National genomic epidemiology investigation revealed the spread of carbapenem-resistant Escherichia coli in healthy populations and the impact on public health.

BACKGROUND: Carbapenem-resistant Escherichia coli (CREC) has been considered as WHO priority pathogens, causing a great public health concern globally. While CREC from patients has been thoroughly investigated, the prevalence and underlying risks of CREC in healthy populations have been overlooked. Systematic research on the prevalence of CREC in healthy individuals was conducted here. We aimed to characterize CREC collected from healthy populations in China between 2020 and 2022 and to compare the genomes of CREC isolates isolated from healthy individuals and clinical patients. METHODS: We present a nationwide investigation of CREC isolates among healthy populations in China, employing robust molecular and genomic analyses. Antimicrobial susceptibility testing, whole-genome sequencing, and bioinformatics were utilized to analyze a cohort of CREC isolates (n = 113) obtained from fecal samples of 5 064 healthy individuals. Representative plasmids were extracted for third-generation nanopore sequencing. We previously collected 113 non-duplicate CREC isolates (59 in 2018, 54 in 2020) collected from ICU patients in 15 provinces and municipalities in China, and these clinical isolates were used to compare with the isolates in this study. Furthermore, we employ comparative genomics approaches to elucidate molecular variations and potential correlations between clinical and non-clinical CREC isolates. RESULTS: A total of 147 CREC isolates were identified from 5 064 samples collected across 11 provinces in China. These isolates were classified into 64 known sequence types (STs), but no dominant STs were observed. In total, seven carbapenemase genes were detected with blaNDM-5 (n = 116) being the most prevalent one. Genetic environments and plasmid backbones of blaNDM were conserved in CREC isolated from healthy individuals. Furthermore, we compared clinical and healthy human-originated CRECs, revealing noteworthy distinctions in 23 resistance genes, including blaNDM-1, blaNDM-5, and blaKPC (χ2 test, p < 0.05). Clinical isolates contained more virulence factors associated with iron uptake, adhesion, and invasion than those obtained from healthy individuals. Notably, CREC isolates generally found healthy people are detected in hospitalized patients. CONCLUSIONS: Our findings underscore the significance of healthy populations-derived CRECs as a crucial reservoir of antibiotic resistance genes (ARGs). This highlights the need for ongoing monitoring of CREC isolates in healthy populations to accurately assess the potential risks posed by clinical CREC isolates.

Phenotypic and genomic characteristics of clinical IMP-producing Klebsiella spp. Isolates in China.

BACKGROUND: IMP-producing Klebsiella spp. (IMPKsp) strains have spread globally, including in China. Currently, the prevalence and genomic characterization of IMPKsp is largely unknown nationwide. Here we aimed to provide a general overview of the phenotypic and genomic characteristics of IMPKsp strains. METHODS: 61 IMPKsp strains were obtained from 13 provinces in China during 2016-2021. All strains were tested for their susceptibility to antimicrobial agents by the microdilution broth method and sequenced with Illumina next-generation sequencing. We performed conjugation experiments on thirteen representative strains which were also sequenced by Oxford nanopore sequencing technology to characterize blaIMP-encoding plasmids. RESULTS: We find that all IMPKsp strains display multidrug-resistant (MDR) phenotypes. All strains belong to 27 different STs. ST307 emerges as a principal IMP-producing sublineage. blaIMP-4 is found to be the major isoform, followed by blaIMP-38. Seven incompatibility types of blaIMP-encoding plasmids are identified, including IncHI5 (32/61, 52.5%), IncN-IncR (10/61, 16.4%), IncFIB(K)-HI1B (7/61, 11.5%), IncN (5/61, 8.2%), IncN-IncFII (2/61, 3.3%), IncFII (1/61, 1.6%) and IncP (1/61, 1.6%). The strains carrying IncHI5 and IncN plasmids belong to diverse ST types, indicating that these two plasmids may play an important role in the transmission of blaIMP genes among Klebsiella spp. strains. CONCLUSIONS: Our results highlight that multi-clonal transmission, multiple genetic environments and plasmid types play a major role in the dissemination process of blaIMP genes among Klebsiella spp. IncHI5 type plasmids have the potential to be the main vectors mediating the spread of the blaIMP genes in Klebsiella spp.

Antibiotic resistance occurs when bacteria evolve to withstand antibiotic drugs. We are aware that a bacteria called Klebsiella is rapidly becoming resistant to carbapenems, a class of broad-spectrum antibiotics. In this study, we conducted a genetic and microbiological surveillance study across 13 provinces of China to understand factors that contribute to the growing bacterial drug resistance. We find that the way the multiple bacterial types interact with each other and swap certain genetic material may be the main cause of growing resistance. These findings call for close monitoring of genetic evolution as a matter of public health management strategy.

Phenotypic and Genomic Characterization of ST133 Siderophore-Encoding Extensively Drug-Resistant Enterobacter hormaechei.

We identified an ST133 extensively drug-resistant Enterobacter hormaechei, C210017, with increased virulence in the Galleria mellonella infection model. Genomic analysis suggested it carried antibiotic resistance genes blaKPC-2 and mcr-9.1, and genes iutAiucABCD and iroBCDEN encoding the virulence factor, siderophores. Comparative genomics of C210017 and the 178 ST133 E. hormaechei strains in the database suggested they all belonged to serotype O3 and most strains (77.5%) carried the IncHI2 superplasmids associated with the resistance, virulence, and adaptation of the host strain.

Increased clonal dissemination of OXA-232-producing ST15 Klebsiella pneumoniae in Zhejiang, China from 2018 to 2021.

BACKGROUND: OXA-232-producing Klebsiella pneumoniae was first identified in China in 2016, and its clonal transmission was reported in 2019. However, there are no prevalence and genotypic surveillance data available for OXA-232 in China. Therefore, we investigated the trends and characteristics of OXA-232 type carbapenemase in Zhejiang Province, China from 2018 to 2021. METHODS: A total of 3278 samples from 1666 patients in the intensive care units were collected from hospitals in Zhejiang Province from 2018 to 2021. Carbapenem-resistant isolates were initially selected by China Blue agar plates supplemented with 0.3 µg/ml meropenem, and further analyzed by matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry identification, immune colloidal gold technique, conjugation experiment, antimicrobial susceptibility testing and whole genome sequencing. RESULTS: A total of 79 OXA-producing strains were recovered, with the prevalence increased from 1.8% [95% confidence interval (CI): 0.7-3.7%] in 2018 to 6.0% (95% CI: 4.4-7.9%) in 2021. Seventy-eight strains produced OXA-232 and one produced OXA-181. The blaOXA-232 gene in all strains was located in a 6141-bp ColKP3-type non-conjugative plasmid and the blaOXA-181 gene was located in a 51,391-bp ColKP3/IncX3-type non-conjugative plasmid. The blaOXA-232-producing K. pneumoniae was dominated (75/76) by isolates of sequence type 15 (ST15) that differed by less than 80 SNPs. All OXA-producing strains (100%, 95% CI: 95.4-100.0%) were multidrug-resistant. CONCLUSIONS: From 2018 to 2021, OXA-232 is the most prevalent OXA-48-like derivative in Zhejiang Province, and ST15 K. pneumoniae isolates belonging to the same clone are the major carriers. The transmission of ColKP3-type plasmid to E. coli highlighted that understanding the transmission mechanism is of great importance to delay or arrest the propagation of OXA-232 to other species.

Comparison of the NG-Test Carba 5, Colloidal Gold Immunoassay (CGI) Test, and Xpert Carba-R for the Rapid Detection of Carbapenemases in Carbapenemase-Producing Organisms.

Carbapenem-resistant Enterobacterales (CRE) are increasingly recognized as an urgent public health concern. The rapid and accurate identification of carbapenemases could provide insights into antimicrobial therapy and infection control. In this study, we evaluated the efficacy of three different methods, including the NG-test Carba 5, colloidal gold immunoassay (CGI) test, and Xpert Carba-R assay, for the rapid detection of five carbapenemases (KPC, NDM, IMP, OXA-48, and VIM). A total of 207 Gram-negative strains collected from patients and hospital sewages were tested. The presence or absence of carbapenemase genes in the whole-genome sequences was used as the gold standard for evaluating the accuracy of the above-mentioned three methods. Among the 192 strains carrying only one carbapenemase gene, the accuracies of the NG-Test Carba 5, CGI test, and Xpert Carba-R were 96.88% (95% CI, 93.01-98.72%), 96.88% (95% CI, 93.01-98.72%), and 97.92% (95% CI, 94.41-99.33%), respectively. Xpert Carba-R was able to detect all 13 types of KPC variants, including KPC-2, KPC-3, KPC-25, KPC-33, KPC-35, KPC-51, KPC-52, KPC-71, KPC-76, KPC-77, KPC-78, KPC-93, and KPC-123, with a detection sensitivity of 100.00% (95% CI, 96.50-100.00%), a specificity of 100.00% (95% CI, 92.38-100.00%), and a κ index of 1.00. For IMP, Carba 5 was superior to the other two methods, with a sensitivity of 100% (95% CI, 71.66-100.00%), a specificity of 100% (95% CI, 97.38-100.00%), and a κ index of 1.00. For the remaining 15 strains carrying two or three kinds of carbapenemase genes, Carba 5 performed the best, which accurately identified all the target genes, followed by Xpert Carba-R (12/15, 80.00%) and the CGI test (10/15, 66.67%). Therefore, all three assays demonstrated reliable performances in carbapenemase detection, and Xpert Carba-R should be recommended for the detection of KPC variants, especially for patients at a high risk of infections caused by ceftazidime/avibactam-resistant strains. IMPORTANCE: CRE was listed as one of the top three pathogens that are in critical need of new antibiotics by the WHO. The rapid and accurate identification of carbapenemases is important for antimicrobial therapy and infection control. In recent years, new beta-lactam/beta-lactamase inhibitor combinations such as ceftazidime/avibactam (CZA) have been approved by the Food and Drug Administration (FDA) to cope with CRE challenges. CZA was effective against class A, class C, and some class D enzymes such as OXA-48-like. However, CZA-resistant KPC variants emerged at an alarming speed, which posed a new challenge for the accurate identification of KPC variants. In this study, we evaluated the performance of two lateral flow immunochromatographic assays, namely, NG-test Carba 5 and the CGI test, and the automated real-time quantitative PCR Xpert Carba-R in the rapid detection of carbapenemases. Notably, 13 types of KPC variants were enrolled in this study, which covered most KPC variants discovered in China. Carba-R was superior to NG-teat Carba 5 and the CGI test; it was able to detect all of the included KPC variants, including KPC-2, KPC-3, KPC-25, KPC-33, KPC-35, KPC-51, KPC-52, KPC-71, KPC-76, KPC-77, KPC-78, KPC-93, and KPC-123.

Effect of platelet-rich plasma vs standard management for the treatment of diabetic foot ulcer wounds: A meta-analysis.

We performed a meta-analysis to evaluate the effect of platelet-rich plasma vs standard management for the treatment of diabetic foot ulcer wounds. A systematic literature search up to March 2022 was performed and 1435 subjects with diabetic foot ulcer wounds at the baseline of the studies; 723 of them were treated with platelet-rich plasma, and 712 used control. Odds ratio (OR) with 95% confidence intervals (CIs) was calculated to assess the effect of platelet-rich plasma vs standard management for the treatment of diabetic foot ulcer wounds using the dichotomous method with a random or fixed-effect model. The use of autologous platelet-rich plasma resulted in significantly higher complete-healed diabetic foot ulcer wounds compared with control (OR, 1.95; 95% CI, 1.49-2.56, P < 0.001). The use of allogeneic platelet-rich plasma resulted in significantly higher complete-healed diabetic foot ulcer wounds compared with control (OR, 6.19; 95% CI, 2.32-16.56, P < 0.001). The use of autologous and allogeneic platelet-rich plasma resulted in significantly higher complete-healed diabetic foot ulcer wounds compared with control. Though, the analysis of outcomes should be with caution because of the low number of studies in certain comparisons, for example, allogeneic platelet-rich plasma compared with control.

An Optimized Screening Approach for the Oxazolidinone Resistance Gene optrA Yielded a Higher Fecal Carriage Rate among Healthy Individuals in Hangzhou, China.

The linezolid resistance mediated by optrA has exhibited an increasing trend among Gram-positive bacteria, which greatly limits the treatment options for severe bacterial infections. However, the prevalence of optrA was usually underestimated based on the existing screening methods. In this study, we used a traditional method and an improved method that included a high-salinity condition treatment after enrichment to screen for optrA-carrying bacteria from stool samples from 1,018 healthy donors in Hangzhou, China. The fecal carriage rate of optrA-carrying bacteria was 19.25% when screened by the improved method (196/1,018), which was much higher than that of the traditional method at 5.89% (60/1,018). Enterococci were the majority of the optrA-positive isolates, while five nonenterococcal isolates were also obtained, including two Streptococcus gallolyticus, one Vagococcus lutrae, one Lactococcus garvieae, and one Lactococcus formosensis isolate. Whole-genome sequencing analysis identified four novel OptrA variants, IDKKGPM, IDKKGP, KLDK, and EYDDI, in these isolates, whose optrA-flanking regions with a fexA gene downstream were bounded by different insertion sequences. In conclusion, our optimized method displayed high sensitivity in the detection of optrA-positive bacteria in fecal samples and revealed a high carriage rate in a healthy population. Although enterococci are dominant, multiple optrA-carrying Gram-positive bacteria were also found. IMPORTANCE This study represented an optimized screening approach for the optrA gene, which is an important mechanism of antimicrobial resistance to linezolid as a last resort for the treatment of infections caused by multiresistant Gram-positive bacteria. We revealed a high fecal carriage rate of the optrA gene among adults by this method and reported the first identification of optrA in Lactococcus formosensis as well as the identification of this gene in Vagococcus lutrae and of the poxtA gene in Ligilactobacillus salivarius of human origin, suggesting the wide spread of the optrA gene in the Gram-positive bacterial community.

Comparison of the Effects of Open Surgery and Minimally Invasive Surgery on the Achilles Tendon Rupture Healing Based on Angiogenesis.

Objective: To compare the effect of three different surgical methods on rabbit Achilles tendon rupture. Methods: The Achilles tendon transection model was constructed by cutting off the inner half of the Achilles tendon. Rabbits were divided into 4 groups: model group, open surgery (OS) group, minimally invasive surgery (MS) group, and conservative treatment (CT) group. Biomechanical evaluation, H&E, and Picrosirius Red staining were applied to evaluate the histological changes and healing. RT-qPCR, Western blot, ELISA, and IHC staining were used to detect the expression of COLIII, IL-1ß, TNF-α, IL-6, CD31, VEGF, bFGF, and TGF-ß1. Results: Different surgery treatments significantly alleviated the histological changes in rabbits. The tension and elasticity of the Achilles tendon were significantly increased after surgery. In addition, surgery treatments notably alleviated the inflammatory responses in vivo via downregulation of IL-1ß, TNF-α, and IL-6 and promoted the tube formation in tissues through upregulating VEGF, bFGF, TGF-ß1, and CD31. Furthermore, MS exhibited best therapeutic efficiency on Achilles tendon rupture healing, compared with OS or CT. Conclusions: Our research revealed the superiority of MS in Achilles tendon rupture treatment at the molecular level compared with OS or CT.

MiR-192-5p Alleviated Fibrosis and Inflammatory Responses of Tendon Cells by Targeting NFAT5.

Objective: To explore the effect of microRNA (miR)-192-5p on the inflammatory and fibrotic responses of tendon cells. Methods: Tendon cells were treated with transforming growth factor-ß1 (TGF-ß1). The expression of miR-192-5p and nuclear factor of activated T cells 5 (NFAT5) in tendon cells were detected by RT-qPCR. The expressions of inflammatory and fibrosis-related factors were detected by RT-qPCR and Western blot. MiR-192-5p binds to NFAT5 targeting by TargetScan and dual-luciferase reporter gene assay. The expression of the NFAT5 gene was detected by RT-qPCR and Western blot. Detection of apoptosis in tendon cells by flow cytometry. Results: MiR-192-5p was downregulated in tendon cells, and the expression level gradually decreased with the prolong of TGF-ß1 treatment. The expression of NFAT5 increased with the treatment time of TGF-ß1. The expression of miR-192-5p decreased collagen III (COLIII), α smooth muscle actin (α-SMA), matrix metalloproteinase- (MMP-) 1, and MMP-8 expression, thereby inhibiting TGF-ß1-induced fibrosis in tendon cells. The expression of miR-192-5p decreased the expression of tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and IL-1ß, thereby alleviating TGF-ß1-induced inflammatory response and reduce apoptosis in tendon cells. NFAT5 is a direct target of miR-192-5p in tendon cells. The upregulation of NFAT5 reversed the effect of miR-192-5p on the fibrotic activity and inflammatory response of TGF-ß1-stimulated tendon cells. Conclusions: MiR-192-5p alleviates fibrosis and inflammatory responses of tendon cells by targeting NFAT5.

A rapid MALDI-TOF mass spectrometry-based method for colistin susceptibility testing in Escherichia coli.

Colistin is recognized as a last-resort treatment option against multi-drug resistant bacteria including carbapenem-resistant Enterobacteriaceae (CRE). However, the plasmid-mediated colistin-resistance gene mcr-1 has been reported globally resulting in an increase of colistin-resistant bacteria. A quick and accurate method for determining the pathogen resistance of colistin is therefore crucial in the clinic. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) is a potential tool forto be applied for antimicrobial susceptibility testing. We compared the growth of Escherichia coli strains in the presence or absence of colistin. Automated analyses of the spectra were performed with a prototype software tool written with package R. Three mcr-1-positive and six mcr-1-negative E. coli were used for establishing the model to obtain the optimal incubation time, the breakpoint concentration of colistin and cut-off of the relative growth (RG) value. The distinction between susceptible and resistant strains was already noticeable after 2 h of incubation. The best separation between the susceptible and resistant strains was achieved at a concentration of 4 µg ml-1 and a relative growth cut-off value of 0.6. Application of the model for the analysis of 128 E. coli isolates, a sensitivity of 97.4% and a specificity of 88.2% were achieved compared with colistin MIC results. The rapid MALDI-TOF MS-based method approach is simple to set-up, uses a short incubation time, and had excellent outcomes with respect to sensitivity and specificity for colistin sensitivity testing in Escherichia coli.

Characterisation of a cointegrate plasmid harbouring blaNDM-1 in a clinical Salmonella Lomita strain.

This study aimed to characterise the molecular events underlying formation and evolution of a cointegrate plasmid harbouring blaNDM-1 and blaCMY-2 in a clinical Salmonella Lomita (S. Lomita) strain. The Salmonella strain SL131 was found to harbour two multidrug resistant (MDR) plasmids. One plasmid, pSL131_IncHI2, is a typical IncHI2 plasmid containing blaOXA-1, catB3, arr-3, sul1, qnrB4 and blaDHA-1 in a complex class 1 integron. The other plasmid, pSL131_IncA/C-IncX3, is a blaNDM-1-bearing cointegrate plasmid consisting of IncX3 and IncA/C backbones, the formation of which is mediated by IS26. Stability assay showed that the cointegrate plasmid was highly stable in its natural host - S. Lomita - but would readily resolve into single plasmids upon conjugation, during which the IncX3 blaNDM-1-bearing plasmid could be transferred to Escherichia coli strain EC600. Plasmid evolution through integration of two or more MDR plasmids would not only expand the resistance profile of the resultant plasmid, but also broaden the host spectrum of such resistance-encoding mobile elements. Better understanding of the underlying and triggering mechanisms of cointegration may facilitate development of intervention measures to curb formation and dissemination of such elements.

Evaluation of Staphylococcus aureus Subtyping Module for Methicillin-Resistant Staphylococcus aureus Detection Based on Matrix-Assisted Laser Desorption Ionization Time-of-Flight Mass Spectrometry.

A recently developed S. aureus subtyping module for rapidly differentiate methicillin-resistant Staphylococcus aureus (MRSA) from methicillin-susceptible S. aureus (MSSA) had been introduced into China. The principle of this method was to identify the methicillin resistance through detection of a specific phenol soluble modulin-mec peak (PSM-mec) by matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS). A total of 347 non-duplicated S. aureus strains were collected from the Second Affiliated Hospital of Zhejiang University School of Medicine during January 2014 to February 2019. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the automated subtyping module in identifying MRSA were evaluated. The specificity and PPV of this method were both 100%, and the sensitivity was 60.2%. PSM-bearing MRSA was reported with different prevalence from different parts of the world, our sample collection has the highest percentage so far. The repeatability showed that 1.7% (6/347) and 18.4% (64/347) were reported differently in the intra- and inter-batch analysis, respectively, which demonstrated that the threshold of this method could be further optimized to increase the sensitivity of MRSA detection. Overall, Bruker™ MALDI Biotyper can detect S. aureus isolates with a quite high specificity and expedite the identification of MRSA isolates without using extra reagent, labor, or time. The reduced turnaround time of MRSA identification is essential for appropriate therapeutic management and timely intervention for infection control.

Evolution of Carbapenem-Resistant Serotype K1 Hypervirulent Klebsiella pneumoniae by Acquisition of blaVIM-1-Bearing Plasmid.

We report the identification of a carbapenem-resistant, hypervirulent Klebsiella pneumoniae (hvKp) strain which produced the carbapenemase VIM-1. Genomic analysis showed that the strain belonged to sequence type ST23 and serotype K1, a major hvKp clone, and harbored three resistance-encoding plasmids. Among them, a blaVIM-1-bearing plasmid was found to possess a mosaic structure presumably generated by multiple gene mobilization events. This finding indicates that hvKp actively acquires mobile resistance-encoding elements, facilitating simultaneous expression of hypervirulence and carbapenem-resistance.

Evaluation of an in-house MALDI-TOF MS rapid diagnostic method for direct identification of micro-organisms from blood cultures.

PURPOSE: Bloodstream infections are major causes of morbidity and mortality among hospitalized patients worldwide. Early identification of micro-organisms from blood culture can facilitate earlier optimization of treatment. The objective of this study was to assess an in-house method based on a new matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) platform (Clin-TOF MS) for direct organism identification. METHODOLOGY: We studied the performance of the in-house method for direct identification and the conventional sub-culture method in parallel. Identification from subcultures was analysed with Bruker MS as the reference method. RESULTS: A total of 666 blood cultures with a single micro-organism that flagged positive after no more than a 3-day incubation period were collected. The identification accuracy of the in-house Clin-TOF MS method for direct identification and the sub-culture method was 88.6 and 100 %, respectively. The in-house method exhibited better performance for Gram-negative bacteria than for Gram-positive bacteria (93.3 vs 81.6 %). The accuracy rate for anaerobes was 100 % (3/3). The lowest accurate identification rate was for yeast; this was only 20 %. Lytic Anaerobic/F (LAF) and Plus Aerobic/F (PAF) provided the highest accurate identification rates, and it was noteworthy that the accuracy rate for FAN Aerobic (FA) was 82 %, which is higher than previously reported and showed that the method was effective. CONCLUSION: Our study provides an effective sample preparation method for the direct identification of pathogens from positive blood culture vials via Clin-TOF MS at a very low cost of about $0.5 per sample and with a short turnaround time of about 20 min. This will help clinicians make precise diagnoses and provide targeted prescriptions, reducing the risk of the potential development of resistance.

Evolution of tigecycline- and colistin-resistant CRKP (carbapenem-resistant Klebsiella pneumoniae) in vivo and its persistence in the GI tract.

Emergence of carbapenem-resistant Klebsiella pneumoniae (CRKP) strains that also exhibit resistance to tigecycline and colistin have become a major clinical concern, as these two agents are the last-resort antibiotics used for treatment of CRKP infections. A leukemia patient infected with CRKP was subjected to follow-up analysis of variation in phenotypic and genotypic characteristics of CRKP strains isolated from various specimens at different stages of treatment over a period of 3 years. Our data showed that (1) carbapenem treatment led to the emergence of CRKP in the gastrointestinal (GI) tract of the patient, which subsequently caused infections at other body sites as well as septicemia; (2) treatment with tigecycline led to the emergence of tigecycline-resistant CRKP, possibly through induction of the expression of a variant tet(A) gene located in a conjugative plasmid; (3) colistin treatment was effective in clearing CRKP from the bloodstream but led to the emergence of mcr-1-positive Enterobacteriaceae strains as well as colistin-resistant CRKP in the GI tract due to inactivation of the mgrB gene; and (4) tigecycline- and colistin-resistant CRKP could persist in the human GI tract for a prolonged period even without antibiotic selection pressure. In conclusion, clinical CRKP strains carrying a conjugative plasmid that harbors the blaKPC-2 and tet(A) variant genes readily evolve into tigecycline- and colistin-resistant CRKP upon treatment with these two antibiotics and persist in the human GI tract.

Anatomical Correlates of Uncontrollable Laughter With Unilateral Subthalamic Deep Brain Stimulation in Parkinson's Disease.

INTRODUCTION: Subthalamic nucleus deep brain stimulation (STN-DBS) is a well-established treatment for the management of motor complications in Parkinson's disease. Uncontrollable laughter has been reported as a rare side effect of STN stimulation. The precise mechanism responsible for this unique phenomenon remains unclear. We examined in detail the DBS electrode position and stimulation parameters in two patients with uncontrollable laughter during programming after STN-DBS surgery and illustrated the anatomical correlates of the acute mood changes with STN stimulation. CASE REPORT: Unilateral STN-DBS induced uncontrollable laughter with activation of the most ventral contacts in both patients. However, the location of the electrodes responsible for this adverse effect differed between the patients. In the first patient, the DBS lead was placed more inferiorly and medially within the STN. In the second patient, the DBS lead was implanted more anteriorly and inferiorly than initially planned at the level of the substantia nigra reticulata (SNr). CONCLUSION: Unilateral STN-DBS can induce acute uncontrollable laughter with activation of electrodes located more anterior, medial, and inferior in relationship with the standard stereotactic STN target. We suggest that simulation of ventral and medial STN, surrounding limbic structures or the SNr, is the most plausible anatomical substrate responsible for this acute mood and behavioral change. Our findings provide insight into the complex functional neuroanatomical relationship of the STN and adjacent structures important for mood and behavior. DBS programming with more dorsal and lateral contacts within the STN should be entertained to minimize the emotional side effects.

Atorvastatin treatment is associated with increased BDNF level and improved functional recovery after atherothrombotic stroke.

BACKGROUND: Statins have a positive impact on ischemic stroke outcome. It has been reported that statin have neuroprotective function after ischemic stroke in addition to lipid-lowering effect in animal model. However, the neuroprotective function of statin after stroke has not been confirmed in clinical studies. The aim of this study was to evaluate in a clinical model if statins induce neuroprotection after stroke. We, therefore, assessed serum brain-derived neurotrophic factor (BDNF) levels and functional recovery in atherothrombotic stroke patients and investigated their relationship with atorvastatin treatment. METHODS: Seventy-eight patients with atherothrombotic stroke were enrolled and randomly assigned to atorvastatin treatment group or placebo control group. Neurological function after stroke was assessed with the National Institutes of Health Stroke Scale, modified Rankin Scale (mRS) and Barthel Index (BI). The serum BDNF levels were both measured at 1 day and 6 weeks after stroke. Linear regression was used to assess the association between BDNF levels and neurological function scores. RESULTS: The mRS and BI were markedly improved in the atorvastatin group when compared to placebo at 6 weeks after stroke. The serum BDNF levels in atorvastatin group were significantly elevated by 6 weeks after stroke and higher than the BDNF levels in controls. In addition, the serum BDNF levels significantly correlated with mRS and BI after stroke. Our results demonstrated that atorvastatin treatment was associated with the increased BDNF level and improved functional recovery after atherothrombotic stroke. CONCLUSION: This study indicates that atorvastatin-related elevation in the BDNF level may promote functional recovery in stroke patients.