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Gema Requena,1 Victoria Banks,2,* Alexandrosz Czira,1 Robert Wood,2 Theo Tritton,2 Rosie Wild,2 Chris Compton,1 Afisi S Ismaila3,4 1Value Evidence and Outcomes, GSK, R&D Global Medical, Brentford, Middlesex, UK; 2Real-World Evidence, Adelphi Real World, Bollington, Cheshire, UK; 3Value Evidence and Outcomes, GSK, Collegeville, PA, USA; 4Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, ON, Canada*At the time of the studyCorrespondence: Gema Requena, Epidemiology, Value Evidence and Outcomes, R&D Global Medical, GSK, Middlesex, UK, Tel +44 20 80476893, Email gema.x.requena@gsk.comPurpose: Selection of treatments for patients with chronic obstructive pulmonary disease (COPD) may impact clinical outcomes, healthcare resource use (HCRU) and direct healthcare costs. We aimed to characterize these outcomes along with treatment patterns, for patients with COPD following initiation of single-inhaler long-acting muscarinic antagonist/long-acting β2-agonist (LAMA/LABA) dual therapy in the primary care setting in England.Patients and Methods: This retrospective cohort study used linked primary care electronic medical record data (Clinical Practice Research Datalink-Aurum) and secondary care administrative data (Hospital Episode Statistics) in England to assess outcomes for patients with COPD who had a prescription for one of four single-inhaler LAMA/LABA dual therapies between 1st June 2015– 31st December 2018 (indexing period). Outcomes were assessed during a 12-month follow-up period from the index date (date of earliest prescription of a single-inhaler LAMA/LABA within the indexing period). Incident users were those without previous LAMA/LABA dual therapy prescriptions prior to index; this manuscript focuses on a subset of incident users: non-triple therapy users (patients without concomitant inhaled corticosteroid use at index).Results: Of 10,991 incident users included, 9888 (90.0%) were non-triple therapy users, indexed on umeclidinium/vilanterol (n=4805), aclidinium/formoterol (n=2109), indacaterol/glycopyrronium (n=1785) and tiotropium/olodaterol (n=1189). At 3 months post-index, 63.3% of non-triple therapy users remained on a single-inhaler LAMA/LABA, and 22.1% had discontinued inhaled therapy. Most patients (86.9%) required general practitioner consultations in the first 3 months post-index. Inpatient stays were the biggest contributor to healthcare costs. Acute exacerbations of COPD (AECOPDs), adherence, time-to-triple therapy, time-to-first on-treatment moderate-to-severe AECOPD, time-to-index treatment discontinuation, HCRU and healthcare costs were similar across indexed therapies.Conclusion: Patients initiating treatment with single-inhaler LAMA/LABA in primary care in England were unlikely to switch treatments in the first three months following initiation, but some may discontinue respiratory medication. Outcomes were similar across indexed treatments.Keywords: COPD, single-inhaler LAMA/LABA dual therapy, primary care setting, treatment patterns, clinical outcomes

Randomized controlled trials (RCTs) comparing triple therapies (inhaled corticosteroid [ICS], long-acting βThis NMA was conducted on the basis of a systematic literature review (SLR), which identified RCTs in adults aged at least 40 years with COPD. The RCTs compared different ICS/LABA/LAMA combinations or an ICS/LABA/LAMA combination with any dual therapy (ICS/LABA or LAMA/LABA). Outcomes of interest included forced expiratory volume in 1 s (FEVThe NMA was informed by five trials reporting FEVThe findings of this NMA suggest favorable efficacy with single-inhaler triple therapy comprising FF/UMEC/VI. Further analysis is required as additional evidence becomes available.

Current climate change is characterised by a growing number of extreme weather events and their impacts, which can have a significant impact on energy production, transmission and supply systems, with the potential for severe damage to assets and permanent or intermittent supply disruptions. In order to identify the likely regional climate impacts on specific elements of solar power generation systems, a complex analysis of the expected changes, the sensitivity of infrastructure and the possibilities to adapt to these changes is needed.Accordingly, one of the objectives of the research is to identify and characterize the climatological information and impacts that may pose a risk to solar energy generation facilities in the context of climate change. We investigate the role and significance of extreme weather events and their long-term projected changes for solar power systems in climate impact assessments. The changes of relevant meteorological events due to climate change and their impact on solar energy systems will be evaluated for Hungary based on data from regional climate model simulations available in EURO-CORDEX.

Key points Cystic fibrosis transmembrane conductance regulator (CFTR) is an important ion channel in epithelial cells. Its malfunction has several serious consequences, like developing or aggravating acute pancreatitis (AP). Here, we investigated the localization and expression of CFTR during cerulein-induced AP in mice and determined the effects of CFTR corrector (VX-661) and potentiator (VX-770) on disease severity. CFTR mRNA expression was significantly increased, and mislocalization of CFTR protein was observed in AP compared to the control group. Interestingly, pre-treatment of AP mice with VX-661 + VX-770 significantly reduced the extent of pancreatic tissue damage by 20-30%. In vitro administration of VX-661 + VX-770 significantly increased the fluid secretion of ducts derived from AP animals. Based on our results, the utilization of CFTR correctors and potentiators should be further investigated in AP. Abstract Cystic fibrosis transmembrane conductance regulator (CFTR) has essential role in maintaining pancreatic ductal function. Impaired CFTR function can trigger acute pancreatitis (AP) and exacerbate disease severity. We aimed to investigate the localization and expression of CFTR during AP, and determined the effects of CFTR corrector (VX-661) and potentiator (VX-770) on disease severity. AP was induced in FVB/n mice by 6-10 hourly intraperitoneal injections of 50μg/kg cerulein. Some mice were pre-treated with 5-6 daily injections of 2mg/kg VX-661+VX-770. Control animals were administered physiological saline instead of cerulein and DMSO instead of VX compounds. AP severity was determined by measuring laboratory and histological parameters; CFTR and CK19 expressions were measured. Activity of ion transporters was followed by intracellular pH or fluid secretion measurement of isolated pancreatic intra-/interlobular ducts. Cerulein-induced AP severity was greatest between 12-24h. CFTR mRNA expression was significantly increased 24h after AP induction. Immunohistochemistry demonstrated disturbed staining morphology of CFTR and CK19 proteins in AP. Mislocalization of CFTR protein was observed from 6h, while expression increased at 24h compared to control. Ductal HCO3 - transport activity was significantly increased 6h after AP induction. AP mice pre-treatment with VX-661+VX-770 significantly reduced the extent of tissue damage by about 20-30%, but other parameters were unchanged. Interestingly, VX-661+VX-770 in vitro administration significantly increased the fluid secretion of ducts derived from AP animals. This study described the course of the CFTR expression and mislocalization in cerulein-induced AP. Our results suggest that the beneficial effects of CFTR correctors and potentiators should be further investigated in AP. This article is protected by copyright. All rights reserved.

Study Objectives Even though numerous studies indicate that sleep disorders are associated with altered brain morphology, MRI studies focusing on periodic limb movements in sleep (PLMS) are scarce. Our aim was to investigate the association of PLMS with global and regional gray matter volumes as well as white matter hyperintensity (WMH) volume. Methods One hundred and eighty-nine subjects (57.0 ± 7.8 years, women: 50.5%) of the population-based BiDirect Study underwent a single-night polysomnography (PSG). Standard criteria of the American Academy of Sleep Medicine were applied to evaluate sleep characteristics and calculate the PLMS index (PLMSI). T1w and FLAIR images were acquired with cerebral MRI at 3 Tesla. Voxel-based morphometry was performed to determine the total gray matter volume as well as the volume of cortical segments and subcortical gray matter areas using SPM12 and CAT12. The WMH volume was quantified with the Brain Intensity AbNormality Classification Algorithm. The independent relationship between MRI markers and PLMSI was analyzed using multivariable linear regression with adjustment for age, sex, body mass index, intracranial volume, PSG scorer, PSG device, sleep apnea, and the use of antidepressants. Results PLMSI was not significantly related to global gray matter volume and WMH volume. However, significant inverse associations of the PLMSI with the volume of the hippocampus (left and right hemisphere) and left amygdala were observed. Conclusions A significant relationship between a higher PLMSI and lower volumes of the hippocampus and amygdala was found among the participants of the BiDirect Study. Since these associations are based on exploratory analyses, further replications are required before drawing firm conclusions.

A napjaink időjárásában tapasztalható változások érezhető hatással vannak nemcsak a környezetre, hanem az emberi szervezetre, a társadalmi és gazdasági folyamatokra is. Bár a koronavírus járvány okozta helyzet időlegesen felülírta a klímakérdés turizmusra gyakorolt hatásainak tárgyalását, azért a téma egyáltalán nem veszített aktualitásából. A szektor érintettsége vitathatatlan e kérdéskörben, hiszen működésének alapját a földrajzi helyekhez kötött vonzerők adják, melyek zömének látogathatósága bizonyos időjárási körülményhez kötődik. Jelen tanulmányban a hazai turizmus szektor egyes kínálat oldali szereplőinek bevonásával vesszük górcső alá a klímaváltozás érzékelhető és változásokat generáló hatásait, valamint a helyi, térségi szintű klímaalkalmazkodás kérdéskörét. Ahogy vizsgálataink is alátámasztják, a folyamatok vesztesei és nyertesei nehezen határolhatók le, azonban a desztinációs szintű klímaalkalmazkodási kérdések széleskörű elemzése egyre inkább időszerű és elkerülhetetlen a turizmus szektorban is.

Few randomised controlled trials (RCTs) have directly compared long-acting muscarinic antagonist/long-acting βA systematic literature review (October 2015-November 2020) was performed to identify RCTs ≥ 8 weeks long in adult patients with COPD that compared LAMA/LABA combinations against any long-acting bronchodilator-containing dual therapy or monotherapy. Data extracted on changes from baseline in trough forced expiratory volume in 1 s (FEVThe NMA included 69 full-length publications (including 10 GSK clinical study reports) reporting 49 studies. At 24 weeks, UMEC/VI provided statistically significant greater improvements in FEVUMEC/VI provided generally better outcomes compared with LAMA or LABA monotherapies, and consistent improvements in lung function (measured by change from baseline in trough FEVBronchodilators are medicines that open the airways, allowing patients with chronic obstructive pulmonary disease (COPD) to breathe more easily. There are two different types of bronchodilators, namely long-acting muscarinic antagonists (LAMAs) and long-acting β

Treatment pathways of patients with chronic obstructive pulmonary disease (COPD) receiving single-inhaler dual therapies remain unclear. We aimed to describe characteristics, prescribed treatments, healthcare resource use (HCRU) and costs of patients with COPD who initiated single-inhaler long-acting muscarinic antagonist/long-acting βRetrospective study using linked data from Clinical Practice Research Datalink Aurum and Hospital Episode Statistics datasets. Patients with COPD with ≥1 single-inhaler LAMA/LABA prescription between June 2015 and December 2018 (index) were included. Demographic and clinical characteristics, prescribed treatments, HCRU and costs were evaluated in the 12 months pre-index. Data are presented for patients not receiving concomitant inhaled corticosteroids at index (non-triple users).Of 10,991 patients initiating LAMA/LABA, 9888 were non-triple users, of whom 21.3% (n=2109) received aclidinium bromide/formoterol, 18.1% (n=1785) received indacaterol/glycopyrronium, 12.0% (n=1189) received tiotropium bromide/olodaterol and 48.6% (n=4805) received umeclidinium/vilanterol. Demographic and clinical characteristics were similar across indexed therapies. LAMA monotherapy was the most frequently prescribed respiratory therapy at 12 (18.4-25.8% of patients) and 3 months (23.9-33.7% of patients) pre-index across indexed therapies; 42.5-59.0% of patients were prescribed no respiratory therapy at these time points. COPD-related HCRU during the 12 months pre-index was similar across indexed therapies (general practitioner consultations: 62.0-68.6% patients; inpatient stays: 19.3-26.1% patients). Pre-index COPD-related costs were similar across indexed therapies, with inpatient stays representing the highest contribution. Mean total direct annual COPD-related costs ranged from £805-£1187.Characteristics of patients newly initiating single-inhaler LAMA/LABA dual therapy were highly consistent across indexed therapies. As half of non-triple users were not receiving respiratory therapy one year prior to LAMA/LABA initiation, there may be an opportunity for early optimization of treatment to relieve clinical burden versus current prescribing patterns in primary care in England.

Treatment pathways of patients with chronic obstructive pulmonary disease (COPD) receiving single-device dual therapies in England remain unclear. This study describes the characteristics of patients with COPD before initiating treatment with a single-device inhaled corticosteroid/long-acting βThis is a retrospective, descriptive study of linked primary and secondary healthcare data (Clinical Practice Research Datalink Aurum, Hospital Episode Statistics). Patients with COPD were indexed on first prescription of fixed-dose, single-device ICS/LABA (June 2015-December 2018). Demographics, clinical characteristics, prescribed treatments, healthcare resource use (HCRU) and direct healthcare costs were assessed over 12 months pre-index. Incident users (indexed on first ever prescription) could be non-triple users (no concomitant long-acting muscarinic antagonist at index); a subset were initial maintenance therapy (IMT) users (no history of pre-index maintenance therapy).Overall, 13 451 incident users (non-triple users: 7448, 55.4%; IMT users: 5162, 38.4%) were indexed on beclomethasone dipropionate/formoterol (6122, 45.5%), budesonide/formoterol (2703, 20.1%) or Other ICS/LABA combinations (4626, 34.4%). Overall, 20.8% of incident users had comorbid asthma and 42.6% had ≥1 moderate-to-severe acute exacerbation of COPD pre-index. Baseline characteristics were similar across indexed therapies. At 3 months pre-index, 45.3% and 35.4% of non-triple and IMT users were receiving maintenance treatment. HCRU and direct healthcare costs were similar across indexed treatments. Prescribing patterns varied regionally.Patient characteristics, prior treatments, prior COPD-related HCRU and direct healthcare costs were similar across single-device ICS/LABAs in primary care in England. A high proportion of patients were not receiving any respiratory medication pre-index, indicating that prescribing in primary care in England is more closely aligned with national guidelines than global treatment strategies. Comorbid asthma may have influenced prescribing decisions. Less than half of users had preindex exacerbations, suggesting that ICS/LABA is not being prescribed principally based on exacerbation history.

IntroductionTreatment pathways of patients with chronic obstructive pulmonary disease (COPD) receiving single-device dual therapies in England remain unclear. This study describes the characteristics of patients with COPD before initiating treatment with a single-device inhaled corticosteroid/long-acting β2-agonist (ICS/LABA) in primary care in England.MethodsThis is a retrospective, descriptive study of linked primary and secondary healthcare data (Clinical Practice Research Datalink Aurum, Hospital Episode Statistics). Patients with COPD were indexed on first prescription of fixed-dose, single-device ICS/LABA (June 2015–December 2018). Demographics, clinical characteristics, prescribed treatments, healthcare resource use (HCRU) and direct healthcare costs were assessed over 12 months pre-index. Incident users (indexed on first ever prescription) could be non-triple users (no concomitant long-acting muscarinic antagonist at index); a subset were initial maintenance therapy (IMT) users (no history of pre-index maintenance therapy).ResultsOverall, 13 451 incident users (non-triple users: 7448, 55.4%; IMT users: 5162, 38.4%) were indexed on beclomethasone dipropionate/formoterol (6122, 45.5%), budesonide/formoterol (2703, 20.1%) or Other ICS/LABA combinations (4626, 34.4%). Overall, 20.8% of incident users had comorbid asthma and 42.6% had ≥1 moderate-to-severe acute exacerbation of COPD pre-index. Baseline characteristics were similar across indexed therapies. At 3 months pre-index, 45.3% and 35.4% of non-triple and IMT users were receiving maintenance treatment. HCRU and direct healthcare costs were similar across indexed treatments. Prescribing patterns varied regionally.ConclusionPatient characteristics, prior treatments, prior COPD-related HCRU and direct healthcare costs were similar across single-device ICS/LABAs in primary care in England. A high proportion of patients were not receiving any respiratory medication pre-index, indicating that prescribing in primary care in England is more closely aligned with national guidelines than global treatment strategies. Comorbid asthma may have influenced prescribing decisions. Less than half of users had preindex exacerbations, suggesting that ICS/LABA is not being prescribed principally based on exacerbation history.

Background: Despite the availability of medium-to-high-dose inhaled corticosteroid-and-long-acting beta agonist (ICS-LABA) combination therapies, some adult patients with asthma remain uncontrolled. This can impact patients’ health-related quality of life (HRQoL), the magnitude of which is currently unknown. Aims: This study aimed to identify and summarize the literature on the humanistic burden in asthma patients who are inadequately controlled on medium-to-high-dose ICS-LABA therapy. Methods: Systematic searches were conducted in MEDLINE, Embase, and the National Health Service’s Economic Evaluation Databases to identify studies published from 1/1/2009-3/20/2019. Methods followed PRISMA guidelines. Observational studies were included and data on humanistic outcomes are presented here. Results: The searches identified 7,496 records, of which 22 studies reporting humanistic outcomes met the criteria for inclusion. Moderate burden was indicated by both mean baseline Asthma Quality of Life Questionnaire scores (n=19) and baseline St. George’s Respiratory Questionnaire total score (n=2); the former ranged from 3.0 to >5.0 while the latter ranged from 45.9 (SD: 2.1) to 53.2 (95% CI: 8.9, 85.0). High burden among patients with severe uncontrolled asthma was evident as measured by the EuroQol Five Dimensions (EQ-5D) questionnaire in selected studies. Baseline EQ-5D-3L (n=4) scores ranged from 0.48 (SD: 0.36) to 0.59 (SD: 0.25). Scores from the 36-item Short Form (SF-36) tool also indicated HRQoL burden in one study. Conclusions: The results suggest that the humanistic burden for adults with asthma remains high despite the availability of efficacious therapies. Method: GSK [HO-18-17246].

Background: The GINA recommendation to consider LAMA as add-on to ICS-LABA is recent and follows the 2014 asthma indication approval for tiotropium in the EU. Data on real world use of LAMA plus ICS-LABA in England is limited. Aim: Describe prescribing of multiple inhaler triple therapy (MITT, ICS-LABA+LAMA) for asthma in 1yr after initiation (discontinuation, step-down therapy, repeat MITT use, adherence). Methods: Retrospective cohort study using CPRD-Aurum primary care data. Index date was MITT initiation (Jan’10-Nov’17) defined as ≥1day overlap of ICS-LABA and LAMA prescriptions. Patients needed ≥1 asthma diagnosis, 1yr data prep B- patients adding ICS-LABA to LAMA. Results: 9375 MITT initiators identified; 70% stepped up from ICS-LABA. Characteristics and treatment patterns are in the Table. Conclusion: A third of patients step up to MITT via a non-recommended treatment sequence. Regardless of route to MITT, most patients discontinued MITT (gap >30days) within 1yr - many reverted to pre-MITT treatment, stopped ICS-LABA or stopped ICS-LABA+LAMA together. Over half received MITT again, suggesting patients see a benefit of MITT, even with inconsistent use. Method: GSK PRJ2753

There are limited published data on the burden of moderate/severe uncontrolled asthma.We conducted a systematic literature review to better understand the impact of moderate-to-severe asthma in the US, the UK, Germany, France, Italy, Spain, Canada, Japan, and Australia in terms of prevalence, clinical measures, health-related quality of life (HRQoL) and economic burden, for patients whose asthma is uncontrolled despite inhaled corticosteroid/long-acting βThe prevalence of uncontrolled asthma among patients with moderate/severe disease varied but was as high as 100% in some subgroups. Patients with uncontrolled asthma generally had poor lung function (mean/median pre-bronchodilator forced expiratory volume in 1 second [FEVOur findings suggest that significant unmet needs exist for patients with uncontrolled asthma despite the availability of ICS/LABA therapy. Novel treatments are needed to help reduce the burden to patients, healthcare systems and society.

Objective: Insomnia complaints are frequent among kidney transplant (kTx) recipients and are associated with fatigue, depression, lower quality of life and increased morbidity. However, it is not known if subjective insomnia symptoms are associated with objective parameters of sleep architecture. Thus, we analyze the association between sleep macrostructure and EEG activity versus insomnia symptoms among kTx recipients. Methods: Participants (n1 = 100) were selected from prevalent adult transplant recipients (n0 = 1214) followed at a single institution. Insomnia symptoms were assessed by the Athens Insomnia Scale (AIS) and standard overnight polysomnography was performed. In a subgroup of patients (n2 = 56) sleep microstructure was also analyzed with power spectral analysis. Results: In univariable analysis AIS score was not associated with sleep macrostructure parameters (sleep latency, total sleep time, slow wave sleep, wake after sleep onset), nor with NREM and REM beta or delta activity in sleep microstructure. In multivariable analysis after controlling for covariables AIS score was independently associated with the proportion of slow wave sleep (β = 0.263; CI: 0.026–0.500) and REM beta activity (β = 0.323; CI = 0.041–0.606) (p < 0.05 for both associations). Conclusions: Among kTx recipients the severity of insomnia symptoms is independently associated with higher proportion of slow wave sleep and increased beta activity during REM sleep but not with other parameters sleep architecture. The results suggest a potential compensatory sleep protective mechanism and a sign of REM sleep instability associated with insomnia symptoms among this population.

Leptin is a hormone made by adipocytes and associated with hypertension, inflammation, and coronary artery disease. Low serum leptin level was associated with higher risk of death in patients with advanced chronic kidney disease. Little is known about the association of serum leptin with outcomes in kidney transplant recipients.Prospective prevalent cohort.We collected sociodemographic and clinical parameters, medical and transplant history, and laboratory data of 979 prevalent kidney transplant recipients. Associations between serum leptin level and death with a functioning graft, all-cause death, and death-censored graft loss over a 6-year follow-up period were examined in survival models.Serum leptin levels showed moderate negative correlation with eGFR (R = -0.21, P .001) and positive correlations with BMI (R = 0.48, P .001) and C-reactive protein (R = 0.20, P .001). Each 10 ng/mL higher serum leptin level was associated with 7% lower risk of death with functioning graft (hazard ratio [HR] (95% confidence interval [CI]), 0.93 (0.87-0.99)), and this association persisted after adjustment for confounders: HR (95% CI), 0.90 (0.82-0.99). Similar associations were found with all-cause death as outcome. The association between serum leptin level and risk of graft loss was nonlinear, and only low serum leptin level was associated with higher risk of graft loss.In prevalent kidney transplant recipients, lower serum leptin was an independent predictor of death.

Study objectives Periodic limb movements in sleep (PLMS) are frequent motor phenomena; however, population-based data are scarce. We assessed the prevalence of PLMS and factors associated with PLMS within two German population-based cohorts, the SHIP-TREND and BiDirect. Methods Single-night polysomnography was performed on 1107 subjects recruited from the general population (mean age: 52.9 years, 54.1% men) in the SHIP-TREND and on 247 participants (mean age: 57.6 years, 50.6% men) in the BiDirect. PLMS were evaluated using the standard criteria of the American Academy of Sleep Medicine. Sociodemographic data, behavioral variables, medical history, current medication, and other sleep disorders were assessed. Results The prevalence of PLMS index (PLMSI) >15/hour was 32.4% (SHIP-TREND) and 36.4% (BiDirect). In multivariable models, age (odds ratio [OR] = 1.05 per +1 year), male gender (OR = 2.20), restless legs syndrome (OR = 2.32), physical inactivity (OR = 1.52), current smoking (OR = 1.49), diabetes (OR = 2.13), antidepressant use (OR = 2.27), lower serum magnesium (OR per -0.1 mmol/L = 1.27) showed a positive, and the intake of beta-blockers an inverse association with PLMSI >15/hour in SHIP-TREND. In BiDirect, age (OR = 1.13 per +1 year), body mass index (OR = 1.11 per +1 kg/m2), and restless legs syndrome (OR = 8.77) were significantly associated with PLMSI >15/hour. Conclusions A high PLMSI is frequent in the German population. Age, male gender, restless legs syndrome, physical inactivity, current smoking, obesity, diabetes, antidepressant use, and lower magnesium were independently associated with PLMSI >15/hour in at least one of the cohorts.