ADA management. This is partly because making valid comparisons of immunogenicity across drugs is fundamentally flawed: the differing types of ADA assay, trial design and included patient population - as well as the molecular structure of the biologic molecules themselves - are all highly influential on reported ADA prevalence and impact on clinical response. Therefore, the first part of this article aims to give an overview of ADA that also clarifies common misconceptions on the subject, whilst the second part of this article outlines Phase III immunogenicity data on commonly used biologics for psoriasis, the most common dermatological indication. Based on this, and acknowledging current limitations in available evidence, we propose a working categorization of biologics together with a broad approach to management: Group 1 - biologics with higher risk of clinically relevant ADA; Group 2 - biologics with lower risk of clinically relevant ADA; and Group 3 - biologics with no established risk of clinically relevant ADA. However, these groupings represent a working concept only; more research is required, using comparable ADA assays and consistent reporting of related outcomes. Finally, there is an urgent need for better characterization of individuals at particular risk of developing ADA to inform future clinical decision-making.

The safety and effectiveness of mind body interventions for women with pregnancy induced hypertension and or preeclampsia: A systematic review and meta-analysis.

OBJECTIVES: To undertake a systematic review of the safety and effectiveness of mind body approaches for women with hypertensive disorders in pregnancy (HDP). DESIGN: A search was undertaken of databases from inception to 2019 for randomised and quasi randomised controlled trials. MAIN OUTCOME MEASURES: The primary outcome was a reduction in systolic and / or diastolic blood pressure for women with hypertension and or preeclampsia in pregnancy. RESULTS: 121 studies were identified and eight studies were included in this review. These included mind body interventions examining yoga, guided imagery, relaxation, music, and acupuncture for HDP. Two studies of relaxation found a reduction in systolic (MD -11.3, 95%CI -13.23 to -9.39) and diastolic blood pressure (MD -6.59, 95%CI -9.43 to -3.75) and reduced stress (MD -11.4, 95%CI -16.5 to -6.3). In one study of yoga, the risk of developing HDP was reduced (RR 0.28, 95% CI 0.09 to 0.91, 59 women) and a second study found a reduction in stress at the end of the intervention of yoga. One trial of guided imagery found a reduction in mean arterial blood pressure compared to the control (4.35, 95% -8.04 to -0.66, p=0.02). Overall there was no effect on the development of preeclampsia, use of anti-hypertensive medication and any neonatal outcomes from the interventions evaluated. Few trials reported on safety outcomes, one trial of acupuncture reported one case of placental abruption and three cases of acupuncture related side effects. CONCLUSION: Few high quality trials have examined the effectiveness and safety of mind body interventions to manage HDP. Relaxation, yoga, guided imagery and music may have some potential benefit. Safety issues are completely unclear and thus the risk-benefit ratio of all interventions could not be determined. Further research is recommended.

Comparing the efficacy and tolerability of biologic therapies in psoriasis: an updated network meta-analysis.

BACKGROUND: The rapid expansion of psoriasis biologics has led to an urgent need to understand their relative efficacy and tolerability to inform treatment decisions better and, specifically, to inform guideline development. OBJECTIVES: To update a 2017 meta-analysis on the comparative efficacy and tolerability of biologic treatments for psoriasis. METHODS: We searched the MEDLINE, PubMed, Embase and Cochrane databases for randomized controlled trials (RCTs), published up to 7 September 2018, of 11 licensed, NICE-approved biologics targeting tumour necrosis factor (adalimumab, etanercept, infliximab, certolizumab pegol), interleukin (IL)-12/IL-23p40 (ustekinumab), IL-17A (secukinumab, ixekizumab), IL-17RA (brodalumab) and IL-23p19 (guselkumab, tildrakizumab, risankizumab). A frequentist network meta-analysis ascertained direct or indirect evidence comparing biologics with one another, methotrexate or placebo. This was combined with hierarchical cluster analyses to consider efficacy (≥ 90% improvement in Psoriasis Area and Severity Index (PASI 90) or Physician's Global Assessment 0 or 1; PASI 75; Dermatology Life Quality Index improvement) and tolerability (drug withdrawal due to adverse events) outcomes at 10-16 weeks, followed by assessments of study quality, heterogeneity and inconsistency. RESULTS: We identified 62 RCTs presenting data on direct comparisons (31 899 participants). All biologics were efficacious compared with placebo or methotrexate at 10-16 weeks. Hierarchical cluster analyses revealed that adalimumab, brodalumab, certolizumab pegol, guselkumab, risankizumab, secukinumab, tildrakizumab and ustekinumab were comparable with respect to high short-term efficacy and tolerability. Infliximab and ixekizumab clustered together, with high short-term efficacy but relatively lower tolerability than the other agents, although the number of drug withdrawal events across the network was low, so these findings should be treated with caution. CONCLUSIONS: Using our methodology we found that most biologics cluster together with respect to short-term efficacy and tolerability, and we did not identify any single agent as 'best'. These data need to be interpreted in the context of longer-term efficacy, effectiveness data, safety, posology and drug acquisition costs when making treatment decisions.

Analysis of the genes controlling three quantitative traits in three diverse plant species reveals the molecular basis of quantitative traits.

Most traits of agricultural importance are quantitative traits controlled by numerous genes. However, it remains unclear about the molecular mechanisms underpinning quantitative traits. Here, we report the molecular characteristics of the genes controlling three quantitative traits randomly selected from three diverse plant species, including ginsenoside biosynthesis in ginseng (Panax ginseng C.A. Meyer), fiber length in cotton (Gossypium hirsutum L. and G. barbadense L.) and grain yield in maize (Zea mays L.). We found that a vast majority of the genes controlling a quantitative trait were significantly more likely spliced into multiple transcripts while they expressed. Nevertheless, only one to four, but not all, of the transcripts spliced from each of the genes were significantly correlated with the phenotype of the trait. The genes controlling a quantitative trait were multiple times more likely to form a co-expression network than other genes expressed in an organ. The network varied substantially among genotypes of a species and was associated with their phenotypes. These findings indicate that the genes controlling a quantitative trait are more likely pleiotropic and functionally correlated, thus providing new insights into the molecular basis underpinning quantitative traits and knowledge necessary to develop technologies for efficient manipulation of quantitative traits.

Evaluating unmet needs in patients undergoing surgery for colorectal cancer: a patient reported outcome measures study.

AIM: Patient reported outcome measures (PROMs) are self-reported measures of patients' health status or health-related quality of life at a single point in time. We aimed to evaluate the use of a colorectal PROM and conducted a focus group to further explore this and other unmet needs in our patient population treated surgically for colorectal cancer. METHOD: A multidisciplinary research group consisting of colorectal surgeons, nurse specialists, psychologists, sociologists and patient representatives devised a composite tool of new and existing outcome measures which was piloted in our local population (n = 35). Participants were subsequently invited to attend a semi-structured focus group during which the PROM was reviewed and an unmet needs analysis was performed. Thematic analysis of focus group transcripts was undertaken for emergent themes. RESULTS: Initial consensus was for a tool including the EQ-5D, Functional Assessment of Cancer Therapy - Colorectal (FACT-C), the distress thermometer, a validated measure of stigma, an unmet needs analysis, and questions assessing the psychological impact of cancer. Median and interquartile range values suggested that all metrics were discriminatory with the exception of FACT-C. All participants agreed that the tool was acceptable and reflected the current state of their health and emotions. Thematic analysis of focus group transcripts identified four major themes: physical symptoms, emotional response, information provision and coping mechanisms. CONCLUSION: Through expert consensus, local piloting and patient focus groups we have evaluated a novel PROM for colorectal cancer. Furthermore, through our direct engagement with patients we have identified several unmet needs which we are currently exploring within the clinical service.

Adapting Maslow's Hierarchy of Needs as a Framework for Resident Wellness.

ISSUE: Burnout in graduate medical education is pervasive and has a deleterious impact on career satisfaction, personal well-being, and patient outcomes. Interventions in residency programs have often addressed isolated contributors to burnout; however, a more comprehensive framework for conceptualizing wellness is needed. EVIDENCE: In this article the authors propose Maslow's hierarchy of human needs (physiologic, safety, love/belonging, esteem, and self-actualization) as a potential framework for addressing wellness initiatives. There are numerous contributors to burnout among physician-trainees, and programs to combat burnout must be equally multifaceted. A holistic approach, considering both the trainees personal and professional needs, is recommended. Maslow's Needs can be adapted to create such a framework in graduate medical education. The authors review current evidence to support this model. IMPLICATIONS: This work surveys current interventions to mitigate burnout and organizes them into a scaffold that can be used by residency programs interested in a complete framework to supporting wellness.

Are polyphenol antioxidants at the root of medicinal plant anti-cancer success?

ETHNOPHARMACOLOGICAL RELEVANCE: Given the severe side effects associated with most of the conventional cancer medications, as well as the expanding body of evidence indicating secondary toxicity of these drugs, individuals with cancer are increasingly turning to natural alternatives. Similarly, the pharmaceutical industry is in search of natural products to treat cancer. An understanding of the specific active components in plant products with which anti-cancer efficacy is achieved is required for this research to move forward. AIM OF THE STUDY: To integrate data from cancer-relatestudies on plant-derived products or extracts, to elucidate whether these products may have similar active ingredients and/or mechanisms of action, that can explain their efficacy. This review also includes a discussion of the methodological complexities and important considerations involved in accurate isolation and characterisation of active substances from plant material. CONCLUSIONS: From the literature reviewed, most plant products with consistently reported anti-cancer efficacy contains high levels of polyphenols or other potent antioxidants and their mechanisms of action correlate to that reported for isolated antioxidants in the context of cancer. This suggests that natural products may indeed become the panacea against this chronic disease - either as therapeutic medicine strategy or to serve as templates for the design of novel synthetic drugs. The recommendation is made that antioxidant activity of plant actives and especially polyphenols, should be the focus of anti-cancer drug discovery initiatives. Lastly, researchers are advised to exploit current techniques of chemical compound characterisation when investigating polyphenol-rich plants to enable the easy consolidation of research findings from different laboratories.

Sceletium tortuosum may delay chronic disease progression via alkaloid-dependent antioxidant or anti-inflammatory action.

The link between obesity-induced systemic inflammation and decreased insulin signalling is well-known. It is also known that peripherally produced inflammatory cytokines can cross the blood-brain barrier, resulting in the release of neurotoxins that can ultimately lead to the demise of central nervous system integrity. A high-mesembrine Sceletium tortuosum extract was recently shown to possess cytoprotective and mild anti-inflammatory properties in monocytes and to target specific p450 enzymes to reduce adrenal glucocorticoid synthesis. This is significant since the aetiology of both obesity and diabetes is linked to inflammation and excess glucocorticoid production. Given the interlinked nature of glucocorticoid action and inflammation, central immunomodulatory effects of two Sceletium tortuosum extracts prepared by different extraction methods were investigated. Human astrocytes were pre-treated for 30 min, before exposure to Escherichia coli lipopolysaccharide for 23.5 h (in the presence of treatment). Cytotoxicity, mitotoxicity and cytokine responses (basally and in response to inflammatory stimulus) were assessed. In addition, total polyphenol content, antioxidant capacity and selected neural enzyme inhibition capacity were assessed for both extracts. The high-mesembrine Sceletium extract exerted cytoprotective and anti-inflammatory effects. In contrast, the high delta7-mesembrenone extract, rich in polyphenols, exhibited potent antioxidant effect, although with relatively higher risk of adverse effects with overdose. We conclude that both Sceletium tortuosum extracts may be employed as either a preventative supplement or complimentary treatment in the context of obesity and diabetes; however, current data also highlights the impact that extraction methods can have on plant product mechanism of action.

Validez factorial y fiabilidad de la versión española del Sport Imagery Ability Questionnaire (SIAQ) / Validade fatorial e fabilidade da versão em espanhol do questionário Sport Imagery Ability Questionnaire (SIAQ) / Factorial validity and reliability of the spanish version of Sport Imagery Ability Questionnaire (SIAQ)

Esta investigación tuvo como objetivo encontrar evidencias de validez factorial y fiabilidad del Sport Imagery Ability Questionnaire SIAQ (Williams y Cumming, 2011) en una versión traducida al castellano y denominada Cuestionario de Habilidad de Imaginería en el Deporte (CHID). Evalúa la facilidad a la hora de generar imágenes de diferente contenido de los y las deportistas en cinco ámbitos diferentes Estrategia, Adversidad, Habilidad, Afectos y Logro. Se ha llevado a cabo un estudio con una muestra de 360 deportistas, 93 mujeres y 267 hombres, de diferentes modalidades tanto individuales como colectivas. Tomando el modelo teórico final del estudio de Williams y Cumming (2011) se llevó a cabo un Análisis Factorial Confirmatorio (AFC) que reveló un modelo de 5 factores y 15 ítems con evidencias de validez factorial. Asimismo, se llevaron a cabo un análisis de consistencia interna (alfa de Cronbach, fabilidad compuesta y promedio de varianza explicada), y otro de estabilidad temporal (test-retest con un intervalo de un mes entre la primera y la segunda vez que completan el cuestionario) para hallar evidencias de fabilidad del instrumento. En general, el CHID demuestra una buena validez factorial y consistencia interna (AU)

This research aimed to find evidence of the validity and reliability of the Sport Imagery Ability Questionnaire SIAQ (Williams and Cumming, 2011) in a Spanish translated version called "Cuestionario de Habilidad de Imaginería en el Deporte" (CHID). The SIAQ is a 15 item questionnaire to assess five types of athlete imagery ability: skill imagery ability, strategy imagery ability, goal imagery ability, affect imagery ability, and mastery imagery ability. The study consisted of a sample of 360 athletes, 93 women and 267 men, of different individual and team sports. Taking the final theoretical model of Williams and Cumming (2011), the researchers conducted a Confirmatory Factor Analysis (CFA) that revealed a model of 5 factors and 15 items with evidence of factorial validity. Furthermore, an analysis of internal consistency (Cronbach's alpha, composite reliability and Average Variance Extracted) and a test-retest analysis were carried out, with a time interval of a month in between, to find evidence of the reliability of the instrument. In general, the CHID demonstrates good factorial validity and internal reliability (AU)

Esta pesquisa teve como objetivo encontrar evidências de validade e confiabilidade do questionário Sport Imagery Ability Questionnaire SIAQ (Williams e Cumming, 2011) em uma versão traduzida em espanhol chamada «Cuestionario de Habilidad de Imaginería en el Deporte» (CHID, Cuestionário de Habilidade de Imagiologia no Deporte). O SIAQ é um questionário de 15 itens para avaliar cinco tipos de habilidades de imaginação de atleta diferentes: habilidade de imaginação, habilidade de capacidade de estratégia, habilidade de imagem de objetivo, habilidade de imagem de afeto e habilidade de imagem de domínio. O estudo consistiu de uma amostra de 360 atletas, 93 mulheres e 267 Homens, de diferentes esportes individuais e de equipe. Considerando o modelo teórico final de Williams e Cumming (2011), os pesquisadores realizaram uma análise de fatores confrmatória (CFA) que revelou um modelo de 5 fatores e 15 itens com evidência de validade. Realizou-se também uma análise de consistência interna (alfa de Cronbach, confiabilidade composta e variância média extraída). Por fim, foi feita uma análise teste-reateste com um intervalo de tempo de um mês entre os dois. Em geral, o CHID que demonstra boa validade fatorial e confiabilidade interna (AU)

Comparative effectiveness of biological therapies on improvements in quality of life in patients with psoriasis.

BACKGROUND: Evidence of the comparative effectiveness of biological therapies for psoriasis on health-related quality of life (HRQoL) in routine clinical practice is limited. OBJECTIVES: To examine the comparative effectiveness of adalimumab, etanercept and ustekinumab on HRQoL in patients with psoriasis, and to identify potential predictors for improved HRQoL. METHODS: This was a prospective cohort study in which changes in HRQoL were assessed using the Dermatology Life Quality Index (DLQI) and EuroQoL-5D (EQ-5D) at 6 and 12 months. Multivariable regression models were developed to identify factors associated with achieving a DLQI of 0/1 and improvements in the EQ-5D utility score. RESULTS: In total, 2152 patients with psoriasis were included, with 1239 patients on adalimumab, 517 on etanercept and 396 on ustekinumab; 81% were biologic naïve. For the entire cohort, the median (interquartile range) DLQI and EQ-5D improved from 18 (13-24) and 0·73 (0·69-0·80) at baseline to 2 (0-7) and 0·85 (0·69-1·00) at 6 months, respectively (P < 0·001). Similar improvements were achieved at 12 months. At 12 months, multivariable regression modelling showed that female sex, multiple comorbidities, smoking and a higher DLQI or a lower EQ-5D utility score at baseline predicted a lower likelihood of achieving a DLQI of 0/1 or improvement in the EQ-5D. Compared with adalimumab, patients receiving etanercept, but not ustekinumab, were less likely to achieve a DLQI of 0/1. There was no significant difference between the biological therapies in EQ-5D improvement. CONCLUSIONS: In routine clinical practice biological therapies produce marked improvement in HRQoL, which is influenced by the choice of biological therapy, baseline impairment in HRQoL, lifestyle characteristics and comorbidities. These findings should help inform selection of optimal biological therapy for patients related to improvements in HRQoL.

Identification of factors that may influence the selection of first-line biological therapy for people with psoriasis: a prospective, multicentre cohort study.

BACKGROUND: The Psoriasis Stratification to Optimise Relevant Therapy (PSORT) consortium has a collective aim to develop a prescribing algorithm to help stratify eligible patients with psoriasis to the most appropriate biological treatment. To facilitate the adoption of a stratified approach, it is necessary to first understand the factors driving the choice of first-line biological therapy. OBJECTIVES: To identify and quantify factors that influence the selection of the first-line biological therapy for people with psoriasis. METHODS: Multinomial logistic regression was used to determine the factors that influenced the probability of treatment selection, using data from the British Association of Dermatologists Biologic Interventions Register from January 2012 to December 2015. Sensitivity analyses were performed to assess the robustness of the findings to key assumptions. RESULTS: The main analysis was based on a dataset comprising 3040 people with psoriasis. The identified factors affecting first-line biological selection within the available therapies were: presence of psoriatic arthritis; patient weight; employment status; country of registration; and baseline disease severity. Importantly, the analysis showed a general shift in prescribing behaviour over time. These results were robust to sensitivity analysis. CONCLUSIONS: This study offers important insights into the factors influencing current prescribing practice for first-line biological therapies for people with psoriasis. It provides baseline data to inform the evaluation of future potential changes that may affect prescribing behaviour, such as stratified medicine.

Relaxin-3/RXFP3 signalling in mouse hypothalamus: no effect of RXFP3 activation on corticosterone, despite reduced presynaptic excitatory input onto paraventricular CRH neurons in vitro.

Relaxin-3/RXFP3 signalling is proposed to be involved in the neuromodulatory control of arousal- and stress-related neural circuits. Furthermore, previous studies in rats have led to the proposal that relaxin-3/RXFP3 signalling is associated with activation of the hypothalamic-pituitary-adrenal axis, but direct evidence for RXFP3-related actions on the activity of hypothalamic corticotropin-releasing hormone (CRH) neurons is lacking. In this study, we investigated characteristics of the relaxin-3/RXFP3 system in mouse hypothalamus. Administration of an RXFP3 agonist (RXFP3-A2) intra-cerebroventricularly or directly into the paraventricular nucleus of hypothalamus (PVN) of C57BL/6J mice did not alter corticosterone levels. Similarly, there were no differences between serum corticosterone levels in Rxfp3 knockout (C57BL/6JRXFP3TM1) and wild-type mice at baseline and after stress, despite detection of the predicted stress-induced increases in serum corticosterone. We examined the nature of the relaxin-3 innervation of PVN in wild-type mice and in Crh-IRES-Cre;Ai14 mice that co-express the tdTomato fluorophore in CRH neurons, identifying abundant relaxin-3 fibres in the peri-PVN region, but only sparse fibres associated with densely packed CRH neurons. In whole-cell voltage-clamp recordings of tdTomato-positive CRH neurons in these mice, we observed a reduction in sEPSC frequency following local application of RXFP3-A2, consistent with an activation of RXFP3 on presynaptic glutamatergic afferents in the PVN region. These studies clarify the relationship between relaxin-3/RXFP3 inputs and CRH neurons in mouse PVN, with implications for the interpretation of current and previous in vivo studies and future investigations of this stress-related signalling network in normal and transgenic mice, under normal and pathological conditions.

Patterns of biologic therapy use in the management of psoriasis: cohort study from the British Association of Dermatologists Biologic Interventions Register (BADBIR).

BACKGROUND: Treatment modifications, including dose escalations, dose reductions, switches, discontinuations and restarts of biologics may be necessary in the management of psoriasis but the patterns of usage are incompletely defined. OBJECTIVES: To examine the treatment utilization patterns of adalimumab, etanercept and ustekinumab among biologic-naïve and non-naïve patients with psoriasis enrolled in the British Association of Dermatologists Biologic Interventions Register (BADBIR). METHODS: The study cohort included adults with chronic plaque psoriasis who were followed up for ≥ 12 months. Treatment modifications were assessed during the first year of therapy. The time-trend method, comparing the cumulative dose (CD) patients received with the recommended cumulative dose (RCD), was used to assess dosing patterns. Concomitant use of other systemic treatments was also examined. RESULTS: In total, 2980 patients (adalimumab: 1675; etanercept: 996; ustekinumab: 309) were included; 79·2% were biologic-naïve. Over 12 months, 77·4% of patients continued the biologic, 2·6% restarted therapy after a break of ≥ 90 days, 2·5% discontinued, and 17·5% switched biologic therapy. Most patients (85·7%) received the RCD of the biologic, although 8·1% were exposed to a higher CD. In total, 749 (25·1%) patients used conventional systemic therapies concomitantly with a biologic at some stage; methotrexate was used most commonly (458; 61·2%). Of those using combination therapy, 454 (60·6%) continued the use of the conventional systemic therapy for > 120 days after the start of the biologic. CONCLUSIONS: More than one-third of patients experienced treatment modifications within the first year of initiating a biologic. Conventional systemic therapies, particularly methotrexate, were commonly used concurrently, which should be considered when evaluating treatment response and adverse events to biologics in real-world observational studies.