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New trend in material engineering are composites with biological-based fillers. On of aim in biological-bases composite is how to use waste from agriculture production i.e. unused secondary products known as residues. The aim of this research is experimental investigation of wear resistance of bio-polymer composite reinforce by cotton post-harvest line residues. These residues come from cotton production as a waste which contain cotton stems and plant roots. Most of these residues are burned as energy source, but residues can find other utilization. Composites based on polymer can solve friction and wear problems in industry for their advantages as self-lubrication, light weight, easy of properties modification, etc. This research is part of wide study dealing with material utilization of post-harvest line residues. Mass loss of wear resistance at composite PCFC 500 with short fibres decrease against the matrix up to 21% on 19.28 mg.

Finding optimal parameters for acceleration structures for raytracing is key to improved performance. Previous research has shown that a speedup of over 10% of rendering time is possible. Some parameters are interdependent which complicates the process of finding an optimal configuration. It is hence interesting to find them efficiently. Autotuning is an automatic optimization scheme able to search for optimal configurations and has been applied successfully to kD-trees in the past, which we apply today on BVHs. The more parameters to optimize, the more difficult it is to find optimal solutions. In this paper, we analyze in detail the behavior of the parameters and their impact on acceleration structure building and rendering time. We show the interdependence and context sensitivity (i.e., scene, viewpoint) of the parameters. Based on the use case, this allows to target only crucial parameters. Convergence speed towards an optimal configuration is essential. To find better parameters, the autotuner needs to build the acceleration structure over and over, changing parameters every time. We introduce a hybrid model-based prediction and online autotuning method to address this issue. The prediction model allows for both instantaneous near-optimal configurations when inputs are known or similar, and efficient search of the configuration space when inputs are completely new. Online autotuning outperforms configurations recommended in literature by up to 11% median. The prediction model achieves 95% of the maximum speedup of the autotuner while reducing 90% of its overhead. Thus, hybrid online autonuning enables always-on tuning in ray tracing.

The article deals with the promotion of the German language abroad through Germany’s foreign cultural and educational policy. An important concern of the German intermediary organizations abroad is access to culture and education across geographic, political and social borders, but scientific and economic policy. interests, which benefit the needs of the German market, also play a major role. Regarding the fact that more and more skilled workers who are ultimately lacking in their countries of origin are migrating to Germany, the article questions whether it is always a so-called triple-win model.

Anti-CD38 monoclonal antibodies have consistently shown increased efficacy when added to standard of care for patients with multiple myeloma. We aimed to assess the efficacy of isatuximab in addition to lenalidomide, bortezomib, and dexamethasone in patients with newly diagnosed transplantation-eligible multiple myeloma.This open-label, multicentre, randomised, active-controlled, phase 3 trial was done at 67 academic and oncology practice centres in Germany. This study is ongoing and divided into two parts; herein, we report results from part 1. Eligible patients were aged 18-70 years; had a confirmed diagnosis of untreated multiple myeloma requiring systemic treatment and a WHO performance status of 0-2; and were eligible for induction therapy, high-dose melphalan and autologous haematopoietic stem-cell transplantation, and maintenance treatment. Patients were randomly assigned (1:1) to receive three 42-day cycles of induction therapy either with isatuximab plus lenalidomide, bortezomib, and dexamethasone (isatuximab group) or lenalidomide, bortezomib, and dexamethasone alone (control group) using a web-based system and permuted blocks. Patients in both groups received lenalidomide (25 mg orally on days 1-14 and 22-35), bortezomib (1·3 mg/mBetween Oct 23, 2018, and Sep 22, 2020, 660 patients were included in the ITT analysis (331 in the isatuximab group and 329 in the control group). 654 (99%) patients were White, two were African, one was Arabic, and three were Asian. 250 (38%) were women and 410 (62%) were men. The median age was 59 years (IQR 54-64). MRD negativity after induction therapy was reached in 166 (50%) patients in the isatuximab group versus 117 (36%) in the control group (OR 1·82 [95% CI 1·33-2·48]; p=0·00017). Median follow-up time from start to end of induction therapy was 125 days (IQR 125-131) versus 125 days (125-132). At least one grade 3 or 4 adverse event occurred in 208 (63%) of 330 patients versus 199 (61%) of 328 patients. Neutropenia of grade 3 or 4 occurred in 77 (23%) versus 23 (7%) patients and infections of grade 3 or 4 occurred in 40 (12%) versus 32 (10%) patients. Among 12 deaths during induction therapy, one death due to septic shock in the isatuximab group and four deaths (one cardiac decompensation, one hepatic and renal failure, one cardiac arrest, and one drug-induced enteritis) in the control group were considered treatment-related.Addition of isatuximab to lenalidomide, bortezomib, and dexamethasone for induction therapy improved rates of MRD negativity with no new safety signals in patients with newly diagnosed transplantation-eligible multiple myeloma.Sanofi and Bristol Myers Squibb (Celgene).

Item does not contain fulltext BACKGROUND: Etrolizumab is a gut-targeted anti-β7 integrin monoclonal antibody. In a previous phase 2 induction study, etrolizumab significantly improved clinical remission versus placebo in patients with moderately to severely active ulcerative colitis. We aimed to compare the safety and efficacy of etrolizumab with infliximab in patients with moderately to severely active ulcerative colitis. METHODS: We conducted a randomised, double-blind, double-dummy, parallel-group, phase 3 study (GARDENIA) across 114 treatment centres worldwide. We included adults (age 18-80 years) with moderately to severely active ulcerative colitis (Mayo Clinic total score [MCS] of 6-12 with an endoscopic subscore of ≥2, a rectal bleeding subscore of ≥1, and a stool frequency subscore of ≥1) who were naive to tumour necrosis factor inhibitors. Patients were required to have had an established diagnosis of ulcerative colitis for at least 3 months, corroborated by both clinical and endoscopic evidence, and evidence of disease extending at least 20 cm from the anal verge. Participants were randomly assigned (1:1) to receive subcutaneous etrolizumab 105 mg once every 4 weeks or intravenous infliximab 5 mg/kg at 0, 2, and 6 weeks and every 8 weeks thereafter for 52 weeks. Randomisation was stratified by baseline concomitant treatment with corticosteroids, concomitant treatment with immunosuppressants, and baseline disease activity. All participants and study site personnel were masked to treatment assignment. The primary endpoint was the proportion of patients who had both clinical response at week 10 (MCS ≥3-point decrease and ≥30% reduction from baseline, plus ≥1-point decrease in rectal bleeding subscore or absolute rectal bleeding score of 0 or 1) and clinical remission at week 54 (MCS ≤2, with individual subscores ≤1); efficacy was analysed using a modified intention-to-treat population (all randomised patients who received at least one dose of study drug). GARDENIA was designed to show superiority of etrolizumab over infliximab for the primary endpoint. This trial is registered with ClinicalTrials.gov, NCT02136069, and is now closed to recruitment. FINDINGS: Between Dec 24, 2014, and June 23, 2020, 730 patients were screened for eligibility and 397 were enrolled and randomly assigned to etrolizumab (n=199) or infliximab (n=198). 95 (48%) patients in the etrolizumab group and 103 (52%) in the infliximab group completed the study through week 54. At week 54, 37 (18·6%) of 199 patients in the etrolizumab group and 39 (19·7%) of 198 in the infliximab group met the primary endpoint (adjusted treatment difference -0·9% [95% CI -8·7 to 6·8]; p=0·81). The number of patients reporting one or more adverse events was similar between treatment groups (154 [77%] of 199 in the etrolizumab group and 151 [76%] of 198 in the infliximab group); the most common adverse event in both groups was ulcerative colitis (55 [28%] patients in the etrolizumab group and 43 [22%] in the infliximab group). More patients in the etrolizumab group reported serious adverse events (including serious infections) than did those in the infliximab group (32 [16%] vs 20 [10%]); the most common serious adverse event was ulcerative colitis (12 [6%] and 11 [6%]). There was one death during follow-up, in the infliximab group due to a pulmonary embolism, which was not considered to be related to study treatment. INTERPRETATION: To our knowledge, this trial is the first phase 3 maintenance study in moderately to severely active ulcerative colitis to use infliximab as an active comparator. Although the study did not show statistical superiority for the primary endpoint, etrolizumab performed similarly to infliximab from a clinical viewpoint. FUNDING: F Hoffmann-La Roche.

This study investigated how the double application of adhesives and dentin moisture level influence the microtensile bond strength (µTBS) of universal adhesives containing different hydrophilic monomers to bur-cut dentin. Four universal adhesives (Scotchbond Universal, Clearfil Universal Bond Quick, PrimeBond Universal, BeautiBond Universal) were applied to wet and dry bur-cut dentin either in one or two layers. The µTBS test was performed after 25,000 thermal cycles, and scanning electron microscopy was used for the analysis of failure mode and interfacial ultrastructure. Double application significantly improved µTBS on wet dentin (p0.001), but the effect was not significant on dry dentin (p0.050). Double application also enhanced the formation of resin tags and limited voids within the adhesive layer of BeautiBond Universal. Dentin moisture had a significant effect on µTBS only if the adhesives were applied in a single layer (p=0.007). Except for PrimeBond Universal, the tested universal adhesives performed better on dry dentin.

Neuromodulatory signalingviaG protein-coupled receptor (GPCRs) plays a pivotal role in regulating neural network function and animal behavior. Recent efforts have led to the development of optogenetic tools to induce G protein-mediated signaling, with the promise of acute and cell type-specific manipulation of neuromodulatory signals. However, designing and deploying optogenetically functionalized GPCRs (optoXRs) with accurate specificity and activity to mimic endogenous signalingin vivoremains challenging. Here we optimized the design of optoXRs by considering evolutionary conserved GPCR-G protein interactions and demonstrate the feasibility of this approach using twoDrosophilaDopamine receptors (optoDopRs). We validated these optoDopRs showing that they exhibit high signaling specificity and light sensitivityin vitro.In vivowe detected receptor and cell type-specific effects of dopaminergic signaling in various behaviors including the ability of optoDopRs to rescue loss of the endogenous receptors. This work demonstrates that OptoXRs can enable optical control of neuromodulatory receptor specific signaling in functional and behavioral studies.

Let ( U n ) n ∈ N (U_n)_{n\in \mathbb {N}} be a fixed linear recurrence sequence defined over the integers (with some technical restrictions). We prove that there exist effectively computable constants B B and N 0 N_0 such that for any b , c ∈ Z b,c\in \mathbb {Z} with b > B b> B the equation U n − b m = c U_n - b^m = c has at most two distinct solutions ( n , m ) ∈ N 2 (n,m)\in \mathbb {N}^2 with n ≥ N 0 n\geq N_0 and m ≥ 1 m\geq 1 . Moreover, we apply our result to the special case of Tribonacci numbers given by T 1 = T 2 = 1 T_1= T_2=1 , T 3 = 2 T_3=2 and T n = T n − 1 + T n − 2 + T n − 3 T_{n}=T_{n-1}+T_{n-2}+T_{n-3} for n ≥ 4 n\geq 4 . By means of the LLL-algorithm and continued fraction reduction we are able to prove N 0 = 2 N_0=2 and B = e 438 B=e^{438} . The corresponding reduction algorithm is implemented in Sage.

Ammonia (NH3), the only basic gas in the atmosphere, constitutes one of the most reactive nitrogen species. It mainly originates from agricultural-related activities, with emissions contributing over 80% globally, while locally they can reach as high as 94%. Once it is emitted, it is transported and deposited to water bodies, soil or vegetation and can then lead to eutrophication of water bodies, modulate soil pH and burn vegetation. It also reacts in the atmosphere with the abundant sulfuric and nitric acids forming fine particulate matter (PM2.5), which affect Earth’s radiative balance, causes visibility problems, but also affects human health, as it penetrates the human respiratory system. However, despite its significance, ammonia source emissions are poorly constrained due to lack of ground-based measurement. Today, several satellite products have become available mainly from satellite sounders. In the present study, we use direct comparisons between the CrIS (Cross-track Infrared Sounder ) observations and model retrievals using the Least Squares with Adaptive Prior Covariance (LS-APC) algorithm, which reduces the number of tuning parameters in the method significantly using variational Bayes approximation technique. We constrain ammonia emissions over Europe over 2013–2020 and validate the results against ground-based observations from the EMEP (European Monitoring and Evaluation Programme). We find that emissions of ammonia decreased from 5431 Gg in 2013 to 3994 Gg in 2020 (-26%). Regionally, emissions declined by 38% in Central and Eastern Europe, 37% in Western Europe, 8% in Southern Europe and -17% in Northern Europe.

Software engineering was recognized as its own type of engineering in the 1960s. At first, the tools and guidelines developed for it were mostly based on common sense, intuition, and personal experience, but not empirical evidence. It took until the late 1990s for researchers in the area to embrace empirical methods. This article is a personal story of how I experienced the maturing of Software Engineering research into an evidence-based science. I will interpret this development using two competing philosophical concepts, rationalism and empiricism, and describe how pragmatism reconciles them.

Falsifiability is a cornerstone of science. It states that scientific claims---propositions, hypotheses, theories---must be testable by experiment. A scientific claim is falsified if an empirical test contradicts it; if a claim withstands repeated attempts at falsification, it is accepted as fact. This article discusses three examples of falsified theories about software. They address the reliability of multi-version programs, the prediction of program bugs by means of software metrics, and the advantages of software models (UML). These examples demonstrate how falsifiability can eliminate incorrect theories and help reorient research and practice.

Real-world data on the use of interleukin-17 (IL-17) inhibitors for the treatment of psoriasis are limited.To evaluate and compare the efficacy, safety, and drug survival of IL-17 inhibitors.This retrospective study analyzed the BIOREP registry data of patients treated with at least one IL-17 inhibitor (secukinumab, ixekizumab, and brodalumab).In total, 949 patients were included. The improvement in PASI score was significant for all drugs, and the proportion of patients achieving PASI 75, 90, and 100 after both 3 and 24 months of therapy was highest for brodalumab, followed by ixekizumab and secukinumab. The Dermatology Life Quality Index score decreased to ˂3 after 3 months and to ˂2 after 24 months of therapy for all inhibitors. Loss of effectiveness was the major reason for discontinuation in 17.2% of patients, followed by adverse events in 3.2% of patients. The drug survival probability was the highest for brodalumab, followed by ixekizumab and secukinumab. Negative predictors for treatment discontinuation were obesity and the number of treatment lines, whereas a positive predictor was the presence of concomitant psoriatic arthritis; sex had no influence.This real-life study demonstrated the effectiveness and good safety profile of all currently available IL-17 inhibitors.

Adrenal computed tomography characteristics (aCTc) in healthy cats are known, but reference intervals for diseased cats are lacking. aCTc of cats without evidence of adrenal disease (NAD group) were compared to parameters of cats with possible concurrent adrenal disease (PAD group). The PAD group was assessed for adrenal masses or other morphological deviations using the NAD group as reference. Associations of aCTc with patient variables were explored, and all results were compared with published aCTc of healthy cats. No incidental adrenal masses were identified in the PAD group (n = 92), and only few aCTc differed compared to the NAD group (n = 30). The NAD group showed similar associations of patient variables and aCTc as length (right: 11.5 ± 2.2 mm, left: 11.8 ± 1.7 mm), width (right: 6.4 ± 1.2 mm, left: 5.4 ± 0.8 mm), height (right: 4.5 ± 0.9 mm, left: 4.5 ± 0.8 mm), attenuation (right: 33.1 ± 5.0 Hounsfield units, left: 32.5 ± 5.3 Hounsfield units) and position, but markedly more mineralization (right: 10%, left: 13.3%) than reported in healthy cats. This study provides references of aCTc for diseased cats without evidence of adrenal disease. The result suggests that adrenal incidentalomas seem to be rare in cats.

Patients on long-term home parenteral nutrition (HPN) occasionally develop glomerulonephritis due to chronic central venous catheter (CVC)-related infection. Most previously reported cases were membranoproliferative glomerulonephritis (MPGN). This is a case report of a 16-year-old girl receiving HPN for short bowel syndrome. After 11 years on HPN, she developed acute kidney injury with macroscopic hematuria, nephrotic-range proteinuria, and a reduced glomerular filtration rate (GFR). Initially, MPGN associated with chronic bacteremia was suspected with the assumption that the condition would be treated with antibiotics and CVC replacement. However, her kidney biopsy revealed antineutrophil cytoplasmic autoantibody (ANCA)-associated glomerulonephritis (AAG). This was consistent with the fact that the patient tested positive for proteinase 3-ANCA. Immunosuppressive therapy with methylprednisolone pulses (followed by oral prednisone) and rituximab led to remission. Her GFR and protein excretion returned to normal. Chronic bacteremia as a complication of long-term HPN may cause various types of glomerulonephritis including, rarely, AAG requiring immunosuppressive therapy.

Establishing an immunohistochemical approach for semi-quantitative assessment of the presence of immunoglobulin G (IgG) in equine, canine, and feline corneas.Healthy corneas of horses, dogs, and cats, euthanized because of a fatal disease or an unrecoverable trauma unrelated to and without a history of ophthalmic disease were formalin-fixed, paraffin-embedded, and determined to be pathomorphologically healthy by light microscopy. Automated immunohistochemistry was performed using primary antibodies against IgG, biotin-conjugated secondary antibodies, and streptavidin-peroxidase, as well as diaminobenzidine for visualization. After counterstaining with hematoxylin, epithelium, stroma, Descemet´s membrane (DM), and endothelium were semi-quantitatively scored for the presence of IgG on a 4-grade scale (0 = no, 1 = faint, 2 = medium, 3 = strong staining) by light microscopy.Corneal specimens of 20 horses (40 eyes) with a median age of 15.5 years (range 2-31 years), 12 dogs (21 eyes) with a median age of 10.0 years (range 4-16), and 13 cats (24 eyes) with a median age of 10.0 years (range 2-18) were included in the study. Different sexes and breeds were represented. In all corneas (100%), significant medium signal intensity in the stroma was observed. Variable immunosignal was obtained in epithelium, DM, and endothelium.This method reproducibly allows for the detection of IgG in healthy equine, canine, and feline corneas, particularly stroma. Semi-quantitative results evidence medium presence of IgG in the corneal stroma. Further research is needed to evaluate IgG presence in diseased corneas.

Objectives The aim of this study was to determine whether ultrasonographic pancreatic echogenicity, especially hypoechogenicity, has an impact on the prognosis of cats with suspected pancreatitis. We hypothesised that cats with a hypoechoic pancreas have a longer duration of hospitalisation, higher treatment costs and a higher mortality rate. Methods This was a retrospective study, which included cats with clinical signs of pancreatitis, a SNAP fPL test result above the reference interval and ultrasonographic abnormalities consistent with pancreatitis. Medical records and follow-up information were retrieved from the local electronic database. Cases were assigned to one of three groups based on pancreatic echogenicity: hypoechoic, hyperechoic or mixed echogenicity. Statistical analysis aimed to assess differences in outcome, ultrasonographic abnormalities, historical features, physical examination findings, laboratory results, concurrent diseases or treatment costs. Results Thirty-six (64%) cats with a hypoechoic, seven (13%) with a hyperechoic and 13 (23%) cats with a mixed echoic pancreas were included. Cats with a hypoechoic pancreas had a significantly lower median body weight ( P = 0.010) and lower median body condition score ( P = 0.004) compared with the other cats. Furthermore, they were presented as being lethargic significantly more often ( P = 0.014), were more likely to have a homogeneously enlarged pancreas ( P Conclusions and relevance In this study, echogenicity was of no prognostic value in cats with suspected pancreatitis. Cats with a hypoechoic pancreas were not associated with a poorer outcome than cats with a hyperechoic or mixed echoic pancreas.

Zusammenfassung Gegenstand und Ziel Epilepsie gehört auch bei Katzen zu den häufigeren chronischen neurologischen Erkrankungen. Bei der diagnostischen Aufarbeitung spielt die magnetresonanztomographische (weiters: MRT) Untersuchung eine zentrale Rolle. Bei hippocampalen MRT-Veränderungen kann die Frage, ob diese Veränderungen die Ursache oder die Folge der Symptome repräsentieren, oft nicht beantwortet werden.Ziel der Studie war die retrospektive Aufarbeitung der MRT-Befunde einer großen Patientenkohorte an epileptischen Katzen. Material und Methoden Insgesamt wurden 143 Katzen aufgeteilt in 3 Altersgruppen (< 1 Jahr, zw. 1–6 Jahre, > 6 Jahre) in die Studie aufgenommen. Die MRT-Befunde wurden in die folgenden 4 Kategorien aufgeteilt: Unauffällig, extrahippocampale Veränderungen, hippocampale Signaländerungen ohne und mit Kontrastmittelaufnahme. Die Prävalenz und die Auftrittswahrscheinlichkeit der unterschiedlichen MRT-Veränderungen wurden in den Altersgruppen mittels Chi-Quadrat-Test und nominaler Regression geprüft. Ergebnisse Etwa die Hälfte der Katzen (49 %) wies einen unauffälligen MRT-Befund auf. Extrahippocampale Veränderungen wurden in 18 % der Katzen festgestellt. Hippocampale Veränderungen waren bei 33 % der Katzen zu finden. Die hippocampale Sklerose konnte histopathologisch in allen vier MRT-Gruppen (unauffällige MRT, extrahippocampale Veränderungen, hippocampale Signaländerung mit und ohne Kontrastmittelanreicherung) nachgewiesen werden. Schlussfolgerung und klinische Relevanz Bei etwa 50 % der epileptischen Katzen ergibt die Gehirn MRT einen unauffälligen Befund; extrahippocampale Veränderungen sind insbesondere bei älteren Katzen zu erwarten. Die hippocampalen MRT-Veränderungen sind oft ätiologisch nicht zuzuordnen. Weitere Untersuchungen sind erforderlich, um die Bedeutung von hippocampalen Veränderungen zu verstehen.

Purpose To report historical patterns of pharmaceutical expenditures, to identify factors that may influence future spending, and to predict growth in drug spending in 2023 in the United States, with a focus on the nonfederal hospital and clinic sectors. Methods Historical patterns were assessed by examining data on drug purchases from manufacturers using the IQVIA National Sales Perspectives database. Factors that may influence drug spending in hospitals and clinics in 2023 were reviewed, including new drug approvals, patent expirations, and potential new policies or legislation. Focused analyses were conducted for biosimilars, cancer drugs, diabetes medications, generics, COVID-19 pandemic influence, and specialty drugs. For nonfederal hospitals, clinics, and overall (all sectors), estimates of growth of pharmaceutical expenditures in 2023 were based on a combination of quantitative analyses and expert opinion. Results In 2022, overall pharmaceutical expenditures in the US grew 9.4% compared to 2021, for a total of $633.5 billion. Utilization (a 5.9% increase), price (a 1.7% increase) and new drugs (a 1.8% increase) drove this increase. Adalimumab was the top-selling drug in 2022, followed by semaglutide and apixaban. Drug expenditures were $37.2 billion (a 5.9% decrease) and $116.9 billion (a 10.4% increase) in nonfederal hospitals and clinics, respectively. In clinics, new products and increased utilization growth drove growth, with a small impact from price changes. In nonfederal hospitals, a drop in utilization led to a decrease in expenditures, with price changes and new drugs contributing to growth in spending. Several new drugs that will influence spending have been or are expected to be approved in 2023. Specialty and cancer drugs will continue to drive expenditures along with the evolution of the COVID-19 pandemic. Conclusion For 2023, we expect overall prescription drug spending to rise by 6.0% to 8.0%, whereas in clinics and hospitals we anticipate increases of 8.0% to 10.0% and 1.0% to 3.0%, respectively, compared to 2022. These national estimates of future pharmaceutical expenditure growth may not be representative of any particular health system because of the myriad of local factors that influence actual spending.

The goal of the RENEB inter-laboratory comparison 2021 exercise was to simulate a large-scale radiation accident involving a network of biodosimetry labs. Labs were required to perform their analyses using different biodosimetric assays in triage mode scoring and to rapidly report estimated radiation doses to the organizing institution. This article reports the results obtained with the cytokinesis-block micronucleus assay. Three test samples were exposed to blinded doses of 0, 1.2 and 3.5 Gy X-ray doses (240 kVp, 13 mA, ∼75 keV, 1 Gy/min). These doses belong to 3 triage categories of clinical relevance: a low dose category, for no exposure or exposures inferior to 1 Gy, requiring no direct treatment of subjects; a medium dose category, with doses ranging from 1 to 2 Gy, and a high dose category, after exposure to doses higher than 2 Gy, with the two latter requiring increasing medical attention. After irradiation the test samples (no. 1, no. 2 and no. 3) were sent by the organizing laboratory to 14 centers participating in the micronucleus assay exercise. Laboratories were asked to setup micronucleus cultures and to perform the micronucleus assay in triage mode, scoring 500 binucleated cells manually, or 1,000 binucleated cells in automated/semi-automated mode. One laboratory received no blood samples, but scored pictures from another lab. Based on their calibration curves, laboratories had to provide estimates of the administered doses. The accuracy of the reported dose estimates was further analyzed by the micronucleus assay lead. The micronucleus assay allowed classification of samples in the corresponding clinical triage categories (low, medium, high dose category) in 88% of cases (manual scoring, 88%; semi-automated scoring, 100%; automated scoring, 73%). Agreement between scoring laboratories, assessed by calculating the Fleiss' kappa, was excellent (100%) for semi-automated scoring, good (83%) for manual scoring and poor (53%) for fully automated scoring. Correct classification into triage scoring dose intervals (reference dose ±0.5 Gy for doses ≤2.5 Gy, or reference dose ±1 Gy for doses >2.5 Gy), recommended for triage biodosimetry, was obtained in 79% of cases (manual scoring, 73%; semi-automated scoring, 100%; automated scoring, 67%). The percentage of dose estimates whose 95% confidence intervals included the reference dose was 58% (manual scoring, 48%; semi-automated scoring, 72%; automated scoring, 60%). For the irradiated samples no. 2 and no. 3, a systematic shift towards higher dose estimations was observed. This was also noticed with the other cytogenetic assays in this intercomparison exercise. Accuracy of the rapid triage modality could be maintained when the number of manually scored cells was scaled down to 200 binucleated cells. In conclusion, the micronucleus assay, preferably performed in a semi-automated or manual scoring mode, is a reliable technique to perform rapid biodosimetry analysis in large-scale radiation emergencies.

This file contains the combined supplementary figures and tables. Table S1. Prediction methods used in this study. Table S2. In silico predicted and in vitro validated binding affinities of peptides derived from HPV16 E6 and E7 proteins for the HLA types A1, A2, A3, A11, A24, B7 and B15. Figure S1. Performance evaluation of HLA binding prediction algorithms: the capacity to separate HLA-A1, A11, B7 and B15 binders from non-binders. Figure S2. Performance evaluation for the predictor SYFPEITII. Figure S3. Decision threshold-dependent performance analysis of indicated HLA-binding prediction methods for HLA-A1, A11, B7 and B15. Figure S4. Assessment of prediction performance for HLA-A1, A3, A11, A24, B7 and B15 using thresholds individually recommended for each HLA-type and peptide length vs. general intermediate and low binding affinity thresholds. Figure S5. Comparison of prediction accuracies obtained by applying criteria-based and bootstrapping-validated thresholds for each analyzed predictor for HLA-A1, A11, B7 and B15. Figure S6. Effect of using individually calculated criteria-based thresholds vs. commonly used thresholds for the prediction of HPV16 E6 and E7 derived ligands to HLA A1, A3, A11, A24, B7 and B15. Figure S7. Peptide sequence motifs of HLA-type- specific epitope entries from the immune epitope data base (IEDB) and the HPV dataset.

Knowing whether a protein can be processed and the resulting peptides presented by major histocompatibility complex (MHC) is highly important for immunotherapy design. MHC ligands can be predicted by in silico peptide–MHC class-I binding prediction algorithms. However, prediction performance differs considerably, depending on the selected algorithm, MHC class-I type, and peptide length. We evaluated the prediction performance of 13 algorithms based on binding affinity data of 8- to 11-mer peptides derived from the HPV16 E6 and E7 proteins to the most prevalent human leukocyte antigen (HLA) types. Peptides from high to low predicted binding likelihood were synthesized, and their HLA binding was experimentally verified by in vitro competitive binding assays. Based on the actual binding capacity of the peptides, the performance of prediction algorithms was analyzed by calculating receiver operating characteristics (ROC) and the area under the curve (AROC). No algorithm outperformed others, but different algorithms predicted best for particular HLA types and peptide lengths. The sensitivity, specificity, and accuracy of decision thresholds were calculated. Commonly used decision thresholds yielded only 40% sensitivity. To increase sensitivity, optimal thresholds were calculated, validated, and compared. In order to make maximal use of prediction algorithms available online, we developed MHCcombine, a web application that allows simultaneous querying and output combination of up to 13 prediction algorithms. Taken together, we provide here an evaluation of peptide–MHC class-I binding prediction tools and recommendations to increase prediction sensitivity to extend the number of potential epitopes applicable as targets for immunotherapy.

After large-scale radiation accidents where many individuals are suspected to be exposed to ionizing radiation, biological and physical retrospective dosimetry assays are important tools to aid clinical decision making by categorizing individuals into unexposed/minimally, moderately or highly exposed groups. Quality-controlled inter-laboratory comparisons of simulated accident scenarios are regularly performed in the frame of the European legal association RENEB (Running the European Network of Biological and Physical retrospective Dosimetry) to optimize international networking and emergency readiness in case of large-scale radiation events. In total 33 laboratories from 22 countries around the world participated in the current RENEB inter-laboratory comparison 2021 for the dicentric chromosome assay. Blood was irradiated in vitro with X rays (240 kVp, 13 mA, ∼75 keV, 1 Gy/min) to simulate an acute, homogeneous whole-body exposure. Three blood samples (no. 1: 0 Gy, no. 2: 1.2 Gy, no. 3: 3.5 Gy) were sent to each participant and the task was to culture samples, to prepare slides and to assess radiation doses based on the observed dicentric yields from 50 manually or 150 semi-automatically scored metaphases (triage mode scoring). Approximately two-thirds of the participants applied calibration curves from irradiations with γ rays and about 1/3 from irradiations with X rays with varying energies. The categorization of the samples in clinically relevant groups corresponding to individuals that were unexposed/minimally (0–1 Gy), moderately (1–2 Gy) or highly exposed (>2 Gy) was successfully performed by all participants for sample no. 1 and no. 3 and by ≥74% for sample no. 2. However, while most participants estimated a dose of exactly 0 Gy for the sham-irradiated sample, the precise dose estimates of the samples irradiated with doses >0 Gy were systematically higher than the corresponding reference doses and showed a median deviation of 0.5 Gy (sample no. 2) and 0.95 Gy (sample no. 3) for manual scoring. By converting doses estimated based on γ-ray calibration curves to X-ray doses of a comparable mean photon energy as used in this exercise, the median deviation decreased to 0.27 Gy (sample no. 2) and 0.6 Gy (sample no. 3). The main aim of biological dosimetry in the case of a large-scale event is the categorization of individuals into clinically relevant groups, to aid clinical decision making. This task was successfully performed by all participants for the 0 Gy and 3.5 Gy samples and by 74% (manual scoring) and 80% (semi-automatic scoring) for the 1.2 Gy sample. Due to the accuracy of the dicentric chromosome assay and the high number of participating laboratories, a systematic shift of the dose estimates could be revealed. Differences in radiation quality (X ray vs. γ ray) between the test samples and the applied dose effect curves can partly explain the systematic shift. There might be several additional reasons for the observed bias (e.g., donor effects, transport, experimental conditions or the irradiation setup) and the analysis of these reasons provides great opportunities for future research. The participation of laboratories from countries around the world gave the opportunity to compare the results on an international level.

MotivationTandem mass spectrometry is an essential technology for characterizing chemical compounds at high sensitivity and throughput, and is commonly adopted in many fields. However, computational methods for automated compound identification from their MS/MS spectra are still limited, especially for novel compounds that have not been previously characterized. In recent years,in silicomethods were proposed to predict the MS/MS spectra of compounds, which can then be used to expand the reference spectral libraries for compound identification. However, these methods did not consider the compounds’ three-dimensional (3D) conformations, and thus neglected critical structural information.ResultsWe present the3D Molecular Network forMassSpectra Prediction (3DMolMS), a deep neural network model to predict the MS/MS spectra of compounds from their 3D conformations. We evaluated the model on the experimental spectra collected in several spectral libraries. The results showed that 3DMolMS predicted the spectra with the average cosine similarity of 0.687 and 0.475 with the experimental MS/MS spectra acquired in positive and negative ion modes, respectively. Furthermore, 3DMolMS model can be generalized to the prediction of MS/MS spectra acquired by different labs on different instruments through minor fine-tuning on a small set of spectra. Finally, we demonstrate that themolecular representationlearned by 3DMolMS from MS/MS spectra prediction can be adapted to enhance the prediction of chemical properties such as the elution time (ET) in the liquid chromatography and the Collisional Cross Section (CCS) measured by ion mobility spectrometry (IMS), both of which are often used to improve compound identification.Contacthatang@indiana.eduSupplementary informationThe codes of 3DMolMS is available athttps://github.com/JosieHong/3DMolMSand the web service is athttps://spectrumprediction.gnps2.org.

Resident macrophages exist in a variety of tissues, including tendon, and play context-specific roles in their tissue of residence. In this study, we define the spatiotemporal distribution and phenotypic profile of tendon resident macrophages and their crosstalk with neighboring tendon fibroblasts and the extracellular matrix (ECM) during murine tendon development, growth, and homeostasis. Fluorescent imaging of cryosections revealed that F4/80+ tendon resident macrophages reside adjacent to Col1a1-CFP+ Scx-GFP+ fibroblasts within the tendon fascicle from embryonic development (E15.5) into adulthood (P56). Through flow cytometry and qPCR, we found that these tendon resident macrophages express several well-known macrophage markers, including Adgre1 (F4/80), Mrc1 (CD206), Lyve1, and Folr2, but not Ly-6C, and express the Csf1r-EGFP (“MacGreen”) reporter. The proportion of Csf1r-EGFP+ resident macrophages in relation to the total cell number increases markedly during early postnatal growth, while the density of macrophages per mm2 remains constant during this same time frame. Interestingly, proliferation of resident macrophages is higher than adjacent fibroblasts, which likely contributes to this increase in macrophage proportion. The expression profile of tendon resident macrophages also changes with age, with increased pro-inflammatory and anti-inflammatory cytokine expression in P56 compared to P14 macrophages. In addition, the expression profile of limb tendon resident macrophages diverges from that of tail tendon resident macrophages, suggesting differential phenotypes across anatomically and functionally different tendons. As macrophages are known to communicate with adjacent fibroblasts in other tissues, we conducted ligand-receptor analysis and found potential two-way signaling between tendon fibroblasts and resident macrophages. Tendon fibroblasts express high levels of Csf1, which encodes macrophage colony stimulating factor (M-CSF) that acts on the CSF1 receptor (CSF1R) on macrophages. Importantly, Csf1r-expressing resident macrophages preferentially localize to Csf1-expressing fibroblasts, supporting the “nurturing scaffold” model for tendon macrophage patterning. Lastly, we found that tendon resident macrophages express high levels of ECM-related genes, including Mrc1 (mannose receptor), Lyve1 (hyaluronan receptor), Lair1 (type I collagen receptor), Ctss (elastase), and Mmp13 (collagenase), and internalize DQ Collagen in explant cultures. Overall, our study provides insights into the potential roles of tendon resident macrophages in regulating fibroblast phenotype and the ECM during tendon growth.

IntroductionRomani people have a high prevalence of kidney failure. This study examined a Romani cohort for pathogenic variants in the COL4A3, COL4A4, and COL4A5 genes that are affected in Alport syndrome (AS), a common cause of genetic kidney disease, characterized by hematuria, proteinuria, end-stage kidney failure, hearing loss, and eye anomalies.Materials and methodsThe study included 57 Romani from different families with clinical features that suggested AS who underwent next-generation sequencing (NGS) of the COL4A3, COL4A4, and COL4A5 genes, and 83 family members.ResultsIn total, 27 Romani (19%) had autosomal recessive AS caused by a homozygous pathogenic c.1598G>A, p.Gly533Asp variant in COL4A4 (n = 20) or a homozygous c.415G>C, p.Gly139Arg variant in COL4A3 (n = 7). For p.Gly533Asp, 12 (80%) had macroscopic hematuria, 12 (63%) developed end-stage kidney failure at a median age of 22 years, and 13 (67%) had hearing loss. For p.Gly139Arg, none had macroscopic hematuria (p = 0.023), three (50%) had end-stage kidney failure by a median age of 42 years (p = 0.653), and five (83%) had hearing loss (p = 0.367). The p.Gly533Asp variant was associated with a more severe phenotype than p.Gly139Arg, with an earlier age at end-stage kidney failure and more macroscopic hematuria. Microscopic hematuria was very common in heterozygotes with both p.Gly533Asp (91%) and p.Gly139Arg (92%).ConclusionThese two founder variants contribute to the high prevalence of kidney failure in Czech Romani. The estimated population frequency of autosomal recessive AS from these variants and consanguinity by descent is at least 1:11,000 in Czech Romani. This corresponds to a population frequency of autosomal dominant AS from these two variants alone of 1%. Romani with persistent hematuria should be offered genetic testing.

The impact of human activity on the environment is an ongoing concern not only in the natural sciences but also in economics. Special attention is focused on the transport system, which is one of the largest producers of so-called externalities. However, its regulation may mean a serious disruption of global logistics links, which are crucial for maintaining international and national trade, gross domestic product formation and, therefore, to maintain the economic level to which mankind is accustomed to and which brings a quality of human life that is the highest in the human history. The article, therefore, examines possible economic approaches and theories to the problem of the relationship between human activity and the environment and the possible reduction of negative externalities. Typical approaches to dealing with externalities include the theories of the English economist Arthur Pigou, who proposed the application of various taxes and subsidies to limit the so-called social costs, whereas the extreme solution is the explicit prohibition of certain activities. In contrast to this approach is the theory known as the environmental Kuznets curve, which states the relationship between environmental damage and the economic performance of a given geographical area. It must be respected that the reduction of negative externalities, or their so-called internalisation, cannot be expected to be a trivial solution. The application of additional taxes or subsidies can lead to many unintended consequences, which may ultimately have a greater negative economic impact than the externalities themselves. Therefore, the conclusion of this article is devoted to a discussion of the potential risks of such regulatory interventions from the government position.

Embryonic stem cells (ESCs) give rise to all cell types of the organism. Given the importance of these cells in this process, ESCs must employ robust mechanisms to protect genomic integrity or risk catastrophic propagation of mutations throughout the organism. Should such an event occur in daughter cells that will eventually contribute to the germline, the overall species health could dramatically decline. This review describes several key mechanisms employed by ESCs that are unique to these cells, in order to maintain their genomic integrity. Additionally, the contributions of cell cycle regulators in modulating ESC differentiation, after DNA damage exposure, are also examined. Where data are available, findings reported in ESCs are extended to include observations described in induced pluripotent stem cells (IPSCs).

Objective: To evaluate the impact of immediate (first day after surgery) mobilization compared to standard five weeks cast immobilization on the functional outcome after volar locking plate fixation of distal radius fractures. Design: Prospective randomized parallel group comparative trial. Setting: Trauma Hospital, Austria. Participants: Patients with isolated unstable distal radius fractures, stabilized with volar angular stable locking plate. Interventions: The immediate mobilization group received a removable forearm splint for one week and active supervised group physiotherapy and home exercises for the shoulder, elbow, wrist, and fingers from the first postoperative day. The cast immobilization group received a non-removable cast for five weeks. In the first five weeks supervised group physiotherapy and home exercises were performed for shoulder, elbow, and fingers. Thereafter additional supervised and home exercises for the wrist were started. Main measures: At regular intervals of six and nine weeks, three and six months, and one year post surgery range of motion, grip strength, and x-rays were evaluated. Additionally, the shortened disabilities of the arm, shoulder and hand ( QuickDASH) score, Patient-rated Wrist Evaluation, Mayo Wrist score, and pain according to the Visual Analog Scale score were analyzed. Results: One hundred and sixteen patients were prospectively randomized into two study groups. At the one-year follow-up, patients in the immediate mobilization group showed a significantly higher range of motion in extension/flexion (mean difference 10.2°, 99% confidence interval 0.6–19.8), grip strength (mean difference 5.1 kg, 99% confidence interval −0.5 to 10.7), and Mayo Wrist score (mean difference 7.9 points, 99% confidence interval 2.3–13.5) than the cast immobilization group. Range of motion in supination/pronation (mean difference 13.4°, 99% confidence interval 1.5–25.3) and in radial/ulnar deviation (mean difference 6.3°, 99% confidence interval 0.9–11.7) differed significantly up to nine weeks favoring the immediate mobilization group. The Patient-rated Wrist Evaluation revealed significantly better scores after three months (mean difference 9.3 points, 99% confidence interval 0.5–18.1) and QuickDASH after six months (mean difference 7.3 points, 99% confidence interval 0.3–14.3) in the immediate mobilization group. All other subsequent follow-up examinations indicated no significant differences in respect of pain, range of motion, and patient-reported outcome measurements between the study groups. There were no significant differences in respect of radiological loss of reduction and complications between the groups. Conclusions: Immediate mobilization in combination with supervised physiotherapy of the wrist after volar locking plate fixation of unstable distal radius fractures results in a significantly improved range of motion and grip strength after one year compared to cast immobilization. No increased risk for loss of reduction and other complications was observed.

The effect of long-term water storage on the regional ultimate tensile strength (UTS), water sorption (Wsp) and water solubility (Wsl) of conventional and bulk-fill resin composites at various depths was investigated. Composite specimens light-cured from one side were sectioned into beams corresponding to different depths (1-5 mm) and stored in water for 24 h, 1 week, 1 month, 6 months or 1 year. UTS increased during the first week and then gradually decreased over time, especially in deeper regions. Bulk-fill composites initially exhibited similar UTS at all depths, whereas the UTS of conventional composites at 1 mm and 5 mm differed significantly at all time points. Wsp and Wsl increased with depth and storage time, markedly at 3-5 mm after 1 month for conventional composites and after 6 months for bulk-fill composites. The signs of degradation at depths beyond 3 mm suggested that even bulk-fill composites have suboptimal properties in layers more than 3 mm in thickness.

Summary Gastrointestinal lymphomas are uncommon in dogs and little is known about their distinct subtypes or proliferation rate. The aim of this study was to stratify 33 canine gastrointestinal lymphoma samples according to the latest World Health Organization classification and to determine the Ki67 proliferation index by manual counting, digital image analysis and visual estimation. The Ki67 index was then correlated with subtype, immunophenotype, mitotic index, grade and tumour location. The mitotic index correlated positively with the Ki67 index. A significantly higher number of Ki67-positive cells was found in enteropathy-associated T-cell lymphoma type I and in diffuse large B-cell lymphoma compared with enteropathy-associated T-cell lymphoma type II. There was also a significant difference in Ki67 immunolabelled cells between grade 1 and grade 2 lymphomas. Moderate agreement was found between the Ki67 index as obtained by manual counting and visual estimation, but there was strong agreement between manual counting and digital image analysis. The user-friendly digital imaging system used in this study could have potential for future determination of the Ki67 index in lymphoid neoplasms.

Object Epilepsy surgery is an effective treatment for selected patients with focal intractable epilepsy. Complete removal of the epileptogenic zone significantly increases the chances for postoperative seizure-freedom. In complex surgical candidates, delineation of the epileptogenic zone requires a long-term invasive video/EEG from intracranial electrodes. It is especially challenging to achieve a complete resection in deep brain structures such as opercular-insular cortex. We report a novel approach utilizing intraoperative visual detection of stereotactically implanted depth electrodes to inform and guide the extent of surgical resection. Methods We retrospectively reviewed data of pediatric patients operated in Motol Epilepsy Center between October 2010 and June 2020 who underwent resections guided by intraoperative visual detection of depth electrodes following SEEG. The outcome in terms of seizure- and AED-freedom was assessed individually in each patient. Results Nineteen patients (age at surgery 2.9–18.6 years, median 13 years) were included in the study. The epileptogenic zone involved opercular-insular cortex in eighteen patients. The intraoperative detection of the electrodes was successful in seventeen patients and the surgery was regarded complete in sixteen. Thirteen patients were seizure-free at final follow-up including six drug-free cases. The successful intraoperative detection of the electrodes was associated with favorable outcome in terms of achieving complete resection and seizure-freedom in most cases. On the contrary, the patients in whom the procedure failed had poor postsurgical outcome. Conclusion The reported technique helps to achieve the complete resection in challenging patients with the epileptogenic zone in deep brain structures.