Cyclic natural product oligomers: diversity and (bio)synthesis of macrocycles.

Cyclic compounds are generally preferred over linear compounds for functional studies due to their enhanced bioavailability, stability towards metabolic degradation, and selective receptor binding. This has led to a need for effective cyclization strategies for compound synthesis and hence increased interest in macrocyclization mediated by thioesterase (TE) domains, which naturally boost the chemical diversity and bioactivities of cyclic natural products. Many non-ribosomal peptide synthetase (NRPS) and polyketide synthase (PKS) derived natural products are assembled to form cyclodimeric compounds, with these molecules possessing diverse structures and biological activities.

Who gets the bed: Factors influencing the intensive care exit block: A qualitative study.

Background: Patient flow problems, including discharge delay and after-hours discharge, have been a consistently major issue, especially for intensive care units (ICUs). Evidence suggests that discharge delay and after-hours discharge are associated with increased ICU and hospital length of stay, leading to worsened patient outcomes and increased healthcare costs. They can also increase ICU readmission and post-ICU mortality.

Loss of fluorine during crosslinking by the biarylitide P450 proceeds due to restricted peptide orientation.

The biarylitide crosslinking enzyme P450 can perform crosslinking between -F-Tyr-3 and His-5 residues within peptide substrates with concomitant and specific loss of fluorine. Our investigations suggest that a small intrinsic preference for coupling to fluorine is magnified by the binding of the peptide in a specific orientation that enforces the loss of fluorine during peptide crosslinking, likely a two-step reaction mechanism involving the non-enzyme catalysed reductive elimination of fluoride.

Contextual Factors Influencing Intensive Care Patients' Discharge Processes: A Multicentre Prospective Observational Study.

Aims: To compare contextual factors influencing discharge practices in three intensive care units (ICUs).

Design: A prospective observational study.

Methods: Data were collected using a discharge process report form (DPRF) between May and September 2023.

Interventions to improve patient admission and discharge practices in adult intensive care units: A systematic review.

Objectives: To identify and synthesise interventions and implementation strategies to optimise patient flow, addressing admission delays, discharge delays, and after-hours discharges in adult intensive care units.

Methods: This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guidelines. Five electronic databases, including CINAHL, PubMed, Emcare, Scopus, and the Cochrane Library, were searched from 2007 to 2023 to identify articles describing interventions to enhance patient flow practices in adult intensive care units.

Stereodynamic Strategies to Induce and Enrich Chirality of Atropisomers at a Late Stage.

Enantiomers, where chirality arises from restricted rotation around a single bond, are atropisomers. Due to the unique nature of the origins of their chirality, synthetic strategies to access these compounds in an enantioselective manner differ from those used to prepare enantioenriched compounds containing point chirality arising from an unsymmetrically substituted carbon center. In particular stereodynamic transformations, such as dynamic kinetic resolutions, thermodynamic dynamic resolutions, and deracemizations, which rely on the ability to racemize or interconvert enantiomers, are a promising set of transformations to prepare optically pure compounds in the late stage of a synthetic sequence.

Establishing critical care nursing research priorities for three Australian regional public hospitals: A mixed method priority setting study.

Objective: To determine key priorities for critical care nursing research in three Australian regional public hospitals, representing the shared priorities of healthcare professionals and patient representatives.

Methods: A three phase priority setting study, including consensus methods (nominal group), survey, qualitative interviews and focus groups were conducted between May 2021 and March 2022. Healthcare professionals and patient representatives from critical care units in regional public hospitals in Australia participated.

Stress response during early sedation with dexmedetomidine compared with usual-care in ventilated critically ill patients.

Background: Sedative agents may variably impact the stress response. Dexmedetomidine is a sympatholytic alpha-adrenergic agonist mainly used as a second-line sedative agent in mechanically ventilated patients. We hypothesised that early sedation with dexmedetomidine as the primary agent would result in a reduced stress response compared to usual sedatives in critically ill ventilated adults.

Job satisfaction and symptoms of depression, anxiety, stress, and burnout: A survey of Australian and New Zealand intensive care research coordinators.

Introduction: Intensive care unit clinical research is often implemented by specialised research coordinators (RCs). Clinical research activity within Australian and New Zealand intensive care units has escalated, particularly during the COVID-19 pandemic. Growth of the intensive care RC workforce to match research demand is poorly understood.

Structural Basis of Stereospecific Vanadium-Dependent Haloperoxidase Family Enzymes in Napyradiomycin Biosynthesis.

Vanadium-dependent haloperoxidases (VHPOs) from bacteria differ from their counterparts in fungi, macroalgae, and other bacteria by catalyzing organohalogenating reactions with strict regiochemical and stereochemical control. While this group of enzymes collectively uses hydrogen peroxide to oxidize halides for incorporation into electron-rich organic molecules, the mechanism for the controlled transfer of highly reactive chloronium ions in the biosynthesis of napyradiomycin and merochlorin antibiotics sets the vanadium-dependent chloroperoxidases apart. Here we report high-resolution crystal structures of two homologous VHPO family members associated with napyradiomycin biosynthesis, NapH1 and NapH3, that catalyze distinctive chemical reactions in the construction of meroterpenoid natural products.

Prevalence and factors associated with polypharmacy: a systematic review and Meta-analysis.

Introduction: Polypharmacy is commonly associated with adverse health outcomes. There are currently no meta-analyses of the prevalence of polypharmacy or factors associated with polypharmacy. We aimed to estimate the pooled prevalence of polypharmacy and factors associated with polypharmacy in a systematic review and meta-analysis.

Image statistics determine the integration of visual cues to motion-in-depth.

Motion-in-depth perception is critical in enabling animals to avoid hazards and respond to potential threats. For humans, important visual cues for motion-in-depth include changing disparity (CD) and changing image size (CS). The interpretation and integration of these cues depends upon multiple scene parameters, such as distance moved, object size and viewing distance, posing a significant computational challenge.

Biocatalytic oxidative cross-coupling reactions for biaryl bond formation.

Biaryl compounds, with two connected aromatic rings, are found across medicine, materials science and asymmetric catalysis. The necessity of joining arene building blocks to access these valuable compounds has inspired several approaches for biaryl bond formation and challenged chemists to develop increasingly concise and robust methods for this task. Oxidative coupling of two C-H bonds offers an efficient strategy for the formation of a biaryl C-C bond; however, fundamental challenges remain in controlling the reactivity and selectivity for uniting a given pair of substrates.

Biomimetic synthesis of the non-canonical PPAP natural products yezo'otogirin C and hypermogin D, and studies towards the synthesis of norascyronone A.

Oxidative degradation and rearrangement of polycyclic polyprenylated acylphloroglucinols (PPAPs) has created diverse families of unique natural products that are attractive targets for biomimetic synthesis. Herein, we report a racemic synthesis of hyperibrin A and its oxidative radical cyclization to give yezo'otogirin C, followed by epoxidation and House-Meinwald rearrangement to give hypermogin D. We also investigated the biomimetic synthesis of norascyronone A a similar radical cyclization pathway, with unexpected results that give insight into its biosynthesis.

A Diazo-Hooker Reaction, Inspired by the Biosynthesis of Azamerone.

Motivated by the biosynthesis of azamerone, we report the first example of a diazo-Hooker reaction, which involves the formation of a phthalazine ring system by the oxidative rearrangement of a diazoketone. Computational studies indicate that the diazo-Hooker reaction proceeds via an 8π-electrocyclization followed by ring contraction and aromatization. The biosynthetic origin of the diazoketone functional group was also chemically mimicked using a related natural product, naphterpin, as a model system.

Sodium chloride or Plasmalyte-148 evaluation in severe diabetic ketoacidosis (SCOPE-DKA): a cluster, crossover, randomized, controlled trial.

Purpose: To determine whether treatment with Plasmalyte-148 (PL) compared to sodium chloride 0.9% (SC) results in faster resolution of diabetic ketoacidosis (DKA) and whether the acetate in PL potentiates ketosis.

Methods: We conducted a cluster, crossover, open-label, randomized, controlled Phase 2 trial at seven hospitals in adults admitted to intensive care unit (ICU) with severe DKA with hospital randomised to PL or SC as fluid therapy.

Intensive care doctors and nurses personal preferences for Intensive Care, as compared to the general population: a discrete choice experiment.

Background: To test the hypothesis that Intensive Care Unit (ICU) doctors and nurses differ in their personal preferences for treatment from the general population, and whether doctors and nurses make different choices when thinking about themselves, as compared to when they are treating a patient.

Methods: Cross sectional, observational study conducted in 13 ICUs in Australia in 2017 using a discrete choice experiment survey. Respondents completed a series of choice sets, based on hypothetical situations which varied in the severity or likelihood of: death, cognitive impairment, need for prolonged treatment, need for assistance with care or requiring residential care.

COVID-19 Outbreak in A Forward-Deployed Expeditionary Military Command: A Retrospective Review on Preventative Measures and Outbreak Characteristics.

Background: An outbreak of coronavirus disease 2019 (COVID-19) occured within a land based 2,000-member cohort stationed on a remote air base in the Middle East from June to August 2020. We retrospectively reviewed base characteristics and mitigation measures instituted during the outbreak. We also reviewed documentation on the individuals that were either quarantined or placed in isolation and provide data on demographics, real-time reverse transcriptase polymerase chain reaction (rRT-PCR) results, occupation, and workdays lost.

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited.

Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19.

Design, Setting, And Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin.

Meroterpenoid natural products from Streptomyces bacteria - the evolution of chemoenzymatic syntheses.

Covering: Up to January 2020Meroterpenoids derived from the polyketide 1,3,6,8-tetrahydroxynaphthalene (THN) are complex natural products produced exclusively by Streptomyces bacteria. These antibacterial compounds include the napyradiomycins, merochlorins, marinones, and furaquinocins and have inspired many attempts at their chemical synthesis. In this review, we highlight the role played by biosynthetic studies in the stimulation of biomimetic and, ultimately, chemoenzymatic total syntheses of these natural products.

Total Synthesis of Naphterpin and Marinone Natural Products.

A concise and divergent strategy for the synthesis of the naphterpin and marinone meroterpenoid families has been developed. The approach features a succession of pericyclic reactions-an aromatic Claisen rearrangement, a retro-6π-electrocyclization, and two Diels-Alder reactions-which facilitated the first total synthesis of naphterpin itself in five steps from 2,5-dimethoxyphenol, alongside similar syntheses of 7-demethylnaphterpin and debromomarinone. Late-stage oxidation and bromination reactions were also investigated, leading to the first total syntheses of naphterpins B and C and isomarinone.

The role of one-carbon metabolism and homocysteine in Parkinson's disease onset, pathology and mechanisms.

Parkinson's disease (PD) is the second most common neurodegenerative disorder. It is characterised by the progressive degeneration of dopaminergic (DA) neurons. The cause of degeneration is not well understood; however, both genetics and environmental factors, such as nutrition, have been implicated in the disease process.