Effectiveness of ceftazidime-avibactam versus ceftolozane-tazobactam for multidrug-resistant Pseudomonas aeruginosa infections in the USA (CACTUS): a multicentre, retrospective, observational study.

Background: Ceftolozane-tazobactam and ceftazidime-avibactam are preferred treatment options for multidrug-resistant Pseudomonas aeruginosa infections; however, real-world comparative effectiveness studies are scarce. Pharmacokinetic and pharmacodynamic differences between the agents might affect clinical response rates. We aimed to compare the effectiveness of ceftolozane-tazobactam and ceftazidime-avibactam for treatment of invasive multidrug-resistant P aeruginosa infections.

Cytomegalovirus viremia and hepatitis B reactivation in patient with RET fusion-positive non-small cell lung cancer treated with pralsetinib.

Introduction: Mutated rearranged during transfection (RET) kinase is found in approximately 1-2% non-small-cell lung cancer (NSCLC) patients. These patients are typically younger, non-smokers, and have non-squamous histology. Pralsetinib is a novel RET inhibitor that showed promising efficacy and tolerability in the ARROW trial.

A Comparison of Different Strategies for Optimizing the Selection of Empiric Antibiotic Therapy for Pneumonia Caused by Gram-Negative Bacteria in Intensive Care Units: Unit-Specific Combination Antibiograms Versus Patient-Specific Risk Factors.

Background: Guidelines suggest dual antipseudomonal therapy for empiric treatment of pneumonia caused by gram-negative bacteria in intensive care unit (ICU) patients. Additionally, consideration of local susceptibility data and patient-specific risk factors for resistance is recommended for selecting optimal empiric regimens. However, data assessing how to best do this are lacking, and it is unclear whether a local susceptibility data-based or a patient-specific risk factor-based approach will better drive appropriate empiric treatment.

The generation of stable microvessels in ischemia is mediated by endothelial cell derived TRAIL.

Reversal of ischemia is mediated by neo-angiogenesis requiring endothelial cell (EC) and pericyte interactions to form stable microvascular networks. We describe an unrecognized role for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in potentiating neo-angiogenesis and vessel stabilization. We show that the endothelium is a major source of TRAIL in the healthy circulation compromised in peripheral artery disease (PAD).

Publisher Correction: Novel immunotherapeutics against LGR5 to target multiple cancer types.

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Weak Local Adaptation to Climate in Seedlings of a Deciduous Conifer Suggests Limited Benefits and Risks of Assisted Gene Flow.

Assisted migration provides a potential solution to mitigate the increasing risks of forest maladaptation under climate change. Western larch ( Nutt.) is a deciduous conifer species undergoing assisted migration beyond its natural range in British Columbia into areas that have become suitable based on climatic niche modelling.

The genetic architecture of repeated local adaptation to climate in distantly related plants.

Closely related species often use the same genes to adapt to similar environments. However, we know little about why such genes possess increased adaptive potential and whether this is conserved across deeper evolutionary lineages. Adaptation to climate presents a natural laboratory to test these ideas, as even distantly related species must contend with similar stresses.

Novel immunotherapeutics against LGR5 to target multiple cancer types.

We have developed and validated a highly specific, versatile antibody to the extracellular domain of human LGR5 (α-LGR5). α-LGR5 detects LGR5 overexpression in >90% of colorectal cancer (CRC), hepatocellular carcinoma (HCC) and pre-B-ALL tumour cells and was used to generate an Antibody-Drug Conjugate (α-LGR5-ADC), Bispecific T-cell Engager (α-LGR5-BiTE) and Chimeric Antigen Receptor (α-LGR5-CAR). α-LGR5-ADC was the most effective modality for targeting LGR5 cancer cells in vitro and demonstrated potent anti-tumour efficacy in a murine model of human NALM6 pre-B-ALL driving tumour attrition to less than 1% of control treatment.

Titration of RAS alters senescent state and influences tumour initiation.

Oncogenic RAS-induced senescence (OIS) is an autonomous tumour suppressor mechanism associated with premalignancy. Achieving this phenotype typically requires a high level of oncogenic stress, yet the phenotype provoked by lower oncogenic dosage remains unclear. Here we develop oncogenic RAS dose-escalation models in vitro and in vivo, revealing a RAS dose-driven non-linear continuum of downstream phenotypes.

Planting long-lived trees in a warming climate: Theory shows the importance of stage-dependent climatic tolerance.

Climate change poses a particular threat to long-lived trees, which may not adapt or migrate fast enough to keep up with rising temperatures. Assisted gene flow could facilitate adaptation of populations to future climates by using managed translocation of seeds from a warmer location (provenance) within the current range of a species. Finding the provenance that will perform best in terms of survival or growth is complicated by a trade-off.

Strand-resolved mutagenicity of DNA damage and repair.

DNA base damage is a major source of oncogenic mutations. Such damage can produce strand-phased mutation patterns and multiallelic variation through the process of lesion segregation. Here we exploited these properties to reveal how strand-asymmetric processes, such as replication and transcription, shape DNA damage and repair.

Genetic architecture of disease resistance and tolerance in Douglas-fir trees.

Understanding the genetic basis of how plants defend against pathogens is important to monitor and maintain resilient tree populations. Swiss needle cast (SNC) and Rhabdocline needle cast (RNC) epidemics are responsible for major damage of forest ecosystems in North America. Here we investigate the genetic architecture of tolerance and resistance to needle cast diseases in Douglas-fir (Pseudotsuga menziesii) caused by two fungal pathogens: SNC caused by Nothophaeocryptopus gaeumannii, and RNC caused by Rhabdocline pseudotsugae.

Patient Factors Influencing Prescription of Antithrombotic Medication After Lower Limb Endovascular Intervention.

Objective: There is significant practice variation in the use of antithrombotic therapy after endovascular intervention for lower limb peripheral arterial disease, with differences in medication choice and duration. Prescriber decision making is complex, and patient factors have been shown to substantially contribute to prescribing variation. To determine the influence of patient factors on antithrombotic prescribing, a discrete choice experiment was distributed to vascular surgeons and trainees across Australia and Aotearoa New Zealand.

Implementation of an Automated Antibiotic Time-out at a Comprehensive Cancer Center.

Background: Antimicrobial stewardship programs can optimize antimicrobial use and have been federally mandated in all hospitals. However, best stewardship practices in immunocompromised patients with cancer are not well established.

Methods: An antimicrobial time out, in the form of an email, was sent to physicians caring for hospitalized patients reaching 5 days of therapy for targeted antimicrobials (daptomycin, linezolid, tigecycline, vancomycin, imipenem/cilastatin, meropenem) in a comprehensive cancer center.

DNA lesion bypass and the stochastic dynamics of transcription-coupled repair.

DNA base damage is a major source of oncogenic mutations and disruption to gene expression. The stalling of RNA polymerase II (RNAP) at sites of DNA damage and the subsequent triggering of repair processes have major roles in shaping the genome-wide distribution of mutations, clearing barriers to transcription, and minimizing the production of miscoded gene products. Despite its importance for genetic integrity, key mechanistic features of this transcription-coupled repair (TCR) process are controversial or unknown.

The Growing Threat of NDM-Producing Escherichia coli With Penicillin-Binding Protein 3 Mutations in the United States-Is There a Potential Role for Durlobactam?

We report identification of 5 patients with infections caused by NDM-5-producing Escherichia coli harboring PBP3 mutations that showed reduced susceptibility to aztreonam-avibactam and cefiderocol. Durlobactam, a novel diazabicyclooctane β-lactamase inhibitor, demonstrated minimum inhibitory concentrations ranging from 0.5 to 2 µg/mL supporting future investigations into a potential role in clinical management.

Single-mitosis dissection of acute and chronic DNA mutagenesis and repair.

How chronic mutational processes and punctuated bursts of DNA damage drive evolution of the cancer genome is poorly understood. Here, we demonstrate a strategy to disentangle and quantify distinct mechanisms underlying genome evolution in single cells, during single mitoses and at single-strand resolution. To distinguish between chronic (reactive oxygen species (ROS)) and acute (ultraviolet light (UV)) mutagenesis, we microfluidically separate pairs of sister cells from the first mitosis following burst UV damage.

Conserving Evolutionary Potential: Combining Landscape Genomics with Established Methods to Inform Plant Conservation.

Biodiversity conservation requires conserving evolutionary potential-the capacity for wild populations to adapt. Understanding genetic diversity and evolutionary dynamics is critical for informing conservation decisions that enhance adaptability and persistence under environmental change. We review how emerging landscape genomic methods provide plant conservation programs with insights into evolutionary dynamics, including local adaptation and its environmental drivers.

How useful are genomic data for predicting maladaptation to future climate?

Methods using genomic information to forecast potential population maladaptation to climate change or new environments are becoming increasingly common, yet the lack of model validation poses serious hurdles toward their incorporation into management and policy. Here, we compare the validation of maladaptation estimates derived from two methods-Gradient Forests (GF) and the risk of non-adaptedness (RONA)-using exome capture pool-seq data from 35 to 39 populations across three conifer taxa: two Douglas-fir varieties and jack pine. We evaluate sensitivity of these algorithms to the source of input loci (markers selected from genotype-environment associations [GEA] or those selected at random).