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The topic of this article is the team in interdisciplinary multimodal pain therapy (IMPT) in the context of the development of the team concept. The starting points are historical developments, both social and scientific. After World War II numerous war victims continued to suffer from persistent pain. On the part of medicine, the consequences were the failure of the usual procedures for acute pain and the resulting helplessness. Both the concept of pain as a symptom of physical injury and also the previous treatment options were no longer adequate. Very early on an interdisciplinary approach to pain management was organized. This involved the communication of experts from various disciplines with very different competencies and opinions. Various medical disciplines and psychotherapy were the core subjects. Crucial for functioning teams is an effective cooperation and interaction. Related organizational issues, conflicts, peculiarities, and possibilities for solutions are presented. In the meantime, IMPT as a procedure has become a regular service provided in health care., (© 2023. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Artificial intelligence (AI) offers opportunities but also challenges for biomedical research and healthcare. This position paper shares the results of the international conference "Fair medicine and AI" (online 3-5 March 2021). Scholars from science and technology studies (STS), gender studies, and ethics of science and technology formulated opportunities, challenges, and research and development desiderata for AI in healthcare. AI systems and solutions, which are being rapidly developed and applied, may have undesirable and unintended consequences including the risk of perpetuating health inequalities for marginalized groups. Socially robust development and implications of AI in healthcare require urgent investigation. There is a particular dearth of studies in human-AI interaction and how this may best be configured to dependably deliver safe, effective and equitable healthcare. To address these challenges, we need to establish diverse and interdisciplinary teams equipped to develop and apply medical AI in a fair, accountable and transparent manner. We formulate the importance of including social science perspectives in the development of intersectionally beneficent and equitable AI for biomedical research and healthcare, in part by strengthening AI health evaluation., Competing Interests: Declaration of competing interest None., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Representing knowledge in a comprehensible and maintainable way and transparently providing inferences thereof are important issues, especially in the context of applications related to artificial intelligence in medicine. This becomes even more obvious if the knowledge is dynamically growing and changing and when machine learning techniques are being involved. In this paper, we present an approach for representing knowledge about cancer therapies collected over two decades at St.-Johannes-Hospital in Dortmund, Germany. The presented approach makes use of InteKRator, a toolbox that combines knowledge representation and machine learning techniques, including the possibility of explaining inferences. An extended use of InteKRator's reasoning system will be introduced for being able to provide the required inferences. The presented approach is general enough to be transferred to other data, as well as to other domains. The approach will be evaluated, e. g., regarding comprehensibility, accuracy and reasoning efficiency.

Background: Comorbidities are expected to impact the pathophysiology of heart failure (HF) with preserved ejection fraction (HFpEF). However, comorbidity profiles are usually reduced to a few comorbid disorders. Systems medicine approaches can model phenome-wide comorbidity profiles to improve our understanding of HFpEF and infer associated genetic profiles., Methods: We retrospectively explored 569 comorbidities in 29,047 HF patients, including 8062 HFpEF and 6585 HF with reduced ejection fraction (HFrEF) patients from a German university hospital. We assessed differences in comorbidity profiles between HF subtypes via multiple correspondence analysis. Then, we used machine learning classifiers to identify distinctive comorbidity profiles of HFpEF and HFrEF patients. Moreover, we built a comorbidity network (HFnet) to identify the main disease clusters that summarized the phenome-wide comorbidity. Lastly, we predicted novel gene candidates for HFpEF by linking the HFnet to a multilayer gene network, integrating multiple databases. To corroborate HFpEF candidate genes, we collected transcriptomic data in a murine HFpEF model. We compared predicted genes with the murine disease signature as well as with the literature., Results: We found a high degree of variance between the comorbidity profiles of HFpEF and HFrEF, while each was more similar to HFmrEF. The comorbidities present in HFpEF patients were more diverse than those in HFrEF and included neoplastic, osteologic and rheumatoid disorders. Disease communities in the HFnet captured important comorbidity concepts of HF patients which could be assigned to HF subtypes, age groups, and sex. Based on the HFpEF comorbidity profile, we predicted and recovered gene candidates, including genes involved in fibrosis (COL3A1, LOX, SMAD9, PTHL), hypertrophy (GATA5, MYH7), oxidative stress (NOS1, GSST1, XDH), and endoplasmic reticulum stress (ATF6). Finally, predicted genes were significantly overrepresented in the murine transcriptomic disease signature providing additional plausibility for their relevance., Conclusions: We applied systems medicine concepts to analyze comorbidity profiles in a HF patient cohort. We were able to identify disease clusters that helped to characterize HF patients. We derived a distinct comorbidity profile for HFpEF, which was leveraged to suggest novel candidate genes via network propagation. The identification of distinctive comorbidity profiles and candidate genes from routine clinical data provides insights that may be leveraged to improve diagnosis and identify treatment targets for HFpEF patients., (© 2023. The Author(s).)

These S1 guidelines are an updated and expanded version of the S1 guidelines on long COVID differential diagnostic and management strategies. They summarize the state of knowledge on postviral conditions like long/post COVID at the time of writing. Due to the dynamic nature of knowledge development, they are intended to be "living guidelines". The focus is on practical applicability at the level of primary care, which is understood to be the appropriate place for initial access and for primary care and treatment. The guidelines provide recommendations on the course of treatment, differential diagnostics of the most common symptoms that can result from infections like with SARS-CoV-2, treatment options, patient management and care, reintegration and rehabilitation. The guidelines have been developed through an interdisciplinary and interprofessional process and provide recommendations on interfaces and possibilities for collaboration., (© 2023. The Author(s).)

Aim of the Study: Family life and professional practice are both highly important for young physicians. Accordingly, a good balancing of both areas of life is necessary. Despite political framework conditions and legal requirements that have been in place for years, implementation of measures to achieve this seems to be difficult, especially in medicine, and is associated with great reservations and problems on the part of those involved., Methods: By means of an online survey, the medical mid-level staff from university and peripheral hospitals was questioned on topics related to family, children and professional biographical as well as career-relevant topics and subsequently analyzed on a gender-specific basis., Results: Of the study participants, 65.1% were married and already had children or expressed a desire to have children (86.0%). Most were employed full-time (80.8%). The majority of part-time employees were female (87.4%). For 34.6%, there was a career break of 18.5±21.3 months, 87.8% of which were taken due to pregnancy or children. Female physicians generally took significantly more parental leave than male physicians (6-12 months: females 62.2%; males 22.4%; 12 months or more: females 25.2%; males 6.6%). Family planning received little support from superiors (21.2% much to very much support) and 45.6% reported having experienced problems with their return to work or career advancement. Almost 60% of the participants did not have any specific working time models in their own hospital for employees with children who need to be cared for., Conclusion: In order to implement a work-life balance for physicians, changes are first and foremost necessary on the part of the institutions. In addition, the respective superiors must rethink in order to enable a parallelization of these two areas of their employees' lives. However, young physicians must also rethink their view of this issue. Demanding changes in labor law while continuing traditional family constellations at home does not seem to do address this issue adequately., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

Background: Although allergic diseases are among the most important health disorders, allergology is not anchored as an independent subject in the clinical part of medical studies in Germany., Objective: As all universities and institutes face the same challenge, the aim of our project was to establish exemplary coordination and networking of education in allergology at one location in agreement with all involved departments and institutes. Particularly, Comprehensive Allergy Centers (CAC) offer an established infrastructure via which the revised allergology education program can be transferred to other universities., Materials and Methods: After an extensive inventory of the current allergological curriculum at the University Medical Center Göttingen, a new teaching concept was developed in interdisciplinary consensus, supplemented by first-time provision of additional digital contents ("blended learning"), and finally evaluated., Results: Initially, we observed a high level of fragmentation in the teaching of allergology in the clinical study sections of human medicine, with no coordination between the 12 clinical departments/institutes involved and no coherent framework for the specific learning content. Within the established structure of the interdisciplinary CAC, we revised, coordinated, and defined key areas for improved student education in clinical allergology. The allocation of new interactive learning elements as well as supplementary materials for self-studies was welcomed by the students and positively evaluated. A survey among students after completing the former vs. current curricula showed significant improvements in achieving the desired educational objectives., (© 2022. The Author(s).)

Premedical students typically pursue undergraduate specialization in basic biological and other sciences, learning to understand living systems at a microscopic, genetic, or molecular level. However, curricula in the basic sciences do not traditionally include courses that enable students to learn about living systems at the macro level-understanding individuals within their environment, as well as understanding and managing the health of populations, especially those with underlying conditions or the underserved. This disconnect can be bridged by creating novel curricular programs intersecting medicine and business. Population health management is a multidisciplinary field that aims to improve the patient experience, reduce health care costs, and improve treatment outcomes. Though related to public health, the 2 fields differ in significant ways. Population health management emphasizes health outcomes and their measurements and seeks to improve health outcomes based on a full understanding of risk, behaviors, lifestyle, environment, and all social determinants of health. A shift in premedical education that connects the medical sciences with business requires curricular reform with the emerging field of population health management at their intersection, allowing students to be better prepared for future medical practices and to understand expectations, benchmarks, business, and economics in a new value-based health care system.

Aim: For several years now, medical students have also been taught general practice at academic medical teaching practices. Specialty practices have not yet been included in the curricular education. Since 1998, we have conducted a block seminar in hematology twice per semester for eighth-semester medical students. This block seminar was offered from 1998-2001 to students at the Philipps University in Marburg and since 2001 to students at the Johannes Gutenberg University in Mainz. Since 2010 our block seminar has been part of the curriculum at the Johannes Gutenberg University. Method: Standardized course evaluation by students who had attended our block seminar between January 2010 and March 2022. Courses that were held virtually due to corona were not included in the analysis. The questionnaire used to evaluate courses in the medical degree program at the Johannes Gutenberg University served as the evaluation instrument. Results: Since 1998 more than 1,000 students have attended our seminar. The systematic evaluation of the course by 500 students who participated in the curricular, classroom-based seminar sessions since 2010 shows that the highest ratings possible are given for practical relevance, learning atmosphere, teaching and effectiveness. Conclusion: High quality in teaching curricular courses to medical students at a specialty practice is possible. Insights into the possibilities connected with working in the outpatient setting at a medical practice broadens students' experience. This teaching format facilitates external university instructors in terms of teaching and, at the same time, relieves the university in terms of staff and financial budget., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2022 Weide et al.)

Background: Rising surgery rates have raised questions about the indications for spinal surgery. The study investigated patient-level and regional factors associated with spinal surgery for patients with spinal diseases., Methods: We undertook a cohort study based on routine healthcare data from Germany of 18.4 million patients within 60.9 million episodes of two patient-years before a possible spinal surgery in the time period 2008 to 2016. Using a Poisson model, the effects of a broad range of patient-related (sociodemographic, morbidity, social status), disease- and healthcare-related (physicians' specialty, conservative treatments) and regional variables were analyzed., Results: There was substantial regional heterogeneity in the occurrence of spinal surgery which decreased by only one quarter when controlling for the various determinants assessed. Previous musculoskeletal and mental health disorders as well as physical therapy were associated with a lower probability of surgery in the fully-adjusted model. Prescriptions for pain medication and consultations of specialists were associated with a higher probability of surgery. However, the specific severity of the vertebral diseases could not be taken into account in the analysis. Furthermore, a substantial proportion of patients with surgery did not receive a consultation with an outpatient specialist (29.5%), preoperative diagnostics (37.0%) or physical therapy (48.3%) before hospital admission., Conclusion: This large study on spinal diseases in Germany highlights important patterns in medical care of spinal diseases and their association with the probability of spinal surgery. However, only a relatively small proportion of the regional heterogeneity in spinal surgery could be explained by the extensive consideration of confounders, which suggests the relevance of other unmeasured factors like physicians' preferences., (© 2022. The Author(s).)

Introduction: The field of medicine is characterized by within-field gender segregation: Gender ratios vary systematically by subdisciplines. This segregation might be, in part, due to gender bias in the assessment of women and men medical doctors., Methods: We examined whether the assessments, i.e. overall score, department scores and skills scores, interns receive by their superiors during their internship year, vary as a function of their gender and the representation of women in the field. We analyzed an archival data set from a large hospital in Israel which included 3326 assessments that were given to all interns who completed their internship year between 2015 and 2019., Results: Women received lower department scores and skills scores in fields with a low (versus high) representation of women. Men received higher scores in fields with a high (versus low) representation of men, yet there was no difference in their skills scores., Conclusions: Women are evaluated more negatively in fields with a low representation of women doctors. Similarly, men are evaluated more negatively in fields with a low representation of men, yet this cannot be explained by their skills. This pattern of results might point to a gender bias in assessments. A better understanding of these differences is important as assessments affect interns' career choices and options.

In laboratory medicine, much effort has been put into analytical quality in the past decades, making this medical profession one of the most standardized with the lowest rates of error. However, even the best analytical quality cannot compensate for errors or low quality in the pre or postanalytical phase of the total testing process. Guidelines for data reporting focus solely on defined data elements, which have to be provided alongside the analytical test results. No guidelines on how to format laboratory reports exist. The habit of reporting as much diagnostic data as possible, including supplemental information, may lead to an information overload. Considering the multiple tasks physicians have to do simultaneously, unfiltered data presentation may contribute to patient risk, as important information may be overlooked, or juxtaposition errors may occur. As laboratories should aim to answer clinical questions, rather than providing sole analytical results, optimizing formatting options may help improve the effectiveness and efficiency of medical decision-making. In this narrative review, we focus on the underappreciated topic of laboratory result reporting. We present published literature, focusing on the impact of laboratory result report formatting on medical decisions as well as approaches, potential benefits, and limitations for alternative report formats. We discuss influencing variables such as, for example, the type of patient (e.g. acute versus chronic), the medical specialty of the recipient of the report, the display of reference intervals, the medium or platform on which the laboratory report is presented (printed paper, within electronic health record systems, on handheld devices, etc.), the context in which the report is viewed in, and difficulties in formatting single versus cumulative reports. Evidence on this topic, especially experimental studies, is scarce. When considering the medical impact, it is of utmost importance that laboratories focus not only on the analytical aspects but on the total testing process. The achievement of high analytical quality may be of minor value if essential results get lost in overload or scattering of information by using a non-formatted tabular design. More experimental studies to define guidelines and to standardize effective and efficient reporting are most definitely needed.

The Swedish medico-legal concept of "science and proven experience" is both legally important and ambiguous. The conceptual uncertainty associated with it can hamper effective assessment of medical evidence in legal proceedings and encourage medical professionals to distrust legal regulation. We examine normative criteria a functioning medico-legal notion should presumably meet, e.g. clarity, acceptability and consistency with existing laws. We also survey healthcare professionals to see how they understand science and proven experience and thus determine the extent to which their understanding meets the normative criteria. The survey suggests that medical professionals feel more certain about "science and proven experience" in the medical context than they do in a legal context. They still have substantial trust in the legal use of the notion, but they do not believe that legal professionals should be allowed to determine the meaning of "science and proven experience" in the legal context. With these results in mind, we argue that the best way to meet the normative criteria and resolve conceptual uncertainty is to specify sub-questions that clarify the notion. We recommend an analytical-deliberative approach that will close the gap between the medical and legal professions' perceptions of how law and medicine relate., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

Process mining can provide greater insight into medical treatment processes and organizational processes in healthcare. To enhance comparability between processes, the quality of the labelled-data is essential. A literature review of the clinical case studies by Rojas et al. in 2016 identified several common aspects for comparison, which include methodologies, algorithms or techniques, medical fields, and healthcare specialty. However, clinical aspects are not reported in a uniform way and do not follow a standard clinical coding scheme. Further, technical aspects such as details of the event log data are not always described. In this paper, we identified 38 clinically-relevant case studies of process mining in healthcare published from 2016 to 2018 that described the tools, algorithms and techniques utilized, and details on the event log data. We then correlated the clinical aspects of patient encounter environment, clinical specialty and medical diagnoses using the standard clinical coding schemes SNOMED CT and ICD-10. The potential outcomes of adopting a standard approach for describing event log data and classifying medical terminology using standard clinical coding schemes are further discussed. A checklist template for the reporting of case studies is provided in the Appendix A to the article.

Background and Objectives: Following the amendment of the Medical Licensure Act (ÄAppO) in 2012, pain medicine was introduced as a mandatory subject for students during undergraduate medical training. Medical schools were required to define and to implement adequate curricular and formal teaching structures based on interdisciplinary and multiprofessional requirements according to the curriculum for pain medicine of the German Pain Society. These aspects were considered in the new interdisciplinary curriculum for pain medicine, the so-called Mainz model., Study Design and Methods: A new curriculum based on the Kern cycle was developed and implemented at the Medical Center of the Johannes Gutenberg University in Mainz. Different teaching methods (lectures, interprofessional tutorials and bedside coaching in small groups) were used to impart professional expertise in pain medicine to medical students in an interdisciplinary clinical context., Results: The new curriculum was put into practice and evaluated starting from the winter semester 2014/2015. Before and after the first implementation, medical students were asked about the relevance of pain medicine and their perception of personal competence., Conclusion: The interdisciplinary course in pain medicine was successfully introduced into the degree program based on the curriculum of the German Pain Society and the Kern cycle. With educational support, interdepartmental and multiprofessional collaboration the process of implementation of new interdisciplinary courses can be facilitated. In the future, the question how to increase the amount of practical lessons without increasing the load on teaching resources has to be resolved. Blended learning modules, such as a combination of E‑learning and practical lessons are currently being studied in smaller cohorts.

The utilization of health care services in children and adolescents with chronic benign pain was studied in a Dutch population sample of 254 chronic pain sufferers aged 0-18 years. Children and adolescents who had reported chronic pain (continuous or recurrent pain >3 months) in our previous prevalence study were asked to keep a 3-week diary on their pain and to fill out questionnaires on background factors, health care use and the impact of pain. Parent ratings were used for children aged 0-11 years, self-report was used in adolescents (12-18 years). In a 3-month period, in 53.4% of the cases medication was used for pain, and general practitioners and specialists were consulted for pain in 31.1% and 13.9% of subjects, respectively. Physiotherapists, psychologists and alternative health providers were visited by 11.5, 2.8, and 4.0%, respectively. In the preceding year, 6.4% had been hospitalized due to pain. The most important factors linked to utilizing medical services were gender, various pain characteristics, school absenteeism and disability. Although consulters reported to be less physically fit and less satisfied with health, their parents were better adapted to the pain, by talking and sharing, mutual support, normalization of the child and heightened self-esteem, than non-consulters. Prospective studies are needed to test causality of coping on care-seeking behavior.

Abstract Introduction Medical education, especially in ultrasound training, is undergoing significant changes. This study examines practical issues in ultrasound medical education, emphasizing state-of-the-art teaching methods, their effectiveness, and implementation challenges. Methods The study analyzed advancements in ultrasound education, including randomized controlled trials comparing peer-to-peer teaching with traditional faculty-led instruction. It evaluated the effectiveness of collaborative small-group training and group size impact in simulation-based training. The study also assessed practical training components outlined in the WFUMB Position Paper Part II. Results Findings indicate that peer-to-peer and collaborative small-group training are effective and cost-efficient. Group size did not significantly affect training outcomes. Key practical training elements, including early hands-on sessions and exposure to various equipment, substantially improved learning outcomes. Simulation tools like virtual reality (VR), augmented reality (AR), and phantoms were crucial for teaching standardized procedures and rare pathologies. Challenges identified include developing robust image acquisition skills, scarcity of qualified student tutors, and the need for reliable ultrasound skill assessment methods. Conclusion Integrating peer-to-peer teaching and advanced simulation technologies significantly advances ultrasound medical education. These methods enhance cognitive and psychomotor skills but also present challenges such as ensuring quality education and developing effective assessment methods. Future research should compare different simulation tools and establish objective ultrasound proficiency assessment criteria. Continual method evaluation and improvement are essential for effective and standardized ultrasound training, ultimately enhancing patient care and clinical outcomes.

Abstract The uniqueness in each person’s cancer cells and variation in immune infiltrates means that each tumor represents a unique problem, but therapeutic targets can be found among their shared features. Radiation therapy alters the interaction between the cancer cells and the stroma through release of innate adjuvants. The extranuclear DNA that can result from radiation damage of cells can result in production of the second messenger cyclic guanosine monophosphate–adenosine monophosphate (cGAMP) by cyclic GMP-AMP synthase (cGAS). In turn, cGAMP can activate the innate sensor stimulator of interferon genes (STING), resulting in innate immune activation. Ectonucleotide pyrophosphatase/phosphodiesterase 1 (Enpp1) is a phosphodiesterase that can be expressed by cancer cells that can degrade cGAMP, thus can decrease or block STING activation following radiation therapy, impairing the innate immunity that is critical to support adaptive immune control of tumors. We observed that many human and murine cancer cells lack Enpp1 expression, but that Enpp1 is expressed in cells of the tumor stroma where it limits tumor control by radiation therapy. We demonstrate in preclinical models the efficacy of a novel Enpp1 inhibitor and show that this inhibitor improves tumor control by radiation even where the cancer cells lack Enpp1. This mechanism requires STING and type I interferon (IFN) receptor expression by non-cancer cells and is dependent on CD8 T cells as a final effector mechanism of tumor control. This suggests that Enpp1 inhibition may be an effective partner for radiation therapy regardless of whether cancer cells express Enpp1. This broadens the potential patient base for whom Enpp1 inhibitors can be applied to improve innate immune responses following radiation therapy.

Abstract Owing to the simultaneous increase in the risk of thrombosis and bleeding in critically ill patients, point-of-care-available diagnostic tests to guide parenteral anticoagulation are warranted. We evaluated the detection of enoxaparin and argatroban, two commonly used parenteral anticoagulants, using the novel ClotPro viscoelastic coagulometer. For this experimental in vitro study at a tertiary care academic center, blood samples were drawn from twelve (six female, six male) healthy volunteers without intake of antithrombotic medication and no history of hemostatic disorders. Blood samples were spiked with enoxaparin (IU.ml− 1) and argatroban (µg.ml− 1) at increasing concentrations ranging from 0 to 1. The ClotPro Russell’s viper venom (RVV)-test and the ClotPro ecarin (ECA)-test clotting time were performed in parallel with conventional coagulation tests (anti-Xa activity, activated partial thromboplastin time, and diluted thrombin time). We observed a strong correlation between anti-Xa activity and the RVV-test clotting time (r = 0.88 (95% confidence interval (CI) 0.8–0.92; p

Abstract Resting heart rate (RHR) has prognostic implications in heart failure with reduced ejection fraction, where ≤ 70 bpm is targeted. Whether a RHR > 70 bpm assessed within clinical practice goes along with elevated cardiovascular risk in implantable cardioverter-defibrillator (ICD) / cardiac resynchronization therapy-defibrillator (CRT-D) recipients remains incompletely understood. A total of 1589 patients (ICD n = 1172 / CRT-D n = 417, median age 65 years, 22.6% female) undergoing ICD/CRT-D implantation or revision in the prospective German DEVICE multicenter registry were analyzed. RHR was assessed via a 12-channel electrocardiogram at enrollment. 1-year outcomes (all-cause mortality, major cardio- and cerebrovascular events (MACCE), all-cause hospital admission) were compared between patients with a RHR ≤ 70 bpm and > 70 bpm. 733 patients (46.1%) showed a RHR > 70 bpm. Median RHR was 63 (interquartile range 59; 68) bpm (≤ 70 bpm group) and 80 (75; 89) bpm (> 70 bpm group). Heart failure with reduced ejection fraction was present in 76.3%, a prior myocardial infarction in 32.4% and non-ischemic heart disease in 44.9%. One-year all-cause mortality was similar between RHR groups (≤ 70 bpm 5.4% vs. > 70 bpm 5.4%, p = 0.96), and subgroup analysis regarding patient characteristics and comorbidities revealed only a significantly higher rate of patients with dual chamber ICD in the > 70 bpm group (0.8% vs. 9.2%, p = 0.003). MACCE (5.9% vs. 6.1%, p = 0.87) and defibrillator shock rates (9.9% vs. 9.8%, p = 1.0) were similar. Higher all-cause hospital admission rates were observed in patients with > 70 bpm RHR (23.1% vs. 29.0%, p = 0.027) driven by non-cardiovascular events (6.0% vs. 11.7%, p = 0.001). In conclusion, in ICD and CRT-D recipients a RHR at admission > 70 bpm may indicate patients at increased risk of all-cause hospital admission but not of other adverse cardiovascular events or death at 1-year follow-up.

Abstract Metal–organic framework nanosheets (MONs) have proved themselves to be useful additives for enhancing the performance of a variety of thin film solar cell devices. However, to date only isolated examples have been reported. In this work we take advantage of the modular structure of MONs in order to resolve the effect of their different structural and optoelectronic features on the performance of organic photovoltaic (OPV) devices. Three different MONs were synthesized using different combinations of two porphyrin-based ligands meso-tetracarboxyphenyl porphyrin (TCPP) or tetrapyridyl-porphyrin (TPyP) with either zinc and/or copper ions and the effect of their addition to polythiophene-fullerene (P3HT-PC71BM) OPV devices was investigated. The power conversion efficiency (PCE) of devices was found to approximately double with the addition of MONs of Zn2(ZnTCPP) -4.7% PCE, 10.45 mA/cm2 short-circuit current density (J SC), 0.69 open-circuit voltage (V OC), 64.20% fill-factor (FF), but was unchanged with the addition of Cu2(ZnTPyP) (2.6% PCE, 3.68 mA/cm2 J SC, 0.59 V OC, 46.27% FF) and halved upon the addition of Cu2(CuTCPP) (1.24% PCE, 6.72 mA/cm2 J SC, 0.59 V OC, 56.24% FF) compared to devices without nanosheets (2.6% PCE, 6.61 mA/cm2 J SC, 0.58 V OC, 56.64% FF). Our analysis indicates that there are three different mechanisms by which MONs can influence the photoactive layer – light absorption, energy level alignment, and morphological changes. Analysis of external quantum efficiency, UV–vis and photoelectron spectroscopy data found that MONs have similar effects on light absorption and energy level alignment. However, atomic force and Raman microscopy studies revealed that the nanosheet thickness and lateral size are crucial parameters in enabling the MONs to act as beneficial additives resulting in an improvement of the OPV device performance. We anticipate this study will aid in the design of MONs and other 2D materials for future use in other light harvesting and emitting devices.

Abstract Recent research in patients with functionally univentricular hearts (UVH) is focusing on pathologies of the lymphatic vessels. Morphology of the abdominal lymphatic vessels was analyzed by MRI in patients with UVH following total cavopulmonary connection (TCPC) and it was examined, if clinical and laboratory parameters correlate with changes after TCPC. We prospectively examined 33 patients at the age of 19.8 (14.6;30.2) years [median (Q1;Q3)] after TCPC (follow-up 14.3 years (9.7;24.9) with a heavily T2-weighted MRI sequence on a 3.0 T scanner. Examinations in coronal orientation were performed with respiratory gating, slice thickness 0.6 mm, TR 2400 ms, TE 692 ms, FoV 460 mm (covering thoracic and abdominal regions), scan time 14:41 min (13:18;16:30) after a solid meal and a cup of pineapple juice. The findings were classified according to delineation of abdominal lymphatic vessels. Type 1: 6 av and/or oedematous changes or ascites. The results were correlated with parameters obtained at the annual routine check-up. Statistical analysis was performed using U-test and Chi-square test. Fifteen patients (group 1) showed type 3 lymphatic morphologies, two of which had ascites. Eighteen patients (group 2) showed lower grade morphologies (type 1–2). Image quality was rated considering the delineation of the common hepatic duct and did not differ between groups (p = 0.134). “Lymphatic burden” was automatically examined and was indexed to the number of delineated abdominal vessels and showed quantification according to the chosen categories type 1–3. Patients in group 1 were younger at MRI examination (17.4;14.3/18.9 vs. 26.2;18.2/32.3 years, p = 0.03). Superior cavopulmonary connection (SCPC) had been performed earlier in group 1 (9.9;7.9/25.5 vs. 29.2;13.7/66.6 months, p = 0.018). Laboratory examinations in group 1 showed lower levels for Immunoglobulin G (IgG), Lipase, α-Antitrypsin, Cystatin C and TSH. There were no significant differences for total protein, NTproBNP, lymphocytes or platelets. A history of chylothorax was present in 7/15 versus 2/18 p = 0.022. Protein-losing enteropathy (PLE) occurred in 4/15 versus 1/18 (p = 0.092). T2 weighted MRI is feasible for noninvasive delineation of abdominal lymphatic vessel in patients following TCPC. In the long-term follow-up, patients with more pronounced changes of the abdominal lymphatic vessels were younger at SCPC and were more likely to show a history of chylothorax and lower IgG values.

Abstract Background As ultrasound is one of the most utilized imaging procedures in clinical practice in Germany, its integration into undergraduate medical education is imperative. Thereby, the limited availability of qualified instructors is a major challenge. Peer tutors, who are trained to instruct their peers collaboratively, could resolve staff constraints. This systematic review explores the literature on peer teaching in undergraduate ultrasound education, aiming to provide an overview of methodologies, outcomes, and peer teacher training concepts. Methods Following the PRISMA guidelines, a systematic literature review was conducted on the subject of peer teaching in undergraduate ultrasound education. Using PubMed and Google Scholar as databases, studies in English or German involving training concepts for peer teachers in undergraduate ultrasound education, published up to November 21, 2023, were included. Data extraction of original studies followed the PICOS schema with special respect to didactic concepts of peer tutor training programs and the effectiveness of peer teachers compared to faculty instructors. A modified version of the Newcastle–Ottawa Scale (NOS) was used to assess the quality of included studies. Results Finally, the search resulted in 20 relevant original studies, including 16 studies exploring peer teacher training concepts. Predominantly, peer teachers studied in their 4th year of medical school and on average one year further compared to their students. Peer teacher training was integrated into curricula by course-based concepts (93.8%) and internships (50.0%). Didactic modalities varied, encompassing laboratory rotations including the scanning of patients, the scanning of fellow students, lectures, and didactic training. The median training duration was about ten days. Of six comparative studies, five found peer-assisted learning to be comparably effective and one even better than faculty-led courses. Conclusion Despite the growing amount of literature underlining the effectiveness and wide application of peer teaching in ultrasound education, training concepts stay heterogenous without a standardized system for training and qualifying peer teachers. Developing comprehensive guidelines for peer tutor education could increase acceptance and recognition of peer-assisted learning and ensure minimum training standards.

Abstract Non-invasive brain stimulation (NIBS) techniques such as transcranial direct current stimulation (tDCS) or transcranial magnetic stimulation (TMS) have made great progress in recent years and offer boundless potential for the neuroscientific research and treatment of disorders. However, the possible use of NIBS devices for neuro-doping and neuroenhancement in healthy individuals and the military are poorly regulated. The great potentials and diverse applications can have an impact on the future development of the technology and society. This participatory study therefore aims to summarize the perspectives of different stakeholder groups with the help of qualitative workshops. Nine qualitative on-site and virtual workshops were conducted in the study with 91 individuals from seven stakeholder groups: patients, students, do-it-yourself home users of tDCS, clinical practitioners, industry representatives, philosophers, and policy experts. The co-creative and design-based workshops were tailored to each group to document the wishes, fears, and general comments of the participants. The outlooks from each group were collected in written form and summarized into different categories. The result is a comprehensive overview of the different aspects that need to be considered in the field of NIBS. For example, several groups expressed the wish for home-based tDCS under medical supervision as a potential therapeutic intervention and discussed the associated technical specifications. Other topics that were addressed were performance enhancement for certain professional groups, training requirements for practitioners, and questions of agency, among others. This qualitative participatory research highlights the potential of tDCS and repetitive TMS as alternative therapies to medication, with fewer adverse effects and home-based use for tDCS. The ethical and societal impact of the abuse of NIBS for non-clinical use must be considered for policy-making and regulation implementations. This study adds to the neuroethical debate on the responsible use and application of NIBS technologies, taking into consideration the different perspectives of important stakeholders in the field.

Abstract Choroidal nevi are common benign melanocytic lesions often incidentally found during routine ophthalmic examinations. Patients with choroidal nevi are frequently referred to ocular oncology centers to differentiate these from choroidal melanoma and to exclude a malignant transformation which rarely occurs. However, this causes a high workload for referral centers and may delay diagnosis and treatment of patients with potentially severe conditions. To overcome this, the MOLES score was previously developed which may empower non-specialists to differentiate choroidal nevi from melanoma. In this retrospective study, the performance of the MOLES score was assessed in 695 patients with choroidal nevi and 53 with choroidal melanoma. With a specificity of 96% (choroidal nevi) and a sensitivity of 100% (melanoma) the MOLES score was highly successful in differentiating choroidal nevi from melanoma and may offer great potential to optimize monitoring and referral decisions, and for teleophthalmology applications. Furthermore, the TFSOM-DIM score using risk factors for determining tumor progression was applied and showed a good correlation with MOLES. A complementary use of MOLES and TFSOM-DIM may be beneficial for clinical routine: MOLES for screening by non-experts with limited diagnostic tools and TFSOM-DIM in a referral setting to counsel also regarding potential transformation.

Abstract Background High levels of the polyunsaturated fatty acid arachidonic acid (AA) within the ovarian carcinoma (OC) microenvironment correlate with reduced relapse-free survival. Furthermore, OC progression is tied to compromised immunosurveillance, partially attributed to the impairment of natural killer (NK) cells. However, potential connections between AA and NK cell dysfunction in OC have not been studied. Methods We employed a combination of phosphoproteomics, transcriptional profiling and biological assays to investigate AA’s impact on NK cell functions. Results AA (i) disrupts interleukin-2/15-mediated expression of pro-inflammatory genes by inhibiting STAT1-dependent signaling, (ii) hampers signaling by cytotoxicity receptors through disruption of their surface expression, (iii) diminishes phosphorylation of NKG2D-induced protein kinases, including ERK1/2, LYN, MSK1/2 and STAT1, and (iv) alters reactive oxygen species production by transcriptionally upregulating detoxification. These modifications lead to a cessation of NK cell proliferation and a reduction in cytotoxicity. Conclusion Our findings highlight significant AA-induced alterations in the signaling network that regulates NK cell activity. As low expression of several NK cell receptors correlates with shorter OC patient survival, these findings suggest a functional linkage between AA, NK cell dysfunction and OC progression.

Abstract Early and accurate diagnosis is crucial to prevent disease development and define therapeutic strategies. Due to predominantly unspecific symptoms, diagnosis of autoimmune diseases (AID) is notoriously challenging. Clinical decision support systems (CDSS) are a promising method with the potential to enhance and expedite precise diagnostics by physicians. However, due to the difficulties of integrating and encoding multi-omics data with clinical values, as well as a lack of standardization, such systems are often limited to certain data types. Accordingly, even sophisticated data models fall short when making accurate disease diagnoses and presenting data analyses in a user-friendly form. Therefore, the integration of various data types is not only an opportunity but also a competitive advantage for research and industry. We have developed an integration pipeline to enable the use of machine learning for patient classification based on multi-omics data in combination with clinical values and laboratory results. The application of our framework resulted in up to 96% prediction accuracy of autoimmune diseases with machine learning models. Our results deliver insights into autoimmune disease research and have the potential to be adapted for applications across disease conditions.

Abstract Current tuberculosis (TB) treatment is typically effective against drug-susceptible Mycobacterium tuberculosis, but can fail due to acquired drug resistance or phenotypic resistance. M. tuberculosis persisters, a subpopulation of viable but non-replicating (VBNR) antibiotic-tolerant bacteria, are thought to contribute to poor TB treatment outcomes. In this exploratory study, we investigated treatment-naïve drug-susceptible clinical isolates collected from people with TB, who subsequently had unsuccessful treatment outcomes. These were compared to isolates from cured individuals in terms of their ability to form VBNR subpopulations. Clinical isolates from individuals with unfavorable treatment outcomes form larger subpopulations of VBNR M. tuberculosis (2.67−13.71%) than clinical isolates from cured cases (0− 1.63%) following infection of THP-1 macrophages. All isolates were drug susceptible based on phenotypic and genotypic analysis. Whole genome sequencing identified 23 non-synonymous genomic variants shared by treatment failure clinical isolates, that were not present in isolates from cured cases. This exploratory study highlights the ability of treatment-naïve clinical isolates to form heterogeneous populations containing VBNR M. tuberculosis. We also demonstrate that clinical isolates from individuals with unsuccessful treatment outcomes form higher percentages of VBNR M. tuberculosis. The findings of this exploratory study suggest that an increased propensity to form VBNR subpopulations may impact TB treatment outcome.

Abstract This article investigates the short- and long-term impacts of retirement on loneliness using panel data from the Survey of Health, Aging, and Retirement in Europe. To identify causal effects, we exploit differences in retirement rules across and within countries and use retirement thresholds in an instrumental variable setting. On average, we find that entering retirement leads to a reduction in loneliness in the long run and no clear effect in the short run. The reduction is driven by individuals being less likely to feel socially isolated and lacking companionship. Our results suggest that individuals adapt to retirement by increasing their activity levels and reap the benefits in terms of reduced loneliness and social isolation. The heterogeneity analysis shows that this is particularly true among the higher educated. The heterogeneity analysis also reveals that retirement increases feelings of loneliness for women in the short term and that the effect seems to be driven by women lacking companionship when their partner is not yet retired.

Abstract The storage of rAAV vectors for gene therapy applications is critical for ensuring a constant product quality and defined amount of medication at the time of administration. Therefore, we determined the influence of different storage conditions on the physicochemical and biological properties of rAAV8 and rAAV9 preparations. Particular attention was paid to short-term storage, which plays a crucial role in both the manufacturing process and in clinical applications. Additionally, we addressed the question, of viability of rAAV8 and rAAV9 when subjected to very low-temperature storage conditions (below −65 °C) or lyophilization. To determine the impact on rAAV vectors, various analyses were used, including the quantification of capsid and genome titers, as well as biopotency assessments, which are pivotal determinants in characterizing vector behavior and efficacy. Our data showed that freeze/thaw cycles hardly affected the functionality of rAAV9-aGAL vectors. In contrast, prolonged storage at room temperature for several days, resulted in a discernible decrease in biopotency despite consistent capsid and genome titers. When the storage temperature was further increased, the rAAV8-aGAL decay accelerated. For example, a short-term exposure of + 40 °C and more, led to a reduction in the physical viral titer and to an even faster decline in efficacy determined by biopotency. However, the addition of sucrose and sorbitol to the rAAV9-aGAL and rAAV9-GAA preparations reduced the temperature sensitivity of rAAV and improved its stability. Furthermore, exposure of rAAV9-aGAL to highly acidic conditions (pH 2.5) dramatically reduced its biopotency by 70% or more. Most interestingly, a long-term storage of rAAV9-aGAL and rAAV8-FVIII vectors over 12 and 36 months, respectively, demonstrated exceptional stability at storage temperatures below −65 °C. Also, lyophilization conserved functionality for at least 10 months. Our data showed how to maintain rAAV biopotency levels over the time without substantial loss. Storage at very low temperatures (below −65 °C) preserved its effectiveness over years. Overall, pH and temperature conditions during the manufacturing process, storage and clinical application are worth considering. Consistency in the rAAV capsid titer determination did not necessarily indicate the preservation of biopotency. In conclusion, our approach determined several options for maximizing rAAV stability.

Abstract Juvenile crossbred pigs are widely used for acute and chronic animal testing due to their anatomical and physiological resemblance to humans. They are particularly prevalent in preclinical cardiovascular research, including studies investigating extracorporeal resuscitation and mechanical circulatory support devices. However, the availability of comprehensive laboratory reference values is limited. In a single-center study at the University Medical Center Freiburg, Germany, the hematologic and biochemical laboratory values of anesthetized healthy juvenile German crossbred farm pigs were determined. Blood samples were collected at the beginning of surgical procedures, either arterially or venously. Females and males were compared, and correlation with body weight was assessed. In total, 268 animals (weight 57.8 ± 12.4 kg) were included, thereof 180 castrated males (55.2 ± 7.7 kg) and 79 females (63.6 ± 18.3 kg). There were significant differences between males and females in 11 of 45 parameters and a moderate correlation between body weight and creatinine (R = 0.41, p

Abstract The actin-binding protein filamin c (FLNc) is a key mediator in the response of skeletal muscle cells to mechanical stress. In addition to its function as a structural scaffold, FLNc acts as a signaling adaptor which is phosphorylated at S2234 in its mechanosensitive domain 20 (d20) through AKT. Here, we discovered a strong dephosphorylation of FLNc-pS2234 in cultured skeletal myotubes under acute mechanical stress, despite high AKT activity. We found that all three protein phosphatase 1 (PP1) isoforms are part of the FLNc d18-21 interactome. Enzymatic assays demonstrate that PP1 efficiently dephosphorylates FLNc-pS2234 and in vitro and in cells upon PP1 activation using specific modulators. FLNc-pS2234 dephosphorylation promotes the interaction with FILIP1, a mediator for filamin degradation. Altogether, we present a model in which dephosphorylation of FLNc d20 by the dominant action of PP1c prevails over AKT activity to promote the binding of the filamin degradation-inducing factor FILIP1 during acute mechanical stress.

Abstract Identifying biomarkers able to discriminate individuals on different health trajectories is crucial to understand the molecular basis of age-related morbidity. We investigated multi-omics signatures of general health and organ-specific morbidity, as well as their interconnectivity. We examined cross-sectional metabolome and proteome data from 3,142 adults of the Cooperative Health Research in South Tyrol (CHRIS) study, an Alpine population study designed to investigate how human biology, environment, and lifestyle factors contribute to people’s health over time. We had 174 metabolites and 148 proteins quantified from fasting serum and plasma samples. We used the Cumulative Illness Rating Scale (CIRS) Comorbidity Index (CMI), which considers morbidity in 14 organ systems, to assess health status (any morbidity vs. healthy). Omics-signatures for health status were identified using random forest (RF) classifiers. Linear regression models were fitted to assess directionality of omics markers and health status associations, as well as to identify omics markers related to organ-specific morbidity. Next to age, we identified 21 metabolites and 10 proteins as relevant predictors of health status and results confirmed associations for serotonin and glutamate to be age-independent. Considering organ-specific morbidity, several metabolites and proteins were jointly related to endocrine, cardiovascular, and renal morbidity. To conclude, circulating serotonin was identified as a potential novel predictor for overall morbidity.

Abstract Aim was to compare image-guided navigation with a robot-assisted solution for performing MISS regarding precision, required time and subjective aspects. 90 pedicles were instrumented on two torsos, half with navigation, half robot-assisted. Precision analysis between both solutions didn’t show a significant difference. Time measurement showed a significantly longer duration per wire for the robot-arm on the first torso and a not significant longer duration on the second torso, where a significant reduction in the mean duration was shown. There was no significant difference in the subjective impressions comparing navigation and robot except the possibility to change the procedure. Precision of both methods is suitable for clinical use. A time advantage using the robot-arm couldn’t be demonstrated in the present study. A significant learning curve was shown, so a reduction in the longer duration on the robot can be expected. Further studies in clinical use are necessary.