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Background: Infection with the Epstein-Barr virus (EBV) elicits a complex T-cell response against a broad range of viral proteins. Hence, identifying potential differences in the cellular immune response of patients with different EBV-associated diseases or different courses of the same disorder requires interrogation of a maximum number of EBV antigens. Here, we tested three novel EBV-derived antigen formulations for their ability to reactivate virus-specific T cells ex vivo in patients with EBV-associated infectious mononucleosis (IM)., Methods: We comparatively analyzed EBV-specific CD4+ and CD8+ T-cell responses to three EBV-derived antigen formulations in 20 pediatric patients during the early phase of IM: T-activated EBV proteins (BZLF1, EBNA3A) and EBV-like particles (EB-VLP), both able to induce CD4+ and CD8+ T-cell responses ex vivo, as well as an EBV-derived peptide pool (PP) covering 94 well-characterized CD8+ T-cell epitopes. We assessed the specificity, magnitude, kinetics, and functional characteristics of EBV-specific immune responses at two sequential time points (v1 and v2) within the first six weeks after IM symptom onset (T onset )., Results: All three tested EBV-derived antigen formulations enabled the detection of EBV-reactive T cells during the early phase of IM without prior T-cell expansion in vitro. EBV-reactive CD4+ and CD8+ T cells were mainly mono-functional (CD4+: mean 64.92%, range 56.15-71.71%; CD8+: mean 58.55%, range 11.79-85.22%) within the first two weeks after symptom onset (v1) with IFN-γ and TNF-secreting cells representing the majority of mono-functional EBV-reactive T cells. By contrast, PP-reactive CD8+ T cells were primarily bi-functional (>60% at v1 and v2), produced IFN-γ and TNF and had more tri-functional than mono-functional components. We observed a moderate correlation between viral load and EBNA3A, EB-VLP, and PP-reactive CD8+ T cells (r s = 0.345, 0.418, and 0.356, respectively) within the first two weeks after T onset , but no correlation with the number of detectable EBV-reactive CD4+ T cells., Conclusions: All three EBV-derived antigen formulations represent innovative and generic recall antigens suitable for monitoring EBV-specific T-cell responses ex vivo. Their combined use facilitates a thorough analysis of EBV-specific T-cell immunity and allows the identification of functional T-cell signatures linked to disease development and severity., (© 2024. The Author(s).)

Background: Multimodal pain therapy usually take place in the context of group therapy lasting several weeks and is based on a generally activating approach. Due to the specificity of stress intolerance with postexertional malaise (PEM) in patients with postviral syndromes, physical as well as psychological overload must be urgently avoided in these cases; however, these aspects can only be insufficiently considered in current medical pain therapy concepts., Methods: Summary of the current literature and presentation of clinical characteristics as well as presentation of a model project for a multimodal pain therapy in postviral syndromes with PEM., Model Concept: The presented model project describes a day clinic treatment setting for interdisciplinary multimodal pain therapy adapted to the individual resilience with minimization of the risk of strain-induced deterioration of the condition., (© 2023. The Author(s).)

Background: Infectious mononucleosis after primary infection with Epstein-Barr virus (EBV-IM) has been linked to the development of myalgic encephalomyelitis/chronic fatigue-syndrome (ME/CFS) in children, adolescents, and young adults. Here, we present clinical phenotypes and follow-up data from a first German cohort of young people with ME/CFS following EBV-IM., Methods: 12 adolescents and 13 young adults were diagnosed with IM-triggered ME/CFS at our specialized tertiary outpatient service by clinical criteria requiring post-exertional malaise (PEM) and a history of confirmed EBV primary infection as triggering event. Demographic information, laboratory findings, frequency and severity of symptoms, physical functioning, and health-related quality of life (HRQoL) were assessed and re-evaluated 6 and 12 months later., Results: Young adults displayed more severe symptoms as well as worsening of fatigue, physical and mental functioning, and HRQoL throughout the study, compared to adolescents. After one year, 6/12 (54%) adolescents no longer met the diagnostic criteria for ME/CFS while all young adults continued to fulfill the Canadian consensus criteria. Improvement in adolescents was evident in physical functioning, symptom frequency and severity, and HRQoL, while young adults showed little improvement. EBV serology and EBV DNA load did not correlate with distinct clinical features of ME/CFS, and clinical chemistry showed no evidence of inflammation. Remarkably, the median time from symptom onset to ME/CFS diagnosis was 13.8 (IQR: 9.1-34.9) months., Conclusions: ME/CFS following EBV-IM is a severely debilitating disease often diagnosed late and with limited responses to conventional medical care, especially in adults. Although adolescents may have a better prognosis, their condition can fluctuate and significantly impact their HRQoL. Our data emphasize that biomarkers and effective therapeutic options are also urgently needed to improve medical care and pave the way to recovery., Competing Interests: UB received research grants from Federal Ministry of Education and Research (BMBF), the Federal Ministry of Health (BMG), the Bavarian Ministry of Health and Care (StMGP), the Bavarian Ministry of Science and Arts (StMWK), the German Center for Infection Research (DZIF), the People for Children (Menschen für Kinder) Foundation, the Weidenhammer-Zöbele Foundation, the Lost-Voices Foundation, and the ME/CFS Research Foundation. CS was consulting Roche, Celltrend, and Bayer; she received support for clinical trials by Bayer, Fresenius, and Miltenyi, honoraria for lectures by Fresenius, AstraZeneca, BMS, Roche, Bayer, and Novartis, and research grants from the German Research Association (DFG), the BMBF, the BMG, the Weidenhammer-Zoebele Foundation, the Lost-Voices Foundation, and the ME/CFS Research Foundation. 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., (© 2024 Pricoco, Meidel, Hofberger, Zietemann, Mueller, Wiehler, Michel, Paulick, Leone, Haegele, Mayer-Huber, Gerrer, Mittelstrass, Scheibenbogen, Renz-Polster, Mihtasch and Behrends.)

Objectives: Interdisciplinary treatment programmes are the gold standard for patients suffering from chronic pain. However, several patient-related factors seem to influence the patients' outcome. The aim of our study was to inquire whether patients with personality disorders (PD) might benefit less from an interdisciplinary treatment programme compared to patients without PD., Methods: A prospective, observational study with chronic pain patients attending a 5-week interdisciplinary treatment programme was performed. Main outcome parameters were psychological stabilization and pain intensity before and after the programme., Results: Out of the 104 included patients, 71 (68.3%) showed personality accentuations and 16 (15.4%) were diagnosed with PDs. PDs were mostly classified as histrionic, followed by borderline and narcistic personality. Patients diagnosed with histrionic accentuation showed a significantly better treatment response in terms of pain. Reduction in ADS (Allgemeine Depressionsskala - depression scale) was 3.4 in patients with PD and 11.1 in those without PD. Borderline patients showed a significant increase of ADS (by 2.0; p  < 0.05) after programme completion., Discussion: Patients with chronic pain and personality accentuations or disorder only showed a slightly different outcome after interdisciplinary treatment programme and should therefore not be excluded from these programmes. Registered at German Clinical Trials Register (DRKS-ID: DRKS00015141).

Introduction: This study compares five augmented reality (AR) vasculature visualization techniques in a mixed-reality laparoscopy simulator with 50 medical professionals and analyzes their impact on the surgeon. Material and methods : ​​The different visualization techniques' abilities to convey depth were measured using the participant's accuracy in an objective depth sorting task. Demographic data and subjective measures, such as the preference of each AR visualization technique and potential application areas, were collected with questionnaires. Results : Despite measuring differences in objective measurements across the visualization techniques, they were not statistically significant. In the subjective measures, however, 55% of the participants rated visualization technique II, 'Opaque with single-color Fresnel highlights', as their favorite. Participants felt that AR could be useful for various surgeries, especially complex surgeries (100%). Almost all participants agreed that AR could potentially improve surgical parameters, such as patient safety (88%), complication rate (84%), and identifying risk structures (96%). Conclusions : More studies are needed on the effect of different visualizations on task performance, as well as more sophisticated and effective visualization techniques for the operating room. With the findings of this study, we encourage the development of new study setups to advance surgical AR.

Purpose: Only a few studies have evaluated Augmented Reality (AR) in in vivo simulations compared to traditional laparoscopy; further research is especially needed regarding the most effective AR visualization technique. This pilot study aims to determine, under controlled conditions on a 3D-printed phantom, whether an AR laparoscope improves surgical outcomes over conventional laparoscopy without augmentation., Methods: We selected six surgical residents at a similar level of training and had them perform a laparoscopic task. The participants repeated the experiment three times, using different 3D phantoms and visualizations: Floating AR, Occlusion AR, and without any AR visualization (Control). Surgical performance was determined using objective measurements. Subjective measures, such as task load and potential application areas, were collected with questionnaires., Results: Differences in operative time, total touching time, and SurgTLX scores showed no statistical significance ([Formula: see text]). However, when assessing the invasiveness of the simulated intervention, the comparison revealed a statistically significant difference ([Formula: see text]). Participants felt AR could be useful for various surgeries, especially for liver, sigmoid, and pancreatic resections (100%). Almost all participants agreed that AR could potentially lead to improved surgical parameters, such as operative time (83%), complication rate (83%), and identifying risk structures (83%)., Conclusion: According to our results, AR may have great potential in visceral surgery and based on the objective measures of the study, may improve surgeons' performance in terms of an atraumatic approach. In this pilot study, participants consistently took more time to complete the task, had more contact with the vascular tree, were significantly more invasive, and scored higher on the SurgTLX survey than with AR., (© 2022. The Author(s).)

Multidisciplinary pain treatment programs (MPTP) have been considered to be the most effective treatment of chronic pain. In this study, we analyzed the influence of seasons on the outcome of chronic pain patients undergoing MPTP. Therefore, a prospective, observational trial was conducted in patients with chronic pain undergoing a 5-week interdisciplinary treatment program. Psychological stabilization (measured by ADS - Allgemeine Depressionsskala) and pain levels (measured by NRS - numeric rating scale) were considered as primary endpoints. As a result of this study, we could show that chronic pain patients (exempt patients with chronic headache) showed a highly significant better improvement in terms of ADS after MPTP when participating in autumn (coefficient: -11.67, p = .004). Patients treated during winter showed a tendency towards a better improvement in ADS scores (coefficient: -6.89, p = .051). These effects were not found in patients suffering from chronic headache. Finally, patients participating in MPTPs during summer, autumn, and winter presented a tendency of higher reduction in pain scores when compared to patients participating in spring. In conclusion, the effect of MPTPs in terms of psychological stabilization is considered to be best during autumn. This should be therefore considered in planning an MPTP in all patients who do not need immediate psychological stabilization. The treatment effect of MPTP on pain seems not being dependent on a specific season.

Objective: The contribution of physician assistants (PAs) to the German healthcare workforce has increased significantly since their introduction in 2005. From five training programs, the number has increased to the current 18, with 560 PAs awarded the PA bachelor of science degree as of 2020. Despite the growth, researchers lack systemic and reliable empirical data that provide insight into the German PA educational and professional profile. The German University Association Physician Assistant (DHPA) undertook the first nationwide cross-sectional survey on PAs in Germany to understand the German PA movement. This survey aimed to describe German PAs' entry into the profession and PA educational and job satisfaction., Methods: PA alumni of all universities affiliated with the DHPA and all subscribers of the Facebook online social media platform PA Blog were invited to complete an online questionnaire., Results: Of the 282 PAs who completed the survey, 77% were female and under age 25 years. Almost all (94%) were employed, predominantly as PAs (91%, 241 of 265), although some held other positions. Most worked full time (87%), with some citing child-care needs as reasons for part-time employment (n = 21). Few reported unemployment (1.4%, 4 of 282). Eighty-two percent said they would probably or very likely choose the same course of study again. Most employed participants found the inclusion of frequent rotations between didactic and clinical training in PA programs beneficial. However, a small number of participants (26.8%) agreed that German PA programs' didactic and clinical teaching objectives were well aligned., Conclusions: German PAs have a high level of satisfaction with their profession and report low unemployment. Improvement in the alignment of didactic and clinical educational objectives to improve academic qualifications and satisfaction emerged as an area of research., (Copyright © 2022 American Academy of Physician Associates.)

Due to the spread of COVID-19, a key challenge was to reduce potential staff shortages in the healthcare sector. Besides recruiting retired healthcare workers, medical students were considered to support this task. Commitment of medical students in Germany during the COVID-19 pandemic was evaluated using an online survey, with particular focus on their burdens and anxieties. This survey was distributed to students within a 2-week period in April and May 2020. Ultimately, 1241 participants were included in the analysis. During the pandemic, 67.9% (65.3% to 70.5%) of the participants reported that they had volunteered. Furthermore, 88.9% (86.9% to 90.5%) stated that they were against compulsory recruitment in this context. Students who volunteered (committed students) had a significantly lower anxiety index than non-committed students. Additionally, students were more concerned about infecting other patients and relatives than themselves. Higher levels of anxiety were related to lower levels of commitment. A mandatory assignment during the pandemic was rejected by the students and does not seem to be necessary due to the large number of volunteers., Competing Interests: Competing interests: JH is employee of Sandoz/Hexal. His occupation neither affected on the planning and execution of the study nor on the manuscript. All other authors declare no conflict of interest., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Cardiopulmonary bypass during cardiac surgery is associated with metabolic changes after operation and results inter alia in increased levels of lactate and bilirubin. Since prediction of the course after operation has become very important for the management of an ICU and the patients themselves, we evaluated easily assessable markers (lactate and bilirubin), regarding their potential to predict mortality 90 days after surgery and the length of stay in ICU., Methods: All patients within a period of five years undergoing cardiac surgery were enrolled in the study. Among others peak levels of lactate and bilirubin within 48 hours after operation were recorded. A Cox proportional hazard model as well as a logistic regression model were used to predict mortality or rather length of stay in ICU., Results: Increased levels of bilirubin and lactate were associated with a significantly increase in mortality and length of stay in ICU (in a concentration-related manner). Interestingly, creatinine serum levels before operation showed a similar performance., Conclusions: Three easily assessable and cheap laboratory parameters (bilirubin, lactate, and creatinine) are useful to predict 90-day mortality and length of stay in ICU. These findings might be helpful to give patients a reliable prediction about short and mid-term-survival and to improve the management of an ICU.

Studies reported a strong impact on mental health during the first wave of the COVID-19 pandemic in March-June, 2020. In this study, we assessed the impact of the pandemic on mental health in general and on schizotypal traits in two independent general population samples of the United Kingdom (May sample N: 239, October sample N: 126; participation at both timepoints: 21) and in two independent general population samples of Germany (May sample N: 543, October sample N: 401; participation at both timepoints: 100) using online surveys. Whereas general psychological symptoms (global symptom index, GSI) and percentage of responders above clinical cut-off for further psychological investigation were higher in the May sample compared to the October sample, schizotypy scores (Schizotypal Personality Questionnaire) were higher in the October sample. We investigated potential associations, using general linear regression models (GLM). For schizotypy scores, we found that loneliness, use of drugs, and financial burden were more strongly corrected with schizotypy in the October compared to the May sample. We identified similar associations for GSI, as for schizotypy scores, in the May and October samples. We furthermore found that living in the United Kingdom was related to higher schizotypal scores or GSI. However, individual estimates of the GLM are highly comparable between the two countries. In conclusion, this study shows that while the general psychological impact is lower in the October than the May sample, potentially showing a normative response to an exceptional situation; schizotypy scores are higher at the second timepoint, which may be due to a stronger impact of estimates of loneliness, drug use, and financial burden. The ongoing, exceptional circumstances within this pandemic might increase the risk for developing psychosis in some individuals. The development of general psychological symptoms and schizotypy scores over time requires further attention and investigation., 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 © 2021 Daimer, Mihatsch, Ronan, Murray and Knolle.)

Chronic cytomegalovirus (CMV) infection leads to long-term maintenance of extraordinarily large CMV-specific T cell populations. The magnitude of this so-called 'memory inflation' is thought to mainly depend on antigenic stimulation during the chronic phase of infection. However, by mapping the long-term development of CD8 + T cell families derived from single naive precursors, we find that fate decisions made during the acute phase of murine CMV infection can alter the level of memory inflation by more than 1,000-fold. Counterintuitively, a T cell family's capacity for memory inflation is not determined by its initial expansion. Instead, those rare T cell families that dominate the chronic phase of infection show an early transcriptomic signature akin to that of established T central memory cells. Accordingly, a T cell family's long-term dominance is best predicted by its early content of T central memory precursors, which later serve as a stem-cell-like source for memory inflation.

Adaptive evolution is a key feature of T cell immunity. During acute immune responses, T cells harboring high-affinity T cell antigen receptors (TCRs) are preferentially expanded, but whether affinity maturation by clonal selection continues through the course of chronic infections remains unresolved. Here we investigated the evolution of the TCR repertoire and its affinity during the course of infection with cytomegalovirus, which elicits large T cell populations in humans and mice. Using single-cell and bulk TCR sequencing and structural affinity analyses of cytomegalovirus-specific T cells, and through the generation and in vivo monitoring of defined TCR repertoires, we found that the immunodominance of high-affinity T cell clones declined during the chronic infection phase, likely due to cellular senescence. These data showed that under conditions of chronic antigen exposure, low-affinity TCRs preferentially expanded within the TCR repertoire, with implications for immunotherapeutic strategies.

Natural killer (NK) cells show some features of adaptive immunity but have not been studied at the clonal level. Here, we used retrogenic color-barcoding and single-cell adoptive transfers to track clonal immune responses to murine cytomegalovirus (MCMV) infection, derived from individual NK cells expressing activating receptor Ly49H. Clonal expansion of single NK cells varied substantially, and this variation could not be attributed to the additional presence or absence of inhibitory Ly49 receptors. Instead, single-cell-derived variability correlated with distinct surface expression levels of Ly49H itself. Ly49H hi NK cell clones maintained higher Ly49H expression and expanded more than their Ly49H lo counterparts in response to MCMV. Thus, akin to adaptive processes shaping an antigen-specific T cell receptor (TCR) repertoire, the Ly49H + NK cell population adapts to MCMV infection. This process relies on the clonal maintenance of distinct Ly49H expression levels, generating a repertoire of individual NK cells outfitted with distinct reactivity to MCMV., (Copyright © 2019 Elsevier Inc. All rights reserved.)