Karakearns2119

The intracellular tyrosine kinase inhibitor nintedanib has shown great efficacy for the treatment of idiopathic pulmonary fibrosis (IPF) and other interstitial lung diseases. However, the incidence rate of myocardial infarction (MI) among participants in landmark IPF trials was remarkable, peaking at 3/100 patient-years. Although subjects with IPF often have a high cardiovascular (CV) risk profile, the occurrence of MI in nintedanib-treated patients may not be fully explained by clustering of CV risk factors. Nintedanib inhibits the vascular endothelial growth factor, platelet-derived growth factor and fibroblast growth factor pathways, which play important roles in the biology of the atherosclerotic plaque and in the response of the heart to ischaemia. Hence, unwanted CV effects may partly account for nintedanib-related MI. We review the evidence supporting this hypothesis and discuss possible actions for a safe implementation of nintedanib in clinical practice, building on the experience with tyrosine kinase inhibitors acquired in cardio-oncology.The Baltic Sea is one of the most polluted seas in the world, with widespread eutrophication and radionuclide contamination. Using key species of the Baltic Sea, the effects of eutrophication on uptake and trophic transfer of the radioactive micronutrients commonly found in nuclear power plant effluents were investigated experimentally using the brown macroalgae Fucus vesiculosus and the grazers Idotea balthica and Theodoxus fluviatilis in a controlled environment. Rapid uptake of 54 Mn, 57 Co, and 65 Zn from water was observed in all biota; and eutrophication combined with grazing pressure strongly influenced the uptake in F. vesiculosus. Uptake of 54 Mn, 57 Co, and 65 Zn to I. balthica and T. fluviatilis grazing on F. vesiculosus were also observed. The results indicate that ecosystems could be open for further trophic transfer as radionuclides accumulate quickly in the producers and are transferred to primary consumers. Environ Toxicol Chem 2021;401694-1705. © 2021 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.The sacroiliac joint (SIJ) is a known pain generator that, in severe cases, may require surgical fixation to reduce intra-articular displacements and allow for arthrodesis. The objective of this computational study was to analyze how the number of implants affected SIJ stabilization with patient-specific characteristics such as the pelvic geometry and bone quality. Detailed finite element models were developed to account for three pelvises of differing anatomy. Each model was tested with a normal and low bone density (LD) under two types of loading compression only and compression with flexion and extension moments. These models were instrumented with one to three cylindrical, threaded and fenestrated implants through a posterior oblique trajectory, requiring less muscle dissection than the more common lateral trajectory used with triangular implants. Compared with the noninstrumented pelvis, the change in range of motion (ROM) and stress distribution were used to characterize joint stabilization. Noninstrumented mobility ranged from 0.86 to 2.55 mm and from 1.37° to 6.11°. Across patient-specific characteristics, the ROM reduction with one implant varied from 3% to 21% for vertical and 15% to 47% for angular displacements. With two implants, the ROM reduction ranged from 12% to 41% for vertical and from 28% to 61% for angular displacements. Three implants, however, did not further improve the joint stability (14% to 42% for vertical and 32% to 63% for angular displacements). With respect to patient characteristics, an LD led to a decreased stabilization and a higher volume of stressed bone (>75% of yield stress). A better understanding of how patient characteristics affect the implant performance could help improve surgical planning of sacroiliac arthrodesis.We analyzed antibody response patterns according to the level of disease severity in patients with novel coronavirus disease 2019 (COVID-19) in Japan. We analyzed 611 serum specimens from 231 patients with COVID-19 (mild, 170; severe, 31; critical, 30). Immunoglobulin M (IgM) and IgG antibodies against nucleocapsid protein (N) and spike 1 protein (S1) were detected by enzyme-linked immunosorbent assays. this website The peaks of fitting curves for the optical density (OD) values of IgM and IgG antibodies against N appeared simultaneously, while those against S1 were delayed compared with N. The OD values of IgM against N and IgG against both N and S1 were significantly higher in the severe and critical cases than in the mild cases at 11 days after symptom onset. The seroconversion rates of IgG were higher than those of IgM against both N and S1 during the clinical course based on the optimal cut-off values defined in this study. The seroconversion rates of IgG and IgM against N and S1 were higher in the severe and critical cases than in the mild cases. Our findings show that a stronger antibody response occurred in COVID-19 patients with greater disease severity and there were low seroconversion rates of antibodies against N and S1 in the mild cases.Microplastic pollution in soils is an emerging topic in the scientific community, with researchers striving to determine the occurrence and the impact of microplastics on soil health, ecology, and functionality. However, information on the microplastic contamination of soils is limited because of a lack of suitable analytical methods. Because micro-Fourier-transform infrared spectroscopy (µ-FTIR), next to Raman spectroscopy, is one of the few methods that allows the determination of the number, polymer type, shape, and size of microplastic particles, the present study addresses the challenge of purifying soil samples sufficiently to allow a subsequent µ-FTIR analysis. A combination of freeze-drying, sieving, density separation, and a sequential enzymatic-oxidative digestion protocol enables removal of the mineral mass (>99.9% dry wt) and an average reduction of 77% dry weight of the remaining organic fraction. In addition to visual integrity, attenuated total reflectance FTIR, gel permeation chromatography, and differential scanning calorimetry showed that polyamide, polyethylene, polyethylene terephthalate, and polyvinyl chloride in the size range of 100 to 400 µm were not affected by the approach. However, biodegradable polylactic acid showed visible signs of degradation and reduced molecular weight distribution after protease treatment. Nevertheless, the presented purification protocol is a reliable and robust method to purify relatively large soil samples of approximately 250 g dry weight for spectroscopic analysis in microplastic research and has been shown to recover various microplastic fibers and fragments down to a size of 10 µm from natural soil samples. Environ Toxicol Chem 2022;41844-857. © 2021 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.The reported COVID-19 cases in the United States of America have crossed over 10 million and a large number of infected cases are undetected whose estimation can be done if country-wide antibody testing is performed. In this study, we estimate this undetected fraction of the population by a modeling and simulation approach. We employ an epidemic model SIPHERD in which three categories of infection carriers, symptomatic, purely asymptomatic, and exposed are considered with different transmission rates that are taken dependent on the social distancing conditions, and the detection rate of the infected carriers is taken dependent on the tests done per day. The model is first validated for Germany and South Korea and then applied for prediction of the total number of confirmed, active and dead, and daily new positive cases in the United States. Our study predicts the possible outcomes of the infection if social distancing conditions are relaxed or kept stringent. We estimate that around 30.1 million people are already infected, and in the absence of any vaccine, 66.2 million (range 64.3-68.0) people, or 20% (range 19.4-20.5) of the population will be infected by mid-February 21 if social distancing conditions are not made stringent. We find the infection-to-fatality ratio to be 0.65% (range 0.63-0.67).Tegaserod, a gastroprokinetic agent, is used to treat irritable bowel syndrome. Despite its extensive clinical use, little is known about the effects of tegaserod on vascular ion channels, especially K+ channels. Therefore, we examined the effects of tegaserod on voltage-gated K+ (Kv) channels in rabbit coronary arterial smooth muscle cells using the whole-cell patch-clamp technique. Tegaserod inhibited Kv channels in a concentration-dependent manner with an IC50 value of 1.26 ± 0.31 µmol/L and Hill coefficient of 0.81 ± 0.10. Although tegaserod had no effect on the steady-state activation curves of the Kv channels, the steady-state inactivation curve was shifted toward a more negative potential. These results suggest that tegaserod inhibits Kv channels by influencing their voltage sensors. The recovery time constant of channel inactivation was extended in the presence of tegaserod. Furthermore, application of train steps (1 and 2 Hz) in the presence of tegaserod progressively increased the inhibition of Kv currents suggesting that tegaserod-induced Kv channel inhibition is use (state)-dependent. Pretreatment with a Kv1.5 subtype inhibitor suppressed the Kv current. However, additional application of tegaserod did not induce further inhibition. Pretreatment with a Kv2.1 or Kv7 inhibitor did not affect the inhibitory effect of tegaserod on Kv channels. Based on these results, we conclude that tegaserod inhibits vascular Kv channels in a concentration- and use (state)-dependent manner independent of its own functions. Furthermore, the major Kv channel target of tegaserod is the Kv1.5 subtype.We highlight a recent study exploring the hand-off of UV damage to several key nucleotide excision repair (NER) proteins in the cascade UV-DDB, XPC and TFIIH. The delicate dance of DNA repair proteins is choreographed by the dynamic hand-off of DNA damage from one recognition complex to another damage verification protein or set of proteins. These DNA transactions on chromatin are strictly chaperoned by post-translational modifications (PTM). This new study examines the role that ubiquitylation and subsequent DDB2 degradation has during this process. In total, this study suggests an intricate cellular timer mechanism that under normal conditions DDB2 helps recruit and ubiquitylate XPC, stabilizing XPC at damaged sites. If DDB2 persists at damaged sites too long, it is turned over by auto-ubiquitylation and removed from DNA by the action of VCP/p97 for degradation in the 26S proteosome.Nonresident mothers who formally pay child support are becoming increasingly prevalent. If the profile of female payers differs from that of men or if their payment is motivated differently, existing gender-based child support policies and enforcement strategies face significant challenges. This study uses the payment framework of male compliance to map the differences between male and female payers of child support. The analysis applies discriminant analysis to a combination of register and fiscal data of separated parents. Whereas the separate aspects of the payment framework did not reach the threshold for acceptable discrimination, the full model revealed considerable differences between male and female payers. The aspect of willingness to pay showed the greatest discriminating power, suggesting that paying mothers have a higher willingness to do so than fathers. We conclude that while the discrepancies between nonresident mothers and fathers who pay child support can be partly attributed to demographic differences and residency patterns of children, differing motivations are also of importance.