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Wound pH has emerged as a promising therapeutic target in diabetic foot ulcers (DFU). Here, we aimed to develop a microparticle-loaded hydrogel for pH modulation in wound fluid. In a screen of polymeric and inorganic microparticles, zeolites were identified as pH-modulating microparticles. Zeolites were encapsulated in a calcium cross-linked alginate hydrogel, a biocompatible matrix clinically used as a wound dressing. This hydrogel potently neutralized hydroxide ions in serum-containing simulated wound fluid. These findings encourage a further development of this pH-modulating device as a molecular therapeutic system for DFUs.

Chronic wounds, defined by their prolonged healing process, significantly impair patient quality of life and impose a hefty financial burden on healthcare systems worldwide. Sex/gender-specific mechanisms regulate inflammation and infection, angiogenesis, matrix synthesis, and cell recruitment contribute to cutaneous wound healing, but remain largely understudied. This review is aimed to spotlight the innovative realm of bioengineering and nanomedicine, which is at the helm of revolutionizing complex chronic wound care. It underscores the significance of integrating patient sex into the development and (pre)clinical testing of these avant-garde treatment modalities, in order to enhance healing prospects for both women and men. Moreover, we explore the representation of both sexes in clinical trials of bioengineered and nanomedicine products. Finally, we examine the primary reasons for the historical neglect in translating sex-specific wound healing research into clinical practice and propose strategic solutions. By tackling these issues, the article advocates for advanced treatment frameworks that could significantly improve healing outcomes for individuals of all sexes, thereby optimizing both efficacy and inclusivity in chronic wound management., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists.)

Significance: Chronic diabetic wounds on the lower extremities (diabetic foot ulcers, DFU) are one of the most prevalent and life-threatening complications of diabetes, responsible for significant loss of quality of life and cost to the health care system. Available pharmacologic treatments fail to achieve complete healing in many patients. Recent studies and investigational treatments have highlighted the potential of modulating wound pH in DFU. Recent Advances: Data from in vitro , preclinical, and clinical studies highlight the role of pH in the pathophysiology of DFU, and topical administration of pH-lowering agents have shown promise as a therapeutic strategy for diabetic wounds. In this critical review, we describe the role of pH in DFU pathophysiology and present selected low-molecular-weight and hydrogel-based pH-modulating systems for wound healing and infection control in diabetic wounds. Critical Issues: The molecular mechanisms leading to pH alterations in diabetic wounds are complex and may differ between in vitro models, animal models of diabetes, and the human pathophysiology. Wound pH-lowering bandages for DFU therapy must be tested in established animal models of diabetic wound healing and patients with diabetes to establish a comprehensive benefit-risk profile. Future Directions: As our understanding of the role of pH in the pathophysiology of diabetic wounds is deepening, new treatments for this therapeutic target are being developed and will be tested in preclinical and clinical studies. These therapeutic systems will establish a target product profile for pH-lowering treatments such as an optimal pH profile for each wound healing stage. Thus, controlling wound bed pH could become a powerful tool to accelerate chronic diabetic wound healing.

Ammonia is a key biomarker in inborn and acquired liver disease. As clinical point-of-care blood ammonia assays are lacking, we developed a polymersome formulation for point-of-care blood ammonia sensing combined with a portable fluorometer. A pH-sensitive near-infrared (NIR) fluorescent dye was identified, which showed a strong fluorescence increase at acidic pH values. Building on reports on ammonia-selective PS- b -PEG polymersomes, these polymersomes were loaded with the NIR dye. These NIR fluorescent polymersomes sensed ammonia in a clinically relevant range in ammonia-spiked fresh whole blood with high linearity ( R 2 = 0.9948) after 5 min using a conventional tabletop plate reader. Subsequently, the assay was tested with a portable fluorometer. An ammonia-dependent fluorescence increase was detected in ammonia-spiked fresh mouse blood after 5 min using the portable fluorometer. The NIR dye-loaded PS- b -PEG polymersomes rapidly sensed ammonia with high linearity in whole blood. This assay was successfully combined with a portable fluorometer and only required 3 μL of blood. These findings motivate a further development and clinical translation of this point-of-care blood ammonia assay., Competing Interests: The authors declare the following competing financial interest(s): SM is a co-inventor on a patent application related to the technology described in this study., (© 2024 The Authors. Published by American Chemical Society.)

Competing Interests: The authors have no conflicts of interest to report.

Gender is an important risk factor for adverse drug reactions. Women report significantly more adverse drug reactions than men. There is a growing consensus that gender differences in drug PK is a main contributor to higher drug toxicity in women. These differences stem from physiological differences (body composition, plasma protein concentrations, and liver and kidney function), drug interactions, and comorbidities. Contrast agents are widely used to enhance diagnostic performance in computed tomography and magnetic resonance imaging. Despite their broad use, these contrast agents can lead to important adverse reactions including hypersensitivity reactions, nephropathy, and hyperthyroidism. Importantly, female gender is one of the main risk factors for contrast agent toxicity. As these adverse reactions may be related to gender differences in PK, this perspective aims to describe distribution and elimination pathways of commonly used contrast agents and to critically discuss gender differences in these processes., Competing Interests: The authors declare no competing financial interest., (© 2023 American Chemical Society.)

Background: Switzerland ranks among the top three healthcare systems in the world with regards to healthcare access, suggesting a high degree of health equity. However, Switzerland has few preventive strategies against smoking abuse. The aim of this study is to clarify whether educational level and citizenship status have an influence on the prevalence of smoking in Switzerland and whether there is health inequity related to a lack of preventive strategies., Methods: We based our analysis on publicly available health data published in the Swiss government's Swiss health survey (1992-2017). We compared the prevalence of smoking across the years and correlated these data with levels of educational attainment, citizenship status and age., Results: A continuous significant decline in smokers is observed in the highest education group (TERT). Over time, prevalence was reduced from 29% in 1992 to 23% in 2017 ( p < 0.001). The intermediate-level educational group (SEK 2) showed smaller but also significant decline on a 0.05 sigificance level over the same period, from 31% to 29% ( p = 0.003). The lowest educational group showed a nonsignificant decline from 28% to 27% ( p = 0.6). The population who holds Swiss citizenship showed a decrease in smoking from 28% to 26% within the time frame ( p < 0.001). People without Swiss citizenship had a much higher prevalence of smokers, at 38% in 1992 and declining to 32% in 2017 ( p < 0.001). All cohorts from age 15 to age 64 have a far higher prevalence of smokers than cohorts at an older age, with the highest prevalence in the 25-34 age group., Conclusion: In Switzerland, individuals with lower levels of education and non-Swiss populations are more susceptible to health risk of smoking. This is despite the existence of a high-quality healthcare system that has nevertheless failed to negated health inequities., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Wehrli, Gilljam, Koh, Matoori, Sartoretti, Boes, Hartmann, Roser, Ort, Wanner, Harder, Bech-Hohenberger, Froehlich, Fröhlich, Mutschler, Plümecke and Gutzeit.)

Introduction: A trend towards less male radiologists specializing in breast ultrasound was observed. A common notion in the field of breast radiology is, that female patients feel more comfortable being treated by female radiologists. The aim of the study was to understand and report the needs of women undergoing breast ultrasound with regards to the sex of the radiologist performing the investigation., Methods: Informed consent was obtained from all patients prior to inclusion in a prospective bi-center quality study. At center 1 (72 patients), the women were examined exclusively by female radiologists, at center 2 (100 patients) only by male radiologists. After the examination the patients were asked about their experiences and their wishes for the future., Results: Overall, women made no distinction between female and male radiologists; 25% of them wanted a female radiologist and 1.2% wanted a male radiologist. The majority (74%) stated that it made no difference whether a female or male radiologist performed the examination. The majority of women in group 2, who were investigated exclusively by male radiologists, stated that they had no preferences with regard to the sex of the radiologist (93%); 5% of the women wished to be investigated solely by a female radiologist and 2% exclusively by a male radiologist., Discussion: The majority of women undergoing breast ultrasound are unconcerned about the radiologist's sex. It would appear that women examined by male radiologists are less selective about the sex of the examining radiologist., Trial Registration: Written informed consent was obtained from all patients. All patient data were anonymized. The physicians had no access to any further personal data. National regulations did not require dedicated ethics approval with anonymized lists or retrospective questionnaires., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Sartoretti et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Hydrogel-based biomaterials have gained broad acceptance for tissue engineering and drug delivery applications. As their function generally depends on their localization, identifying the hydrogel position in the body is relevant and will alert physicians about potentially dangerous hydrogel migration. Monitoring the localization of hydrogels by imaging is challenging due to their high water content. Here, we developed a method to render alginate hydrogels visible on computed tomography (CT) and X-ray for real-time tracking of hydrogels inside the body. This method is based on physically immobilizing emulsion droplets of ethiodized oil, an FDA-approved positive CT contrast agent, in calcium-crosslinked alginate hydrogels. We prepared an oil-in-water emulsion of ethiodized oil with micron-sized emulsion droplets and encapsulated it in a calcium-crosslinked alginate hydrogel. This injectable in situ-forming hydrogel was stable for at least 2 weeks in vitro, visible on CT and X-ray in mice, and showed contrast agent concentration-dependent signal intensities. Hydrogels retrieved from mice after imaging had suitable rheological properties with a storage modulus of about 2 kPa and a loss modulus of about 0.35 kPa. This proof-of-concept study highlights the potential of ethiodized oil to localize hydrogels in real time inside the body and identifies a new use of this FDA-approved contrast agent., (© 2023. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

The way a drug molecule is administered has always had a profound impact on people requiring medical interventions - from vaccine development to cancer therapeutics. In the Controlled Release Society Fall Symposium 2022, a trans-institutional group of scientists from industry, academia, and non-governmental organizations discussed what a breakthrough in the field of drug delivery constitutes. On the basis of these discussions, we classified drug delivery breakthrough technologies into three categories. In category 1, drug delivery systems enable treatment for new molecular entities per se, for instance by overcoming biological barriers. In category 2, drug delivery systems optimize efficacy and/or safety of an existing drug, for instance by directing distribution to their target tissue, by replacing toxic excipients, or by changing the dosing reqimen. In category 3, drug delivery systems improve global access by fostering use in low-resource settings, for instance by facilitating drug administration outside of a controlled health care institutional setting. We recognize that certain breakthroughs can be classified in more than one category. It was concluded that in order to create a true breakthrough technology, multidisciplinary collaboration is mandated to move from pure technical inventions to true innovations addressing key current and emerging unmet health care needs., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Bilirubin was first detected in blood in 1847 and since then has become one of the most widely used biomarkers for liver disease. Clinical routine bilirubin testing is performed at the hospital laboratory, and the gold standard colorimetric test is prone to interferences. The absence of a bedside test for bilirubin delays critical clinical decisions for patients with liver disease. This clinical care gap has motivated the development of a new generation of bioengineered point-of-care bilirubin assays. In this Perspective, recently developed bilirubin assays are critically discussed, and their translational potential evaluated., (© 2023 The Authors. Advanced Healthcare Materials published by Wiley-VCH GmbH.)

Skin injuries across the body continue to disrupt everyday life for millions of patients and result in prolonged hospital stays, infection, and death. Advances in wound healing devices have improved clinical practice but have mainly focused on treating macroscale healing versus underlying microscale pathophysiology. Consensus is lacking on optimal treatment strategies using a spectrum of wound healing products, which has motivated the design of new therapies. We summarize advances in the development of novel drug, biologic products, and biomaterial therapies for wound healing for marketed therapies and those in clinical trials. We also share perspectives for successful and accelerated translation of novel integrated therapies for wound healing.

In sepsis, plasma lactate is a key biomarker of disease severity, prognosis, and treatment success. However, the median time to result for clinical lactate tests is 3 h. We recently reported a near-infrared fluorescent (NIRF) blood lactate assay that relies on a two-step enzymatic reaction in a liposomal reaction compartment. This assay was optimized in human blood and was capable of quantifying lactate in fresh capillary blood from human volunteers at clinically relevant concentrations in 2 min. However, these studies were performed with a tabletop fluorescence plate reader. For translation to the point of care, the liposomal lactate assay needs to be combined with a small portable NIR fluorometer. Portable NIR fluorometers were successfully used for the analysis of skin and soil samples, but reports for blood metabolite assays are scarce. We aimed at testing the performance of the liposomal lactate assay in combination with a commercial small portable NIR fluorometer. First, we tested the fluorophore of the liposomal lactate assay using the NIR dye sulfo-cyanine 7; we observed strong fluorescence signals and high linearity. Second, we performed the liposomal lactate assay in lactate-spiked human arterial blood using the portable fluorometer as the detector and observed strong and highly linear lactate sensing at clinically relevant lactate concentrations after 2 min. Finally, spiking fresh mouse blood with three clinically relevant lactate concentrations led to a significantly different response to all three concentrations after 5 min. These results highlight the usefulness of the tested portable NIR fluorometer for the liposomal lactate assay and motivate a clinical evaluation of this rapid and easy-to-use lactate assay., Competing Interests: The authors declare the following competing financial interest(s): SM is a co-inventor on a patent application related to the lactate sensing technology., (© 2023 American Chemical Society.)

Background: We compared T1- and T2-weighted signal intensities of liver-specific (gadoxetate, gadobenate) and non-specific (gadoterate) gadolinium contrast agents (CAs) in a bile phantom., Methods: In a phantom study, gadoxetate, gadobenate, and gadoterate were diluted in saline, blood, and bile at different concentrations (0, 0.25, 0.5. 1, 2.5, 5, 10, and 25 mM) and imaged in a 3-T magnetic resonance imaging (MRI) system using T1- and T2-weighted sequences. The maximum signal intensities of CAs were compared for each sequence separately and across all T1-weighted sequences using one-way ANOVA., Results: Using T1-weighted sequences, CA concentration-dependent signal intensity increase was followed by decrease due to T2* effects. Comparing CAs for each sequence in bile yielded higher maximum signal intensities with gadobenate than gadoxetate and gadoterate using T1-weighted spin-echo (p < 0.010), multiecho gradient- and spin-echo (p < 0.001), and T1-weighted high-resolution isotropic volume excitation (eTHRIVE) sequences (p < 0.010). Comparing across all T1-weighted sequences in the bile phantom, gadobenate imaged using T1-weighted turbo field-echo (TFE) sequence showed the highest signal intensity, significantly higher than that using other CAs agents or sequences (p < 0.004) except for gadobenate and gadoxetate evaluated with three-dimensional multiecho fast field-echo (3D-mFFE) and gadoxetate with T1-weighted TFE sequence (p > 0.141). Signal reduction with CA concentration-dependent decrease was observed on T2-weighted images., Conclusion: In this bile phantom study of gadolinium-based CA, gadobenate and gadoxetate showed high signal intensity with T1-weighted TFE and 3D-mFFE sequences, which supports their potential utility for contrast-enhanced hepatobiliary MRI., Key Points: • Contrast-enhanced magnetic resonance (MR) cholangiography depends on contrast agent type, kinetics, and concentration in bile, • We compared signal intensities of three contrast agents in a bile phantom study. • Gadobenate, gadoxetate, and gadoterate demonstrated different signal intensities at identical concentrations. • Gadoxetate and gadobenate showed high signal intensities on T1-weighted MR sequences., (© 2023. The Author(s).)

Liposomes are a highly successful drug delivery system with over 15 FDA-approved formulations. Beyond delivering drugs, lipid and polymer vesicles have successfully been used for diagnostic applications. These applications range from more traditional uses, such as releasing diagnostic agents in a controlled manner, to leveraging the unique membrane properties to separate analytes and provide isolated reaction compartments in complex biological matrices. In this Spotlight on Applications, I highlight the complexities in the development and translation of diagnostic vesicles with two case studies, a liposomal reaction compartment for lactate sensing and a transmembrane pH-gradient polymersome for ammonia sensing.

Competing Interests: The authors declare no conflicts of interests regarding this manuscript.

Background: Breast cancer screening is essential in detecting breast tumors, however, the examination is stressful. In this study we analyzed whether humor enhances patient satisfaction., Methods: In this prospective randomized study 226 patients undergoing routine breast cancer screening at a single center during October 2020 to July 2021 were included. One hundred thirty-two were eligible for the study. Group 1 (66 patients) received an examination with humorous intervention, group 2 (66 patients) had a standard breast examination. In the humor group, the regular business card was replaced by a self-painted, humorous business card, which was handed to the patient at the beginning of the examination. Afterwards, patients were interviewed with a standardized questionnaire. Scores between the two study groups were compared with the Mann-Whitney U test or Fisher's exact test. P-values were adjusted with the Holm's method. Two-sided p-values < 0.05 were considered significant., Results: One hundred thirty-two patients, 131 female and 1 male, (mean age 59 ± 10.6 years) remained in the final study cohort. Patients in the humor group remembered the radiologist's name better (85%/30%, P < .001), appreciated the final discussion with the radiologist more (4.67 ± 0.73-5;[5, 5] vs. 4.24 ± 1.1-5;[4, 5], P = .017), felt the radiologist was more empathetic (4.94 ± 0.24-5;[5, 5] vs.4.59 ± 0.64-5;[4, 5], P < .001), and rated him as a humorous doctor (4.91 ± 0.29-5;[5, 5] vs. 2.26 ± 1.43-1;[1, 4], P < .001). Additionally, patients in the humor group tended to experience less anxiety (p = 0.166) and felt the doctor was more competent (p = 0.094)., Conclusion: Humor during routine breast examinations may improve patient-radiologist relationship because the radiologist is considered more empathetic and competent, patients recall the radiologist's name more easily, and value the final discussion more., Trial Registration: We have a general approval from our ethics committee because it is a retrospective survey, the patient lists for the doctors were anonymized and it is a qualitative study, since the clinical processes are part of the daily routine examinations and are used independently of the study. The patients have given their consent to this study and survey., (© 2022. The Author(s).)

Chronic lower extremity wounds (diabetic foot ulcers) are a serious and prevalent complication of diabetes. These wounds exhibit low healing rates and present a high risk of amputation. Current diagnostic options for foot ulcers are limited to macroscopic wound analysis such as wound depth, implicated tissues, and infection. Molecular diagnostics promises to improve foot ulcer diagnosis, staging, and assessment of the treatment response. In this perspective, we report recent progress in understanding the pathophysiology of diabetic wound healing and point to recently emerged novel molecular targets for wound diagnostics. We discuss selected diagnostic wound dressings under preclinical development that detect one or several inflammatory markers, bacterial secretions, hyperglycemia, and mechanical stress. We also highlight key translational challenges of investigational diagnostic bandages for diabetic foot ulcers., Competing Interests: The authors declare no competing financial interest., (© 2022 The Authors. Published by American Chemical Society.)

Background & Aims: To determine if radiological hard- and software offers options beyond the binary female / male classification., Methods: We surveyed thirteen radiological hardware and six radiological software vendors about the options to enter patient gender., Results: Six of thirteen hardware and five of six software vendors replied to our inquiry. All vendors except one offered a third option in addition to male / female., Conclusion: We found that most hard- and software systems provide with a third option for patient gender. These systems allow radiology personnel to accurately document patient gender in the medical record and contribute to an inclusive patient experience in the radiology department. Registering the biological sex in addition to gender may further improve medical care., (Copyright © 2022 Elsevier B.V. All rights reserved.)

In emergency medicine, blood lactate is a commonly used biomarker of hypoxia (e.g., sepsis, trauma, cardiac arrest) but the median time to obtain the results from a clinical lactate test is 3 h. We recently developed a near-infrared fluorescent blood lactate assay based on a two-step enzymatic cascade in a vesicular reaction compartment. Previously, we reported a response of this assay to lactate-spiked bovine blood after 10 min. To develop a point-of-care test, we optimized this assay in commercial human blood, validated it in fresh capillary blood of healthy volunteers in an institutional review board-approved study, and improved the stability of the formulation. External pH and luminal enzyme concentrations were identified as key parameters of sensor response and kinetics, as they impact transmembrane lactate diffusion and turnover rate. The preparation process was also simplified and the stability was improved to allow storage at 4 °C for at least 5 days. The final formulation exhibited a strong and linear response to lactate-spiked human blood in a clinically relevant range, and accurately quantified a lactate standard at a clinically used cut-off in fresh capillary blood after 2 min. These findings motivate a clinical evaluation of this rapid and easy-to-use lactate assay., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objectives: We investigate in what percentage of cases and to what extent radiological reports change when radiologists directly communicate with patients after imaging examinations., Methods: One hundred twenty-two consecutive outpatients undergoing MRI examinations at a single center were prospectively included. Radiological reports of the patients were drafted by two radiologists in consensus using only the clinical information that was made available by the referring physicians. Thereafter, one radiologist talked directly with the patient and recorded the duration of the conversation. Afterwards, the additional information from the patient was used to reevaluate the imaging studies in consensus. The radiologists determined whether the radiological report changed based on additional information and, if yes, to what extent. The degree of change was graded on a 4-point Likert scale (1, non-relevant findings, to 4, highly relevant findings)., Results: Following direct communication (duration 170.9 ± 53.9 s), the radiological reports of 52 patients (42.6%) were changed. Of the 52 patients, the degree of change was classified as grade 1 for 8 patients (15.4 %), grade 2 for 27 patients (51.9%), grade 3 for 13 patients (25%), and grade 4 for 4 patients (7.7%). The reasons leading to changes were missing clinical information in 50 cases (96.2%) and the lack of additional external imaging in 2 cases (3.8%)., Conclusions: Radiologists should be aware that a lack of accurate information from the clinician can lead to incorrect radiological reports or diagnosis. Radiologists should communicate directly with patients, especially when the provided information is unclear, as it may significantly alter the radiological report., Key Points: • Direct communication between radiologists and patients for an average of 170's resulted in a change in the radiological reports of 52 patients (42.6%). • Of the 42.6% of cases where the reports were changed, the alterations were highly relevant (grades 3 and 4) in 32.7%, indicating major changes with significant impact towards patient management., (© 2021. European Society of Radiology.)

Faced with the COVID-19 pandemic, many countries both in Europe and across the world implemented strict stay-at-home orders. These measures helped to slow the spread of the coronavirus but also led to increased mental and physical health issues for the domestically confined population, including an increase in the occurrence of intimate partner violence (IPV) in many countries. IPV is defined as behavior that inflicts physical, psychological, or sexual harm within an intimate relationship. We believe that as radiologists, we can make a difference by being cognizant of this condition, raising an alert when appropriate and treating suspected victims with care and empathy. The aim of this Special Report is to raise awareness of IPV among radiologists and to suggest strategies by which to identify and support IPV victims. KEY POINTS: • The COVID-19 pandemic led to a marked increase in the number of intimate partner violence (IPV) cases, potentially leading to increased emergency department visits and radiological examinations. • Most IPV-related fractures affect the face, fingers, and upper trunk, and may easily be misinterpreted as routine trauma. • Radiologists should carefully review the medical history of suspicious cases, discuss the suspicion with the referring physician, and proactively engage in a private conversation with the patient, pointing to actionable resources for IPV victims.

Current treatment options for foot ulcers, a serious and prevalent complication of diabetes, remain nonspecific. In this Perspective, we present recent advances in understanding the pathophysiology of diabetic wound healing and the emergence of previously unidentified targets. We discuss wound dressings tailored to the diabetic wound environment currently under development., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Liposome-supported peritoneal dialysis (LSPD) with transmembrane pH-gradient liposomes was previously shown to enhance ammonia removal in cirrhotic rats and holds promise for the treatment of hyperammonemic crises-associated disorders. The main objective of this work was to conduct the preclinical evaluation of LSPD in terms of pharmacokinetics, ammonia uptake, and toxicology to seek regulatory approval for a first-in-human study. The formulation containing citric acid-loaded liposomes was administered intraperitoneally at two different doses once daily for ten days to healthy minipigs. It was also tested in a domestic pig model of hyperammonemia. The pharmacokinetics of citric acid and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine was linear following intraperitoneal administration of medium and high dose. There was no systemic accumulation following daily doses over ten days. The systemic exposure to phospholipids remained low. Furthermore, the liposome-containing peritoneal fluid contained significantly higher ammonia levels than the liposome-free control, demonstrating efficient ammonia sequestration in the peritoneal space. This was indeed confirmed by the ability of LSPD to decrease plasmatic ammonia levels in artificially induced hyperammonemic pigs. LSPD was well tolerated, and no complement activation-related pseudoallergy reactions were observed. The safety profile, the linear pharmacokinetics of citric acid following repeated administrations of LSPD as well as the linear dose-dependent ammonia sequestration in the peritoneal space provide a strong basis for the clinical investigation of LSPD., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

In emergency medicine, blood lactate levels are commonly measured to assess the severity and response to treatment of hypoperfusion-related diseases (e.g., sepsis, trauma, cardiac arrest). Clinical blood lactate testing is conducted with laboratory analyzers, leading to a delay of 3 h between triage and lactate result. Here, a fluorescence-based blood lactate assay, which can be utilized for bedside testing, based on measuring the hydrogen peroxide generated by the enzymatic oxidation of lactate is described. To establish a hydrogen peroxide assay, near-infrared cyanine derivatives are screened and sulfo-cyanine 7 is identified as a new horseradish peroxidase (HRP) substrate, which loses its fluorescence in presence of HRP and hydrogen peroxide. As hydrogen peroxide is rapidly cleared by erythrocytic catalase and glutathione peroxidase, sulfo-cyanine 7, HRP, and lactate oxidase are encapsulated in a liposomal reaction compartment. In lactate-spiked bovine whole blood, the newly developed lactate assay exhibits a linear response in a clinically relevant range after 10 min. Substituting lactate oxidase with glucose and alcohol oxidase allows for blood glucose, ethanol, and methanol biosensing, respectively. This easy-to-use, rapid, and versatile assay may be useful for the quantification of a variety of enzymatically oxidizable metabolites, drugs, and toxic substances in blood and potentially other biological fluids., (© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: The aim of the study is to investigate how well patients remember the radiologist's name after a radiological examination, and whether giving the patient a business card improves the patient's perception of the radiologist's professionalism and esteem., Methods: In this prospective and randomized two-centre study, a total of 141 patients with BI-RADS 1 and 2 scores were included. After screening examination comprising mammography and ultrasound by a radiologist, 71 patients received a business card (group 1), while 70 received no business card (group 2). Following the examination, patients were questioned about their experiences., Results: The patients in group 1 could remember the name of the radiologist in 85% of cases. The patients in group 2, in contrast, could only remember the name in 7% of cases (p < 0.001). 90% of the patients in group 1 believed it was very important that they are able to contact the radiologist at a later time, whereas only 76% of patients in group 2 felt that this was a very important service (p < 0.025). A total of 87% of the patients in group 1 indicated that they would contact the radiologist if they had any questions whereas 73% of the patients in group 2 would like to contact the radiologist but were not able to do so, because they could not remember the name (p < 0.001). All questions were analysed with a Cochran-Mantel-Haenszel (CMH) test that took study centre as stratification into account. In some cases, two categories were collapsed to avoid zero cell counts., Conclusions: Using business cards significantly increased the recall of the radiologist's name and could be an important tool in improving the relationships between patients and radiologists and enhancing service professionalism., Trial Registration: We have a general approval from our ethics committee. The patients have given their consent to this study.

Ammonia-scavenging transmembrane pH-gradient poly(styrene)-b-poly(ethylene oxide) polymersomes are investigated for the oral treatment and diagnosis of hyperammonemia, a condition associated with serious neurologic complications in patients with liver disease as well as in infants with urea cycle disorders. While these polymersomes are highly stable in simulated intestinal fluids at extreme bile salt and osmolality conditions, they unexpectedly do not reduce plasmatic ammonia levels in cirrhotic rats after oral dosing. Incubation in dietary fiber hydrogels mimicking the colonic environment suggests that the vesicles are probably destabilized during the dehydration of the intestinal chyme. The findings question the relevance of commonly used simulated intestinal fluids for studying vesicular stability. With the encapsulation of a pH-sensitive dye in the polymersome core, the local pH increase upon ammonia influx could be exploited to assess the ammonia concentration in the plasma of healthy and cirrhotic rats as well as in other fluids. Due to its high sensitivity and selectivity, this polymersome-based assay could prove useful in the monitoring of hyperammonemic patients and in other applications such as drug screening tests., (© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Purpose: To identify independent confounding variables of gadoxetate-enhanced hepatobiliary-phase liver MRI using multiple regression analysis., Materials and Methods: The institutional review board generally approved retrospective analyses and all patients provided written informed consent. One hundred ten patients who underwent a standardized 3.0-T gadoxetate-enhanced liver MRI between November 2008 and June 2013 were retrospectively reviewed. The gadoxetate liver enhancement normalized to enhancement in the erector spinae muscle (relative signal enhancement, SE) was related to biochemical laboratory parameters and descriptive patient characteristics (patient age, body mass index) using non-parametric univariate correlation analysis followed by a multiple linear regression model., Results: Using univariate statistics, relative SE was inversely correlated with patient age, ALP, AST, total bilirubin, gamma-glutamyltransferase, INR, model of end-stage liver disease score, and proportionally with albumin and hemoglobin (all p < 0.01). In a multiple regression analysis, total bilirubin (p = 0.001), serum albumin (p = 0.016), and patient age (p = 0.018) were independently correlated with relative liver SE (n = 110)., Conclusion: A multiple regression analysis showed that high total bilirubin, low serum albumin, or advanced age was associated with low hepatobiliary-phase gadoxetate parenchymal liver enhancement. In these patients, the lower contrast-to-noise ratio might impair diagnostic evaluation of non-enhancing liver lesions (e.g., HCC, liver metastasis)., Key Points: • A multiple regression analysis identified independent confounding variables of hepatobiliary-phase gadoxetate liver enhancement. • High bilirubin, low albumin, or advanced age was associated with low enhancement. • Diagnostic evaluation might be hampered in these patients.

Background: Externally controlling and monitoring drug release at a desired time and location is currently lacking in the gastrointestinal tract. The aim of the study was to develop a thermoresponsive wax-coated capsule and to trigger its release upon applying a magnetic resonance imaging (MRI)-guided high-intensity focused ultrasound (HIFU) pulse., Methods: Capsules containing a lyophilised gadolinium-based contrast agent (GBCA) were coated with a 1:1 (mass/mass) mixture of lanolin and cetyl alcohol (melting point ≈43 °C) and exposed to simulated gastric and intestinal fluids (United States Pharmacopoeia) at 37 °C for 2 and 24 h, respectively. In a HIFU gel phantom, wax-coated capsules (n = 3) were tracked based on their T1- and T2-hypointensity by 1.5-T T1- and T2-weighted MRI pre- and post-exposure to an MRI-guided HIFU pulse., Results: Lanolin/cetyl alcohol-coated capsules showed high resistance to simulated gastrointestinal fluids. In a gel phantom, an MRI-guided HIFU pulse punctured the wax coating, resulting in the hydration and release of the encapsulated lyophilised GBCA and yielding a T1-hyperintense signal close to the wax-coated capsule., Conclusion: We provide the proof-of-concept of applying a non-invasive MRI-guided HIFU pulse to actively induce the disintegration of the wax-coated capsule, and a method to monitor the release of the cargo via T1-weighted MRI based on the hydration of an encapsulated lyophilised GBCA. The wax-coated capsule platform enables temporally and spatially supertargeted drug release via the oral route and promises to address a currently unmet clinical need for personalised local therapy in gastrointestinal diseases such as inflammatory bowel diseases and cancer.

Objectives: To assess the occurrence of transient interruption of contrast (TIC) phenomenon in pulmonary computed tomography angiography (CTPA) exams performed in inspiratory breath-hold after patients were told to inspire gently., Methods: In this retrospective single-centre study, CTPA exams of 225 consecutive patients scanned on a 16-slice CT scanner system were analysed. A-priori to measurements, exams were screened for inadequate pulmonary artery contrast due to incorrect bolus tracking or failure of i.v. contrast administration. Those exams were excluded. Attenuation values in the thoracic aorta and in the pulmonary trunk were assessed in duplicate measurements (M1 and M2) and the aorto-pulmonary density ratio was calculated. An aorto-pulmonary ratio > 1 with still contrast inflow being visible within the superior vena cava was defined as TIC., Results: 3 patients were excluded due to incorrect bolus tracking. Final analysis was performed in 222 patients (mean age 65 ± 19 years, range 18 to 99 years). Mean density in the pulmonary trunk was 275±17 HU, in the aorta 208 ± 15 HU. Mean aorto-pulmonary ratio was 0.81± 0.29. 48 patients (21.6%) had an aorto-pulmonary ratio >1. Correlation of mean aorto-pulmonary ratio and age was: -0.213 (p = 0.001). Age was not significantly different for an aorto-pulmonary ratio >1 vs. ≤1 (p = 0.122). Both in M1 and M2, 33/222 patients presented with absolute HU values of < 200 HU within the pulmonary artery. In M1 measurements, 24 of these 33 patients (72%) fulfilled TIC criteria (M2: 25/33 patients (75%))., Conclusions: TIC is a common phenomenon in CTPA studies with inspiratory breath-hold commands after patients were told to inspire gently with an incidence of 22% in our retrospective cohort. Occurrence of TIC shows a significant negative correlation with increasing age and disproportionately often occurs in patients with lower absolute contrast density values within their pulmonary arteries., Competing Interests: The authors have declared that no competing interests exist.

Peritoneal dialysis (PD) performed with transmembrane pH-gradient liposomes was reported to efficiently remove ammonia from the body, representing a promising alternative to current standard-of-care for patients with severe hepatic encephalopathy. In this study, we further characterized the properties of liposome-supported peritoneal dialysis (LSPD) by 1) assessing its in-use stability in the presence of ascitic fluids from liver-disease patients; 2) investigating its interactions with drugs that are commonly administered to acute-on-chronic liver failure patients; and 3) analyzing the in vivo extraction profile of LSPD. We found that LSPD fluid maintained its in vitro ammonia uptake capability when combined with ascitic fluids. The co-incubation of selected drugs (e.g., beta-blockers, antibiotics, diuretics) with LSPD fluids and ammonia resulted in limited interaction effects for most compounds except for two fluoroquinolones and propranolol. However, considering the experimental set-up, these results should be interpreted with caution and confirmatory drug-drug interaction studies in a clinical setting will be required. Finally, metabolite-mapping analysis on dialysates of LSPD-treated rats revealed that the liposomes did not remove important metabolites more than a conventional PD fluid. Overall, these findings confirm that LSPD is a potentially safe and effective approach for treating hyperammonemic crises in the context of acute-on-chronic liver failure., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objectives: Aim was to investigate hygienic conditions of ultrasound probes before and after hygiene training in radiology institutions in comparison to bacterial contamination in public places., Methods: In three radiology departments, bacterial contamination was evaluated using baseline agar plates for cultures taken from 36 ultrasound probes. Afterwards teams were trained by a hygiene service centre and 36 ultrasound probes were routinely disinfected with regular disinfecting wipes and then evaluated. In comparison, bacterial contamination in public places (bus poles, n = 11; toilet seats, n = 10) were analysed. Plates were routinely incubated and the number of colony forming units (CFU) analysed., Results: Cultures taken from the probes showed a median of 53 CFU before and 0 CFU after training (p < 0.001). Cultures taken from public places showed a median of 4 CFU from toilets and 28 from bus poles and had lower bacterial load in comparison to ultrasound probes before training (p = 0.055, toilets; p = 0.772, bus poles), without statistical significance., Conclusions: Bacterial contamination of ultrasound probes prior to hygiene training proved to be high and showed higher bacterial load than toilets seats or bus poles. Radiologists should be aware that the lack of hygiene in the field of ultrasound diagnostics puts patients at risk of healthcare-associated infections., Key Points: • Hospital-associated infections are a problem for patient care. • Hygiene training of staff prevents bacterial contamination of ultrasound probes. • Disinfection of ultrasound probes is an easy method to protect patients.

The first-line therapy in metastatic renal cell carcinoma (mRCC), sunitinib, exhibits an objective response rate of approximately 30%. Therapeutic alternatives such as other tyrosine kinase inhibitors, VEGF inhibitors, or mTOR inhibitors emphasize the clinical need to predict the patient's response to sunitinib therapy before treatment initiation. In this study, we evaluated the prognostic value of pretreatment portal venous phase contrast-enhanced computed tomography (CECT) mean tumor density on overall survival (OS), progression-free survival (PFS), and tumor growth in 63 sunitinib-treated mRCC patients. Higher pretreatment CECT tumor density was associated with longer PFS and OS [hazard ratio (HR)=0.968, P=.002, and HR=0.956, P=.001, respectively], and CECT density was inversely correlated with tumor growth (P=.010). Receiver operating characteristic analysis identified two CECT density cut-off values (63.67 HU, sensitivity 0.704, specificity 0.694; and 68.67 HU, sensitivity 0.593, specificity 0.806) which yielded subpopulations with significantly different PFS and OS (P<.001). Pretreatment CECT is therefore a promising noninvasive strategy for response prediction in sunitinib-treated mRCC patients, identifying patients who will derive maximum therapeutic benefit., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To investigate whether a trained group of technicians using a modified breathing command during gadoxetate-enhanced liver MRI reduces respiratory motion artefacts compared to non-trained technicians using a traditional breathing command., Materials and Methods: The gadoxetate-enhanced liver MR images of 30 patients acquired using the traditional breathing command and the subsequent 30 patients after training the technicians to use a modified breathing command were analyzed. A subgroup of patients (n = 8) underwent scans both by trained and untrained technicians. Images obtained using the traditional and modified breathing command were compared for the presence of breathing artefacts [respiratory artefact-based image quality scores from 1 (best) to 5 (non-diagnostic)]., Results: There was a highly significant improvement in the arterial phase image quality scores in patients using the modified breathing command compared to the traditional one (P < 0.001). The percentage of patients with severe and extensive breathing artefacts in the arterial phase decreased from 33.3 % to 6.7 % after introducing the modified breathing command (P = 0.021). In the subgroup that underwent MRI using both breathing commands, arterial phase image quality improved significantly (P = 0.008) using the modified breathing command., Conclusion: Training technicians to use a modified breathing command significantly improved arterial phase image quality of gadoxetate-enhanced liver MRI., Key Points: • A modified breathing command reduced respiratory artefacts on arterial-phase gadoxetate-enhanced MRI (P < 0.001). • The modified command decreased severe and extensive arterial-phase breathing artefacts (P = 0.021). • Training technicians to use a modified breathing command improved arterial-phase images.

Objectives: To identify correlations of signal enhancements (SE) and SE normalized to reference tissues of the spleen, kidney, liver, musculus erector spinae (MES) and ductus hepatocholedochus (DHC) on hepatobiliary phase gadoxetate-enhanced MRI with patient age in non-cirrhotic patients., Methods: A heterogeneous cohort of 131 patients with different clinical backgrounds underwent a standardized 3.0-T gadoxetate-enhanced liver MRI between November 2008 and June 2013. After exclusion of cirrhotic patients, a cohort of 75 patients with no diagnosed diffuse liver disease was selected. The ratio of signal intensity 20 min post- to pre-contrast administration (SE) in the spleen, kidney, liver, MES and DHC, and the SE of the kidney, liver and DHC normalized to the reference tissues spleen or MES were compared to patient age., Results: Patient age was inversely correlated with the liver SE normalized to the spleen and MES SE (both p < 0.001) and proportionally with the SE of the spleen (p = 0.043), the MES (p = 0.030) and the kidney (p = 0.022). No significant correlations were observed for the DHC (p = 0.347) and liver SE (p = 0.606)., Conclusion: The age dependence of hepatic SE normalized to the enhancement in the spleen and MES calls for a cautious interpretation of these quantification methods., Key Points: • Patient age was inversely correlated with spleen- and MES-corrected liver rSE (p < 0.001). • Patient age was correlated with spleen (p = 0.043) and MES SE (p = 0.030). • Patient age may confound quantitative liver function assessment using gadoxetate-enhanced liver MRI.

Since the first attempt to administer insulin orally in humans more than 90years ago, the oral delivery of macromolecular drugs (>1000g/mol) has been rather disappointing. Although several clinical pilot studies have demonstrated that the oral absorption of macromolecules is possible, the bioavailability remains generally low and variable. This article reviews the formulations and biopharmaceutical aspects of orally administered biomacromolecules on the market and in clinical development for local and systemic delivery. The most successful approaches for systemic delivery often involve a combination of enteric coating, protease inhibitors and permeation enhancers in relatively high amounts. However, some of these excipients have induced local or systemic adverse reactions in preclinical and clinical studies, and long-term studies are often missing. Therefore, strategies aimed at increasing the oral absorption of macromolecular drugs should carefully take into account the benefit-risk ratio. In the absence of specific uptake pathways, small and potent peptides that are resistant to degradation and that present a large therapeutic window certainly represent the best candidates for systemic absorption. While we acknowledge the need for systemically delivering biomacromolecules, it is our opinion that the oral delivery to local gastrointestinal targets is currently more promising because of their accessibility and the lacking requirement for intestinal permeability enhancement., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Ammonia is a neurotoxic agent that is primarily generated in the intestine and detoxified in the liver. Toxic increases in systemic ammonia levels predominantly result from an inherited or acquired impairment in hepatic detoxification and lead to potentially life-threatening neuropsychiatric symptoms. Inborn deficiencies in ammonia detoxification mainly affect the urea cycle, an endogenous metabolic removal system in the liver. Hepatic encephalopathy, on the other hand, is a hyperammonemia-related complication secondary to acquired liver function impairment. A range of therapeutic options is available to target either ammonia generation and absorption or ammonia removal. Therapies for hepatic encephalopathy decrease intestinal ammonia production and uptake. Treatments for urea cycle disorders eliminate ammoniagenic amino acids through metabolic transformation, preventing ammonia generation. Therapeutic approaches removing ammonia activate the urea cycle or the second essential endogenous ammonia detoxification system, glutamine synthesis. Recent advances in treating hyperammonemia include using synergistic combination treatments, broadening the indication of orphan drugs, and developing novel approaches to regenerate functional liver tissue. This manuscript reviews the various pharmacological treatments of hyperammonemia and focuses on biopharmaceutical and drug delivery issues., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Methods to stabilize and retain enzyme activity in the gastrointestinal tract are investigated rarely because of the difficulty of protecting proteins from an environment that has evolved to promote their digestion. Preventing the degradation of enzymes under these conditions, however, is critical for the development of new protein-based oral therapies. Here we show that covalent conjugation to polymers can stabilize orally administered therapeutic enzymes at different locations in the gastrointestinal tract. Architecturally and functionally diverse polymers are used to protect enzymes sterically from inactivation and to promote interactions with mucin on the stomach wall. Using this approach the in vivo activity of enzymes can be sustained for several hours in the stomach and/or in the small intestine. These findings provide new insight and a firm basis for the development of new therapeutic and imaging strategies based on orally administered proteins using a simple and accessible technology.

Celiac disease (CD) is an immune-mediated enteropathy triggered by the ingestion of gluten-containing grains that affects ~1% of the white ethnic population. In the last decades, a rise in prevalence of CD has been observed that cannot be fully explained by improved diagnostics. Genetic predisposition greatly influences the susceptibility of individuals towards CD, though environmental factors also play a role. With no pharmacological treatments available, the only option to keep CD in remission is a strict and permanent exclusion of dietary gluten. Such a gluten-free diet is difficult to maintain because of gluten's omnipresence in food (e.g., additive in processed food). The development of adjuvant therapies which would permit the intake of small amounts of gluten would be desirable to improve the quality of life of patients on a gluten-free diet. Such therapies include gluten-degrading enzymes, polymeric binders, desensitizing vaccines, anti-inflammatory drugs, transglutaminase 2 inhibitors, and HLA-DQ2 blockers. However, many of these approaches pose pharmaceutical challenges with respect to drug formulation and stability, or application route and dosing interval. This perspective article discusses how pharmaceutical scientists may deal with these challenges and contribute to the implementation of novel therapeutic options for patients with CD.