Long-term toxicity and efficacy of FLASH radiotherapy in dogs with superficial malignant tumors.

Introduction: FLASH radiotherapy (RT) has emerged as a promising modality, demonstrating both a normal tissue sparing effect and anticancer efficacy. We have previously reported on the safety and efficacy of single fraction FLASH RT in the treatment of oral tumors in canine cancer patients, showing tumor response but also a risk of radiation-induced severe late adverse effects (osteoradionecrosis) for doses ≥35 Gy. Accordingly, the objective in this study was to investigate if single fraction high dose FLASH RT is safe for treating non-oral tumors. Methods: Privately-owned dogs with superficial tumors or microscopic residual disease were included. Treatment was generally delivered as a single fraction of 15-35 Gy 10 MeV electron FLASH RT, although two dogs were re-irradiated at a later timepoint. Follow-up visits were conducted up to 12 months post-treatment to evaluate treatment efficiency and adverse effects. Results: Fourteen dogs with 16 tumors were included, of which nine tumors were treated for gross disease whilst seven tumors were treated post-surgery for microscopic residual disease. Four treatment sites treated with 35 Gy had ulceration post irradiation, which was graded as severe adverse effect. Only mild adverse effects were observed for the remaining treatment sites. None of the patients with microscopic disease experienced recurrence (0/7), and all patients with macroscopic disease showed either a complete (5/9) or a partial response (4/9). Five dogs were euthanized due to clinical disease progression. Discussion: Our study demonstrates that single fraction high dose FLASH RT is generally safe, with few severe adverse effects, particularly in areas less susceptible to radiation-induced damage. In addition, our study indicates that FLASH has anti-tumor efficacy in a clinical setting. No osteoradionecrosis was observed in this study, although other types of high-grade adverse effects including ulcer-formations were observed for the highest delivered dose (35 Gy). Overall, we conclude that osteoradionecrosis following single fraction, high dose FLASH does not appear to be a general problem for non-oral tumor locations. Also, as has been shown previously for oral tumors, 30 Gy appeared to be the maximum safe dose to deliver with single fraction FLASH RT.

Microsatellite instability and mismatch repair protein deficiency: equal predictive markers?

Current clinical guidelines recommend mismatch repair (MMR) protein immunohistochemistry (IHC) or molecular microsatellite instability (MSI) tests as predictive markers of immunotherapies. Most of the pathological guidelines consider MMR protein IHC as the gold standard test to identify cancers with MMR deficiency and recommend molecular MSI tests only in special circumstances or to screen for Lynch syndrome. However, there are data in the literature which suggest that the two test types may not be equal. For example, molecular epidemiology studies reported different rates of deficient MMR (dMMR) and MSI in various cancer types. Additionally, direct comparisons of the two tests revealed relatively frequent discrepancies between MMR IHC and MSI tests, especially in non-colorectal and non-endometrial cancers and in cases with unusual dMMR phenotypes. There are also scattered clinical data showing that the efficacy of immune checkpoint inhibitors is different if the patient selection was based on dMMR versus MSI status of the cancers. All these observations question the current dogma that dMMR phenotype and genetic MSI status are equal predictive markers of the immunotherapies.

The Intersectoral Coordination Unit for the Sustainable Intensification of Peritoneal Dialysis in Schleswig-Holstein (SKIP-SH) cohort study.

BACKGROUND: Peritoneal dialysis (PD) remains underutilised in Germany, prompting the initiation of the Sustainable Intensification of Peritoneal Dialysis in Schleswig-Holstein (SKIP-SH) project. The SKIP-SH cohort study aims to demonstrate the presumed benefits of PD, including enhanced quality of life and reduced healthcare personnel requirements, and to generate data to strengthen the use of PD. METHODS: The prospective SKIP-SH cohort study recruits patients with advanced chronic kidney disease (CKD) and their caregivers. Comprehensive data, including demographic information, medical history, clinical course, laboratory data, and quality-of-life assessments, are collected. Additionally, biomaterials will be obtained. Primary study objectives are documenting the clinical course and complications, time on therapy for new dialysis patients, reasons influencing treatment modality choices, circumstances at the initiation of dialysis, and quality of life for patients with CKD and their caregivers. The collected biomaterials will serve as a basis for further translational research. Secondary objectives include identifying factors impacting disease-related quality of life, clinical complications, and therapy dropout, estimating ecological footprints, and evaluating healthcare costs and labour time for initiating and sustaining PD treatment. DISCUSSION: PD is notably underutilised in Germany. The current therapy approach for advanced CKD often lacks emphasis on patient-focused care and quality-of-life considerations. Furthermore, adequate explorative research programs to improve our knowledge of mechanisms leading to disease progression and therapy failure in PD patients are scarce. The overarching goal of the SKIP-SH cohort study is to address the notably low PD prevalence in Germany whilst advocating for a shift towards patient-focused care, quality-of-life considerations, and robust translational research. TRIAL REGISTRATION: This study was registered with the German trial registry (Deutsches Register klinischer Studien) on November 7, 2023, under trial number DRKS00032983.

Comparison of standard mismatch repair deficiency and microsatellite instability tests in a large cancer series.

BACKGROUND: The tumor-agnostic indication of immune checkpoint inhibitors to treat cancers with mismatch repair deficiency (dMMR)/microsatellite instability (MSI) increased the demand for such tests beyond Lynch syndrome. International guideline recommendations accept immunohistochemistry (IHC) for dMMR or molecular techniques (PCR or NGS) for MSI status determinations considering the two tests are equal, although there are scattered reports contradicting to this presumption. MATERIALS AND METHODS: Here we have directly compared four protein MMR immunohistochemistry (IHC) to MSI Pentaplex PCR test in a large cancer patient cohort (n = 1306) of our diagnostic center where the two tests have been run parallel in 703 cases. RESULTS: In this study we have found a high discrepancy rate (19.3%) of the two tests which was independent of the tumor types. The MSI PCR sensitivity for MMR IHC status was found to be very low resulting in a relatively low positive and negative predicting values. As a consequence, the correlation of the two tests was low (kappa < 0.7). During analysis of the possible contributing factors of this poor performance, we have excluded low tumor percentage of the samples, but identified dMMR phenotypes (classic versus non-classic or unusual) as possible contributors. CONCLUSION: Although our cohort did not include samples with identified technical errors, our data strongly support previous reports that unidentified preanalytical factors might have the major influence on the poor performance of the MSI PCR and MMR IHC. Furthermore, the case is open whether the two test types are equally powerful predictive markers of immunotherapies.

Characterization of pSer129-αSyn Pathology and Neurofilament Light-Chain Release across In Vivo, Ex Vivo, and In Vitro Models of Pre-Formed-Fibril-Induced αSyn Aggregation.

Protein aggregation is a predominant feature of many neurodegenerative diseases, including synucleinopathies, which are characterized by cellular inclusions containing α-Synuclein (αSyn) phosphorylated at serine 129 (pSer129). In the present study, we characterized the development of αSyn pre-formed fibril (PFF)-induced pSer129-αSyn pathology in F28tg mice overexpressing human wild-type αSyn, as well as in ex vivo organotypic cultures and in vitro primary cultures from the same mouse model. Concurrently, we collected cerebrospinal fluid (CSF) from mice and conditioned media from ex vivo and in vitro cultures and quantified the levels of neurofilament light chain (NFL), a biomarker of neurodegeneration. We found that the intra-striatal injection of PFFs induces the progressive spread of pSer129-αSyn pathology and microglial activation in vivo, as well as modest increases in NFL levels in the CSF. Similarly, PFF-induced αSyn pathology occurs progressively in ex vivo organotypic slice cultures and is accompanied by significant increases in NFL release into the media. Using in vitro primary hippocampal cultures, we further confirmed that pSer129-αSyn pathology and NFL release occur in a manner that correlates with the fibril dose and the level of the αSyn protein. Overall, we demonstrate that αSyn pathology is associated with NFL release across preclinical models of seeded αSyn aggregation and that the pharmacological inhibition of αSyn aggregation in vitro also significantly reduces NFL release.

Playing the pipes: acoustic sensing and machine learning for performance feedback during endotracheal intubation simulation.

Objective: In emergency medicine, airway management is a core skill that includes endotracheal intubation (ETI), a common technique that can result in ineffective ventilation and laryngotracheal injury if executed incorrectly. We present a method for automatically generating performance feedback during ETI simulator training, potentially augmenting training outcomes on robotic simulators. Method: Electret microphones recorded ultrasonic echoes pulsed through the complex geometry of a simulated airway during ETI performed on a full-size patient simulator. As the endotracheal tube is inserted deeper and the cuff is inflated, the resulting changes in geometry are reflected in the recorded signal. We trained machine learning models to classify 240 intubations distributed equally between six conditions: three insertion depths and two cuff inflation states. The best performing models were cross validated in a leave-one-subject-out scheme. Results: Best performance was achieved by transfer learning with a convolutional neural network pre-trained for sound classification, reaching global accuracy above 98% on 1-second-long audio test samples. A support vector machine trained on different features achieved a median accuracy of 85% on the full label set and 97% on a reduced label set of tube depth only. Significance: This proof-of-concept study demonstrates a method of measuring qualitative performance criteria during simulated ETI in a relatively simple way that does not damage ecological validity of the simulated anatomy. As traditional sonar is hampered by geometrical complexity compounded by the introduced equipment in ETI, the accuracy of machine learning methods in this confined design space enables application in other invasive procedures. By enabling better interaction between the human user and the robotic simulator, this approach could improve training experiences and outcomes in medical simulation for ETI as well as many other invasive clinical procedures.

Evaluation of single-fraction high dose FLASH radiotherapy in a cohort of canine oral cancer patients.

Background: FLASH radiotherapy (RT) is a novel method for delivering ionizing radiation, which has been shown in preclinical studies to have a normal tissue sparing effect and to maintain anticancer efficacy as compared to conventional RT. Treatment of head and neck tumors with conventional RT is commonly associated with severe toxicity, hence the normal tissue sparing effect of FLASH RT potentially makes it especially advantageous for treating oral tumors. In this work, the objective was to study the adverse effects of dogs with spontaneous oral tumors treated with FLASH RT. Methods: Privately-owned dogs with macroscopic malignant tumors of the oral cavity were treated with a single fraction of ≥30Gy electron FLASH RT and subsequently followed for 12 months. A modified conventional linear accelerator was used to deliver the FLASH RT. Results: Eleven dogs were enrolled in this prospective study. High grade adverse effects were common, especially if bone was included in the treatment field. Four out of six dogs, who had bone in their treatment field and lived at least 5 months after RT, developed osteoradionecrosis at 3-12 months post treatment. The treatment was overall effective with 8/11 complete clinical responses and 3/11 partial responses. Conclusion: This study shows that single-fraction high dose FLASH RT was generally effective in this mixed group of malignant oral tumors, but the risk of osteoradionecrosis is a serious clinical concern. It is possible that the risk of osteonecrosis can be mitigated through fractionation and improved dose conformity, which needs to be addressed before moving forward with clinical trials in human cancer patients.

Sarcoma Predisposition in Dogs with a Comparative View to Human Orthologous Disease.

Sarcomas are malignant tumors arising from the embryonic mesodermal cell lineage. This group of cancers covers a heterogenous set of solid tumors arising from soft tissues or bone. Many features such as histology, biological behavior and molecular characteristics are shared between sarcomas in humans and dogs, suggesting that human sarcoma research can be informative for canine disease, and that dogs with sarcomas can serve as relevant translational cancer models, to aid in the understanding of human disease and cancer biology. In the present paper, risk factors for the development of sarcoma in dogs are reviewed, with a particular focus on recent advances in clinical genetics, and on the identification of simple and complex genetic risk factors with a comparison with what has been found in human orthologous disease.

Surface guided electron FLASH radiotherapy for canine cancer patients.

BACKGROUND: During recent years FLASH radiotherapy (FLASH-RT) has shown promising results in radiation oncology, with the potential to spare normal tissue while maintaining the antitumor effects. The high speed of the FLASH-RT delivery increases the need for fast and precise motion monitoring to avoid underdosing the target. Surface guided radiotherapy (SGRT) uses surface imaging (SI) to render a 3D surface of the patient. SI provides real-time motion monitoring and has a large scanning field of view, covering off-isocentric positions. However, SI has so far only been used for human patients with conventional setup and treatment. PURPOSE: The aim of this study was to investigate the performance of SI as a motion management tool during electron FLASH-RT of canine cancer patients. METHODS: To evaluate the SI system's ability to render surfaces of fur, three fur-like blankets in white, grey, and black were used to imitate the surface of canine patients and the camera settings were optimized for each blanket. Phantom measurements using the fur blankets were carried out, simulating respiratory motion and sudden shift. Respiratory motion was simulated using the QUASAR Respiratory Motion Phantom with the fur blankets placed on the phantom platform, which moved 10 mm vertically with a simulated respiratory period of 4 s. Sudden motion was simulated with an in-house developed phantom, consisting of a platform which was moved vertically in a stepwise motion at a chosen frequency. For sudden measurements, 1, 2, 3, 4, 5, 6, 7, and 10 Hz were measured. All measurements were both carried out at the conventional source-to-surface distance (SSD) of 100 cm, and in the locally used FLASH-RT setup at SSD = 70 cm. The capability of the SI system to reproduce the simulated motion and the sampling time were evaluated. As an initial step towards clinical implementation, the feasibility of SI for surface guided FLASH-RT was evaluated for 11 canine cancer patients. RESULTS: The SI camera was capable of rendering surfaces for all blankets. The deviation between simulated and measured mean peak-to-peak breathing amplitude was within 0.6 mm for all blankets. The sampling time was generally higher for the black fur than for the white and grey fur, for the measurement of both respiratory and sudden motion. The SI system could measure sudden motion within 62.5 ms and detect motion with a frequency of 10 Hz. The feasibility study of the canine patients showed that the SI system could be an important tool to ensure patient safety. By using this system we could ensure and document that 10 out of 11 canine patients had a total vector offset from the reference setup position <2 mm immediately before and after irradiation. CONCLUSIONS: We have shown that SI can be used for surface guided FLASH-RT of canine patients. The SI system is currently not fast enough to interrupt a FLASH-RT beam while irradiating but with the short sampling time sudden motion can be detected. The beam can therefore be held just prior to irradiation, preventing treatment errors such as underdosing the target.

Obvious benefits but hidden costs: A critical exploration of the impact of adopting the "master narrative" in Alcoholics Anonymous.

INTRODUCTION: New members of Alcoholics Anonymous (AA) typically acquire a distinct "alcoholic" identity, including AA-specific understandings of their "alcoholism" and what it means to be in recovery. Although much qualitative research on AA has presented the experiences of members who have embraced this identity and have been wholly praising of AA, other theorists have been strongly critical of the organization, often arguing that it emulates a cult. To contribute towards reconciling these competing bodies of research, the current study aimed to critically explore the impact of adopting AA's master narrative. METHODS: The study involved 19 prospective, in-depth semi-structured interviews with six AA members recruited from meetings across Sydney, Australia. Data were analyzed thematically using a master narrative theoretical framework. RESULTS: The study identified three core components of AA's master narrative: (1) Powerlessness over alcohol ("alcoholics" are powerless over alcohol); (2) Internalized pathologization ("alcoholics" are mentally and emotionally sick, above and beyond their problems with alcohol); and (3) AA as the only solution for wellness (involvement in AA is the necessary requirement for "alcoholics" to become and remain well). Although most participants emphasized the positive experiences from internalizing the AA narrative, our analysis also revealed potentially negative ramifications of this narrative on their self-conceptions and worldviews that were seemingly unrecognized by participants themselves. CONCLUSIONS: The master narrative framework facilitated a critical and balanced exploration of AA members' experiences. Although AA's master narrative is valuable for members, it could also carry costs that need to be mitigated by resources both inside and outside of AA.

The Influence of Myopia on the Foveal Avascular Zone and Density of Blood Vessels of the Macula-An OCTA Study.

Background and Objectives: Myopia is the most common refractive eye anomaly with a prevalence that is constantly increasing. High myopia is associated with numerous complications that can lead to permanent vision loss. It is believed that the basis of these complications lies in changes in the microvasculature of the retina caused by an increase in the longitudinal axis of the eye. Materials and Methods: Optical coherence tomography angiography (OCTA) was used to analyze differences in macular zone vascular and perfusion density and foveal avascular zone (FAZ) parameters in myopic subjects. The following OCTA parameters were analyzed: the vessel and perfusion density of retinal blood vessels in the superficial plexus; the area, perimeter, and index of circularity of the foveal avascular zone (FAZ); and foveal and ganglion cell complex (GCC) thickness. Results: Subjects with low myopia did not show statistically significant differences compared to the control for any of the analyzed parameters. Groups with moderate and high myopia showed a significant decrease in vessel and perfusion density in the parafoveal and the entire 3 × 3 mm analyzed field. Foveal vessel and perfusion densities in the myopic groups were similar to those of the control regardless of the degree of myopia. The area and perimeter of the FAZ, as well as foveal and mean GCC thickness, did not differ significantly no matter the degree of myopia, while the index of circularity was lower in highly myopic subjects. The minimal thickness of the GCC was also lower in the high myopia group. Conclusions: High and moderate myopia led to a loss of blood vessels in the macular region. Perfusion and vascular densities were preserved in the foveal region and were not affected by different degrees of myopia. The FAZ was not significantly larger in myopic subjects, but its circularity was lower in subjects with high myopia.

Loss of Adgra3 causes obstructive azoospermia with high penetrance in male mice.

The adhesion receptor ADGRA3 (GPR125) is a known spermatogonial stem cell marker, but its impact on male reproduction and fertility has not been examined. Using a mouse model lacking Adgra3 (Adgra3-/- ), we show that 55% of the male mice are infertile from puberty despite having normal spermatogenesis and epididymal sperm count. Instead, male mice lacking Adgra3 exhibited decreased estrogen receptor alpha expression and transient dilation of the epididymis. Combined with an increased estradiol production, this indicates a post-pubertal hormonal imbalance and fluid retention. Dye injection revealed a blockage between the ejaculatory duct and the urethra, which is rare in mice suffering from infertility, thereby mimicking the etiologies of obstructive azoospermia found in human male infertility. To summarize, male reproductive tract development is dependent on ADGRA3 function that in concert with estrogen signaling may influence fluid handling during sperm maturation and storage.

Immersive Virtual Reality in Basic Point-of-Care Ultrasound Training: A Randomized Controlled Trial.

This study was aimed at comparing the learning efficacy of a traditional instructor-led lesson with that of a completely virtual, self-directed lesson in immersive virtual reality (IVR) in teaching basic point-of-care ultrasound (PoCUS) skills. We conducted a blinded, non-inferiority, parallel-group, randomized controlled trial in which final-year medical students were randomized to an instructor-led (n = 53) or IVR (n = 51) lesson. Participants' learning efficacy was evaluated by blinded assessors, who rated each participant's performance using the Objective Structured Assessment of Ultrasound Skills (OSAUS) assessment tool.The mean total scores for participants were 11.0 points (95% confidence interval: 9.8-12.2) for the instructor-led lesson and 10.3 points (95% confidence interval: 9.0-11.5) for the IVR lesson. No significant differences were observed between the groups with respect to total score (p = 0.36) or subgroup objectives of the OSAUS score (p = 0.34 for familiarity, p = 0.45 for image optimization, p = 0.96 for systematic approach and p = 0.07 for interpretation). Maintenance costs for both courses were estimated at 400 euros each. Startup costs for the instructor-led course were estimated 16 times higher than those for the IVR course. The learning efficacy of an instructor-led lesson on basic US did not differ significantly from that of a self-directed lesson in IVR, as assessed using the OSAUS. The results suggest that IVR could be an equivalent alternative to instructor-led lessons in future basic US courses, but further research is warranted to clarify the role of IVR in PoCUS courses.

Ultra-low dose computed tomography of the chest in an emergency setting: A prospective agreement study.

Ultra-low dose computed tomography (ULD-CT) assessed by non-radiologists in a medical Emergency Department (ED) has not been examined in previous studies. To (i) investigate intragroup agreement among attending physicians caring for ED patients (i.e., radiologists, senior- and junior clinicians) and medical students for the detection of acute lung conditions on ULD-CT and supine chest X-ray (sCXR), and (ii) evaluate the accuracy of interpretation compared to the reference standard. In this prospective study, non-traumatic patients presenting to the ED, who received an sCXR were included. Between February and July 2019, 91 patients who underwent 93 consecutive examinations were enrolled. Subsequently, a ULD-CT and non-contrast CT were performed. The ULD-CT and sCXR were assessed by 3 radiologists, 3 senior clinicians, 3 junior clinicians, and 3 medical students for pneumonia, pneumothorax, pleural effusion, and pulmonary edema. The non-contrast CT, assessed by a chest radiologist, was used as the reference standard. The results of the assessments were compared within each group (intragroup agreement) and with the reference standard (accuracy) using kappa statistics. Accuracy and intragroup agreement improved for pneumothorax on ULD-CT compared with the sCXR for all groups. Accuracy and intragroup agreement improved for pneumonia on ULD-CT when assessed by radiologists and for pleural effusion when assessed by medical students. In patients with acute lung conditions ULD-CT offers improvement in the detection of pneumonia by radiologists and the detection of pneumothorax by radiologists as well as non-radiologists compared to sCXR. Therefore, ULD-CT may be considered as an alternative first-line imaging modality to sCXR for non-traumatic patients who present to EDs.

Biochemical analysis of novel NAA10 variants suggests distinct pathogenic mechanisms involving impaired protein N-terminal acetylation.

NAA10 is the catalytic subunit of the N-terminal acetyltransferase complex, NatA, which is responsible for N-terminal acetylation of nearly half the human proteome. Since 2011, at least 21 different NAA10 missense variants have been reported as pathogenic in humans. The clinical features associated with this X-linked condition vary, but commonly described features include developmental delay, intellectual disability, cardiac anomalies, brain abnormalities, facial dysmorphism and/or visual impairment. Here, we present eight individuals from five families with five different de novo or inherited NAA10 variants. In order to determine their pathogenicity, we have performed biochemical characterisation of the four novel variants c.16G>C p.(A6P), c.235C>T p.(R79C), c.386A>C p.(Q129P) and c.469G>A p.(E157K). Additionally, we clinically describe one new case with a previously identified pathogenic variant, c.384T>G p.(F128L). Our study provides important insight into how different NAA10 missense variants impact distinct biochemical functions of NAA10 involving the ability of NAA10 to perform N-terminal acetylation. These investigations may partially explain the phenotypic variability in affected individuals and emphasise the complexity of the cellular pathways downstream of NAA10.

Diagnostic accuracy of ultra-low-dose chest computed tomography in an emergency department.

BACKGROUND: This study examined whether ultra-low-dose chest computed tomography (ULD-CT) could improve detection of acute chest conditions. PURPOSE: To determine (i) whether diagnostic accuracy of ULD-CT is superior to supine chest X-ray (sCXR) for acute chest conditions and (ii) the feasibility of ULD-CT in an emergency department. MATERIAL AND METHODS: From 1 February to 31 July 2019, 91 non-traumatic patients from the Emergency Department were prospectively enrolled in the study if they received an sCXR. An ULD-CT and a non-contrast chest CT (NCCT) scan were then performed. Three radiologists assessed the sCXR and ULD-CT examinations for cardiogenic pulmonary edema, pneumonia, pneumothorax, and pleural effusion. Resources and effort were compared for sCXR and ULD-CT to evaluate feasibility. Diagnostic accuracy was calculated for sCXR and ULD-CT using NCCT as the reference standard. RESULTS: The mean effective dose of ULD-CT was 0.05±0.01 mSv. For pleural effusion and cardiogenic pulmonary edema, no difference in diagnostic accuracy between ULD-CT and sCXR was observed. For pneumonia and pneumothorax, sensitivities were 100% (95% confidence interval [CI] 69-100) and 50% (95% CI 7-93) for ULD-CT and 60% (95% CI 26-88) and 0% (95% CI 0-0) for sCXR, respectively. Median examination time was 10 min for ULD-CT vs. 5 min for sCXR (P<0.001). For ULD-CT 1-2 more staff members were needed compared to sCXR (P<0.001). ULD-CT was rated more challenging to perform than sCXR (P<0.001). CONCLUSION: ULD-CT seems equal or better in detecting acute chest conditions compared to sCXR. However, ULD-CT examinations demand more effort and resources.

Emulsifier peptides derived from seaweed, methanotrophic bacteria, and potato proteins identified by quantitative proteomics and bioinformatics.

Global focus on sustainability has accelerated research into alternative non-animal sources of food protein and functional food ingredients. Amphiphilic peptides represent a class of promising biomolecules to replace chemical emulsifiers in food emulsions. In contrast to traditional trial-and-error enzymatic hydrolysis, this study utilizes a bottom-up approach combining quantitative proteomics, bioinformatics prediction, and functional validation to identify novel emulsifier peptides from seaweed, methanotrophic bacteria, and potatoes. In vitro functional validation reveal that all protein sources contained embedded novel emulsifier peptides comparable to or better than sodium caseinate (CAS). Thus, peptides efficiently reduced oil-water interfacial tension and generated physically stable emulsions with higher net zeta potential and smaller droplet sizes than CAS. In silico structure modelling provided further insight on peptide structure and the link to emulsifying potential. This study clearly demonstrates the potential and broad applicability of the bottom-up approach for identification of abundant and potent emulsifier peptides.

Establishment and Initial Experience of Clinical FLASH Radiotherapy in Canine Cancer Patients.

FLASH radiotherapy has emerged as a treatment technique with great potential to increase the differential effect between normal tissue toxicity and tumor response compared to conventional radiotherapy. To evaluate the feasibility of FLASH radiotherapy in a relevant clinical setting, we have commenced a feasibility and safety study of FLASH radiotherapy in canine cancer patients with spontaneous superficial solid tumors or microscopic residual disease, using the electron beam of our modified clinical linear accelerator. The setup for FLASH radiotherapy was established using a short electron applicator with a nominal source-to-surface distance of 70 cm and custom-made Cerrobend blocks for collimation. The beam was characterized by measuring dose profiles and depth dose curves for various field sizes. Ten canine cancer patients were included in this initial study; seven patients with nine solid superficial tumors and three patients with microscopic disease. The administered dose ranged from 15 to 35 Gy. To ensure correct delivery of the prescribed dose, film measurements were performed prior to and during treatment, and a Farmer-type ion-chamber was used for monitoring. Treatments were found to be feasible, with partial response, complete response or stable disease recorded in 11/13 irradiated tumors. Adverse events observed at follow-up ranging from 3-6 months were mild and consisted of local alopecia, leukotricia, dry desquamation, mild erythema or swelling. One patient receiving a 35 Gy dose to the nasal planum, had a grade 3 skin adverse event. Dosimetric procedures, safety and an efficient clincal workflow for FLASH radiotherapy was established. The experience from this initial study will be used as a basis for a veterinary phase I/II clinical trial with more specific patient inclusion selection, and subsequently for human trials.

Assessing Delivery of Selected Public Health Operations via Essential Public Health Operation Framework.

BACKGROUND: To assess the conduct of delivery of public health services at the municipal level in Denmark by applying services enlisted in the Essential Public Health Operation framework (EPHO) of WHO. METHODS: We conducted individual qualitative interviews with key informants working with public health using a self-assessment survey tool in order to obtain an in-depth understanding of the interrelation or multidisciplinary work in Kolding Municipality. The developed self-assessment survey tool entailed questions about essential public health activities performed in a municipality. RESULTS: The Municipality organizes and contributes to core service delivery EPHOs, namely health protection, health promotion, and disease prevention. It collaborates with the general practitioners and the Region of Southern Denmark, responsible for hospital care, to fulfill the selected EPHOs. CONCLUSIONS: To obtain a comprehensive picture of the organizations that deliver public health services within a municipality, it is necessary to conduct interviews with representatives from those organizations as well. Additionally, the results from this study can be used to improve the survey tool further and hereafter conduct a nationwide survey in Denmark, as well as other European countries.