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Aim:
The most suitable method for assessment of response to peptide receptor radionuclide therapy (PRRT) of neuroendocrine tumors (NET) is still under debate. In this study we aimed to compare size (RECIST 1.1), density (Choi), Standardized Uptake Value (SUV) and a newly defined ZP combined parameter derived from Somatostatin Receptor (SSR) PET/CT for prediction of both response to PRRT and overall survival (OS).
Material and Methods:
Thirty-four NET patients with progressive disease (F:M 23:11; mean age 61.2 y; SD ± 12) treated with PRRT using either Lu-177 DOTATOC or Lu-177 DOTATATE and imaged with Ga-68 SSR PET/CT approximately 10–12 weeks prior to and after each treatment cycle were retrospectively analyzed. Median duration of follow-up after the first cycle was 63.9 months (range 6.2–86.2). A total of 77 lesions (2–8 per patient) were analyzed. Response assessment was performed according to RECIST 1.1, Choi and modified EORTC (MORE) criteria. In addition, a new parameter named ZP, the product of Hounsfield unit (HU) and SUVmean (Standard Uptake Value) of a tumor lesion, was tested. Further, SUV values (max and mean) of the tumor were normalized to SUV of normal liver parenchyma. Tumor response was defined as CR, PR, or SD. Gold standard for comparison of baseline parameters for prediction of response of individual target lesions to PRRT was change in size of lesions according to RECIST 1.1. For prediction of overall survival, the response after the first and second PRRT were tested.
Results:
Based on RECIST 1.1, Choi, MORE, and ZP, 85.3%, 64.7%, 61.8%, and 70.6% achieved a response whereas 14.7%, 35.3%, 38.2%, and 29.4% demonstrated PD (progressive disease), respectively. Baseline ZP and ZPnormalized were found to be the only parameters predictive of lesion progression after three PRRT cycles (AUC ZP 0.753; 95% CI 0.6–0.9, p 0.037; AUC ZPnormalized 0.766; 95% CI 0.6–0.9; p 0.029). Based on a cut-off-value of 1201, ZP achieved a sensitivity of 86% and a specificity of 67%, while ZPnormalized reached a sensitivity of 86% and a specificity of 76% at a cut-off-value of 198. Median OS in the total cohort was not reached. In univariate analysis amongst all parameters, only patients having progressive disease according to MORE after the second cycle of PRRT were found to have significantly shorter overall survival (median OS in objective responders not reached, in PD 29.2 months; p 0.015). Patients progressive after two cycles of PRRT according to ZP had shorter OS compared to those responding (median OS for responders not reached, for PD 47.2 months, p 0.066).
Conclusions:
In this explorative study, we showed that Choi, RECIST 1.1, and SUVmax-based response evaluation varied significantly from each other. Only patients showing progressive disease after two PRRT cycles according to MORE criteria had a worse prognosis while baseline ZP and
ZPnormalized performed best in predicting lesion progression after three cycles of PRRT.
Methods for standard meta-analysis of diagnostic test accuracy studies are well established and understood. For the more complex case in which studies report test accuracy across multiple thresholds, several approaches have recently been proposed. These are based on similar ideas, but make different assumptions. In this article, we apply four different approaches to data from a recent systematic review in the area of nephrology and compare the results. The four approaches use: a linear mixed effects model, a Bayesian multinomial random effects model, a time-to-event model and a nonparametric model, respectively. In the case study data, the accuracy of neutrophil gelatinase-associated lipocalin for the diagnosis of acute kidney injury was assessed in different scenarios, with sensitivity and specificity estimates available for three thresholds in each primary study. All approaches led to plausible and mostly similar summary results. However, we found considerable differences in results for some scenarios, for example, differences in the area under the receiver operating characteristic curve (AUC) of up to 0.13. The Bayesian approach tended to lead to the highest values of the AUC, and the nonparametric approach tended to produce the lowest values across the different scenarios. Though we recommend using these approaches, our findings motivate the need for a simulation study to explore optimal choice of method in various scenarios.
In this study, we calculated the energetics of hydrogen atoms adsorbing on and diffusing into the first few layers of γ-Fe for the (100), (110) and (111) surfaces and for the non-magnetic (NM), ferromagnetic (FM), and antiferromagnetic single (AFM1) and double layer (AFMD) structures. These studies are relevant as they atomistically simulate the early stages of hydrogen embrittlement in steels. We employed density functional theory to establish adsorption sites and energies for each plane and the minimum energy pathways for diffusion through the first few layers with associated activation barriers. Adsorption energies for all cases vary between ∼3.7 and 4.4 eV, and the energy barriers to diffusion in the bulk region vary between ∼0.2 and 1.2 eV for the twelve cases, with the highest and lowest bulk diffusion barriers occurring in the NM(111) and the FM(100) case, respectively. We conclude that the texturing of steels in order to expose certain cleavage planes or magnetic structures can decrease the likelihood of hydrogen embrittlement.
To design cost-effective prevention strategies against mastitis in dairy cow farms, knowledge about infection pathways of causative pathogens is necessary. Therefore, we investigated the reservoirs of bacterial strains causing intramammary infections in one dairy cow herd. Quarter foremilk samples (n = 8056) and milking- and housing-related samples (n = 251; from drinking troughs, bedding material, walking areas, cow brushes, fly traps, milking liners, and milker gloves), were collected and examined using culture-based methods. Species were identified with MALDI-TOF MS, and selected Staphylococcus and Streptococcus spp. typed with randomly amplified polymorphic DNA-PCR. Staphylococci were isolated from all and streptococci from most investigated locations. However, only for Staphylococcus aureus, matching strain types (n = 2) were isolated from milk and milking-related samples (milking liners and milker gloves). Staphylococcus epidermidis and Staphylococcus haemolyticus showed a large genetic diversity without any matches of strain types from milk and other samples. Streptococcus uberis was the only Streptococcus spp. isolated from milk and milking- or housing-related samples. However, no matching strains were found. This study underlines the importance of measures preventing the spread of Staphylococcus aureus between quarters during milking.
To effectively prevent and control bovine mastitis, farmers and their advisors need to take infection pathways and durations into account. Still, studies exploring both aspects through molecular epidemiology with sampling of entire dairy cow herds over longer periods are scarce. Therefore, quarter foremilk samples were collected at 14-d intervals from all lactating dairy cows (n = 263) over 18 wk in one commercial dairy herd. Quarters were considered infected with Staphylococcus aureus, Streptococcus uberis, or Streptococcus dysgalactiae when ≥100 cfu/mL of the respective pathogen was detected, or with Staphylococcus epidermidis or Staphylococcus haemolyticus when ≥500 cfu/mL of the respective pathogen was detected. All isolates of the mentioned species underwent randomly amplified polymorphic DNA (RAPD)-PCR to explore strain diversity and to distinguish ongoing from new infections. Survival analysis was used to estimate infection durations. Five different strains of Staph. aureus were isolated, and the most prevalent strain caused more than 80% of all Staph. aureus infections (n = 46). In contrast, 46 Staph. epidermidis and 69 Staph. haemolyticus strains were isolated, and none of these caused infections in more than 2 different quarters. The 3 most dominant strains of Strep. dysgalactiae (7 strains) and Strep. uberis (18 strains) caused 81% of 33 and 49% of 37 infections in total, respectively. The estimated median infection duration for Staph. aureus was 80 d, and that for Staph. epidermidis and Staph. haemolyticus was 28 and 22 d, respectively. The probability of remaining infected with Strep. dysgalactiae or Strep. uberis for more than 84 and 70 d was 58.7 and 53.5%, respectively. Staphylococcus epidermidis and Staph. haemolyticus were not transmitted contagiously and the average infection durations were short, which brings into question whether antimicrobial treatment of intramammary infections with these organisms is justified. In contrast, infections with the other 3 pathogens lasted longer and largely originated from contagious transmission.
Although Corynebacterium spp. can be regularly associated with subclinical and clinical mastitis cases in dairy cows, knowledge on their reservoirs in dairy farms is sparse. Therefore, samples were collected at 10 visits with 14 day intervals from bedding material (n = 50), drinking troughs (n = 20), different walking areas (n = 60), cow brushes (n = 8), fly traps (n = 4), the passage to pasture (n = 9) as well as milking liners (n = 80) and milker gloves (n = 20) in one dairy cow farm. Additionally, quarter foremilk samples from all lactating cows (approximately 200) were collected at each visit. All samples underwent microbiological examination and cultured isolates were identified using MALDI-TOF MS. Most Corynebacterium spp. that were cultivated from milk were also isolated from the housing environment and milking-related niches (C. amycolatum, C. confusum, C. stationis, C. variabile, C. xerosis) or from milking-related niches only (C. frankenforstense, C. pilosum, C. suicordis). C. bovis was not cultivated from any environmental niche, while being the dominant species in milk samples. This study demonstrates that many Corynebacterium spp. present in milk samples can also be isolated from the cows’ environment. For C. bovis, the most relevant Corynebacterium species with regard to intramammary infections, it indicates that environmental reservoirs are of little relevance.
The optimization of lubricated sealing systems with respect to the stick-slip effect requires a friction model that describes the complex friction behavior in the lubricated contact area. This paper presents an efficient dynamic friction model based on the Stribeck curve, which allows to investigate the influencing parameters through finite element (FE) simulations. The simulation of a tribometer test using this friction model proofs that the model correlates well with the tribometer test results. It is shown that the system stiffness has a significant influence on the stick-slip tendency of the system.
Within the HiGHmeducation consortium various online learning modules shall be developed by members of the consortium to address the increasing need for skilled professionals in a networked and digitalized healthcare system. Transferability of these modules to other locations is one main objective for the design of online learning modules. Thus, a didactical framework for online learning modules was developed. To ensure feasibility of the framework, the participating universities were analyzed concerning availability of e-learning support structures and infrastructures including learning management systems (LMS). The analysis especially focuses on the various LMS learning tools and their suitability for the framework. The framework is the basis for 12 HiGHmeducation online learning modules of which a part has firstly been conducted in winter 2019/20 and leads to a comparable structure of the modules.
Radioisotope-guided sentinel lymph node dissection (sLND) has shown high diagnostic reliability in prostate (PCa) and other cancers. To overcome the limitations of the radioactive tracers, magnetometer-guided sLND using superparamagnetic iron oxide nanoparticles (SPIONs) has been successfully used in PCa. This prospective study (SentiMag Pro II, DRKS00007671) determined the diagnostic accuracy of magnetometer-guided sLND in intermediate- and high-risk PCa. Fifty intermediate- or high-risk PCa patients (prostate-specific antigen (PSA) >= 10 ng/mL and/or Gleason score >= 7; median PSA 10.8 ng/mL, IQR 7.4–19.2 ng/mL) were enrolled. After the intraprostatic SPIONs injection a day earlier, patients underwent magnetometer-guided sLND and extended lymph node dissection (eLND, followed by radical prostatectomy. SLNs were detected in in vivo and in ex vivo samples. Diagnostic accuracy of sLND was assessed using eLND as the reference. SLNs were detected in all patients (detection rate 100%), with 447 sentinel lymph nodes SLNs (median 9, IQR 6–12) being identified and 966 LNs (median 18, IQR 15–23) being removed. Thirty-six percent (18/50) of patients had LN metastases (median 2, IQR 1–3). Magnetometer-guided sLND had 100% sensitivity, 97.0% specificity, 94.4% positive predictive value, 100% negative predictive value, 0.0% false negative rate, and 3.0% additional diagnostic value (LN metastases only in SLNs outside the eLND template). In vivo, one positive SLN/LN-positive patient was missed, resulting in a sensitivity of 94.4%. In conclusion, this new magnetic sentinel procedure has high accuracy for nodal staging in intermediate- and high-risk PCa. The reliability of intraoperative SLN detection using this magnetometer system requires verification in further multicentric studies.
The velocity distribution of He atoms evaporating from a slab of liquid dodecane has been simulated. The distribution composed of ∼10 000 He trajectories is shifted to fractionally faster velocities as compared to a Maxwell–Boltzmann distribution at the temperature of the liquid dodecane with an average translational energy of 1.05 × 2RT (or 1.08 × 2RT after correction for a cylindrical liquid jet), compared to the experimental work by Nathanson and co-workers (1.14 × 2RT) on liquid jets. Analysis of the trajectories allows us to infer mechanistic information about the modes of evaporation, and their contribution to the overall velocity distribution.