Surveillance of seasonal influenza viruses during the COVID-19 pandemic in Tokyo, Japan, 2018-2023, a single-center study.

Introduction: COVID-19 pandemic led to significant reductions in influenza detection worldwide, fueling debates on whether influenza truly ceased circulating in communities. The number of influenza cases decreased significantly in Japan, raising concerns about the potential risk of decreased immunity to influenza in the population. Our single-center study aimed to investigate influenza trends before and during the COVID-19 pandemic in Tokyo, Japan. Materials and Methods: This cross-sectional study included patients of all ages who visited Tokyo Shinagawa Hospital between April 1, 2018, and March 31, 2023. Influenza and COVID-19 tests were conducted using Quick Navi-Flu2 and polymerase chain reaction (PCR). We analyzed data from before and during the COVID-19 epidemic, based on patient background, hospitalization, and deaths, collected from medical records. Results: A total of 12 577 influenza tests were conducted, with approximately 100 tests consistently performed each month even in the influenza off-season. Throughout the observation period, 962 positive cases were identified. However, no cases were observed for 27 months between March 2020 and November 2022. Influenza A cases were reobserved in December 2022, followed by influenza B cases in March 2023, similar to the influenza incidence reports from Tokyo. The positivity rate during the 2022-2023 winter season was lower than before the COVID-19 epidemic and decreased in elderly patients, with no hospitalizations or deaths observed. Conclusion: This single-center study provided actual trend data for influenza patients before and during COVID-19 outbreaks in Tokyo, which could offer insights into the potential impact and likelihood of influenza virus infection in Japan.

High Fever, Wide Distribution of Viral Pneumonia, and Pleural Effusion are More Critical Findings at the First Visit in Predicting the Prognosis of COVID-19: A Single Center, retrospective, Propensity Score-Matched Case-Control Study.

Introduction: Currently, infection control measures for SARS-COV2 are being relaxed, and it is important in daily clinical practice to decide which findings to focus on when managing patients with similar background factors. Methods: We retrospectively evaluated 66 patients who underwent blood tests (complete blood count, blood chemistry tests, and coagulation tests) and thin slice CT between January 1 and May 31, 2020, and performed a propensity score-matched case-control study. Cases and controls were a severe respiratory failure group (non-rebreather mask, nasal high-flow, and positive-pressure ventilation) and a non-severe respiratory failure group, matched at a ratio of 1:3 by propensity scores constructed by age, sex, and medical history. We compared groups for maximum body temperature up to diagnosis, blood test findings, and CT findings in the matched cohort. Two-tailed P-values <0.05 were considered statistically significant. Results: Nine cases and 27 controls were included in the matched cohort. Significant differences were seen in maximum body temperature up to diagnosis (p=0.0043), the number of shaded lobes (p=0.0434), amount of ground-glass opacity (GGO) in the total lung field (p=0.0071), amounts of GGO (p=0.0001), and consolidation (p=0.0036) in the upper lung field, and pleural effusion (p=0.0117). Conclusion: High fever, the wide distribution of viral pneumonia, and pleural effusion may be prognostic indicators that can be easily measured at diagnosis in COVID-19 patients with similar backgrounds.

A case of reinfection with a different variant of SARS-CoV-2: case report.

Background: Coronavirus disease 2019 (COVID-19) was previously thought to have a low reinfection rate, but there are concerns that the reinfection rate will increase with the emergence and spread of mutant variants. This report describes the case of a 36-year-old, non-immunosuppressed man who was infected twice by two different variants of COVID-19 within a relatively short period. Case presentation: A 36-year-old Japanese man with no comorbidities was infected with the E484K variant (R.1 lineage) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Symptoms were mild and improved with symptomatic treatment alone. About four months later he presented to another outpatient department with high fever and headache. We diagnosed him as infected with the Alpha variant (B.1.1.7) of SARS-CoV-2 based on SARS-CoV-2 real-time reverse transcription polymerase chain reaction testing (RT-PCR). The patient was hospitalized with high fever. The patient received treatment in the form of anti-inflammatory therapy with corticosteroid and antibacterial chemotherapy. The patient improved without developing severe disease. Conclusion: Concerns have been raised that the reinfection rate of COVID-19 will increase with the emergence of mutant variants. Particularly in mild cases, adequate amounts of neutralizing antibodies may not be produced, and reinfection may thus occur. Continued attention to sufficient infection control is thus essential.

Distinct immune cell dynamics correlate with the immunogenicity and reactogenicity of SARS-CoV-2 mRNA vaccine.

Two doses of Pfizer/BioNTech BNT162b2 mRNA vaccine elicit robust severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-neutralizing antibodies with frequent adverse events. Here, by applying a high-dimensional immune profiling on 92 vaccinees, we identify six vaccine-induced immune dynamics that correlate with the amounts of neutralizing antibodies, the severity of adverse events, or both. The early dynamics of natural killer (NK)/monocyte subsets (CD16+ NK cells, CD56high NK cells, and non-classical monocytes), dendritic cell (DC) subsets (DC3s and CD11c- Axl+ Siglec-6+ [AS]-DCs), and NKT-like cells are revealed as the distinct cell correlates for neutralizing-antibody titers, severity of adverse events, and both, respectively. The cell correlates for neutralizing antibodies or adverse events are consistently associated with elevation of interferon gamma (IFN-γ)-inducible chemokines, but the chemokine receptors CCR2 and CXCR3 are expressed in distinct manners between the two correlates: vaccine-induced expression on the neutralizing-antibody correlate and constitutive expression on the adverse-event correlate. The finding may guide vaccine strategies that balance immunogenicity and reactogenicity.

Longitudinal Analysis of Neutralizing Potency against SARS-CoV-2 in the Recovered Patients after Treatment with or without Favipiravir.

The effect of treatment with favipiravir, an antiviral purine nucleoside analog, for coronavirus disease 2019 (COVID-19) on the production and duration of neutralizing antibodies for SARS-CoV-2 was explored. There were 17 age-, gender-, and body mass index-matched pairs of favipiravir treated versus control selected from a total of 99 patients recovered from moderate COVID-19. These subjects participated in the longitudinal (>6 months) analysis of (i) SARS-CoV-2 spike protein's receptor-binding domain IgG, (ii) virus neutralization assay using authentic virus, and (iii) neutralization potency against original (WT) SARS-CoV-2 and cross-neutralization against B.1.351 (beta) variant carrying triple mutations of K417N, E484K, and N501Y. The results demonstrate that the use of favipiravir: (1) significantly accelerated the elimination of SARS-CoV-2 in the case vs. control groups (p = 0.027), (2) preserved the generation and persistence of neutralizing antibodies in the host, and (3) did not interfere the maturation of neutralizing potency of anti-SARS-CoV-2 and neutralizing breadth against SARS-CoV-2 variants. In conclusion, treatment of COVID-19 with favipiravir accelerates viral clearance and does not interfere the generation or maturation of neutralizing potency against both WT SARS-CoV-2 and its variants.

Predictive value of 3'-deoxy-3'-18F-fluorothymidine PET in the early response to anti-programmed death-1 therapy in patients with advanced non-small cell lung cancer.

BACKGROUND: Anti-programmed death-1 (anti-PD-1) therapy has shown clinical success in patients with advanced non-small cell lung cancer (NSCLC). However, it is difficult to evaluate the early response to anti-PD-1 therapy. We determined whether changes in 3'-deoxy-3'-[18F]-fluorothymidine (18F-FLT) PET parameters before and soon after treatment initiation predicted the therapeutic effect of anti-PD-1 antibody. METHODS: Twenty-six patients with advanced NSCLC treated with anti-PD-1 antibody were enrolled prospectively and underwent 18F-FLT PET before and at 2 and 6 weeks after treatment initiation. Changes in maximal standardized uptake value (ΔSUVmax), proliferative tumor volume (ΔPTV) and total lesion proliferation (ΔTLP) of the lesions were calculated and evaluated for their associations with the clinical response to therapy. RESULTS: The disease control rate was 64%. Patients with non-progressive disease (non-PD) had significantly decreased TLP at 2 weeks, and decreased SUVmax, PTV, and TLP at 6 weeks, compared with those with PD, while three of eight (37.5%) patients who responded had increased TLP from baseline at 2 weeks (ie, pseudoprogression). Among the parameters that changed between baseline and 2 weeks, ΔPTV0-2 and ΔTLP0-2 had the highest accuracy (76.0%) to predict PD. Among the parameters that changed between baseline and 6 weeks, ΔSUVmax0-6, ΔPTV0-6 and ΔTLP0-6 had the highest accuracy (90.9%) to predict PD. ΔTLP0-2 (≥60%, HR 3.41, 95% CI 1.34-8.65, p=0.010) and ΔTLP0-6 (≥50%, HR 31.4, 95% CI 3.55 to 276.7, p=0.0019) were indicators of shorter progression-free survival. CONCLUSIONS: Changes in 18F-FLT PET parameters may have value as an early predictive biomarker for the response to anti-PD-1 therapy in patients with NSCLC. However, it should be noted that pseudoprogression was observed in 18F-FLT PET imaging at 2 weeks after treatment initiation. TRIAL REGISTRATION NUMBER: jRCTs051180147.

Two Cases of Severe COVID-19 Pneumonia Effectively Treated with Extracorporeal Membrane Oxygenation in Addition to Favipiravir and Corticosteroid.

Case 1: A 65-year-old man with novel coronavirus infection (COVID-19) complicated with acute respiratory failure. On admission, the patient was started on favipiravir and corticosteroid. However, due to a lack of significant improvement, he was introduced to mechanical ventilation and extracorporeal membrane oxygenation (ECMO). Although iliopsoas hematoma occurred as a complication, the patient recovered. Case 2: A 49-year-old man with COVID-19 had been started on favipiravir and corticosteroid. Due to progressive respiratory failure, the patient underwent mechanical ventilation and ECMO. The patient recovered without complications. We successfully treated these severe cases with a multimodal combination of pharmacological and non-pharmacological supportive therapy.

A case of COVID-19 pneumonia successfully treated with favipiravir (Avigan) in which serum SARS-CoV-2 RNA detected by LAMP method was clinically useful.

A 49-year-old Japanese male was managed by mechanical ventilation due to coronavirus disease 2019 (COVID-19) pneumonia. Favipiravir as an antiviral therapy, and anti-inflammatory treatment were administered. SARS-CoV-2 RNA was detected in serum by the loop-mediated isothermal amplification (LAMP) method on Day 9; favipiravir treatment was continued. On Day 13, negative serum RNA was confirmed, followed by mechanical ventilation was removed. On Day 23, LAMP negative was confirmed in nasopharynx, after that the patient discharged on Day 27. We could treat successfully for severe COVID-19 pneumonia based on the LAMP method. We consider this method will be useful in COVID-19 treatment.

Clinical Features of 154 COVID-19 Patients and the Parameters for the Effective Detection of Pneumonia at the Time of the Initial Diagnosis in Japan.

Objective We aimed to clarify clinical and laboratory characteristics of coronavirus disease 2019 (COVID-19) patients, and further explore the features to detect COVID-19 pneumonia at the first visit to community-based hospitals. Methods Diagnoses of COVID-19 were based on positive results from real-time reverse-transcription polymerase chain reaction testing of nasopharyngeal-swab specimens. We retrospectively reviewed the medical records of patients showing positive results. The clinical characteristics and results of blood tests were compared between the patients with and without pneumonia. The risk factors associated with pneumonia were then evaluated by a multivariable analysis. Results The study cohort comprised 154 patients, including 117 patients (76.0%) with pneumonia at first visit. Significant differences were seen in age, the frequency of fever, tachycardia, desaturation (peripheral oxygen saturation ≤95%), any comorbidity, neutrocyte count and fraction, lymphocyte count and fraction, platelet count, lactate dehydrogenase (LDH), C-reactive protein (CRP), and fibrinogen between the patients with and without pneumonia. Using a multivariable analysis, CRP ≥0.3 mg/dL and fibrinogen >400 mg/dL were found to be associated with the presence of pneumonia. Conclusion Community-based settings for screening COVID-19 patients should perform chest X-ray and blood tests for white blood cell fractions, fibrinogen, LDH, and CRP. Of these, elevations in the CRP and fibrinogen levels could be critically associated with the presence of COVID-19 pneumonia.

Predictive value of integrated 18F-FDG PET/MRI in the early response to nivolumab in patients with previously treated non-small cell lung cancer.

BACKGROUND: The early response to treatment with immune-checkpoint inhibitors is difficult to evaluate. We determined whether changes in integrated [18F]-fluoro-2-deoxy-D-glucose positron emission tomography/MRI (18F-FDG PET/MRI) parameters after the first 2 weeks of antiprogrammed death-1 antibody nivolumab therapy could predict the response of patients with non-small cell lung cancer (NSCLC). METHODS: Twenty-five patients with previously treated NSCLC were enrolled prospectively and underwent 18F-FDG PET/MRI before and at 2 weeks after nivolumab therapy. Changes in maximal standardized uptake value, total lesion glycolysis (ΔTLG) and apparent diffusion coefficient (ΔADC) between the two scans were calculated and evaluated for their associations with the clinical response to therapy. RESULTS: The disease control rate was 64%. Patients with non-progressive disease (non-PD) had significantly decreased TLG, increased ADCmean (ie, negative ΔADCmean) and lower ΔTLG+ΔADCmean than patients with PD. Among the parameters tested, receiver operating characteristic curve analysis revealed that a cut-off value of 16.5 for ΔTLG+ΔADCmean had the highest accuracy (92%) for distinguishing between patients with non-PD and PD. A ΔTLG+ΔADCmean value <16.5 was significantly associated with longer median progression-free survival (9.0 vs 1.8 months, p<0.00001) and overall survival (23.6 vs 4.7 months, p=0.0001) compared with ΔTLG+ΔADCmean value ≥16.5. A multivariate Cox model revealed that ≥16.5 ΔTLG+ΔADCmean was an independent predictor of shorter progression-free survival (HR 37.7) and overall survival (HR 9.29). CONCLUSIONS: A combination of ΔTLG and ΔADCmean measured by integrated 18F-FDG PET/MRI may have value as a predictor of the response and survival of patients with NSCLC following nivolumab therapy. TRIAL REGISTRATION NUMBER: UMIN 000020707.

The vertebral 3'-deoxy-3'-18F-fluorothymidine uptake predicts the hematological toxicity after systemic chemotherapy in patients with lung cancer.

OBJECTIVES: Although hematological toxicities (HT) are the leading adverse events of systemic chemotherapy, the estimation of severe HT is challenging. Recently, 3'-deoxy-3'-[18F]-fluorothymidine (18F-FLT) accumulation with PET has been considered a biomarker of the cell proliferation. This study aims to elucidate whether the vertebral accumulation of 18F-FLT could estimate severe HT during platinum-doublet chemotherapy. METHODS: In this Institutional Review Board-approved retrospective study, 50 patients with primary lung cancer underwent 18F-FLT PET scan before platinum-doublet chemotherapy. We evaluated the standardized uptake value, total vertebral proliferation (TVP), and TVP/body surface area (TVP/BSA) of the vertebral body (Th4, Th8, Th12, and L4), and then the associations between those parameters and frequency of severe HT during platinum-doublet chemotherapy were assessed. RESULTS: Severe HT (grade 3/4) was observed in 40.0% of patients during the first cycle. The ROC curve analyses revealed that the TVP/BSA of L4 was the most discriminative parameter among PET parameters for the prediction of severe HT. The multivariate logistic regression analysis revealed the TVP/BSA of L4 (odds ratio [OR], 0.94; p = 0.0036) and the frequency of the grade 3/4 hematological toxicity in previous clinical trials (OR, 1.03; p = 0.023) were independent predictors. Furthermore, the sensitivity, specificity, and accuracy of the TVP/BSA of L4 cut-off of 68.7 to predict grade 3/4 HT were 80.0%, 86.7%, and 84.0%, respectively. A low TVP/BSA of L4 (< 68.7) as a binary variable was a significant indicator of severe HT (OR, 26.0; p = 0.000026). CONCLUSIONS: The low 18F-FLT uptake in the lower vertebral body is a predictor of severe HT in patients with lung cancer who receive platinum-doublet chemotherapy. TRIAL REGISTRATION: Trial registration: UMIN000027540 KEY POINTS: • The vertebral 18 F-FLT uptake with PET is an independent predictor of the severe hematological toxicity during the first cycle of platinum-doublet chemotherapy. • The 18 F-FLT uptake in L4 vertebral body estimated hematological toxicities better than that in the upper vertebra (Th4, Th8, and Th12). • The evaluation of the amount and activity of hematopoietic cells in the bone marrow cavity using 18 F-FLT PET imaging could provide predictive data of severe hematological toxicities and help determine an appropriate drug combination or dose intensity in patients with advanced malignant diseases.

Extracellular acidification-induced CXCL8 production through a proton-sensing receptor OGR1 in human airway smooth muscle cells: a response inhibited by dexamethasone.

BACKGROUND: Human airway smooth muscle cells (ASMCs) contribute to bronchial contraction and airway hyperresponsiveness in patients with bronchial asthma. They also generate cytokines, chemokines, and matricellular proteins. Ovarian cancer G protein-coupled receptor 1 (OGR1) senses extracellular protons and mediates the production of interleukin-6 (IL-6) and connective tissue growth factor (CTGF) in ASMCs. METHODS: ASMCs were stimulated for the indicated time by pH 6.3 or pH 7.4-adjusted Dulbecco's Modified Eagle Medium (DMEM) containing 0.1% bovine serum albumin (BSA) (0.1% BSA-DMEM). As a control stimulant, pH 7.4-adjusted 0.1% BSA-DMEM containing 10 ng/mL tumor necrosis factor-α (TNF-α) was used. Interleukin-8/C-X-C motif chemokine ligand 8 (CXCL8) mRNA expression in ASMCs was quantified by RT-PCR using real-time TaqMan technology. CXCL8 secreted from ASMCs was measured by enzyme-linked immunosorbent assay (ELISA). Phosphorylation at serine 536 of NF-κB p65 and binding of p65 to oligonucleotide containing an NF-κB consensus binding site were analyzed by Western blotting and an ELISA-based kit. RESULTS: Acidic pH induced a significant increase of CXCL8 mRNA expression and CXCL8 protein secretion in ASMCs. ASMCs transfected with small interfering RNA (siRNA) targeted for OGR1 produced less CXCL8 compared with those transfected with non-targeting siRNA. Protein kinase C (PKC) inhibitor, MEK1/2 inhibitor, and the inhibitor of IκB phosphorylation reduced acidic pH-stimulated CXCL8 production in ASMCs. Dexamethasone also inhibited acidic pH-stimulated CXCL8 production of ASMCs in a dose-dependent manner. Dexamethasone did not affect either phosphorylation or binding to the consensus DNA site of NF-κB p65. CONCLUSIONS: CXCL8 released from ASMCs by extracellular acidification may play a pivotal role in airway accumulation of neutrophils. Glucocorticoids inhibit acidic pH-stimulated CXCL8 production independent of serine 536 phosphorylation and the binding to DNA of NF-κB p65, although NF-κB activity is essential for CXCL8 production in ASMCs.

Influence of UGT1A1 polymorphism on etoposide plus platinum-induced neutropenia in Japanese patients with small-cell lung cancer.

BACKGROUND: The association between UGT1A1 polymorphism and etoposide-induced toxicities is still not clear. The aim of this study was to assess the association between uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) gene polymorphism and severe hematologic toxicities in Japanese patients receiving etoposide plus platinum chemotherapy for small-cell lung cancer. METHODS: This retrospective analysis included patients with small-cell lung cancer who had received their first-line chemotherapy with etoposide plus cisplatin or carboplatin, between October 2008 and April 2018, at the University of Fukui Hospital. The relationship between UGT1A1 polymorphisms and first-cycle neutropenia as well as thrombocytopenia was evaluated. RESULTS: A total of 55 patients were enrolled. The incidence of grade 4 neutropenia during the first cycle of etoposide-based chemotherapy was higher in patients with homozygous (hmz) polymorphisms for UGT1A1*28 and *6 (*28/*28, *6/*6, and *6/*28) than in patients with wild-type (wt) (*1/*1) and heterozygous (htz) (*1/*28 and *1/*6) polymorphisms (88% vs 43% P = 0.03). The incidence of febrile neutropenia and grade 4 thrombocytopenia, however, was not significantly different. Multivariate analysis suggested that grade 4 neutropenia associated significantly with an hmz UGT1A1 genotype [odds ratio (OR) 11.3; P = 0.04] and administration of granulocyte colony-stimulating factor (G-CSF) before the neutrophil counts dropped to < 500 cells/µL (OR; P = 0.01). CONCLUSIONS: UGT1A1*28 and UGT1A1*6 mutations might be regarded as predictors for etoposide-induced grade 4 neutropenia.

Efficacy and safety of nanoparticle albumin-bound paclitaxel monotherapy as second-line therapy of cytotoxic anticancer drugs in patients with advanced non-small cell lung cancer.

BACKGROUND: Nanoparticle albumin-bound paclitaxel (nab-PTX), which avoids toxicities associated with a vehicle used in solvent-based PTX, has already shown safety and efficacy in patients with non-small cell lung cancer (NSCLC). METHODS: A phase II study was performed to assess the safety and efficacy of nab-PTX monotherapy as second-line chemotherapy after cytotoxic anticancer drugs for previously treated advanced NSCLC. Thirty-two patients with advanced NSCLC who had previously undergone 1 regimen of cytotoxic anticancer drugs were enrolled. Nab-PTX was administered intravenously at a dose of 100 mg/m on days 1, 8, and 15 of a 28-day cycle. The objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and toxicity profile were evaluated. RESULTS: The ORR was 28.1%, the DCR was 71.9%, median PFS was 3.9 months (95% confidence interval [CI] 2.7-5.1 months), and median OS was 10.9 months (95% CI 9.5-12.3 months). The mean relative dose intensity of nab-PTX was 77%. Grade 3 or 4 neutropenia, and grade 3 febrile neutropenia were observed in 11 and 1 of 32 patients, respectively. As nonhematologic toxicities, grade 3 peripheral sensory neuropathy and pneumonitis were each observed in 2 of 32 patients. CONCLUSION: Nab-PTX is an active and well-tolerated regimen in patients with previously treated NSCLC.

Problems of elderly patients on inhalation therapy: Difference in problem recognition between patients and medical professionals.

BACKGROUND: There is no systematic analysis to identify problems involved with instruction on inhalation therapy for elderly patients. We conducted a nationwide questionnaire survey for patients and medical professionals. METHODS: A questionnaire survey was conducted of adult patients on inhaled drugs (ages 18-92 years, 820 individuals) and medical professionals (pharmacists or nurses) who provided instruction on inhalation therapy to these patients in 23 institutions in Japan to investigate the technique and the level of understanding (knowledge) of the inhalation therapy. Changes in the recognition of performance of inhalation technique and inhalation knowledge with increasing age were analyzed. RESULTS: According to patients' subjective assessment, there was no deterioration in the performance of the inhalation technique or loss of the knowledge with increasing age. On the other hand, medical professionals' objective assessment revealed a significant loss of both inhalation technique and knowledge with increasing age. Not many elderly patients noticed their own problems themselves, revealing a great perception gap between elderly patients and medical professionals. Thus, there was concern that patients would unconsciously practice the inhalation procedure improperly. On the other hand, in comparison with non-elderly patients, elderly patients were less resistant to continuation of therapy, suggesting that they would be more likely to accept instruction on inhalation therapy. CONCLUSIONS: Elderly patients are apt to assume that they "understand well", therefore, in order to recognize and close the perception gap between elderly patients and medical professionals, it is necessary to provide them with more aggressive (frequent) instructions on inhalation therapy.

[A CASE OF EOSINOPHILIC BRONCHIOLITIS COMPLICATED WITH BRONCHIAL ASTHMA AND CHRONIC EOSINOPHILIC PNEUMONIA].

A 62-year-old man was admitted to our hospital because of wheezing and dyspnea. Chest computed tomography showed ground-glass opacity and some centrilobular nodules. Chronic eosinophilic pneumonia complicated with Mycoplasma pneumoniae infection was diagnosed on the basis of bronchoalveolar lavage eosinophilia and blood findings. However, based on the clinical course, the patient was suspected to have eosinophilic bronchiolitis. This case suggests the possibility that eosinophilic inflammation can occur concomitantly in the central airway and distal airway.

Prognostic Value of Dual-Time-Point 18F-FDG PET for Idiopathic Pulmonary Fibrosis.

UNLABELLED: The aim of this prospective study was to clarify whether dual-time-point (18)F-FDG PET imaging results are useful to predict long-term survival of idiopathic pulmonary fibrosis (IPF) patients. METHODS: Fifty IPF patients underwent (18)F-FDG PET examinations at 2 time points: 60 min (early imaging) and 180 min (delayed imaging) after (18)F-FDG injection. The standardized uptake value (SUV) at each point and retention index value (RI-SUV) calculated from those were evaluated, and then the results were compared with overall and progression-free survival. RESULTS: A multivariate Cox proportional hazards model showed higher RI-SUV and higher extent of fibrosis score as independent predictors of shorter progression-free survival. The median progression-free survival for patients with negative RI-SUV was better than that for those with positive RI-SUV (27.9 vs. 13.3 mo, P = 0.0002). On the other hand, multivariate Cox analysis showed higher RI-SUV and lower forced vital capacity to be independent predictors of shorter overall survival. The 5-y survival rate for patients with negative RI-SUV was better than that for those with positive RI-SUV (76.8% vs. 14.3%, P = 0.00001). In addition, a univariate Cox model showed that positive RI-SUV as a binary variable was a significant indicator of mortality (hazard ratio, 7.31; 95% confidence interval, 2.64-20.3; P = 0.0001). CONCLUSION: Our results demonstrate that positive RI-SUV is strongly predictive of earlier deterioration of pulmonary function and higher mortality in patients with IPF.

Blunted activation of Rho-kinase in yak pulmonary circulation.

Yaks have adapted to high altitude and they do not develop hypoxic pulmonary hypertension. Although we previously identified the important role of augmented nitric oxide synthase activity in the yak pulmonary circulatory system, evidence of the direct involvement of Rho-kinase as a basal vascular tone regulator is lacking. Four domesticated male pure-bred yaks and four bulls that were born and raised at an altitude of 3000 m in the Tien-Shan mountains were studied at an altitude of 3,100 m. Mean pulmonary artery pressure (mPAP) was measured before and after fasudil (60 mg in 20 mL of saline) was intravenously administered using a Swan-Ganz catheter at a rate of 3.3 mL/min for 30 min. Fasudil decreased mPAP in bulls from 67.8±14.9 to 32.3±5.3 mmHg (P < 0.05) after 15 min and the level was maintained for 30 min, but it merely blunted mPAP in yaks from 28.2±4.5 to 25.1±11.1 and 23.2±2.7 mmHg after 5 and 30 min, respectively. These findings comprise the first evidence of a modest role of Rho-kinase in the maintenance of pulmonary artery pressure in the yak.