Syrian hamster convalescence from prototype SARS-CoV-2 confers measurable protection against the attenuated disease caused by the Omicron variant.

The mutation profile of the SARS-CoV-2 Omicron (lineage BA.1) variant posed a concern for naturally acquired and vaccine-induced immunity. We investigated the ability of prior infection with an early SARS-CoV-2 ancestral isolate (Australia/VIC01/2020, VIC01) to protect against disease caused by BA.1. We established that BA.1 infection in naïve Syrian hamsters resulted in a less severe disease than a comparable dose of the ancestral virus, with fewer clinical signs including less weight loss. We present data to show that these clinical observations were almost absent in convalescent hamsters challenged with the same dose of BA.1 50 days after an initial infection with ancestral virus. These data provide evidence that convalescent immunity against ancestral SARS-CoV-2 is protective against BA.1 in the Syrian hamster model of infection. Comparison with published pre-clinical and clinical data supports consistency of the model and its predictive value for the outcome in humans. Further, the ability to detect protection against the less severe disease caused by BA.1 demonstrates continued value of the Syrian hamster model for evaluation of BA.1-specific countermeasures.

VirA+EmiC project: Evaluating real-world effectiveness and sustainability of integrated routine opportunistic hepatitis B and C testing in a large urban emergency department.

Innovative testing approaches and care pathways are required to meet global hepatitis B virus (HBV) and hepatitis C virus (HCV) elimination goals. Routine blood-borne virus (BBV) testing in emergency departments (EDs) in high-prevalence areas is suggested by the European Centre for Disease Prevention and Control (ECDC) but there is limited evidence for this. Universal HIV testing in our ED according to UK guidance has been operational since 2015. We conducted a real-world service evaluation of a modified electronic patient record (EPR) system to include opportunistic opt-out HBV/reflex-HCV tests for any routine blood test orders for ED attendees aged ≥16 years. Reactive laboratory results were communicated directly to specialist clinical teams. Our model for contacting patients requiring linkage to care (new diagnoses/known but disengaged) evolved from initially primarily hospital-led to collaborating with regional health and community service networks. Over 11 months, 81,088 patients attended the ED; 36,865 (45.5%) had a blood test. Overall uptake for both HBV and HCV testing was 75%. Seroprevalence was 0.9% for hepatitis B surface antigen (HBsAg) and 0.9% for HCV antigen (HCV-Ag). 79% of 140 successfully contacted HBsAg+patients required linkage to care, of which 87% engaged. 76% of 130 contactable HCV-Ag+patients required linkage, 52% engaged. Our results demonstrate effectiveness and sustainability of universal ED EPR opt-out HBV/HCV testing combined with comprehensive linkage to care pathways, allowing care provision particularly for marginalized at-risk groups with limited healthcare access. The findings support the ECDC BBV testing guidance and may inform future UK hepatitis testing guidance.

Universal testing for hepatitis B and hepatitis C in the emergency department: a cost-effectiveness and budget impact analysis of two urban hospitals in the United Kingdom.

BACKGROUND: Numerous studies have shown the effectiveness of testing for hepatitis B (HBV) and hepatitis C (HCV) in emergency departments (ED), due to the elevated prevalence amongst attendees. The aim of this study was to conduct a cost-effectiveness analysis of universal opt-out HBV and HCV testing in EDs based on 2 long-term studies of the real-world effectiveness of testing in 2 large ED's in the UK. METHODS: A Markov model was used to evaluate ED-based HBV and HCV testing versus no ED testing, in addition to current testing practice. The two EDs had a HBV HBsAg prevalence of 0.5-0.9% and an HCV RNA prevalence of 0.9-1.0%. The analysis was performed from a UK health service perspective, over a lifetime time horizon. Costs are reported in British pounds (GBP), and outcomes as quality adjusted life years (QALYs), with both discounted at 3.5% per year. Incremental cost-effectiveness ratios (ICER) are calculated as costs per QALY gained. A willingness-to-pay threshold of £20,000/QALY was used. The cost-effectiveness was estimated for both infections, in both ED's. RESULTS: HBV and HCV testing were highly cost-effective in both settings, with ICERs ranging from £7,177 to £12,387 per QALY gained. In probabilistic analyses, HBV testing was 89-94% likely to be cost-effective at the threshold, while HCV testing was 94-100% likely to be cost-effective, across both settings. In deterministic sensitivity analyses, testing remained cost-effective in both locations at ≥ 0.25% HBsAg prevalence, and ≥ 0.49% HCV RNA prevalence. This is much lower than the prevalence observed in the two EDs included in this study. CONCLUSIONS: HBV and HCV testing in urban EDs is highly cost-effective in the UK, and can be cost-effective at relatively low prevalence. These results should be reflected in UK and European hepatitis testing guidelines.

Increasing emergency department attendances in central London with methamphetamine toxicity and associated harms.

BACKGROUND: Methamphetamine is a stimulant drug of abuse with increasing prevalence of use worldwide leading to public health concern. While previous research by our group a decade ago found no evidence of increasing harms associated with methamphetamine use in the UK, there are conflicting data on whether or not this is still the case. This paper aims to identify trends in methamphetamine-related harms and characterise the clinical features of ED presentations involving methamphetamine with gamma-hydroxybutyrate/gamma-butyrolactone (GHB/GBL). METHODS: We retrospectively interrogated a database of all toxicology-related presentations to two central London EDs, extracting data on drugs involved for presentations relating to methamphetamine between 2005 and 2018 to enable analysis of trends. Further clinical data were extracted for presentations between 2014 and 2018 to give a 4-year case series. RESULTS: A total of 1244 presentations involving the use of methamphetamine were identified. The number of presentations rose from 4 in 2005 (1.9% of all recreational drug presentations) to 294 (16.2%) in 2018. A total of 850 cases were identified for the 2014-2018 case series, 94.9% were male with a median (range) age of 35.1 (16-67) years. The most common clinical features in the methamphetamine presentations were neuropsychiatric: agitation (41.5%), anxiety (35.2%), hallucinations (16.5%) and psychosis (14.8%). GHB/GBL was co-used in 54.2% of presentations and appeared to attenuate the neuropsychiatric features seen. Use of GHB/GBL was associated with a higher Poisoning Severity Score and requirement for level 2/3 (high dependency unit/intensive care unit (ICU)) care. CONCLUSION: ED attendances in central London relating to methamphetamine use have risen over the last decade. Combining methamphetamine with GHB/GBL is common and is associated with a higher Poisoning Severity Score and need for ICU level care. Further work is required to establish whether further resources need to be directed at this clinical and public health problem.

Longitudinal study of the cutaneous microbiota of healthy horses.

BACKGROUND: Next-generation sequencing techniques have revealed that human and animal skin is colonised by a rich and diverse population of bacteria, and that microbial composition varies between different body sites and individuals. Very little is known about the normal microbiota of healthy equine skin. HYPOTHESIS/OBJECTIVES: To describe the taxonomic distributions of cutaneous bacterial microbiota in a population of healthy horses in Ontario, Canada, and to evaluate the effects of body site, individual and time of year on microbial diversity and community composition. ANIMALS: Samples were collected from four body sites (dorsum, ventral abdomen, pastern and groin) from 12 clinically healthy horses from the same farm. Samples were collected from all individuals at four time points (winter, spring, summer, autumn) within a calendar year. METHODS AND MATERIALS: Illumina sequencing of the V4 region of the 16S rRNA gene was performed following DNA extraction. Data were analysed using mothur software. RESULTS: Bacteria from 38 phyla and 1,665 genera were identified. Alpha diversity was higher in the winter and summer than spring and autumn although this was not statistically significant. Community membership and structure clustered more based on season than skin site. CONCLUSIONS AND CLINICAL IMPORTANCE: Healthy equine skin is inhabited by a marked diversity of microbiota. Individuals living in a similar environment share overlapping cutaneous microbial populations. These populations vary significantly over time and between body sites.

An Economic Evaluation of the Cost-Effectiveness of Opt-Out Hepatitis B and Hepatitis C Testing in an Emergency Department Setting in the United Kingdom.

OBJECTIVES: The prevalence of hepatitis is high in emergency department (ED) attendees in the United Kingdom, with a prevalence of up to 2% for hepatitis B (HBV) HBsAg, and 2.9% for hepatitis C (HCV) RNA. The aim of this paper is to perform an economic evaluation of opt-out ED-based HCV and HBV testing. METHODS: A Markov model was developed to analyze the cost-effectiveness of opt-out HCV and HBV testing in EDs in the UK. The model used data from UK studies of ED testing to parameterize the HCV and HBV prevalence (1.4% HCV RNA, 0.84% HBsAg), test costs, and intervention effects (contact rates and linkage to care). For HCV, we used an antibody test cost of £3.64 and RNA test cost of £68.38, and assumed direct-acting antiviral treatment costs of £10 000. For HBV, we used a combined HBsAg and confirmatory test cost of £5.79. We also modeled the minimum prevalence of HCV (RNA-positive) and HBV (HBsAg) required to make ED testing cost-effective at a £20 000 willingness to pay per quality-adjusted life-year threshold. RESULTS: In the base case, ED testing was highly cost-effective, with HCV and HBV testing costing £8019 and £9858 per quality-adjusted life-year gained, respectively. HCV and HBV ED testing remained cost-effective at 0.25% HCV RNA or HBsAg prevalence or higher. CONCLUSIONS: Emergency department testing for HCV and HBV is highly likely to be cost-effective in many areas across the UK depending on their prevalence. Ongoing studies will help evaluate ED testing across different regions to inform testing guidelines.

Cost-Effectiveness of Immediate Magnetic Resonance Imaging In the Management of Patients With Suspected Scaphoid Fracture: Results From a Randomized Clinical Trial.

OBJECTIVES: Given the limited diagnostic accuracy of radiographs on presentation to the emergency department (ED), the management of suspected scaphoid fractures remains clinically challenging and poses an unknown economic burden to healthcare systems. We aimed to evaluate the cost-effectiveness of immediate magnetic resonance imaging (MRI) in the management of patients presenting with suspected scaphoid fracture to an ED in England. METHODS: A pragmatic, randomized, single-center trial compared the use of immediate MRI in the ED against standard care with radiographs only. Participants' use of healthcare services and costs were estimated from primary care and secondary care databases and questionnaires at baseline, 1, 3, and 6 months postrecruitment. Costs were compared using generalized linear models and combined with quality-adjusted life years (QALYs, based on the EQ-5D-5L) to estimate cost-effectiveness at 6 months postrecruitment. Cost-effectiveness acceptability curves and bootstrapping techniques were used to estimate the probability of cost-effectiveness at different willingness-to-pay (WTP) thresholds. Four deterministic sensitivity scenarios were considered around key parameters. RESULTS: The MRI intervention dominated standard care in the base case and all 4 deterministic sensitivity scenarios, costing less and achieving more QALY gains, with a probability of 100% of being cost-effective at 6 months using the conventional United Kingdom WTP thresholds of £20 000 to £30 000 per QALY. CONCLUSION: The use of immediate MRI is a cost-effective intervention in the management of suspected scaphoid fractures in a Central Hospital in London. Routine clinical practice at our institution has been changed to include the intervention.

A maximum-likelihood approach for building cell-type trees by lifting.

BACKGROUND: In cell differentiation, a less specialized cell differentiates into a more specialized one, even though all cells in one organism have (almost) the same genome. Epigenetic factors such as histone modifications are known to play a significant role in cell differentiation. We previously introduce cell-type trees to represent the differentiation of cells into more specialized types, a representation that partakes of both ontogeny and phylogeny. RESULTS: We propose a maximum-likelihood (ML) approach to build cell-type trees and show that this ML approach outperforms our earlier distance-based and parsimony-based approaches. We then study the reconstruction of ancestral cell types; since both ancestral and derived cell types can coexist in adult organisms, we propose a lifting algorithm to infer internal nodes. We present results on our lifting algorithm obtained both through simulations and on real datasets. CONCLUSIONS: We show that our ML-based approach outperforms previously proposed techniques such as distance-based and parsimony-based methods. We show our lifting-based approach works well on both simulated and real data.

Chloroquine inhibited Ebola virus replication in vitro but failed to protect against infection and disease in the in vivo guinea pig model.

Ebola virus (EBOV) is highly pathogenic, with a predisposition to cause outbreaks in human populations accompanied by significant mortality. Owing to the lack of approved therapies, screening programmes of potentially efficacious drugs have been undertaken. One of these studies has demonstrated the possible utility of chloroquine against EBOV using pseudotyped assays. In mouse models of EBOV disease there are conflicting reports of the therapeutic effects of chloroquine. There are currently no reports of its efficacy using the larger and more stringent guinea pig model of infection. In this study we have shown that replication of live EBOV is impaired by chloroquine in vitro. However, no protective effects were observed in vivo when EBOV-infected guinea pigs were treated with chloroquine. These results advocate that chloroquine should not be considered as a treatment strategy for EBOV.

Inefficient prioritization of task-relevant attributes during instrumental information demand.

In natural settings, people evaluate complex multi-attribute situations and decide which attribute to request information about. Little is known about how people make this selection and specifically, how they identify individual observations that best predict the value of a multi-attribute situation. Here show that, in a simple task of information demand, participants inefficiently query attributes that have high individual value but are relatively uninformative about a total payoff. This inefficiency is robust in two instrumental conditions in which gathering less informative observations leads to significantly lower rewards. Across individuals, variations in the sensitivity to informativeness is associated with personality metrics, showing negative associations with extraversion and thrill seeking and positive associations with stress tolerance and need for cognition. Thus, people select informative queries using sub-optimal strategies that are associated with personality traits and influence consequential choices.

Comparative pathology of experimental pulmonary tuberculosis in animal models.

Research in human tuberculosis (TB) is limited by the availability of human tissues from patients, which is often altered by therapy and treatment. Thus, the use of animal models is a key tool in increasing our understanding of the pathogenesis, disease progression and preclinical evaluation of new therapies and vaccines. The granuloma is the hallmark lesion of pulmonary tuberculosis, regardless of the species or animal model used. Although animal models may not fully replicate all the histopathological characteristics observed in natural, human TB disease, each one brings its own attributes which enable researchers to answer specific questions regarding TB immunopathogenesis. This review delves into the pulmonary pathology induced by Mycobacterium tuberculosis complex (MTBC) bacteria in different animal models (non-human primates, rodents, guinea pigs, rabbits, cattle, goats, and others) and compares how they relate to the pulmonary disease described in humans. Although the described models have demonstrated some histopathological features in common with human pulmonary TB, these data should be considered carefully in the context of this disease. Further research is necessary to establish the most appropriate model for the study of TB, and to carry out a standard characterisation and score of pulmonary lesions.

Characterisation and development of histopathological lesions in a guinea pig model of Mycobacterium tuberculosis infection.

Tuberculosis (TB) remains a very significant infectious disease worldwide. New vaccines and therapies are needed, even more crucially with the increase of multi-drug resistant Mycobacterium tuberculosis strains. Preclinical animal models are very valuable for the development of these new disease control strategies. Guinea pigs are one of the best models of TB, sharing many features with the pathology observed in human TB. Here we describe the development of TB lesions in a guinea pig model of infection. We characterise the granulomatous lesions in four developmental stages (I-IV), using histopathological analysis and immunohistochemical (IHC) techniques to study macrophages, T cells, B cells and granulocytes. The granulomas in the guinea pigs start as aggregations of macrophages and few heterophils, evolving to larger lesions showing central caseous necrosis with mineralisation and abundant acid-fast bacilli, surrounded by a rim of macrophages and lymphocytes in the outer layers of the granuloma. Multinucleated giant cells are very rare and fibrotic capsules are not formed in this animal model.

Tumour Necrosis Factor-α, Chemokines, and Leukocyte Infiltrate Are Biomarkers for Pathology in the Brains of Venezuelan Equine Encephalitis (VEEV)-Infected Mice.

Venezuelan equine encephalitis virus (VEEV) is a disease typically confined to South and Central America, whereby human disease is characterised by a transient systemic infection and occasionally severe encephalitis, which is associated with lethality. Using an established mouse model of VEEV infection, the encephalitic aspects of the disease were analysed to identify biomarkers associated with inflammation. Sequential sampling of lethally challenged mice (infected subcutaneously) confirmed a rapid onset systemic infection with subsequent spread to the brain within 24 h of the challenge. Changes in inflammatory biomarkers (TNF-α, CCL-2, and CCL-5) and CD45+ cell counts were found to correlate strongly to pathology (R>0.9) and present previously unproven biomarkers for disease severity in the model, more so than viral titre. The greatest level of pathology was observed within the olfactory bulb and midbrain/thalamus. The virus was distributed throughout the brain/encephalon, often in areas not associated with pathology. The principal component analysis identified five principal factors across two independent experiments, with the first two describing almost half of the data: (1) confirmation of a systemic Th1-biased inflammatory response to VEEV infection, and (2) a clear correlation between specific inflammation of the brain and clinical signs of disease. Targeting strongly associated biomarkers of deleterious inflammation may ameliorate or even eliminate the encephalitic syndrome of this disease.

Digest: Evolution of plasticity and its potential role in the decline of specialists.

How does plasticity evolve over relatively short timescales? Through a series of common garden and reciprocal transplant experiments, Walter et al. found distinct patterns of variation in the phenotype and gene expression for two closely related Sicilian daisy species of the genus Senecio across an elevational gradient. This suggests that adaptive divergence may produce interspecific differences in both the magnitude and direction of plasticity. The nonadaptive nature of the plasticity found in Senecio aethnensis has important implications for conservation efforts and evolutionary modeling.

Childhood violence exposure and externalizing behaviors: A systematic review of the role of physiological biomarkers.

Childhood exposure to violence has been consistently linked to externalizing behaviors like delinquency and aggression. Growing evidence indicates that physiological biomarkers from the parasympathetic and sympathetic nervous systems (PNS and SNS) and hypothalamic-pituitary-adrenal (HPA) axis may moderate or mediate the relation between childhood violence exposure and externalizing behaviors. We conducted a systematic review to synthesize recent findings on physiological biomarkers as mediators and/or moderators of this association across the life course, using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Our search yielded 3878 articles, of which 44 met inclusion criteria (describing a total of 46 independent studies). We found consistent evidence for blunted HPA-axis reactivity as a mediator of the relation between childhood violence exposure and subsequent externalizing behaviors, and for non-reciprocal PNS/SNS activation as moderators exacerbating this relation. However, the results of the majority of included studies that demonstrated significant moderating effects of physiological biomarkers varied by participant sex, type of childhood violence exposure, and type of stimuli used to induce physiological reactivity. The observed mixed findings are consistent with some theories that emphasize that both high and low stress reactivity can be adaptive depending on one's early environment. These findings highlight the need for systematic explorations of heterogeneity, theory-driven research questions, and longitudinal studies that span multiple developmental periods and multiple biological systems. Clinical implications include the need to assess physiological biomarkers in treatment and intervention studies and the potential to target interventions based on both autonomic functioning and environmental contexts.

Rapid risk stratification of acute coronary syndrome: adoption of an adapted European Society of Cardiology 0/1-hour troponin algorithm in a real-world setting.

Aims: To evaluate the clinical feasibility of implementing the 2020 ESC 0/1 hr algorithm for rapid rule-out/rule-in of acute coronary syndrome (ACS). Methods and results: Data were collected retrospectively from 5496 patients in 2020 and 7363 patients in 2021 who received cardiac troponin measurements through the ACS algorithm in acute care settings within a large tertiary cardiac centre in the United Kingdom. This period overlapped the introduction of the 2020 ESC 0/1 hr algorithm. After exclusion of haemolysis, 1905 patients underwent repeat troponin measurement within the study period in 2020 and 2658 in 2021. Median time to repeat was significantly reduced from 3 h 14 min for intermediate low risk patients (5-12 ng/L) in 2020 to 1 h 22 min in 2021, and from 3 h 30 min to 1 h 59 min in intermediate high-risk patients (12-51 ng/L). Less than 15% of patients requiring repeat testing had dynamic changes in troponin of sufficient magnitude to change their initial risk category. Of all patients, 58.1% of patients in 2020 were ultimately classified as 'low risk', 19.2% deemed 'ACS likely', and 22.7% as 'ACS possible', with similar distributions in 2021. Conclusion: Whilst an efficient algorithm, our study demonstrates multi-faceted, practical limitations of achieving the 1 h target for the triage of patients with suspected ACS. Despite challenges predominantly of logistic nature, the algorithm enables rapid, streamlined, and efficient triage of large patient cohorts. Further work is required to streamline this process and achieve the targeted 1 h repeat in a resource-constrained healthcare environment, which would invariably require second blood draw before the result of first, as recommended by the ESC.

Pathology in Practice.

In collaboration with the American College of Veterinary Pathologists.

Histopathological and Immunological Findings in the Common Marmoset Following Exposure to Aerosolized SARS-CoV-2.

There is an enduring requirement to develop animal models of COVID-19 to assess the efficacy of vaccines and therapeutics that can be used to treat the disease in humans. In this study, six marmosets were exposed to a small particle aerosol (1-3 µm) of SARS-CoV-2 VIC01 that delivered the virus directly to the lower respiratory tract. Following the challenge, marmosets did not develop clinical signs, although a disruption to the normal diurnal temperature rhythm was observed in three out of six animals. Early weight loss and changes to respiratory pattern and activity were also observed, yet there was limited evidence of viral replication or lung pathology associated with infection. There was a robust innate immunological response to infection, which included an early increase in circulating neutrophils and monocytes and a reduction in the proportion of circulating T-cells. Expression of the ACE2 receptor in respiratory tissues was almost absent, but there was ubiquitous expression of TMPRSS2. The results of this study indicate that exposure of marmosets to high concentrations of aerosolised SARS-CoV-2 did not result in the development of clear, reproducible signs of COVID-19.

Prospective RandOmised Trial of Emergency Cardiac Computerised Tomography (PROTECCT).

OBJECTIVE: Many patients presenting with suspected acute coronary syndrome (ACS) have high-sensitivity cardiac troponin (hs-cTn) concentrations between rule-in and rule-out thresholds and hence need serial testing, which is time consuming. The Prospective RandOmised Trial of Emergency Cardiac Computerised Tomography (PROTECCT) assessed the utility of coronary CT angiography (CCTA) in patients with suspected ACS, non-ischaemic ECG and intermediate initial hs-cTn concentration. METHODS: Patients were randomised to CCTA-guided management versus standard of care (SOC). The primary outcome was hospital length of stay (LOS). Secondary outcomes included cost of in-hospital stay and major adverse cardiac events (MACE) at 12 months of follow-up. Data are mean (SD); for LOS harmonic means, IQRs are shown. RESULTS: 250 (aged 55 (14) years, 25% women) patients were randomised. Harmonic mean (IQR) LOS was 7.53 (6.0-9.6) hours in the CCTA arm and 8.14 (6.3-9.8) hours in the SOC arm (p=0.13). Inpatient cost was £1285 (£2216) and £1108 (£3573), respectively, p=0.68. LOS was shorter in the CCTA group in patients with <25% stenosis, compared with SOC; 6.6 (5.6-7.8) hours vs 7.5 (6.1-9.4) hours, respectively; p=0.021. More referrals for cardiology outpatient clinic review and cardiac CT-related outpatient referrals occurred in the SOC arm (p=0.01). 12-month MACE rates were similar between the two arms (7 (5.6%) in the CCTA arm and 8 (6.5%) in the SOC arm-log-rank p=0.78). CONCLUSIONS: CCTA did not lead to reduced hospital LOS or cost, largely because these outcomes were influenced by the detection of ≥25% grade stenosis in a proportion of patients. TRIAL REGISTRATION NUMBER: NCT03583320.