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.

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.

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.

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.

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.

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.

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.

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.

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.

Pathology in Practice.

In collaboration with the American College of Veterinary Pathologists.

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.

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.

Constitutive TRIM22 Expression in the Respiratory Tract Confers a Pre-Existing Defence Against Influenza A Virus Infection.

The induction of antiviral effector proteins as part of a homeostatically controlled innate immune response to infection plays a critical role in limiting the propagation and transmission of respiratory pathogens. However, the prolonged induction of this immune response can lead to lung hyperinflammation, tissue damage, and respiratory failure. We hypothesized that tissues exposed to the constant threat of infection may constitutively express higher levels of antiviral effector proteins to reduce the need to activate potentially harmful innate immune defences. By analysing transcriptomic data derived from a range of human tissues, we identify lung tissue to express constitutively higher levels of antiviral effector genes relative to that of other mucosal and non-mucosal tissues. By using primary cell lines and the airways of rhesus macaques, we show the interferon-stimulated antiviral effector protein TRIM22 (TRIpartite Motif 22) to be constitutively expressed in the lung independently of viral infection or innate immune stimulation. These findings contrast with previous reports that have shown TRIM22 expression in laboratory-adapted cell lines to require interferon stimulation. We demonstrate that constitutive levels of TRIM22 are sufficient to inhibit the onset of human and avian influenza A virus (IAV) infection by restricting the onset of viral transcription independently of interferon-mediated innate immune defences. Thus, we identify TRIM22 to confer a pre-existing (intrinsic) intracellular defence against IAV infection in cells derived from the respiratory tract. Our data highlight the importance of tissue-specific and cell-type dependent patterns of pre-existing immune gene expression in the intracellular restriction of IAV from the outset of infection.

Efficacy of Communication Techniques and Health Outcomes of Bushfire Smoke Exposure: A Scoping Review.

Public health officials communicate the relevant risks of bushfire smoke exposure and associated health protection measures to affected populations. Increasing global bushfire incidence in the context of climate change motivated this scoping review. English-language publications related to adverse health outcomes following bushfire smoke exposure and publications relating to communication during natural disasters were included. Bushfire smoke events potentially increase healthcare contact, especially presentations triggered by respiratory illness. At-risk populations include those with underlying cardiorespiratory disease, elderly, paediatric, pregnant persons, and First Nations people. We found that social media, television, and radio are among the most common information sources utilised in bushfire smoke events. Message style, content, and method of delivery can directly influence message uptake and behaviour modification. Age, rurality, and geographical location influence information source preferences. Culturally and linguistically diverse groups and those with hearing, vision, and mobility-related disabilities may benefit from targeted health recommendations. This review emphasises the health effects of bushfire smoke exposure and related communication recommendations during and after bushfire smoke events. Additional investigation may further clarify the health effects of bushfire smoke exposure and efficacy of related health messaging, particularly in at-risk populations. Quantitative comparison of communication methods may yield more specific recommendations for future bushfire smoke events.

Digest: Data tests and testable definitions of evolutionary phenomena.

How can we best test evolutionary phenomena that have historically muddled definitions? How do we ascertain whether data are appropriate or sufficient to explore our hypotheses? Moen et al. demonstrate a framework for accomplishing these goals that can be applied to most studies that use trait and tree data. Simultaneously, they provide a generalized approach for testing for adaptive radiation, a phenomenon with potential to help us understand drivers of evolution.

Digest: Macroevolutionary pattern from microevolutionary processes.

How can we bridge the gap between studies concerning microevolution and those concerning macroevolution? Taverne et al. provide a framework for how to study both intraspecific and interspecific variations simultaneously through their examination of how craniomandibular skeletal and muscle shape responds to ecological pressures in Podarcis lizards.

Immunological and pathological outcomes of SARS-CoV-2 challenge following formalin-inactivated vaccine in ferrets and rhesus macaques.

There is an urgent requirement for safe and effective vaccines to prevent COVID-19. A concern for the development of new viral vaccines is the potential to induce vaccine-enhanced disease (VED). This was reported in several preclinical studies with both SARS-CoV-1 and MERS vaccines but has not been reported with SARS-CoV-2 vaccines. We have used ferrets and rhesus macaques challenged with SARS-CoV-2 to assess the potential for VED in animals vaccinated with formaldehyde-inactivated SARS-CoV-2 (FIV) formulated with Alhydrogel, compared to a negative control vaccine. We showed no evidence of enhanced disease in ferrets or rhesus macaques given FIV except for mild transient enhanced disease seen 7 days after infection in ferrets. This increased lung pathology was observed at day 7 but was resolved by day 15. We also demonstrate that formaldehyde treatment of SARS-CoV-2 reduces exposure of the spike receptor binding domain providing a mechanistic explanation for suboptimal immunity.

Heart Rate and Heart Rate Variability Change with Sleep Stage in Dairy Cows.

Changes to the amount and patterns of sleep stages could be a useful tool to assess the effects of stress or changes to the environment in animal welfare research. However, the gold standard method, polysomnography PSG, is difficult to use with large animals such as dairy cows. Heart rate (HR) and heart rate variability (HRV) can be used to predict sleep stages in humans and could be useful as an easier method to identify sleep stages in cows. We compared the mean HR and HRV and lying posture of dairy cows at pasture and when housed, with sleep stages identified through PSG. HR and HRV were higher when cows were moving their heads or when lying flat on their side. Overall, mean HR decreased with depth of sleep. There was more variability in time between successive heart beats during REM sleep, and more variability in time between heart beats when cows were awake and in REM sleep. These shifts in HR measures between sleep stages followed similar patterns despite differences in mean HR between the groups. Our results show that HR and HRV measures could be a promising alternative method to PSG for assessing sleep in dairy cows.