Decreased risk of renal cell carcinoma in patients with type 2 diabetes treated with sodium glucose cotransporter-2 inhibitors.

Patients with type 2 diabetes (T2D) are at a higher risk of developing renal cell carcinoma (RCC) than the general population. In vitro and in vivo investigations of the effects of sodium glucose cotransporter-2 inhibitors (SGLT2I) have shown a significantly reduced risk of RCC. However, the impact of these drugs on the incidence of RCC in the human population is unclear. This study aimed to examine the association between SGLT2I use and RCC risk in patients with T2D. We undertook a nationwide retrospective cohort study using the Health and Welfare Data Science Center database (2016-2020). The primary outcome was the risk of incident RCC by estimating hazard ratios (HRs) and 95% confidence intervals (CIs). Multiple Cox regression modeling was applied to analyze the association between SGLT2I use and RCC risk in patients with T2D. In a cohort of 241,772 patients with T2D who were using SGLT2Is and 483,544 participants who were not, 220 and 609 RCC cases, respectively, were recorded. The mean follow-up period of the study subjects was 2 years. There was a decreased risk of RCC for SGLT2I users after adjusting for the index year, sex, age, comorbidities, and concurrent medication (adjusted HR 0.68; 95% CI, 0.58-0.81). The sensitivity test for the propensity score 1:1-matched analyses showed similar results (adjusted HR 0.67; 95% CI, 0.55-0.81). The subgroup analysis revealed consistent results for sex, age (<70 years), and comorbidity with chronic kidney disease. The present study indicates that SGLT2I therapy significantly decreases RCC risk in patients with T2D. This finding was also consistent among the sensitivity test and subgroup analysis for those with or without chronic kidney disease/hypertension.

Global epidemiology and antimicrobial resistance of Enterobacterales harbouring genes encoding OXA-48-like carbapenemases: insights from the results of the Antimicrobial Testing Leadership and Surveillance (ATLAS) programme 2018-2021.

OBJECTIVES: The recent emergence of carbapenem-resistant Enterobacterales poses a major and escalating threat to global public health. This study aimed to analyse the global distribution and antimicrobial resistance of Enterobacterales harbouring variant OXA-48-like carbapenemase-related genes. METHODS: Enterobacterales isolates were collected from the Antimicrobial Testing Leadership and Surveillance (ATLAS) programme during 2018-2021. Comprehensive antimicrobial susceptibility testing and ß-lactamase gene detection were also conducted, along with statistical analysis of the collected data. RESULTS: Among the 72 244 isolates, 1934 Enterobacterales isolates were identified to harbour blaOXA-48-like genes, predominantly Klebsiella spp. (86.9%). High rates of multidrug resistance were observed, with only ceftazidime/avibactam and tigecycline showing favourable susceptibility. A discrepancy between the genotype and phenotype of carbapenem resistance was evident: 16.8% (233 out of 1384) of the Enterobacterales isolates with blaOXA-48-like genes exhibited susceptibility to meropenem. Specifically, 37.4% (64/95) of Escherichia coli strains with blaOXA-48-like genes displayed meropenem susceptibility, while the corresponding percentages for Klebsiella pneumoniae and Enterobacter cloacae complex were 25.2% (160/1184) and 0% (0/36), respectively (P < 0.05). Geographical analysis revealed that the highest prevalence of blaOXA-48-like genes occurred in Asia, the Middle East and Eastern Europe. The proportion of K. pneumoniae isolates harbouring blaOXA-232 increased from 23.9% in 2018 to 56.0% in 2021. By contrast, the proportion of blaOXA-48 decreased among K. pneumoniae isolates during 2018-2021. CONCLUSIONS: This study underscores the widespread and increasing prevalence of blaOXA-48-like genes in Enterobacterales and emphasizes the need for enhanced surveillance, improved diagnostic methods and tailored antibiotic stewardship to combat the spread of these resistant pathogens.

Imipenem reduces the efficacy of vancomycin against Elizabethkingia species.

BACKGROUND: Elizabethkingia spp. are emerging as nosocomial pathogens causing various infections. These pathogens express resistance to a broad range of antibiotics, thus requiring antimicrobial combinations for coverage. However, possible antagonistic interactions between antibiotics have not been thoroughly explored. This study aimed to evaluate the effectiveness of antimicrobial combinations against Elizabethkingia infections, focusing on their impact on pathogenicity, including biofilm production and cell adhesion. METHODS: Double-disc diffusion, time-kill, and chequerboard assays were used for evaluating the combination effects of antibiotics against Elizabethkingia spp. We further examined the antagonistic effects of antibiotic combinations on biofilm formation and adherence to A549 human respiratory epithelial cells. Further validation of the antibiotic interactions and their implications was performed using ex vivo hamster precision-cut lung sections (PCLSs) to mimic in vivo conditions. RESULTS: Antagonistic effects were observed between cefoxitin, imipenem and amoxicillin/clavulanic acid in combination with vancomycin. The antagonism of imipenem toward vancomycin was specific to its effects on the genus Elizabethkingia. Imipenem further hampered the bactericidal effect of vancomycin and impaired its inhibition of biofilm formation and the adhesion of Elizabethkingia meningoseptica ATCC 13253 to human cells. In the ex vivo PCLS model, vancomycin exhibited dose-dependent bactericidal effects; however, the addition of imipenem also reduced the effect of vancomycin. CONCLUSIONS: Imipenem reduced the bactericidal efficacy of vancomycin against Elizabethkingia spp. and compromised its capacity to inhibit biofilm formation, thereby enhancing bacterial adhesion. Clinicians should be aware of the potential issues with the use of these antibiotic combinations when treating Elizabethkingia infections.

Burnout during the COVID-19 pandemic among nurses in Taiwan: the parental role effect on burnout.

BACKGROUND: During the COVID-19 pandemic, medical workers were concerned about the care of their children or family members and the impact of being separated from them. This increased stress could harm the relationship between nurses and patients. This study assessed how medical workers' parental role may affect burnout during such a high-stress period. METHODS: This cross-sectional observational study was carried out in 2021 during the COVID-19 pandemic. The client burnout (CB) scale of the Copenhagen Burnout Inventory, the Nordic Musculoskeletal Questionnaire, and a demographic questionnaire were used. Statistical methods such as the t-test, one-way ANOVA, and univariable/multiple linear regression were applied. RESULTS: A total of 612 nurses were included in this study. The likely risk factors of CB were identified and the parenthood effect was found to be associated with reduced CB. The parental role and leisure activity with family and friends on CB were found to have an impact. Engaging in leisure activity with family and playing the role of a parent diligently will help relieve nurses' burnout from frequent contact with patients and their families, thus lowering the risk of clinical burnout. CONCLUSION: The parental role, family/friends relationships, and a complex work environment associated with nurses' burnout during the COVID-19 pandemic. This finding allows us to re-examine the importance of family life and parent-child relationships in high-stress work environments.

Long Noncoding RNA lncCAMTA1 Promotes Proliferation and Cancer Stem Cell-Like Properties of Liver Cancer by Inhibiting CAMTA1.

Hepatocellular carcinoma (HCC) is the most common subtype of liver malignancy, and it is characterized by poor prognosis because of cancer stem cell (CSC)-mediated high postsurgical recurrence rates. Thus, targeting CSCs, or HCC cells with CSC-like properties, is an effective strategy for HCC therapy. Here, using long noncoding RNA (lncRNA) microarray analysis, we identified a novel lncRNA termed lncCAMTA1 that is increased in both liver CSCs and HCC. High lncCAMTA1 expression in HCC indicates poor clinical outcome. In vitro and in vivo functional experiments showed that overexpression of lncCAMTA1 promotes HCC cell proliferation, CSC-like properties, and tumorigenesis. Conversely, depletion of lncCAMTA1 inhibits HCC cell proliferation, CSC-like properties, and tumorigenesis. Mechanistically, we demonstrated that lncCAMTA1 physically associates with the calmodulin binding transcription activator 1 (CAMTA1) promoter, induces a repressive chromatin structure, and inhibits CAMTA1 transcription. Furthermore, CAMTA1 is required for the effects of lncCAMTA1 on HCC cell proliferation and CSC-like properties, and the expression of lncCAMTA1 and CAMTA1 is significantly negatively correlated in HCC tissues. Collectively, our study revealed the important roles and underlying molecular mechanisms of lncCAMTA1 on HCC, and suggested that lncCAMTA1 could be an effective prognostic factor and a potential therapeutic target for HCC.

The safety and immunogenicity of a MF59-adjuvanted H5N1 prepandemic influenza vaccine in healthy adults primed with homologous or heterologous H5N1 vaccines: an observational study.

BACKGROUND: World Health Organization (WHO) has recommended individuals with increased risk of contracting influenza A H5N1 infection to be immunized against the virus during the inter-pandemic period. Safety and immunogenicity of H5N1 vaccine among participants primed with homologous or heterologous H5N1 vaccines produced by diverse manufactures have not been reported. METHODS: Healthy individuals aged 20 to 60 years old were recruited and stratified into three groups: participants without priming (control group), participants primed with A/Indonesia/05/2005 vaccine, participants primed with A/Vietnam/1194/2004 vaccine and A/Indonesia/05/2005 vaccine. Enrolled participants received two doses of MF59-adjuvanted A/Vietnam/1194/2004 vaccine (study vaccine). Solicited reactions were recorded by vaccine recipients. Blood samples were obtained for hemagglutination inhibition test. RESULTS: A total of 131 participants were enrolled. No significant adverse events were recorded. Tenderness, fatigue and general muscle ache were the most common solicited reactions which alleviated within one week of immunization. Three weeks after two doses of the study vaccine, 63%, 68% and 88% were in seroprotective status in the control group, A/Indonesia/05/2005 primed group and A/Vietnam/1194/2004 and A/Indonesia/05/2005 primed group, respectively. Participants primed with A/Vietnam/1194/2004 and A/Indonesia/05/2005 showed high immune response after booster with one dose of the study vaccine. CONCLUSION: The study vaccine did not cause severe adverse events. It elicited mostly mild to moderate reactions among participants. Participants primed with A/Vietnam/1194/2004 and A/Indonesia/05/2005 vaccine showed higher immune response than those without priming or primed with A/Indonesia/05/2005 vaccine. The report suggested those with an increased risk of influenza A H5N1 virus exposure may benefit from receiving influenza A H5N1 priming during the inter-pandemic period if the antigenicity of the pandemic influenza strain is similar to that of the priming strain.

Type Disparity in Sodium-Glucose Cotransporter-2 Inhibitors in Incidences of Renal Cell Carcinoma: A Propensity-Score-Matched Cohort Study.

(1) Background: Recently, sodium-glucose cotransporter-2 inhibitors (SGLT2Is) have been reported to significantly reduce renal cell carcinoma (RCC) risk. However, the effect between individual SGLT2Is on RCC incidence in patients with type 2 diabetes (T2D) or heart failure is unclear. We conducted an observational analysis to explore type disparity in the prescription of SGLT2Is on RCC risk. (2) Methods: A nationwide retrospective cohort study using the Health and Welfare Data Science Center database (2016-2021) was conducted. Patients aged ≥40 years who took SGLT2Is were designated as the SGLT2I group, whereas propensity score 1:1-matched randomly selected patients without SGLT2Is were assigned to the non-SGLT2I group. The primary outcome was the risk of incident RCC between individual SGLT2Is. Multiple Cox regression modeling was conducted to analyze the association between individual SGLT2I use and RCC risk. (3) Results: After a 5.5-year follow-up, SGLT2I use was associated with a significantly lower risk of incident RCC (hazard: 0.62; 95% confidence interval [CI]: 0.44-0.89). Compared with non-users and after adjusting for the index year, sex, age, comorbidities, concurrent medication, and the risk of developing RCC, the hazard ratios of dapagliflozin, canagliflozin, and empagliflozin were 0.66 (95% CI: 0.53-0.83), 0.84 (95% CI: 0.46-1.30), and 0.71 (95% CI: 0.56-0.90), respectively. (4) Conclusions: Our data show a type-based effect of SGLT2Is on RCC risk. The type-based effect of SGLT2Is should be further studied for better clinical management information and for reducing RCC incidence in patients with T2D.

Puerperal mastitis caused by limited community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) clones.

Objective: To outline the epidemiology of puerperal mastitis caused by methicillin-resistant Staphylococcus aureus (MRSA) and evaluate the effect of an infection control bundle on its incidence. Methods: A surge in MRSA puerperal mastitis was noted in a community hospital in September 2009. MRSA samples from mastitis cases and the environment underwent typing using multilocus sequence typing (MLST), staphylococcal cassette chromosome mec (SCCmec), gene encoding surface protein A (spa), accessory gene regulator (agr), and pulsed-field gel electrophoresis (PFGE). The phenotypic characteristics, including superantigen toxin profiles, gene encoding Panton-Valentine leucocidin (pvl), and minimal inhibitory concentration (MIC) against vancomycin, were ascertained. Subsequently, an infection control bundle emphasizing contact precautions was introduced, and mastitis incidence rates pre- and post-intervention were compared. Results: The majority of cases occurred within 6 weeks post-delivery in first-time mothers. Of the 42 S. aureus isolates (27 from mastitis and 15 from colonized staff and environmental sources), 25 (92.6%) clinical and 3 (20%) colonized MRSA were identified as ST59-SCCmecVT-spa t437-agr group I with a vancomycin MIC of 1 mg/L, pvl-positive, and predominantly with a consistent toxin profile (seb-selk-selr). PFGE revealed 13 patterns; pulsotype B exhibited clonal relatedness between two clinical and three colonized MRSA samples. Post-intervention, the incidence of both mastitis and MRSA mastitis notably decreased from 13.01 to 1.78 and from 3.70 to 0.99 episodes per 100 deliveries, respectively. Conclusion: Distinct community-associated MRSA (CA-MRSA) clones were detected among puerperal mastitis patients and colonized staff. The outbreak was effectively controlled following the implementation of a targeted infection control bundle.

Comparative Analysis of Two Commercial Automated Systems with Agar Dilution for Oxacillin Susceptibility and Their Association with Genotypes of Invasive Staphylococcus aureus Isolates (2011-2021).

Background: Determining oxacillin susceptibility using reference methods and automated systems is crucial for treating invasive infections caused by Staphylococcus aureus. This study compares the oxacillin susceptibility results from the two automated systems with agar dilution and correlates them with genotypes of invasive S. aureus. Methods: Non-duplicate S. aureus invasive isolates were collected over an 11-year period. The oxacillin susceptibility was determined with Phoenix 100 (Jan 2011 to Aug 2018) or Vitek 2 (Sep 2018 to Dec 2021), and susceptibility for oxacillin and cefoxitin was determined with agar dilution. Methicillin-resistant S. aureus (MRSA) was confirmed with mecA existence, and the genotype was determined using SCCmec. The association between genotype and antibiotic susceptibility using two automated systems and agar dilution was evaluated. Results: A total of 842 invasive S. aureus, including 443 mecA+ MRSA and 399 mecA- MSSA, were collected. The susceptibility rates of oxacillin determined by two automated systems and agar dilution were 68.8% (76.8% for Phoenix 100 and 57.6% for Vitek 2) and 54.0%, respectively. When compared with the oxacillin susceptibility using agar dilution, the categorical agreement for Phoenix 100 and Vitek 2 were 0.46% and 0.88%, respectively (p < 0.001). One hundred and forty-three isolates were misinterpreted as oxacillin-susceptible S. aureus (OSSA) using automated systems while comparing with agar dilution, among which molecularly community-associated MRSA (CA-MRSA) outnumbered healthcare-associated MRSA (HA-MRSA) (99 vs 34, p < 0.001). There were 70 mecA+ OSSA (OS-MRSA) using agar dilution, among which 42 harbored SCCmec types were predominantly categorized as CA-MRSA (38, p < 0.001). Conclusion: The categorical agreement of Vitek 2 in determining oxacillin susceptibility and predicting mecA existence is comparable with agar dilution, whereas Phoenix 100 is not. Most of those ORSA determined by agar dilution but misinterpreted as OSSA by automated systems and OS-MRSA are categorized as CA-MRSA.

Endemic melioidosis in central Taiwan-A longitudinal case cohort study.

Background: Melioidosis is a systemic and suppurative disease endemic in the Southeast Asia. In Taiwan, most cases are reported in the southern region and no relevant profiles have been reported in central region. In this study, we performed the epidemiologic and clinical analyses from the melioidosis cases in central Taiwan. Methods: The demographic, clinical, laboratory, radiologic, and outcome profiles were collected retrospectively and analyzed from patients whom Burkhoderia pseudomallei was isolated from clinical specimens during the 12-year study period (2011-2022). Results: Totally 11 melioidosis cases (10 males and 1 female) were diagnosed, among them only 2 (18.2%) cases lived in suburban areas. Seven (63.6%) cases were diagnosed during 2019-2020, and diabetes mellitus was the most relevant comorbidity (5, 45.4%). All cases presented with fever at arrival, but only 4 (36.4%) and 2 (18.2%) cases presented with dyspnea and shock, respectively. Pneumonitis and extrapulmonary involvement were found in 5 cases (45.4%) each. Appropriate empiric and targeted antibiotic treatments were found in 4 (36.4%) and 10 (91.0%) case, respectively. Two cases (18.2%) succumbed to infection despite appropriate treatment including targeted antibiotics. Conclusion: Melioidosis has become endemic in central Taiwan. Septic patients who present with suppurative or undetermined foci and have unsatisfied responses to standard treatment should arouse clinicians to take melioidosis into consideration.

GLP-1 enhances hyperpolarization-activated currents of mouse cerebellar Purkinje cell in vitro.

Glucagon-like peptide-1 (GLP-1) is mainly secreted by preglucagonergic neurons in the nucleus tractus solitarius, which plays critical roles in regulation of neuronal activity in the central nervous system through its receptor. In the cerebellar cortex, GLP-1 receptor is abundantly expressed in the molecular layer, Purkinje cell (PC) layer and granular layer, indicating that GLP-1 may modulate the cerebellar neuronal activity. In this study, we investigated the mechanism by which GLP1 modulates mouse cerebellar PC activity in vitro. After blockade of glutamatergic and GABAergic synaptic transmission in PCs, GLP1 increased the spike firing rate accompanied by depolarization of membrane potential and significantly depressed the after-hyperpolarizing potential and outward rectifying current of spike firing discharges via GLP1 receptors. In the presence of TTX and Ba2+, GLP1 significantly enhanced the hyperpolarized membrane potential-evoked instant current, steady current, tail current (I-tail) and hyperpolarization-activated (IH) current. Application of a selective IH channel antagonist, ZD7288, blocked IH and abolished the effect of GLP1 on PC membrane currents. The GLP1 induced enhancement of membrane currents was also abolished by a selective GLP1 receptor antagonist, exendin-9-39, as well as by protein kinase A (PKA) inhibitors, KT5720 and H89. In addition, immunofluorescence detected GLP1 receptor in the mouse cerebellar cortex, mostly in PCs. These results indicated that GLP1 receptor activation enhanced IH channel activity via PKA signaling, resulting in increased excitability of mouse cerebellar PCs in vitro. The present findings indicate that GLP1 plays a critical role in modulating cerebellar function by regulating the spike firing activity of mouse cerebellar PCs.

Genotyping of methicillin-resistant Staphylococcus aureus isolates causing invasive infections using spa typing and their correlation with antimicrobial susceptibility.

Correlation of antimicrobial susceptibility patterns with particular spa types could help physicians select appropriate antibiotics for the treatment of invasive methicillin-resistant Staphylococcus aureus (MRSA) infections. The aim of this study was to investigate invasive MRSA isolates through delineating the molecular typing results and correlating them with antibiotic susceptibility testing results. A total of 670 non-duplicate mecA-positive MRSA isolates from patients with invasive infections were collected from a 5-year nationwide antimicrobial surveillance programme [Tigecycline In vitro Surveillance in Taiwan (TIST)] and 58 spa types were identified among 639 isolates (95.4%) by determining the allelic profile of the spa gene using PCR and nucleotide sequencing. Six major spa types, including spa t002 (n = 103; 15.4%) and t037 (n = 253, 37.8%), were classified as healthcare-associated MRSA (HA-MRSA; 53.1%), while t437 (n = 151; 22.5%), t441 (n = 13; 1.9%), t1081 (n = 19; 2.8%) and t3525 (n = 14; 2.1%) were classified as community-associated MRSA (CA-MRSA; 29.4%). Antimicrobial susceptibility was determined by agar dilution or broth microdilution for various antibiotics, and Etest was also used both for daptomycin and vancomycin. The declining trend in vancomycin minimum inhibitory concentration (MIC) was in parallel with an increasing frequency of CA-MRSA. Antibiotic susceptibility patterns were correlated with particular spa types and this correlation could help physicians select appropriate antibiotics for the treatment of invasive MRSA infections.

Molecular epidemiology and phenotypes of invasive methicillin-resistant vancomycin-intermediate Staphylococcus aureus in Taiwan.

BACKGROUND: Patients with invasive infections caused by methicillin-resistant Staphylococcus aureus (MRSA), especially those with an elevated minimal inhibitory concentration (MIC) of vancomycin (VA), are likely to have treatment failure and poor outcomes. The aim of this study was to delineate and correlate the genotypes and phenotypes of clinical VA-intermediate S. aureus (VISA) from invasive infections in Taiwan. METHODS: Between 2006 and 2010, a total of 670 non-duplicate MRSA isolates were collected from patients with invasive infections, mostly from blood, as part of a nationwide antimicrobial surveillance program named Tigecycline in vitro Surveillance in Taiwan. Among them, 10 (1.5%) VISA (VA MIC = 4 mg/L) isolates were identified. Molecular typing with staphylococcal cassette chromosome mec (SCCmec), multilocus sequence typing, staphylococcal protein A (spa), mec-associated hypervariable region (dru), accessory gene regulator (agr), and pulse-field gel electrophoresis, and phenotypic analysis including antibiotic susceptibility testing, gene encoding Panton-Valentine leukocidin (pvl), and superantigenic toxin profiles, were analyzed. RESULTS: All but one isolate was defined as molecular health-care-associated MRSA: 6 as SCCmecIII-ST239-spa t037-agrI-dru7 (1 isolate) and dru14 (5 isolates), 2 as SCCmecII-ST5-spa t586-agrII-dru4, and one as SCCmecII-ST89-spa t3520-agrIII-dru7. One isolate was defined as SCCmecIV-ST59-spa t437-agrI-dru8, which was categorized as molecular community-associated MRSA. Five pulsotypes were identified; only one had a positive D-test and 3 were insusceptible to daptomycin (MIC ≧1 mg/L). Five isolates possessed sea-selk-selq, among them 4 belonged to SCCmecIII-ST239-spa t037-agrI. CONCLUSION: In this study, VISA was rarely isolated from invasive MRSA infections, and most cases harbored limited genotypes and corresponding phenotypes.

A case series report on successful management of patients with COVID-19-associated lymphopenia and potential application of PG2.

Background: Lymphopenia and the resultant high neutrophil-to-lymphocyte ratio (NLR) are hallmark signs of severe COVID-19, and effective treatment remains unavailable. We retrospectively reviewed the outcomes of COVID-19 in a cohort of 26 patients admitted to Chung Shan Medical University Hospital (Taichung City, Taiwan). Twenty-five of the 26 patients recovered, including 9 patients with mild/moderate illness and 16 patients with severe/critical illness recovered. One patient died after refusing treatment. Case presentation: We report the cases of four patients with high NLRs and marked lymphopenia, despite receiving standard care. A novel injectable botanical drug, PG2, containing Astragalus polysaccharides, was administered to them as an immune modulator. The decrease in the NLR in these four patients was faster than that of other patients in the cohort (0.80 vs. 0.34 per day). Conclusion: All patients recovered from severe COVID-19 showed decreased NLR and normalized lymphocyte counts before discharge. Administration of PG2 may be of benefit to patients with moderate to severe COVID-19 and lymphopenia.