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Cytokinesis physically separates daughter cells at the end of cell division. This step is particularly challenging for epithelial cells, which are connected to their neighbors and to the extracellular matrix by transmembrane protein complexes. To systematically evaluate the impact of the cell adhesion machinery on epithelial cytokinesis efficiency, we performed an RNAi-based modifier screen in the Drosophila follicular epithelium. Strikingly, this unveiled adhesion molecules and transmembrane receptors that facilitate cytokinesis completion. Among these is Dystroglycan, which connects the extracellular matrix to the cytoskeleton via Dystrophin. Live imaging revealed that Dystrophin and Dystroglycan become enriched in the ingressing membrane, below the cytokinetic ring, during and after ring constriction. Using multiple alleles, including Dystrophin isoform-specific mutants, we show that Dystrophin/Dystroglycan localization is linked with unanticipated roles in regulating cytokinetic ring contraction and in preventing membrane regression during the abscission period. Altogether, we provide evidence that, rather than opposing cytokinesis completion, the machinery involved in cell-cell and cell-matrix interactions has also evolved functions to ensure cytokinesis efficiency in epithelial tissues., Competing Interests: Disclosure and competing interests statement The authors declare no competing interests., (© 2024. The Author(s).)

Paralysis of the muscles controlling the hand dramatically limits the quality of life for individuals living with spinal cord injury (SCI). Here, with a non-invasive neural interface, we demonstrate that eight motor complete SCI individuals (C5-C6) are still able to task-modulate in real-time the activity of populations of spinal motor neurons with residual neural pathways. In all SCI participants tested, we identified groups of motor units under voluntary control that encoded various hand movements. The motor unit discharges were mapped into more than 10 degrees of freedom, ranging from grasping to individual hand-digit flexion and extension. We then mapped the neural dynamics into a real-time controlled virtual hand. The SCI participants were able to match the cue hand posture by proportionally controlling four degrees of freedom (opening and closing the hand and index flexion/extension). These results demonstrate that wearable muscle sensors provide access to spared motor neurons that are fully under voluntary control in complete cervical SCI individuals. This non-invasive neural interface allows the investigation of motor neuron changes after the injury and has the potential to promote movement restoration when integrated with assistive devices., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

The Alberta reconstructive technique (ART) is an innovative surgical procedure performed on patients undergoing primary jaw resection and reconstruction. The ART procedure was developed in collaboration with the Institute for Reconstructive Sciences in Medicine and the Division of Otolaryngology-Head and Neck Surgery, University of Alberta., (© 2024 The Authors. Head & Neck published by Wiley Periodicals LLC.)

Objective: Surface electromyography (sEMG) can sense the motor commands transmitted to the muscles. This work presents a deep learning method that can decode the electrophysiological activity of the forearm muscles into the movements of the human hand., Methods: We have recorded the kinematics and kinetics of the hand during a wide range of grasps and individual digit movements that cover 22 degrees of freedom of the hand at slow (0.5 Hz) and comfortable (1.5 Hz) movement speeds in 13 healthy participants. The input of the model consists of 320 non-invasive EMG sensors placed on the extrinsic hand muscles., Results: Our network achieves accurate continuous estimation of both kinematics and kinetics, surpassing the performance of comparable networks reported in the literature. By examining the latent space of the network, we find evidence that it mapped EMG activity into the anatomy of the hand at the individual digit level. In contrast to what is observed from the low-pass filtered EMG and linear decoding approaches, we found that the full-bandwidth EMG (monopolar unfiltered) signals during synergistic and individual digit movements contain distinct neural embeddings that encode each movement of the human hand. These manifolds consistently represent the anatomy of the hand and are generalized across participants. Moreover, we found a task-specific distribution of the embeddings without any presence of correlated activations during multi- and individual-digit tasks., Conclusion/significance: The proposed method could advance the control of assistive hand devices by providing a robust and intuitive interface between muscle signals and hand movements.

Hydrogels appear to be an attractive class of biomaterial for cartilage tissue engineering due to their high water content, excellent biocompatibility, tunable stiffness, etc. The crosslinking density of the hydrogel can affect their viscoelastic property, and therefore potentially impact the chondrogenic phenotype of re-differentiated chondrocytes in a 3D microenvironment through physical cues. To understand the effect of crosslinking densities on chondrocytes phenotype and cellular interaction with the hydrogel, this study utilized a clinical grade thiolate hyaluronic acid and thiolate gelatin (HA-Gel) hydrogel, crosslinked with poly(ethylene glycol) diacrylate to create various crosslinking densities. The HA-Gel hydrogels were then mixed with human nasal chondrocytes to generate neocartilage in vitro. The influence of the hydrogel crosslinking density and the viscoelastic property on the cell behaviours on the gene and matrix levels were evaluated using biochemistry assays, histology, quantitative polymerase chain reaction (qPCR) and next-generation sequencing (RNA seq). In general, the differences in the storage modulus of the HA-Gel hydrogel are not enough to alter the cartilaginous gene expression of chondrocytes. However, a positively correlated trend of PPAR-γ gene expression to the crosslinking density was measured by qPCR. The RNA-seq results have shown that 178 genes are significantly negatively correlated and 225 genes are positively correlated to the crosslinking density, which is worth investigating in the future studies., (© 2023. The Author(s) under exclusive licence to Biomedical Engineering Society.)

The avascular nature of hyaline cartilage results in limited spontaneous self-repair and regenerative capabilities when damaged. Recent advances in three-dimensional bioprinting have enabled the precise dispensing of cell-laden biomaterials, commonly referred to as 'bioinks', which are emerging as promising solutions for tissue regeneration. An effective bioink for cartilage tissue engineering needs to create a micro-environment that promotes cell differentiation and supports neocartilage tissue formation. In this study, we introduced an innovative bioink composed of photocurable acrylated type I collagen (COLMA), thiol-modified hyaluronic acid (THA), and poly(ethylene glycol) diacrylate (PEGDA) for 3D bioprinting cartilage grafts using human nasal chondrocytes. Both collagen and hyaluronic acid, being key components of the extracellular matrix (ECM) in the human body, provide essential biological cues for tissue regeneration. We evaluated three formulations - COLMA, COLMA+THA, and COLMA+THA+PEGDA - for their printability, cell viability, structural integrity, and capabilities in forming cartilage-like ECM. The addition of THA and PEGDA significantly enhanced these properties, showcasing the potential of this bioink in advancing applications in cartilage repair and reconstructive surgery., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Importance: Restoration of dental occlusion and oral rehabilitation is the ultimate goal of functional jaw reconstruction., Objective: To evaluate the prefabricated fibula flap (PFF) technique in occlusion-driven jaw reconstruction for benign or previously treated malignant disease., Design, Setting, and Participants: This cohort study was conducted from January 2000 to December 2019 at the University of Alberta Hospital and Institute of Reconstructive Sciences in Medicine in Edmonton, Alberta, Canada, among patients who underwent PFF or bone-driven and delayed osseointegrated implant installation (BDD). Patients were followed up for a minimum of 1 year after occlusal rehabilitation. Data were analyzed from July 2021 to June 2022., Exposures: Patients underwent BDD or PFF, which consists of osseointegrated dental implant installation and skin grafting of the fibular bone 3 to 6 months before jaw tumor resection or defect reconstruction. The implant osseointegration is completed at the time of jaw reconstruction, allowing for full reconstruction, loading, and restoration of the dental occlusion in the immediate postoperative period., Main Outcomes and Measure: Safety, effectiveness, accuracy, timeliness of occlusal reconstruction, and aesthetic appeal were compared between PFF and BDD. Groups were compared for the following variables: postoperative complications, number of bony segments used, number of procedures needed, total operative time, time to occlusal rehabilitation, and number of implants installed, exposed, lost, and used (ie, exposed implants - lost implants). Aesthetic appeal was assessed using standardized full-face and profile digital photographs taken before and 6 to 12 months after the operation and analyzed by 3 naive raters., Results: Among 9 patients receiving PFF (mean [SD] age, 43.3 [13.0] years; 7 men [77.8%]) and 12 patients receiving BDD (mean [SD] age, 41.9 [18.0] years; 8 men [66.7%]), the overall complication rate was similar (4 patients [44.4%] vs 3 patients [25.0%], respectively; relative risk, 1.78 [95% CI, 0.52 to 6.04]). The number of patients with implant loss was similar between PFF and BDD groups (0 patients vs 3 patients [25.0%], respectively; difference, -25.0 percentage points [95% CI, -48.4 to 9.7 percentage points]). PFF had a clinically meaningful faster mean (SD) occlusal rehabilitation compared with BDD (12.1 [1.9] months vs 60.4 [23.1] months; difference, -48.3 months [95% CI, -64.5 to -32.0 months]). The mean (SD) difference in preoperative to postoperative aesthetic score was similar between PFF and BDD groups (-0.8 [1.5] vs -0.2 [0.8]; difference, -0.6 [95% CI, -1.6 to 0.4])., Conclusions and Relevance: This study found that PFF compared with BDD was a safe, effective, and aesthetic reconstructive option for patients with benign or previously treated jaw malignant tumors. This technique may provide rapid occlusal reconstruction and oral rehabilitation.

Background: Glioblastomas are characterized by aggressive and infiltrative growth, and by striking heterogeneity. The aim of this study was to investigate whether tumor cell proliferation and invasion are interrelated, or rather distinct features of different cell populations., Methods: Tumor cell invasion and proliferation were longitudinally determined in real-time using 3D in vivo 2-photon laser scanning microscopy over weeks. Glioblastoma cells expressed fluorescent markers that permitted the identification of their mitotic history or their cycling versus non-cycling cell state., Results: Live reporter systems were established that allowed us to dynamically determine the invasive behavior, and previous or actual proliferation of distinct glioblastoma cells, in different tumor regions and disease stages over time. Particularly invasive tumor cells that migrated far away from the main tumor mass, when followed over weeks, had a history of marked proliferation and maintained their proliferative capacity during brain colonization. Infiltrating cells showed fewer connections to the multicellular tumor cell network, a typical feature of gliomas. Once tumor cells colonized a new brain region, their phenotype progressively transitioned into tumor microtube-rich, interconnected, slower-cycling glioblastoma cells. Analysis of resected human glioblastomas confirmed a higher proliferative potential of tumor cells from the invasion zone., Conclusions: The detection of glioblastoma cells that harbor both particularly high proliferative and invasive capabilities during brain tumor progression provides valuable insights into the interrelatedness of proliferation and migration-2 central traits of malignancy in glioma. This contributes to our understanding of how the brain is efficiently colonized in this disease., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Cell proliferation is central to epithelial tissue development, repair, and homeostasis. During cell division, small RhoGTPases control both actomyosin dynamics and cell-cell junction remodeling to faithfully segregate the genome while maintaining tissue polarity and integrity. To decipher the mechanisms of RhoGTPase spatiotemporal regulation during epithelial cell division, we generated a transgenic fluorescently tagged library for the 48 Drosophila Rho guanine exchange factors (RhoGEFs) and GTPase-activating proteins (GAPs), and we systematically characterized their endogenous distributions by time-lapse microscopy. Therefore, we unveiled candidate regulators of the interplay between actomyosin and junctional dynamics during epithelial cell division. Building on these findings, we established that the conserved RhoGEF Cysts and RhoGEF4 play sequential and distinct roles to couple cytokinesis with de novo junction formation. During ring contraction, Cysts via Rho1 participates in the neighbor mechanosensing response, promoting daughter-daughter cell membrane juxtaposition in preparation to de novo junction formation. Subsequently and upon midbody formation, RhoGEF4 via Rac acts in the dividing cell to ensure the withdrawal of the neighboring cell membranes, thus controlling de novo junction length and cell-cell arrangements upon cytokinesis. Altogether, our findings delineate how the RhoGTPases Rho and Rac are locally and temporally activated during epithelial cytokinesis, highlighting the RhoGEF/GAP library as a key resource to understand the broad range of biological processes regulated by RhoGTPases., Competing Interests: Declaration of interests The authors declare no competing interests, (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Diffuse gliomas, particularly glioblastomas, are incurable brain tumours 1 . They are characterized by networks of interconnected brain tumour cells that communicate via Ca 2+ transients 2-6 . However, the networks' architecture and communication strategy and how these influence tumour biology remain unknown. Here we describe how glioblastoma cell networks include a small, plastic population of highly active glioblastoma cells that display rhythmic Ca 2+ oscillations and are particularly connected to others. Their autonomous periodic Ca 2+ transients preceded Ca 2+ transients of other network-connected cells, activating the frequency-dependent MAPK and NF-κB pathways. Mathematical network analysis revealed that glioblastoma network topology follows scale-free and small-world properties, with periodic tumour cells frequently located in network hubs. This network design enabled resistance against random damage but was vulnerable to losing its key hubs. Targeting of autonomous rhythmic activity by selective physical ablation of periodic tumour cells or by genetic or pharmacological interference with the potassium channel KCa3.1 (also known as IK1, SK4 or KCNN4) strongly compromised global network communication. This led to a marked reduction of tumour cell viability within the entire network, reduced tumour growth in mice and extended animal survival. The dependency of glioblastoma networks on periodic Ca 2+ activity generates a vulnerability 7 that can be exploited for the development of novel therapies, such as with KCa3.1-inhibiting drugs., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Thoracic aortic aneurysms (TAA) may be associated with complications such as rupture and dissection, which can lead to a fatal outcome. Increased central arterial stiffness has been proposed to be present in patients with TAA compared to unmatched controls. We aimed to assess whether wall properties in patients with TAA are also altered when compared to a matched control group. Applanation tonometry was performed in 74 adults with TAA and 74 sex, age, weight, height, and left ventricular ejection fraction matched controls. Subsequently analysis of the pulse wave was done using the SphygmoCor System. For comparing the two groups, AIx was adjusted to a heart rate of 75/min (AIx@75). 148 1-to-1 matched participants were included in the final model. There was no significant difference in the Alx@75 between the TAA group and the matched control group [mean (SD) of 24.7 (11.2) % and 22.8 (11.2) %, p = 0.240]. Adjusted for known cardiovascular risk factors, there was no association between TAA and AIx@75. Patients with TAA showed comparable arterial wall properties to cardiovascular risk factor matched controls. Since higher arterial stiffness is associated with TAA progression, it remains to be investigated if increased central arterial stiffness is a relevant factor of TAA emergence.

Exhaled breath contains valuable information at the molecular level and offers promising potential for precision medicine. However, few breath tests transition to routine clinical practice, partly because of the missing validation in multicenter trials. Therefore, we developed and applied an interoperability framework for standardized multicenter data acquisition and processing for breath analysis with secondary electrospray ionization-high resolution mass spectrometry. We aimed to determine the technical variability and metabolic coverage. Comparison of multicenter data revealed a technical variability of ∼20% and a core signature of the human exhaled metabolome consisting of ∼850 features, corresponding mainly to amino acid, xenobiotic, and carbohydrate metabolic pathways. In addition, we found high inter-subject variability for certain metabolic classes (e.g., amino acids and fatty acids), whereas other regions such as the TCA cycle were relatively stable across subjects. The interoperability framework and overview of metabolic coverage presented here will pave the way for future large-scale multicenter trials., Competing Interests: P.S. and M.K. are co-founders of Deep Breath Intelligence AG (Switzerland). K.S. and F.S. are consultants for Deep Breath Intelligence AG (Switzerland). P.S., K.S., A.G., M.K., U.F., and M.O. hold a patent on data processing for breath analysis by SESI-HRMS. P.S. and K.S. hold a patent on a system suitability test for SESI-HRMS. All other authors declare no competing interests., (© 2022 The Authors.)

The ideal jaw reconstruction involves the restoration and maintenance of jaw continuity, jaw relations, joint alignment, and facial contour, and, most importantly, dental occlusal reconstruction. One of the essential requirements of achieving a consistent functional outcome is to place the bony reconstruction in the correct three-dimensional position as it relates to the other jaw segments and dentition. A protocol of occlusion-driven reconstruction of prefabricated fibular free flaps that are customized to the patient with surgical design and simulation (SDS)-planned osseointegrated implant installation was developed by our institution. This innovation introduced significant flexibility and efficiency to jaw reconstructions, but functional and cosmetic outcomes were dependent on the accuracy of the final reconstructions when compared to the SDS plan. The purpose of this study was to examine the accuracy of the SDS-planned fibular flap prefabrication in a cohort of patients undergoing jaw reconstruction. All patients that had undergone primary jaw reconstruction with prefabricated fibular free flaps were reviewed. The primary outcome of this study was the accuracy of the postoperative implant positions as compared to the SDS plan. A total of 23 implants were included in the analysis. All flaps survived, there was no implant loss postoperatively, and all the patients underwent all stages of the reconstruction. SDS planning of fibular flap prefabrication resulted in better than 2 mm accuracy of osteointegrated implant placement in a cohort of patients undergoing jaw reconstruction. This accuracy could potentially result in improved functional and cosmetic outcomes.

Apical-basal polarity is an essential epithelial trait controlled by the evolutionarily conserved PAR-aPKC polarity network. Dysregulation of polarity proteins disrupts tissue organization during development and in disease, but the underlying mechanisms are unclear due to the broad implications of polarity loss. Here, we uncover how Drosophila aPKC maintains epithelial architecture by directly observing tissue disorganization after fast optogenetic inactivation in living adult flies and ovaries cultured ex vivo. We show that fast aPKC perturbation in the proliferative follicular epithelium produces large epithelial gaps that result from increased apical constriction, rather than loss of apical-basal polarity. Accordingly, we can modulate the incidence of epithelial gaps by increasing and decreasing actomyosin-driven contractility. We traced the origin of these large epithelial gaps to tissue rupture next to dividing cells. Live imaging shows that aPKC perturbation induces apical constriction in non-mitotic cells within minutes, producing pulling forces that ultimately detach dividing and neighboring cells. We further demonstrate that epithelial rupture requires a global increase of apical constriction, as it is prevented by the presence of non-constricting cells. Conversely, a global induction of apical tension through light-induced recruitment of RhoGEF2 to the apical side is sufficient to produce tissue rupture. Hence, our work reveals that the roles of aPKC in polarity and actomyosin regulation are separable and provides the first in vivo evidence that excessive tissue stress can break the epithelial barrier during proliferation., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Study Objectives: Patients with sarcoidosis experience fatigue and excessive daytime sleepiness (EDS). However, the underlying pathomechanism is unclear. Studies suggested undiagnosed obstructive sleep apnea (OSA) to be an important contributor, but reliable data on prevalence and impact of OSA in sarcoidosis are scarce., Methods: 71 adult patients with sarcoidosis, 1-to-1 matched to 71 adult controls according to sex, age, and body mass index were included. Participants underwent structured interviews (including Epworth Sleepiness Scale [ESS], Fatigue Assessment Scale [FAS], and Functional Outcome of Sleep Questionnaire [FOSQ-30]) and level-3 respiratory polygraphy. OSA was defined as apnea-hypopnea index ≥ 5 events/h. Prevalence of OSA was assessed and possible risk factors for OSA in sarcoidosis were investigated., Results: Mild OSA (AHI ≥ 5 events/h) was prevalent in 32 (45%) sarcoidosis patients vs 22 (31%) controls ( P = .040). Sarcoidosis patients presented higher ESS compared with matched controls ( P = .037). FAS scores (median [quartile] of 21.5 [16, 27.5]) indicated fatigue in sarcoidosis patients. Patients with EDS (ESS ≥ 11) presented reduced FOSQ-30 results (median [quartile] of 16.7 [15.2, 17.8]). ESS, FAS, and FOSQ were not associated with AHI in sarcoidosis patients. Body mass index, sex, neck circumference, and NoSAS score were predictors for OSA in sarcoidosis., Conclusions: The risk for mild OSA is 2.5-fold higher in sarcoidosis patients compared with matched controls. OSA seems not to be the reason for increased sleepiness or fatigue in sarcoidosis. Risk factors such as body mass index, sex, neck circumference, and NoSAS score can be used to screen for OSA in sarcoidosis patients., Clinical Trial Registration: Registry: ClinicalTrials.gov; Name: Obstructive Sleep Apnoea in Sarcoidosis (OSASA); URL: https://clinicaltrials.gov/ct2/history/NCT04156789?V_2=View; Identifier: NCT04156789., Citation: Roeder M, Sievi NA, Schneider A, et al. The prevalence of obstructive sleep apnea in sarcoidosis and its impact on sleepiness, fatigue, and sleep-associated quality of life: a cross-sectional study with matched controls (the OSASA study). J Clin Sleep Med . 2022;18(10):2415-2422., (© 2022 American Academy of Sleep Medicine.)

Rapid and reliable tools for the diagnosis and monitoring of obstructive sleep apnea (OSA) are currently lacking. Prior studies using a chemical analysis of exhaled breath have suggested the existence of an OSA-specific metabolic signature. Here, we validated this diagnostic approach and the proposed marker compounds, as well as their potential to reliably diagnose OSA. In this cross-sectional observational study, exhaled breath was analyzed using secondary electrospray ionization high-resolution mass spectrometry. The study cohort included untreated OSA patients, OSA patients treated with continuous positive airway pressure and healthy subjects. The robustness of previously reported OSA markers was validated based on detectability, significant differences between groups (Mann-Whitney U test) and classification performance. The breath analysis of 118 participants resulted in 42 previously reported markers that could be confirmed in this independent validation cohort. Nine markers were significantly increased in untreated OSA compared to treated OSA, with a subset of them being consistent with a previous validation study. An OSA prediction based on the confirmed OSA signature performed with an AUC of 0.80 (accuracy 77%, sensitivity 73% and specificity 80%). As several breath markers were clearly found to be repeatable and robust in this independent validation study, these results underscore the clinical potential of breath analysis for OSA diagnostics and monitoring.

The human hand possesses a large number of degrees of freedom. Hand dexterity is encoded by the discharge times of spinal motor units (MUs). Most of our knowledge on the neural control of movement is based on the discharge times of MUs during isometric contractions. Here we designed a noninvasive framework to study spinal motor neurons during dynamic hand movements with the aim to understand the neural control of MUs during sinusoidal hand digit flexion and extension at different rates of force development. The framework included 320 high-density surface EMG electrodes placed on the forearm muscles, with markerless 3D hand kinematics extracted with deep learning, and a realistic virtual hand that displayed the motor tasks. The movements included flexion and extension of individual hand digits at two different speeds (0.5 Hz and 1.5 Hz) for 40 seconds. We found on average 4.7±1.7 MUs across participants and tasks. Most MUs showed a biphasic pattern closely mirroring the flexion and extension kinematics. Indeed, a factor analysis method (non-negative matrix factorization) was able to learn the two components (flexion/extension) with high accuracy at the individual MU level ( R=0.87±0.12). Although most MUs were highly correlated with either flexion or extension movements, there was a smaller proportion of MUs that was not task-modulated and controlled by a different neural module (7.1% of all MUs with ). This work shows a noninvasive visually guided framework to study motor neurons controlling the movement of the hand in human participants during dynamic hand digit movements.

Natural control of assistive devices requires continuous positional encoding and decoding of the user's volition. Human movement is encoded by recruitment and rate coding of spinal motor units. Surface electromyography provides some information on the neural code of movement and is usually decoded into finger joint angles. However, the current approaches to mapping the electrical signal into joint angles are unsatisfactory. There are no methods that allow precise estimation of joint angles during natural hand movements within the large numbers of degrees of freedom of the hand. We propose a framework to train a neural network from digital cameras and high-density surface electromyography from the extrinsic (forearm and wrist) hand muscles. Furthermore, we show that our 3D convolutional neural network optimally predicted 14 functional flexion/extension joints of the hand. We found in our experiments (4 subjects; mean age of 26±2.12 years) that our model can predict individual sinusoidal finger movement at different speeds (0.5 and 1.5 Hz), as well as two and three finger pinching, and hand opening and closing, covering 14 degrees of freedom of the hand. Our deep learning method shows a mean absolute error of 2.78±0.28 degrees with a mean correlation coefficient between predicted and expected joint angles of 0.94, 95% confidence interval (CI) [0.81, 0.98] with simulated real-time inference times lower than 30 milliseconds. These results demonstrate that our approach is capable of predicting the user's volition similar to digital cameras through a non-invasive wearable neural interface. Clinical relevance- This method establishes a viable interface that can be used for both immersive virtual reality medical simulations environments and assistive devices such as exoskeleton and prosthetics.

Introduction: Jaw defect reconstructions have been transformed by the development of free tissue transfer using vascularized bone incorporating osseointegrated dental implants. We recently developed a modification our method this procedure and termed it the Modified Alberta Reconstruction Technique (MART). The objective of this study aimed to assess the soft tissue component and outcomes of the MART as compared to the Alberta Reconstructive Technique (ART) or conventional (BDD) reconstructions., Patients and Methods: This was a prospective cohort study of adult patients who underwent jaw reconstruction with dental implant rehabilitation between 2000 and 2019 in Edmonton, Alberta. Patients were aged-matched and placed into a cohort based on the type of reconstruction they received. Outcomes were compared between the groups. Expert and aesthetic analyses were performed. Statistical analysis was conducted to determine significance., Results: A total of 46 patients (15 BDD, 15 ART and 16 MART) were included. Demographics were similar between groups. There was no difference in complications. The soft tissue component of the MART cohort was more favourable to work with as judged by the occlusal reconstructive experts. The MART was rated as more aesthetically appealing in comparison to the BDD and ART (p = 0.049)., Conclusions: The MART is a safe, effective, and aesthetically appealing procedure. It yields a good functional result and a clinically better soft tissue component for occlusal reconstructions. For a select group of patients requiring jaw reconstruction, the MART is an ideal reconstructive option as the modification provides good control of the soft tissue around the implants., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The removal of skin cancer lesions on the nose often results in the loss of nasal cartilage. The cartilage loss is either surgically replaced with autologous cartilage or synthetic grafts. However, these replacement options come with donor-site morbidity and resorption issues. 3-dimensional (3D) bioprinting technology offers the opportunity to engineer anatomical-shaped autologous nasal cartilage grafts. The 3D bioprinted cartilage grafts need to embody a mechanically competent extracellular matrix (ECM) to allow for surgical suturing and resistance to contraction during scar tissue formation. We investigated the effect of culture period on ECM formation and mechanical properties of 3D bioprinted constructs of human nasal chondrocytes (hNC)-laden type I collagen hydrogel in vitro and in vivo. Tissue-engineered nasal cartilage constructs developed from hNC culture in clinically approved collagen type I and type III semi-permeable membrane scaffold served as control. The resulting 3D bioprinted engineered nasal cartilage constructs were comparable or better than the controls both in vitro and in vivo. This study demonstrates that 3D bioprinted constructs of engineered nasal cartilage are feasible options in nasal cartilage reconstructive surgeries., Competing Interests: Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2022.)

Continuous monitoring of metabolites in exhaled breath has recently been introduced as an advanced method to allow non-invasive real-time monitoring of metabolite shifts during rest and acute exercise bouts. The purpose of this study was to continuously measure metabolites in exhaled breath samples during a graded cycle ergometry cardiopulmonary exercise test (CPET), using secondary electrospray high resolution mass spectrometry (SESI-HRMS). We also sought to advance the research area of exercise metabolomics by comparing metabolite shifts in exhaled breath samples with recently published data on plasma metabolite shifts during CPET. We measured exhaled metabolites using SESI-HRMS during spiroergometry (ramp protocol) on a bicycle ergometer. Real-time monitoring through gas analysis enabled us to collect high-resolution data on metabolite shifts from rest to voluntary exhaustion. Thirteen subjects participated in this study (7 female). Median age was 30 years and median peak oxygen uptake (VO 2 max) was 50 mL·/min/kg. Significant changes in metabolites ( n = 33) from several metabolic pathways occurred during the incremental exercise bout. Decreases in exhaled breath metabolites were measured in glyoxylate and dicarboxylate, tricarboxylic acid cycle (TCA), and tryptophan metabolic pathways during graded exercise. This exploratory study showed that selected metabolite shifts could be monitored continuously and non-invasively through exhaled breath, using SESI-HRMS. Future studies should focus on the best types of metabolites to monitor from exhaled breath during exercise and related sources and underlying mechanisms.

Fibrin-associated diffuse large B cell lymphoma (FA-DLBCL) is a rare Epstein-Barr viruspositive B cell lymphoma that is nonmass-forming, does not directly produce symptoms, and is incidentally discovered on histological examination of tissues excised for other reasons. Despite overlap in morphologic and immunophenotypic features with aggressive B cell neoplasms, FA-DLBCL shows an excellent clinical outcome, even with surgical excision alone. We report an extremely rare occurrence of FA-DLBCL found in association with a metallic implant on revision arthroplasty of the knee. This report also illustrates the need for an integrated multidisciplinary approach for accurate diagnosis and avoidance of overtreatment.

Sleep is crucial to restore body functions and metabolism across nearly all tissues and cells, and sleep restriction is linked to various metabolic dysfunctions in humans. Using exhaled breath analysis by secondary electrospray ionization high-resolution mass spectrometry, we measured the human exhaled metabolome at 10-s resolution across a night of sleep in combination with conventional polysomnography. Our subsequent analysis of almost 2,000 metabolite features demonstrates rapid, reversible control of major metabolic pathways by the individual vigilance states. Within this framework, whereas a switch to wake reduces fatty acid oxidation, a switch to slow-wave sleep increases it, and the transition to rapid eye movement sleep results in elevation of tricarboxylic acid (TCA) cycle intermediates. Thus, in addition to daily regulation of metabolism, there exists a surprising and complex underlying orchestration across sleep and wake. Both likely play an important role in optimizing metabolic circuits for human performance and health., Competing Interests: Declaration of interests M.K. and P.S. are co-founders of a company employing SESI-MS commercially, Deep Breath Intelligence (DBI)., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

While catalytic electron flow and photoreactivation of CPD-photolyases are increasingly understood, the microscopic details of the 64-photolyase repair mechanism are perpetually debated. Here, we investigate in long-time (μs) molecular dynamics simulations combined with extensive quantum mechanical/molecular mechanical (QM/MM) simulations the primary electron transfer (ET) reactions in 64-photolyase of Drosophila melanogaster ( D. melanogaster ). The characterization of the relative energetics of locally excited and charge separated states in the (6-4) photoproduct enzyme repair complex reveals a charge-separated state involving the adenine moiety of the FADH - cofactor that facilitates reduction of the photoproduct. Microscopic details of the collective reaction coordinate of ET reactions are identified that involve the reorganization of the hydrogen bond network and structural relaxation of the active site. The simulations reveal complex active site relaxation dynamics involving distinguished amino acids (Lys246, His365, and His369), conformational reorganization of the hydroxyl group of the (6-4) photoproduct, and a strengthening of hydrogen bonds with immobilized water molecules. In particular, rotation of the Lys246 side chain is found to impose a double-well character along the reaction coordinate of the ET reaction. Our findings suggest that the primary ET reactions in the (6-4) photoproduct enzyme repair complex of D. melanogaster are governed by a complex multi-minima active site relaxation dynamics and potentially precede the equilibration of the protein. ET pathways mediated by the adenine moiety and the 5' side of the photoproduct are proposed to be relevant for triggering the catalytic (6-4) photoproduct reactivation.

Background: Therapeutic management of epilepsy remains a challenge, since optimal systemic antiseizure medication (ASM) concentrations do not always correlate with improved clinical outcome and minimal side effects. We tested the feasibility of noninvasive real-time breath metabolomics as an extension of traditional therapeutic drug monitoring for patient stratification by simultaneously monitoring drug-related and drug-modulated metabolites., Methods: This proof-of-principle observational study involved 93 breath measurements of 54 paediatric patients monitored over a period of 2.5 years, along with an adult's cohort of 37 patients measured in two different hospitals. Exhaled breath metabolome of epileptic patients was measured in real time using secondary electrospray ionisation-high-resolution mass spectrometry (SESI-HRMS)., Results: We show that systemic ASM concentrations could be predicted by the breath test. Total and free valproic acid (VPA, an ASM) is predicted with concordance correlation coefficient (CCC) of 0.63 and 0.66, respectively. We also find (i) high between- and within-subject heterogeneity in VPA metabolism; (ii) several amino acid metabolic pathways are significantly enriched ( p  < 0.01) in patients suffering from side effects; (iii) tyrosine metabolism is significantly enriched ( p  < 0.001), with downregulated pathway compounds in non-responders., Conclusions: These results show that real-time breath analysis of epileptic patients provides reliable estimations of systemic drug concentrations along with risk estimates for drug response and side effects., Competing Interests: Competing interestsPS and MK are cofounders of Deep Breath Intelligence AG (Switzerland), which develops breath-based diagnostic tools. KS is consultant for Deep Breath Intelligence AG (Switzerland). All other authors declare no competing interests. The breath-analysis concept of predicting drug concentrations and risk scores, and the data-processing pipeline discussed here have been incorporated in the European patents 20186274.5, filed on July 16th 2020 and 21185400.5, filed on July 13th 2021, respectively., (© The Author(s) 2021.)