Taking molecular pathology to the next level: Whole slide multicolor confocal imaging with the Pannoramic Confocal digital pathology scanner.

The emergence and fast advance of digital pathology allows the acquisition, digital storage, interactive recall and analysis of morphology at the tissue level. When applying immunohistochemistry, it also affords the correlation of morphology with the expression of one or two specific molecule of interest. The rise of fluorescence pathology scanners expands the number of detected molecules based on multiplex labeling. The Pannoramic Confocal (created by 3DHistech, Hungary) is a first-of-the-kind digital pathology scanner that affords not only multiplexed fluorescent detection on top of conventional transmission imaging, but also confocality. We have benchmarked this scanner in terms of stability, precision, light efficiency, linearity and sensitivity. X-Y stability and relocalisation precision were well below resolution limit (≤50 nm). Light throughput in confocal mode was 4-5 times higher than that of a point scanning confocal microscope, yielding similar calculated confocal intensities but with the potential for improving signal to noise ratio or scan speed. Response was linear with R2 ≥ 0.9996. Calibrated measurements showed that using indirect labeling ≥2000 molecules per cell could be well detected and imaged on the cell surface. Both standard-based and statistical post-acquisition flatfield corrections are implemented. We have also measured the point spread function (PSF) of the instrument. The dimensions of the PSF are somewhat larger and less symmetric than of the theoretical PSF of a conventional CLSM, however, the spatial homogeneity of these parameters allows for obtaining a specific system PSF for each optical path and using it for optional on-the-fly deconvolution. In conclusion, the Pannoramic Confocal provides sensitive, quantitative widefield and confocal detection of multiplexed fluorescence signals, with optical sectioning and 3D reconstruction, in addition to brightfield transmission imaging. High speed scanning of large samples, analysis of tissue heterogeneity, and detection of rare events open up new ways for quantitatively analyzing tissue sections, organoid cultures or large numbers of adherent cells.

Dynamics of an SIRWS model with waning of immunity and varying immune boosting period.

SIRS models capture transmission dynamics of infectious diseases for which immunity is not lifelong. Extending these models by a W compartment for individuals with waning immunity, the boosting of the immune system upon repeated exposure may be incorporated. Previous analyses assumed identical waning rates from R to W and from W to S. This implicitly assumes equal length for the period of full immunity and of waned immunity. We relax this restriction, and allow an asymmetric partitioning of the total immune period. Stability switches of the endemic equilibrium are investigated with a combination of analytic and numerical tools. Then, continuation methods are applied to track bifurcations along the equilibrium branch. We find rich dynamics: Hopf bifurcations, endemic double bubbles, and regions of bistability. Our results highlight that the length of the period in which waning immunity can be boosted is a crucial parameter significantly influencing long term epidemiological dynamics.

In Silico Evaluation of Paxlovid's Pharmacometrics for SARS-CoV-2: A Multiscale Approach.

Paxlovid is a promising, orally bioavailable novel drug for SARS-CoV-2 with excellent safety profiles. Our main goal here is to explore the pharmacometric features of this new antiviral. To provide a detailed assessment of Paxlovid, we propose a hybrid multiscale mathematical approach. We demonstrate that the results of the present in silico evaluation match the clinical expectations remarkably well: on the one hand, our computations successfully replicate the outcome of an actual in vitro experiment; on the other hand, we verify both the sufficiency and the necessity of Paxlovid's two main components (nirmatrelvir and ritonavir) for a simplified in vivo case. Moreover, in the simulated context of our computational framework, we visualize the importance of early interventions and identify the time window where a unit-length delay causes the highest level of tissue damage. Finally, the results' sensitivity to the diffusion coefficient of the virus is explored in detail.

Early Phase of the COVID-19 Outbreak in Hungary and Post-Lockdown Scenarios.

COVID-19 epidemic has been suppressed in Hungary due to timely non-pharmaceutical interventions, prompting a considerable reduction in the number of contacts and transmission of the virus. This strategy was effective in preventing epidemic growth and reducing the incidence of COVID-19 to low levels. In this report, we present the first epidemiological and statistical analysis of the early phase of the COVID-19 outbreak in Hungary. Then, we establish an age-structured compartmental model to explore alternative post-lockdown scenarios. We incorporate various factors, such as age-specific measures, seasonal effects, and spatial heterogeneity to project the possible peak size and disease burden of a COVID-19 epidemic wave after the current measures are relaxed.

Risk Assessment of Novel Coronavirus COVID-19 Outbreaks Outside China.

We developed a computational tool to assess the risks of novel coronavirus outbreaks outside of China. We estimate the dependence of the risk of a major outbreak in a country from imported cases on key parameters such as: (i) the evolution of the cumulative number of cases in mainland China outside the closed areas; (ii) the connectivity of the destination country with China, including baseline travel frequencies, the effect of travel restrictions, and the efficacy of entry screening at destination; and (iii) the efficacy of control measures in the destination country (expressed by the local reproduction number R loc ). We found that in countries with low connectivity to China but with relatively high R loc , the most beneficial control measure to reduce the risk of outbreaks is a further reduction in their importation number either by entry screening or travel restrictions. Countries with high connectivity but low R loc benefit the most from policies that further reduce R loc . Countries in the middle should consider a combination of such policies. Risk assessments were illustrated for selected groups of countries from America, Asia, and Europe. We investigated how their risks depend on those parameters, and how the risk is increasing in time as the number of cases in China is growing.