Objectives: The objective of this study was to determine the effectiveness of WGS in identifying resistance genotypes of MDR Escherichia coli and whether these correlate with observed phenotypes. ...Methods: Seventy-six E. coli strains were isolated from farm cattle and measured for phenotypic resistance to 15 antimicrobials with the Sensititrew system. Isolates with resistance to at least four antimicrobials in three classes were selected for WGS using an Illumina MiSeq. Genotypic analysis was conducted with in-house Perl scripts using BLAST analysis to identify known genes and mutations associated with clinical resistance. Results: Over 30 resistance genes and a number of resistance mutations were identified among the E. coli isolates. Resistance genotypes correlated with 97.8% specificity and 99.6% sensitivity to the identified phenotypes. The majority of discordant results were attributable to the aminoglycoside streptomycin, whereas there was a perfect genotype–phenotype correlation for most antibiotic classes such as tetracyclines, quinolones and phenicols. WGS also revealed information about rare resistance mechanisms, such as structural mutations in chromosomal copies of ampC conferring third-generation cephalosporin resistance. Conclusions: WGS can provide comprehensive resistance genotypes and is capable of accurately predicting resistance phenotypes, making it a valuable tool for surveillance. Moreover, the data presented here showing the ability to accurately predict resistance suggest that WGS may be used as a screening tool in selecting anti-infective therapy, especially as costs drop and methods improve.
An important vision of modern magnetic research is to use antiferromagnets (AFMs) as controllable and active ultrafast components in spintronic devices. Hematite (α‐Fe2O3) is a promising model ...material in this respect because its pronounced Dzyaloshinskii‐Moriya interaction leads to the coexistence of antiferromagnetism and weak ferromagnetism. Here, femtosecond laser pulses are used to drive terahertz (THz) spin currents from α‐Fe2O3 into an adjacent Pt layer. Two contributions to the generation of the spin current with distinctly different dynamics are found: the impulsive stimulated Raman scatting that relies on the AFM order and the ultrafast spin Seebeck effect that relies on the net magnetization. The total THz spin current dynamics can be manipulated by a medium‐strength magnetic field below 1 T. The control of the THz spin current achieved in α‐Fe2O3 opens the pathway toward tailoring the exact spin current dynamics from ultrafast AFM spin sources.
An important vision of modern magnetic research is to use antiferromagnets (AFMs) as controllable and active ultrafast components in spintronic devices. The total terahertz (THz) spin current dynamics in hematite are manipulated by a medium‐strength magnetic field. The control of the THz spin current opens the pathway toward tailoring the exact spin current dynamics from ultrafast AFM spin sources.
Flux calculations demonstrate that many estuaries are natural filters for trace metals. Yet, the underlying processes are poorly investigated. In the present study, it was hypothesized that ...intertidal marshes contribute significantly to the contaminant filter function of estuaries. Trace metal concentrations and sediment characteristics were measured along a transect from the subtidal, over an intertidal flat and marsh to a restored marsh with controlled reduced tide. Metal concentrations in the intertidal and restored marsh were found to be a factor two to five higher than values in the subtidal and intertidal flat sediments. High metal concentrations and high accretion rates indicate a high metal accumulation capacity of the intertidal marshes. Overbank sedimentation in the tidal marshes of the entire estuary was calculated to remove 25% to 50% of the riverine metal influx, even though marshes comprise less than 8% of the total surface of the estuary. In addition, the large-scale implementation of planned tidal marsh restoration projects was estimated to almost double the trace metal storage capacity of the present natural tidal marshes in the estuary.
D-501036 2,5-bis(5-hydroxymethyl-2-selenienyl)-3-hydroxymethyl-N-methylpyrrole is herein identified as a novel antineoplastic agent with a broad spectrum of antitumoral activity against several human ...cancer cells and an IC(50) value in the nanomolar range. The IC(50) values for D-501036 in the renal proximal tubule, normal bronchial epithelial, and fibroblast cells were >10 mumol/L. D-501036 exhibited no cross-resistance with vincristine- and paclitaxel-resistant cell lines, whereas a low level of resistance toward the etoposide-resistant KB variant was observed. Cell cycle analysis established that D-501036 treatment resulted in a dose-dependent accumulation in S phase with concomitant loss of both the G(0)-G(1) and G(2)-M phase in both Hep 3B and A-498 cells. Pulsed-field gel electrophoresis showed D-501036-induced, concentration-dependent DNA breaks in both Hep 3B and A-498 cells. These breaks did not involve interference with either topoisomerase-I and topoisomerase-II function or DNA binding. Rapid reactive oxygen species production and formation of Se-DNA adducts were evident following exposure of cells to D-501036, indicating that D-501036-mediated DNA breaks were attributable to the induction of reactive oxygen species and DNA adduct formation. Moreover, D-501036-induced DNA damage activated ataxia telangiectasia-mutated nuclear protein kinase, leading to hyperphosphorylation of Chk1, Chk2, and p53, decreased expression of CDC25A, and up-regulation of p21(WAF1) in both p53-proficient and p53-deficient cells. Collectively, the results indicate that D-501036-induced cell death was associated with DNA damage-mediated induction of ataxia telangiectasia-mutated activation, and p53-dependent and -independent apoptosis pathways. Notably, D-501036 shows potent activity against the growth of xenograft tumors of human renal carcinoma A-498 cells. Thus, D-501036 is a promising anticancer compound that has strong potential for the management of human cancers.
The first interim analysis of the KEYNOTE-564 study showed improved disease-free survival with adjuvant pembrolizumab compared with placebo after surgery in patients with clear cell renal cell ...carcinoma at an increased risk of recurrence. The analysis reported here, with an additional 6 months of follow-up, was designed to assess longer-term efficacy and safety of pembrolizumab versus placebo, as well as additional secondary and exploratory endpoints.
In the multicentre, randomised, double-blind, placebo-controlled, phase 3 KEYNOTE-564 trial, adults aged 18 years or older with clear cell renal cell carcinoma with an increased risk of recurrence were enrolled at 213 hospitals and cancer centres in North America, South America, Europe, Asia, and Australia. Eligible participants had an Eastern Cooperative Oncology Group performance status of 0 or 1, had undergone nephrectomy 12 weeks or less before randomisation, and had not received previous systemic therapy for advanced renal cell carcinoma. Participants were randomly assigned (1:1) via central permuted block randomisation (block size of four) to receive pembrolizumab 200 mg or placebo intravenously every 3 weeks for up to 17 cycles. Randomisation was stratified by metastatic disease status (M0 vs M1), and the M0 group was further stratified by ECOG performance status and geographical region. All participants and investigators involved in study treatment administration were masked to the treatment group assignment. The primary endpoint was disease-free survival by investigator assessment in the intention-to-treat population (all participants randomly assigned to a treatment). Safety was assessed in the safety population, comprising all participants who received at least one dose of pembrolizumab or placebo. As the primary endpoint was met at the first interim analysis, updated data are reported without p values. This study is ongoing, but no longer recruiting, and is registered with ClinicalTrials.gov, NCT03142334.
Between June 30, 2017, and Sept 20, 2019, 994 participants were assigned to receive pembrolizumab (n=496) or placebo (n=498). Median follow-up, defined as the time from randomisation to data cutoff (June 14, 2021), was 30·1 months (IQR 25·7–36·7). Disease-free survival was better with pembrolizumab compared with placebo (HR 0·63 95% CI 0·50–0·80). Median disease-free survival was not reached in either group. The most common all-cause grade 3–4 adverse events were hypertension (in 14 3% of 496 participants) and increased alanine aminotransferase (in 11 2%) in the pembrolizumab group, and hypertension (in 13 3% of 498 participants) in the placebo group. Serious adverse events attributed to study treatment occurred in 59 (12%) participants in the pembrolizumab group and one (<1%) participant in the placebo group. No deaths were attributed to pembrolizumab.
Updated results from KEYNOTE-564 support the use of adjuvant pembrolizumab monotherapy as a standard of care for participants with renal cell carcinoma with an increased risk of recurrence after nephrectomy.
Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc, Rahway, NJ, USA.
Fecal prevalence of Escherichia coli O157 in ruminants is highest in the summer decreasing to very low levels in the winter. We hypothesize that this seasonal variation is a result of physiological ...responses within the host animal to changing day-length. To determine the effects of melatonin (MEL) on fecal shedding of E. coli O157:H7 in cattle, eight crossbred beef steers identified as shedding E. coli O157:H7, were allotted to treatment: control or MEL (0.5 mg/kg body weight (BW); 1x) administered orally daily for 7 days. After a 5-day period of no treatment, a second MEL dose (5.0 mg/kg BW; 10x) was administered daily for 4 days. Fecal samples were collected daily for qualification of E. coli O157:H7. No differences (P > 0.10) were observed in the percentage of E. coli O157:H7 positive fecal samples in steers receiving the 1x MEL dose, however the 10x dose decreased (P = 0.05) the percentage of fecal samples E. coli O157:H7 positive. Serum MEL concentrations were higher in the 1x, but not 10x, treated animals compared to control animals. Although it is difficult to explain, this may be a result of decreasing day-length increasing serum melatonin concentrations that may have masked any treatment effect on serum melatonin. In a second similar experiment, a second group of cattle (heifers and steers) were administered tryptophan (TRP) over a 17-day experimental period (5 g/head/day for 10 days followed by 10 g/head/day for 7 days). Tryptophan had no effect (P > 0.20) on the percentage of fecal samples positive for E. coli O157. Serum TRP (P < 0.05), but not MEL (P > 0.20), concentrations were elevated in TRP-treated animals. The decrease in the number of positive fecal samples observed in the first experiment, may be related to gastrointestinal MEL, affected by the 10x, but not 1x MEL dose.
The aim of the present study was to survey a cohort population for the risk factors of post‐traumatic stress disorder (PTSD) and major depression, and the prevalence of different psychiatric ...disorders at 6 months and 2 and 3 years after a major earthquake. The Disaster‐Related Psychological Screening Test (DRPST), part I, and the Mini‐International Neuropsychiatric Interview (MINI) were, respectively, administered by trained interviewers and psychiatrists in this community‐interview program. The prevalence of PTSD decreased from 8.3% at 6 months to 4.2% at 3 years after the earthquake. Suicidality increased from 4.2% at 6 months and 5.6% at 2 years to 6.0% at 3 years after the earthquake; drug abuse/dependence increased from 2.3% at 6 months to 5.1% at 3 years after the disaster. The risk factors for PTSD and major depression in various post‐disaster stages were determined. Earthquake survivors had a high percentage of psychiatric disorders in the first 2 years, and then the prevalence declined. Following the devastation caused by the Chi‐Chi earthquake, it is important to focus on treating symptoms of major depression and PTSD and eliminating the risk factors for both of these disorders in survivors to avoid the increase in suicidality.
Discovery and development of podocarpic acid dimers (e.g., 3–5) are described.
Liver X receptors are nuclear receptors that regulate metabolism of cholesterol. They are activated by oxysterols ...resulting in increased transcription of the ABCA1 gene, promoting cholesterol efflux and HDL formation. We have identified podocarpic acid anhydride as a 1
nM agonist of LXRα and β receptors. Functionally this agonist was over 8–10-fold better activator of LXR receptors compared to one of the natural ligands, 22-(
R)-hydroxy cholesterol, in HEK-293 cells. An imide analog increased the level of HDL by 26%, decreased LDL by 10.6%, and increased triglyceride by 51% in hamsters. Discovery, synthesis, SAR and details of the activities of dimers have been described.
There has been increasing interest in the research of flavonoids from dietary sources, due to growing evidence of the versatile health benefits of flavonoids through epidemiological studies. As ...occurrence of flavonoids is directly associated with human daily dietary intake of antioxidants, it is important to evaluate flavonoid sources in food. Fruits and vegetables are the main dietary sources of flavonoids for humans, along with tea and wine. However, there is still difficulty in accurately measuring the daily intake of flavonoids because of the complexity of existence of flavonoids from various food sources, the diversity of dietary culture, and the occurrence of a large amount of flavonoids itself in nature. Nevertheless, research on the health aspects of flavonoids for humans is expanding rapidly. Many flavonoids are shown to have antioxidative activity, free-radical scavenging capacity, coronary heart disease prevention, and anticancer activity, while some flavonoids exhibit potential for anti-human immunodeficiency virus functions. As such research progresses. further achievements will undoubtedly lead to a new era of flavonoids in either foods or pharmaceutical supplements. Accordingly, an appropriate model for a precise assessment of intake of flavonoids needs to be developed. Most recent research has focused on the health aspects of flavonoids from food sources for humans. This paper reviews the current advances in flavonoids in food, with emphasis on health aspects on the basis of the published literature, which may provide some guidance for researchers in further investigations and for industries in developing practical health agents.
Objective: To investigate quality of life (QOL) and related risk factors in Taiwanese earthquake survivors diagnosed with different psychiatric disorders 3 years after the 1999 Chi-Chi earthquake.
...Method: This study was a population survey. Trained assistants used the Medical Outcomes Study Short Form-36 (MOS SF-36) and questionnaires to interview 405 respondents (189 men and 216 women) aged 16 years or older, who had been exposed to the earthquake. Psychiatrists interviewed the same respondents using the Mini-International Neuropsychiatric Interview, with an adjusted response rate of 70.2%.
Results: The prevalence range for psychiatric disorders in the earthquake survivors was 0.2–7.2% 3 years after the Chi-Chi earthquake, with rates for major depression (MD) and posttraumatic stress disorder (PTSD) of 6.4% and 4.4%, respectively. The QOL scores for the PTSD/MD group were lower than for the other two diagnostic groups, as determined by assessment of physical and mental aspects of functional integrity from MOS SF-36 scores. The predictors for poor QOL were age, female gender, economic problems, physical illness, subjective assessment of memory and social-activity decline and diagnosis of PTSD or MD.
Conclusion: The QOL for earthquake survivors with psychiatric disorders, especially PTSD or MD, was inferior compared with the mentally healthy analogues, with contemporaneous decreases in mental and physical function scores across the QOL subscales. The persistence of long-term economic problems was one of many important factors affecting QOL.
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