Abstract
Introduction
This study aims to assess the association of piperacillin/tazobactam and meropenem minimum inhibitory concentration (MIC) and beta-lactam resistance genes with mortality in the ...MERINO trial.
Methods
Blood culture isolates from enrolled patients were tested by broth microdilution and whole genome sequencing at a central laboratory. Multivariate logistic regression was performed to account for confounders. Absolute risk increase for 30-day mortality between treatment groups was calculated for the primary analysis (PA) and the microbiologic assessable (MA) populations.
Results
In total, 320 isolates from 379 enrolled patients were available with susceptibility to piperacillin/tazobactam 94% and meropenem 100%. The piperacillin/tazobactam nonsusceptible breakpoint (MIC >16 mg/L) best predicted 30-day mortality after accounting for confounders (odds ratio 14.9, 95% confidence interval CI 2.8–87.2). The absolute risk increase for 30-day mortality for patients treated with piperacillin/tazobactam compared with meropenem was 9% (95% CI 3%–15%) and 8% (95% CI 2%–15%) for the original PA population and the post hoc MA populations, which reduced to 5% (95% CI −1% to 10%) after excluding strains with piperacillin/tazobactam MIC values >16 mg/L. Isolates coharboring extended spectrum β-lactamase (ESBL) and OXA-1 genes were associated with elevated piperacillin/tazobactam MICs and the highest risk increase in 30-day mortality of 14% (95% CI 2%–28%).
Conclusions
After excluding nonsusceptible strains, the 30-day mortality difference from the MERINO trial was less pronounced for piperacillin/tazobactam. Poor reliability in susceptibility testing performance for piperacillin/tazobactam and the high prevalence of OXA coharboring ESBLs suggests that meropenem remains the preferred choice for definitive treatment of ceftriaxone nonsusceptible Escherichia coli and Klebsiella.
Piperacillin/tazobactam should be avoided for ceftriaxone nonsusceptible Escherichia coli and Klebsiella spp. bloodstream infections, especially when minimum inhibitory concentrations are > 16 mg/L. Further assessment of current testing is warranted given disparity between commonly used methods and broth microdilution.
Forests are being converted to agriculture throughout the Afrotropics, driving declines in sensitive rainforest taxa such as understorey birds. The ongoing expansion of cocoa agriculture, a common ...small‐scale farming commodity, has contributed to the loss of 80% rainforest cover in some African countries. African cocoa farms may provide habitat for biodiversity, yet little is known about their suitability for vertebrate fauna, or the effect of farm management on animal communities.
Here, we report the first in‐depth investigation into avian diversity and community composition in African cocoa, by assembling a dataset of 9,566 individual birds caught across 83 sites over 30 years in Southern Cameroon. We compared bird diversity in mature forest and cocoa using measures of alpha, beta and gamma diversity, and we investigated the effect of cocoa farm shade and forest cover on bird communities.
Gamma diversity was higher in cocoa than forest, though alpha diversity was similar, indicating a higher dissimilarity (beta diversity) between cocoa farms. Cocoa farms differed from forest in community composition, with a distinctive decrease in relative abundance of insectivores, forest specialists and ant‐followers and an increase in frugivores.
Within cocoa farms, we found that farms with high shade cover in forested landscapes resulted in higher relative abundance and richness of sensitive forest species; shady farms contained up to five times the proportion of forest specialists than sunny farms.
Synthesis and applications. Sunny African cocoa farms were less able to support sensitive bird guilds compared with shaded farms in forested landscapes. Our findings support the notion that certain ecological and dietary guilds, such as ant‐followers and forest specialists are disproportionately affected by land‐use change. In light of the current push to increase cocoa production in sub‐Saharan Africa, our results provide policymakers opportunities for more wildlife‐friendly cocoa schemes that maximize avian diversity.
Sunny African cocoa farms were less able to support sensitive bird guilds compared with shaded farms in forested landscapes. Our findings support the notion that certain ecological and dietary guilds, such as ant‐followers and forest specialists are disproportionately affected by land‐use change. In light of the current push to increase cocoa production in sub‐Saharan Africa, our results provide policymakers opportunities for more wildlife‐friendly cocoa schemes that maximize avian diversity.
Murray cod Maccullochella peelii (Mitchell) have a key ecological role in ensuring the health of Australia's largest inland waterway, but many aspects surrounding its reproductive strategies in the ...wild are unknown. From 2015 to 2019 within the Northern Murray-Darling Basin, Australia, we used a combination of bio-telemetry and underwater imagery to quantify the behaviour of Murray cod across their breeding cycle in a natural riverine environment. In most years, breeding behaviour including nest site selection was observed from early-August and spawning from late-August through to late-October, which is considerably earlier than previously reported. There was a positive correlation between the onset of breeding behaviour and week-of-year, and spawning was correlated with moon-phase. Whilst some nesting sites were amongst woody debris and in hollow logs, the majority were located in shallow water on hard substrate underneath undercuts along the riverbank edge. Nests were frequently established in isolated and disconnected pools with little or no measurable flow, suggesting that river hydraulics is not a key component driving spawning of Murray cod across at least some areas of its range. Larvae were observed actively swimming and controlling their position within and near nests and used a scatter tactic when dispersing. We also established that disturbing nesting Murray cod had a negative impact on egg and larval survival. We suggest a review of current regulations to safeguard the long-term conservation of the species across all sections of its range.
•First description of the breeding behaviour of one of the great freshwater leviathans.•The positioning of nesting sites under the riverbank edge contradicts previous thinking.•Latitudinal location is likely a strong indicator of the timing of breeding.•Disturbing nesting individuals may lead to the loss of broods.•River hydraulics may not be a primary contributor to reproductive success.
Scleroderma is a life-threatening autoimmune disease in need of more effective treatment. A randomized trial of myeloablative therapy followed by autologous CD34+ hematopoietic stem-cell ...transplantation showed outcomes that were superior to those with monthly cyclophosphamide.
Patients with metastatic pancreatic cancer often have a detriment in health-related quality of life (HRQoL). In the randomized, double-blind, phase III POLO trial progression-free survival was ...significantly longer with maintenance olaparib, a poly(ADP-ribose) polymerase inhibitor, than placebo in patients with a germline BRCA1 and/or BRCA2 mutation (gBRCAm) and metastatic pancreatic cancer whose disease had not progressed during first-line platinum-based chemotherapy. The prespecified HRQoL evaluation is reported here.
Patients were randomized to receive maintenance olaparib (300mg b.i.d.; tablets) or placebo. HRQoL was assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item module at baseline, every 4weeks until disease progression, at discontinuation, and 30days after last dose. Scores ranged from 0 to 100; a ≥10-point change or difference between arms was considered clinically meaningful. Adjusted mean change from baseline was analysed using a mixed model for repeated measures. Time to sustained clinically meaningful deterioration (TSCMD) was analysed using a log-rank test.
Of 154 randomized patients, 89 of 92 olaparib-arm and 58 of 62 placebo-arm patients were included in HRQoL analyses. The adjusted mean change in Global Health Status (GHS) score from baseline was <10 points in both arms and there was no significant between-group difference −2.47; 95% confidence interval (CI) −7.27, 2.33; P=0.31. Analysis of physical functioning scores showed a significant between-group difference (−4.45 points; 95% CI −8.75, −0.16; P=0.04). There was no difference in TSCMD for olaparib versus placebo for GHS P=0.25; hazard ratio (HR) 0.72; 95% CI 0.41, 1.27 or physical functioning (P=0.32; HR 1.38; 95% CI 0.73, 2.63).
HRQoL was preserved with maintenance olaparib treatment with no clinically meaningful difference compared with placebo. These results support the observed efficacy benefit of maintenance olaparib in patients with a gBRCAm and metastatic pancreatic cancer.
NCT02184195.
Rising feed costs and recurring feed shortages necessitate the investigation into alternative and underutilized feed resources. Nutritional characteristics of species are either unknown or limited to ...leaves and ground material from small stems. Therefore, the objective was to quantify nutritional characteristics, 48-h true IVDMD (tIVDMD), microbial gas production, and secondary compound characteristics of entire woody plant material of 4 species-, , , and -at immature and mature stages of growth. Immature plants had greater CP concentrations and lower NDF concentrations ( < 0.001) than mature plants regardless of species. Mature plants also had greater ( < 0.001) concentrations of ADF compared with immature plants with the exception of . In general, immature , , and had greater ( < 0.02) tIVDMD and total 48-h and asymptotic gas production than mature plants. Immature and plants were more digested (tIVDMD; < 0.001) than immature and , but tIVDMD did not differ in mature plant material across species. Condensed tannins (CT) were greater ( < 0.001) in immature and than mature plants; differences in CT concentrations among immature species were also detected ( < 0.04). Volatile oil yields were similar across maturity and species with 1 exception: immature yielded more ( < 0.02) volatile oil than mature material. Volatile oil composition across species varied and contained a range of 65 to 70 terpene compounds. The dominant terpenes across species were generally greater ( < 0.05) in immature vs. mature plant material with the exception of . Labdane acids were negligible in , , and and greater in ( < 0.001). Ground material from mature juniper species, although inferior in nutritional quality compared with immature plants, is comparable to traditional low-quality roughage ingredients. Given that has been successfully fed in lamb feedlot diets, the similarities of , and suggest that all three species have potential to be effective roughage ingredients.
A chimeric metallopeptide derived from the sequences of two structurally superimposable motifs was designed as an artificial nuclease. Both DNA recognition and nuclease activity have been ...incorporated into a small peptide sequence. P3W, a 33-mer peptide comprising helices α2 and α3 from the engrailed homeodomain and the consensus EF-hand Ca-binding loop binds one equivalent of lanthanides or calcium and folds upon metal binding. The conditional formation constants (in the presence of 50 mM Tris) of P3W for Eu(III) (K a = (2.1 ± 0.1) × 105 M-1) and Ce(IV) (K a = (2.6 ± 0.1) × 105 M-1) are typical of isolated EF-hand peptides. Circular dichroism studies show that 1:1 CeP3W is 26% α-helical and EuP3W is up to 40% α-helical in the presence of excess metal. The predicted helicity of the folded peptide based on helix length and end effects is about 50%, showing the metallopeptides are significantly folded. EuP3W has considerably more secondary structure than our previously reported chimeras (Welch, J. T.; Sirish, M.; Lindstrom, K. M.; Franklin, S. J. Inorg. Chem. 2001, 40, 1982−1984). Eu(III)P3W and Ce(IV)P3W nick supercoiled DNA at pH 6.9, although EuP3W is more active at pH 8. CeP3W cleaves linearized, duplex DNA as well as supercoiled plasmid. The cleavage of a 5‘-32P-labeled 121-mer DNA fragment was followed by polyacrylamide gel electrophoresis. The cleavage products are 3‘-OPO3 termini exclusively, suggesting a regioselective or multistep mechanism. In contrast, uncomplexed Ce(IV) and Eu(III) ions produce both 3‘-OPO3 and 3‘-OH, and no evidence of 4‘-oxidative cleavage termini with either metal. The complementary 3‘-32P-labeled oligonucleotide experiment also showed both 5‘-OPO3 and 5‘-OH termini were produced by the free ions, whereas CeP3W produces only 5‘-OPO3 termini. In addition to apparent regioselectivity, the metallopeptides cut DNA with modest sequence discrimination, which suggests that the HTH motif binds DNA as a folded domain and thus cleaves selected sequences. The de novo artificial nuclease LnP3W represents the first small, underivatized peptide that is both active as a nuclease and sequence selective.
Background: The aim of the study was to investigate whether pre-therapy vascular delivery assessment using dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) can predict reduction in ...breast cancer metabolism detected using 2-18F fluoro-2-deoxy-D-glucose positron emission tomography (18F−FDG-PET) after a single cycle of chemotherapy. Reduction in 18F-FDG PET metabolism has previously been shown to correlate with histological response to primary chemotherapy. Patients and methods: Seventeen patients with large or locally advanced invasive ductal carcinomas of the breast were imaged using DCE-MRI and 18F-FDG-PET prior to therapy and 20 days after the first cycle of chemotherapy. MRI data were analysed using a multi-compartment model. PET data were analysed using standardised uptake value (SUV) analysis. Results: A significant association (P <0.05) was observed between pre-therapy DCE-MRI vascular parameters and the reduction in PET metabolism resulting from administration of one cycle of chemotherapy. Conclusions: A relationship was demonstrated between pre-therapy DCE-MRI vascular parameters and the reduction in PET metabolism after a single cycle of chemotherapy. This suggests that reduction in PET metabolism as a result of chemotherapy may be dependent, at least in part, on pre-therapy vascular delivery. These pre-therapy vascular characteristics may be suitable for use as a surrogate measure for initial chemotherapy delivery, a key factor in chemotherapeutic efficacy.
In an open-label, randomized, noninferiority trial, dolutegravir-based antiretroviral therapy was compared with standard care in children and adolescents starting first- or second-line therapy for ...HIV type 1 infection. Dolutegravir-based ART was superior to standard-care ART.
Summary
Interstitial injury is the hallmark of glomerulonephritis which is progressing to end‐stage renal disease (ESRD). In humans and experimental animals, we have shown that interstitial disease ...is accompanied by up‐regulation of complement components in tubular epithelial cells. Glomerulonephritis was induced in mice by the intraperitoneal injection of horse spleen apoferritin (HSA) and lipopolysaccharide (LPS). In addition to wild‐type C57/B6 mice, animals in which the C5a receptor had been deleted (C5aR KO) were used. Animals were killed after 3 or 6 weeks, and kidneys harvested. At three weeks, both groups had evidence of mild mesangial matrix expansion and increased cellularity; there were no crescents, sclerotic lesions, or interstitial disease. At six weeks, glomerular lesions were advanced, but identical in the two groups. Both groups had evidence of an identical pattern of C3 gene expression in the tubular epithelium by in situ hybridization. There was a marked difference, however, in the extent of interstitial injury. Wild‐type animals had significantly greater numbers of infiltrating interstitial cells, greater expansion of the peritubular space, more tubular atrophy, and more apoptotic tubular cells than did C5aR KOs. The anaphylotoxic fragment of C5, C5a, is not likely to be important in the glomerular component of this model of progressive glomerulonephritis. On the other hand, the interstitial component is markedly attenuated in knockout animals. These data support a role for complement in the interstitial component of this glomerulonephritis model. They are consistent with our hypotheses of a role for complement in the progression of some forms of glomerulonephritis to ESRD.
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