Exploring the relationship between generalised anxiety/depression scales and asthma-specific quality of life/control questionnaires in a specialist asthma clinic.

INTRODUCTION: Psychological issues are common in patients with chronic disabling diseases such as asthma. National guidance recommends that specialist asthma clinic attendees should complete questionnaires screening for psychological comorbidities. However, completing these in addition to asthma specific questionnaires can be burdensome. In order to investigate whether anxiety and depression questionnaires can be used in a targeted manner, this study investigates the correlation between the respective scores. We hypothesize that there is correlation between asthma-specific and anxiety/depression questionnaire scores. METHODS: Three-hundred individuals with poorly controlled asthma attending a specialist clinic were asked to complete Asthma Control Questionnaire (ACQ), mini-Asthma Quality of Life Questionnaire (mini-AQLQ), Generalized Anxiety Disorder (GAD-7) and Patient Health Questionnaires (PHQ-9). A Pearson correlation coefficient was generated and area under ROC and confusion matrices were used to assess correlation. RESULTS: 49% and 47% of patients completing the GAD-7 or PHQ-9 questionnaires, respectively had scores above the screening level for co-morbid anxiety and depression. Additional questionnaires were often incomplete (GAD-7 = 150 and PHQ-9 = 140). GAD-7 and PHQ-9 correlated with ACQ and mini-AQLQ (all p = <0.001, r values 0.53-0.65). Asthma-specific questionnaire scores were predictive of GAD-7 and PHQ-9 scores (AUCs of 0.78 to 0.84). 75% of patients with a mini-AQLQ score of <3 met the threshold GAD-7 and PHQ-9 score of 10. CONCLUSIONS: ACQ and mini-AQLQ correlate with GAD-7 and PHQ-9 amongst specialist asthma clinic attendees. A mini-AQLQ >3 suggests patients are unlikely to have anxiety or depression. These findings could be used to identify patients requiring formal screening for psychological co-morbidity.

Ustekinumab for the treatment of moderate-to-severe plaque psoriasis in paediatric patients (≥ 6 to < 12 years of age): efficacy, safety, pharmacokinetic and biomarker results from the open-label CADMUS Jr study.

BACKGROUND: Limited options are available for treatment of paediatric psoriasis. OBJECTIVES: To evaluate the efficacy and safety of ustekinumab in paediatric patients with psoriasis (≥ 6 to < 12 years of age). METHODS: CADMUS Jr, a phase III, open-label, single-arm, multicentre study, evaluated ustekinumab in paediatric patients with moderate-to-severe plaque psoriasis. Patients received weight-based dosing of ustekinumab (< 60 kg: 0·75 mg kg-1 ; ≥ 60 to ≤ 100 kg: 45 mg; > 100 kg: 90 mg) administered by subcutaneous injection at weeks 0 and 4, then every 12 weeks through week 40. Study endpoints (all at week 12) included the proportions of patients achieving a Physician's Global Assessment score of cleared/minimal (PGA 0/1) and ≥ 75%/90% improvement in Psoriasis Area and Severity Index (PASI 75/90), and change in Children's Dermatology Life Quality Index (CDLQI). Serum ustekinumab concentrations, antidrug antibodies and cytokine levels were measured through week 52. Safety was evaluated through week 56. RESULTS: In total, 44 patients (median age 9·5 years) received at least one dose of ustekinumab. Three patients discontinued the study agent through week 40. At week 12, 77% of patients achieved PGA 0/1, 84% achieved PASI 75 and 64% achieved PASI 90 response. The mean change in CDLQI was -6·3. Trough serum ustekinumab concentrations reached steady state at weeks 28-52. The incidence of antidrug antibodies was 10% (n = 4). Mean serum concentrations of interleukin-17A/F and interleukin-22 were significantly reduced at weeks 12 and 52. Overall, 34 patients (77%) had at least one adverse event and three (7%) had a serious adverse event. CONCLUSIONS: Ustekinumab effectively treated moderate-to-severe psoriasis in paediatric patients, and no new safety concerns were identified. What is already known about this topic? Ustekinumab is approved for use in adolescents (≥ 12 to < 18 years of age) and adults (≥ 18 years) with moderate-to-severe psoriasis. What does this study add? Ustekinumab effectively treats moderate-to-severe psoriasis in paediatric patients (≥ 6 to < 12 years of age), with no new safety concerns. Linked Comment: Reich. Br J Dermatol 2020; 183:606-607.

Apremilast for the treatment of moderate-to-severe palmoplantar psoriasis: results from a double-blind, placebo-controlled, randomized study.

BACKGROUND: Palmoplantar psoriasis is a variant of psoriasis vulgaris which can severely impair quality of life. OBJECTIVES: The main objectives of this double-blind, placebo-controlled, randomized study were to assess the efficacy and impact on quality of life and work productivity of apremilast for the treatment of moderate-to-severe palmoplantar psoriasis. METHODS: A total of 100 patients with moderate-to-severe palmoplantar psoriasis were randomized to either apremilast 30 mg bid or placebo for 16 weeks. At Week 16, all patients received apremilast 30 mg bid until Week 32. The primary endpoint was the proportion of patients who achieved a Palmoplantar Psoriasis Physician Global Assessment (PPPGA) of 0/1 at Week 16. RESULTS: There was no significant difference in the proportion of patients who achieved a PPPGA of 0/1 at Week 16 between patients randomized to apremilast (14%) and placebo (4%; P = 0.1595). After 32 weeks of treatment with apremilast, 24% of patients achieved a PPGA of 0/1. In addition, apremilast was superior to placebo in achieving Palmoplantar Psoriasis Area Severity Index (PPPASI) 75 (apremilast: 22%; placebo: 8%; P = 0.0499), in improving PPPASI (apremilast: -7.4 ± 7.1; placebo: -3.6 ± 5.9; P = 0.0167), Dermatology Life Quality Index score (apremilast: -4.3 ± 5.1; placebo: -0.8 ± 4.5; P = 0.0004) and in reducing activity impairment (apremilast: -11.0 ± 22.3; placebo: 2.5 ± 25.5; P = 0.0063). CONCLUSION: Despite the absence of a significant difference between apremilast and placebo in proportion of patients achieving a PPPGA of 0/1, the presence of significant differences observed for several secondary endpoints suggests that apremilast may have a role in the treatment of moderate-to-severe palmoplantar psoriasis.

The influence of citrate and oxalate on 99TcVII, Cs, NpV and UVI sorption to a Savannah River Site soil.

Batch sorption experiments were conducted with 0.5-50 ppb 99Tc, 133Cs, 237Np and U in the presence and absence of citrate and/or oxalate in a 25 g/L Savannah River Site (SRS) soil suspension. Citrate and oxalate were the ligands of choice due to their relevancy to plant exudates, the nuclides were selected for their wide range of biogeochemical behavior, and the soil from SRS was selected as a model Department of Energy (DOE) site soil. Batch samples were continually mixed on a rotary shaker and maintained at a pH of approximately 5. Analysis via ICP-MS indicated that sorption of 237Np increased with ligand concentration compared to baseline studies, as did sorption of 99Tc although to a lesser extent. The increased sorption of 237Np is proposed to be due to a combination of factors that are dependent on the ligand(s) present in the specific system including, ligand dissolution of the soil by citrate and formation of tertiary soil-oxalate-Np complexes. The increased 99Tc sorption is attributed to the dissolution of the soil by the ligands, leading to an increase in the number of available sorption sites for 99Tc. Uranium sorption decreased and dissolution of native uranium was also observed with increasing ligand concentration, thought to be a result of the formation of strong U-ligand complexes remaining in the aqueous phase. The majority of these effects were observed at the highest ligand concentrations of 50 mgC/L. No notable changes were observed for the 133Cs system which is ascribed to the minimal interaction of Cs+ with these organic ligands.

The Role of Choledochoscopy: The Eternal Problem of How to Remove a CBD Stone.

BACKGROUND: Identifying and surgically removing bile duct calculi is challenging and critical in order to provide good patient outcomes. The history of this surgical pursuit since the introduction of anesthesia is both enlightening and fascinating. METHODS: A systematic review of the literature was conducted to identify the techniques and technology used to remove bile duct calculi. RESULTS: All bile duct surgical exploration advances have involved creation of tools to look within the bile duct and extract stones. The Hopkin's rod lens system was a major breakthrough in light and image transmission. However, flexible endoscope technology added the ability to maneuver better within the bile duct as well as apply the technology via laparoscopy enabling laparoscopic bile duct exploration. CONCLUSION: Digital, image enhanced, distal tipped chip flexible endoscopes have significantly improved the surgeons' ability to see within the bile duct, improving the efficiency and ease of stone visualization and removal from both the most proximal and distal ends of the bile duct.

Search for patterns by combining cosmic-ray energy and arrival directions at the Pierre Auger Observatory.

Energy-dependent patterns in the arrival directions of cosmic rays are searched for using data of the Pierre Auger Observatory. We investigate local regions around the highest-energy cosmic rays with [Formula: see text] eV by analyzing cosmic rays with energies above [Formula: see text] eV arriving within an angular separation of approximately 15[Formula: see text]. We characterize the energy distributions inside these regions by two independent methods, one searching for angular dependence of energy-energy correlations and one searching for collimation of energy along the local system of principal axes of the energy distribution. No significant patterns are found with this analysis. The comparison of these measurements with astrophysical scenarios can therefore be used to obtain constraints on related model parameters such as strength of cosmic-ray deflection and density of point sources.

Non-melanoma skin cancer in Canada chapter 1: introduction to the guidelines

BACKGROUND: Non-melanoma skin cancer (NMSC), including basal and squamous cell carcinoma, represents the most common malignancy. OBJECTIVE: The aim of this document is to provide guidance to Canadian health care practitioners on NMSC management. METHODS: After conducting a literature review, the group developed recommendations for prevention, management, and treatment of basal cell carcinomas, squamous cell carcinomas, and actinic keratoses. These tumour types are considered separately in the accompanying articles. The Grading of Recommendations Assessment, Development and Evaluation system was used to assign strength to each recommendation. RESULTS: This introduction describes the scope and structure of the guidelines and the methods used to develop them. The epidemiology of NMSC is reviewed, as are the pathophysiologic changes occurring with damage to the skin, which lead to the formation of actinic keratoses and invasive squamous or basal cell carcinomas. CONCLUSIONS: This introduction describes the need for primary prevention and offers an overview of treatment options that are discussed in later chapters of the guidelines.(AU)

Etanercept for patients with psoriasis who did not respond or who lost their response to adalimumab or infliximab.

BACKGROUND: There is a paucity of data on the use of etanercept in patients who have previously failed a different tumour necrosis factor (TNF) alpha antagonist. OBJECTIVES: To study etanercept in patients who did not achieve a satisfactory response to adalimumab or who lost their response to adalimumab or infliximab and to explore the role of anti-adalimumab and anti-infliximab antibodies in etanercept response. METHODS: Patients with psoriasis who did not achieve a satisfactory response to adalimumab or who lost their response to adalimumab or infliximab were included. All patients received etanercept 50 mg twice a week for 12 weeks followed by 50 mg once a week for 12 more weeks. Anti-infliximab and anti-adalimumab antibodies were measured at baseline. The primary objective was to study the efficacy of etanercept using the proportion of patients who achieved a physician global assessment (PGA) of 0 or 1. RESULTS: A total of 81 patients were included. The proportion of patients who achieved a PGA of 0 or 1 after 24 weeks of etanercept was 20.0% (95% CI 4.8-35.2%) for patients who had an unsatisfactory response to adalimumab, 35.1% (95% CI 19.0-51.3%) and 35.7% (95% CI 7.0-64.4%) for patients who lost their response to adalimumab and infliximab respectively. The proportion of patients who achieved a PGA of 0 or 1 at week 24 was numerically higher for patients who had anti-adalimumab or anti-infliximab antibodies (36.5%) as compared to those without (17.2%; P = 0.08). CONCLUSIONS: Etanercept can be effective in patients with psoriasis who failed a previous TNF alpha antagonist.

Improvements in patient-reported outcomes in patients with psoriasis receiving etanercept plus topical therapies: results from REFINE.

BACKGROUND: The REFINE study examined the efficacy and safety of adding topical corticosteroid therapy to etanercept when stepping down from the initial dose of etanercept to the maintenance dose. Clinical responses were shown to be similar in patients who remained on etanercept 50 mg twice weekly (BIW) and those who received etanercept 50 mg once weekly (QW) plus topical therapies through week 24. OBJECTIVE: The purpose of this analysis was to evaluate the effect of treatment on health-related quality of life (HRQoL) for patients in REFINE. METHODS: All patients received etanercept 50 mg BIW for 12 weeks and were then randomized to etanercept 50 mg BIW or etanercept 50 mg QW plus topical corticosteroid as required to clear through week 24. HRQoL measures included the Dermatology Life Quality Index (DLQI), Treatment Satisfaction Questionnaire for Medication (TSQM) and the Economic Implications of Psoriasis Patient Questionnaire. No comparative testing was performed for this descriptive analysis. Missing data were imputed using the last observation carried forward. RESULTS: For 287 randomized patients (144 etanercept; 143 etanercept plus topical), the mean change [standard deviation (SD)] in DLQI from baseline to week 24 was 10.7 (7.8) for etanercept and 9.9 (6.9) for etanercept plus topical. Mean change (SD) in TSQM effectiveness, convenience, side-effects and global satisfaction was 27.1 (36.1), 14.8 (25.9), -0.7 (22.0) and 26.7 (32.5) for the etanercept arm and 32.5 (40.3), 18.5 (29.0), 1.3 (19.4) and 28.4 (35.9) for etanercept plus topical. Economic implications, including healthcare visits, employment status, work productivity, ability to perform daily activities and out-of-pocket expenses were similar between treatment arms. CONCLUSION: At week 24 of REFINE, measures of HRQoL were numerically similar in patients who stayed on etanercept 50 mg BIW and patients who received etanercept 50 mg QW plus topical therapies.

A Randomized, blinded assessor study to Evaluate the efFIcacy and safety of etanercept 50 mg once weekly plus as Needed topical agent vs. Etanercept 50 mg twice weekly in patients with moderate to severe plaque psoriasis (REFINE).

BACKGROUND: Topical corticosteroids are used with systemic therapies for treatment of plaque psoriasis, but data from randomized clinical trials to document efficacy of combination therapy are lacking. OBJECTIVE: To evaluate efficacy and safety of adding topical corticosteroid therapy from the time that etanercept dosage is reduced from initial label dose [50 mg twice weekly (BIW)] to maintenance dose [50 mg once weekly (QW)]. METHODS: In this phase 3b, multicentre, randomized, open-label study, patients with moderate-to-severe plaque psoriasis received etanercept 50 mg BIW for 12 weeks, and then were randomized to etanercept 50 mg BIW or 50 mg QW plus topical agent as needed to achieve static physician global assessment (sPGA) status of clear for 12 weeks. Endpoints included percentage change in Psoriasis Area and Severity Index (PASI) score from week 12 to week 24 (primary endpoint); proportion of patients achieving 50% improvement in (PASI 50), PASI 75 and PASI 90; patients achieving sPGA of clear/almost clear; and change in affected body surface area (BSA). RESULTS: Mean difference [95% confidence interval (CI)] between etanercept arm (n = 140) and etanercept plus topical arm (n = 142) in change in PASI score from week 12 to week 24 was 16.2% (-3.5%, 35.8%). PASI response rates were similar between groups. Percentage (95% CI) of patients achieving sPGA status of clear/almost clear was 40.6% (32.5%, 48.6%) and 45.8% (37.6%, 54.0%) at week 12 for patients in etanercept and etanercept plus topical arms, respectively, and 53.5% (45.3%, 61.7%) and 45.4% (37.2%, 53.6%) at week 24. Difference (95% CI) between groups in change in affected BSA from week 12 to week 24 was 4.9% (-23.4%, 33.2%). CONCLUSION: Patients who received etanercept 50 mg QW at week 12 plus as-needed topical therapy and those who stayed on etanercept 50 mg BIW maintained clinical response through week 24 with no notable differences in PASI responses.

IL-1α released from damaged epithelial cells is sufficient and essential to trigger inflammatory responses in human lung fibroblasts.

Activation of the innate immune system plays a key role in exacerbations of chronic lung disease, yet the potential role of lung fibroblasts in innate immunity and the identity of epithelial danger signals (alarmins) that may contribute to this process are unclear. The objective of the study was to identify lung epithelial-derived alarmins released during endoplasmic reticulum stress (ER stress) and oxidative stress and evaluate their potential to induce innate immune responses in lung fibroblasts. We found that treatment of primary human lung fibroblasts (PHLFs) with conditioned media from damaged lung epithelial cells significantly upregulated interleukin IL-6, IL-8, monocyte chemotactic protein-1, and granulocyte macrophage colony-stimulating factor expression (P<0.05). This effect was reduced with anti-IL-1α or IL-1Ra but not anti-IL-1ß antibody. Costimulation with a Toll-like receptor 3 ligand, polyinosinic-polycytidylic acid (poly I:C), significantly accentuated the IL-1α-induced inflammatory phenotype in PHLFs, and this effect was blocked with inhibitor of nuclear factor kappa-B kinase subunit beta and TGFß-activated kinase-1 inhibitors. Finally, Il1r1-/- and Il1a-/- mice exhibit reduced bronchoalveolar lavage (BAL) neutrophilia and collagen deposition in response to bleomycin treatment. We conclude that IL-1α plays a pivotal role in triggering proinflammatory responses in fibroblasts and this process is accentuated in the presence of double-stranded RNA. This mechanism may be important in the repeated cycles of injury and exacerbation in chronic lung disease.

Measurement of the proton-air cross section at √s=57 TeV with the Pierre Auger Observatory.

We report a measurement of the proton-air cross section for particle production at the center-of-mass energy per nucleon of 57 TeV. This is derived from the distribution of the depths of shower maxima observed with the Pierre Auger Observatory: systematic uncertainties are studied in detail. Analyzing the tail of the distribution of the shower maxima, a proton-air cross section of [505±22(stat)(-36)(+28)(syst)] mb is found.

Cost-effectiveness evaluation of clobetasol propionate shampoo (CPS) maintenance in patients with moderate scalp psoriasis: a Pan-European analysis.

BACKGROUND: Scalp psoriasis is a difficult to treat and usually chronic manifestation of psoriasis. The CalePso study showed that CPS (Clobex(®) Shampoo) in maintenance therapy of scalp psoriasis (twice weekly) significantly increases the probability of keeping patient under remission during 6 months, compared with vehicle (40.3% relapses vs. 11.6% relapses, ITT). OBJECTIVE: The objective of the study was to assess the cost-effectiveness of a maintenance therapy with CPS vs. its vehicle in nine European countries. METHODS: A 24-week decision tree model was developed with 4-weekly time steps. The considered population has moderate scalp psoriasis successfully treated with a daily application of CPS up to 4 weeks. Data were taken from the CalePso study and from national experts' recommendations for alternative treatment choices, with their probabilities of success taken from literature to develop country-specific models. Health benefits are measured in disease-free days (DFD). The economic analysis includes drug and physician costs. A probabilistic sensitivity analysis (PrSA) assesses the uncertainty of the model. RESULTS: Depending on the country, the mean total number of DFDs per patient is 21-42% higher with CPS compared with vehicle, and the mean total cost is 11-31% lower. The mean costs per DFD are 30-46% lower with CPS compared with the vehicle. The PrSA showed in 1000 simulations that CPS is more effective vs. vehicle in 100% of the cases and less expensive than its vehicle in 80-99% of the cases. CONCLUSION: This model suggests that CPS is cost-effective in maintaining the success achieved in moderate scalp psoriasis patients.

Role of innate cytokines in mycobacterial infection.

Cells of the innate immune system produce cytokines and lipid mediators that strongly influence the outcome of mycobacterial infection. In the case of Mycobacterium tuberculosis, the lung is a critical site for this interaction. Here, we review current information on the role of the major innate cytokine pathways both in controlling initial infection as well as in promoting and maintaining adaptive T-cell responses that mediate host resistance or immunopathology. Understanding this important feature of the host-pathogen interaction can provide major insights into the mechanisms of virulence and can lead to new approaches for immunological intervention in tuberculosis and other mycobacterial diseases.

Measurement of the depth of maximum of extensive air showers above 10{18} eV.

We describe the measurement of the depth of maximum, X{max}, of the longitudinal development of air showers induced by cosmic rays. Almost 4000 events above 10;{18} eV observed by the fluorescence detector of the Pierre Auger Observatory in coincidence with at least one surface detector station are selected for the analysis. The average shower maximum was found to evolve with energy at a rate of (106{-21}{+35}) g/cm{2}/decade below 10{18.24+/-0.05} eV, and (24+/-3) g/cm{2}/decade above this energy. The measured shower-to-shower fluctuations decrease from about 55 to 26 g/cm{2}. The interpretation of these results in terms of the cosmic ray mass composition is briefly discussed.

Effects of pimecrolimus cream 1% in the treatment of patients with atopic dermatitis who demonstrate a clinical insensitivity to topical corticosteroids: a randomized, multicentre vehicle-controlled trial.

BACKGROUND: Colonization with Staphylococcus aureus in atopic dermatitis (AD) is often associated with worsening of clinical symptoms. Staphylococcus aureus produces superantigens that contribute to cutaneous inflammation and corticosteroid (CS) resistance. OBJECTIVES: To investigate the relationship between CS insensitivity, S. aureus colonization and superantigen production in AD, and to explore the efficacy of pimecrolimus cream in CS-insensitive AD. METHODS: This was a randomized, double-blind, vehicle-controlled, multicentre, parallel-group study. Seventy-three patients with AD, aged 2-49 years, who had a documented clinical insensitivity to topical CS, were recruited. The primary efficacy parameters combined laboratory (including S. aureus colonization, superantigens) and clinical assessments [including Eczema Area and Severity Index (EASI), whole body Investigator's Global Assessment (IGA), pruritus assessment score, patient's assessment score of disease control]. RESULTS: An increase in S. aureus counts correlated with worsening of clinical score (week 6 vs. baseline) when assessed by IGA, pruritus severity and patient assessment. The presence of superantigens correlated with this worsening. During the 6-week double-blind phase, disease improvement in the pimecrolimus cream group was demonstrated by decreasing EASI scores compared with vehicle. Mean EASI scores for the head and neck showed greater improvement in the pimecrolimus cream group than in the vehicle group at all observed time points. CONCLUSIONS: In a cohort of patients with clinical insensitivity to CS there was a significant positive correlation between S. aureus and disease severity. Results suggest that for some of these patients, treatment with pimecrolimus cream 1% is useful, especially in the head/neck area.

Onychomycosis: therapy directed by morphology and mycology.

Onychomycosis is one of the most common nail disorders. Despite recent therapeutic advances with the introduction of effective systemic agents and transungual drug delivery systems, the incidence of onychomycosis is increasing. This is of concern, as the morbidity related to this infection also increases as our population ages with associated conditions, such as diabetes and immunosuppression from illness and medical therapy. Rational and effective treatment plans are needed.