Obesity is a major risk factor for the development of obstructive sleep apnea (OSA) and obesity hypoventilation syndrome (OHS), which manifest as intermittent hypercapnia and sustained plus intermittent hypercapnia, respectively. In this study, we investigated whether CO2 affects adipocyte differentiation (adipogenesis) and maturation (hypertrophy). Human visceral or subcutaneous preadipocytes were grown to confluence and then induced to differentiate to adipocytes under hypocapnia, normocapnia, and hypercapnia with or without hypoxia. Adipogenesis was also induced under intermittent or sustained hypercapnia. Differentiated adipocytes were maintained to maturity under normocapnia or hypercapnia. Our main findings are as follows: (1) hypercapnia accelerated adipogenesis in visceral and subcutaneous preadipocytes, whereas hypocapnia inhibited adipogenesis; (2) hypercapnia did not affect adipocyte hypertrophy; (3) hypercapnia-accelerated adipogenesis was independent of extracellular acidosis, oxygen concentration, or either intermittent or sustained exposure to high CO2; and (4) the mechanisms underlying hypercapnia-accelerated adipogenesis involved increased production of cyclic adenosine monophosphate (cAMP) via soluble adenylyl cyclase, leading to the activation of protein kinase A and exchanger protein directly activated by cAMP, which, in turn, activated proadipogenic transcription factors, such as cAMP response element binding protein, CCAAT/enhancer binding protein β, and peroxisome proliferator–activated receptor γ. This study reveals a novel role of high CO2 in promoting adipogenesis, which provides mechanistic clues to a pathoetiological interaction between OSA/OHS and obesity. Our data suggest a vicious cycle of disease progression via the following mechanism: OSA/OHS → hypoventilation → hypercapnia → increased adipogenesis → increased fat mass → exacerbated OSA/OHS.

Glecaprevir and pibrentasvir are oral direct-acting antiviral agents approved in combination for treatment of chronic hepatitis C viral infection. In vitro studies identified the combination as potential clinically relevant inhibitors of the efflux transporters P glycoprotein (P-gp), breast cancer resistance protein (BCRP), and hepatic uptake transporters organic anion transporting polypeptide (OATP) 1B1/3. Glecaprevir inhibited P-gp, BCRP, OATP1B1, and OATP1B3 with IC50 values of 0.33, 2.3, 0.017, and 0.064 µM, respectively. Pibrentasvir inhibited P-gp, BCRP, and OATP1B1 with IC50 values of 0.036, 14, and 1.3 µM, respectively. Neither agent inhibited organic cation transporter (OCT) 1, OCT2, organic anion transporter (OAT) 1, OAT3, multidrug and toxin extrusion (MATE) 1, or MATE2K. Open-label Phase 1 clinical drug-drug interaction studies were conducted in healthy subjects to evaluate interaction potential of glecaprevir/pibrentasvir and coadministered selective substrates for P-gp (digoxin, dabigatran etexilate, sofosbuvir), BCRP (rosuvastatin, sofosbuvir), and OATP1B1/3 (pravastatin, rosuvastatin). Pharmacokinetic parameters maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) were evaluated for probe substrates alone and in combination with glecaprevir/pibrentasvir. Cmax central values increased by 72%, 105%, 123%, 462%, and 66% for digoxin, dabigatran, pravastatin, rosuvastatin, and sofosbuvir, respectively. AUC central values increased by 48%, 138%, 130%, 115%, and 125% for digoxin, dabigatran, pravastatin, rosuvastatin, and sofosbuvir, respectively. Exposure of sofosbuvir metabolite GS-331007 was similar with or without glecaprevir/pibrentasvir. Outcomes of the clinical drug-drug interaction studies confirmed clinically relevant inhibition of P-gp, BCRP, and OATP1B1/3, and were used to provide dosing guidance for the concomitant use of glecaprevir/pibrentasvir with relevant transporter substrates. SIGNIFICANCE STATEMENT N/A

Interstitial lung abnormalities (ILAs) are immune checkpoint inhibitor (ICI)-related pneumonitis (ICI-P) risk factors. However, the relationship between imaging patterns and immunotherapy outcomes, and treatment strategies remain unclear in patients with non-small cell lung cancer (NSCLC) and ILAs. We retrospectively evaluated patients with ILAs-complicated NSCLC who received ICI therapy. ILAs were subcategorized as non-subpleural, subpleural non-fibrotic, and subpleural fibrotic (SF) based on the 2020 position paper by the Fleischner Society. We investigated ICI-P incidence, ICI-P risk factors, lung cancer prognosis, and ILAs radiological progression. Of the 481 ICI-treated patients, 79 (16.4%) had ILAs (45 non-SF and 34 SF). The ICI-P cumulative incidence (hazard ratio, 4.57; 95% confidence interval [CI], 1.90–10.98; p = 0.001) and any grade and grade ≥ 3 ICI-P incidences were higher in patients with SF-ILAs than in those with non-SF-ILAs (all grades: 7/45 [15.6%)] vs. 18/34 [52.9%]; p < 0.001; grade ≥ 3: 1/45 [2.2%] vs. 10/34 [29.4%]; p = 0.001). According to multivariate analysis, SF-ILAs independently predicted ICI-P (odds ratio, 5.35; 95% CI 1.62–17.61; p = 0.006). Patients with SF-ILAs had shorter progression-free and overall survival and higher ICI-P-related respiratory failure death rates than those with non-SF-ILAs. Approximately 2.5 times more patients with SF-ILAs showed progression by the 2-year follow-up than those with non-SF-ILAs. SF-ILAs is an independent strong predictor of ICI-P development in patients with NSCLC, may increase ICI-P severity, worsen prognosis, and accelerate ILAs progression. ILAs subcategorization is an important treatment strategy for patients with lung cancer treated with ICIs.

As part of control techniques, gust-alleviation systems using airborne Doppler lidar technology are expected to enhance aviation safety by significantly reducing the risk of turbulence-related accidents. Accurate measurement and estimation of the vertical wind velocity are very important in the successful implementation of such systems. An estimation algorithm for the airflow vector based on data from airborne lidars is proposed and investigated for preview control to prevent turbulence-induced aircraft accidents in flight. An existing technique – simple vector conversion – assumes that the wind field between the lidars is homogeneous, but this assumption fails when turbulence occurs due to a large wind-velocity fluctuation. The proposed algorithm stores the line-of-sight (LOS) wind data at every moment and uses recent and past LOS wind data to estimate the airflow vector and to extrapolate the wind field between the airborne twin lidars without the assumption of homogeneity. Two numerical experiments – using the ideal vortex model and numerical weather prediction, respectively – were conducted to evaluate the estimation performance of the proposed method. The proposed method has much better performance than simple vector conversion in both experiments, and it can estimate accurate two-dimensional wind-field distributions, unlike simple vector conversion. The estimation performance and the computational cost of the proposed method can satisfy the performance demand for preview control.

Background: Interstitial lung disease (ILD) in patients with non‐small cell lung cancer (NSCLC) worsens the prognosis for overall survival (OS) due to chemotherapy‐triggered acute exacerbation (AE)‐ILD. The Glasgow Prognostic Score (GPS), which is based on serum C‐reactive protein and albumin levels, has been suggested as a reliable prognostic tool for mortality in cancer patients, including NSCLC. In this study, we investigated whether GPS is a predictor for chemotherapy‐triggered AE‐ILD and the prognosis in patients with NSCLC and pre‐existing ILD.Methods: We conducted a retrospective review on 56 NSCLC and ILD patients at our hospital who received platinum agent‐based treatment as first‐line chemotherapy between June 2010 and May 2019. We categorized these patients according to their GPS (0–2) and compared the incidence of chemotherapy‐triggered AE‐ILD and OS.Results: The GPS 0, 1, and 2 groups included 31, 16, and nine patients, respectively, out of 56. A total of 12 (21.4%) patients showed chemotherapy‐triggered AE‐ILD. The median OS was at 11.5 months (95% confidence interval: 8.0–15.1). The incidence of chemotherapy‐triggered AE‐ILD within the first year of chemotherapy in the GPS 0, 1, and 2 groups was three (9.6%), four (25.0%), and five (55.5%), and the median OS time was 16.9, 9.8 and 7.6 months, respectively. Univariate and multivariate analyses indicated that only GPS 2 could predict both chemotherapy‐triggered AE‐ILD and OS (P < 0.05).Conclusions: GPS assessment of patients with NSCLC and pre‐existing ILD is a valuable prognostic tool for predicting chemotherapy‐triggered AE‐ILD and OS.Key points: Significant findings of the study: We found that GPS 2 was an independent risk factor for chemotherapy‐triggered AE‐ILD and prognosis in patients with ILD associated with NSCLC.What this study adds: GPS may potentially enable the discrimination of patients tolerant of chemotherapy from those at an increased risk of AE‐ILD and predict the prognosis in patients with NSCLC and ILD receiving chemotherapy.

Background: Predicting the incidence of chemotherapy‐triggered acute exacerbation of interstitial lung disease (AE‐ILD) in patients with lung cancer is important because AE‐ILD confers a poor prognosis. The Glasgow prognostic score (GPS), which is an inflammation‐based index composed of serum levels of C‐reactive protein and albumin, predicts prognosis in patients with small cell lung cancer (SCLC) without ILD. In this study, we investigated AE‐ILD and survival outcome based on the GPS in patients with ILD associated with SCLC who were receiving chemotherapy.Methods: Medical records of patients who received platinum‐based first‐line chemotherapy between June 2010 and May 2019 were retrospectively reviewed to compare the incidence of AE‐ILD and overall survival (OS) between GPS 0, 1, and 2.Results: Among our cohort of 31 patients, six (19.3%) experienced chemotherapy‐triggered AE‐ILD. The AE‐ILD incidence increased from 9.5% to 25.0% and 50.0% with increase in GPS of 0, 1, and 2, respectively. Univariate and multivariate analyses revealed remarkable associations between GPS 2 and both AE‐ILD (odds ratio for GPS 2, 18.69; p = 0.046) and prognosis (hazard ratio of GPS 2, 13.52; p = 0.002). Furthermore, median OS in the GPS 0, 1, and 2 groups was 16.2, 9.8, and 7.1 months, respectively (p < 0.001).Conclusions: Our results suggest that GPS 2 is both a predictor of risk of chemotherapy‐triggered AE‐ILD and a prognostic indicator in patients with ILD associated with SCLC. We propose that GPS may be used as a guide to distinguish chemotherapy‐tolerant patients from those at high risk of AE‐ILD.