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Background Quinolones comprise a class of antibiotics that are globally preferred for treating a wide range of bacterial infections due to their potency, broad coverage, favorable pharmacologic profile, and mostly mild to moderate adverse reactions. Spontaneous reports on adverse drug events (ADE) and data from some pharmacoepidemiologic studies have raised concerns regarding quinolones and risk of retinal detachment (RD). This study examined ADE reports submitted to FDA adverse event reporting system (FAERS) for evidence on quinolone-associated RD risk. Research design and methods We identified all reports of RD in FAERS between 2010-2019. We compared ADE signals between quinolones and selected medications that were previously associated with RD, and with reference drugs not known to cause RD. For signal detection, we used two disproportionality techniques: the proportional reporting ratio (PRR) and multi-item gamma Poisson shrinker (MGPS), which are known for their higher sensitivity and specificity for ADE signal detection, respectively. Results Moxifloxacin showed a positive and significant PRR signal for RD [PRR: 2.54 (1.60, 4.04)], and a marginally significant EBGM signal [EBGM: 2.21 (1.41, 3.02)]. Conclusion Moxifloxacin is the only quinolone showing a positive disproportionality signal for RD. Further epidemiologic research is needed to clarify the association between moxifloxacin and the risk of RD.

Objectives We investigated the effect of disease activity-guided dose optimization (DAGDO) of TNF inhibitor (TNFi) on disease activity and TNFi dose in PsA and axial spondyloarthritis (axSpA) patients with low disease activity (LDA). Methods A retrospective cohort study was conducted in PsA and axSpA patients doing well on TNFi and eligible for TNFi DAGDO. Three different treatment periods were defined: (i) full dose continuation period, (ii) TNFi DAGDO period, and (iii) period with stable TNFi dose after DAGDO. A mixed-model analysis was used to estimate mean Disease Activity Score 28-joint count CRP (DAS28-CRP) and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) during these periods, and a mean percentage of the daily defined dose (%DDD) was calculated as secondary outcome. Results Three hundred and twenty-four patients (153 PsA and 171 axSpA) were included, with a mean of 6.5 DAS28-CRP and 6.4 BASDAI measurements and a median follow-up duration of 46 and 44 months, respectively. A corrected difference of 0.06 (95% CI: −0.09, 0.21) in mean DAS28-CRP was found for the TNFi DAGDO period and 0.03 (95% CI: −0.14, 0.20) for the period with stable TNFi dose, compared with full dose continuation period. Differences for BASDAI were 0.03 (95% CI: −0.21, 0.27) and 0.05 (95% CI: −0.24, 0.34), respectively. The mean %DDD for the three treatment periods was for PsA 108%, 62% and 78%, and for axSpA 108%, 62% and 72%, respectively. Conclusion DAGDO of TNFi reduces drug exposure and has no negative effects on disease activity in PsA and axSpA patients compared with full dose continuation.

Altered miRNA expressions are assigned pathogenic properties in several cancers including mycosis fungoides and could play a role in the early onset of the disease. The aim of this study was to examine disease-specific miRNA expression in early-stage mycosis fungoides patch and plaque lesions. A quantitative real-time PCR platform of 384 human miRNAs was used to study miRNA expression in 154 diagnostic mycosis fungoides biopsies. A total of 110 miRNAs were significantly differentially expressed (>2-fold, p 2-fold, p

Background and Aim Quinolones are a potent and globally popular group of antibiotics that are used to treat a wide range of infections. Some case reports have raised concern about their possible association with acute hepatic failure (AHF). Data from the US FDA Adverse Event Reporting System were evaluated for signals of AHF in association with systemically administered quinolone antibiotics. Methods AHF reports between 1969 and 2019q2, with a focus on 2010–2019q2, were analyzed. Specifically, AHF reports linked to non‐quinolone antibiotics of known hepatotoxicity were compared to reports with non‐quinolone, non‐hepatotoxic (reference) antibiotics; and AHF reports with quinolones were also compared to reports with the same group of reference antibiotics. Two disproportionality signal detection techniques (proportional reporting ratio, PRR, and empirical Bayes geometric mean, EBGM) were used to assess the AHF signal for both analyses. Results Only ciprofloxacin showed a marginal and significant AHF signal (PRR: 1.85 [1.21, 2.81]; EBGM: 1.54 [1.06, 1.81]); moxifloxacin, levofloxacin, and ofloxacin showed weak and nonsignificant signals. Conclusion Further pharmacovigilance studies are required to confirm the association between ciprofloxacin and AHF seen in the present analysis., Concerns have been raised about a possible association between quinolone and acute hepatic failure (AHF). Analysis of reports of AHF in the US FDA Adverse Events Reporting System database identified a possible safety signal for ciprofloxacin. AHF reports were most frequently reported in women, those younger than 10 years of age, and those older than 90 years of age.

Background Postoperative urinary retention (POUR) is a known complication in the postanesthesia care unit (PACU). The variations in catheterization thresholds contribute to unnecessary invasive procedures. Objective In the current study, we implemented an algorithm for a sterile intermittent catheterization (SIC) threshold of 800 ml with volume-dependent bladder scan intervals and compared the incidence of SIC with that of a matched patient cohort threshold of 400 ml. Design, setting, and participants This comparative study of two prospective historical cohorts represented two thresholds for POUR, set at 400 ml without a standardized bladder scan protocol and 800 ml with a volume-dependent bladder scan protocol. Outcome measurements and statistical analysis The primary outcome was the frequency of catheterization during the PACU stay. Secondary outcomes evaluated patient safety aspects in occurrence of thresholds above 400/800 ml. The study was set at the PACU under the Department of Anesthesia, Center for Cancer and Organ Diseases, Rigshospitalet, Denmark. Results and limitations In total, 741 patients were consecutively included, with 307 in the POUR-400 and 434 in the POUR-800 group, and with comparable group characteristics. Significantly fewer patients fulfilled the SIC/catheter a’ demeure (CAD) criteria in the POUR-800 (5.0%) versus POUR-400 (14.3%) group, equivalent to a 65.0% relative reduction in SIC. Conclusions Implementation of a standardized ultrasound-guided protocol with volume-dependent scan intervals and an evidence-based catheterization threshold of 800 ml decreases the need for SIC by >65%, without increasing the need for urinary catheterization at the wards. Patient summary In this study, we implemented an algorithm for a sterile intermittent catheterization threshold of 800 ml with volume-dependent bladder scan intervals. A marked reduction was seen in catheterization in the postanesthesia care unit, without increasing catheterization rates at the ward., Take Home Message An algorithm for an intermittent catheterization threshold of 800 ml, with volume-dependent bladder scan intervals during patients’ stay at the postanesthesia care unit, reduces the incidence of urinary bladder catheterization. Extensive patient-clinician communication on bladder symptomatology is a crucial prerequisite.

Background and Aim Quinolones are globally popular antibiotics with proven potency, broad coverage, and reasonable safety. However, some concerns were raised as to their possible association with acute liver failure (ALF). The aim of this study is to assess ALF risk within 30 days of receiving a systemically administered quinolone antibiotic, in individuals with no history of liver/diseases. Methods We conducted a nested case–control study using electronic health records from the Cerner Health Facts. The initial cohort (n = 35 349 943) included all patients who were admitted between 2000 and 2016, with no history of liver diseases, and had a minimum medical history of one year. Eligible cases were inpatients who were first diagnosed with ALF between 2010 and 2015. Using incidence density sampling, each case was matched with up to five unique controls by sex, race, age at index encounter, and period‐at‐risk. We used conditional logistic regression to calculate the odds ratio and 95% confidence interval for ALF risk, upon adjusting for exposure to other medications, and major confounders (diabetes mellitus and alcohol abuse). We used the STROBE Statement for reporting on our study. Results We identified 3151 cases and 15 657 controls. Our primary analysis did not reveal an association between quinolones and ALF risk. However, some risk was identified among those with no or few comorbidities, those ≤ 60 years of age, women, men, African Americans, and Caucasians. Conclusion Although our study does not suggest an overall association between quinolones and ALF, elevated risks seen in some subgroups warrant further investigation.

Introduction Biologics serve as a cornerstone in psoriasis treatment, with low disease activity or sometimes even clinical remission as a realistic treatment outcome. So far, it is unclear whether biologics should be tapered when this target is achieved. Dose tapering could offer potential benefits by decreasing side effects, the burden of repetitive injections and costs of biological therapy. However, clinical guidelines on dose tapering of biologicals in psoriasis patients are lacking. This scoping review was conducted to provide an overview of the current literature on dose tapering and offer guidance for clinicians in daily clinical practice. Methods Dose tapering is defined as the administration of a lower dose per administration, or the prolongation of the regular dose interval, after initial treatment according to the standard dosing. Four electronic databases (PubMed, EMBASE, Cochrane, and Web of Science) were systematically searched for literature on tapering of biologics in adult patients with psoriasis from 1 January 2000. Results We included 19 original articles on biologic tapering in psoriasis patients: four randomized controlled trials and 15 observational studies. Tapering eligibility criteria, tapering strategies, tapering outcomes, and recapture of response after relapse were assessed. Furthermore, the available evidence on possible predictors for successful tapering, and the effect of tapering on safety, quality of life and costs is summarized. The definition of low disease activity as a measure for tapering eligibility varied widely. Beside tapering criteria, tapering strategies were also heterogeneous. Of note, quality-of-life measurements were barely integrated in the evaluation of tapering outcomes. Literature on regaining response after relapse due to tapering was limited, but restored remission has been described. The included studies did not proclaim a significant effect of tapering on the occurrence of (severe) adverse events. Even though cost savings have been reported, no proper cost-effectiveness analysis has been conducted yet. Conclusion Biologic tapering seems to be effective and safe in psoriasis patients with stable low disease activity or clinical remission. Available data on biologic dose tapering in patients with psoriasis are promising, but more research is warranted to fill the current gaps in knowledge. Supplementary Information The online version contains supplementary material available at 10.1007/s40265-020-01448-z., Plain Language Summary Biologics are effective in treating psoriasis amongst other diseases, such as rheumatoid arthritis and Crohn’s disease. However, biologics are costly, and can cause side effects, such as an increased risk of infection. In patients with rheumatoid arthritis, it is not uncommon to lower the dose of these biologics (also called “dose tapering”), once stable low disease activity, or even remission, is reached. However, in psoriasis patients, dose tapering of biologics is not common practice. In this “scoping review,” we provide an overview of the available literature on dose tapering of biologics in adult patients with plaque psoriasis in order to address the current gaps in literature. We found 19 studies that addressed dose tapering. These studies used different criteria to determine which patients were eligible for tapering, which led to various interpretations of tapering success. This made it difficult for us to draw general conclusions on which tapering criteria and strategies should be further investigated. Dose tapering seems to be effective and safe in patients with a stable low disease activity, although more (high-quality) research is needed. Future studies should focus on generating more data on long-term safety, finding predictors for successful tapering, calculating the cost-effectiveness of dose tapering, and evaluating dose tapering in the newest generation of biologics. Supplementary Information The online version contains supplementary material available at 10.1007/s40265-020-01448-z.

Simple Summary Rapid and reliable identification of patients with homologous recombination deficient (HRD) tumors is important for treatment choice as these tumors tend to respond well to platinum-based chemotherapy and PARP inhibitors (PARPi). In this study, a RAD51-based functional HRD test that can be performed on routine diagnostic formalin-fixed paraffin-embedded (FFPE) tissues (RAD51-FFPE test), was further improved and optimal test parameters were determined. The RAD51-FFPE test was able to determine tumor HR status with high sensitivity and specificity, making it an attractive test to be applied as routine diagnostic tool in the near future. Abstract PARP inhibitor (PARPi) sensitivity is related to tumor-specific defects in homologous recombination (HR). Therefore, there is great clinical interest in tests that can rapidly and reliably identify HR deficiency (HRD). Functional HRD tests determine the actual HR status by using the (dis)ability to accumulate RAD51 protein at sites of DNA damage as read-out. In this study, we further improved and calibrated a previously described RAD51-based functional HRD test on 74 diagnostic formalin-fixed paraffin-embedded (FFPE) specimens (RAD51-FFPE test) from endometrial cancer (EC n = 25) and epithelial ovarian cancer (OC n = 49) patients. We established optimal parameters with regard to RAD51 foci cut-off (≥2) and HRD threshold (15%) using matched endometrial and ovarian carcinoma specimens for which HR status had been established using a RAD51-based test that required ex vivo irradiation of fresh tissue (RECAP test). The RAD51-FFPE test detected BRCA deficient tumors with 90% sensitivity and RECAP-HRD tumors with 87% sensitivity, indicating that it is an attractive alternative to DNA-based tests with the potential to be applied in routine diagnostic pathology.

Background Norway and Sweden have similar populations and health care systems, but different reactions to the COVID-19 pandemic. Norway closed educational institutions, and banned sports and cultural activities; Sweden kept most institutions and training facilities open. We aimed to compare peoples’ attitudes towards authorities and control measures, and perceived impact of the pandemic and implemented control measures on life in Norway and Sweden. Methods Anonymous web-based surveys for individuals age 15 or older distributed through Facebook using the snowball method, in Norway and Sweden from mid-March to mid-April, 2020. The survey contained questions about perceived threat of the pandemic, views on infection control measures, and impact on daily life. We performed descriptive analyses of the responses and compared the two countries. Results 3508 individuals participated in the survey (Norway 3000; Sweden 508). 79% were women, the majority were 30–49 years (Norway 60%; Sweden 47%), and about 45% of the participants in both countries had more than 4 years of higher education. Participants had high trust in the health services, but differed in the degree of trust in their government (High trust in Norway 17%; Sweden 37%). More Norwegians than Swedes agreed that school closure was a good measure (Norway 66%; Sweden 18%), that countries with open schools were irresponsible (Norway 65%; Sweden 23%), and that the threat from repercussions of the mitigation measures were large or very large (Norway 71%; Sweden 56%). Both countries had a high compliance with infection preventive measures (> 98%). Many lived a more sedentary life (Norway 69%; Sweden 50%) and ate more (Norway 44%; Sweden 33%) during the pandemic. Conclusion Sweden had more trust in the authorities, while Norwegians reported a more negative lifestyle during the pandemic. The level of trust in the health care system and self-reported compliance with preventive measures was high in both countries despite the differences in infection control measures.

Background Dose loading of biological disease modifying anti-rheumatic drugs (bDMARDs) in auto-immune rheumatic diseases (AIRDs) is performed to achieve steady state drug concentrations earlier after treatment start compared to dosing regimens without loading. Although loading inherently results in increased costs, treatment targets in terms of reduced disease activity may be achieved at an earlier state. It is an interesting topic that, surprisingly, has not received much attention in literature. Methods In this review, we aimed at providing a theoretical description of the pharmacodynamic / -kinetic rationale for dose loading of bDMARDs in AIRDs and to systematically review the clinical evidence on the effectiveness of dose loading on disease activity in AIRDs. Results Only a small number of studies (n = 5) has been published comparing the effectiveness of dose loading versus a regimen without dose loading of bDMARDs in AIRDs, addressing abatacept (n = 2), certolizumab pegol (n = 1), and secukinumab (n = 2). These studies provide insufficient evidence on superiority of dose loading in terms of disease activity compared to a dosing regimen without loading, while safety issues might be comparable. Conclusions Although dose loading is commonly adopted for several bDMARDs in AIRDs, scientific evidence on its effectiveness and safety is surprisingly scarce and does not suggest superiority compared to a regimen without dose loading. More research in this field, also with regard to the pharmaco-economic consequences of dose loading, is urgently needed.

Sézary syndrome (SS) is a heterogeneous leukemic subtype of cutaneous T-cell lymphoma (CTCL) with generalized erythroderma, lymphadenopathy, and a poor prognosis. Advanced disease is invariably associated with severe immune dysregulation and the majority of patients die from infectious complications caused by microorganisms such as, Staphylococcus aureus, rather than from the lymphoma per se. Here, we examined if staphylococcal enterotoxins (SE) may shape the phenotype of malignant SS cells, including expression of the regulatory T-cell-associated marker FOXP3. Our studies with primary and cultured malignant cells show that SE induce expression of FOXP3 in malignant cells when exposed to nonmalignant cells. Mutations in the MHC class II binding domain of SE-A (SEA) largely block the effect indicating that the response relies at least in part on the MHC class II-mediated antigen presentation. Transwell experiments show that the effect is induced by soluble factors, partly blocked by anti-IL-2 antibody, and depends on STAT5 activation in malignant cells. Collectively, these findings show that SE stimulate nonmalignant cells to induce FOXP3 expression in malignant cells. Thus, differences in exposure to environmental factors, such as bacterial toxins may explain the heterogeneous FOXP3 expression in malignant cells in SS.

BackgroundTumour necrosis factor inhibitors (TNFi) are effective in the treatment of patients with spondyloarthritis (SpA), including psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA). However, these drugs come with some disadvantages such as adverse events, practical burden for patients and high costs. Dose optimisation of TNFi after patients have reached low disease activity (LDA) has been shown feasible and safe in rheumatoid arthritis (RA). However, data on TNFi dose optimisation in PsA and axSpA are scarce, especially pragmatic, randomised strategy studies.MethodsWe developed an investigator-driven, pragmatic, open-label, randomised, controlled, non-inferiority trial (DRESS-PS) to compare the effects of a disease activity-guided treat-to-target strategy with or without a tapering attempt in patients with SpA (PsA and axSpA combined), ≥ 16 years of age, who are being treated with TNFi, and have had at least 6 months of low disease activity. The primary outcome is the percentage of patients in LDA after 12 months of follow up. Patients are assessed at baseline, 3, 6, 9, and 12 months of follow up. Bayesian power analyses with a weakened prior based on a similar study performed in RA resulted in a sample size of 95 patients in total.DiscussionMore knowledge on disease activity-guided treatment algorithms would contribute to better treatment choices and cost savings and potentially decrease the risk of side effects. In this article we elucidate some of our design choices on TNFi dose optimisation and its clinical and methodological consequences.Trial registrationDutch Trial Register,NL6771. Registered on 27 November 2018 (CMO NL66181.091.18, 23 October 2018).

BackgroundRoad traffic noise has been linked to increased risk of ischemic heart disease, yet evidence on stroke shows mixed results. We examine the association between long-term exposure to road traffic noise and incidence of stroke, overall and by subtype (ischemic or hemorrhagic), after adjustment for air pollution.MethodsTwenty-five thousand six hundred and sixty female nurses from the Danish Nurse Cohort recruited in 1993 or 1999 were followed for stroke-related first-ever hospital contact until December 31st, 2014. Full residential address histories since 1970 were obtained and annual means of road traffic noise (Lden[dB]) and air pollutants (particulate matter with diameter 2.5and PM10], nitrogen dioxide [NO2], nitrogen oxides [NOx]) were determined using validated models. Time-varying Cox regression models were used to estimate hazard ratios (HR) (95% confidence intervals [CI]) for the associations of one-, three-, and 23-year running means of Ldenpreceding stroke (all, ischemic or hemorrhagic), adjusting for stroke risk factors and air pollutants. The World Health Organization and the Danish government’s maximum exposure recommendations of 53 and 58 dB, respectively, were explored as potential Ldenthresholds.ResultsOf 25,660 nurses, 1237 developed their first stroke (1089 ischemic, 148 hemorrhagic) during 16 years mean follow-up. For associations between a 1-year mean of Ldenand overall stroke incidence, the estimated HR (95% CI) in the fully adjusted model was 1.06 (0.98–1.14) per 10 dB, which attenuated to 1.01 (0.93–1.09) and 1.00 (0.91–1.09) in models further adjusted for PM2.5or NO2, respectively. Associations for other exposure periods or separately for ischemic or hemorrhagic stroke were similar. There was no evidence of a threshold association between Ldenand stroke.ConclusionsLong-term exposure to road traffic noise was suggestively positively associated with the risk of overall stroke, although not after adjusting for air pollution.

Staphylococcal enterotoxins are believed to fuel disease activity in cutaneous T-cell lymphoma. Recent data support this by showing that antibiotics inhibit malignant T cells in skin lesions in mycosis fungoides and Sézary syndrome, the most common forms of cutaneous T-cell lymphoma. Yet, it remains incompletely characterized how staphylococcal enterotoxins fuel disease activity. In this study, we show that staphylococcal enterotoxins induce the expression of the oncogenic microRNA miR-155 in primary malignant T cells. Thus, staphylococcal enterotoxins and Staphyloccocus aureus isolates from lesional skin of patients induce miR-155 expression at least partly through the IL-2Rg‒Jak‒signal transducer and activator of transcription 5 pathway, and the effect is augmented by the presence of nonmalignant T cells. Importantly, mycosis fungoides lesions harbor S. aureus, express Y-phosphorylated signal transducer and activator of transcription 5, and display enhanced miR-155 expression, when compared with nonlesional and healthy skin. Preliminary data show that aggressive antibiotic therapy is associated with decreased Y-phosphorylated signal transducer and activator of transcription 5 and miR-155 expression in lesional skin in two patients with Sézary syndrome. In conclusion, we show that S. aureus and its enterotoxins induce enhanced expression of oncogenic miR-155, providing mechanistic insight into the role of S. aureus in cutaneous T-cell lymphoma. Our findings support that environmental stimuli such as bacteria can fuel disease progression in cutaneous T-cell lymphoma.

Supplemental digital content is available in the text., Objective The aims of this study were (1) to compare physical capacity at 1-yr follow-up with physical capacity before and after the training period for the HandbikeBattle event and (2) to identify determinants of the course of physical capacity during follow-up. Design This was a prospective observational study. Former rehabilitation patients (N = 33) with health conditions such as spinal cord injury or amputation were included. A handcycling/arm crank graded exercise test was performed before (January, T1) and after the training period (June, T2) and at 1-yr follow-up (June, T4). Outcomes were peak power output (W) and peak oxygen uptake (L/min). Determinants were sex (male/female); age (years); classification; physical capacity, musculoskeletal pain, exercise stage of change, and exercise self-efficacy at T1; and HandbikeBattle participation at T4. Results Multilevel regression analyses showed that peak power output and peak oxygen uptake increased during the training period and did not significantly change during follow-up (T1: 112 ± 37 W, 1.70 ± 0.48 L/min; T2: 130 ± 40 W, 2.07 ± 0.59 L/min; T4: 126 ± 42 W, 2.00 ± 0.57 L/min). Participants who competed again in the HandbikeBattle showed slight improvement in physical capacity during follow-up, whereas participants who did not compete again showed a decrease. Conclusion Physical capacity showed an increase during the training period and remained stable after 1-yr follow-up. Being (repeatedly) committed to a challenge might facilitate long-term exercise maintenance.

BACKGROUND: Associations between long-term exposure to air pollution and road traffic noise have been established for ischemic heart disease, but findings have been mixed for atrial fibrillation (AF). OBJECTIVES: The goal of the study was to examine associations of long-term exposure to road traffic noise and air pollution with AF. METHODS: Time-varying Cox regression models were used to estimate associations of 1-, 3-, and 23-y mean road traffic noise and air pollution exposures with AF incidence in 23,528 women enrolled in the Danish Nurse Cohort (age >44 y at baseline in 1993 or 1999). AF diagnoses were ascer-tained via the Danish National Patient Register. Annual mean weighted 24-h average road traffic noise levels (L den) at the nurses’ residences, since 1970, were estimated using the Nord2000 model, and annual mean levels of particulate matter with a diameter 2:5) and nitrogen dioxide (NO 2) were estimated using the DEHM/UBM/AirGIS model. RESULTS: Of 23,528 nurses with no prior AF diagnosis at the cohort baseline, 1,522 developed AF during follow-up. In a fully adjusted model (including PM 2:5), the estimated risk of AF was 18% higher [hazard ratio (HR); 95% confidence interval (CI): 1.18; 1.02, 1.36] in nurses with residential 3-y mean L den levels >58 dB vs. 3 increase in 3-y mean PM 2:5 was associated with incident AF before and after adjustment for concurrent exposure to road traffic noise (HR 1.09; 95% CI: 1.00, 1.20 and 1.08; 95% CI: 0.97, 1.19, respectively). Associations with 1-y mean PM 2:5 exposures were positive but closer to the null and not significant. Associations with NO 2 were null for all time periods before and after adjustment for road traffic noise and inverse when adjusted for concurrent PM 2:5. CONCLUSION: Our analysis of prospective data from a cohort of Danish female nurses followed for up to 14 y provided suggestive evidence of independent associations between incident AF and 1-and 3-y exposures to road traffic noise and PM 2:5. https://doi.org/10.1289/EHP8090.

This study aims to estimate the mortality risk associated with air pollution in a Swedish cohort with relatively low exposure. Air pollution models were used to estimate annual mean concentrations of particulate matter with aerodynamic diameter ≤ 2.5 µm (PM2.5 ), primary emitted car-bonaceous particles (BC/pOC), sea salt, chemically formed particles grouped as secondary inorganic and organic aerosols (SIA and SOA) as well as ozone (O3 ) and nitrogen dioxide (NO2 ). The exposure, as a moving average was calculated based on home address for the time windows 1 year (lag 1), 1–5 years (lag 1–5) and 1–10 years (lag 1–10) preceding the death. During the study period, 1151 cases of natural mortality, 253 cases of cardiovascular disease (CVD) mortality and 113 cases of respiratory and lung cancer mortality were observed during 369,394 person-years of follow-up. Increased natural mortality was observed in association with NO2 (3% [95% CI −8–14%] per IQR) and PM2.5 (2% [95% CI −5–9%] for an IQR increase) and its components, except for SOA where a decreased risk was observed. Higher risk increases were observed for CVD mortality (e.g., 18% [95% CI 1–39%] per IQR for NO2 ). These findings at low exposure levels are relevant for future decisions concerning air quality policies.

BACKGROUND: Several cancers, including mycosis fungoides (MF), have reported dysregulation of miR-195-5p. miR-195-5p plays a role in cell cycle regulation in several malignant diseases.OBJECTIVES: This study aimed to investigate: (a) the expression level of miR-195-5p in lesional MF skin biopsies and (b) the potential regulatory roles of miR-195-5p in MF.METHODS: Quantitative real-time polymerase chain reaction (RT-qPCR) was used to determine miR-195-5p expression in MF skin biopsies and cell lines. The effect of miR-195-5p and ADP-ribosylation factor-like protein 2 (ARL2) on cell cycle and apoptosis was measured by flow cytometry assays. Changes in ARL2 expression were determined by RT-qPCR and Western blotting (WB).RESULTS: We found lower expression levels of miR-195-5p in lesional skin from MF patients compared with non-lesional MF skin and skin from healthy volunteers. Additionally, miR-195-5p showed lower expression levels in the skin from patients with disease progression compared with patients with stable disease. In vitro studies showed that overexpression of miR-195-5p induced a cell cycle arrest in G0G1. Using microarray analysis, we identified several genes that were regulated after miR-195-5p overexpression. The most downregulated gene after miR-195-5p mimic transfection was ARL2. RT-qPCR and WB analyses confirmed downregulation of ARL2 following transfection with miR-195-5p mimic. Lastly, transfection with siRNA against ARL2 also induced a G0G1 arrest.CONCLUSION: Upregulation of miR-195-5p in MF inhibits cycle arrest by downregulation of ARL2. miR-195-5p may thus function as a tumor suppressor in MF and low miR-195-5p expression in lesional MF skin may promote disease progression.

Summary Background Rituximab is an effective treatment for rheumatoid arthritis, given as either two doses of 1000 mg (2 weeks apart) every 6 months (the dose recommended by the US Food and Drug Administration and European Medicines Agency) or two doses of 500 mg (2 weeks apart) or one dose of 1000 mg (a standard low dose) every 6 months. Findings of several small uncontrolled studies suggest that doses lower than the recommended dose or standard low dose might be sufficient for maintenance treatment, potentially improving safety and reducing costs. Therefore, we aimed to compare the efficacy of ultra-low doses of rituximab (one dose of 500 mg or 200 mg) with a standard low dose of rituximab (one dose of 1000 mg) for patients with rheumatoid arthritis who respond to standard doses of rituximab. Methods The REDO study is a randomised, double-blind, non-inferiority trial done at five centres in the Netherlands. Adults (aged ≥18 years) with rheumatoid arthritis responding well to rituximab were randomly allocated (1:2:2) to receive intravenous rituximab as one dose of either 1000 mg, 500 mg, or 200 mg, respectively. Volumes of all doses were equal to achieve masking. Randomisation lists were computer-generated and stratified by rheumatoid factor or anti-citrullinated protein antibody status (positive or negative) and concomitant use of conventional synthetic disease modifying antirheumatic drugs (yes or no). The primary analysis was a per-protocol hierarchical testing procedure comparing ultra-low doses with a standard low dose (500 mg vs 1000 mg at 3 months, followed by 500 mg vs 1000 mg at 6 months, 200 mg vs 1000 mg at 3 months, and 200 mg vs 1000 mg at 6 months), using a non-inferiority margin of 0·60 on change from baseline in the 28-joint disease activity score based on C-reactive protein levels (DAS28-CRP). The study is registered at www.trialregister.nl , NTR6117. Findings Between Dec 15, 2016, and Sept 20, 2018, 142 patients were randomly allocated to either 1000 mg rituximab (n=29), 500 mg rituximab (n=58), or 200 mg rituximab (n=55). The 500 mg dose was non-inferior to 1000 mg at 3 months (mean change from baseline in DAS28-CRP, −0·07, 95% CI −0·41 to 0·27) but not at 6 months (0·29, −0·08 to 0·65). Because of the hierarchical testing procedure, non-inferiority could not be tested for the 200 mg dose. 13 patients had serious adverse events, three (10%) in the 1000 mg group, six (10%) in the 500 mg group, and four (7%) in the 200 mg group. The most frequently reported serious adverse events were cardiovascular. No deaths occurred during the study. A significantly lower incidence of infections was seen in the ultra-low-dose groups compared with the standard dose group (1·24 infections per patient-year with the 1000 mg dose vs 0·52 per patient-year with the 500 mg dose and 0·55 per patient-year with the 200 mg dose; rate ratio 0·42, 95% CI 0·21–0·83; p=0·013 for 500 mg vs 1000 mg; 0·44, 0·22–0·88; p=0·019 for 200 mg vs 1000 mg). Interpretation Our study did not show non-inferiority of ultra-low doses of rituximab for continued treatment of patients with rheumatoid arthritis. Nonetheless, in clinical practice, a strategy with an ultra-low dose of rituximab might be considered after evaluation of risks and benefits, although further studies are needed to establish non-inferiority. Further analyses and a 2-year observational extension are ongoing and should provide further insight into efficacy and safety. Funding Menzis and Centraal Ziekenfonds.

ObjectiveTo determine the hemodynamic conditions associated with optimal neurologic improvement in individuals with acute traumatic spinal cord injury (SCI) who had lumbar intrathecal catheters placed to measure CSF pressure (CSFP).MethodsNinety-two individuals with acute SCI were enrolled in this multicenter prospective observational clinical trial. We monitored mean arterial pressure (MAP) and CSFP during the first week after injury and assessed neurologic function at baseline and 6 months after injury. We used relative risk iterations to determine transition points at which the likelihood of either improving neurologically or remaining unchanged neurologically was equivalent. These transition points guided our analyses in which we examined the linear relationships between time spent within target hemodynamic ranges (i.e., clinical adherence) and neurologic recovery.ResultsRelative risk transition points for CSFP, MAP, and spinal cord perfusion pressure (SCPP) were linearly associated with neurologic improvement and directed the identification of key hemodynamic target ranges. Clinical adherence to the target ranges was positively and linearly related to improved neurologic outcomes. Adherence to SCPP targets, not MAP targets, was the best indicator of improved neurologic recovery, which occurred with SCPP targets of 60 to 65 mm Hg. Failing to maintain the SCPP within the target ranges was an important detrimental factor in neurologic recovery, particularly if the target range is set lower.ConclusionWe provide an empirical, data-driven approach to aid institutions in setting hemodynamic management targets that accept the real-life challenges of adherence to specific targets. Our results provide a framework to guide the development of widespread institutional management guidelines for acute traumatic SCI.

Purpose: Increasing knowledge suggests that nutrition and lifestyle factors affect multiple sclerosis. This study explores how people with multiple sclerosis experience daily multiple sclerosis disease activity and the influence of nutrition and lifestyle factors (e.g., stress, sleep, and environmental temperature).Methods: Four phases mix qualitative and quantitative elements in an exploratory study. The initial two phases consisted of an exploratory study with 14 participants followed by 15 semi-structured interviews. Results from the two first phases were substantiated in a survey completed by 425 respondents (response rate: 42.5%). Finally, findings and inconsistencies were elaborated in three focus group interviews.Results: In the initial exploratory study, several of the participants linked nutrition and lifestyle factors to disease activity. Results from the semi-structured interviews showed that particularly stress, meat, fatty foods, and processed sugar were perceived to have a negative impact on disease activity, and some participants had experienced immediate effects of these factors on their disease activity. The survey supported these findings that were further elaborated in focus groups.Conclusion: People with multiple sclerosis perceive nutrition and lifestyle to affect daily disease activity. Individuals who have experienced links between their multiple sclerosis, and nutrition and lifestyle attribute some of these changes to e.g., stress, and the consumption of sugar, meat, and fatty food.Implications for rehabilitationA majority of the participants in this study perceived nutrition and lifestyle factors to have an effect on their multiple sclerosis, particularly stress, meat, fatty foods, and processed sugar.Some participants with multiple sclerosis experienced that nutrition, stress, environmental temperature, and physical activity had a direct effect on the severity of daily symptom manifestations.Nutrition and lifestyle factors that potentially influence multiple sclerosis disease activity should be considered when organizing rehabilitation and care to better meet the needs of the individual with multiple sclerosis.

This study presents the evaluation of the high-resolution air pollution model UBMv10, which has been set-up for a 2,900,000 km2 domain covering Norway, Sweden, Finland and Denmark with a 1 km x 1 km resolution and run for the time period 1979-2018. The UBMv10 is coupled to a long-range transport-chemistry model, DEHM, for boundary conditions. High-resolution emission data input and measurements of urban and rural air pollution concentrations have been obtained within the NordicWelfAir project from the four countries, in order to provide input and basis for evaluation of the UBM model.In the NordicWelfAir project, the modelled hourly mean concentrations of air pollutants for the 40 year time period on this high resolution are applied in various epidemiological studies of the link between air pollution and health effects. The model results represent concentrations at the rural and urban background local scale level which in this study are evaluated for the components NO2, O3 and PM2.5, which are the most important components to address when studying health effects of air pollution.The simplicity of the model makes it possible to perform model runs for a combination of large domains with high resolution and long time periods that is currently very difficult to obtain with more comprehensive Eulerian high-resolution models, which take much longer time to run, since they are limited by the Courant–Friedrichs–Lewy (CFL) stability criteria. When studying the long-term effects of air pollution components, e.g. with the home address of individuals in a cohort as proxy, these high-resolution model runs are required.The evaluation is part of a study with the aim to investigate, how well the UBM model with its relatively simple description of atmospheric dispersion and chemistry captures the temporal and spatial variations in the four Nordic countries. In general, the model performs relatively well for describing the temporal variations with correlation coefficients around 0.5-0.8. The model has a tendency to overestimate NO2 levels with a few µg for all four countries, and overestimate PM2.5 with for Norway and Sweden with 3-5 µg across all stations.The coupled model setup will be presented together with examples of 40 years of high-resolution model results for the four Nordic countries as well as the results of the model evaluation against measurements in the domain.

Objectives A significant proportion of RA patients, particularly those associated with poor prognostic factors, fail on conventional DMARDs (cDMARDs). Although rituximab (RTX) has been effective in these patients, the cost of therapy makes it unaffordable, particularly in poor and developing countries. Numerous, albeit small, studies using lower doses have shown contradictory results. We aimed to analyse the effectiveness of a low-dose RTX protocol based on clinical outcomes in RA patients. Methods Seropositive RA patients with moderate to high disease activity (DAS28-ESR > 3.2) despite combination cDMARDs, treated with RTX, were included in retrospective analysis. All patients were treated according to a predefined protocol, using 500 mg RTX with ongoing cDMARDs at baseline and repeat dosing at 6 weeks or beyond, on lack of moderate to good EULAR response. The B cell count was assessed at baseline, 2 and 24 weeks. Results At 12 weeks, 93% of 166 patients [mean (s.d.) age, 51.5 (11.96) years, 25 men and 141 women, with a disease duration of 10.4 (6.29) years] achieved moderate to good EULAR response. At 24 weeks, 90.8% of patients achieved moderate to good EULAR response, 19.8% achieved low disease activity and 29.5% achieved remission, with a mean change in DAS28-ESR from baseline of 2.9 (1.3). RTX failure and relapse were seen in 5.4% and 3.6%, respectively. The response was maintained for 12.3 (7.2) months with a mean RTX dose 521.1 (100.8) mg. Adverse events were seen in 9.6%. When compared with the standard dosing regimen with the originator molecule, a cost reduction of 90% was achieved. Conclusion A low-dose RTX regimen achieved reasonably good clinical outcomes at the end of 6 months, with a significantly lower cost.

A major obstacle for translational research in acute spinal cord injury (SCI) is the lack of biomarkers that can objectively stratify injury severity and predict outcome. Ubiquitin C-terminal hydrolase L1 (UCH-L1) is a neuron-specific enzyme that shows promise as a diagnostic biomarker in traumatic brain injury (TBI), but has not been studied in SCI. In this study, cerebrospinal fluid (CSF) and serum samples were collected over the first 72-96 h post-injury from 32 acute SCI patients who were followed prospectively to determine neurological outcomes at 6 months post-injury. UCH-L1 concentration was measured using the Quanterix Simoa platform (Quanterix, Billerica, MA) and correlated to injury severity, time, and neurological recovery. We found that CSF UCH-L1 was significantly elevated by 10- to 100-fold over laminectomy controls in an injury severity- and time-dependent manner. Twenty-four-hour post-injury CSF UCH-L1 concentrations distinguished between American Spinal Injury Association Impairment Scale (AIS) A and AIS B, and AIS A and AIS C patients in the acute setting, and predicted who would remain "motor complete" (AIS A/B) at 6 months with a sensitivity of 100% and a specificity of 86%. AIS A patients who did not improve their AIS grade at 6 months post-injury were characterized by sustained elevations in CSF UCH-L1 up to 96 h. Similarly, the failure to gain8 points on the total motor score at 6 months post-injury was associated with higher 24-h CSF UCH-L1. Unfortunately, serum UCH-L1 levels were not informative about injury severity or outcome. In conclusion, CSF UCH-L1 in acute SCI shows promise as a biomarker to reflect injury severity and predict outcome.

Objective Owing to lower mean uric acid excretion in women compared with men, uricosuric agents might be preferred in women over xanthine oxidase (XO) inhibitors. We therefore investigated the differences in response to two urate-lowering therapies (ULTs) with different modes of action within and between sexes. Methods This retrospective cohort study included patients with a clinical diagnosis of gout who started allopurinol and/or benzbromarone. The successful response to ULT, defined as reaching a serum uric acid (sUA) target of Results Allopurinol was started in 255 women and 1045 men, and benzbromarone in 60 women and 205 men. After 6 months, the proportions of women reaching the sUA target were 58.4% and 66.7% for allopurinol and benzbromarone, respectively (difference, −8%; 95% CI: −22%, 5%). The respective proportions in men were 61.0% and 75.6%, respectively (difference, −15%; 95% CI: −21%, −8%). Corrected for confounding, the odds ratio (OR) of reaching the target on benzbromarone vs allopurinol within women was 0.91 (95% CI: 0.47, 1.75), and within men 1.55 (95% CI: 1.04, 2.32). Corrected for confounding, sex was not an effect modifier of the difference in allopurinol and benzbromarone response (OR, 0.59; 95% CI: 0.28, 1.24). Conclusion This study did not demonstrate between-sex differences regarding the response to either a uricosuric agent or an XO inhibitor, negating different treatment choices by sex.

Cardiovascular disease is one of the main causes of death and disability in the Western world, and there is increasing evidence that air pollution is a risk factor for developing sub-clinical cardiovascular diseases. Previous studies have shown a correlation between cardiovascular disease and short-term exposure to elevated air pollution levels. However, the literature on the impact of long-term effect of air pollution is limited. We have a unique opportunity to evaluate this correlation. The DEHM/UBM/AirGIS model system calculates air pollution in a high temporal and spatial resolution and traces air pollution retrospectively to year 1979. The model calculates accumulated exposure using annual exposure from PM2.5 in relation to home and work addresses and takes into account working hours and holidays. We link the results from this model system to a population-based cardiovascular screening cohort of 33,723 individuals in the age of 60–74 to assess the contribution of the specific accumulated air pollution to the presence of sub-clinical arteriosclerosis in the coronary vessels, abdominal aortic aneurysms, and peripheral arterial disease. This correlation will be further analyzed in relation to specific air pollutants. This study will introduce more precise data for a longer period of time and incorporate participant’s home and work addresses.

Background: The thioredoxin-interacting protein (TXNIP) is involved in cellular metabolism and cell proliferation, and recently, deficient expression of TXNIP has been associated with progression and poor outcome for cancer patients. Objectives: To assess TXNIP expression and function in malignant T cells from cutaneous T-cell lymphoma (CTCL). Methods: CTCL-derived malignant (MyLa2059, PB2B) and non-malignant (MyLa1850) cell lines were analysed by Western blotting and qPCR for TXNIP expression. Subsequently, the malignant CTCL cell lines were treated with GSK126 – an inhibitor of enhancer of zeste homolog 2 (EZH2) methyltransferase activity or assessed by bisulphite sequencing for TXNIP promoter methylation. Methylation was also assessed with the demethylating agent 5-azacytidine (5AZA). Finally, TXNIP was overexpressed in the malignant PB2B cell line via plasmid transduction, and the effect of TXNIP was further analysed by flow cytometry. Results: We report on low expression of TXNIP protein in all cell lines representing different subtypes and stages of CTCL when compared to non-malignant T cells. Epigenetic silencing and other mechanisms were involved in the repression of TXNIP whereas forced expression of TXNIP strongly inhibited proliferation of malignant T cells. Conclusions: Epigenetic silencing and other as yet unknown mechanisms repress TXNIP expression in malignant T cells. As forced expression of TXNIP inhibits malignant proliferation, we propose that TXNIP is a putative tumour suppressor in CTCL.

Introduction Asthma is a complex, heterogeneous disease and one of the most common chronic diseases among children. Exposure to ambient air pollution in early life and childhood may influence asthma aetiology, but it is uncertain which specific components of air pollution and exposure windows are of importance. The role of socio-economic status (SES) is also unclear. The aims of the present study are, therefore, to investigate how various exposure windows of different pollutants affect risk-induced asthma in early life and to explore the possible effect SES has on that relationship. Methods The study population was constructed using register data on all singleton births in the greater Stockholm area between 2006 and 2013. Exposure to ambient black carbon (BC), fine particulate matter (PM2.5), primary organic carbon (pOC) secondary organic aerosols (SOA), secondary inorganic aerosols, and oxidative potential at the residential address was modelled as mean values for the entire pregnancy period, the first year of life and the first three years of life. Swedish national registers were used to define the outcome: asthma diagnosis assessed at hospital during the first six years of life. Hazard ratios (HRs) and their 95% confidence intervals (CIs) were modelled with Cox proportional hazards model with age as the underlying time-scale, adjusting for relevant potential confounding variables. Results An increased risk for developing childhood asthma was observed in association with exposure to PM2.5, pOC and SOA during the first three years of life. With an interquartile range increase in exposure, the HRs were 1.06 (95% CI: 1.01–1.10), 1.05 (95% CI: 1.02–1.09) and 1.02 (95% CI: 1.00–1.04), for PM2.5, pOC and SOA, respectively, in the fully adjusted models. Exposure during foetal life or the first year of life was not associated with asthma risk, and the other pollutants were not statistically significantly associated with increased risk. Furthermore, the increase in risk associated with PM2.5 and the components BC, pOC and SOA were stronger in areas with lower SES. Conclusion Our results suggest that exposure to air pollution during the first three years of life may increase the risk for asthma in early childhood. The findings further imply a possible increased vulnerability to air pollution-attributed asthma among low SES children.

Background Closed fitness centers during the Covid-19 pandemic may negatively impact health and wellbeing. We assessed whether training at fitness centers increases the risk of SARS-CoV-2 virus infection. Methods In a two-group parallel randomized controlled trial, fitness center members aged 18 to 64 without Covid-19-relevant comorbidities, were randomized to access to training at a fitness center or no-access. Fitness centers applied physical distancing (1 m for floor exercise, 2 m for high-intensity classes) and enhanced hand and surface hygiene. Primary outcomes were SARS-CoV-2 RNA status by polymerase chain reaction (PCR) after 14 days, hospital admission after 21 days. The secondary endpoint was SARS-CoV-2 antibody status after 1 month. Results 3764 individuals were randomized; 1896 to the training arm and 1868 to the no-training arm. In the training arm, 81.8% trained at least once, and 38.5% trained ≥six times. Of 3016 individuals who returned the SARS-CoV-2 RNA tests (80.5%), there was one positive test in the training arm, and none in the no-training arm (risk difference 0.053%; 95% CI − 0.050 to 0.156%; p = 0.32). Eleven individuals in the training arm (0.8% of tested) and 27 in the no-training arm (2.4% of tested) tested positive for SARS-CoV-2 antibodies (risk difference − 0.87%; 95%CI − 1.52% to − 0.23%; p = 0.001). No outpatient visits or hospital admissions due to Covid-19 occurred in either arm. Conclusion Provided good hygiene and physical distancing measures and low population prevalence of SARS-CoV-2 infection, there was no increased infection risk of SARS-CoV-2 in fitness centers in Oslo, Norway for individuals without Covid-19-relevant comorbidities. Trial registration The trial was prospectively registered in ClinicalTrials.gov on May 13, 2020. Due to administrative issues it was first posted on the register website on May 29, 2020: NCT04406909.

Calmodulin (CaM) engages in Ca2+-dependent interactions with numerous proteins, including a still incompletely understood physical and functional interaction with the human Na+/H+-exchanger NHE1. Using nuclear magnetic resonance (NMR) spectroscopy, isothermal titration calorimetry, and fibroblasts stably expressing wildtype and mutant NHE1, we discovered multiple accessible states of this functionally important complex existing in different NHE1:CaM stoichiometries and structures. We determined the NMR solution structure of a ternary complex in which CaM links two NHE1 cytosolic tails. In vitro, stoichiometries and affinities could be tuned by variations in NHE1:CaM ratio and calcium ([Ca2+]) and by phosphorylation of S648 in the first CaM-binding α-helix. In cells, Ca2+-CaM-induced NHE1 activity was reduced by mimicking S648 phosphorylation and by mutation of the first CaM-binding α-helix, whereas it was unaffected by inhibition of Akt, one of several kinases phosphorylating S648. Our results demonstrate a diversity of NHE1:CaM interaction modes and suggest that CaM may contribute to NHE1 dimerization and thereby augment NHE1 regulation. We propose that a similar structural diversity is of relevance to many other CaM complexes.

Background: Mycosis fungoides (MF), the most common form of cutaneous T-cell lymphoma (CTCL), is a lymphoproliferative disorder characterized by proliferation of malignant T cells in a chronic inflammatory environment in the skin. The nature of MF is still not fully understood, but aberrant microRNA (miR) expression and function seem to play an important role in the pathogenesis and disease progression and have been proposed as a putative disease marker. Recent studies have reported aberrant expression of miR-93 in situin MF lesions and linked dysregulated miR-93 expression to advanced stages of MF. However, the pathophysiological role of miR-93 in MF is unknown. Objective: Here, we provide the first evidence that miR-93 targets the cell cycle regulator cyclin-dependent kinase inhibitor p21 and promotes growth of malignant T cells in MF. Methods/Results: Thus, inhibition of miR-93 in MF patient-derived malignant T-cell lines increases expression of p21 and inhibition of malignant proliferation. Notably, treatment with the histone deacetylase inhibitor Vorinostat (SAHA) reduces miR-93 expression and enhances p21 expression in the malignant T cells. Importantly, transfection with an miR-93 mimic partly blocks SAHA-induced p21 expression. Conclusions: we provide evidence that enhanced expression of the putative oncogenic miR, miR-93, represses the cell cycle inhibitor p21 and promotes proliferation of malignant T cells. Moreover, we demonstrate that SAHA triggers p21 expression – at least partly – through an inhibition of miR-93.

BackgroundWhile air pollution has been linked to the development of chronic obstructive pulmonary disease (COPD), evidence on the role of environmental noise is just emerging. We examined the associations of long-term exposure to air pollution and road traffic noise with COPD incidence.MethodsWe defined COPD incidence for 24 538 female nurses from the Danish Nurse Cohort (age >44 years) as the first hospital contact between baseline (1993 or 1999) and 2015. We estimated residential annual mean concentrations of particulate matter with an aerodynamic diameter 2.5) since 1990 and nitrogen dioxide (NO2) since 1970 using the Danish Eulerian Hemispheric Model/Urban Background Model/Air Geographic Information System modelling system, and road traffic noise (Lden) since 1970 using the Nord2000 model. Time-varying Cox regression models were applied to assess the associations of air pollution and road traffic noise with COPD incidence.Results977 nurses developed COPD during a mean of 18.6 years’ follow-up. We observed associations with COPD for all three exposures with HRs and 95% CIs of 1.19 (1.01–1.41) per 6.26 µg·m−3 for PM2.5, 1.13 (1.05–1.20) per 8.19 µg·m−3 for NO2 and 1.15 (1.06–1.25) per 10 dB for Lden. Associations with NO2 and Lden attenuated slightly after mutual adjustment, but were robust to adjustment for PM2.5. Associations with PM2.5 were attenuated to null after adjustment for either NO2 or Lden. No potential interaction effect was observed between air pollutants and noise.ConclusionLong-term exposure to air pollution, especially traffic-related NO2, and to road traffic noise were independently associated with COPD.