Evaluation of peri-implant perfusion in patients who underwent avascular augmentation or microvascular reconstruction using laser Doppler flowmetry and tissue spectrophotometry: a prospective comparative clinical study.

OBJECTIVES: The aim of this study was to evaluate the peri-implant perfusion, such as oxygen saturation, the relative amount of hemoglobin, and blood flow, in implants placed in pristine bone and avascular and microvascular grafts using a non-invasive measurement method. MATERIALS AND METHODS: A total of 58 patients with 241 implants were included. Among them, 106 implants were based in native bone (group I), 75 implants were inserted into avascular bone grafts (group II), and 60 implants were placed in microvascular bone grafts (group III). Gingival perfusion was measured using laser Doppler flowmetry and tissue spectrophotometry (LDF-TS). Implants with signs of gingival inflammation were excluded to analyze healthy implant perfusion in different bony envelopes. RESULTS: The mean values for oxygen saturation, relative hemoglobin levels, and blood flow did not differ significantly between the groups (p = 0.404, p = 0.081, and p = 0.291, respectively). There was no significant difference in perfusion between implants that were surrounded by mucosa and implants based within cutaneous transplants (p = 0.456; p = 0.628, and p = 0.091, respectively). CONCLUSION: No differences in perfusion were found between implants inserted into native bone and implants involving bone or soft tissue augmentation. However, implants based in avascular and microvascular transplants showed higher rates of peri-implant inflammation. CLINICAL RELEVANCE: Peri-implant perfusion seems to be comparable for all implants after they heal, irrespective of their bony surroundings. Although perfusion does not differ significantly, other factors may make implants in avascular and microvascular transplants vulnerable to peri-implant inflammation.

Does the Anastomosis Recipient Vessel Have an Influence on Free Flap Perfusion in Microvascular Head and Neck Reconstruction-A Retrospective Analysis of 338 Cases with Comparison of Flap Perfusion between Different Arterial and Venous Recipient Vessels in Radial Free Forearm Flaps, Anterolateral Thigh Flaps, and Fibula Free Flaps.

Background: Flap perfusion is a prerequisite for microvascular free flap survival and a parameter routinely used for flap monitoring. The aim of this study was to investigate the influence of the anastomosis recipient vessel on flap perfusion. Methods: Flap perfusion was retrospectively analyzed in 338 patients who underwent head and neck reconstruction with microvascular free flaps between 2011 and 2020. The Oxygen-to-see tissue oxygen analysis system measurements for intraoperative and postoperative flap blood flow, hemoglobin concentration, and hemoglobin oxygen saturation at 8 and 2 mm tissue depths were compared between arterial anastomosis recipient vessels (external carotid artery [ECA], facial artery [FAA], lingual artery [LIA], and superior thyroid artery [STA]) and venous anastomosis recipient vessels (internal jugular vein [IJV], combination of IJV and IJV branches, IJV branches, and external jugular vein). Results: The postoperative hemoglobin concentration at 2 mm tissue depth differed significantly between arterial anastomosis recipient vessels (ECA, 41.0 arbitrary units [AU]; FAA, 59.0 AU; LIA, 51.5 AU; STA, 59.0 AU; p = 0.029). This difference did not persist in the multivariable testing (p = 0.342). No other differences in flap blood flow, hemoglobin concentration, or hemoglobin oxygen saturation were observed between the arterial and venous anastomosis recipient vessels (p > 0.05 for all). Conclusions: The arterial and venous recipient vessels used for anastomosis did not influence microvascular free flap perfusion. This underlines the capability of the studied recipient vessels to adequately perfuse free flaps, may explain the observed indifferent flap survival rates between commonly used anastomosis recipient vessels, and implies that the recipient vessel is not a confounding variable for flap monitoring with the Oxygen-to-see tissue oxygen analysis system. Further prospective studies are needed to confirm the findings.

Development of a universal cutting guide for raising deep circumflex iliac artery flaps.

PURPOSE: The deep circumflex iliac crest flap (DCIA) is used for the reconstruction of the jaw. For fitting of the transplant by computer-aided planning (CAD), a computerized tomography (CT) of the jaw and the pelvis is necessary. Ready-made cutting guides save a pelvic CT and healthcare resources while maintaining the advantages of the CAD planning. METHODS: A total of 2000 CTs of the pelvis were divided into groups of 500 by sex and age (≤ 45 and > 45 years). Three-dimensional (3D) pelvis models were aligned and averaged. Cutting guides were designed on the averaged pelvis for each group and an overall averaged pelvis. The cutting guides and 50 randomly selected iliac crests (10 from each group and 10 from the whole collective) were 3D printed. The appropriate cutting guide was mounted to the iliac crest and a cone beam CT was performed. The thickness of the space between the iliac crest and the cutting guide was evaluated. RESULTS: Overall the mean thickness of the space was 2.137 mm and the mean volume of the space was 4513 mm3. The measured values were significantly different between the different groups. The overall averaged group had not the greatest volume, maximum thickness and mean thickness of the space. CONCLUSION: Ready-made cutting guides for the DCIA flap fit to the iliac crest and make quick and accurate flap raising possible while radiation dose and resources can be saved. The cutting guides fit sufficient to the iliac crest and should keep the advantages of a standard CAD planning.

Optical Three-Dimensional Imaging for Objective Evaluation of the Donor Site after Anterolateral Thigh Flap Surgery.

Background: The high volume of the fasciomyocutaneous anterolateral thigh flaps (ALT) is suitable for the reconstruction of pronounced soft tissue defects. At the same time, harvesting ALT results in a drastic change in thigh shape. Here, we present an optical three-dimensional imaging method for thigh comparison, which can be an objective and reproducible method for evaluating donor sites after ALT harvesting. Methods: In total, 128 thighs were scanned with an optical three-dimensional scanner, Vectra XT ®. Sixty-eight non-operated right and left thighs were compared and served as a control. Sixty thighs were scanned in the ALT group. The average surface area deviations, thigh volume, thigh circumference, and flap ratio to thigh circumference were calculated. The results were correlated with Δthigh circumference and Δvolume of the unoperated thighs of the control group. Results: No significant difference between the thigh volumes of the right and left thighs was found in the control group. Removal of an ALT flap showed a significant (p < 0.007) volume reduction compared to unoperated thighs (2.7 ± 0.8 L and 3.3 ± 0.9 L, respectively). Flap area correlated strongly with the Δthigh circumference (r = 0.66, p < 0.001) and Δvolume (r = 0.68, p < 0.001). Strong correlations were observed between flap ratio and thigh circumference with Δhigh circumference (r = 0.57, p < 0.001) and Δvolume (r = 0.46, p < 0.05). Conclusions: Optical three-dimensional imaging provides an objective and reproducible tool for detecting changes in thigh morphology volume differences after ALT harvesting.

Evaluation of bone contact area and intercondylar distance changes in orthognathic surgery - a comparison between BSSO and HSSO technique depending on mandibular displacement extent.

OBJECTIVES: The present study aims to assess the impact of bilateral and high oblique sagittal split osteotomy (BSSO/HSSO), as well as displacement distances and directions on the expected and achievable bone contact area (BCA) and changes in the intercondylar distance (ICD). The primary question addressed is whether mandibular splitting through BSSO results in a greater BCA and/or ICD when compared to splitting through HSSO. MATERIALS AND METHODS: Totally 80 mandibular displacements were performed on 20 fresh cadavers, for each subject, four splints were produces to facilitate mandibular advancement as well as setbacks of 4 and 8 mm. Pre- and postoperative CBCT scans were performed to plan the surgical procedures and to analyze the expected and achieved BCA and ICD. RESULTS: Regarding the maximum mandibular displacement, the expected BCA for HSSO/BSSO were 352.58 ± 96.55mm2 and 1164.00 ± 295.50mm2, respectively, after advancement and 349.11 ± 98.42mm2 and 1344.70 ± 287.23mm2, respectively, after setback. The achieved BCA for HSSO/BSSO were 229.37 ± 75.90mm2 and 391.38 ± 189.01mm2, respectively, after advancement and 278.03 ± 97.65mm2 and 413.52 ± 169.52 mm2, respectively after setback. The expected ICD for HSSO/BSSO were 4.51 ± 0.73 mm and 3.25 ± 1.17 mm after advancement and - 5.76 ± 1.07 mm and - 4.28 ± 1.58 mm after setback. The achieved ICD for HSSO/BSSO were 2.07 ± 2.9 mm and 1.7 ± 0.60 mm after advancement and - 2.57 ± 2.78 mm and - 1.28 ± 0.84 mm after setback. Significant differences between the BCA after HSSO and BSSO were at each displacement (p < 0.001), except for the achieved BCA after 8-mm setback and advancement (p ≥ 0.266). No significant differences were observed regarding ICD, except for the expected ICD after 8-mm setback and advancement (p ≤ 0.037). CONCLUSIONS: Compared to the virtual planning, the predictability regarding BCA and ICD was limited. ICD showed smaller clinical changes, BCA decreased significantly in the BSSO group. CLINICAL RELEVANCE: BCA and ICD might have been less important in choosing the suitable split technique. in orthognathic surgery.

Influence of microvascular mandibular bony reconstruction on the posterior airway space: A retrospective cohort study.

INTRODUCTION: The posterior airway space (PAS) is a common site of passive obstructions with high morbidity. Surgical changes to the craniomandibular system may affect the PAS. Data regarding the effects of mandibular reconstruction using vascularized bone flaps on PAS are insufficient. This retrospective cohort study aimed to investigate changes in PAS after mandibular reconstruction. MATERIALS AND METHODS: Pre- and post-reconstructive computed tomography scans of 40 patients undergoing segmental mandibulectomy and mandibular reconstruction with deep circumflex iliac artery or fibula flaps were analyzed. Absolute differences in PAS geometry and relative trends of PAS volume changes were compared within the study population and between subgroups formed according to the extent of resection, timing and type of reconstruction, and presence of pre-reconstructive radiotherapy. RESULTS: Irradiated patients were characterized by an increase in PAS volume after reconstruction. Absolute differences in total PAS volume after reconstruction were significantly different (p = 0.024) compared to non-irradiated patients. Reconstruction of central mandible segments resulted in decrease of the cross-sectional PAS areas. Absolute differences in middle cross-sectional PAS area after reconstruction were significantly different (p = 0.039) compared to non-central reconstructions. Patients who received radiotherapy were less likely to show a total PAS volume reduction after reconstruction (OR: 0.147; p = 0.007), with values adjusted for gender, age, body mass index, timing and type of reconstruction, and transplant length. CONCLUSIONS: Mandibular reconstruction causes changes in PAS geometry. Specifically, reconstructions of central mandibular segments can lead to a reduction in the cross-sectional areas of PAS, and mandibular reconstructions in irradiated sites may cause an increase in PAS volume.

Attached compared with unattached surface probes for monitoring flap perfusion in microvascular head and neck reconstruction: a feasibility study.

Unattached surface probes are commonly used with the O2C analysis system (LEA Medizintechnik, Germany) to monitor microvascular free flap perfusion. This study compared attached and unattached surface probes for extraoral free flaps. The study included 34 patients who underwent extraoral microvascular head and neck reconstruction between 2020 and 2022. Flap perfusion was monitored postoperatively using the O2C analysis system at 0, 12, 24, 36, and 48 h, with an attached surface probe at 3 mm tissue depth and an unattached surface probe at 2 mm and 8 mm tissue depths. Clinical complications, technical errors, and perfusion measurement values were compared. No clinical complications (attachment suture infections) or technical errors (probe detachment) occurred. Flap blood flow values of the probes were partially different (3 mm vs. 2 and 8 mm: p < 0.001; p = 0.308) and moderately correlated (3 mm with 2 and 8 mm: r = 0.670, p < 0.001; r = 0.638, p < 0.001). Hemoglobin concentration and oxygen saturation values were generally different (3 mm vs. 2 and 8 mm: all p < 0.001) and variably correlated (3 mm with 2 and 8 mm: r = 0.756, r = 0.645; r = 0.633, r = 0.307; all p < 0.001). Both probes are comparable in terms of technical feasibility and patient safety, with flap perfusion values dependent on tissue measurement depth.

Predictive factors and repetition numbers for intraoperative additional resection of initially involved soft tissue resection margins in oral squamous cell carcinoma: a retrospective study.

BACKGROUND: Intraoperative additional resection (IAR) of initially microscopically involved soft tissue resection margins negatively impacts tumor recurrence in oral squamous cell carcinoma (OSCC). Increasing the selected initial macroscopic resection margin distance beyond the tumor tissue may help prevent IAR; however, the existence of predictive factors for IAR and IAR repetition numbers remains unclear. This study aimed to identify predictive factors for IAR and to evaluate the IAR repetition numbers in soft tissue for surgically treated OSCC. METHODS: A cohort of 197 patients surgically treated for OSCC between 2008 and 2019 was retrospectively reviewed (44 patients with IAR and 153 patients without IAR). Clinical parameters (tumor location, midline involvement, clinical T-status, time between staging imaging and surgery, bone resection, monopolar use, and reconstruction flap size) and histopathological parameters (pathologic T-status [pT-status], grading, vascular invasion, and lymphatic invasion) of the two groups were compared. RESULTS: Patients with and without IAR differed in their histopathological parameters, such as pT-status above 2 (47.7% vs. 28.1%, p = 0.014) and lymphatic invasion (13.6% vs. 4.6%, p = 0.033); however, their clinical parameters were similar (all p > 0.05). Only pT-status above 2 was predictive for IAR in a multivariable regression analysis (odds ratio 2.062 [confidence interval 1.008-4.221], p = 0.048). The IAR repetition numbers varied from zero to two (zero = 84.4%, one = 11.4%, and two = 2.3%). CONCLUSIONS: Only postoperative available pT-status was identified as a predictive factor for IAR, underscoring the importance of improving preoperative or intraoperative tumor visualization in OSCC before selecting the initial macroscopic resection margin distance to avoid IAR.

Regulation of ABCA1 by miR-33 and miR-34a in the Aging Eye.

Many age-related diseases, including age-related macular degeneration (AMD), go along with local lipid accumulation and dysregulated lipid metabolism. Several genes involved in lipid metabolism, including ATP-binding cassette transporter A1 (ABCA1), were associated with AMD through genome-wide association studies. Recent studies have shown that loss of ABCA1 in the retinal pigment epithelium (RPE) leads to lipid accumulation and RPE atrophy, a hallmark of AMD, and that antagonizing ABCA1-targeting microRNAs (miRNAs) attenuated pathological changes to the RPE or to macrophages. Here, we focus on two lipid metabolism-modulating miRNAs, miR-33 and miR-34a, which show increased expression in aging RPE cells, and on their potential to regulate ABCA1 levels, cholesterol efflux, and lipid accumulation in AMD pathogenesis.

Flap perfusion monitoring with an attached surface probe in microvascular reconstruction of the oral cavity.

OBJECTIVES: Postoperative flap monitoring is essential in oral microvascular reconstruction for timely detection of vascular compromise. This study investigated the use of attached surface probes for the oxygen-2-see (O2C) analysis system (LEA Medizintechnik, Germany) for intraoral flap perfusion monitoring. MATERIALS AND METHODS: The study included 30 patients who underwent oral reconstruction with a microvascular radial-free forearm flap (RFFF) or anterolateral thigh flap (ALTF) between 2020 and 2022. Flap perfusion was measured with attached (3-mm measurement depth) and unattached surface probes (2- and 8-mm measurement depths) for the O2C analysis system at 0, 12, 24, 36, and 48 h postoperatively. Flap perfusion monitoring with attached surface probes was evaluated for cut-off values for flap blood flow, hemoglobin concentration, and hemoglobin oxygen saturation indicative of vascular compromise and for accuracy and concordance with unattached surface probes. RESULTS: Three RFFFs were successfully revised, and one ALTF was unsuccessfully revised. The cut-off values indicative of vascular compromise for flap perfusion monitoring with attached surface probes were for RFFF and ALTF: blood flow < 60 arbitrary units (AU) and < 40AU, hemoglobin concentration > 100AU and > 80AU (both > 10% increase), and hemoglobin oxygen saturation < 40% and < 30%. Flap perfusion monitoring with attached surface probes yielded a 97.1% accuracy and a Cohen's kappa of 0.653 (p < 0.001). CONCLUSIONS: Flap perfusion monitoring with attached surface probes for the O2C analysis system detected vascular compromise accurately and concordantly with unattached surface probes. CLINICAL RELEVANCE: Attached surface probes for the O2C analysis system are a feasible option for intraoral flap perfusion monitoring.

Evaluation of an artificial intelligence-based algorithm for automated localization of craniofacial landmarks.

OBJECTIVES: Due to advancing digitalisation, it is of interest to develop standardised and reproducible fully automated analysis methods of cranial structures in order to reduce the workload in diagnosis and treatment planning and to generate objectifiable data. The aim of this study was to train and evaluate an algorithm based on deep learning methods for fully automated detection of craniofacial landmarks in cone-beam computed tomography (CBCT) in terms of accuracy, speed, and reproducibility. MATERIALS AND METHODS: A total of 931 CBCTs were used to train the algorithm. To test the algorithm, 35 landmarks were located manually by three experts and automatically by the algorithm in 114 CBCTs. The time and distance between the measured values and the ground truth previously determined by an orthodontist were analyzed. Intraindividual variations in manual localization of landmarks were determined using 50 CBCTs analyzed twice. RESULTS: The results showed no statistically significant difference between the two measurement methods. Overall, with a mean error of 2.73 mm, the AI was 2.12% better and 95% faster than the experts. In the area of bilateral cranial structures, the AI was able to achieve better results than the experts on average. CONCLUSION: The achieved accuracy of automatic landmark detection was in a clinically acceptable range, is comparable in precision to manual landmark determination, and requires less time. CLINICAL RELEVANCE: Further enlargement of the database and continued development and optimization of the algorithm may lead to ubiquitous fully automated localization and analysis of CBCT datasets in future routine clinical practice.

Effect of systemic antiresorptive medication on the histopathological parameters of implant osseointegration in an in vivo rodent study.

BACKGROUND: The purpose of this study was to evaluate the osseointegration of zirconia and titanium implants in the rat maxilla in specimens under systemic antiresorptive therapy. MATERIALS AND METHODS: After 4 weeks of systematic medication administration (either zoledronic acid or alendronic acid), 54 rats received one zirconia and one titanium implants that were immediately inserted in the rat maxilla after tooth extraction. Twelve weeks after implant placement, histopathological samples were evaluated for implant osteointegration parameters. RESULTS: The bone-implant-contact (BIC) ratio revealed no significant inter-group or inter-material differences. The distance between the implant shoulder to the bone level was significantly greater around the titanium implants of the zoledronic acid group compared to the zirconia implants of the control group (p = 0.0005). On average, signs of new bone formation could be detected in all groups, although often without statistical differences. Signs of bone necrosis were only detected around the zirconia implants of the control group (p < 0.05). CONCLUSIONS: At the 3-month follow-up, no implant material was demonstrably better than the others in terms of osseointegration metrics under systemic antiresorptive therapy. Further studies are necessary to determine whether there are differences in the osseointegration behavior of the different materials.

Mandible segmentation from CT data for virtual surgical planning using an augmented two-stepped convolutional neural network.

PURPOSE: For computer-aided planning of facial bony surgery, the creation of high-resolution 3D-models of the bones by segmenting volume imaging data is a labor-intensive step, especially as metal dental inlays or implants cause severe artifacts that reduce the quality of the computer-tomographic imaging data. This study provides a method to segment accurate, artifact-free 3D surface models of mandibles from CT data using convolutional neural networks. METHODS: The presented approach cascades two independently trained 3D-U-Nets to perform accurate segmentations of the mandible bone from full resolution CT images. The networks are trained in different settings using three different loss functions and a data augmentation pipeline. Training and evaluation datasets consist of manually segmented CT images from 307 dentate and edentulous individuals, partly with heavy imaging artifacts. The accuracy of the models is measured using overlap-based, surface-based and anatomical-curvature-based metrics. RESULTS: Our approach produces high-resolution segmentations of the mandibles, coping with severe imaging artifacts in the CT imaging data. The use of the two-stepped approach yields highly significant improvements to the prediction accuracies. The best models achieve a Dice coefficient of 94.824% and an average surface distance of 0.31 mm on our test dataset. CONCLUSION: The use of two cascaded U-Net allows high-resolution predictions for small regions of interest in the imaging data. The proposed method is fast and allows a user-independent image segmentation, producing objective and repeatable results that can be used in automated surgical planning procedures.

Guided discovery learning: A follow-up study of try-it-yourself surgery and subsequent video-assisted teaching for oral surgical skills training.

INTRODUCTION: The purpose of this follow-up study was to assess the effects of discovery learning and subsequent standardised teaching on students' advanced dental surgical skills. MATERIALS AND METHODS: A total of 29 dental students who had no theoretical education on the Rehrmann flap were included in the skills training programme. Without prior teaching, the students were initially asked to perform a discovery surgery with a subsequent multiple-choice test (MCT) on the first day. This was followed by a video-assisted teaching lecture. On the same day and after 122 days, the surgery and MCT were repeated. Aside from the practical and theoretical assessment forms, the training was evaluated by the students themselves. RESULTS: Regarding the evaluation of surgery (EOS), significant improvements were measured between the first surgery and the second and third surgeries (p > .001). In addition, the theoretical test scores showed significant improvements after the first test when compared with the second (p = .004) and third tests (p < .001). For both assessments, no significant difference was found between the second and third attempts. The MCT and EOS in the second and third attempts strongly correlated (r = .77 and r = .71 respectively). CONCLUSION: The dental students in this study successfully learned a complex oral surgical procedure, the Rehrmann flap technique, for closing oro-antral communications. The participants indicated their high satisfaction with the teaching approach. After 122 days of follow-up, their practical and theoretical test scores remained high and presented no significant difference, which suggests that the newly learnt individual skills were retained.

A basic macroeconomic agent-based model for analyzing monetary regime shifts.

In macroeconomics, an emerging discussion of alternative monetary systems addresses the dimensions of systemic risk in advanced financial systems. Monetary regime changes with the aim of achieving a more sustainable financial system have already been discussed in several European parliaments and were the subject of a referendum in Switzerland. However, their effectiveness and efficacy concerning macro-financial stability are not well-known. This paper defines the economic requirements for modeling the current monetary system and introduces the corresponding macroeconomic agent-based model (MABM) in a continuous-time stochastic agent-based simulation environment with a provenance model. This MABM aims to present a starting point for exploring and analyzing monetary reforms. In this context, the monetary system affects the lending potential of banks and might impact the dynamics of financial crises. MABMs are predestined to replicate emergent financial crisis dynamics, analyze institutional changes within a financial system, and thus measure macro-financial stability. The used simulation environment makes the model more accessible and facilitates exploring the impact of different hypotheses and mechanisms in a less complex way. Moreover, the model replicates a wide range of stylized economic facts, which validates it as an analysis tool to implement and compare monetary regime shifts.

Evaluation of the long-term results of vascular anastomosis using polyurethane adhesive and shape-memory stent in the rat carotid artery model.

INTRODUCTION: In free flaps, 5%-10% of complications are related to failure of sutured vascular anastomoses. Adhesive-based microvascular anastomoses are potential alternatives but are associated with failure rates of 70% in research studies. VIVO is a new adhesive with slow biodegradation within 6 months that has shown a 100% patency rate in research studies over 2 h observation time but long-term patency has not been evaluated. The authors hypothesize that VIVO will enable a reliable microvascular procedure comparable to sutured anastomoses over a 28-day period. MATERIALS AND METHODS: The right common carotid artery of 60 male Sprague Dawley rats, ~450 g, were used for microvascular end-to-end anastomosis. VIVO was applied with reduced sutures with a temporary catheter in one group and in the other with a custom-shaped memory stent. Anastomoses with eight interrupted sutures served as control. All groups were n = 20. Anastomosis time and bleeding were recorded for each procedure. Doppler flowmetry was performed 20 min, 1, 10, and 28 days postoperatively. Postmortem toluidine staining was used for semi-quantitative analysis of stenosis, thrombosis, necrosis, and aneurysm formation by histologic evaluation. RESULTS: No occlusion was detected 20 min and 1 day postoperative, and after 28 days of observation in all anastomoses. The anastomosis time of the VIVO with catheter group was about 32% significantly faster than the VIVO with stent group. In the VIVO group with stent, the bleeding time was ~80% shorter than in the control group with 2.1 ± 0.3 and VIVO with catheter 2.0 ± 0.5 (p ≤ .001 each). Minor and nonsignificant stent-associated thrombus formation and stent-typical intraluminal stenosis were detected exclusively in the VIVO with stent group. CONCLUSION: Within the limitations of a rat study, the use of VIVO in anastomosis showed promising results. VIVO with catheter was found to be advantageous.

HIF1 and DROSHA are involved in MMACHC repression in hypoxia.

The MMACHC gene encodes for an enzyme involved in intracellular vitamin B12 metabolism, and autosomal recessive defects in MMACHC represent the most common disorder of intracellular vitamin B12 metabolism. Recent studies have identified increased levels of reactive oxygen species in cells and tissues with MMACHC dysfunction, suggesting a role for oxidative stress in disease. To investigate the link between oxidative stress and MMACHC, we exposed mice as well as human and mouse cells to hypoxia, and found significant repression of MMACHC in all investigated tissues (retina, eyecup, liver, kidney) and cell lines (HeLa, ARPE-19, human and mouse fibroblasts, 661W). Furthermore, in HeLa cells, we found transcriptional repression already at 5% oxygen, which was stable during prolonged hypoxia up to 5 days, and a return of MMACHC transcripts to normal levels only 24 h after reoxygenation. This hypoxia-induced downregulation of MMACHC was not due to altered function of the known MMACHC controlling transcription factor complex HCFC1/THAP11/ZNF143. Using in vitro RNA interference against hypoxia-induced transcription factors (HIF1A, HIF2A and REST) as well as the microRNA transcription machinery (DROSHA), we observed release of hypoxia-dependent downregulation of MMACHC expression by HIF1A and DROSHA knockdowns, whose combined effect was additive. Together, these results strongly indicate that MMACHC is a hypoxia-regulated gene whose downregulation appears to be partially mediated through both hypoxia-induced transcription factor and microRNA machinery. These findings suggest that oxidative stress could impair vitamin B12 metabolism by repression of MMACHC in healthy as well as in diseased individuals.

Augmented Reality-Based Surgery on the Human Cadaver Using a New Generation of Optical Head-Mounted Displays: Development and Feasibility Study.

BACKGROUND: Although nearly one-third of the world's disease burden requires surgical care, only a small proportion of digital health applications are directly used in the surgical field. In the coming decades, the application of augmented reality (AR) with a new generation of optical-see-through head-mounted displays (OST-HMDs) like the HoloLens (Microsoft Corp) has the potential to bring digital health into the surgical field. However, for the application to be performed on a living person, proof of performance must first be provided due to regulatory requirements. In this regard, cadaver studies could provide initial evidence. OBJECTIVE: The goal of the research was to develop an open-source system for AR-based surgery on human cadavers using freely available technologies. METHODS: We tested our system using an easy-to-understand scenario in which fractured zygomatic arches of the face had to be repositioned with visual and auditory feedback to the investigators using a HoloLens. Results were verified with postoperative imaging and assessed in a blinded fashion by 2 investigators. The developed system and scenario were qualitatively evaluated by consensus interview and individual questionnaires. RESULTS: The development and implementation of our system was feasible and could be realized in the course of a cadaver study. The AR system was found helpful by the investigators for spatial perception in addition to the combination of visual as well as auditory feedback. The surgical end point could be determined metrically as well as by assessment. CONCLUSIONS: The development and application of an AR-based surgical system using freely available technologies to perform OST-HMD-guided surgical procedures in cadavers is feasible. Cadaver studies are suitable for OST-HMD-guided interventions to measure a surgical end point and provide an initial data foundation for future clinical trials. The availability of free systems for researchers could be helpful for a possible translation process from digital health to AR-based surgery using OST-HMDs in the operating theater via cadaver studies.

Host inflammatory response and clinical parameters around implants in a rat model using systemic alendronate and zoledronate acid drug administrations.

Implant outcomes in comparison to a natural tooth in a rat model using systemic alendronate and zoledronate acid drug administrations were assessed. Fifty-four Sprague-Dawley rats were randomly allocated into two experimental groups (drug application of zoledronic acid; 0.04 mg/kg intravenously once a week and alendronic acid; 0.2 mg/kg subcutaneously five times a week) and one control group with 18 animals in each group. Drug delivery was conducted for a period of 4 months. After 4 weeks either a zirconia or a titanium implant was immediately inserted in the socket of the first molar of the upper jaw. In vivo investigations included host inflammatory parameters and the implant survival and success rates for up to 3 months. Material incompatibilities against titanium and zirconia nanoparticles were evaluated in vitro after stimulation of rat spleen cells. In vivo, IL-6 release around titanium implants demonstrated significantly higher values in the control group (p = 0.02) when compared to the zoledronic acid group. Around the natural tooth without drug administration, the control group showed higher IL-6 values compared with the alendronic acid group (p = 0.01). In vitro, only lipopolysaccharide and not the implant's nanoparticles stimulated significant IL-6 and TNFα production. In terms of the primary aim of in vivo and in vitro IL-6 and TNFα measurements, no implant material was superior to the other. No significant in vitro stimulation of rat spleen cells was detected with respect to titanium oxide and zirconium oxide nanoparticles.

Regulation of ABCA1 by AMD-Associated Genetic Variants and Hypoxia in iPSC-RPE.

Age-related macular degeneration (AMD) is a progressive disease of the macula characterized by atrophy of the retinal pigment epithelium (RPE) and photoreceptor degeneration, leading to severe vision loss at advanced stages in the elderly population. Impaired reverse cholesterol transport (RCT) as well as intracellular lipid accumulation in the RPE are implicated in AMD pathogenesis. Here, we focus on ATP-binding cassette transporter A1 (ABCA1), a major cholesterol transport protein in the RPE, and analyze conditions that lead to ABCA1 dysregulation in induced pluripotent stem cell (iPSC)-derived RPE cells (iRPEs). Our results indicate that the risk-conferring alleles rs1883025 (C) and rs2740488 (A) in ABCA1 are associated with increased ABCA1 mRNA and protein levels and reduced efficiency of cholesterol efflux from the RPE. Hypoxia, an environmental risk factor for AMD, reduced expression of ABCA1 and increased intracellular lipid accumulation. Treatment with a liver X receptor (LXR) agonist led to an increase in ABCA1 expression and reduced lipid accumulation. Our data strengthen the homeostatic role of cholesterol efflux in the RPE and suggest that increasing cellular cholesterol export by stimulating ABCA1 expression might lessen lipid load, improving RPE survival and reducing the risk of developing AMD.