Modeling the COVID-19 epidemic in Croatia: a comparison of three analytic approaches

AimTo facilitate the development of a COVID-19 predictive model in Croatia by analyzing three different methodological approaches.MethodWe used the historical data to explore the fit of the extended SEIRD compartmental model, the Heidler function, an exponential approximation in analyzing electromagnetic phenomena related to lightning strikes, and the Holt-Winters smoothing (HWS) for short-term epidemic predictions. We also compared various methods for the estimation of R0.ResultsThe R0 estimates for Croatia varied from 2.09 (95% CI 1.77-2.40) obtained by using an empirical post-hoc method to 2.28 (95% CI 2.27-2.28) when we assumed an exponential outbreak at the very beginning of the COVID-19 epidemic in Croatia. Although the SEIRD model provided a good fit for the early epidemic stages, it was outperformed by the Heidler function fit. HWS achieved accurate short-term predictions and depended the least on model entry parameters. Neither model performed well across the entire observed period, which was characterized by multiple wave-form events, influenced by the re-opening for the tourist season during the summer, mandatory masks use in closed spaces, and numerous measures introduced in retail stores and public places. However, an extension of the Heidler function achieved the best overall fit.ConclusionsPredicting future epidemic events remains difficult because modeling relies on the accuracy of the information on population structure and micro-environmental exposures, constant changes of the input parameters, varying societal adherence to anti-epidemic measures, and changes in the biological interactions of the virus and hosts.

Epidemiological modeling is one of the main tools in infectious disease epidemic management. The recent COVID-19 pandemic is no exception, despite the prevalent neglect of evidence-based medicine principles (1,2). One of the most commonly used tools for epidemiological modeling are compartmental models, which assume that the dynamics of an epidemic depends on several discrete states, including susceptible, infected, and recovered status (3). The main advantage of these models includes the possibility of predicting the overall epidemic pattern, and their main limitation is heavy dependence on the input parameters (4,5). Numerous other approaches have been used for this purpose, relying on exploring historical patterns in predicting future events (6). The main disadvantage of such models is dependence on the initial parameters and the inability to capture the timely and relevant information in the population, which raises the need for reliable predictive tools that depend less on the starting assumptions.Therefore, we aimed to compare various methodological approaches to epidemic prediction, with a particular focus on the performance of methods that do not require numerous inputs and rely less on the initial assumptions.     

Effect of Withania somnifera root extract on haloperidol-induced catalepsy in albino mice

The objective of the study was to evaluate the anticataleptic effect of Withania somnifera (WS) extract, on haloperidol-induced catalepsy in albino mice. Catalepsy was induced with haloperidol (1 mg/kg) i.p. in five groups of male albino mice (n = 6). Three groups received Withania somnifera extract (1.7, 4.25, 8.5 mg/kg) respectively, one group received scopolamine (1 mg/kg) and one group received the vehicle (1% gum acacia) orally, 30 min prior to haloperidol administration. Catalepsy was measured by using standard bar test at 30, 60, 90, 120 and 240 min. This constituted the acute study. For the chronic study, the drugs were administered for 6 more days. Catalepsy was again measured on day 7. Animals were then sacrificed by cervical dislocation and superoxide dismutase (SOD) activity was estimated in the brain. In this study, Withania somnifera extract treated groups showed a dose dependent reduction in cataleptic scores, both in the acute and chronic study. The SOD activity in brain was also found to be lowered in the WS (4.25 mg, 8.5 mg/kg) treated groups. In conclusion, Withania somnifera was found to be more efficacious than scopolamine in reversing haloperidol induced catalepsy. A clear correlation between the SOD levels and cataleptic scores was observed. We believe that the antioxidant properties of this drug could have contributed to the anticataleptic effect.     

Rational design of large flat nitrogen-doped graphene oxide quantum dots with green-luminescence suitable for biomedical applications

Rational synthesis and simple methodology for the purification of large (35–45 nm in lateral size) and flat (1.0–1.5 nm of height) nitrogen-doped graphene oxide quantum dots (GOQDs) are presented. The methodology allows robust metal-free and acid-free preparation of N-GOQDs with a yield of about 100% and includes hydrothermal treatment of graphene oxide with hydrogen peroxide and ammonia. It was demonstrated that macroscopic impurities can be separated from N-GOQD suspension by their coagulation with 0.9% NaCl solution. Redispersible in water and saline solutions, particles of N-GOQDs were characterized using tip-enhanced Raman spectroscopy (TERS), photoluminescent, XPS, and UV-VIS spectroscopies. The size and morphology of N-GOQDs were studied by dynamic light scattering, AFM, SEM, and TEM. The procedure proposed allows nitrogen-doped GOQDs to be obtained, having 60–51% of carbon, 34–45% of oxygen, and up to 7.2% of nitrogen. The N-GOQD particles obtained in two hours of synthesis contain only pyrrolic defects of the graphene core. The fraction of pyridine moieties grows with the time of synthesis, while the fraction of quaternary nitrogen declines. Application of TERS allows demonstration that the N-GOQDs consist of a graphene core with an average crystallite size of 9 nm and an average distance between nearest defects smaller than 3 nm. The cytotoxicity tests reveal high viability of the monkey epithelial kidney cells Vero in the presence of N-GOQDs in a concentration below 60 mg L⁻¹. The N-GOQDs demonstrate green luminescence with an emission maximum at 505 nm and sedimentation stability in the cell culture medium.

This paper reveals the methodology for robust preparation of purified nitrogen-doped graphene oxide quantum dots with non-cytotoxic activity against monkey epithelial kidney cells (Vero ATCC® CCL-81™).     

Graphene oxide quantum dots immobilized on mesoporous silica: preparation,characterization and electroanalytical application

Because of its high surface area and combination of various functional groups, graphene oxide (GO) is currently one of the most actively studied materials for electroanalytical applications. It is not practical to utilize self-supported GO on its own and thus it is commonly integrated with different supporting carriers. Having a large lateral size, GO can only wrap the particles of the support and thus can significantly reduce the surface area of porous materials. To achieve synergy from the high surface area and polyfunctional nature of GO, and the rigid structure of a porous support, the lateral size of GO must essentially be decreased. Recently reported graphene oxide quantum dots (GOQDs) can fulfil this task. Here we report the successful preparation of an SiO₂-GOQDs hybrid, where GOQDs have been incorporated into the mesoporous network of silica. The SiO₂-GOQDs emit a strong luminescence with a band maximum at 404 nm. The Raman spectrum of SiO₂-GOQDs shows two distinct peaks at 1585 cm⁻¹ (G-peak) and 1372 cm⁻¹ (D-peak), indicating the presence of a graphene ordered basal plane with aromatic sp²-domains and a disordered oxygen-containing structure. Covalent immobilization of GOQDs onto aminosilica via such randomly structured oxygen fragments was proven with the help of Fourier transform infrared spectroscopy, solid-state cross-polarization magic angle spinning ¹³C nuclear magnetic resonance, and X-ray photoelectron spectroscopy. SiO₂-GOQDs were used as a modifier of a carbon paste electrode for differential pulse voltammetry determination of two antibiotics (sulfamethoxazole and trimethoprim) and two endocrine disruptors (diethylstilbestrol (DES) and estriol (EST)). The modified electrodes demonstrated a significant signal enhancement for EST (370%) and DES (760%), which was explained by a π–π stacking interaction between GOQDs and the aromatic system of the analytes.

Graphene oxide quantum dots incorporated into a mesoporous silica network have been used as a modifier of a carbon paste electrode for the determination of antibiotics and hormones.     

Redirecting intracellular trafficking and the secretion pattern of FSH dramatically enhances ovarian function in mice

FSH and luteinizing hormone (LH) are secreted constitutively or in pulses, respectively, from pituitary gonadotropes in many vertebrates, and regulate ovarian function. The molecular basis for this evolutionarily conserved gonadotropin-specific secretion pattern is not understood. Here, we show that the carboxyterminal heptapeptide in LH is a gonadotropin-sorting determinant in vivo that directs pulsatile secretion. FSH containing this heptapeptide enters the regulated pathway in gonadotropes of transgenic mice, and is released in response to gonadotropin-releasing hormone, similar to LH. FSH released from the LH secretory pathway rescued ovarian defects in Fshb-null mice as efficiently as constitutively secreted FSH. Interestingly, the rerouted FSH enhanced ovarian follicle survival, caused a dramatic increase in number of ovulations, and prolonged female reproductive lifespan. Furthermore, the rerouted FSH vastly improved the in vivo fertilization competency of eggs, their subsequent development in vitro and when transplanted, the ability to produce offspring. Our study demonstrates the feasibility to fine-tune the target tissue responses by modifying the intracellular trafficking and secretory fate of a pituitary trophic hormone. The approach to interconvert the secretory fate of proteins in vivo has pathophysiological significance, and could explain the etiology of several hormone hyperstimulation and resistance syndromes.During vertebrate evolution, the female reproductive pattern underwent a remarkable transition from spawning of large number of eggs in primitive species under favorable conditions to more tightly controlled ovarian cycles in higher vertebrates, such that only a limited number (rodents) or a single (human and nonhuman primates) egg is released per cycle (1, 2). Coincident with this event, the single pituitary gonadotropic hormone that exists in primitive vertebrates has given rise to two gonadotropins, FSH and luteinizing hormone (LH), which coordinate gametogenesis and steroidogenesis (3–7). FSH and LH are heterodimeric glycoproteins that contain a common α-subunit and a hormone-specific β-subunit (3). Although synthesized in the same cell, the gonadotrope, FSH is mostly constitutively released in many species, whereas LH is stored in dense core granules (DCGs) and secreted in pulses via the regulated pathway in response to gonadotropin-releasing hormone (GnRH) (8, 9). Although this pattern is evolutionarily conserved, how distinct modes of gonadotropin secretion affect ovarian development and target cell responses remain unclear. Although models in which variations in secretion of gonadotropins have been achieved in vivo (10) and in vitro, including basolateral and apically polarized secretion (11), the in vivo consequences of altered mode of gonadotropin trafficking and release (constitutive vs. regulated) from pituitary are untested. We sought to identify why the two gonadotropins, LH and FSH, expressed in the same pituitary cell have evolved to exit via different routes to regulate ovarian physiology.     

Toll‐like receptor 4 signaling regulates the acute local inflammatory response to injury and the fibrosis/neovascularization of sterile wounds

The role of Toll‐like receptor 4 (TLR4) in the regulation of inflammation and fibrosis in sterile wounds was investigated in TLR4 signal‐deficient (C3H/HeJ or TLR4^?/?) and control mice using the subcutaneously implanted polyvinyl alcohol sponge wound model. Total and differential wound cell counts 1, 3, and 7 days after injury did not differ between C3H/HeJ and C3H/HeOuJ animals. Blood monocytes from both strains expressed CCR2 equally. Day one wounds in C3H/HeJ mice contained fewer Gr‐1^high wound macrophages, CCL3, and CCL5, and more CCL17 than those in controls. The accumulation of CCL2, CX3CL1, tumor necrosis factor‐α, interleukin (IL)‐6, IL‐10, IL‐12, and interferon‐γ in wound fluids was not TLR4 dependent. Wound macrophages from C3H/HeJ and C3H/HeOuJ mice expressed CCR4 and CCR5, but not CCR1 or CCR3. Wound macrophage recruitment was not altered in CCR5^?/? mice or in C3H/HeOuJ animals injected with neutralizing anti‐CCL3 and anti‐CCL5 antibodies. Neutralization of the CCR4 ligand CCL17 in C3H/HeJ mice did not alter wound macrophage populations. There was a twofold increase in collagen content and number of neovessels in 21‐day‐old wounds in C3H/HeJ vs. C3H/HeOuJ mice. There were no differences between strains in the number of myofibroblasts in the wounds 7 or 21 days postwounding. The increased fibrosis and angiogenesis in wounds from /HeJ mice correlated with higher concentrations of transforming growth factor‐β and fibroblast growth factor 2 in wound fluids from these animals. Wound fluids did not contain detectable lipopolysaccharide and did not induce IκBα degradation in J774.A1 macrophages. Results support a role for endogenous ligands of TLR4 in the regulation of inflammation and repair in sterile wounds.     

Dieulafoy’s disease of the lung: a report of three cases with review of pathological aspects

Dieulafoy’s disease of the lung is one of the causes of cryptogenic hemoptysis often massive and recurrent, caused by dysplastic superficially located arteries in the bronchial wall. Being a rare condition, available literature on this condition is limited to a few case reports and series. We report three such cases presenting with severe hemoptysis uncontrolled by bronchial artery embolization who subsequently underwent resection of the involved lobe of the lung. The clinical, radiological, bronchoscopic, and pathological features are discussed with emphasis on the gross and microscopic characteristics that aid in the pathological diagnosis in the resected specimens.     

Study of the Hydrolytic Stability of Fine-Grained Ceramics Based on Y2.5Nd0.5Al5O12 Oxide with a Garnet Structure under Hydrothermal Conditions

The hydrolytic stability of ceramics based on Y_2.5Nd_0.5Al₅O₁₂ oxide with a garnet structure obtained by the spark plasma sintering (SPS) method has been studied. The tests were carried out in distilled water under hydrothermal conditions in an autoclave and, for comparison, in a static mode at room temperature. The mechanism of leaching of Y and Nd from the ceramics was investigated. It has been shown that at “low” temperatures (25 and 100 °C), the destruction of pores occured, and the intensity of the leaching process was limited by the diffusion of ions from the inner part of the sample to the surface. At “high” test temperatures (200 and 300 °C), intense destruction of the ceramic grain boundaries was observed. It was assumed that the accelerated leaching of neodymium is due to the formation of grain-boundary segregations of Nd³⁺ in sintered ceramics.