Evaluation of the immunotoxicity potential of nanomaterials using THP-1 cells.

With the expansion of nanomaterials (NMs) usage, concerns about their toxicity are increasing, and the wide variety of NMs makes it difficult to assess their toxicity. Therefore, the development of a high-throughput, accurate, and certified method to evaluate the immunotoxicity of NMs is required. In this study, we assessed the immunotoxicity potential of various NMs, such as nanoparticles of silver, silica, and titanium dioxide, using the human Cell Line Activation Test (h-CLAT) at the cellular level. After exposure to silver nanoparticle dispersions, the expression levels of CD86 and CD54 increased, suggesting the activation of antigen-presenting cells (APCs) by silver nanoparticles. Quantification of silver ions eluted from silver nanoparticles and the activation of APCs by silver ions suggested that it was due to the release of silver ions. Silica nanoparticles also increased the expression of CD86 and/or CD54, and their activation ability correlated with the synthesis methods and hydrodynamic diameters. The ability of titanium dioxide to activate APCs differed depending on the crystal type and hydrodynamic diameter. These results suggest a potential method to evaluate the immunotoxicity potential of various NMs based on their ability to activate APCs using human monocytic THP-1 cells. This method will be valuable in assessing the immunotoxicity potential and elucidating the immunotoxic mechanisms of NMs.

Coronary computed tomography-angiography for traumatic coronary artery transection.

Background: Penetrating thoracic trauma with coronary artery transection is a lethal injury, but is rare. We report a case of a cardiac stab wound with coronary artery transection that was successfully treated after preoperative diagnosis. Case Presentation: A 36-year-old man was transferred to our emergency department with a left chest stab wound. A coronary computed tomography-angiography scan, including coronary angiography, revealed left hemopneumothorax and left anterior descending branch transection, with ischemic changes in the left ventricular myocardium. Given the diagnosis of coronary artery transection and the absence of injury to the surrounding arteries, we were able to perform coronary artery bypass surgery using the left internal thoracic artery. The patient's postoperative course was good, and he was discharged on foot without major complications 18 days after surgery. Conclusion: Unless a resuscitative thoracotomy is required, a preoperative computed tomography scan, including coronary angiography, may be useful for accurate preoperative diagnosis for patients at high risk of myocardial or coronary artery injury.

Radiological and audiological predictors of stapes destruction in adherent pars tensa.

PURPOSE: Progressive adherent pars tensa occasionally induces ossicular erosion. Specifically, stapes discontinuity adversely affects postoperative hearing. However, this irretrievable sequela is challenging to prove preoperatively, partly because perimatrix inflammation on the pars tensa can obscure the visibility of the ossicles or the partial volume effect of computed tomography (CT) imaging can hamper detailed ossicular visualization. Therefore, there is no consensus regarding the ideal timing for switching from a wait-and-see approach to a surgical one. Herein, we aimed to explore the potential predictors of stapes superstructure destruction in adherent pars tensa. METHODS: This retrospective cohort study enrolled consecutive patients who underwent primary tympanoplasty for adherent pars tensa categorized as grade IV on Sadé's grading scale between April 2016 and September 2021. The impact of features on otoscopy and CT and air-bone gap (ABG) on stapes superstructure destruction was assessed using uni- and multivariable logistic regression analyses. RESULTS: Sixty-four ears were included. Multivariate analysis revealed the presence of debris on the adherent pars tensa (odds ratio [OR] [95% confidence interval {CI}]): 4.799 [1.063-21.668], p = 0.0415), presence of soft-tissue density occupying the oval window (OR [95% CI]: 13.876 [3.084-62.437], p = 0.0006), and a ≥ 20-dB preoperative ABG at 3 kHz (OR [95% CI]: 7.595 [1.596-36.132], p = 0.0108) as independent predictors for stapes superstructure destruction. CONCLUSION: High preoperative awareness of the possibility of destruction of the stapes superstructure would enable the surgeon to make a timely decision to provide surgical intervention before progression to severe stapes destruction, thereby maintaining long-term satisfactory hearing.

A variant of Takotsubo syndrome concomitant with left atrial myxoma.

We treated an 80-year-old Japanese woman who had Takotsubo syndrome (TTS) concomitant with a left atrial (LA) tumor. Left ventriculography revealed a variant of TTS. In cardiac surgery, the LA mass was successfully resected without embolism, with the pathological diagnosis of myxoma.

Safety and Effectiveness of Aortic Occlusion for Those Undergoing Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA): A Retrospective Single-Center Study.

BACKGROUND: Resuscitative endovascular balloon occlusion of the aorta (REBOA) is used to temporarily control bleeding and maintain the cerebral and coronary blood flow in cases in which it is difficult to control hemorrhagic shock. However, the safety and effectiveness of REBOA remains uncertain. OBJECTIVES: This study aimed to estimate the safety and effectiveness of aortic occlusion in patients who undergo REBOA catheter placement. METHODS: We conducted a retrospective study of patients who underwent REBOA catheter placement at Fukuyama City Hospital Emergency Medical Center from August 1, 2008 to March 31, 2020. A propensity score-matching analysis was used to compare 30-day survival between patients who undergo REBOA catheter placement with and without aortic occlusion. RESULTS: Overall, 122 of the 147 who underwent REBOA catheter placement at Fukuyama City Hospital were eligible for inclusion. Thirty-five patients in the Occlusion group and 35 patients in the Nonocclusion group were selected by propensity score matching. According to the 30-day survival rate, the difference between the two groups was not statistically significant (p = 0.288 log-rank test). Moreover, the required treatment, the types and incidence of complications, and other outcomes did not differ according to the presence or absence of aortic occlusion in patients who underwent REBOA catheter placement. CONCLUSION: According to the results of this study, in trauma patients who undergo REBOA catheter placement, the presence of aortic occlusion was not significantly associated with 30-day mortality. Furthermore, the performance of aortic occlusion was not associated with a significant increase in complications.

Characterisation of cefiderocol-non-susceptible Acinetobacter baumannii isolates from Taiwan.

OBJECTIVES: Cefiderocol (CFDC), a siderophore cephalosporin, is active against Gram-negative bacteria including carbapenem-resistant Acinetobacter baumannii (CRAB). In this study, 100 CRAB isolates from patients with bacteraemia in Taiwan were characterised, among which 21 CFDC-non-susceptible isolates were identified with a minimum inhibitory concentration (MIC) of ≥8 mg/L. METHODS: The effect of avibactam on CFDC activity was evaluated using broth microdilution methods according to Clinical and Laboratory Standards Institute (CLSI) guidelines. Whole-genome sequencing (WGS) was performed on all CFDC-non-susceptible isolates (MIC ≥ 8 mg/L) for multilocus sequence typing (MLST) analysis, possession of ß-lactamase genes and identification of possible variations in the PiuA iron transporter. RESULTS: Addition of avibactam, a diazabicyclooctane inhibitor for serine-type ß-lactamases, resulted in a ≥8-fold decrease in the CFDC MIC for 15 of 21 CFDC-non-susceptible isolates compared with only 1 of 79 CFDC-susceptible isolates (MIC ≤ 4 mg/L). WGS analysis confirmed that all CFDC-non-susceptible isolates harboured multiple ß-lactamases including ADC-30 homologues, OXA-23 and OXA-66. One isolate with a high MIC (>32 mg/L) had a PER-type extended-spectrum ß-lactamase (ESBL) gene. Twenty other isolates belonged to ST455, ST473 and ST787. Among these, thirteen ST455 isolates were deficient in PiuA, a siderophore uptake receptor that may be required for optimal penetration of CFDC. CONCLUSION: MICs of CFDC-non-susceptible CRAB isolates from Taiwan could be significantly decreased to susceptible levels by the addition of avibactam, suggesting the involvement of ß-lactamases in resistance. Among the 21 CFDC-non-susceptible isolates, 1 isolate had a PER-type ESBL gene and 13 isolates lacked a PiuA iron siderophore transporter.

Effect of 6-Week Balance Exercise by Real-Time Postural Feedback System on Walking Ability for Patients with Chronic Stroke: A Pilot Single-Blind Randomized Controlled Trial.

Stroke causes balance dysfunction, leading to decreased physical activity and increased falls. Thus, effective balance exercises are needed to improve balance dysfunction. This single-blind, single-center randomized controlled trial evaluated the long-term and continuous effects of balance exercise using a real-time postural feedback system to improve balancing ability safely. Thirty participants were randomized into intervention (n = 15) and control (n = 15) groups; 11 in each group completed the final evaluation. The effect of the intervention was evaluated by muscle strength of knee extension, physical performance (short physical performance battery, the center of pressure trajectory length per second, and Timed Up and Go test [TUG]), and self-reported questionnaires (modified Gait Efficacy Scale [mGES] and the Fall Efficacy Scale) at pre (0 week), post (6-week), and at follow-up (10-week) visits. The TUG and mGES showed a significant interactive (group * time) effect (p = 0.007 and p = 0.038, respectively). The intervention group showed significant decreasing time to perform TUG from pre- to post-intervention (p = 0.015) and pre-intervention to follow-up (p = 0.016); mGES showed a significant change from pre-intervention to follow-up (p = 0.036). Thus, balance exercise using a real-time postural feedback system can confer a positive effect on the walking ability in patients with chronic stroke and increase their self-confidence in gait performance.

Gender Differences in Anxiety Among COVID-19 Inpatients Under Isolation: A Questionnaire Survey During the First and Second Waves of the COVID-19 Pandemic in Japan.

This study assesses the gender differences in health and anxiety, especially pertaining to mental health problems and time-course effects. We surveyed 121 patients admitted to a hospital with a COVID-19 diagnosis between March 1 and August 31, 2020. Their mental status was evaluated on admission using the Japanese General Health Questionnaire-28 (GHQ-28) and State-Trait Anxiety Inventory-Form JYZ (STAI). The patients were divided into two groups depending on the period of prevalence, that is, the first and second waves of the pandemic in Japan (from the beginning of March to the end of May 2020, Time 1 = T1; and from the beginning of June to the end of August 2020, Time 2 = T2). A multivariate analysis of covariance revealed significant differences in gender by time interactions in the GHQ-28 subscale "Insomnia and anxiety" and STAI subscale "State-Anxiety." Post-hoc t-tests revealed that the scores of "Insomnia and Anxiety" and "State-Anxiety" were higher in women than in men at T1. However, no difference was observed at T2. Further, "Insomnia and Anxiety" and "State-Anxiety" were significantly higher at T1 than at T2 in female patients. There was no significant difference in males. Thus, female patients were more anxious and depressed in the early phase of the pandemic, whereas male patients had difficulties in coping with anxiety. We suggest more gender-specific mental care, particularly for women at the early stages of infection.

Characterization of the Biosynthetic Gene Cluster of Enterocin F4-9, a Glycosylated Bacteriocin.

Enterocin F4-9 belongs to the glycocin family having post-translational modifications by two molecules of N-acetylglucosamine ß-O-linked to Ser37 and Thr46. In this study, the biosynthetic gene cluster of enterocin F4-9 was cloned and expressed in Enterococcus faecalis JH2-2. Production of glycocin by the JH2-2 expression strain was confirmed by expression of the five genes. The molecular weight was greater than glycocin secreted by the wild strain, E. faecalis F4-9, because eight amino acids from the N-terminal leader sequence remained attached. This N-terminal extension was eliminated after treatment with the culture supernatant of strain F4-9, implying an extracellular protease from E. faecalis F4-9 cleaves the N-terminal sequence. Thus, leader sequences cleavage requires two steps: the first via the EnfT protease domain and the second via extracellular proteases. Interestingly, the long peptide, with N-terminal extension, demonstrated advanced antimicrobial activity against Gram-positive and Gram-negative bacteria. Furthermore, enfC was responsible for glycosylation, a necessary step prior to secretion and cleavage of the leader peptide. In addition, enfI was found to grant self-immunity to producer cells against enterocin F4-9. This report demonstrates specifications of the minimal gene set responsible for production of enterocin F4-9, as well as a new biosynthetic mechanism of glycocins.

A mid-ventricular variant of Takotsubo syndrome: was it triggered by insular cortex damage?

Takotsubo syndrome (TTS) is a transient cardiomyopathy that is often associated with cerebrovascular diseases. Earlier studies have supported the concept that the cardiovascular system is regulated by a central autonomic network (CAN) consisting of the insular cortex (IC), anterior cingulate gyrus and amygdala. We report the case of a 79-year-old female diagnosed with a mid-ventricular variant of TTS concomitant with right IC ischaemic stroke. After 12 h of hospitalization, she experienced a sudden collapse. Rapid cardiopulmonary resuscitation resulted in a return of spontaneous circulation. Subsequent left ventriculography revealed akinesis in the mid-portion of the left ventricle with vigorous contraction of the basal and apex segment. Two weeks after admission, cardiac ultrasound showed improved left ventricular contraction. Right IC ischaemia in this patient might have been associated with a dysregulation of the CAN and subsequent increased sympathetic nervous system activity that triggered TTS.

Functional Predictors for Home Discharge after Hip Fracture in Patients Living in Sloped Neighborhoods or Islands: An 8-Year Retrospective Cohort Study.

Functional predictors of home discharge after hip fractures have been widely reported; however, no study has considered the geographical features surrounding patients' homes. This study aimed to identify home discharge predictors and determine the cutoff points required for home discharge of patients living in sloped neighborhoods or islands. A total of 437 postoperative hip fracture patients were included and classified into the flat, slope, and island groups according to their residential area before the fracture. Multivariate logistic regression analysis was used to identify significant home discharge predictors, and receiver-operating characteristic analysis to calculate cutoff values. In all the groups, the functional independence measure-motor score was a significant home discharge predictor, with cutoff values of 69 for the flat group and 65 points for the slope and island group. In the slope group, the 6-minute walking distance (odds ratio, 1.02; 95% confidence interval, 1.01-1.04) and revised Hasegawa dementia scale score (odds ratio, 1.06; 95% confidence interval, 1.01-1.12) were also identified as predictors, with cutoff values of 150 m and 18 points, respectively. The outcomes required for home discharge after hip fracture differ depending on the neighborhood terrain, especially for patients living in areas with many slopes and stairs.

Processing and secretion of non-cognate bacteriocins by EnkT, an ABC transporter from a multiple-bacteriocin producer, Enterococcus faecium NKR-5-3.

EnkT is an ATP-binding cassette (ABC) transporter produced by Enterococcus faecium NKR-5-3, which is responsible for the secretion of multiple bacteriocins; enterocins NKR-5-3A, C, D, and Z (Ent53A, C, D, and Z). EnkT has been shown to possess a tolerant recognition mechanism that enables it to secrete the mature Ent53C from a chimeric precursor peptide containing the leader peptide moieties that are derived from different heterologous bacteriocins. In this study, to further characterize EnkT, we aimed to investigate the capacity of EnkT to recognize, process, and secrete non-cognate bacteriocins, which belong to different subclasses of class II. For this, the non-cognate bacteriocin precursor peptides, including enterocin A, pediocin PA-1, lactococcin Q, lactococcin A, and lacticin Q were co-expressed with EnkT, and thereafter, the production of the mature forms of these non-cognate bacteriocins was assessed. Our results revealed that EnkT could potentially recognize, process, and secrete the non-cognate bacteriocins with an exception of the leaderless bacteriocin, lacticin Q. Moreover, the processing and secretion efficiencies of these heterologous non-cognate bacteriocins by EnkT were further enhanced when the leader peptide moiety was replaced with the Ent53C leader peptide (derived from a native NKR-5-3 bacteriocin). The findings of this study describe the wide substrate tolerance of this ABC transporter, EnkT, that can be exploited in the future in establishing effective bacteriocin production systems adaptive to complex fermentation conditions common in many food systems.

Discovery of 3,5-Dimethylpyridin-4(1H)-one Derivatives as Activators of AMP-Activated Protein Kinase (AMPK).

Novel 3,5-dimethylpyridin-4(1H)-one scaffold compounds were synthesized and evaluated as AMP-activated protein kinase (AMPK) activators. Unlike direct AMPK activators, this series of compounds showed selective cell growth inhibitory activity against human breast cancer cell lines. By optimizing the lead compound (4a) from our library, 2-[({1'-[(4-fluorophenyl)methyl]-2-methyl-1',2',3',6'-tetrahydro[3,4'-bipyridin]-6-yl}oxy)methyl]-3,5-dimethylpyridin-4(1H)-one (25) was found to have potent AMPK activating activity. Compound 25 also showed good aqueous solubility while maintaining the unique selectivity in cell growth inhibitory activity.

Molecular characterization of the possible regulation of multiple bacteriocin production through a three-component regulatory system in Enterococcus faecium NKR-5-3.

Enterococcus faecium NKR-5-3 produces multiple-bacteriocins, enterocins NKR-5-3A, B, C, D, and Z (Ent53A, Ent53B, Ent53C, Ent53D, and Ent53Z). However, the biosynthetic mechanisms on how their productions are regulated are yet to be fully understood. In silico analysis revealed putative promoters and terminators in the enterocin NKR-5-3ACDZ gene cluster, and the putative direct repeats (5'-ATTTTAGGATA-3') were conserved upstream of each promoter. Transcriptional analysis by quantitative real-time polymerase chain reaction (PCR) of the biosynthetic genes for the enterocins NKR-5-3 suggested that an inducing peptide (Ent53D) regulates the transcription of the structure genes and corresponding biosynthetic genes of enterocins NKR-5-3, except for Ent53B (a circular bacteriocin), thus consequently regulating their production. Moreover, transcriptional analysis of some knock-out mutants showed that the production of Ent53A, C, D and Z is controlled by a three-component regulatory system (TCS) consisting of Ent53D, EnkR (response regulator), and EnkK (histidine kinase). The production of the circular bacteriocin Ent53B appeared to be independent from this TCS. Nevertheless, disrupting the TCS by deletion of a single component (enkD, enkR and enkK) resulted in a slight increase of enkB transcription and consequently the production of Ent53B, presumably, as an indirect consequence of the increase of available energy to the strain NKR-5-3. Here, we demonstrate the regulatory control of the multiple bacteriocin production of strain NKR-5-3 likely through the TCS consisting of Ent53D, EnkR, and EnkK. The information of the sharing of the regulatory machinery between bacteriocins in strain NKR-5-3 can be useful in its future application such as designing strategies to effectively dispense its multiple bacteriocin arsenal.

Bidirectional loop-snare technique for adherent inferior vena cava filter retrieval.

Placement of a Günther Tulip Inferior Vena Cava (IVC) Filter™ (Cook, Bloomington, IN, USA) is an alternative treatment option to prevent pulmonary embolism in patients in whom anticoagulation therapy is contraindicated. Most patients require filter placement for only short periods, after which it can be retrieved. IVC filter retrieval becomes more difficult as the indwelling time increases. We developed a new method to retrieve the Günther Tulip IVC Filter™, namely, the bidirectional loop-snare technique (BLT). The key to the BLT procedure is to use 2 snares from both the jugular and femoral access routes. The jugular snare catches the filter hook and the femoral snare relieves the adhesion between the filter leg and IVC wall. Pulling from both the jugular and femoral ends increases the power to retrieve the IVC filter, and leads to successful filter retrieval. .

Stability and low induction propensity of cefiderocol against chromosomal AmpC ß-lactamases of Pseudomonas aeruginosa and Enterobacter cloacae.

Objectives: The siderophore cephalosporin cefiderocol possesses in vitro activity against MDR Gram-negative bacteria. The stability of cefiderocol against serine- and metallo-type carbapenemases has been reported previously, but little is known about how cefiderocol interacts with chromosomal AmpC ß-lactamases. We investigated a number of features of cefiderocol, namely antibacterial activity against AmpC overproducers, stability against AmpC ß-lactamases and propensity for AmpC induction using Pseudomonas aeruginosa and Enterobacter cloacae. Methods: MICs were determined by broth microdilution according to CLSI guidelines. The MIC of cefiderocol was determined in iron-depleted CAMHB. Hydrolysis of the antibiotics was determined by monitoring the changes in the absorbance in the presence of AmpC ß-lactamase, and AmpC induction was evaluated by double disc diffusion and nitrocefin degradation assays. Results: The MICs of ceftazidime and cefepime for PAO1 increased 4- to 16-fold with inactivation of either ampD or dacB, whereas cefiderocol MICs were little affected by these inactivations (<2-fold increase). Cefiderocol has 17- and 740-fold lower affinity (higher Ki) to AmpCs of P. aeruginosa SR24-12 and E. cloacae P99, respectively, compared with ceftazidime. Both disc diffusion and nitrocefin degradation assays indicated that cefiderocol did not induce AmpC ß-lactamases of P. aeruginosa PAO1 and ATCC 27853 and E. cloacae ATCC 13047, whereas imipenem did. Conclusions: Cefiderocol showed in vitro activity against the AmpC-overproducing strains, low affinity for chromosomal AmpC ß-lactamases, and a low propensity of temporal induction of AmpC ß-lactamases of P. aeruginosa and E. cloacae. These features relating to chromosomal AmpC could explain the potent antibacterial activity of cefiderocol against drug-resistant strains producing AmpC ß-lactamases.

Characterisation of the action mechanism of a Lactococcus-specific bacteriocin, lactococcin Z.

Lactococcin Z is a novel Lactococcus-specific bacteriocin produced by Lactococcus lactis QU 7 that shares 55.6% identity with lactococcin A. To identify the receptor targeted by lactococcin Z, several lactococcin Z-resistant mutants were generated from the sensitive strain, L. lactis IL1403. The resistant mutants showed difficulties in utilising mannose and glucose as sole carbon sources, contrary to their pattern of growth in the presence of galactose as a sole carbon source. Mutations were found in the ptnC and ptnD genes of lactococcin Z-resistant mutants, which encode the mannose phosphotransferase system (Man-PTS) components, IIC and IID, respectively; therefore, IIC and IID are proposed as potential receptors employed by lactococcin Z and are the same receptors targeted by lactococcin A. Both lactococcins A and Z share a high percentage identity in their N-termini regions in contrast to their C-termini that show less similarity; this may explain the difference in their action mechanisms as well as the lack of cross-immunity between them. Although lactococcin Z showed bactericidal activity, it neither dissipated membrane potential nor formed pores on the membranes of sensitive cells, in sharp contrast to the pore-forming lactococcin A.

Evaluation of leader peptides that affect the secretory ability of a multiple bacteriocin transporter, EnkT.

EnkT is a novel ATP-binding cassette (ABC) transporter responsible for secretion of four bacteriocins, enterocins NKR-5-3A, C, D, and Z (Ent53A, C, D, and Z), produced by Enterococcus faecium NKR-5-3. It is generally recognized that the secretion of a bacteriocin requires a dedicated ABC transporter, although molecular mechanisms of this secretion are yet to be revealed. In order to characterize the unique ability of EnkT to secrete multiple bacteriocins, the role of N-terminal leader peptides of bacteriocin precursors was evaluated using Ent53C precursor as a model. The 18-amino acid leader peptide of Ent53C (Lc) was modified by site-directed mutagenesis to generate various point mutations, truncations, or extensions, and substitutions with other leader peptides. The impact of these Lc mutations on Ent53C secretion was evaluated using a quantitative antimicrobial activity assay. We observed that Ent53C production increased with Ala substitution of the highly conserved C-terminal double glycine residues that are recognized as the cleavage site. In contrast, Ent53C antimicrobial activity decreased, with decrease in the length of the putative α-helix-forming region of Lc. Furthermore, EnkT recognized and transported Ent53C of the transformants possessing heterologous leader peptides of enterocin A, pediocin PA-1, brochocins A and B, and lactococcins Qα and Qß. These results indicated that EnkT shows significant tolerance towards the sequence and length of leader peptides, to secrete multiple bacteriocins. This further demonstrates the functional diversity of bacteriocin ABC transporters and the importance of leader peptides as their recognition motif.

In Vitro Antibacterial Properties of Cefiderocol, a Novel Siderophore Cephalosporin, against Gram-Negative Bacteria.

Cefiderocol (CFDC; S-649266), a novel parenteral siderophore cephalosporin conjugated with a catechol moiety, has a characteristic antibacterial spectrum with a potent activity against a broad range of aerobic Gram-negative bacterial species, including carbapenem-resistant strains of Enterobacteriaceae and nonfermenting bacteria such as Pseudomonas aeruginosa and Acinetobacter baumannii Cefiderocol has affinity mainly for penicillin-binding protein 3 (PBP3) of Enterobacteriaceae and nonfermenting bacteria similar to that of ceftazidime. A deficiency of the iron transporter PiuA in P. aeruginosa or both CirA and Fiu in Escherichia coli caused 16-fold increases in cefiderocol MICs, suggesting that these iron transporters contribute to the permeation of cefiderocol across the outer membrane. The deficiency of OmpK35/36 in Klebsiella pneumoniae and the overproduction of efflux pump MexA-MexB-OprM in P. aeruginosa showed no significant impact on the activity of cefiderocol.