Comparing antiviral strategies against COVID-19 via multiscale within-host modelling

Within-host models of COVID-19 infection dynamics enable the merits of different forms of antiviral therapy to be assessed in individual patients. A stochastic agent-based model of COVID-19 intracellular dynamics is introduced here, that incorporates essential steps of the viral life cycle targeted by treatment options. Integration of model predictions with an intercellular ODE model of within-host infection dynamics, fitted to patient data, generates a generic profile of disease progression in patients that have recovered in the absence of treatment. This is contrasted with the profiles obtained after variation of model parameters pertinent to the immune response, such as effector cell and antibody proliferation rates, mimicking disease progression in immunocompromised patients. These profiles are then compared with disease progression in the presence of antiviral and convalescent plasma therapy against COVID-19 infections. The model reveals that using both therapies in combination can be very effective in reducing the length of infection, but these synergistic effects decline with a delayed treatment start. Conversely, early treatment with either therapy alone can actually increase the duration of infection, with infectious virions still present after the decline of other markers of infection. This suggests that usage of these treatments should remain carefully controlled in a clinical environment.

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Modeling Within-Host Dynamics of SARS-CoV-2 Infection: A Case Study in Ferrets

Viruses ◽

10.3390/v13081635 ◽

2021 ◽

Vol 13 (8) ◽

pp. 1635

Author(s):

Naveen K. Vaidya ◽

Angelica Bloomquist ◽

Alan S. Perelson

Keyword(s):

Animal Model ◽

Infectious Virus ◽

Antiviral Agents ◽

Virus Production ◽

Cell Loss ◽

Model Parameters ◽

Infection Period ◽

Infection Dynamics ◽

Host Infection ◽

Experimental Trials

The pre-clinical development of antiviral agents involves experimental trials in animals and ferrets as an animal model for the study of SARS-CoV-2. Here, we used mathematical models and experimental data to characterize the within-host infection dynamics of SARS-CoV-2 in ferrets. We also performed a global sensitivity analysis of model parameters impacting the characteristics of the viral infection. We provide estimates of the viral dynamic parameters in ferrets, such as the infection rate, the virus production rate, the infectious virus proportion, the infected cell death rate, the virus clearance rate, as well as other related characteristics, including the basic reproduction number, pre-peak infectious viral growth rate, post-peak infectious viral decay rate, pre-peak infectious viral doubling time, post-peak infectious virus half-life, and the target cell loss in the respiratory tract. These parameters and indices are not significantly different between animals infected with viral strains isolated from the environment and isolated from human hosts, indicating a potential for transmission from fomites. While the infection period in ferrets is relatively short, the similarity observed between our results and previous results in humans supports that ferrets can be an appropriate animal model for SARS-CoV-2 dynamics-related studies, and our estimates provide helpful information for such studies.

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Squamous cell carcinoma of the scrotum in HIV: two case reports

African Journal of Urology ◽

10.1186/s12301-021-00177-3 ◽

2021 ◽

Vol 27 (1) ◽

Author(s):

Jeff John ◽

Ken Kesner ◽

John Lazarus

Keyword(s):

Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Squamous Cell ◽

Case Reports ◽

Treatment Options ◽

Punch Biopsy ◽

Delayed Treatment ◽

Clinical Presentations ◽

T1 N0 M0

Abstract Background Squamous cell carcinoma (SCC) of the scrotum was the first malignancy known to be associated with exposure to an occupational carcinogen—in this case, soot trapped in the breeches of chimney sweeps. Better civil rules and regulations and the replacement of hearths with other forms of heating have rendered SCC of the scrotum a rarity. We report two cases of scrotal SCC with vastly differing clinical presentations and management. Case presentation Case 1 had T1 N0 M0 disease and presented with a small (< 2 cm), innocuous-looking, non-healing ulcer of eight years duration. A punch biopsy revealed a superficially invasive SCC confirmed on immunohistochemical profiling. A wide local excision of the lesion was subsequently performed. Follow-up at three years showed no signs of recurrence. Case 2 presented with T4 N1 M1 disease and rapidly progressing locally destructive mass. A punch biopsy of the scrotal lesion confirmed invasive moderately differentiated focally keratinising SCC. The metastatic evaluation confirmed the presence of metastatic, extensive para-aortic lymphadenopathy. He was managed with cisplatin-based chemoradiotherapy. Conclusion Early detection and management of patients with SCC of the scrotum are essential. If the diagnosis is delayed, treatment options become limited, and the prognosis is poor. Notwithstanding the rarity of this disease, multicentre trials are needed to provide more precise guidelines as to the optimal management of these patients.

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Modeling infection dynamics and mitigation strategies to support K-6 in-person instruction during the COVID-19 pandemic

10.1101/2021.02.27.21252535 ◽

2021 ◽

Author(s):

Douglas E. Morrison ◽

Roch Nianogo ◽

Vladimir Manuel ◽

Onyebuchi A. Arah ◽

Nathaniel Anderson ◽

...

Keyword(s):

School Attendance ◽

Secondary Infection ◽

Mitigation Strategies ◽

Transmission Dynamics ◽

Model Parameters ◽

Safety Education ◽

Vaccination Rates ◽

Health Authorities ◽

Infection Dynamics ◽

Public Health Authorities

AbstractObjectiveTo support safer in-person K-6 instruction during the coronavirus disease 2019 (COVID- 19) pandemic by providing public health authorities and school districts with a practical model of transmission dynamics and mitigation strategies.MethodsWe developed an agent-based model of infection dynamics and preventive mitigation strategies such as distancing, health behaviors, surveillance and symptomatic testing, daily symptom and exposure screening, quarantine policies, and vaccination. The model parameters can be updated as the science evolves and are adjustable via an online user interface, enabling users to explore the effects of interventions on outcomes of interest to states and localities, under a variety of plausible epidemiological and policy assumptions.ResultsUnder default assumptions, secondary infection rates and school attendance are substantially affected by surveillance testing protocols, vaccination rates, class sizes, and effectiveness of safety education.ConclusionsOur model helps policymakers consider how mitigation options and the dynamics of school infection risks affect outcomes of interest. The model’s parameters can be immediately updated in response to changes in epidemiological conditions, science of COVID-19 transmission dynamics, testing and vaccination resources, and reliability of mitigation strategies.

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Microscale tracking of coral disease reveals timeline of infection and heterogeneity of polyp fate

10.1101/302778 ◽

2018 ◽

Cited By ~ 5

Author(s):

Assaf R. Gavish ◽

Orr H. Shapiro ◽

Esti Kramarsky-Winter ◽

Assaf Vardi

Keyword(s):

Disease Progression ◽

Defense Mechanism ◽

Coral Disease ◽

Coral Host ◽

Pocillopora Damicornis ◽

Spatial And Temporal Scales ◽

Infection Dynamics ◽

Key Steps ◽

Coral Pathogen ◽

Gastrovascular System

AbstractCoral disease is often studied at scales ranging from single colonies to the entire reef. This is particularly true for studies following disease progression through time. To gain a mechanistic understanding of key steps underlying infection dynamics, it is necessary to study disease progression, and host-pathogen interactions, at relevant microbial scales. Here we provide a dynamic view of the interaction between the model coral pathogen Vibrio coralliilyticus and its coral host Pocillopora damicornis at unprecedented spatial and temporal scales. This view is achieved using a novel microfluidics-based system specifically designed to allow microscopic study of coral infection in-vivo under controlled environmental conditions. Analysis of exudates continuously collected at the system’s outflow, allows a detailed biochemical and microbial analyses coupled to the microscopic observations of the disease progression. The resulting multilayered dataset provides the most detailed description of a coral infection to-date, revealing distinct pathogenic processes as well as the defensive behavior of the coral host. We provide evidence that infection in this system occurs following ingestion of the pathogen, and may then progress through the gastrovascular system. We further show infection may spread when pathogens colonize lesions in the host tissue. Copious spewing of pathogen-laden mucus from the polyp mouths results in effective expulsion of the pathogen from the gastrovascular system, possibly serving as a first line of defense. A secondary defense mechanism entails the severing of calicoblastic connective tissues resulting in the controlled isolation of diseased polyps, or the survival of individual polyps within infected colonies. Further investigations of coral-pathogen interactions at these scales will help to elucidate the complex interactions underlying coral disease, as we as the versatile adaptive response of the coral ecosystems to fluctuating environments.

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Abstract 3736: Applying the Carotid Atherosclerosis Score in a Clinical Environment: a Feasibility Study

Stroke ◽

10.1161/str.43.suppl_1.a3736 ◽

2012 ◽

Vol 43 (suppl_1) ◽

Author(s):

Dongxiang Xu ◽

Jie Sun ◽

Yan Song ◽

Daniel S Hippe ◽

Min Chen ◽

...

Keyword(s):

Neurological Symptom ◽

Carotid Atherosclerosis ◽

Treatment Options ◽

Outer Wall ◽

Classification Performance ◽

Clinical Environment ◽

Plaque Instability ◽

Wall Area ◽

Increasing Trend ◽

Symptom Status

Background Carotid atherosclerosis is a leading cause of stoke. Recent studies have shown that its severity can be stratified by the Carotid Atherosclerosis Score (CAS) as measured by MRI. However, these studies were performed using customized imaging sequences, coils and comprehensive plaque analysis by specialized human reviewers, which are not generally available in a clinical environment. Whether CAS can be applied for clinical risk assessment is unknown. In this study, we used clinically collected MRI data to compute CAS. We investigated the correlation between CAS and the prevalence of neurological symptoms and disrupted luminal surface (DLS), an indicator of plaque instability, to evaluate the feasibility of translating CAS for clinical use. Methods Seventy six patients with either symptomatic or asymptomatic carotid disease detected by ultrasound were recruited. All patients underwent a multi-contrast MRI with clinical sequences and a commercially available coil. The lumen and outer wall boundaries and DLS were outlined manually and the plaque components were identified automatically using histologically validated image analysis software. The maximum wall thickness (MWT) and maximum % area (100 x area/[wall area]) of lipid-rich necrotic core (LRNC) were outputted by the software to compute CAS as follows: CAS=1 with MWT&lt2.0mm, CAS=2 with LRNC&lt20%, CAS=3 with LRNC between 20% and 40% and CAS=4 with LRNC&gt40%. Trend analysis was done to evaluate the associations between CAS and prevalence of symptoms and DLS. The area under the receiver operating characteristic (ROC) curve was used to evaluate the classification performance of CAS. Results Of the 76 patients, there was a significant increasing trend (p=0.01) between CAS scores and neurological symptom status. The presence of DLS also demonstrated a significant increasing trend (p&lt0.001) versus CAS with rates 0% (0/7), 7% (2/27), 35% (7/20) and 59% (13/22). ROC analysis of CAS also showed it was a good classifier of symptom status (AUC = 0.67, p=0.01) and DLS (AUC = 0.80, p&lt0.001) Conclusion In this study, we conclude that the CAS computed from clinically collected MRI data can stratify the severity of carotid atherosclerotic disease as indicated by neurological symptom status and DLS, both of which are important in monitoring patients and evaluating treatment options. Further study is needed to assess how a fully automated CAS analysis affects the quality of the score and how well the score can stratify the risk of future outcomes.

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Craniopharyngioma

Pediatric Neurosurgery ◽

10.1093/med/9780190617073.003.0023 ◽

2019 ◽

pp. 207-216

Author(s):

Lissa C. Baird

Keyword(s):

Initial Treatment ◽

Pediatric Population ◽

Intraoperative Complications ◽

Treatment Options ◽

Benign Neoplasm ◽

Tumor Control ◽

Delayed Treatment ◽

Pituitary Dysfunction ◽

Treatment Morbidity

Pediatric craniopharyngioma is a histologically benign neoplasm with potential for malignant clinical behavior. Presenting vision and endocrine deficits are common, and the natural history carries unacceptable morbidity, including blindness, complete hypothalamic and pituitary dysfunction, and death. The goal of initial treatment for craniopharyngioma in the pediatric population should be permanent tumor control or cure in order to minimize morbidity from recurrent and progressive disease. Treatment-related morbidity is acute with surgical intervention and requires immediate postoperative endocrinological care. Radiotherapy is associated with delayed treatment morbidity, and long-term monitoring is critical. Inadequate tumor control after initial treatment will result in inevitable recurrence, with more complex and less effective treatment options and higher associated treatment morbidity. Unexpected intraoperative complications can be avoided with careful preoperative planning and good surgical technique.

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Imaging for acute aortic syndromes

Heart ◽

10.1136/heartjnl-2019-314897 ◽

2019 ◽

Vol 106 (3) ◽

pp. 182-189 ◽

Cited By ~ 5

Author(s):

Brett J Carroll ◽

Marc L Schermerhorn ◽

Warren J Manning

Keyword(s):

Surgical Repair ◽

Surgical Intervention ◽

Multimodality Imaging ◽

Imaging Modality ◽

Treatment Options ◽

High Morbidity ◽

Delayed Treatment ◽

Acute Aortic Syndromes ◽

Type A Dissection ◽

Delayed Intervention

Acute aortic syndromes (AAS) represent a spectrum of disorders with a common theme of disruption in aortic integrity. AAS are associated with high morbidity and mortality and warrant emergent medical or surgical intervention as delayed treatment is associated with worse outcomes. There are multiple advanced imaging modalities for the diagnosis and complimentary assessment of AAS, each with advantages and limitations. CT angiography remains the imaging modality of choice for diagnosis in the overwhelming majority of patients as it is rapidly acquired and widely available; however, transoesophageal echocardiogram also offers excellent diagnostic accuracy in addition to complimentary data for surgical repair in those with type A dissection. Transthoracic echocardiography and magnetic resonance angiography can also be valuable in select patients. Imaging is increasingly important for risk stratification in the subacute and chronic phases of AAS. Additionally, imaging is vital for planning of interventions in both acute and delayed intervention. Endovascular treatment options are used with increasing frequency—multimodality imaging during the procedure allows for optimisation of these increasingly complex procedures.

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From Mouse to Man and Back: Closing the Correlation Gap between Imaging and Histopathology for Lung Diseases

Diagnostics ◽

10.3390/diagnostics10090636 ◽

2020 ◽

Vol 10 (9) ◽

pp. 636 ◽

Cited By ~ 2

Author(s):

Birger Tielemans ◽

Kaat Dekoster ◽

Stijn E. Verleden ◽

Stefan Sawall ◽

Bartosz Leszczyński ◽

...

Keyword(s):

Lung Disease ◽

Disease Progression ◽

Lung Diseases ◽

Imaging Techniques ◽

Treatment Options ◽

Space Technology ◽

Study Results ◽

Life Threatening ◽

End Stage

Lung diseases such as fibrosis, asthma, cystic fibrosis, infection and cancer are life-threatening conditions that slowly deteriorate quality of life and for which our diagnostic power is high, but our knowledge on etiology and/or effective treatment options still contains important gaps. In the context of day-to-day practice, clinical and preclinical studies, clinicians and basic researchers team up and continuously strive to increase insights into lung disease progression, diagnostic and treatment options. To unravel disease processes and to test novel therapeutic approaches, investigators typically rely on end-stage procedures such as serum analysis, cyto-/chemokine profiles and selective tissue histology from animal models. These techniques are useful but provide only a snapshot of disease processes that are essentially dynamic in time and space. Technology allowing evaluation of live animals repeatedly is indispensable to gain a better insight into the dynamics of lung disease progression and treatment effects. Computed tomography (CT) is a clinical diagnostic imaging technique that can have enormous benefits in a research context too. Yet, the implementation of imaging techniques in laboratories lags behind. In this review we want to showcase the integrated approaches and novel developments in imaging, lung functional testing and pathological techniques that are used to assess, diagnose, quantify and treat lung disease and that may be employed in research on patients and animals. Imaging approaches result in often novel anatomical and functional biomarkers, resulting in many advantages, such as better insight in disease progression and a reduction in the numbers of animals necessary. We here showcase integrated assessment of lung disease with imaging and histopathological technologies, applied to the example of lung fibrosis. Better integration of clinical and preclinical imaging technologies with pathology will ultimately result in improved clinical translation of (therapy) study results.

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SARS-CoV-2 Antibody Avidity Responses in COVID-19 Patients and Convalescent Plasma Donors

The Journal of Infectious Diseases ◽

10.1093/infdis/jiaa581 ◽

2020 ◽

Vol 222 (12) ◽

pp. 1974-1984 ◽

Cited By ~ 1

Author(s):

Sarah E Benner ◽

Eshan U Patel ◽

Oliver Laeyendecker ◽

Andrew Pekosz ◽

Kirsten Littlefield ◽

...

Keyword(s):

Prevalence Ratio ◽

Post Exposure Prophylaxis ◽

Plasma Therapy ◽

Cross Sectional ◽

Antibody Avidity ◽

Igg Avidity ◽

Screening Parameter ◽

Duration Of Infection ◽

Antibody Titers ◽

Exposure Prophylaxis

Abstract Background Convalescent plasma therapy is a leading treatment for conferring temporary immunity to COVID-19–susceptible individuals or for use as post-exposure prophylaxis. However, not all recovered patients develop adequate antibody titers for donation and the relationship between avidity and neutralizing titers is currently not well understood. Methods SARS-CoV-2 anti-spike and anti-nucleocapsid IgG titers and avidity were measured in a longitudinal cohort of COVID-19 hospitalized patients (n = 16 individuals) and a cross-sectional sample of convalescent plasma donors (n = 130). Epidemiologic correlates of avidity were examined in donors by linear regression. The association of avidity and a high neutralizing titer (NT) were also assessed in donors using modified Poisson regression. Results Antibody avidity increased over duration of infection and remained elevated. In convalescent plasma donors, higher levels of anti-spike avidity were associated with older age, male sex, and hospitalization. Higher NTs had a stronger positive correlation with anti-spike IgG avidity (Spearman ρ = 0.386; P < .001) than with anti-nucleocapsid IgG avidity (Spearman ρ = 0.211; P = .026). Increasing levels of anti-spike IgG avidity were associated with high NT (≥160) (adjusted prevalence ratio = 1.58 [95% confidence interval = 1.19–2.12]), independent of age, sex, and hospitalization. Conclusions SARS-CoV-2 antibody avidity correlated with duration of infection and higher neutralizing titers, suggesting a potential alternative screening parameter for identifying optimal convalescent plasma donors.

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Treatment options for deciduous molar hypomineralization: a report of three cases

Dental Update ◽

10.12968/denu.2019.46.6.546 ◽

2019 ◽

Vol 46 (6) ◽

pp. 546-553

Author(s):

Yasmy Quintero ◽

Manuel Restrepo ◽

Jenny Angélica Saldarriaga ◽

Alexandra Saldarriaga ◽

Lourdes Santos-Pinto

Keyword(s):

Differential Diagnosis ◽

Early Diagnosis ◽

Treatment Options ◽

Clinical Implications ◽

Therapeutic Approaches ◽

Enamel Defect ◽

Delayed Treatment ◽

Molar Incisor Hypomineralization ◽

Permanent Molars ◽

Deciduous Molar

Deciduous molar hypomineralization (DMH) is an enamel defect of systemic and multifactorial origin that affects the second deciduous molar. Currently, its treatment is based on guidelines for Molar Incisor Hypomineralization (MIH), a disturbance that affects permanent molars and may or may not be associated with permanent incisors. To date, there are no guidelines for DMH. Therefore, three different therapeutic approaches are presented to treat DMH, emphasizing the relevance of early diagnosis, differential diagnosis and treatment options, and tailored to take into account each patient's and parents' specific needs, as well as the involved tooth, severity of DMH, patients' symptoms and behaviour. CPD/Clinical Relevance: To understand the clinical implications of DMH since the diagnosis and delayed treatment of this enamel alteration could have important complications in both the primary and permanent dentition.

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