Two-tiered deep-learning-based model for histologic diagnosis of Helicobacter gastritis.

AIMS: Helicobacter pylori (HP) infection is the most common cause of chronic gastritis worldwide. Due to the small size of HP and limited resolution, diagnosing HP infections is more difficult when using digital slides. METHODS AND RESULTS: We developed a two-tier deep-learning-based model for diagnosing HP gastritis. A whole-slide model was trained on 885 whole-slide images (WSIs) with only slide-level labels (positive or negative slides). An auxiliary model was trained on 824 areas with HP in nine positive WSIs and 446 negative WSIs for localizing HP. The whole-slide model performed well, with an area under the receiver operating characteristic curve (AUC) of 0.9739 (95% confidence interval [CI], 0.9545-0.9932). The calculated sensitivity and specificity were 93.3% and 90.1%, respectively, whereas those of pathologists were 93.3% and 84.2%, respectively. Using the auxiliary model, the highlighted areas of the localization maps had an average precision of 0.5796. CONCLUSIONS: HP gastritis can be diagnosed on haematoxylin-and-eosin-stained WSIs with human-level accuracy using a deep-learning-based model trained on slide-level labels and an auxiliary model for localizing HP and confirming the diagnosis. This two-tiered model can shorten the diagnostic process and reduce the need for special staining.

Molecular characteristics and in vitro effects of antimicrobial combinations on planktonic and biofilm forms of Elizabethkingia anophelis.

OBJECTIVES: To investigate the in vitro activity of antibiotics against clinical Elizabethkingia anophelis isolates and to find a suitable antibiotic combination with synergistic effects to combat antibiotic-resistant E. anophelis and its associated biofilm. METHODS: E. anophelis isolates were identified by 16S rRNA sequencing; 30 strains with different pulsotypes were identified and the MIC, antibiotic resistance mechanism, antibiotic combination activity and killing effects of antimicrobial agents on biofilms of these strains were determined. RESULTS: All E. anophelis isolates were susceptible to minocycline and cefoperazone/sulbactam (1:1). More than 90% of clinical isolates were susceptible to cefoperazone/sulbactam (1:0.5), piperacillin/tazobactam and rifampicin. Some novel mutations, such as gyrA G81D, parE D585N and parC P134T, that have never been reported before, were identified. The synergistic effect was most prominent for the combination of minocycline and rifampicin, with 93.3% of their FIC index values ≤0.5, and no antagonism was observed using the chequerboard method. This synergistic effect between minocycline and rifampicin was also observed using time-killing methods for clinical E. anophelis isolates at both normal inoculum and high inoculum. Twenty-nine isolates tested positive for biofilm formation. Minocycline remained active against biofilm-embedded and biofilm-released planktonic E. anophelis cells; however, the enhanced effect of minocycline by adding rifampicin was only observed at 24 h (not at 72 and 120 h). CONCLUSIONS: Although E. anophelis was resistant to many antibiotics and could exhibit biofilm formation, minocycline showed potent in vitro activity against this pathogen and its associated biofilm.

Identification of nodal micrometastasis in colorectal cancer using deep learning on annotation-free whole-slide images.

Detection of nodal micrometastasis (tumor size: 0.2-2.0 mm) is challenging for pathologists due to the small size of metastatic foci. Since lymph nodes with micrometastasis are counted as positive nodes, detecting micrometastasis is crucial for accurate pathologic staging of colorectal cancer. Previously, deep learning algorithms developed with manually annotated images performed well in identifying micrometastasis of breast cancer in sentinel lymph nodes. However, the process of manual annotation is labor intensive and time consuming. Multiple instance learning was later used to identify metastatic breast cancer without manual annotation, but its performance appears worse in detecting micrometastasis. Here, we developed a deep learning model using whole-slide images of regional lymph nodes of colorectal cancer with only a slide-level label (either a positive or negative slide). The training, validation, and testing sets included 1963, 219, and 1000 slides, respectively. A supercomputer TAIWANIA 2 was used to train a deep learning model to identify metastasis. At slide level, our algorithm performed well in identifying both macrometastasis (tumor size > 2.0 mm) and micrometastasis with an area under the receiver operating characteristics curve (AUC) of 0.9993 and 0.9956, respectively. Since most of our slides had more than one lymph node, we then tested the performance of our algorithm on 538 single-lymph node images randomly cropped from the testing set. At single-lymph node level, our algorithm maintained good performance in identifying macrometastasis and micrometastasis with an AUC of 0.9944 and 0.9476, respectively. Visualization using class activation mapping confirmed that our model identified nodal metastasis based on areas of tumor cells. Our results demonstrate for the first time that micrometastasis could be detected by deep learning on whole-slide images without manual annotation.

Efficiency enhancement of light color conversion through surface plasmon coupling.

The efficiency enhancement of light color conversion from blue quantum well (QW) emission into red quantum dot (QD) emission through surface plasmon (SP) coupling by coating CdSe/ZnS QDs on the top of an InGaN/GaN QW light-emitting diode (LED) is demonstrated. Ag nanoparticles (NPs) are fabricated within a transparent conductive Ga-doped ZnO interlayer to induce localized surface plasmon (LSP) resonance for simultaneously coupling with the QWs and QDs. Such a coupling process generates three enhancement effects, including QW emission, QD absorption at the QW emission wavelength, and QD emission, leading to an overall enhancement effect of QD emission intensity. An Ag NP geometry for inducing an LSP resonance peak around the middle between the QW and QD emission wavelengths results in the optimized condition for maximizing QD emission enhancement. Internal quantum efficiency and photoluminescence (PL) decay time measurements are performed to show consistent results with LED performance characterizations, even though the QD absorption of PL excitation laser may mix with the SP-induced QD absorption enhancement effect in PL measurement.

Short-term glutamine supplementation decreases lung inflammation and the receptor for advanced glycation end-products expression in direct acute lung injury in mice.

BACKGROUND: Glutamine (GLN) has been reported to improve clinical and experimental sepsis outcomes. However, the mechanisms underlying the actions of GLN remain unclear, and may depend upon the route of GLN administration and the model of acute lung injury (ALI) used. The aim of this study was to investigate whether short-term GLN supplementation had an ameliorative effect on the inflammation induced by direct acid and lipopolysaccharide (LPS) challenge in mice. METHODS: Female BALB/c mice were divided into two groups, a control group and a GLN group (4.17% GLN supplementation). After a 10-day feeding period, ALI was induced by intratracheal administration of hydrochloric acid (pH 1.0; 2 mL/kg of body weight [BW]) and LPS (5 mg/kg BW). Mice were sacrificed 3 h after ALI challenge. In this early phase of ALI, serum, lungs, and bronchoalveolar lavage fluid (BALF) from the mice were collected for further analysis. RESULTS: The results of this study showed that ALI-challenged mice had a significant increase in myeloperoxidase activity and expression of interleukin (IL)-1ß, IL-6, and tumor necrosis factor-α in the lung compared with unchallenged mice. Compared with the control group, GLN pretreatment in ALI-challenged mice reduced the levels of receptor for advanced glycation end-products (RAGE) and IL-1ß production in BALF, with a corresponding decrease in their mRNA expression. The GLN group also had markedly lower in mRNA expression of cyclooxygenase-2 and NADPH oxidase-1. CONCLUSIONS: These results suggest that the benefit of dietary GLN may be partly contributed to an inhibitory effect on RAGE expression and pro-inflammatory cytokines production at an early stage in direct acid and LPS-induced ALI in mice.

In vitro efficacies and resistance profiles of rifampin-based combination regimens for biofilm-embedded methicillin-resistant Staphylococcus aureus.

To compare the in vitro antibacterial efficacies and resistance profiles of rifampin-based combinations against methicillin-resistant Staphylococcus aureus (MRSA) in a biofilm model, the antibacterial activities of vancomycin, teicoplanin, daptomycin, minocycline, linezolid, fusidic acid, fosfomycin, and tigecycline alone or in combination with rifampin against biofilm-embedded MRSA were measured. The rifampin-resistant mutation frequencies were evaluated. Of the rifampin-based combinations, rifampin enhances the antibacterial activities of and even synergizes with fusidic acid, tigecycline, and, to a lesser extent, linezolid, fosfomycin, and minocycline against biofilm-embedded MRSA. Such combinations with weaker rifampin resistance induction activities may provide a therapeutic advantage in MRSA biofilm-related infections.

Measuring the environmental efficiency of countries: a directional distance function metafrontier approach.

This paper measures environmental efficiency (EE) in 63 countries over the period 1981-2005 and analyzes whether the adoption of the Kyoto Protocol is accompanied by an increase in environmental efficiency during the same period. Differences in EE across countries under distinct country-specific production frontiers are measured using a directional distance function model, which incorporates a desirable output (GDP) and an undesirable output (CO2 emissions). It is further assumed that a stochastic meta-technology-frontier exists and represents potential outputs available to all countries given inputs. The metafrontier for four country groups, high income countries, upper-middle income countries, low-middle income countries, and low income countries, are estimated using balanced panel data for the sample countries over the study period. The overall results indicate that the four country groups operated under distinct stochastic production frontiers and therefore used different production technologies. It is found that high income countries achieved the highest progress in their average environmental efficiency relative to the metafrontier, while lower-middle income countries and low income countries recorded negative growth in their average EE relative to the metafrontier.

In vitro activities of antimicrobial combinations against planktonic and biofilm forms of Stenotrophomonas maltophilia.

Objectives: To investigate the in vitro activity of antibiotic combinations against Stenotrophomonas maltophilia isolates and their associated biofilms. Methods: Thirty-two S. maltophilia clinical isolates with at least twenty-five different pulsotypes were tested. The antibacterial activity of various antibiotic combinations against seven randomly selected planktonic and biofilm-embedded S. maltophilia strains with strong biofilm formation was assessed using broth methods. Extraction of bacterial genomic DNA and PCR detection of antibiotic resistance and biofilm-related genes were also performed. Results: The susceptibility rates of levofloxacin (LVX), fosfomycin (FOS), tigecycline (TGC) and sulfamethoxazole-trimethoprim (SXT) against 32 S. maltophilia isolates were 56.3, 71.9, 71.9 and 90.6%, respectively. Twenty-eight isolates were detected with strong biofilm formation. Antibiotic combinations, including aztreonam-clavulanic (ATM-CLA) with LVX, ceftazidime-avibactam (CZA) with LVX and SXT with TGC, exhibited potent inhibitory activity against these isolates with strong biofilm formation. The antibiotic resistance phenotype might not be fully caused by the common antibiotic-resistance or biofilm-formation gene. Conclusion: S. maltophilia remained resistant to most antibiotics, including LVX and ß-lactam/ß-lactamases; however, TGC, FOS and SXT still exhibited potent activity. Although all tested S. maltophilia isolates exhibited moderate-to-strong biofilm formation, combination therapies, especially ATM-CLA with LVX, CZA with LVX and SXT with TGC, exhibited a higher inhibitory activity for these isolates.

Antimicrobial Susceptibility of E. coli Isolates from Intra-Abdominal Infections in the Asia-Pacific Region: Trends in Ciprofloxacin, Ceftriaxone, Cefepime, and Piperacillin/Tazobactam Susceptibility.

Purpose: To investigate the antibiotic susceptibility of Escherichia coli isolates in patients diagnosed with intra-abdominal infections (IAIs) in the Asia-Pacific region. Patients and Methods: This study was conducted at 50 medical hospitals across 9 countries/regions as part of the Study for Monitoring Antimicrobial Resistance Trends (SMART) surveillance program from 2014 to 2018. Nonduplicate isolates of aerobic and facultative gram-negative bacilli were collected and processed for further antimicrobial susceptibility testing. Results: A total of 10,709 isolates were collected, with E. coli (n=4737, 44.2%) being the leading pathogen causing IAIs, followed by Klebsiella pneumoniae (n=2429, 22.7%) and Pseudomonas aeruginosa (n=931, 8.7%). Community-associated (CA) E. coli isolates generally exhibited higher susceptibility rates for most antibiotics than hospital-associated (HA) isolates. In countries/regions other than Hong Kong, South Korea, and Singapore, HA isolates displayed lower susceptibility rates for multiple classes (≥4) of antibiotics. Among the commonly used antibiotics in IAIs, the overall susceptibility rate for ciprofloxacin was low, with an average of 41.3%. Ceftriaxone susceptibility rates in all selected countries were below 80% starting in 2018, ranging from 23.3% to 75.8%. The cefepime susceptibility rates varied across regions, with consistently reduced susceptibility ranging from 45.5% to 57.8% in India, Thailand, and Vietnam. Piperacillin/tazobactam demonstrated effectiveness against E. coli isolates in almost all countries except India, with a downward trend observed in the Philippines and Taiwan. Carbapenems remained effective against more than 90% of E. coli isolates, except in India. Conclusion: Prudent use of fluoroquinolones and ceftriaxone is advised when treating both CA and HA IAIs in the Asia-Pacific region. The low susceptibility rate of cefepime in India, Thailand, and Vietnam needs careful consideration in its administration. Moreover, the increase in nonsusceptibility to piperacillin/tazobactam in the Philippines and Taiwan poses a potential risk that should be closely monitored.

Emergence and dissemination of multidrug-resistant Escherichia coli ST8346 coharboring blaNDM-5 and blaOXA-181 in Southern Taiwan, 2017-2021.

BACKGROUND: Enterobacterales carrying blaNDM represent an emerging challenge in treating infectious diseases. In this study, we aimed to investigate the characteristics of blaNDM-producing Enterobacterales from three hospitals in southern Taiwan. METHODS: Enterobacterales strains that were nonsusceptible to more than one carbapenem (ertapenem, meropenem, imipenem, or doripenem) were collected from hospitalized patients. Molecular typing for New Delhi metallo-ß-lactamase (NDM) and antibiotic susceptibility tests were performed, followed by multilocus sequence typing (MLST), pulsed-field gel electrophoresis (PFGE), and plasmid analysis by PCR-based replicon typing. RESULTS: A total of 1311 carbapenem-nonsusceptible Enterobacterales were isolated from 2017 to 2021. blaNDM-encoding genes were detected in 108 isolates, with 53 (49.1%) harboring blaNDM-1 and 55 (50.9%) harboring blaNDM-5. The rate of blaNDM-1 detection among isolates decreased to 2% in 2021. However, the rate of E. coli harboring blaNDM-5 increased from 1% to 12% of total isolates during the study period. Of 47 NDM-5-positive E. coli isolates, 44 (93.6%) were ST8346 with high genetic relatedness. E. coli ST8346 isolates showed high-level resistance to both carbapenems and aminoglycosides. Most (38 out of 47, 80.9%) blaNDM-5-harboring E. coli isolates co-harbored blaOXA-181. We analyzed the regions harboring blaNDM-5 in E. coli ST8346 via PCR amplification. blaNDM-5 and blaOXA-181 were located on two separate plasmids, IncF and IncX3, respectively. CONCLUSION: The dissemination of E. coli ST8346 caused an increase in blaNDM-5 and blaOXA-181 co-harboring Enterobacterales in southern Taiwan, which show high-level resistance to both carbapenems and aminoglycosides. We identified a distinct IncF plasmid encoding blaNDM-5 that has the potential for rapid spread and needs further surveillance.

Use of Carbapenems against clinical, nontyphoid Salmonella isolates: results from in vitro and in vivo animal studies.

The emergence of multidrug-resistant Salmonella isolates has created the need for new therapeutic agents. We evaluated the intracellular activity of four carbapenem compounds against clinical nontyphoid Salmonella (NTS) isolates in vitro and ex vivo. Subsequently, the efficacy of carbapenem treatment against selected Salmonella isolates in vivo was assessed using a murine peritonitis model. The MIC(50) and MIC(90) for doripenem, ertapenem, imipenem, and meropenem against 126 NTS isolates were found to be 0.062 and 0.062, 0.015 and 0.015, 0.5 and 1, and 0.031 and 0.031 µg/ml, respectively. The intracellular killing effect of ertapenem was sustained for 24 h and was superior to that of imipenem, meropenem, and doripenem; its effect was comparable to that of ceftriaxone. Ertapenem demonstrated an excellent pharmacokinetic profile with a percent time above the MIC of 75.5% and an area under the concentration-time curve/MIC ratio of 20,733. When peritoneal exudate cells were examined directly ex vivo from mice with Salmonella-induced peritonitis, cells from mice treated with ertapenem and ceftriaxone had intracellular and extracellular bacterial counts reduced 10(2)- to 10(4)-fold and exhibited killing effects similar to each other. The survival rates of mice inoculated with 1 × 10(5) and 10(6) CFU of a ceftriaxone-susceptible Salmonella isolate that were subsequently treated with ertapenem or ceftriaxone were 100% and 90%, respectively. When mice were inoculated with 5 × 10(4) and 10(5) CFU of a ceftriaxone-resistant and ciprofloxacin-resistant Salmonella isolate, mice treated with ertapenem had a higher survival rate than mice treated with ceftriaxone (70% versus 0% and 50% versus 0%, respectively; P < 0.001). Our results suggest that ertapenem is at least as effective as ceftriaxone in treating murine Salmonella infections and show that further clinical investigations on the potential use of ertapenem in treatment of human Salmonella infections are warranted.

In vitro efficacy of fosfomycin-containing regimens against methicillin-resistant Staphylococcus aureus in biofilms.

OBJECTIVES: To compare the in vitro antibacterial efficacy of antistaphylococcal antibiotics in combination with fosfomycin or rifampicin, using a biofilm model. METHODS: The antibacterial activities of fusidic acid, linezolid, vancomycin, teicoplanin, rifampicin, minocycline, fosfomycin and tigecycline, individually and in fosfomycin or rifampicin combinations, were measured against planktonic or biofilm-embedded methicillin-resistant Staphylococcus aureus (MRSA) with susceptible and resistant breakpoint concentrations (SBCs and RBCs, respectively), using the MTT-staining method and by counting the number of cfu in the biofilms. RESULTS: Linezolid alone at its SBC, and fosfomycin, linezolid, minocycline and tigecycline at their RBCs, exhibited killing effects on biofilm-embedded MRSA (P < 0.0001). Of the eight fosfomycin combinations studied, fosfomycin combined with linezolid, minocycline, vancomycin or teicoplanin at their respective SBCs, exhibited enhanced antibacterial activities (P < 0.0001) when compared with the control group, and outperformed rifampicin combinations (P < 0.01). The killing effects of fosfomycin combinations at their respective RBCs were better than those at their respective SBCs (P < 0.05). Significantly enhanced killing effects were observed with fosfomycin in combination with vancomycin or teicoplanin, compared with vancomycin or teicoplanin alone. For 10 randomly selected MRSA isolates, the results of colony counting in biofilms were comparable with those of the MTT-staining method. CONCLUSIONS: Fosfomycin enhanced the activities of linezolid, minocycline, vancomycin and teicoplanin. These combinatorial treatments were even better than rifampicin combination regimens, and may provide therapeutic advantages in catheter-related or prosthetic joint infections.

Effects of Tocilizumab on Adults With COVID-19 Pneumonia: A Meta-Analysis.

Background: Coronavirus disease-2019 (COVID-19), a worldwide disaster, has already affected lots of people. Effective care and therapy are currently being evaluated in full swing. Purpose: Our purpose was to investigate the effects of tocilizumab, an interleukin-6 receptor inhibitor, on treatment of adult patients with COVID-19 pneumonia. Data Sources Study Selection and Data Extraction: We conducted a meta-analysis and searched for relevant studies on Pubmed, Embase, and the Cochrane Library without restrictions on language from inception until February 1, 2021. Fifteen studies were included for this meta-analysis. Two authors independently selected and screened these studies, assessed the quality of included studies, and extracted related information. Results: Fifteen studies were included in this meta-analysis. The main studies showed that tocilizumab was associated with lower mortality (risk ratio = 0.62, 95% confidence interval = 0.46-0.83; and hazard ratio = 0.61, 95% confidence interval = 0.51-0.72). Using tocilizumab might also affect biochemistry indicators (lowered C-reactive protein and ferritin, increased lymphocyte count). Conclusion: These current bodies of evidence could indicate that early use of tocilizumab was associated with lower mortality in adult patients with COVID-19. Early use of tocilizumab could reduce the mortality rate of adult patients with COVID-19 without obvious fatal side effects, which may be a treatment option in patients with COVID-19 pneumonia. Systematic Review Registration: The study protocol was registered on PROSPERO (ID:242811).

Circulating pediatric respiratory pathogens in Taiwan during 2020: Dynamic change under low COVID-19 incidence.

BACKGROUND: In Taiwan, there were only 799 confirmed COVID-19 cases in 2020. The unique backdrop amidst a pandemic and promotion of nonpharmaceutical interventions generated some distinct changes in the epidemiology of common respiratory pathogens. In this study, we aimed to investigate the dynamic changes in respiratory pathogens in children during 2020. METHODS: We performed a retrospective cohort study at a tertiary hospital in southern Taiwan during 2020. Patients aged 0-18 years who visited the pediatric emergency department were enrolled. Children who presented with clinical symptoms (fever or respiratory illness) and received nasopharyngeal swabs for multiplex polymerase chain reaction (PCR) were included in our analysis. We also compared respiratory syncytial virus (RSV) trends from previous years by PCR and lateral flow immunochromatographic assays from 2017 to 2020. RESULTS: A total of 120 children were tested. The overall detection rate was 55%. With strengthened restrictions, the detection rate dropped from 70% to 30%. However, non-enveloped viruses (rhinovirus/enterovirus and adenovirus) were in constant circulation. Upon easing prevention measures, the detection rate remained above 60%, and an outbreak of an enveloped virus (RSV and parainfluenza virus) was noted. Compared with 2017-2019, the cyclical RSV epidemic was delayed, with a large surge in late 2020. CONCLUSIONS: We observed a constant circulation of non-enveloped viruses when strict nonpharmaceutical interventions were employed and a delayed surge of enveloped viruses during the easing of restrictions. Continuous surveillance and monitoring of the evolutionary dynamics of respiratory viruses is important, while easing restrictions requires balanced judgment.

Distribution of ß-lactamases and emergence of carbapenemases co-occurring Enterobacterales isolates with high-level antibiotic resistance identified from patients with intra-abdominal infection in the Asia-Pacific region, 2015-2018.

PURPOSE: In this study, we aimed to assess the geographic distribution and molecular characteristics of ß-lactamases among Enterobacterales isolates causing intra-abdominal infections (IAIs) from 2015 to 2018 in the Asia-Pacific region. METHOD: Isolates were investigated for extended-spectrum ß-lactamases (ESBLs), AmpC ß-lactamases, and carbapenemases using multiplex PCR assays and full-gene DNA sequencing. RESULT: A total of 832 Enterobacterales isolates from 8 different countries with ß-lactamase genes were analysed. Plasmid-mediated ESBLs and AmpC ß-lactamases were encoded in 598 (71.9 %) and 314 (37.7 %) isolates, respectively. In 710 (85.3 %) carbapenemase-negative isolates, positivity for both AmpC ß-lactamases and ESBLs was identified in 51 (8.5 %) Escherichia coli and 24 (3.4 %) Klebsiella pneumoniae isolates. The most prevalent countries were Taiwan and Vietnam, and the co-occurrence of CMY/CTX-M in E. coli and DHA-1/ESBLs in K. pneumoniae was predominant. All isolates showed high susceptibility to colistin, but susceptibility to carbapenems varied among different resistance mechanism combinations. Among 122 (14.7 %) isolates encoding carbapenemase, NDM (n = 67, including 64.2 % NDM-1) was the most common, followed by the OXA-48-type (n = 49), KPC (n = 24) and IMP (n = 4). The most prevalent country was Thailand (n = 44), followed by Vietnam (n = 35) and the Philippines (n = 21). Twenty-two isolates were found to encode multiple carbapenemases, 16 of which were collected from Thailand and harbored NDM-1, OXA-232 and CTX-M-15. Despite high susceptibility to amikacin, susceptibility to colistin was only 56 %. CONCLUSION: The emergence of carbapenem-non-susceptible AmpC/ESBL co-occurring Enterobacterales and colistin non-susceptible carbapenemases co-occurring K. pneumoniae highlights potential therapeutic challenges in the Asia-Pacific region.

The effect of Lactobacillus with prebiotics on KPC-2-producing Klebsiella pneumoniae.

Objectives: This study investigated the inhibitory effect of Lactobacillus spp. with prebiotics against Klebsiella pneumoniae carbapenemase-2 (KPC-2)-producing Klebsiella pneumoniae using both in vitro experiments and animal models. Methods: Thirty-three Lactobacillus spp. strains were confirmed by 16S rDNA sequencing, and four different PFGE genotyped KPC-2-producing K. pneumoniae strains were selected for investigation. In vitro studies, including broth microdilution assays, changes in pH values in lactobacilli cultures with different prebiotics, time-kill tests of Lactobacillus spp. against KPC-2-producing K. pneumoniae and further in vivo Lactobacillus alone or in combination with prebiotics against KPC-2-producing K. pneumoniae in an animal model, were performed. Results: The lower pH value of the cell-free supernatant was associated with a lower minimal inhibitory percentage of the Lactobacillus strain against KPC-2-producing K. pneumoniae. Furthermore, lactulose/isomalto-oligosaccharide/inulin and fructo-oligosaccharide can enhance the inhibitory effect of all 107 CFU/ml Lactobacillus strains against KPC001. Three Lactobacillus strains (LYC1154, LYC1322, and LYC1511) that could be persistently detected in the stool were tested for their ability to reduce the amount of KPC001 in the feces individually or in combination. A significantly better effect in reducing the amount of KPC001 was observed for the combination of three different Lactobacillus species than for each of them alone. Furthermore, their inhibitory effect was enhanced after adding lactulose or isomalto-oligosaccharide (both p < 0.05). Conclusion: This study demonstrates the inhibitory effect of probiotic Lactobacillus, including LYC1154, LYC1322, and LYC1511, with prebiotics such as lactulose or isomalto-oligosaccharide against the colonization of KPC-2-producing K. pneumoniae.

Deep neural network trained on gigapixel images improves lymph node metastasis detection in clinical settings.

The pathological identification of lymph node (LN) metastasis is demanding and tedious. Although convolutional neural networks (CNNs) possess considerable potential in improving the process, the ultrahigh-resolution of whole slide images hinders the development of a clinically applicable solution. We design an artificial-intelligence-assisted LN assessment workflow to facilitate the routine counting of metastatic LNs. Unlike previous patch-based approaches, our proposed method trains CNNs by using 5-gigapixel images, obviating the need for lesion-level annotations. Trained on 5907 LN images, our algorithm identifies metastatic LNs in gastric cancer with a slide-level area under the receiver operating characteristic curve (AUC) of 0.9936. Clinical experiments reveal that the workflow significantly improves the sensitivity of micrometastasis identification (81.94% to 95.83%, P < .001) and isolated tumor cells (67.95% to 96.15%, P < .001) in a significantly shorter review time (-31.5%, P < .001). Cross-site evaluation indicates that the algorithm is highly robust (AUC = 0.9829).

In vitro and in vivo intracellular killing effects of tigecycline against clinical nontyphoid Salmonella isolates using ceftriaxone as a comparator.

Salmonella is an important, worldwide food-borne pathogen. Resistance to fluoroquinolones and cephalosporins has been increasingly reported, and new therapeutic agents are desperately needed. In this study, we evaluated the in vitro antimicrobial susceptibility of clinical nontyphoidal Salmonella isolates to tigecycline. Antibacterial activity of tigecycline, ceftriaxone, and ciprofloxacin were investigated by time-kill studies and the murine peritonitis model. The MIC50/MIC90 values of tigecycline, ceftriaxone, and ciprofloxacin against 76 Salmonella isolates were 0.25/0.5, 1/8, and 0.125/0.5 µg/ml, respectively. The intracellular inhibitory activity of tigecycline at 0.5 µg/ml (1 × MIC) against Salmonella isolates in human peripheral blood mononuclear cells was sustained for 24 h. In a mouse peritonitis model, tigecycline reduced the extracellular and intracellular bacterial counts from 107 CFU/ml and 105 CFU/ml, respectively, to an undetectable level within 96 h. The results were similar to those obtained with ceftriaxone. The survival rate of mice exposed to tigecycline after being infected by an inoculum of 1 × 105 CFU was 80%, and that of mice exposed to ceftriaxone was 100%. When the inoculum was increased to 1.3 × 106 CFU, the survival rate of mice treated by tigecycline was 20%, and that of mice exposed to ceftriaxone was 0% (P = 0.2). When a ceftriaxone- and ciprofloxacin-resistant but tigecycline-susceptible isolate was tested, mice treated by tigecycline had a higher survival rate than those treated by ceftriaxone (15/20 [75%] versus 6/20 [30%]; P = 0.011). Our results suggest that tigecycline is at least as effective as ceftriaxone for murine Salmonella infections and warrants further clinical investigations to delineate its potential against human Salmonella infections.

Antimicrobial ability and mechanism analysis of Lactobacillus species against carbapenemase-producing Enterobacteriaceae.

BACKGROUND: This study aims to investigate the antimicrobial ability and mechanism analysis of Lactobacillus species against carbapenemase-producing Enterobacteriaceae (CPE). METHODS: Five Lactobacillus spp. strains and 18 CPE clinical isolates were collected. Their anti-CPE effects were assessed by agar well diffusion and broth microdilution assay, as well as time-kill test. Finally, the specific anti-CPE mechanism, especially for the effect of organic acids was determined using broth microdilution method. RESULTS: All of five Lactobacilli isolates displayed the potent activity against most CPE isolates with mean zones of inhibition ranging 10.2-21.1 mm. The anti-CPE activity was not affected by heating, catalase, and proteinase treatment. Under the concentration of 50% LUC0180 cell-free supernatant (CFS), lactic acid, and mix acid could totally inhibit the growth of carbapenem-resistant Klebsiella pneumoniae (CPE0011), and acetic acid could inhibit 67.8%. In contrast, succinic acid and citric acid could not inhibit the growth of CPE0011. While we decreased the concentration to 25%, only lactic acid and mix acid displayed 100% inhibition. In contrast, succinic acid, citric acid and acetic acid did not show any inhibitory effect. CONCLUSIONS: Lactobacillus strains exhibit potent anti-CPE activity, and lactic acid produced by Lactobacillus strains is the major antimicrobial mechanism.

Improvement of p-Type AlGaN Conductivity with an Alternating Mg-Doped/Un-Doped AlGaN Layer Structure.

Using molecular beam epitaxy, we prepared seven p-type AlGaN samples of ~25% in Al content, including six samples with Mg-doped/un-doped AlGaN alternating-layer structures of different layer-thickness combinations, for comparing their p-type performances. Lower sheet resistance and higher effective hole mobility are obtained in a layer-structured sample, when compared with the reference sample of uniform Mg doping. The improved p-type performance in a layer-structured sample is attributed to the diffusion of holes generated in an Mg-doped layer into the neighboring un-doped layers, in which hole mobility is significantly higher because of weak ionized impurity scattering. Among the layer-structured samples, that of 6/4 nm in Mg-doped/un-doped thickness results in the lowest sheet resistance (the highest effective hole mobility), which is 4.83 times lower (4.57 times higher) when compared with the sample of uniform doping. The effects of the Mg-doped/un-doped layer structure on p-type performance in AlGaN and GaN are compared.