Investigating focal spot position drift in a mobile imaging system equipped with a monobloc-based x-ray generator.

BACKGROUND: Misalignment or double-contouring artifacts can appear in high-resolution 3D cone beam computed tomography (CBCT) images, potentially indicating geometric accuracy issues in the projection data. Such artifacts may go unnoticed in low-resolution images and could be associated with changes in the focal spot (FS) position. PURPOSE: High-resolution 3D-CBCT imaging by a mobile imaging device with a large gantry clearance offers more versatility for clinical workflows in image-guided brachytherapy (IGBT), intraoperative radiation therapy (IORT), and spinal, as well as maxillofacial surgery. However, misalignment or double-contouring artifacts hinder workflow advancements in these domains. This paper introduces intrinsic calibration and geometrical correction methods as extensions to a well-established technique for addressing geometrical deviations resulting from factors such as gravity or mechanical inconsistencies. These extensions cover shifts and drifts of the FS depending on FS size selection, temperature, tube current, and tube potential. The proposed methods effectively mitigate artifacts in high-resolution CBCT images stemming from geometrical inaccuracies in projection data, without requiring additional equipment like a pinhole device. METHODS: Geometrical offsets and drifts of the x-ray tube FS were characterized on a mobile multi-purpose imaging system, the ImagingRing-m. A pinhole-like experiment was simulated by adjusting the movable collimation unit to a small rectangular aperture within the FS size range. The influence of filament selection, that is, FS size, temperature, the relatively low tube currents, as well as tube potential settings have been studied on two different monobloc types sharing the same x-ray tube insert. The Catphan 504 and an Alderson head phantom were used to assess resulting image artifacts. RESULTS: Switching the FS size to one different from what was used for geometrical (gravitation, mechanical variations) calibration induced the most notable position changes of the x-ray FS, resulting in double-contouring artifacts and blurring of high-resolution 3D-CBCT images. Incorporating these shifts into a geometrical correction method effectively minimized these artifacts. Thermal drifts exhibited the second largest geometrical changes, comparable to FS size shifts across the thermal operating conditions of the x-ray system. The proposed thermal drift compensation markedly reduced thermal drift effects. Tube current and potential had little impact within the range of available tube currents, eliminating the need for compensation in current applications. CONCLUSIONS: Augmenting the geometrical calibration pipeline with proposed FS drift compensations yielded significant enhancements in image quality for high-resolution reconstructions. While compensation for thermal effects posed challenges, it proved achievable. The roles of tube current and potential were found to be negligible.

A Gradient of Intestinal Inflammation in Primary Sclerosing Cholangitis.

BACKGROUND: Primary sclerosing cholangitis (PSC) is a progressive liver disease associated with inflammatory bowel disease (IBD). The percentage of PSC patients diagnosed with concomitant IBD varies considerably between studies. This raises the question whether all PSC patients would show intestinal inflammation if screened thoroughly, even in the absence of symptoms. METHODS: To address this question, we collected intestinal biopsies of healthy controls (n = 34), PSC (n = 25), PSC-IBD (n = 41), and IBD (n = 51) patients in a cross-sectional study and carried out cytokine expression profiling, 16S sequencing, in-depth histology, and endoscopy scoring. RESULTS: We found that the vast majority of PSC patients even without clinically manifest IBD showed infiltration of immune cells and increased expression of IL17A and IFNG in intestinal biopsies. However, expression of IL10 and FOXP3 were likewise increased, which may explain why these PSC patients have intestinal inflammation only on a molecular level. This subclinical inflammation in PSC patients was focused in the distal colon, whereas PSC-IBD patients showed inflammation either at the distal colon or on the right side of the colon and the terminal ileum. Furthermore, we observed that PSC patients without IBD showed signs of dysbiosis and exhibited a distinct microbial profile compared with healthy controls. CONCLUSIONS: We found a gradient of intestinal inflammation in the vast majority of PSC patients even in the absence of IBD. Thus, further studies evaluating the effect of anti-inflammatory therapies in PSC patients and their impact on the emergence of clinically manifest IBD and colorectal cancer development are needed.

Templated encapsulation of platinum-based catalysts promotes high-temperature stability to 1,100 °C.

Stable catalysts are essential to address energy and environmental challenges, especially for applications in harsh environments (for example, high temperature, oxidizing atmosphere and steam). In such conditions, supported metal catalysts deactivate due to sintering-a process where initially small nanoparticles grow into larger ones with reduced active surface area-but strategies to stabilize them can lead to decreased performance. Here we report stable catalysts prepared through the encapsulation of platinum nanoparticles inside an alumina framework, which was formed by depositing an alumina precursor within a separately prepared porous organic framework impregnated with platinum nanoparticles. These catalysts do not sinter at 800 °C in the presence of oxygen and steam, conditions in which conventional catalysts sinter to a large extent, while showing similar reaction rates. Extending this approach to Pd-Pt bimetallic catalysts led to the small particle size being maintained at temperatures as high as 1,100 °C in air and 10% steam. This strategy can be broadly applied to other metal and metal oxides for applications where sintering is a major cause of material deactivation.

Cancer Control Outcomes Following Focal Therapy Using High-intensity Focused Ultrasound in 1379 Men with Nonmetastatic Prostate Cancer: A Multi-institute 15-year Experience.

BACKGROUND: Focal therapy aims to treat areas of cancer to confer oncological control whilst reducing treatment-related functional detriment. OBJECTIVE: To report oncological outcomes and adverse events following focal high-intensity focused ultrasound (HIFU) for treating nonmetastatic prostate cancer. DESIGN, SETTING, AND PARTICIPANTS: An analysis of 1379 patients with ≥6 mo of follow-up prospectively recorded in the HIFU Evaluation and Assessment of Treatment (HEAT) registry from 13 UK centres (2005-2020) was conducted. Five or more years of follow-up was available for 325 (24%) patients. Focal HIFU therapy used a transrectal ultrasound-guided device (Sonablate; Sonacare Inc., Charlotte, NC, USA). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Failure-free survival (FFS) was primarily defined as avoidance of no evidence of disease to require salvage whole-gland or systemic treatment, or metastases or prostate cancer-specific mortality. Differences in FFS between D'Amico risk groups were determined using a log-rank analysis. Adverse events were reported using Clavien-Dindo classification. RESULTS AND LIMITATIONS: The median (interquartile range) age was 66 (60-71) yr and prostate-specific antigen was 6.9 (4.9-9.4) ng/ml with D'Amico intermediate risk in 65% (896/1379) and high risk in 28% (386/1379). The overall median follow-up was 32 (17-58) mo; for those with ≥5 yr of follow-up, it was 82 (72-94). A total of 252 patients had repeat focal treatment due to residual or recurrent cancer; overall 92 patients required salvage whole-gland treatment. Kaplan-Meier 7-yr FFS was 69% (64-74%). Seven-year FFS in intermediate- and high-risk cancers was 68% (95% confidence interval [CI] 62-75%) and 65% (95% CI 56-74%; p = 0.3). Clavien-Dindo >2 adverse events occurred in 0.5% (7/1379). The median 10-yr follow-up is lacking. CONCLUSIONS: Focal HIFU in carefully selected patients with clinically significant prostate cancer, with six and three of ten patients having, respectively, intermediate- and high-risk cancer, has good cancer control in the medium term. PATIENT SUMMARY: Focal high-intensity focused ultrasound treatment to areas of prostate with cancer can provide an alternative to treating the whole prostate. This treatment modality has good medium-term cancer control over 7 yr, although 10-yr data are not yet available.

The TUDID Study - Background and Design of a Prospective Cohort.

Prevalence of both type 1 and type 2 diabetes mellitus is growing worldwide and one major cause for morbidity and mortality. However, not every patient develops diabetes-related complications, but causes for the individual susceptibility are still not fully understood. As a platform to address this, we initiated the TUDID (TUebingen DIabetes Database) study, a prospective, monocentric, observational study that includes adults with diabetes mellitus who are treated in the inpatient clinic of a University Hospital in southern Germany. Besides a thorough clinical examination and extensive laboratory tests (with integrated biobanking), major study focuses are the kidneys, the eyes, the vasculature as well as cognition and mood where standardized investigations for early stages for diabetes complications are performed. Analyses of the data generated by this precise characterization of diabetes-related complications will contribute to our understanding of the development and course of such complications, and thus facilitate the implementation of tailored treatment options that can reduce the risk and severity of diabetes-related complications.

Reproducibility and discrimination of different indices of insulin sensitivity and insulin secretion.

AIMS: Insulin sensitivity and insulin secretion can be estimated by multiple indices from fasting blood samples or blood samples obtained during oral glucose tolerance tests. The test-retest reliability of these indices in repeated measurements within the same individuals can strongly vary. METHODS: We analyzed data of persons without diabetes who underwent two repeated OGTTs. For each measurement pair, we calculated multiple commonly used indices for the assessment of insulin secretion and insulin sensitivity. We then evaluated the coefficient of variation (standard deviation/mean) and discriminant ratio for each index. RESULTS: 89 persons underwent two OGTTs with a median interval of 86 days (IQR 64-249). Among indices of insulin sensitivity derived from fasting blood samples, the revised quantitative insulin sensitivity check index had the smallest coefficient of variation (2.8 ± 2.1%) whereas the C-peptide based homeostasis model assessment 2 had the highest discriminant ratio (1.97 (1.65-2.39)). As for insulin sensitivity indices that are based on OGTT, the oral glucose insulin sensitivity index had the smallest coefficient of variation (6.5 ± 5.1%). The highest discriminant ratio was found for the non-esterified fatty acids-based insulin sensitivity index (NEFA-ISI, 2.70 (2.30-3.22)). For the assessment of insulin secretion from fasting variables, the lowest mean coefficient of variation was found for C-peptide based homeostasis model assessment 2 beta with 10.8 ± 8% and the highest discriminant ratio for the C-peptide / Glucose-Ratio (2.18 (1.84-2.63)). Among indices assessing insulin secretion from an OGTT, the lowest coefficient of variation was found for the ratio of the areas under the C-peptide and glucose curves from 0 to 120 minutes with 11.3 ± 9.7%. CONCLUSION: The data reveal large differences in the reproducibility and the discrimination capability of different indices that assess insulin sensitivity or insulin secretion. Our findings can aid the selection of an appropriate index in clinical studies.

Focal HIFU therapy for anterior compared to posterior prostate cancer lesions.

OBJECTIVE: To compare cancer control in anterior compared to posterior prostate cancer lesions treated with a focal HIFU therapy approach. MATERIALS AND METHODS: In a prospectively maintained national database, 598 patients underwent focal HIFU (Sonablate®500) (March/2007-November/2016). Follow-up occurred with 3-monthly clinic visits and PSA testing in the first year with PSA, every 6-12 months with mpMRI with biopsy for MRI-suspicion of recurrence. Treatment failure was any secondary treatment (ADT/chemotherapy, cryotherapy, EBRT, RRP, or re-HIFU), tumour recurrence with Gleason ≥ 3 + 4 on prostate biopsy without further treatment or metastases/prostate cancer-related mortality. Cases with anterior cancer were compared to those with posterior disease. RESULTS: 267 patients were analysed following eligibility criteria. 45 had an anterior focal-HIFU and 222 had a posterior focal-HIFU. Median age was 64 years and 66 years, respectively, with similar PSA level of 7.5 ng/ml and 6.92 ng/ml. 84% and 82%, respectively, had Gleason 3 + 4, 16% in both groups had Gleason 4 + 3, 0% and 2% had Gleason 4 + 4. Prostate volume was similar (33 ml vs. 36 ml, p = 0.315); median number of positive cores in biopsies was different in anterior and posterior tumours (7 vs. 5, p = 0.009), while medium cancer core length, and maximal cancer percentage of core were comparable. 17/45 (37.8%) anterior focal-HIFU patients compared to 45/222 (20.3%) posterior focal-HIFU patients required further treatment (p = 0.019). CONCLUSION: Treating anterior prostate cancer lesions with focal HIFU may be less effective compared to posterior tumours.

Influence of the Infill Orientation on the Properties of Zirconia Parts Produced by Fused Filament Fabrication.

The fused filament fabrication (FFF) of ceramics enables the additive manufacturing of components with complex geometries for many applications like tooling or prototyping. Nevertheless, due to the many factors involved in the process, it is difficult to separate the effect of the different parameters on the final properties of the FFF parts, which hinders the expansion of the technology. In this paper, the effect of the fill pattern used during FFF on the defects and the mechanical properties of zirconia components is evaluated. The zirconia-filled filaments were produced from scratch, characterized by different methods and used in the FFF of bending bars with infill orientations of 0°, ±45° and 90° with respect to the longest dimension of the specimens. Three-point bending tests were conducted on the specimens with the side in contact with the build platform under tensile loads. Next, the defects were identified with cuts in different sections. During the shaping by FFF, pores appeared inside the extruded roads due to binder degradation and or moisture evaporation. The changes in the fill pattern resulted in different types of porosity and defects in the first layer, with the latter leading to earlier fracture of the components. Due to these variations, the specimens with the 0° infill orientation had the lowest porosity and the highest bending strength, followed by the specimens with ±45° infill orientation and finally by those with 90° infill orientation.

IL22BP Mediates the Antitumor Effects of Lymphotoxin Against Colorectal Tumors in Mice and Humans.

BACKGROUND & AIMS: Unregulated activity of interleukin (IL) 22 promotes intestinal tumorigenesis in mice. IL22 binds the antagonist IL22 subunit alpha 2 (IL22RA2, also called IL22BP). We studied whether alterations in IL22BP contribute to colorectal carcinogenesis in humans and mice. METHODS: We obtained tumor and nontumor tissues from patients with colorectal cancer (CRC) and measured levels of cytokines by quantitative polymerase chain reaction, flow cytometry, and immunohistochemistry. We measured levels of Il22bp messenger RNA in colon tissues from wild-type, Tnf-/-, Lta-/-, and Ltb-/- mice. Mice were given azoxymethane and dextran sodium sulfate to induce colitis and associated cancer or intracecal injections of MC38 tumor cells. Some mice were given inhibitors of lymphotoxin beta receptor (LTBR). Intestine tissues were analyzed by single-cell sequencing to identify cell sources of lymphotoxin. We performed immunohistochemistry analysis of colon tissue microarrays from patients with CRC (1475 tissue cores, contained tumor and nontumor tissues) and correlated levels of IL22BP with patient survival times. RESULTS: Levels of IL22BP were decreased in human colorectal tumors, compared with nontumor tissues, and correlated with levels of lymphotoxin. LTBR signaling was required for expression of IL22BP in colon tissues of mice. Wild-type mice given LTBR inhibitors had an increased tumor burden in both models, but LTBR inhibitors did not increase tumor growth in Il22bp-/- mice. Lymphotoxin directly induced expression of IL22BP in cultured human monocyte-derived dendritic cells via activation of nuclear factor κB. Reduced levels of IL22BP in colorectal tumor tissues were associated with shorter survival times of patients with CRC. CONCLUSIONS: Lymphotoxin signaling regulates expression of IL22BP in colon; levels of IL22BP are reduced in human colorectal tumors, associated with shorter survival times. LTBR signaling regulates expression of IL22BP in colon tumors in mice and cultured human dendritic cells. Patients with colorectal tumors that express low levels of IL22BP might benefit from treatment with an IL22 antagonist.

A Monte Carlo based scatter removal method for non-isocentric cone-beam CT acquisitions using a deep convolutional autoencoder.

The primary cone-beam computed tomography (CBCT) imaging beam scatters inside the patient and produces a contaminating photon fluence that is registered by the detector. Scattered photons cause artifacts in the image reconstruction, and are partially responsible for the inferior image quality compared to diagnostic fan-beam CT. In this work, a deep convolutional autoencoder (DCAE) and projection-based scatter removal algorithm were constructed for the ImagingRingTM system on rails (IRr), which allows for non-isocentric acquisitions around virtual rotation centers with its independently rotatable source and detector arms. A Monte Carlo model was developed to simulate (i) a non-isocentric training dataset of ≈1200 projection pairs (primary + scatter) from 27 digital head-and-neck cancer patients around five different virtual rotation centers (DCAENONISO), and (ii) an isocentric dataset existing of ≈1200 projection pairs around the physical rotation center (DCAEISO). The scatter removal performance of both DCAE networks was investigated in two digital anthropomorphic phantom simulations and due to superior performance only the DCAENONISO was applied on eight real patient acquisitions. Measures for the quantitative error, the signal-to-noise ratio, and the similarity were evaluated for two simulated digital head-and-neck patients, and the contrast-to-noise ratio (CNR) was investigated between muscle and adipose tissue in the real patient image reconstructions. Image quality metrics were compared between the uncorrected data, the currently implemented heuristic scatter correction data, and the DCAE corrected image reconstruction. The DCAENONISO corrected image reconstructions of two digital patient simulations showed superior image quality metrics compared to the uncorrected and corrected image reconstructions using a heuristic scatter removal. The proposed DCAENONISO scatter correction in this study was successfully demonstrated in real non-isocentric patient CBCT acquisitions and achieved statistically significant higher CNRs compared to the uncorrected or the heuristic corrected image data. This paper presents for the first time a projection-based scatter removal algorithm for isocentric and non-isocentric CBCT imaging using a deep convolutional autoencoder trained on Monte Carlo composed datasets. The algorithm was successfully applied to real patient data.

An Exploratory Study of Dose Escalation vs Standard Focal High-Intensity Focused Ultrasound for Treating Nonmetastatic Prostate Cancer.

Objective: Analysis of treatment success regarding oncological recurrence rate between standard and dose escalation focal high-intensity focused ultrasound (HIFU) of prostate cancer. Materials and Methods: In this analysis of our prospectively maintained HIFU (Sonablate® 500) database, 598 patients were identified who underwent a focal HIFU (Sonablate 500) between March 2007 and November 2016. Follow-up occurred with 3-monthly clinic visits and prostate specific antigen (PSA) testing in the first year. Thereafter, PSA was measured 6-monthly or annually at least. Routine and for-cause multiparametric MRI (mpMRI) was conducted with biopsy for MRI suspicion of recurrence. Treatments were delivered in a quadrant or hemiablation fashion depending on the gland volume as well as tumor volume and location. Before mid-2015, standard focal HIFU was used (two HIFU blocks); after this date, some urologists conducted dose escalation focal HIFU (three overlapping HIFU blocks). Propensity matching was used to ensure two matched groups, leading to 162 cases for this analysis. Treatment failure was defined by any secondary treatment (systemic therapy, cryotherapy, radiotherapy, prostatectomy, or further HIFU), metastasis from prostate cancer without further treatment, tumor recurrence with Gleason score ≥7 (≥3 + 4) on prostate biopsy without further treatment, or prostate cancer-related mortality. Complications and side-effects were also compared. Results: Median age was 64.5 years (interquartile range [IQR] 60-73.5) in the standard focal-HIFU group and 64.5 years (IQR 60-69) in the dose-escalation group. Median prostate volume was 37 mL (IQR 17-103) in the standard group and 47.5 mL (IQR 19-121) in the dose-escalation group. As tumor volume on mpMRI and Gleason score were major matching criteria, these were identical with 0.43 mL (IQR 0.05-2.5) and Gleason 3 + 3 = 6 in 1 out of 32 (3%), 3 + 4 = 7 in 27 out of 32 (84%), and 4 + 3 = 7 in 4 out of 32 (13%). Recurrence in treated areas was found in 10 out of 32 (31%) when standard treatment zones were applied, and in 6 out of 32 (19%) of dose-escalation focal HIFU (p = 0.007). Conclusion: This exploratory study shows that dose escalation focal HIFU may achieve higher rates of disease control compared with standard focal HIFU. Further prospective comparative studies are needed.

Prostate Specific Antigen Criteria to Diagnose Failure of Cancer Control following Focal Therapy of Nonmetastatic Prostate Cancer Using High Intensity Focused Ultrasound.

PURPOSE: We determined whether prostate specific antigen criteria after focal high intensity focused ultrasound to treat prostate cancer could diagnose treatment failure. MATERIALS AND METHODS: A total of 598 patients in a prospectively maintained national database underwent focal high intensity focused ultrasound with a Sonablate® 500 device from March 2007 to November 2016. Followup consisted of 3-month clinic visits and prostate specific antigen testing in year 1 with prostate specific antigen measurement every 6 to 12 months and multiparametric magnetic resonance imaging with biopsy for magnetic resonance imaging suspicious for recurrence. Treatment failure was considered any secondary treatment, tumor recurrence with Gleason 3 + 4 or greater disease on prostate biopsy without further treatment or metastasis and/or prostate cancer related mortality. To diagnose failure we evaluated a series of nadir + x thresholds with x values of 0.1 to 2.0 ng/ml. RESULTS: Median patient age was 65 years (IQR 60-71) and the median Gleason score was 7 (range 6-9). Gleason 3 + 4 or greater disease was present in 80% of cases. Tumors were radiologically staged as T1c-T2c in 522 of the 596 patients (88%) and as T3a/b in 74 (12.4%). Baseline median prostate specific antigen was 7.80 ng/ml (IQR 5.96-10.45) in failed cases and 6.77 ng/ml (IQR 2.65-9.71) in cases without failure. Optimal performance according to the Youden index to indicate the most appropriate nadir + x at all analyzed time points at 3-month intervals showed that nadir + 1.0 ng/ml would have 27.3% to 100% sensitivity and 39.4% to 85.6% specificity depending on the time of evaluation in the first 3 years. Nadir + 1.5 ng/ml showed 18.2% to 100% sensitivity and 60.6% to 91.8% specificity with nadir + 2.0 ng/ml leading to similar sensitivity and specificity ranges. Nadir + 1.0 ng/ml at 12 months and nadir + 1.5 ng/ml at 24 and 36 months had 100% sensitivity and 96.1% to 100% negative predictive value. CONCLUSIONS: Following focal high intensity focused ultrasound a prostate specific antigen nadir of 1.0 ng/ml at 12 months and 1.5 ng/ml at 24 to 36 months might be used to triage men requiring magnetic resonance imaging and biopsy. These data need prospective validation.

Intensified and Standardized Digital Communication with Cystectomy Patients as a Potentially Simple and Effective Modality for Early Detection of Postoperative Complications: Results from a Pilot Study.

BACKGROUND: Postoperative readmission rates following radical cystectomy remain significant. Early identification of emerging complications could potentially allow for immediate institution of therapy. OBJECTIVE: To intensify postoperative patient-physician communication via a cellphone-based health care application (CHA) and to evaluate its potential for early detection of complications. DESIGN SETTING AND PARTICIPANTS: This was a pilot study involving 18 radical cystectomy patients. During the first 30 d, patients received a push cellphone notification twice a week requesting data input into the CHA. This was reduced to once a week from day 31 to day 90. De-identified recorded data were reviewed by the surgeon involved. If deemed necessary, patients were contacted by the surgeon via telephone to obtain more detailed clinical information. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Descriptive statistics were used. RESULTS AND LIMITATIONS: Of the 18 patients enrolled, all completed the 90-d reporting period. On two occasions, interventions were necessary on the basis of data recorded on the CHA. One neobladder patient was given antibiotic therapy for pyelonephritis. Another patient reported weight loss and nausea with clinical suspicion of metabolic acidosis, and his sodium bicarbonate and fluid intake were increased. Limitations include the small number of cases from a single low-volume center. CONCLUSIONS: CHA-based monitoring of clinical parameters within the crucial 90-d postoperative period following radical cystectomy provides meaningful information. In this pilot study, two potential readmissions were possibly avoided on the basis of recorded basic vital signs and early intervention. PATIENT SUMMARY: Besides regular clinic follow-up visits after radical cystectomy, additional aids such as a cellphone-based health care application can provide treating physicians with relevant clinical information and may help to identify imminent deviations from normal postoperative recovery at an early stage.

A Protective Function of IL-22BP in Ischemia Reperfusion and Acetaminophen-Induced Liver Injury.

Acute liver injury can be secondary to a variety of causes, including infections, intoxication, and ischemia. All of these insults induce hepatocyte death and subsequent inflammation, which can make acute liver injury a life-threatening event. IL-22 is a dual natured cytokine which has context-dependent protective and pathogenic properties during tissue damage. Accordingly, IL-22 was shown to promote liver regeneration upon acute liver damage. However, other studies suggest pathogenic properties of IL-22 during chronic liver injury. IL-22 binding protein (IL-22BP, IL-22Ra2) is a soluble inhibitor of IL-22 that regulates IL-22 activity. However, the significance of endogenous IL-22BP in acute liver injury is unknown. We hypothesized that IL-22BP may play a role in acute liver injury. To test this hypothesis, we used Il22bp-deficient mice and murine models of acute liver damage induced by ischemia reperfusion and N-acetyl-p-aminophenol (acetaminophen) administration. We found that Il22bp-deficient mice were more susceptible to acute liver damage in both models. We used Il22 × Il22bp double-deficient mice to show that this effect is indeed due to uncontrolled IL-22 activity. We could demonstrate mechanistically increased expression of Cxcl10 by hepatocytes, and consequently increased infiltration of inflammatory CD11b+Ly6C+ monocytes into the liver in Il22bp-deficient mice upon liver damage. Accordingly, neutralization of CXCL10 reversed the increased disease susceptibility of Il22bp-deficient mice. In conclusion, our data indicate that IL-22BP plays a protective role in acute liver damage, via controlling IL-22-induced Cxcl10 expression.

Nine-degrees-of-freedom flexmap for a cone-beam computed tomography imaging device with independently movable source and detector.

PURPOSE: Couch-mounted cone-beam computed tomography (CBCT) imaging devices with independently rotatable x-ray source and flat-panel detector arms for acquisitions of arbitrary regions of interest (ROI) have recently been introduced in image-guided radiotherapy (IGRT). This work analyzes mechanical limitations and gravity-induced effects influencing the geometric accuracy of images acquired with arbitrary angular constellations of source and detector in nonisocentric trajectories, which is considered essential for IGRT. In order to compensate for geometric inaccuracies of this modality, a 9-degrees-of-freedom (9-DOF) flexmap correction approach is presented, focusing especially on the separability of the flexmap parameters of the independently movable components of the device. METHODS: The 9-DOF comprise a 3D translation of the x-ray source focal spot, a 3D translation of the flat-panel's active area center and three Euler-rotations of the detector's row and column vectors. The flexmap parameters are expressed with respect to the angular position of each of the devices arms. Estimation of the parameters is performed, using a CT-based structure set of a table-mounted, cylindrical ball-bearing phantom. Digitally reconstructed radiograph (DRR) patches are derived from the structure set followed by local 2D in-plane registration and subsequent 3D transform estimation by nonlinear regression with outlier detection. RESULTS: Flexmap parameter evaluations for the factory-calibrated system in clockwise and counter-clockwise rotation direction have shown only minor differences for the overall set of flexmap parameters. High short-term reproducibility of the flexmap parameters has been confirmed by experiments over 10 acquisitions for both directions, resulting in standard deviation values of ≤0.183 mm for translational components and ≤0.0219 deg for rotational components, respectively. A comparison of isocentric and nonisocentric flexmap evaluations showed that the mean differences of the parameter curves reside within their standard deviations, confirming the ability of the proposed calibration method to handle both types of trajectories equally well. Reconstructions of 0.1 mm and 0.25 mm steel wires showed similar results for the isocentric and nonisocentric cases. The full-width at half maximum (FWHM) measure indicates an average improvement of the calibrated reconstruction of 85% over the uncalibrated reconstruction. The contrast of the point spread function (PSF) improved by 310% on average over all experiments. Moreover, a reduced amount of artifacts visible in nonisocentric reconstructions of a head phantom and a line-pair phantom has been achieved by separate application of the 9-DOF flexmap on the geometry described by the independently moving source arm and detector arm. CONCLUSIONS: Using a 9-DOF flexmap approach for correcting the geometry of projections acquired with a device capable of independent movements of the source and panel arms has been shown to be essential for IGRT use cases such as CBCT reconstruction and 2D/3D registration tasks. The proposed pipeline is able to create flexmap curves which are easy to interpret, useful for mechanical description of the device and repetitive quality assurance as well as system-level preventive maintenance. Application of the flexmap has shown improvements of image quality for planar imaging and volumetric imaging which is crucial for patient alignment accuracy.

A Specific Mapping Study Using Fluorescence Sentinel Lymph Node Detection in Patients with Intermediate- and High-risk Prostate Cancer Undergoing Extended Pelvic Lymph Node Dissection.

Sentinel lymph node (SLN) detection techniques have the potential to change the standard of surgical care for patients with prostate cancer. We performed a lymphatic mapping study and determined the value of fluorescence SLN detection with indocyanine green (ICG) for the detection of lymph node metastases in intermediate- and high-risk patients undergoing radical prostatectomy and extended pelvic lymph node dissection. A total of 42 patients received systematic or specific ICG injections into the prostate base, the midportion, the apex, the left lobe, or the right lobe. We found (1) that external and internal iliac regions encompass the majority of SLNs, (2) that common iliac regions contain up to 22% of all SLNs, (3) that a prostatic lobe can drain into the contralateral group of pelvic lymph nodes, and (4) that the fossa of Marcille also receives significant drainage. Among the 12 patients who received systematic ICG injections, 5 (42%) had a total of 29 lymph node metastases. Of these, 16 nodes were ICG positive, yielding 55% sensitivity. The complex drainage pattern of the prostate and the low sensitivity of ICG for the detection of lymph node metastases reported in our study highlight the difficulties related to the implementation of SNL techniques in prostate cancer. PATIENT SUMMARY: There is controversy about how extensive lymph node dissection (LND) should be during prostatectomy. We investigated the lymphatic drainage of the prostate and whether sentinel node fluorescence techniques would be useful to detect node metastases. We found that the drainage pattern is complex and that the sentinel node technique is not able to replace extended pelvic LND.

Fast calculating surrogate models for leg and head impact in vehicle-pedestrian collision simulations.

OBJECTIVE: In previous research, a tool chain to simulate vehicle-pedestrian accidents from ordinary driving state to in-crash has been developed. This tool chain allows for injury criteria-based, vehicle-specific (geometry, stiffness, active safety systems, etc.) assessments. Due to the complex nature of the included finite element analysis (FEA) models, calculation times are very high. This is a major drawback for using FEA models in large-scale effectiveness assessment studies. Therefore, fast calculating surrogate models to approximate the relevant injury criteria as a function of pedestrian vehicle collision constellations have to be developed. METHOD: The development of surrogate models for head and leg injury criteria to overcome the problem of long calculation times while preserving high detail level of results for effectiveness analysis is shown in this article. These surrogate models are then used in the tool chain as time-efficient replacements for the FEA model to approximate the injury criteria values. The method consists of the following steps: Selection of suitable training data sets out of a large number of given collision constellations, detailed FEA calculations with the training data sets as input, and training of the surrogate models with the FEA model's input and output values. RESULTS: A separate surrogate model was created for each injury criterion, consisting of a response surface that maps the input parameters (i.e., leg impactor position and velocity) to the output value. In addition, a performance test comparing surrogate model predictions of additional collision constellations to the results of respective FEA calculations was carried out. The developed method allows for prediction of injury criteria based on impact constellation for a given vehicle. Because the surrogate models are specific to a certain vehicle, training has to be redone for a new vehicle. Still, there is a large benefit regarding calculation time when doing large-scale studies. CONCLUSION: The method can be used in prospective effectiveness assessment studies of new vehicle safety features and takes into account specific local features of a vehicle (geometry, stiffness, etc.) as well as external parameters (location and velocity of pedestrian impact). Furthermore, it can be easily extended to other injury criteria or accident scenarios; for example, cyclist accidents.

Activation of survival pathways in the degenerating retina of rd10 mice.

Blinding diseases of the retina are frequently characterized by loss of photoreceptor cells. The retinal degeneration 10 (rd10) mouse expresses a mutant form of rod phosphodiesterase leading to autosomal recessive photoreceptor degeneration. In contrast to rd1, rd10 mice have remaining rod function mimicking more closely most forms of human Retinitis Pigmentosa. Here we use morphology, biochemistry, retinal whole mounts, real-time PCR, Western blotting and immunofluorescence to compile a comprehensive report on progression of retinal degeneration in the rd10 retina up to one year of age. We show that retinal development, morphology, gene expression pattern and retinal vasculature was normal until postnatal day 15. Thereafter, a bi-phasic pattern of rod cell death emerged with a first rapid phase peaking around 3 weeks of age followed by a slower second phase. Death of cone cells followed with a delay and vessel dropout was prominent in the retinal periphery of 6 months old rd10 mice. At one year of age, RPE atrophy was evident. The degenerating retina rapidly induced expression of transcriptional regulators Atf3 and Cebpd. Induction of Atf3 was transient and lasted only for several days at the beginning of degeneration whereas levels of Cebpd remained elevated throughout the period of photoreceptor loss. Several protective genes such as Lif, Edn2 and Fgf2 which are implicated in a potent endogenous survival pathway, and Mt1 and Mt2 were strongly upregulated in the rd10 retina. In addition, increased expression of Casp1 and Il1b suggested an inflammatory response.

Standardized protocol for a depletion of intramyocellular lipids (IMCL).

Intramyocellular lipids (IMCL) are flexible fuel stores that are depleted by physical exercise and replenished by fat intake. IMCL or their degradation products are thought to interfere with insulin signaling thereby contributing to insulin resistance. From a practical point of view it is desirable to deplete IMCL prior to replenishing them. So far, it is not clear for how long and at which intensity subjects have to exercise in order to deplete IMCL. We therefore aimed at developing a standardized exercise protocol that is applicable to subjects over a broad range of exercise capacity and insulin sensitivity and allows measuring reliably reduced IMCL levels.Twelve male subjects, including four diabetes type 2 patients, with wide ranges of exercise capacity (VO(2)peak per total body weight 27.9-55.8 ml x kg(-1) x min(-1)), insulin sensitivity (glucose infusion rate per lean body mass 4.7-15.3 mg x min(-1) x kg(-1)), and BMI (21.7-31.5 kg x m(-2)), respectively, were enrolled. Using (1)H magnetic resonance spectroscopy ((1)H-MRS), IMCL was measured in m.tibialis anterior and m.vastus intermedius before and during a depletion protocol of a week, consisting of a moderate additional physical activity (1 h daily at 60% VO(2)peak) and modest low-fat (10-15%) diet.Absolute IMCL-levels were significantly reduced in both muscles during the first 3 days and stayed constant for the next 3 days of an identical diet/exercise-scheme. These reduced IMCL levels were independent of insulin sensitivity, yet a tendency to lower depleted IMCL levels has been observed in subjects with higher VO(2)peak.The proposed protocol is feasible in subjects with large differences in exercise capacity, insulin sensitivity, and BMI, leading to reduced IMCL levels that neither depend on the exact duration of the depletion protocol nor on insulin sensitivity. This allows for a standardized preparation of IMCL levels either for correlation with other physiological parameters or for replenishment studies.

Biological treatment of ammonium-rich wastewater by partial nitritation and subsequent anaerobic ammonium oxidation (anammox) in a pilot plant.

In wastewater treatment plants with anaerobic sludge digestion, 15-20% of the nitrogen load is recirculated to the main stream with the return liquors from dewatering. Separate treatment of this ammonium-rich digester supernatant would significantly reduce the nitrogen load of the activated sludge system. Some years ago, a novel biological process was discovered in which ammonium is converted to nitrogen gas under anoxic conditions with nitrite as the electron acceptor (anaerobic ammonium oxidation, anammox). Compared to conventional nitrification and denitrification, the aeration and carbon-source demand is reduced by over 50 and 100%, respectively. The combination of partial nitritation to produce nitrite in a first step and subsequent anaerobic ammonium oxidation in a second reactor was successfully tested on a pilot scale (3.6 m(3)) for over half a year. This report focuses on the feasibility of nitrogen removal from digester effluents from two different wastewater treatment plants (WWTPs) with the combined partial nitritation/anammox process. Nitritation was performed in a continuously stirred tank reactor (V=2.0 m(3)) without sludge retention. Some 58% of the ammonium in the supernatant was converted to nitrite. At 30 degrees C the maximum dilution rate D(x) was 0.85 d(-1), resulting in nitrite production of 0.35 kg NO(2)-N m(-3)(reactor) d(-1). The nitrate production was marginal. The anaerobic ammonium oxidation was carried out in a sequencing batch reactor (SBR, V=1.6 m(3)) with a nitrogen elimination rate of 2.4 kg N m(-3)(reactor) d(-1) during the nitrite-containing periods of the SBR cycle. Over 90% of the inlet nitrogen load to the anammox reactor was removed and the sludge production was negligible. The nitritation efficiency of the first reactor limited the overall maximum rate of nitrogen elimination.