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IntroductionMacrophage dysfunction is a common feature of inflammatory disorders such as asthma, which is characterized by a strong circadian rhythm.Methods and resultsWe monitored the protein expression pattern of the molecular circadian clock in human peripheral blood monocytes from healthy, allergic, and asthmatic donors during a whole day. Monocytes cultured of these donors allowed us to examine circadian protein expression in human monocyte-derived macrophages, M1- and M2- polarized macrophages. In monocytes, particularly from allergic asthmatics, the oscillating expression of circadian proteins CLOCK, BMAL, REV ERBs, and RORs was significantly altered. Similar changes in BMAL1 were observed in polarized macrophages from allergic donors and in tissue-resident macrophages from activated precision cut lung slices. We confirmed clock modulating, anti-inflammatory, and lung-protective properties of the inverse ROR agonist SR1001 by reduced secretion of macrophage inflammatory protein and increase in phagocytosis. Using a house dust mite model, we verified the therapeutic effect of SR1001 in vivo.DiscussionOverall, our data suggest an interaction between the molecular circadian clock and monocytes/macrophages effector function in inflammatory lung diseases. The use of SR1001 leads to inflammatory resolution in vitro and in vivo and represents a promising clock-based therapeutic approach for chronic pulmonary diseases such as asthma.

Background The use and approval of immune checkpoint inhibitors for the treatment of non-small cell lung cancer (NSCLC) depends on PD-L1 expression in the tumor tissue. Nevertheless, PD-L1 often fails to predict response to treatment. One possible explanation could be a change in PD-L1 expression during the course of the disease and the neglect of reassessment. The purpose of this study was a longitudinal analysis of PD-L1 expression in patients with relapsed NSCLC.Methods We retrospectively analyzed PD-L1 expression in patients with early-stage NSCLC and subsequent relapse in preoperative samples, matched surgical specimens and biopsy samples of disease recurrence. Ventana PD-L1 (SP263) immunohistochemistry assay was used for all samples. PD-L1 expression was scored based on clinically relevant groups (0%, 1%–49%, and ≥50%). The primary endpoint was the change in PD-L1 score group between preoperative samples, matched surgical specimens and relapsed tumor tissue.Results 395 consecutive patients with stages I–III NSCLC and 136 (34%) patients with a subsequent relapse were identified. For 87 patients at least two specimens for comparison of PD-L1 expression between early stage and relapsed disease were available. In 72 cases, a longitudinal analysis between preoperative biopsy, the surgically resected specimen and biopsy of disease recurrence was feasible. When comparing preoperative and matched surgical specimens, a treatment-relevant conversion of PD-L1 expression group was found in 25 patients (34.7%). Neoadjuvant treatment showed no significant effect on PD-L1 alteration (p=0.39). In 32 (36.8%) out of 87 cases, a change in PD-L1 group was observed when biopsies of disease relapse were compared with early-stage disease. Adjuvant treatment was not significantly associated with a change in PD-L1 expression (p=0.53). 39 patients (54.2%) showed at least 1 change into a different PD-L1 score group during the course of disease. 14 patients (19.4%) changed the PD-L1 score group twice, 5 (6.9%) of them being found in all different score groups.Conclusion PD-L1 expression shows dynamic changes during the course of disease. There is an urgent need for consensus guidelines to define a PD-L1 testing strategy including time points of reassessment, the number of biopsies to be obtained and judgment of surgical specimens.

Background: Pulmonary arterial hypertension (PAH) is a life-threatening, progressive disease often diagnosed late in its course. Objectives: To present patient-reported data that were captured within a large, multinational, point-in-time survey of PAH-treating physicians and their patients to better understand the diagnostic journey. Design: Cross-sectional survey conducted in five European countries (EU5), Japan and the USA. Methods: PAH-treating pulmonologists, cardiologists, rheumatologists or internists (USA only) completed a patient record form (PRF) for the next four consecutive adult PAH patients they saw; these patients filled in a patient self-completion (PSC) form on an anonymous, voluntary basis. Our report focuses on patient data; data are from PSC forms unless stated otherwise. Results: Physician-reported PRFs and self-completed PSC forms were obtained for 1152 and 572 patients, respectively. Patients’ mean (SD) age was 59.1 (14.0) years, 55.6% were female, and 57.3% had idiopathic PAH. Patient-reported data showed an average delay of 17.0 months between symptom onset and PAH diagnosis. This is longer than physicians estimated (13.8 months): this disparity may be partly due to the time taken by patients to consult a physician about their symptoms [9.6 months overall, longest in the USA (15.3 months)]. Most patients (71.6%) initially consulted primary care physicians about their symptoms and 76.4% of patients were referred to a specialist. Misdiagnoses occurred in 40.9% of patients [most frequent in the USA (51.3%), least common in Japan (27.6%)] and they saw an average of 2.9 physicians overall (3.5 in EU5 versus 2.0 in Japan/USA) before being diagnosed. Diagnosis was most often made by cardiologists (50.4%) or pulmonologists (49.3%). Conclusion: Our data suggest that diagnostic delay in PAH results from patient- and physician-related factors, which differ across regions and include lack of awareness of PAH on both sides. Development of better screening strategies may help address this barrier to timely PAH diagnosis.

**Background:** Single-tablet combination therapies (STCTs) combine multiple drugs into one formulation, making drug administration more convenient for patients. STCTs were developed to address concerns with treatment adherence and persistence, but the impact of STCT use is not fully understood across indications. **Objectives:** We conducted a systematic literature review (SLR) to examine STCT-associated outcomes across 4 evidence domains: clinical trials, real-world evidence (RWE), health-related quality of life (HRQoL) studies, and economic evaluations. **Methods:** Four SLRs were conducted across the aforementioned domains. Included studies compared STCTs as well as fixed-dose combinations (\[FDCs\] of non-tablet formulations) with the equivalent active compounds and doses in loose-dose combinations (LDCs). Original research articles were included; case reports, case series, and non-English-language sources were excluded. Databases searched included EconLit, Embase, and Ovid MEDLINE® ALL. Two independent reviewers assessed relevant studies and extracted data. Conflicts were resolved with a third reviewer or consensus-based discussion. **Results:** In all, 109 studies were identified; 27 studies were identified in more than one SLR. Treatment adherence was significantly higher in patients receiving FDCs vs LDCs in 12 of 13 RWE studies and 3 of 13 clinical trials. All 18 RWE studies reported higher persistence with FDCs. In RWE studies examining clinical outcomes (n = 17), 14 reported positive findings with FDCs, including a reduced need for add-on medication, blood pressure control, and improved hemoglobin A1C. HRQoL studies generally reported numerical improvements with STCTs or similarities between STCTs and LDCs. Economic outcomes favored STCT use. All 6 cost-effectiveness or cost-utility analyses found FDCs were less expensive and more efficacious than LDCs. Four budget impact models found that STCTs were associated with cost savings. Medical costs and healthcare resource use were generally lower with FDCs than with LDCs. **Discussion:** Evidence from RWE and economic studies strongly favored STCT use, while clinical trials and HRQoL studies primarily reported similarity between STCTs and LDCs. This may be due to clinical trial procedures aimed at maximizing adherence and HRQoL measures that are not designed to evaluate drug administration. **Conclusions:** Our findings highlight the value of STCTs for improving patient adherence, persistence, and clinical outcomes while also offering economic advantages.