Publications by authors named "Christian Bauer"

157 Publications

Microbial short-chain fatty acids modulate CD8 T cell responses and improve adoptive immunotherapy for cancer.

Nat Commun 2021 07 1;12(1):4077. Epub 2021 Jul 1.

Institute for Medical Microbiology and Hygiene, Philipps-University Marburg, Marburg, Germany.

Emerging data demonstrate that the activity of immune cells can be modulated by microbial molecules. Here, we show that the short-chain fatty acids (SCFAs) pentanoate and butyrate enhance the anti-tumor activity of cytotoxic T lymphocytes (CTLs) and chimeric antigen receptor (CAR) T cells through metabolic and epigenetic reprograming. We show that in vitro treatment of CTLs and CAR T cells with pentanoate and butyrate increases the function of mTOR as a central cellular metabolic sensor, and inhibits class I histone deacetylase activity. This reprogramming results in elevated production of effector molecules such as CD25, IFN-γ and TNF-α, and significantly enhances the anti-tumor activity of antigen-specific CTLs and ROR1-targeting CAR T cells in syngeneic murine melanoma and pancreatic cancer models. Our data shed light onto microbial molecules that may be used for enhancing cellular anti-tumor immunity. Collectively, we identify pentanoate and butyrate as two SCFAs with therapeutic utility in the context of cellular cancer immunotherapy.
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http://dx.doi.org/10.1038/s41467-021-24331-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8249424PMC
July 2021

Facilitating Study and Item Level Browsing for Clinical and Epidemiological COVID-19 Studies.

Stud Health Technol Inform 2021 May;281:794-798

ZB MED - Information Centre for Life Sciences.

COVID-19 poses a major challenge to individuals and societies around the world. Yet, it is difficult to obtain a good overview of studies across different medical fields of research such as clinical trials, epidemiology, and public health. Here, we describe a consensus metadata model to facilitate structured searches of COVID-19 studies and resources along with its implementation in three linked complementary web-based platforms. A relational database serves as central study metadata hub that secures compatibilities with common trials registries (e.g. ICTRP and standards like HL7 FHIR, CDISC ODM, and DataCite). The Central Search Hub was developed as a single-page application, the other two components with additional frontends are based on the SEEK platform and MICA, respectively. These platforms have different features concerning cohort browsing, item browsing, and access to documents and other study resources to meet divergent user needs. By this we want to promote transparent and harmonized COVID-19 research.
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http://dx.doi.org/10.3233/SHTI210284DOI Listing
May 2021

Does Size Matter? The Influence of Size, Load Factor, Range Autonomy, and Application Type on the Life Cycle Assessment of Current and Future Medium- and Heavy-Duty Vehicles.

Environ Sci Technol 2021 04 18;55(8):5224-5235. Epub 2021 Mar 18.

= INFRAS, 3012 Bern, Switzerland.

The transparent, flexible, and open-source Python library is introduced to perform the life cycle assessment of a series of medium- and heavy-duty trucks across different powertrain types, size classes, fuel pathways, and years in a European context. Unsurprisingly, greenhouse gas emissions per ton-km reduce as size and load factor increase. By 2040, battery and fuel cell electric trucks appear to be promising options to reduce greenhouse gas emissions per ton-km on long distance segments, even where the required range autonomy is high. This requires that various conditions are met, such as improvements at the energy storage level and a drastic reduction of the greenhouse gas intensity of the electricity used for battery charging and hydrogen production. Meanwhile, these options may be considered for urban and regional applications, where they have a competitive advantage thanks to their superior engine efficiency. Finally, these alternative options will have to compete against more mature combustion-based technologies which, despite lower drivetrain efficiencies, are expected to reduce their exhaust emissions via engine improvements, hybridization of their powertrain, as well as the use of biomass-based and synthetic fuels.
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http://dx.doi.org/10.1021/acs.est.0c07773DOI Listing
April 2021

Quantum Algorithm for High Energy Physics Simulations.

Phys Rev Lett 2021 Feb;126(6):062001

Physics Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA.

Simulating quantum field theories is a flagship application of quantum computing. However, calculating experimentally relevant high energy scattering amplitudes entirely on a quantum computer is prohibitively difficult. It is well known that such high energy scattering processes can be factored into pieces that can be computed using well established perturbative techniques, and pieces which currently have to be simulated using classical Markov chain algorithms. These classical Markov chain simulation approaches work well to capture many of the salient features, but cannot capture all quantum effects. To exploit quantum resources in the most efficient way, we introduce a new paradigm for quantum algorithms in field theories. This approach uses quantum computers only for those parts of the problem which are not computable using existing techniques. In particular, we develop a polynomial time quantum final state shower that accurately models the effects of intermediate spin states similar to those present in high energy electroweak showers with a global evolution variable. The algorithm is explicitly demonstrated for a simplified quantum field theory on a quantum computer.
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http://dx.doi.org/10.1103/PhysRevLett.126.062001DOI Listing
February 2021

The German National Case Collection for Familial Pancreatic Carcinoma (FaPaCa)—Knowledge Gained in 20 Years.

Dtsch Arztebl Int 2021 03 5;118(Forthcoming). Epub 2021 Mar 5.

Background: Familial pancreatic carcinoma (FPC) is a rare hereditary tumor syndrome with a heterogeneous clinical phenotype. The study of FPC also contributes to a better understanding of the more common sporadic pancreatic ductal adenocarcinoma (PDAC). We report on the past 20 years' experience of the German National Case Collection for Familial Pancreatic Carcinoma (FaPaCa) of the German Cancer Aid (Deutsche Krebshilfe).

Methods: From 1999 onward, families in which at least two first-degree relatives had PDAC, and which did not meet the criteria for any other tumor syndrome, have been entered into the FaPaCa registry and analyzed both clinically and with molecular genetic techniques. Persons at risk are offered the opportunity to participate in an early detection program.

Results: From June 1999 to June 2019, 227 families (a total of 2579 persons) met the criteria for entry into the FaPaCa registry. PDAC was the sole tumor entity present in 37% of the families (95% confidence interval [31.1; 44.1]); in the remaining 63% [55.9; 68.9], other tumor types were present as well, particularly breast cancer (70 families, 31% [24.9; 37.3]), colon carcinoma (25 families, 11% [7.3; 15.8]) , and melanoma (22 families, 9.7% [6.2; 14.3]). The mode of inheritance of PDAC was autosomal dominant in 72% [65.5; 77.6] of the families. Predisposing germ-line mutations were found in 25 of the 150 (16.7%) families studied, in the following genes: BRCA2 (9 families), CDKN2A (5 families), PALB2 (4 families), BRCA1 (3 families), ATM (2 families), and CHEK2 (2 families). The early detection program revealed high-grade cancer precursor lesions or a PDAC in 5 of the participating 110 persons at risk (4.5%, [1.5; 10.3] during a period of observation of at least five years.

Conclusion: The care of families with FPC is complex and should be provided in centers with the necessary expertise. Prospective, controlled longitudinal studies are needed to determine whether the screening of persons at risk for PDAC truly lessens mortality and is cost-effective.
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http://dx.doi.org/10.3238/arztebl.m2021.0004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8220029PMC
March 2021

Echinococcus multilocularis infection in horses in Poland.

Vet Parasitol Reg Stud Reports 2020 12 4;22:100486. Epub 2020 Nov 4.

Institute of Parasitology, Justus Liebig University Giessen, 35392 Giessen, Germany. Electronic address:

A cross-sectional survey was performed to obtain first information on the prevalence of Echinococcus multilocularis infection in slaughter horses from central, eastern and southern Poland, a country with a highly endemic occurrence of this tapeworm in red foxes. White tough nodular lesions being 3-10 mm in size, sharply demarcated and spherically or irregularly shaped were found in 54 of 365 livers examined. Histologically, focal granulomatous necrotizing inflammations and sometimes PAS-positive acellular lamellar structures being characteristic of the E. multilocularis metacestode stage were visible; protoscoleces were not found. E. multilocularis DNA was detected in six of 19 hepatic lesions examined by nested PCR. Our results from molecular and morphological diagnostics suggest an overall prevalence of alveolar echinococcosis between 4.7% and 14.8% in the horse population studied. Horses as dead-end hosts do not play any role in the life cycle of E. multilocularis but may serve as additional sentinel animals in monitoring the environmental contamination with tapeworm eggs.
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http://dx.doi.org/10.1016/j.vprsr.2020.100486DOI Listing
December 2020

Multiple Sclerosis Data Alliance - A global multi-stakeholder collaboration to scale-up real world data research.

Mult Scler Relat Disord 2021 Jan 21;47:102634. Epub 2020 Nov 21.

Institute of Experimental Neurology, Ospedale San Raffaele, Via Olgettina, 48, 20132, Milan, Italy.

The Multiple Sclerosis Data Alliance (MSDA), a global multi-stakeholder collaboration, is working to accelerate research insights for innovative care and treatment for people with multiple sclerosis (MS) through better use of real-world data (RWD). Despite the increasing reliance on RWD, challenges and limitations complicate the generation, collection, and use of these data. MSDA aims to tackle sociological and technical challenges arising with scaling up RWD, specifically focused on MS data. MSDA envisions a patient-centred data ecosystem in which all stakeholders contribute and use big data to co-create the innovations needed to advance timely treatment and care of people with MS.
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http://dx.doi.org/10.1016/j.msard.2020.102634DOI Listing
January 2021

IL-18 but Not IL-1 Signaling Is Pivotal for the Initiation of Liver Injury in Murine Non-Alcoholic Fatty Liver Disease.

Int J Mol Sci 2020 Nov 14;21(22). Epub 2020 Nov 14.

Department of Medicine II, University Hospital, LMU Munich, 81377 Munich, Germany.

Non-alcoholic fatty liver disease (NAFLD) is rising in prevalence, and a better pathophysiologic understanding of the transition to its inflammatory phenotype (NASH) is key to the development of effective therapies. To evaluate the contribution of the NLRP3 inflammasome and its downstream effectors IL-1 and IL-18 in this process, we applied the true-to-life "American lifestyle-induced obesity syndrome" (ALiOS) diet mouse model. Development of obesity, fatty liver and liver damage was investigated in mice fed for 24 weeks according to the ALiOS protocol. Lipidomic changes in mouse livers were compared to human NAFLD samples. Receptor knockout mice for IL-1 and IL-18 were used to dissect the impact of downstream signals of inflammasome activity on the development of NAFLD. The ALiOS diet induced obesity and liver steatosis. The lipidomic changes closely mimicked changes in human NAFLD. A pro-inflammatory gene expression pattern in liver tissue and increased serum liver transaminases indicated early liver damage in the absence of histological evidence of NASH. Mechanistically, - but not mice were protected from early liver damage, possibly due to silencing of the pro-inflammatory gene expression pattern. Our study identified NLRP3 activation and IL-18R-dependent signaling as potential modulators of early liver damage in NAFLD, preceding development of histologic NASH.
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http://dx.doi.org/10.3390/ijms21228602DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7696705PMC
November 2020

The POLD1 variant increases the sensitivity of colorectal cancer cells to ATR and CHK1 inhibitors.

Sci Rep 2020 11 3;10(1):18924. Epub 2020 Nov 3.

Department of Gastroenterology, Endocrinology, Metabolism, and Infectiology, University Hospital of Marburg, Philipps-University Marburg, Baldingerstraße, 35043, Marburg, Germany.

Inhibition of the kinase ATR, a central regulator of the DNA damage response, eliminates subsets of cancer cells in certain tumors. As previously shown, this is at least partly attributable to synthetic lethal interactions between ATR and POLD1, the catalytic subunit of the polymerase δ. Various POLD1 variants have been found in colorectal cancer, but their significance as therapeutic targets for ATR pathway inhibition remains unknown. Using CRISPR/Cas9 in the colorectal cancer cell line DLD-1, which harbors four POLD1 variants, we established heterozygous POLD1-knockout clones with exclusive expression of distinct variants to determine the functional relevance of these variants individually by assessing their impact on ATR pathway activation, DNA replication, and cellular sensitivity to inhibition of ATR or its effector kinase CHK1. Of the four variants analyzed, only POLD1 affected POLD1 function, as demonstrated by compensatory ATR pathway activation and impaired DNA replication. Upon treatment with ATR or CHK1 inhibitors, POLD1 strongly decreased cell survival in vitro, which was attributable at least partly to S phase impairment and apoptosis. Similarly, treatment with the ATR inhibitor AZD6738 inhibited growth of murine xenograft tumors, harboring the POLD1 variant, in vivo. Our POLD1-knockout model thus complements algorithm-based models to predict the pathogenicity of tumor-specific variants of unknown significance and illustrates a novel and potentially clinically relevant therapeutic approach using ATR/CHK1 inhibitors in POLD1-deficient tumors.
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http://dx.doi.org/10.1038/s41598-020-76033-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641191PMC
November 2020

Pterygodermatites nycticebi infections in golden lion tamarins (Leontopithecus rosalia rosalia) and aye-ayes (Daubentonia madagascariensis) from a German zoo.

Zoo Biol 2021 Jan 2;40(1):59-64. Epub 2020 Nov 2.

Institute of Parasitology, Faculty of Veterinary Medicine, Justus Liebig University Giessen, Giessen, Germany.

In a golden lion tamarin (Leontopithecus rosalia rosalia) colony kept indoors in a German zoo, two animals presented a sudden onset of reduced general condition, lethargy, and diarrhea. At animal capture for clinical examination, adult nematode stages were observed after stress-induced defecation. Despite treatment, two golden lion tamarins died in the following 2 days. At necropsy, spirurid stages were found in the lungs and intestine. Additionally, adult Pterygodermatites spp. were identified in histopathological samples of intestine and pancreas, confirming the previous diagnosis. Upon diagnosis, all animals were treated with ivermectin (0.2 mg/kg; SC). Thereafter, the general condition of the golden lion tamarins improved, whereby some of them excreted spirurid nematodes over 3 days. Four weeks after treatment, 20 fecal samples from the colony were examined and proved negative for parasitic stages. Given that common German cockroaches (Blattella germanica) are suitable intermediate hosts of Pterygodermatites nycticebi, 30 specimens were collected from seven different locations around the golden lion tamarins housing. Third-stage larvae of Pterygodermatites spp. were recovered from those cockroaches. Regular anthelmintic treatments, coprological screenings, and controls for intermediate hosts were recommended. More than 2 years later, P. nycticebi infection was diagnosed again histopathologically in an aye-aye (Daubentonia madagascariensis) which suddenly died. Coprological analysis confirmed the presence of spirurid eggs. Due to prosimian primates' cockroach-eating habits and given that total cockroach eradication proved impossible, continuous cockroach control strategies and regular treatments of primates are currently performed to prevent further P. nycticebi infections.
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http://dx.doi.org/10.1002/zoo.21578DOI Listing
January 2021

Endoscopic ultrasound-fine needle biopsies of pancreatic lesions: Prospective study of histology quality using Franseen needle.

World J Gastroenterol 2020 Oct;26(37):5693-5704

Division of Endoscopy, Department of Gastroenterology, Endocrinology, Metabolism and Clinical Infectiology, University Hospital Marburg, Marburg 35043, Hessen, Germany.

Background: The introduction of fine needle biopsies (FNB) to clinical practice presents a changing trend towards histology in the endoscopic ultrasound-guided tissue acquisition (EUS-TA).

Aim: To evaluate the clinical performance of a new FNB needle, the 22-gauge (22G) Franseen needle, when sampling pancreatic solid lesions.

Methods: Consecutive patients with an indication for EUS-TA for the assessment of pancreatic solid lesions were included in this prospective, single-center, single-arm trial. Each patient underwent a puncture of the lesion two times using the 22G Franseen needle and the obtained samples were directly placed into formalin for histological analysis. The primary study endpoint was the rate of high-quality obtained specimen. Secondary endpoints included the length and diameter of the core specimen, the diagnostic accuracy and the complication rate.

Results: From June 2017 to December 2018, forty patients with pancreatic solid lesions (22 females; mean age 67.2 years) were enrolled. Tissue acquisition was achieved in all cases. High-quality histology, rated with Payne score 3, was obtained in 37/40 cases (92.5%) after two needle passes. The mean size of the acquired histological core tissue was 1.54 mm × 0.39 mm. The diagnostic accuracy for the correct diagnosis was 85% (34/40). Only one adverse event was occurred, consisting of a self-limiting bleeding in the puncture site.

Conclusion: The 22G Franseen needle achieved according to our standardized protocol a high rate of histological core procurement, and a high diagnostic accuracy, with one minor adverse event reported.
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http://dx.doi.org/10.3748/wjg.v26.i37.5693DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7545386PMC
October 2020

The Immune Microenvironment in Pancreatic Cancer.

Int J Mol Sci 2020 Oct 3;21(19). Epub 2020 Oct 3.

Department of Gastroenterology, Endocrinology, Metabolism and Infectiology, Center for Tumor- and Immunology (ZTI), Philipps University Marburg, 35043 Marburg, Germany.

The biology of solid tumors is strongly determined by the interactions of cancer cells with their surrounding microenvironment. In this regard, pancreatic cancer (pancreatic ductal adenocarcinoma, PDAC) represents a paradigmatic example for the multitude of possible tumor-stroma interactions. PDAC has proven particularly refractory to novel immunotherapies, which is a fact that is mediated by a unique assemblage of various immune cells creating a strongly immunosuppressive environment in which this cancer type thrives. In this review, we outline currently available knowledge on the cross-talk between tumor cells and the cellular immune microenvironment, highlighting the physiological and pathological cellular interactions, as well as the resulting therapeutic approaches derived thereof. Hopefully a better understanding of the complex tumor-stroma interactions will one day lead to a significant advancement in patient care.
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http://dx.doi.org/10.3390/ijms21197307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583843PMC
October 2020

Motor fatigue is associated with asymmetric connectivity properties of the corticospinal tract in multiple sclerosis.

Neuroimage Clin 2020 25;28:102393. Epub 2020 Aug 25.

Danish Research Centre for Magnetic Resonance, Centre for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital Hvidovre, Denmark.

Multiple Sclerosis (MS) is characterized by demyelination and neurodegeneration of the central nervous system and causes excessive fatigue in more than 80% of the patients. The pathophysiologic mechanisms causing fatigue are still largely unknown. In 46 right-handed patients with relapsing-remitting MS and 25 right-handed controls, we performed diffusion MRI and applied streamline based probabilistic tractography to derive unilateral anatomical connectivity maps for the white matter of the right and left hemispheres. The maps provide an indication how often a streamline has passed through a given voxel. Since tractography based anatomical connectivity mapping (ACM) is sensitive to disease-induced changes in anatomical connectivity, we used ACM to test whether motor fatigue is associated with altered ipsi-hemispherical anatomical connectivity in the major motor output pathway, the corticospinal tract (CST). Patients had higher mean ACM values in the CST than healthy controls. This indicated that a higher number of streamlines, starting from voxels in the same hemisphere, travelled through the CST and may reflect an accumulated disease-induced disintegration of CST. The motor subscale of the Fatigue Scale for Motor and Cognitive functions (FSMC) was used to define sub-groups with (n = 29, FSMC score ≥ 27) and without motor fatigue (n = 17, FSMS score ≤ 26). Patients without fatigue only showed higher ACM values in right CST, while mean ACM values were unaltered in left CST. The higher the mean ACM values in the left relative to the right CST, the more patients reported motor fatigue. Left-right asymmetry in anatomical connectivity outside the CST did not scale with individual motor fatigue. Our results link lateralized changes of tractography-based microstructural properties in the CST with motor fatigue in relapsing-remitting MS.
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http://dx.doi.org/10.1016/j.nicl.2020.102393DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7490847PMC
June 2021

Bovine Babesiosis Diagnosed in Formalin-Fixed, Paraffin-Embedded Tissues by Using In Situ Hybridization.

Vet Pathol 2020 11 25;57(6):812-820. Epub 2020 Aug 25.

26556University of Veterinary Medicine Hannover, Hannover, Germany.

Bovine babesiosis, caused by , is in general a rare disease in Europe. Nonetheless, local outbreaks can cause severe economic damage, and postmortem identification represents a diagnostic challenge. During a recent outbreak in May 2018 in northern Germany, 21 animals of a herd of 150 cattle died within 40 days having had clinical signs of fever and hemoglobinuria. Gross examination of 4 of the 21 deceased animals revealed a tick infestation, jaundice, and dark brown staining of urine and kidneys. Histologically, there were iron-positive deposits, hyperplasia of the red pulp of the spleen, and centrilobular necrosis of hepatocytes. In several locations, small basophilic granules suggestive of intraerythrocytic parasites were visible in hematoxylin-eosin- and Giemsa-stained sections. Peripheral blood smears from a living cow from the herd and polymerase chain reaction (PCR) of feeding ticks revealed infection. In situ hybridization (ISH) was applied on formalin-fixed, paraffin-embedded (FFPE) tissue of the necropsied cattle to confirm babesiosis in these animals postmortem. Digoxigenin-labeled DNA probes were generated based on a specific nucleotide sequence for , obtained by PCR and sequencing of DNA isolates from infected ticks from deceased cattle. ISH using these probes allowed postmortem diagnosis of infection in routinely fixed FFPE tissues.
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http://dx.doi.org/10.1177/0300985820948816DOI Listing
November 2020

Breeding Habitat Preferences of Major Species (Diptera: Ceratopogonidae) in Germany.

Int J Environ Res Public Health 2020 07 11;17(14). Epub 2020 Jul 11.

Institute of Infectology, Friedrich-Loeffler-Institut, Federal Research Institute for Animal Health, 17493 Greifswald, Germany.

Biting midges of the genus (Diptera, Ceratopognidae) are demonstrably or putatively involved in the transmission of both bluetongue (BTV) and Schmallenberg viruses (SBV) in Central Europe. Although these insects are ubiquitous in Europe, relatively little is known about their requirements in terms of breeding habitats and substrates. species composition and relative abundance in potential breeding habitats were therefore studied at various locations in Northeastern Germany and one location in Western Germany by emergence trap collections. Forty-three potential breeding sites were analyzed in ten landscape structures, with 28,091 adult biting midges emerging from them. Among these, 2116 specimens belonged to the genus . Species of the culicoid subgenus were most abundant (70.6% of all specimens) and widespread (91.6% of all sites), while the subgenus accounted for 15.6% of the specimens registered but emerged from 70.8% of all sites sampled. species of other subgenera were collected in 75.0% of all studied sites, with a relative abundance of 8.7%. The results indicate that various types of dung, but probably also some landscape habitats, offer suitable substrates for the development of potential vector species. Adaptations in dung management on farms and landscape design and use might therefore be appropriate approaches to reduce the risk of BTV or SBV transmission.
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http://dx.doi.org/10.3390/ijerph17145000DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7400431PMC
July 2020

Multisite Technical and Clinical Performance Evaluation of Quantitative Imaging Biomarkers from 3D FDG PET Segmentations of Head and Neck Cancer Images.

Tomography 2020 06;6(2):65-76

Electrical and Computer Engineering.

Quantitative imaging biomarkers (QIBs) provide medical image-derived intensity, texture, shape, and size features that may help characterize cancerous tumors and predict clinical outcomes. Successful clinical translation of QIBs depends on the robustness of their measurements. Biomarkers derived from positron emission tomography images are prone to measurement errors owing to differences in image processing factors such as the tumor segmentation method used to define volumes of interest over which to calculate QIBs. We illustrate a new Bayesian statistical approach to characterize the robustness of QIBs to different processing factors. Study data consist of 22 QIBs measured on 47 head and neck tumors in 10 positron emission tomography/computed tomography scans segmented manually and with semiautomated methods used by 7 institutional members of the NCI Quantitative Imaging Network. QIB performance is estimated and compared across institutions with respect to measurement errors and power to recover statistical associations with clinical outcomes. Analysis findings summarize the performance impact of different segmentation methods used by Quantitative Imaging Network members. Robustness of some advanced biomarkers was found to be similar to conventional markers, such as maximum standardized uptake value. Such similarities support current pursuits to better characterize disease and predict outcomes by developing QIBs that use more imaging information and are robust to different processing factors. Nevertheless, to ensure reproducibility of QIB measurements and measures of association with clinical outcomes, errors owing to segmentation methods need to be reduced.
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http://dx.doi.org/10.18383/j.tom.2020.00004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7289247PMC
June 2020

Quantitative Imaging Informatics for Cancer Research.

JCO Clin Cancer Inform 2020 05;4:444-453

Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.

Purpose: We summarize Quantitative Imaging Informatics for Cancer Research (QIICR; U24 CA180918), one of the first projects funded by the National Cancer Institute (NCI) Informatics Technology for Cancer Research program.

Methods: QIICR was motivated by the 3 use cases from the NCI Quantitative Imaging Network. 3D Slicer was selected as the platform for implementation of open-source quantitative imaging (QI) tools. Digital Imaging and Communications in Medicine (DICOM) was chosen for standardization of QI analysis outputs. Support of improved integration with community repositories focused on The Cancer Imaging Archive (TCIA). Priorities included improved capabilities of the standard, toolkits and tools, reference datasets, collaborations, and training and outreach.

Results: Fourteen new tools to support head and neck cancer, glioblastoma, and prostate cancer QI research were introduced and downloaded over 100,000 times. DICOM was amended, with over 40 correction proposals addressing QI needs. Reference implementations of the standard in a popular toolkit and standalone tools were introduced. Eight datasets exemplifying the application of the standard and tools were contributed. An open demonstration/connectathon was organized, attracting the participation of academic groups and commercial vendors. Integration of tools with TCIA was improved by implementing programmatic communication interface and by refining best practices for QI analysis results curation.

Conclusion: Tools, capabilities of the DICOM standard, and datasets we introduced found adoption and utility within the cancer imaging community. A collaborative approach is critical to addressing challenges in imaging informatics at the national and international levels. Numerous challenges remain in establishing and maintaining the infrastructure of analysis tools and standardized datasets for the imaging community. Ideas and technology developed by the QIICR project are contributing to the NCI Imaging Data Commons currently being developed.
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http://dx.doi.org/10.1200/CCI.19.00165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7265794PMC
May 2020

Applying FAIRness: Redesigning a Biomedical Informatics Research Data Management Pipeline.

Methods Inf Med 2019 Dec 29;58(6):229-234. Epub 2020 Apr 29.

Department of Medical Informatics, University Medical Center Göttingen, Göttingen, Niedersachsen, Germany.

Background:  Managing research data in biomedical informatics research requires solid data governance rules to guarantee sustainable operation, as it generally involves several professions and multiple sites. As every discipline involved in biomedical research applies its own set of tools and methods, research data as well as applied methods tend to branch out into numerous intermediate and output data objects, making it very difficult to reproduce research results.

Objectives:  This article gives an overview of our implementation status applying the Findability, Accessibility, Interoperability and Reusability (FAIR) Guiding Principles for scientific data management and stewardship onto our research data management pipeline focusing on the software tools that are in use.

Methods:  We analyzed our progress FAIRificating the whole data management pipeline, from processing non-FAIR data up to data usage. We looked at software tools for data integration, data storage, and data usage as well as how the FAIR Guiding Principles helped to choose appropriate tools for each task.

Results:  We were able to advance the degree of FAIRness of our data integration as well as data storage solutions, but lack enabling more FAIR Guiding Principles regarding Data Usage. Existing evaluation methods regarding the FAIR Guiding Principles (FAIRmetrics) were not applicable to our analysis of software tools.

Conclusion:  Using the FAIR Guiding Principles, we FAIRificated relevant parts of our research data management pipeline improving findability, accessibility, interoperability and reuse of datasets and research results. We aim to implement the FAIRmetrics to our data management infrastructure and-where required-to contribute to the FAIRmetrics for research data in the biomedical informatics domain as well as for software tools to achieve a higher degree of FAIRness of our research data management pipeline.
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http://dx.doi.org/10.1055/s-0040-1709158DOI Listing
December 2019

Sensor Positioning Influences the Accuracy of Knee Rom Data of an E-Rehabilitation System: A Preliminary Study with Healthy Subjects.

Sensors (Basel) 2020 Apr 15;20(8). Epub 2020 Apr 15.

Science Office of the Orthopedic and Joint Replacement Department, Schoen Clinic Hamburg Eilbek, Dehnhaide 120, D-22081 Hamburg, Germany.

E-rehabilitation is the term used to define medical rehabilitation programs that are implemented at home with the use of information and communication technologies. The aim was to test whether sensor position and the sitting position of the patient influence the accuracy of knee range of movement (ROM) data displayed by the BPMpathway e-rehabilitation system. A preliminary study was conducted in a laboratory setting with healthy adults. Knee ROM data was measured with the BPMpathway e-rehabilitation system and simultaneously with a BIOPAC twin-axis digital goniometer. The main outcome was the root mean squared error (RMSE). A 20% increase or reduction in sitting height led to a RMSE increase. A ventral shift of the BPMpathway sensor by 45° and 90° caused significant measurement errors. A vertical shift was associated with a diminution of the measurement errors. The lowest RMSE (2.4°) was achieved when the sensor was placed below the knee. The knee ROM data measured by the BPMpathway system is comparable to the data of the concurrent system, provided the instructions of the manufacturer are respected concerning the sitting position of the subject for knee exercises, and disregarding the same instructions for sensor positioning, by placing the sensor directly below the knee.
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http://dx.doi.org/10.3390/s20082237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7218858PMC
April 2020

The influence of prolonged strength training upon muscle and fat in healthy and chronically diseased older adults.

Exp Gerontol 2020 07 8;136:110939. Epub 2020 Apr 8.

Institute of Sports Medicine Copenhagen, Department of Orthopaedic Surgery M81 and Centre for Translational Research, Bispebjerg and Frederiksberg Hospital, Bispebjerg Bakke 23, 2400 Copenhagen, NV, Denmark; Center for Healthy Aging, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, N, Denmark.

Background: Physical muscle function and brain hippocampus size declines with age, accelerating after the age of 60. Strength training over a few months improves physical function, but less is known about how long-term strength training affects physical function and hippocampus volume. Therefore, we aimed to investigate the effect of 1-year strength training of two different intensities upon muscle mass, function, and hippocampus volume in retirement-age individuals.

Methods: In this multidisciplinary randomized controlled trial (clinicaltrials.gov: NCT02123641), participants were allocated to either a) supervised, heavy resistance training (HRT, n = 149, 3/wk), b) moderate intensity resistance training (MIT, n = 154, 3/wk) or c) non-exercise activities (CON, n = 148). 451 participants were randomized (62-70 yrs., women 61%, ≈80% with a chronic medical disease) and 419 were included in the intention-to-treat analysis (n = 143, 144 and 132; HRT, MIT and CON). Changes in muscle power (primary outcome), strength and size, physical function, body composition, hippocampus volume and physical/mental well-being were analyzed.

Findings: Of the participants (HRT + MIT), 83% completed training at least 2/week. Leg extensor power was unchanged in all groups, but strength training had a positive effect on isometric knee extensor strength in both groups, whereas an increased muscle mass, cross-sectional area of vastus lateralis muscle, a decreased whole-body fat percentage, visceral fat content and an improved mental health (SF-36) occurred in HRT only. Further, chair-stand performance improved in all groups, whereas hippocampus volume decreased in all groups over time with no influence of strength training.

Interpretation: Together, the results indicate that leg extensor power did not respond to long-term supervised strength training, but this type of training in a mixed group of healthy and chronically diseased elderly individuals can be implemented with good compliance and induces consistent changes in physiological parameters of muscle strength, muscle mass and abdominal fat.
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http://dx.doi.org/10.1016/j.exger.2020.110939DOI Listing
July 2020

Energy System Pathways with Low Environmental Impacts and Limited Costs: Minimizing Climate Change Impacts Produces Environmental Cobenefits and Challenges in Toxicity and Metal Depletion Categories.

Environ Sci Technol 2020 04 30;54(8):5081-5092. Epub 2020 Mar 30.

Interdisciplinary Research Laboratory on Sustainable Engineering and Ecodesign (LIRIDE), Civil and Building Engineering Department, Sherbrooke University, 2500 Boul. de l'Université, Sherbrooke, Québec J1K 2R1, Canada.

Environmental indicators based on the life cycle assessment method are integrated into an energy system model. This integration allows for the generation of comprehensive environmental assessments of future energy systems and for determining energy scenarios with less environmental impacts and moderate cost increases. In Switzerland, which is used as a case study to demonstrate the feasibility of our approach, it is possible to generate pathways with a 5% cost increase on the cost-optimal situation, causing an impact score for climate change that is 2% higher than the minimum feasible solution. The minimization of life-cycle impacts on climate change generates substantial environmental cobenefits with regard to human health, air pollution, ozone depletion, acidification, and land transformation. However, this minimization also creates trade-offs that exacerbate the effects of metal depletion and human toxicity caused by upstream extraction and manufacturing linked to technologies such as solar panels and electric vehicles. Finally, ambitious reduction targets of 95% direct (i.e., within the country) CO emissions for the year 2050 might still result in substantial climate change impacts should emissions embodied in the infrastructure and upstream supply chain not be jointly mitigated jointly.
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http://dx.doi.org/10.1021/acs.est.9b06484DOI Listing
April 2020

The fractal geometry of bronchial trees differs by strain in mice.

J Appl Physiol (1985) 2020 02 9;128(2):362-367. Epub 2020 Jan 9.

Department of Electrical and Computer Engineering, University of Iowa, Iowa City, Iowa.

Fractal biological structures are pervasive throughout the plant and animal kingdoms, with the mammalian lung being a quintessential example. The lung airway and vascular trees are generated during embryogenesis from a small set of building codes similar to Turing mechanisms that create robust trees ideally suited to their functions. Whereas the blood flow pattern generated by these fractal trees has been shown to be genetically determined, the geometry of the trees has not. We explored a newly established repository providing high-resolution bronchial trees from the four most commonly studied laboratory mice (B6C3F1, BALB/c, C57BL/6 and CD-1). The data fit a fractal model well for all animals with the fractal dimensions ranging from 1.54 to 1.67, indicating that the conducting airway of mice can be considered a self-similar and space-filling structure. We determined that the fractal dimensions of these airway trees differed by strain but not sex, reinforcing the concept that airway branching patterns are encoded within the DNA. The observations also highlight that future study design and interpretations may need to consider differences in airway geometry between mouse strains. Similar to larger mammals such as humans, the geometries of the bronchial tree in mice are fractal structures that have repeating patterns from the trachea to the terminal branches. The airway geometries of the four most commonly studied mice are different and need to be considered when comparing results that employ different mouse strains. This variability in mouse airway geometries should be incorporated into computer models exploring toxicology and aerosol deposition in mouse models.
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http://dx.doi.org/10.1152/japplphysiol.00838.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7052590PMC
February 2020

A 3D deep convolutional neural network approach for the automated measurement of cerebellum tracer uptake in FDG PET-CT scans.

Med Phys 2020 Mar 6;47(3):1058-1066. Epub 2020 Jan 6.

Department of Electrical and Computer Engineering, The University of Iowa, Iowa City, IA, 52242, USA.

Purpose: The purpose of this work was to assess the potential of deep convolutional neural networks in automated measurement of cerebellum tracer uptake in F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) scans.

Methods: Three different three-dimensional (3D) convolutional neural network architectures (U-Net, V-Net, and modified U-Net) were implemented and compared regarding their performance in 3D cerebellum segmentation in FDG PET scans. For network training and testing, 134 PET scans with corresponding manual volumetric segmentations were utilized. For segmentation performance assessment, a fivefold cross-validation was used, and the Dice coefficient as well as signed and unsigned distance errors were calculated. In addition, standardized uptake value (SUV) uptake measurement performance was assessed by means of a statistical comparison to an independent reference standard. Furthermore, a comparison to a previously reported active-shape-model-based approach was performed.

Results: Out of the three convolutional neural networks investigated, the modified U-Net showed significantly better segmentation performance. It achieved a Dice coefficient of 0.911 ± 0.026, a signed distance error of 0.220 ± 0.103 mm, and an unsigned distance error of 1.048 ± 0.340 mm. When compared to the independent reference standard, SUV uptake measurements produced with the modified U-Net showed no significant error in slope and intercept. The estimated reduction in total SUV measurement error was 95.1%.

Conclusions: The presented work demonstrates the potential of deep convolutional neural networks in automated SUV measurement of reference regions. While it focuses on the cerebellum, utilized methods can be generalized to other reference regions like the liver or aortic arch. Future work will focus on combining lesion and reference region analysis into one approach.
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http://dx.doi.org/10.1002/mp.13970DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7067677PMC
March 2020

lapdMouse: associating lung anatomy with local particle deposition in mice.

J Appl Physiol (1985) 2020 02 27;128(2):309-323. Epub 2019 Nov 27.

University of Iowa, Department of Electrical and Computer Engineering, Iowa City, Iowa.

To facilitate computational toxicology, we developed an approach for generating high-resolution lung-anatomy and particle-deposition mouse models. Major processing steps of our method include mouse preparation, serial block-face cryomicrotome imaging, and highly automated image analysis for generating three-dimensional (3D) mesh-based models and volume-based models of lung anatomy (airways, lobes, sublobes, and near-acini structures) that are linked to local particle-deposition measurements. Analysis resulted in 34 mouse models covering 4 different mouse strains (B6C3F1: 8, BALB/C: 11, C57Bl/6: 8, and CD-1: 7) as well as both sexes (16 male and 18 female) and different particle sizes [2 μm ( = 15), 1 μm ( = 16), and 0.5 μm ( = 3)]. On average, resulting mouse airway models had 1,616.9 ± 298.1 segments, a centerline length of 597.6 ± 59.8 mm, and 1,968.9 ± 296.3 outlet regions. In addition to 3D geometric lung models, matching detailed relative particle-deposition measurements are provided. All data sets are available online in the lapdMouse archive for download. The presented approach enables linking relative particle deposition to anatomical structures like airways. This will in turn improve the understanding of site-specific airflows and how they affect drug, environmental, or biological aerosol deposition. Computer simulations of particle deposition in mouse lungs play an important role in computational toxicology. Until now, a limiting factor was the lack of high-resolution mouse lung models and measured local particle-deposition information, which are required for developing accurate modeling approaches (e.g., computational fluid dynamics). With the developed imaging and analysis approach, we address this issue and provide all of the raw and processed data in a publicly accessible repository.
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http://dx.doi.org/10.1152/japplphysiol.00615.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7052583PMC
February 2020

How to Save a Life From Macroscopic Fat Embolism: A Narrative Review of Treatment Options.

Aesthet Surg J 2020 09;40(10):1098-1107

Department of Plastic, Reconstructive, and Aesthetic Surgery, University Hospital of Amiens, Amiens, France.

Macroscopic fat embolism (MAFE) has grabbed the attention of the plastic surgery community in recent years because of its high mortality rate. Many articles on preventing MAFE during gluteal fat grafting are available in the literature. However, total prevention is difficult: a number of factors, both technical and human, mean that MAFE remains a potential complication. This review was written with the main goal of providing a treatment plan. MAFE shares many similar pathophysiologic and hemodynamic features with massive thrombotic pulmonary embolism (PE), especially the associated cardiopulmonary decompensation. Lessons learned from PE management were used to devise a management algorithm for MAFE. The use of extracorporeal membrane oxygenation and its potential application as a main modality of treatment for MAFE was explored. The lack of evidence in the literature for the treatment of MAFE, and its high mortality, lent urgency to the need to write an article on the management aspect in the form of a narrative review, to ensure that every plastic surgeon practicing gluteal fat grafting is knowledgeable about the treatment aspect of this deadly complication.
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http://dx.doi.org/10.1093/asj/sjz277DOI Listing
September 2020

Provenance Solutions for Medical Research in Heterogeneous IT-Infrastructure: An Implementation Roadmap.

Stud Health Technol Inform 2019 Aug;264:298-302

Department of Medical Informatics, University Medical Center, Göttingen, Germany.

Research data generated in large projects raise challenges about not only data analytics but also data quality assessments and data governance. The provenance of a data set - that is the history of data sets - holds information relevant to technicians and non-technicians and is able to answer questions regarding data quality, transparency, and more. We propose an implementation roadmap to extract, store, and utilize provenance records in order to make provenance available to data analysts, research subjects, privacy officers, and machines (machine readability). Each aspect is tackled separately, resulting in the implementation of a provenance toolbox. We aim to do so within the context of HiGHmed, a research consortium established within the medical informatics initiative in Germany. In this testbed of federated IT-infrastructures, the toolbox shall assist each stakeholder in answering domain-specific and domain-agnostic questions regarding the provenance of data sets. This way, we will improve data re-use, transparency, and reproducibility.
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http://dx.doi.org/10.3233/SHTI190231DOI Listing
August 2019

[Simulation of difficult airway management for residents: prospective comparative study].

Braz J Anesthesiol 2019 Jul - Aug;69(4):358-368. Epub 2019 Jul 29.

Hospices Civils de Lyon, Département d'Anesthésie-Réanimation, Lyon, França; Université Claude Bernard Lyon 1, Centre Lyonnais d'Enseignement par Simulation en Santé, SAMSEI, Lyon, França; Université Claude Bernard Lyon 1, Pathophysiology of Injury Induced Immunosuppression, Lyon, França.

Background And Objectives: Procedural simulation training for difficult airway management offers acquisition opportunities. The hypothesis was that 3 hours of procedural simulation training for difficult airway management improves: acquisition, behavior, and patient outcomes as reported 6 months later.

Methods: This prospective comparative study took place in two medical universities. Second-year residents of anesthesiology and intensive care from one region participated in 3h procedural simulation (intervention group). No intervention was scheduled for their peers from the other region (control). Prior to simulation and 6 months later, residents filled-out the same self-assessment form collecting experience with different devices. The control group filled-out the same forms simultaneously. The primary endpoint was the frequency of use of each difficult airway management device within groups at 6 months. Secondary endpoints included modifications of knowledge, skills, and patient outcomes with each device at 6 months. Intervention cost assessment was provided.

Results: 44 residents were included in the intervention group and 16 in the control group. No significant difference was observed for the primary endpoint. In the intervention group, improvement of knowledge and skills was observed at 6 months for each device, and improvement of patient outcomes was observed with the use of malleable intubation stylet and Eschmann introducer. No such improvement was observed in the control group. Estimated intervention cost was 406€ per resident.

Conclusions: A 3h procedural simulation training for difficult airway management did not improve the frequency of use of devices at 6 months by residents. However, other positive effects suggest exploring the best ratio of time/acquisition efficiency with difficult airway management simulation. CLINICALTRIALS.

Gov Identifier: NCT02470195.
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http://dx.doi.org/10.1016/j.bjan.2019.02.002DOI Listing
February 2020

Efficacy of prefabricated carbon-composite ankle foot orthoses for children with unilateral spastic cerebral palsy exhibiting a drop foot pattern.

J Pediatr Rehabil Med 2019 ;12(2):171-180

School of Medicine, Social Pediatrics, Technical University of Munich, Munich, Germany.

Purpose: This study aims to evaluate the effectiveness of a prefabricated carbon-composite ankle foot orthoses (c-AFOs) on gait parameters in children with unilateral spastic cerebral palsy (USCP) exhibiting a drop foot pattern.

Methods: Sixteen ambulatory children with USCP and a drop foot pattern were included (mean age: 9 years; gross motor function classification system: I = 14, II = 2) and three-dimensional gait analysis was applied under randomly assigned conditions (barefoot; shoe; c-AFO). Kinematics, kinetics, time-distance parameters and gait indices were investigated.

Results: Effects on the drop foot pattern were investigated while the children walked in shoes only. The shoes already increased the maximum ankle dorsiflexion in swing (p= 0.004) and initiated more knee flexion during single support (p⩽ 0.013). Compared to shoe walking, the c-AFO led to additional benefits regarding further ankle dorsiflexion during swing (p⩽ 0.001) and initial contact (p< 0.001), ankle movement during loading response (p= 0.002), improved the sole angle during initial contact (p< 0.001) and during mid stance (p= 0.015). Plantarflexion and ankle power generation during push-off decreased when wearing the c-AFO (p⩽ 0.008).

Conclusion: Investigated c-AFOs are beneficial for improving drop foot patterns in children with USCP. Significant effects on pathological barefoot pattern were already achieved with the child's regular shoes. This could be considered in clinical decision processes. In comparison to shoe walking, c-AFO additionally improved foot clearance and normalized initial heel contact. The third rocker deteriorates with the c-AFO. Since kinematics improved with the orthoses during swing and early stance phase, c-AFOs might reduce tripping and falling caused by a drop foot during long distance walking.
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http://dx.doi.org/10.3233/PRM-170524DOI Listing
May 2020

Long-term use of yeast fermentation products in comparison to halofuginone for the control of cryptosporidiosis in neonatal calves.

Vet Parasitol 2019 May 19;269:57-64. Epub 2019 Apr 19.

Institute of Parasitology, Justus Liebig University Giessen, Schubertstrasse 81, 35392, Giessen, Germany. Electronic address:

The objective of this study was to compare the effect of non-GMO Saccharomyces cerevisiae fermentation products (SCFP) with that of a halofuginone treatment against Cryptosporidium parvum infection in pre-weaned calves on a commercial dairy farm. A total of 123 neonatal female calves, housed in individual hutches, were enrolled sequentially based on date of birth in 41 blocks of 3 animals each. Calves within each block were allocated to one of 3 treatments: remaining untreated, fed with SCFP (Diamond V SmartCare at 1 g/d in milk and NutriTek at 5 g/d in starter grain) for the first 63 days of life, or treated with halofuginone (0.1 mg/kg/d) for the first 7 days of life. Fecal samples collected on days 4-21 post-partum were examined for both Cryptosporidium oocysts and coproantigen. The presence and intensity of diarrhea were monitored by scoring daily for the first 4 weeks of life. Calves were weighed at 0, 21, 42 and 63 days of age. Almost all calves were Cryptosporidium-positive at least once during the study. Halofuginone significantly reduced the number of Cryptosporidium-positive fecal samples as compared to the two other groups. Based on the coproantigen scores, both halofuginone and SCFP feeding significantly reduced the intensity of Cryptosporidium infection as compared to the untreated group. Diarrhea was recorded in almost all calves at least once. Neither the proportion of diarrheic calves nor the intensity and duration of diarrhea differed among the 3 treatment groups significantly. The mean daily weight gain during the first 3 weeks of life was significantly lower in halofuginone treated calves than in both other groups; however, at the end of the study period the total weight gain did not significantly differ among the 3 treatment groups. In conclusion, the clinical results and weight gains of pre-weaning supplementation with the SCFP were neither better nor worse than the 7-day halofuginone treatment suggesting that the SCFP feeding may be from the clinical point of view a natural alternative measure, instead of halofuginone treatment, in bovine cryptosporidiosis.
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http://dx.doi.org/10.1016/j.vetpar.2019.04.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7117046PMC
May 2019
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