The impact of comorbidities on interleukin-17 inhibitor therapy in psoriatic arthritis: a Danish population-based cohort study.

Objective: To investigate the influence of comorbidities on treatment response, disease activity and persistence with first-line IL-17 inhibitor (IL-17i) treatment in patients with PsA. Methods: Patients were divided into three groups depending on the presence and/or severity of comorbidities using the Charlson Comorbidity Index (CCI). Groups were CCI 0: no comorbidities, CCI 1: one comorbidity and CCI ≥2: two or more comorbidities or one or more severe comorbidities. Outcomes in the groups were compared for treatment persistence, treatment response and disease activity. Results: A higher CCI score was associated to an elevation in baseline CRP, swollen joint count and frequency of depression and/or anxiety. The median drug persistence in the groups were CCI 0: 1.8 years, CCI 1: 1.9 years and CCI ≥2: 1.5 years, but was not statistically significant to the CCI score. There were no significant differences in clinical response rates between the groups. Conclusion: The presence of comorbidities was associated with increased baseline disease activity and frequency of depression and/or anxiety, but was not associated with shorter treatment persistence or lower clinical response rates in a cohort of 155 Danish patients with PsA treated with first-line IL-17i.

Optimal control and comprehensive cost-effectiveness analysis for COVID-19.

Cost-effectiveness analysis is a mode of determining both the cost and economic health outcomes of one or more control interventions. In this work, we have formulated a non-autonomous nonlinear deterministic model to study the control of COVID-19 to unravel the cost and economic health outcomes for the autonomous nonlinear model proposed for the Kingdom of Saudi Arabia. We calculated the strength number and noticed the strength number is less than zero, meaning the proposed model does not capture multiple waves, hence to capture multiple wave new compartmental model may require for the Kingdom of Saudi Arabia. We proposed an optimal control problem based on a previously studied model and proved the existence of the proposed optimal control model. The optimality system associated with the non-autonomous epidemic model is derived using Pontryagin's maximum principle. The optimal control model captures four time-dependent control functions, thus, u 1 -practising physical or social distancing protocols; u 2 -practising personal hygiene by cleaning contaminated surfaces with alcohol-based detergents; u 3 -practising proper and safety measures by exposed, asymptomatic and symptomatic infected individuals; u 4 -fumigating schools in all levels of education, sports facilities, commercial areas and religious worship centres. We have performed numerical simulations to investigate extensive cost-effectiveness analysis for fourteen optimal control strategies. Comparing the control strategies, we noticed that; Strategy 1 (practising physical or social distancing protocols) is the most cost-saving and most effective control intervention in Saudi Arabia in the absence of vaccination. But, in terms of the infection averted, we saw that strategy 6, strategy 11, strategy 12, and strategy 14 are just as good in controlling COVID-19.

Population Pharmacokinetics of Intraventricular Vancomycin in Neonatal Ventriculitis, A Preterm Pilot Study.

AIM: Intraventricular vancomycin is an effective treatment for neonatal ventriculitis, as the cerebrospinal fluid (CSF) vancomycin levels reach adequate concentrations to achieve microbiological cure. There is no robust data on intraventricular vancomycin pharmacokinetics in the preterm population. This pilot population pharmacokinetic modelling study examines the pharmacokinetic behaviour of intraventricular vancomycin in the preterm population of < 28 weeks gestation, to inform the feasibility of future prospective studies. METHODS: The study comprised 8 preterm infants with neonatal ventriculitis (median gestation age 25.3 weeks; range 23.9 - 27.7). Population pharmacokinetics (non-linear mixed effects modelling) were described with one- and two-compartment models to fit plasma concentrations of vancomycin. A CSF compartment was added to the plasma modelling and mass transfer examined. Three covariates (serum creatinine, ventricular index (VI) and CSF protein) were tested on the final model. Area under the curve (AUC) and average CSF concentration (C average) predictions were generated from the final model and compared with time to microbiological cure. RESULTS: A one-compartment model provided the best fit to the data. There was no appreciable transfer between plasma and CSF. None of the covariates provided a significant reduction in the objective function value (OFV). Generally, time to sterilisation with higher CSF AUC (0-24) and C average tends to be shorter, however this should be interpreted with caution as data is erratic. CONCLUSION: This pilot population pharmacokinetic analysis provides important information to warrant changes in the management of intraventricular vancomycin treatment in the preterm population, such as the current use of VI as a dosing parameter. Further study with a larger data pool is necessary to investigate the influence of VI on CSF vancomycin and ascertain dosing strategies.

Measuring psoriatic arthritis symptoms: A core domain in psoriasis clinical trials.

BACKGROUND: The International Dermatology Outcome Measures established a set of core domains to be measured in all psoriasis trials. This set requires that symptoms of psoriatic arthritis (PsA) be measured in all psoriasis studies. OBJECTIVE: To identify the approach to PsA screening and the most appropriate outcome measure for capturing PsA symptoms. METHODS: Following guidelines (ie, the COnsensus-based Standards for the selection of health Measurement INstruments, Core Outcome Measures in Effectiveness Trials Initiative, and Outcome Measures in Rheumatology Handbook), we conducted a consensus-building study that included patients, physicians, industry partners, and patient association representatives. The process consisted of a literature review and quality appraisal of measures for PsA symptoms, a pre-Delphi exercise, a Delphi survey, and a consensus meeting. RESULTS: Among the 297 expert participants in the Delphi survey, 87.5% agreed that all patients in a psoriasis trial should be screened for PsA with a validated screening tool. Regarding the measurement of PsA symptoms, the preferred instrument was the Psoriatic Arthritis Impact of Disease-9 (PsAID9), with the Routine Assessment Patient Index Data-3 (RAPID3) representing an acceptable alternative. LIMITATIONS: Only International Dermatology Outcome Measures members participated in the consensus meeting. CONCLUSION: The overwhelming majority of expert stakeholders agreed that all psoriasis trial participants should be screened for PsA, with PsA symptoms measured by using PsAID9 (or alternatively with RAPID3).

Role of public involvement in the Royal College of Physicians' Future Hospitals healthcare improvement programme: an evaluation.

OBJECTIVES: The Royal College of Physician's (RCP) Future Hospital Programme (FHP) set out a blueprint for a radical new model of care that put patient experience centre stage. This paper reports on the results of an independent evaluation of the FHP and focuses on the role public patient involvement (PPI) played in these projects. The paper explores the perceptions and experiences of those involved in the FHP of how PPI was operationalised in this context, and develops an 'ex-post' programme theory of PPI in the FHP. We conclude by assessing the benefits and challenges of this work. SETTING: Secondary care. The FHP consisted of eight clinician-led healthcare improvement hospital development sites with two phases. PARTICIPANTS: Development site clinical teams, patient representatives, the RCP's Patient and Carer Network, members of the FHP team, and fellows and members of the RCP. DESIGN/METHODS: We conducted an independent evaluation of the FHP using FHP documentation and data collected specifically for the evaluation: qualitative interviews, focus groups and a web-based survey. RESULTS: The PPI initiatives set out to develop more patient-centred care and improve the patient experience. The mechanisms designed to meet these goals were (1) a programme of PPI in the development site's projects, (2) a better understanding of patient experience and (3) evaluation of patient experience. CONCLUSION: This evaluation of the FHP identifies some key elements that need to be considered when attempting to more closely integrate PPI and co-production in service re-design. The structure of FHP over two phases enabled learning from phase I to be incorporated into phase II. Having the PPI representatives closely involved, developing communities of practice, and the oversight and measuring activities acted as 'disciplinary structures' that contributed to embedding PPI in the FHP and kept the patient experience at the forefront of the improvement initiatives.

Achieving international consensus on the assessment of psoriatic arthritis in psoriasis clinical trials: an International Dermatology Outcome Measures (IDEOM) initiative.

Psoriatic arthritis (PsA) is rarely assessed in psoriasis randomized controlled trials (RCT); thus, the effect of psoriasis therapy on PsA is unknown. The International Dermatology Outcome Measures (IDEOM) has included "PsA Symptoms" as part of the core domains to be measured in psoriasis RCT. This study aimed to achieve consensus about screening for PsA and how to measure for "PsA Symptoms" in psoriasis RCT. At the IDEOM 2017 Annual Meeting, stakeholders voted on the role of PsA screening in psoriasis RCT. To select measures for "PsA Symptoms", we adapted the Consensus-Based Standards for the Selection of Health Measurement Instruments (COSMIN) guidelines. Three potential measures were selected. At the meeting, stakeholders voted on the validity, feasibility, and responsiveness of these measures. Of the 47 stakeholders, 93% voted that all psoriasis trial participants should be screened for PsA. "PsA Symptoms" measures included Patient Global (PG)-arthritis, Routine Assessment Patient Index Data (RAPID)-3, and Psoriatic Arthritis Impact of Disease (PsAID)-9. During the voting, more than 50% of the voters agreed that RAPID3 and PsAID9 were good measures for PsA Symptoms, able to capture all its essential elements. PsAID9 was considered the most feasible instrument, followed by RAPID3 and PG-arthritis, respectively. Finally, most participants agreed that RAPID3 and PsAID9 were responsive measures. Most study participants voted that all subjects in a psoriasis clinical trial should be screened for PsA. RAPID3 and PsAID9 outperformed PG-arthritis in measuring PsA Symptoms. This will be followed by a Delphi survey involving a larger stakeholder group.

Current role of saphenous vein graft in coronary artery bypass grafting.

Saphenous vein was the conduit used in the first series of coronary artery bypass grafting (CABG), and, with the exception of surgical revascularization of the left anterior descending artery, it remains the most commonly used bypass conduit. However, its durability and longevity are not ideal. Arterial grafts have better patency than saphenous vein grafts and therefore should be preferred over them. However, in certain situations, like grafting right coronary arteries with lesser degree of proximal stenosis and higher competitive flow, or in certain patient populations, like those at very high risk of wound infections and octogenarians, arterial grafting may not be the best option and saphenous vein grafting should be considered instead.

Implementing the future hospital.

For the last 4 years, this part of the Future Healthcare Journal has been the place to find regular overview updates on progress made by the Future Hospital Programme of the Royal College of Physicians, together with its partners, in realising the vision of the Future Hospital Commission. As outlined in this article, the Future Hospital Programme has now concluded. However, much of its work is being carried on by the RCP Quality Improvement Programme, which can be contacted on RCPQI@rcplondon.ac.uk. Follow the Quality Improvement Programme on Twitter: @RCP_QI.

Metabolic and immune effects of immunotherapy with proinsulin peptide in human new-onset type 1 diabetes.

Immunotherapy using short immunogenic peptides of disease-related autoantigens restores immune tolerance in preclinical disease models. We studied safety and mechanistic effects of injecting human leukocyte antigen-DR4(DRB1*0401)-restricted immunodominant proinsulin peptide intradermally every 2 or 4 weeks for 6 months in newly diagnosed type 1 diabetes patients. Treatment was well tolerated with no systemic or local hypersensitivity. Placebo subjects showed a significant decline in stimulated C-peptide (measuring insulin reserve) at 3, 6, 9, and 12 months versus baseline, whereas no significant change was seen in the 4-weekly peptide group at these time points or the 2-weekly group at 3, 6, and 9 months. The placebo group's daily insulin use increased by 50% over 12 months but remained unchanged in the intervention groups. C-peptide retention in treated subjects was associated with proinsulin-stimulated interleukin-10 production, increased FoxP3 expression by regulatory T cells, low baseline levels of activated ß cell-specific CD8 T cells, and favorable ß cell stress markers (proinsulin/C-peptide ratio). Thus, proinsulin peptide immunotherapy is safe, does not accelerate decline in ß cell function, and is associated with antigen-specific and nonspecific immune modulation.

Update on the Future Hospital Programme.

This part of the Future Hospital Journal is where you will find regular overview updates on -progress made by the Future Hospital Programme of the Royal -College of Physicians, together with its -partners, in realising the vision of the Future -Hospital -Commission. We very much welcome your feedback. If you have any comments, or would like to be involved in the work of the Programme, please contact futurehospital@rcplondon.ac.uk.

The future physician.

Both hospital-based care and physician training have undergone significant changes within the past decade. Current physician training in the UK is failing to meet the needs of patients, with significant numbers of acute and general medicine posts unfilled. Building on the themes of the 2013 Shape of Training review, we propose a model that places an alternative model of generalist - the 'future hospitalist' - at the centre of patient care and medical training. The reinstatement of the general physician at the heart of hospital care will increase flexibility in both training and workforce planning, and embed active leadership, patient safety and quality improvement in care delivery.

Update from the Future Hospital Programme.

This part of the Future Hospital Journal is where you will find regular overview updates on progress made by the Future Hospital Programme of the Royal College of Physicians, together with its partners, in realising the vision of the Future Hospital Commission. We very much welcome your feedback. If you have any comments, or would like to be involved in the work of the Programme, please contact futurehospital@rcplondon.ac.uk. Follow the Future Hospital Programme on Twitter: @RCPFutureHosp.

Update from the Future Hospital Programme.

This part of the Future Healthcare Journal is where you will find regular overview updates on progress made by the Future Hospital Programme of the Royal College of Physicians, together with its partners, in realising the vision of the Future Hospital Commission. We very much welcome your feedback. If you have any comments, or would like to be involved in the work of the Programme, please contact futurehospital@rcplondon.ac.uk. Follow the Future Hospital Programme on Twitter: @RCPFutureHosp.

pH-responsive and enzymatically-responsive hydrogel microparticles for the oral delivery of therapeutic proteins: Effects of protein size, crosslinking density, and hydrogel degradation on protein delivery.

Two potential platform technologies for the oral delivery of protein therapeutics were synthesized and tested. pH-responsive poly(itaconic acid-co-N-vinyl-2-pyrrolidone) (P(IA-co-NVP)) hydrogel microparticles were tested in vitro with model proteins salmon calcitonin, urokinase, and rituximab to determine the effects of particle size, protein size, and crosslinking density on oral delivery capability. Particle size showed no significant effect on overall delivery potential but did improve percent release of encapsulated protein over the micro-scale particle size range studied. Protein size was shown to have a significant impact on the delivery capability of the P(IA-co-NVP) hydrogel. We show that when using P(IA-co-NVP) hydrogel microparticles with 3 mol% tetra(ethylene glycol) dimethacrylate crosslinker, a small polypeptide (salmon calcitonin) loads and releases up to 45 µg/mg hydrogel while the mid-sized protein urokinase and large monoclonal antibody rituximab load and release only 19 and 24 µg/mg hydrogel, respectively. We further demonstrate that crosslinking density offers a simple method for tuning hydrogel properties to variously sized proteins. Using 5 mol% TEGDMA crosslinker offers optimal performance for the small peptide, salmon calcitonin, whereas lower crosslinking density of 1 mol% offers optimal performance for the much larger protein rituximab. Finally, an enzymatically-degradable hydrogels of P(MAA-co-NVP) crosslinked with the peptide sequence MMRRRKK were synthesized and tested in simulated gastric and intestinal conditions. These hydrogels offer ideal loading and release behavior, showing no degradative release of encapsulated salmon calcitonin in gastric conditions while yielding rapid and complete release of encapsulated protein within 1h in intestinal conditions.

Adipose tissue and adipokines: the association with and application of adipokines in obesity.

2014 marks the 20th anniversary of adipokines. Through the identification of leptin, our perceived understanding of adipose tissue was changed instantaneously. From a simple dormant site of energy storage, adipose tissue is now recognized as an integral hub of various hormones known as adipokines. Although great strides have been made in characterizing these hormones in health, research also shows they are significantly implicated in a series of pathologies. One such condition is obesity. Defined as an excess of adipose tissue, obesity remains one of the greatest healthcare epidemics of the 21st century. With no definitive treatment, attention has shifted to understanding the role of adipokines in obesity. This review provides an introduction to the salient obesity-related adipokines and their possible application as a treatment for obesity.

The association of circulating ferritin with serum concentrations of fibroblast growth factor-23 measured by three commercial assays.

BACKGROUND: The measurement of the serum concentration of fibroblast growth factor-23 (FGF-23) is beginning to be used as a diagnostic tool in renal phosphate wasting disorders. Having observed an increased serum FGF-23 in three subjects with low circulating ferritin concentrations we investigated the association between low ferritin and raised serum FGF-23. METHODS: We measured FGF-23 in 150 random anonymized serum samples with ferritin concentrations between <5 and 50 microg/L using three commercially available enzyme-linked immunosorbent assay (ELISA) kits. One kit, Human FGF-23[C-term] (Immutopics Inc, USA) measures total FGF-23 whereas the other two kits, Immutopics intact and FGF-23 ELISA (Kainos, Japan) are reported to measure only the biologically active intact molecule. RESULTS: We have detected a significant inverse correlation of -0.565 (P<0.0001) between serum ferritin when <50 microg/L and FGF-23 using the C-terminal assay. This relationship is also shown with the Immutopics intact assay but is not demonstrated with the Kainos intact assay. CONCLUSION: The measurement of FGF-23 by both Immutopics assays is altered in the presence of low circulating concentrations of serum ferritin whereas with the Kainos intact assay this effect was not demonstrated. Serum ferritin should be measured when an elevated FGF-23 is obtained using the Immutopics C-terminal or intact FGF-23 assay to prevent misdiagnosis of the cause of this abnormality.