Anti-Mycobacterial Activity of Bacterial Topoisomerase Inhibitors with Dioxygenated Linkers.

Developing new classes of drugs that are active against infections caused by is a priority for treating and managing this deadly disease. Here, we describe screening a small library of 20 DNA gyrase inhibitors and identifying new lead compounds. Three structurally diverse analogues were identified with minimal inhibitory concentrations of 0.

Recurring incursions and dissemination of novel Eurasian-origin H5Nx avian influenza viruses in Atlantic Canada.

Wild birds are important hosts of influenza A viruses (IAVs) and play an important role in their ecology. The emergence of the A/goose/Guangdong/1/1996 H5N1 (Gs/GD) lineage marked a shift in IAV ecology, leading to recurrent outbreaks and mortality in wild birds from 2002 onwards. This lineage has evolved and diversified over time, with a recent important derivative being the 2.

Avian influenza virus circulation and immunity in a wild urban duck population prior to and during a highly pathogenic H5N1 outbreak.

Highly pathogenic avian influenza (HPAI) H5N1 clade 2.3.4.

UK Foot and Ankle Thromboembolism (UK-FATE).

Aims: Venous thromboembolism (VTE) is a potential complication of foot and ankle surgery. There is a lack of agreement on contributing risk factors and chemical prophylaxis requirements. The primary outcome of this study was to analyze the 90-day incidence of symptomatic VTE and VTE-related mortality in patients undergoing foot and ankle surgery and Achilles tendon (TA) rupture.

Emergence of antibiotic-specific phenotypes during prolonged treatment of mice.

A major challenge in tuberculosis (TB) therapeutics is that antibiotic exposure leads to changes in the physiologic state of () which may enable the pathogen to withstand treatment. While antibiotic-treated have been evaluated in short-term experiments, it is unclear if and how long-term treatment with diverse antibiotics with varying treatment-shortening activity (sterilizing activity) affect physiologic states differently. Here, we used SEARCH-TB, a pathogen-targeted RNA-sequencing platform, to characterize the transcriptome in the BALB/c high-dose aerosol infection mouse model following 4-week treatment with three sterilizing and three non-sterilizing antibiotics.

Blending census and paleolimnological data allows for tracking the establishment and growth of a major gannet colony over several centuries.

Seabird colonies with long-term monitoring records, i.e., > 50 years, are rare.

Enhancing the therapeutic window for Spectinamide anti-tuberculosis Agents: Synthesis, Evaluation, and activation of phosphate prodrug 3408.

Spectinamides are a novel class of narrow-spectrum antitubercular agents with the potential to treat drug-resistant tuberculosis infections. Spectinamide 1810 has shown a good safety record following subcutaneous injection in mice or infusion in rats but exhibits transient acute toxicity following bolus administration in either species. To improve the therapeutic index of 1810, an injectable prodrug strategy was explored.

Plastic ingestion, accumulated heavy metals, and health metrics of four Larus gull species feeding at a coastal landfill in eastern Canada.

The objectives of this research were to assess ingested plastics and accumulated heavy metals in four urban gull species. Additionally, the relationships between ingested plastics and selected demographic and health metrics were assessed. Between 2020-2021 during the non-breeding seasons, 105 gulls (46 American herring gulls (HERG, Larus argentatus smithsonianus), 39 great black-backed gulls (GBBG, Larus marinus), 16 Iceland gulls (Larus glaucoides), 4 glaucous gulls (Larus hyperboreus)) were killed at a landfill in coastal Newfoundland and Labrador, Canada, as part of separate, permitted kill-to-scare operations related to aircraft safety.

Mtb-Selective 5-Aminomethyl Oxazolidinone Prodrugs: Robust Potency and Potential Liabilities.

Linezolid is a drug with proven human antitubercular activity whose use is limited to highly drug-resistant patients because of its toxicity. This toxicity is related to its mechanism of action─linezolid inhibits protein synthesis in both bacteria and eukaryotic mitochondria. A highly selective and potent series of oxazolidinones, bearing a 5-aminomethyl moiety (in place of the typical 5-acetamidomethyl moiety of linezolid), was identified.

Clinical Experience of a Novel Optical Coherence Tomography-Guided Coronary Chronic Total Occlusion Re-Entry Device.

We demonstrated a first-in-human case of successful antegrade dissection and re-entry using an image-guided re-entry catheter that enables real-time high-resolution visualization with graphical augmentation, and precision steering and advancement of a guidewire. The total time from over-the-wire deployment in the proximity of the distal cap to successful re-entry was <20 minutes. ().

A Modified BPaL Regimen for Tuberculosis Treatment replaces Linezolid with Inhaled Spectinamides.

Unlabelled: The Nix-TB clinical trial evaluated a new 6-month regimen containing three-oral- drugs; bedaquiline (B), pretomanid (Pa) and linezolid (L) (BPaL regimen) for treatment of tuberculosis (TB). This regimen achieved remarkable results as almost 90% of the multidrug resistant (MDR) or extensively drug resistant (XDR) TB participants were cured but many patients also developed severe adverse events (AEs). The AEs were associated with the long-term administration of the protein synthesis inhibitor linezolid.

Inter-colony variation in predation, mercury burden and adult survival in a declining seabird.

Migratory species with disjunct and localized breeding distributions, including many colonial marine birds, pose challenges for management and conservation as their dynamics are shaped by both broad oceanographic changes and specific factors affecting individual breeding colonies. We compare six colonies of the declining Leach's storm-petrel, Hydrobates leucorhous, across their core range in Atlantic Canada using standard capture-mark-recapture methods to estimate annual survival of individually marked populations of breeding adults. Over the period analysed (5-20 years per colony; 2003-2022), mean annual survival varied among colonies (0.

Transcriptional adaptation of that survives prolonged multi-drug treatment in mice.

A major reason that curing tuberculosis requires prolonged treatment is that drug exposure changes bacterial phenotypes. The physiologic adaptations of that survive drug exposure have been obscure due to low sensitivity of existing methods in drug-treated animals. Using the novel SEARCH-TB RNA-seq platform, we elucidated phenotypes in mice treated for with the global standard 4-drug regimen and compared them with the effect of the same regimen .

Lung microenvironments harbor phenotypes with distinct treatment responses.

Tuberculosis lung lesions are complex and harbor heterogeneous microenvironments that influence antibiotic effectiveness. Major strides have been made recently in understanding drug pharmacokinetics in pulmonary lesions, but the bacterial phenotypes that arise under these conditions and their contribution to drug tolerance are poorly understood. A pharmacodynamic marker called the RS ratio quantifies ongoing rRNA synthesis based on the abundance of newly synthesized precursor rRNA relative to mature structural rRNA.

Global assessment of marine plastic exposure risk for oceanic birds.

Plastic pollution is distributed patchily around the world's oceans. Likewise, marine organisms that are vulnerable to plastic ingestion or entanglement have uneven distributions. Understanding where wildlife encounters plastic is crucial for targeting research and mitigation.

Development of a Minimalistic Physiologically Based Pharmacokinetic (mPBPK) Model for the Preclinical Development of Spectinamide Antibiotics.

Spectinamides 1599 and 1810 are lead spectinamide compounds currently under preclinical development to treat multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis. These compounds have previously been tested at various combinations of dose level, dosing frequency, and route of administration in mouse models of () infection and in healthy animals. Physiologically based pharmacokinetic (PBPK) modeling allows the prediction of the pharmacokinetics of candidate drugs in organs/tissues of interest and extrapolation of their disposition across different species.

Rare Cause of Late Left Aortic Sinus Obstruction Following Transcatheter Aortic Valve Replacement.

A 74-year-old woman with a history aortic stenosis with prior transcatheter aortic valve replacement presented with non-ST-segment elevation myocardial infarction secondary to a delayed left coronary sinus obstruction. With physiology and intravascular ultrasound guidance, the patient was treated with stents through the valve struts and to the left main. ().

Characterization of spectinamide 1599 efficacy against different mycobacterial phenotypes.

Spectinamides are a novel series of spectinomycin analogs being developed for the treatment of tuberculosis. The preclinical lead spectinamide 1599 is an antituberculosis drug that possesses robust in vivo efficacy, good pharmacokinetic properties, and excellent safety profiles in rodents. In individuals infected with Mycobacterium tuberculosis or Mycobacterium bovis, causative agents of tuberculosis, the host immune system is capable of restraining these mycobacteria within granulomatous lesions.

Standardized RS Ratio Metrics To Assess Tuberculosis Antimicrobial Efficacy and Potency.

The sigmoid E model was used to describe the rRNA synthesis ratio (RS ratio) response of Mycobacterium tuberculosis to antimicrobial concentration. RS-E measures the maximal ability of a drug to inhibit the RS ratio and can be used to rank-order drugs based on their RS ratio effect. RS-EC is the concentration needed to achieve 90% of the RS-E, which may guide dose selection to achieve a maximal RS ratio effect .