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The production of staple articles such as cable ducts offers reductions in resource and production energy consumption if the process is optimized. Side recesses made of polyvinyl chloride (PVC) have already been punched successfully as one of the process steps during the production of cable ducts. However, punching cable ducts made of flame-retardant polycarbonate/acrylonitrile–butadiene–styrene (PC/ABS) is challenging because increased burr and film formation occurs. This study introduces the correct dimensioning of the clearance as a means of reducing the burr and film formation and presents the ideal clearance dimensions. This new process design approach comprises the dimensioning of the clearance and its subsequent successful application. Tools with clearances in the relevant size range were purchased and examined by means of punching tests. The punch-outs were evaluated regarding the quality characteristics, such as the burr, film, cut surface quality, shear droop, and plastic flow characteristics. Excerpts from high-speed recordings were used to assess the punch-outs qualitatively. The burr formation is significantly decreased by the use of a correctly dimensioned clearance, allowing for the crack initiated at the punch side and the crack initiated at the die side to meet perfectly. It is assumed that film formation can be avoided via a significant reduction in the friction or heat input during the punching process.

Graphene-based materials (GBMs) have promising applications in various sectors, including pulmonary nanomedicine. Nevertheless, the influence of GBM physicochemical characteristics on their fate and impact in lung has not been thoroughly addressed. To fill this gap, the biological response, distribution, and bio-persistence of four different GBMs in mouse lungs up to 28 days after single oropharyngeal aspiration are investigated. None of the GBMs, varying in size (large versus small) and carbon to oxygen ratio as well as thickness (few-layers graphene (FLG) versus thin graphene oxide (GO)), induce a strong pulmonary immune response. However, recruited neutrophils internalize nanosheets better and degrade GBMs faster than macrophages, revealing their crucial role in the elimination of small GBMs. In contrast, large GO sheets induce more damages due to a hindered degradation and long-term persistence in macrophages. Overall, small dimensions appear to be a leading feature in the design of safe GBM pulmonary nanovectors due to an enhanced degradation in phagocytes and a faster clearance from the lungs for small GBMs. Thickness also plays an important role, since decreased material loading in alveolar phagocytes and faster elimination are found for FLGs compared to thinner GOs. These results are important for designing safer-by-design GBMs for biomedical application.

Cystic fibrosis (CF) has been linked to altered drug disposition in various studies. However, the magnitude of these changes, influencing factors, and underlying mechanisms remain a matter of debate. The primary aim of this work was therefore to quantify changes in drug disposition (top-down) and the pathophysiological parameters known to affect pharmacokinetics (PKs; bottom-up). This was done through meta-analyses and meta-regressions in addition to theoretical PK simulations. Volumes of distribution and clearances were found to be elevated in people living with CF. These increases were larger in studies which included patients with pulmonary exacerbations. Differences in clearance were smaller in more recent studies and when results were normalized to body surface area or lean body mass instead of body weight. For the physiological parameters investigated, measured glomerular filtration rate and serum cytokine concentrations were found to be elevated in people living with CF, whereas serum albumin and creatinine levels were decreased. Possible pathophysiological mechanisms for these alterations relate to renal hyperfiltration, increases in free fraction, and inflammation. No differences were detected for cardiac output, body fat, fat free mass, hematocrit, creatinine clearance, and the activity of drug metabolizing enzymes. These findings imply that, in general, lower total plasma concentrations of drugs can be expected in people living with CF, especially when pulmonary exacerbations are present. Given the potential effect of CF on plasma protein binding and the variability in outcome observed between studies, the clinical relevance of adapting existing dosage regimens should be evaluated on a case-by-case basis.

Photothermal therapy has the characteristics of minimal invasiveness, controllability, high efficiency, and strong specificity, which can effectively make up for the toxic side effects and tumor resistance caused by traditional drug treatment. However, due to the limited tissue penetration of infrared light, it is difficult to promote and apply in clinical practice. The eye is the only transparent tissue in human, and infrared light can easily penetrate the eye tissue, so it is expected that photothermal therapy can be used to treat fundus diseases. Here in, a new nano-platform assembled by liposome and indocyanine green (ICG) was used to treat retinoblastoma. ICG was assembled in liposomes to overcome some problems of ICG itself. For example, ICG is easily quenched, self-aggregating and instability. Moreover, liposomes can prevent free ICG from being cleared through the systemic circulation. The construction of the nano-platform not only ensured the stability of ICG in vivo, but also realized imaging-guided photothermal therapy, which created a new strategy for the treatment of retinoblastoma.

Angular contact ball bearings are common basic components in rotating machinery. During the operation of the bearing, the rolling slips, resulting in contact sliding friction between it and the raceway, which in turn causes wear in the rolling element and increase in the radial clearance of the bearing. The increase in clearance also affects the stiffness of the bearing, which in turn affects the natural frequency and fatigue life of the bearing. At present, there are few studies on the influence of bearing wear (variation of clearance) on life. In this paper, the finite element model based on the theory of contact mechanics is established for the angular contact ball bearing with medium- and high-speed rotation, and the mechanical properties and fatigue life influenced by the internal action of the bearing are analyzed. The effects of radial load and deflection angle on the mechanical properties and fatigue life of the bearing are also studied. Based on the analysis results of bearing contact mechanical properties and clearance changes, the calculation method of bearing life under rolling element wear is established. The influence of the variation of clearance and preload clearance on bearing life is analyzed, and the optimal preload is obtained. The research results of this paper can provide a theoretical basis for optimizing the installation of angular contact ball bearings, reasonably determining the service conditions, and prolonging the service life of bearings, which is necessary for engineering practice.

The discovery that genetic variation within the interferon lambda locus has a profound effect on the outcome of hepatitis C virus (HCV) treatment and spontaneous clearance of HCV is one of the great triumphs of genomic medicine. Subsequently, the IFNL4 gene was discovered and proposed as the causal gene underlying this association. However, there has been a lively debate within the field concerning the causality, which has been further complicated by a change in naming. This review summarizes the genetic data available for the IFNL3/IFNl4 loci and provides an in-depth discussion of causality. We also discuss a new series of interesting data suggesting that the genetic variation at the IFNL4 loci influences the evolution of the HCV virus and the implication this relationship between our genetic makeup and virus evolution has upon our understanding of the IFNL4 system. Finally, new data support an influence of the IFNL4 gene upon liver inflammation and fibrosis that is independent of etiology, thereby linking the IFNL4 gene to some of the major liver diseases of today.

Animal pharmacokinetic (PK) data as well as human and animal in vitro systems are utilized in drug discovery to define the rate and route of drug elimination. Accurate prediction and mechanistic understanding of drug clearance and disposition in animals provide a degree of confidence for extrapolation to humans. In addition, prediction of in vivo properties can be used to improve design during drug discovery, help select compounds with better properties, and reduce the number of in vivo experiments. In this study, we generated machine learning models able to predict rat in vivo PK parameters and concentration-time PK profiles based on the molecular chemical structure and either measured or predicted in vitro parameters. The models were trained on internal in vivo rat PK data for over 3000 diverse compounds from multiple projects and therapeutic areas, and the predicted endpoints include clearance and oral bioavailability. We compared the performance of various traditional machine learning algorithms and deep learning approaches, including graph convolutional neural networks. The best models for PK parameters achieved R2 = 0.63 [root mean squared error (RMSE) = 0.26] for clearance and R2 = 0.55 (RMSE = 0.46) for bioavailability. The models provide a fast and cost-efficient way to guide the design of molecules with optimal PK profiles, to enable the prediction of virtual compounds at the point of design, and to drive prioritization of compounds for in vivo assays.

Zolpidem is a non-benzodiazepine agonist at the benzodiazepine binding site in GABAA receptors. It is a hypnotic agent which has been shown to be effective in inducing and maintaining sleep in adults and is one of the most frequently prescribed hypnotics in the world. This study aimed to perform an in silico study to assess both EMA and FDA positions on the dose adjustment of Zolpidem based on sex. Both agencies based their position on clinical studies but endorsed different approaches to the need for dose adjustments between men and females. Clinical studies of Zolpidem tablets in single-and multiple-dose regimens were gathered and digitized from the literature. The collected profiles were used for model building, evaluation, and simulation. A 2-compartment model with first-order absorption, lag-time, and linear elimination best described the data. To minimize bias, the distribution of data on females and males were balanced, comprising, respectively, four and eight patients. Simulation of dose regimen comparing the efficacy and safety of 10 and 12.5 mg zolpidem tablets showed that with the 10 mg tablets there was a 69% chance of being more efficient for an individual of the population simulated, for the selected dose of regimen, while the 12.5 mg tablet there was only a 42% chance of being more efficient. Moreover, the safety target for 12.5 mg was very low, with only a 14% of chance of being a safe treatment for an individual of this population. Based on these differences, this study compared the results gathered in simulations with the rationale behind EMA and FDA positions. It is very important that all health care professionals and patients have access to the same and most up-to-date safety and efficacy information, especially in this situation where the discussion focuses on the same active substance, same formulations, same treatment indications, and same target populations.

Athletes performing sports on high level are at increased risk for sudden cardiac death. This includes paediatric athletes, even though data on screening strategies in this age group remain scarce. This study aimed to assess electrocardiogram interpretation criteria in paediatric athletes and to evaluate the cost of screening. National, multicentre, retrospective, observational study on 891 athletes of paediatric age (

Summary: Purpose: Carbamazepine (CBZ)-evoked liver-injury is multifaceted and can be serious. Specific drug-antidote versus CBZ's hepatotoxicity has been absent. The effects of omega(ω)-3-FAs (Eicosapentaenoic acid, EPA, and Docosahexaenoic acid, DHA), on CBZ-toxicity, and possibly-involved mechanisms, have remained unknown. Here, we investigated whether and, how then, two-ω-3-FAs (DHA/EPA) may alleviate CBZ's hepatotoxicity, relieve the disrupted organelles of liver, and possibly alter CBZ-plasma levels. Methods: Rats were treated with CBZ (100 mg/kg orally, daily) for 1-2-weeks in the presence-and-absence of DHA (EPA). Biochemical-markers of hepatotoxicity (ALT, Albumin, ALP, γ-GT), oxidative-stress (MDA, GSH, TAC) and inflammation (IL-6, TNF-α, CRP) were assessed at one-week-intervals. Further, pharmacokinetic-studies assessed plasma-CBZ levels, with/without co-administered-ω-3-FAs, with immunoassays. Liver-histopathological sections were examined and correlated with functional and biochemical-markers. Results: either of the ω-3-FAs, DHA or EPA, in a rank-order of potency, significantly abolished all liver injury-markers, for oxidative-stress and inflammation. Kinetic-immunoassays revealed no interaction of DHA with serum-CBZ-levels. However, EPA significantly-increased CBZ-level than control. Histopathological-studies revealed only minimal portal inflammation with DHA. EPA, also, elicited additional degenerative-changes in the surrounding hepatocytes. Conclusions: ω-3-FAs mitigated CBZ-induced liver-toxicity by suppressing oxidative-stress and inflammation, without altering of its clearance, (DHA). EPA evoked a rise of plasma-CBZ levels and inferior-liver protection than DHA. Histopathological assessment showed ω-3-FAs to also protect liver-integrity and its organelles, thereby implying a fruitful therapeutic-regimen with CBZ.

The blood-brain barrier significantly limits effective drug delivery to central nervous system (CNS) targets. The recently characterized glymphatic system offers a perivascular highway for intrathecally (i.t.) administered drugs to reach deep brain structures. Although periarterial cerebrospinal fluid (CSF) influx and concomitant brain drug delivery can be enhanced by pharmacological or hyperosmotic interventions, their effects on drug delivery to the spinal cord, an important target for many drugs, have not been addressed. Hence, we studied in rats whether enhancement of periarterial flow by systemic hypertonic solution might be utilized to enhance spinal delivery and efficacy of i.t. morphine. We also studied whether the hyperosmolar intervention affects brain or cerebrospinal fluid drug concentrations after systemic administration. Periarterial CSF influx was enhanced by intraperitoneal injection of hypertonic saline (HTS, 5.8%, 20 ml/kg, 40 mOsm/kg). The antinociceptive effects of morphine were characterized, using tail flick, hot plate and paw pressure tests. Drug concentrations in serum, tissue and microdialysis samples were determined by liquid chromatography-tandem mass spectrometry. Compared with isotonic solution, HTS increased concentrations of spinal i.t. administered morphine by 240% at the administration level (T13-L1) at 60 min and increased the antinociceptive effect of morphine in tail flick, hot plate, and paw pressure tests. HTS also independently increased hot plate and paw pressure latencies but had no effect in the tail flick test. HTS transiently increased the penetration of intravenous morphine into the lateral ventricle, but not into the hippocampus. In conclusion, acute systemic hyperosmolality is a promising intervention for enhanced spinal delivery of i.t. administered morphine. The relevance of this intervention should be expanded to other i.t. drugs and brought to clinical trials.

Antiglycoprotein (anti-GP) antibodies play an important role in the pathophysiology of immune thrombocytopenia (ITP). The sequestration pattern of platelets in the spleen and liver can be studied with 111In-labeled autologous platelet scans. No studies have investigated the role of anti-GP antibodies in sequestration patterns in ITP patients. In this study, we examined the association between antibodies and (1) platelet sequestration site and (2) clearance rate of platelets. All ITP patients receiving an 111In-labeled autologous platelet study between 2014 and 2018 were included. Antibodies were measured using the direct MAIPA method to determine the presence and titer of anti-GPIIb/IIIa, anti-GPIb/IX, and anti-GPV antibodies. Multivariate regression models were used to study the association between anti-GP antibodies, sequestration site, and clearance rate. Seventy-four patients were included, with a mean age of 36 years. Forty-seven percent of the patients showed a predominantly splenic sequestration pattern, 29% mixed, and 25% a hepatic pattern. In 53% of the patients, anti-GP antibodies were detected. Regression models showed a significant association between splenic sequestration and GPV autoantibodies. Furthermore, in patients where antibodies were present, the clearance rate was higher in patients with a splenic sequestration. Anti-GPV antibodies are associated with a splenic sequestration pattern in ITP patients. These associations provide insight into the possible pathophysiological mechanisms of ITP, which may lead to better detection and treatment of this partly idiopathic and prevalent disease.

Existing international studies consistently report increased numbers of pedestrian and cyclist falls in the winter months, particularly in icy/snowy conditions. Until now, reliable information on the factors contributing to these falls has been rare. This study investigates possible correlates of pedestrian and cyclist falls in icy/snowy conditions in Germany and takes into consideration factors such as behavior and surface conditions with the aim to develop recommendations for improving safety for vulnerable road users. As part of this study, 3,300 people in online surveys and 2,100 in field surveys were asked about their experiences and opinions in relation to icy/snowy conditions and winter maintenance. Of those surveyed, 1,100 pedestrians and 2,200 cyclists also reported details about their most recent fall within the last five years. Furthermore, the behavior of 7,000 pedestrians and 4,500 cyclists was observed with cameras in both snowy and other weather conditions. The presence of snow/ice itself was indicated as a reason for three quarters of pedestrian and two thirds of cyclist falls in snowy/icy conditions. For nearly all of the falls in snowy/icy conditions, surfaces were reported as poorly cleared or not cleared at all. Compared to other weather more pedestrians fell on sidewalks and less while crossing the street during snowy and icy conditions. Cyclists increased their speed on downhill sidewalks in dry conditions and reduced their speed in snowy conditions compared to flat or uphill sidewalks. Most cyclists chose to cycle on sidewalks instead of their own dedicated, but not maintained, facilities (even though they are obliged by law to cycle on the carriageway in such cases). In snowy/icy conditions, 5 % of pedestrians varied their pace or step sequence and 8 % of cyclists drove "wavy lines" or made obvious corrective steering movements, particularly on poorly maintained facilities (compared to very few of such observations in other weather conditions). Half of the respondents rated the winter maintenance at pedestrian facilities to be good and three quarters rated the maintenance at public transport stops as good. In contrast, only 12 % rated winter maintenance on cycling facilities as good. Reasons for not being satisfied included poor quality, delay and insufficient frequency of cleaning as well as the type of grit used. The lack of seamless reliably-cleaned cycle routes was listed as a major problem by most respondents. More than 50 % claimed that previously cleaned pedestrian or cyclist facilities were re-covered with snow from clearing the carriageway.

BACKGROUND AND OBJECTIVE: Fentanyl is an opioid commonly used to prevent and treat severe pain in neonates; however, its use is off label and mostly based on bodyweight. Given the limited pharmacokinetic information across the entire neonatal age range, we characterized the pharmacokinetics of fentanyl across preterm and term neonates to individualize dosing. METHODS: We pooled data from two previous studies on 164 newborns with a median gestational age of 29.0 weeks (range 23.9-42.3), birthweight of 1055 g (range 390-4245), and postnatal age (PNA) of 1 day (range 0-68). In total, 673 plasma samples upon bolus dosing (69 patients; median dose 2.1 μg/kg, median 2 boluses per patient) or continuous infusions (95 patients; median dose 1.1 μg/kg/h for 30 h) with and without boluses were used for population pharmacokinetic modeling in NONMEM® 7.4. RESULTS: Clearance in neonates with birthweight of 2000 and 3000 g was 2.8- and 5.0-fold the clearance in a neonate with birthweight of 1000 g, respectively. Fentanyl clearance at PNA of 7, 14, and 21 days was 2.7-fold, 3.8-fold, and 4.6-fold the clearance at 1 day, respectively. Bodyweight-based dosing resulted in large differences in fentanyl concentrations. Depending on PNA and birthweight, fentanyl concentrations increased slowly after the start of therapy for both intermittent boluses and continuous infusion and reached a maximum concentration at 12-48 h. CONCLUSIONS: As both prenatal and postnatal maturation are important for fentanyl exposure, we propose a birthweight- and PNA-based dosage regimen. To provide rapid analgesia in the first 24 h of treatment, additional loading doses need to be considered. ispartof: CLINICAL PHARMACOKINETICS vol:61 issue:3 pages:401-412 ispartof: location:Switzerland status: published

Perivascular spaces (PVS) are compartments surrounding cerebral blood vessels that become visible on MRI when enlarged. Enlarged PVS (EPVS) are commonly seen in patients with cerebral small vessel disease (CSVD) and have been suggested to reflect dysfunctional perivascular clearance of soluble waste products from the brain. In this study, we investigated histopathological correlates of EPVS and how they relate to vascular amyloid-beta (A beta) in cerebral amyloid angiopathy (CAA), a form of CSVD that commonly co-exists with Alzheimer's disease (AD) pathology. We used ex vivo MRI, semi-automatic segmentation and validated deep-learning-based models to quantify EPVS and associated histopathological abnormalities. Severity of MRI-visible PVS during life was significantly associated with severity of MRI-visible PVS on ex vivo MRI in formalin fixed intact hemispheres and corresponded with PVS enlargement on histopathology in the same areas. EPVS were located mainly around the white matter portion of perforating cortical arterioles and their burden was associated with CAA severity in the overlying cortex. Furthermore, we observed markedly reduced smooth muscle cells and increased vascular A beta accumulation, extending into the WM, in individually affected vessels with an EPVS. Overall, these findings are consistent with the notion that EPVS reflect impaired outward flow along arterioles and have implications for our understanding of perivascular clearance mechanisms, which play an important role in the pathophysiology of CAA and AD.

After almost a decade of using CRISPR/Cas9 systems to edit target genes, CRISPR/Cas9 and related technologies are rapidly moving to clinical trials. Hepatitis B virus (HBV), which causes severe liver disease, cannot be cleared by modern antivirals, but represents an ideal target for CRISPR/Cas9 systems. Early studies demonstrated very high antiviral potency of CRISPR/Cas9 and supported its use for developing a cure against chronic HBV infection. This review discusses the key issues that must be solved to make CRISPR/Cas9 an anti-HBV therapy.

Anna Kastelik-Hryniewiecka,1,2 Pawel Jewula,3 Karolina Bakalorz,1 Gabriela Kramer-Marek,2,4 Nikodem Kuźnik1 1Silesian University of Technology, Faculty of Chemistry, Gliwice, Poland; 2Radiopharmacy and Preclinical PET Imaging Unit, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice, Poland; 3Central European Institute of Technology, Brno University of Technology, Brno, Czech Republic; 4Division of Radiotherapy and Imaging, The Institute of Cancer Research, London, UKCorrespondence: Nikodem Kuźnik; Gabriela Kramer-Marek Tel +48 694 22 00 77; +44 208 722 4412Fax +48 32 237 13 08; +44 207 370 5261Email nikodem.kuznik@polsl.pl; Gabriela.Kramer-Marek@icr.ac.ukAbstract: Recently, the demand for hybrid PET/MRI imaging techniques has increased significantly, which has sparked the investigation into new ways to simultaneously track multiple molecular targets and improve the localization and expression of biochemical markers. Multimodal imaging probes have recently emerged as powerful tools for improving the detection sensitivity and accuracy—both important factors in disease diagnosis and treatment; however, only a limited number of bimodal probes have been investigated in preclinical models. Herein, we briefly describe the strengths and limitations of PET and MRI modalities and highlight the need for the development of multimodal molecularly-targeted agents. We have tried to thoroughly summarize data on bimodal probes available on PubMed. Emphasis was placed on their design, safety profiles, pharmacokinetics, and clearance properties. The challenges in PET/MR probe development using a number of illustrative examples are also discussed, along with future research directions for these novel conjugates.Keywords: medical imaging, bioresponsive probes, targeting, contrast agents, relaxivity, clearance

In the drilling process, unwanted materials which extend beyond the work-piece surface are called burr. The main objective is to find out optimum drilling condition which minimize the burr height and burr thickness. For this purpose, an experimental study has been performed on aluminium alloys using an HSS twist drill according to L27 experimental run. For this experiment the input process parameters spindle speed, feed rate and depth inside backup support and for the response parameters burr height and burr thickness have been considered. The response surface methodology-based regression equation has been developed for burr height and burr thickness using this experimental dataset and compared with the experimental result that shows a close matching. The effect of the input process parameters i.e. spindles speed; feed rate and depth inside backup support are presented in contour plots to understand the effect of them. Finally, optimum drilling process has been obtained by using Biogeography Based Optimisation (BBO) technique to minimize the burr height and burr thickness. From BBO optimization it cleared that minimum burr height is found at a speed of 320 rpm, feed of 0.08 mm/rev and depth inside backup support of 0.20 mm, also minimum burr thickness is produced at a speed of 125 rpm, feed of 0.9395 mm/rev and depth inside backup support of 0.56 mm.

Morphological analyses are key outcome assessments for nerve regeneration studies but are historically limited to tissue sections. Novel optical tissue clearing techniques enabling three-dimensional imaging of entire organs at a subcellular resolution have revolutionized morphological studies of the brain. To extend their applicability to experimental nerve repair studies we adapted these techniques to nerves and their motor and sensory targets in rats. The solvent-based protocols rendered harvested peripheral nerves and their target organs transparent within 24 hours while preserving tissue architecture and fluorescence. The optical clearing was compatible with conventional laboratory techniques, including retrograde labeling studies, and computational image segmentation, providing fast and precise cell quantitation. Further, optically cleared organs enabled three-dimensional morphometry at an unprecedented scale including dermatome-wide innervation studies, tracing of intramuscular nerve branches or mapping of neurovascular networks. Given their wide-ranging applicability, rapid processing times, and low costs, tissue clearing techniques are likely to be a key technology for next-generation nerve repair studies. All procedures were approved by the Hospital for Sick Children's Laboratory Animal Services Committee (49871/9) on November 9, 2019.

Solving the hydroelastic problem by using Ansys System Coupling (Mechanical and CFX) for floating and fixed rings of a deformable annular seal made it possible to analyze the influence of the cylindrical shell thickness, the inlet and outlet edge dimensions, inlet pressure, and shaft radial displacement on the hydrostatic pressure distribution and the clearance value on length, leakages, stress-strain state, and radial force. The analysis of static stability at an inlet pressure of 10 MPa for the basic seal design showed that the static radial force in the range of radial movements of the shaft from 0 to 50% of the clearance is centering, even though the inlet part of the seal clearance has a confusor, and the outlet part has diffuser form. However, the dynamic coefficients of the fixed sealing ring have a negative value of direct stiffness but positive values of direct and cross-coupled damping and cross-coupled stiffness. Verifying computational 2D and 3D models with experimental results from the literature showed that the maximum relative error does not exceed 10.7% for the hydrostatic pressure, 18% for the clearance, and 8.6% for the leakage value. Simultaneously, according to the trend, all calculated dependencies are identical to the experimental results.

The introduction of direct-acting antiviral (DAA) treatment of hepatitis C virus (HCV) infected patients has greatly increased treatment success rates. However, viral response kinetics to DAA treatment may depend on pre-existing resistance-associated substitutions (RASs) in HCV. The aim of this study was to describe how pre-existing RASs affect DAA treatment-induced reduction in HCV RNA titers in HCV genotypes 1- and 3-infected individuals. Patients with HCV genotype 1 infection (N = 31) treated with either sofosbuvir/ledipasvir/ribavirin or paritaprevir/ombitasvir/ritonavir/dasabuvir/ribavirin and HCV genotype 3-infected patients (N = 16) treated with either sofosbuvir/daclatasvir/ribavirin or sofosbuvir/ribavirin were analyzed. HCV RNA levels were determined at baseline and frequently during treatment, and RAS profiles were obtained by deep sequencing at baseline. In total, 33/47 (70.2%) of the patients had baseline RASs. However, treatment-specific RASs were detected at baseline only in 12.9% and 18.8% of HCV genotypes 1- and 3-infected patients, respectively. In genotype 1-infected individuals, reduction in HCV RNA titer during the first week of treatment was not affected by evidence of either treatment-specific RASs or cirrhosis or treatment regimen. In genotype 3-infected individuals receiving sofosbuvir/daclatasvir/ribavirin, the presence of daclatasvir-specific NS5A RASs at baseline correlated with a reduced decline of HCV RNA in the first treatment week. For both genotypes 1- and 3-infected individuals, cirrhosis but not treatment-specific RAS were associated with the time of clearance of HCV RNA. It is, however, important to note that this study involves DAA regimens that were used only during the original introduction of interferon-free DAA-based treatments.

A theoretical model of a pin-lug fitting in the presence of a pin-lug gap is developed that accounts for the nonlinear link between the load and the pin-lug angular width in this progressive contact, which is assumed frictionless. This model adopts a simplified lug geometry, described by a purely flexural partial ring whose extremities are fixed to a base, solved with the virtual work principle. Based on an already available load factor regrouping the effect on the contact angular extent of the applied load, of the Young’s modulus, and of the gap, but not of the lug geometry, an enhanced load factor is developed that includes, although approximately, the influence of the lug geometry on the contact angle. This approach is useful in selecting a suitable clearance between the lug and the pin, which keeps the contact pressure to a minimum for an imposed load.

The global burden of diarrhea caused by Cryptosporidium parasite is underestimated. In immunocompromised hosts, chronic and severe presentation of intestinal cryptosporidiosis can result in long-term morbidity and high illness costs. The evidence of effective treatments for cryptosporidiosis has been lacking. We reviewed the published clinical trials to bring forward the feasible therapeutic options of human cryptosporidiosis in various populations and settings according to clinical improvement and parasite clearance rates. A total of 42 studies consisting of the use of nitazoxanide, paromomycin, macrolides, somatostatin analogues, letrazuril, albendazole, rifaximin, miltefosine, clofazimine, and colostrum were included in the review. The trials were mostly conducted in small number of individuals infected with human immunodeficiency virus (HIV), and there is inadequate data of controlled trials to suggest the use of these treatment modalities. Nitazoxanide was reported to be highly efficacious only in immunocompetent hosts and was found to be superior to paromomycin in the same group of patients. Macrolides showed no effective results in both clinical and parasitological improvement. Human bovine colostrum should possibly be administered as one of complementary therapeutic modalities along with other antimicrobials to reach optimal parasite eradication. Other trials of therapeutic modalities were terminated due to futility. Currently, available data is intended to aid the development of strategies for improving access to treatments in different clinical settings, as well as to help guide further studies on treatments of human intestinal cryptosporidiosis., Graphical abstract Image 1

Significance Statement Posttranslational guanidinylation of ApoC3, a major constituent of triglyceride-rich lipoproteins, enhances ApoC3?s proinflammatory properties in uremia. Guanidinylated ApoC3 (gApoC3) is generated by guanidine and urea, and accumulates significantly in the plasma of patients with CKD, and in the kidneys of mouse models of CKD. In humanized mice, gApoC3 promotes kidney tissue fibrosis and suppresses regeneration after vascular injury. Importantly, in a large observational trial examining the clinical relevance of this posttranslational modification in patients with CKD, higher plasma gApoC3 intensity was associated with adverse renal and cardiovascular outcomes. Therefore, gApoC3 represents a novel mediator of kidney injury and CKD-associated vascular disease and offers a potential treatment target to halt progression and to prevent vascular disease in patients with CKD.Background Coexistent CKD and cardiovascular diseases are highly prevalent in Western populations and account for substantial mortality. We recently found that apolipoprotein C-3 (ApoC3), a major constituent of triglyceride-rich lipoproteins, induces sterile systemic inflammation by activating the NOD-like receptor protein-3 (NLRP3) inflammasome in human monocytes via an alternative pathway.Methods To identify posttranslational modifications of ApoC3 in patients with CKD, we used mass spectrometry to analyze ApoC3 from such patients and from healthy individuals. We determined the effects of posttranslationally modified ApoC3 on monocyte inflammatory response in vitro, as well as in humanized mice subjected to unilateral ureter ligation (a kidney fibrosis model) and in a humanized mouse model for vascular injury and regeneration. Finally, we conducted a prospective observational trial of 543 patients with CKD to explore the association of posttranslationally modified ApoC3 with renal and cardiovascular events in such patients.Results We identified significant posttranslational guanidinylation of ApoC3 (gApoC3) in patients with CKD. We also found that mechanistically, guanidine and urea induce guanidinylation of ApoC3. A 2D-proteomic analysis revealed that gApoC3 accumulated in kidneys and plasma in a CKD mouse model (mice fed an adenine-rich diet). In addition, gApoC3 augmented the proinflammatory effects of ApoC3 in monocytes in vitro. In humanized mice, gApoC3 promoted kidney tissue fibrosis and impeded vascular regeneration. In CKD patients, higher gApoC3 plasma levels (as determined by mass spectrometry) were associated with increased mortality as well as with renal and cardiovascular events.Conclusions Guanidinylation of ApoC3 represents a novel pathogenic mechanism in CKD and CKD-associated vascular injury, pointing to gApoC3 as a potential therapeutic target.

This study aimed to develop a single photo emission computed tomography/fluorescence (SPECT/FL) bimodal imaging probe to image blood cells. Hyperbranched polyglycerol (HPG) was synthesized by anionic ring-opening polymerization. Succinic anhydride was used to functionalize HPG. Then, indocyanine green (ICG) was bound to HPG, with a 73.59% binding yield. Deferoxamine (DFO) was subsequently bound to ICG-HPG, and DFO-ICG-HPG was radiolabeled with technetium-99m, with 100% yield. The molecular weight of HPG in this study was found to be 6.8 kDa. In in vitro studies, the radiolabeled nanoconjugates remained stable even after 6 h (last timepoint when stability was assessed), and when the nanoconjugates were applied to K562 chronic myeloid leukemia cells, the highest cell viability was observed at a concentration of 5 mu g/mL and binding efficiency increased over time, reaching 30% at 6 h (last timepoint when binding efficiency was assessed). The results support the feasibility of the developed probe to image blood cells, which would be useful for applications such as detecting internal bleeding. [GRAPHICS] ., Ege University Research Fund [2018 FBE 006]; NIH/NCI Cancer Support Grant [P30 CA008748], This work was financially supported by Ege University Research Fund (2018 FBE 006) and partially presented at HEZARFEN International Congress of Science, Mathematics, and Engineering Sciences held in Izmir/Turkey on November 8-10, 2019. Dr. Omer Aras was partially supported through the NIH/NCI Cancer Support Grant P30 CA008748.

A dynamic model of the working mechanism of a compound pendulum jaw crusher with clearance is established by the Lagrange multiplier method (LMD) based on the L-N contact force model and modified Coulomb friction force model. The correctness of the dynamic model is verified by MATLAB and Adams comparison simulation, and the best selection range of driving speed and clearance size is determined according to the laminating crushing theory (LCT). The effects of driving speed and clearance size on the shock and chaos phenomenon in the clearance mechanism are analyzed, as well as the vibration force applied to the foundation. The results show that, under the premise of meeting the requirements of crusher production capacity, increasing the driving speed and reducing the clearance size can weaken the shock and chaos phenomenon during the operation of the mechanism, improve the dynamic performance and enhance the operation stability, and the service life of foundation is prolonged with the stability of vibration force. Furthermore, the optimal combination of driving speed and clearance size is determined, which provides a theoretical basis for the optimization of the vibration force of the jaw crusher.

Дана робота пов’язана із виникненням у конструкції зазорів, що перевищують допустимі значення вказані на кресленнях та у технічних документах. Попри те, що існує процедура заміру таких зазорів, та вкладання прокладки у цей зазор для подальшої постійної збірки, виявлено що не враховується прогин від тимчасових кріплень що застосовуються для тимчасової фіксації конструкції з метою заміру зазору. Оскільки ці технологічні деформації, не враховано, то вони будуть присутній у постій збірці теж. Тож актуальність роботи полягає у розробці методу підрахування додаткових локальних деформацій від тимчасових кріплень, маючи геометрію з’єднання та навантаження на кріплення, а також у наданні оцінки впливу цього неврахованого зазору на залишкову міцність з’єднання. Об’єктом дослідження в даній роботі вибрано 3D модель з’єднання двох секцій фюзеляжу літака на прикладі двох стрингерних прольотів, що розріховані за допомогою МСЕ. З’єднання складається зі стрингерів, що підтримують обшивку, полоси що особисто з’єднує дві обшивки та кутиків що з’єднують стрингери передньої із стрингерами задньої секції. За мету роботи було покладено визначення впливу додаткових локальних напружень від тимчасових технологічних застосувань на міцність з’єднання, а саме на найкритичнішу деталь у з’єднанні – на фітинг- кутик, що з’єднує стрингери. Дана робота пов’язана із виникненням у конструкції зазорів, що перевищують допустимі значення вказані на кресленнях та у технічних документах. Попри те, що існує процедура заміру таких зазорів, та вкладання прокладки у цей зазор для подальшої постійної збірки, виявлено що не враховується прогин від тимчасових кріплень що застосовуються для тимчасової фіксації конструкції з метою заміру зазору. Оскільки ці технологічні деформації, не враховано, то вони будуть присутній у постій збірці теж. Тож актуальність роботи полягає у розробці методу підрахування додаткових локальних деформацій від тимчасових кріплень, маючи геометрію з’єднання та навантаження на кріплення, а також у наданні оцінки впливу цього неврахованого зазору на залишкову міцність з’єднання. Об’єктом дослідження в даній роботі вибрано 3D модель з’єднання двох секцій фюзеляжу літака на прикладі двох стрингерних прольотів, що розріховані за допомогою МСЕ. З’єднання складається зі стрингерів, що підтримують обшивку, полоси що особисто з’єднує дві обшивки та кутиків що з’єднують стрингери передньої із стрингерами задньої секції. За мету роботи було покладено визначення впливу додаткових локальних напружень від тимчасових технологічних застосувань на міцність з’єднання, а саме на найкритичнішу деталь у з’єднанні – на фітинг- кутик, що з’єднує стрингери.

We developed a brain thick-section-clearing (BTS-C) procedure to observe coronal sections of the entire mouse brain with conventional epifluorescence microscopy (EFM). After clearing with the BTS procedure, the white light transmittance of the 1-mm-thick mouse brain sections was more than 96%. The distribution patterns of amyloid plaques or α-synuclein in 1-mm-thick brain sections of five different mouse strains cleared with this procedure were easily observed by EFM. In addition, the detailed distribution of antigens at higher magnifications was revealed by observing the same slides with a confocal laser scanning microscope (CLSM). In conclusion, we have shown that the BTS protocol can replace laborious and time-consuming semi-thin-sectioning procedures, and the cleared 1-mm-thick sections can be examined by EFM and CLSM to elucidate the distribution patterns of antigens.

Treatment of SARS-CoV-2 targeting its RNA dependent RNA polymerase (RdRp) is of current interest. Remdesivir has been approved for the treatment of COVID-19 around the world. However, the drug has been linked with pharmacological limitations like adverse effects and reduced efficiency. Nevertheless, recent advancements have depicted molnupiravir as an effective therapeutic agent to target the SARS-CoV-2 RdRp. The drug has cleared both in vitro and in vivo screening. It is in phase-III clinical trial. Nonetheless, there are no data on themolecular binding interaction of molnupiravir with RdRp. Therefore, it is of interest to report the binding interaction of molnupiravir using molecular docking. It is also of interest to show its stability during interaction using molecular dynamics and binding free energy calculations along with drug likeliness and pharmacokinetic properties in comparison with remdesivir.

AIM AND OBJECTIVE This study aimed to evaluate the effect of ozonated water used as an irrigant and dentin-cleaning solution on the bond strength of fiberglass pins in vitro, comparing it with the commonly used solutions. MATERIAL AND METHODS Seventy-seven bovine roots were randomly divided into seven groups according to the irrigant and dentin-cleaning solution to be used: HP/HP, 2.5% sodium hypochlorite; DA/DA, distilled water; CHX/CHX, 2% chlorhexidine; OA/OA, 4 ppm ozonated water; HP/DA; HP/CHX; and HP/OA. In each group, the root canals were endodontically prepared by using the corresponding irrigant and stored in DA; after 7 days, they were cleared and cleaned with the corresponding cleaning solution. The fiberglass pins were cemented by using self-adhesive cement. After 7 days, the roots were sectioned (six discs each) and submitted to the push-out test. The type of fracture was analyzed with a 4.5x stereoscopic magnifying glass. The data were analyzed by the analysis of variance and the Tukey test at a 5% significance level. RESULTS The OA/OA (11.67), HP/HP (11.21), and HP/OA (9.71) groups showed the highest mean push-out bond strength (MPa) in the cervical third. The same trend was maintained in the middle and apical thirds. CONCLUSION Ozonated water and 2.5% sodium hypochlorite are the most relevant solutions for root dentin treatment. CLINICAL RELEVANCE Teeth treated with ozonated water, sodium hypochlorite, and a combination of the two showed greater bond strength than those treated with other solutions.

In the treatment of obesity, nutritional and behavioral modifications are difficult to implement and maintain. Since vegetable consumption is a fundamental part of many dietary interventions and daily nutrient requirements, we developed a novel cellulose-based superabsorbent hydrogel (CB-SAH) platform, inspired by the composition and mechanical properties of raw vegetables, as a mechanobiological therapy. The CB-SAHs properties were studied in a simulated gastrointestinal environment, while their impact on gut tissue was investigated by an ex vivo organ culture (EVOC) model. Functional fibers and raw vegetables were used as reference. CB-SAHs demonstrated orders of magnitude higher elasticity in comparison to the tested functional fibers, however performed similar to the tested raw vegetables. Notably, the biomimetic CB-SAHs with elasticity levels similar to raw vegetables showed benefits in preserving and regulating the gut tissue in the EVOC model. Non-systemic oral mechanotherapeutics based on this technology were advanced through clinical studies, with a first product cleared as an aid for weight management in the US and Europe.

Background Severe COVID-19 caused by SARS-CoV-2 should closely be cared because of the relatively high mortality rate. If SARS-CoV-2 could be cleared as soon as possible, the mortality rate might lower. In the present study, we analyzed factors which might be related to the clearance of SARS-CoV-2. Methods One hundred and twenty-eight severe COVID-19 cases were enrolled. All of them had been isolated and treated at Shenzhen Third People’s Hospital because they were positive for nucleic acid of SARS-CoV-2 tested by qRT-PCR. Their baseline clinical characteristics and antiviral regimens were collected and analyzed, respectively. Results Of the 128 enrolled severe COVID-19 cases, unfortunately 3 died. The mean viral duration of all patients was 23.5 (range 17−32) days. All patients achieved viral clearance during 9 weeks. 13.4% of patients achieved viral clearance within 2 weeks, and 63.0% of patients achieved viral clearance within 4 weeks. The combined regimens of three or more antiviral drugs, the use of invasive mechanical ventilation, and late admission might be related to the delay of viral clearance within 2 weeks. The use of arbidol, the use of invasive mechanical ventilation, and late admission might be related to the delay of viral clearance within 4 weeks. Patients often had a prolonged course of COVID-19 and hospitalization, and were more likely transferred to intensive care unit (ICU) for treatment, if they could not clear SARS-CoV-2 during 23 days. Conclusion Severe COVID-19 cases should be admitted to hospital as soon as possible. The combined regimens of three or more antiviral drugs might not be useful for viral clearance, and should be performed carefully and cautiously.

This was a level III-retrospective cohort study.The objective of this study was to present an unbiased report of the current rate of severe complications for Federal Drug Administration (FDA) 510(k) cleared sacroiliac joint (SIJ) fusions and investigate the underlying cause of these complications.The number of yearly SIJ fusions is on an upward trend. Currently, the most utilized implants to fuse the SIJ have been FDA 510(k) cleared devices. Studies reporting on complications following SIJ fusions are mostly industry-sponsored.The Manufacturer and User Facility Device Experience (MAUDE) database was searched for all reported FDA 510(k) cleared SIJ fusion device complications. Several data points were obtained from each report and recorded. The Hospital Inpatient National Statistics and the Center for Medicare and Medicaid Services (CMS) was also searched for the number of SIJ fusions performed each year.A search of the MAUDE database returned 1115 reports, with the first report on June 30, 2011, and the last report on July 28, 2020. Patient injury was the most common type of event reported at 97.5% (1080/1107). Death was reported in 3 patients (0.3%). Malposition was the most common device problem at 49.5% (548/1107). The root cause of these events was primarily user error at 58.2% (644/1107). Revision surgery or reoperation occurred in 92.8% (1028/1107) of reports. Data for SIJ fusions through CMS showed an overall trend of increasing yearly SIJ fusions.The majority of complications reported to MAUDE for FDA 510(k) cleared SIJ fusion devices are user error due to improper placement of implants. These complications are likely underreported, and there is currently no formal tracking system of total SIJ fusions performed to calculate accurate complication and revision rates. Patient injury and health care costs can potentially be reduced with improved education, training, and oversight, which is currently lacking.

Background: Menarche, among Adolescence girls, signifies the adaptation to womanhood as it is associated with pubertal changes and beginning of the capacity to reproduce. This is a period of gonadal development and growth spurt. Menstrual hygiene is crucial to healthy reproductive system and in return to good physical health and wellbeing. Therefore, enhanced awareness regarding menstruation and related hygiene, right from adolescence may escalate safe practices that are helpful in alleviating the distress of millions of women. Aim: To assess the knowledge and practices related to menstruation and menstrual hygiene among adolescent girls of selected schools of District Ambala, Haryana A descriptive cross sectional study was conducted in selected schools of Mullana and Barara District Ambala, Haryana. Materials and Methods: Total enumeration sampling technique was used to enroll 192 adolescent girls from class 9 to class 12 from selected schools after obtaining written informed consent from parents and verbal consent from girls. Ethical clearance was obtained from Institute Ethics committee. Doubts of the participants were cleared after data collection. Results: Among 192 girls, nearly half girls were aware of menstrual hygiene and reported use of sanitary nepkins and 40.1% girls were aware of the symptoms of poor menstrual hygiene. . Conclusion: There is a need to implement an education program for adolescent girls on menstruation and menstrual hygiene to ensure healthy menstrual practices. Keywords: Menstruation, Menstrual Hygiene, Menses, Sanitary pads, Dysmenorrhea, Vaginal discharge

Purpose: To determine the margin of resection (MOR) for periocular basal cell carcinoma (BCC) and compare the outcomes of BCC treatment, namely Mohs micrographic surgery (MMS) and wide excision with later reconstruction (WELR). Methods: This is a retrospective, comparative, interventional study of patients who underwent surgical treatment of periocular BCC. One hundred forty-two patients were included. One hundred patients were treated with MMS and 42 with WELR. Inclusion criteria were primary periocular BCC with postoperative follow-up of ≥6 months, age more than 18-year-old. Exclusion criteria were, orbital extension, BCC origin outside the periocular area, or those associated with Gorling or nevoid BCC. The main outcome measure was variables associates with MOR >4 mm.Results: There was a positive correlation between the preoperative tumor horizontal and vertical diameter with the corresponding MOR, of 0.27 (p = 0.01) and 0.28 (p = 0.007), respectively. Receiver operating characteristics suggest that a tumor with a horizontal diameter ≥5 mm or a vertical diameter of ≥6 mm, might need MOR >4 mm. One patient in the MMS group had BCC recurrence compared to none in the WELR group, and one patient in the WELR had a positive surgical margin, which was cleared during the reconstruction.Conclusions: BCC tumor margins may extend far beyond clinical margins and the MOR required is often more than 3–4 mm. MMS ensures clear tumor margins but is not practical for all patients. A stratification system could help divide patients between the treatment strategies.

Knotted peptides present a wealth of structurally diverse, biologically active molecules, with the inhibitor cystine knot/knottin class among the most ecologically common ones. Many of these natural products interact with extracellular targets such as voltage-gated ion channels with exquisite selectivity and potency, making them intriguing therapeutic modalities. Such compounds are often produced in low concentrations by intractable organisms, making structural and biological characterization challenging, which is frequently overcome by various expression strategies. Here, we sought to test a biosynthetic route for the expression and study of knotted peptides. We screened expression constructs for a biosynthesized knotted peptide to determine the most influential parameters for successful disulfide folding and used NMR spectroscopic fingerprinting to validate topological structures. We performed pharmacokinetic characterization, which indicated that the interlocking disulfide structure minimizes liabilities of linear peptide sequences, and propose a mechanism by which knotted peptides are cleared. We then developed an assay to monitor solution folding in real time, providing a strategy for studying the folding process during maturation, which provided direct evidence for the importance of backbone organization as the driving force for topology formation.

Aim and objective To assess and compare the cleaning efficacy and instrumentation time of K files, ProTaper, and Kedo-S rotary files in primary molars. Materials and methods India ink was injected into 120 root canals of selected primary molars. The root canals were randomly and equally divided into three groups based on instrumentation technique: group I-K files, group II-ProTaper, and group III-Kedo-S. After instrumentation with respective method, the canals were cleared and observed under a stereomicroscope, the instrumentation time for each root canal was also measured with a stopwatch. Statistical analysis was done with one-way analysis of variance (ANOVA) and post hoc Bonferroni. Result Kedo-S rotary files performed significantly better cleaning of the canals in the coronal and middle third than ProTaper and K files (p = 0.0001). In the apical third, the difference between the two rotary systems was not significant. The time taken for instrumentation was lowest with Kedo-S followed by ProTaper and K files. Conclusion Kedo-S pediatric rotary system showed significantly better cleaning than ProTaper rotary system and K files in cleaning primary molar root canals. Clinical relevance The anatomy and morphology of primary teeth demand a specialized file system that will overcome the shortcomings of conventional biomechanical preparation. Kedo-S files, being exclusive pediatric rotary files, might prove to be a boon in primary canal preparation. How to cite this article Kalita S, Agarwal N, Jabin Z, et al. Comparative Evaluation of Cleaning Capacity and Efficiency of Kedo-S Pediatric Rotary Files, Rotary ProTaper, and Hand K Files in Primary Molar Pulpectomy. Int J Clin Pediatr Dent 2021;14(3):383-387.

OBJECTIVE: The purpose of this study was to explore the utilization of the Y Balance Test (YBT) alongside the Balance Error Scoring System (BESS) during examination of healthy adolescent athletes (14-18 years old) as well as those with acute and chronic concussion. DESIGN: A repeated measures study of balance in a cross-sectional convenience sample of adolescents participating in high school athletics. SETTING: Data were collected on healthy athletes in their school setting for comparison purposes and on concussed athletes in the physical therapy rehabilitation center at the hospital. PARTICIPANTS: Participants were a convenience sample of male and female athletes between the ages of 14-18 years old (180 healthy [111 male, 69 female] and 44 [ 28 male, 16 female] with concussion). ASSESSMENT OF RISK FACTORS: All participants were cleared for participation via pre-participation examination or by the treating sport medicine physician. MAIN OUTCOME MEASURES: Healthy athletes performed the YBT, a dynamic assessment of balance. Athletes with concussion also performed the BESS, a static assessment of balance. RESULTS: Means for each YBT reach direction were statistically different for both healthy males and females (p≤ 0.05). Within both the acute and chronic subsets of the concussed sample, some participants performed over the median value for the BESS but not the YBT. CONCLUSIONS: These data may suggest that dynamic balance testing in conjunction with static balance testing could be valuable in both the acute and chronic phases of concussion to ensure a comprehensive assessment of the necessary balance skills for athletic play.

To present the outcomes of attempts to salvage total graft detachment following Descemet's membrane endothelial keratoplasty (DMEK).A search of the electronic medical records of two tertiary medical centers for all patients who underwent DMEK yielded six cases of postoperative total graft detachment (2.54%). Graft salvage was attempted in all cases using repeated intracameral graft staining, unfolding, and reattachment to the stroma under 20% hexafluoride gas.In all cases, a free-floating totally detached graft was identified in the anterior chamber shortly after surgery. Salvage surgery resulted in a central, well-oriented, and fully attached graft. In three cases, the primary graft failed, and in two, the corneas cleared at first but failed after 2 months and 1 year respectively. In one case, the cornea remained clear during 1 year of follow-up but had a very low endothelial cell density.Reattachment of fully detached DMEK graft is technically possible, but graft manipulation during the primary and secondary operations is likely to damage the endothelial cells, resulting in primary or early graft failure. If graft salvage is attempted, the probability of primary or early graft failure should be discussed with the patient, and expectations should be tempered accordingly.ZIEL: Präsentation der Ergebnisse der Rettungsversuche nach vollständiger Transplantatablösung nach Descemet-Membran-Transplantation (Descemetʼs membrane endothelial keratoplasty – DMEK-Methode).Datenbankrecherche des Rabin Medical Center und des Rambam Medical Center in Israel für alle Patienten, die zwischen Januar 2015 und Januar 2020 eine Hornhauttransplantation erhielten, wobei bei 236 Patienten eine DMEK durchgeführt wurde, in 6 Fällen wurde eine vollständige Transplantatablösung beobachtet (2,54%). Die Rettung des Transplantats wurde mit erneuter intrakameraler Transplantatfärbung, -entfaltung und erneuter Anheftung an das Stroma mit 20% Hexafluoridgas versucht.In allen Fällen konnte in der Vorderkammer ein komplett abgelöstes Transplantat kurz nach der Operation gefunden werden. Mit der Revisionsoperation gelang es in allen Fällen, ein zentriertes, richtig orientiertes, total angebrachtes Transplantat wiederherzustellen. In 3 Fällen ist die Hornhaut nach der Revisionsoperation nicht aufgeklart. In 2 Fällen waren die Hornhäute zuerst klar, aber das Transplantat versagte nach 2 Monaten und 1 Jahr. In einem Fall war die Hornhaut 1 Jahr lang klar, hatte dann aber eine sehr niedrige Endothelzelldichte.Das erneute Anbringen eines frei schwimmenden DMEK-Transplantats nach vollständiger Ablösung ist technisch möglich, aber die Manipulation des Transplantats während der primären und sekundären Operation kann die Endothelzellen beschädigen, was zu einem primären oder frühen Versagen des Transplantats führt. Wenn eine Transplantatrettung versucht wird, sollte die Wahrscheinlichkeit eines primären oder frühen Transplantatversagens mit dem Patienten besprochen und seine Erwartungen entsprechend relativiert werden.

This article investigates why individuals utilize euphemism words in political wrangle about and whether that exertion is beneficial. In expansion to the numerous euphemism words that are acknowledged by for all intents and purposes everyone, the political cleared out has its claim set of euphemism words related with political rightness, whereas the political right has its possess set connected to energetic rightness.

This study aimed to examine the magnitude of age-related change in hepatic clearance by integrating the data of multiple drugs and to compare this with renal clearance, considering associations with age-related changes in organ weight and blood flow. The results of multiple population pharmacokinetic analyses that detected age-related clearance changes in hepatically eliminated drugs were collected. The relationship between hepatic clearance of the unbound drug and age was then analyzed using the nonlinear least-squares method, adjusting for interdrug differences. The obtained change in hepatic clearance was compared with age-related changes in liver weight and hepatic blood flow in Japanese and Westerners. For comparison, the changes in renal clearance were analyzed similarly. In total, 18 drugs were analyzed. The hepatic unbound clearance decreased by 32% at age 80 years and by 40% at age 90 years, compared with age 40 years, suggesting that it decreased by 0.80% per year with aging. The rate of the decrease was consistent with decreases in hepatic weight per person or blood flow per person, regardless of ethnicity and sex. Since age-related change in body weight varied somewhat by sex or ethnicity, hepatic weight per body weight was less consistent to account for age-related change in hepatic clearance. As for an index of renal clearance, the changes in inulin clearance with age were similar to those in renal blood flow, with a decrease of 0.97% per year from the age of 40 years. Hepatic clearance consistently decreased by 0.80% per year from the age of 40 years, with aging for multiple drugs analyzed in this study. Changes in organ weight and blood flow are considered to be primarily responsible for the age-related changes in hepatic and renal clearance.

Purpose Imaging of PARP expression has emerged as valuable strategy for prediction of tumor malignancy. While [18F]PARPi and [18F]FTT are already in clinical translation, both suffer from mainly hepatobiliary clearance hampering their use for detection of abdominal lesions, e.g., liver metastases. Our novel radiotracer [18F]FPyPARP aims to bridge this gap with a higher renal clearance and an easily translatable synthesis route for potential clinical application. Methods We developed a less lipophilic variant of [18F]PARPi by exchange of the fluorobenzoyl residue with a fluoronicotinoyl group and automated the radiosyntheses of the three radiotracers. We then conducted a comparative side-by-side study of [18F]PARPi, [18F]FPyPARP, and [18F]FTT in NOD.CB17-Prkdcscid/J mice bearing HCC1937 xenografts to assess xenograft uptake and pharmacokinetics focusing on excretion pathways. Results Together with decent uptake of all three radiotracers in the xenografts (tumor-to-blood ratios 3.41 ± 0.83, 3.99 ± 0.99, and 2.46 ± 0.35, respectively, for [18F]PARPi, [18F]FPyPARP, and [18F]FTT), a partial shift from hepatobiliary to renal clearance of [18F]FPyPARP was observed, whereas [18F]PARPi and [18F]FTT show almost exclusive hepatobiliary clearance. Conclusion These findings imply that [18F]FPyPARP is an alternative to [18F]PARPi and [18F]FTT for PET imaging of PARP enzymes.

Glomerular filtration rate (GFR) is a key index of renal function. The classic method for assessing GFR is the clearance of inulin. Several current methods using isotopic (125I-iothalamate, 51Cr-EDTA, or 99Tc-DTPA) or nonisotopic (iohexol or iothalamate) markers are available. Clinically, GFR is estimated (eGFR) from serum creatinine or cystatin C levels. Estimated GFR based on creatinine and/or cystatin are less accurate than measured GFR. The creatinine-based equations calculate higher eGFR values (suggesting better kidney function) for black individuals. This upward adjustment for all black individuals is embedded in eGFR calculations on the belief of higher serum creatinine concentrations among black individuals than among white individuals. Thus “race-corrected” eGFR has become a widely accepted and scientifically valid procedure. However, race is not a genetic or biological category. Rather, race is a social construction defined by region-specific cultural and historical ideas. Furthermore, there is no accepted scientific method for classifying people as black or white individuals. Studies typically rely on self-identification of race. However, any person in the United States with any known black ancestry is considered to be a black individual. This is known as the “one-drop rule,” meaning that a single drop of “black blood” makes anyone a black individual. It does not matter if an individual has 50%, 25%, 5%, or 0.5% African ancestry. The limited accuracy and reliability of this approach would not be allowed for any other scientific variable. Admixture and migration have produced such broad variations that race categories should not be used as experimental variables.

Purpose of review Improvement in hemodialysis treatment and membrane technology are focused on two aims: the first one is to achieve a better control of circulating uremic solutes by enhancing removal capacity and by broadening molecular weight spectrum of solutes cleared; the second one is to prevent inflammation by improving hemocompatibility of the global dialysis system. Recent findings Despite impressive progresses in polymers chemistry few hazards are still remaining associated with leaching or sensitization to polymer additives. Research has focused on developing more stable polymers by means of additives or processes aiming to minimize such risks. Membrane engineering manufacturing with support of nanocontrolled spinning technology has opened up membrane to middle and large molecular weight substances, while preserving albumin losses. Combination of diffusive and enhanced convective fluxes in the same hemodialyzer module, namely hemodiafiltration, provides today the highest solute removal capacity over a broad spectrum of solutes. Summary Dialysis membrane is a crucial component of the hemodialysis system to optimize solute removal efficacy and to minimize blood membrane biological reactions. Hemodialyzer is much more than a membrane. Dialysis membrane and hemodialyzer choice are parts of a treatment chain that should be operated in optimized conditions and adjusted to patient needs and tolerance, to improve patient outcomes.

The Covid-19 has shifted the face of many markets including e-commerce and online business with many bottlenecks to be cleared. The last-mile delivery project has the greatest effect on all types of e-commerce companies because it has many consumer touchpoints as well as the Covid-19 pain points. Due to these interconnected issues, the delivery projects itself requires modern solutions. The purpose of this paper is to identify, analyse and categorize the major factors that affect the last mile delivery projects in e-commerce, food sector, retail sector and so on using total interpretive structural modelling approach during the Covid-19. Ten major factors are identified from literature review, and expert opinions are collected from multiple organizations that are involved in the last mile delivery projects. The results indicate that types of goods, achieving routing efficiency and meeting fulfilment timeline are the key factors for last mile delivery projects during the time of Covid-19. This study helps the managers to identify the key factors and to focus on these factors for the successful implementation of last mile delivery project.

Background As intravitreal anti-VEGF injections became the mainstay of treatment for many retinal diseases, the cause of a secondary sustained elevated intraocular pressure is still unclear. The aim of our study was to study the clearance of Aflibercept from the anterior chamber angle, in a rat model, to test if an aggregation exists. Methods Choroidal neovascular lesions (CNV) were induced in the right eye of 12 brown Norway rats, using indirect laser ophthalmoscope. Intravitreal Aflibercept injection (0.12 mg/3 µl) was performed 3 days after CNV induction. Rats were euthanized at predetermine time intervals of 3, 6, 24 and 48 h post injection, with immediate enucleation for histological analysis with H&E and immunofluorescence staining. Aflibercept molecules were stained with red fluorescence thanks to the formation of the immune complex Aflibercept-Rabbit anti human IgG-Anti rabbit antibodies-Cy3. Results Immediately after the injection, a strong fluorescence signal was detected, indicating the presence of Aflibercept in the iridocorneal angle. At 3- and 6-h interval a strong signal of Aflibercept was still seen. Six hours post injection, the signal was highly concentrated in Schlemm’s canal. In the 2 eyes harvested 24 h post Aflibercept injection, red fluorescence signal intensity was decreased in one eye, occupying mainly intra scleral venous plexuses, and absent in the other eye. At 48 h there was no fluorescence signal, confirming complete clearance of Aflibercept. Conclusions In our rat model, a complete clearance of Aflibercept from the anterior chamber angle, was seen 48 h after the injection. This finding refutes the theory of possible connection between IOP elevation and mechanical obstruction. Evacuation time of Aflibercept through the angle is of the same magnitude as that of Bevacizumab in the same rat model.

Quantitative understanding of pharmacokinetics of topically applied ocular drugs requires more research to further understanding and to eventually allow predictive in silico models to be developed. To this end, a topical cocktail of betaxolol, timolol and atenolol was instilled on albino rabbit eyes. Tear fluid, corneal epithelium, corneal stroma with endothelium, bulbar conjunctiva, anterior sclera, iris-ciliary body, lens and vitreous samples were collected and analysed using LC-MS/MS. Iris-ciliary body was also analysed after intracameral cocktail injection. Non-compartmental analysis was utilized to estimate the pharmacokinetics parameters. The most lipophilic drug, betaxolol, presented the highest exposure in all tissues except for tear fluid after topical administration, followed by timolol and atenolol. For all drugs, iris-ciliary body concentrations were higher than that of the aqueous humor. After topical instillation the most hydrophilic drug, atenolol, had 3.7 times higher AUCiris-ciliary body than AUCaqueous humor, whereas the difference was 1.4 and 1.6 times for timolol and betaxolol, respectively. This suggests that the non-corneal route (conjunctival-scleral) was dominating the absorption of atenolol, while the corneal route was more important for timolol and betaxolol. The presented data increase understanding of ocular pharmacokinetics of a cocktail of drugs and provide data that can be used for quantitative modeling and simulation.

Advanced CUBIC clearing method can clear diverse organs and even the entire body of a mouse to enable high-resolution 3D imaging. Advanced CUBIC reagent has often been used due to its low toxicity and easy preparation. However, Advanced CUBIC has a long experimental cycle, which reduces the efficiency of data acquisition. In this study, we first tracked the clarity changes of different organs cleared by Advanced CUBIC and identified the shortest time required for optimal transparency in individual organs. We then introduced ultrasound processing and developed a decolorization cocktail to optimize the clearing efficiency of the Advanced CUBIC method. With the optimized clearing CUBIC-Plus method, we achieved high resolution 3D imaging of mouse organs. Our CUBIC-Plus provides an efficient procedure to clear different organ for 3D imaging at high resolution.