Zeolite-Loaded Hydrogels as Wound pH-Modulating Dressings for Diabetic Wound Healing.

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.

Gender Differences in Pharmacokinetics: A Perspective on Contrast Agents.

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.

Wound pH-Modulating Strategies for Diabetic Wound Healing.

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.

Smoking trends and health equity in Switzerland between 1992 and 2017: dependence of smoking prevalence on educational level and social determinants.

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.

Understanding the needs of women undergoing breast ultrasound: Are male radiologists still needed?

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.

Real-Time Tracking of In Situ-Forming Alginate Hydrogel by Contrast-Enhanced Computed Tomography.

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.

Drug delivery breakthrough technologies - A perspective on clinical and societal impact.

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.

Portable Near-Infrared Fluorometer for a Liposomal Blood Lactate Assay.

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.

Breakthrough treatments for accelerated wound healing.

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.

175 Years of Bilirubin Testing: Ready for Point-of-Care?

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.

Comparison of gadolinium-based contrast agents for MR cholangiography in saline, blood and bile: a phantom study.

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.

Vesicular Diagnostics: A Spotlight on Lactate- and Ammonia-Sensing Systems.

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.

Humor in radiological breast cancer screening: a way of improving patient service?

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.

Transgender health and medicine - Are radiological devices prepared?

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.

Development of a liposomal near-infrared fluorescence lactate assay for human blood.

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.