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New antibiotics are needed for the treatment of patients with life-threatening carbapenem-resistant Gram-negative infections. We assessed the efficacy and safety of cefiderocol versus best available therapy in adults with serious carbapenem-resistant Gram-negative infections. We did a randomised, open-label, multicentre, parallel-group, pathogen-focused, descriptive, phase 3 study in 95 hospitals in 16 countries in North America, South America, Europe, and Asia. We enrolled patients aged 18 years or older admitted to hospital with nosocomial pneumonia, bloodstream infections or sepsis, or complicated urinary tract infections (UTI), and evidence of a carbapenem-resistant Gram-negative pathogen. Participants were randomly assigned (2:1 by interactive web or voice response system) to receive either a 3-h intravenous infusion of cefiderocol 2 g every 8 h or best available therapy (pre-specified by the investigator before randomisation and comprised of a maximum of three drugs) for 7–14 days. For patients with pneumonia or bloodstream infection or sepsis, cefiderocol treatment could be combined with one adjunctive antibiotic (excluding polymyxins, cephalosporins, and carbapenems). The primary endpoint for patients with nosocomial pneumonia or bloodstream infection or sepsis was clinical cure at test of cure (7 days [plus or minus 2] after the end of treatment) in the carbapenem-resistant microbiological intention-to-treat population (ITT; ie, patients with a confirmed carbapenem-resistant Gram-negative pathogen receiving at least one dose of study drug). For patients with complicated UTI, the primary endpoint was microbiological eradication at test of cure in the carbapenem-resistant microbiological ITT population. Safety was evaluated in the safety population, consisting of all patients who received at least one dose of study drug. Mortality was reported through to the end of study visit (28 days [plus or minus 3] after the end of treatment). Summary statistics, including within-arm 95% CIs calculated using the Clopper-Pearson method, were collected for the primary and safety endpoints. This trial is registered with ClinicalTrials.gov (NCT02714595) and EudraCT (2015-004703-23). Between Sept 7, 2016, and April 22, 2019, we randomly assigned 152 patients to treatment, 101 to cefiderocol, 51 to best available therapy. 150 patients received treatment: 101 cefiderocol (85 [85%] received monotherapy) and 49 best available therapy (30 [61%] received combination therapy). In 118 patients in the carbapenem-resistant microbiological ITT population, the most frequent carbapenem-resistant pathogens were Acinetobacter baumannii (in 54 patients [46%]), Klebsiella pneumoniae (in 39 patients [33%]), and Pseudomonas aeruginosa (in 22 patients [19%]). In the same population, for patients with nosocomial pneumonia, clinical cure was achieved by 20 (50%, 95% CI 33·8–66·2) of 40 patients in the cefiderocol group and ten (53%, 28·9–75·6) of 19 patients in the best available therapy group; for patients with bloodstream infection or sepsis, clinical cure was achieved by ten (43%, 23·2–65·5) of 23 patients in the cefiderocol group and six (43%, 17·7–71·1) of 14 patients in the best available therapy group. For patients with complicated UTIs, microbiological eradication was achieved by nine (53%, 27·8–77·0) of 17 patients in the cefiderocol group and one (20%, 0·5–71·6) of five patients in the best available therapy group. In the safety population, treatment-emergent adverse events were noted for 91% (92 patients of 101) of the cefiderocol group and 96% (47 patients of 49) of the best available therapy group. 34 (34%) of 101 patients receiving cefiderocol and nine (18%) of 49 patients receiving best available therapy died by the end of the study; one of these deaths (in the best available therapy group) was considered to be related to the study drug. Cefiderocol had similar clinical and microbiological efficacy to best available therapy in this heterogeneous patient population with infections caused by carbapenem-resistant Gram-negative bacteria. Numerically more deaths occurred in the cefiderocol group, primarily in the patient subset with Acinetobacter spp infections. Collectively, the findings from this study support cefiderocol as an option for the treatment of carbapenem-resistant infections in patients with limited treatment options. Shionogi.

Nosocomial pneumonia due to multidrug-resistant Gram-negative pathogens poses an increasing challenge. We compared the efficacy and safety of cefiderocol versus high-dose, extended-infusion meropenem for adults with nosocomial pneumonia. We did a randomised, double-blind, parallel-group, phase 3, non-inferiority trial in 76 centres in 17 countries in Asia, Europe, and the USA (APEKS-NP). We enrolled adults aged 18 years and older with hospital-acquired, ventilator-associated, or health-care-associated Gram-negative pneumonia, and randomly assigned them (1:1 by interactive response technology) to 3-h intravenous infusions of either cefiderocol 2 g or meropenem 2 g every 8 h for 7–14 days. All patients also received open-label intravenous linezolid (600 mg every 12 h) for at least 5 days. An unmasked pharmacist prepared the assigned treatments; investigators and patients were masked to treatment assignment. Only the unmasked pharmacist was aware of the study drug assignment for the infusion bags, which were administered in generic infusion bags labelled with patient and study site identification numbers. Participants were stratified at randomisation by infection type and Acute Physiology and Chronic Health Evaluation II (APACHE II) score (≤15 and ≥16). The primary endpoint was all-cause mortality at day 14 in the modified intention-to-treat (ITT) population (ie, all patients receiving at least one dose of study drug, excluding patients with Gram-positive monomicrobial infections). The analysis was done for all patients with known vital status. Non-inferiority was concluded if the upper bound of the 95% CI for the treatment difference between cefiderocol and meropenem groups was less than 12·5%. Safety was investigated to the end of the study in the safety population, which included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT03032380, and EudraCT, 2016-003020-23. Between Oct 23, 2017, and April 14, 2019, we randomly assigned 148 participants to cefiderocol and 152 to meropenem. Of 292 patients in the modified ITT population, 251 (86%) had a qualifying baseline Gram-negative pathogen, including Klebsiella pneumoniae (92 [32%]), Pseudomonas aeruginosa (48 [16%]), Acinetobacter baumannii (47 [16%]), and Escherichia coli (41 [14%]). 142 (49%) patients had an APACHE II score of 16 or more, 175 (60%) were mechanically ventilated, and 199 (68%) were in intensive care units at the time of randomisation. All-cause mortality at day 14 was 12·4% with cefiderocol (18 patients of 145) and 11·6% with meropenem (17 patients of 146; adjusted treatment difference 0·8%, 95% CI −6·6 to 8·2; p=0·002 for non-inferiority hypothesis). Treatment-emergent adverse events were reported in 130 (88%) of 148 participants in the cefiderocol group and 129 (86%) of 150 in the meropenem group. The most common treatment-emergent adverse event was urinary tract infection in the cefiderocol group (23 patients [16%] of 148) and hypokalaemia in the meropenem group (23 patients [15%] of 150). Two participants (1%) of 148 in the cefiderocol group and two (1%) of 150 in the meropenem group discontinued the study because of drug-related adverse events. Cefiderocol was non-inferior to high-dose, extended-infusion meropenem in terms of all-cause mortality on day 14 in patients with Gram-negative nosocomial pneumonia, with similar tolerability. The results suggest that cefiderocol is a potential option for the treatment of patients with nosocomial pneumonia, including those caused by multidrug-resistant Gram-negative bacteria. Shionogi.

The generation of regulatory T (Treg) cells is driven by Foxp3 and is responsible for dampening inflammation and reducing autoimmunity. In this study, the epigenetic regulation of inducible Treg (iTreg) cells was examined and an H3K4 histone methyltransferase, SMYD3 (SET and MYND Domain 3), which regulates the expression of Foxp3 by a TGFβ1/Smad3 (transforming growth factor-β1/Smad3)-dependent mechanism, was identified. Using chromatin immunoprecipitation assays, SMYD3 depletion led to a reduction in H3K4me3 in the promoter region and CNS1 (conserved noncoding DNA sequence) of the foxp3 locus. SMYD3 abrogation affected iTreg cell formation while allowing dysregulated interleukin-17 production. In a mouse model of respiratory syncytial virus (RSV) infection, a model in which iTreg cells have a critical role in regulating lung pathogenesis, SMYD3−/− mice demonstrated exacerbation of RSV-induced disease related to enhanced proinflammatory responses and worsened pathogenesis within the lung. Our data highlight a novel activation role for the TGFβ-inducible SMYD3 in regulating iTreg cell formation leading to increased severity of virus-related disease.

Properties of deuterium (D) supersaturated surface layers (DSSLs) formed in tungsten (W), such as thickness, internal microstructures, and D retention, are experimentally investigated as a function of the incident ion energy, E i . W samples were exposed to D plasmas in the PISCES-A linear plasma device in a range of E i ∼ 45–175 eV, while other plasma exposure parameters were fixed: sample temperature, T s , ∼423 K, ion flux, Γ i , ∼1.2 × 10 21 m −2 s −1 , and fluence, Φ i , ∼3.0 × 10 24 m −2 . High-resolution, cross-sectional, transmission electron microscopy observations confirm that (1) a DSSL forms even at the lowest E i ∼ 45 eV, (2) the DSSL thickness, Δ t DSSL , is found to decrease with decreasing E i from ∼11–12 nm at E i ∼ 175 eV to ∼5–6 nm at ∼45 eV, and to agree with approximately the maximum implantation depth calculated using SDTrimSP, and (3) high-density D nanobubbles with a diameter of ∼1 nm or less exist inside the DSSL, which is deemed to validate a theory-predicted vacancy stabilization process due to trapping of a solute D atom(s). Utilizing a D areal density of ∼4.2 × 10 19 m −2 in the first 14 nm from the surface at E i ∼ 75 eV from nuclear reaction analysis and the measured E i dependence of Δ t DSSL , our previous laser-induced breakdown spectroscopy data is updated: both dynamic and static D retention increase with decreasing E i , and the D/W atomic fraction during plasma exposure reaches ∼0.3 at E i ∼ 45 eV. A possible DSSL formation mechanism is proposed.

We reply to the comment by Li et al (submitted to Nucl. Fusion with this response) on our recent paper Nishijima et al (2023 Nucl. Fusion 63 126003). In this response, we address the existence of an incident ion energy, E i, threshold for the deuterium (D) supersaturated surface layer (DSSL) formation with a newly conducted D plasma exposure experiment at E i ∼ 20 eV. It is also further demonstrated, based on new experiments where the ion flux, fluence, and sample temperature are scanned, that non-kinetic (ballistic) processes play a role in the DSSL formation and growth. In addition, the effect of impurities in our plasma is discussed also with a new analysis of the surface composition made after a D plasma exposure.

A 68-year-old man on hemodialysis treatment for end-stage kidney disease secondary to autosomal dominant polycystic kidney disease (ADPKD) complained of right ankle pain that impaired walking ability two weeks after the initiation of intravenous levofloxacin as a treatment for concomitant liver cyst infection. A systemic workup led us to conclude that our patient had a fluoroquinolone-associated tendon injury. Such a disease condition has been recognized as a serious adverse event resulting from the receipt of fluoroquinolones in various clinical settings. Fluoroquinolones have received focus as standard therapeutic agents for liver and/or renal cyst infection because of their lipophilic properties that lead to good penetration into infected cysts. However, reports on fluoroquinolone-associated tendinopathy in patients with ADPKD associated with cyst infection are sparse. We believe the current report illustrates the pitfalls associated with managing patients with ADPKD who are subjected to the administration of fluoroquinolones due to infectious complications.

Gene therapies may be promising for the treatment of peritoneal fibrosis (PF) in subjects undergoing peritoneal dialysis (PD). However, a method of delivery of treatment genes to the peritoneum is lacking. We attempted to develop an in vivo small interfering RNA (siRNA) delivery system with liposome-based nanoparticles (NPs) to the peritoneum to inhibit PF. Transforming growth factor (TGF)-β 1 -siRNAs encapsulated in NPs (TGF-β 1 -siRNAs-NPs) dissolved in PD fluid were injected into the peritoneum of mice with PF three times a week for 2 weeks. TGF-β 1 -siRNAs-NPs knocked down TGF-β 1 expression significantly in the peritoneum and inhibited peritoneal thickening with fibrous changes. TGF-β 1 -siRNAs-NPs also inhibited the increase of expression of α-smooth muscle actin-positive myofibroblasts. These results suggest that the TGF-β 1 -siRNA delivery system with NPs described here could be an effective therapeutic option for PF in subjects undergoing PD.

We have obtained a state‐of‐the‐art picture of substorm‐associated evolution of the near‐Earth magnetotail and the inner magnetosphere for understanding the substorm triggering mechanism. We performed superposed epoch analysis of Geotail, Polar, and GOES data with 2‐min resolution, utilizing a total of 3787 substorms for each of which auroral breakup was determined from Polar UVI or IMAGE FUV auroral imager data. The decrease of the north‐south magnetic field associated with plasmoids and the initial total pressure decrease suggest that the magnetic reconnection first occurs in the premidnight tail, on average, at X ∼ −16 to −20 RE at least 2 min before auroral onset. The magnetic reconnection site is located near the tailward edge of a region of considerably taillike magnetic field lines and intense cross‐tail current, which extends from X ∼ −5 to −20 RE in the premidnight sector. Then the plasmoid substantially evolves tailward of X ∼ −20 RE immediately after onset. Almost simultaneously with the magnetic reconnection, the dipolarization begins first at X ∼ −7 to −10 RE 2 min before onset. The dipolarization region then expands tailward as well as in the dawn‐dusk directions and earthward. We find that the total pressure generally enhances in association with the dipolarization, with the contribution of high‐energy particles. Also, energy release is more significant between the regions of the magnetic reconnection and the initial dipolarization. The present results will be helpful as a reference guide to developing the overall picture of magnetotail evolution and studying the causal relationship between the magnetic reconnection and the dipolarization as well as detailed mechanisms of each of the two processes on the basis of multispacecraft observations.

Deep-sea coral distribution and composition are unknown in much of the global ocean, but repurposing ocean industry surveys can fill that gap. In Santos Basin, southeast Brazil, areas (241–963 m depth) were surveyed during seven Petrobras cruises, mapping bottom topography with multibeam sonar, then collecting video with remotely operated vehicles. Here, we defined deep-sea coral species distribution and richness, using these surveys, correlating them to physical oceanographic properties. Solenosmilia variabilis was the most prevalent colonial species in coral mounds. Overall, 67% of species were Octocorallia. Coral assemblage structure, abundance, and richness varied among sites both within and among depths, with higher density and richness in the northernmost Santos basin. Depth was the strongest predictor for scleractinian coral distribution, with depth ranges varying by species. Assemblage differences corresponded to changes in water mass. Desmophyllum pertusum was more abundant in South Atlantic Central Water and S. variabilis in Antarctic Intermediate Water influenced areas.

Understanding the molecular evolution and diversity changes of begomoviruses is crucial for predicting future outbreaks of the begomovirus disease in tomato crops. Thus, a molecular diversity study using high-throughput sequencing (HTS) was carried out on samples of infected tomato leaves collected between 2003 and 2016 from Central Brazil. DNA samples were subjected to rolling circle amplification and pooled in three batches, G1 (2003–2005, N = 107), G2 (2009–2011, N = 118), and G3 (2014–2016, N = 129) prior to HTS. Nineteen genome-sized geminivirus sequences were assembled, but only 17 were confirmed by PCR. In the G1 library, five begomoviruses and one capula-like virus were detected, but the number of identified viruses decreased to three begomoviruses in the G2 and G3 libraries. The bipartite begomovirus tomato severe rugose virus (ToSRV) and the monopartite tomato mottle leaf curl virus (ToMoLCV) were found to be the most prevalent begomoviruses in this survey. Our analyses revealed a significant increase in both relative abundance and genetic diversity of ToMoLCV from G1 to G3, and ToSRV from G1 to G2; however, both abundance and diversity decreased from G2 to G3. This suggests that ToMoLCV and ToSRV outcompeted other begomoviruses from G1 to G2 and that ToSRV was being outcompeted by ToMoLCV from G2 to G3. The possible evolutionary history of begomoviruses that were likely transferred from wild native plants and weeds to tomato crops after the introduction of the polyphagous vector Bemisia tabaci MEAM1 and the wide use of cultivars carrying the Ty-1 resistance gene are discussed, as well as the strengths and limitations of the use of HTS in identification and diversity analysis of begomoviruses.