Search

Purpose: Endometrial cancer (EC) is one of the most common types of cancer affecting women. While the hematoxylin-and-eosin (H&E) staining remains the standard for histological analysis, the immunohistochemistry (IHC) method provides molecular-level visualizations. Our study proposes a digital staining method to generate the hematoxylin-3,3'-diaminobenzidine (H-DAB) IHC stain of Ki-67 for the whole slide image of the EC tumor from its H&E stain counterpart., Approach: We employed a color unmixing technique to yield stain density maps from the optical density (OD) of the stains and utilized the U-Net for end-to-end inference. The effectiveness of the proposed method was evaluated using the Pearson correlation between the digital and physical stain's labeling index (LI), a key metric indicating tumor proliferation. Two different cross-validation schemes were designed in our study: intraslide validation and cross-case validation (CCV). In the widely used intraslide scheme, the training and validation sets might include different regions from the same slide. The rigorous CCV validation scheme strictly prohibited any validation slide from contributing to training., Results: The proposed method yielded a high-resolution digital stain with preserved histological features, indicating a reliable correlation with the physical stain in terms of the Ki-67 LI. In the intraslide scheme, using intraslide patches resulted in a biased accuracy (e.g., R = 0.98 ) significantly higher than that of CCV. The CCV scheme retained a fair correlation (e.g., R = 0.66 ) between the LIs calculated from the digital stain and its physical IHC counterpart. Inferring the OD of the IHC stain from that of the H&E stain enhanced the correlation metric, outperforming that of the baseline model using the RGB space., Conclusions: Our study revealed that molecule-level insights could be obtained from H&E images using deep learning. Furthermore, the improvement brought via OD inference indicated a possible method for creating more generalizable models for digital staining via per-stain analysis., (© 2024 The Authors.)

Objective: We aimed to investigate the impact of preceding seasonal influenza on the clinical characteristics of adult patients with invasive pneumococcal disease (IPD) in Japan., Methods: Data for 1722 adult patients with IPD were analyzed before (2017-2019) and during the COVID-19 pandemic (2020-2022)., Results: The seasonal influenza epidemic disappeared soon after the emergence of the pandemic. Compared with that before the pandemic (66.7%), we observed a lower bacteremic pneumonia proportion in patients with IPD during the pandemic (55.6%). The clinical presentations of IPD cases significantly differed between those with and without preceding influenza. The proportion of bacteremic pneumonia was higher in IPD patients with preceding influenza than in those without in both younger (44.9% vs 84.2%) and older adults (65.5% vs 87.0%) before the pandemic. The case fatality rate was significantly higher in IPD patients with preceding influenza (28.3%) than in those without (15.3%) in older adults before the pandemic (P = 0.020). Male and aging are high risk factors for death in older patients with IPD who had preceding influenza., Conclusion: Our study reveals that preceding seasonal influenza plays a role in the development of bacteremic pneumococcal pneumonia, increasing the risk of death in older adults., Competing Interests: Declaration of competing interest The authors have no competing interests relevant to this article to disclose., (Copyright © 2024. Published by Elsevier Ltd.)

Human pulmonary dirofilariasis (HPD) is a zoonotic disease caused by Dirofilaria immitis. Most HPD cases are asymptomatic and are either detected during annual health checkups or incidentally identified during the investigation of other diseases, particularly primary or metastatic pulmonary lung cancers. However, the frequency and clinical features of Japanese patients with HPD remain unclear. We analyzed data from the Japanese Medical Abstract Society database and identified 69 cases between 1978 and 2022. The incidence of HPD increased until the 2000s but declined markedly in the 2010s. The incidence is higher in the southwestern region and lower in the northeastern region of Japan. Health checkups are the primary diagnostic opportunities. The Chugoku and Shikoku regions have had high incidence rates per population. The diagnosis of HPD using a noninvasive procedure is typically difficult because of the absence of specific clinical symptoms, and approximately 70% of the cases are detected using video-assisted thoracoscopic surgery. Climate change may increase the incidence of HPD in the northeastern region of Japan, and travel to countries with poor vector control may be a risk factor for HPD transmission. Physicians should consider this parasitic infectious disease when examining patients presenting with solitary lung nodules.

Metallo-beta-lactamases (MBLs) are enzymes that break down carbapenem antibiotics, leading to carbapenem-resistant organisms. Carbapenemase-resistant Enterobacterales (CRE) is one of them. Outbreaks of CRE infection can occur in healthcare facilities and lead to increased deaths, illness, and medical costs. This study was conducted to detect MBLs using non-carbapenem agents and exclude MBLs among CRE isolates. A total of 3776 non-duplicate sequential Enterobacterales isolates from a single facility were screened between January 2019 and December 2022 using non-carbapenem agents, ceftazidime and cefoperazone/sulbactam. Positive 153 isolates (4.0%) were further tested using carbapenemase-confirmation tests and verified through polymerase chain reaction (PCR) testing. Fifteen imipenemase (IMP)-type MBL-producing Enterobacterales (0.4%) including one susceptible to carbapenems were identified. Moreover, 160 isolates (4.2%) meeting the criteria for CRE were directly subjected to PCR testing. All fourteen CRE isolates with MBLs identified through PCR testing were found to be the same strains screened using ceftazidime and cefoperazone/sulbactam. Screening using ceftazidime and cefoperazone/sulbactam can effectively detect MBL-producing Enterobacterales strains. This screening method showed comparable results to screening with meropenem, potentially serving as a supplementary approach and contributing to differentiating between MBL- and non-MBL-producing CRE strains. Our findings support these screening methods, particularly in regions where IMP-type MBLs are prevalent.

Coronavirus disease 2019 (COVID-19) is associated with coagulopathy. However, the underlying mechanisms are not completely understood. We evaluated the association between COVID-19 coagulopathy and extracellular vesicle (EV) levels. We hypothesized that several EV levels would be higher in COVID-19 coagulopathy patients than in non-coagulopathy patients. This prospective observational study was conducted in four tertiary care faculties in Japan. We enrolled 99 COVID-19 patients (48 with coagulopathy and 51 without coagulopathy) aged ≥20 years who required hospitalization, and 10 healthy volunteers; we divided the patients into coagulopathy and non-coagulopathy groups according to the D-dimer levels (≥1 μg/mL and <1 μg/mL, respectively). We used flow cytometry to measure the tissue-factor-bearing, endothelium-derived, platelet-derived, monocyte-derived, and neutrophil-derived EV levels in platelet-free plasma. The EV levels were compared between the two COVID-19 groups as well as among the coagulopathy patients, non-coagulopathy patients, and healthy volunteers. No significant difference was found in EV levels between the two groups. Meanwhile, the cluster of differentiation (CD) 41 + EV levels were significantly higher in COVID-19 coagulopathy patients than in healthy volunteers (549.90 [255.05-984.65] vs. 184.3 [150.1-254.1] counts/µL, p = 0.011). Therefore, CD41+ EVs might play an essential role in COVID-19 coagulopathy development.

Purpose: We describe the epidemiology of invasive Haemophilus influenzae disease (IHD) among adults in Japan., Methods: Data for 200 adult IHD patients in 2014-2018 were analyzed. The capsular type of H. influenzae was determined by bacterial agglutination and polymerase chain reaction (PCR), and non-typeable Haemophilus influenzae (NTHi) was identified by PCR., Results: The annual incidence of IHD (cases per 100,000 population) was 0.12 for age 15-64 years and 0.88 for age ≥ 65 years in 2018. The median age was 77 years, and 73.5% were aged ≥ 65 years. About one-fourth of patients were associated with immunocompromising condition. The major presentations were pneumonia, followed by bacteremia, meningitis and other than pneumonia or meningitis (other diseases). The case fatality rate (CFR) was 21.2% for all cases, and was significantly higher in the ≥ 65-year group (26.1%) than in the 15-64-year group (7.5%) (p = 0.013). The percentage of cases with pneumonia was significantly higher in the ≥ 65-year group than in the 15-64-year group (p < 0.001). The percentage of cases with bacteremia was significantly higher in the 15-64-year group than in the ≥ 65-year group (p = 0.027). Of 200 isolates, 190 (95.0%) were NTHi strains, and the other strains were encapsulated strains. 71 (35.5%) were resistant to ampicillin, but all were susceptible to ceftriaxone., Conclusion: The clinical presentations of adult IHD patients varied widely; about three-fourths of patients were age ≥ 65 years and their CFR was high. Our findings support preventing strategies for IHD among older adults, including the development of NTHi vaccine., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Background : Bloodstream infections (BSIs), including persistent bacteremia (PB), are a leading source of morbidity and mortality globally. PB has a higher mortality rate than non- PB, but the clinical aspects of PB in terms of the causative pathogens and the presence of clearance of PB are not well elucidated. Therefore, this study aimed to describe the clinical and epidemiological characteristics of PB in a real-world clinical setting. Methods : We performed a retrospective observational survey of patients who underwent blood culture between January 2012 and December 2021 at Tohoku University Hospital. Cases of PB were divided into three groups depending on the causative pathogen: gram-positive cocci (GPC), gram-negative rods (GNRs), and Candida spp. For each group, we examined the clinical and epidemiological characteristics of PB, including differences in clinical features depending on the clearance of PB. The main outcome variable was mortality, assessed as early (30-day), late (30-90 day), and 90-day mortality. Results : Overall, we identified 31,591 cases of single bacteremia; in 6709 (21.2%) cases, the first blood culture was positive, and in 3124 (46.6%) cases, a follow-up blood culture (FUBC) was performed. Of the cases with FUBCs, 414 (13.2%) were confirmed to be PB. The proportion of PB cases caused by Candida spp. was significantly higher (29.6%, 67/226 episodes) than that for GPC (11.1%, 220/1974 episodes, p < 0.001) and GNRs (12.1%, 100/824 episodes, p < 0.001). The Candida spp. group also had the highest late (30-90 day) and 90-day mortality rates. In all three pathogen groups, the subgroup without the clearance of PB tended to have a higher mortality rate than the subgroup with clearance. Conclusions : Patients with PB due to Candida spp. have a higher late (30-90 day) and 90-day mortality rate than patients with PB due to GPC or GNRs. In patients with PB, FUBCs and confirming the clearance of PB are useful to improve the survival rate.

Competing Interests: Declaration of interests We declare no competing interests.

Tuberculosis remains a major public health concern. Millions of tuberculosis cases and associated deaths have been reported worldwide. The Indo-Oceanic lineage Mycobacterium tuberculosis is common in Southeast Asia and causes extrapulmonary lesions. Only a few case studies on this lineage with genetic analysis using whole-genome sequencing have been reported in the literature. We present a case of disseminated tuberculosis, characterized by a variety of extrapulmonary lesions and paradoxical reactions, caused by the Indo-Oceanic lineage M. tuberculosis in a woman in Myanmar. A 22-year-old Burmese woman had arthritis in the right knee, with unknown aetiology, and was referred to our hospital. Computed tomography of the trunk revealed multiple nodular shadows in both lungs; swollen mediastinal lymph nodes; and small, low-density areas in the spleen. M. tuberculosis was detected in the sputum sample, joint aspirate, subcutaneous tumor, and exudate. She experienced a variety of paradoxical reactions together with aggressive tuberculosis dissemination in all areas of the body. Whole-genome sequencing of the DNA of MTB obtained from sputum and the right cervical subcutaneous abscess confirmed the Indo-Oceanic lineage of M. tuberculosis, the predominant strain in Myanmar. The Indo-Oceanic lineage M. tuberculosis causes disseminated tuberculosis all over the body including the periungual region. When patients show unusual symptoms, physicians should consider the introduction of new strains from foreign countries. Genetic analyses of the strains are recommended to define and confirm the lineages., (Copyright © 2022 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Nationwide population-based surveillance for invasive pneumococcal disease (IPD) is being conducted in few Asian countries. We aimed to evaluate the clinical characteristics and serotype distribution among Japanese adult patients with IPD after introduction of the pediatric 13-valent pneumococcal conjugate vaccine (PCV13) in 2013. IPD surveillance was conducted among adults between 2013 and 2019, and 1,995 patients were analyzed by time period (early, 2013-2015; middle, 2016-2017; late, 2018-2019). We found that the period of 2018-2019 was independently associated with a lower risk of fatal outcome, compared with the period of 2013-2015. The proportion of those with serotype PCV13-nonPCV7 decreased significantly in patients aged 15-64 years and in those aged ≥ 65 years within 3 years after the introduction of pediatric PCV13. By contrast, the proportion of those with nonvaccine serotype increased significantly in those aged ≥ 65 years, but not in those aged 15-64 years. No significant change was found in the proportion of 23-valent polysaccharide pneumococcal vaccine (PPSV23)-nonPCV13 in both of adults aged 15-64 years and ≥ 65 years. The proportions of PCV15-, PCV20- and PCV24-covered serotypes were 38%, 56% and 58% in adult patients with IPD aged ≥ 65 years during the late period. Our data on the serotype distribution support an indirect effect from pediatric PCV13 use among adults, and afford a basis for estimates of protection against IPD by vaccination with newly developed PCVs in older adults in Japan., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Here, we report a 60-year-old chronically bedridden man with cerebral palsy who had septic shock following a history of urinary tract infection with extended spectrum β-lactamase-producing and auxotrophic Proteus mirabilis detected on blood and urine cultures. This auxotroph formed small colonies only on the blood agar at 24 h in 5% CO 2 , but not in the conditions without CO 2 , and lacked motility and some biochemical activities. The five-year history of stones in the right renal pelvis suggests chronic urinary tract infection with P. mirabilis requiring a 28-day antibiotic treatment. This paper highlights that the CO 2 -dependent P. mirabilis small colony variant may cause sepsis, probably due to chronic infection in uroliths, which should warrant immediate identification., (Copyright © 2021 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

We assessed the impact of the pediatric 13-valent pneumococcal conjugate vaccine (PCV13) on pneumococcal meningitis in adults in Japan in 2014-2018 by comparing epidemiological characteristics of adults with invasive pneumococcal disease with (n = 222) and without (n = 1258) meningitis. The annual incidence of pneumococcal meningitis in 2016-2018 was 0.20-0.26 cases/100,000 population. Age (p < 0.001) and case fatality rate (p = 0.003) were significantly lower in patients with meningitis than in those without meningitis. The odds of developing meningitis were higher in asplenic/hyposplenic or splenectomized patients (adjusted odds ratio [aOR] 2.29, 95% CI 1.27-4.14), for serotypes 10A (aOR 3.26, 95% CI 2.10-5.06) or 23A (aOR 3.91, 95% CI 2.47-6.19), but lower for those aged ≥ 65 years (aOR 0.59, 95% CI 0.44-0.81). PCV13 had an indirect effect on nonmeningitis, but its impact on meningitis was limited because of an increase in non-PCV13 serotypes. Of meningitis isolates, 78 (35.1%) and 3 (1.4%) were penicillin G- or ceftriaxone-resistant, respectively. We also confirmed an association of the pbp1bA641C mutation with meningitis (aOR 2.92, 95% CI 1.51-5.65)., (© 2022. The Author(s).)

Pneumococcal surface protein A (PspA) is a surface protein of Streptococcus pneumoniae that may be a candidate antigen for new pneumococcal vaccines. This study investigates the distribution of PspA clades of the causative strains of adult invasive pneumococcal disease (IPD) in Japan. Of the 1,939 strains isolated from cases of adult IPD during 2014-2019, the PspA clades of 1,932 (99.6%) strains were determined, and no pspA was detected in the remaining 7 strains (0.4%). PspA clades 1-6 were detected in 786 (40.5%), 291 (15.0%), 443 (22.8%), 369 (19.0%), 33 (1.7%), and 6 (0.3%) strains, respectively. New PspA clades (0.2%) were identified in two non-typeable and two serotype 35B pneumococci. The proportions of clade 1 and clade 2 showed significantly decreased and increased trends, respectively. Furthermore, the PspA clade of pneumococcal strains was partially serotype- and sequence type-dependent. The majority of strains belonging to serotypes contained in both the 13-valent pneumococcal conjugate vaccine (PCV13) and the 23-valent pneumococcal polysaccharide vaccine (PPSV23) belonged to PspA clades 1 or 3. In contrast, the distribution of clades in non-vaccine serotypes was wider than that of vaccine serotype pneumococci. Our findings demonstrate that almost all pneumococcal strains from adult IPD express PspA clades 1-4, especially for non-vaccine serotypes. These results may be useful for the development of a new pneumococcal vaccine with PspA., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Chang, Kinjo, Morita, Tamura, Watanabe, Tanabe, Kuronuma, Fujita, Oshima, Maruyama, Abe, Kasahara, Nishi, Kubota, Ohnishi, Suga and Oishi.)

Mycobacterium marinum can cause pulmonary infection and can grow at ≤32°C. Physicians should consider M. marinum when examining patients with pulmonary infection and low body temperature or anorexia nervosa, and grow the specimen at ≤32°C. https://bit.ly/3jkzBeq., Competing Interests: Conflicts of interest: K. Oshima has nothing to disclose. Conflicts of interest: Y. Niinuma has nothing to disclose. Conflicts of interest: H. Saito has nothing to disclose. Conflicts of interest: H. Baba has nothing to disclose. Conflicts of interest: H. Kanamori has nothing to disclose. Conflicts of interest: T. Aoyagi has nothing to disclose. Conflicts of interest: K. Tokuda has nothing to disclose. Conflicts of interest: M. Kaku has nothing to disclose., (Copyright ©The authors 2021.)

We reviewed 18 listeriosis cases in Japan and performed molecular analysis of causative Listeria monocytogenes (LM) isolates. Strains genetically related to those from other countries caused various types of listeriosis, including vascular listeriosis in immunocompetent elderly people. Our results highlight the importance of integrated clinical and genomic analysis of LM., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The decline in the proportion of pneumococcal conjugate vaccine (PCV)-covered serotypes among adult invasive pneumococcal disease (IPD) patients might change the overall effectiveness of the 23-valent pneumococcal polysaccharide vaccine (PPSV23) because its effectiveness differs according to serotype. Using the indirect cohort method, we calculated the effectiveness of PPSV23 against IPD among adults in Japan to assess the impact of the national pediatric PCV program. Clinical and epidemiologic information and pneumococcal isolates were collected from IPD patients >20 years of age through enhanced IPD surveillance during April 2013-December 2017. Adjusted effectiveness against PPSV23-serotype IPD was 42.2%. Despite a substantial decline in the proportion of 13-valent PCV serotypes during the study period (45% to 31%), the change in effectiveness for PPSV23-serotype IPD was limited (47.1% to 39.3%) and only marginal in the elderly population (39.9% to 39.4%). The pediatric PCV program had limited impact on PPSV23 effectiveness against IPD in adults.

We report a severe case of Chromobacterium haemolyticum pneumonia associated with near-drowning and detail the investigation of the pathogen and river water. Our genomic and environmental investigation demonstrated that river water in a temperate region can be a source of C. haemolyticum causing human infections.

Bacillus cereus commonly causes catheter-related bloodstream infections (BSIs) in hospital settings, and occasionally occurs fatal central nervous system (CNS) complications. B. cereus harboring Ba813, a specific chromosomal marker of Bacillus anthracis, has been found in patients with severe infection and nosocomial BSI. However, the bacteriological profile and clinical feature of Ba813 (+) B. cereus are unclear. Fifty-three patients with B. cereus BSI were examined. Isolates were evaluated for Ba813, B. anthracis-related and food poisoning-related virulence, multilocus sequencing typing, and biofilm formation. Patients' clinical records were reviewed retrospectively. The 53 isolates were comprised of 29 different sequence types in two distinct clades. Seventeen of the 53 (32%) B. cereus isolates including five sequence types possessed Ba813 and were classified into Clade-1/Cereus-III lineage which is most closely related to Anthracis lineage. No B. cereus possessed B. anthracis-related virulence genes. Ba813 (+) strains showed a lower prevalence of enterotoxin genes than Clade-2 strains (n = 4), but no difference from Clade-1. Ba813 (+) strains showed significantly lower biofilm formation than Clade-1/non-Cereus-III (n = 22) and Clade-2 strains, respectively. Compared to Clade-1/non-Cereus-III and Clade-2 B. cereus, Ba813 (+) strains were isolated more frequently from elderly patients, patients with indwelling central venous catheter rather than peripheral venous catheter, and patients who remained in the hospital for longer before BSI onset. No significant differences in disease severity or mortality were observed. Though two of the ten Ba813 (-) strains in Clade-1/Cereus III were isolated from the patients with CNS complication, no significant difference was observed in the bacterial profile and clinical characteristics among Clade-1/Cereus III strains. In conclusion, our report suggested that Ba813-harboring B. cereus strains, genetically closely related to B. anthracis, were abundant among B. cereus strains in the hospital setting, and might cause catheter-related nosocomial BSI. However, it did not affect the clinical outcomes., Competing Interests: The authors have declared that no competing interests exist.

Shiga toxin-producing Escherichia coli (STEC) can cause severe gastrointestinal disease and colonization among food handlers. In Japan, STEC infection is a notifiable disease, and food handlers are required to undergo routine stool examination for STEC. However, the molecular epidemiology of STEC is not entirely known. We investigated the genomic characteristics of STEC from patients and asymptomatic food handlers in Miyagi Prefecture, Japan. Whole-genome sequencing (WGS) was performed on 65 STEC isolates obtained from 38 patients and 27 food handlers by public health surveillance in Miyagi Prefecture between April 2016 and March 2017. Isolates of O157:H7 ST11 and O26:H11 ST21 were predominant (n = 19, 29%, respectively). Non-O157 isolates accounted for 69% (n = 45) of all isolates. Among 48 isolates with serotypes found in the patients (serotype O157:H7 and 5 non-O157 serotypes, O26:H11, O103:H2, O103:H8, O121:H19 and O145:H28), adhesion genes eae, tir, and espB, and type III secretion system genes espA, espJ, nleA, nleB, and nleC were detected in 41 to 47 isolates (85-98%), whereas isolates with other serotypes found only in food handlers were negative for all of these genes. Non-O157 isolates were especially prevalent among patients younger than 5 years old. Shiga-toxin gene stx1a, adhesion gene efa1, secretion system genes espF and cif, and fimbrial gene lpfA were significantly more frequent among non-O157 isolates from patients than among O157 isolates from patients. The most prevalent resistance genes among our STEC isolates were aminoglycoside resistance genes, followed by sulfamethoxazole/trimethoprim resistance genes. WGS revealed that 20 isolates were divided into 9 indistinguishable core genomes (<5 SNPs), demonstrating clonal expansion of these STEC strains in our region, including an O26:H11 strain with stx1a+stx2a. Non-O157 STEC with multiple virulence genes were prevalent among both patients and food handlers in our region of Japan, highlighting the importance of monitoring the genomic characteristics of STEC., Competing Interests: The authors have declared that no competing interests exist. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Excessive inflammation reactions with a cytokine storm in the lungs have historically been thought as the primary cause of fatal acute respiratory distress syndrome (ARDS). However, interruption of inflammatory cytokine activation failed to attenuate ARDS, suggesting that other therapies are required to treat this illness and improve survival. Etoposide (ET), a cytotoxic agent, and prednisolone (PSL), a corticosteroid with strong anti-inflammatory activity, have been used to treat other disease involving similar cytokine-activated macrophages and hemophagocytic activity. However, they have not been previously tested as ARDS therapeutics alone or in combination. In the present study, we used a fatal ARDS mouse model induced via administration of α-galactosylceramide and lipopolysaccharide, which resulted in the development of severe lung injury with hypercytokinemia and hemophagocytosis, all of which were observed in ARDS patients infected with highly pathogenic respiratory viruses. The ET and PSL combination therapy, but not ET or PSL alone, reduced the recruitment and activation of inflammatory cells including macrophages, natural killer T cells, and neutrophils, and significantly improved the survival rate in this model. Furthermore, whereas ET alone improved lung edema, it did not increase the survival rate, indicating the necessity of PSL in the treatment of ARDS. Surprisingly, combination therapy did not reduce the production of cytokines and chemokines in the lungs, demonstrating that inflammatory cells, rather than hypercytokinemia, are the direct target of these compounds and primary cause of ARDS-related death. Thus, combination therapy with ET and PSL that targets inflammatory cells has the potential to attenuate fatal ARDS.

Enhanced surveillance of invasive pneumococcal disease (IPD) in adults was conducted during April 2013-March 2018 in 10 of 47 prefectures in Japan, and a total of 1277 IPD patients were enrolled. An emergence of IPD caused by serotype 12F was identified during May 2015-March 2018 through this surveillance. 12F isolates were composed of four related sequence types. In total, 120 patients with 12F IPD were reported during this period. To characterize the clinical features of 12F IPD, the disease characteristics of these patients were compared with those of 1157 patients with non-12F IPD. Compared with the non-12F IPD patients, a significantly lower proportion of 12F IPD patients was aged 65 years or older (55% vs. 70%), vaccinated with 23-valent pneumococcal polysaccharide (4% vs. 14%), had comorbid illness (65% vs. 77%), or were immunocompromised (19% vs. 30%; all P < 0.05). No significant difference in the proportion of case fatalities was found between the two groups. The proportions of those aged 65 years or older (53% vs. 69%) and with bacteremic pneumonia (35% vs. 69%) were significantly lower in 17 patients who died from 12F IPD than in 205 patients who died from non-12F IPD (all P < 0.05). Differences in clinical features were similarly found between 12F IPD patients and patients in low- or intermediate-level invasive potential serogroups. Our data demonstrated that serotype 12F was associated with IPD in younger adults and a lower proportion of comorbid illness, including immunocompromised conditions, in adult IPD, suggesting the high invasive potential of the serotype 12F. In addition, patients who died from 12F IPD were younger and had proportionately more bacteremia without focus. These findings may provide new insight into the pathogenesis of IPD in adults caused by 12F serotype with a high invasive potential., Competing Interests: The authors have declared that no competing interests exist.

Background: In Japan, the clinical characteristics and recent serotype distribution among adult patients of invasive pneumococcal disease (IPD) have not been fully investigated since the introduction of the pneumococcal conjugate vaccine (PCV) in children. From November 2010, PCV7 was encouraged by an official program, funded by government, subsequently included in the routine schedule in April 2013, and replaced with a PCV13 in November 2013., Methods: Between April 2013 and March 2015, patients with IPD older than 15 years were evaluated based on the enhanced national surveillance in ten prefectures of Japan. The serotype distribution of the isolates was analyzed in these patients., Results: The analysis included 291 patients: 107 patients (37%) were female and the median age was 70 years. Of 281 patients with available data, 202 (72%) had underlying diseases, including 107 patients (38%) with immunocompromised status. The case fatality proportion for all case was 20%. In subgroup analysis, the case fatality proportion (29%) in immunocompromised patients was much higher than that (0-16%) in each age group of nonimmunocompromised patients (15-39 years, 40-64 years, and ≥ 65 years). While the proportion of bacteremia without any focus (27%) was higher than that (8-10%) in nonimmunocompromised patients, the proportions of vaccine types (PCV13, 32%; PPSV23, 51%) of the causative isolates were lower than those in each age group of nonimmunocompromised patients. Among 291 isolates, the most frequent serotypes were 3 (17%), 19A (13%), and 22F (10%). Twelve percent of the isolates were PCV7 serotypes, 46% were PCV13 serotypes, and 66% were PPSV23 serotypes., Conclusions: The majority of adult patients of IPD had underlying diseases, including immunocompromised conditions. A low proportion (12%) of PCV7-type IPD was observed in this population where PCV7 for children had been included in the routine immunization schedule.

Molecular characterization of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) is generally conducted referred to staphylococcal cassette chromosome mec (SCCmec) type IV or V. CA-MRSA is now a cause of concern since such strains have been isolated not only from individuals in a community but also from patients in healthcare settings. The aim of this study was to analyze microbiological and molecular epidemiological features of CA-MRSA strains at a Japanese tertiary care hospital using PCR based-open reading frame typing (POT). This technique allows for molecular classification into CA-MRSA (POT-CA) and hospital-associated (HA-) MRSA (POT-HA) with clonal discrimination. Clinical MRSA isolates obtained from consecutive patients between October 1, 2012 and September 30, 2013 at the hospital were analyzed in combination with the clinical definition for CA-MRSA by the Centers for Disease Control and Prevention and POT. Of 219 isolates (76 clonal groups), 64 (29.3%) were clinical-HA/POT-CA isolates (22 clonal groups). Some clones of them accumulated in this hospital and might be involved in nosocomial transmission. Virulent factors of the isolates were analyzed, and only one (1.6%) Panton-Valentine leukocidin gene positive isolate but no arginine catabolic mobile element genes positive isolate were found in clinical-HA/POT-CA. Additionally, clinical-HA/POT-CA isolates showed higher antimicrobial susceptibility than clinical-HA/POT-HA, especially to minocycline, doxycycline, and amikacin. The most frequent genotype of molecular CA-MRSA was multi-locus sequence type 5-SCCmecIV, previously not detected in Japan. Although CA-MRSA at this hospital showed low virulence and higher antimicrobial susceptibility, the risk of nosocomial infection from them should be recognized, requiring stricter infection control measures., (Copyright © 2015 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: Erlotinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, which is an effective treatment for patients with non-small cell lung cancer (NSCLC), especially those harboring activating EGFR mutations. A previous phase III trial suggested that patients with EGFR wild-type (EGFR-wt) NSCLC or elderly patients with disease progression after cytotoxic chemotherapy might benefit from erlotinib monotherapy. However, few studies have prospectively evaluated the efficacy and safety of second- or third-line erlotinib monotherapy for elderly patients with EGFR-wt advanced or recurrent NSCLC., Methods: Pretreated patients aged ≥70 years with EGFR-wt stage IIIB/IV NSCLC or those with postoperative recurrence were enrolled and received oral erlotinib at a dose of 150 mg/day until disease progression. Primary outcome was the objective response rate (ORR). Secondary end points included the disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and toxicity profile., Results: This study was terminated early because of the results from a Japanese phase III trial (DELTA trial). Sixteen patients were enrolled between April 2010 and May 2013. The median age was 78 years (range 70-84 years). Six patients were female. Five patients had an Eastern Cooperative Oncology Group performance status of 0. Eleven (69%) patients had adenocarcinoma. Fifteen (94%) patients were treated with erlotinib as a second-line therapy. The ORR was 0% [95% confidence interval (CI) 0-17.1]. DCR was 56.3% (95% CI 33.2-76.9). The median PFS and OS were 1.7 months (95% CI 1.3-2.2) and 7.2 months (95% CI 5.6-8.7), respectively. The most commonly occurring adverse events included acneiform eruption (31.3%) and skin rash (25.0%). One patient developed grade 3 interstitial lung disease, which improved following steroid therapy., Conclusions: In pretreated elderly patients with advanced or recurrent EGFR-wt NSCLC, daily oral erlotinib was well tolerated; however, administration of the drug should not be considered as a second line therapy., Trial Registration: University Hospital Medical Information Network (UMIN) Clinical Trials Registry UMIN000004561 (Date of registration: November 15th, 2010).

Sarcoidosis is a multi-organ disorder of unknown etiology characterized by noncaseating epithelioid cell granulomas. The specimen for histopathological diagnosis is usually obtained by transbronchial lung biopsy (TBLB), but the diagnostic accuracy rate of TBLB is not satisfactory, especially for stage I patients. Since hilar and mediastinal lymphadenopathy is a common finding in patients with sarcoidosis, an approach to lymph nodes is expected to have a good diagnosis yield. We present 3 sarcoidosis patients in whom specimens obtained by TBLB, transbronchial needle aspiration (TBNA) and transesophageal endoscopic ultrasonography guided-fine needle aspiration (EUS-FNA). The histopathological appearance of specimens obtained by EUS-FNA for swollen mediastinal lymph nodes showed noncaseating epithelioid granulomas which are characteristic of sarcoidosis in all 3 patients. On the other hand, no specific findings were recognized in the specimens obtained by TBLB and TBNA in 2 out of 3 patients. These results suggest that EUS-FNA is useful to obtain diagnostic specimens in cases of sarcoidosis.

Peripheral blood samples were collected from 23 human T-lymphotropic virus type-1 (HTLV-1) carriers residing in Kakeroma Island, Japan (Kagoshima Prefecture, Oshima County, Setouchi Town), one of the most highly endemic areas in Japan. The samples were subjected to amplification by PCR and sequencing of the Long Terminal Repeat in order to reconstruct a phylogenetic tree of HTLV-1 isolates. Restriction Fragment Length Polymorphism (RFLP) analysis of env region was also conducted for subgrouping of HTLV-1. Although one sample could not be amplified by PCR, and three more could not be sequenced due to the existence of conspicuous nonspecific bands or repeated sequences, the phylogenetic analysis revealed that the remaining 19 isolates obtained from Kakeroma Island belonged to either the Transcontinental or the Japanese subgroups of the Cosmopolitan subtype, one of the three major subtypes. The RFLP data corresponded closely with the typing data throughout the sequencing. The proportion of the Transcontinental subgroup among the isolates was 26.3% (5 of 19) by sequence analysis and 27.3% (6 of 22) by RFLP. Unlike in Taiwan, China and Okinawa, the Japanese subgroup was dominant in Kakeroma Island. The analysis would also suggest that the Japanese subgroup seems not to have derived from the Transcontinental subgroup, but rather that the Transcontinental subgroup came to Japan first and was followed later by the Japanese one., (2009 Wiley-Liss, Inc.)

Idiopathic pulmonary fibrosis (IPF), a chronic progressive lung disease of unknown etiology, is characterized by the expansion of myofibroblasts and abnormal deposition of extracellular matrix in the lung parenchyma. To elucidate the molecular mechanisms that lead to IPF, we analyzed myofibroblasts established from patients with IPF by oligonucleotide microarrays. Gene expression profiles clearly suggested that lipid peroxidation is enhanced in myofibroblasts, which was confirmed by measuring cellular lipid hydroperoxides. One of the most highly up-regulated proteins in myofibroblasts was selenoprotein P, an antioxidant protein not previously associated with IPF. Subsequent analysis demonstrated that selenoprotein P reduces lipid hydroperoxides and maintains the viability of myofibroblasts. Thus, our results reveal a novel pathophysiologic function of myofibroblasts as a generator of lipid hydroperoxides, and a self-defense mechanism against self-generated oxidative stress.

A 65-year-old man was admitted to our hospital because of dyspnea on exertion. He had oculocutaneous albinism innately and his parents were consanguineous. His chest roentgenogram on admission showed reticulo-nodular infiltrates and cystic changes throughout both lung fields, and 7 cm mass in the left middle field. Cytology of bronchoalveolar lavage fluid (BALF) revealed macrophages containing ceroid. The diagnosis of HPS was made clinically and the tumor was diagnosed as poorly differentiated adenocarcinoma of the lung. He died of respiratory failure. By autopsy, additional well-differentiated adenocarcinoma was detected. Cytology of BALF was useful to confirm ceroid accumulation in the lung.