Three-dimensional volumetric assessment of hard tissue alterations following horizontal guided bone regeneration using a split-thickness flap design: A case series.

OBJECTIVES: To analyze morphological, volumetric, and linear hard tissue changes following horizontal ridge augmentation using a three-dimensional radiographic method. METHODS: As part of a larger ongoing prospective study, 10 lower lateral surgical sites were selected for evaluation. Horizontal ridge deficiencies were treated with guided bone regeneration (GBR) using a split-thickness flap design and a resorbable collagen barrier membrane. Following the segmentation of baseline and 6-month follow-up cone-beam computed tomography scans, volumetric, linear, and morphological hard tissue changes and the efficacy of the augmentation were assessed (expressed by the volume-to-surface ratio). RESULTS: Volumetric hard tissue gain averaged 605.32 ± 380.68 mm3. An average of 238.48 ± 127.82 mm3 hard tissue loss was also detected at the lingual aspect of the surgical area. Horizontal hard tissue gain averaged 3.00 ± 1.45 mm. Midcrestal vertical hard tissue loss averaged 1.18 ± 0.81 mm. The volume-to-surface ratio averaged 1.19 ± 0.52 mm3/mm2. The three-dimensional analysis showed slight lingual or crestal hard tissue resorption in all cases. In certain instances, the greatest extent of hard tissue gain was observed 2-3 mm apical to the initial level of the marginal crest. CONCLUSIONS: With the applied method, previously unreported aspects of hard tissue changes following horizontal GBR could be examined. Midcrestal bone resorption was demonstrated, most likely caused by increased osteoclast activity following the elevation of the periosteum. The volume-to-surface ratio expressed the efficacy of the procedure independent of the size of the surgical area.

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.

CBCT subtraction analysis of 3D changes following alveolar ridge preservation: a case series of 10 patients with 6-months follow-up.

AIM: The purpose of this article is to present a novel method for the CBCT subtraction analysis of 3D changes following alveolar ridge preservation (ARP) with the application of a semi-automatic segmentation workflow and spatial registration. The study hypothesis was that by utilizing our novel approach, better 3D visualization and improved volumetric and linear evaluations of alveolar reconstructive procedures could be achieved following ARP compared with existing methodologies. MATERIALS AND METHODS: Ten surgical sites of 10 partially edentulous patients were treated with a tunneled guided bone regeneration approach for ARP. Spatial registration and a semi-automatic segmentation method were utilized to create 3D digital models of pre- and postoperative CBCT datasets for subtraction analysis. The primary outcome variable of the study was the volumetric difference between pre- and postoperative CBCT scans. Secondary outcome variables were horizontal and vertical linear measurements at the mesial, distal, and middle aspects of the alveolus. RESULTS: Change of hard tissue volume averaged at 0.34 ± 0.99 cm3. The mean change of vertical hard tissue dimension was 5.97 ± 3.18 mm at the mesial, 6.40 ± 3.03 mm at the distal, and 7.01 ± 3.02 mm at the middle aspect of the extraction sites. Horizontal linear changes averaged at 6.19 ± 0.68 mm at the mesial, 6.32 ± 1.52 mm at the distal, and 6.90 ± 1.48 mm at the middle aspects of the extraction sites. CONCLUSION: The digital reconstruction of CBCT datasets with the presented approach may provide a better understanding of the healing mechanisms following ARP. Not only the direct effect on extraction socket healing, but also the indirect positive effect on adjacent teeth can be visualized.

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.

Loop-F of the α-subunit determines the pharmacologic profile of novel competitive inhibitors of GABAA receptors.

The neurotransmitter γ-amino butyric acid (GABA) has a fundamental role in CNS function and ionotropic (GABAA) receptors that mediate many of the actions of GABA are important therapeutic targets. This study reports the mechanism of action of novel GABAA antagonists based on a tricyclic oxazolo-2,3-benzodiazepine scaffold. These compounds are orthosteric antagonists of GABA on heteropentameric GABAA receptors of αxß2γ2 configuration expressed in HEK293 cells. In silico modelling predicted that the test compounds docked in the GABA binding-pocket and would interact with amino-acid residues in the α- and ß-subunit interface that are known to be important for the binding of GABA. Intriguingly, optimal docking also required an interaction with the non-conserved amino-terminal segment of Loop-F of the α-subunit. Testing of a compound with altered regiochemistry of the oxazolone moiety supported the model with respect to the conserved GABA-interacting residues in vitro as well as in vivo. The prediction regarding loop-F was examined by replacing the amino-terminal variable segment of loop-F of the α5-subunit with the corresponding residues in the α1- and α2-subunits. When tested with the novel inhibitors, the receptors formed by the modified α5-subunits displayed the pharmacologic phenotype of the source of loop-F. In summary, these data show that the variable amino-terminal segment of loop-F of the α-subunit determines the pharmacologic selectivity of the novel tricyclic inhibitors of GABAA receptors.

Characterizing the structural and folding properties of long-sequence hypomurocin B peptides and their analogs.

We studied the folding processes of long-sequence hypomurocin (HM) peptides and their analogs by means of molecular dynamics methods, focusing on the formation of various helical structures and intramolecular H-bonds. The evolution of different helical conformations, such as the 310 -, α-, and left-handed α-helices, was examined, taking into account the entire sequence and each amino acid of peptides. The results indicated that the HM peptides and their analogs possessed a propensity to adopt helical conformations, and they showed a preference for the 310 -helical structure over the α-helical one. The evolution of a variety of the intramolecular H-bonds, including local and non-local interactions, was also investigated. The results pointed out that on the one hand, the appearance of local, helix-stabilizing H-bonds correlated with the presence of helical conformations, and on the other hand, the non-local H-bonds did not affect significantly the formation of helical structures. Additionally, comparing the structural and folding features of HM peptides and their analogs, our study led to the observation that the L-D isomerism of isovaline amino acid induced effects on the folding processes of these long-sequence peptaibol molecules. Accordingly, the HM peptides and their analogs could be characterized by typical structural and folding properties. © 2016 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 645-657, 2016.

On the Hofmeister effect: fluctuations at the protein-water interface and the surface tension.

We performed molecular dynamics simulations on the tryptophane-cage miniprotein using a nonpolarizable force field, in order to model the effect of concentrated water solutions of neutral salts on protein conformation, which is a manifestation of Hofmeister effects. From the equilibrium values and the fluctuations of the solvent accessible surface area of the miniprotein, the salt-induced changes of the mean value of protein-water interfacial tension were determined. At 300 K, the chaotropic ClO4(-) and NO3(-) decreased the interfacial tension according to their position in the Hofmeister series (by approximately 5 and 2.7 mN/m, respectively), while the kosmotropic F(-) increased it (by 1 mN/m). These values were compared to those obtained from the Gibbs equation using the excess surface adsorption calculated from the probability distribution of the water molecules and ions around the miniprotein, and the two sets were found to be very close to each other. Our results present a direct evidence for the central role of interfacial tension and fluctuations at the protein-water interface in Hofmeister phenomena, and provide a computational method for the determination of the protein-water interfacial tension, establishing a link between the phenomenological and microscopic description of protein-water interfaces.