NMR structures of small molecules bound to a model of an RNA CUG repeat expansion.

Trinucleotide repeat expansions fold into long, stable hairpins and cause a variety of incurable RNA gain-of-function diseases such as Huntington's disease, the myotonic dystrophies, and spinocerebellar ataxias. One approach for treating these diseases is to bind small molecules to the structured RNAs. Both Huntington's disease-like 2 (HDL2) and myotonic dystrophy type 1 (DM1) are caused by a r(CUG) repeat expansion, or r(CUG)exp. The RNA folds into a hairpin structure with a periodic array of 1×1 nucleotide UU loops (5'CUG/3'GUC; where the underlined nucleotides indicate the Us in the internal loop) that sequester various RNA-binding proteins (RBP) and hence the source of its gain-of-function. Here, we report NMR-refined structures of single 5'CUG/3'GUC motifs in complex with three different small molecules, a di-guandinobenzoate (1), a derivative of 1 where the guanidino groups have been exchanged for imidazole (2), and a quinoline with improved drug-like properties (3). These structures were determined using nuclear magnetic resonance (NMR) spectroscopy and simulated annealing with restrained molecular dynamics (MD). Compounds 1, 2, and 3 formed stacking and hydrogen bonding interactions with the 5'CUG/3'GUC motif. Compound 3 also formed van der Waals interactions with the internal loop. The global structure of each RNA-small molecule complexes retains an A-form conformation, while the internal loops are still dynamic but to a lesser extent compared to the unbound form. These results aid our understanding of ligand-RNA interactions and enable structure-based design of small molecules with improved binding affinity for and biological activity against r(CUG)exp. As the first ever reported structures of RNA r(CUG) repeats bound to ligands, these structures can enable virtual screening campaigns combined with machine learning assisted de novo design.

Laparoscopy training of novices with complex curved instruments using 2D- and 3D-visualization.

PURPOSE: Beside many advantages, disadvantages such as reduced degrees of freedom and poorer depth perception are still apparent in laparoscopic surgery. 3D visualization and the development of complex instruments are intended to counteract the disadvantages. We want to find out whether the use of complex instruments and 3D visualization has an influence on the performance of novices. METHODS: 48 medical students with no experience in laparoscopic surgery or simulator-based laparoscopy training were included. They were randomized in four groups according to a stratification assessment. During a structured training period they completed the FLS-Tasks "PEG Transfer", "Pattern Cut" and "Intracorporeal Suture" and a transfer task based on these three. Two groups used conventional laparoscopic instruments with 3D or 2D visualization, two groups used complex curved instruments. The groups were compared in terms of their performance. RESULTS: In 2D laparoscopy there was a better performance with straight instruments vs. curved instruments in PEG Transfer and Intracorporeal Suture. In the transfer task, fewer errors were made with straight instruments. In 2D vs. 3D laparoscopy when using complex curved instruments there was an advantage in Intracorporeal Suture and PEG Transfer for 3D visualization. Regarding the transfer exercise, a better performance was observed and fewer errors were made in 3D group. CONCLUSION: We could show that learning laparoscopic techniques with complex curved instruments is more difficult with standard 2D visualization and can be overcome using 3D optics. The use of curved instruments under 3D vision seems to be advantageous when working on more difficult tasks.

Functional outcome after late cranioplasty after decompressive craniectomy: a single-center retrospective study.

OBJECTIVE: The best time for cranioplasty (CP) after decompressive craniectomy (DC) is controversial, and there are no authoritative guidelines yet. Both complications as well as outcome may depend on the timing of CP. The aim of this single-center study was to evaluate the impact of late CP on procedural safety as well as on patient outcome. METHODS: All patients receiving CP at a tertiary university medical center between 01/2015 and 12/2022 were included retrospectively. Patients' conditions were assessed according to the modified Rankin Scale (mRS) prior to CP and 6 months after. Baseline characteristics, indication for DC, time from DC to CP, and postoperative complications according to the Landriel Ibañez Classification were analyzed. RESULTS: CP was performed in 271 patients who previously underwent DC due to traumatic brain injury (25.5%), ischemic stroke (29.5%), aneurysmal subarachnoid hemorrhage (26.9%), or intracerebral hemorrhage (18.1%). The median interval between DC and CP was 143 days (interquartile range 112-184 days). Receiver operating characteristic analysis revealed a cut-off of 149 days, where CP performed within 149 days after DC led to an improvement on mRS after CP (p = 0.001). In multivariate analysis, additional rehabilitation after and better mRS before CP were independently associated with improvement of outcome. The rate of complications was similar between early and late CP (24.8% and 25.4%, respectively, p = 0.562). CONCLUSIONS: Late cranioplasty is a safe procedure. The outcome was improved when additional rehabilitation was performed after cranioplasty and was not associated with the timing of cranioplasty.

The single-cell transcriptome program of nodule development cellular lineages in Medicago truncatula.

Legumes establish a symbiotic relationship with nitrogen-fixing rhizobia by developing nodules. Nodules are modified lateral roots that undergo changes in their cellular development in response to bacteria, but the transcriptional reprogramming that occurs in these root cells remains largely uncharacterized. Here, we describe the cell-type-specific transcriptome response of Medicago truncatula roots to rhizobia during early nodule development in the wild-type genotype Jemalong A17, complemented with a hypernodulating mutant (sunn-4) to expand the cell population responding to infection and subsequent biological inferences. The analysis identifies epidermal root hair and stele sub-cell types associated with a symbiotic response to infection and regulation of nodule proliferation. Trajectory inference shows cortex-derived cell lineages differentiating to form the nodule primordia and, posteriorly, its meristem, while modulating the regulation of phytohormone-related genes. Gene regulatory analysis of the cell transcriptomes identifies new regulators of nodulation, including STYLISH 4, for which the function is validated.

A 97-Channel Read-Out ASIC for an Electrophysiological Mapping Catheter With an Optical Link.

Electrophysiological (EP) mapping catheters are medical equipment, which are widely used to diagnose and treat atrial fibrillation. The electrophysiology signals are sensed by the catheter's electrodes, for which a large electrode count becomes more and more essential because of the demand for a higher local resolution. A drawback of the large electrode count is the effort to pass through and to integrate the wires inside the catheter shaft. To overcome with this issue, this article describes the realization of an EP ASIC, which is placed close to the 97 electrodes and to perform an in-tip digitization. Thanks to an integrated optical link, only a single fiber is required to connect the catheter tip to an externally located electro-optical unit and thus shrinking the shaft volume to a minimum. The fiber is used to guide light from the electro-optical unit to the catheter tip and illuminate a blue LED, which is located close to the EP ASIC and acts as a photovoltaic cell. The EP ASIC is designed to use the LED as power source and a data transceiver while performing signal conditioning and digitization of the EP signals at the same time. The EP signals are captured with the ASIC's multi-channel read-out circuit consisting of 97 fully differential preamplifiers and additional filter stages. A switch network sequentially selects one single channel for further amplification and digitization of the EP signal. The read-out circuit is designed to process signals in the range of 500 µVpp to 20 mVpp with a bandwidth of 5 Hz to 100 Hz.

AR visualizations in laparoscopy: surgeon preferences and depth assessment of vascular anatomy.

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.

Tracking and evaluating motion skills in laparoscopy with inertial sensors.

BACKGROUND: Analysis of surgical instrument motion is applicable in surgical skill assessment and monitoring of the learning progress in laparoscopy. Current commercial instrument tracking technology (optical or electromagnetic) has specific limitations and is expensive. Therefore, in this study, we apply inexpensive, off-the-shelf inertial sensors to track laparoscopic instruments in a training scenario. METHODS: We calibrated two laparoscopic instruments to the inertial sensor and investigated its accuracy on a 3D-printed phantom. In a user study during a one-week laparoscopy training course with medical students and physicians, we then documented and compared the training effect in laparoscopic tasks on a commercially available laparoscopy trainer (Laparo Analytic, Laparo Medical Simulators, Wilcza, Poland) and the newly developed tracking setup. RESULTS: Eighteen participants (twelve medical students and six physicians) participated in the study. The student subgroup showed significantly poorer results for the count of swings (CS) and count of rotations (CR) at the beginning of the training compared to the physician subgroup (p = 0.012 and p = 0.042). After training, the student subgroup showed significant improvements in the rotatory angle sum, CS, and CR (p = 0.025, p = 0.004 and p = 0.024). After training, there were no significant differences between medical students and physicians. There was a strong correlation between the measured learning success (LS) from the data of our inertial measurement unit system (LSIMU) and the Laparo Analytic (LSLap) (Pearson's r = 0.79). CONCLUSION: In the current study, we observed a good and valid performance of inertial measurement units as a possible tool for instrument tracking and surgical skill assessment. Moreover, we conclude that the sensor can meaningfully examine the learning progress of medical students in an ex-vivo setting.

[Physiological reactions in the interface between cementless implants and bone]. / Physiologische Reaktionen im Interface zementfreier Implantate.

BACKGROUND: Surgical treatment of patients with osteoarthritis of the hip and persisting symptoms under conservative therapy has become increasingly important against the background of an aging population. OBJECTIVES: What are the physiological reactions in the interface between cementless implants and bone? METHODS: The literature is reviewed, expert opinions and animal models are analyzed and discussed. RESULTS: Surface coating of implants with hydroxyapatite or titanium can have positive effects on osteointegration. Additional local application of mediators might be beneficial for osteointegration in the future. CONCLUSION: Early peri-implant bone healing directly after implantation and late remodeling of the bone-implant interface are essential for secondary implant stability.

Practicability of a Virtual Consultation to Evaluate the Shoulder Joint. / Durchführbarkeit einer digitalen Sprechstunde zur Untersuchung des Schultergelenkes.

OBJECTIVE: In the course of the corona pandemic, resource conservation and the protection of further infections have made it necessary to break new ground in the organisation of orthopaedic and trauma surgery consultations. One solution is consistent digitisation and the offer of video consultation hours. In this study, non-contact examination of patients with shoulder disorders is described and critically examined. METHODS: Thirty patients who presented with pathologies of the shoulder joint in a university outpatient clinic were subjected to a physical examination in a conventional and contactless manner. The data obtained on mobility, function and provocation test of both examinations were compared to draw conclusions about the virtual feasibility. RESULTS: 46% of the patients suffered from a traumatic shoulder lesion, and 54% showed degenerative lesions. The assessment of mobility showed a high correlation of 70 - 90% between the two examinations. Common tests to evaluate the supraspinatus, infraspinatus, subscapularis and the long head of the biceps could be adequately performed in a contactless version by more than three quarters of the patients, but with low-to-moderate performance values. CONCLUSION: Contact-less examination is particularly disadvantageous when evaluating stability criteria. For the medical history and functional test, there were no significant differences between the classic consultation and contactless consultation. Although virtual consultation is a widespread and valuable addition in pandemic times, it cannot replace a safe assessment and indication by personal examination.

Phantom study on surgical performance in augmented reality laparoscopy.

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.

Economic Effects of the SARS-CoV-2 Pandemic in 2020. / Wirtschaftliche Auswirkungen der SARS-CoV-2-Pandemie im Jahr 2020.

INTRODUCTION: In 2020, the SARS-CoV-2 pandemic necessitated an adjustment to the care structure in all medical facilities in Germany. In this study we analysed the effects of the SARS-CoV-2 pandemic using the data from the annual balance sheet of a university department and maximum care provider for orthopaedics and trauma surgery. METHODS: Data analysis was performed on the clinic's performance parameters from 2019 and 2020. The analysis included 52943 outpatient and 7980 inpatient cases, together with the Case Mix Index (CMI), and the costs and revenues. RESULTS: As a result of the reduction in scheduled surgeries, the mean number of inpatients in March and April 2020 decreased by 10.4% (p = 0.004). Due to the focus on complex cases, the CMI increased by 29.5% (p = 0.007). The number of outpatient surgical procedures increased by 16.9% (n = 84). Rising costs of consumables due to the purchase of protective equipment were offset by a reduced need for orthopaedic implants. CONCLUSION: By reducing the number of elective inpatient surgical treatments, the focus was shifted to treating complex cases; this is reflected in the increased CMI. Due to internal compensation mechanisms, the clinic was able to conserve intensive care capacities while still achieving an increase in revenue.

Intra-arterial versus negative-staining of embryonal resection borders with indocyanine green (ICG) fluorescence for total mesorectal excision in colorectal cancer - an experimental feasibility study in a porcine model.

BACKGROUND: Colorectal cancer (CRC) is one of the most common malignancies worldwide. Laparoscopic lower rectal resections in accordance with the oncological principles are recommended as the gold standard for CRC surgical management. However, the learning curve for adopting these techniques is quite steep and the incomplete resections are predictive of local recurrence. This study was conducted in an attempt to find a way to help surgeons to overcome some of these difficulties and define the right resection margins. MATERIAL AND METHODS: As such, we carried out two laparoscopic lower rectal resections in porcine models. The first resection was performed following the ligation and selective infusion of Indocyanine Green (ICG) into the inferior mesenteric artery (IMA), and the second after the ligation of both inferior mesenteric artery and vein (IMV) and systemic intravenous infusion of ICG. Fluorescence was detected in real time by means of an infrared imaging system. RESULTS: Sharp resection margins were defined after intra-arterial infusion, and all the tissues in the IMA basin were colored in the first case. In the second model every organ and tissue was colored except the rectum, urinary bladder and ductus deferens. CONCLUSIONS: Although systemic intra-venous application of ICG and negative-staining of the rectum including the mesorectum is much easier compared to laparoscopic inter-arterial perfusion through IMA, image results of selevtive IMA-perfusion appear in sharper discrimination of the several layers. Further investigation should focus on simplifying this technique.

Balance of carbon species combined with stable isotope ratios show critical switch towards bicarbonate uptake during cyanobacteria blooms.

Next to water quality deterioration, cyanobacteria blooms can affect turnover of aqueous carbon, including dissolved inorganic carbon (DIC), dissolved organic carbon (DOC), and particulate organic carbon (POC). We investigated interactions of these three phases and their stable isotopes in a freshwater pond with periodic cyanobacterial blooms over a period of 23 months. This helped to map turnover and sources of aqueous carbon before, during, and after bloom events. During bloom events POC isotope values (δ13CPOC) increased up to -17.4‰, after aqueous CO2 (CO2(aq)) fell below an atmospheric equilibration value of 412 µatm. Additionally, carbon isotope enrichment between CO2(aq) and POC (εCO2-phyto) ranged from 2.0 to 21.5‰ with lowest fractionations observed at pH values above 8.9. The increase of δ13CPOC and decrease of εCO2-phyto values at low pCO2 and high pH was most likely caused by the activation of the carbon concentrating mechanism (CCM). This mechanism correlated with prevalent assimilation of 13C-enriched HCO3-. Surprisingly, CO2(aq) still contributed more than 50% to the POC pool down to pCO2 values of around 150 µatm. Only after this threshold the reduced εCO2-phyto suggested incorporation of 13C-enriched HCO3-.

Evaluation of an Integrated Smart Sensor System for Real-Time Characterization and Digitalization of Postoperative Abdominal Drain Output: A Pilot Study.

Background: For centuries, surgeons have relied on surgical drains during postoperative care. Despite all advances in modern medicine and the area of digitalization, as of today, most if not all assessment of abdominal secretions excreted via surgical drains are carried out manually. We here introduce a novel integrated Smart Sensor System (Smart Drain) that allows for real-time characterization and digitalization of postoperative abdominal drain output at the patient's bedside. Methods: A prototype of the Smart Drain was developed using a sophisticated spectrometer for assessment of drain output. The prototype measures 10 × 6 × 6 cm and therefore easily fits at the bedside. At the time of measurement with our Smart Drain, the drain output was additionally sent off to be analyzed in our routine laboratory for typical markers of interest in abdominal surgery such as bilirubin, lipase, amylase, triglycerides, urea, protein, and red blood cells. A total of 45 samples from 19 patients were included. Results: The measurements generated were found to correlate with conventional laboratory measurements for bilirubin (r = .658, P = .000), lipase (r = .490, P = .002), amylase (r = .571, P = .000), triglycerides (r = .803, P = .000), urea (r = .326, P = .033), protein (r = .387, P = .012), and red blood cells (r = .904, P = .000). Conclusions: To our best knowledge, for the first time we describe a device using a sophisticated spectrometer that allows for real-time characterization and digitalization of postoperative abdominal drain output at the patient's bedside.

A 96-Channel Electrophysiology Catheter with Integrated Read-Out ASIC and Optical Link.

This paper describes a realization of an electrophysiology (EP) catheter with 96 electrodes which requires no electrical wiring to the outside by relying on an optical link for both power supply and data communication. The catheter tip is constructed from a liquid crystal polymer (LCP) material. It features 96 gold electrodes, which are uniformly arranged along an expandable basket. An integrated ASIC amplifies, filters and digitizes the EP signals and establishes communication to a data processing unit outside the patient's body. The optical interface consists of a conventional multi-mode fiber and a single blue LED inside the catheter. The external unit used to generate optical power, establish communication and perform data post-processing comprises a laser module, optics, and electrical components. The catheter is designed to capture EP signals in the range of 600 µVpp to 20 mVpp in a frequency range between 8 Hz and 120 Hz.

Probabilistic Deep Learning to Quantify Uncertainty in Air Quality Forecasting.

Data-driven forecasts of air quality have recently achieved more accurate short-term predictions. However, despite their success, most of the current data-driven solutions lack proper quantifications of model uncertainty that communicate how much to trust the forecasts. Recently, several practical tools to estimate uncertainty have been developed in probabilistic deep learning. However, there have not been empirical applications and extensive comparisons of these tools in the domain of air quality forecasts. Therefore, this work applies state-of-the-art techniques of uncertainty quantification in a real-world setting of air quality forecasts. Through extensive experiments, we describe training probabilistic models and evaluate their predictive uncertainties based on empirical performance, reliability of confidence estimate, and practical applicability. We also propose improving these models using "free" adversarial training and exploiting temporal and spatial correlation inherent in air quality data. Our experiments demonstrate that the proposed models perform better than previous works in quantifying uncertainty in data-driven air quality forecasts. Overall, Bayesian neural networks provide a more reliable uncertainty estimate but can be challenging to implement and scale. Other scalable methods, such as deep ensemble, Monte Carlo (MC) dropout, and stochastic weight averaging-Gaussian (SWAG), can perform well if applied correctly but with different tradeoffs and slight variations in performance metrics. Finally, our results show the practical impact of uncertainty estimation and demonstrate that, indeed, probabilistic models are more suitable for making informed decisions.

Primary Stability in Hip Revision Arthroplasty: Comparison of the Stability of Cementless Fixed Augments on a Modular Acetabular Cage System with and without Cranial Straps.

The goal of this study is to evaluate the primary stability of a cementless augment-and-modular-cage system with and without the addition of cranial straps in a standardized in vitro setting. As the surrogate parameter for the evaluation of primary stability, the measurement of relative motion between the implant components themselves and the bone will be used. Acetabular revision components with a trabecular titanium augment in combination with a large fourth-generation composite left hemipelvis were assembled. These constructs were divided into two groups with (S) and without cranial straps (nS). A total of 1000 cycles was applied at each of three load levels. Relative movements (RM) between the components were measured. Load levels display a significant effect on the amount of RM at all interfaces except between shell/augment. The group assignment appears to have an effect on RM due to significantly differing means at all interfaces. Between bone/shell RM increased as load increased. NS displayed significantly more RM than S. Between shell/augment RM remained constant as load increased. Between shell/cup S showed more RM than nS while both groups' RM increased with load. We conclude a significant increase of primary stability between the shell and the bone through the addition of cranial straps. Relative motion between components (shell/cup) increases through the addition of cranial straps. A clinical impact of this finding is uncertain and requires further investigation. Finally, the cementless fixation of the augment against the rim-portion of the shell appears stable and compares favorably to prior investigation of different fixation techniques.