Aging Process of Lateral Facial Fat Compartments: A Retrospective Study.

BACKGROUND: Since 2007, when the anatomy of facial fat compartment was described, an increasing number of studies on the aging process of the compartment of cadavers has emerged. OBJECTIVES: The authors evaluated the aging changes of lateral facial fat compartments on the same person. METHODS: Sixty-three patients were included in this retrospective study. All patients had magnetic resonance imaging scans with at least 4 years apart. The authors targeted the fat compartments of the superficial temporal, subcutaneous temporal, and buccal fat pad, comparing the data on different time points. RESULTS: The thickness of the subcutaneous temporal fat did not change significantly. The 3 diameters of the superficial temporal fat compartment all became thinner on the axial view (P < 0.05). On the sagittal view, the superficial temporal fat elongated from 38.89 mm to 43.74 mm (P < 0.05). The buccal fat compartment also lengthened from 68.73 mm to 74.39 mm (P < 0.05) and had a positive correlation with follow-up duration only. CONCLUSIONS: The study revealed the fat compartment change on the same person with time. The temporal hollow mainly originates from the thinner part of the superficial temporal fat. The descending of the buccal fat pad aggravates the labiomandibular fold. By understanding the aging process more fully, we can rejuvenate our patients more naturally.

Augmentation Index Predicts the Sweat Volume in Young Runners.

Sweating during exercise is regulated by objective parameters, body weight, and endothelial function, among other factors. However, the relationship between vascular arterial stiffness and sweat volume in young adults remains unclear. This study aimed to identify hemodynamic parameters before exercise that can predict sweat volume during exercise, and post-exercise parameters that can be predicted by the sweat volume. Eighty-nine young healthy subjects (aged 21.9 ± 1.7 years, 51 males) were recruited to each perform a 3-km run on a treadmill. Demographic and anthropometric data were collected and hemodynamic data were obtained, including heart rate, blood pressure and pulse wave analysis using non-invasive tonometry. Sweat volume was defined as pre-exercise body weight minus post-exercise body weight. Post-exercise hemodynamic parameters were also collected. Sweat volume was significantly associated with gender, body surface area (BSA) (b = 0.288, p = 0.010), peripheral systolic blood pressure (SBP), peripheral and central pulse pressure (PP), and was inversely associated with augmentation index at an HR of 75 beats/min (AIx@HR75) (b = -0.005, p = 0.019) and ejection duration. While BSA appeared to predict central PP (B = 19.271, p ≤ 0.001), central PP plus AIx@HR75 further predicted sweat volume (B = 0.008, p = 0.025; B = -0.009, p = 0.003 respectively). Sweat volume was associated with peripheral SBP change (B = -17.560, p = 0.031). Sweat volume during a 3-km run appears to be influenced by hemodynamic parameters, including vascular arterial stiffness and central pulse pressure. Results of the present study suggest that vascular arterial stiffness likely regulates sweat volume during exercise.

Critical involvement of atypical chemokine receptor CXCR7 in allergic airway inflammation.

Trafficking and recruitment of immune cells to the site of inflammation with spatial and temporal synchronization is crucial for the development of allergic airway inflammation. Particularly, chemokines are known to be key players in these processes. Previous studies revealed that the CXCL12/CXCR4 axis plays an important role in regulating allergic airway inflammation. However, the role of CXCR7, a recently discovered second receptor for CXCL12, in regulating airway inflammation has not been explored. Initially, CXCR7 was considered as a decoy receptor; however, numerous subsequent studies revealed that engagement of CXCR7 triggered its own signalling or modulated CXCR4-mediated signalling. In the present study, we detected the expression of CXCR7 in airway epithelial cells. Use of a lentiviral delivery system to knock down the expression of CXCR7 in the lung of sensitized mice abrogated the cardinal features of asthma, indicating that CXCR7 plays a role in regulating allergic airway inflammation. The activation of mitogen-activated protein kinase and Akt signalling in response to CXCL12 in the mouse epithelial cell line MLE-12 was reduced when CXCR7 expression was knocked down. However, either knockdown or overexpression of CXCR7 in MLE-12 did not affect CXCL12-mediated calcium influx, indicating that CXCR7 does not modulate CXCR4-mediated signalling, and that it functions as a signalling receptor rather than a decoy receptor. Finally, we found that the expression of chemokine CCL2 is regulated by CXCR7/CXCL12-mediated signalling through ß-arrestin in airway epithelial cells. Hence, regulating the expression of CCL2 in airway epithelial cells may be one mechanism by which CXCR7 participates in regulating allergic airway inflammation.

Photocytotoxic Copper(II) Complexes with Schiff-Base Scaffolds for Photodynamic Therapy.

Photodynamic therapy (PDT) is a promising and minimally invasive method for the treatment of superficial diseases, and photosensitizers with high phototoxicity indices (defined as (IC50dark )/(IC50irradiation )) are essential for the development of ideal photosensitizing properties for this technology. Herein, we report a series of photocytotoxic copper(II) complexes [Cu(R QYMP)(dppn)] (R QYMP=N,N,O-tridentate Schiff-base derivatives, dppn=benzo[i]dipyrido[3,2-a;2',3'-c]phenazine), the structures of which have been confirmed by mass spectrometry and FTIR spectroscopy. X-ray crystallography revealed that the CuN4 O core of the [Cu(cumyl QYMP)(dppn)](ClO4 ) complex (3) has a distorted square-pyramidal geometry. Phototoxicity indices of 329 against human squamous cell carcinoma (SCC15) and 296 against basal cell carcinoma (BCC) cell lines have been determined with [Cu(3-OMe QYMP)(dppn)](ClO4 ) (4). This can be attributed to the formation of reactive oxygen species, cell apoptosis, and caspase-3 activation, indicating high potential of complex 4 as a photosensitizer candidate in PDT. Thus, copper complexes bearing suitable Schiff-base ligands with a dppn co-ligand may be considered for the design of efficient metal-based anticancer agents for PDT.

Gold-catalyzed annulations of allenes with N-hydroxyanilines to form indole derivatives with benzaldehyde as a promoter.

Gold-catalyzed syntheses of 2,3-disubstituted indole derivatives from N-hydroxyanilines and allenes are described; these reactions require benzaldehyde as an additive to generate nitrones in situ. Our control experiments indicate that nitrones and water were indispensable in the reactions whereas N-hydroxyanilines alone were inactive nucleophiles. This synthetic method is compatible with allenes and N-hydroxyanilines with a reasonable range, further highlighting its synthetic utility.

3D Printing of Glass Micro-Optics with Subwavelength Features on Optical Fiber Tips.

Integration of functional materials and structures on the tips of optical fibers has enabled various applications in micro-optics, such as sensing, imaging, and optical trapping. Direct laser writing is a 3D printing technology that holds promise for fabricating advanced micro-optical structures on fiber tips. To date, material selection has been limited to organic polymer-based photoresists because existing methods for 3D direct laser writing of inorganic materials involve high-temperature processing that is not compatible with optical fibers. However, organic polymers do not feature stability and transparency comparable to those of inorganic glasses. Herein, we demonstrate 3D direct laser writing of inorganic glass with a subwavelength resolution on optical fiber tips. We show two distinct printing modes that enable the printing of solid silica glass structures ("Uniform Mode") and self-organized subwavelength gratings ("Nanograting Mode"), respectively. We illustrate the utility of our approach by printing two functional devices: (1) a refractive index sensor that can measure the indices of binary mixtures of acetone and methanol at near-infrared wavelengths and (2) a compact polarization beam splitter for polarization control and beam steering in an all-in-fiber system. By combining the superior material properties of glass with the plug-and-play nature of optical fibers, this approach enables promising applications in fields such as fiber sensing, optical microelectromechanical systems (MEMS), and quantum photonics.

Ultrafast Metal-Free Microsupercapacitor Arrays Directly Store Instantaneous High-Voltage Electricity from Mechanical Energy Harvesters.

Harvesting renewable mechanical energy is envisioned as a promising and sustainable way for power generation. Many recent mechanical energy harvesters are able to produce instantaneous (pulsed) electricity with a high peak voltage of over 100 V. However, directly storing such irregular high-voltage pulse electricity remains a great challenge. The use of extra power management components can boost storage efficiency but increase system complexity. Here utilizing the conducting polymer PEDOT:PSS, high-rate metal-free micro-supercapacitor (MSC) arrays are successfully fabricated for direct high-efficiency storage of high-voltage pulse electricity. Within an area of 2.4 × 3.4 cm2 on various paper substrates, large-scale MSC arrays (comprising up to 100 cells) can be printed to deliver a working voltage window of 160 V at an ultrahigh scan rate up to 30 V s-1. The ultrahigh rate capability enables the MSC arrays to quickly capture and efficiently store the high-voltage (≈150 V) pulse electricity produced by a droplet-based electricity generator at a high efficiency of 62%, significantly higher than that (<2%) of the batteries or capacitors demonstrated in the literature. Moreover, the compact and metal-free features make these MSC arrays excellent candidates for sustainable high-performance energy storage in self-charging power systems.

A bovine whey protein extract can induce the generation of regulatory T cells and shows potential to alleviate asthma symptoms in a murine asthma model.

The number of people with asthma has dramatically increased over the past few decades and the cost of care is more than $11·3 billion per year. The use of steroids is the major treatment to control asthma symptoms, but the side effects are often devastating. Seeking new drugs or new strategies to reduce the dose of steroid taken has always been an important task. A bovine whey protein extract (WPE), which is enriched in transforming growth factor-ß (TGF-ß), has been demonstrated to have the potential for reducing symptoms associated with mild-to-moderate T-helper cell type 1-mediated psoriasis in human subjects. However, whether WPE also has potential for inhibiting T-helper cell type 2 (Th2)-mediated disease remains unclear. In the present study, using a murine asthma model, we found that sensitised mice fed WPE daily, before they were challenged, resulted in reducing airway inflammation, serum ovalbumin-specific IgE, Th2-related cytokine production and airway hyperresponsiveness. Increase in the regulatory T cell (Treg) population in vitro and in vivo was observed when treated with WPE. According to the results from the TGF-ß-blocking antibody study, we suggest that TGF-ß is the main component that endows WPE with the potential to reduce the generation of Treg. Thus, the present data suggest that WPE has the potential to alleviate the symptoms of asthma by inducing the generation of Treg. Therefore, regular administration of WPE might be potentially beneficial for patients with asthma.

DEFAEK: Domain Effective Fast Adaptive Network for Face Anti-Spoofing.

Existing deep learning based face anti-spoofing (FAS) or deepfake detection approaches usually rely on large-scale datasets and powerful networks with significant amount of parameters to achieve satisfactory performance. However, these make them resource-heavy and unsuitable for handheld devices. Moreover, they are limited by the types of spoof in the dataset they train on and require considerable training time. To produce a robust FAS model, they need large datasets covering the widest variety of predefined presentation attacks possible. Testing on new or unseen attacks or environments generally results in poor performance. Ideally, the FAS model should learn discriminative features that can generalize well even on unseen spoof types. In this paper, we propose a fast learning approach called Domain Effective Fast Adaptive nEt-worK (DEFAEK), a face anti-spoofing approach based on the optimization-based meta-learning paradigm that effectively and quickly adapts to new tasks. DEFAEK treats differences in an environment as domains and simulates multiple domain shifts during training. To further improve the effectiveness and efficiency of meta-learning, we adopt the metric learning in the inner loop update with careful sample selection. With extensive experiments on the challenging CelebA-Spoof and FaceForensics++ datasets, the evaluation results show that DEFAEK can learn cues independent of the environment with good generalization capability. In addition, the resulting model is lightweight following the design principle of modern lightweight network architecture and still generalizes well on unseen classes. In addition, we also demonstrate our model's capabilities by comparing the numbers of parameters, FLOPS, and model performance with other state-of-the-art methods.

Nuclear-localized CTEN is a novel transcriptional regulator and promotes cancer cell migration through its downstream target CDC27.

C-terminal tensin-like (CTEN) is a tensin family protein typically localized to the cytoplasmic side of focal adhesions, and primarily contributes to cell adhesion and migration. Elevated expression and nuclear accumulation of CTEN have been reported in several types of cancers and found to be associated with malignant behaviors. However, the function of nuclear CTEN remains elusive. In this study, we report for the first time that nuclear CTEN associates with chromatin DNA and occupies the region proximal to the transcription start site in several genes. The mRNA expression level of CTEN positively correlates with that of one of its putative target genes, cell division cycle protein 27 (CDC27), in a clinical colorectal cancer dataset, suggesting that CTEN may play a role in the regulation of CDC27 gene expression. Furthermore, we demonstrated that CTEN is recruited to the promoter region of the CDC27 gene and that the mRNA expression and promoter activity of CDC27 are both reduced when CTEN is downregulated. In addition, we found that enhanced nuclear accumulation of CTEN in HCT116 cells by overexpression of CTEN fused with nuclear localization signals increases CDC27 transcript levels and promoter activity. The increased nuclear-localized CTEN also significantly promotes cell migration, and the migratory ability is suppressed when CDC27 is knocked down. These results demonstrate that nuclear CTEN regulates CDC27 expression transcriptionally and promotes cell migration through CDC27. Our findings provide new insights into CTEN moonlighting in the nucleus as a DNA-associated protein and transcriptional regulator involved in modulating cancer cell migration.

Three-dimensional printing of silica glass with sub-micrometer resolution.

Silica glass is a high-performance material used in many applications such as lenses, glassware, and fibers. However, modern additive manufacturing of micro-scale silica glass structures requires sintering of 3D-printed silica-nanoparticle-loaded composites at ~1200 °C, which causes substantial structural shrinkage and limits the choice of substrate materials. Here, 3D printing of solid silica glass with sub-micrometer resolution is demonstrated without the need of a sintering step. This is achieved by locally crosslinking hydrogen silsesquioxane to silica glass using nonlinear absorption of sub-picosecond laser pulses. The as-printed glass is optically transparent but shows a high ratio of 4-membered silicon-oxygen rings and photoluminescence. Optional annealing at 900 °C makes the glass indistinguishable from fused silica. The utility of the approach is demonstrated by 3D printing an optical microtoroid resonator, a luminescence source, and a suspended plate on an optical-fiber tip. This approach enables promising applications in fields such as photonics, medicine, and quantum-optics.

Child-Pugh Score and ABCG2-rs2231142 Genotype Independently Predict Survival in Advanced Hepatoma Patients Treated with Sorafenib.

Patients with advanced hepatocellular carcinoma (HCC) are treated by immunotherapy and/or targeted agents, such as sorafenib. Several single nucleotide polymorphisms (SNPs) and clinical scores have been proposed as prognostic markers in HCC patients treated with sorafenib. This study aimed to validate the prognostic values of these markers in a tertiary referral medical center. Two independent cohorts (cohort-1 [n = 97] and cohort-2 [n = 60]) of advanced HCC patients treated with sorafenib monotherapy were enrolled. Univariate followed by multivariate Cox proportional hazard analysis identified Child−Pugh (CP) score (p < 0.001) and renal insufficiency during treatment (p < 0.001) as independent predictors in cohort-1 patients. The same analytic method revealed ascites (p = 0.000), CP score (p = 0.001), infection during treatment (p < 0.001), and ATP-binding cassette subfamily G member 2 (ABCG2)-rs2231142 genotype (p = 0.003) as independent predictors in cohort-2 patients. ABCG2-rs2231142 genotype "CC" was associated with unfavorable overall survival in sorafenib-treated HCC patients. In conclusion, the CP score and ABCG2-rs2231142 genotype served as independent survival predictors for advanced HCC patients receiving sorafenib treatment.

Risk Factors for the Development of Colistin Resistance during Colistin Treatment of Carbapenem-Resistant Klebsiella pneumoniae Infections.

Colistin is one of the last-resort options for carbapenem-resistant Klebsiella pneumoniae (CRKP) infections if novel antibiotics are unavailable, where the development of colistin resistance during treatment represents a major challenge for clinicians. We aimed to investigate the risk factors associated with the development of colistin resistance in patients with CRKP infections following colistin treatment. We conducted a retrospective case-control study of patients with CRKP strains available before and after colistin treatment at a medical center in Taiwan, between October 2016 and November 2020. Cases (n = 35) included patients with an initial colistin-susceptible CRKP (ColS-CRKP) strain and a subsequent colistin-resistant CRKP (ColR-CRKP) strain. Controls (n = 18) included patients with ColS-CRKP as both the initial and subsequent strains. The 30-day mortality rate after the subsequent CRKP isolation was not different between cases and controls (12/35 [34%] versus 5/18 [28%] [P = 0.631]). blaKPC (n = 38) and blaOXA-48 (n = 11) accounted for the major mechanisms of carbapenem resistance. Alterations in mgrB were found in 18/35 (51%) ColR-CRKP strains, and mcr-1 was not detected in any of the strains. More patients received combination therapy in the control group than in the case group (17/18 versus 21/35 [P = 0.008]). The logistic regression model indicated that combination therapy with tigecycline was protective against the acquisition of colistin resistance (odds ratio, 0.17; 95% confidence interval, 0.05 to 0.62 [P = 0.008]). We observed that the inclusion of tigecycline in colistin treatment mitigated the risk of acquiring colistin resistance. These results offer insight into using the combination of tigecycline and colistin for the treatment of CRKP infections in antimicrobial stewardship. IMPORTANCE Treatment of carbapenem-resistant Klebsiella pneumoniae (CRKP) infections is challenging due to the limited options of antibiotics. Colistin is one of the last-resort antibiotics if novel antimicrobial agents are not available. It is crucial to identify modifiable clinical factors associated with the emergence of resistance during colistin treatment. Here, we found that the addition of tigecycline to colistin treatment prevented the acquisition of colistin resistance. Colistin-tigecycline combination therapy is therefore considered a hopeful option in antimicrobial stewardship to treat CRKP infections.

Increased antibiotic exposure in early life is associated with adverse outcomes in very low birth weight infants.

BACKGROUND: The use of antibiotics in the early lives of premature infants may alter the microbiota and influence their clinical outcomes. However, whether the administration of probiotics can influence these outcomes remains unknown. In our study, probiotics were routinely administered unless contraindicated. We explored whether increased antibiotic exposure with the routine use of probiotics was associated with necrotizing enterocolitis (NEC) or bronchopulmonary dysplasia (BPD). METHODS: A retrospective cohort study was conducted, enrolling very low birth weight (VLBW) infants admitted between January 1, 2016, and March 31, 2020, to a medical center. Days of antibiotic exposure in the first 14 days of life were recorded. The primary outcomes were NEC and BPD. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were calculated using multivariable regression analyses to assess risk factors. RESULTS: Of 185 VLBW infants admitted to the medical center, 132 met the inclusion criteria. Each additional day of antibiotic treatment was associated with increased odds of NEC (aOR, 1.278; 95% CI, 1.025-1.593) and BPD (aOR, 1.630; 95% CI, 1.233-2.156). The association remained in the NEC analysis after adjustment for probiotic use. CONCLUSION: Increased antibiotic exposure in the early lives of VLBW infants was associated with increased risks of NEC and BPD. The probiotics did not influence the outcomes. Our findings suggest that clinicians should be alerted to the adverse outcomes of antibiotic use in infants with VLBWs.

Alcohol patch test with hue-saturation-value model analysis predicts ALDH2 genetic polymorphism.

BACKGROUND: The alcohol patch test (APT) can detect aldehyde dehydrogenase (ALDH) genetic polymorphisms used to diagnose cutaneous erythema. However, the subjective results can vary owing to confounding factors. The hue-saturation-value (HSV) model provides an objective means of image analysis with APT. METHODS: This study enrolled 57 participants (27.7 ± 9.0 years, 52.6% females) with ALDH2*1/*1, ALDH2*1/*2, and ALDH2*2/*2 percentages of 50.9%, 43.8%, and 5.3%, respectively. In total, 56 APT protocols were applied and analyzed employing both visual inspection and the HSV model. The value of the delta standard deviation (SD) of the hue histogram, which manifests the difference between the APT reaction and the baseline skin color, was obtained using the HSV model. The receiver operating characteristic (ROC) curve and area under the ROC curve (AUC) were used to predict the ALDH2*2 allele with the HSV model. RESULTS: Upon visual inspection, a maximal Youden index with a sensitivity of 82.1% and a specificity of 96.6% was determined for the ALDH2 genetic mutation. Using the delta SD of hue obtained in the HSV model, a maximal Youden index with 85.7% sensitivity and 96.6% specificity was determined using the ROC curve analysis (AUC = 0.948, p < 0.001). Thus, the use of the HSV model analysis with APT resulted in equal specificity, but better sensitivity, compared to those obtained upon visual inspection. CONCLUSION: The HSV model took into account the potential confounding factors, and thus, could help in the prediction of ALDH2 genetic polymorphisms.

Metabolic engineering of probiotic Escherichia coli for cytolytic therapy of tumors.

Bacterial cancer therapy was developed using probiotic Escherichia coli Nissle 1917 (EcN) for medical intervention of colorectal cancer. EcN was armed with HlyE, a small cytotoxic protein, under the control of the araBAD promoter (PBAD). The intrinsic limitation of PBAD for the gene expression is known to be negated by glucose and afflicted with all-or-nothing induction in host bacteria. This issue was addressed by metabolic engineering of EcN to uncouple the glucose-mediated control circuit and the L-arabinose transport-induction loop and to block L-arabinose catabolism. As a result, the reprogrammed strain (designated EcNe) enabled efficient expression of HlyE in a temporal control manner. The HlyE production was insensitive to glucose and reached a saturated level in response to L-arabinose at 30-50 µM. Moreover, the administrated EcNe exhibited tumor-specific colonization with the tumor-to-organ ratio of 106:1. Equipped with HlyE, EcNe significantly caused tumor regression in mice xenografted with human colorectal cancer cells. Overall, this study proposes a new strategy for the bacteria-mediated delivery of therapeutic proteins to tumors.

Clinical characteristics and outcomes of 56 patients with pneumonia caused by carbapenem-resistant Klebsiella pneumoniae.

OBJECTIVES: Pneumonia caused by carbapenem-resistant Klebsiella pneumoniae (CRKP) is associated with high mortality. However, clinical studies on CRKP infections often exclusively involve bacteraemia, with only a few studies having focused on pneumonia. This retrospective study was conducted to investigate the clinical and microbiological characteristics of pneumonia caused by CRKP. METHODS: Adult patients diagnosed with CRKP monomicrobial pneumonia treated with at least one active antimicrobial agent within 5 days of the pneumonia diagnosis were identified in a medical centre in Taiwan between January 2017 and April 2019. Clinical characteristics and outcomes of these patients were determined. Resistance mechanisms and capsular types of the CRKP isolates were determined by PCR. RESULTS: A total of 56 patients with CRKP monomicrobial pneumonia were identified. The 7-day and 14-day mortality rates were 7.1% and 23.2%, respectively. Malignancy [adjusted odds ratio (aOR) = 8.87, 95% confidence interval (CI) 1.66-47.26; P = 0.011] and Acute Physiology and Chronic Health Evaluation (APACHE) II score (aOR = 1.12, 95% CI 1-1.25; P = 0.048) were independently associated with 14-day mortality. Most CRKP clinical isolates were carbapenemase-producers (39/44; 88.6%), of which K. pneumoniae carbapenemase type 2 (KPC-2)-producing isolates were most prevalent (30/39; 76.9%). The most prevalent capsular type in these isolates was K47 (30/44; 68.2%). CONCLUSION: CRKP pneumonia is associated with high 14-day mortality. Malignancy and APACHE II score were independently associated with 14-day mortality.

Decoupled Glucose and Lipid Metabolic Recovery after Viral Clearance in Direct-Acting Antiviral-Treated HCV Patients: A 3-Year Prospective Cohort Study.

BACKGROUND/AIM: The recovery pattern of hepatitis C virus (HCV)-associated metabolic alteration after sustained virological response (SVR) following direct-acting antivirals (DAAs) remains elusive. METHODS: A prospective cohort study of chronic HCV-infected (CHC) patients (n = 415) receiving DAAs (n = 365) was conducted. Metabolic profiles were examined in SVR patients (n = 360) every 3-6 months after therapy and compared with those of sex- and age-matched controls (n = 470). RESULTS: At baseline, of 415, 168 (40.5%) had insulin resistance (IR). The following were associated: levels of high-density lipoprotein cholesterol (HDL-C), triglycerides (TGs), HCV RNA, fibrosis-4 score, and interferon-λ3-rs12979860 genotype with total cholesterol (TC) levels; and TG levels and BMI with HOMA-IR. Over a 3-year follow-up, in SVR patients, BMI and TC levels and TG/HDL-C ratios increased from baseline, while HOMA-IR trended downward by 72 weeks after therapy and then increased. The increased HDL-C levels began to decrease after 72 weeks after therapy. TC and HOMA-IR were negatively associated with each other until 24 weeks after therapy. Earlier increases in BMI and decreases in HOMA-IR were noted in SVR patients with than in those without baseline IR. Compared with controls, in the subgroup without baseline IR, SVR patients had increased BMI and HOMA-IR levels. Metabolic profiles were similar between SVR patients and controls in the subgroup with baseline IR. CONCLUSIONS: In SVR patients treated with DAAs, the recovery of altered lipid and glucose metabolism was not coupled until 72-week post-therapy, when HOMA-IR reached its nadir. SVR patients with baseline IR recovered from HCV-associated metabolic alterations earlier than those without baseline IR.

Characterization of a mcr-1 and CRISPR-Cas System Co-harboring Plasmid in a Carbapenemase-Producing High-Risk ST11 Klebsiella pneumoniae Strain.

We set out to study the prevalence of the mcr-1 gene in carbapenemase-producing Klebsiella pneumoniae (CPKP) strains, and to determine whether its presence is associated with a fitness cost. A total of 234 clinical CPKP isolates were collected from a tertiary medical center in Taiwan from January 2018 to January 2019. The mcr-1 and carbapenemase genes were detected by polymerase chain reaction (PCR) followed by Sanger sequencing. The mcr-1-positive carbapenemase-producing strain was characterized by whole genome sequencing, a plasmid stability test and a conjugation assay. In vitro growth rate and an in vivo virulence test were compared between the parental mcr-1-positive strain and its mcr-1 plasmid-cured strain. We identified only one mcr-1 positive strain (KP2509), co-harboring bla KPC- 2 and bla OXA- 48, among 234 (1/234, 0.43%) CPKP strains. KP2509 and its Escherichia coli mcr-1 transconjugant showed moderate colistin resistance (MIC = 8 mg/L). The mcr-1 is located on a large conjugative plasmid (317 kb), pKP2509-MCR, with three replicons, IncHI, IncFIB, and IncN. Interestingly, a complete Type IV-A3 CRISPR-Cas system was identified in pKP2509-MCR. Plasmid pKP2509-MCR was highly stable in KP2509 after 270 generation of passage, and the pKP2509-MCR cured strain PC-KP2509 showed similar growth rate and in vivo virulence in comparison to KP2509. The prevalence of mcr-1 in CPKP strains remains low in our center. Notably, we identified a large plasmid with multiple replicons containing both the mcr-1 and the Type IV-3A CRISPR-Cas genes. The further spread of this highly stable plasmid raises concern that it may promote the increase of mcr-1 prevalence in CPKP.

Risk factors and mechanisms of in vivo emergence of colistin resistance in carbapenem-resistant Klebsiella pneumoniae.

Colistin is one of the last-resort antibiotics for treating carbapenem-resistant Klebsiella pneumoniae (CRKP). However, colistin resistance in CRKP poses a global antimicrobial crisis, as therapeutic options are limited. We investigated risk factors for in vivo emergence of colistin resistance in CRKP and explored the underlying resistance mechanisms. We conducted this matched case-control study of patients with sequential CRKP clinical strains at a medical centre in Taiwan between October 2016 and June 2019. The case group included patients with an index colistin-resistant CRKP (ColR-CRKP) strain and a previous colistin-susceptible CRKP (ColS-CRKP) counterpart. The control group encompassed patients with both an index and previous ColS-CRKP strains. Cases and controls were matched according to the time at risk, and conditional logistic regression was used to evaluate potential risk factors. Alterations in genes associated with resistance were compared between ColR-CRKP and ColS-CRKP strains. We identified 24 CRKP cases with in vivo-emergent colistin resistance, matched in a 1:2 ratio with controls. Multivariate analysis showed that colistin exposure is the only independent risk factor predisposing to colistin resistance (adjusted odds ratio = 19.09, 95% confidence interval 1.26-290.45; P = 0.034). Alteration in the mgrB gene was the predominant mechanism for emergent colistin resistance (17/24; 71%). In conclusion, colistin use is a risk factor for in vivo emergence of colistin resistance in CRKP. Given the lack of a rapid and reliable method to detect colistin resistance in daily practice, physicians should be vigilant for the emergence of resistance during colistin treatment.