An atlas of combinatorial transcriptional regulation in mouse and man.

Combinatorial interactions among transcription factors are critical to directing tissue-specific gene expression. To build a global atlas of these combinations, we have screened for physical interactions among the majority of human and mouse DNA-binding transcription factors (TFs). The complete networks contain 762 human and 877 mouse interactions. Analysis of the networks reveals that highly connected TFs are broadly expressed across tissues, and that roughly half of the measured interactions are conserved between mouse and human. The data highlight the importance of TF combinations for determining cell fate, and they lead to the identification of a SMAD3/FLI1 complex expressed during development of immunity. The availability of large TF combinatorial networks in both human and mouse will provide many opportunities to study gene regulation, tissue differentiation, and mammalian evolution.

Thyroid abscess associated with thyrotoxicosis caused by Yersinia enterocolitica subsp. palearctica in a patient with follicular adenoma of the thyroid gland.

BACKGROUND: Yersinia enterocolitica is a gram-negative zoonotic bacterial pathogen that is typically transmitted via the fecal-oral route. The most common clinical manifestation of a Y. enterocolitica infection is self-limited gastroenteritis. Although various extraintestinal manifestations of Y. enterocolitica infection have been reported, there are no reports of thyroid abscesses. CASE PRESENTATION: An 89-year-old Japanese man with follicular adenoma of the left thyroid gland was admitted to our hospital with a 2-day history of fever and left neck pain. Laboratory tests revealed low levels of thyroid stimulating hormone and elevated levels of free thyroxine 4. Contrast-enhanced computed tomography showed low-attenuation areas with peripheral enhancement in the left thyroid gland. He was diagnosed with thyroid abscess and thyrotoxicosis, and treatment with intravenous piperacillin-tazobactam was initiated after collecting blood, drainage fluid, and stool samples. The isolated Gram-negative rod bacteria from blood and drainage fluid cultures was confirmed to be Y. enterocolitica. He was diagnosed with thyroid abscess and thyrotoxicosis due to be Y. enterocolitica subsp. palearctica. The piperacillin-tazobactam was replaced with levofloxacin. CONCLUSION: We report a novel case of a thyroid abscess associated with thyrotoxicosis caused by Y. enterocolitica subsp. palearctica in a patient with a follicular thyroid adenoma.

Risk Factors for Teicoplanin-Associated Acute Kidney Injury in Patients with Hematological Malignancies: Focusing on Concomitant Use of Tazobactam/Piperacillin.

Patients with hematological malignancies (HM) often receive tazobactam/piperacillin (TAZ/PIPC) and glycopeptide antibiotics for febrile neutropenia. The effect of concomitant use of TAZ/PIPC on risk of teicoplanin (TEIC)-associated acute kidney injury (AKI) remains unclear. We investigated the impact of concomitant TAZ/PIPC use on TEIC-associated AKI in HM patients and identified the risk factors. In this retrospective, single-center, observational cohort study, 203 patients received TEIC, 176 of whom satisfied the selection criteria and were divided into TEIC cohort (no TAZ/PIPC; n = 118) and TEIC + TAZ/PIPC cohort (n = 58). AKI was defined as serum creatinine increase ≥0.3 mg/dL within 48 h or ≥50% from baseline. Incidence of AKI in TEIC cohort before and after propensity score matching was 9.3 and 5.9%, respectively, and that in TEIC + TAZ/PIPC cohort was 10.3 and 11.8%. AKI incidence and risk were not significantly different between two cohorts before (p = 0.829; odds ratio (OR) 1.122, 95% confidence interval (CI) 0.393-3.202) and after matching (p = 0.244; OR 2.133, 95% CI 0.503-9.043). Logistic regression analysis with factors clinically or mechanistically potentially related to TEIC-associated AKI, including concomitant TAZ/PIPC use, as independent variables identified baseline hemoglobin level as the only significant risk factor for TEIC-associated AKI (p = 0.011; OR 0.484, 95% CI 0.276-0.848). In HM patients treated with TEIC, concomitant TAZ/PIPC use did not increase AKI risk whereas lower hemoglobin levels had higher risk for TEIC-associated AKI development, suggesting the necessity to monitor serum creatinine when using TEIC in patients with anemia.

Seroprevalence kinetics of SARS-CoV-2 antibodies in pediatric patients visiting a hospital during COVID-19 pandemic in Japan.

Children infected with SARS-CoV-2 are often asymptomatic or have mild symptoms. The studies on the seroprevalence kinetics of SARS-CoV-2 antibodies in children are limited. We conducted a cross-sectional survey of the positive rate of the SARS-CoV-2 IgG in pediatric patients without suspected COVID-19 infection between January 2007 and March 2022. We defined the serum samples from the pre-pandemic and pandemic groups (1st-6th waves). Totally, 2557 samples were collected and no samples from the pre-pandemic group or the 1st-4th waves were positive for IgG. There were 4/661 and 16/373 positives at the 5th and 6th waves, respectively. At the 5th wave, the prevalence of IgG was 1.3% in children aged 1-4 years. At the 6th wave, in children <1 year of age, the prevalence was 4.0%, and 2.4%, 5.3%, 5.2% and 10% in age groups 1-4, 5-9, 10-14 and 15-18 years, respectively. In conclusions, the pre-pandemic samples were negative, and the IgG positivity increased during the later period of the pandemic.

Comparison of the effects of cefmetazole and meropenem on microbiome: A pilot study.

BACKGROUND: Cefmetazole (CMZ) is a carbapenem-sparing option in the treatment of extended-spectrum beta-lactamase (ESBL)-producing bacterial infection. In this pilot study, we aimed to compare the effects of antimicrobial treatment (meropenem [MP] and CMZ) with those of no antimicrobial treatment (control group) on the microbiome. METHODS: The study was a multicenter, prospective, observational pilot study conducted from October 2020 to October 2022. Feces and saliva samples were collected for microbiome analyses at two time points (early-period: days 1-3; and late-period: days 4-30) for the antimicrobial treatment group, and at one time point for the control group. RESULTS: Five feces (MP-F and CMZ-F) and five saliva (MP-S and CMZ-S) samples were included in the MP and the CMZ groups. Ten feces (C-F) and saliva (C-S) samples were included in the control group. Group α diversity was notably lower in the late-period MP-F group than the control group as determined with the Shannon richness index. ß diversity analysis of the feces samples based on weighted and unweighted UniFrac distances revealed distinctions in both the late-period CMZ-F and MP-F groups compared with the control group. Weighted UniFrac analysis showed that only the early-period MP-F group differed from the control group. In the saliva samples, weighted and unweighted UniFrac analyses showed significant differences between the control group and the early CMZ, late CMZ, and late MP groups. CONCLUSIONS: MP treatment may cause larger impact on the feces microbiome than CMZ in Japanese patients.

Bacillus subtilis Bacteremia from Gastrointestinal Perforation after Natto Ingestion, Japan.

We report a case of Bacillus subtilis variant natto bacteremia from a gastrointestinal perforation in a patient who ingested natto. Genotypic methods showed the bacteria in a blood sample and the ingested natto were the same strains. Older or immunocompromised patients could be at risk for bacteremia from ingesting natto.

Effectiveness of cefmetazole versus meropenem for invasive urinary tract infections caused by extended-spectrum ß-lactamase-producing Escherichia coli.

Cefmetazole is active against extended-spectrum ß-lactamase-producing Escherichia coli (ESBLEC) and is a potential candidate for carbapenem-sparing therapy. This multicenter, observational study included patients hospitalized for invasive urinary tract infection due to ESBLEC between March 2020 and November 2021 at 10 facilities in Japan, for whom either cefmetazole or meropenem was initiated as a definitive therapy within 96 h of culture collection and continued for at least 3 d. Outcomes included clinical and microbiological effectiveness, recurrence within 28 d, and all-cause mortality (14 d, 30 d, in-hospital). Outcomes were adjusted for the inverse probability of propensity scores for receiving cefmetazole or meropenem. Eighty-one and forty-six patients were included in the cefmetazole and meropenem groups, respectively. Bacteremia accounted for 43% of the cefmetazole group, and 59% of the meropenem group. The crude clinical effectiveness, 14 d, 30 d, and in-hospital mortality for patients in the cefmetazole and meropenem groups were 96.1% vs 90.9%, 0% vs 2.3%, 0% vs 12.5%, and 2.6% vs 13.3%, respectively. After propensity score adjustment, clinical effectiveness, the risk of in-hospital mortality, and the risk of recurrence were similar between the two groups (P = 0.54, P = 0.10, and P = 0.79, respectively). In all cases with available data (cefmetazole : n = 61, meropenem : n = 22), both drugs were microbiologically effective. In all isolates, bla CTX-M was detected as the extended-spectrum ß-lactamase gene. The predominant CTX-M subtype was CTX-M-27 (47.6%). Cefmetazole showed clinical and bacteriological effectiveness comparable to meropenem against invasive urinary tract infection due to ESBLECs.

Comparison of Incidence of Hyponatremia between Linezolid and Vancomycin by Propensity Score Matching Analysis.

Several cases of severe hyponatremia induced by linezolid (LZD) were reported. However, severe infections could also cause hyponatremia by increasing vasopressin secretion. To prove that hyponatremia is associated with LZD rather than infection, we compared the incidence and risk of developing hyponatremia between patients receiving LZD and those receiving vancomycin (VCM). A retrospective, single-center, observational cohort study was conducted in patients aged 18 years or older who received intravenous LZD or VCM for 7 d or longer. Hyponatremia was defined as serum sodium level lower than 134 mEq/L and more than 5% decrease from baseline after treatment initiation. The incidence and risk of developing hyponatremia were analyzed between LZD and VCM groups using chi-square test. Four hundred and fifty patients who satisfied the selection criteria were divided into LZD (n = 97) and VCM groups (n = 353). Significant differences in patient characteristics between LZD and VCM groups were observed before propensity score matching, but no significant differences were found after matching. LZD group showed a significantly higher incidence and risk of developing hyponatremia compared to VCM group both before (LZD: 16.5%, VCM: 5.4%; p < 0.001, odds ratio 3.472 [95% confidence interval (CI) 1.711-7.048]) and after (LZD: 17.8%, VCM: 5.5%; p = 0.020, odds ratio 3.738 [95% CI 1.157-12.076]) propensity score matching. In conclusion, propensity score analyses suggest that the risk of hyponatremia associated with LZD is approximately 3.7-fold higher than that associated with VCM, regardless of patient background.

Prevalence of antimicrobial resistant genes in Bacteroides spp. isolated in Oita Prefecture, Japan.

INTRODUCTION: Bacteroides spp. are the most common anaerobic bacteria isolated from the human gastrointestinal tract. Several resistant genes are present in Bacteroides spp. However, most studies have focused on the prevalence of the cfiA gene in Bacteroides fragilis alone. We assessed the susceptibility to antimicrobial agents and the prevalence of cepA, cfiA, cfxA, ermF, nim, and tetQ genes in Bacteroides strains isolated from clinical specimens in our hospital. METHODS: We isolated 86 B. fragilis and 58 non-fragilis Bacteroides strains from human clinical specimens collected from January 2011 to November 2021. Resistance against piperacillin (PIPC), cefotaxime (CTX), cefepime (CFPM), meropenem (MEPM), clindamycin, and minocycline was determined. RESULTS: The resistant rates of penicillins and cephalosporins in non-fragilis isolates were significantly higher than those in B. fragilis isolates. In B. fragilis isolates, the resistant rates of PIPC, CTX, and CFPM in cfxA-positive isolates were significantly higher than those in cfxA-negative isolates (71% vs. 16%, 77% vs. 19%, and 77% vs. 30%, respectively). Thirteen B. fragilis isolates harbored the cfiA gene, two of which were resistant to MEPM. Six of the 13 cfiA-positive B. fragilis isolates were heterogeneously resistant to MEPM. CONCLUSION: It is important to evaluate the use of MEPM as empirical therapy for Bacteroides spp. infections, considering the emergence of carbapenem resistance during treatment, existence of MEPM-resistant strains, and heterogeneous resistance.

Perception of overseas experiences among medical students in Japan: a national online survey.

BACKGROUND: Data on the perceptions of medical students on international experience in non-English-speaking high-income countries (HICs) are very limited. This study aimed to assess the perceptions of medical students in Japan toward overseas experience while in school and post-graduation, as well as to characterize the support they require to pursue their profession in international settings. METHODS: A cross-sectional national survey was administered online between September 16, 2020, and October 8, 2020. Participants were recruited from 69 medical schools using snowball sampling through acquaintances and social media platforms. The survey results were analyzed by two researchers. RESULTS: A total of 548 students from 59 medical schools responded to the survey. Among them, 381 respondents (69%) expressed interest in working abroad, while only 40% seriously considered it. The majority of students responded that they would like to pursue clinical training abroad for a short term or while they were medical students (54%) or during a residency/fellowship (53%). The most popular regions among the respondents for future international experiences were North America and Europe. Finally, the most reported reasons for hesitation to work abroad were language barriers (70%), followed by lack of clarity regarding career options after working abroad (67%), difficulties obtaining medical licensure abroad (62%), and the lack of role models (42%). CONCLUSIONS: Although nearly 70% of participants reported a high interest in working overseas, various barriers to working abroad were identified. Our findings identified key problem areas that could be targeted when promoting international experiences for medical students in Japan.

Association of Vancomycin Trough Concentration and Clearance With Febrile Neutropenia in Pediatric Patients.

BACKGROUND: Febrile neutropenia promotes renal drug excretion. Adult and pediatric patients with febrile neutropenia exhibit a lower vancomycin concentration/dose (relative to bodyweight) ratio than those with other infections. In pediatric patients, renal function relative to bodyweight varies depending on age, and vancomycin clearance is age dependent. This study aimed to analyze the effects of febrile neutropenia on the pharmacokinetics of vancomycin in age-stratified pediatric patients. METHODS: This retrospective, single-center, observational cohort study analyzed 112 hospitalized pediatric patients who met the selection criteria and intravenously received vancomycin at the Department of Pediatrics of the Oita University Hospital between April 2011 and October 2019. RESULTS: The febrile neutropenia (n = 46) cohort exhibited a significantly higher estimated glomerular filtration rate than the nonfebrile neutropenia (n = 66) cohort. Compared with those in the nonfebrile neutropenia cohort, the daily vancomycin dose relative to bodyweight and vancomycin clearance were significantly higher, and the vancomycin trough concentration and vancomycin concentration/dose ratio were significantly lower in the febrile neutropenia cohort. In the age groups of 1-6 and 7-12 years, compared with those in the nonfebrile neutropenia cohort, the vancomycin concentration/dose ratio was significantly lower, and vancomycin clearance was significantly higher in the febrile neutropenia cohort. Univariate and multivariate analyses identified febrile neutropenia as the independent factor influencing vancomycin concentration/dose ratio and clearance only in pediatric patients aged 1-6 years. CONCLUSIONS: Increased initial dosage and therapeutic drug monitoring-guided dose optimization are critical for the therapeutic efficacy of vancomycin in pediatric patients with febrile neutropenia, especially in those aged 1-6 years.

Impact of Inflammation on Intra-individual Variation in Trough Voriconazole Concentration in Patients with Hematological Malignancies.

The pharmacokinetics of voriconazole shows large intra-individual and inter-individual variability and is affected by various factors. Recently, inflammation has been focused as a significant factor affecting the variability. This study aimed to compare the influence of C-reactive protein (CRP) and other clinical laboratory parameters on intra-individual variability in trough voriconazole concentration and examine the impact of inflammation in patients with hematological malignancies. We conducted a retrospective, single-center, observational cohort study. Forty-two patients with hematological malignancy who received oral voriconazole for prophylaxis against deep mycosis and underwent multiple measurements of trough plasma voriconazole concentration were recruited. Quantitative changes in pharmacological and clinical laboratory parameters (Δ) were calculated as the difference between the current and preceding measurements. Voriconazole concentration/maintenance dose per weight (C/D) was found to correlate positively with CRP level (n = 202, rs = 0.314, p < 0.001). Furthermore, ΔC/D correlated positively with ΔCRP level (n = 160, rs = 0.442, p < 0.001), and ΔCRP showed the highest correlation coefficient among the laboratory parameters. Univariate and multivariate analyses identified ΔCRP (p < 0.001) and Δgamma-glutamyl transpeptidase (γGTP) (p = 0.019) as independent factors associated with ΔC/D. Partial R2 were 0.315 for ΔCRP and 0.024 for ΔγGTP, suggesting markedly greater contribution of ΔCRP to ΔC/D. In conclusion, since clinical laboratory parameters other than CRP had little influence on trough plasma voriconazole concentration, therapeutic drug monitoring and dose adjustment considering fluctuation in CRP level would be important for proper use of voriconazole in patients with hematological malignancies.

Septic shock due to Yersinia pseudotuberculosis infection in an adult immunocompetent patient: a case report and literature review.

BACKGROUND: Yersinia pseudotuberculosis infection can occur in an immunocompromised host. Although rare, bacteremia due to Y. pseudotuberculosis may also occur in immunocompetent hosts. The prognosis and therapeutic strategy, especially for immunocompetent patients with Y. pseudotuberculosis bacteremia, however, remains unknown. CASE PRESENTATION: A 38-year-old Japanese man with a mood disorder presented to our hospital with fever and diarrhea. Chest computed tomography revealed consolidation in the right upper lobe with air bronchograms. He was diagnosed with pneumonia, and treatment with intravenous ceftriaxone and azithromycin was initiated. The ceftriaxone was replaced with doripenem and the azithromycin was discontinued following the detection of Gram-negative rod bacteria in 2 sets of blood culture tests. The isolated Gram-negative rod bacteria were confirmed to be Y. pseudotuberculosis. Thereafter, he developed septic shock. Doripenem was switched to cefmetazole, which was continued for 14 days. He recovered without relapse. CONCLUSIONS: We herein report a case of septic shock due to Y. pseudotuberculosis infection in an adult immunocompetent patient. The appropriate microorganism tests and antibiotic therapy are necessary to treat patients with Y. pseudotuberculosis bacteremia.

A Retrospective Study of the Optimal Number of Blood Cultures at a Hospital in Japan.

Blood culture tests have a major role in rapid and accurate diagnosis and selection of optimal antibiotic treatment for infectious diseases. The true-positive and contamination rates of blood cultures are performance indicators for the practice of blood culture. However, the optimal number of blood cultures has not been adequately elucidated. We aimed to assess the validity of the number of blood cultures obtained in the hospital. We conducted a retrospective study of blood cultures collected from hospitalized patients between 2010 and 2014 at a tertiary care hospital in Japan and assessed the validity of the number of blood cultures per 1,000 admissions as an indicator for the optimal practice of obtaining blood culture, considering the average length of stay. We also investigated the validity of true-positive and contamination rates of blood cultures in the hospital. The number of blood cultures in this study ranged from 28.6 to 56 per 1,000 patient-days and from 404.4 to 894.6 per 1,000 admissions. The median true-positive and contamination rates of blood cultures per year was 10.1% and 2.8%, respectively. The median contamination rate of blood cultures in a community-acquired group was significantly higher than that in a hospital-acquired group (4.1% vs. 1.9%, p = 0.029). We conclude that there is a possibility that the number of blood cultures per 1,000 admissions is a more appropriate factor to evaluate than per patient-days. Moreover, the true-positive and contamination rates of blood cultures in our hospital are valid.

Asthma Exacerbation Coincident with Saddle Pulmonary Embolism and Paradoxical Embolism.

Saddle pulmonary embolism (PE) and paradoxical embolism (PDE) are life-threatening disorders carrying a risk of sudden death, and their prompt diagnosis is extremely important. Saddle PE is a radiologic definition and refers to a thrombus that straddles the bifurcation of the pulmonary artery trunk, carrying a risk of sudden hemodynamic collapse. PDE is defined as a systemic arterial embolus due to the passage of a venous thrombus though a right-to-left shunt, such as patent foramen ovale (PFO). We herein present the rare case of asthma exacerbation coincident with saddle PE and PDE. A 69-year-old woman with asthma was suffering from dyspnea, pulse attenuation of the left radial artery and left upper limb pain. An arterial blood gas analysis revealed hypoxemia, and a pulmonary function test demonstrated an obstructive pattern. Enhanced computed tomography (CT) revealed saddle PE, right popliteal venous thrombosis, and left brachial artery occlusion. After the treatment with edoxaban, an anticoagulant, and aspirin, the PE was significantly alleviated, and the brachial artery occlusion was recanalized. Subsequently, the right-to-left shunt through PFO was confirmed, and PDE was suspected of inducting her brachial artery embolism. In the present case, the pulse attenuation of the radial artery and upper limb pain prompted us to consider peripheral vascular disease or coagulation disorders. Physicians should keep in mind that patients with asthma are at considerable risk of PE, and it is important to be aware of possible PFO in patients presenting with the coexistence of PE and systemic arterial embolism.

A case report of Vibrio furnissii bacteremia and cellulitis in a malnourished patient without an apparent site of entry.

We herein report a case of Vibrio furnissii bacteremia with bilateral lower limb cellulitis. A 53-year-old Japanese man with a mood disorder presented to our hospital with fever and a complaint of an inability to walk. Two sets of blood cultures became positive for V. furnissii. The treatment regimen was modified to ceftazidime and doxycycline. The patient recovered without relapse. Despite thorough examinations, portal of entry of V. furnissii remained unclear. Although the bacteria was first misidentified as V. fluvialis by the phenotyping assay (API rapid ID 32E) and matrix-assisted laser-desorption/ionization time-of-flight mass spectrometry, it was later confirmed as V. furnissii by dnaJ gene sequencing.

Real-time PCR investigation of the prevalence of Fusobacterium necrophorum in patients with pharyngitis in Japan.

PURPOSE: Recent data suggest an association between Fusobacterium necrophorum infection and pharyngotonsillitis among adolescents and adults. However, existing reports are only from North America and Europe. We aimed to identify and compare the prevalence of F. necrophorum among patients with pharyngitis and asymptomatic controls in Japan and clarify the epidemiological characteristics of pharyngitis. METHODS: Patients aged ≥16 years with pharyngitis and asymptomatic controls were prospectively included. F. necrophorum was detected by using both conventional culture methods and real-time F. necrophorum-specific PCR targeting the rpoB gene. The prevalence of ß-hemolytic streptococci was also identified and compared between groups. RESULTS: Forty-four pharyngitis patients and 31 asymptomatic controls were included. F. necrophorum was identified using PCR in 6 (13.6%) pharyngitis cases and 2 (6.5%) controls, with no significant difference (p = 0.457). The median bacterial load of F. necrophorum identified with real-time PCR was significantly higher in pharyngitis cases than in controls (p = 0.046). Patients with a high Centor Score tended to have a higher bacterial load than those with a low Centor Score and controls. In cases of pharyngitis, the prevalence of F. necrophorum was similar to that of Streptococcus pyogenes (F. necrophorum-positive: 6 [13.6%] vs. S. pyogenes-positive: 5 [11.4%], p = 0.99). CONCLUSION: F. necrophorum was similarly prevalent among pharyngitis cases as S. pyogenes in Japan. The association of higher F. necrophorum bacterial load with symptomatic pharyngitis in accordance with the previous findings from a different geographical region suggests that F. necrophorum is an important causative agent of bacterial pharyngitis.

Amoxicillin and Ceftriaxone as Treatment Alternatives to Penicillin for Maternal Syphilis.

There is no proven alternative to penicillin for treatment of maternal syphilis. We report 2 case-patients with maternal syphilis who were successfully treated without penicillin. We used amoxicillin and probenecid for the first case-patient and amoxicillin, probenecid, and ceftriaxone for the second case-patient.

Importation of Zika Virus from Vietnam to Japan, November 2016.

We report a case of Zika virus infection that was imported to Japan by a traveler returning from Vietnam. We detected Zika virus RNA in the patient's saliva, urine, and whole blood. In the Zika virus strain isolated from the urine, we found clearly smaller plaques than in previous strains.

A fatal case of melioidosis with pancytopenia in a traveler from Indonesia.

Melioidosis, an infectious disease with high mortality, caused by Burkholderia pseudomallei, is endemic in southeast Asia and northern Australia. In Indonesia, autochthonous cases have been rarely reported, with most cases being sporadic and occurring in travelers. Herein, we report a fatal case of neurological melioidosis in a traveler from Indonesia presenting with septic shock.