Ascertainment rate of SARS-CoV-2 infections from healthcare and community testing in the UK.

The proportion of SARS-CoV-2 infections ascertained through healthcare and community testing is generally unknown and expected to vary depending on natural factors and changes in test-seeking behaviour. Here we use population surveillance data and reported daily case numbers in the United Kingdom to estimate the rate of case ascertainment. We mathematically describe the relationship between the ascertainment rate, the daily number of reported cases, population prevalence, and the sensitivity of PCR and Lateral Flow tests as a function time since exposure. Applying this model to the data, we estimate that 20%-40% of SARS-CoV-2 infections in the UK were ascertained with a positive test with results varying by time and region. Cases of the Alpha variant were ascertained at a higher rate than the wild type variants circulating in the early pandemic, and higher again for the Delta variant and Omicron BA.1 sub-lineage, but lower for the BA.2 sub-lineage. Case ascertainment was higher in adults than in children. We further estimate the daily number of infections and compare this to mortality data to estimate that the infection fatality rate increased by a factor of 3 during the period dominated by the Alpha variant, and declined in line with the distribution of vaccines. This manuscript was submitted as part of a theme issue on "Modelling COVID-19 and Preparedness for Future Pandemics".

Protein phosphatase 5 mediates corticosteroid insensitivity in airway smooth muscle in patients with severe asthma.

BACKGROUND: The mechanisms driving glucocorticoid (GC) insensitivity in patients with severe asthma are still unknown. Recent evidence suggests the existence of GC-insensitive pathways in airway smooth muscle (ASM) caused by a defect in GC receptor (GRα) function. We examined whether other mechanisms could potentially explain the reduced sensitivity of ASM cells to GC in severe asthmatics. METHODS: Airway smooth muscle cells from healthy and severe asthmatic subjects were treated with TNF-α and responses to corticosteroids in both cohorts were compared by ELISA, immunoblot, immunohistochemistry and real-time PCR. Immunohistochemistry and flow cytometry assays were used to assess the expression of the protein phosphatase PP5 in endobronchial biopsies and ASM cells. RESULTS: The production of CCL11 and CCL5 by TNF-α was insensitive to both fluticasone and dexamethasone in ASM cells from severe asthmatic compared to that in healthy subjects. Fluticasone-induced GRα nuclear translocation, phosphorylation at serine 211 and expression of GC-induced leucine zipper (GILZ) were significantly reduced in ASM cells from severe asthmatics compared to responses in healthy subjects. Levels of PP5 were increased in ASM cells from severe asthmatics and PP5 knockdown using siRNA restored fluticasone repressive action on chemokine production and its ability to induce GRα nuclear translocation and GRE-dependent GILZ expression. In vivo PP5 expression was also increased in the ASM bundles in endobronchial biopsies in severe asthmatics. CONCLUSIONS: PP5-dependent impairment of GRα function represents a novel mechanism driving GC insensitivity in ASM in severe asthma.

Abnormal corticosteroid signalling in airway smooth muscle: mechanisms and perspectives for the treatment of severe asthma.

Growing in vivo evidence supports the concept that airway smooth muscle produces various immunomodulatory factors that could contribute to asthma pathogenesis via the regulation of airway inflammation, airway narrowing and remodelling. Targeting ASM using bronchial thermoplasty has provided undeniable clinical benefits for patients with uncontrolled severe asthma who are refractory to glucocorticoid therapy. The present review will explain why the failure of glucocorticoids to adequately manage patients with severe asthma could derive from their inability to affect the immunomodulatory potential of ASM. We will support the view that ASM sensitivity to glucocorticoid therapy can be blunted in severe asthma and will describe some of the factors and mechanisms that could be responsible for glucocorticoid insensitivity.

Mechanisms of glucocorticoid action and insensitivity in airways disease.

Glucocorticoids are the mainstay for the treatment of chronic inflammatory diseases including asthma and chronic obstructive pulmonary disease (COPD). However, it has been recognized that glucocorticoids do not work well in certain patient populations suggesting reduced sensitivity. The ultimate biologic responses to glucocorticoids are determined by not only the concentration of glucocorticoids but also the differences between individuals in glucocorticoid sensitivity, which is influenced by multiple factors. Studies are emerging to understand these mechanisms in detail, which would help in increasing glucocorticoid sensitivity in patients with chronic airways disease. This review aims to highlight both classical and emerging concepts of the anti-inflammatory mechanisms of glucocorticoids and also review some novel strategies to overcome steroid insensitivity in airways disease.

Network analysis of pig movement data as an epidemiological tool: an Austrian case study.

Animal movements represent a major risk for the spread of infectious diseases in the domestic swine population. In this study, we adopted methods from social network analysis to explore pig trades in Austria. We used a dataset of daily records of swine movements covering the period 2015-2021. We analyzed the topology of the network and its structural changes over time, including seasonal and long-term variations in the pig production activities. Finally, we studied the temporal dynamics of the network community structure. Our findings show that the Austrian pig production was dominated by small-sized farms while spatial farm density was heterogeneous. The network exhibited a scale-free topology but was very sparse, suggesting a moderate impact of infectious disease outbreaks. However, two regions (Upper Austria and Styria) may present a higher structural vulnerability. The network also showed very high assortativity between holdings from the same federal state. Dynamic community detection revealed a stable behavior of the clusters. Yet trade communities did not correspond to sub-national administrative divisions and may be an alternative zoning approach to managing infectious diseases. Knowledge about the topology, contact patterns, and temporal dynamics of the pig trade network can support optimized risk-based disease control and surveillance strategies.

A Metapopulation Model for Preventing the Reintroduction of Bovine Viral Diarrhea Virus to Naïve Herds: Scotland Case Study.

Background: Bovine viral diarrhea (BVD) virus is one of the most problematic infectious pathogens for cattle. Since 2013, a mandatory BVD eradication program has successfully reduced the number of infected cattle living on Scottish farms; however, England remains at high prevalence and presents a risk to Scotland through animal movement. Methods: We analyze cattle movements in the UK from 2008 to 2017 and recorded incidence of BVD in Scotland from 2017 to 2020. To simulate BVD reintroduction into Scotland, we developed an epidemiological model that combines transmission between cattle and animal movements between farms. A total of four control strategies were implemented in the model: no intervention, import restriction, targeted vaccination, and combined strategy. Results: During the course of the eradication scheme, movements into Scotland became increasingly distributed in regions close to the England-Scotland border. The prevalence of BVD in this region decreased at a slower rate than the rest of Scotland during the eradication scheme. Our model showed that the change in the prevalence is expected, given that the change in the patterns of movement and if vaccination is targeted to the border areas that decrease in the prevalence will be seen throughout the whole of Scotland. Conclusion: Scottish farms are susceptible to BVD virus reintroduction through animal imports from non-BVD-free nations with farms in border areas being the most vulnerable. Protecting the border regions provides direct and indirect protection to the rest of Scottish farms by interrupting chains of transmission.

Double-stranded RNA-mediated suppression of Period2 expression in the suprachiasmatic nucleus disrupts circadian locomotor activity in rats.

Circadian behavioral rhythms in mammals are controlled by a central clock located in the suprachiasmatic nucleus (SCN). PER2, the protein product of the clock gene, Period 2 (Per2), is expressed rhythmically in the SCN [Beaule C, Houle LM, Amir S (2003) Expression profiles of PER2 immunoreactivity within the shell and core regions of the rat suprachiasmatic nucleus: Lack of effect of photic entrainment and disruption by constant light. J Mol Neurosci 21:133-148] and has been implicated in the control of circadian behavioral rhythms based on the evidence that genetic mutations in Per2 abolish free running locomotor activity rhythms in mice [Zheng B, Larkin DW, Albrecht U, Sun ZS, Sage M, Eichele G, Lee CC, Bradley A (1999) The mPer2 gene encodes a functional component of the mammalian circadian clock. Nature 400:169-173; Bae K, Jin X, Maywood ES, Hastings MH, Reppert SM, Weaver DR (2001) Differential functions of mPer1, mPer2, and mPer3 in the SCN circadian clock. Neuron 30:525-536]. Such mutations eradicate PER2 expression in the SCN and disrupt the SCN molecular clockwork, however, they also affect PER2 in the rest of the brain and body leaving open the possibility that the changes in behavioral rhythms might be influenced, at least in part, by disruptions in PER2 functioning outside the SCN. We used RNA interference-mediated transient knockdown of Per2 to study the effect of selective suppression of PER2 expression in the SCN, per se, on behavioral circadian rhythms. We found that transient suppression of PER2 in the SCN disrupted free running locomotor activity rhythms for up to 10 days in rats. Infusions of control dsRNA into the SCN or infusions of dsRNA to Per2 immediately dorsal to the SCN had no effect. These results constitute evidence for a direct link between PER2 expression in the SCN and the expression of behavioral circadian rhythms in mammals.

Hypercalcemia associated with squamous cell carcinoma of tongue.

OBJECTIVE: To present a case and to review the relationship between tumor production of parathyroid hormone-related protein (PTHrP) and hypercalcemia in oral squamous cell carcinoma (SCC), with emphasis on tongue cancer. METHODS: We describe a patient with advanced, locally invasive SCC of the tongue in whom hypercalcemia developed as a result of PTHrP production by the tumor. In addition, the medical literature regarding PTHrP and hypercalcemia associated with malignant disease is reviewed. RESULTS: A 65-year-old man, who was admitted to the hospital because of one episode of unresponsiveness, was found to have a large, necrotic, ulcerated lesion overlying the left mandibular area. After biopsy of the tumor and total body imaging, he was diagnosed with advanced, locally invasive, poorly differentiated SCC of the tongue, stage T4 N1 M0. On admission, the serum calcium concentration was 12.5 mg/dL (normal range, 8.5 to 10.7), and the serum albumin level was 2.2 g/dL (normal range, 3.5 to 5.5). The serum intact parathyroid hormone level was 26 pg/mL (normal range, 10 to 65); the PTHrP level was 13.1 pmol/L (normal, <1.3). Hypercalcemia attributable to production of PTHrP by the tongue SCC was diagnosed. Initial treatment of the hypercalcemia with vigorous hydration yielded a limited response. Intravenous administration of pamidronate initially decreased the serum calcium level to 5.2 mg/dL, but then it progressively increased to 8.6 mg/dL during the next 4 weeks. The patient refused further treatment and died after 1 month. CONCLUSION: To our knowledge, this is the first case of hypercalcemia associated with SCC of the tongue in which the serum PTHrP level was measured and reported to be high. It should be measured in other similar cases.

Circulating leptin levels are not associated with cardiovascular morbidity and mortality in women with diabetes: a prospective cohort study.

AIMS/HYPOTHESIS: Leptin, an adipocyte-secreted hormone, plays an important role in regulating neuroendocrine and immune function as well as insulin resistance and metabolism. Our objective was to examine the relationship between leptin levels and cardiovascular morbidity and overall mortality in women with type 2 diabetes. SUBJECTS AND METHODS: This prospective cohort study included 1,194 women with a confirmed diagnosis of type 2 diabetes, who provided a blood sample at baseline in 1989-1990. Participants were followed for 12 years for the development of health outcomes including cardiovascular disease (CVD) events as well as total mortality. RESULTS: There were 218 new CVD events and 228 deaths from all causes. Cox proportional hazards analysis was used to estimate the relative risks (RRs) for each quintile level of leptin compared with the lowest quintile. Leptin levels were positively associated with several CVD risk factors including BMI and inflammatory markers, but were not independently associated with the incidence of CVD or total mortality in women with diabetes. The multivariate RRs (95% CIs) for CVD across the quintiles of leptin were 0.96 (0.61-1.53), 0.99 (0.61-1.61), 1.04 (0.63-1.71), 1.02 (0.59-1.75) (p for trend = 0.83). CONCLUSIONS/INTERPRETATION: Although circulating leptin levels are associated with obesity and inflammatory markers, they are not significantly related to the risk of CVD or mortality in women with diabetes.

C-reactive protein, prothrombotic imbalance and endothelial dysfunction in acute coronary syndromes without ST elevation.

UNLABELLED: Inflammation is considered a crucial step in the pathogenesis of acute coronary syndromes (ACS). C-reactive protein (CRP) is proposed to be included in risk stratification of ACS patients. However, it is not yet known if CRP is only a risk marker, or merely a risk factor in the development of ACS. Our study looked at the links between inflammation and the prothrombotic factors present in patients with ACS without ST elevation. MATERIAL AND METHODS: 86 patients (pts), 46 men (53.4%), mean age = 58.2+/-12.4 years-old, with acute coronary syndromes (unstable angina and NSTEMI). The following parameters were measured in all pts on admission: CRP, fibrinogen, blood white cell count, and coagulation parameters: coagulation factor V and VIII, von Willebrand factor (vWf), antithrombin III (AT III), D-dimers (DD), C and S proteins. RESULTS: Mean CRP in the study group was 22.42+/-19.81 mg/dl (limits 1.40-88.8 mg/dl). We worked with quartiles of CRP plasmatic levels, in order to see how magnitude of inflammation correlates with different coagulation and fibrinolysis parameters. When comparing the 1st with the 4th CRP quartiles, we noted that important inflammation (4th quartile) was associated with higher factor von Willebrand (141.3 vs 108.9%, p<0.05), factor 5 (127.5% vs 88%, p<0.01), factor 8 (121.5 vs 117.1%, p=0.04), lower AT III (101.6 vs 118.2%, p<0.05), lower protein C and S. The associations did not keep for PAI-I or D-dimers, which might be associated with the lack of sensibility of fibrinolysis markers in the early period after thrombosis. CONCLUSIONS: Inflammation, as quantified by CRP, appears to be associated with a significant prothrombotic status and endothelial dysfunction (as reflected by high von Willebrand factor).