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Abstract The differentiation of B cells into plasma cells is associated with substantial transcriptional and epigenetic remodeling. H3.3 histone variant marks active chromatin via replication-independent nucleosome assembly. However, its role in plasma cell development remains elusive. Herein, we show that during plasma cell differentiation, H3.3 is downregulated, and the deposition of H3.3 and chromatin accessibility are dynamically changed. Blockade of H3.3 downregulation by enforced H3.3 expression impairs plasma cell differentiation in an H3.3-specific sequence-dependent manner. Mechanistically, enforced H3.3 expression inhibits the upregulation of plasma cell-associated genes such as Irf4, Prdm1, and Xbp1 and maintains the expression of B cell-associated genes, Pax5, Bach2, and Bcl6. Concomitantly, sustained H3.3 expression prevents the structure of chromatin accessibility characteristic for plasma cells. Our findings suggest that appropriate H3.3 expression and deposition control plasma cell differentiation.

Abstract Objectives A set of orofacial signs and symptoms completely or partially present in individuals who replace the correct pattern of nasal breathing with an oral or mixed pattern is defined as mouth breathing syndrome (MBS). In a previous report, it was clarified that an incompetent lip seal (ILS) affected the occurrence of MBS among primary school children. However, the factors related to MBS and the effect of ILS in preschool children remain unclear. The purpose of this study was to clarify the factors relevant to MBS in preschool children and investigate the relationship of ILS to MBS. Material and Methods We surveyed 285 preschool children between 3 and 5 years of age. Their guardians completed the questionnaire, which consisted of 44 questions regarding the children's daily health conditions and lifestyle habits. To classify the closely related questions into their respective factors and to examine the strength of the correlation between the newly revealed factors, an exploratory factor analysis with promax rotation was performed. Results The factor analysis identified nine items representing four factors. Factors 1–4 were defined as “diseases of the nose,” “ILS,” “problem with swallowing and chewing,” and “eating and drinking habits,” respectively. Factor 2 most strongly correlated with Factor 1, and both Factors showed a relatively strong correlation with Factor 3. Conclusions The initial stage of MBS may be present in preschool children. ILS and diseases of the nose can cause poor development of oral functions, such as breathing and eating.

ABSTRACTAs an established spatial analytical tool, Geographically Weighted Regression (GWR) has been applied across a variety of disciplines. However, its usage can be challenging for large datasets, which are increasingly prevalent in today’s digital world. In this study, we propose two high-performance R solutions for GWR via Multi-core Parallel (MP) and Compute Unified Device Architecture (CUDA) techniques, respectively GWR-MP and GWR-CUDA. We compared GWR-MP and GWR-CUDA with three existing solutions available in Geographically Weighted Models (GWmodel), Multi-scale GWR (MGWR) and Fast GWR (FastGWR). Results showed that all five solutions perform differently across varying sample sizes, with no single solution a clear winner in terms of computational efficiency. Specifically, solutions given in GWmodel and MGWR provided acceptable computational costs for GWR studies with a relatively small sample size. For a large sample size, GWR-MP and FastGWR provided coherent solutions on a Personal Computer (PC) with a common multi-core configuration, GWR-MP provided more efficient computing capacity for each core or thread than FastGWR. For cases when the sample size was very large, and for these cases only, GWR-CUDA provided the most efficient solution, but should note its I/O cost with small samples. In summary, GWR-MP and GWR-CUDA provided complementary high-performance R solutions to existing ones, where for certain data-rich GWR studies, they should be preferred.

Objective The documented variation in gastric cancer (GC) detection among endoscopists has often been dismissed as a coincidental artefact of the low incidence of gastric neoplasms; it is not considered associated with differences in physicians’ performance of the esophagogastroduodenoscopy procedure. This study is to confirm whether significant variations among endoscopists in early GC detection suggest the individual performance of the upper endoscopy.Design A retrospective observational study at a single centre in Japan assessed the results of 218 early GCs detected during 25 688 routine esophagogastroduodenoscopies by 12 endoscopists. The main outcome was the rate of early GC detection for each endoscopist under the same circumstances. Other measures included the major diameters and locations of the lesions, Helicobacter pylori infection status, and baseline patient characteristics that could affect the prevalence of GC.Results The early GC detection rates exhibited wide variation among endoscopists (0.09%–2.87%) despite performing routine esophagogastroduodenoscopies in a population with a similar background. Endoscopists were assigned to a low-detection group (n=6; detection rate: 0.47% (range: 0.09%–0.55%)) and a high-detection group (n=5; detection rate: 0.83% (range: 0.63%–1.12%)), with the single highest detector analysed separately due to his distinct detection rate (2.87%). Endoscopists in the high-detection group had better detection rates for minute (major diameter ≤5 mm) and small (major diameter 6–10 mm) GCs than the low-detection group (0.19%/0.23% vs 0.085%/0.098%). These differences were significant (p

Accurate temperature forecasting is critical for various sectors, yet traditional methods struggle with complex atmospheric dynamics. Deep neural networks (DNNs), especially transformer-based DNNs, offer potential advantages, but face challenges with domain adaptation across different geographical regions. We evaluated the effectiveness of DNN-based domain adaptation for daily maximum temperature forecasting in experimental low-resource settings. We used an attention-based transformer deep learning architecture as the core forecasting framework and used kernel mean matching (KMM) for domain adaptation. Domain adaptation significantly improved forecasting accuracy in most experimental settings, thereby mitigating domain differences between source and target regions. Specifically, we observed that domain adaptation is more effective than exclusively training on a small amount of target-domain training data. This study reinforces the potential of using DNNs for temperature forecasting and underscores the benefits of domain adaptation using KMM. It also highlights the need for caution when using small amounts of target-domain data to avoid overfitting. Future research includes investigating strategies to minimize overfitting and to further probe the effect of various factors on model performance.

Abstract Late-onset noninfectious pulmonary complications (LONIPC) are a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). However, the clinical impact of lung function deterioration itself in long-term adult survivors of HSCT remains to be fully investigated. This retrospective, longitudinal study aimed to investigate pulmonary function following HSCT in terms of its change and the clinical significance of its decline. We examined 167 patients who survived for at least 2 years without relapse. The median follow-up period was 10.3 years. A linear mixed-effects model showed that the slope of pulmonary function tests values, including percent vital capacity (%VC), percent forced expiratory volume in one second (%FEV1), and FEV1/forced VC ratio (FEV1%), decreased over time. The cumulative incidence of newly obstructive and restrictive lung function impairment (LFI) at 10 years was 15.7% and 19.5%, respectively. Restrictive LFI was a significant, independent risk factor for overall survival (hazard ratio 7.11, P = 0.007) and non-relapse mortality (hazard ratio 12.19, P = 0.003). Our data demonstrated that lung function declined over time after HSCT and that the decline itself had a significant impact on survival regardless of LONIPC.

We devised a data-driven framework for uncovering hidden control strategies used by an evolutionary system described by an evolutionary probability distribution. This innovative framework enables deciphering of the concealed mechanisms that contribute to the progression or mitigation of such situations as the spread of COVID-19. Novel algorithms are used to estimate the optimal control in tandem with the parameters for evolution in general dynamical systems, thereby extending the concept of model predictive control. This marks a significant departure from conventional control methods, which require knowledge of the system to manipulate its evolution and of the controller’s strategy or parameters. We use a generalized additive model, supplemented by extensive statistical testing, to identify a set of predictor covariates closely linked to the control. Using real-world COVID-19 data, we delineate the descriptive behaviors of the COVID-19 epidemics in five prefectures in Japan and nine countries. We compare these nine countries and group them on the basis of shared profiles, providing valuable insights into their pandemic responses. Our findings underscore the potential of our framework as a powerful tool for understanding and managing complex evolutionary processes.

Abstract Objectives Weakening of lip‐closing strength (LCS) associated with an incompetent lip seal (ILS) may affect the oral balance between the lip and tongue pressures. The purpose of this study was to evaluate the effects of lip‐closing training in children with lower LCS and/or abnormal habits across different age groups and to compare its effects on increasing LCS in children with malocclusion and/or oral habits. Material and Methods Lip‐closing training was performed by 154 Japanese children aged 3–12 years using a specialized training device at home for 3 months. Children with oral habits and/or exhibiting less than standard LCS were included. LCS was measured using a digital strain force gauge at a dental clinic at the beginning (T0) and after each month (after 3 months: T3). Results Children had higher LCS responses after lip‐closing training. The first month of lip‐closing training was more effective than the subsequent months. With lip‐closing training, the LCS increased from an average of 6.2 N (T0) to 11.4 N (T3) in Group I, 7.9 N (T0) to 12.8 N (T3) in Group II, and 6.8 N to 11.4 N in Group III. Anterior cross bite, including reverse bite, open bite, and tongue thrusting, significantly reduced training effects. Conclusion Our findings showed that lower LCS in children with ILS resulted in greater responses to lip‐closing training in a short period, but oral dysfunction, such as abnormal habits, inhibited the positive effects of training. Our results suggest that less detrimental effects of malocclusion and abnormal oral habits lip‐closing training enhances LCS in younger children.

BackgroundA primary colorectal cancer (CRC) tumor can contain heterogeneous cancer cells. As clones of cells with different properties metastasize to lymph nodes (LNs), they could show different morphologies. Cancer histologies in LNs of CRC remains to be described.MethodsOur study enrolled 318 consecutive patients with CRC who underwent primary tumor resection with lymph node dissection between January 2011 and June 2016. 119 (37.4%) patients who had metastatic LNs (mLNs) were finally included in this study. Cancer histologies in LNs were classified and compared with pathologically diagnosed differentiation in the primary lesion. The association between histologies in lymph node metastasis (LNM) and prognosis in patients with CRC was investigated.ResultsThe histologies of the cancer cells in the mLNs were classified into four types: tubular, cribriform, poorly differentiated, and mucinous. Same degree of pathologically diagnosed differentiation in the primary tumor produced various histological types in LNM. In Kaplan-Meier analysis, prognosis was worse in CRC patients with moderately differentiated adenocarcinoma who had at least some mLN also showing cribriform carcinoma than for those whose mLNs all showed tubular carcinoma.ConclusionsHistology in LNM from CRC might indicate the heterogeneity and malignant phenotype of the disease.

Abstract Background Cytomegalovirus (CMV)-associated gastrointestinal diseases usually occur in immunocompromised patients; however, few cases has also been described in healthy hosts despite still unclear pathological mechanisms. CMV esophagitis causes various lesions, such as erythematous mucosa, erosions, and ulcers, although such inflammatory changes can appear in superficial esophageal cancers or in surrounding areas. CMV-associated esophagitis has been also reported in cancer patients, but typically in those with advanced and/or terminal stage cancers secondary to chemoradiotherapy-induced immunosuppression or the physiologic demands of the malignancy itself. To our best knowledge, we firstly report on an immunocompetent patient subject to endoscopic submucosal dissection (ESD) for early esophageal cancer complicated with CMV infection. Case presentation A 77-year-old man underwent esophagogastroduodenoscopy (EGD) at a local clinic. EGD revealed a lugol-unstained reddish lesion with whitish exudates in the middle-distal esophagus. Histological evaluation of lesion biopsy revealed atypical squamous epithelium with CMV-positive granulation tissue and aggregates of macrophages, prompting referral for further examination and treatment. Magnifying endoscopy with narrow-band imaging showed an erosive lesion with white moss in a well-demarcated brownish area with irregular mesh-like microvessels. ESD was performed for diagnosis and treatment. Histopathological examination of the resected specimen revealed superficial, moderately differentiated squamous cell carcinoma (SCC) with multiple lymphatic infiltration, and few CMV-positive cells were found in the erosive part of the SCC. Interestingly, he had no underlying conditions to predispose to CMV infection and no risk factors for esophageal cancer, other than gender and age. He received neither steroids for stricture prevention nor antiviral agents post-EGD and 4-month follow-up was negative for esophagitis. Conclusions This is the first report of a case of CMV esophagitis superimposed on early esophageal cancer in an immunocompetent host and might provide valuable information for possible adverse effects of steroid administration during ESD procedures, despite their common use for prevention of post-ESD stricture.

Abstract Background Systemic and local factors may lead to disruption of craniofacial growth and development, causing an imbalance between the orofacial skeleton, muscle and soft tissue, dental occlusion, and the dental arch during growth periods. We aimed to reveal whether the prevalence of incompetent lip seal (ILS) varies with age and region, as well as to clarify the factors related to an ILS, in a national, large-scale epidemiological study. Methods We surveyed 3399 children, from 3 to 12 years of age, visiting 66 pediatric dental clinics throughout Japan. For this survey, we employed a questionnaire consisting of 44 questions regarding daily health conditions and lifestyle habits. We evaluated the differences in ILS prevalence by age and region (using a Cochran-Armitage test for trend and a Kruskal-Wallis test), and the relationship between ILS and factors investigated in the questionnaire (using Spearman’s rank correlation coefficient). Results We observed that 30.7% of Japanese children exhibited an ILS and that the ILS rate increased with age (p

Abstract Preoperative ctDNA status in relation to recurrence in cases of CRC remains unclear. We examined preoperative ctDNA detection by targeting KRAS gene mutations as a predictive marker for recurrence after CRC surgery. We measured the preoperative KRAS mutated ctDNA status and analyzed the correlation with clinicopathologic features of 180 patients that underwent surgery for CRC. We studied the association between preoperative KRAS mutated ctDNA and postoperative recurrence in patients (n = 150) that underwent radical surgery. KRAS mutated ctDNA was detected in 59 patients (32.8%). Median mutant allele frequency of KRAS in ctDNA was 0.20%. KRAS status in ctDNA and lymph node metastasis and distant metastasis were not significantly different. Among patients that underwent radical resection, recurrence occurred in 21 (14.0%, median follow-up 24 months). In Kaplan–Meier analysis, preoperative detection of KRAS mutated ctDNA was associated with inferior recurrence-free interval (RFI) (p = 0.002) and recurrence-free survival (RFS) (p = 0.025). In a multivariate Cox proportional hazards model, preoperative detection of KRAS mutated ctDNA was an independent factor related to both RFI (HR = 3.08; p = 0.012) and RFS (HR = 2.18; p = 0.044). Preoperative measurement of KRAS mutated ctDNA could be useful to decide postoperative treatment.

Transportation networks have a hierarchical structure, and the spatial scale of their impact on urban growth differs depending on the hierarchy. However, in empirical analyses of the impacts that transportation has on land use and prices, such hierarchy is often examined using dummy variables, and the network dependence and heterogeneity of impacts are often ignored. Thus, this study develops a spatial regression method that considers not only spatial dependence, but also network dependence within a hierarchical transportation network. This method was developed by extending the random effects eigenvector spatial filtering approach. Subsequently, it was applied to a pre-existing analysis that focused on the impacts that high-speed rail (HSR) had on residential land prices in Japan over the last 30 years. The results of the analysis suggested that HSR lines had hierarchical effects on residential land prices. The results also provide interesting insight into the ongoing problem of Japanese urban hierarchy; that is, the excessive concentration of population and industry in the Tokyo metropolitan area.

Background/Aims: Endoscopic transpapillary gallbladder drainage (ETGBD) is useful for the treatment of acute cholecystitis; however, the technique is difficult to perform. When intraductal ultrasonography (IDUS) is combined with ETGBD, the orifice of the cystic duct in the common bile duct may be more easily detected in the cannulation procedure. The aim of this study was to evaluate the efficacy of ETGBD with IDUS compared with that of ETGBD alone. Methods: A total of 100 consecutive patients with acute cholecystitis requiring ETGBD were retrospectively recruited. The first 50 consecutive patients were treated using ETGBD without IDUS, and the next 50 patients were treated using ETGBD with IDUS. Through propensity score matching analysis, we compared the clinical outcomes between the groups. The primary outcome was the technical success rate. Results: The technical success rate of ETGBD with IDUS was significantly higher than that of ETGBD without IDUS (92.0% vs. 76.0%, p=0.044). There was no significant difference in procedure length between the two groups (74.0 min vs. 66.7 min, p=0.310). The complication rate of ETGBD with IDUS was significantly higher than that of ETGBD without IDUS (6.0% vs. 0%, p

In the era of open data, Poisson and other count regression models are increasingly important. Still, conventional Poisson regression has remaining issues in terms of identifiability and computational efficiency. Especially, due to an identification problem, Poisson regression can be unstable for small samples with many zeros. Provided this, we develop a closed-form inference for an over-dispersed Poisson regression including Poisson additive mixed models. The approach is derived via mode-based log-Gaussian approximation. The resulting method is fast, practical, and free from the identification problem. Monte Carlo experiments demonstrate that the estimation error of the proposed method is a considerably smaller estimation error than the closed-form alternatives and as small as the usual Poisson regressions. For counts with many zeros, our approximation has better estimation accuracy than conventional Poisson regression. We obtained similar results in the case of Poisson additive mixed modeling considering spatial or group effects. The developed method was applied for analyzing COVID-19 data in Japan. This result suggests that influences of pedestrian density, age, and other factors on the number of cases change over periods.

IntroductionThe interaction of CD155 with its ligand, the T cell immunoreceptor with Ig and ITIM domains (TIGIT), is being studied owing to its potential to act as a target in the treatment of various solid tumors. However, the relationship between CD155 and TIGIT in colorectal cancer (CRC) prognosis is not known. We hypothesized that the TIGIT-CD155 pathway suppresses the attack of T cells on tumors, thereby affecting CRC prognosis.MethodsWe examined the expression of CD155 and TIGIT using immunohistochemical staining in 100 consecutive patients with CRC who underwent complete resection of ≤Stage III tumors at Wakayama Medical University Hospital between January and December 2013. We assessed the correlation between CD155 and TIGIT expressions and prognosis as well as the clinicopathological background of CD155 and TIGIT.ResultsPatients with high CD155 and TIGIT expressions showed worse prognosis than those with other levels of expression (p = 0.026). In multivariate analysis that also included the existing prognostic markers, high CD155 and TIGIT expressions were identified as independent poor prognostic factors.ConclusionsThe interaction between CD155 and TIGIT possibly plays an important role in the immunological mechanism of CRC. Therefore, it may be possible to effectively predict the postoperative prognosis of CRC by evaluating the combined expression of CD155 and TIGIT. The study findings suggest that CD155 and TIGIT can predict clinical outcomes, thereby contributing to the personalized care of CRC.

Historical and future spatially explicit population and gross domestic product (GDP) data are essential for the analysis of future climate risks. Unlike population projections that are generally available, GDP projections—particularly for scenarios compatible with shared socioeconomic pathways (SSPs)—are limited. Our objective is to perform a high-resolution and long-term GDP estimation under SSPs utilizing a wide variety of geographic auxiliary information. We estimated the GDP in a 1/12-degree grid scale. The estimation is done through downscaling of historical GDP data for 1850–2010 and SSP future scenario data for 2010–2100. In the downscaling, we first modeled the spatial and economic interactions among cities and projected different future urban growth patterns according to the SSPs. Subsequently, the projected patterns and other auxiliary geographic data were used to estimate the gridded GDP distributions. Finally, the GDP projections were visualized via three-dimensional mapping to enhance the clarity for multiple stakeholders. Our results suggest that the spatial pattern of urban and peri-urban GDP depends considerably on the SSPs; the GDP of the existing major cities grew rapidly under SSP1, moderately grew under SSP 2 and SSP4, slowly grew under SSP3, and dispersed growth under SSP5.

Abstract Background Alpha-fetoprotein (AFP) is produced by some tumors, such as hepatocellular carcinoma and yolk sac tumors, leading to an increase in serum AFP level. However, AFP in colorectal cancer is extremely rare. Treatment for AFP-producing cancer is often performed according to conventional methods, but oncological outcomes of both surgery and chemotherapy are poor. We report a case of a patient with AFP-producing rectal cancer which successfully responded to preoperative chemoradiotherapy. Case presentation Rectal tumor was diagnosed in a 68-year-old man referred to our hospital. Colonoscopy showed a type 2 tumor in the lower rectum, and biopsy revealed an adenocarcinoma with enteroblastic differentiation. Serum tumor marker levels were 8.8 ng/ml in carcinoembryonic antigen (CEA) and 28.3 ng/ml in AFP. Clinical diagnosis was stage IIIB (T3N1M0), and preoperative chemoradiotherapy was performed to prevent local recurrence. Effective tumor reduction was observed, and serum tumor marker levels decreased to normal range. Low anterior resection with temporary diverting ileostomy was performed, and histology revealed residual adenocarcinoma. Pathological diagnosis was stage I (T2N0M0). The tumor was found to be an AFP-producing adenocarcinoma on further immunohistopathological examination. The postoperative course was uneventful, and the patient received adjuvant chemotherapy for 3 months. Conclusions The outcomes of preoperative chemoradiotherapy against AFP-producing rectal cancer are reported here for the first time. Based on our experience with this patient, it appears preoperative chemoradiotherapy for patients with AFP-producing advanced rectal cancer is feasible.

Abstract Background Cap polyposis is a rare gastrointestinal disease with endoscopically and pathologically distinctive features. Its exact etiology has not been fully elucidated. In a few cases, there was recurrence after inadequate treatment. Efficacy of Helicobacter pylori eradication therapy, however, has been shown in some published research. Case presentation A 70-year-old female patient developed intermittent mucous diarrhea with loss of body weight and visited a physician. Total colonoscopy showed multiple sessile polyps which were partially coadunated from the rectum to the sigmoid colon. Histopathological finding was tubular adenoma with mild atypia. The patient stayed for observation. Worsening symptoms following protein-losing enteropathy demanded surgical treatment because malignancy could not be ruled out. Laparoscopic resection was performed, and the surgical specimens revealed that the polypoid lesion mainly consisted of mild adenomatous glands which were covered with purulent granulation tissues. We made final diagnosis of cap polyposis and saw rapid improvement of her symptoms. Long-term observation is required after surgery. Conclusions We reported a case of successful laparoscopic resection of cap polyposis with protein-losing enteropathy (170 words).

Abstract Although appendiceal bleeding is rare, physicians should keep this finding in mind as a possible cause of bleeding from the right colon because the colonoscopic diagnosis may be essential in determining the need for surgical intervention.

The recent emergence of antibiotic-resistant bacteria requires the development of new antibiotics or new agents capable of enhancing antibiotic activity. This study evaluated the antibacterial activity of lysozyme-chitosan oligosaccharide conjugates (LYZOX) against Pseudomonas aeruginosa, Acinetobacter baumannii and methicillin-resistant Staphylococcus aureus (MRSA), which should resolve the problem of antibiotic-resistant bacteria. Bactericidal tests showed that LYZOX killed 50% more P. aeruginosa (NBRC 13275), A. baumannii and MRSA than the control treatment after 60 min. In addition, LYZOX was shown to inhibit the growth of P. aeruginosa (NBRC 13275 and PAO1), A. baumannii and MRSA better than its components. To elucidate the antibacterial mechanism of LYZOX, we performed cell membrane integrity assays, N-phenyl-1-naphthylamine assays, 2-nitrophenyl β-D-galactopyranoside assays and confocal laser scanning microscopy. These results showed that LYZOX affected bacterial cell walls and increased the permeability of the outer membrane and the plasma membrane. Furthermore, each type of bacteria treated with LYZOX was observed by electron microscopy. Electron micrographs revealed that these bacteria had the morphological features of both lysozyme-treated and chitosan oligosaccharide-treated bacteria and that LYZOX destroyed bacterial cell walls, which caused the release of intracellular contents from cells. An acquired drug resistance test revealed that these bacteria were not able to acquire resistance to LYZOX. The hemolytic toxicity test demonstrated the low hemolytic activity of LYZOX. In conclusion, LYZOX exhibited antibacterial activity and low drug resistance in the presence of P. aeruginosa, A. baumannii and MRSA and showed low hemolytic toxicity. LYZOX affected bacterial membranes, leading to membrane disruption and the release of intracellular contents and consequent bacterial cell death. LYZOX may serve as a novel candidate drug that could be used for the control of refractory infections.

Objective. The number of patients with type 2 diabetes has increased in Japan, and type 2 diabetes has attracted attention as a risk factor for asthma. However, the risk factors for the development of asthma in patients with type 2 diabetes have not been determined. This study was performed to clarify whether visceral fat accumulation (VFA) and insulin resistance are risk factors for the development of asthma in patients with type 2 diabetes. Materials and Methods. A cross-sectional study was conducted. The study group comprised 15 patients with type 2 diabetes with asthma, and the control group comprised 145 patients with type 2 diabetes without asthma. Their fat distribution was evaluated by measuring the VFA by abdominal computed tomography at the umbilical level. Their glucose status was assessed by measuring the fasting plasma glucose (FPG) concentration, fasting immunoreactive insulin concentration, homeostasis model assessment (HOMA) index, and hemoglobin A1c concentration. Results. Among patients with type 2 diabetes, VFA was significantly greater in patients with asthma than those without asthma (P