Regional neural activation defines a gateway for autoreactive T cells to cross the blood-brain barrier.

Although it is believed that neural activation can affect immune responses, very little is known about the neuroimmune interactions involved, especially the regulators of immune traffic across the blood-brain barrier which occurs in neuroimmune diseases such as multiple sclerosis (MS). Using a mouse model of MS, experimental autoimmune encephalomyelitis, we show that autoreactive T cells access the central nervous system via the fifth lumbar spinal cord. This location is defined by IL-6 amplifier-dependent upregulation of the chemokine CCL20 in associated dorsal blood vessels, which in turn depends on gravity-induced activation of sensory neurons by the soleus muscle in the leg. Impairing soleus muscle contraction by tail suspension is sufficient to reduce localized chemokine expression and block entry of pathogenic T cells at the fifth lumbar cord, suggesting that regional neuroimmune interactions may offer therapeutic targets for a variety of neurological diseases.

Innovation and Team Spirit: The Magic of Science Competitions Seen through the Lens of the Compound Challenge.

For five years now, Merck KGaA, Darmstadt, Germany has hosted The Compound Challenge-a global retrosynthesis competition. When the event kicked off in 2018 on the occasion of the 350th anniversary of the company, no one could have predicted the path it would take-from a novel competition to a pivotal event within the synthetic chemistry community. But what makes the Compound Challenge tick and what drives its popularity? And, more importantly, what lessons can be taken from the Compound Challenge and applied to other challenges in scientific education and outreach? In this Viewpoint Article we will tell the story of the Compound Challenge, from its inception to its current status. Through examining feedback following each of its iterations, we begin to define what makes an open innovation challenge so compelling. It is our hope that educators, leaders, and innovators will be able to learn from our successes as well as our mistakes and apply these lessons to their future outreach activities.

The INDICATE Knee expectations survey detects general patient treatment goals for total knee arthroplasty and the influence of demographic factors on patients expectations.

PURPOSE: Post-operative outcome after total knee arthroplasty (TKA) in the treatment of end-stage osteoarthritis correlates strongly with pre-operative impairment-driven patient treatment goals. However, a clinical tool for measuring patient treatment goals in correlation to impairments is still missing, which impedes patient-oriented indication in TKA. METHODS: Patients scheduled for TKA were recruited in four German hospitals. All patients were handed the INDICATE Knee Score pre-operatively. The score contains 31 treatment goals with respective impairments, subdivided into seven categories. They were asked to rank all treatment goals and impairments on a 3-point scale. Treatment goals and impairments were then checked for frequency of occurrence. Correlation of goal and impairment was tested. Analysis for associations of treatment goals and different cohort characteristics (age, sex, BMI) was conducted. RESULTS: 1.298 patients were included in the study. Seven treatment goals were categorised as "main goal" from more than 90% of all patients ("knee pain", "range of motion", "walking distance", "overall physical function", "climbing stairs", "quality of life", "implant survival"). Comparing age groups, there were significant associations towards higher expectations regarding working, physical and sports related treatment goals in younger patients (< 65y) ("ability to work" (P ≤ .001), "sports activities" (P ≤ .001), "sex life" (P ≤ .001), "dependence on help of others" (P = .015), "preventing secondary impairment" (P = .03), "dependence on walking aids" (P = .005)). Higher BMI resulted in increasing relevance of "weight reduction" (P ≤ .001), "climbing stairs" (P = .039) "global health status" (P = .015) and "long standing" (P = .007) as a "main goal". Analysis for differences in treatment goals regarding sex showed women choosing more treatment goals as "main goals" than men. CONCLUSION: Seven treatment goals which were expected by > 90% in our collective can be classified as general treatment goals for TKA. Demographic factors (age, sex, BMI) were significantly associated with patients' expectations for TKA. We conclude physicians should clearly assess their patients' demands prior to TKA to maximise post-operative outcome. LEVEL OF EVIDENCE: Prognostic Level III.

Simultaneous bilateral TKA in the context of fast track surgery - Do patients meet discharge criteria as anticipated?

BACKGROUND: The efficacy and safety of enhanced recovery after surgery (ERAS) protocols for patients undergoing total knee arthroplasty (TKA) have been generally proven. Previous studies investigating patients undergoing simultaneous bilateral TKA (SBTKA) focused on complications, mortality, and pain and did not examine patients' functional limitations. Therefore, the aim of this study was to investigate to what extent patients undergoing SBTKA are able to meet functional discharge criteria originally designed for their counterparts undergoing unilateral TKA (UTKA) in an ERAS setting. MATERIALS AND METHODS: All patients who received primary SBTKA between June 2015 and December 2018 were included in this retrospective analysis. For comparison, UTKA patients were matched 1:1 to SBTKA patients using Propensity Score Matching based on age, gender, and BMI. The times to achieving the rehabilitation checkpoints of walking 150 m, walking a flight of stairs, and 90° knee flexion were evaluated. RESULTS: 63 (SBTKA group) and 64 (UTKA group) patients were included. Due to the Propensity-Score-Matching there were no differences regarding age, gender, and BMI. The mean length of stay (LOS) was 9.1 days in the SBTKA and 7.6 days in the UTKA group (p = 0.003). On average, it took SBTKA patients 5.4 days to achieve an uninterrupted walking distance of at least 150 m, while it took UTKA patients 4.1 days (p < 0.001). Mean time to walking a flight of stairs was 6.3 days for SBTKA patients and 4.7 days for UTKA patients (p < 0.001). 90° flexion was achieved after 4.1 days by SBTKA patients and 3.5 days by UTKA patients (p = 0.241). CONCLUSION: The vast majority of SBTKA patients were able to achieve functional discharge criteria within their inpatient stay when allowed about 30% extra time. Therefore, functional discharge criteria in ERAS protocols designed for UTKA can be considered appropriate for SBTKA patients. LEVEL OF EVIDENCE: Therapeutic Level III.

AI-Based Detection of Aspiration for Video-Endoscopy with Visual Aids in Meaningful Frames to Interpret the Model Outcome.

Disorders of swallowing often lead to pneumonia when material enters the airways (aspiration). Flexible Endoscopic Evaluation of Swallowing (FEES) plays a key role in the diagnostics of aspiration but is prone to human errors. An AI-based tool could facilitate this process. Recent non-endoscopic/non-radiologic attempts to detect aspiration using machine-learning approaches have led to unsatisfying accuracy and show black-box characteristics. Hence, for clinical users it is difficult to trust in these model decisions. Our aim is to introduce an explainable artificial intelligence (XAI) approach to detect aspiration in FEES. Our approach is to teach the AI about the relevant anatomical structures, such as the vocal cords and the glottis, based on 92 annotated FEES videos. Simultaneously, it is trained to detect boluses that pass the glottis and become aspirated. During testing, the AI successfully recognized the glottis and the vocal cords but could not yet achieve satisfying aspiration detection quality. While detection performance must be optimized, our architecture results in a final model that explains its assessment by locating meaningful frames with relevant aspiration events and by highlighting suspected boluses. In contrast to comparable AI tools, our framework is verifiable and interpretable and, therefore, accountable for clinical users.

[Discharge readiness versus discharge-Results of the PROMISE study]. / Entlassbarkeit versus Entlassung ­ Ergebnisse der PROMISE-Studie.

BACKGROUND: In the context of optimized treatment processes for knee and hip replacements, lengths of stay are given for Germany that clearly exceed the internationally published ones. In this context, the present analysis of data from the PROMISE study deals with the relationship between discharge readiness and discharge. METHODS: In the PROMISE study, a jointly developed, optimized standard of care was established in three hospitals of different levels of care and realized for a typical, largely unselected cohort of patients. Among others, data were collected on achievement of discharge criteria (DC) and actual discharge. Univariate comparisons were performed by chi-square tests or the Mann-Whitney­U tests. RESULTS: A total of 1782 patients were included, of whom a mean of 85.3% achieved all previously defined DCs at a mean of 2.4 (median 2) days postoperatively. Discharge for this group occurred after a mean of 5.4 (median 5) days. 14.7% of the participants did not achieve at least one DC. This group was discharged after a mean of 6.5 (median 6) days. Significant differences in outcomes were observed for different subgroups. CONCLUSION: The so-called DCs are used as relative criteria. Achievement generally does not result in timely discharge. If this were to happen, internationally established lengths of stay would also be a reality in Germany. What actually determines discharge from inpatient treatment remains open. A variety of medical, organizational, structural and financial factors could be of importance.

Classification and Automated Interpretation of Spinal Posture Data Using a Pathology-Independent Classifier and Explainable Artificial Intelligence (XAI).

Clinical classification models are mostly pathology-dependent and, thus, are only able to detect pathologies they have been trained for. Research is needed regarding pathology-independent classifiers and their interpretation. Hence, our aim is to develop a pathology-independent classifier that provides prediction probabilities and explanations of the classification decisions. Spinal posture data of healthy subjects and various pathologies (back pain, spinal fusion, osteoarthritis), as well as synthetic data, were used for modeling. A one-class support vector machine was used as a pathology-independent classifier. The outputs were transformed into a probability distribution according to Platt's method. Interpretation was performed using the explainable artificial intelligence tool Local Interpretable Model-Agnostic Explanations. The results were compared with those obtained by commonly used binary classification approaches. The best classification results were obtained for subjects with a spinal fusion. Subjects with back pain were especially challenging to distinguish from the healthy reference group. The proposed method proved useful for the interpretation of the predictions. No clear inferiority of the proposed approach compared to commonly used binary classifiers was demonstrated. The application of dynamic spinal data seems important for future works. The proposed approach could be useful to provide an objective orientation and to individually adapt and monitor therapy measures pre- and post-operatively.

The PROMISE study protocol: a multicenter prospective study of process optimization with interdisciplinary and cross-sectoral care for German patients receiving hip and knee endoprostheses.

Background and purpose - Knee and hip replacement are common and increasing procedures, and an optimized care process that could be implemented in different settings would be useful. The PROMISE trial investigates whether a new care process works equally in different German settings and how the results compare with current non-standardized care.Patients and methods - This multi-center prospective mixed-method study includes 2,000 German patients receiving arthritis-related hip or knee endoprostheses. An interdisciplinary and cross-sectoral care process was developed and implemented in 3 German hospitals with different levels of care, and corresponding rehabilitation centers were included to bridge the gap after acute care.Duration and outcome - The PROMISE trial recruited patients between May 2018 and March 2020. Follow-up will end in February 2021. Assessments are performed at: examination on clinical indication, 1 week before surgery, on the day of surgery, at the end of hospitalization, end of the rehabilitation program, and 3 months, 6 months, and 12 months after surgery. Outcomes include patient-reported outcomes, medical examination findings, and routinely collected data regarding the surgery and complications. Guideline-based interviews are conducted with selected patients and care partners. The primary endpoint is the presence of chronic pain at 12 months after surgery. Secondary endpoints are the number of recognized pre-existing conditions, physical activity at 12 months after surgery, use of medical services, quality of life, and interactions between care partners.Trial registration - The trial is registered with the German Clinical Trials Register (https://www.drks.de; DRKS00013972; March 23, 2018).

Site-Specific Conjugation of Native Antibodies Using Engineered Microbial Transglutaminases.

Site-specific bioconjugation technologies are frequently employed to generate homogeneous antibody-drug conjugates (ADCs) and are generally considered superior to stochastic approaches like lysine coupling. However, most of the technologies developed so far require undesired manipulation of the antibody sequence or its glycan structures. Herein, we report the successful engineering of microbial transglutaminase enabling efficient, site-specific conjugation of drug-linker constructs to position HC-Q295 of native, fully glycosylated IgG-type antibodies. ADCs generated via this approach demonstrate excellent stability in vitro as well as strong efficacy in vitro and in vivo. As it employs different drug-linker structures and several native antibodies, our study additionally proves the broad applicability of this approach.

Economic analyses of fast-track total hip and knee arthroplasty: a systematic review.

PURPOSE: The number of total hip (THA) and knee arthroplasties (TKA) grows constantly which causes enormously rising costs for healthcare systems. The aim of this systematic literature review was to evaluate whether a cost reduction can be achieved by THA or TKA fast-track protocols, which is a multidisciplinary approach aiming at faster recovery. METHODS: A systematic literature research was undertaken for the timeframe from 2007/01/01 to 2019/03/04 in PubMed. Abstracts and title of the identified records were checked for eligible criteria and afterward the full text was assessed. RESULTS: Seven studies were included in the review. All studies showed a reduction in the total cost for fast-track THA and TKA. Most studies based their cost calculations on the amount of days the patients spend in the hospital. CONCLUSION: Using a fast-track protocol can significantly reduce the overall costs of the treatment.

The Darmstadt Science Declaration: Make Science Not War.

"… We will only be able to solve significant challenges with further progress in science and technology applied to the benefit of humanity. The Darmstadt Science Declaration is a global call to action to devote more resources to the advancement of science and technology to enable humanity to solve the challenges of today and to realize the dreams of a better tomorrow …" Read more in the Guest Editorial by Ulrich A. K. Betz.

PROLink-Single Step Circularization and Purification Procedure for the Generation of an Improved Variant of Human Growth Hormone.

Human growth hormone (hGH) plays an important role during human development and is also an approved therapeutic for the treatment of several diseases. However, one major drawback of hGH is its short circulating half-life requiring frequent administration, which is inconvenient and painful for the patients. Recent publications indicate that circularization greatly increases the stability of proteins due to their protection from exoproteolytic attack and a higher thermal stability of the circular form. Using sortase A, a transpeptidase isolated from Staphylococcus aureus, we developed a single step solid-phase circularization and purification procedure resulting in a circular version of hGH with improved properties. We could show that circular hGH binds to the recombinant hGH receptor with binding kinetics similar to those of linear hGH and that circularization does not alter the biological activity of hGH in vitro. Besides, circular hGH showed almost complete resistance toward exoproteolytic attack and slightly increased thermal stability which could possibly translate into an extended plasma half-life. The single step solid-phase circularization and purification procedure is in principle a generic process, which could also be applied for other proteins that meet the requirements for circularization.

Locked by Design: A Conformationally Constrained Transglutaminase Tag Enables Efficient Site-Specific Conjugation.

Based on the crystal structure of a natural protein substrate for microbial transglutaminase, an enzyme that catalyzes protein crosslinking, a recognition motif for site-specific conjugation was rationally designed. Conformationally locked by an intramolecular disulfide bond, this structural mimic of a native conjugation site ensured efficient conjugation of a reporter cargo to the therapeutic monoclonal antibody cetuximab without erosion of its binding properties.

Time-Dependent Prediction Models for Individual Prognosis of Chronic Postsurgical Pain following Knee Replacement Based on an Extensive Multivariable Data Set.

(1) Background: Clinically useful prediction models for chronic postsurgical pain (CPSP) in knee replacement (TKA) are lacking. (2) Methods: In our prospective, multicenter study, a wide-ranging set of 91 variables was collected from 933 TKA patients at eight time points up to one year after surgery. Based on this extensive data pool, simple and complex prediction models were calculated for the preoperative time point and for 6 months after surgery, using least absolute shrinkage and selection operator (LASSO) 1se and LASSO min, respectively. (3) Results: Using preoperative data only, LASSO 1se selected age, the Revised Life Orientation Test on pessimism, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC)-subscore pain and the Timed "Up and Go" Test for prediction, resulting in an area under the curve (AUC) of 0.617 and a Brier score of 0.201, expressing low predictive power only. Using data up to 6 months after surgery, LASSO 1se included preoperative Patient Health Questionnaire-4, Knee Injury and Osteoarthritis Outcome Score (KOOS)-subscore pain (pain) 3 months after surgery (month), WOMAC pain 3 and 6 months, KOOS subscore symptoms 6 months, KOOS subscore sport 6 months and KOOS subscore Quality of Life 6 months. This improved the predictive power to an intermediate one (AUC 0.755, Brier score 0.168). More complex models computed using LASSO min did little to further improve the strength of prediction. (4) Conclusions: Even using multiple variables and complex calculation methods, the possibility of individual prediction of CPSP after TKA remains limited.

Enhancing biomechanical machine learning with limited data: generating realistic synthetic posture data using generative artificial intelligence.

Objective: Biomechanical Machine Learning (ML) models, particularly deep-learning models, demonstrate the best performance when trained using extensive datasets. However, biomechanical data are frequently limited due to diverse challenges. Effective methods for augmenting data in developing ML models, specifically in the human posture domain, are scarce. Therefore, this study explored the feasibility of leveraging generative artificial intelligence (AI) to produce realistic synthetic posture data by utilizing three-dimensional posture data. Methods: Data were collected from 338 subjects through surface topography. A Variational Autoencoder (VAE) architecture was employed to generate and evaluate synthetic posture data, examining its distinguishability from real data by domain experts, ML classifiers, and Statistical Parametric Mapping (SPM). The benefits of incorporating augmented posture data into the learning process were exemplified by a deep autoencoder (AE) for automated feature representation. Results: Our findings highlight the challenge of differentiating synthetic data from real data for both experts and ML classifiers, underscoring the quality of synthetic data. This observation was also confirmed by SPM. By integrating synthetic data into AE training, the reconstruction error can be reduced compared to using only real data samples. Moreover, this study demonstrates the potential for reduced latent dimensions, while maintaining a reconstruction accuracy comparable to AEs trained exclusively on real data samples. Conclusion: This study emphasizes the prospects of harnessing generative AI to enhance ML tasks in the biomechanics domain.

Dynamic surface topography data for assessing intra- and interindividual variation of vertebral motion.

Spinal function is substantially related to the motion of the particular vertebrae and the spine as a whole. For systematic assessment of individual motion, data sets are required which cover the kinematics comprehensively. Additionally, the data should enable a comparison of inter- and intraindividual variation of vertebral orientation in dedicated motion tasks like gait. For this purpose, this article provides surface topography (ST) data which were acquired while the individual test persons were walking on a treadmill at three different speed levels (2 km/h, 3 km/h, 4 km/h). In each recording, ten full walking cycles were included per test case to enable a detailed analysis of motion patterns. The provided data reflects asymptomatic and pain-free volunteers. Each data set contains the vertebral orientation in all three motion directions for the vertebra prominens down to L4 as well as the pelvis. Additionally, spinal parameters like balance, slope, and lordosis / kyphosis parameters as well as an assignment of the motion data to single gait cycles are included. The complete raw data set without any preprocessing is provided. This allows to apply a broad range of further signal processing and evaluation steps in order to identify characteristic motion patterns as well as intra- and inter-individual variation of vertebral motion.

Falls during oxaliplatin-based chemotherapy for gastrointestinal malignancies - (lessons learned from) a prospective study.

This prospective cohort study aimed to characterise the impact of oxaliplatin-based chemotherapy and its neurotoxic side effects (i.e., chemotherapy-induced neuropathy) on functional fall-risk and falls. Twenty chemotherapy-naïve participants (mean age, 59 years; 16 males) were consecutively included. A multimodal fall risk assessment was performed at four time points within 6 months. Polyneuropathy was assessed using the Neurologic Disability Scale; the fall risk was assessed by functional tests (Tinetti Test, Chair-Rising Test, and Timed up and Go Test). Patient-reported outcomes comprised the Hospitality Anxiety and Depression Scale (HADS), the Falls Efficacy Scale - International (FES-I) to assess the fear of falling, and the Physical Activity for the Elderly (PASE) questionnaire. Three falls occurred during the study. All fallen participants had a high fall risk-index (≥4 more risk factors) compared to only 30% of the non-fallen participants (p = 0.03) and suffered more frequently from pre-existing mild polyneuropathy (p = 0.049). Study discontinuation (n = 12) was associated with a higher rate of polypharmacy (p = 0.045), anxiety (HADS-A, p = 0.03), and specific fear of falling (FES-I, p = 0.025). In contrast, study completers (n = 8) reported an improvement in physical activity (PASE) (p = 0.018). In summary, pre-existing fall-risk factors impacted more falls than chemotherapy. A fall risk index offers a time-efficient screening option in an outpatient oncological setting.

Reference values and functional descriptions of transverse plane spinal dynamics during gait based on surface topography.

Spinal dynamics during gait have been of interest in research for many decades. Based on respective previous investigations, the pelvis is generally expected to be maximally forward rotated on the side of the reference leg at the beginning of each gait cycle and to reach its maximum counterrotation approximately at the end of the reference leg's stance phase. The pelvic-upper-thoracic-spine coordination converges towards an anti-phase movement pattern in high velocities during ambulation. The vertebral bodies around the seventh thoracic vertebra are considered to be an area of transition during human ambulation where no or at least little rotary motion can be observed. The respective cranial and caudal vertebrae meanwhile are expected to rotate conversely around this spinal point of intersection. However, these previous assumptions are based on scarce existing research, whereby only isolated vertebrae have been analyzed contemporaneously. Due to huge methodological differences in data capturing approaches, the results are additionally hardly comparable to each other and involved measurement procedures are often not implementable in clinical routines. Furthermore, none of the above-mentioned methods provided reference data for spinal motion during gait based on an appropriate number of healthy participants. Hence, the aim of this study was to present such reference data for spinal rotary motion of every vertebral body from C7 down to L4 and the pelvis derived from surface topographic back shape analyses in a cohort of 201 healthy participants walking on a treadmill at a given walking speed of 5 km/h. Additionally, the spine's functional movement behavior during gait should be described in the transverse plane based on data derived from this noninvasive, clinically suitable measurement approach and, in conclusion, the results shall be compared against those of previous research findings derived from other measurement techniques. Contrary to the previous functional understanding, the area of the mid-thoracic spine was found to demonstrate the largest amplitude of rotary motion of all investigated vertebrae and revealed an approximately counterrotated movement behavior compared to the rotary motion of the pelvis. In both directions, spinal rotation during gait seemed to be initiated by the pelvis. The overlying vertebrae followed in succession in the sense of an ongoing movement. Therefore, the point of intersection was not statically located in a specific anatomical section of the spine. Instead, it was found to be dynamic, ascending from one vertebra to the next from caudal to cranial in dependence of the pelvis's rotation initiation.

Consistency of vertebral motion and individual characteristics in gait sequences.

Vertebral motion reveals complex patterns, which are not yet understood in detail. This applies to vertebral kinematics in general but also to specific motion tasks like gait. For gait analysis, most of existing publications focus on averaging characteristics of recorded motion signals. Instead, this paper aims at analyzing intra- and inter-individual variation specifically and elaborating motion parameters, which are consistent during gait cycles of particular persons. For this purpose, a study design was utilized, which collected motion data from 11 asymptomatic test persons walking at different speed levels (2, 3, and 4 km/h). Acquisition of data was performed using surface topography. The motion signals were preprocessed in order to separate average vertebral orientations (neutral profiles) from basic gait cycles. Subsequently, a k-means clustering technique was applied to figure out, whether a discrimination of test persons was possible based on the preprocessed motion signals. The paper shows that each test sequence could be assigned to the particular test person without additional prior information. In particular, the neutral profiles appeared to be highly consistent intra-individually (across the gait cycles as well as speed levels), but substantially different between test persons. A full discrimination of test persons was achieved using the neutral profiles with respect to flexion/extension data. Based on this, these signals can be considered as individual characteristics for the particular test persons.