The laboratory investigation, management, and infection prevention and control of Candida auris: a narrative review to inform the 2024 national guidance update in England.

The emergent fungal pathogen Candida auris is increasingly recognised as an important cause of healthcare-associated infections globally. It is highly transmissible, adaptable, and persistent, resulting in an organism with significant outbreak potential that risks devastating consequences. Progress in the ability to identify C. auris in clinical specimens is encouraging, but laboratory diagnostic capacity and surveillance systems are lacking in many countries. Intrinsic resistance to commonly used antifungals, combined with the ability to rapidly acquire resistance to therapy, substantially restricts treatment options and novel agents are desperately needed. Despite this, outbreaks can be interrupted, and mortality avoided or minimised, through the application of rigorous infection prevention and control measures with an increasing evidence base. This review provides an update on epidemiology, the impact of the COVID-19 pandemic, risk factors, identification and typing, resistance profiles, treatment, detection of colonisation, and infection prevention and control measures for C. auris. This review has informed a planned 2024 update to the United Kingdom Health Security Agency (UKHSA) guidance on the laboratory investigation, management, and infection prevention and control of Candida auris. A multidisciplinary response is needed to control C. auris transmission in a healthcare setting and should emphasise outbreak preparedness and response, rapid contact tracing and isolation or cohorting of patients and staff, strict hand hygiene and other infection prevention and control measures, dedicated or single-use equipment, appropriate disinfection, and effective communication concerning patient transfers and discharge.

Application of a new MDCKII-MDR1 cell model to measure the extent of drug distribution in vitro at equilibrium for prediction of in vivo unbound brain-to-plasma drug distribution.

INTRO: Reliable estimates of drug uptake from blood to brain parenchyma are crucial in CNS drug discovery and development. While in vivo Kp,uu,brain estimates are the gold standard for investigating brain drug disposition, animal usage is a limitation to high throughput application. This study investigates an in vitro model using P-gp expressing MDCKII-MDR1 cells for predicting in vivo brain drug penetration. METHODS: In vitro equilibrium distribution studies were conducted in apical and basolateral solutions with high protein content to estimate Kp,brain and Kp,uu,brain values. The correlation between in vitro and in vivo Kp,brain values for a set of compounds was examined. RESULTS: We observed a good correlation between in vitro and in vivo Kp,brain values (R2 = 0.69, Slope: 1.6), indicating that the in vitro model could predict in vivo drug brain penetration. The 'unilateral (Uni-L)' in vitro setup correctly classified 5 out of 5 unrestricted compounds and 3 out of 5 restricted compounds. Possible reasons for the observed disparities for some compounds have been discussed, such as difference in transport areas between in vitro and in vivo settings and effect of pH changes. CONCLUSION: The in vitro assay setup developed in this study holds promise for predicting in vivo drug brain penetration in CNS drug discovery. The correlation between in vitro and in vivo Kp,brain values, underscores that the model may have potential for early-stage screening. With minor refinements, this in vitro approach could reduce the reliance on in vivo experiments, accelerating the pace of CNS drug discovery and promoting a more ethical research approach.

Selective access to dihydrophenanthridines and phenanthridinones via cyclisation of aryl amines onto N-tethered arynes.

5,6-Dihydrophenanthridines are prepared from aryl amines via intramolecular addition to N-tethered arynes under mild conditions. A new o-silylaryl triflate precursor was developed to increase reactivity and enable electron-rich and electron-poor aryl amines to undergo cyclisation. A complete switch in product selectivity occurs when the reaction is conducted in air, affording the corresponding phenanthridin-6(5H)-one as the sole product under otherwise identical reaction conditions.

Assessing extent of brain penetration in vivo (Kp,uu,brain) in Göttingen minipig using a diverse set of reference drugs.

The application of Göttingen minipigs for non-rodent pharmacokinetics (PK) and drug safety testing has seen a dramatic increase in recent years. The aim of this study was to determine the total and unbound brain-to-plasma ratios (Kp,brain and Kp,uu,brain) for a diverse set of reference compounds in female Göttingen minipigs and compare these with Kp,uu,brain values from other species to assess the suitability of Göttingen minipigs as a model for CNS drug safety testing and brain PK in clinical translation. The reference set consisted of 17 compounds with varying physico-chemical properties and included known human P-glycoprotein (P-gp) substrates. The results of the study showed, that minipig Kp,brain and Kp,uu,brain values for the tested compounds were in the range 0.03-86 and 0.02-2.4 (n = 3-4) respectively. The Kp,uu,brain values were comparable between minipig and rat for a large proportion of the compounds (71% within 2-fold, n = 17). Comparisons of brain penetration across several species for a subset of reference compounds revealed that minipig values were quite similar to those of rat, dog, monkey and human. The study highlighted that the largest Kp,uu,brain species differences were observed for compounds classified as transporter substrates (e.g. cimetidine, risperidone, Way-100635 and altanserin). In conclusion these brain penetration data add substantially to the available literature on PK and drug disposition for minipigs and support use of Göttingen minipig as a non-rodent drug safety model for CNS drug candidates and as a brain PK model for clinical translation.

Pyridine Functionalized Carbon Nanotubes: Unveiling the Role of External Pyridinic Nitrogen Sites for Oxygen Reduction Reaction.

Pyridinic nitrogen has been recognized as the primary active site in nitrogen-doped carbon electrocatalysts for the oxygen reduction reaction (ORR), which is a critical process in many renewable energy devices. However, the preparation of nitrogen-doped carbon catalysts comprised of exclusively pyridinic nitrogen remains challenging, as well as understanding the precise ORR mechanisms on the catalyst. Herein, a novel process is developed using pyridyne reactive intermediates to functionalize carbon nanotubes (CNTs) exclusively with pyridine rings for ORR electrocatalysis. The relationship between the structure and ORR performance of the prepared materials is studied in combination with density functional theory calculations to probe the ORR mechanism on the catalyst. Pyridinic nitrogen can contribute to a more efficient 4-electron reaction pathway, while high level of pyridyne functionalization result in negative structural effects, such as poor electrical conductivity, reduced surface area, and small pore diameters, that suppressed the ORR performance. This study provides insights into pyridine-doped CNTs-functionalized for the first time via pyridyne intermediates-as applied in the ORR and is expected to serve as valuable inspiration in designing high-performance electrocatalysts for energy applications.

Quantifying the Mechanical Properties of Yeast Candida albicans Using Atomic Force Microscopy-based Force Spectroscopy.

Fungi can adapt to a wide range of environmental stresses in the wild and host milieu by employing their plastic genome and great diversity in morphology. Among different adaptive strategies, mechanical stimuli, such as changes in osmotic pressure, surface remodeling, hyphal formation, and cell divisions, could guide the physical cues into physiological responses through a complex signaling network. While fungal pathogens require a pressure-driven force to expand and penetrate host tissues, quantitatively studying the biophysical properties at the host-fungal interface is critical to understand the development of fungal diseases. Microscopy-based techniques have enabled researchers to monitor the dynamic mechanics on fungal cell surface in responses to the host stress and antifungal drugs. Here, we describe a label-free, high-resolution method based on atomic force microscopy, with a step-by-step protocol to measure the physical properties in human fungal pathogen Candida albicans.

Impact Electrochemistry of MoS2: Electrocatalysis and Hydrogen Generation at Low Overpotentials.

MoS2 materials have been extensively studied as hydrogen evolution reaction (HER) catalysts. In this study nanoparticulate MoS2 is explored as a HER catalyst through impact voltammetry. The onset potential was found to be -0.10 V (vs RHE) at pH 2, which was confirmed to be due to HER by scale-up of the impact experiment to generate and collect a sufficient volume of the gas to enable its identification as hydrogen via gas chromatography. This is in contrast to electrodeposited MoS2, which was found to be stable in pH 2 sulfuric acid solution with an onset potential of -0.29 V (vs RHE), in good agreement with literature. XPS was used to categorize the materials and confirm the chemical composition of both nanoparticles and electrodeposits, with XRD used to analyze the crystal structure of the nanoparticles. The early onset of HER was postulated from kinetic analysis to be due to the presence of nanoplatelets of about 1-3 trilayers participating in the impact reactions, and AFM imaging confirmed the presence of these platelets.

Characterisation of intravenous pharmacokinetics in Göttingen minipig and clearance prediction using established in vitro to in vivo extrapolation methodologies.

The use of the Göttingen minipig as an animal model for drug safety testing and prediction of human pharmacokinetics (PK) continues to gain momentum in pharmaceutical research and development. The aim of this study was to evaluate in vitro to in vivo extrapolation (IVIVE) methodologies for prediction of hepatic, metabolic clearance (CLhep,met) in Göttingen minipig, using a comprehensive set of compounds.In vivo clearance was determined in Göttingen minipig by intravenous cassette dosing and hepatocyte intrinsic clearance, plasma protein binding and non-specific incubation binding were determined in vitro. Prediction of CLhep,met was performed by IVIVE using conventional and adapted formats of the well-stirred liver model.The best prediction of in vivo CLhep,met from scaled in vitro kinetic data was achieved using an empirical correction factor based on a 'regression offset' of the IVIV relationship.In summary, these results expand the in vitro and in vivo PK knowledge in Göttingen minipig. We show regression corrected IVIVE provides superior prediction of in vivo CLhep,met in minipig offering a practical, unified scaling approach to address systematic under-predictions. Finally, we propose a reference set for researchers to establish their own 'lab-specific' regression correction for IVIVE in minipig.

Practical Application of Rodent Transporter Knockout Models to Assess Brain Penetration in Drug Discovery.

BACKGROUND AND OBJECTIVE: Compound X is a drug candidate for the treatment of neurodegenerative diseases. Its brain distribution was evaluated as part of the lead identification and optimization activities undertaken in early drug discovery. METHODS: The brain distribution of compound X was studied in genetic transporter knockout rodent models, in vivo models with a chemical inhibitor, and in vitro transporter cell systems. RESULTS: Compound X was found to be a substrate for human Breast Cancer-Resistance Protein (BCRP) in vitro (efflux ratio 8.1) and rodent Bcrp in vivo (Kp, uuKO/Kp, uuWT = 0.15/0.057 = 2.7, p< 0.05) but not a substrate for human P-glycoprotein (P-gp) in vitro (efflux ratio 1.0) nor rodent P-gp in vivo (Kp, uuKO/Kp, uuWT = 0.056/ 0.051 = 1.1, p> 0.05). When both transporters were knocked out in vivo, Kp, uu increased to 0.51±0.02. A similar pattern observed across compounds with related chemistry corroborating the structure-activity relationship. CONCLUSION: While in vitro assays showed compound X to be a substrate for human BCRP and not P-gp, in vivo studies indicated a synergistic effect between rodent efflux transporters. However, this only accounted for ~50% of restricted BBB-transport, suggesting involvement of other efflux transporters. Considering Kp, uu as a key criterion for assessing the technical quality of CNS candidates before progression into clinical development, it is important to identify relevant screening assays for a better understanding of low Kp, uu and brain distribution in pre-clinical models for translation to humans.

Activity-State Dependent Reversal of Ketamine-Induced Resting State EEG Effects by Clozapine and Naltrexone in the Freely Moving Rat.

Ketamine is a non-competitive N-Methyl-D-aspartate receptor (NMDAR) antagonist used in the clinic to initiate and maintain anaesthesia; it induces dissociative states and has emerged as a breakthrough therapy for major depressive disorder. Using local field potential recordings in freely moving rats, we studied resting state EEG profiles induced by co-administering ketamine with either: clozapine, a highly efficacious antipsychotic; or naltrexone, an opioid receptor antagonist reported to block the acute antidepressant effects of ketamine. As human electroencephalography (EEG) is predominantly recorded in a passive state, head-mounted accelerometers were used with rats to determine active and passive states at a high temporal resolution to offer the highest translatability. In general, pharmacological effects for the three drugs were more pronounced in (or restricted to) the passive state. Specifically, during inactive periods clozapine induced increases in delta (0.1-4 Hz), gamma (30-60 Hz) and higher frequencies (>100 Hz). Importantly, it reversed the ketamine-induced reduction in low beta power (10-20 Hz) and potentiated ketamine-induced increases in gamma and high frequency oscillations (130-160 Hz). Naltrexone inhibited frequencies above 50 Hz and significantly reduced the ketamine-induced increase in high frequency oscillations. However, some frequency band changes, such as clozapine-induced decreases in delta power, were only seen in locomoting rats. These results emphasise the potential in differentiating between activity states to capture drug effects and translate to human resting state EEG. Furthermore, the differential reversal of ketamine-induced EEG effects by clozapine and naltrexone may have implications for the understanding of psychotomimetic as well as rapid antidepressant effects of ketamine.

Impact of the COVID-19 pandemic on routine surveillance for adults with chronic hepatitis B virus (HBV) infection in the UK.

Background: To determine the impact of the COVID-19 pandemic on the population with chronic Hepatitis B virus (HBV) infection under hospital follow-up in the UK, we quantified the coverage and frequency of measurements of biomarkers used for routine surveillance (alanine transferase [ALT] and HBV viral load). Methods: We used anonymized electronic health record data from the National Institute for Health Research (NIHR) Health Informatics Collaborative (HIC) pipeline representing five UK National Health Service (NHS) Trusts. Results: We report significant reductions in surveillance of both biomarkers during the pandemic compared to pre-COVID-19 years, both in terms of the proportion of patients who had ≥1 measurement annually, and the mean number of measurements per patient. Conclusions: These results demonstrate the real-time utility of HIC data in monitoring health-care provision, and support interventions to provide catch-up services to minimise the impact of the pandemic. Further investigation is required to determine whether these disruptions will be associated with increased rates of adverse chronic HBV outcomes.

A simple Hückel model-driven strategy to overcome electronic barriers to retro-Brook silylation relevant to aryne and bisaryne precursor synthesis.

ortho-Silylaryl triflate precursors (oSATs) have been responsible for many recent advances in aryne chemistry and are most commonly accessed from the corresponding 2-bromophenol. A retro-Brook O- to C-silyl transfer is a key step in this synthesis but not all aromatic species are amenable to the transformation, with no functionalized bisbenzyne oSATs reported. Simple Hückel models are presented which show that the calculated aromaticity at the brominated position is an accurate predictor of successful retro-Brook reaction, validated synthetically by a new success and a predicted failure. From this, the synthesis of a novel difunctionalized bisaryne precursor has been tested, requiring different approaches to install the two C-silyl groups. The first successful use of a disubstituted o-silylaryl sulfonate bisbenzyne precursor in Diels-Alder reactions is then shown.

National Institute for Health Research Health Informatics Collaborative: development of a pipeline to collate electronic clinical data for viral hepatitis research.

OBJECTIVE: The National Institute for Health Research (NIHR) Health Informatics Collaborative (HIC) is a programme of infrastructure development across NIHR Biomedical Research Centres. The aim of the NIHR HIC is to improve the quality and availability of routinely collected data for collaborative, cross-centre research. This is demonstrated through research collaborations in selected therapeutic areas, one of which is viral hepatitis. DESIGN: The collaboration in viral hepatitis identified a rich set of datapoints, including information on clinical assessment, antiviral treatment, laboratory test results and health outcomes. Clinical data from different centres were standardised and combined to produce a research-ready dataset; this was used to generate insights regarding disease prevalence and treatment response. RESULTS: A comprehensive database has been developed for potential viral hepatitis research interests, with a corresponding data dictionary for researchers across the centres. An initial cohort of 960 patients with chronic hepatitis B infections and 1404 patients with chronic hepatitis C infections has been collected. CONCLUSION: For the first time, large prospective cohorts are being formed within National Health Service (NHS) secondary care services that will allow research questions to be rapidly addressed using real-world data. Interactions with industry partners will help to shape future research and will inform patient-stratified clinical practice. An emphasis on NHS-wide systems interoperability, and the increased utilisation of structured data solutions for electronic patient records, is improving access to data for research, service improvement and the reduction of clinical data gaps.

Applying Design Thinking in Health Care: Reflections of Nursing Honors Program Students.

Nursing faculty at the University of Alabama at Birmingham (UAB) incorporated design thinking (DT) into the curriculum of the UAB School of Nursing Honors Program as a framework for undergraduate students' immersion into research experiences. This article describes the experiences of students who participated in the first honors class that used DT and discusses how to incorporate DT into nursing research and quality improvement projects. Active learning strategies provided students various opportunities to conceptualize and apply the five-step DT process by identifying possible solutions to problems in clinical settings. Three major themes emerged from these reflections: trusting the process, cultivating empathy, and applying DT in the future. Students found that trusting the process of learning about DT facilitated their understanding of empathy's role in health care as they recognized DT's far-reaching applications beyond the honors program. A pragmatic, intuitive, and innovative approach to identifying problems and solutions, DT empowers nurses to creatively and confidently address issues they encounter to improve outcomes for their patients, health-care systems, and communities.

Structure-Based Drug Discovery of N-((R)-3-(7-Methyl-1H-indazol-5-yl)-1-oxo-1-(((S)-1-oxo-3-(piperidin-4-yl)-1-(4-(pyridin-4-yl)piperazin-1-yl)propan-2-yl)amino)propan-2-yl)-2'-oxo-1',2'-dihydrospiro[piperidine-4,4'-pyrido[2,3-d][1,3]oxazine]-1-carboxamide (HTL22562): A Calcitonin Gene-Related Peptide Receptor Antagonist for Acute Treatment of Migraine.

Structure-based drug design enabled the discovery of 8, HTL22562, a calcitonin gene-related peptide (CGRP) receptor antagonist. The structure of 8 complexed with the CGRP receptor was determined at a 1.6 Å resolution. Compound 8 is a highly potent, selective, metabolically stable, and soluble compound suitable for a range of administration routes that have the potential to provide rapid systemic exposures with resultant high levels of receptor coverage (e.g., subcutaneous). The low lipophilicity coupled with a low anticipated clinically efficacious plasma exposure for migraine also suggests a reduced potential for hepatotoxicity. These properties have led to 8 being selected as a clinical candidate for acute treatment of migraine.

Bilateral Quadriceps Tendon Repair with Suture Anchors: Case Series.

INTRODUCTION: Bilateral and simultaneous quadriceps tendon rupture is rarely observed. This case series evaluates 3 patients with bilateral ruptures of the quadriceps tendon. The purpose of this case series is to display the effectiveness of the suture anchor surgical repair technique in these patients. CASE PRESENTATIONS: Three obese male patients experienced some type of traumatic injury to the knee extensor mechanism, resulting in bilateral quadriceps tendon ruptures. Each of the patients was evaluated and given operative and nonoperative treatment options, and they all elected to undergo surgical tendon repair. Two double-loaded anchors were placed into the superior pole of the patella, allowing the tendons to be reduced back to their original positioning. Postoperatively, all patients were given the same guidelines for physical therapy, and their progress was monitored periodically. Each patient returned to his normal level of physical activity. Range of motion at the knee and weight bearing were reestablished in all 3 patients. DISCUSSION: These quadriceps tendon ruptures occurred in patients with a predisposition to injury as a result of excessive weight bearing. When addressing bilateral quadriceps tendon ruptures in this patient population, we found that a suture anchor-based construct allows for a secure repair, early initiation of physical therapy, and a noted improvement in pain scores on the Visual Analog Scale.