@article{HartmannsbergerScribaGuidolinetal.2024,
  author    = {Hartmannsberger, Beate and Scriba, Sabrina and Guidolin, Carolina and Becker, Juliane and Mehling, Katharina and Doppler, Kathrin and Sommer, Claudia and Rittner, Heike L.},
  title     = {Transient immune activation without loss of intraepidermal innervation and associated Schwann cells in patients with complex regional pain syndrome},
  series = {Journal of Neuroinflammation},
  volume    = {21},
  journal   = {Journal of Neuroinflammation},
  doi       = {10.1186/s12974-023-02969-6},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-357164},
  year      = {2024},
  abstract  = {Background Complex regional pain syndrome (CRPS) develops after injury and is characterized by disproportionate pain, oedema, and functional loss. CRPS has clinical signs of neuropathy as well as neurogenic inflammation. Here, we asked whether skin biopsies could be used to differentiate the contribution of these two systems to ultimately guide therapy. To this end, the cutaneous sensory system including nerve fibres and the recently described nociceptive Schwann cells as well as the cutaneous immune system were analysed. Methods We systematically deep-phenotyped CRPS patients and immunolabelled glabrous skin biopsies from the affected ipsilateral and non-affected contralateral finger of 19 acute (< 12 months) and 6 chronic (> 12 months after trauma) CRPS patients as well as 25 sex- and age-matched healthy controls (HC). Murine foot pads harvested one week after sham or chronic constriction injury were immunolabelled to assess intraepidermal Schwann cells. Results Intraepidermal Schwann cells were detected in human skin of the finger—but their density was much lower compared to mice. Acute and chronic CRPS patients suffered from moderate to severe CRPS symptoms and corresponding pain. Most patients had CRPS type I in the warm category. Their cutaneous neuroglial complex was completely unaffected despite sensory plus signs, e.g. allodynia and hyperalgesia. Cutaneous innate sentinel immune cells, e.g. mast cells and Langerhans cells, infiltrated or proliferated ipsilaterally independently of each other—but only in acute CRPS. No additional adaptive immune cells, e.g. T cells and plasma cells, infiltrated the skin. Conclusions Diagnostic skin punch biopsies could be used to diagnose individual pathophysiology in a very heterogenous disease like acute CRPS to guide tailored treatment in the future. Since numbers of inflammatory cells and pain did not necessarily correlate, more in-depth analysis of individual patients is necessary.},
  language  = {en}
}
@article{StanglPoppReisetal.2024,
  author    = {Stangl, Stephanie and Popp, Maria and Reis, Stefanie and Sitter, Magdalena and Saal-Bauernschubert, Lena and Schießer, Selina and Kranke, Peter and Choorapoikayil, Suma and Weibel, Stephanie and Meybohm, Patrick},
  title     = {Reported outcomes in patients with iron deficiency or iron deficiency anemia undergoing major surgery: a systematic review of outcomes},
  series = {Systematic Reviews},
  volume    = {13},
  journal   = {Systematic Reviews},
  doi       = {10.1186/s13643-023-02431-x},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-357213},
  year      = {2024},
  abstract  = {Background Iron deficiency (ID) is the leading cause of anemia worldwide. The prevalence of preoperative ID ranges from 23 to 33\%. Preoperative anemia is associated with worse outcomes, making it important to diagnose and treat ID before elective surgery. Several studies indicated the effectiveness of intravenous iron supplementation in iron deficiency with or without anemia (ID(A)). However, it remains challenging to establish reliable evidence due to heterogeneity in utilized study outcomes. The development of a core outcome set (COS) can help to reduce this heterogeneity by proposing a minimal set of meaningful and standardized outcomes. The aim of our systematic review was to identify and assess outcomes reported in randomized controlled trials (RCTs) and observational studies investigating iron supplementation in iron-deficient patients with or without anemia. Methods We searched MEDLINE, CENTRAL, and ClinicalTrials.gov systematically from 2000 to April 1, 2022. RCTs and observational studies investigating iron supplementation in patients with a preoperative diagnosis of ID(A), were included. Study characteristics and reported outcomes were extracted. Outcomes were categorized according to an established outcome taxonomy. Quality of outcome reporting was assessed with a pre-specified tool. Reported clinically relevant differences for sample size calculation were extracted. Results Out of 2898 records, 346 underwent full-text screening and 13 studies (five RCTs, eight observational studies) with sufficient diagnostic inclusion criteria for iron deficiency with or without anemia (ID(A)) were eligible. It is noteworthy to mention that 49 studies were excluded due to no confirmed diagnosis of ID(A). Overall, 111 outcomes were structured into five core areas including nine domains. Most studies (92\%) reported outcomes within the 'blood and lymphatic system' domain, followed by "adverse event" (77\%) and "need for further resources" (77\%). All of the latter reported on the need for blood transfusion. Reported outcomes were heterogeneous in measures and timing. Merely, two (33\%) of six prospective studies were registered prospectively of which one (17\%) showed no signs of selective outcome reporting. Conclusion This systematic review comprehensively depicts the heterogeneity of reported outcomes in studies investigating iron supplementation in ID(A) patients regarding exact definitions and timing. Our analysis provides a systematic base for consenting to a minimal COS. Systematic review registration PROSPERO CRD42020214247},
  language  = {en}
}
@article{DresenLeeHilletal.2023,
  author    = {Dresen, Ellen and Lee, Zheng-Yii and Hill, Aileen and Notz, Quirin and Patel, Jayshil J. and Stoppe, Christian},
  title     = {History of scurvy and use of vitamin C in critical illness: A narrative review},
  series = {Nutrition in Clinical Practice},
  volume    = {38},
  journal   = {Nutrition in Clinical Practice},
  number    = {1},
  doi       = {10.1002/ncp.10914},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-318176},
  pages     = {46 -- 54},
  year      = {2023},
  abstract  = {In 1747, an important milestone in the history of clinical research was set, as the Scottish surgeon James Lind conducted the first randomized controlled trial. Lind was interested in scurvy, a severe vitamin C deficiency which caused the death of thousands of British seamen. He found that a dietary intervention with oranges and lemons, which are rich in vitamin C by nature, was effective to recover from scurvy. Because of its antioxidative properties and involvement in many biochemical processes, the essential micronutrient vitamin C plays a key role in the human biology. Moreover, the use of vitamin C in critical illness—a condition also resulting in death of thousands in the 21st century—has gained increasing interest, as it may restore vascular responsiveness to vasoactive agents, ameliorate microcirculatory blood flow, preserve endothelial barriers, augment bacterial defense, and prevent apoptosis. Because of its redox potential and powerful antioxidant capacity, vitamin C represents an inexpensive and safe antioxidant, with the potential to modify the inflammatory cascade and improve clinical outcomes of critically ill patients. This narrative review aims to update and provide an overview on the role of vitamin C in the human biology and in critically ill patients, and to summarize current evidence on the use of vitamin C in diverse populations of critically ill patients, in specific focusing on patients with sepsis and coronavirus disease 2019.},
  language  = {en}
}
@article{WeibelPoppReisetal.2023,
  author    = {Weibel, Stephanie and Popp, Maria and Reis, Stefanie and Skoetz, Nicole and Garner, Paul and Sydenham, Emma},
  title     = {Identifying and managing problematic trials: A research integrity assessment tool for randomized controlled trials in evidence synthesis},
  series = {Research Synthesis Methods},
  volume    = {14},
  journal   = {Research Synthesis Methods},
  number    = {3},
  doi       = {10.1002/jrsm.1599},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-318236},
  pages     = {357 -- 369},
  year      = {2023},
  abstract  = {Evidence synthesis findings depend on the assumption that the included studies follow good clinical practice and results are not fabricated or false. Studies which are problematic due to scientific misconduct, poor research practice, or honest error may distort evidence synthesis findings. Authors of evidence synthesis need transparent mechanisms to identify and manage problematic studies to avoid misleading findings. As evidence synthesis authors of the Cochrane COVID-19 review on ivermectin, we identified many problematic studies in terms of research integrity and regulatory compliance. Through iterative discussion, we developed a research integrity assessment (RIA) tool for randomized controlled trials for the update of this Cochrane review. In this paper, we explain the rationale and application of the RIA tool in this case study. RIA assesses six study criteria: study retraction, prospective trial registration, adequate ethics approval, author group, plausibility of methods (e.g., randomization), and plausibility of study results. RIA was used in the Cochrane review as part of the eligibility check during screening of potentially eligible studies. Problematic studies were excluded and studies with open questions were held in awaiting classification until clarified. RIA decisions were made independently by two authors and reported transparently. Using the RIA tool resulted in the exclusion of >40\% of studies in the first update of the review. RIA is a complementary tool prior to assessing "Risk of Bias" aiming to establish the integrity and authenticity of studies. RIA provides a platform for urgent development of a standard approach to identifying and managing problematic studies.},
  language  = {en}
}
@article{DresenPimientoPateletal.2023,
  author    = {Dresen, Ellen and Pimiento, Jose M. and Patel, Jayshil J. and Heyland, Daren K. and Rice, Todd W. and Stoppe, Christian},
  title     = {Overview of oxidative stress and the role of micronutrients in critical illness},
  series = {Journal of Parenteral and Enteral Nutrition},
  volume    = {47},
  journal   = {Journal of Parenteral and Enteral Nutrition},
  doi       = {10.1002/jpen.2421},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-318186},
  pages     = {S38 -- S49},
  year      = {2023},
  abstract  = {Inflammation and oxidative stress represent physiological response mechanisms to different types of stimuli and injury during critical illness. Its proper regulation is fundamental to cellular and organismal survival and are paramount to outcomes and recovery from critical illness. A proper maintenance of the delicate balance between inflammation, oxidative stress, and immune response is crucial for resolution from critical illness with important implications for patient outcome. The extent of inflammation and oxidative stress under normal conditions is limited by the antioxidant defense system of the human body, whereas the antioxidant capacity is commonly significantly compromised, and serum levels of micronutrients and vitamins significantly depleted in patients who are critically ill. Hence, the provision of antioxidants and anti-inflammatory nutrients may help to reduce the extent of oxidative stress and therefore improve clinical outcomes in patients who are critically ill. As existing evidence of the beneficial effects of antioxidant supplementation in patients who are critically ill is still unclear, actual findings about the most promising anti-inflammatory and antioxidative candidates selenium, vitamin C, zinc, and vitamin D will be discussed in this narrative review. The existing evidence provided so far demonstrates that several factors need to be considered to determine the efficacy of an antioxidant supplementation strategy in patients who are critically ill and indicates the need for adequately designed multicenter prospective randomized control trials to evaluate the clinical significance of different types and doses of micronutrients and vitamins in selected groups of patients with different types of critical illness.},
  language  = {en}
}
@article{SalvadorKoepplHoermannetal.2023,
  author    = {Salvador, Ellaine and K{\"o}ppl, Theresa and H{\"o}rmann, Julia and Sch{\"o}nh{\"a}rl, Sebastian and Bugaeva, Polina and Kessler, Almuth F. and Burek, Malgorzata and Ernestus, Ralf-Ingo and L{\"o}hr, Mario and Hagemann, Carsten},
  title     = {Tumor Treating Fields (TTFields) induce cell junction alterations in a human 3D in vitro model of the blood-brain barrier},
  series = {Pharmaceutics},
  volume    = {15},
  journal   = {Pharmaceutics},
  number    = {1},
  issn      = {1999-4923},
  doi       = {10.3390/pharmaceutics15010185},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-304830},
  year      = {2023},
  abstract  = {In a recent study, we showed in an in vitro murine cerebellar microvascular endothelial cell (cerebEND) model as well as in vivo in rats that Tumor-Treating Fields (TTFields) reversibly open the blood-brain barrier (BBB). This process is facilitated by delocalizing tight junction proteins such as claudin-5 from the membrane to the cytoplasm. In investigating the possibility that the same effects could be observed in human-derived cells, a 3D co-culture model of the BBB was established consisting of primary microvascular brain endothelial cells (HBMVEC) and immortalized pericytes, both of human origin. The TTFields at a frequency of 100 kHz administered for 72 h increased the permeability of our human-derived BBB model. The integrity of the BBB had already recovered 48 h post-TTFields, which is earlier than that observed in cerebEND. The data presented herein validate the previously observed effects of TTFields in murine models. Moreover, due to the fact that human cell-based in vitro models more closely resemble patient-derived entities, our findings are highly relevant for pre-clinical studies.},
  language  = {en}
}
@article{LoebLinsmeierHerbertetal.2023,
  author    = {L{\"o}b, Sanja and Linsmeier, Eva and Herbert, Saskia-Laureen and Schlaiß, Tanja and Kiesel, Matthias and Wischhusen, J{\"o}rg and Salmen, Jessica and Kranke, Peter and Quenzer, Anne and Kurz, Florian and Weiss, Claire and Gerhard-Hartmann, Elena and W{\"o}ckel, Achim and Diessner, Joachim},
  title     = {Prognostic effect of HER2 evolution from primary breast cancer to breast cancer metastases},
  series = {Journal of Cancer Research and Clinical Oncology},
  volume    = {149},
  journal   = {Journal of Cancer Research and Clinical Oncology},
  number    = {8},
  doi       = {10.1007/s00432-022-04486-0},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-324068},
  pages     = {5417-5428},
  year      = {2023},
  abstract  = {Purpose Therapeutic options for breast cancer (BC) treatment are constantly evolving. The Human Epidermal Growth Factor 2 (HER2)-low BC entity is a new subgroup, representing about 55\% of all BC patients. New antibody-drug conjugates demonstrated promising results for this BC subgroup. Currently, there is limited information about the conversion of HER2 subtypes between primary tumor and recurrent disease. Methods This retrospective study included women with BC at the University Medical Centre Wuerzburg from 1998 to 2021. Data were retrieved from patients' records. HER2 evolution from primary diagnosis to the first relapse and the development of secondary metastases was investigated. Results In the HR-positive subgroup without HER2 overexpression, HER2-low expression in primary BC was 56.7 vs. 14.6\% in the triple-negative subgroup (p < 0.000). In the cohort of the first relapse, HER2-low represented 64.1\% of HR-positive vs. 48.2\% of the triple-negative cohort (p = 0.03). In patients with secondary metastases, HER2-low was 75.6\% vs. 50\% in the triple negative subgroup (p = 0.10). The subgroup of HER2-positive breast cancer patients numerically increased in the course of disease; the HER2-negative overall cohort decreased. A loss of HER2 expression from primary BC to the first relapse correlated with a better OS (p = 0.018). No clinicopathological or therapeutic features could be identified as potential risk factors for HER2 conversion. Conclusion HER2 expression is rising during the progression of BC disease. In view of upcoming therapeutical options, the re-analysis of newly developed metastasis will become increasingly important.},
  language  = {en}
}
@phdthesis{Sun2023,
  author    = {Sun, Aili},
  title     = {Effect of Tjap1 knock-down on blood-brain barrier properties under normal and hypoxic conditions},
  doi       = {10.25972/OPUS-34645},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-346450},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2023},
  abstract  = {Stroke is one of the leading causes of mortality and disability worldwide. The blood-brain barrier (BBB) plays an important role in maintaining brain homeostasis by tightly regulating the exchange of substances between circulating blood and brain parenchyma. BBB disruption is a common pathologic feature of stroke and traumatic brain injury. Understanding the cellular and molecular events that affect the BBB after ischaemic brain injury is important to improve patient prognosis. We have previously shown that microRNA-212/132 is elevated in hypoxic brain microvascular endothelial cells and acts through suppressing the expression of direct microRNA-212/132 target genes with function at the BBB: claudin-1, junctional adhesion molecule 3 (Jam3) and tight-junction associated protein 1 (Tjap1). While the role of claudin-1 and Jam3 at the BBB is well known, the role of Tjap1 is still unclear. The aim of this work was therefore to characterize the role of Tjap1 in brain endothelial cells using a knock-down (KD) approach in established murine in vitro BBB models cEND and cerebEND. Tjap1 KD was established by stable transfection of a plasmid expressing shRNA against Tjap1. The successful downregulation of Tjap1 mRNA and protein was demonstrated by qPCR and Western blot. Tjap1 KD resulted in impaired barrier properties of endothelial cells as shown by lower TEER values and higher paracellular permeability. Interestingly, the Tjap1 KD cells showed lower cell viability and proliferation but migrated faster in a wound healing assay. In the tube formation assay, Tjap1 KD cell lines showed a lower angiogenic potential due to a significantly lower tube length and number as well as a lower amount of branching points in formed capillaries. Tjap1 KD cells showed changes in gene and protein expression. The TJ proteins claudin-5, Jam3 and ZO-1 were significantly increased in Tjap1 KD cell lines, while occludin was strongly decreased. In addition, efflux pump P-glycoprotein was downregulated in Tjap1 KD cells. Oxygen-glucose deprivation (OGD) is a method to mimic stroke in vitro. Brain endothelial cell lines treated with OGD showed lower barrier properties compared to cells cultured under normal condition. These effects were more severe in Tjap1 KD cells, indicating active Tjap1 involvement in the OGD response in brain microvascular endothelial cells. We thus have shown that Tjap1 contributes to a tight barrier of the BBB, regulates cell viability and proliferation of endothelial cells, suppresses their migration and promotes new vessel formation. This means that Tjap1 function is important for mature BBB structure in health and disease.},
  subject      = {Schlaganfall},
  language  = {en}
}
@article{HenckertMalorgioSchweigeretal.2023,
  author    = {Henckert, David and Malorgio, Amos and Schweiger, Giovanna and Raimann, Florian J. and Piekarski, Florian and Zacharowski, Kai and Hottenrott, Sebastian and Meybohm, Patrick and Tscholl, David W. and Spahn, Donat R. and Roche, Tadzio R.},
  title     = {Attitudes of anesthesiologists toward artificial intelligence in anesthesia: a multicenter, mixed qualitative-quantitative study},
  series = {Journal of Clinical Medicine},
  volume    = {12},
  journal   = {Journal of Clinical Medicine},
  number    = {6},
  issn      = {2077-0383},
  doi       = {10.3390/jcm12062096},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-311189},
  year      = {2023},
  abstract  = {Artificial intelligence (AI) is predicted to play an increasingly important role in perioperative medicine in the very near future. However, little is known about what anesthesiologists know and think about AI in this context. This is important because the successful introduction of new technologies depends on the understanding and cooperation of end users. We sought to investigate how much anesthesiologists know about AI and what they think about the introduction of AI-based technologies into the clinical setting. In order to better understand what anesthesiologists think of AI, we recruited 21 anesthesiologists from 2 university hospitals for face-to-face structured interviews. The interview transcripts were subdivided sentence-by-sentence into discrete statements, and statements were then grouped into key themes. Subsequently, a survey of closed questions based on these themes was sent to 70 anesthesiologists from 3 university hospitals for rating. In the interviews, the base level of knowledge of AI was good at 86 of 90 statements (96\%), although awareness of the potential applications of AI in anesthesia was poor at only 7 of 42 statements (17\%). Regarding the implementation of AI in anesthesia, statements were split roughly evenly between pros (46 of 105, 44\%) and cons (59 of 105, 56\%). Interviewees considered that AI could usefully be used in diverse tasks such as risk stratification, the prediction of vital sign changes, or as a treatment guide. The validity of these themes was probed in a follow-up survey of 70 anesthesiologists with a response rate of 70\%, which confirmed an overall positive view of AI in this group. Anesthesiologists hold a range of opinions, both positive and negative, regarding the application of AI in their field of work. Survey-based studies do not always uncover the full breadth of nuance of opinion amongst clinicians. Engagement with specific concerns, both technical and ethical, will prove important as this technology moves from research to the clinic.},
  language  = {en}
}
@article{SchweigerMalorgioHenckertetal.2023,
  author    = {Schweiger, Giovanna and Malorgio, Amos and Henckert, David and Braun, Julia and Meybohm, Patrick and Hottenrott, Sebastian and Froehlich, Corinna and Zacharowski, Kai and Raimann, Florian J. and Piekarski, Florian and Noethiger, Christoph B. and Spahn, Donat R. and Tscholl, David W. and Roche, Tadzio R.},
  title     = {Visual Blood, a 3D animated computer model to optimize the interpretation of blood gas analysis},
  series = {Bioengineering},
  volume    = {10},
  journal   = {Bioengineering},
  number    = {3},
  issn      = {2306-5354},
  doi       = {10.3390/bioengineering10030293},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-304150},
  year      = {2023},
  abstract  = {Acid-base homeostasis is crucial for all physiological processes in the body and is evaluated using arterial blood gas (ABG) analysis. Screens or printouts of ABG results require the interpretation of many textual elements and numbers, which may delay intuitive comprehension. To optimise the presentation of the results for the specific strengths of human perception, we developed Visual Blood, an animated virtual model of ABG results. In this study, we compared its performance with a conventional result printout. Seventy physicians from three European university hospitals participated in a computer-based simulation study. Initially, after an educational video, we tested the participants' ability to assign individual Visual Blood visualisations to their corresponding ABG parameters. As the primary outcome, we tested caregivers' ability to correctly diagnose simulated clinical ABG scenarios with Visual Blood or conventional ABG printouts. For user feedback, participants rated their agreement with statements at the end of the study. Physicians correctly assigned 90\% of the individual Visual Blood visualisations. Regarding the primary outcome, the participants made the correct diagnosis 86\% of the time when using Visual Blood, compared to 68\% when using the conventional ABG printout. A mixed logistic regression model showed an odds ratio for correct diagnosis of 3.4 (95\%CI 2.00-5.79, p < 0.001) and an odds ratio for perceived diagnostic confidence of 1.88 (95\%CI 1.67-2.11, p < 0.001) in favour of Visual Blood. A linear mixed model showed a coefficient for perceived workload of -3.2 (95\%CI -3.77 to -2.64) in favour of Visual Blood. Fifty-one of seventy (73\%) participants agreed or strongly agreed that Visual Blood was easy to use, and fifty-five of seventy (79\%) agreed that it was fun to use. In conclusion, Visual Blood improved physicians' ability to diagnose ABG results. It also increased perceived diagnostic confidence and reduced perceived workload. This study adds to the growing body of research showing that decision-support tools developed around human cognitive abilities can streamline caregivers' decision-making and may improve patient care.},
  language  = {en}
}