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Due to their well-established fracture risk reduction, bisphosphonates are the most frequently used therapeutic agent to treat osteoporosis. Bisphosphonates reduce fracture risk by suppressing bone resorption, but the lower bone turnover could have a negative impact on bone quality at the tissue level. Here, we directly assess the structural and mechanical characteristics of cancellous bone from the lumbar vertebrae (L5) in non-treated osteoporotic controls (n = 21), mid-term alendronate-treated osteoporotic patients (n = 6), and long-term alendronate-treated osteoporotic patients (n = 7). The strength and toughness of single trabeculae were evaluated, while the structure was characterised through measurements of microdamage accumulation, mineralisation distribution, and histological indices. The alendronate-treated cases had a reduced eroded surface (ES/BS, p < 0.001) and a higher bone mineralisation in comparison to non-treated controls (p = 0.037), which is indicative of low turnover associated with treatment. However, the amount of microdamage and the mechanical properties were similar among the control and treatment groups. As the tissue mineral density (TMD) increased significantly with alendronate treatment compared to non-treated osteoporotic controls, the reduction in resorption cavities could counterbalance the higher TMD allowing the alendronate-treated bone to maintain its mechanical properties and resist microdamage accumulation. A multivariate analysis of the possible predictors supports the theory that multiple factors (e.g., body mass index, TMD, and ES/BS) can impact the mechanical properties. Our results suggest that long-term alendronate treatment shows no adverse impact on mechanical cancellous bone characteristics.

Abstract The aim of this study was to evaluate the long-term efficacy of a single ultrasound-guided high-intensity focused ultrasound (US-HIFU) treatment in patients with breast fibroadenoma (FA) in terms of volume and pain reduction as well as palpation findings. From december 2013 until november 2014 27 women with a symptomatic FA were treated in one HIFU-session. Follow-up visits were performed after 7 days, 6 months and 1, 2, 3 and 5 years with clinical examination and ultrasound. One year after the procedure, a core needle biopsy of the residual lesion was offered. There was a significant volume reduction 6 months after HIFU from 1083.10 to 347.13 mm3 (p

Abstract Background Early identification of patients with chronic kidney disease (CKD) and advancing kidney insufficiency, followed by specialist care, can decelerate the progression of the disease. However, awareness of the importance and possible consequences of kidney insufficiency is low among doctors and patients. Since kidney insufficiency can be asymptomatic even in higher stages, it is often not even known to those belonging to risk groups. This study aims to clarify whether, for hospitalised patients with advanced chronic kidney disease, a risk-based appointment with a nephrology specialist reduces disease progression. Methods The target population of the study is hospitalised CKD patients with an increased risk of end-stage renal disease (ESRD), more specifically with an ESRD risk of at least 9% in the next 5 years. This risk is estimated by the internationally validated Kidney Failure Risk Equation (KFRE). The intervention consists of a specific appointment with a nephrology specialist after the hospital stay, while control patients are discharged from the hospital as usual. Eight medical centres include participants according to a stepped-wedge design, with randomised sequential centre-wise crossover from recruiting patients into the control group to recruitment to the intervention. The estimated glomerular filtration rate (eGFR) is measured for each patient during the hospital stay and after 12 months within the regular care by the general practitioner. The difference in the change of the eGFR over this period is compared between the intervention and control groups and considered the primary endpoint. Discussion This study is designed to evaluate the effect of risk-based appointments with nephrology specialists for hospitalised CKD patients with an increased risk of end-stage renal disease. If the intervention is proven to be beneficial, it may be implemented in routine care. Limitations will be examined and discussed. The evaluation will include further endpoints such as non-guideline-compliant medication, economic considerations and interviews with contributing physicians to assess the acceptance and feasibility of the intervention. Trial registration German Clinical Trials Register DRKS00029691 . Registered on 12 September 2022.

Premature fusion of cranial sutures is a common problem with an incidence of 3-5 per 10,000 live births. Despite progress in understanding molecular/genetic factors affecting suture function, the complex process of premature fusion is still poorly understood. In the present study, corresponding excised segments of nine patent and nine prematurely fused sagittal sutures from infants (age range 3-7 months) with a special emphasis on their hierarchical structural configuration were compared. Cell, tissue and architecture characteristics were analysed by transmitted and polarised light microscopy, 2D-histomorphometry, backscattered electron microscopy and energy-dispersive-x-ray analyses. Apart from wider sutural gaps, patent sutures showed histologically increased new bone formation compared to reduced new bone formation and osseous edges with a more mature structure in the fused portions of the sutures. This pattern was accompanied by a lower osteocyte lacunar density and a higher number of evenly mineralised osteons, reflecting pronounced lamellar bone characteristics along the prematurely fused sutures. In contrast, increases in osteocyte lacunar number and size accompanied by mineralisation heterogeneity and randomly oriented collagen fibres predominantly signified woven bone characteristics in patent, still growing suture segments. The already established woven-to-lamellar bone transition provides evidence of advanced bone development in synostotic sutures. Since structural and compositional features of prematurely fused sutures did not show signs of pathological/defective ossification processes, this supports the theory of a normal ossification process in suture synostosis – just locally commencing too early. These histomorphological findings may provide the basis for a better understanding of the pathomechanism of craniosynostosis, and for future strategies to predict suture fusion and to determine surgical intervention.

Abstract This document reports a brief update to the previously published protocol of the MinDial study. Trial registration German Clinical Trials Register DRKS00029691. Registered on 12 Sept. 2022, https://drks.de/search/en/trial/DRKS00029691 .

Summary: Caspase recruitment domain family member 14 (CARD14) and its variants are associated with both atopic dermatitis (AD) and psoriasis, but their mechanistic impact on skin barrier homeostasis is largely unknown. CARD14 is known to signal via NF-κB; however, CARD14-NF-κB signaling does not fully explain the heterogeneity of CARD14-driven disease. Here, we describe a direct interaction between CARD14 and MYC and show that CARD14 signals through MYC in keratinocytes to coordinate skin barrier homeostasis. CARD14 directly binds MYC and influences barrier formation in an MYC-dependent fashion, and this mechanism is undermined by disease-associated CARD14 variants. These studies establish a paradigm that CARD14 activation regulates skin barrier function by two distinct mechanisms, including activating NF-κB to bolster the antimicrobial (chemical) barrier and stimulating MYC to bolster the physical barrier. Finally, we show that CARD14-dependent MYC signaling occurs in other epithelia, expanding the impact of our findings beyond the skin.

Summary: Omicron surged as a variant of concern in late 2021. Several distinct Omicron variants appeared and overtook each other. We combined variant frequencies and infection estimates from a nowcasting model for each US state to estimate variant-specific infections, attack rates, and effective reproduction numbers (Rt). BA.1 rapidly emerged, and we estimate that it infected 47.7% of the US population before it was replaced by BA.2. We estimate that BA.5 infected 35.7% of the US population, persisting in circulation for nearly 6 months. Other variants—BA.2, BA.4, and XBB—together infected 30.7% of the US population. We found a positive correlation between the state-level BA.1 attack rate and social vulnerability and a negative correlation between the BA.1 and BA.2 attack rates. Our findings illustrate the complex interplay between viral evolution, population susceptibility, and social factors during the Omicron emergence in the US.

Introduction Transurethral resection of bladder tumour (TURBT) is one of the more common procedures performed by urologists. It is often described as an ‘incision-free’ and ‘well-tolerated’ operation. However, many patients experience distress and discomfort with the procedure. Substantial opportunity exists to improve the TURBT experience. An enhanced recovery after surgery (ERAS) protocol designed by patients with bladder cancer and their providers has been developed.Methods and analysis This is a single-centre, randomised controlled trial to investigate the effectiveness of an ERAS protocol compared with usual care in patients with bladder cancer undergoing ambulatory TURBT. The ERAS protocol is composed of preoperative, intraoperative and postoperative components designed to optimise each phase of perioperative care. 100 patients with suspected or known bladder cancer aged ≥18 years undergoing initial or repeat ambulatory TURBT will be enrolled. The change in Quality of Recovery 15 score, a measure of the quality of recovery, between the day of surgery and postoperative day 1 will be compared between the ERAS and control groups.Ethics and dissemination The trial has been approved by the Johns Hopkins Institutional Review Board #00392063. Participants will provide informed consent to participate before taking part in the study. Results will be reported in a separate publication.Trial registration number NCT05905276

IntroductionEnfortumab vedotin (EV) is an antibody drug conjugate approved for advanced urothelial cancer, consisting of a monomethyl auristatin E payload linked to a human monoclonal antibody targeting nectin-4. No validated biomarker predictive of or correlated with response exists for EV. Cutaneous toxicity is among the most common EV-related toxicities and typically emerges in early cycles. This retrospective experience of patients with urothelial cancer treated with EV monotherapy evaluated whether EV-related cutaneous toxicity correlated with improved outcomes including progression-free (PFS) and overall (OS) survival and overall response rate (ORR).Patients and methodsPatients treated with EV monotherapy at Johns Hopkins were identified, and baseline characteristics, treatment, and toxicity details were extracted through chart review. Univariable Cox hazard ratios (HRs) were calculated for assessing the effect of baseline patient characteristics and cutaneous toxicity in PFS and OS. Based on the univariable analysis and known risk factors, all subsequent analyses were adjusted for: Eastern Cooperative Oncology Group performance status, visceral metastases at baseline, gender as well as EV dose, and weight to account for dosing differences. Multivariable Cox proportional HRs were used for comparing PFS and OS between patients with and without cutaneous toxicity, assessing toxicity and EV dose as a time-dependent variables. Adjusted p-values were calculated to compare ORR and disease control rate (DCR) between groups using the Poisson regression model.ResultsOf the 78 patients analyzed, 42 (53.8%) experienced EV-related cutaneous toxicity that appeared early during treatment (median time to occurrence 0.5 months from EV initiation). Cutaneous toxicity correlated with significantly improved OS [HR, 0.48; 95% confidence interval (CI), 0.25, 0.9; P = 0.0235], ORR (68.3% vs. 20.7%, P = 0.0033) and DCR (82.9% vs. 48.3%, P = 0.0122). Median PFS was numerically longer in the cutaneous toxicity group (6.3 vs. 1.7 months), although no significance was achieved in the multivariable analysis (HR, 0.62; 95% CI: 0.35, 0.108; P = 0.0925).ConclusionIn this retrospective study, EV-related cutaneous toxicity was associated with improved patient outcomes. Confirming this observation and understanding its mechanism could lead to discovery of a new clinical biomarker of EV response that can emerge in the first cycle.

Tunnel inspection, i.e. detection of damages and defects on concrete surfaces, is essential for monitoring structural reliability and health conditions of transport facilities, thus providing safe and sustainable urban transportation infrastructures. In this study, an innovative visual-based system is developed for damage and object detection tasks in roadway tunnels based on deep learning techniques. The main components of the developed Machine Vision System such as industrial cameras, flash-based light sources, controller, the synchronization unit and corresponding software programs are designed to collect high-resolution images with sufficient quality from dimly lit tunnel environments in normal traffic flows with an operating speed of 30–50 km/h. Unlike recent studies, the training data includes multiple types of damage such as cracks, spalling, rust, delamination and other surface changes. Furthermore, 10 classes of common tunnel objects including traffic signs, traffic cameras, traffic lights, ventilation ducts, various sensors and cables are labeled for object detection. As state-of-the-art Convolutional Neural Networks, DeepLab and U-Net are trained and evaluated using accuracy metrics for image segmentation. The results highlight the most important parameters of the discussed Machine Vision System as well as the performance of DeepLab and U-Net for object and damage detection.

Enfortumab vedotin (EV) is an antibody-drug conjugate approved for the treatment of refractory advanced urothelial cancer. Cutaneous toxicity is well described but has not been correlated with response. In this retrospective single-center study, data from patients treated with more than one dose of EV between December 2017 and June 2022 were analyzed. Of 56 patients with a median age of 69 yr, 41 (73.2%) were male and 27 (48.2%) had any-grade skin toxicity. For all 51 patients evaluable by physician-assessed Response Evaluation Criteria in Solid Tumors (RECIST) criteria, the response rate was 41.2%. For those with cutaneous toxicity, the response rate was 57.7%; for those without cutaneous toxicity, it was 24.0% (p = 0.0145). All three patients with complete response experienced cutaneous toxicity, and two of these responses remain durable 5 and 24 mo off EV. The median starting weight and body mass index (BMI) were, respectively, 80.86 kg and 26.53 kg/m2 among patients with cutaneous toxicity, and 69.37 kg and 23.29 kg/m2 in patients without (p = 0.0129 and 0.0014, respectively). In this small dataset, EV-related cutaneous toxicity was more common in patients with higher weight and BMI at baseline, and was associated with disease response. Confirmation in prospective trials may confirm this association and lead to an important clinical biomarker of response. Patient summary: We evaluated patients with urothelial cancer who were treated at our institution with enfortumab vedotin (EV). We found that patients who experienced the common side effect of any type of skin toxicity, such as rash or itching, were more likely to have improvement in their cancer from EV treatment than those who did not experience skin toxicity. Patients with higher weight and body mass index when starting EV tended to have more skin toxicity. We conclude that presence of skin toxicity might help doctors make decisions about how to manage the care of patients with EV in the future.

We evaluated daily rapid antigen test (RAT) data from 323 COVID-19–positive university students in Connecticut, USA, during an Omicron-dominant period. Day 5 positivity was 47% for twice-weekly screeners and 26%–28% for less-frequent screeners, approximately halving each subsequent day. Testing negative >10 days before diagnosis (event time ratio (ETR) 0.85 [95% CI 0.75–0.96]) and prior infection >90 days (ETR 0.50 [95% CI 0.33–0.76]) were significantly associated with shorter RAT positivity duration. Symptoms before or at diagnosis (ETR 1.13 [95% CI 1.02–1.25]) and receipt of 3 vaccine doses (ETR 1.20 [95% CI 1.04–1.39]) were significantly associated with prolonged positivity. Exit RATs enabled 53%–74% of students to leave isolation early when they began isolation at the time of the first positive test, but 15%–22% remained positive beyond the recommended isolation period. Factors associated with RAT positivity duration should be further explored to determine relationships with infection duration.

The Bladder Cancer Advocacy Network established the UC-GENOME study in order to create a biobank and data repository for metastatic urothelial carcinoma. Here, the authors present the first characterization and analysis of DNA and RNA sequencing data from the 218 patients included in the UC-GENOME.

Cisplatin-based chemotherapy has been associated with durable disease control in a small subset of patients with metastatic urothelial cancer. However, the mechanistic basis for this phenomenon has remained elusive. Antitumor immunity may underlie these exceptional responders. In a phase II trial evaluating a phased schedule of gemcitabine and cisplatin followed by gemcitabine and cisplatin with ipilimumab for metastatic urothelial cancer, 4 of 36 patients achieved durable disease-free treatment-free survival (DDFTFS) and remain in remission over 5 years after enrolment on the study. We sought to identify the genomic and immunological mechanisms associated with functional cures of such patients. Whole exome sequencing was performed on pretreatment archival tumor tissue. Neoantigen prediction and ranking were performed using a novel pipeline. For a subset of patients with available biospecimens, selected peptides were tested for neoantigen-specific T cell reactivity in peripheral blood CD4+ and CD8+ T cells cultured with autologous antigen-presenting cells at baseline, postchemotherapy, and postchemotherapy and ipilimumab timepoints. Multiplex assays of serum protein analytes were also assessed at each time point. Serum proteomic analysis revealed that pretreatment, patients achieving DDFTFS demonstrated an immune activated phenotype with elevations in TH1 adaptive immunity, costimulatory molecules, and immune checkpoint markers. After combination cisplatin-based chemotherapy and ipilimumab treatment, DDFTFS patients again displayed enrichment for markers of adaptive immunity, as well as T cell cytotoxicity. CD27 was uniquely enriched in DDFTFS patients at all timepoints. Neoantigen reactivity was not detected in any patient at baseline or post two cycles of chemotherapy. Both CD4+ and CD8+ neoantigen-specific T cell reactivity was detected in two of two DDFTFS patients in comparison to zero of five non-DDFTFS patients after combination cisplatin-based chemotherapy and ipilimumab treatment. Antitumor immunity may underlie functional cures achieved in patients with metastatic urothelial cancer treated with cisplatin-based chemotherapy and immune checkpoint blockade. Probing the mechanistic basis for DDFTFS may facilitate the identification of biomarkers, therapeutic components, and optimal treatment sequences necessary to extend this ultimate goal to a larger subset of patients.

Summary: Although it is known that psoriasis is strongly associated with obesity, the mechanistic connection between diet and skin lesions is not well established. Herein, we showed that only dietary fat, not carbohydrates or proteins, exacerbates psoriatic disease. Enhanced psoriatic skin inflammation was associated with changes in the intestinal mucus layer and microbiota composition by high-fat diet (HFD). Change of intestinal microbiota by vancomycin treatment effectively blocked activation of psoriatic skin inflammation by HFD, inhibited the systemic interleukin-17 (IL-17) response, and led to increased mucophilic bacterial species such as Akkermansia muciniphila. By using IL-17 reporter mice, we could show that HFD facilitates IL-17-mediated γδ T cell response in the spleen. Notably, oral gavage with live or heat-killed A. muciniphila effectively inhibited HFD-induced enhancement of psoriatic disease. In conclusion, HFD exacerbates psoriatic skin inflammation through changing the mucus barrier and the intestine microbial composition, which leads to an enhanced systemic IL-17 response.

We present a study of spectral line width measurements from the Extreme-ultraviolet Imaging Spectrometer on Hinode. We used spectral line profiles of Fe xvi 262.984 Å, Fe xiv 264.787 Å, Fe xiv 270.519 Å, Fe xiv 274.203 Å, and Fe xv 284.160 Å, and studied 11 active regions. Previous studies of spectral line widths have shown that in hot loops in the cores of active regions, the observed nonthermal velocities are smaller than predicted from models of reconnection jets in the corona or shock heating associated with Alfvén waves. The observed line widths are also inconsistent with models of chromospheric evaporation due to coronal nanoflares. We show that recent advances in higher resolution Alfvén wave turbulence modeling enables us to obtain nonthermal velocities similar to those measured in active regions. The observed nonthermal velocities for the 11 active regions in our study are in the range of 17–30 km s ^−1 , consistent with the spectral line nonthermal widths predicted from our model of 16 interacting flux tubes, which are in the range of 15–37 km s ^−1 .

Podosomes are actin structures important in multiple cell functions. Here, the authors use iPALM microscopy to reveal an “hourglass” shape of the podosome actin core, a protruding “knob” at the bottom of the core, and two actin networks extending from it.

Lightweight constructions made of different materials are becoming increasingly important and joining of metal-plastic hybrids is a major challenge in this context. This paper investigates experimentally the electromagnetic joining of tubes made of aluminum alloy 6082 and thermoplastic polycarbonate. Therefore, electromagnetic joining tests, combined with destructive push-out tests and non-destructive computer tomography scans were conducted. The investigations showed a fundamental dependence of the joint strength on the diameter ratio of the inner joining partner. By increasing the ratio of inner to outer diameter, the transferable push-out force was increased by factor fifteen. Furthermore, for lower ratios, macroscopic cracks were detected that limited the transferable forces.

Changes in intracellular GTP levels are not considered as a regulatory event in RAC1 activation in live cells since total GTP levels are substantially higher than the RAC1 GTP dissociation constant determined in vitro. Here, the authors demonstrate that the availability of free GTP in live cells controls the activity of RAC1 and cell invasion.

Background:. Keloids are disfiguring, scar-like lesions that are challenging to treat, with low response rates to current interventions and frequent recurrence. It has been widely reported that keloids are characterized by myofibroblasts, specialized contractile fibroblasts that express alpha-smooth muscle actin (α-SMA). However, evidence supporting a role for myofibroblasts in keloid pathology is inconclusive, with conflicting reports in the literature. This complicates development of more effective therapies, as the benefit of interventions targeting myofibroblasts is unclear. This study was undertaken to determine whether myofibroblasts can be considered characteristic of keloids. Methods:. Myofibroblasts in tissue sections from keloids, hypertrophic scars (HTSs), and normal skin were localized by α-SMA immunostaining. Expression of α-SMA mRNA (ACTA2 gene) in normal skin and keloid tissue, and in fibroblasts from normal skin, keloid, and HTSs, was measured using quantitative polymerase chain reaction. Results:. Normal skin did not exhibit α-SMA-expressing myofibroblasts, but myofibroblasts were identified in 50% of keloids and 60% of HTSs. No significant differences in ACTA2 expression between keloid and normal skin tissue were observed. Mean ACTA2 expression was higher in HTS (2.54-fold, P = 0.005) and keloid fibroblasts (1.75-fold, P = 0.046) versus normal fibroblasts in vitro. However, α-SMA expression in keloids in vivo was not associated with elevated ACTA2 in keloid fibroblasts in vitro. Conclusions:. Despite elevated ACTA2 in cultured keloid fibroblasts, myofibroblast presence is not a consistent feature of keloids. Therefore, therapies that target myofibroblasts may not be effective for all keloids. Further research is required to define the mechanisms driving keloid formation for development of more effective therapies.

BackgroundEarly detection and intervention research is expected to improve the outcomes for patients with high grade muscle invasive urothelial carcinoma (InvUC). With limited patients in suitable high-risk study cohorts, relevant animal model research is critical. Experimental animal models often fail to adequately represent human cancer. The purpose of this study was to determine the suitability of dogs with high breed-associated risk for naturally-occurring InvUC to serve as relevant models for early detection and intervention research. The feasibility of screening and early intervention, and similarities and differences between canine and human tumors, and early and later canine tumors were determined.MethodsSTs (n=120) ≥ 6 years old with no outward evidence of urinary disease were screened at 6-month intervals for 3 years with physical exam, ultrasonography, and urinalysis with sediment exam. Cystoscopic biopsy was performed in dogs with positive screening tests. The pathological, clinical, and molecular characteristics of the “early” cancer detected by screening were determined. Transcriptomic signatures were compared between the early tumors and published findings in human InvUC, and to more advanced “later” canine tumors from STs who had the typical presentation of hematuria and urinary dysfunction. An early intervention trial of an oral cyclooxygenase inhibitor, deracoxib, was conducted in dogs with cancer detected through screening.ResultsBiopsy-confirmed bladder cancer was detected in 32 (27%) of 120 STs including InvUC (n=29, three starting as dysplasia), grade 1 noninvasive cancer (n=2), and carcinoma in situ (n=1). Transcriptomic signatures including druggable targets such as EGFR and the PI3K-AKT-mTOR pathway, were very similar between canine and human InvUC, especially within luminal and basal molecular subtypes. Marked transcriptomic differences were noted between early and later canine tumors, particularly within luminal subtype tumors. The deracoxib remission rate (42% CR+PR) compared very favorably to that with single-agent cyclooxygenase inhibitors in more advanced canine InvUC (17-25%), supporting the value of early intervention.ConclusionsThe study defined a novel naturally-occurring animal model to complement experimental models for early detection and intervention research in InvUC. Research incorporating the canine model is expected to lead to improved outcomes for humans, as well as pet dogs, facing bladder cancer.

Francisella tularensis subspecies tularensis is a category-A biothreat agent that can cause lethal tularemia. Ceftobiprole medocaril is being explored as a medical countermeasure for the treatment of pneumonic tularemia. The efficacy of ceftobiprole medocaril against inhalational tularemia was evaluated in the Fischer 344 rat model of infection. The dose was expected to be effective against F. tularensis isolates with ceftobiprole minimum inhibitory concentrations ≤0.5 µg/mL. Animals treated with ceftobiprole medocaril exhibited a 92% survival rate 31 days post-challenge, identical to the survival of levofloxacin-treated rats. By comparison, rats receiving placebo experienced 100% mortality. Terminally collected blood, liver, lung, and spleen samples confirmed disseminated F. tularensis infections in most animals that died prior to completing treatments (placebo animals and a rat treated with ceftobiprole medocaril), although levels of bacteria detected in the placebo samples were significantly elevated compared to the ceftobiprole-medocaril-treated group geometric mean. Furthermore, no evidence of infection was detected in any rat that completed ceftobiprole medocaril or levofloxacin treatment and survived to the end of the post-treatment observation period. Overall, survival rates, body weights, and bacterial burdens consistently demonstrated that treatment with ceftobiprole medocaril is efficacious against otherwise fatal cases of pneumonic tularemia in the rat model.

Aims: Displaced distal radius fractures were investigated at a level 1 major trauma centre during the COVID-19 2020 lockdown due to the implementation of temporary changes in practice. The primary aim was to establish if follow-up at one week in place of the 72-hour British Orthopaedic Association Standards for Trauma & Orthopaedics (BOAST) guidance was safe following manipulation under anaesthetic. A parallel adaptation during lockdown was the non-expectation of Bier’s block. The secondary aim was to compare clinical outcomes with respect to block type. Methods: Overall, 90 patients were assessed in a cross-sectional cohort study using a mixed, retrospective-prospective approach. Consecutive sampling of 30 patients pre-lockdown (P1), 30 during lockdown (P2), and 30 during post-lockdown (P3) was applied. Type of block, operative status, follow-up, and complications were extracted. Primary endpoints were early complications (≤ one week). Secondary endpoints were later complications including malunion, delayed union or osteotomy. Results: In P1, 86.6% of patients were seen between days one to three, 26.7% in P2, and 56.7% in P3. There were no documented complications from days one to three. Operative rate was 35.5%, which did not vary significantly (p= 0.712). Primary endpoints occurred between day four to seven, and included one patient each period treated for plaster cast pain. Secondary endpoints in P1 included delayed union (one patient). During P2, this included malunion (one patient), a pressure sore (one patient) and ulnar cutaneous nerve symptoms (two patients). In P3, malunion was identified in one patient. Mean follow-up was six months (4 to 9) with union rate 96%. Change in block practice varied significantly (p =＜0.05). The risk ratio of complications using regional block (Bier’s) over haematoma block was 0.65. Conclusion: Follow-up adaptations during lockdown did not adversely affect patient outcomes. Regional anaesthesia is gold standard for manipulation of displaced distal radial fractures.

Summary: Four types of primary cells—dermal fibroblasts, dermal microvascular endothelial cells, epidermal keratinocytes, and epidermal melanocytes—can be isolated simultaneously from a single human skin sample, without the use of xenogeneic murine feeder cells. This protocol describes the procedures for isolation of these cells from adult full-thickness skin obtained from surgical discard tissue. The cells isolated using this protocol contain stem cell populations and are competent to form functional skin tissue in three-dimensional reconstructed skin models.For complete details on the use and execution of this profile, please refer to Supp et al. (2002), Boyce et al. (2015), Boyce et al. (2017a), Boyce et al. (2017b), and Supp et al. (2019).

Traffic management applications including congestion detection and tracking rely on traffic from multiple sources to model the traffic conditions. The sources are either stationary sensors which include inductive loop detectors (ILD), radar stations and Bluetooth/WiFi/BLE sensors or Floating Car Data (FCD) from moving vehicles which transmit their locations and speeds. The different sources have their inherent strengths and weaknesses but when used together, they have the potential to provide traffic information with increased robustness. Multi-sensor data fusion has the potential to enhance the estimation of traffic state in real-time by reducing the uncertainty of individual sources, extending the temporal and spatial coverage and increasing the confidence of data inputs. In this study, we fuse data from different FCD providers to improve travel time and average segment speeds estimation. We use data from INRIX, HERE and TomTom FCD commercial services and fuse the speeds based on their confidence values and granularity on virtual sub-segments of 250 m. Speeds differences between each pair of datasets are evaluated by calculating the absolute mean and standard deviation of differences. The evaluation of systematic differences is also performed for peak periods depending on the day of the week. INRIX FCD speeds are compared with ground truth spot speeds where both datasets are measured at a 1-minute interval which show good agreement with an error rate of between 8–20%. Some issues that affect FCD accuracy which include data availability and reliability problems are identified and discussed.

Automation of 3D LiDAR point cloud processing is expected to increase the production rate of many applications including automatic map generation. Fast development on high-end hardware has boosted the expansion of deep learning research for 3D classification and segmentation. However, deep learning requires large amount of high quality training samples. The generation of training samples for accurate classification results, especially for airborne point cloud data, is still problematic. Moreover, which customized features should be used best for segmenting airborne point cloud data is still unclear. This paper proposes semi-automatic point cloud labelling and examines the potential of combining different tailor-made features for pointwise semantic segmentation of an airborne point cloud. We implement a Dynamic Graph CNN (DGCNN) approach to classify airborne point cloud data into four land cover classes: bare-land, trees, buildings and roads. The DGCNN architecture is chosen as this network relates two approaches, PointNet and graph CNNs, to exploit the geometric relationships between points. For experiments, we train an airborne point cloud and co-aligned orthophoto of the Surabaya city area of Indonesia to DGCNN using three different tailor-made feature combinations: points with RGB (Red, Green, Blue) color, points with original LiDAR features (Intensity, Return number, Number of returns) so-called IRN, and points with two spectral colors and Intensity (Red, Green, Intensity) so-called RGI. The overall accuracy of the testing area indicates that using RGB information gives the best segmentation results of 81.05% while IRN and RGI gives accuracy values of 76.13%, and 79.81%, respectively.

Fast and efficient detection and reconstruction of buildings have become essential in real-time applications such as navigation, 3D rendering, augmented reality, and 3D smart cities. In this study, a modern Deep Learning (DL)-based framework is proposed for automatic detection, localization, and height estimation of buildings, simultaneously, from a single aerial image. The proposed framework is based on a Y-shaped Convolutional Neural Network (Y-Net) which includes one encoder and two decoders. The input of the network is a single RGB image, while the outputs are predicted height information of buildings as well as the rooflines in three classes of eave, ridge, and hip lines. The extracted knowledge by the Y-Net (i.e. buildings’ heights and rooflines) is utilized for 3D reconstruction of buildings based on the third Level of Detail (LoD2). The main steps of the proposed approach are data preparation, CNNs training, and 3D reconstruction. For the experimental investigations airborne data from Potsdam are used, which were provided by ISPRS. For the predicted heights, the results show an average Root Mean Square Error (RMSE) and a Normalized Median Absolute Deviation (NMAD) of about 3.8 m and 1.3 m, respectively. Moreover, the overall accuracy of the extracted rooflines is about 86%.

A high level of particulate matter in the atmosphere has an adverse long-term effect on human health. It has been associated with increased pulmonary tract and lung infections. It is more common in urban areas, especially megacities due to the confluence of industries and motorized machinery. Considering that most of the world’s population lives in urban areas, there is a need to monitor air pollution arising from particulate matter in order to ensure clean and safe air in cities in accordance with goal 11 of the Sustainable Development Goals. One way of doing this is through the use of Recurrent Neural Networks (RNN), which are suited for time varying data. Particulate matter concentration recorded by a network of low-cost sensors in Stuttgart is trained on three of the most popular RNN variants: Standard LSTM, Peephole LSTM and Gated Recurrent Unit. Two optimizers are used, Stochastic Gradient descent and Adam. Training is done on a single sensor and the optimum weights transferred and used in the prediction of other sensor values. This study concludes that Gated Recurrent Unit with Stochastic Gradient Descent is the most effective of the three variants in predicting particulate matter PM2.5 concentrations. In addition to this, weight transfer between sensors is not affected by temperature, wind direction, wind speed and geographic distance between sensors but rather by atmospheric pressure and the similarity of recorded Particulate matter levels.

Vendor-provided rational polynomial coefficients (RPCs) are commonly used to generate digital elevation models (DEMs) from high-resolution satellite images. This results in a level of accuracy that can be improved using ground control points (GCPs). It is well known that due to the inherent bias of sensor orientation the generated DEM is distorted. In the traditional way of working, the bias is corrected by integrating GCPs into the standard processing chain. This involves additional effort, since the provision of GCPs and the measurement of their image coordinates are required.In this paper, we examine whether and how the data recorded by NASA's ICESat (Ice, Cloud, and Land Elevation Satellite) mission can be used as GCPs without measuring image coordinates. The starting point are DEMs that are generated by image matching from KOMPSAT-3 satellite images with given RPCs. We developed a point-to-surface matching method that matches the ICESat points to the DEM in order to correct the DEM and improve its precision. For the experimental investigations a KOMPSAT 3 image pair is used that covers an area of 20 by 16 km2 in the Yangsan city regions. The generated DEM has a height accuracy of about 9 m. The point-to-surface algorithm with 505 ICESat points led to an improvement of the DEM height accuracy to about 2 m.

Abstract The central goals of mechanobiology are to understand how cells generate force and how they respond to environmental mechanical stimuli. A full picture of these processes requires high-resolution, volumetric imaging with time-correlated force measurements. Here we present an instrument that combines an open-top, single-objective light sheet fluorescence microscope with an atomic force microscope (AFM), providing simultaneous volumetric imaging with high spatiotemporal resolution and high dynamic range force capability (10 pN – 100 nN). With this system we have captured lysosome trafficking, vimentin nuclear caging, and actin dynamics on the order of one second per single-cell volume. To showcase the unique advantages of combining Line Bessel light sheet imaging with AFM, we measured the forces exerted by a macrophage during FcɣR-mediated phagocytosis while performing both sequential two-color, fixed plane and volumetric imaging of F-actin. This unique instrument allows for a myriad of novel studies investigating the coupling of cellular dynamics and mechanical forces.

Abstract Background Pancreatic cancer remains a fatal disease. Experimental systems are needed for personalized treatment strategies, drug testing and to further understand tumor biology. Cell cultures can serve as an excellent preclinical platform, but their generation remains challenging. Methods Tumor cells from surgically removed pancreatic ductal adenocarcinoma (PDAC) specimens were cultured under novel protocols. Cellular growth and composition were analyzed and culture conditions were continuously optimized. Characterization of cell cultures and primary tumors was performed via hematoxylin and eosin (HE) and immunofluorescence (IF) staining. Results Protocols for two- and three-dimensional PDAC primary cell cultures could successfully be established. Primary cell culture depended on dissociation techniques, growth factor supplementation and extracellular matrix components containing Matrigel being crucial for the transformation to three-dimensional PDAC organoids. The generated cultures showed to be highly resemblant to established PDAC primary cell cultures. HE and IF staining for cell culture and corresponding primary tumor characterization could successfully be performed. Conclusions The work presented herein shows novel and effective methods to successfully establish primary PDAC cell cultures in a distinct time frame. Factors contributing to cell growth and differentiation could be identified with important implications for further primary cell culture protocols. The established protocols might serve as novel tools in personalized tumor therapy.

During development, organs undergo large scale forces driven by the cytoskeleton but the precise molecular regulation of cytoskeletal networks remains unclear. Here, the authors report a Cdc42-dependent supracellular cytoskeletal network integrates local actomyosin contraction at tissue scale and drives global tissue elongation.

Super-resolution microscopy typically requires high laser powers which can induce photobleaching and degrade image quality. Here the authors augment structured illumination microscopy (SIM) with deep learning to reduce the number of raw images required and boost its performance under low light conditions.

The accuracy of biosensor ratio imaging is limited by signal/noise. Signals can be weak when biosensor concentrations must be limited to avoid cell perturbation. This can be especially problematic in imaging of low volume regions, e.g., along the cell edge. The cell edge is an important imaging target in studies of cell motility. We show how the division of fluorescence intensities with low signal-to-noise at the cell edge creates specific artifacts due to background subtraction and division by small numbers, and that simply improving the accuracy of background subtraction cannot address these issues. We propose a new approach where, rather than simply subtracting background from the numerator and denominator, we subtract a noise correction factor (NCF) from the numerator only. This NCF can be derived from the analysis of noise distribution in the background near the cell edge or from ratio measurements in the cell regions where signal-to-noise is high. We test the performance of the method first by examining two noninteracting fluorophores distributed evenly in cells. This generated a uniform ratio that could provide a ground truth. We then analyzed actual protein activities reported by a single chain biosensor for the guanine exchange factor (GEF) Asef, and a dual chain biosensor for the GTPase Cdc42. The reduction of edge artifacts revealed persistent Asef activity in a narrow band (∼640 nm wide) immediately adjacent to the cell edge. For Cdc42, the NCF method revealed an artifact that would have been obscured by traditional background subtraction approaches.

This study generates a process in GEE (Google Earth Engine) for SUHI (Surface Urban Heat islands) identification derived from TIRS (Thermal Infrared Sensor) and OLI (Operational Land Imager) sensors of Landsat 8 imagery in the area of Stuttgart, Germany. By comparing the temperature images in winter and summer seasons through a regression model, a relation between the Surface Cover (SC), the Terrain Shape (DEM) and the LST (Land Surface Temperature) is established. A Python code is developed for modelling the data and displaying the results linked to GEE. Three different models are used to establish the relationship between different variables (Temperature, Height, Wind etc.). Accuracy/goodness of fit of these models are measured using R-squared and standard error. Results shows that polynomial regression of 3rd order degree fits best to the dataset used in this study. Moreover, it is found that temperature values are not perfect for this study, as Landsat 8 have been acquired at 10’o clock in the morning (local time), whereas night time acquisition (which was not available for Stuttgart, Germany) would be best suited for the study. The results indicate that urban areas and meadow (open areas without vegetation) get the bigger values of temperature. Terrain Shape with respect to height indicates that the bigger the height, the lower the temperature in most of the regions. This project provides insight into the development of applications using a web-based platform and leads to a fast and accurate result for identifying the SUHI effect. It can contribute to the necessity of planning more vegetation areas in order to reduce hot temperature values in Stuttgart.

Integration of Sentinel-2 and Landsat-8 imagery is a key factor to provide earth observation data at a global scale with higher temporal resolution. Integration of data from two sensors is possible with the consistent harmonized data framed in common reference and processing, which can be used for comparing geophysical surface characteristics. This study focuses on the analysis of the atmospheric correction methods available for both Landsat-8 and Sentinel-2 products to convert the top of the atmosphere to the bottom of atmosphere reflectance. Other investigations (De Keukelaere, 2018) carried out similar analyses focusing on data acquired over water, while this study emphasises the analyses over land covers. Two processing algorithms iCOR and Sen2COR are utilized to perform atmospheric corrections, and results are statistically and visually compared. Comparisons based on same images processed with different algorithms show very strong correlation for some classes (urban: 0.99), while correlation values around 0.85 were achieved between images from different sensors.

The effect of particulate matter is increasingly gaining significance due to its harmful effects on human and urban ecosystems. In view of it, many communities worldwide are collecting air quality data privately to influence their policy makers to make stricter provisions for reducing harmful emissions and thereby improving their quality of life. Likewise, in many German cities, a community of air quality monitors which rely on low-cost PM Sensors is gathering momentum. Such communities possess privately-owned & low-cost air quality monitoring devices that claim to accurately measure PM concentrations and are openly accessible via internet. One such initiative is an air quality monitoring network viz. “luftdaten.info”, which contains of more than 300 low-cost sensors that consistently obtains PM data, colloquially referred as fine dust, in the city of Stuttgart as well as its surrounding districts. Besides, eight stations are continuously monitoring PM concentration in Stuttgart; these are operated by the State Environmental Agency (LuBW- Landesanstalt für Umwelt Baden-Württemberg). Stuttgart University of Applied Sciences (HFT) has currently installed 7 low-cost PM sensors to monitor and study PM concentration in one of its projects. This study endeavors to relate PM 2.5 and PM 10.0 using low-cost sensors. It intends to investigate the reliability of the measured PM concentration using such low-costs sensors once these are placed horizontally and vertically apart and comparing the measures of the 7 sensors. Another objective is to compare the PM concentration measurements with a meteorological station operated by the State of Baden-Wuerttemberg in the vicinity. A correlation analysis is performed to develop understanding of relationships of PM concentration with meteorological parameters, viz. with respect to ambient temperature, air pressure, humidity, wind speed and wind direction. Furthermore, it attempts to develop a regression model using above listed meteorological parameters. Finally, deficiencies in the measurement of low-costs and its placement effects are commented. Further suggestions are made for improving the data capturing and analytical procedures while using low-cost sensors.

A 15-year-old neutered female domestic shorthair cat was presented for weight loss, polydipsia/polyuria and lethargy. A large fluctuant mass was palpated in the ventral right cervical region. Biochemistry results were consistent with primary hyperparathyroidism. Parathyroid hormone level in the fluid was higher to that observed in the plasma, consistent with a cystic parathyroid lesion. Right parathyroidectomy and thyroidectomy were performed without complications. Ionized calcium normalized within a few hours. Histopathology yielded a diagnosis of cystic parathyroid adenoma. Follow-up showed complete recovery of clinical signs and normalization of ionized calcium. This case shows an uncommon presentation of feline primary hyperparathyroidism secondary to a cystic parathyroid adenoma and is, to our knowledge, the first case presented with a large palpable mass in which parathyroid hormone concentration was measured. This report highlights the value of selective hormonal analyses of the cystic fluid to confirm the origin of the cystic lesion pre-operatively.

The ability of Salmonella enterica subspecies enterica serovar Typhi (S. Typhi) to cause chronic gallbladder infections is dependent on biofilm growth on cholesterol gallstones. Non-typhoidal Salmonella (e.g. S. Typhimurium) also utilize the biofilm state to persist in the host and the environment. How the pathogen maintains recalcitrance to the host response, and oxidative stress in particular, during chronic infection is poorly understood. Previous experiments demonstrated that S. Typhi and S. Typhimurium biofilms are tolerant to hydrogen peroxide (H2O2), but that mutations in the biofilm extracellular polymeric substances (EPSs) O antigen capsule, colanic acid, or Vi antigen reduce tolerance. Here, biofilm-mediated tolerance to oxidative stress was investigated using a combination of EPS and catalase mutants, as catalases are important detoxifiers of H2O2. Using co-cultured biofilms of wild-type (WT) bacteria with EPS mutants, it was demonstrated that colanic acid in S. Typhimurium and Vi antigen in S. Typhi have a community function and protect all biofilm-resident bacteria rather than to only protect the individual cells producing the EPSs. However, the H2O2 tolerance deficiency of a O antigen capsule mutant was unable to be compensated for by co-culture with WT bacteria. For curli fimbriae, both WT and mutant strains are tolerant to H2O2 though unexpectedly, co-cultured WT/mutant biofilms challenged with H2O2 resulted in sensitization of both strains, suggesting a more nuanced oxidative resistance alteration in these co-cultures. Three catalase mutant (katE, katG and a putative catalase) biofilms were also examined, demonstrating significant reductions in biofilm H2O2 tolerance for the katE and katG mutants. Biofilm co-culture experiments demonstrated that catalases exhibit a community function. We further hypothesized that biofilms are tolerant to H2O2 because the physical barrier formed by EPSs slows penetration of H2O2 into the biofilm to a rate that can be mitigated by intra-biofilm catalases. Compared to WT, EPS-deficient biofilms have a heighted response even to low-dose (2.5 mM) H2O2 challenge, confirming that resident bacteria of EPS-deficient biofilms are under greater stress and have limited protection from H2O2. Thus, these data provide an explanation for how Salmonella achieves tolerance to H2O2 by a combination of an EPS-mediated barrier and enzymatic detoxification.