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Objectives: To compare the accuracy and chair time of self-ligating brackets using direct bonding, traditional indirect bonding (IB), and computer-aided design/computer-aided manufacturing (CAD/CAM) IB techniques after orthodontic leveling and alignment., Materials and Methods: Forty-five patients were randomly assigned to three bonding groups (G1 [n = 15], G2 [n = 15], and G3 [n = 15]). Evaluation after the alignment and leveling phases used two parameters of the objective grading system of the American Board of Orthodontics for root parallelism and posterior marginal ridges, assessed using panoramic radiographies (PR I and PR II), a digital model, and a plaster model. Blinding was only applied for outcome assessment. No serious harm was observed except for gingivitis associated with plaque accumulation., Results: Although G3 showed better numerical results, they were not statistically significant in the radiographic or model evaluations (P > .001). Mean chair time was significantly shorter in G3 (1.1 ± 11.8 min) vs. G1 (56.7 ± 7.3 min) and G2 (52.8 ± 8.3 min; P < .001)., Conclusions: The CAD/CAM IB system for self-ligating brackets was as effective as conventional methods, with a shorter chair time., (© 0000 by The EH Angle Education and Research Foundation, Inc.)

Background: Contrast-induced nephropathy is a prevalent cause of hospital-acquired renal insufficiency and increases adverse events in older patients undergoing angiography and percutaneous coronary intervention. The Mehran risk score has been widely used in Vietnam to assess contrast-induced nephropathy risk in patients before coronary angiography and percutaneous coronary intervention. Recently, there has been a shift toward the adoption of simpler risk prediction models, such as the contrast volume-to-glomerular filtration rate ratio. This study aimed to (1) determine the incidence of contrast-induced nephropathy in older patients undergoing coronary angiography and/or percutaneous coronary intervention, and (2) compare the validity of the contrast volume-to-glomerular filtration rate ratio and the Mehran score in predicting contrast-induced nephropathy., Method: This is a prospective cohort study conducted at a hospital in Vietnam from September 2019 to May 2020. Consecutive patients aged ⩾60 years who underwent coronary angiography and/or percutaneous coronary intervention were recruited. The contrast volume-to-glomerular filtration rate ratio and the Mehran score were evaluated for their predictive utility regarding contrast-induced nephropathy risk. The receiver operator characteristic was employed to calculate the area under the curve for both the contrast volume-to-glomerular filtration rate ratio and the Mehran score in predicting contrast-induced nephropathy., Results: The study included 170 participants with a mean age of 70 years and 33.1% were female. Contrast-induced nephropathy was diagnosed in 9.4% of the participants. Participants with contrast-induced nephropathy exhibited a higher prevalence of chronic kidney disease, anemia, and heart failure. There was no significant difference between the area under the curves of the contrast volume-to-glomerular filtration rate ratio (0.79, 95% CI: 0.65-0.92), and the Mehran score (0.65, 95% CI: 0.51-0.82) in predicting contrast-induced nephropathy., Conclusion: Our findings indicate that contrast-induced nephropathy was prevalent among older patients following percutaneous coronary intervention. The contrast volume-to-glomerular filtration rate ratio demonstrated a good prognostic value for predicting contrast-induced nephropathy comparable to that of the Mehran score. Further research is needed to identify optimal cutoff values for the contrast volume-to-glomerular filtration rate ratio in older patients., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

Background: Fluorine 18-labelled tetrafluoroborate ([ 18 F]TFB) is a substrate for the sodium/iodide symporter. In thyroid cancer, [ 18 F]TFB-PET/CT may be an alternative to iodine imaging to evaluate the extent of disease, eligibility for radioiodine treatment, and success of redifferentiation therapies. We report the results of a pilot study to determine tumor uptake of [ 18 F]TFB and compare its properties to [ 124 I]IodinePET/CT in patients with metastatic thyroid cancer., Methods: Five patients were included in a prospective study. All patients received PET/CT 1 h after injection of 356 ± 12 MBq [ 18 F]TFB and were given 230 ± 9 MBq [ 124 I]Iodine orally on the same day, followed by PET/CT after 48 h. Before redifferentiation therapy, patients underwent an additional baseline [ 124 I]Iodine PET/CT. Cases were analyzed by two board-certified specialists. Detection rates and Spearman correlation for [ 18 F]TFB and [ 124 I]Iodine were calculated., Results: Three patients had poorly differentiated thyroid cancer and received trametinib in a redifferentiation trial. Two patients had papillary thyroid cancer and did not receive redifferentiation therapy. Of the 33 lesions seen before/without redifferentiation therapy, 19 (58%) were visible on [ 18 F]TFB and 30 (91%) on [ 124 I]Iodine imaging. In the patients who underwent redifferentiation therapy, 48 lesions were newly seen on [ 124 I]Iodine PET/CT with a median SUV max of 3.3 (range, 0.4-285.0). All of these lesions were [ 18 F]TFB-negative., Conclusion: [ 18 F]TFB failed to predict radioactive iodine uptake in patients with poorly differentiated thyroid cancer who underwent redifferentiation therapy with trametinib. It is unclear whether such discrepancies may also occur in other redifferentiation therapies or may even be encountered in redifferentiation-naïve thyroid cancer., Trial Registration Number: NCT03196518, registered on June 22, 2017., (© 2024. The Author(s).)

Health restoration and disease prevention are important strategies to achieve health and well-being. This Perspective provides a conceptual overview of the key concepts of salutogenesis (health restoration), chronic stress, resilience, and emotional well-being, and describes how they are distinct and interrelated. We posit, and demonstrate through scientific evidence, that complementary and integrative health approaches, including mind and body interventions, can be used to mitigate the effects of chronic stress and promote salutogenic pathways. Our goal is to identify research gaps and opportunities and suggest ways to advance the knowledge base for mechanistic and clinical research in this field., 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 © 2024 Quinlan, Baumgartner, Chen, Weber, Horgusluoglu and Edwards.)

Competing Interests: The authors declare that they have no conflict of interest.

Sickle cell disease (SCD) is a lifelong monogenic, autosomal-recessive blood disease that predominantly affects individuals of African descent and those who self-identify as Black or Hispanic. Common SCD pathophysiological processes include adhesion, hemolysis, hypoxia, ischemia, oxidative stress, and vaso-occlusion, which often lead to substantial comorbidities and complications. Pain is one of the most common and significant clinical complications for individuals with SCD. Despite advancements in understanding the pathophysiology of SCD, the ways in which SCD pathophysiological processes contribute to nociception and pain signaling, processing, and perception remain largely unclear. Pain management for individuals with SCD is complex and presents unique challenges that must be considered depending on the presenting pain type (eg, acute pain episode vs chronic pain). Racism, stigma (including stigma associated with opioid use), and limited resources present additional challenges. Limited research has been conducted on major clinical features of SCD pain such as its ischemic, inflammatory, and neuropathic components; on its transition from acute to chronic form and across the lifespan; and on factors influencing SCD pain perception. Research on and management of SCD pain requires a whole-person approach, bringing together investigators from multiple disciplines such as hematologists, organ biologists, pain experts, physiologists, neuroscientists, psychologists, geneticists, microbiologists, immunologists, behavioral scientists, and clinicians. Multidisciplinary cross-training, with different platforms for information dissemination and communication, could help promote basic, mechanistic, and translational research to inform the optimization of current treatment strategies and the development of novel therapies for SCD pain. PERSPECTIVE: This review presents the research challenges and negative impact of SCD pain, a grossly understudied condition in a highly underserved population. It also highlights the barriers and opportunities in SCD pain research and could help clinicians better understand current treatment strategies from the whole-person perspective., (Published by Elsevier Inc.)

Circumventing the limitations of current bioassays, we introduce a light-controlled assay, OptoAssay, toward wash- and pump-free point-of-care diagnostics. Extending the capabilities of standard bioassays with light-dependent and reversible interaction of optogenetic switches, OptoAssays enable a bidirectional movement of assay components, only by changing the wavelength of light. Demonstrating exceptional versatility, the OptoAssay showcases its efficacy on various substrates, delivering a dynamic bioassay format. The applicability of the OptoAssay is successfully demonstrated by the calibration of a competitive model assay, resulting in a superior limit of detection of 8 pg ml -1 , which is beyond those of conventional ELISA tests. In the future, combined with smartphones, OptoAssays could obviate the need for external flow control systems such as pumps or valves and signal readout devices, enabling on-site analysis in resource-limited settings.

Background: Mechanical thrombectomy is a cornerstone treatment for acute ischemic stroke (AIS) with large vessel occlusion (LVO), yet the optimal technique remains debated. The SOFIA/SOFIA PLUS catheter has emerged as a promising tool for direct aspiration thrombectomy., Purpose: This prospective multi-center study, adhering Good-Clinical-Practice guidelines, aimed to evaluate the safety and efficacy of the SOFIA/SOFIA PLUS catheter for direct aspiration as a first-line treatment technique in patients with acute anterior circulation LVO., Materials and Methods: Between 10/2017 and 12/2021, 246 consecutive patients presenting with AIS due to anterior circulation LVO were enrolled from 14 European centers. Primary treatment with SOFIA catheters was performed within 6 h of symptom onset. Clinical and radiological data were collected, and statistical analyses were conducted., Results: The mean age of the included patients was 71.6 ± 13.9 years, with 44.7% being male. Primary aspiration achieved complete recanalization in 72.8% of patients, with functional independence observed in 63.8% after 90 days. Secondary outcomes included a median NIHSS of 4 at 24 h post-procedure, median ASPECTS of 7 on follow-up imaging, and a mortality rate of 24.4% at 90 days. No device malfunctions were observed, and the rate of symptomatic intracranial hemorrhage was 4.4%., Conclusion: Primary aspiration with the SOFIA/SOFIA PLUS catheter demonstrates favorable safety and efficacy profiles in the treatment of anterior circulation LVO. These findings support the utilization of this technique as a first-line approach in mechanical thrombectomy for AIS, contributing to the growing body of evidence endorsing the effectiveness of direct aspiration thrombectomy in stroke management., Competing Interests: GT has received compensation by the University Heidelberg for activities as member of the CEC within the study, and fees as consultant or lecturer from Acandis, Alexion, Amarin, Astra Zeneca, Bayer, Boehringer Ingelheim, BristolMyersSquibb, Daiichi Sankyo, Portoly, Stryker outside this study. GM reports consulting fees from Microvention Europe, Stryker Neurovascular, Balt SAS, Sim and Cure and paid lectures from Medtronic, Phenox, Cerenovus, Bracco. All of these were outside this study. AP is the principal investigator of the SEALANT study sponsored by Microvention. MM received research grants from Acandis, Balt, Medtronic, Microvention, Phenox, Stryker* (*industry payments are made to the research fund of the institution), receives payment or honoraria for lectures from Balt, Medtronic, Stryker* (*industry payments are made to the research fund of the institution). SESAME was an investigator-initiated study (IIT). A grant for conducting the study was provided by Microvention. However, Microvention did not exert any influence on the study’ design. The remaining 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 © 2024 Neuberger, Marnat, Barreau, Pitrone, Caragliano, Killer-Oberpfalzer, Pfaff, Maurer, Berlis, Bokkers, Uyttenboogaart, Sourour, Clarençon, Wodarg, Cognard, Bohner, Trenkler, Spelle, Weber, Nouri, Bonekamp, Thomalla, Fiehler, Bendszus and Möhlenbruch.)

Background: Data sharing improves the value, synthesis, and integrity of research, but rates are low. Data sharing might be improved if data sharing policies were prominent and actionable at every stage of research. We aimed to systematically describe the epidemiology of data sharing policies across the health research lifecycle., Methods: This was a cross-sectional analysis of the data sharing policies of the largest health research funders, all national ethics committees, all clinical trial registries, the highest-impact medical journals, and all medical research data repositories. Stakeholders' official websites, online reports, and other records were reviewed up to May 2022. The strength and characteristics of their data sharing policies were assessed, including their policies on data sharing intention statements (a.k.a. data accessibility statements) and on data sharing specifically for coronavirus disease studies. Data were manually extracted in duplicate, and policies were descriptively analysed by their stakeholder and characteristics., Results: Nine hundred and thirty-five eligible stakeholders were identified: 110 funders, 124 ethics committees, 18 trial registries, 273 journals, and 410 data repositories. Data sharing was required by 41% (45/110) of funders, no ethics committees or trial registries, 19% (52/273) of journals and 6% (24/410) of data repositories. Among funder types, a higher proportion of private (63%, 35/55) and philanthropic (67%, 4/6) funders required data sharing than public funders (12%, 6/49)., Conclusion: Data sharing requirements, and even recommendations, were insufficient across health research. Where data sharing was required or recommended, there was limited guidance on implementation. We describe multiple pathways to improve the implementation of data sharing. Public funders and ethics committees are two stakeholders with particularly important untapped opportunities., (© 2024 The Author(s). Research Synthesis Methods published by John Wiley & Sons Ltd.)

Phase separation of biomolecules into condensates is a key mechanism in the spatiotemporal organization of biochemical processes in cells. However, the impact of the material properties of biomolecular condensates on important processes, such as the control of gene expression, remains largely elusive. Here, the material properties of optogenetically induced transcription factor condensates are systematically tuned, and probed for their impact on the activation of target promoters. It is demonstrated that transcription factors in rather liquid condensates correlate with increased gene expression levels, whereas stiffer transcription factor condensates correlate with the opposite effect, reduced activation of gene expression. The broad nature of these findings is demonstrated in mammalian cells and mice, as well as by using different synthetic and natural transcription factors. These effects are observed for both transgenic and cell-endogenous promoters. The findings provide a novel materials-based layer in the control of gene expression, which opens novel opportunities in optogenetic engineering and synthetic biology., (© 2024 The Authors. Small published by Wiley‐VCH GmbH.)

This study aimed to investigate the influence of adding an alkalizing agent to the scalding water of a slaughterhouse in Brazil to inactivate hygiene indicator bacteria in pig carcasses. Scalding is critical during carcass processing because slaughterhouses' scalding water is constantly renewed; therefore, it is usually contaminated with organic matter, such as faeces and dirt from the previous carcasses. The treatments evaluated consisted of counting Enterobacteriaceae and mesophilic bacteria in pork jowls at 62 °C, 65 °C, 68 C, and 72 °C after 0.0, 1.5, 3.0, 4.5, 6.0, and 7.5 min of simulated scalding at the pHs of 7.0 (control) and 11.0 (after addition of alkalizing agent). Decimal reduction times of hygiene indicator bacteria for all treatments were estimated with different nonlinear bacterial inactivation models. As a result, adding the alkalizing agent did not significantly inactivate most of the bacteria in the studied samples. However, it contributed to the inactivation of some bacteria, mostly belonging to the mesophilic group, at some specific temperatures. The results obtained in the current study can provide useful insights into dealing with pig carcass contamination in a real-world scenario and applying the obtained information in the industrial environment., (© 2024. The Author(s) under exclusive licence to Sociedade Brasileira de Microbiologia.)

In 2018, an outbreak of human rabies caused by the hematophagous bat Desmodus rotundus hit the Brazilian Amazon Basin community of Melgaço, Brazil, resulting in the death of 10 people, 9 of them children. The incidence of rabies has been on the rise among populations in conditions of vulnerability in this ecosystem due to human expansion into sylvatic environments and limited access to public health services. To address this issue, in September 2019, a collaborative effort from national, local, and international institutions promoted and executed a pilot for pre-exposure prophylaxis of a population in high-risk areas for hematophagous bat-mediated rabies. This measure is usually only implemented in response to outbreaks. The pilot was conducted in Portel, in a nearby location to the previous outbreak, with the use of fluvial transportation, and 2987 individuals in 411 dwellings were successfully vaccinated. It established a methodology for pre-exposure prophylaxis for populations in conditions of vulnerability, identifying logistics and costs, as well as characterizing the target riverine population regarding risk factors associated with bites by hematophagous bats. This approach offers a proactive measure to prevent future outbreaks and provides valuable insights into how to address the issue of rabies in remote and difficult-to-reach areas.

Case Presentation: We report a case of an 89-year-old female who presented with pain in her right shoulder following a fall onto her outstretched hand. Upon presentation, her right hand was held behind her head and elbow held above her head in flexion. There was obvious deformity seen and felt in her axilla. Radiograph of the shoulder showed an inferior shoulder dislocation and impacted humeral neck fracture. Given her age and comorbid osteoporosis, a bedside reduction was performed by orthopedics where the humeral head was intentionally dislocated from the humeral shaft. Thirteen days after the initial shoulder dislocation, the patient's shoulder was successfully repaired by open reduction., Discussion: Luxatio erecta, which means "erect dislocation" in Latin, refers to an inferior shoulder dislocation. It accounts for less than 1% of shoulder dislocations. Our case report highlights an inferior shoulder dislocation with a rare, concomitant humeral neck fracture, managed via staged reduction by orthopedics with intentional dislocation of the humeral head given concern over patient's age and osteoporosis. The patient was eventually successfully repaired via arthroplasty within two weeks., Competing Interests: Conflicts of Interest: By the CPC-EM article submission agreement, all authors are required to disclose all affiliations, funding sources and financial or management relationships that could be perceived as potential sources of bias. The authors disclosed none.

We report a case of a patient with dermal piercings of the hand that were used to anchor body jewelry. The piercings had become infected and were causing the patient pain. She requested that they be removed in the emergency department (ED). Both piercings were successfully removed by anesthetizing the area and creating a small linear incision at the base of the stud before gentle removal of the dermal anchor with a hemostat. This report outlines a simple way to remove the piercings while minimizing tissue damage., Competing Interests: Declaration of competing interest The authors do not have any conflicts of interest to report., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Arabidopsis (Arabidopsis thaliana) plants can produce photosynthetic tissue with active chloroplasts at temperatures as low as 4°C, and this process depends on the presence of the nuclear-encoded, chloroplast-localized RNA-binding protein CP29A. In this study, we demonstrate that CP29A undergoes phase separation in vitro and in vivo in a temperature-dependent manner, which is mediated by a prion-like domain (PLD) located between the two RNA recognition motif domains of CP29A. The resulting droplets display liquid-like properties and are found near chloroplast nucleoids. The PLD is required to support chloroplast RNA splicing and translation in cold-treated tissue. Together, our findings suggest that plant chloroplast gene expression is compartmentalized by inducible condensation of CP29A at low temperatures, a mechanism that could play a crucial role in plant cold resistance., Competing Interests: Conflict of interest statement. None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Society of Plant Biologists. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Objective: The present study investigated the impact of two different light intensities on the pain-modulated pupillary light response (PLR). Additionally, it aimed to demonstrate parasympathetic and sympathetic influences on PLR parameters in response to pain, as predicted by functional models., Method: A total of 24 participants were included in a randomized, repeated-measures design. The PLR was measured in response to both dark and bright light stimuli within two test cycles. Pain was induced using the cold pressor test (CPT), which involved immersing participants' feet in ice water. PLR measurements were taken during baseline and ice-water immersion within each test cycle. The assessed PLR parameters included initial diameter (INIT), latency (LAT), amplitude (AMP), and re-dilation time (ReDIL25). Along with these parameters, heart rate (HR) and pain ratings were also computed and analyzed., Main Results: The CPT caused moderate pain in participants, and the resulting PLR parameters were found to be congruent with the expected parasympathetic and sympathetic nervous system activities. Although the luminance of the stimulus did influence PLR parameters, no interaction with pain exposure was found., Significance: The results showed that different aspects of pain experienced by an individual, as modulated through the sympathetic and parasympathetic nervous systems, are visible in their pupillary reactions to light. Notably, within the range used in the current study, light intensity did not significantly affect the pain-related PLR effects., 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 © 2024 Kursawe, Ehrlichmann, Weber, Krabbe and Kraus.)

Background/aim: Extracellular vesicle DNA (EV-DNA) has emerged as a novel biomarker for tumor mutation detection using liquid biopsies, exhibiting biological advantages compared to cell-free DNA (cfDNA). This study assessed the feasibility of EV-DNA and cfDNA extraction and sequencing in old serum samples of patients with breast cancer (BC)., Patients and Methods: A total of 28 serum samples of 27 patients with corresponding clinical information were collected between 1983 and 1991. EV-DNA was extracted using Exo-GAG kit (Nasabiotech) and cfDNA using QIAsymphony DSP Virus/Pathogen Midi Kit (Qiagen), respectively. Subsequently, 10 matched samples (EV-DNA n=5, cfDNA n=5) of five patients were subjected to sequencing using the Oncomine™ Breast cfDNA Research Assay v2 (Thermo Fisher Scientific)., Results: Samples were collected on median 1.9 years after primary diagnosis [interquartile range (IQR)=0.2-7.2]. Median follow-up was 9.5 years (IQR=5.2-14.2). Median age of serum samples was 36.1 years (IQR=34.5-37.3). EV-DNA and cfDNA were extracted from 100% (28/28) of the included samples. Both, DNA quantity and concentration were comparable between EV-DNA and cfDNA. Sequencing was successfully performed in 100% (10/10) of the included samples. Two matched analyses yielded equivalent results in EV-DNA and cfDNA (no mutations, n=1; PIK3CA mutation, n=1), whilst in two analyses, PIK3CA mutation was only found in cfDNA, and in one analysis, a TP53 mutation was only found in EV-DNA., Conclusion: EV-DNA extraction and sequencing in old serum samples of patients with BC is feasible and has the potential to address clinically relevant questions in longitudinal studies., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

The treatment of war injuries represents a continuing and recurrent challenge in modern reconstructive surgery. Previously, tumor resections and sepsis-related resections were mainly responsible for lengthy bone defects in Germany. In recent years another picture has increasingly emerged, particularly caused by the medical support of Ukraine. Aspects of military surgery are also becoming more important in civil hospitals, especially in the treatment of gunshot and explosion injuries. In Germany, war injuries are currently secondarily treated, as the distribution of patients is carried out according to the cloverleaf principle, weeks or months after the occurrence of the primary injury. In addition to complex bone and soft tissue defects of the extremities following such injuries, which often affect neural and vascular structures, reconstruction is often complicated by an increasing spectrum of multidrug-resistant pathogens. The definition of microbiological terms, such as contamination, colonization, critical colonization, local and systemic infections are important in the clinical routine in order to initiate a targeted treatment, especially in treatment with antibiotics. Wound swabs for determination of the spectrum of pathogens and the optimal testing of resistance are important for selecting the appropriate antibiotic agents. The concept of antibiotic stewardship (ABS) is established in many hospitals to improve the quality of antibiotic treatment and to minimize the formation of resistance. The selection of the method of reconstruction depends on the condition of the patient, the overall clinical constellation and the function to be expected after completion of treatment. The treatment of injuries due to violence and terrorism necessitates clear concepts and an interdisciplinary approach, especially with respect to microbiological challenges and increasing resistance situations., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Metastasis-directed therapy has the potential to improve progression-free and overall survival in oligometastatic disease (OMD). For breast cancer, however, randomized trials have failed so far to confirm this finding. Because the concept of metastasis-directed therapy in OMD is highly dependent on the accuracy of the imaging modality, we aimed to assess the impact of 18 F-FDG PET/CT on the definition of OMD in breast cancer patients. Methods: Eighty patients with a total of 150 18 F-FDG PET/CT images (between October 2006 and January 2022) were enrolled in this retrospective study at the Technical University of Munich. The inclusion criteria were OMD, defined as 1-5 distant metastases, at the time of 18 F-FDG PET/CT. For the current study, we systemically compared the metastatic pattern on 18 F-FDG PET/CT with conventional CT. Results: At the time of 18 F-FDG PET/CT, 21.3% of patients ( n = 32) had a first-time diagnosis of metastatic disease, 40.7% ( n = 61) had a previous history of OMD, and 38% ( n = 57) had a previous history of polymetastatic disease. In 45.3% of cases, the imaging modality ( 18 F-FDG PET/CT vs. conventional CT) had an impact on the assessment of whether OMD was present. An identical metastatic pattern was observed in only 32% of cases. 18 F-FDG PET/CT detected additional metastases in 33.3% of cases, mostly in the nonregional lymph node system. Conclusion: The use of 18 F-FDG PET/CT had a substantial impact on the definition of OMD and detection of metastatic pattern in breast cancer. Our results emphasize the importance of establishing a standardized definition for imaging modalities in future trials and clinical practices related to metastasis-directed therapy in breast cancer patients., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Molecular optogenetics utilizes genetically encoded, light-responsive protein switches to control the function of molecular processes. Over the last two years, there have been notable advances in the development of novel optogenetic switches, their utilization in elucidating intricate signaling pathways, and their progress toward practical applications in biotechnological processes, material sciences, and therapeutic applications. In this review, we discuss these areas, offer insights into recent developments, and contemplate future directions., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Die 3. Überarbeitung der S3-Leitlinie Polytrauma/Schwerverletzten-Behandlung wurde unter der Federführung der Deutschen Gesellschaft für Unfallchirurgie (DGU) von insgesamt 26 Fachgesellschaften und Organisationen durchgeführt und stellt eine umfassende Aktualisierung der Handlungsempfehlungen zur Schwerverletzten-Versorgung auf Basis neuer wissenschaftlicher Erkenntnisse und Studien dar. Die Leitlinie enthält 332 Kernempfehlungen unterschiedlicher Empfehlungsgrade und dazugehörige Erläuterungen, die Expertenwissen und über 2400 zitierte Literaturstellen berücksichtigen und somit das höchste Niveau (S3) einer Leitlinie erfüllen. Die Änderungen, insbesondere zur Schockraumalarmierung, sind für den Rettungsdienst von besonderer Bedeutung. Zwei neue Kapitel mit Empfehlungen für die Blutstillung und Schmerzbehandlung in der prähospitalen Versorgung wurden hinzugefügt, insgesamt bleibt die Leitlinie ein wichtiger Standard für Entscheidungsfindungen bei Diagnostik und Therapie von Schwerverletzten., Competing Interests: DB ist Leitlinienkoordinator der aktuellen Aktualisierung der S3-Leitlinie Polytrauma. Alle anderen Autoren geben keinen Interessenkonflikt an., (Thieme. All rights reserved.)

Background and Purpose: Intracranial aneurysm treatment using flow-diverters and flow-disruptors requires a higher level of expertise when compared to more traditional methods. Our hypothesis was that the procedural success and the rate of complications are dependent on the annual case load of a center., Materials and Methods: Conducting a retrospective analysis on the Database of the German Society for Interventional Radiology for the years 2020 to 2021, we examined flow-diverter and flow-disruptor procedures. We categorized centers into four groups according to their annual case load and proceeded to analyze success rates, complication rates, and fluoroscopy times across these centers., Results: No statistically significant differences were observed among the groups in both flow-diverter and flow-disruptor cases concerning fluoroscopy time and the incidence of technical complications. However, within the subgroup of flow-disruptor cases, centers with lower case load exhibited significantly higher rates of hemorrhagic and clinically relevant complications. Additionally, it was noted that the rate of therapeutic success in the flow-diverter group significantly increased in centers with higher case volumes., Conclusion: Our findings support the intention towards centralization of medical care especially for complex neuroendovascular procedures. Furthermore, our findings are an argument to further develop a standardized educational and procedural algorithm based on defined case numbers and training modules for complex neurovascular procedures as already implemented by the Database of the German Society for Interventional Radiology., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Gibberellins (GAs) are major regulators of developmental and growth processes in plants. Using the degradation-based signaling mechanism of GAs, we have built transcriptional regulator (DELLA)-based, genetically encoded ratiometric biosensors as proxies for hormone quantification at high temporal resolution and sensitivity that allow dynamic, rapid and simple analysis in a plant cell system, i.e. Arabidopsis protoplasts. These ratiometric biosensors incorporate a DELLA protein as a degradation target fused to a firefly luciferase connected via a 2A peptide to a renilla luciferase as a co-expressed normalization element. We have implemented these biosensors for all five Arabidopsis DELLA proteins, GA-INSENSITIVE, GAI; REPRESSOR-of-ga1-3, RGA; RGA-like1, RGL1; RGL2 and RGL3, by applying a modular design. The sensors are highly sensitive (in the low pm range), specific and dynamic. As a proof of concept, we have tested the applicability in three domains: the study of substrate specificity and activity of putative GA-oxidases, the characterization of GA transporters, and the use as a discrimination platform coupled to a GA agonists' chemical screening. This work demonstrates the development of a genetically encoded quantitative biosensor complementary to existing tools that allow the visualization of GA in planta., (© 2024 The Authors. The Plant Journal published by Society for Experimental Biology and John Wiley & Sons Ltd.)

Purpose: To summarize evidence on the comparative value of amino acid (AA) PET and conventional MRI for prediction of overall survival (OS) in patients with recurrent high grade glioma (rHGG) under bevacizumab therapy., Methods: Medical databases were screened for studies with individual data on OS, follow-up MRI, and PET findings in the same patient. MRI images were assessed according to the RANO criteria. A receiver operating characteristic curve analysis was used to predict OS at 9 months., Results: Five studies with a total of 72 patients were included. Median OS was significantly lower in the PET-positive than in the PET-negative group. PET findings predicted OS with a pooled sensitivity and specificity of 76% and 71%, respectively. Corresponding values for MRI were 32% and 82%. Area under the curve and sensitivity were significantly higher for PET than for MRI., Conclusion: For monitoring of patients with rHGG under bevacizumab therapy, AA-PET should be preferred over RANO MRI., (© 2024. The Author(s).)

The functional analysis of protein nanopores is typically conducted in planar lipid bilayers or liposomes exploiting high-resolution but low-throughput electrical and optical read-outs. Yet, the reconstitution of protein nanopores in vitro still constitutes an empiric and low-throughput process. Addressing these limitations, nanopores can now be analyzed using the functional nanopore (FuN) screen exploiting genetically encoded fluorescent protein sensors that resolve distinct nanopore-dependent Ca 2+ in- and efflux patterns across the inner membrane of Escherichia coli . With a primary proof-of-concept established for the S 21 68 holin, and thereof based recombinant nanopore assemblies, the question arises to what extent alternative nanopores can be analyzed with the FuN screen and to what extent alternative fluorescent protein sensors can be adapted. Focusing on self-assembling membrane peptides, three sets of 13 different nanopores are assessed for their capacity to form nanopores in the context of the FuN screen. Nanopores tested comprise both natural and computationally designed nanopores. Further, the FuN screen is extended to K + -specific fluorescent protein sensors and now provides a capacity to assess the specificity of a nanopore or ion channel. Finally, a comparison to high-resolution biophysical and electrophysiological studies in planar lipid bilayers provides an experimental benchmark for future studies.

As a regulator of alveolo-capillary barrier integrity, Transient Receptor Potential Vanilloid 4 (TRPV4) antagonism represents a promising strategy for reducing pulmonary edema secondary to chemical inhalation. In an experimental model of acute lung injury induced by exposure of anesthetized swine to chlorine gas by mechanical ventilation, the dose-dependent effects of TRPV4 inhibitor GSK2798745 were evaluated. Pulmonary function and oxygenation were measured hourly; airway responsiveness, wet-to-dry lung weight ratios, airway inflammation, and histopathology were assessed 24 h post-exposure. Exposure to 240 parts per million (ppm) chlorine gas for ≥50 min resulted in acute lung injury characterized by sustained changes in the ratio of partial pressure of oxygen in arterial blood to the fraction of inspiratory oxygen concentration (PaO 2 /FiO 2 ), oxygenation index, peak inspiratory pressure, dynamic lung compliance, and respiratory system resistance over 24 h. Chlorine exposure also heightened airway response to methacholine and increased wet-to-dry lung weight ratios at 24 h. Following 55-min chlorine gas exposure, GSK2798745 marginally improved PaO 2 /FiO 2 , but did not impact lung function, airway responsiveness, wet-to-dry lung weight ratios, airway inflammation, or histopathology. In summary, in this swine model of chlorine gas-induced acute lung injury, GSK2798745 did not demonstrate a clinically relevant improvement of key disease endpoints.

Synthetic biology applies concepts from electrical engineering and information processing to endow cells with computational functionality. Transferring the underlying molecular components into materials and wiring them according to topologies inspired by electronic circuit boards has yielded materials systems that perform selected computational operations. However, the limited functionality of available building blocks is restricting the implementation of advanced information-processing circuits into materials. Here, a set of protease-based biohybrid modules the bioactivity of which can either be induced or inhibited is engineered. Guided by a quantitative mathematical model and following a design-build-test-learn (DBTL) cycle, the modules are wired according to circuit topologies inspired by electronic signal decoders, a fundamental motif in information processing. A 2-input/4-output binary decoder for the detection of two small molecules in a material framework that can perform regulated outputs in form of distinct protease activities is designed. The here demonstrated smart material system is strongly modular and can be used for biomolecular information processing for example in advanced biosensing or drug delivery applications., (© 2024 The Authors. Advanced Materials published by Wiley‐VCH GmbH.)

Patients in custody due to arrest or incarceration are a vulnerable population that present a unique ethical and logistical challenge for emergency physicians (EPs). People incarcerated in the United States have a constitutional right to health care. When caring for these patients, EPs must balance their ethical obligations to the patient with security and safety concerns. They should refer to their institutional policy for guidance and their local, state, and federal laws, when applicable. Hospital legal counsel and risk management also can be helpful resources. EPs should communicate early and openly with law enforcement personnel to ensure security and emergency department staff safety is maintained while meeting the patient's medical needs. Physicians should consider the least restrictive restraints necessary to ensure security while allowing for medical evaluation and treatment. They should also protect patient privacy as much as possible within departmental constraints, promote the patient's autonomous medical decision-making, and be mindful of ways that medical information could interact with the legal system., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Authors. Journal of the American College of Emergency Physicians Open published by Wiley Periodicals LLC on behalf of American College of Emergency Physicians.)

Optogenetics is a versatile and powerful tool for the control and analysis of cellular signaling processes. The activation of cellular receptors by light using optogenetic switches usually requires genetic manipulation of cells. However, this considerably limits the application in primary, nonengineered cells, which is crucial for the study of physiological signaling processes and for controlling cell fate and function for therapeutic purposes. To overcome this limitation, we developed a system for the light-dependent extracellular activation of cell surface receptors of nonengineered cells termed OptoREACT ( Opto genetic Re ceptor Act ivation) based on the light-dependent protein interaction of A. thaliana phytochrome B (PhyB) with PIF6. In the OptoREACT system, a PIF6-coupled antibody fragment binds the T cell receptor (TCR) of Jurkat or primary human T cells, which upon illumination is bound by clustered phytochrome B to induce receptor oligomerization and activation. For clustering of PhyB, we either used tetramerization by streptavidin or immobilized PhyB on the surface of cells to emulate the interaction of a T cell with an antigen-presenting cell. We anticipate that this extracellular optogenetic approach will be applicable for the light-controlled activation of further cell surface receptors in primary, nonengineered cells for versatile applications in fundamental and applied research.

Background: Clinical empathy is considered a crucial element in patient-centered care. The advent of digital technology in healthcare has introduced new dynamics to empathy which needs to be explored in the context of the technology, particularly within the context of written live chats. Given the growing prevalence of written live chats, this study aimed to explore and evaluate techniques of digital clinical empathy within a familial cancer-focused live chat, focusing on how health professionals can (a) understand, (b) communicate, and (c) act upon users' perspectives and emotional states., Methods: The study utilized a qualitative approach in two research phases. It examined the expected and implemented techniques and effectiveness of digital clinical empathy in a live chat service, involving semi-structured interviews with health professionals (n = 9), focus group discussions with potential users (n = 42), and two rounds of usability tests between health professionals (n = 9) and users (n = 18). Data were examined using qualitative content analysis., Results: Expected techniques of digital clinical empathy, as articulated by both users and health professionals, involve reciprocal engagement, timely responses, genuine authenticity, and a balance between professionalism and informality, all while going beyond immediate queries to facilitate informed decision-making. Usability tests confirm these complexities and introduce new challenges, such as balancing timely, authentic responses with effective, personalized information management and carefully framed referrals., Conclusions: The study reveals that the digital realm adds layers of complexity to the practice of clinical empathy. It underscores the importance of ongoing adaptation and suggests that future developments could benefit from a hybrid model that integrates the strengths of both AI and human health professionals to meet evolving user needs and maintain high-quality, empathetic healthcare interactions., (© 2024. The Author(s).)

Background: Radiohybrid PSMA-targeted ligands (rhPSMA) have been introduced as a novel platform for theranostic applications. Among a variety of rhPSMA-ligands developed for radioligand therapy, two stereoisomers [ 177 Lu]Lu-rhPSMA-10.1 and -10.2 have been synthesized and initially characterized in preclinical experiments with the aim to provide an optimized binding profile to human serum albumin, a reduction of charge, and thus accelerated kidney excretion, and unaffected or even improved tumor uptake. As both isomers showed similar in vitro characteristics and tumor uptake at 24 h post injection in tumor bearing mice and in order to identify the isomer with the most favorable pharmacokinetics for radioligand therapy, we carried out in-depth biodistribution and dosimetry studies in tumor-bearing and healthy mice., Results: rhPSMA-10.1 and -10.2 were radiolabeled with lutetium-177 according to the established procedures of other DOTA-based PSMA ligands and displayed a high and comparable stability in all buffers and human serum (> 97%, 24 h). Biodistribution studies revealed fast clearance from the blood pool (0.3-0.6%ID/g at 1 h) and other background tissues within 48 h. Distinctive differences were found in the kidneys, where [ 177 Lu]Lu-rhPSMA-10.1 displayed lower initial uptake and faster excretion kinetics compared to [ 177 Lu]Lu-rhPSMA-10.2 expressed by a 1.5-fold and ninefold lower uptake value at 1 h and 24 h in healthy animals, respectively. Tumor uptake was comparable and in the range of 8.6-11.6%ID/g for both isomers over 24 h and was maintained up to 168 h at a level of 2.2 ± 0.8 and 4.1 ± 1.4%ID/g for [ 177 Lu]Lu-rhPSMA-10.1 and [ 177 Lu]Lu-rhPSMA-10.2, respectively., Conclusion: Our preclinical data on biodistribution and dosimetry indicate a more favorable profile of [ 177 Lu]Lu-rhPSMA-10.1 compared to [ 177 Lu]Lu-rhPSMA-10.2 for PSMA-targeted radioligand therapy. [ 177 Lu]Lu-rhPSMA-10.1 shows fast kidney clearance kinetics resulting in excellent tumor-to-organ ratios over a therapy relevant time course. Meanwhile, [ 177 Lu]Lu-rhPSMA-10.1 is currently being investigated in clinical phase I/II studies in patients with mCRPC (NCT05413850), in patients with high-risk localized PC (NCT06066437, Nautilus Trial) and after external beam radiotherapy (NCT06105918)., (© 2024. The Author(s).)

Vascular graft/endograft infection (VGEI) is a serious complication after aortic surgery. This study investigates VGEI and patient characteristics, PET/CT quantification before surgical or conservative management of VGEI and post-intervention outcomes in order to identify patients who might benefit from such a procedure. PET standard uptake values (SUV) were quantitatively assessed and compared to a non-VGEI cohort. The primary endpoints were in-hospital mortality and aortic reintervention-free survival at six months. Ninety-three patients (75% male, 65 ± 10 years, 82% operated) were included. The initial operation was mainly for aneurysm (67.7%: 31% EVAR, 12% TEVAR, 57% open aortic repair). Thirty-two patients presented with fistulae. PET SUV TLR (target-to-liver ratio) showed 94% sensitivity and 89% specificity. Replacement included silver-coated Dacron (21.3%), pericardium (61.3%) and femoral vein (17.3%), yet the material did not influence the overall survival ( p = 0.745). In-hospital mortality did not differ between operative and conservative treatment (19.7% vs. 17.6%, p = 0.84). At six months, 50% of the operated cohort survived without aortic reintervention. Short- and midterm morbidity and mortality remained high after aortic graft removal. Neither preoperative characteristics nor the material used for reconstruction influenced the overall survival, and, with limitations, both the in-hospital and midterm survival were similar between the surgically and conservatively managed patients.

Healthy aging is an integrated "whole person" process that involves an individual's biology, behavior, and social/physical environment. With the recent development of antiaging drugs, careful consideration of the respective roles of pharmacologic and nonpharmacologic approaches to both health and aging is in order. Recent advances in understanding the cellular and molecular mechanisms of aging are providing new measures that can be used as clinical outcomes in studying the impact of antiaging interventions in humans. This paper outlines the strategic interest of the National Center for Complementary and Integrative Health (NCCIH) in supporting the development, testing, and implementation of effective, scalable, and integrated multicomponent interventions to support healthy aging of the whole person., (Published 2023. This article is a U.S. Government work and is in the public domain in the USA. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

The α-synucleinopathies are a group of neurodegenerative diseases characterized by the deposition of α-synuclein aggregates (α-syn) in the brain. Currently, there is no suitable tracer to enable a definitive early diagnosis of these diseases. We reported candidates based on 4,4'-disarylbisthiazole (DABTA) scaffold with a high affinity towards α-syn and excellent selectivity over Aβ and tau fibrils. Based on prior in silico studies, a focused library of 23 halogen-containing and O-methylated DABTAs was prepared. The DABTAs were synthesized via a modified two-step Hantzsch thiazole synthesis, characterized, and used in competitive binding assays against [ 3 H]PiB and [ 3 H]DCVJ. The DABTAs were obtained with an overall chemical yield of 15-71%, and showed a calculated lipophilicity of 2.5-5.7. The ligands demonstrated an excellent affinity to α-syn with both [ 3 H]PiB and [ 3 H]DCVJ: K i 0.1-4.9 nM and up to 20-3900-fold selectivity over Aβ and tau fibrils. It could be concluded that in silico simulation is useful for the rational design of a new generation of DABTAs. Further investigation of the leads in the next step is encouraged: radiolabeling of the ligands with radioisotopes such as fluorine-18 or carbon-11 for in vivo, ex vivo, and translational research and for further in vitro experiments on human-derived protein aggregates.

Lung adenocarcinoma (ADC) is the most common non-small cell lung cancer. Surgical resection is the primary treatment for early-stage lung ADC while lung-sparing surgery is an alternative for non-aggressive cases. Identifying histopathologic subtypes before surgery helps determine the optimal surgical approach. Predominantly solid or micropapillary (MIP) subtypes are aggressive and associated with a higher likelihood of recurrence and metastasis and lower survival rates. This study aims to non-invasively identify these aggressive subtypes using preoperative 18 F-FDG PET/CT and diagnostic CT radiomics analysis. We retrospectively studied 119 patients with stage I lung ADC and tumors ≤ 2 cm, where 23 had aggressive subtypes (18 solid and 5 MIPs). Out of 214 radiomic features from the PET/CT and CT scans and 14 clinical parameters, 78 significant features (3 CT and 75 PET features) were identified through univariate analysis and hierarchical clustering with minimized feature collinearity. A combination of Support Vector Machine classifier and Least Absolute Shrinkage and Selection Operator built predictive models. Ten iterations of 10-fold cross-validation (10 ×10-fold CV) evaluated the model. A pair of texture feature (PET GLCM Correlation) and shape feature (CT Sphericity) emerged as the best predictor. The radiomics model significantly outperformed the conventional predictor SUV max (accuracy: 83.5% vs. 74.7%, p = 9e-9) and identified aggressive subtypes by evaluating FDG uptake in the tumor and tumor shape. It also demonstrated a high negative predictive value of 95.6% compared to SUV max (88.2%, p = 2e-10). The proposed radiomics approach could reduce unnecessary extensive surgeries for non-aggressive subtype patients, improving surgical decision-making for early-stage lung ADC patients., Competing Interests: This work was supported in part by the NIH/NCI Grant No. R01 CA172638 and the NIH/NCI Cancer Center Support Grant P30 CA008748 and 5P30 CA056036. The authors have no relevant conflicts of interest to disclose., (© 2023 The Authors.)

Background: Evaluation of endovascular therapies for cerebral vasospasm (CVS) documented in the DeGIR registry from 2018-2021 to analyse the current clinical care situation in Germany., Methods: Retrospective analysis of the clinical and procedural data on endovascular spasm therapies (EST) documented anonymously in the DeGIR registry. We analysed: pre-interventional findings of CTP and consciousness; radiation dose applied, interventional-technical parameters (local medication, devices, angiographic result), post-interventional symptoms, complications and mortality., Results: 3584 patients received a total of 7628 EST (median age/patient: 53 [range: 13-100, IQR: 44-60], 68.2 % women) in 91 (2018), 92 (2019), 100 (2020) and 98 (2021) centres; 5388 (70.6 %) anterior circulation and 378 (5 %) posterior circulation (both involved in 1862 cases [24.4 %]). EST was performed once in 2125 cases (27.9 %), with a mean of 2.1 EST/patient. In 7476 times, purely medicated EST were carried out (nimodipine: 6835, papaverine: 401, nitroglycerin: 62, other drug not specified: 239; combinations: 90). Microcatheter infusions were documented in 1132 times (14.8 %). Balloon angioplasty (BA) (additional) was performed in 756 EST (9.9 %), other mechanical recanalisations in 154 cases (2 %) and stenting in 176 of the EST (2.3 %). The median dose area product during ET was 4069 cGycm² (drug: 4002/[+]BA: 8003 [p < 0.001]). At least 1 complication occurred in 95 of all procedures (1.2 %) (drug: 1.1 %/[+]BA: 4.2 % [p < 0.001]). Mortality associated with EST was 0.2 % (n = 18). After EST, overall improvement or elimination of CVS was found in 94.2 % of cases (drug: 93.8 %/[+]BA: 98.1 % [p < 0.001]). In a comparison of the locally applied drugs, papaverine eliminated CVS more frequently than nimodipine (p = 0.001)., Conclusion: EST have a moderate radiation exposure and can be performed with few complications. Purely medicated EST are predominantly performed, especially with nimodipine. With (additional) BA, radiation exposure, complication rates and angiographic results are higher or better. When considering drug EST alone, there is evidence for an advantage of papaverine over nimodipine, but a different group size has to be taken into account. In the analysis of EST, the DeGIR registry data are suitable for answering more specific questions, especially due to the large number of cases; for this purpose, further subgroupings should be sought in the data documentation., Key Points: · In Germany, there are currently no guidelines for the endovascular treatment of cerebral vasospasm following spontaneous subarachnoid hemorrhage.. · In addition to oral nimodipine administration endovascular therapy is used to treat cerebral vasospasm in most hospitals.. · This is the first systematic evaluation of nationwide registry data on endovascular treatment of cerebral vasopasm in Germany.. · This real-world data shows that endovascular treatment for cerebral vasospasm has a moderate radiation exposure and can be performed with few complications overall. With (additional) balloon angioplasty, radiation exposure, complication rates and angiographic therapy results are higher or better.., Citation Format: · Neumann A, Weber W, Küchler J et al. Evaluation of DeGIR registry data on endovascular treatment of cerebral vasospasm in Germany 2018-2021: an overview of the current care situation. Fortschr Röntgenstr 2023; 195: 1018 - 1026., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Background: Endovascular embolization is a feasible treatment for cranial dural arteriovenous fistulas (DAVFs). New embolic agents aim to improve the success of DAVF embolization., Objective: To assess the safety, efficacy, and short-term outcome of the treatment of DAVFs using the new liquid embolic agent Squid., Methods: The LIQUID study is a prospective, observational multicenter study on the treatment of high-grade (Cognard type ≥3) DAVFs with the embolic agent Squid. The primary outcome measures were safety (ie, morbidity and mortality), as well as the occlusion rate 90 to 180 days after treatment., Results: In eight centers, 53 patients (mean age 59.8 years, 22.6% female) were treated in 55 treatment sessions. Of the DAVFs, 56.6% were Cognard type III, 41.5% type IV, and 18.9% were ruptured. Squid 18 was used in 83.6% and Squid 12 in 32.7% of the treatments. The overall rate of intraprocedural or postprocedural adverse events (AEs) was 18.2%. Procedure-related AEs resulting in permanent morbidity were observed in 3.6%. One patient (1.8%) died unrelated to the procedure due to pulmonary embolism. The final complete occlusion rate at 90 to 180 days was 93.2%. After a mean follow-up of 5.5 months, the modified Rankin Scale (mRS) score was stable or improved in 93.0%. In one of the patients, worsening of the mRS score was related to the procedure (1.8%)., Conclusion: Squid is a safe and effective liquid embolic agent for the treatment of high-grade DAVFs., Competing Interests: Competing interests: DFV reports consultancy for Medtronic and payed lectures for Cerenovus, and a research grant by MicroVention (unrelated to this work). TB reports payment for lectures and presentations from Stryker, Penumbra, and support for attending meeting and/or travel from Phenox, Microvention, and Stryker in the last 3 years. ABe reports proctoring for Microvention, Stryker, and Medtronic; payments for lectures for Stryker, Phenox and Penumbra; and board fees for CEC (Phenox) and Bayer. SM reports consultancy for Stryker, Medtronic, Acandis GmbH, Novartis Pharma GmbH (unrelated to study) and a travel grant by Balt (unrelated to study). TL has proctored and consulted for CERUS, Stryker, Phenox, Acandis, Medtronic, Pfizer and Microvention within the past three years but has no direct conflict of interest in the realm of this study. MB reports the following conflicts of interest outside the present work: board membership: DSMB Vascular Dynamics; consultancy: Roche, Guerbet, Codman; grants/grants pending: DFG, Hopp Foundation, Novartis, Siemens, Guerbet, Stryker, Covidien; payment for lectures (including service on speakers bureaus): Novartis, Roche, Guerbet, Teva, Bayer, Codman. MAM has received consulting honoraria, speaker honoraria, and travel support outside this work from Codman, Covidien/Medtronic, MicroVention, Phenox, and Stryker. The other authors declared no specific conflict of interest., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The 18th St Gallen International Breast Cancer Conference held in March 2023, in Vienna, Austria, assessed significant new findings for local and systemic therapies for early breast cancer with a focus on the evaluation of multimodal treatment options. The emergence of more effective, innovative agents in both the preoperative (primary or neoadjuvant) and post-operative (adjuvant) settings has underscored the pivotal role of a multidisciplinary approach in treatment decision making, particularly when selecting systemic therapy for an individual patient. The importance of multidisciplinary discussions regarding the clinical benefits of interventions was explicitly emphasized by the consensus panel as an integral part of developing an optimal treatment plan with the 'right' degree of intensity and duration. The panelists focused on controversies surrounding the management of common ductal/no special type and lobular breast cancer histology, which account for the vast majority of breast tumors. The expert opinion of the panelists was based on interpretations of available data, as well as current practices in their professional environments, personal and socioeconomic factors affecting patients, and cognizant of varying reimbursement and accessibility constraints around the world. The panelists strongly advocated patient participation in well-designed clinical studies whenever feasible. With these considerations in mind, the St Gallen Consensus Conference aims to offer guidance to clinicians regarding appropriate treatments for early-stage breast cancer and assist in balancing the realistic trade-offs between treatment benefit and toxicity, enabling patients and clinicians to make well-informed choices through a shared decision-making process., (Copyright © 2023 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Membranes provide a highly selective barrier that defines the boundaries of any cell while providing an interface for communication and nutrient uptake. However, despite their central physiological role, our capacity to study or even engineer the permeation of distinct solutes across biological membranes remains rudimentary. This especially applies to Gram-negative bacteria, where the outer and inner membrane impose two permeation barriers. Addressing this analytical challenge, we exemplify how the permeability of the Escherichia coli cell envelope can be dissected using a small-molecule-responsive fluorescent protein sensor. The approach is exemplified for the biotechnologically relevant macrolide rapamycin, for which we first construct an intensiometric rapamycin detector (iRapTor) while comprehensively probing key design principles in the iRapTor scaffold. Specifically, this includes the scope of minimal copolymeric linkers as a function of topology and the concomitant need for gate post residues. In a subsequent step, we apply iRapTors to assess the permeability of the E. coli cell envelope to rapamycin. Despite its lipophilic character, rapamycin does not readily diffuse across the E. coli envelope but can be enhanced by recombinantly expressing a nanopore in the outer membrane. Our study thus provides a blueprint for studying and actuating the permeation of small molecules across the prokaryotic cell envelope., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

Each cell in a multicellular organism permanently adjusts the concentration of its cell surface proteins. In particular, epithelial cells tightly control the number of carriers, transporters and cell adhesion proteins at their plasma membrane. However, sensitively measuring the cell surface concentration of a particular protein of interest in live cells and in real time represents a considerable challenge. Here, we introduce a novel approach based on split luciferases, which uses one luciferase fragment as a tag on the protein of interest and the second fragment as a supplement to the extracellular medium. Once the protein of interest arrives at the cell surface, the luciferase fragments complement and generate luminescence. We compared the performance of split Gaussia luciferase and split Nanoluciferase by using a system to synchronize biosynthetic trafficking with conditional aggregation domains. The best results were achieved with split Nanoluciferase, for which luminescence increased more than 6000-fold upon recombination. Furthermore, we showed that our approach can separately detect and quantify the arrival of membrane proteins at the apical and basolateral plasma membrane in single polarized epithelial cells by detecting the luminescence signals with a microscope, thus opening novel avenues for characterizing the variations in trafficking in individual epithelial cells., (© 2023 The Authors. Traffic published by John Wiley & Sons Ltd.)

We evaluated the cost-effectiveness of 2-[ 18 F]FDG-PET/CT compared to CE-CT for response monitoring in metastatic breast cancer (MBC) patients. The study included 300 biopsy-verified MBC patients treated at Odense University Hospital (Denmark). CE-CT was used in 144 patients, 83 patients underwent 2-[ 18 F]FDG-PET/CT, and 73 patients received a combination of both. Hospital resource-based costs (2007-2019) were adjusted to the 2019 level. The incremental cost-effectiveness ratio (ICER) was calculated by comparing average costs per patient and gained survival with CE-CT. During a median follow-up of 33.0 months, patients in the 2-[ 18 F]FDG-PET/CT group had more short admissions (median 6 vs. 2) and fewer overnight admissions (5 vs. 12) compared to the CE-CT group. The mean total cost per patient was €91,547 for CE-CT, €83,965 for 2-[ 18 F]FDG-PET/CT, and €165,784 for the combined group. The ICER for 2-[ 18 F]FDG-PET/CT compared to CE-CT was €-527/month, indicating gaining an extra month of survival at a lower cost (€527). 2-[ 18 F]FDG-PET/CT was more cost-effective in patients with favorable prognostic factors (oligometastatic or estrogen receptor-positive disease), while CE-CT was more cost-effective in poor prognosis patients (liver/lung metastases or performance status ≥ 2 at baseline). In conclusion, our study suggests that 2-[ 18 F]FDG-PET/CT is a cost-effective modality for response monitoring in metastatic breast cancer., (© 2023. The Author(s).)

Background: An important prerequisite for actively engaging in cancer prevention and early detection measures, which is particularly recommended in cases of familial cancer risk, is the acquisition of information. Although a lot of cancer information is available, not all social groups are equally well reached because information needs and communicative accessibility differ. Previous research has shown that a live chat service provided by health professionals could be an appropriate, low-threshold format to meet individual information needs on sensitive health topics such as familial cancer risk. An established German Cancer Information Service is currently developing such a live chat service. As it is only worthwhile if accepted by the target groups, formative evaluation is essential in the course of the chat service's development and implementation., Objective: This study aimed to explore the acceptance of a live chat on familial cancer risk by patients with cancer and their relatives (research question [RQ] 1) and examine the explanatory power of factors associated with their intentions to use such a service (RQ2). Guided by the Extended Unified Theory of Acceptance and Use of Technology (UTAUT2), we examined the explanatory power of the following UTAUT2 factors: performance expectancy, effort expectancy, social influence, facilitating conditions, and habit, supplemented by perceived information insufficiency, perceived susceptibility, perceived severity, and cancer diagnosis as additional factors related to information seeking about familial cancer., Methods: We conducted a cross-sectional survey via a German web-based access panel in March 2022 that was stratified by age, gender, and education (N=1084). The participants are or have been diagnosed with cancer themselves (n=144) or have relatives who are or have been affected (n=990). All constructs were measured with established scales. To answer RQ1, descriptive data (mean values and distribution) were used. For RQ2, a blockwise multiple linear regression analysis was conducted., Results: Overall, 32.7% of participants were (rather) willing, 28.9% were undecided, and 38.4% were (rather) not willing to use a live chat on familial cancer risk in the future. A multiple linear regression analysis explained 47% of the variance. It revealed that performance expectancy, social influence, habit, perceived susceptibility, and perceived severity were positively associated with the intention to use a live chat on familial cancer risk. Effort expectancy, facilitating conditions, information insufficiency, and cancer diagnosis were not related to usage intentions., Conclusions: A live chat seems promising for providing information on familial cancer risk. When promoting the service, the personal benefits should be addressed in particular. UTAUT2 is an effective theoretical framework for explaining live chat usage intentions and does not need to be extended in the context of familial cancer risk., (©Paula Memenga, Eva Baumann, Hanna Luetke Lanfer, Doreen Reifegerste, Julia Geulen, Winja Weber, Andrea Hahne, Anne Müller, Susanne Weg-Remers. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 28.08.2023.)

Background: In dealing with familial cancer risk, seeking web-based health information can be a coping strategy for different stakeholder groups (ie, patients, relatives, and those suspecting an elevated familial cancer risk). In the vast digital landscape marked by a varied quality of web-based information and evolving technologies, trust emerges as a pivotal factor, guiding the process of health information seeking and interacting with digital health services. This trust formation in health information can be conceptualized as context dependent and multidimensional, involving 3 key dimensions: information seeker (trustor), information provider (trustee), and medium or platform (application). Owing to the rapid changes in the digital context, it is critical to understand how seekers form trust in new services, given the interplay among these different dimensions. An example of such a new service is a live chat operated by physicians for the general public with personalized cancer-related information and a focus on familial cancer risk., Objective: To gain a comprehensive picture of trust formation in a cancer-related live chat service, this study investigates the 3 dimensions of trust-trustor, trustee, and application-and their respective relevant characteristics based on a model of trust in web-based health information. In addition, the study aims to compare these characteristics across the 3 different stakeholder groups, with the goal to enhance the service's trustworthiness for each group., Methods: This qualitative study triangulated the different perspectives of medical cancer advisers, advisers from cancer support groups, and members of the public in interviews and focus group discussions to explore the 3 dimensions of trust-trustor, trustee, and application-and their determinants for a new live chat service for familial cancer risk to be implemented at the German Cancer Information Service., Results: The results indicate that experience with familial cancer risk is the key trustor characteristic to using, and trusting information provided by, the live chat service. The live chat might also be particularly valuable for people from minority groups who have unmet needs from physician-patient interactions. Participants highlighted trustee characteristics such as ability, benevolence, integrity, and humanness (ie, not a chatbot) as pivotal in a trustworthy cancer live chat service. Application-related characteristics, including the reputation of the institution, user-centric design, modern technology, and visual appeal, were also deemed essential. Despite the different backgrounds and sociodemographics of the 3 stakeholder groups, many overlaps were found among the 3 trust dimensions and their respective characteristics., Conclusions: Trust in a live chat for cancer information is formed by different dimensions and characteristics of trust. This study underscores the importance of understanding trust formation in digital health services and suggests potential enhancements for effective, trustworthy interactions in live chat services (eg, by providing biographies of the human medical experts to differentiate them from artificial intelligence chatbots)., (©Hanna Luetke Lanfer, Doreen Reifegerste, Annika Berg, Paula Memenga, Eva Baumann, Winja Weber, Julia Geulen, Anne Müller, Andrea Hahne, Susanne Weg-Remers. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 23.08.2023.)

177 Lu-labeled prostate-specific membrane antigen (PSMA) radioligand therapy (RLT) is a new treatment option for metastatic castration-resistant prostate cancer (mCRPC). Its low toxicity profile favors use in elderly patients or in patients with critical comorbidities. The purpose of this analysis was to evaluate the efficacy and safety of [ 177 Lu]-PSMA RLT in mCRPC patients at least 80 y old. Methods: Eighty mCRPC patients at least 80 y old underwent [ 177 Lu]-PSMA-I&T RLT and were retrospectively selected. The patients were previously treated by androgen receptor-directed therapy, received taxane-based chemotherapy, or were chemotherapy-ineligible. The best prostate-specific antigen (PSA) response was calculated, as well as clinical progression-free survival (cPFS) and overall survival (OS). Toxicity data were acquired until 6 mo after the last treatment cycle. Results: Of 80 patients, 49 (61.3%) were chemotherapy-naïve and 16 (20%) had visceral metastases. The median number of previous mCRPC treatment regimens was 2. In total, 324 cycles (median, 4 cycles; range, 1-12) with a median cumulative activity of 23.8 GBq (interquartile range, 14.8-42.2) were applied. A PSA decline of 50% was achieved in 37 (46.3%) patients. Chemotherapy-naïve patients showed higher 50% PSA response rates than chemotherapy-pretreated patients (51.0% vs. 38.7%, respectively). Overall, median cPFS and OS were 8.7 and 16.1 mo, respectively. The median cPFS and OS of chemotherapy-naïve patients were significantly longer than those of chemotherapy-pretreated patients (10.5 vs. 6.5 mo and 20.7 vs. 11.8 mo, respectively, P < 0.05). A lower hemoglobin level and higher lactate dehydrogenase level at baseline were independent predictors of shorter cPFS and OS. Treatment-emergent grade 3 toxicities were anemia in 4 patients (5%), thrombocytopenia in 3 patients (3.8%), and renal impairment in 4 patients (5%). No nonhematologic grade 3 and no grade 4 toxicities were observed. The most frequent clinical side effects were grade 1-2 xerostomia, fatigue, and inappetence. Conclusion: [ 177 Lu]-PSMA-I&T RLT in mCRPC patients at least 80 y old is safe and effective, comparable to previously published data on non-age-selected cohorts with a low rate of high-grade toxicities. Chemotherapy-naïve patients showed a better and longer response to therapy than taxane-pretreated patients. [ 177 Lu]-PSMA RLT seems to be a meaningful treatment option for older patients., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

Encapsulated cell-based therapies involve the use of genetically-modified cells embedded in a material in order to produce a therapeutic agent in a specific location in the patient's body. This approach has shown great potential in animal model systems for treating diseases such as type I diabetes or cancer, with selected approaches having been tested in clinical trials. Despite the promise shown by encapsulated cell therapy, though, there are safety concerns yet to be addressed, such as the escape of the engineered cells from the encapsulation material and the resulting production of therapeutic agents at uncontrolled sites in the body. For that reason, there is great interest in the implementation of safety switches that protect from those side effects. Here, we develop a material-genetic interface as safety switch for engineered mammalian cells embedded into hydrogels. Our switch allows the therapeutic cells to sense whether they are embedded in the hydrogel by means of a synthetic receptor and signaling cascade that link transgene expression to the presence of an intact embedding material. The system design is highly modular, allowing its flexible adaptation to other cell types and embedding materials. This autonomously acting switch constitutes an advantage over previously described safety switches, which rely on user-triggered signals to modulate activity or survival of the implanted cells. We envision that the concept developed here will advance the safety of cell therapies and facilitate their translation to clinical evaluation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: The CLinical Assessment of WEB device in Ruptured aneurYSms (CLARYS) study has shown that the endovascular treatment of ruptured bifurcation aneurysms with the Woven EndoBridge (WEB) is safe and effective and provides protection against rebleeding at 1 month and 1 year. The 12-month angiographic follow-up is an important endpoint of the study., Methods: The CLARYS study is a prospective multicenter study conducted in 13 European centers. The study enrolled 60 patients with 60 ruptured aneurysms of the anterior and posterior circulation. The study was conducted with an independent assessment of safety outcomes and imaging., Results: Sixty patients with 60 ruptured bifurcation aneurysms to be treated with the WEB were included. Fifty-three aneurysms (88.3%) had a broad base with a dome to neck ratio <2 (mean 1.6). Of these, 46 patients were evaluated by an independent core laboratory with follow-up imaging performed at 12 months or before eventual retreatment. At 1 year, 19/46 aneurysms (41.3%) were completely occluded (Raymond-Roy grade I), 21/46 (45.7%) had a residual neck and 6/46 (13.0%) had residual aneurysm filling. Adequate occlusion was reported in 40/46 (87%) aneurysms. Six patients underwent target aneurysm retreatment., Conclusions: The CLARYS study has previously shown that the use of the WEB in the endovascular treatment of ruptured bifurcation aneurysms provides effective protection against rebleeding with a good safety profile. The angiographic occlusion rates at 1 year reported here are comparable to those already seen in previous multicenter studies which primarily included unruptured aneurysms., Competing Interests: Competing interests: JF is an associate editor of the Journal of NeuroInterventional Surgery. MM is a member of the editorial board of Neuroradiology., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)