Single-Shot Diagnosis of Electron Energy Evolution via Streaked Betatron X Rays in a Curved Laser Wakefield Accelerator.

We report on an experimental observation of the streaking of betatron x rays in a curved laser wakefield accelerator. The streaking of the betatron x rays was realized by launching a laser pulse into a plasma with a transverse density gradient. By controlling the plasma density and the density gradient, we realized the steering of the laser driver, electron beam, and betatron x rays simultaneously. Moreover, we observed an energy-angle correlation of the streaked betatron x rays and utilized it in diagnosing the electron acceleration process in a single-shot mode. Our work could also find applications in advanced control of laser beam and particle propagation. More importantly, the angular streaked betatron x ray has an intrinsic spatiotemporal correlation, which makes it a promising tool for single-shot pump-probe applications.

dtiRIM: A generalisable deep learning method for diffusion tensor imaging.

Diffusion weighted MRI is an indispensable tool for routine patient screening and diagnostics of pathology. Recently, several deep learning methods have been proposed to quantify diffusion parameters, but poor generalisation to new data prevents broader use of these methods, as they require retraining of the neural network for each new scan protocol. In this work, we present the dtiRIM, a new deep learning method for Diffusion Tensor Imaging (DTI) based on the Recurrent Inference Machines. Thanks to its ability to learn how to solve inverse problems and to use the diffusion tensor model to promote data consistency, the dtiRIM can generalise to variations in the acquisition settings. This enables a single trained network to produce high quality tensor estimates for a variety of cases. We performed extensive validation of our method using simulation and in vivo data, and compared it to the Iterated Weighted Linear Least Squares (IWLLS), the approach of the state-of-the-art MRTrix3 software, and to an implementation of the Maximum Likelihood Estimator (MLE). Our results show that dtiRIM predictions present low dependency on tissue properties, anatomy and scanning parameters, with results comparable to or better than both IWLLS and MLE. Further, we demonstrate that a single dtiRIM model can be used for a diversity of data sets without significant loss in quality, representing, to our knowledge, the first generalisable deep learning based solver for DTI.

The KNee OsteoArthritis Prediction (KNOAP2020) challenge: An image analysis challenge to predict incident symptomatic radiographic knee osteoarthritis from MRI and X-ray images.

OBJECTIVES: The KNee OsteoArthritis Prediction (KNOAP2020) challenge was organized to objectively compare methods for the prediction of incident symptomatic radiographic knee osteoarthritis within 78 months on a test set with blinded ground truth. DESIGN: The challenge participants were free to use any available data sources to train their models. A test set of 423 knees from the Prevention of Knee Osteoarthritis in Overweight Females (PROOF) study consisting of magnetic resonance imaging (MRI) and X-ray image data along with clinical risk factors at baseline was made available to all challenge participants. The ground truth outcomes, i.e., which knees developed incident symptomatic radiographic knee osteoarthritis (according to the combined ACR criteria) within 78 months, were not provided to the participants. To assess the performance of the submitted models, we used the area under the receiver operating characteristic curve (ROCAUC) and balanced accuracy (BACC). RESULTS: Seven teams submitted 23 entries in total. A majority of the algorithms were trained on data from the Osteoarthritis Initiative. The model with the highest ROCAUC (0.64 (95% confidence interval (CI): 0.57-0.70)) used deep learning to extract information from X-ray images combined with clinical variables. The model with the highest BACC (0.59 (95% CI: 0.52-0.65)) ensembled three different models that used automatically extracted X-ray and MRI features along with clinical variables. CONCLUSION: The KNOAP2020 challenge established a benchmark for predicting incident symptomatic radiographic knee osteoarthritis. Accurate prediction of incident symptomatic radiographic knee osteoarthritis is a complex and still unsolved problem requiring additional investigation.

Impact of Bepanthen® and dexpanthenol on human nasal ciliary beat frequency in vitro.

BACKGROUND: Dexpanthenol-containing ointments/fluids are recommended to restore impaired nasal mucosa. To date, there are no data about the influence of dexpanthenol or formulations including dexpanthenol on ciliary beat frequency (CBF) of nasal epithelial cells. METHODS: We tested the ciliary beat frequency of human nasal epithelial cells in RPMI 1640 cell solution using in vitro high-frequency video microscopy every 60 s over a period of 15 min (min). Bepanthen® solution and dexpanthenol in two clinically relevant concentrations (1.67% and 3.33%) were added to the cells. Addition of sterile water served as control group. To get a better overview, the measurements after 1 min, 5 min and 15 min were combined. RESULTS: The CBF in the control group (n = 17) after 15 min was 7.3 ± 2.6 Hz. In comparison, the CBF after 15 min was 1.8 ± 1.0 Hz in the 3.33% Bepanthen® group (n = 17) and 3.2 ± 1.2 Hz in the 1.67% group, which was statistically significantly lower in both groups (p < 0.001). With regard to the dexpanthenol group (n = 17) a CBF of 6.0 ± 2.6 Hz with 3.33% and 6.1 ± 2.4 Hz with 1.67% dexpanthenol, was detected, which was again statistically significantly lower (p = 0.06) compared to the control group except CBF at 15 min with 1.57% (n = 17; p = 0.04). In general, the effect on CBF was less pronounced with dexpanthenol compared with Bepanthen® with a statistically significant difference between the two formulations. The results were verified by calculating an analysis of variance (ANOVA). CONCLUSIONS: Bepanthen® as an ointment, solution or inhalation is commonly used in ENT for mucosal care. Our results have shown that both substances reduce CBF in clinically relevant concentrations, although the effect was more pronounced with Bepanthen® compared to dexpanthenol solution, which could be related to additives or change of physical properties in the solution. Further research is needed to assess potential clinical relevance.

Pediatric Project ECHO® for Pain: implementation and mixed methods evaluation of a virtual medical education program to support interprofessional pain management in children and youth.

BACKGROUND: Pediatric pain is a complex health challenge requiring a multi-modal management approach. It is critical that healthcare providers (HCPs) have access to ongoing, flexible education and mentorship specific to pediatric pain. However, there are significant gaps in available pain education and a need for more opportunities to support interprofessional training. Project Extension for Community Healthcare Outcomes (Project ECHO®) is a model for delivering online HCP education and cultivating a virtual community of practice. Within the pediatric pain setting, ECHO® has potential to improve local access to specialized pain knowledge, particularly among the physicians, nurses, and allied health providers who primarily manage these cases in community and hospital settings across rural and urban environments. The purpose of this study was three-fold. First, to evaluate the feasibility (participation levels, acceptability) of implementing Project ECHO® in the context of pediatric pain. Second, to measure preliminary program impacts on HCP knowledge, self-efficacy, and clinical practice. Third, to characterize HCP program engagement levels before and after onset of the COVID-19 pandemic. METHODS: A needs assessment was conducted to identify interprofessional education gaps and inform the program curriculum. The no-cost Pediatric ECHO® for Pain program offered TeleECHO sessions (didactic and case-based learning) as well as foundational education. Surveys were distributed at baseline and 6 months to assess outcomes using 7-point Likert scales. Participant engagement was assessed for periods prior to and during the COVID-19 pandemic. Descriptive and inferential statistical analyses were conducted. RESULTS: Eighty-five TeleECHO sessions were hosted, with a mean attendance of 34.1 ± 23.4 HCPs. Acceptability scores at 6 months (n = 33) ranged from 5.0 ± 1.4 to 6.5 ± 0.5. Participants reported statistically significant (p < 0.05) improvements in knowledge (7 out of 7 topics) and self-efficacy (8 out of 9 skills). Most participants reported positive practice impacts, including improved satisfaction with managing children with pain. Exploratory analyses showed a trend of greater engagement from ECHO® learners after onset of the COVID-19 pandemic. CONCLUSIONS: Project ECHO® is a feasible and impactful model for virtual education of interprofessional HCPs in managing pediatric pain.

Covering of wound infection in hip arthroplasty with local cutaneous flaps.

Total hip arthroplasty is a very common procedure to treat osteoarthritis. One of the complication is the infection which occurs in about 1% of the cases. The manifestation of infection can be poor wound healing with dehiscence and exposition of bone or prosthetic components. Hip arthroplasty infections are difficult to treat. It required an associated multidisciplinary approach with infectiology, orthopedic and plastic surgeries. The study included five patients with hip wound dehiscence after total hip arthroplasty. Coverage after orthopedic surgery was provided by local cutaneous flap. These cutaneous flaps were either a deep inferior epigastric perforator flap (DIEP) or a transposition flap. The orthopedic and the plastic treatment were done at the same time. Two deep inferior epigastric flaps were performed for patients with a deep defect with bone or prosthesis exposure. Four transposition flaps were done in three patients with wound dehiscence but without direct contact with the prosthesis. Three transposition flaps were done from the abdominal wall and one from the posterior thigh. The mean follow up was 18 months, ranging from 10 to 24months. After healing, there was no recurrence of the infection. In all cases, the coverage was obtained. The prosthesis was salvage and the gait was possible. Cutaneous flaps are easy and safe to cover the hip. They are reliable flaps even in patients with multiple co-morbidities. They do not cause sequelae on the recipient site. This study is the first about cutaneous flap for covering hip defects in hip arthroplasty infections.

PD-L1 Checkpoint Inhibition Narrows the Antigen-Specific T Cell Receptor Repertoire in Chronic Lymphocytic Choriomeningitis Virus Infection.

Checkpoint inhibitors are effective in restoring exhausted CD8+ T cell responses in persistent viral infections or tumors. Several compounds are in clinical use for different malignancies, but trials in patients with chronic viral infections have also been conducted. In a mouse model of persistent lymphocytic choriomeningitis virus (LCMV) infection, it was shown that checkpoint inhibitor treatment increased T cell proliferation and functionality, but its influence on the antigen-specific T cell receptor (TCR) repertoire is unknown. NP396-specific CD8+ T cells dominate during acute LCMV infection and are predominantly exhausted during chronic infection. Next-generation sequencing of NP396-specific TCRs showed that exhaustion corresponds with a significantly reduced NP396-specific TCR repertoire diversity: Shannon indices of 4 in immunized mice to 2.6 in persistently infected mice. Anti-PD-L1 treatment during persistent LCMV infection restored NP396-specific T cell responses and reduced viral titers. Nevertheless, anti-PD-L1-treated mice showed an even more narrowed TCR repertoire, with reduced TCR diversity compared to that of persistently infected control mice (Shannon indices of 2.1 and 2.6, respectively). Interestingly, anti-PD-L1 treatment-induced narrowing of the TCR repertoire negatively correlates with functional and physical restoration of the antigen-specific T cell response. Further, we found that private, hyperexpanded TCR clonotypes dominated the T cell response after anti-PD-L1 treatment. Although being private, these top clonotypes from anti-PD-L1-treated mice revealed a more closely related CDR3 motif than those of top clonotypes from persistently infected control mice. In conclusion, although targeting the PD-1/PD-L1 pathway reinvigorates exhausted CD8+ T cells, it fails to restore T cell repertoire diversity.IMPORTANCE Checkpoint inhibitors are effective immunotherapeutics to restore cancer- and virus-induced exhausted CD8+ T cells, by enhancing the quality and survival of immune responses. Although checkpoint inhibitors are already used as therapy against various cancers, not much is known about their multifaceted impact on the exhausted CD8+ T cell receptor (TCR) repertoire. This report describes for the first time the evolvement of an exhausted antigen-specific CD8+ TCR repertoire under checkpoint inhibitor treatment. By using a well-established virus model, we were able to show major shifts toward oligoclonality of the CD8+ TCR repertoire response against a massively exhausted lymphocytic choriomeningitis virus (LCMV) epitope. While supporting viral control in the LCMV model, oligoclonality and more private of TCR repertoires may impact future pathogenic challenges and may promote viral escape. Our results may explain the ongoing problems of viral escapes, unpredictable autoimmunity, and heterogeneous responses appearing as adverse effects of checkpoint inhibitor treatments.

Are changes in meniscus volume and extrusion associated to knee osteoarthritis development? A structural equation model.

OBJECTIVE: To explore the interplay between (changes in) medial meniscus volume, meniscus extrusion and radiographic knee osteoarthritis (OA) development over 30 months follow-up (FU). METHODS: Data from the PRevention of knee Osteoarthritis in Overweight Females study were used. This cohort included 407 middle-aged women with a body mass index ≥27 kg/m2, who were free of knee OA at baseline. Demographics were collected by questionnaires at baseline. All menisci at both baseline and FU were automatically segmented from MRI scans to obtain the meniscus volume and the change over time (delta volume). Baseline and FU meniscus body extrusion was quantitatively measured on mid-coronal proton density MR images. A structural equation model was created to assess the interplay between both medial meniscus volume and central extrusion at baseline, delta volume, delta extrusion, and incident radiographic knee OA at FU. RESULTS: The structural equation modeling yielded a fair to good fit of the data. The direct effects of both medial meniscus volume and extrusion at baseline on incident OA were statistically significant (Estimate = 0.124, p = 0.029, and Estimate = 0.194, p < 0.001, respectively). Additional indirect effects on incident radiographic OA through delta meniscus volume or delta meniscus extrusion were not statistically significant. CONCLUSION: Baseline medial meniscus volume and extrusion were associated to incidence of radiographic knee OA at FU in middle-aged overweight and obese women, while their changes were not involved in these effects. To prevent knee OA, interventions might need to target the onset of meniscal pathologies rather than their progression.

Single-step genomic best linear unbiased predictor genetic parameter estimations and genome-wide associations for milk fatty acid profiles, interval from calving to first insemination, and ketosis in Holstein cattle.

Milk fatty acids (FA) have been suggested as biomarkers for early-lactation metabolic diseases and for female fertility status. The aim of the present study was to infer associations between FA, the metabolic disorder ketosis (KET), and the interval from calving to first insemination (ICF) genetically and genomically. In this regard, we focused on a single-step genomic BLUP approach, allowing consideration of genotyped and ungenotyped cows simultaneously. The phenotypic data set considered 38,375 first-lactation Holstein cows, kept in 45 large-scale co-operator herds from 2 federal states in Germany. The calving years for these cows were from 2014 to 2017. Concentrations in milk from the first official milk recording test-day for saturated, unsaturated (UFA), monounsaturated (MUFA), polyunsaturated, palmitic, and stearic (C18:0) FA were determined via Fourier-transform infrared spectroscopy. Ketosis was defined as a binary trait according to a veterinarian diagnosis key, considering diagnoses within a 6-wk interval after calving. A subset of 9,786 cows was genotyped for 40,989 SNP markers. Variance components and heritabilities for all Gaussian distributed FA and for ICF, and for binary KET were estimated by applying single-step genomic BLUP single-trait linear and threshold models, respectively. Genetic correlations were estimated in series of bivariate runs. Genomic breeding values for the single-step genomic BLUP estimations were dependent traits in single-step GWAS. Heritabilities for FA were moderate in the range from 0.09 to 0.20 (standard error = 0.02-0.03), but quite small for ICF (0.08, standard error = 0.01) and for KET (0.05 on the underlying liability scale, posterior standard deviation = 0.02). Genetic correlations between KET and UFA, MUFA, and C18:0 were large (0.74 to 0.85, posterior standard deviation = 0.14-0.19), and low positive between KET and ICF (0.17, posterior standard deviation = 0.22). Genetic correlations between UFA, MUFA, and C18:0 with ICF ranged from 0.34 to 0.46 (standard error = 0.12). In single-step GWAS, we identified a large proportion of overlapping genomic regions for the different FA, especially for UFA and MUFA, and for saturated and palmitic FA. One identical significantly associated SNP was identified for C18:0 and KET on BTA 15. However, there was no genomic segment simultaneously significantly affecting all trait categories ICF, FA, and KET. Nevertheless, some of the annotated potential candidate genes DGKA, IGFBP4, and CXCL8 play a role in lipid metabolism and fertility mechanisms, and influence production diseases in early lactation. Genetic and genomic associations indicate that Fourier-transform infrared spectroscopy FA concentrations in milk from the first official test-day are valuable predictors for KET and for ICF.

Aspects of transition cow metabolomics-Part I: Effects of a metaphylactic butaphosphan and cyanocobalamin treatment on the metabolome in liver, blood, and urine in cows with different liver metabotypes.

Dairy cows in modern production systems are at risk to develop metabolic disorders during the transition period. Reasons for individual differences in susceptibility, as well as the underlying pathomechanisms, are still only partially understood. The development of metaphylactic treatment protocols is needed. In this context, an on-farm prospective 3-fold blinded randomized study involving 80 German Holstein cows was performed throughout 1 yr. The trial involved a thorough recording of the production and clinical traits, clinical chemistry, and liver biopsies and blood and urine sampling at d 14 (mean: 12 d, range: 1-26 d) antepartum (AP), and d 7 (7, 4-13) and 28 (28, 23-34) postpartum (PP) for metabolomics analyses. Two groups received a treatment with butaphosphan and cyanocobalamin (BCC) at either the dosage recommended by the manufacturer or the double dosage (5 or 10 mL/100 kg of body weight 10% butaphosphan and 0.005% cyanocobalamin (Catosal, Bayer Animal Health), n = 20 in each group, parity: 4.2 ± 2.0 and 3.4 ± 1.3, respectively (mean ± SD)] and one group a placebo treatment (NaCl 0.9%, n = 40, parity: 4.0 ± 1.9). The animals were treated at 6 time points (7, 6, and 5 d AP, and 1, 2, and 3 d PP) via intravenous injection. Mass spectroscopy-based targeted metabolomics analysis of blood plasma and liver samples were performed using the AbsoluteIDQ p180 kit (Biocrates Life Sciences), whereas the urine samples were analyzed by nuclear magnetic resonance spectroscopy. Statistical analysis was performed using multivariate [partial least squares discriminant analysis (PLS-DA)] and univariate methods (linear mixed model). Multivariate data analysis (PLS-DA plots) of the liver metabolome revealed 3 different metabotypes (A = medium, B = minor, C = large alterations in liver metabolome profile between AP and PP status). Metabotype B animals were characterized by higher PP lipomobilization (stronger PP body condition decrease and higher blood bilirubin, fatty acids, gamma-glutamyltransferase, and triglyceride levels) and a higher occurrence of transition cow diseases, compared with the animals in metabotype C. Analysis of the feeding data showed that the period of metabotype B animals (calving in a distinct time frame) was characterized by a decreased grass silage quality. The PP liver metabolome of the metabotype C animals was characterized by higher concentrations of AA, acylcarnitines, lysoPC and sphingomyelins compared with metabotype B. For the metaphylactic treatment with BCC a dose-dependent effect was confirmed, differing between the metabotypes. In all matrices and metabotypes at various time points significant treatment effects were observed, with different profiles in clinical chemistry and as well in metabolomics data. The most clear-cut treatment effect was observed in metabotype B in the liver at 7 d PP, characterized by an increase in several acylcarnitines and phosphatidylcholines, indicating a more efficient influx and oxidation of fatty acids in mitochondria and thereby an increase in energy supply and more efficient triglyceride export in the liver. The results from the liver metabolomics analysis support the application of an indication-based metaphylactic treatment with BCC.

Aspects of transition cow metabolomics-Part III: Alterations in the metabolome of liver and blood throughout the transition period in cows with different liver metabotypes.

The liver plays a central role in the postpartum (PP) energy metabolism of the transition dairy cow; however, studies describing the liver metabolome during this period were lacking. The aim of the presented study was therefore to compare the alterations in the liver and blood metabolome of transition dairy cows. For this purpose, an on-farm trial with 80 German Holstein cows (mean lactation number: 3.9; range: 2-9) was performed, with thorough documentation of clinical traits and clinical chemistry, as well as production data. Liver biopsies and blood samples were collected at d 14 (mean: 12 d, range: 1-26 d) antepartum (AP), d 7 (7, 4-13) and 28 (28, 23-34; mean, earliest-latest) PP for targeted mass spectroscopy-based metabolomics analysis using the AbsoluteIDQ p180 kit (Biocrates Life Sciences). Statistical analysis was performed using multivariate (partial least squares discriminant analysis) as well as univariate methods (linear mixed model). Multivariate data analysis of the liver metabolome revealed 3 different metabotypes (A = medium, B = minor, C = large alterations in the liver metabolome profile between AP and PP). In metabotype C, an increase of almost all acylcarnitines, lysophosphatidylcholines (lysoPC), sphingomyelins, and some phosphatidylcholines (PC, mainly at 7 d PP) was observed after calving. In contrast to metabotype C, the clinical data of the metabotype B animals indicated a higher PP lipomobilization and occurrence of transition cow diseases. The liver metabolome profile of these animals most likely mirrors a failure of adaptation to the PP state. This strong occurrence of metabotypes was much less pronounced in the blood metabolome. Additionally, differences in metabolic patterns were observed across the transition period when comparing liver and blood matrices (e.g., in different biogenic amines, acylcarnitines and sphingolipids). In summary, the blood samples at 7 d PP showed lower acylcarnitines and PC, with minor alterations and a heterogeneous pattern in AA, biogenic amines, and sphingomyelins compared with 14 d AP. In contrast to 7 d PP, the blood samples at 28 PP revealed an increase in several AA, lysoPC, PC, and sphingomyelins in comparison to the AP state, irrespective of the metabotype. In the liver biopsies metabotype B differed from metabotype C animals ante partum by following metabolites: higher α aminoadipic acid, lower AA, serotonin, taurine, and symmetric dimethylarginine levels, lower or higher concentrations of certain acylcarnitines (higher: C2, C3, C5, C4:1; lower: C12:1, C14:1-OH, C16:2), and lower lysoPC (a C16:0, C18:0, C20:3, C20:4) and hexose levels. In blood samples, fewer differences were observed, with lower serotonin, acylcarnitine C16:2, lysoPC (a C16:0, C17:0, C18:0 and C18:1), PC aa C38:0, and PC ae C42:2. The results show that the use of only the blood metabolome to assess liver metabolism may be hampered by the fact that blood profiles are influenced by the metabolism of many organs, and metabolomics analysis from liver biopsies is a more suitable method to identify distinct metabotypes. Future studies should investigate the stability and reproducibility of the metabotype and phenotypes observed, and the possible predictive value of the metabolites already differing AP between metabotype B and C.

Cerebrovascular Autoregulation Monitoring in the Management of Adult Severe Traumatic Brain Injury: A Delphi Consensus of Clinicians.

BACKGROUND: Several methods have been proposed to measure cerebrovascular autoregulation (CA) in traumatic brain injury (TBI), but the lack of a gold standard and the absence of prospective clinical data on risks, impact on care and outcomes of implementation of CA-guided management lead to uncertainty. AIM: To formulate statements using a Delphi consensus approach employing a group of expert clinicians, that reflect current knowledge of CA, aspects that can be implemented in TBI management and CA research priorities. METHODS: A group of 25 international academic experts with clinical expertise in the management of adult severe TBI patients participated in this consensus process. Seventy-seven statements and multiple-choice questions were submitted to the group in two online surveys, followed by a face-to-face meeting and a third online survey. Participants received feedback on average scores and the rationale for resubmission or rephrasing of statements. Consensus on a statement was defined as agreement of more than 75% of participants. RESULTS: Consensus amongst participants was achieved on the importance of CA status in adult severe TBI pathophysiology, the dynamic non-binary nature of CA impairment, its association with outcome and the inadvisability of employing universal and absolute cerebral perfusion pressure targets. Consensus could not be reached on the accuracy, reliability and validation of any current CA assessment method. There was also no consensus on how to implement CA information in clinical management protocols, reflecting insufficient clinical evidence. CONCLUSION: The Delphi process resulted in 25 consensus statements addressing the pathophysiology of impaired CA, and its impact on cerebral perfusion pressure targets and outcome. A research agenda was proposed emphasizing the need for better validated CA assessment methods as well as the focused investigation of the application of CA-guided management in clinical care using prospective safety, feasibility and efficacy studies.

An Assessment of Earth's Climate Sensitivity Using Multiple Lines of Evidence.

We assess evidence relevant to Earth's equilibrium climate sensitivity per doubling of atmospheric CO2, characterized by an effective sensitivity S. This evidence includes feedback process understanding, the historical climate record, and the paleoclimate record. An S value lower than 2 K is difficult to reconcile with any of the three lines of evidence. The amount of cooling during the Last Glacial Maximum provides strong evidence against values of S greater than 4.5 K. Other lines of evidence in combination also show that this is relatively unlikely. We use a Bayesian approach to produce a probability density function (PDF) for S given all the evidence, including tests of robustness to difficult-to-quantify uncertainties and different priors. The 66% range is 2.6-3.9 K for our Baseline calculation and remains within 2.3-4.5 K under the robustness tests; corresponding 5-95% ranges are 2.3-4.7 K, bounded by 2.0-5.7 K (although such high-confidence ranges should be regarded more cautiously). This indicates a stronger constraint on S than reported in past assessments, by lifting the low end of the range. This narrowing occurs because the three lines of evidence agree and are judged to be largely independent and because of greater confidence in understanding feedback processes and in combining evidence. We identify promising avenues for further narrowing the range in S, in particular using comprehensive models and process understanding to address limitations in the traditional forcing-feedback paradigm for interpreting past changes.

Genetic and nongenetic profiling of milk ß-hydroxybutyrate and acetone and their associations with ketosis in Holstein cows.

Ketosis is a metabolic disorder of increasing importance in high-yielding dairy cows, but accurate population-wide binary health trait recording is difficult to implement. Against this background, proper Gaussian indicator traits, which can be routinely measured in milk, are needed. Consequently, we focused on the ketone bodies acetone and ß-hydroxybutyrate (BHB), measured via Fourier-transform infrared spectroscopy (FTIR) in milk. In the present study, 62,568 Holstein cows from large-scale German co-operator herds were phenotyped for clinical ketosis (KET) according to a veterinarian diagnosis key. A sub-sample of 16,861 cows additionally had first test-day observations for FTIR acetone and BHB. Associations between FTIR acetone and BHB with KET and with test-day traits were studied phenotypically and quantitative genetically. Furthermore, we estimated SNP marker effects for acetone and BHB (application of genome-wide association studies) based on 40,828 SNP markers from 4,384 genotyped cows, and studied potential candidate genes influencing body fat mobilization. Generalized linear mixed models were applied to infer the influence of binary KET on Gaussian-distributed acetone and BHB (definition of an identity link function), and vice versa, such as the influence of acetone and BHB on KET (definition of a logit link function). Additionally, linear models were applied to study associations between BHB, acetone and test-day traits (milk yield, fat percentage, protein percentage, fat-to-protein ratio and somatic cell score) from the first test-day after calving. An increasing KET incidence was statistically significant associated with increasing FTIR acetone and BHB milk concentrations. Acetone and BHB concentrations were positively associated with fat percentage, fat-to-protein ratio and somatic cell score. Bivariate linear animal models were applied to estimate genetic (co)variance components for KET, acetone, BHB and test-day traits within parities 1 to 3, and considering all parities simultaneously in repeatability models. Pedigree-based heritabilities were quite small (i.e., in the range from 0.01 in parity 3 to 0.07 in parity 1 for acetone, and from 0.03-0.04 for BHB). Heritabilites from repeatability models were 0.05 for acetone, and 0.03 for BHB. Genetic correlations between acetone and BHB were moderate to large within parities and considering all parities simultaneously (0.69-0.98). Genetic correlations between acetone and BHB with KET from different parities ranged from 0.71 to 0.99. Genetic correlations between acetone across parities, and between BHB across parities, ranged from 0.55 to 0.66. Genetic correlations between KET, acetone, and BHB with fat-to-protein ratio and with fat percentage were large and positive, but negative with milk yield. In genome-wide association studies, we identified SNP on BTA 4, 10, 11, and 29 significantly influencing acetone, and on BTA 1 and 16 significantly influencing BHB. The identified potential candidate genes NRXN3, ACOXL, BCL2L11, HIBADH, KCNJ1, and PRG4 are involved in lipid and glucose metabolism pathways.

[Rare diseases of the maxillary sinus]. / Seltene Erkrankungen der Kieferhöhle.

BACKGROUND: Silent sinus syndrome (SSS), organized hematoma (OH), and pneumosinus dilatans (PD) are rare, usually unilateral diseases of the maxillary sinus. Due to misinterpretation, excessive diagnostics and unnecessarily aggressive surgery or a delay in diagnostics and treatment are common. OBJECTIVE: The objective of this study was to develop reasonable and comprehensible diagnostic criteria to improve diagnosis and treatment of these rare diseases. METHODS: In this retrospective study, all patients treated for SSS, OH, and PD from 2012 to 2019 were identified. Patient history, diagnostic tests and results, and postoperative course were analyzed and compared with the available literature. RESULTS: During the study period, 7 patients with SSS, 3 patients with PD, and 2 patients with OH were treated and available for follow-up. Comparison of these patients with the literature allowed us to develop diagnostic criteria. CONCLUSION: Medical history combined with endoscopic and radiologic criteria should improve preoperative diagnosis of these three rare diseases of the maxillary sinus and help to distinguish them from other differential diagnoses. This approach should minimize morbidity for the patients.

Radiomics approach to distinguish between well differentiated liposarcomas and lipomas on MRI.

BACKGROUND: Well differentiated liposarcoma (WDLPS) can be difficult to distinguish from lipoma. Currently, this distinction is made by testing for MDM2 amplification, which requires a biopsy. The aim of this study was to develop a noninvasive method to predict MDM2 amplification status using radiomics features derived from MRI. METHODS: Patients with an MDM2-negative lipoma or MDM2-positive WDLPS and a pretreatment T1-weighted MRI scan who were referred to Erasmus MC between 2009 and 2018 were included. When available, other MRI sequences were included in the radiomics analysis. Features describing intensity, shape and texture were extracted from the tumour region. Classification was performed using various machine learning approaches. Evaluation was performed through a 100 times random-split cross-validation. The performance of the models was compared with the performance of three expert radiologists. RESULTS: The data set included 116 tumours (58 patients with lipoma, 58 with WDLPS) and originated from 41 different MRI scanners, resulting in wide heterogeneity in imaging hardware and acquisition protocols. The radiomics model based on T1 imaging features alone resulted in a mean area under the curve (AUC) of 0·83, sensitivity of 0·68 and specificity of 0·84. Adding the T2-weighted imaging features in an explorative analysis improved the model to a mean AUC of 0·89, sensitivity of 0·74 and specificity of 0·88. The three radiologists scored an AUC of 0·74 and 0·72 and 0·61 respectively; a sensitivity of 0·74, 0·91 and 0·64; and a specificity of 0·55, 0·36 and 0·59. CONCLUSION: Radiomics is a promising, non-invasive method for differentiating between WDLPS and lipoma, outperforming the scores of the radiologists. Further optimization and validation is needed before introduction into clinical practice.

ANTECEDENTES: Es difícil distinguir los liposarcomas bien diferenciados (well-differentiated liposarcomas, WDLPS) de los lipomas. En la actualidad, esta distinción se realiza mediante la prueba de amplificación del gen MDM2 por biopsia. El objetivo de este estudio fue predecir de forma no invasiva el estado de amplificación del gen MDM2 para diferenciar los lipomas de los WDLPS utilizando características radiómicas a partir de la resonancia magnética. MÉTODOS: Se incluyeron los pacientes remitidos al instituto Erasmus MC entre 2009-2018 por un lipoma MDM2 negativo o WDLPS MDM2 positivo y las resonancias magnéticas potenciadas en T1 correspondientes antes del tratamiento. Cuando estaban disponibles, se incluyeron otras secuencias de MRI en el análisis radiómico. Se describieron la intensidad, forma y textura de la región tumoral. Para la clasificación se utilizaron varios modelos de aprendizaje automático (machine learning). La evaluación se realizó mediante una validación cruzada aleatoria 100x. Se comparó el rendimiento de los modelos con la clasificación realizada por tres radiólogos expertos. RESULTADOS: Se incluyeron 116 pacientes (58 lipomas, 58 WDLPS) y 41 aparatos de MRI, con una gran heterogeneidad en las técnicas y protocolos para la adquisición de imágenes. El modelo radiómico basado únicamente en las características de las imagen en T1 dio como resultado una AUC media de 0,83, con una sensibilidad de 0,68 y una especificidad de 0,84. Un análisis adicional incorporando las imágenes ponderadas en T2 mejoró el modelo con una AUC media de 0,89, una sensibilidad de 0,74 y una especificidad de 0,88. Los tres radiólogos obtuvieron una AUC de 0,74/0,72/0,61, una sensibilidad de 0,74/0,91/0,64 y una especificidad de 0,55/0,36/0,59, respectivamente. CONCLUSIÓN: La radiómica es un método prometedor y no invasivo para diferenciar entre WDLPS y lipomas, superando la valoración de los radiólogos. Sin embargo, se necesita la optimización y validación de esta técnica antes de su introducción en la práctica clínica diaria.

Magnetized Disruption of Inertially Confined Plasma Flows.

The creation and disruption of inertially collimated plasma flows are investigated through experiment, simulation, and analytical modeling. Supersonic plasma jets are generated by laser-irradiated plastic cones and characterized by optical interferometry measurements. Targets are magnetized with a tunable B field with strengths of up to 5 T directed along the axis of jet propagation. These experiments demonstrate a hitherto unobserved phenomenon in the laboratory, the magnetic disruption of inertially confined plasma jets. This occurs due to flux compression on axis during jet formation and can be described using a Lagrangian-cylinder model of plasma evolution implementing finite resistivity. The basic physical mechanisms driving the dynamics of these systems are described by this model and then compared with two-dimensional radiation-magnetohydrodynamic simulations. Experimental, computational, and analytical results discussed herein suggest that contemporary models underestimate the electrical conductivity necessary to drive the amount of flux compression needed to explain observations of jet disruption.

Allogeneic donor split skin grafts for treatment of refractory ulcers in cutaneous chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation-a retrospective analysis on seven patients.

Refractory skin ulcers due to severe chronic graft-versus-host disease (cGVHD) remain to be associated with significant morbidity and mortality.We performed an allogeneic donor skin transplantation in seven adult patients after allogeneic hematopoietic stem cell transplantation for cGVHD-associated refractory skin ulcers. While four patients received a split skin graft (SSG), in one patient, a full thickness skin graft for two small refractory ulcers of the ankle was performed, and one patient received in vitro expanded donor keratinocyte grafts derived from hair roots of the original unrelated donor. In one additional patient, a large deep fascial defect of the lower leg was covered with an autologous greater omentum free graft before coverage with an allogeneic SSG. An additional patient was treated with an autologous scrotal skin graft for a refractory ulcer associated with deep sclerosis of cGVHD after unrelated donor transplantation.All skin grafts engrafted and resulted in permanent coverage of the grafted ulcers without any signs of immunological mediated damage. In the patient receiving in vitro expanded keratinocyte grafts, two localized ulcers were permanently covered by donor skin while this approach failed to cover extensive circular ulcers of the lower legs.Allogeneic donor skin grafts are a valuable treatment option in refractory ulcers due to cGVHD but are restricted mainly to related donors while keratinocyte grafts from unrelated donors remain experimental. In male patients lacking a related donor, autologous scrotal skin graft may be an alternative option.

Anastomotic leak after transanal total mesorectal excision: grading of severity and management aimed at preservation of the anastomosis.

AIM: The transanal approach to total mesorectal excision (TaTME) as an alternative to conventional anterior resection offers an improved view to otherwise restricted anatomical regions in obese and narrow male pelves and unfavourable tumour locations. Guidelines for the management of anastomotic leakage (AL) following low rectal resections are scarce. PATIENTS AND METHODS: Prospectively collected data of all consecutive patients undergoing TaTME between December 2014 and April 2017 in our centre were analysed retrospectively. Existing classification systems for AL were modified with regard to transanal anastomotic-preserving management. RESULTS: TaTME was performed in 66 patients with a median age of 56.2 years. The overall incidence of AL was 12.1% (n = 8). AL grading was differentiated in Grades I to V according to the severity of necrosis and abscess development. Two patients suffered from AL Grade II, one patient from Grade III, three patients from Grade IV and two patients from Grade V. Preservation of the anastomosis following AL was achieved by the damage control concept in six of eight patients (75%) with a median duration of hospital stay of 36 days. Two patients received a Hartmann procedure (Grades IV and V). CONCLUSION: Our study demonstrates that management of AL following TaTME is challenging but definitely amenable to strategies aimed at preserving the anastomosis by appropriate damage control. The modified classification system might serve as guidance for anastomosis-preserving management.

Single layer colloid centrifugation technique improves motility, viability and chromatin integrity of ram spermatozoa after thawing.

The cell membrane of ram spermatozoa is more sensitive to the freezing process than in other species due to its composition. As a result, the quality and viability of frozen thawed ram spermatozoa are often poor, which together with the specific structure of the ewe's cervix are the main reasons for lower fertility in ewes after intracervical insemination. In the present study we investigated the effects of semen centrifugation through a single layer of a species-specific colloid (Androcoll-O) on post-thaw quality of ram spermatozoa. Motility, viability and morphology were analysed 0, 6, 12 and 24 h after thawing. DNA fragmentation index (%DFI) of the samples was assessed 0 h after thawing, by SCSA™. Membrane and acrosome integrity of spermatozoa were analysed by Sybr-14/PI/PNA test 0 h after thawing. The proportion of motile spermatozoa was significantly higher in SLC - selected samples in comparison to control (not SLC - selected) samples at 0, 6, 12 (P < 0.001) and 24 h (P < 0.05). The proportion of viable spermatozoa was also significantly higher in SLC - selected samples in comparison to control samples at all times (P < 0.001). The proportion of abnormal acrosomes and morphologically abnormal spermatozoa (MAS) were significantly lower in SLC - selected samples compared to control samples at all times (P < 0.001). Analysis of chromatin stability revealed significantly lower %DFI values in SLC - selected samples compared to control samples (P < 0.001). The SYBR-14/PI/PNA test also revealed significantly better values in SLC - selected compared to control samples (P < 0.05). In conclusion, single layer colloid centrifugation significantly improved post-thaw quality and longevity of ram spermatozoa, making it suitable for artificial insemination initiatives.