Greater preservation of SARS-CoV-2 neutralising antibody responses following the ChAdOx1-S (AZD1222) vaccine compared with mRNA vaccines in haematopoietic cell transplant recipients.

Whilst SARS-CoV-2 mRNA vaccines generate high neutralising antibodies (nAb) in most individuals, haematopoietic stem cell transplant (HSCT) and chimeric antigen receptor T-cell (CAR-T) recipients respond poorly. HSCT/CAR-T treatment ablates existing immune memory, with recipients requiring revaccination analogous to being vaccine naive. An optimal revaccination strategy for this cohort has not been defined.

Microfluidic qPCR for detection of 21 common respiratory viruses in children with influenza-like illness.

Multiple respiratory viruses lead to high morbidity and mortality, yet global surveillance platforms focus primarily on seasonal influenza viruses. The COVID-19 pandemic and new RSV vaccines highlight the importance of a broader approach. Upper respiratory tract swabs from children aged 24-59 months presenting with influenza-like illness in The Gambia were collected during follow-up of a live-attenuated influenza vaccine randomised controlled trial in 2017-18.

Establishing therapeutic and supportive relationships throughout delivery of a school-based group parenting program via telehealth: Exploring causal pathways.

Background: Access to specialised early intervention mental health services for children, including group counselling for parents/carers, is still a challenge in non-metropolitan areas of Australia.

Aim: To gain understanding of the acceptability of a school-based targeted parenting group program delivered via telehealth by exploring the experiences of parents/carers, clinicians and school staff, and asking what works, how, why and in what circumstances.

Methods: Caregivers, clinicians and school staff involved in the delivery of a mental health program via telehealth into primary schools in two rural Local Health Districts (LHDs) in southern New South Wales (NSW) were invited to participate in interviews and/or focus group discussions.

Factors affecting turnaround time of SARS-CoV-2 sequencing for inpatient infection prevention and control decision making: analysis of data from the COG-UK HOCI study.

Background: Barriers to rapid return of sequencing results can affect the utility of sequence data for infection prevention and control decisions.

Aim: To undertake a mixed-methods analysis to identify challenges that sites faced in achieving a rapid turnaround time (TAT) in the COVID-19 Genomics UK Hospital-Onset COVID-19 Infection (COG-UK HOCI) study.

Methods: For the quantitative analysis, timepoints relating to different stages of the sequencing process were extracted from both the COG-UK HOCI study dataset and surveys of study sites.

Risk factors for SARS-CoV-2 seroprevalence following the first pandemic wave in UK healthcare workers in a large NHS Foundation Trust.

We aimed to measure SARS-CoV-2 seroprevalence in a cohort of healthcare workers (HCWs) during the first UK wave of the COVID-19 pandemic, explore risk factors associated with infection, and investigate the impact of antibody titres on assay sensitivity.  HCWs at Sheffield Teaching Hospitals NHS Foundation Trust were prospectively enrolled and sampled at two time points. We developed an in-house ELISA for testing participant serum for SARS-CoV-2 IgG and IgA reactivity against Spike and Nucleoprotein.

Long-term survivors following autologous haematopoetic stem cell transplantation have significant defects in their humoral immunity against vaccine preventable diseases, years on from transplant.

Current international guidelines recommend routinely vaccinating haematopoetic stem cell transplant (HSCT) recipients. Despite significant infection-related mortality following autologous HSCT, routine vaccination programmes (RVP) completion is poor. For recovered HSCT recipients, it is uncertain whether catch-up vaccination remains worthwhile years later.

Risk factors for SARS-CoV-2 seroprevalence following the first pandemic wave in UK healthcare workers in a large NHS Foundation Trust.

Background: We aimed to measure SARS-CoV-2 seroprevalence in a cohort of healthcare workers (HCWs) during the first UK wave of the COVID-19 pandemic, explore risk factors associated with infection, and investigate the impact of antibody titres on assay sensitivity.

Methods: HCWs at Sheffield Teaching Hospitals NHS Foundation Trust (STH) were prospectively enrolled and sampled at two time points. SARS-CoV-2 antibodies were tested using an in-house assay for IgG and IgA reactivity against Spike and Nucleoprotein (sensitivity 99·47%, specificity 99·56%).

Roll-out of SARS-CoV-2 testing for healthcare workers at a large NHS Foundation Trust in the United Kingdom, March 2020.

Healthcare workers (HCW) are potentially at increased risk of infection with coronavirus disease (COVID-19) and may transmit severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to vulnerable patients. We present results from staff testing at Sheffield Teaching Hospitals NHS Foundation Trust, United Kingdom. Between 16 and 29 March 2020, 1,533 symptomatic HCW were tested, of whom 282 (18%) were positive for SARS-CoV-2.

Evaluation of early chronic functional outcomes and their relationship to pre-frontal cortex and hippocampal pathology following moderate-severe traumatic brain injury.

TBI is a significant risk factor for the development of dementia, with the interaction between structural damage from TBI and neuroinflammation potentially driving this relationship. This study investigated the early chronic post-TBI neuroinflammatory response and its relationship to both neurodegenerative pathology and functional impairment up to 3 months post-injury. Sprague-Dawley rats underwent either sham surgery or the Marmarou model of diffuse moderate-severe TBI.

Serum Natriuretic Peptides as Differential Biomarkers Allowing for the Distinction between Physiologic and Pathologic Left Ventricular Hypertrophy.

Given the proven utility of natriuretic peptides as serum biomarkers of cardiovascular maladaptation and dysfunction in humans and the high cross-species sequence conservation of atrial natriuretic peptides, natriuretic peptides have the potential to serve as translational biomarkers for the identification of cardiotoxic compounds during multiple phases of drug development. This work evaluated and compared the response of N-terminal proatrial natriuretic peptide (NT-proANP) and N-terminal probrain natriuretic peptide (NT-proBNP) in rats during exercise-induced and drug-induced increases in cardiac mass after chronic swimming or daily oral dosing with a peroxisome proliferator-activated receptor γ agonist. Male Sprague-Dawley rats aged 8 to 10 weeks were assigned to control, active control, swimming, or drug-induced cardiac hypertrophy groups.

Cross-laboratory analytical validation of the cardiac biomarker NT-proANP in rat.

Introduction: Natriuretic peptides, including N-terminal-proatrial natriuretic peptide (NT-proANP) are cardiac hormones that are produced in response to myocardial stretch and have been used in rats and humans as blood based functional cardiac biomarkers. There are limited validation data of these assays in rats and therefore the Predictive Safety Testing Consortium, Cardiac Hypertrophy Working Group (PSTC-CHWG) performed a cross-laboratory (5 laboratories) analytical evaluation of a commercially available NT-proANP ELISA for use with rat samples.

Methods: Serum samples were collected from normal Sprague Dawley (SD) rats and were spiked with kit calibrator material or rat heart tissue extracts to provide specimens for the validation.

Integrated approach to early detection of cardiovascular toxicity induced by a ghrelin receptor agonist.

Cardiovascular (CV) safety concerns are among the leading causes of compound attrition in drug development. This work describes a strategy of applying novel end points to a 7-day rodent study to increase the opportunity to detect and characterize CV injury observed in a longer term (ie, 28 days) study. Using a ghrelin receptor agonist (GSK894281), a compound that produces myocardial degeneration/necrosis in rats after 28 days at doses of 0.

An initial characterization of N-terminal-proatrial natriuretic peptide in serum of Sprague Dawley rats.

In the clinical setting, natriuretic peptides (NPs) have proven to be reliable noninvasive markers for diagnostic, prognostic, and therapeutic monitoring of heart failure. Given their proven utility in humans, NPs are potential candidates for translational biomarkers during drug development to detect drug-induced hemodynamic stress resulting in cardiac hypertrophy in preclinical species. We evaluated the intra- and interassay precision and the stability of serum N-terminal-proatrial natriuretic peptide (NT-proANP) using a commercially available enzyme-linked immunoassay (EIA).

Apolipoprotein E modifies the CNS response to injury via a histamine-mediated pathway.

Recent evidence demonstrates that apolipoprotein E (apoE) influences the central nervous system (CNS) response to both acute and chronic injury. To address the mechanisms by which apoE influences neurological disease, we examined differential gene expression in the brains of apoE transgenic mice after closed head injury. Apart from confirming the knockout of apoE, the largest differential gene expression occurred for the interleukin-9 receptor (IL-9R), which was > 100-fold up-regulated in apoE-deficient versus wild-type mice.

Flow cytometric assessment of peroxisome proliferation from frozen liver of fibrate-treated monkeys.

Multiple methods currently exist for the assessment of peroxisome proliferation, including gene expression, enzyme activity, immunolabeling coupled with image analysis, and electron microscopy. This study describes a novel flow cytometric method to efficiently quantify peroxisome proliferation in cells from frozen livers. Frozen livers from cynomolgus monkeys treated with ciprofibrate at doses of 0, 3, 30, 150, and 400 mg/kg/day for 15 days were mechanically disaggregated using an automated dispersion method.

Gene expression profiling of the PPAR-alpha agonist ciprofibrate in the cynomolgus monkey liver.

Fibrates, such as ciprofibrate, fenofibrate, and clofibrate, are peroxisome proliferator-activated receptor-alpha (PPARalpha) agonists that have been in clinical use for many decades for treatment of dyslipidemia. When mice and rats are given PPARalpha agonists, these drugs cause hepatic peroxisome proliferation, hypertrophy, hyperplasia, and eventually hepatocarcinogenesis. Importantly, primates are relatively refractory to these effects; however, the mechanisms for the species differences are not clearly understood.

Fibrates induce hepatic peroxisome and mitochondrial proliferation without overt evidence of cellular proliferation and oxidative stress in cynomolgus monkeys.

There is little primate risk factor data in the literature evaluating the relationship between proposed mechanisms of PPAR agonist-induced hepatocarcinogenesis at clinically relevant therapeutic exposures. These studies were conducted to characterize the hepatic effects of fenofibrate and ciprofibrate in the cynomolgus monkey. Male cynomolgus monkeys were given fenofibrate (250, 1250 or 2500 mg/kg/day) or ciprofibrate (3, 30, 150 or 400 mg/kg/day) for up to 15 days.

Visualization and quantitation of peroxisomes using fluorescent nanocrystals: treatment of rats and monkeys with fibrates and detection in the liver.

Peroxisome proliferation in the liver is a well-documented response that occurs in some species upon treatment with hypolipidemic drugs, such as fibrates. Typically, liver peroxisome proliferation has been estimated by direct counting via electron microscopy, as well as by gene expression, enzyme activity, and immunolabeling. We have developed a novel method for the immunofluorescent labeling of peroxisomes, using an antibody to the 70-kDa peroxisomal membrane protein (PMP70) coupled with fluorescent nanocrystals, Quantum Dots.

Transcriptional and physiological responses of HepG2 cells exposed to diethyl maleate: time course analysis.

Expression levels of 767 genes were measured in HepG2 cells at eight time points (0, 0.5, 1, 6, 12, 16, 20, and 24 h) following exposure to the oxidizing agent, diethyl maleate (DEM). DEM treatment caused an immediate and sustained loss of intracellular GSH, with a concomitant increase in GSSG.

Fluorescent microsphere-based readout technology for multiplexed human single nucleotide polymorphism analysis and bacterial identification.

Large-scale human genotyping requires technologies with a minimal number of steps, high accuracy, and the ability to automate at a reasonable cost. In this regard, we have developed a rapid, cost-effective readout method for single nucleotide polymorphism (SNP) genotyping that combines an easily automatable single-tube allele-specific primer extension (ASPE) with an efficient high throughput flow cytometric analysis performed on a Luminex 100 flow cytometer. This robust technique employs an ASPE reaction using PCR-derived target DNA containing the SNP and a pair of synthetic complementary capture probes that differ at their 3' end-nucleotide defining the alleles.