Retinoids in the treatment of photoageing: A histological study of topical retinoid efficacy in black skin.

BACKGROUND: Photoageing describes complex cutaneous changes that occur due to chronic exposure to solar ultraviolet radiation (UVR). The 'gold standard' for the treatment of photoaged white skin is all-trans retinoic acid (ATRA); however, cosmetic retinol (ROL) has also proven efficacious. Recent work has identified that black skin is susceptible to photoageing, characterized by disintegration of fibrillin-rich microfibrils (FRMs) at the dermal-epidermal junction (DEJ). However, the impact of topical retinoids for repair of black skin has not been well investigated. OBJECTIVES: To determine the potential of retinoids to repair photoaged black skin. METHODS: An exploratory intervention study was performed using an in vivo, short-term patch test protocol. Healthy but photoaged black volunteers (>45 years) were recruited to the study, and participant extensor forearms were occluded with either 0.025% ATRA (n = 6; 4-day application due to irritancy) or ROL (12-day treatment protocol for a cosmetic) at concentrations of 0.3% (n = 6) or 1% (n = 6). Punch biopsies from occluded but untreated control sites and retinoid-treated sites were processed for histological analyses of epidermal characteristics, melanin distribution and dermal remodelling. RESULTS: Treatment with ATRA and ROL induced significant acanthosis (all p < 0.001) accompanied by a significant increase in keratinocyte proliferation (Ki67; all p < 0.01), dispersal of epidermal melanin and restoration of the FRMs at the DEJ (all p < 0.01), compared to untreated control. CONCLUSIONS: This study confirms that topical ATRA has utility for the repair of photoaged black skin and that ROL induces comparable effects on epidermal and dermal remodelling, albeit over a longer timeframe. The effects of topical retinoids on black photoaged skin are similar to those reported for white photoaged skin and suggest conserved biology in relation to repair of UVR-induced damage. Further investigation of topical retinoid efficacy in daily use is warranted for black skin.

Revealing uncertainty in the status of biodiversity change.

Biodiversity faces unprecedented threats from rapid global change1. Signals of biodiversity change come from time-series abundance datasets for thousands of species over large geographic and temporal scales. Analyses of these biodiversity datasets have pointed to varied trends in abundance, including increases and decreases. However, these analyses have not fully accounted for spatial, temporal and phylogenetic structures in the data. Here, using a new statistical framework, we show across ten high-profile biodiversity datasets2-11 that increases and decreases under existing approaches vanish once spatial, temporal and phylogenetic structures are accounted for. This is a consequence of existing approaches severely underestimating trend uncertainty and sometimes misestimating the trend direction. Under our revised average abundance trends that appropriately recognize uncertainty, we failed to observe a single increasing or decreasing trend at 95% credible intervals in our ten datasets. This emphasizes how little is known about biodiversity change across vast spatial and taxonomic scales. Despite this uncertainty at vast scales, we reveal improved local-scale prediction accuracy by accounting for spatial, temporal and phylogenetic structures. Improved prediction offers hope of estimating biodiversity change at policy-relevant scales, guiding adaptive conservation responses.

Maximizing organs for donation: the potential for ex situ normothermic machine perfusion.

Currently, there is a shortfall in the number of suitable organs available for transplant resulting in a high number of patients on the active transplant waiting lists worldwide. To address this shortfall and increase the utilization of donor organs, the acceptance criteria for donor organs is gradually expanding including increased use of organs from donation after circulatory death. Use of such extended criteria donors and exposure of organs to more prolonged periods of warm or cold ischaemia also increases the risk of primary graft dysfunction occurring. Normothermic machine perfusion (NMP) offers a unique opportunity to objectively assess donor organ function outside the donor body and potentially recondition those deemed unsuitable on initial evaluation prior to implantation in the recipient. Furthermore, NMP provides a platform to support the use of established and novel therapeutics delivered directly to the organ, without the need to worry about potential deleterious 'off-target' side effects typically considered when treating the whole patient. This review will explore some of the novel therapeutics currently being added to perfusion platforms during NMP experimentally in an attempt to improve organ function and post-transplant outcomes.

Health-Related Quality of Life Following Simultaneous Resection for Synchronous Colorectal Cancer Liver Metastases.

INTRODUCTION: Up to 25% of colorectal cancer patients present with synchronous liver metastases that can be treated with two operations or a single 'simultaneous' operation. Morbidity and mortality appear similar between approaches, however changes in health-related quality-of-life following simultaneous resection are not well reported. METHODS: A prospective, feasibility trial for simultaneous resection of synchronous colorectal liver metastases was conducted. Patients completed the European Organization for Research and Treatment of Cancer QLQ-C30 and LMC21 at baseline (preoperatively), and 4 and 12 weeks postoperatively. Week 4 and 12 scores were compared with baseline using t-tests. Minimally important clinical differences were considered as a 10-point difference from baseline. RESULTS: C30 and QLQ-LMC21 were completed at baseline, 4 weeks, and 12 weeks by 39 (95%), 35 (85%) and 34 (83%) patients, and 39 (95%), 33 (80%) and 33 (80%) patients, respectively; 79% and 75% had at least one MICD according to QLQ-C30 at 4 and 12 weeks. At 4 weeks, physical functioning (mean difference (MD) - 11.9%, p = 0.002), role functioning (MD - 23.6, p = 0.007), and pain (MD + 19.7, p = 0.017) had significant worsening from baseline. At 12 weeks postoperatively, role functioning (MD - 19.7, p = 0.011) and fatigue (MD + 14.3, p = 0.03) were the only domains that remained significantly worse. By 12 weeks, pain and physical functioning had returned to baseline. There were no major demographic differences among those with and without an MICD at 12 weeks. CONCLUSIONS: Simultaneous resection of colorectal liver metastases led to clinically significant worsening fatigue and role functioning that persisted at 12 weeks post-surgery.

Investigating how researcher-defined buffers and self-drawn neighbourhoods capture adolescent availability to physical activity facilities and greenspaces: An exploratory study.

BACKGROUND: Modifying the environment is considered an effective population-level approach for increasing healthy behaviours, but associations remain ambiguous. This exploratory study aims to compare researcher-defined buffers and self-drawn neighbourhoods (SDN) to objectively measured availability of physical activity (PA) facilities and greenspaces in adolescents. METHODS: Seven consecutive days of GPS data were collected in an adolescent sample of 14-18 year olds (n = 69). Using Points of Interest and greenspace data, availability of PA opportunities within activity spaces were determined. We compared 30 different definitions of researcher-defined neighbourhoods and SDNs to objectively measured availability. RESULTS: Findings showed low agreement for all researcher-defined buffers in measuring the availability of PA facilities in activity spaces. However, results were less clear for greenspace. SDNs also demonstrate low agreement for capturing availability to the PA environment. CONCLUSION: This exploratory study highlights the inadequacy of researcher-defined buffers and SDNs to define availability to environmental features.

Medical management of severe obstructive sleep apnoea in two cases during the coronavirus disease 2019 pandemic.

OBJECTIVE: Severe paediatric obstructive sleep apnoea in typically developing children with adenotonsillar hypertrophy is primarily managed surgically. Non-emergency ENT surgery was paused early in the coronavirus disease 2019 pandemic and children were offered medical management for obstructive sleep apnoea. METHODS: A service evaluation was performed to assess the impact of continuous positive airway pressure alongside medical management for severe obstructive sleep apnoea. RESULTS: Over 5 months during 2020, in a tertiary care setting, two children (one boy and one girl), aged 2.7 years and 4.1 years, were offered continuous positive airway pressure and medical treatments for severe obstructive sleep apnoea whilst surgery was paused during the coronavirus disease 2019 pandemic. Both children failed to establish continuous positive airway pressure therapy because of ongoing disturbed sleep on ventilation, and they proceeded to adenotonsillectomy. Sleep-Related Breathing Disorder scale scores improved following surgical intervention. CONCLUSION: Continuous positive airway pressure therapy is poorly tolerated in children with severe obstructive sleep apnoea secondary to adenotonsillar hypertrophy. Surgery remains the most appropriate treatment.

Implementation fidelity of an Integrated Healthy Lifestyle Service: a process evaluation.

AIMS: The current study aimed to evaluate implementation fidelity of an Integrated Healthy Lifestyle Service (IHLS). METHODS: A pragmatic sample of 28 individual interviews and 11 focus groups were conducted. This resulted in a total of 81 (22 male) individuals comprising key stakeholders (n = 18), as well as intervention staff across senior management (n = 4), team lead (n = 14) and practitioner (n = 11) roles, and intervention clients (n = 34). RESULTS: A mixed degree of implementation fidelity was demonstrated throughout the five a priori fidelity domains of study design, provider training, intervention delivery, intervention receipt, and enactment. Stakeholders, staff and clients alike noted a high degree of intervention receipt across all services offered. Contrastingly, practitioners noted that they received minimal formal operational, data systems, clinical, and curriculum training as well as a lack of personal development opportunities. Consequently, practitioners reported low confidence in delivering sessions and collecting and analysing any data. A top-down approach to information dissemination within the service was also noted among practitioners which affected motivation and overall team morale. CONCLUSION: Results can be used to conceptualise best practices as a process to further strengthen the design, delivery and recruitment strategies of the IHLS.

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.

Anakinra for palmoplantar pustulosis: results from a randomized, double-blind, multicentre, two-staged, adaptive placebo-controlled trial (APRICOT).

BACKGROUND: Palmoplantar pustulosis (PPP) is a rare, debilitating, chronic inflammatory skin disease that affects the hands and feet. Clinical, immunological and genetic findings suggest a pathogenic role for interleukin (IL)-1. OBJECTIVES: To determine whether anakinra (an IL-1 receptor antagonist) delivers therapeutic benefit in PPP. METHODS: This was a randomized (1 : 1), double-blind, two-staged, adaptive, UK multicentre, placebo-controlled trial [ISCRTN13127147 (registered 1 August 2016); EudraCT number: 2015-003600-23 (registered 1 April 2016)]. Participants had a diagnosis of PPP (> 6 months) requiring systemic therapy. Treatment was 8 weeks of anakinra or placebo via daily, self-administered subcutaneous injections. Primary outcome was the Palmoplantar Pustulosis Psoriasis Area and Severity Index (PPPASI) at 8 weeks. RESULTS: A total of 374 patients were screened; 64 were enrolled (31 in the anakinra arm and 33 in the placebo arm) with a mean (SD) baseline PPPASI of 17·8 (10·5) and a PPP investigator's global assessment of severe (50%) or moderate (50%). The baseline adjusted mean difference in PPPASI favoured anakinra but did not demonstrate superiority in the intention-to-treat analysis [-1·65, 95% confidence interval (CI) -4·77 to 1·47; P = 0·30]. Similarly, secondary objective measures, including fresh pustule count (2·94, 95% CI -26·44 to 32·33; favouring anakinra), total pustule count (-30·08, 95% CI -83·20 to 23·05; favouring placebo) and patient-reported outcomes, did not show superiority of anakinra. When modelling the impact of adherence, the PPPASI complier average causal effect for an individual who received ≥ 90% of the total treatment (48% in the anakinra group) was -3·80 (95% CI -10·76 to 3·16; P = 0·285). No serious adverse events occurred. CONCLUSIONS: No evidence for the superiority of anakinra was found. IL-1 blockade is not a useful intervention for the treatment of PPP.

Effect of baseline disease severity on achievement of treatment target with apremilast: results from a pooled analysis.

BACKGROUND: Treating to absolute treatment targets rather than relative measures such as Psoriasis Area and Severity Index (PASI)-75 is emerging as an important clinical concept included in psoriasis guidelines and clinical practice. Achieving treatment targets is associated with achievement of long-term outcomes. OBJECTIVE: To evaluate the relationship between psoriasis severity, disease characteristics and achievement of PASI ≤2 with apremilast in a pooled analysis of the phase 3 ESTEEM 1 and 2 (NCT01194219 and NCT01232283), phase 3b LIBERATE (NCT01690299) and phase 4 UNVEIL (NCT02425826) clinical trials. METHODS: Pooled data from patients with moderate-to-severe plaque psoriasis randomized to apremilast 30 mg BID were analysed by baseline PASI quartiles (Q1: 2.4-13.1; Q2: 13.2-15.9; Q3: 16.0-20.0; Q4: 20.1-57.8). Assessments included PASI, Dermatology Life Quality Index (DLQI), Scalp Physician's Global Assessment (ScPGA; ScPGA ≥1) and target (worst) Nail Psoriasis Severity Index (NAPSI; NAPSI ≥1). RESULTS: Of 1062 patients, 963 had ScPGA ≥1 and 643 had NAPSI ≥1; 771 patients with baseline and Week 32 PASI assessments were included in analyses of Week 32 PASI target achievement. Rates of PASI ≤2 at Week 32 were greater in lower PASI quartiles (Q1: 43.5%; Q2: 31.2%; Q3: 26.8%; Q4: 18.4%). Most patients achieving PASI ≤2 target (83.6%) achieved DLQI ≤5 at Week 32; 59.3% of patients who did not achieve PASI ≤2 target achieved DLQI ≤5. At Week 32, mean improvements in ScPGA and NAPSI were similar with more moderate vs. more severe disease (ScPGA, range: 1.1-1.4; NAPSI, range: 1.6-2.5). In a subgroup analysis, achievement of PASI ≤2 target was higher in the lowest PASI quartile and with disease duration <5 years. CONCLUSIONS: Greater achievement of PASI ≤2 was observed in patients with more moderate vs. more severe skin disease. Apremilast may be particularly beneficial in more moderate disease early in the treatment paradigm.

Five-year maintenance of clinical response and health-related quality of life improvements in patients with moderate-to-severe psoriasis treated with guselkumab: results from VOYAGE 1 and VOYAGE 2.

BACKGROUND: Psoriasis is a chronic disease requiring long-term therapy. OBJECTIVES: Physician- and patient-reported outcomes were evaluated through week 252 in VOYAGE 1 and VOYAGE 2. METHODS: In total, 1829 patients were randomized at baseline to receive guselkumab 100 mg every 8 weeks, placebo or adalimumab. Patients receiving placebo crossed over to guselkumab at week 16. Patients receiving adalimumab crossed over to guselkumab at week 52 in VOYAGE 1, and randomized withdrawal and retreatment occurred at weeks 28-76 in VOYAGE 2; all patients then received open-label guselkumab through week 252. Efficacy and health-related quality of life (HRQoL) endpoints were analysed through week 252. Safety was monitored through week 264. RESULTS: The proportions of patients in the guselkumab group who achieved clinical responses at week 252 in VOYAGE 1 and VOYAGE 2, respectively, were 84·1% and 82·0% [≥ 90% improvement in Psoriasis Area and Severity Index (PASI)]; 82·4% and 85·0% [Investigator's Global Assessment (IGA) 0 or 1]; 52·7% and 53·0% (100% improvement in PASI) and 54·7% and 55·5% (IGA 0). HRQoL endpoints were achieved as follows: 72·7% and 71·1% of patients (Dermatology Life Quality Index 0 or 1: no effect on patient's life); 42·4% and 42·0% [Psoriasis Symptoms and Signs Diary (PSSD) symptom score = 0] and 33·0% and 31·0% (PSSD sign score = 0). As measured in VOYAGE 2 only, approximately 45% of patients achieved ≥ 5-point reduction in Short Form-36 physical and mental component scores, and 80% reported no anxiety or depression (Hospital Anxiety and Depression Scale scores < 8). Similar findings were reported for adalimumab crossovers. These effects were maintained from week 52 in VOYAGE 1 and week 100 in VOYAGE 2. No new safety signals were identified. CONCLUSIONS: Guselkumab maintains high levels of clinical response and improvement in patient-reported outcomes through 5 years in patients with moderate-to-severe psoriasis.

Alcohol misuse is associated with poor response to systemic therapies for psoriasis: findings from a prospective multicentre cohort study.

BACKGROUND: Factors that might influence response to systemic treatment for moderate-to-severe psoriasis are varied, and generally, are poorly understood, aside from high bodyweight, suggesting that other unidentified factors may be relevant in determining response to treatment. The impact of alcohol misuse on treatment response has not been previously investigated. OBJECTIVES: To investigate whether alcohol misuse is associated with poor response to treatment for psoriasis. METHODS: This was a prospective cohort study in which response to systemic therapies was assessed using the Psoriasis Area and Severity Index (PASI). The CAGE (Cut down, Annoyed, Guilty, Eye opener) questionnaire was used to screen for alcohol misuse. A multivariable factional polynomial linear regression model was used to examine factors associated with change in PASI between baseline and follow-up. RESULTS: The cohort comprised 266 patients (biologic cohort, n = 134; conventional systemic cohort, n = 132). For the entire cohort, the median (interquartile range) PASI improved from 13 (10·0-18·3) at baseline to 3 (1·0-7·5) during follow-up. A higher CAGE score [regression coefficient: 1·40, 95% confidence interval (CI) 0·04-2·77]; obesity (1·84, 95% CI 0·48-3·20); and receiving a conventional systemic rather than a biologic therapy (4·39, 95% CI 2·84-5·95) were significantly associated with poor response to treatment; whereas a higher baseline PASI (-0·83, 95% CI -0·92 to -0·74) was associated with a better response to treatment. CONCLUSIONS: The poor response to therapy associated with alcohol misuse and obesity found in people with psoriasis calls for lifestyle behaviour change interventions and support as part of routine clinical care. Targeting interventions to prevent, detect and manage alcohol misuse among people with psoriasis is needed to minimize adverse health consequences and improve treatment response.