Interventions for postburn pruritus.

BACKGROUND: Postburn pruritus (itch) is a common and distressing symptom experienced on healing or healed burn or donor site wounds. Topical, systemic, and physical treatments are available to control postburn pruritus; however, it remains unclear how effective these are. OBJECTIVES: To assess the effects of interventions for treating postburn pruritus in any care setting. SEARCH METHODS: In September 2022, we searched the Cochrane Wounds Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), Ovid MEDLINE (including In-Process & Other Non-Indexed Citations), Ovid Embase, and EBSCO CINAHL Plus. We also searched clinical trials registries and scanned references of relevant publications to identify eligible trials. There were no restrictions with respect to language, publication date, or study setting. SELECTION CRITERIA: Randomised controlled trials (RCTs) that enrolled people with postburn pruritus to compare an intervention for postburn pruritus with any other intervention, placebo or sham intervention, or no intervention. DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures expected by Cochrane. We used GRADE to assess the certainty of the evidence. MAIN RESULTS: We included 25 RCTs assessing 21 interventions with 1166 randomised participants. These 21 interventions can be grouped into six categories: neuromodulatory agents (such as doxepin, gabapentin, pregabalin, ondansetron), topical therapies (such as CQ-01 hydrogel, silicone gel, enalapril ointment, Provase moisturiser, beeswax and herbal oil cream), physical modalities (such as massage therapy, therapeutic touch, extracorporeal shock wave therapy, enhanced education about silicone gel sheeting), laser scar revision (pulsed dye laser, pulsed high-intensity laser, fractional CO2 laser), electrical stimulation (transcutaneous electrical nerve stimulation, transcranial direct current stimulation), and other therapies (cetirizine/cimetidine combination, lemon balm tea). Most RCTs were conducted at academic hospitals and were at a high risk of performance, attrition, and detection bias. While 24 out of 25 included studies reported change in burn-related pruritus, secondary outcomes such as cost-effectiveness, pain, patient perception, wound healing, and participant health-related quality of life were not reported or were reported incompletely. Neuromodulatory agents versus antihistamines or placebo There is low-certainty evidence that doxepin cream may reduce burn-related pruritus compared with oral antihistamine (mean difference (MD) -2.60 on a 0 to 10 visual analogue scale (VAS), 95% confidence interval (CI) -3.79 to -1.42; 2 studies, 49 participants). A change of 2 points represents a minimal clinically important difference (MCID). Due to very low-certainty evidence, it is uncertain whether doxepin cream impacts the incidence of somnolence as an adverse event compared to oral antihistamine (risk ratio (RR) 0.64, 95% CI 0.32 to 1.25; 1 study, 24 participants). No data were reported on pain in the included study. There is low-certainty evidence that gabapentin may reduce burn-related pruritus compared with cetirizine (MD -2.40 VAS, 95% CI -4.14 to -0.66; 1 study, 40 participants). A change of 2 points represents a MCID. There is low-certainty evidence that gabapentin reduces the incidence of somnolence compared to cetirizine (RR 0.02, 95% CI 0.00 to 0.38; 1 study, 40 participants). No data were reported on pain in the included study. There is low-certainty evidence that pregabalin may result in a reduction in burn-related pruritus intensity compared with cetirizine with pheniramine maleate (MD -0.80 VAS, 95% CI -1.24 to -0.36; 1 study, 40 participants). A change of 2 points represents a MCID. There is low-certainty evidence that pregabalin reduces the incidence of somnolence compared to cetirizine (RR 0.04, 95% CI 0.00 to 0.69; 1 study, 40 participants). No data were reported on pain in the included study. There is moderate-certainty evidence that ondansetron probably results in a reduction in burn-related pruritus intensity compared with diphenhydramine (MD -0.76 on a 0 to 10 numeric analogue scale (NAS), 95% CI -1.50 to -0.02; 1 study, 38 participants). A change of 2 points represents a MCID. No data were reported on pain and adverse events in the included study. Topical therapies versus relevant comparators There is moderate-certainty evidence that enalapril ointment probably decreases mean burn-related pruritus compared with placebo control (MD -0.70 on a 0 to 4 scoring table for itching, 95% CI -1.04 to -0.36; 1 study, 60 participants). No data were reported on pain and adverse events in the included study. Physical modalities versus relevant comparators Compared with standard care, there is low-certainty evidence that massage may reduce burn-related pruritus (standardised mean difference (SMD) -0.86, 95% CI -1.45 to -0.27; 2 studies, 166 participants) and pain (SMD -1.32, 95% CI -1.66 to -0.98). These SMDs equate to a 4.60-point reduction in pruritus and a 3.74-point reduction in pain on a 10-point VAS. A change of 2 VAS points in itch represents a MCID. No data were reported on adverse events in the included studies. There is low-certainty evidence that extracorporeal shock wave therapy (ESWT) may reduce burn-related pruritus compared with sham stimulation (SMD -1.20, 95% CI -1.65 to -0.75; 2 studies, 91 participants). This equates to a 5.93-point reduction in pruritus on a 22-point 12-item Pruritus Severity Scale. There is low-certainty evidence that ESWT may reduce pain compared with sham stimulation (MD 2.96 on a 0 to 25 pressure pain threshold (PPT), 95% CI 1.76 to 4.16; 1 study, 45 participants). No data were reported on adverse events in the included studies. Laser scar revision versus untreated or placebo controls There is moderate-certainty evidence that pulsed high-intensity laser probably results in a reduction in burn-related pruritus intensity compared with placebo laser (MD -0.51 on a 0 to 1 Itch Severity Scale (ISS), 95% CI -0.64 to -0.38; 1 study, 49 participants). There is moderate-certainty evidence that pulsed high-intensity laser probably reduces pain compared with placebo laser (MD -3.23 VAS, 95% CI -5.41 to -1.05; 1 study, 49 participants). No data were reported on adverse events in the included studies. AUTHORS' CONCLUSIONS: There is moderate to low-certainty evidence on the effects of 21 interventions. Most studies were small and at a high risk of bias related to blinding and incomplete outcome data. Where there is moderate-certainty evidence, practitioners should consider the applicability of the evidence for their patients.

Retrospective evaluation of radiological and clinical outcomes after surgical treatment of proximal femoral fractures utilizing PFNA and PFNA augmented.

INTRODUCTION: The primary aim of this study was to evaluate the clinical and radiological outcomes after surgical treatment of proximal femoral fractures utilizing the Proximal Femoral Nail Antirotation (PFNA), with the main focus on complications and reoperations. The secondary aim was to compare the outcomes of patients with and without cement augmentation of the cephalomedullary nails. MATERIALS AND METHODS: All patients with an acute proximal femoral fracture consequently treated with a PFNA between January 2011 and Dezember  2018 were evaluated. Clinical and radiological data were assessed for intra- and postoperative complications, including treatment failure. In addition, intra- and postoperative radiographs were used to determine the position of the implant, and any migration, via Tip-Apex-Distance (TAD) and the caput-collum-diaphyseal angle (CCD). The accuracy of the fracture reduction was rated according to Baumgaertners criteria. RESULTS: Two hundred sixty-four consecutive patients (mean age 78.8 ± 12.0; 73.1% female) were included. The predominant OTA/AO fracture classification was 31A1 (153 cases, 58.0%). The average duration of surgery was 63.1 ± 28.0 min and showed no significant differences between PFNA and PFNA with augmentation. The implant positioning was rated as good in 222 cases (84.1%). Two hundred sixty-three patients (99.6%) showed evidence of healing within the time frame of three months postoperatively, one case of delayed union healed after secondary dynamization. During the observational period, 18 patients (6.8%) required a total of 23 additional surgeries. Overall, a lower reoperation rate was observed following the use of the augmentation option (2/86 patients (2.3%) vs. 16/178 patients (9.0%), p = 0.04). In particular, there were no cases of cut-out or cut-through among patients who underwent augmentation as part of osteosynthesis. CONCLUSIONS: Overall reoperation rate after surgical treatment of proximal femoral fractures utilizing the Proximal Femoral Nail Antirotation (PFNA) was 6.8%, with 23 additional surgeries performed in 18 patients. The usage of the PFNA with augmentation showed equally good implant positioning, excellent healing rates and fewer postoperative complications compared to the PFNA implant alone with a similar overall duration of surgery.

[Basic principles of surgical treatment of distal radius fractures]. / Grundprinzipien der operativen Versorgung der distalen Radiusfraktur.

Distal radius fractures are one of the most frequent fractures of the upper extremities. The decision for conservative or surgical treatment is made after appropriate diagnostics using conventional radiographic and usually computed tomography imaging examinations. If the indications for surgical treatment are present, various options for reduction and fixation are available. The spectrum ranges from closed to open procedures up to accompanying arthroscopic support. Appropriate preoperative patient education about the procedure and the planned postinterventional treatment is essential. The goal of treatment is to restore wrist function while maintaining mobility and strength with a low risk of complications. All surgical procedures share the principle of reduction to restore anatomical relationship followed by fixation. Closed procedures include fixation with Kirschner wires and the construction of an external fixator. Volar locking plate osteosynthesis has become established in recent years as the method of choice for the majority of the fractures to be treated. For special fracture patterns and the treatment of accompanying injuries, arthroscopic support can be indicated. There is no uniform consensus on the best choice of procedure. This article discusses the possible procedures including the approaches, fixation techniques and specific follow-up treatment.

Deep Convolutional Neural Networks Provide Motion Grading for High-Resolution Peripheral Quantitative Computed Tomography of the Scaphoid.

In vivo high-resolution peripheral quantitative computed tomography (HR-pQCT) studies on bone characteristics are limited, partly due to the lack of standardized and objective techniques to describe motion artifacts responsible for lower-quality images. This study investigates the ability of such deep-learning techniques to assess image quality in HR-pQCT datasets of human scaphoids. In total, 1451 stacks of 482 scaphoid images from 53 patients, each with up to six follow-ups within one year, and each with one non-displaced fractured and one contralateral intact scaphoid, were independently graded by three observers using a visual grading scale for motion artifacts. A 3D-CNN was used to assess image quality. The accuracy of the 3D-CNN to assess the image quality compared to the mean results of three skilled operators was between 92% and 96%. The 3D-CNN classifier reached an ROC-AUC score of 0.94. The average assessment time for one scaphoid was 2.5 s. This study demonstrates that a deep-learning approach for rating radiological image quality provides objective assessments of motion grading for the scaphoid with a high accuracy and a short assessment time. In the future, such a 3D-CNN approach can be used as a resource-saving and cost-effective tool to classify the image quality of HR-pQCT datasets in a reliable, reproducible and objective way.

Handheld hyperspectral imaging as a tool for the post-mortem interval estimation of human skeletal remains.

In forensic medicine, estimating human skeletal remains' post-mortem interval (PMI) can be challenging. Following death, bones undergo a series of chemical and physical transformations due to their interactions with the surrounding environment. Post-mortem changes have been assessed using various methods, but estimating the PMI of skeletal remains could still be improved. We propose a new methodology with handheld hyperspectral imaging (HSI) system based on the first results from 104 human skeletal remains with PMIs ranging between 1 day and 2000 years. To differentiate between forensic and archaeological bone material, the Convolutional Neural Network analyzed 65.000 distinct diagnostic spectra: the classification accuracy was 0.58, 0.62, 0.73, 0.81, and 0.98 for PMIs of 0 week-2 weeks, 2 weeks-6 months, 6 months-1 year, 1 year-10 years, and >100 years, respectively. In conclusion, HSI can be used in forensic medicine to distinguish bone materials >100 years old from those <10 years old with an accuracy of 98%. The model has adequate predictive performance, and handheld HSI could serve as a novel approach to objectively and accurately determine the PMI of human skeletal remains.

Long-Term Comparison of Two- and Three-Dimensional Computed Tomography Analyses of Cranial Bone Defects in Severe Parietal Thinning.

Parietal thinning was detected in a 72-year-old with recurrent headaches. Quantification of bone loss was performed applying two- and three-dimensional methods using computerized tomographies. Two-dimensional methods provided accurate measurements using single-line analyses of bone thicknesses (2.13 to 1.65 and 1.86 mm on the left and 4.44 to 3.08 and 4.20 mm on the right side), single-point analyses of bone intensities (693 to 375 and 403 on the left and 513 to 393 and 411 Houndsfield Units on the right side) and particle-size analyses of low density areas (16 to 22 and 12 on the left and 18 to 23 and 14 on the right side). Deteriorations between days 0 and 220 followed by bone stability on day 275 were paralleled using the changed volumes of bone defects to 1200 and finally 1133 mm3 on the left side and to 331 and finally 331 mm3 on the right side. Interfolding as measurement of the bones' shape provided changes to -1.23 and -1.72 mm on the left and to -1.42 and -1.30 mm on the right side. These techniques suggest a stabilizing effect of corticosteroids between days 220 and 275. Reconstruction of computerized tomographies appears justified to allow for quantification of bone loss during long-term follow-up.

Medial Patellofemoral Ligament Reconstruction Using Pedicled Quadriceps Tendon Autograft Yields Similar Clinical and Patient-Reported Outcomes but Less Donor-Site Morbidity Compared With Gracilis Tendon Autograft.

PURPOSE: To compare clinical and patient-reported outcome measures (PROMs) in patients with recurrent patellar dislocation after medial patellofemoral ligament (MPFL) reconstruction using either a gracilis tendon (GT) or quadriceps tendon autograft (QT). METHODS: All MPFL reconstruction performed between 2017 and 2019 were reviewed retrospectively. Only patients with isolated MPFL reconstruction, without any major patellofemoral risk factors and a minimum follow-up of 24 months, were included in the study. Patients were matched with respect to sex, age, and body mass index. All patients were evaluated clinically and using PROMs. RESULTS: A total of 64 patients with an average follow up of 28.7 ± 7.5 months were included in this study. The mean Kujala score (GT: 84.8 ± 12.9, QT: 88.9 ± 10.1), Lysholm score (GT: 89.4 ± 10.2, QT: 88.4 ± 5.0), and visual analog scale score for pain (GT: 1.9 ± 1.8, QT: 1.1 ± 1.3) did not significantly differ between both groups. Tegner activity level was significantly greater (P = .027) in the QT group (5.5 ± 1.9) compared with the GT group (4.6 ± 1.8), but within the minimal clinically important differences. Occasional patellar instability events, but no recurrent dislocation, were reported in 12.5% in the GT group and 6.3% in the QT group (P = .39). Of all patients, 90.6% in the QT and 68.8% in the HT group exceeded the PASS for the Kujala score (P = .06). Significantly more patients (59.4%) treated with GT reported donor-site morbidity in the form of sensitivity deficit at the lower leg compared with those treated with QT (3.1%, P = .001). CONCLUSIONS: GT and QT MPFL reconstruction have comparable PROMs and patellar redislocation rates 2 years' postoperatively. Significantly more patients treated with GT reported lower-leg sensitivity deficit compared with those treated with QT. LEVEL OF EVIDENCE: Level III, retrospective case-control study.

Injury Incidence, Outcomes, and Return to Competition Times after Sports-Related Concussions during One Professional Ice Hockey Season: A Prospective Cohort Study.

OBJECTIVE: The objective of this study was to analyze the incidence and characteristics of sports-related concussions (SRCs) for a professional ice hockey team during one regular season in the International Central European Hockey League. BACKGROUND: Repeated concussions are a common cause of long periods of absence in team contact sports, with a wide range of potential short- and long-term consequences for the affected athlete. Questions mainly regarding early diagnosis and ideal follow-up treatment remain unanswered, especially regarding the timing of return to sports (RTS). METHOD: A prospective data analysis for a professional ice hockey team during a regular season was conducted. Firstly, concussions per 1000 athlete exposure (AE) and average time loss due to SRC were calculated. Secondly, the data from ImPACT Applications were analyzed for those players who were diagnosed with an SRC. RESULTS: Five SRCs were evaluated during the regular season, which resulted in 1.35 concussions/1000 AEs, a maximum of 17 missed games, and a median of three games per SRC. The average symptom count was 9.6, with the most common symptoms being headache, sensitivity to light, and dizziness. CONCLUSIONS: SRCs sustained in professional ice hockey are a common in-competition injury, while practices play a subsidiary role. The duration of RTS is highly individual and can be associated with symptoms lasting days to months.

Influence of demographic factors on the occurrence of motion artefacts in HR-pQCT.

The study shows a high incidence of motion artefacts in a central European population and a significant increase of those artefacts with higher age. These findings may impact on the design and conduct of future in vivo HR-pQCT studies or at least help to estimate the potential number of drop outs due to unusable image quality. PURPOSE: Motion artefacts in high-resolution peripheral quantitative computed tomography (HR-pQCT) are challenging, as they introduce error into the resulting measurement data. The aim of this study was to assess the general occurrence of motion artefacts in healthy distal radius and to evaluate the influence of demographic factors. METHODS: The retrospective study is based on 525 distal radius second-generation HR-pQCT scans of 95 patients. All stacks were evaluated by two experienced observers and graded according to the visual grading scale recommended by the manufacturer, ranging from grade 1 (no visible motion artefacts) to grade 5 (severe motion artefacts). Correlations between demographic factors and image quality were evaluated using a linear mixed effects model analysis. RESULTS: The average visual grading was 2.7 (SD ± 0.7). Age and severity of motion artefacts significantly correlated (p = 0.026). Patients aged 65 years or above had an average image quality between grades 1 and 3 in 72.7% of cases, while patients younger than 65 had an average image quality between grades 1 and 3 in 91.9% of cases. Gender, smoking behaviour, and handedness had no significant influence on motion artefacts. CONCLUSION: This study showed a high incidence of motion artefacts in a representative central European population, but also a significant increase of motion artefacts with higher age. This could impact further study designs by planning for a sufficiently large and if possible a more selective study population to gain a representative amount of high-quality image data.

Retrospective Analysis of Nosocomial SARS-CoV-2 Infections in Orthopedic and Traumatological Inpatients.

SARS-CoV-2 has had a measurable impact on the field of orthopedic and traumatological surgery. To date, scarce data on intramural SARS-CoV-2 infections in orthopedic and traumatological patients have been reported. Therefore, the aim of our study was to investigate the effect of nosocomial SARS-CoV-2 infections in orthopedic and traumatological inpatients regarding symptoms of infection, mortality, duration of hospitalization, and other relevant patient-dependent factors. Patients admitted to hospital for an orthopedic or traumatological indication were screened retrospectively for nosocomial SARS-CoV-2 infections and included in this study. An age-, sex-, and ICD 10-matched control group was assigned and demographic data, clinical symptoms of a SARS-CoV-2 infection as well as mortality, length of hospital stays, time to surgery, pre-existing conditions, LKF-points representing the financial effort, and the Charlson Comorbidity Index were collected. A significantly higher length of stay was observed in the SARS-CoV-2 group (25 days; 4-60; SD 12.5) when compared to the control group (11 days; 2-36; SD 7; p < 0.05). LKF points were significantly higher in the SARS-CoV-2 group (13,939 points vs. 8542 points). No significant difference in mortality could be observed. An infection with SARS-CoV-2 in inpatients significantly increases length of hospital stay and cost of treatment. Although no significant difference in mortality was found, care should be taken to avoid intramural SARS-CoV-2 infections, resulting in prolonged hospitalization, higher costs, and potentially further individual risks.

Comparison of Mid-Infrared Handheld and Benchtop Spectrometers to Detect Staphylococcus epidermidis in Bone Grafts.

Bone analyses using mid-infrared spectroscopy are gaining popularity, especially with handheld spectrometers that enable on-site testing as long as the data quality meets standards. In order to diagnose Staphylococcus epidermidis in human bone grafts, this study was carried out to compare the effectiveness of the Agilent 4300 Handheld Fourier-transform infrared with the Perkin Elmer Spectrum 100 attenuated-total-reflectance infrared spectroscopy benchtop instrument. The study analyzed 40 non-infected and 10 infected human bone samples with Staphylococcus epidermidis, collecting reflectance data between 650 cm-1 and 4000 cm-1, with a spectral resolution of 2 cm-1 (Agilent 4300 Handheld) and 0.5 cm-1 (Perkin Elmer Spectrum 100). The acquired spectral information was used for spectral and unsupervised classification, such as a principal component analysis. Both methods yielded significant results when using the recommended settings and data analysis strategies, detecting a loss in bone quality due to the infection. MIR spectroscopy provides a valuable diagnostic tool when there is a tissue shortage and time is of the essence. However, it is essential to conduct further research with larger sample sizes to verify its pros and cons thoroughly.

Spatial transcriptomics reveals distinct and conserved tumor core and edge architectures that predict survival and targeted therapy response.

The spatial organization of the tumor microenvironment has a profound impact on biology and therapy response. Here, we perform an integrative single-cell and spatial transcriptomic analysis on HPV-negative oral squamous cell carcinoma (OSCC) to comprehensively characterize malignant cells in tumor core (TC) and leading edge (LE) transcriptional architectures. We show that the TC and LE are characterized by unique transcriptional profiles, neighboring cellular compositions, and ligand-receptor interactions. We demonstrate that the gene expression profile associated with the LE is conserved across different cancers while the TC is tissue specific, highlighting common mechanisms underlying tumor progression and invasion. Additionally, we find our LE gene signature is associated with worse clinical outcomes while TC gene signature is associated with improved prognosis across multiple cancer types. Finally, using an in silico modeling approach, we describe spatially-regulated patterns of cell development in OSCC that are predictably associated with drug response. Our work provides pan-cancer insights into TC and LE biology and interactive spatial atlases ( http://www.pboselab.ca/spatial_OSCC/ ; http://www.pboselab.ca/dynamo_OSCC/ ) that can be foundational for developing novel targeted therapies.

[Conservative treatment of distal radial fractures]. / Die konservative Behandlung der distalen Radiusfraktur.

OBJECTIVE: Distal fracture of the radius is common in all age groups. Under careful consideration of individual indications and contraindications, conservative treatment with reduction and immobilization can have significant advantages over the frequently applied surgical approach, particularly in older patients. THERAPEUTIC GOAL: Immobilization after closed reduction enables satisfactory wrist function to be achieved according to individual patient expectations. INDICATIONS: A. Patients with a. significant comorbidities, b. high surgical risk from an anesthesiology perspective (ASA > 3), c. low functional requirements, d. low cosmetic expectations regarding residual visible deformity. B. Young patients with an extension fracture and additional a. < 10° dorsal tilt in the case of extraarticular fractures after closed reduction, b. < 5 mm radial shortening after closed reduction, c. < 2 mm intraarticular displacement after closed reduction. CONTRAINDICATIONS: A. Patient age < 65 years with an extension fracture and additional a. > 10° dorsal tilt in the case of extraarticular fractures after closed reduction, b. > 5 mm radial shortening after closed reduction, c. > 2 mm intraarticular displacement after closed reduction. B. Flexion fracture for which ligamentotaxis for closed reduction is not possible. C. Open distal radial fracture. D. Fracture dislocations. E. Impairments of peripheral circulation, motor or sensory function of the hand after reduction. TECHNIQUE: After puncturing the fracture hematoma and infiltrating the fracture gap with local anesthetic, the forearm is suspended using Chinese finger traps on the thumb and middle finger. Constant traction in the longitudinal axis of the forearm is ensured by a weight applied via a wide cushioned cuff to the distal upper arm. Reduction then is enabled with the additional reductive effect of ligamentotaxis. After minimal cushioning of the forearm with cotton wool and crepe bandage, a dorsal gypsum longuette is applied. After the plaster bandage has hardened, peripheral circulation, motor function, and sensitivity are checked. The reduction is controlled by X­ray and documented. POSTPROCEDURAL MANAGEMENT: A. General procedures to reduce swelling; sufficient analgesics should be prescribed. B. The circular plaster cast is applied once swelling has subsided sufficiently, generally after 2-3 days. C. The duration of cast wearing should be planned at 5 weeks. RESULTS: A total of 73 patients (55 women and 18 men) aged 65-88 years were followed up for 12 months to investigate functional outcomes after surgical and conservative therapy. While surgical patients had better functional scores up to 12 weeks after treatment begin, there was no longer a significant difference in the 6­ and 12-month follow-up results. The measured grip strength was consistently better in the surgically treated group. Clinically visible deformities were present in 78% of the conservatively treated patients; however, the patients were satisfied with the functional or cosmetic results. No deformities were seen in the surgically treated patients. All fractures were completely healed after 6 months. The rate of complications was significantly higher in the surgery group, with 13 complications compared to 5 in the conservative treatment group.

Tripterygium wilfordii derivative celastrol, a YAP inhibitor, has antifibrotic effects in systemic sclerosis.

OBJECTIVES: Systemic sclerosis (SSc) is characterised by extensive tissue fibrosis maintained by mechanotranductive/proadhesive signalling. Drugs targeting this pathway are therefore of likely therapeutic benefit. The mechanosensitive transcriptional co-activator, yes activated protein-1 (YAP1), is activated in SSc fibroblasts. The terpenoid celastrol is a YAP1 inhibitor; however, if celastrol can alleviate SSc fibrosis is unknown. Moreover, the cell niches required for skin fibrosis are unknown. METHODS: Human dermal fibroblasts from healthy individuals and patients with diffuse cutaneous SSc were treated with or without transforming growth factor ß1 (TGFß1), with or without celastrol. Mice were subjected to the bleomycin-induced model of skin SSc, in the presence or absence of celastrol. Fibrosis was assessed using RNA Sequencing, real-time PCR, spatial transcriptomic analyses, Western blot, ELISA and histological analyses. RESULTS: In dermal fibroblasts, celastrol impaired the ability of TGFß1 to induce an SSc-like pattern of gene expression, including that of cellular communication network factor 2, collagen I and TGFß1. Celastrol alleviated the persistent fibrotic phenotype of dermal fibroblasts cultured from lesions of SSc patients. In the bleomycin-induced model of skin SSc, increased expression of genes associated with reticular fibroblast and hippo/YAP clusters was observed; conversely, celastrol inhibited these bleomycin-induced changes and blocked nuclear localisation of YAP. CONCLUSIONS: Our data clarify niches within the skin activated in fibrosis and suggest that compounds, such as celastrol, that antagonise the YAP pathway may be potential treatments for SSc skin fibrosis.

ENRICHing medical imaging training sets enables more efficient machine learning.

OBJECTIVE: Deep learning (DL) has been applied in proofs of concept across biomedical imaging, including across modalities and medical specialties. Labeled data are critical to training and testing DL models, but human expert labelers are limited. In addition, DL traditionally requires copious training data, which is computationally expensive to process and iterate over. Consequently, it is useful to prioritize using those images that are most likely to improve a model's performance, a practice known as instance selection. The challenge is determining how best to prioritize. It is natural to prefer straightforward, robust, quantitative metrics as the basis for prioritization for instance selection. However, in current practice, such metrics are not tailored to, and almost never used for, image datasets. MATERIALS AND METHODS: To address this problem, we introduce ENRICH-Eliminate Noise and Redundancy for Imaging Challenges-a customizable method that prioritizes images based on how much diversity each image adds to the training set. RESULTS: First, we show that medical datasets are special in that in general each image adds less diversity than in nonmedical datasets. Next, we demonstrate that ENRICH achieves nearly maximal performance on classification and segmentation tasks on several medical image datasets using only a fraction of the available images and without up-front data labeling. ENRICH outperforms random image selection, the negative control. Finally, we show that ENRICH can also be used to identify errors and outliers in imaging datasets. CONCLUSIONS: ENRICH is a simple, computationally efficient method for prioritizing images for expert labeling and use in DL.

Design, synthesis and characterisation of a novel type II B-RAF paradox breaker inhibitor.

The mutation V600E in B-Raf leads to mitogen activated protein kinase (MAPK) pathway activation, uncontrolled cell proliferation, and tumorigenesis. ATP competitive type I B-Raf inhibitors, such as vemurafenib (1) and PLX4720 (4) efficiently block the MAPK pathways in B-Raf mutant cells, however these inhibitors induce conformational changes in the wild type B-Raf (wtB-Raf) kinase domain leading to heterodimerization with C-Raf, causing paradoxical hyperactivation of the MAPK pathway. This unwanted activation may be avoided by another class of inhibitors (type II) which bind the kinase in the DFG-out conformation, such as AZ628 (3) preventing heterodimerization. Here we present a new B-Raf kinase domain inhibitor, based on a phenyl(1H-pyrrolo [2,3-b]pyridin-3-yl)methanone template, that represents a hybrid between 4 and 3. This novel inhibitor borrows the hinge binding region from 4 and the back pocket binding moiety from 3. We determined its binding mode, performed activity/selectivity studies, and molecular dynamics simulations in order to study the conformational effects induced by this inhibitor on wt and V600E mutant B-Raf kinase. We discovered that the inhibitor was active and selective for B-Raf, binds in a DFG-out/αC-helix-in conformation, and did not induce the aforementioned paradoxical hyperactivation in the MAPK pathway. We propose that this merging approach can be used to design a novel class of B-Raf inhibitors for translational studies.

The impact of motion induced artifacts in the evaluation of HR-pQCT scans of the scaphoid bone: an assessment of inter- and intraobserver variability and quantitative parameters.

Background: In-vivo high-resolution peripheral quantitative computed tomography (HR-pQCT) has high potential in scaphoid bone pathologies' scientific and clinical fields. The manufacturer's visual grading scale (VGS) classifies motion artifacts and divides scans into five quality grades ranging from grade 1 (good quality) to grade 5 (poor quality). This prospective study aimed to investigate the feasibility of the VGS and the influence of image quality on bone density and microarchitecture parameters for the scaphoid bone. Methods: Within one year, twenty-two patients with scaphoid fractures received up to six scans of their fractured and contralateral wrist (each consisting of three stacks) using second-generation HR-pQCT (total 256 scans). Three experienced observers graded each stack following the visual grading system, and inter- and intraobserver variability were assessed. The contralateral uninjured scaphoids were then compared pairwise within each patient to high-quality grade 1 scans to determine the influence of image quality on density and microarchitecture parameters. Results: Inter- and intraobserver variability among the three observers significantly revealed fair to moderate agreement, P<0.001 and P<0.05, respectively. Bone volume (BV) fraction tended to increase with poorer image quality but did not exceed four percent. Trabecular bone mineral density (Tb.BMD) decreased with poorer image quality but did not exceed five percent. Trabecular number and trabecular thickness significantly increased by 15.5% and 6.8% at grade five (P<0.001), respectively, and trabecular separation significantly decreased by 13.7% at grade five (P<0.001). Conclusions: This study revealed a considerable influence of motion on bone morphometry parameters of the scaphoid. Therefore, high image quality must be a central point in studies focusing on the histomorphometry of small objects. The high inter- and intraobserver variability limit the VGS. Future research may focus on other grading systems or automated techniques leading to more consistent and reproducible results. Currently, the use of microarchitectural analysis should be limited to cases without motion artefacts or, at most low graded motion artefacts.

Continuous Shoulder Activity Tracking after Open Reduction and Internal Fixation of Proximal Humerus Fractures.

Postoperative shoulder activity after proximal humerus fracture treatment could influence the outcomes of osteosynthesis and may depend on the rehabilitation protocol. This multi-centric prospective study aimed at evaluating the feasibility of continuous shoulder activity monitoring over the first six postoperative weeks, investigating potential differences between two different rehabilitation protocols. Shoulder activity was assessed with pairs of accelerometer-based trackers during the first six postoperative weeks in thirteen elderly patients having a complex proximal humerus fracture treated with a locking plate. Shoulder angles and elevation events were evaluated over time and compared between the two centers utilizing different standard rehabilitation protocols. The overall mean shoulder angle ranged from 11° to 23°, and the number of daily elevation events was between 547 and 5756. Average angles showed longitudinal change <5° over 31 ± 10 days. The number of events increased by 300% on average. Results of the two clinics exhibited no characteristic differences for shoulder angle, but the number of events increased only for the site utilizing immediate mobilization. In addition to considerable inter-patient variation, not the mean shoulder angle but the number of elevations events increased markedly over time. Differences between the two sites in number of daily events may be associated with the different rehabilitation protocols.

Morphological and Tissue Characterization with 3D Reconstruction of a 350-Year-Old Austrian Ardea purpurea Glacier Mummy.

Glaciers are dwindling archives, releasing animal mummies preserved in the ice for centuries due to climate changes. As preservation varies, residual soft tissues may differently expand the biological information content of such mummies. DNA studies have proven the possibility of extracting and analyzing DNA preserved in skeletal residuals and sediments for hundreds or thousands of years. Paleoradiology is the method of choice as a non-destructive tool for analyzing mummies, including micro-computed tomography (micro-CT) and magnetic resonance imaging (MRI). Together with radiocarbon dating, histo-anatomical analyses, and DNA sequencing, these techniques were employed to identify a 350-year-old Austrian Ardea purpurea glacier mummy from the Ötztal Alps. Combining these techniques proved to be a robust methodological concept for collecting inaccessible information regarding the structural organization of the mummy. The variety of methodological approaches resulted in a distinct picture of the morphological patterns of the glacier animal mummy. The BLAST search in GenBank resulted in a 100% and 98.7% match in the cytb gene sequence with two entries of the species Purple heron (Ardea purpurea; Accession number KJ941160.1 and KJ190948.1) and a 98% match with the same species for the 16 s sequence (KJ190948.1), which was confirmed by the anatomic characteristics deduced from micro-CT and MRI.