Development and validation of an automated antimicrobial surveillance system based on indications for antimicrobial administration.

INTRODUCTION: We developed an antimicrobial and patient background surveillance system (APBSS), an automated surveillance system that can calculate surveillance data such as antimicrobial use and detection of antimicrobial resistance for each indication of antimicrobial administration. We evaluated the validity of the APBSS data. METHODS: Eligible patients were hospitalized at the Toyota Kosei Hospital on July 7, 2022. Evaluated surveillance data included antimicrobial administration, indications for antimicrobial administration, and diagnosis. In the APBSS, surveillance data were calculated using the Diagnosis Procedure Combination data and Japan Nosocomial Infections Surveillance laboratory data. Using surveillance data collected by the Point Prevalence Survey (PPS) as a reference standard, the agreement between the results calculated based on the APBSS was evaluated using Cohen's kappa coefficient. Indications for antimicrobial administration and diagnosis were analyzed in patients identified for antimicrobial administration in PPS or APBSS. RESULTS: A total of 582 patients were included in this study, 223 of whom were evaluated for indications for antimicrobial administration and diagnosis. For the indications of antimicrobial administration, the Cohen's kappa coefficient was almost perfect (0.81-1.00) for all items. Cohen's kappa coefficient for the diagnosis of healthcare-associated infections was low. However, in major diseases (pneumonia and intra-abdominal, and symptomatic upper urinary tract infections) among community-acquired infections (CAIs) diagnosis, Cohen's kappa coefficient was substantial (0.61-0.80). CONCLUSIONS: The APBSS can identify indications for antimicrobial administration and major CAIs with high accuracy. Therefore, the APBSS can calculate surveillance data, such as antimicrobial use and detection of antimicrobial resistance, for each of these items.

Effect of rapid cefpodoxime disk screening for early detection of third-generation cephalosporin resistance in Escherichia coli and Klebsiella pneumoniae bacteremia.

BACKGROUND: Several methods have been reported for detecting resistance genes or phenotypic testing on the day of positive blood culture in Escherichia coli or Klebsiella pneumoniae bacteremia. However, some facilities have not introduced these methods because of costs or other reasons. Toyota Kosei Hospital introduced cefpodoxime (CPDX) rapid screening on May 7, 2018, to enable early detection of third-generation cephalosporin resistance. In this study, we aimed to evaluate the effects of intervention with an Antimicrobial Stewardship Team using CPDX rapid screening. METHODS: Cefotaxime (CTX)-resistant E. coli or K. pneumoniae bacteremia cases were selected retrospectively and divided into two groups: the pre-CPDX screening (June 1, 2015, to May 6, 2018) and CPDX screening groups (July 7, 2018, to August 31, 2021). The primary outcome was the proportion of cases in which modifications were made to the administration of susceptible antimicrobial agents within 24 h of blood culture-positive reports. RESULTS: Overall, 63 patients in the pre-CPDX screening group and 84 patients in the CPDX screening group were eligible for analysis. The proportion of patients who modified to susceptible antimicrobial agents within 24 h of blood culture-positive reports was significantly increased in the CPDX screening group compared to that in the pre-CPDX screening group (6.3% vs. 22.6%, p = 0.010). CONCLUSION: The results demonstrated that in CTX-resistant E. coli or K. pneumoniae bacteremia, CPDX rapid screening increased the proportion of early initiation of appropriate antimicrobial agents.

Nationwide surveillance of bacterial respiratory pathogens conducted by the surveillance committee of the Japanese Society of Chemotherapy, the Japanese Association for Infectious Diseases, and the Japanese Society for Clinical Microbiology in 2019-2020: General view of the pathogens' antibacterial susceptibility.

The trends and prevalence of antimicrobial susceptibility of pathogens vary by country, region, and time. Long-term regular surveillance is required to investigate trends in the antimicrobial resistance of various isolated bacterial pathogens. We report the results of a nationwide surveillance on the antimicrobial susceptibility of bacterial respiratory pathogens in Japan conducted by the Japanese Society of Chemotherapy, the Japanese Association for Infectious Diseases, and the Japanese Society for Clinical Microbiology. The isolates were collected from clinical specimens obtained from adult patients who visited a collaborating medical facility between June 2019 and December 2020 and were diagnosed with respiratory tract infections by a physician. Antimicrobial susceptibility testing was performed in a centralized laboratory according to the methods recommended by the Clinical and Laboratory Standards Institute. Susceptibility testing was performed for 932 strains (201 Staphylococcus aureus, 158 Streptococcus pneumoniae, 6 S. pyogenes, 136 Haemophilus influenzae, 127 Moraxella catarrhalis, 141 Klebsiella pneumoniae, and 163 Pseudomonas aeruginosa) collected from 32 facilities in Japan. The proportions of methicillin-resistant S. aureus and penicillin-resistant S. pneumoniae were 35.3% and 0%, respectively. In H. influenzae, 16.2% and 16.9% were ß-lactamase-producing ampicillin resistant and ß-lactamase-negative ampicillin resistant, respectively. Extended-spectrum ß-lactamase-producing K. pneumoniae accounted for 5.0% of all K. pneumoniae infections. Carbapenemase-producing K. pneumoniae and multi-drug-resistant P. aeruginosa with metallo-ß-lactamase were not detected in this study. This surveillance will be a useful reference for treating respiratory infections in Japan and will provide evidence to enhance the appropriate use of antimicrobial agents.

Cytotoxic Effects of Darinaparsin, a Novel Organic Arsenical, against Human Leukemia Cells.

To explore the molecular mechanisms of action underlying the antileukemia activities of darinaparsin, an organic arsenical approved for the treatment of peripheral T-cell lymphoma in Japan, cytotoxicity of darinaparsin was evaluated in leukemia cell lines NB4, U-937, MOLT-4 and HL-60. Darinaparsin was a more potent cytotoxic than sodium arsenite, and induced apoptosis/necrosis in NB4 and HL-60 cells. In NB4 cells exhibiting the highest susceptibility to darinaparsin, apoptosis induction was accompanied by the activation of caspase-8/-9/-3, a substantial decrease in Bid expression, and was suppressed by Boc-D-FMK, a pancaspase inhibitor, suggesting that darinaparsin triggered a convergence of the extrinsic and intrinsic pathways of apoptosis via Bid truncation. A dramatic increase in the expression level of γH2AX, a DNA damage marker, occurred in parallel with G2/M arrest. Activation of p53 and the inhibition of cdc25C/cyclin B1/cdc2 were concomitantly observed in treated cells. Downregulation of c-Myc, along with inactivation of E2F1 associated with the activation of Rb, was observed, suggesting the critical roles of p53 and c-Myc in darinaparsin-mediated G2/M arrest. Trolox, an antioxidative reagent, suppressed the apoptosis induction but failed to correct G2/M arrest, suggesting that oxidative stress primarily contributed to apoptosis induction. Suppression of Notch1 signaling was also confirmed. Our findings provide novel insights into molecular mechanisms underlying the cytotoxicity of darinaparsin and strong rationale for its new clinical application for patients with different types of cancer.

Nationwide surveillance of bacterial respiratory pathogens conducted by the surveillance committee of japanese society of chemotherapy, the japanese association for infectious diseases, and the japanese society for clinical microbiology in 2016: General view of the pathogens' antibacterial susceptibility.

The nationwide surveillance on antimicrobial susceptibility of bacterial respiratory pathogens from the patients in Japan was conducted by the Japanese Society of Chemotherapy, the Japanese Association for Infectious Diseases, and the Japanese Society for Clinical Microbiology in 2016. The isolates were collected from clinical specimens obtained from well-diagnosed adult patients with respiratory tract infections during the period between February 2016 and August 2016 by three societies. Antimicrobial susceptibility testing was conducted at the central reference laboratory according to the method recommended by Clinical Laboratory Standards Institute. Susceptibility testing was evaluated in 1062 strains (143 Staphylococcus aureus, 210 Streptococcus pneumoniae, 17 Streptococcus pyogenes, 248 Haemophilus influenzae, 151 Moraxella catarrhalis, 134 Klebsiella pneumoniae, and 159 Pseudomonas aeruginosa). Ratio of methicillin-resistant S. aureus was 48.3%, and those of penicillin-susceptible S. pneumoniae was 99.5%. Among H. influenzae, 14.1% of them were found to be ß-lactamase-producing ampicillin-resistant strains, and 41.1% to be ß-lactamase-non-producing ampicillin-resistant strains. Extended spectrum ß-lactamase-producing K. pneumoniae and multi-drug resistant P. aeruginosa with metallo ß-lactamase were 4.5% and 0.6%, respectively.

Hydrodecyanation of Secondary Alkyl Nitriles and Malononitriles to Alkanes using DiMeImd-BH3.

The decyanation of secondary aliphatic nitriles and the 2-fold decyanation of malononitriles leading to alkanes in the presence of 1,3-dimethylimidazol-2-ylidene borane (diMeImd-BH3) are reported. These reactions proceed via a radical mechanism that involves the addition of a borane radical to the nitrile to form an iminyl radical, followed by cleavage of a carbon-carbon bond. Theoretical calculations suggest that the ß-cleavage of these iminyl radicals, which affords NHC-BH2CN and the corresponding alkyl radicals, is the rate-determining step in this reaction.

Nationwide surveillance of bacterial respiratory pathogens conducted by the surveillance committee of Japanese Society of Chemotherapy, the Japanese Association for Infectious Diseases, and the Japanese Society for clinical microbiology in 2014: General view of the pathogens' antibacterial susceptibility.

The nationwide surveillance on antimicrobial susceptibility of bacterial respiratory pathogens from the patients in Japan was conducted by Japanese Society of Chemotherapy, the Japanese Association for Infectious Diseases, and the Japanese Society for Clinical Microbiology in 2014. The isolates were collected from clinical specimens obtained from well-diagnosed adult patients with respiratory tract infections during the period between January 2014 and April 2015 by three societies. Antimicrobial susceptibility testing was conducted at the central reference laboratory according to the method recommended by Clinical Laboratory Standards Institute. Susceptibility testing was evaluated in 1534 strains (335 Staphylococcus aureus, 264 Streptococcus pneumoniae, 29 Streptococcus pyogenes, 281 Haemophilus influenzae, 164 Moraxella catarrhalis, 207 Klebsiella pneumoniae, and 254 Pseudomonas aeruginosa). Ratio of methicillin-resistant S. aureus was 43.6%, and those of penicillin-susceptible S. pneumoniae was 100%. Among H. influenzae, 8.2% of them were found to be ß-lactamase-producing ampicillin-resistant strains, and 49.1% to be ß-lactamase-non-producing ampicillin-resistant strains. Extended spectrum ß-lactamase-producing K. pneumoniae and multi-drug resistant P. aeruginosa with metallo ß-lactamase were 9.2% and 0.4%, respectively.

Co-treatment with a C1B5 peptide of protein kinase Cγ and a low dose of gemcitabine strongly attenuated pancreatic cancer growth in mice through T cell activation.

Although gemcitabine is an effective chemotherapeutic for pancreatic cancer, severe side effects often accompany its use. Since we have discovered that locally administered C1B domain peptides effectively control tumor growth without any side effects, the efficacy of co-treatment with this peptide and a low dose of gemcitabine on the growth of pancreatic cancer was examined. Two- and three-dimensional cell culture studies clarified that a co-treatment with C1B5 peptide and gemcitabine significantly attenuated growth of PAN02 mouse and PANC-1 human pancreatic cancer cells in 2D and 3D cultures. Although treatment with the low dose of gemcitabine alone (76%) or the C1B5 peptide alone (39%) inhibited tumor growth moderately, a co-treatment with C1B5 peptide and a low dose of gemcitabine markedly inhibited the growth of PAN02 autografts in the mouse peritoneal cavity (94% inhibition) without any noticeable adverse effect. The number of peritoneal cavity-infiltrating neutrophils and granzyme B+ lymphocytes was significantly higher in the co-treatment group than in the control group. A significant increase of granzyme B mRNA expression was also detected in human T cells by the co-treatment. Taken together, the current study suggests that C1B5 peptide offers a remarkably effective combination treatment strategy to reduce side effects associated with gemcitabine, without losing its tumoricidal effect.

Entomophthoromycosis and mucormycosis as causes of pneumonia in Vietnamese potbellied pigs.

Two Vietnamese potbellied pigs ( Sus scrofa) had respiratory disease and, on autopsy, both pigs had large masses in the lungs and thoracic cavity. Microscopically, pulmonary and pleural masses contained large areas with hyphae surrounded by hypereosinophilic cellular debris rimmed by abundant eosinophils, lymphocytes, plasma cells, and histiocytes with occasional multinucleate giant cells. The hypereosinophilic debris usually formed tight cuffs, or "sleeves" around the hyphae, compatible with Splendore-Hoeppli-like material. The fungal organisms were determined by PCR to be Conidiobolus incongruus in one pig and Mucor circinelloides in the other. Entomophthoromycosis and mucormycosis should be included in the differential diagnoses for swine pneumonia, particularly when there is evidence of granulomatous pulmonary masses and pleural effusion with eosinophilic inflammation.

The palliative efficacy of modified Mohs paste for controlling canine and feline malignant skin wounds.

In veterinary medicine, the management of malignant skin wounds is highly challenging. We conducted a study on seven case animals (four dogs and three cats) which presented with malignant skin wounds. All seven animals had signs and symptoms which were controlled following treatment with a modified Mohs paste. Upon obtaining informed consent from their owners, the animals requiring management of malignant wounds were enrolled in this study. The modified Mohs paste was prepared by mixing zinc chloride, zinc oxide starch powder, glycerin, and distilled water. The modified Mohs paste was topically applied to and left to remain on the malignant wounds for one hour, under controlled conditions. Once the paste was removed, the wounds were irrigated with a solution of sterile saline. At the first examination, the wounds of each animal were observed for signs of exudate, malodor, and bleeding. In every case, visible improvement was observed immediately after the modified Mohs paste treatment. Specifically, the size of the malignant wounds, and the number of times the dressing gauze required changing, significantly decreased (p < 0.05 and p < 0.01, respectively). The open malignant skin wounds caused by mammary gland tumors disappeared in two cases. The Mohs paste has been shown to be a viable option for the palliative treatment in canine and feline malignant skin wound management.

Airborne transmission from a neonate with Netherton syndrome during an outbreak of MRSA.

We encountered a 4 month outbreak of methicillin-resistant Staphylococcus aureus (MRSA) colonization or infection that was difficult to control despite implementation of standard prevention methods. A neonate with Netherton syndrome had accelerated scaling of the skin and continued positive results for MRSA from clinical samples. The results of air sampling suggested the possibility of airborne transmission. The MRSA outbreak stopped after the patient was transferred to an isolation room, suggesting that airborne MRSA can play a role in MRSA colonization. Isolation rooms should be considered in specific circumstances, as described in the present study.

Effective time closures: quantifying the conservation benefits of input control for the Pacific chub mackerel fishery.

Restricting human access to a specific wildlife species, community, or ecosystem, i.e., input control, is one of the most popular tools to control human impacts for natural resource management and wildlife conservation. However, quantitative evaluations of input control are generally difficult, because it is unclear how much human impacts can actually be reduced by the control. We present a model framework to quantify the effectiveness of input control using day closures to reduce actual fishing impact by considering the observed fishery dynamics. The model framework was applied to the management of the Pacific stock of the chub mackerel (Scomber japonicus) fishery, in which fishing was suspended for one day following any day when the total mackerel catch exceeded a threshold level. We evaluated the management measure according to the following steps: (1) we fitted the daily observed catch and fishing effort data to a generalized linear model (GLM) or generalized autoregressive state-space model (GASSM), (2) we conducted population dynamics simulations based on annual catches randomly generated from the parameters estimated in the first step, (3) we quantified the effectiveness of day closures by comparing the results of two simulation scenarios with and without day closures, and (4) we conducted additional simulations based on different sets of explanatory variables and statistical models (sensitivity analysis). In the first step, we found that the GASSM explained the observed data far better than the simple GLM. The model parameterized with the estimates from the GASSM demonstrated that the day closures implemented from 2004 to 2009 would have decreased exploitation fractions by ~10% every year and increased the 2009 stock biomass by 37-46% (median), relative to the values without day closures. The sensitivity analysis revealed that the effectiveness of day closures was particularly influenced by autoregressive processes in the fishery data and by positive relationships between fishing effort and total biomass. Those results indicated the importance of human behavioral dynamics under input control in quantifying the conservation benefit of natural resource management and the applicability of our model framework to the evaluation of the input controls that are actually implemented.

Human umbilical cord matrix mesenchymal stem cells suppress the growth of breast cancer by expression of tumor suppressor genes.

Human and rat umbilical cord matrix mesenchymal stem cells (UCMSC) possess the ability to control the growth of breast carcinoma cells. Comparative analyses of two types of UCMSC suggest that rat UCMSC-dependent growth regulation is significantly stronger than that of human UCMSC. Their different tumoricidal abilities were clarified by analyzing gene expression profiles in the two types of UCMSC. Microarray analysis revealed differential gene expression between untreated naïve UCMSC and those co-cultured with species-matched breast carcinoma cells. The analyses screened 17 differentially expressed genes that are commonly detected in both human and rat UCMSC. The comparison between the two sets of gene expression profiles identified two tumor suppressor genes, adipose-differentiation related protein (ADRP) and follistatin (FST), that were specifically up-regulated in rat UCMSC, but down-regulated in human UCMSC when they were co-cultured with the corresponding species' breast carcinoma cells. Over-expression of FST, but not ADRP, in human UCMSC enhanced their ability to suppress the growth of MDA-231 cells. The growth of MDA-231 cells was also significantly lower when they were cultured in medium conditioned with FST, but not ADRP over-expressing human UCMSC. In the breast carcinoma lung metastasis model generated with MDA-231 cells, systemic treatment with FST-over-expressing human UCMSC significantly attenuated the tumor burden. These results suggest that FST may play an important role in exhibiting stronger tumoricidal ability in rat UCMSC than human UCMSC and also implies that human UCMSC can be transformed into stronger tumoricidal cells by enhancing tumor suppressor gene expression.

Involvement of angiotensin II type 2 receptor (AT2R) signaling in human pancreatic ductal adenocarcinoma (PDAC): a novel AT2R agonist effectively attenuates growth of PDAC grafts in mice.

We have recently discovered the potential involvement of angiotensin II type 2 receptor (AT2R) signaling in pancreatic cancer using AT2R deficient mice. To examine the involvement of AT2R expression in human PDAC, expressions of AT2R as well as the major angiotensin II receptor (type 1 receptor, AT1R) in human PDAC and adjacent normal tissue was evaluated by immunohistochemistry and real time PCR using surgically dissected human PDAC specimens. In immunohistochemical analysis, relatively strong AT1R expression was detected consistently in both normal pancreas and PDAC areas, whereas moderate AT2R expression was detected in 78.5% of PDAC specimens and 100% of normal area of the pancreas. AT1R, but not AT2R, mRNA levels were significantly higher in the PDAC area than in the normal pancreas. AT2R mRNA levels showed a negative correlation trend with overall survival. In cell cultures, treatment with a novel AT2R agonist significantly attenuated both murine and human PDAC cell growth with negligible cytotoxicity in normal epithelial cells. In a mouse study, administrations of the AT2R agonist in tumor surrounding connective tissue markedly attenuated growth of only AT2R expressing PAN02 murine PDAC grafts in syngeneic mice. The AT2R agonist treatment induced apoptosis primarily in tumor cells but not in stromal cells. Taken together, our findings offer clinical and preclinical evidence for the involvement of AT2R signaling in PDAC development and pinpoint that the novel AT2R agonist could serve as an effective therapeutic for PDAC treatment.

APOLLON protein promotes early mitotic CYCLIN A degradation independent of the spindle assembly checkpoint.

In the mammalian cell cycle, both CYCLIN A and CYCLIN B are required for entry into mitosis, and their elimination is also essential to complete the process. During mitosis, CYCLIN A and CYCLIN B are ubiquitylated by the anaphase-promoting complex/cyclosome (APC/C) and then subjected to proteasomal degradation. However, CYCLIN A, but not CYCLIN B, begins to be degraded in the prometaphase when APC/C is inactivated by the spindle assembly checkpoint (SAC). Here, we show that APOLLON (also known as BRUCE or BIRC6) plays a role in SAC-independent degradation of CYCLIN A in early mitosis. APPOLON interacts with CYCLIN A that is not associated with cyclin-dependent kinases. APPOLON also interacts with APC/C, and it facilitates CYCLIN A ubiquitylation. In APPOLON-deficient cells, mitotic degradation of CYCLIN A is delayed, and the total, but not the cyclin-dependent kinase-bound, CYCLIN A level was increased. We propose APPOLON to be a novel regulator of mitotic CYCLIN A degradation independent of SAC.

Naïve rat umbilical cord matrix stem cells significantly attenuate mammary tumor growth through modulation of endogenous immune responses.

BACKGROUND AIMS: Un-engineered human and rat umbilical cord matrix stem cells (UCMSCs) attenuate growth of several types of tumors in mice and rats. However, the mechanism by which UCMSCs attenuate tumor growth has not been studied rigorously. METHODS: The possible mechanisms of tumor growth attenuation by rat UCMSCs were studied using orthotopic Mat B III rat mammary tumor grafts in female F344 rats. Tumor-infiltrating leukocytes were identified and quantified by immunohistochemistry analysis. Potential cytokines involved in lymphocyte infiltration in the tumors were determined by microarray and Western blot analysis. The Boyden chamber migration assay was performed for the functional analysis of identified cytokines. RESULTS: Rat UCMSCs markedly attenuated tumor growth; this attenuation was accompanied by considerable lymphocyte infiltration. Immunohistochemistry analysis revealed that most infiltrating lymphocytes in the rat UCMSC-treated tumors were CD3(+) T cells. In addition, treatment with rat UCMSCs significantly increased infiltration of CD8(+) and CD4(+) T cells and natural killer (NK) cells throughout tumor tissue. CD68(+) monocytes/macrophages and Foxp3(+) regulatory T cells were scarcely observed, only in the tumors of the phosphate-buffered saline control group. Microarray analysis of rat UCMSCs demonstrated that monocyte chemotactic protein-1 is involved in rat UCMSC-induced lymphocyte infiltration in the tumor tissues. CONCLUSIONS: These results suggest that naïve rat UCMSCs attenuated mammary tumor growth at least in part by enhancing host anti-tumor immune responses. Naïve UCMSCs can be used as powerful therapeutic cells for breast cancer treatment, and monocyte chemotactic protein-1 may be a key molecule to enhance the effect of UCMSCs at the tumor site.